Longitudinal studies of time-dependent changes in both bladder and erectile function after streptozotocin-induced diabetes in Fischer 344 male rats.

PubMed

Melman, Arnold; Zotova, Elena; Kim, Mimi; Arezzo, Joseph; Davies, Kelvin; DiSanto, Michael; Tar, Moses

2009-11-01

To provide sensitive physiological endpoints for the onset and long-term progression of deficits induced by diabetes mellitus (DM) in bladder and erectile function in male rats, and to evaluate parallel changes in urogenital and nerve function induced by hyperglycaemia over a protracted period as a model for chronic deficits in patients with diabetes. The study comprised in 877 male, 3-month-old, Fischer 344 rats; 666 were injected intraperitoneally with 35 mg/kg streptozotocin (STZ) and divided into insulin-treated and untreated diabetic groups. The rats were studied over 8 months and measurements made of both erectile and bladder function, as well as nerve conduction studies over the duration of the study. There was an early (first month) abnormality of both erectile and bladder function that persisted through the 8 months of the study. The erectile dysfunction was manifest as reduced intracavernous pressure/blood pressure ratio, and the bladder dysfunction as a persistent increase in detrusor overactivity with no detrusor decompensation. Insulin treatment prevented or modified the abnormality in each organ. Hyperglycaemia caused a progressive decrease in caudal nerve conduction velocity. The mean digital sensory and tibial motor nerve conduction velocity did not deteriorate over time. Correlation measurements of nerve and organ function were not consistent. The results of this extensive long-term study show early and profound effects of hyperglycaemia on the smooth muscle of the penis and bladder, that were persistent and stable in surviving rats over the 8 months. The physiological changes did not correlate well with neurological measurements of those organs. Significantly, diverse smooth-muscle cellular and subcellular events antedated the measured neurological manifestations of the hyperglycaemia by several months. Although autonomic diabetic neuropathy is a primary life-threatening complication of long-term diabetes in humans, this rat model of STZ-induced diabetes showed that the rapid onset of physiological manifestations was based on many molecular changes in the smooth muscle cells in this model of type 1 DM.

Hepatic steatosis and steatohepatitis in human immunodeficiency virus/hepatitis C virus-coinfected patients.

PubMed

Macías, Juan; Berenguer, Juan; Japón, Miguel A; Girón-González, José A; Rivero, Antonio; López-Cortés, Luis F; Moreno, Ana; Márquez, Manuel; Iribarren, José A; Ortega, Enrique; Miralles, Pilar; Merchante, Nicolás; Pineda, Juan A

2012-10-01

Hepatic steatosis (HS) is frequent in human immunodeficiency virus (HIV)- and hepatitis C virus (HCV)-coinfected patients. Antiretroviral therapy (ART) and metabolic alterations could induce HS. However, a protective effect of ART has been reported in a paired biopsy study. Thus, our aim was to examine the changes and predictors of HS progression among HIV/HCV-coinfected patients with sequential biopsies. We also evaluated the rates of steatohepatitis and factors associated thereof. HIV-infected patients with detectable serum HCV RNA, who underwent two biopsies, separated at least by 1 year, were included in this retrospective study. HS progression was defined as increase in one or more HS grades. The median (interquartile range) time between biopsies was 3.3 (2.0-5.2) years. Among 146 individuals, HS at baseline was observed in 86 (60%) patients and in 113 (77%) in the follow-up biopsy (P < 0.001). Progression of HS was observed in 60 (40%) patients. HS regressed in 11 (8%) patients. Factors associated with HS progression were changes in fasting plasma glucose (FPG) between biopsies (per 10 mg/dL increase; odds ratio [OR] [95% confidence interval; CI] = 1.4 [1.04-1.8]; P = 0.024) and cumulative use of dideoxynucleoside analogs (per year; OR [95% CI] = 1.5 [1.2-1.8]; P = 0.001). Persistent steatohepatitis or progression to steatohepatitis between biopsies was observed in 27 (18%) patients. Persistence of or progression to steatohepatitis was associated with progression ≥ 1 fibrosis stages between biopsies (OR [95% CI] = 2.4 [1.01-5.7]; P = 0.047). HS progresses frequently and regression is rarely observed in HIV/HCV-coinfected patients, including in those on ART. Cumulative exposure to dideoxynucleoside analogs and increases in FPG are related with HS progression. Stetatohepatitis is frequently observed in these patients and is linked to fibrosis progression. Copyright © 2012 American Association for the Study of Liver Diseases.

Measles virus, immune control and persistence

PubMed Central

Griffin, Diane E.; Lin, Wen-Hsuan; Pan, Chien-Hsiung

2012-01-01

Measles remains one of the most important causes of child morbidity and mortality worldwide with the greatest burden in the youngest children. Most acute measles deaths are due to secondary infections that result from a poorly understood measles-induced suppression of immune responses. Young children are also vulnerable to late development of subacute sclerosing panencephalitis, a progressive, uniformly fatal neurologic disease caused by persistent measles virus (MeV) infection. During acute infection, the rash marks the appearance of the adaptive immune response and CD8+ T cell-mediated clearance of infectious virus. However, after clearance of infectious virus, MeV RNA persists and can be detected in blood, respiratory secretions, urine and lymphoid tissue for many weeks to months. This prolonged period of virus clearance may help to explain measles immunosuppression and the development of lifelong immunity to re-infection, as well as occasional infection of the nervous system. Once MeV infects neurons, the virus can spread transynaptically and the envelope proteins needed to form infectious virus are unnecessary, accumulate mutations and can establish persistent infection. Identification of the immune mechanisms required for clearance of MeV RNA from multiple sites will enlighten our understanding of the development of disease due to persistent infection. PMID:22316382

Big five personality factors and cigarette smoking: a 10-year study among US adults.

PubMed

Zvolensky, Michael J; Taha, Farah; Bono, Amanda; Goodwin, Renee D

2015-04-01

The present study examined the relation between the big five personality traits and any lifetime cigarette use, progression to daily smoking, and smoking persistence among adults in the United States (US) over a ten-year period. Data were drawn from the Midlife Development in the US (MIDUS) I and II (N = 2101). Logistic regression was used to examine the relationship between continuously measured personality factors and any lifetime cigarette use, smoking progression, and smoking persistence at baseline (1995-1996) and at follow-up (2004-2006). The results revealed that higher levels of openness to experience and neuroticism were each significantly associated with increased risk of any lifetime cigarette use. Neuroticism also was associated with increased risk of progression from ever smoking to daily smoking and persistent daily smoking over a ten-year period. In contrast, conscientiousness was associated with decreased risk of lifetime cigarette use, progression to daily smoking, and smoking persistence. Most, but not all, associations between smoking and personality persisted after adjusting for demographic characteristics, depression, anxiety disorders, and substance use problems. The findings suggest that openness to experience and neuroticism may be involved in any lifetime cigarette use and smoking progression, and that conscientiousness appears to protect against smoking progression and persistence. These data add to a growing literature suggesting that certain personality factors--most consistently neuroticism--are important to assess and perhaps target during intervention programs for smoking behavior. Copyright © 2015 Elsevier Ltd. All rights reserved.

Big five personality factors and cigarette smoking: A 10-year study among US adults

PubMed Central

Zvolensky, Michael J.; Taha, Farah; Bono, Amanda; Goodwin, Renee D.

2015-01-01

The present study examined the relation between the big five personality traits and any lifetime cigarette use, progression to daily smoking, and smoking persistence among adults in the United States (US) over a ten-year period. Data were drawn from the Midlife Development in the US (MIDUS) I and II (N=2,101). Logistic regression was used to examine the relationship between continuously measured personality factors and any lifetime cigarette use, smoking progression, and smoking persistence at baseline (1995–1996) and at follow-up (2004–2006). The results revealed that higher levels of openness to experience and neuroticism were each significantly associated with increased risk of any lifetime cigarette use. Neuroticism also was associated with increased risk of progression from ever smoking to daily smoking and persistent daily smoking over a ten-year period. In contrast, conscientiousness was associated with decreased risk of lifetime cigarette use, progression to daily smoking, and smoking persistence. Most, but not all, associations between smoking and personality persisted after adjusting for demographic characteristics, depression, anxiety disorders, and substance use problems. The findings suggest that openness to experience and neuroticism may be involved in any lifetime cigarette use and smoking progression, and that conscientiousness appears to protect against smoking progression and persistence. These data add to a growing literature suggesting that certain personality factors—most consistently neuroticism—are important to assess and perhaps target during intervention programs for smoking behavior. PMID:25799395

Diabetes-Induced Reactive Oxygen Species: Mechanism of Their Generation and Role in Renal Injury

PubMed Central

Fakhruddin, Selim; Alanazi, Wael

2017-01-01

Diabetes induces the onset and progression of renal injury through causing hemodynamic dysregulation along with abnormal morphological and functional nephron changes. The most important event that precedes renal injury is an increase in permeability of plasma proteins such as albumin through a damaged glomerular filtration barrier resulting in excessive urinary albumin excretion (UAE). Moreover, once enhanced UAE begins, it may advance renal injury from progression of abnormal renal hemodynamics, increased glomerular basement membrane (GBM) thickness, mesangial expansion, extracellular matrix accumulation, and glomerulosclerosis to eventual end-stage renal damage. Interestingly, all these pathological changes are predominantly driven by diabetes-induced reactive oxygen species (ROS) and abnormal downstream signaling molecules. In diabetic kidney, NADPH oxidase (enzymatic) and mitochondrial electron transport chain (nonenzymatic) are the prominent sources of ROS, which are believed to cause the onset of albuminuria followed by progression to renal damage through podocyte depletion. Chronic hyperglycemia and consequent ROS production can trigger abnormal signaling pathways involving diverse signaling mediators such as transcription factors, inflammatory cytokines, chemokines, and vasoactive substances. Persistently, increased expression and activation of these signaling molecules contribute to the irreversible functional and structural changes in the kidney resulting in critically decreased glomerular filtration rate leading to eventual renal failure. PMID:28164134

Effects of vaginal lactobacilli in Chlamydia trachomatis infection.

PubMed

Mastromarino, Paola; Di Pietro, Marisa; Schiavoni, Giovanna; Nardis, Chiara; Gentile, Massimo; Sessa, Rosa

2014-07-01

Increasing evidence indicates that abnormal vaginal flora lacking lactobacilli facilitates the acquisition of several sexually transmitted diseases including Chlamydia trachomatis. C. trachomatis, the most common bacterial agent of genital infections worldwide, can progress from the lower to upper reproductive tract and induce severe sequelae. The ability of C. trachomatis to develop into a persistent form has been suggested as key pathogenetic mechanism underlying chronic infections and sequelae. The aim of our study was to investigate the C. trachomatis interaction with vaginal microbiota analyzing the effects of Lactobacillus strains (L. brevis and L. salivarius) on the different phases of C. trachomatis developmental cycle. In addition, the effect of lactobacilli on persistent chlamydial forms induced by HSV-2 coinfection has also been evaluated. Our results demonstrated significant inhibition of C. trachomatis multiplication by vaginal lactobacilli. L. brevis was significantly more effective than L. salivarius (p<0.05) on all the steps of chlamydial infection cycle suggesting that the ability of lactobacilli to protect from infection is strain-dependent. Lactobacilli had an adverse effect on elementary chlamydial bodies (p<0.05), on chlamydial adsorption to epithelial cells (p<0.001) and on intracellular phases of chlamydial replication (p<0.0001). Our study also demonstrated a protective effect of lactobacilli toward persistent C. trachomatis forms induced by HSV-2 coinfection. A significant increase in the production of C. trachomatis infectious progeny was observed in C. trachomatis/HSV-2 coinfection in the presence of L. brevis (p=0.01) despite a significant inhibition of C. trachomatis multiplication (p=0.028). Our data suggest that a healthy vaginal microbiota can reduce the risk of acquiring C. trachomatis infection and counteract the development of persistent chlamydial forms. Copyright © 2014 Elsevier GmbH. All rights reserved.

Iodine-induced hyperthyroidism as combination of different etiologies: an overlooked entity in the elderly.

PubMed

Foppiani, Luca; Cascio, Christian; Lo Pinto, Giuliano

2016-10-01

Iodine-induced thyrotoxicosis, which raises several diagnostic and therapeutical challenges, is often overlooked. Hyperthyroidism can induce atrial fibrillation, a harmful arrhythmia which can precipitate heart failure and cause stroke. We report the case of an elderly man who was diagnosed with tachyfibrillation secondary to hyperthyroidism. Thyroid hyperfunction was subsequently related both to previous amiodarone therapy (probably mixed form) and the recent use of iodinated contrast medium for computed tomography scan. Thyroid ultrasonography showed a plongeant multinodular goitre. After initial worsening, thyroid function improved slowly but progressively on high-dose thyreostatic therapy combined with steroid therapy; tachyfibrillation caused heart failure and a thrombus in the left atrium, and proved initially resistant to combined antiarrhythmic treatments. Progressive reduction in thyroid hormone levels, together with combined cardiologic therapies, controlled the heart rate, though atrial fibrillation persisted; anticoagulant therapy resolved the atrial thrombus. Alterations in thyroid function are common in amiodarone-treated patients, who therefore require regular hormonal checks. The different forms of amiodarone-induced thyrotoxicosis must be investigated, since they require different therapies, though mixed forms often occur. The superimposition of further iodine excess due to other causes may be catastrophic and cause severe cardiac problems in these patients.

Heat shock factor 1 suppresses the HIV-induced inflammatory response by inhibiting nuclear factor-κB.

PubMed

Pan, Xiaoyan; Lin, Jian; Zeng, Xiaoyun; Li, Wenjuan; Wu, Wenjiao; Lu, Wan Zhen; Liu, Jing; Liu, Shuwen

2018-05-01

The persistent inflammation aggravated by a disordered immune response is considered to be the major cause of CD4 + T cell depletion in lymphoid tissue, which impels the progression of AIDS. Here, we report that heat shock factor 1 (HSF1) works as an innate repressor of HIV-induced inflammation. The activation of HSF1 was found to accompany inflammation during HIV infection. Further research uncovered that HSF1 activation inhibited HIV-induced inflammation. In addition, HSF1 overexpression suppressed the inflammatory response induced by HIV, while HSF1 deficiency exacerbated that inflammation. Mechanistically, HSF1 was found to compete with nuclear factor-κB (NF-κB) in the nucleus. Generally, our report highlights that HSF1 is an important host factor in regulating HIV-induced inflammation and may work as a potential target for curing AIDS. Copyright © 2018 Elsevier Inc. All rights reserved.

Risk estimates for persistent high-risk human papillomavirus infections as surrogate endpoints of progressive cervical disease critically depend on reference category: analysis of the combined prospective cohort of the New Independent States of the Former Soviet Union and Latin American Screening studies.

PubMed

Syrjänen, K; Shabalova, I; Naud, P; Kozachenko, V; Derchain, S; Zakharchenko, S; Roteli-Martins, C; Nerovjna, R; Longatto-Filho, A; Kljukina, L; Tatti, S; Branovskaja, M; Hammes, L S; Branca, M; Grunjberga, V; Eržen, M; Juschenko, A; Costa, S; Sarian, L; Podistov, J; Syrjänen, S

2011-06-01

To make feasible future clinical trials with new-generation human papillomavirus (HPV) vaccines, novel virological surrogate endpoints of progressive disease have been proposed, including high-risk HPV (HR-HPV) persistence for six months (6M+) or 12 months (12M+). The risk estimates (relative risks [RRs]) of these 'virological endpoints' are influenced by several variables, not yet validated adequately. We compared the impact of three referent groups: (i) HPV-negative, (ii) HPV-transient, (iii) HPV-mixed outcome on the risk estimates for 6M+ or 12M+ HR-HPV persistence as predictors of progressive disease. Generalized estimating equation models were used to estimate the strength of 6M+ and 12M+ HR-HPV persistence with disease progression to squamous intraepithelial lesions (SILs), cervical intraepithelial neoplasia (CIN) grade 1+, CIN2+, CIN/SIL endpoints, comparing three optional reference categories (i)-(iii) in a prospective sub-cohort of 1865 women from the combined New Independent States of the Former Soviet Union (NIS) and Latin American Screening (LAMS) studies cohort (n = 15,301). The RRs of these viral endpoints as predictors of progressive disease are affected by the length of viral persistence (6M+ or 12M+) and the surrogate endpoint (SIL, CIN1, CIN2, CIN/SIL). Most dramatic is the effect of the referent group used in risk estimates, with the HPV-negative referent group giving the highest and most consistent RRs for both 6M+ and 12M+ viral persistence, irrespective of which surrogate is used. In addition to deciding on whether to use 6M+ or 12M+ persistence criteria, and cytological, histological or combined surrogate endpoints, one should adopt the HPV-negative referent group as the gold standard in all future studies using viral persistence as the surrogate endpoint of progressive disease.

Persistence of the immune response after MenACWY-CRM vaccination and response to a booster dose, in adolescents, children and infants.

PubMed

Baxter, Roger; Keshavan, Pavitra; Welsch, Jo Anne; Han, Linda; Smolenov, Igor

2016-05-03

Persistence of bactericidal antibodies following vaccination is extremely important for protection against invasive meningococcal disease, given the epidemiology and rapid progression of meningococcal infection. We present an analysis of antibody persistence and booster response to MenACWY-CRM, in adolescents, children and infants, from 7 clinical studies. Immunogenicity was assessed using the serum bactericidal assay with both human and rabbit complement. Post-vaccination hSBA titers were high, with an age- and serogroup-specific decline in titers up to 1 y and stable levels up to 5 y The waning of hSBA titers over time was more pronounced among infants and toddlers and the greatest for serogroup A. However, rSBA titers against serogroup A were consistently higher and showed little decline over time, suggesting that protection against this serogroup may be sustained. A single booster dose of MenACWY-CRM administered at 3 to 5 y induced a robust immune response in all age groups.

Dietary Factors Modulate Helicobacter-Associated Gastric Cancer in Rodent Models

PubMed Central

Fox, James G.; Wang, Timothy C.

2014-01-01

Since its discovery in 1982, the global importance of H. pylori-induced disease, particularly in developing countries, remains high. The use of rodent models particularly mice, and the unanticipated usefulness of the gerbil to study H. pylori pathogenesis have been used extensively to study the interactions of the host, the pathogen and the environmental conditions influencing the outcome of persistent H. pylori infection. Dietary factors in humans are increasingly recognized as being important factors in modulating progression and severity of H. pylori-induced gastric cancer. Studies using rodent models to verify and help explain mechanisms whereby various dietary ingredients impact disease outcome should continue to be extremely productive. PMID:24301796

HIV-1 DNA predicts disease progression and post-treatment virological control

PubMed Central

Williams, James P; Hurst, Jacob; Stöhr, Wolfgang; Robinson, Nicola; Brown, Helen; Fisher, Martin; Kinloch, Sabine; Cooper, David; Schechter, Mauro; Tambussi, Giuseppe; Fidler, Sarah; Carrington, Mary; Babiker, Abdel; Weber, Jonathan

2014-01-01

In HIV-1 infection, a population of latently infected cells facilitates viral persistence despite antiretroviral therapy (ART). With the aim of identifying individuals in whom ART might induce a period of viraemic control on stopping therapy, we hypothesised that quantification of the pool of latently infected cells in primary HIV-1 infection (PHI) would predict clinical progression and viral replication following ART. We measured HIV-1 DNA in a highly characterised randomised population of individuals with PHI. We explored associations between HIV-1 DNA and immunological and virological markers of clinical progression, including viral rebound in those interrupting therapy. In multivariable analyses, HIV-1 DNA was more predictive of disease progression than plasma viral load and, at treatment interruption, predicted time to plasma virus rebound. HIV-1 DNA may help identify individuals who could safely interrupt ART in future HIV-1 eradication trials. Clinical trial registration: ISRCTN76742797 and EudraCT2004-000446-20 DOI: http://dx.doi.org/10.7554/eLife.03821.001 PMID:25217531

Inflammation, atrophy, and gastric cancer

PubMed Central

Fox, James G.; Wang, Timothy C.

2006-01-01

The association between chronic inflammation and cancer is now well established. This association has recently received renewed interest with the recognition that microbial pathogens can be responsible for the chronic inflammation observed in many cancers, particularly those originating in the gastrointestinal system. A prime example is Helicobacter pylori, which infects 50% of the world’s population and is now known to be responsible for inducing chronic gastric inflammation that progresses to atrophy, metaplasia, dysplasia, and gastric cancer. This Review provides an overview of recent progress in elucidating the bacterial properties responsible for colonization of the stomach, persistence in the stomach, and triggering of inflammation, as well as the host factors that have a role in determining whether gastritis progresses to gastric cancer. We also discuss how the increased understanding of the relationship between inflammation and gastric cancer still leaves many questions unanswered regarding recommendations for prevention and treatment. PMID:17200707

Clinical progression of ocular injury following arsenical vesicant lewisite exposure.

PubMed

Tewari-Singh, Neera; Croutch, Claire R; Tuttle, Richard; Goswami, Dinesh G; Kant, Rama; Peters, Eric; Culley, Tara; Ammar, David A; Enzenauer, Robert W; Petrash, J Mark; Casillas, Robert P; Agarwal, Rajesh

2016-12-01

Ocular injury by lewisite (LEW), a potential chemical warfare and terrorist agent, results in edema of eyelids, inflammation, massive corneal necrosis and blindness. To enable screening of effective therapeutics to treat ocular injury from LEW, useful clinically-relevant endpoints are essential. Hence, we designed an efficient exposure system capable of exposing up to six New-Zealand white rabbits at one time, and assessed LEW vapor-induced progression of clinical ocular lesions mainly in the cornea. The right eye of each rabbit was exposed to LEW (0.2 mg/L) vapor for 2.5, 5.0, 7.5 and 10.0 min and clinical progression of injury was observed for 28 days post-exposure (dose-response study), or exposed to same LEW dose for 2.5 and 7.5 min and clinical progression of injury was observed for up to 56 days post-exposure (time-response study); left eye served as an unexposed control. Increasing LEW exposure caused corneal opacity within 6 h post-exposure, which increased up to 3 days, slightly reduced thereafter till 3 weeks, and again increased thereafter. LEW-induced corneal ulceration peaked at 1 day post-exposure and its increase thereafter was observed in phases. LEW exposure induced neovascularization starting at 7 days which peaked at 22-35 days post-exposure, and remained persistent thereafter. In addition, LEW exposure caused corneal thickness, iris redness, and redness and swelling of the conjunctiva. Together, these findings provide clinical sequelae of ocular injury following LEW exposure and for the first time establish clinically-relevant quantitative endpoints, to enable the further identification of histopathological and molecular events involved in LEW-induced ocular injury.

Pathogen dynamics during invasion and establishment of white-nose syndrome explain mechanisms of host persistence.

PubMed

Frick, Winifred F; Cheng, Tina L; Langwig, Kate E; Hoyt, Joseph R; Janicki, Amanda F; Parise, Katy L; Foster, Jeffrey T; Kilpatrick, A Marm

2017-03-01

Disease dynamics during pathogen invasion and establishment determine the impacts of disease on host populations and determine the mechanisms of host persistence. Temporal progression of prevalence and infection intensity illustrate whether tolerance, resistance, reduced transmission, or demographic compensation allow initially declining populations to persist. We measured infection dynamics of the fungal pathogen Pseudogymnoascus destructans that causes white-nose syndrome in bats by estimating pathogen prevalence and load in seven bat species at 167 hibernacula over a decade as the pathogen invaded, became established, and some host populations stabilized. Fungal loads increased rapidly and prevalence rose to nearly 100% at most sites within 2 yr of invasion in six of seven species. Prevalence and loads did not decline over time despite huge reductions in colony sizes, likely due to an extensive environmental reservoir. However, there was substantial variation in fungal load among sites with persisting colonies, suggesting that both tolerance and resistance developed at different sites in the same species. In contrast, one species disappeared from hibernacula within 3 yr of pathogen invasion. Variable host responses to pathogen invasion require different management strategies to prevent disease-induced extinction and to facilitate evolution of tolerance or resistance in persisting populations. © 2016 by the Ecological Society of America.

Metronidazole-induced encephalopathy: not always a reversible situation.

PubMed

Hobbs, Kyle; Stern-Nezer, Sara; Buckwalter, Marion S; Fischbein, Nancy; Finley Caulfield, Anna

2015-06-01

Metronidazole is a nitroimidazole antimicrobial drug prescribed to treat infections caused by anaerobic bacteria and protozoa. Uncommonly, it causes central nervous system (CNS) toxicity manifesting as metronidazole-induced encephalopathy (MIE). Case report. A 65-year-old woman with hepatitis B cirrhosis (Child-Pugh class C, MELD 21) developed progressive encephalopathy to GCS 4 during a 3-week course of metronidazole for cholecystitis. Initial MRI was consistent with CNS metronidazole toxicity, with symmetrical T2 hyperintensity and generally restricted diffusion in bilateral dentate nuclei, corpus callosum, midbrain, superior cerebellar peduncles, internal capsules, and cerebral white matter. Laboratory values did not demonstrate significant electrolyte shifts, and continuous EEG was without seizure. High-dose thiamine was empirically administered. Lumbar puncture was not performed due to coagulopathy and thrombocytopenia. Despite discontinuation of metronidazole and keeping ammonia levels near normal, the patient did not improve. MRI was repeated 1 week after discontinuation of metronidazole. Although there was decreased DWI hyperintensity in the dentate nuclei, diffuse T2 hyperintensity persisted and even progressed in the brainstem, basal ganglia, and subcortical white matter. Petechial hemorrhages developed in bilateral corticospinal tracts and subcortical white matter. T1 hypointensity appeared in the corpus callosum. She was transitioned to comfort measures only and died 12 days later. MIE is an uncommon adverse effect of treatment with metronidazole that characteristically affects the dentate nuclei but may also involve the brainstem, corpus callosum, subcortical white matter, and basal ganglia. While the clinical symptoms and neuroimaging changes are usually reversible, persistent encephalopathy with poor outcome may occur.

Persistent high-risk human papillomavirus (HPV) infections as surrogate endpoints of progressive cervical disease. Potential new endpoint for efficacy studies with new-generation (non-HPV 16/18) prophylactic HPV vaccines.

PubMed

Syrjänen, K

2011-01-01

Recent data indicate that persistent HR-HPV infections represent a significantly increased risk of developing incident high-grade CIN and cervical cancer. Accordingly, 6-month (6M+) or 12-month (12M+) type-specific persistence of HR-HPV have been proposed as powerful surrogates of progressive disease. Because of substantial practical impact in future HPV vaccine trials using non-HPV 16/18 vaccines, studies on HR-HPV persistence as a surrogate endpoint of progressive CIN have been subject to a comprehensive meta-analyses recently. The present communication was solicited to bring this important and timely topic to the awareness of the readers, in a format consisting of a review of the recent literature, supplemented with the author's own experience from different studies. Based on a large number of relevant studies, there remains little doubt that persistence of HR-HPV for 6+ or 12+ months is associated with a significantly increased risk of developing incident high-grade CIN. However, some data also disclosed several important issues that need to be carefully considered and/or adequately resolved before adopting 6M+ or 12M+ HR-HPV persistence as a surrogate of progressive disease. These include i) definitions of HPV persistence, ii) HPV detection techniques and iii) testing intervals and iv) length of follow-up, as well as v) diagnosis of the surrogate endpoints, and vi) other study characteristics, including vii) the type of reference category used in calculating the risk estimates. All these issues are critically discussed in the present communication. Of major impact seems to be the reference category used to calculate these risk estimates, as evident from the NIS-LAMS cohort. Taken together, it is suggested that in all future studies using the 6M+ or 12M+ HR-HPV persistence as a surrogate endpoint of progressive disease, a "gold standard" should be used in calculating the risk estimates. In addition to deciding, 1) whether to use 6M+ or 12M+ persistence criteria, and 2) cytological, histological or combined surrogate endpoints (SIL, CIN1, CIN2, CIN/SIL), one should 3) use exclusively the HPV negative reference group in calculating the risk estimates for viral persistence endpoints. This is supported by the data from the recent meta-analysis as well as from the author's combined NIS-LAMS cohort, both implicating that the most consistent association to progressive disease is obtained when women with persistent HR-HPV are compared with HPV-negative women. It is the conviction of this author that the two other reference categories (HPV transient and HPV mixed outcome) are far too heterogeneous and subject to potential misclassifications to give consistent and reproducible risk estimates for HR-HPV persistence as a surrogate endpoint of progressive CIN.

Disease progression in Chinese chronic hepatitis C patients with persistently normal alanine aminotransaminase levels.

PubMed

Hui, C-K; Zhang, H-Y; Shek, T; Yao, H; Yueng, Y-H; Leung, K-W; Lai, S-T; Lai, J-Y; Leung, N; Lau, G K

2007-06-01

Although chronic hepatitis C virus-infected patients with persistently normal alanine aminotransaminase levels usually have mild liver disease, disease progression can still occur. However, it is uncertain which group of patients is at risk of disease progression. To examine the severity of liver disease on liver biopsy in Chinese patients with persistently normal alanine aminotransaminase levels, and their disease progression over time. Eighty-two patients with persistently normal alanine aminotransaminase levels were followed up longitudinally. The median time of follow-up was 8.1 years. Forty-seven of the 82 patients (57.3%) had a second liver biopsy. At the time of analysis, six of the 82 patients (7.3%) developed decompensated liver cirrhosis. Patients with an initial fibrosis stage F2 or F3 [6/23 (26.1%) vs. 0/59 (0%), P < 0.0001] or inflammatory grade A2 or A3 [5/40 (12.5%) vs. 1/42 (2.4%), P = 0.04] were more likely to develop decompensated liver cirrhosis. On multivariate analysis, initial fibrosis stage F2 or F3 was independently associated with progression to decompensated liver cirrhosis (relative risk 2.3, 95% confidence interval 0.03-2.5, P = 0.02). Chinese chronic hepatitis C virus patients with persistently normal alanine aminotransaminase levels with moderate to severe fibrosis at initial evaluation are more likely to develop decompensated liver cirrhosis.

Resistance may be an important mechanism by which marine microbes respond to environmental toxicants*1

NASA Astrophysics Data System (ADS)

Capriulo, Gerard M.; Flanzenbaum, Jeffrey; Wurster, Charles F.; Rowland, R. George

1983-11-01

The hypothesis, that at least certain marine microbial organisms respond to toxic stress by the development of resistance, was tested using the hypotric marine ciliate Euplotes vannus Muller as the test organism. Resistance to polychlorinated biphenyls (PCB, Aroclor 1254) was developed in E. vannus by exposing the animals to progressively higher PCB concentrations during a period of several months. The resistance to PCB persisted for at least 80 days (greater than 40 generations) after final exposure. This suggests either that genetic selection or persistent (lasting over many cell division cycles) phenotypic trait modification, possibly in the form of Dauermodification, had occurred. If resistance were widespread among marine microbial organisms in polluted environments it would be an important consideration in evaluating the long-term biological impact of both natural and man-induced chemical stress.

Heritable Transmission of Diabetic Metabolic Memory in Zebrafish Correlates With DNA Hypomethylation and Aberrant Gene Expression

PubMed Central

Olsen, Ansgar S.; Sarras, Michael P.; Leontovich, Alexey; Intine, Robert V.

2012-01-01

Metabolic memory (MM) is the phenomenon whereby diabetes complications persist and progress after glycemic recovery is achieved. Here, we present data showing that MM is heritable and that the transmission correlates with hyperglycemia-induced DNA hypomethylation and aberrant gene expression. Streptozocin was used to induce hyperglycemia in adult zebrafish, and then, following streptozocin withdrawal, a recovery phase was allowed to reestablish a euglycemic state. Blood glucose and serum insulin returned to physiological levels during the first 2 weeks of the recovery phase as a result of pancreatic β-cell regeneration. In contrast, caudal fin regeneration and skin wound healing remained impaired to the same extent as in diabetic fish, and this impairment was transmissible to daughter cell tissue. Daughter tissue that was never exposed to hyperglycemia, but was derived from tissue that was, did not accumulate AGEs or exhibit increased levels of oxidative stress. However, CpG island methylation and genome-wide microarray expression analyses revealed the persistence of hyperglycemia-induced global DNA hypomethylation that correlated with aberrant gene expression for a subset of loci in this daughter tissue. Collectively, the data presented here implicate the epigenetic mechanism of DNA methylation as a potential contributor to the MM phenomenon. PMID:22228713

Myofibroblast secretome and its auto-/paracrine signaling

PubMed Central

Bomb, Ritin; Heckle, Mark R.; Sun, Yao; Mancarella, Salvatore; Guntaka, Ramareddy V.; Gerling, Ivan C.; Weber, Karl T.

2016-01-01

Summary Myofibroblasts (myoFb) are phenotypically transformed, contractile fibroblast-like cells expressing α-smooth muscle actin microfilaments. They are integral to collagen fibrillogenesis with scar tissue formation at sites of repair irrespective of the etiologic origins of injury or tissue involved. MyoFb can persist long after healing is complete, where their ongoing turnover of collagen accounts for a progressive structural remodeling of an organ (a.k.a. fibrosis, sclerosis or cirrhosis). Such persistent metabolic activity is derived from a secretome consisting of requisite components in the de novo generation of angiotensin (Ang) II. Autocrine and paracrine signaling induced by tissue AngII is expressed via AT1 receptor ligand binding to respectively promote: i) regulation of myoFb collagen synthesis via the fibrogenic cytokine TGF-β1-Smad pathway; and ii) dedifferentiation and protein degradation of atrophic myocytes immobilized and ensnared by fibrillar collagen at sites of scarring. Several cardioprotective strategies in the prevention of fibrosis and involving myofibroblasts are considered. They include: inducing myoFb apoptosis through inactivation of antiapoptotic proteins; AT1 receptor antagonist to interfere with auto-/paracrine myoFb signaling or to induce counterregulatory expression of ACE2; and attacking the AngII-AT1R-TGF-β1-Smad pathway by antibody or the use of triplex-forming oligonucleotides. PMID:26818589

A Tradeoff Between Accuracy and Flexibility in a Working Memory Circuit Endowed with Slow Feedback Mechanisms

PubMed Central

Pereira, Jacinto; Wang, Xiao-Jing

2015-01-01

Recent studies have shown that reverberation underlying mnemonic persistent activity must be slow, to ensure the stability of a working memory system and to give rise to long neural transients capable of accumulation of information over time. Is the slower the underlying process, the better? To address this question, we investigated 3 slow biophysical mechanisms that are activity-dependent and prominently present in the prefrontal cortex: Depolarization-induced suppression of inhibition (DSI), calcium-dependent nonspecific cationic current (ICAN), and short-term facilitation. Using a spiking network model for spatial working memory, we found that these processes enhance the memory accuracy by counteracting noise-induced drifts, heterogeneity-induced biases, and distractors. Furthermore, the incorporation of DSI and ICAN enlarges the range of network's parameter values required for working memory function. However, when a progressively slower process dominates the network, it becomes increasingly more difficult to erase a memory trace. We demonstrate this accuracy–flexibility tradeoff quantitatively and interpret it using a state-space analysis. Our results supports the scenario where N-methyl-d-aspartate receptor-dependent recurrent excitation is the workhorse for the maintenance of persistent activity, whereas slow synaptic or cellular processes contribute to the robustness of mnemonic function in a tradeoff that potentially can be adjusted according to behavioral demands. PMID:25253801

Long-term consequences of developmental vascular defects on retinal vessel homeostasis and function in a mouse model of Norrie disease.

PubMed

Beck, Susanne C; Feng, Yuxi; Sothilingam, Vithiyanjali; Garcia Garrido, Marina; Tanimoto, Naoyuki; Acar, Niyazi; Shan, Shenliang; Seebauer, Britta; Berger, Wolfgang; Hammes, Hans-Peter; Seeliger, Mathias W

2017-01-01

Loss of Norrin signalling due to mutations in the Norrie disease pseudoglioma gene causes severe vascular defects in the retina, leading to visual impairment and ultimately blindness. While the emphasis of experimental work so far was on the developmental period, we focus here on disease mechanisms that induce progression into severe adult disease. The goal of this study was the comprehensive analysis of the long-term effects of the absence of Norrin on vascular homeostasis and retinal function. In a mouse model of Norrie disease retinal vascular morphology and integrity were studied by means of in vivo angiography; the vascular constituents were assessed in detailed histological analyses using quantitative retinal morphometry. Finally, electroretinographic analyses were performed to assess the retinal function in adult Norrin deficient animals. We could show that the primary developmental defects not only persisted but developed into further vascular abnormalities and microangiopathies. In particular, the overall vessel homeostasis, the vascular integrity, and also the cellular constituents of the vascular wall were affected in the adult Norrin deficient retina. Moreover, functional analyses indicated to persistent hypoxia in the neural retina which was suggested as one of the major driving forces of disease progression. In summary, our data provide evidence that the key to adult Norrie disease are ongoing vascular modifications, driven by the persistent hypoxic conditions, which are ineffective to compensate for the primary Norrin-dependent defects.

Long-term consequences of developmental vascular defects on retinal vessel homeostasis and function in a mouse model of Norrie disease

PubMed Central

Sothilingam, Vithiyanjali; Garcia Garrido, Marina; Tanimoto, Naoyuki; Acar, Niyazi; Shan, Shenliang; Seebauer, Britta; Berger, Wolfgang; Hammes, Hans-Peter; Seeliger, Mathias W.

2017-01-01

Loss of Norrin signalling due to mutations in the Norrie disease pseudoglioma gene causes severe vascular defects in the retina, leading to visual impairment and ultimately blindness. While the emphasis of experimental work so far was on the developmental period, we focus here on disease mechanisms that induce progression into severe adult disease. The goal of this study was the comprehensive analysis of the long-term effects of the absence of Norrin on vascular homeostasis and retinal function. In a mouse model of Norrie disease retinal vascular morphology and integrity were studied by means of in vivo angiography; the vascular constituents were assessed in detailed histological analyses using quantitative retinal morphometry. Finally, electroretinographic analyses were performed to assess the retinal function in adult Norrin deficient animals. We could show that the primary developmental defects not only persisted but developed into further vascular abnormalities and microangiopathies. In particular, the overall vessel homeostasis, the vascular integrity, and also the cellular constituents of the vascular wall were affected in the adult Norrin deficient retina. Moreover, functional analyses indicated to persistent hypoxia in the neural retina which was suggested as one of the major driving forces of disease progression. In summary, our data provide evidence that the key to adult Norrie disease are ongoing vascular modifications, driven by the persistent hypoxic conditions, which are ineffective to compensate for the primary Norrin-dependent defects. PMID:28575130

Progress Report: Access and Persistence of Minority Students in the Arizona Universities.

ERIC Educational Resources Information Center

Cotera, Augustus S.; And Others

One of the working papers in the final report of the Arizona Board of Regents' Task Force on Excellence, Efficiency and Competitiveness, this report presents statistical information on the progress of minority student access and persistence in the three Arizona Universities, Arizona's community colleges, and the Arizona Department of Education.…

Students' Self-Determined Motivation, Emotional Intelligence and Academic Persistence: An Examination of Second Year Students at a Public and a Private Historically Black University

ERIC Educational Resources Information Center

Watts-Martinez, Evanda Shentelle

2015-01-01

Self-determined Motivation, Emotional Intelligence, Persistence Attitudes, and Persistence Behaviors are non-cognitive factors that influence students' academic progression. This study examined the associations between Self-determined Motivation, EI, Persistence Attitudes, and Persistence Behaviors and the degree to which EI, as a mediating…

Persistence of the immune response after MenACWY-CRM vaccination and response to a booster dose, in adolescents, children and infants

PubMed Central

Baxter, Roger; Keshavan, Pavitra; Welsch, Jo Anne; Han, Linda; Smolenov, Igor

2016-01-01

ABSTRACT Persistence of bactericidal antibodies following vaccination is extremely important for protection against invasive meningococcal disease, given the epidemiology and rapid progression of meningococcal infection. We present an analysis of antibody persistence and booster response to MenACWY-CRM, in adolescents, children and infants, from 7 clinical studies. Immunogenicity was assessed using the serum bactericidal assay with both human and rabbit complement. Post-vaccination hSBA titers were high, with an age- and serogroup-specific decline in titers up to 1 y and stable levels up to 5 y The waning of hSBA titers over time was more pronounced among infants and toddlers and the greatest for serogroup A. However, rSBA titers against serogroup A were consistently higher and showed little decline over time, suggesting that protection against this serogroup may be sustained. A single booster dose of MenACWY-CRM administered at 3 to 5 y induced a robust immune response in all age groups. PMID:26829877

Social defeat-induced anhedonia: effects on operant sucrose-seeking behavior

PubMed Central

Riga, Danai; Theijs, J. Trisna; De Vries, Taco J.; Smit, August B.; Spijker, Sabine

2015-01-01

Reduced capacity to experience pleasure, also known as anhedonia, is a key feature of the depressive state and is associated with poor disease prognosis and treatment outcome. Various behavioral readouts (e.g., reduced sucrose intake) have been employed in animal models of depression as a measure of anhedonia. However, several aspects of anhedonia are poorly represented within the repertoire of current preclinical assessments. We recently adopted the social defeat-induced persistent stress (SDPS) paradigm that models a maintained depressive-like state in the rat, including social withdrawal and deficits in short-term spatial memory. Here we investigated whether SDPS elicited persistent deficits in natural reward evaluation, as part of anhedonia. We examined cue-paired operant sucrose self-administration, enabling us to study acquisition, motivation, extinction, and relapse to sucrose seeking following SDPS. Furthermore, we addressed whether guanfacine, an α2-adrenergic agonist that reduces stress-triggered maladaptive behavioral responses to drugs of abuse, could relief from SDPS-induced anhedonia. SDPS, consisting of five social defeat episodes followed by prolonged (≥8 weeks) social isolation, did not affect sucrose consumption during acquisition of self-administration. However, it strongly enhanced the motivational drive to acquire a sucrose reward in progressive ratio training. Moreover, SDPS induced initial resilience to extinction and rendered animals more sensitive to cue-induced reinstatement of sucrose-seeking. Guanfacine treatment attenuated SDPS-induced motivational overdrive and limited reinstatement of sucrose seeking, normalizing behavior to control levels. Together, our data indicate that long after the termination of stress exposure, SDPS induces guanfacine-reversible deficits in evaluation of a natural reward. Importantly, the SDPS-triggered anhedonia reflects many aspects of the human phenotype, including impaired motivation and goal-directed conduct. PMID:26300748

Social defeat-induced anhedonia: effects on operant sucrose-seeking behavior.

PubMed

Riga, Danai; Theijs, J Trisna; De Vries, Taco J; Smit, August B; Spijker, Sabine

2015-01-01

Reduced capacity to experience pleasure, also known as anhedonia, is a key feature of the depressive state and is associated with poor disease prognosis and treatment outcome. Various behavioral readouts (e.g., reduced sucrose intake) have been employed in animal models of depression as a measure of anhedonia. However, several aspects of anhedonia are poorly represented within the repertoire of current preclinical assessments. We recently adopted the social defeat-induced persistent stress (SDPS) paradigm that models a maintained depressive-like state in the rat, including social withdrawal and deficits in short-term spatial memory. Here we investigated whether SDPS elicited persistent deficits in natural reward evaluation, as part of anhedonia. We examined cue-paired operant sucrose self-administration, enabling us to study acquisition, motivation, extinction, and relapse to sucrose seeking following SDPS. Furthermore, we addressed whether guanfacine, an α2-adrenergic agonist that reduces stress-triggered maladaptive behavioral responses to drugs of abuse, could relief from SDPS-induced anhedonia. SDPS, consisting of five social defeat episodes followed by prolonged (≥8 weeks) social isolation, did not affect sucrose consumption during acquisition of self-administration. However, it strongly enhanced the motivational drive to acquire a sucrose reward in progressive ratio training. Moreover, SDPS induced initial resilience to extinction and rendered animals more sensitive to cue-induced reinstatement of sucrose-seeking. Guanfacine treatment attenuated SDPS-induced motivational overdrive and limited reinstatement of sucrose seeking, normalizing behavior to control levels. Together, our data indicate that long after the termination of stress exposure, SDPS induces guanfacine-reversible deficits in evaluation of a natural reward. Importantly, the SDPS-triggered anhedonia reflects many aspects of the human phenotype, including impaired motivation and goal-directed conduct.

The effect of amyotrophic lateral sclerosis-linked exogenous SOD1-G93A on electrophysiological properties and intracellular calcium in cultured rat astrocytes.

PubMed

Milošević, Milena; Bataveljić, Danijela; Nikolić, Ljiljana; Bijelić, Dunja; Andjus, Pavle

2016-01-01

Over 150 mutations in the SOD1 gene that encodes Cu/Zn superoxide dismutase (SOD1) cause 20-25% of familial ALS, albeit without a known gain-of-function mechanism. ALS is also non-cell-autonomous, the interactions between motor neurons and their glial neighbours being implicated in disease progression. The aim here was to investigate the biophysical effects of the exogenous human mutant SOD1-G93A on rat astrocytes in culture. Primary cortical astrocyte cultures were treated with recombinant human apo- mSOD1-G93A vs. wild-type control (wtSOD1) and recorded by patch-clamp and calcium imaging. Results showed that exogenous mSOD1 as well as wtSOD1 induced a decrease of membrane resistance, the effect being persistent (up to 13 min) only for the mutant form. Similarly, whole-cell inward currents in astrocytes were augmented by both wt and mSOD1, but the effect was twice larger and only progressed continuously for the latter. Both forms of SOD1 also induced a rise in intracellular Ca(2+) activity, the effect being dependent on external Ca(2+) and again only persisted with mSOD1, becoming significantly different from wtSOD1 only at longer times (14 min). In conclusion, this study points to membrane permeability and Ca(2+) signalling as processes affected by SOD1-G93A that presents the humoral factor triggering the role of astrocytes in ALS pathophysiology.

Academic Persistence of Online Students in Higher Education Impacted by Student Progress Factors and Social Media

ERIC Educational Resources Information Center

Lint, Anna H.

2013-01-01

This quantitative study evaluated and investigated the theoretical underpinnings of the Kember's (1995) student progress model that examines the direct or indirect effects of student persistence in online education by identifying the relationships between variables. The primary method of data collection in this study was a survey by exploring the…

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

Weber, Nicholas D., E-mail: nweber@fhcrc.org; Department of Laboratory Medicine, University of Washington, Seattle, WA 98195; Aubert, Martine, E-mail: maubert@fhcrc.org

Treatment for most persistent viral infections consists of palliative drug options rather than curative approaches. This is often because long-lasting viral DNA in infected cells is not affected by current antivirals, providing a source for viral persistence and reactivation. Targeting latent viral DNA itself could therefore provide a basis for novel curative strategies. DNA cleavage enzymes can be used to induce targeted mutagenesis of specific genes, including those of exogenous viruses. Although initial in vitro and even in vivo studies have been carried out using DNA cleavage enzymes targeting various viruses, many questions still remain concerning the feasibility of thesemore » strategies as they transition into preclinical research. Here, we review the most recent findings on DNA cleavage enzymes for human viral infections, consider the most relevant animal models for several human viral infections, and address issues regarding safety and enzyme delivery. Results from well-designed in vivo studies will ideally provide answers to the most urgent remaining questions, and allow continued progress toward clinical application. - Highlights: • Recent in vitro and in vivo results for DNA cleavage enzymes targeting persistent viral infections. • Analysis of the best animal models for testing enzymes for HBV, HSV, HIV and HPV. • Challenges facing in vivo delivery of therapeutic enzymes for persistent viral infections. • Safety issues to be addressed with proper animal studies.« less

A human prostatic bacterial isolate alters the prostatic microenvironment and accelerates prostate cancer progression.

PubMed

Simons, Brian W; Durham, Nicholas M; Bruno, Tullia C; Grosso, Joseph F; Schaeffer, Anthony J; Ross, Ashley E; Hurley, Paula J; Berman, David M; Drake, Charles G; Thumbikat, Praveen; Schaeffer, Edward M

2015-02-01

Inflammation is associated with several diseases of the prostate including benign enlargement and cancer, but a causal relationship has not been established. Our objective was to characterize the prostate inflammatory microenvironment after infection with a human prostate-derived bacterial strain and to determine the effect of inflammation on prostate cancer progression. To this end, we mimicked typical human prostate infection with retrograde urethral instillation of CP1, a human prostatic isolate of Escherichia coli. CP1 bacteria were tropic for the accessory sex glands and induced acute inflammation in the prostate and seminal vesicles, with chronic inflammation lasting at least 1 year. Compared to controls, infection induced both acute and chronic inflammation with epithelial hyperplasia, stromal hyperplasia, and inflammatory cell infiltrates. In areas of inflammation, epithelial proliferation and hyperplasia often persist, despite decreased expression of androgen receptor (AR). Inflammatory cells in the prostates of CP1-infected mice were characterized at 8 weeks post-infection by flow cytometry, which showed an increase in macrophages and lymphocytes, particularly Th17 cells. Inflammation was additionally assessed in the context of carcinogenesis. Multiplex cytokine profiles of inflamed prostates showed that distinct inflammatory cytokines were expressed during prostate inflammation and cancer, with a subset of cytokines synergistically increased during concurrent inflammation and cancer. Furthermore, CP1 infection in the Hi-Myc mouse model of prostate cancer accelerated the development of invasive prostate adenocarcinoma, with 70% more mice developing cancer by 4.5 months of age. This study provides direct evidence that prostate inflammation accelerates prostate cancer progression and gives insight into the microenvironment changes induced by inflammation that may accelerate tumour initiation or progression. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Androgen deprivation results in time-dependent hypoxia in LNCaP prostate tumours: informed scheduling of the bioreductive drug AQ4N improves treatment response.

PubMed

Ming, Louise; Byrne, Niall M; Camac, Sarah Nicole; Mitchell, Christopher A; Ward, Claire; Waugh, David J; McKeown, Stephanie R; Worthington, Jenny

2013-03-15

Androgen withdrawal induces hypoxia in androgen-sensitive tissue; this is important as in the tumour microenvironment, hypoxia is known to drive malignant progression. Our study examined the time-dependent effect of androgen deprivation therapy (ADT) on tumour oxygenation and investigated the role of ADT-induced hypoxia on malignant progression in prostate tumours. LNCaP xenografted tumours were treated with anti-androgens and tumour oxygenation measured. Dorsal skin fold (DSF) chambers were used to image tumour vasculature in vivo. Quantitative PCR (QPCR) identified differential gene expression following treatment with bicalutamide. Bicalutamide-treated and vehicle-only-treated tumours were re-established in vitro, and invasion and sensitivity to docetaxel were measured. Tumour growth delay was calculated following treatment with bicalutamide combined with the bioreductive drug AQ4N. Tumour oxygenation measurements showed a precipitate decrease following initiation of ADT. A clinically relevant dose of bicalutamide (2 mg/kg/day) decreased tumour oxygenation by 45% within 24 hr, reaching a nadir of 0.09% oxygen (0.67 ± 0.06 mmHg) by Day 7; this persisted until Day 14 when it increased up to Day 28. Using DSF chambers, LNCaP tumours treated with bicalutamide showed loss of small vessels at Days 7 and 14 with revascularisation occurring by Day 21. QPCR showed changes in gene expression consistent with the vascular changes and malignant progression. Cells from bicalutamide-treated tumours were more malignant than vehicle-treated controls. Combining bicalutamide with AQ4N (50 mg/kg, single dose) caused greater tumour growth delay than bicalutamide alone. Our study shows that bicalutamide-induced hypoxia selects for cells that show malignant progression; targeting hypoxic cells may provide greater clinical benefit. Copyright © 2012 UICC.

Impact assessment of energy-efficient lighting in patients with lupus erythematosus: a pilot study.

PubMed

Fenton, L; Dawe, R; Ibbotson, S; Ferguson, J; Silburn, S; Moseley, H

2014-03-01

Patients with lupus erythematosus (LE) are often abnormally photosensitive. Ultraviolet (UV) exposure can not only induce cutaneous lesions but may also contribute to systemic flares and disease progression. Various forms of energy-efficient lighting have been shown to emit UV radiation. To determine the effects of these emissions on individuals with LE. This assessment investigated cutaneous responses to repeated exposures from three types of lighting: compact fluorescent lamp (CFL), light-emitting diode (LED) and energy-efficient halogen (EEH). The subjects were 15 patients with LE and a control group of five healthy volunteers. No cutaneous LE lesions were induced by any of the light sources. Delayed skin erythema was induced at the site of CFL irradiation in six of the 15 patients with LE and two of the five healthy subjects. Erythema was increased in severity and more persistent in patients with LE. One patient with LE produced a positive delayed erythema to the EEH. A single patient with LE produced immediate abnormal erythemal responses to the CFL, LED and EEH. Further investigation revealed that this patient also had solar urticaria. All other subjects had negative responses to LED exposure. Compact fluorescent lamps emit UV that can induce skin erythema in both individuals with LE and healthy individuals when situated in close proximity. However, this occurs to a greater extent and is more persistent in patients with LE. EEHs emit UVA that can induce erythema in patients with LE. LEDs provide a safer alternative light source without risk of UV exposure. © 2013 British Association of Dermatologists.

From the Cover: Magnetic Resonance Imaging Reveals Progressive Brain Injury in Rats Acutely Intoxicated With Diisopropylfluorophosphate

PubMed Central

Hobson, Brad A.; Sisó, Sílvia; Rowland, Douglas J.; Harvey, Danielle J.; Bruun, Donald A.; Garbow, Joel R.

2017-01-01

Abstract Acute intoxication with organophosphates (OPs) can trigger seizures that progress to status epilepticus, and survivors often exhibit chronic neuropathology, cognitive impairment, affective disorders, and/or electroencephalographic abnormalities. Understanding how acute injury transitions to persistent neurological sequelae is critical to developing medical countermeasures for mitigating damage following OP-induced seizures. Here, we used in vivo magnetic resonance imaging (MRI) to monitor the spatiotemporal patterns of neuropathology for 1 month after acute intoxication with diisopropylfluorophosphate (DFP). Adult male Sprague Dawley rats administered pyridostigmine bromide (0.1 mg/kg, im) 30 min prior to successive administration of DFP (4 mg/kg, sc), atropine sulfate (2 mg/kg, im), and 2-pralidoxime (25 mg/kg, im) exhibited moderate-to-severe seizure behavior. T2-weighted and diffusion-weighted MR imaging prior to DFP exposure and at 3, 7, 14, 21, or 28 days postexposure revealed prominent lesions, tissue atrophy, and ventricular enlargement in discrete brain regions. Lesions varied in intensity and/or extent over time, with the overall magnitude of injury strongly influenced by seizure severity. Importantly, lesions detected by MRI correlated spatially and temporally with histological evidence of brain pathology. Analysis of histogram parameters extracted from frequency distributions of regional apparent diffusion coefficient (ADC) values identified the standard deviation and 90th percentile of the ADC as robust metrics for quantifying persistent and progressive neuropathological changes. The interanimal and interregional variations observed in lesion severity and progression, coupled with potential reinjury following spontaneous recurrent seizures, underscore the advantages of using in vivo imaging to longitudinally monitor neuropathology and, ultimately, therapeutic response, following acute OP intoxication. PMID:28329842

Reversing Melanoma Cross-Resistance to BRAF and MEK Inhibitors by Co-Targeting the AKT/mTOR Pathway

PubMed Central

Attar, Narsis; Ng, Charles; Chu, Connie; Guo, Deliang; Nazarian, Ramin; Chmielowski, Bartosz; Glaspy, John A.; Comin-Anduix, Begonya; Mischel, Paul S.; Lo, Roger S.; Ribas, Antoni

2011-01-01

Background The sustained clinical activity of the BRAF inhibitor vemurafenib (PLX4032/RG7204) in patients with BRAFV600 mutant melanoma is limited primarily by the development of acquired resistance leading to tumor progression. Clinical trials are in progress using MEK inhibitors following disease progression in patients receiving BRAF inhibitors. However, the PI3K/AKT pathway can also induce resistance to the inhibitors of MAPK pathway. Methodology/Principal Findings The sensitivity to vemurafenib or the MEK inhibitor AZD6244 was tested in sensitive and resistant human melanoma cell lines exploring differences in activation-associated phosphorylation levels of major signaling molecules, leading to the testing of co-inhibition of the AKT/mTOR pathway genetically and pharmacologically. There was a high degree of cross-resistance to vemurafenib and AZD6244, except in two vemurafenib-resistant cell lines that acquired a secondary mutation in NRAS. In other cell lines, acquired resistance to both drugs was associated with persistence or increase in activity of AKT pathway. siRNA-mediated gene silencing and combination therapy with an AKT inhibitor or rapamycin partially or completely reversed the resistance. Conclusions/Significance Primary and acquired resistance to vemurafenib in these in vitro models results in frequent cross resistance to MEK inhibitors, except when the resistance is the result of a secondary NRAS mutation. Resistance to BRAF or MEK inhibitors is associated with the induction or persistence of activity within the AKT pathway in the presence of these drugs. This resistance can be potentially reversed by the combination of a RAF or MEK inhibitor with an AKT or mTOR inhibitor. These combinations should be available for clinical testing in patients progressing on BRAF inhibitors. PMID:22194965

Unique Chemokine Profiles of Lung Tissues Distinguish Post-chemotherapeutic Persistent and Chronic Tuberculosis in a Mouse Model.

PubMed

Park, Soomin; Baek, Seung-Hun; Cho, Sang-Nae; Jang, Young-Saeng; Kim, Ahreum; Choi, In-Hong

2017-01-01

There is a substantial need for biomarkers to distinguish latent stage from active Mycobacterium tuberculosis infections, for predicting disease progression. To induce the reactivation of tuberculosis, we present a new experimental animal model modified based on the previous model established by our group. In the new model, the reactivation of tuberculosis is induced without administration of immunosuppressive agents, which might disturb immune responses. To identify the immunological status of the persistent and chronic stages, we analyzed immunological genes in lung tissues from mice infected with M. tuberculosis . Gene expression was screened using cDNA microarray analysis and confirmed by quantitative RT-PCR. Based on the cDNA microarray results, 11 candidate cytokines genes, which were obviously up-regulated during the chronic stage compared with those during the persistent stage, were selected and clustered into three groups: (1) chemokine genes, except those of monocyte chemoattractant proteins (MCPs; CXCL9, CXCL10, CXCL11, CCL5, CCL19); (2) MCP genes (CCL2, CCL7, CCL8, CCL12); and (3) TNF and IFN-γ genes. Results from the cDNA microarray and quantitative RT-PCR analyses revealed that the mRNA expression of the selected cytokine genes was significantly higher in lung tissues of the chronic stage than of the persistent stage. Three chemokines (CCL5, CCL19, and CXCL9) and three MCPs (CCL7, CCL2, and CCL12) were noticeably increased in the chronic stage compared with the persistent stage by cDNA microarray ( p < 0.01, except CCL12) or RT-PCR ( p < 0.01). Therefore, these six significantly increased cytokines in lung tissue from the mouse tuberculosis model might be candidates for biomarkers to distinguish the two disease stages. This information can be combined with already reported potential biomarkers to construct a network of more efficient tuberculosis markers.

Novel synthetic monoketone transmute radiation-triggered NFκB-dependent TNFα cross-signaling feedback maintained NFκB and favors neuroblastoma regression.

PubMed

Aravindan, Sheeja; Natarajan, Mohan; Awasthi, Vibhudutta; Herman, Terence S; Aravindan, Natarajan

2013-01-01

Recently, we demonstrated that radiation (IR) instigates the occurrence of a NFκB-TNFα feedback cycle which sustains persistent NFκB activation in neuroblastoma (NB) cells and favors survival advantage and clonal expansion. Further, we reported that curcumin targets IR-induced survival signaling and NFκB dependent hTERT mediated clonal expansion in human NB cells. Herein, we investigated the efficacy of a novel synthetic monoketone, EF24, a curcumin analog in inhibiting persistent NFκB activation by disrupting the IR-induced NFκB-TNFα-NFκB feedback signaling in NB and subsequent mitigation of survival advantage and clonal expansion. EF24 profoundly suppressed the IR-induced NFκB-DNA binding activity/promoter activation and, maintained the NFκB repression by deterring NFκB-dependent TNFα transactivation/intercellular secretion in genetically varied human NB (SH-SY5Y, IMR-32, SK-PN-DW, MC-IXC and SK-N-MC) cell types. Further, EF24 completely suppressed IR-induced NFκB-TNFα cross-signaling dependent transactivation/translation of pro-survival IAP1, IAP2 and Survivin and subsequent cell survival. In corroboration, EF24 treatment maximally blocked IR-induced NFκB dependent hTERT transactivation/promoter activation, telomerase activation and consequent clonal expansion. EF24 displayed significant regulation of IR-induced feedback dependent NFκB and NFκB mediated survival signaling and complete regression of NB xenograft. Together, the results demonstrate for the first time that, novel synthetic monoketone EF24 potentiates radiotherapy and mitigates NB progression by selectively targeting IR-triggered NFκB-dependent TNFα-NFκB cross-signaling maintained NFκB mediated survival advantage and clonal expansion.

Novel Synthetic Monoketone Transmute Radiation-Triggered NFκB-Dependent TNFα Cross-Signaling Feedback Maintained NFκB and Favors Neuroblastoma Regression

PubMed Central

Aravindan, Sheeja; Natarajan, Mohan; Awasthi, Vibhudutta; Herman, Terence S.; Aravindan, Natarajan

2013-01-01

Recently, we demonstrated that radiation (IR) instigates the occurrence of a NFκB-TNFα feedback cycle which sustains persistent NFκB activation in neuroblastoma (NB) cells and favors survival advantage and clonal expansion. Further, we reported that curcumin targets IR-induced survival signaling and NFκB dependent hTERT mediated clonal expansion in human NB cells. Herein, we investigated the efficacy of a novel synthetic monoketone, EF24, a curcumin analog in inhibiting persistent NFκB activation by disrupting the IR-induced NFκB-TNFα-NFκB feedback signaling in NB and subsequent mitigation of survival advantage and clonal expansion. EF24 profoundly suppressed the IR-induced NFκB-DNA binding activity/promoter activation and, maintained the NFκB repression by deterring NFκB-dependent TNFα transactivation/intercellular secretion in genetically varied human NB (SH-SY5Y, IMR-32, SK–PN–DW, MC-IXC and SK–N-MC) cell types. Further, EF24 completely suppressed IR-induced NFκB-TNFα cross-signaling dependent transactivation/translation of pro-survival IAP1, IAP2 and Survivin and subsequent cell survival. In corroboration, EF24 treatment maximally blocked IR-induced NFκB dependent hTERT transactivation/promoter activation, telomerase activation and consequent clonal expansion. EF24 displayed significant regulation of IR-induced feedback dependent NFκB and NFκB mediated survival signaling and complete regression of NB xenograft. Together, the results demonstrate for the first time that, novel synthetic monoketone EF24 potentiates radiotherapy and mitigates NB progression by selectively targeting IR-triggered NFκB-dependent TNFα-NFκB cross-signaling maintained NFκB mediated survival advantage and clonal expansion. PMID:23967300

Beyond Tryptophan Synthase: Identification of Genes That Contribute to Chlamydia trachomatis Survival during Gamma Interferon-Induced Persistence and Reactivation

PubMed Central

Muramatsu, Matthew K.; Brothwell, Julie A.; Stein, Barry D.; Putman, Timothy E.; Rockey, Daniel D.

2016-01-01

Chlamydia trachomatis can enter a viable but nonculturable state in vitro termed persistence. A common feature of C. trachomatis persistence models is that reticulate bodies fail to divide and make few infectious progeny until the persistence-inducing stressor is removed. One model of persistence that has relevance to human disease involves tryptophan limitation mediated by the host enzyme indoleamine 2,3-dioxygenase, which converts l-tryptophan to N-formylkynurenine. Genital C. trachomatis strains can counter tryptophan limitation because they encode a tryptophan-synthesizing enzyme. Tryptophan synthase is the only enzyme that has been confirmed to play a role in interferon gamma (IFN-γ)-induced persistence, although profound changes in chlamydial physiology and gene expression occur in the presence of persistence-inducing stressors. Thus, we screened a population of mutagenized C. trachomatis strains for mutants that failed to reactivate from IFN-γ-induced persistence. Six mutants were identified, and the mutations linked to the persistence phenotype in three of these were successfully mapped. One mutant had a missense mutation in tryptophan synthase; however, this mutant behaved differently from previously described synthase null mutants. Two hypothetical genes of unknown function, ctl0225 and ctl0694, were also identified and may be involved in amino acid transport and DNA damage repair, respectively. Our results indicate that C. trachomatis utilizes functionally diverse genes to mediate survival during and reactivation from persistence in HeLa cells. PMID:27430273

Synchrony in human, mouse and bacterial cell cultures--a comparison

NASA Technical Reports Server (NTRS)

Helmstetter, Charles E.; Thornton, Maureen; Romero, Ana; Eward, K. Leigh

2003-01-01

Growth characteristics of synchronous human MOLT-4, human U-937 and mouse L1210 cultures produced with a new minimally-disturbing technology were compared to each other and to synchronous Escherichia coli B/r. Based on measurements of cell concentrations during synchronous growth, synchrony persisted in similar fashion for all cells. Cell size and DNA distributions in the mammalian cultures also progressed synchronously and reproducibly for multiple cell cycles. The results demonstrate that unambiguous multi-cycle synchrony, critical for verifying the absence of significant growth imbalances induced by the synchronization procedure, is feasible with these cell lines, and possibly others.

Chronic Inflammatory Microenvironment in Epidermodysplasia Verruciformis Skin Lesions: Role of the Synergism Between HPV8 E2 and C/EBPβ to Induce Pro-Inflammatory S100A8/A9 Proteins.

PubMed

Podgórska, Marta; Ołdak, Monika; Marthaler, Anna; Fingerle, Alina; Walch-Rückheim, Barbara; Lohse, Stefan; Müller, Cornelia S L; Vogt, Thomas; Ustav, Mart; Wnorowski, Artur; Malejczyk, Magdalena; Majewski, Sławomir; Smola, Sigrun

2018-01-01

Persistent genus β-HPV (human papillomavirus) infection is a major co-factor for non-melanoma skin cancer in patients suffering from the inherited skin disease epidermodysplasia verruciformis (EV). Malignant EV lesions are particularly associated with HPV type 5 or 8. There is clinical and molecular evidence that HPV8 actively suppresses epithelial immunosurveillance by interfering with the recruitment of Langerhans cells, which may favor viral persistence. Mechanisms how persistent HPV8 infection promotes the carcinogenic process are, however, less well understood. In various tumor types chronic inflammation has a central role in tumor progression. The calprotectin complex consisting of S100A8 and S100A9 proteins has recently been identified as key driver of chronic and tumor promoting inflammation in skin carcinogenesis. It induces chemotaxis of neutrophil granulocytes and modulates inflammatory as well as immune responses. In this study, we demonstrate that skin lesions of EV-patients are massively infiltrated by inflammatory cells, including CD15 + granulocytes. At the same time we observed a very strong expression of S100A8 and S100A9 proteins in lesional keratinocytes, which was mostly confined to the suprabasal layers of the epidermis. Both proteins were hardly detected in non-lesional skin. Further experiments revealed that the HPV8 oncoproteins E6 and E7 were not involved in S100A8/A9 up-regulation. They rather suppressed differentiation-induced S100A8/A9 expression. In contrast, the viral transcription factor E2 strongly enhanced PMA-mediated S100A8/A9 up-regulation in primary human keratinocytes. Similarly, a tremendous up-regulation of both S100 proteins was observed, when minute amounts of the PMA-inducible CCAAT/enhancer binding protein β (C/EBPβ), which is expressed at low levels in the suprabasal layers of the epidermis, were co-expressed together with HPV8 E2. This confirmed our previous observation that C/EBPβ interacts and functionally synergizes with the HPV8 E2 protein in differentiation-dependent gene expression. Potent synergistic up-regulation of S100A8/A9 was seen at transcriptional and protein levels. S100A8/A9 containing supernatants from keratinocytes co-expressing HPV8 E2 and C/EBPβ significantly induced chemotaxis of granulocytes in migration assays supporting the relevance of our finding. In conclusion, our data suggest that the HPV8 E2 protein actively contributes to the recruitment of myeloid cells into EV skin lesions, which may support chronic inflammation and progression to skin cancer.

Dexmedetomidine Increases Tau Phosphorylation Under Normothermic Conditions In Vivo and In Vitro

PubMed Central

Whittington, Robert A.; Virág, László; Gratuze, Maud; Petry, Franck R.; Noël, Anastasia; Poitras, Isabelle; Truchetti, Geoffrey; Marcouiller, François; Papon, Marie-Amélie; Khoury, Noura El; Wong, Kevin; Bretteville, Alexis; Morin, Françoise; Planel, Emmanuel

2015-01-01

There is developing interest in the potential association between anesthesia and the onset and progression of Alzheimer's disease. Several anesthetics have thus been demonstrated to induce tau hyperphosphorylation, an effect mostly mediated by anesthesia-induced hypothermia. Here, we tested the hypothesis that acute normothermic administration of dexmedetomidine, an intravenous sedative used in intensive care units, would result in tau hyperphosphorylation in vivo and in vitro. When administered to non-transgenic mice, dexmedetomidine induced tau hyperphosphorylation persisting up to 6h in the hippocampus for the AT8 epitope. Pretreatment with atipamezole, a highly specific α2-adrenergic receptor (α2-AR) antagonist, blocked dexmedetomidine-induced tau hyperphosphorylation. Furthermore, dexmedetomidine dose-dependently increased tau phosphorylation at AT8 in SH-SY5Y cells, impaired mice spatial memory in the Barnes maze, and promoted tau hyperphosphorylation and aggregation in transgenic hTau mice. These findings suggest that dexmedetomidine: i) increases tau phosphorylation, in vivo and in vitro, in the absence of anesthetic-induced hypothermia and through α2-AR activation, ii) promotes tau aggregation in a mouse model of tauopathy, and iii) impacts spatial reference memory. PMID:26058840

Novel rodent model of breast cancer survival with persistent anxiety-like behavior and inflammation.

PubMed

Pyter, Leah M; Suarez-Kelly, Lorena P; Carson, William E; Kaur, Jasskiran; Bellisario, Joshua; Bever, Savannah R

2017-07-14

Breast cancer survivors are an expanding population that is troubled by lasting mental health problems, including depression and anxiety. These issues reduce quality-of-life throughout survivorhood. Research indicates that tumor biology, cancer treatments, and stress contribute to these mood disturbances. Although the mechanisms underlying these various causes remain under investigation, neuroinflammation is a leading hypothesis. To date, rodent models of recurrence-free tumor survival for understanding mechanisms by which these behavioral issues persist after cancer are lacking. Here, we test the extent to which potential behavioral symptoms persist after mammary tumor removal in mice (i.e., establishment of a cancer survivor model), while also empirically testing the causal role of tumors in the development of neuroinflammatory-mediated affective-like behaviors. Complete surgical resection of a non-metastatic orthotopic, syngeneic mammary tumor reversed tumor-induced increases of circulating cytokines (IL-6, CXCL1, IL-10) and myeloid-derived cells and modulated neuroinflammatory gene expression (Cd11b, Cxcl1). Multiple anxiety-like behaviors and some central and peripheral immune markers persisted or progressed three weeks after tumor resection. Together, these data indicate that persistent behavioral changes into cancer survivorhood may be due, in part, to changes in immunity that remain even after successful tumor removal. This novel survivor paradigm represents an improvement in modeling prevalent cancer survivorship issues and studying the basic mechanisms by which cancer/cancer treatments influence the brain and behavior. Copyright © 2017 Elsevier B.V. All rights reserved.

S(+)amphetamine induces a persistent leak in the human dopamine transporter: molecular stent hypothesis

PubMed Central

Rodriguez-Menchaca, Aldo A; Solis Jr, Ernesto; Cameron, Krasnodara; De Felice, Louis J

2012-01-01

BACKGROUND AND PURPOSE Wherever they are located, dopamine transporters (DATs) clear dopamine (DA) from the extracellular milieu to help regulate dopaminergic signalling. Exposure to amphetamine (AMPH) increases extracellular DA in the synaptic cleft, which has been ascribed to DAT reverse transport. Increased extracellular DA prolongs postsynaptic activity and reinforces abuse and hedonic behaviour. EXPERIMENTAL APPROACH Xenopus laevis oocytes expressing human (h) DAT were voltage-clamped and exposed to DA, R(-)AMPH, or S(+)AMPH. KEY RESULTS At -60mV, near neuronal resting potentials, S(+)AMPH induced a depolarizing current through hDAT, which after removing the drug, persisted for more than 30 min. This persistent leak in the absence of S(+)AMPH was in contrast to the currents induced by R(-)AMPH and DA, which returned to baseline immediately after their removal. Our data suggest that S(+)AMPH and Na+ carry the initial S(+)AMPH-induced current, whereas Na+ and Cl- carry the persistent leak current. We propose that the persistent current results from the internal action of S(+)AMPH on hDAT because the temporal effect was consistent with S(+)AMPH influx, and intracellular S(+)AMPH activated the effect. The persistent current was dependent on Na+ and was blocked by cocaine. Intracellular injection of S(+)AMPH also activated a DA-induced persistent leak current. CONCLUSIONS AND IMPLICATIONS We report a hitherto unknown action of S(+)AMPH on hDAT that potentially affects AMPH-induced DA release. We propose that internal S(+)AMPH acts as a molecular stent that holds the transporter open even after external S(+)AMPH is removed. Amphetamine-induced persistent leak currents are likely to influence dopaminergic signalling, DA release mechanisms, and amphetamine abuse. PMID:22014068

Smooth muscle in the maintenance of increased airway resistance elicited by methacholine in humans.

PubMed

Chapman, David G; Pascoe, Chris D; Lee-Gosselin, Audrey; Couture, Christian; Seow, Chun Y; Paré, Peter D; Salome, Cheryl M; King, Gregory G; Bossé, Ynuk

2014-10-15

Airway narrowing is maintained for a prolonged period after acute bronchoconstriction in humans in the absence of deep inspirations (DIs). To determine whether maintenance of airway smooth muscle (ASM) shortening is responsible for the persistence of airway narrowing in healthy subjects following transient methacholine (MCh)-induced bronchoconstriction. On two separate visits, five healthy subjects underwent MCh challenges until respiratory system resistance (Rrs) had increased by approximately 1.5 cm H2O/L/s. Subjects took a DI either immediately after or 30 minutes after the last dose. The extent of renarrowing following the bronchodilator effect of DI was used to assess the continued action of MCh (calculated as percent change in Rrs from the pre-DI Rrs). We then used human bronchial rings to determine whether ASM can maintain shortening during a progressive decrease of carbachol concentration. The increased Rrs induced by MCh was maintained for 30 minutes despite waning of MCh concentration over that period, measured as attenuated renarrowing when the DI was taken 30 minutes after compared with immediately after the last dose (7 min post-DI, -36.2 ± 11.8 vs. 14.4 ± 13.2%; 12 min post-DI, -39.5 ± 9.8 vs. 15.2 ± 17.8%). Ex vivo, ASM shortening was largely maintained during a progressive decrease of carbachol concentration, even down to concentrations that would not be expected to induce shortening. The maintenance of airway narrowing despite MCh clearance in humans is attributed to an intrinsic ability of ASM to maintain shortening during a progressive decrease of contractile stimulation.

Risk factors for long-term persistence of serum hepatitis B surface antigen following acute hepatitis B virus infection in Japanese adults.

PubMed

Ito, Kiyoaki; Yotsuyanagi, Hiroshi; Yatsuhashi, Hiroshi; Karino, Yoshiyasu; Takikawa, Yasuhiro; Saito, Takafumi; Arase, Yasuji; Imazeki, Fumio; Kurosaki, Masayuki; Umemura, Takeji; Ichida, Takafumi; Toyoda, Hidenori; Yoneda, Masashi; Mita, Eiji; Yamamoto, Kazuhide; Michitaka, Kojiro; Maeshiro, Tatsuji; Tanuma, Junko; Tanaka, Yasuhito; Sugiyama, Masaya; Murata, Kazumoto; Masaki, Naohiko; Mizokami, Masashi

2014-01-01

The proportion of patients who progress to chronicity following acute hepatitis B (AHB) varies widely worldwide. Moreover, the association between viral persistence after AHB and hepatitis B virus (HBV) genotypes in adults remains unclear. A nationwide multicenter study was conducted throughout Japan to evaluate the influence of clinical and virological factors on chronic outcomes in patients with AHB. For comparing factors between AHB patients with viral persistence and those with self-limited infection, 212 AHB patients without human immunodeficiency virus (HIV) coinfection were observed in 38 liver centers until serum hepatitis B surface antigen (HBsAg) disappeared or a minimum of 6 months in cases where HBsAg persisted. The time to disappearance of HBsAg was significantly longer for genotype A patients than that of patients infected with non-A genotypes. When chronicity was defined as the persistence of HBsAg positivity for more than 6 or 12 months, the rate of progression to chronicity was higher in patients with genotype A, although many cases caused by genotype A were prolonged cases of AHB, rather than chronic infection. Multivariate logistic regression analysis revealed only genotype A was independently associated with viral persistence following AHB. A higher peak level of HBV DNA and a lower peak of alanine aminotransferase (ALT) levels were characteristics of AHB caused by genotype A. Treatment with nucleotide analogs (NAs) did not prevent progression to chronic infection following AHB overall. Subanalysis suggested early NA initiation may enhance the viral clearance. Genotype A was an independent risk factor for progression to chronic infection following AHB. Our data will be useful in elucidating the association between viral persistence after AHB, host genetic factors, and treatment with NAs in future studies. © 2013 by the American Association for the Study of Liver Diseases.

The motivational properties of hope in goal striving.

PubMed

Nelissen, Rob M A

2017-02-01

We argue that hope is not an expectancy based on beliefs about pathways to desired goals and personal capacities to act on them, but an experience of the mere possibility of a desired outcome. We propose that in the latter sense, hope has unique motivational consequences for goal striving. Specifically, we predicted that hope buffers against the detrimental impact of negative feedback on goal-progress. The results of the two studies confirmed this prediction. In Study 1, we measured participants' hopes of attaining a weight-loss goal. In Study 2, we induced hope at solving an unsolvable mathematical puzzle. In both studies, receiving negative feedback on goal-progress resulted in lower levels of success (Study 1) and persistence (Study 2) in goal-striving, but not for participants who experienced hope. We discuss the role of hope as an affective mechanism that functions to regulate energy expenditure in goal-striving.

Single severe traumatic brain injury produces progressive pathology with ongoing contralateral white matter damage one year after injury.

PubMed

Pischiutta, Francesca; Micotti, Edoardo; Hay, Jennifer R; Marongiu, Ines; Sammali, Eliana; Tolomeo, Daniele; Vegliante, Gloria; Stocchetti, Nino; Forloni, Gianluigi; De Simoni, Maria-Grazia; Stewart, William; Zanier, Elisa R

2018-02-01

There is increasing recognition that traumatic brain injury (TBI) may initiate long-term neurodegenerative processes, particularly chronic traumatic encephalopathy. However, insight into the mechanisms transforming an initial biomechanical injury into a neurodegenerative process remain elusive, partly as a consequence of the paucity of informative pre-clinical models. This study shows the functional, whole brain imaging and neuropathological consequences at up to one year survival from single severe TBI by controlled cortical impact in mice. TBI mice displayed persistent sensorimotor and cognitive deficits. Longitudinal T2 weighted magnetic resonance imaging (MRI) showed progressive ipsilateral (il) cortical, hippocampal and striatal volume loss, with diffusion tensor imaging demonstrating decreased fractional anisotropy (FA) at up to one year in the il-corpus callosum (CC: -30%) and external capsule (EC: -21%). Parallel neuropathological studies indicated reduction in neuronal density, with evidence of microgliosis and astrogliosis in the il-cortex, with further evidence of microgliosis and astrogliosis in the il-thalamus. One year after TBI there was also a decrease in FA in the contralateral (cl) CC (-17%) and EC (-13%), corresponding to histopathological evidence of white matter loss (cl-CC: -68%; cl-EC: -30%) associated with ongoing microgliosis and astrogliosis. These findings indicate that a single severe TBI induces bilateral, long-term and progressive neuropathology at up to one year after injury. These observations support this model as a suitable platform for exploring the mechanistic link between acute brain injury and late and persistent neurodegeneration. Copyright © 2017 Elsevier Inc. All rights reserved.

Carotid body potentiation during chronic intermittent hypoxia: implication for hypertension

PubMed Central

Del Rio, Rodrigo; Moya, Esteban A.; Iturriaga, Rodrigo

2014-01-01

Autonomic dysfunction is involved in the development of hypertension in humans with obstructive sleep apnea, and animals exposed to chronic intermittent hypoxia (CIH). It has been proposed that a crucial step in the development of the hypertension is the potentiation of the carotid body (CB) chemosensory responses to hypoxia, but the temporal progression of the CB chemosensory, autonomic and hypertensive changes induced by CIH are not known. We tested the hypothesis that CB potentiation precedes the autonomic imbalance and the hypertension in rats exposed to CIH. Thus, we studied the changes in CB chemosensory and ventilatory responsiveness to hypoxia, the spontaneous baroreflex sensitivity (BRS), heart rate variability (HRV) and arterial blood pressure in pentobarbital anesthetized rats exposed to CIH for 7, 14, and 21 days. After 7 days of CIH, CB chemosensory and ventilatory responses to hypoxia were enhanced, while BRS was significantly reduced by 2-fold in CIH-rats compared to sham-rats. These alterations persisted until 21 days of CIH. After 14 days, CIH shifted the HRV power spectra suggesting a predominance of sympathetic over parasympathetic tone. In contrast, hypertension was found after 21 days of CIH. Concomitant changes between the gain of spectral HRV, BRS, and ventilatory hypoxic chemoreflex showed that the CIH-induced BRS attenuation preceded the HRV changes. CIH induced a simultaneous decrease of the BRS gain along with an increase of the hypoxic ventilatory gain. Present results show that CIH-induced persistent hypertension was preceded by early changes in CB chemosensory control of cardiorespiratory and autonomic function. PMID:25429271

Lesion progression in post-treatment persistent endodontic lesions.

PubMed

Yu, Victoria Soo Hoon; Messer, Harold Henry; Shen, Liang; Yee, Robert; Hsu, Chin-ying Stephen

2012-10-01

Radiographic lesions related to root-filled teeth may persist for long periods after treatment and are considered to indicate failure of initial treatment. Persistent lesions are found in a proportion of cases, but information on lesion progression is lacking. This study examined the incidence of lesion improvement, remaining unchanged, and deterioration among persistent lesions in a group of patients recruited from a university-based clinic and identified potential predictors for lesion progression. Patients of a university clinic with persistent endodontic lesions at least 4 years since treatment and with original treatment radiographs available were recruited with informed consent. Data were obtained by interview and from dental records and clinical and radiographic examinations. Univariate and multivariate statistical analyses were carried out by using SPSS (version 19). One hundred fifty-one persistent lesions were identified in 114 patients. A majority of the lesions (107, 70.9%) received treatment between 4 and 5 years prior. Eighty-six lesions (57.0%) improved, 18 (11.9%) remained unchanged, and 47 (31.1%) deteriorated since treatment. Potential predictors for lesions that did not improve included recall lesion size, pain on biting at recall examination, history of a postobturation flare-up, and a non-ideal root-filling length (P < .05). Lesions that had persisted for a longer period appeared less likely to be improving (relative risk, 1.038; 95% confidence interval, 1.000-1.077). A specific time interval alone should not be used to conclude that a lesion will not resolve without intervention. This study identified several clinical factors that are associated with deteriorating persistent lesions, which should aid in identifying lesions that require further intervention. Copyright © 2012 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Follow-up of patients affected by manganese-induced Parkinsonism after treatment with CaNa2EDTA.

PubMed

Herrero Hernandez, Elena; Discalzi, Gianluigi; Valentini, Consuelo; Venturi, Fabrizio; Chiò, Adriano; Carmellino, Caterina; Rossi, Luigi; Sacchetti, Anna; Pira, Enrico

2006-05-01

In the period of 1998-2004, seven workers affected by manganese-induced Parkinsonism were diagnosed, studied and treated with CaNa2EDTA at our Occupational Health Ward. Biological markers, as well as magnetic resonance imaging and clinical examinations, were used to assess the disease trend. Those workers still employed were immediately removed from exposure. Our results seem to confirm that very good clinical, biological and neuroradiological results can be obtained by timely removal from exposure and chelating treatment, and that amelioration can persist in time. Manganism is, however, a severe condition that can also progress independent of further exposure. Therefore, chelating treatment can be a great aid in overt manganism, but particular attention must be paid to primary prevention, as this disease should now be totally preventable and definitely merits eradication.

The Role of E6 Spliced Isoforms (E6*) in Human Papillomavirus-Induced Carcinogenesis

PubMed Central

Olmedo-Nieva, Leslie; Muñoz-Bello, J. Omar; Contreras-Paredes, Adriana

2018-01-01

Persistent infections with High Risk Human Papillomaviruses (HR-HPVs) are the main cause of cervical cancer development. The E6 and E7 oncoproteins of HR-HPVs are derived from a polycistronic pre-mRNA transcribed from an HPV early promoter. Through alternative splicing, this pre-mRNA produces a variety of E6 spliced transcripts termed E6*. In pre-malignant lesions and HPV-related cancers, different E6/E6* transcriptional patterns have been found, although they have not been clearly associated to cancer development. Moreover, there is a controversy about the participation of E6* proteins in cancer progression. This review addresses the regulation of E6 splicing and the different functions that have been found for E6* proteins, as well as their possible role in HPV-induced carcinogenesis. PMID:29346309

Inflammatory status in human hepatic cirrhosis

PubMed Central

Martínez-Esparza, María; Tristán-Manzano, María; Ruiz-Alcaraz, Antonio J; García-Peñarrubia, Pilar

2015-01-01

This review focuses on new findings about the inflammatory status involved in the development of human liver cirrhosis induced by the two main causes, hepatitis C virus (HCV) infection and chronic alcohol abuse, avoiding results obtained from animal models. When liver is faced to a persistent and/or intense local damage the maintained inflammatory response gives rise to a progressive replacement of normal hepatic tissue by non-functional fibrotic scar. The imbalance between tissue regeneration and fibrosis will determine the outcome toward health recovery or hepatic cirrhosis. In all cases progression toward liver cirrhosis is caused by a dysregulation of mechanisms that govern the balance between activation/homeostasis of the immune system. Detecting differences between the inflammatory status in HCV-induced vs alcohol-induced cirrhosis could be useful to identify specific targets for preventive and therapeutic intervention in each case. Thus, although survival of patients with alcoholic cirrhosis seems to be similar to that of patients with HCV-related cirrhosis (HCV-C), there are important differences in the altered cellular and molecular mechanisms implicated in the progression toward human liver cirrhosis. The predominant features of HCV-C are more related with those that allow viral evasion of the immune defenses, especially although not exclusively, inhibition of interferons secretion, natural killer cells activation and T cell-mediated cytotoxicity. On the contrary, the inflammatory status of alcohol-induced cirrhosis is determined by the combined effect of direct hepatotoxicity of ethanol metabolites and increases of the intestinal permeability, allowing bacteria and bacterial products translocation, into the portal circulation, mesenteric lymph nodes and peritoneal cavity. This phenomenon generates a stronger pro-inflammatory response compared with HCV-related cirrhosis. Hence, therapeutic intervention in HCV-related cirrhosis must be mainly focused to counteract HCV-immune system evasion, while in the case of alcohol-induced cirrhosis it must try to break the inflammatory loop established at the gut-mesenteric lymph nodes-peritoneal-systemic axis. PMID:26556984

Measles virus induces persistent infection by autoregulation of viral replication.

PubMed

Doi, Tomomitsu; Kwon, Hyun-Jeong; Honda, Tomoyuki; Sato, Hiroki; Yoneda, Misako; Kai, Chieko

2016-11-24

Natural infection with measles virus (MV) establishes lifelong immunity. Persistent infection with MV is likely involved in this phenomenon, as non-replicating protein antigens never induce such long-term immunity. Although MV establishes stable persistent infection in vitro and possibly in vivo, the mechanism by which this occurs is largely unknown. Here, we demonstrate that MV changes the infection mode from lytic to non-lytic and evades the innate immune response to establish persistent infection without viral genome mutation. We found that, in the persistent phase, the viral RNA level declined with the termination of interferon production and cell death. Our analysis of viral protein dynamics shows that during the establishment of persistent infection, the nucleoprotein level was sustained while the phosphoprotein and large protein levels declined. The ectopic expression of nucleoprotein suppressed viral replication, indicating that viral replication is self-regulated by nucleoprotein accumulation during persistent infection. The persistently infected cells were able to produce interferon in response to poly I:C stimulation, suggesting that MV does not interfere with host interferon responses in persistent infection. Our results may provide mechanistic insight into the persistent infection of this cytopathic RNA virus that induces lifelong immunity.

Imbalance of tumor necrosis factor receptors during progression in bovine leukemia virus infection

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

Konnai, Satoru; Usui, Tatsufumi; Ikeda, Manabu

2005-09-01

Previously, we found an up-regulation of tumor necrosis factor alpha (TNF)-{alpha} and an imbalance of TNF receptors in sheep experimentally infected with bovine leukemia virus (BLV). In order to investigate the different TNF-{alpha}-induced responses, in this study we examined the TNF-{alpha}-induced proliferative response and the expression levels of two distinct TNF receptors on peripheral blood mononuclear cells (PBMC) derived from BLV-uninfected cattle and BLV-infected cattle that were aleukemic (AL) or had persistent lymphocytosis (PL). The proliferative response of PBMC isolated from those cattle with PL in the presence of recombinant bovine TNF-{alpha} (rTNF-{alpha}) was significantly higher than those from ALmore » cattle and uninfected cattle and the cells from PL cattle expressed significantly higher mRNA levels of TNF receptor type II (TNF-RII) than those from AL and BLV-uninfected cattle. No difference was found in TNF-RI mRNA levels. Most cells expressing TNF-RII in PL cattle were CD5{sup +} or sIgM{sup +} cells and these cells showed resistance to TNF-{alpha}-induced apoptosis. Additionally, there were significant positive correlations between the changes in provirus load and TNF-RII mRNA levels, and TNF-{alpha}-induced proliferation and TNF-RII mRNA levels. These data suggest that imbalance in the expression of TNF receptors could at least in part contribute to the progression of lymphocytosis in BLV infection.« less

BDNF is essential to promote persistence of long-term memory storage

PubMed Central

Bekinschtein, Pedro; Cammarota, Martín; Katche, Cynthia; Slipczuk, Leandro; Rossato, Janine I.; Goldin, Andrea; Izquierdo, Ivan; Medina, Jorge H.

2008-01-01

Persistence is a characteristic attribute of long-term memories (LTMs). However, little is known about the molecular mechanisms that mediate this process. We recently showed that persistence of LTM requires a late protein synthesis- and BDNF-dependent phase in the hippocampus. Here, we show that intrahippocampal delivery of BDNF reverses the deficit in memory persistence caused by inhibition of hippocampal protein synthesis. Importantly, we demonstrate that BDNF induces memory persistence by itself, transforming a nonlasting LTM trace into a persistent one in an ERK-dependent manner. Thus, BDNF is not only necessary, but sufficient to induce a late postacquisition phase in the hippocampus essential for persistence of LTM storage. PMID:18263738

Radiation injury to the temporal bone

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

Guida, R.A.; Finn, D.G.; Buchalter, I.H.

1990-01-01

Osteoradionecrosis of the temporal bone is an unusual sequela of radiation therapy to the head and neck. Symptoms occur many years after the radiation is administered, and progression of the disease is insidious. Hearing loss (sensorineural, conductive, or mixed), otalgia, otorrhea, and even gross tissue extrusion herald this condition. Later, intracranial complications such as meningitis, temporal lobe or cerebellar abscess, and cranial neuropathies may occur. Reported here are five cases of this rare malady representing varying degrees of the disease process. They include a case of radiation-induced necrosis of the tympanic ring with persistent squamous debris in the external auditorymore » canal and middle ear. Another case demonstrates the progression of radiation otitis media to mastoiditis with bony sequestration. Further progression of the disease process is seen in a third case that evolved into multiple cranial neuropathies from skull base destruction. Treatment includes systemic antibiotics, local wound care, and debridement in cases of localized tissue involvement. More extensive debridement with removal of sequestrations, abscess drainage, reconstruction with vascularized tissue from regional flaps, and mastoid obliteration may be warranted for severe cases. Hyperbaric oxygen therapy has provided limited benefit.« less

Bone marrow endothelial progenitors in atherosclerotic plaque resolution

PubMed Central

Yao, Longbiao; Heuser-Baker, Janet; Herlea-Pana, Oana; Barlic-Dicen, Jana

2013-01-01

Atherosclerosis is a major cause of morbidity and mortality in the United States. Persistently elevated circulating low-density lipoprotein, or hypercholesterolemia, and deposition of low-density lipoprotein in the vascular wall are the main inducers of atherosclerosis, which manifests itself as arterial lesions or plaques. Some plaques become thrombosis-prone and rupture, causing acute myocardial infarction or stroke. Lowering plasma cholesterol through the use of statins is the primary intervention against atherosclerosis. Treatment with statins slows progression of atherosclerosis but can only support limited plaque regression. Partially regressed plaques continue to pose a serious threat due to their remaining potential to rupture. Thus, new interventions inducing complete reversal of atherosclerosis are being sought. Implementation of new therapies will require clear understanding of the mechanisms driving plaque resolution. In this Commentary, we highlight the role of bone marrow endothelial progenitors in atherosclerotic plaque regression and discuss how regenerative cell-based interventions could be used in combination with plasma lipid-lowering to induce plaque reversal in order to prevent and/or reduce adverse cardiovascular events. PMID:23538778

A Tradeoff Between Accuracy and Flexibility in a Working Memory Circuit Endowed with Slow Feedback Mechanisms.

PubMed

Pereira, Jacinto; Wang, Xiao-Jing

2015-10-01

Recent studies have shown that reverberation underlying mnemonic persistent activity must be slow, to ensure the stability of a working memory system and to give rise to long neural transients capable of accumulation of information over time. Is the slower the underlying process, the better? To address this question, we investigated 3 slow biophysical mechanisms that are activity-dependent and prominently present in the prefrontal cortex: Depolarization-induced suppression of inhibition (DSI), calcium-dependent nonspecific cationic current (ICAN), and short-term facilitation. Using a spiking network model for spatial working memory, we found that these processes enhance the memory accuracy by counteracting noise-induced drifts, heterogeneity-induced biases, and distractors. Furthermore, the incorporation of DSI and ICAN enlarges the range of network's parameter values required for working memory function. However, when a progressively slower process dominates the network, it becomes increasingly more difficult to erase a memory trace. We demonstrate this accuracy-flexibility tradeoff quantitatively and interpret it using a state-space analysis. Our results supports the scenario where N-methyl-d-aspartate receptor-dependent recurrent excitation is the workhorse for the maintenance of persistent activity, whereas slow synaptic or cellular processes contribute to the robustness of mnemonic function in a tradeoff that potentially can be adjusted according to behavioral demands. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Blast Exposure Causes Early and Persistent Aberrant Phospho- and Cleaved-Tau Expression in a Murine Model of Mild Blast-Induced Traumatic Brain Injury

PubMed Central

Huber, Bertrand R.; Meabon, James S.; Martin, Tobin J.; Mourad, Pierre D.; Bennett, Raymond; Kraemer, Brian C.; Cernak, Ibolja; Petrie, Eric C.; Emery, Michael J.; Swenson, Erik R.; Mayer, Cynthia; Mehic, Edin; Peskind, Elaine R.; Cook, David G.

2014-01-01

Mild traumatic brain injury (mTBI) is considered the ‘signature injury’ of combat veterans that have served during the wars in Iraq and Afghanistan. This prevalence of mTBI is due in part to the common exposure to high explosive blasts in combat zones. In addition to the threats of blunt impact trauma caused by flying objects and the head itself being propelled against objects, the primary blast overpressure (BOP) generated by high explosives is capable of injuring the brain. Compared to other means of causing TBI, the pathophysiology of mild-to-moderate BOP is less well understood. To study the consequences of BOP exposure in mice, we employed a well-established approach using a compressed gas-driven shock tube that recapitulates battlefield-relevant open-field BOP. We found that 24 hours post-blast a single mild BOP provoked elevation of multiple phosphor- and cleaved-tau species in neurons, as well as elevating manganese superoxide-dismutase (MnSOD or SOD2) levels, a cellular response to oxidative stress. In hippocampus, aberrant tau species persisted for at least 30 days post-exposure, while SOD2 levels returned to sham control levels. These findings suggest that elevated phospho- and cleaved-tau species may be among the initiating pathologic processes induced by mild blast exposure. These findings may have important implications for efforts to prevent blast-induced insults to the brain from progressing into long-term neurodegenerative disease processes. PMID:23948882

SLAM- and nectin-4-independent noncytolytic spread of canine distemper virus in astrocytes.

PubMed

Alves, Lisa; Khosravi, Mojtaba; Avila, Mislay; Ader-Ebert, Nadine; Bringolf, Fanny; Zurbriggen, Andreas; Vandevelde, Marc; Plattet, Philippe

2015-05-01

Measles and canine distemper viruses (MeV and CDV, respectively) first replicate in lymphatic and epithelial tissues by using SLAM and nectin-4 as entry receptors, respectively. The viruses may also invade the brain to establish persistent infections, triggering fatal complications, such as subacute sclerosis pan-encephalitis (SSPE) in MeV infection or chronic, multiple sclerosis-like, multifocal demyelinating lesions in the case of CDV infection. In both diseases, persistence is mediated by viral nucleocapsids that do not require packaging into particles for infectivity but are directly transmitted from cell to cell (neurons in SSPE or astrocytes in distemper encephalitis), presumably by relying on restricted microfusion events. Indeed, although morphological evidence of fusion remained undetectable, viral fusion machineries and, thus, a putative cellular receptor, were shown to contribute to persistent infections. Here, we first showed that nectin-4-dependent cell-cell fusion in Vero cells, triggered by a demyelinating CDV strain, remained extremely limited, thereby supporting a potential role of nectin-4 in mediating persistent infections in astrocytes. However, nectin-4 could not be detected in either primary cultured astrocytes or the white matter of tissue sections. In addition, a bioengineered "nectin-4-blind" recombinant CDV retained full cell-to-cell transmission efficacy in primary astrocytes. Combined with our previous report demonstrating the absence of SLAM expression in astrocytes, these findings are suggestive for the existence of a hitherto unrecognized third CDV receptor expressed by glial cells that contributes to the induction of noncytolytic cell-to-cell viral transmission in astrocytes. While persistent measles virus (MeV) infection induces SSPE in humans, persistent canine distemper virus (CDV) infection causes chronic progressive or relapsing demyelination in carnivores. Common to both central nervous system (CNS) infections is that persistence is based on noncytolytic cell-to-cell spread, which, in the case of CDV, was demonstrated to rely on functional membrane fusion machinery complexes. This inferred a mechanism where nucleocapsids are transmitted through macroscopically invisible microfusion events between infected and target cells. Here, we provide evidence that CDV induces such microfusions in a SLAM- and nectin-4-independent manner, thereby strongly suggesting the existence of a third receptor expressed in glial cells (referred to as GliaR). We propose that GliaR governs intercellular transfer of nucleocapsids and hence contributes to viral persistence in the brain and ensuing demyelinating lesions. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Adverse Health Effects of Thirdhand Smoke: From Cell to Animal Models.

PubMed

Hang, Bo; Wang, Pin; Zhao, Yue; Sarker, Altaf; Chenna, Ahmed; Xia, Yankai; Snijders, Antoine M; Mao, Jian-Hua

2017-04-28

The newly identified smoke hazard, thirdhand smoke (THS), has gained public attention in recent years but its health impact and biological effects are largely unknown. THS may be defined by "the four Rs": tobacco chemicals that remain, react, re-emit, and/or are resuspended long after active smoking has ceased. This review summarizes recent research progress in the effects of THS on genotoxicity, metabolism and early life development using cellular and animal models. We first reported that THS generated in laboratory systems caused significant DNA damage in human cell lines. Our finding that THS significantly induces oxidative base lesions has been confirmed in skin wounds of mice models exposed to THS. THS also induced metabolomic changes in human reproductive cell lines. Furthermore, we demonstrated that early exposure to THS not only negatively impacts body weight in both male and female mice, but also induces persistent changes to immunological parameters in peripheral blood in these mice. These results indicate that THS is genotoxic at realistic experimental doses and that there may be a window of susceptibility for some forms of cellular damage induced by THS.

Subtotal Ablation of Parietal Epithelial Cells Induces Crescent Formation

PubMed Central

Sicking, Eva-Maria; Fuss, Astrid; Uhlig, Sandra; Jirak, Peggy; Dijkman, Henry; Wetzels, Jack; Engel, Daniel R.; Urzynicok, Torsten; Heidenreich, Stefan; Kriz, Wilhelm; Kurts, Christian; Ostendorf, Tammo; Floege, Jürgen; Smeets, Bart

2012-01-01

Parietal epithelial cells (PECs) of the renal glomerulus contribute to the formation of both cellular crescents in rapidly progressive GN and sclerotic lesions in FSGS. Subtotal transgenic ablation of podocytes induces FSGS but the effect of specific ablation of PECs is unknown. Here, we established an inducible transgenic mouse to allow subtotal ablation of PECs. Proteinuria developed during doxycycline-induced cellular ablation but fully reversed 26 days after termination of doxycycline administration. The ablation of PECs was focal, with only 30% of glomeruli exhibiting histologic changes; however, the number of PECs was reduced up to 90% within affected glomeruli. Ultrastructural analysis revealed disruption of PEC plasma membranes with cytoplasm shedding into Bowman’s space. Podocytes showed focal foot process effacement, which was the most likely cause for transient proteinuria. After >9 days of cellular ablation, the remaining PECs formed cellular extensions to cover the denuded Bowman’s capsule and expressed the activation marker CD44 de novo. The induced proliferation of PECs persisted throughout the observation period, resulting in the formation of typical cellular crescents with periglomerular infiltrate, albeit without accompanying proteinuria. In summary, subtotal ablation of PECs leads the remaining PECs to react with cellular activation and proliferation, which ultimately forms cellular crescents. PMID:22282596

Repurposing Cytarabine for Treating Primary Effusion Lymphoma by Targeting Kaposi’s Sarcoma-Associated Herpesvirus Latent and Lytic Replications

PubMed Central

Gruffaz, Marion; Zhou, Shenghua; Vasan, Karthik; Rushing, Teresa; Michael, Qing Liu; Lu, Chu

2018-01-01

ABSTRACT Oncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV) is etiologically linked to primary effusion lymphoma (PEL), an aggressive and nontreatable malignancy commonly found in AIDS patients. In this study, we performed a high-throughput screening of 3,731 characterized compounds and identified cytarabine, approved by the FDA for treating numerous types of cancer, as a potent inhibitor of KSHV-induced PEL. We showed the high efficacy of cytarabine in the growth inhibition of various PEL cells by inducing cell cycle arrest and apoptosis. Cytarabine inhibited host DNA and RNA syntheses and therefore induced cellular cytotoxicity. Furthermore, cytarabine inhibited viral DNA and RNA syntheses and induced the rapid degradation of KSHV major latent protein LANA (latency-associated nuclear antigen), leading to the suppression of KSHV latent replication. Importantly, cytarabine effectively inhibited active KSHV replication and virion production in PEL cells. Finally, cytarabine treatments not only effectively inhibited the initiation and progression of PEL tumors but also induced regression of grown PEL tumors in a xenograft mouse model. Altogether, our study has identified cytarabine as a novel therapeutic agent for treating PEL as well as eliminating KSHV persistent infection. PMID:29739902

Dexmedetomidine increases tau phosphorylation under normothermic conditions in vivo and in vitro.

PubMed

Whittington, Robert A; Virág, László; Gratuze, Maud; Petry, Franck R; Noël, Anastasia; Poitras, Isabelle; Truchetti, Geoffrey; Marcouiller, François; Papon, Marie-Amélie; El Khoury, Noura; Wong, Kevin; Bretteville, Alexis; Morin, Françoise; Planel, Emmanuel

2015-08-01

There is developing interest in the potential association between anesthesia and the onset and progression of Alzheimer's disease. Several anesthetics have, thus, been demonstrated to induce tau hyperphosphorylation, an effect mostly mediated by anesthesia-induced hypothermia. Here, we tested the hypothesis that acute normothermic administration of dexmedetomidine (Dex), an intravenous sedative used in intensive care units, would result in tau hyperphosphorylation in vivo and in vitro. When administered to nontransgenic mice, Dex-induced tau hyperphosphorylation persisting up to 6 hours in the hippocampus for the AT8 epitope. Pretreatment with atipamezole, a highly specific α2-adrenergic receptor antagonist, blocked Dex-induced tau hyperphosphorylation. Furthermore, Dex dose-dependently increased tau phosphorylation at AT8 in SH-SY5Y cells, impaired mice spatial memory in the Barnes maze and promoted tau hyperphosphorylation and aggregation in transgenic hTau mice. These findings suggest that Dex: (1) increases tau phosphorylation, in vivo and in vitro, in the absence of anesthetic-induced hypothermia and through α2-adrenergic receptor activation, (2) promotes tau aggregation in a mouse model of tauopathy, and (3) impacts spatial reference memory. Copyright © 2015 Elsevier Inc. All rights reserved.

Radiotherapy-induced hypopituitarism: a review.

PubMed

Sathyapalan, Thozhukat; Dixit, Sanjay

2012-05-01

Hypopituitarism is a disorder caused by impaired hormonal secretions from the hypothalamic-pituitary axis. Radiotherapy is the most common cause of iatrogenic hypopituitarism. The hypothalamic-pituitary axis inadvertently gets irradiated in patients receiving prophylactic cranial radiotherapy for leukemia, total body irradiation and radiotherapy for intracranial, base skull, sinonasal and nasopharyngeal tumors. Radiation-induced hypopituitarism (RIH) is insidious, progressive and largely nonreversible. Mostly, RIH involves one hypothalamic-pituitary axis; however, multiple hormonal axes deficiency starts developing at higher doses. Although the clinical effects of the hypopituitarism are more profound in children and young adults, its implications in older adults are being increasingly recognized. The risk continues to persist or increase up to 10 years following radiation exposure. The clinical management of hypopituitarism is challenging both for the patients and healthcare providers. Here we have reviewed the scale of the problem, the risk factors and the management of RIH.

Cigarette smoke-induced DNA damage and repair detected by the comet assay in HPV-transformed cervical cells.

PubMed

Moktar, Afsoon; Ravoori, Srivani; Vadhanam, Manicka V; Gairola, C Gary; Gupta, Ramesh C

2009-12-01

Human papillomavirus (HPV) is the causative factor in the development and progression of cervical cancers in >97% of the cases, although insufficient. Epidemiological studies suggest an elevated risk of cervical cancer for cigarette smokers; therefore, we examined cigarette smoke-induced DNA damage and repair in HPV16-transformed human ectocervical cells (ECT1/E6 E7). Cells were treated with cigarette smoke condensate (CSC) for 72 h to assess the formation of single- and double-strand DNA breaks, measured by alkaline and neutral single cell gel electrophoresis assays, respectively. The mean tail length of cells with single-strand breaks was increased by 1.8-, 2.7- and 3.7-fold (p<0.001) after treatment with 4, 8 and 12 microg/ml CSC, respectively. The tail length with double-strand breaks was also increased dose-dependently. These results were further supported by measurement of the mean tail moment: the increase in both single- and double-strand breaks were much more pronounced with increasing concentration of CSC, by up to 23.5-fold (p<0.0001 for both assays). To examine the DNA repair, cells were treated with CSC for 72 h, followed by CSC withdrawal and re-incubation of the cells with fresh medium for 24, 48, or 72 h. Both single- and double-strand DNA breaks were removed during the initial 24 h but no further removal of the damage was observed. Up to 80% of residual single- and double-strand DNA breaks (p<0.05) were found to persist at all CSC concentrations examined. Ellagic acid, a known antioxidant and free-radical scavenger, was found to significantly inhibit DNA breaks induced by CSC. Thus, free radicals may be a plausible source of CSC-induced DNA damage. These data show that CSC-mediated DNA strand breaks are highly persistent, and suggest that persistence of cigarette smoke-associated DNA damage in the presence of HPV infection may lead to increased mutations in cervical cells and ultimately higher cancer risk.

Persistent Adaptation by Chronic Alcohol is Facilitated by Neuroimmune Activation Linked to Stress and CRF

PubMed Central

Breese, George R.; Knapp, Darin J.

2016-01-01

This review updates the conceptual basis for the association of alcohol abuse with an insidious adaptation that facilitates negative affect during withdrawal from chronic intermittent alcohol (CIA) exposure – a change that later supports sensitization of stress-induced anxiety following alcohol abstinence. The finding that a CRF1-receptor antagonist (CRF1RA) minimized CIA withdrawal-induced negative affect supported an association of alcohol withdrawal with a stress mechanism. The finding that repeated stresses or multiple CRF injections into selected brain sites prior to a single 5-day chronic alcohol (CA) exposure induced anxiety during withdrawal provided critical support for a linkage of CIA withdrawal with stress. The determination that CRF1RA injection into positive CRF-sensitive brain sites prevented CIA withdrawal-induced anxiety provided support that neural path integration maintains the persistent CIA adaptation. Based upon reports that stress increases neuroimmune function, an effort was undertaken to test whether cytokines would support the adaptation induced by stress/CA exposure. Twenty-four hours after withdrawal from CIA, cytokine mRNAs were found to be increased in cortex as well as other sites in brain. Further, repeated cytokine injections into previously identified brain sites substituted for stress and CRF induction of anxiety during CA withdrawal. Discovery that a CRF1RA prevented the brain cytokine mRNA increase induced by CA withdrawal provided critical evidence for CRF involvement in this neuroimmune induction after CA withdrawal. However, the CRF1RA did not block the stress increase in cytokine mRNA increases in controls. The latter data supported the hypothesis that distinct mechanisms linked to stress and CA withdrawal can support common neuroimmune functions within a brain site. As evidence evolves concerning neural involvement in brain neuroimmune function, a better understanding of the progressive adaptation associated with CIA exposure will advance new knowledge that could possibly lead to strategies to combat alcohol abuse. PMID:27139233

JC virus induces altered patterns of cellular gene expression: Interferon-inducible genes as major transcriptional targets

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

Verma, Saguna; Ziegler, Katja; Ananthula, Praveen

2006-02-20

Human polyomavirus JC (JCV) infects 80% of the population worldwide. Primary infection, typically occurring during childhood, is asymptomatic in immunocompetent individuals and results in lifelong latency and persistent infection. However, among the severely immunocompromised, JCV may cause a fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML). Virus-host interactions influencing persistence and pathogenicity are not well understood, although significant regulation of JCV activity is thought to occur at the level of transcription. Regulation of the JCV early and late promoters during the lytic cycle is a complex event that requires participation of both viral and cellular factors. We have used cDNA microarraymore » technology to analyze global alterations in gene expression in JCV-permissive primary human fetal glial cells (PHFG). Expression of more than 400 cellular genes was altered, including many that influence cell proliferation, cell communication and interferon (IFN)-mediated host defense responses. Genes in the latter category included signal transducer and activator of transcription 1 (STAT1), interferon stimulating gene 56 (ISG56), myxovirus resistance 1 (MxA), 2'5'-oligoadenylate synthetase (OAS), and cig5. The expression of these genes was further confirmed in JCV-infected PHFG cells and the human glioblastoma cell line U87MG to ensure the specificity of JCV in inducing this strong antiviral response. Results obtained by real-time RT-PCR and Western blot analyses supported the microarray data and provide temporal information related to virus-induced changes in the IFN response pathway. Our data indicate that the induction of an antiviral response may be one of the cellular factors regulating/controlling JCV replication in immunocompetent hosts and therefore constraining the development of PML.« less

'Biologic memory' in response to acute kidney injury: cytoresistance, toll-like receptor hyper-responsiveness and the onset of progressive renal disease.

PubMed

Zager, Richard A

2013-08-01

Following the induction of ischemic or toxin-mediated acute kidney injury (AKI), cellular adaptations occur that 're-program' how the kidney responds to future superimposed insults. This re-programming is not simply a short-lived phenomenon; rather it can persist for many weeks, implying that a state of 'biologic memory' has emerged. These changes can be both adaptive and maladaptive in nature and they can co-exist in time. A beneficial adaptation is the emergence of acquired cytoresistance, whereby a number of physiologic responses develop that serve to protect the kidney against further ischemic or nephrotoxic attack. Conversely, some changes are maladaptive, such as a predisposition to Gram-negative or Gram-positive bacteremia due to a renal tubular up-regulation of toll-like receptor responses. This latter change culminates in exaggerated cytokine production, and with efflux into the systemic circulation, extra-renal tissue injury can result (so-called 'organ cross talk'). Another maladaptive response is a persistent up-regulation of pro-inflammatory, pro-fibrotic and vasoconstrictive genes, culminating in progressive renal injury and ultimately end-stage renal failure. The mechanisms by which this biologic re-programming, or biologic memory, is imparted remain subjects for considerable debate. However, injury-induced, and stable, epigenetic remodeling at pro-inflammatory/pro-fibrotic genes seems likely to be involved. The goal of this editorial is to highlight that the so-called 'maintenance phase' of acute renal failure is not a static one, somewhere between injury induction and the onset of repair. Rather, this period is one in which the induction of 'biologic memory' can ultimately impact renal functional recovery, extra-renal injury and the possible transition of AKI into chronic, progressive renal disease.

Validity Assessment of 5 Day Repeated Forced-Swim Stress to Model Human Depression in Young-Adult C57BL/6J and BALB/cJ Mice

PubMed Central

Zheng, Jia; Goodyear, Laurie J.

2016-01-01

The development of animal models with construct, face, and predictive validity to accurately model human depression has been a major challenge. One proposed rodent model is the 5 d repeated forced swim stress (5d-RFSS) paradigm, which progressively increases floating during individual swim sessions. The onset and persistence of this floating behavior has been anthropomorphically characterized as a measure of depression. This interpretation has been under debate because a progressive increase in floating over time may reflect an adaptive learned behavioral response promoting survival, and not depression (Molendijk and de Kloet, 2015). To assess construct and face validity, we applied 5d-RFSS to C57BL/6J and BALB/cJ mice, two mouse strains commonly used in neuropsychiatric research, and measured a combination of emotional, homeostatic, and psychomotor symptoms indicative of a depressive-like state. We also compared the efficacy of 5d-RFSS and chronic social defeat stress (CSDS), a validated depression model, to induce a depressive-like state in C57BL/6J mice. In both strains, 5d-RFSS progressively increased floating behavior that persisted for at least 4 weeks. 5d-RFSS did not alter sucrose preference, body weight, appetite, locomotor activity, anxiety-like behavior, or immobility behavior during a tail-suspension test compared with nonstressed controls. In contrast, CSDS altered several of these parameters, suggesting a depressive-like state. Finally, predictive validity was assessed using voluntary wheel running (VWR), a known antidepressant intervention. Four weeks of VWR after 5d-RFSS normalized floating behavior toward nonstressed levels. These observations suggest that 5d-RFSS has no construct or face validity but might have predictive validity to model human depression. PMID:28058270

Validity Assessment of 5 Day Repeated Forced-Swim Stress to Model Human Depression in Young-Adult C57BL/6J and BALB/cJ Mice.

PubMed

Mul, Joram D; Zheng, Jia; Goodyear, Laurie J

2016-01-01

The development of animal models with construct, face, and predictive validity to accurately model human depression has been a major challenge. One proposed rodent model is the 5 d repeated forced swim stress (5d-RFSS) paradigm, which progressively increases floating during individual swim sessions. The onset and persistence of this floating behavior has been anthropomorphically characterized as a measure of depression. This interpretation has been under debate because a progressive increase in floating over time may reflect an adaptive learned behavioral response promoting survival, and not depression (Molendijk and de Kloet, 2015). To assess construct and face validity, we applied 5d-RFSS to C57BL/6J and BALB/cJ mice, two mouse strains commonly used in neuropsychiatric research, and measured a combination of emotional, homeostatic, and psychomotor symptoms indicative of a depressive-like state. We also compared the efficacy of 5d-RFSS and chronic social defeat stress (CSDS), a validated depression model, to induce a depressive-like state in C57BL/6J mice. In both strains, 5d-RFSS progressively increased floating behavior that persisted for at least 4 weeks. 5d-RFSS did not alter sucrose preference, body weight, appetite, locomotor activity, anxiety-like behavior, or immobility behavior during a tail-suspension test compared with nonstressed controls. In contrast, CSDS altered several of these parameters, suggesting a depressive-like state. Finally, predictive validity was assessed using voluntary wheel running (VWR), a known antidepressant intervention. Four weeks of VWR after 5d-RFSS normalized floating behavior toward nonstressed levels. These observations suggest that 5d-RFSS has no construct or face validity but might have predictive validity to model human depression.

TGF-beta inhibits IL-1beta-activated PAR-2 expression through multiple pathways in human primary synovial cells.

PubMed

Tsai, Shin-Han; Sheu, Ming-Thau; Liang, Yu-Chih; Cheng, Hsiu-Tan; Fang, Sheng-Shiung; Chen, Chien-Ho

2009-10-23

To investigate the mechanism how Transforming growth factor-beta(TGF-beta) represses Interleukin-1beta (IL-1beta)-induced Proteinase-Activated Receptor-2 (PAR-2) expression in human primary synovial cells (hPSCs). Human chondrocytes and hPSCs isolated from cartilages and synovium of Osteoarthritis (OA) patients were cultured with 10% fetal bovine serum media or serum free media before treatment with IL-1beta, TGF-beta1, or Connective tissue growth factor (CTGF). The expression of PAR-2 was detected using reverse transcriptase-polymerase chain reaction (RT-PCR) and western blotting. Collagen zymography was performed to assess the activity of Matrix metalloproteinases-13 (MMP-13). It was demonstrated that IL-1beta induces PAR-2 expression via p38 pathway in hPSCs. This induction can be repressed by TGF-beta and was observed to persist for at least 48 hrs, suggesting that TGF-beta inhibits PAR-2 expression through multiple pathways. First of all, TGF-beta was able to inhibit PAR-2 activity by inhibiting IL-1beta-induced p38 signal transduction and secondly the inhibition was also indirectly due to MMP-13 inactivation. Finally, TGF-beta was able to induce CTGF, and in turn CTGF represses PAR-2 expression by inhibiting IL-1beta-induced phospho-p38 level. TGF-beta could prevent OA from progression with the anabolic ability to induce CTGF production to maintain extracellular matrix (ECM) integrity and to down regulate PAR-2 expression, and the anti-catabolic ability to induce Tissue inhibitors of metalloproteinase-3 (TIMP-3) production to inhibit MMPs leading to avoid PAR-2 over-expression. Because IL-1beta-induced PAR-2 expressed in hPSCs might play a significantly important role in early phase of OA, PAR-2 repression by exogenous TGF-beta or other agents might be an ideal therapeutic target to prevent OA from progression.

Chronic Trypanosoma cruzi infection potentiates adipose tissue macrophage polarization toward an anti-inflammatory M2 phenotype and contributes to diabetes progression in a diet-induced obesity model.

PubMed

Cabalén, María E; Cabral, María F; Sanmarco, Liliana M; Andrada, Marta C; Onofrio, Luisina I; Ponce, Nicolás E; Aoki, María P; Gea, Susana; Cano, Roxana C

2016-03-22

Chronic obesity and Chagas disease (caused by the protozoan Trypanosoma cruzi) represent serious public health concerns. The interrelation between parasite infection, adipose tissue, immune system and metabolism in an obesogenic context, has not been entirely explored. A novel diet-induced obesity model (DIO) was developed in C57BL/6 wild type mice to examine the effect of chronic infection (DIO+I) on metabolic parameters and on obesity-related disorders. Dyslipidemia, hyperleptinemia, and cardiac/hepatic steatosis were strongly developed in DIO mice. Strikingly, although these metabolic alterations were collectively improved by infection, plasmatic apoB100 levels remain significantly increased in DIO+I, suggesting the presence of pro-atherogenic small and dense LDL particles. Moreover, acute insulin resistance followed by chronic hyperglycemia with hypoinsulinemia was found, evidencing an infection-related-diabetes progression. These lipid and glucose metabolic changes seemed to be highly dependent on TLR4 expression since TLR4-/- mice were protected from obesity and its complications. Notably, chronic infection promoted a strong increase in MCP-1 producing macrophages with a M2 (F4/80+CD11c-CD206+) phenotype associated to oxidative stress in visceral adipose tissue of DIO+I mice. Importantly, infection reduced lipid content but intensified inflammatory infiltrates in target tissues. Thus, parasite persistence in an obesogenic environment and the resulting host immunometabolic dysregulation may contribute to diabetes/atherosclerosis progression.

The continuum of spreading depolarizations in acute cortical lesion development: Examining Leão’s legacy

PubMed Central

Shuttleworth, C William; Kirov, Sergei A; Ayata, Cenk; Hinzman, Jason M; Foreman, Brandon; Andrew, R David; Boutelle, Martyn G; Brennan, KC; Carlson, Andrew P; Dahlem, Markus A; Drenckhahn, Christoph; Dohmen, Christian; Fabricius, Martin; Farkas, Eszter; Feuerstein, Delphine; Graf, Rudolf; Helbok, Raimund; Lauritzen, Martin; Major, Sebastian; Oliveira-Ferreira, Ana I; Richter, Frank; Rosenthal, Eric S; Sakowitz, Oliver W; Sánchez-Porras, Renán; Santos, Edgar; Schöll, Michael; Strong, Anthony J; Urbach, Anja; Westover, M Brandon; Winkler, Maren KL; Witte, Otto W; Woitzik, Johannes; Dreier, Jens P

2016-01-01

A modern understanding of how cerebral cortical lesions develop after acute brain injury is based on Aristides Leão’s historic discoveries of spreading depression and asphyxial/anoxic depolarization. Treated as separate entities for decades, we now appreciate that these events define a continuum of spreading mass depolarizations, a concept that is central to understanding their pathologic effects. Within minutes of acute severe ischemia, the onset of persistent depolarization triggers the breakdown of ion homeostasis and development of cytotoxic edema. These persistent changes are diagnosed as diffusion restriction in magnetic resonance imaging and define the ischemic core. In delayed lesion growth, transient spreading depolarizations arise spontaneously in the ischemic penumbra and induce further persistent depolarization and excitotoxic damage, progressively expanding the ischemic core. The causal role of these waves in lesion development has been proven by real-time monitoring of electrophysiology, blood flow, and cytotoxic edema. The spreading depolarization continuum further applies to other models of acute cortical lesions, suggesting that it is a universal principle of cortical lesion development. These pathophysiologic concepts establish a working hypothesis for translation to human disease, where complex patterns of depolarizations are observed in acute brain injury and appear to mediate and signal ongoing secondary damage. PMID:27328690

Occult hepatitis B virus and hepatocellular carcinoma

PubMed Central

Pollicino, Teresa; Saitta, Carlo

2014-01-01

Occult hepatitis B virus (HBV) infection (OBI) is a challenging pathobiological and clinical issue that has been widely debated for several decades. By definition, OBI is characterized by the persistence of HBV DNA in the liver tissue (and in some cases also in the serum) in the absence of circulating HBV surface antigen (HBsAg). Many epidemiological and molecular studies have indicated that OBI is an important risk factor for hepatocellular carcinoma (HCC) development. OBI may exert direct pro-oncogenic effects through the activation of the same oncogenic mechanisms that are activated in the course of an HBsAg-positive infection. Indeed, in OBI as in HBV-positive infection, HBV DNA can persist in the hepatocytes both integrated into the host genome as well as free episome, and may maintain the capacity to produce proteins-mainly X protein and truncated preS-S protein - provided with potential transforming properties. Furthermore, OBI may indirectly favor HCC development. It has been shown that the persistence of very low viral replicative activity during OBI may induce mild liver necro-inflammation continuing for life, and substantial clinical evidence indicates that OBI can accelerate the progression of liver disease towards cirrhosis that is considered the most important risk factor for HCC development. PMID:24876718

Emergence of Persistent Infection due to Heterogeneity

NASA Astrophysics Data System (ADS)

Agrawal, Vidit; Moitra, Promit; Sinha, Sudeshna

2017-02-01

We explore the emergence of persistent infection in a closed region where the disease progression of the individuals is given by the SIRS model, with an individual becoming infected on contact with another infected individual. We investigate the persistence of contagion qualitatively and quantitatively, under increasing heterogeneity in the partitioning of the population into different disease compartments, as well as increasing heterogeneity in the phases of the disease among individuals within a compartment. We observe that when the initial population is uniform, consisting of individuals at the same stage of disease progression, infection arising from a contagious seed does not persist. However when the initial population consists of randomly distributed refractory and susceptible individuals, a single source of infection can lead to sustained infection in the population, as heterogeneity facilitates the de-synchronization of the phases in the disease cycle of the individuals. We also show how the average size of the window of persistence of infection depends on the degree of heterogeneity in the initial composition of the population. In particular, we show that the infection eventually dies out when the entire initial population is susceptible, while even a few susceptibles among an heterogeneous refractory population gives rise to a large persistent infected set.

The Culture of the Independent Progressive School

ERIC Educational Resources Information Center

Kloss, Dean

2018-01-01

Even in this "Age of Data," independent progressive schools have shown a remarkable persistence in offering an alternative educational model. As Traditional Public Schools (TPS) become even more committed to a testing model of achievement, there are schools that continue to operate on identified progressive educational principles. This…

Commonly prescribed β-lactam antibiotics induce C. trachomatis persistence/stress in culture at physiologically relevant concentrations

PubMed Central

Kintner, Jennifer; Lajoie, Dawn; Hall, Jennifer; Whittimore, Judy; Schoborg, Robert V.

2014-01-01

Chlamydia trachomatis, the most common bacterial sexually transmitted disease agent worldwide, enters a viable, non-dividing and non-infectious state (historically termed persistence and more recently referred to as the chlamydial stress response) when exposed to penicillin G in culture. Notably, penicillin G-exposed chlamydiae can reenter the normal developmental cycle upon drug removal and are resistant to azithromycin-mediated killing. Because penicillin G is less frequently prescribed than other β-lactams, the clinical relevance of penicillin G-induced chlamydial persistence/stress has been questioned. The goal of this study was to determine whether more commonly used penicillins also induce C. trachomatis serovar E persistence/stress. All penicillins tested, as well as clavulanic acid, induced formation of aberrant, enlarged reticulate bodies (RB) (called aberrant bodies or AB) characteristic of persistent/stressed chlamydiae. Exposure to the penicillins and clavulanic acid also reduced chlamydial infectivity by >95%. None of the drugs tested significantly reduced chlamydial unprocessed 16S rRNA or genomic DNA accumulation, indicating that the organisms were viable, though non-infectious. Finally, recovery assays demonstrated that chlamydiae rendered essentially non-infectious by exposure to ampicillin, amoxicillin, carbenicillin, piperacillin, penicillin V, and clavulanic acid recovered infectivity after antibiotic removal. These data definitively demonstrate that several commonly used penicillins induce C. trachomatis persistence/stress at clinically relevant concentrations. PMID:24783061

Loss of Cyclin-dependent Kinase 2 in the Pancreas Links Primary β-Cell Dysfunction to Progressive Depletion of β-Cell Mass and Diabetes*

PubMed Central

Kim, So Yoon; Lee, Ji-Hyeon; Merrins, Matthew J.; Gavrilova, Oksana; Bisteau, Xavier; Kaldis, Philipp; Satin, Leslie S.; Rane, Sushil G.

2017-01-01

The failure of pancreatic islet β-cells is a major contributor to the etiology of type 2 diabetes. β-Cell dysfunction and declining β-cell mass are two mechanisms that contribute to this failure, although it is unclear whether they are molecularly linked. Here, we show that the cell cycle regulator, cyclin-dependent kinase 2 (CDK2), couples primary β-cell dysfunction to the progressive deterioration of β-cell mass in diabetes. Mice with pancreas-specific deletion of Cdk2 are glucose-intolerant, primarily due to defects in glucose-stimulated insulin secretion. Accompanying this loss of secretion are defects in β-cell metabolism and perturbed mitochondrial structure. Persistent insulin secretion defects culminate in progressive deficits in β-cell proliferation, reduced β-cell mass, and diabetes. These outcomes may be mediated directly by the loss of CDK2, which binds to and phosphorylates the transcription factor FOXO1 in a glucose-dependent manner. Further, we identified a requirement for CDK2 in the compensatory increases in β-cell mass that occur in response to age- and diet-induced stress. Thus, CDK2 serves as an important nexus linking primary β-cell dysfunction to progressive β-cell mass deterioration in diabetes. PMID:28100774

Disease course and management strategy of pouch neoplasia in patients with underlying inflammatory bowel diseases.

PubMed

Wu, Xian-Rui; Remzi, Feza H; Liu, Xiu-Li; Lian, Lei; Stocchi, Luca; Ashburn, Jean; Shen, Bo

2014-11-01

To evaluate the disease course and management strategy for pouch neoplasia. Patients undergoing ileal pouch surgery for underlying ulcerative colitis who developed low-grade dysplasia (LGD), high-grade dysplasia, or adenocarcinoma in the pouch were identified. All eligible 44 patients were evaluated. Of the 22 patients with initial diagnosis of pouch LGD, 6 (27.3%) had persistence or progression after a median follow-up of 9.5 (4.1-17.6) years. Family history of colorectal cancer was shown to be a risk factor associated with persistence or progression of LGD (P = 0.03). Of the 12 patients with pouch high-grade dysplasia, 5 (41.7%) had a history of (n = 2, 16.7%) or synchronous (n = 4, 33.3%) pouch LGD. Pouch high-grade dysplasia either persisted or progressed in 3 patients (25.0%) after the initial management, during a median time interval of 5.4 (2.2-9.2) years. Of the 14 patients with pouch adenocarcinoma, 12 (85.7%) had a history of (n = 2, 14.3%) or synchronous dysplasia (n = 12, 85.7%). After a median follow-up of 2.1 (0.6-5.2) years, 6 patients with pouch cancer (42.9%) died. Comparison of patients with a final diagnosis of pouch adenocarcinoma (14, 32.6%), and those with dysplasia (29, 67.4%) showed that patients with adenocarcinoma were older (P = 0.04) and had a longer duration from IBD diagnosis or pouch construction to the detection of pouch neoplasia (P = 0.007 and P = 0.0013). The risk for progression of pouch dysplasia can be stratified. The presence of family history of colorectal cancer seemed to increase the risk for persistence or progression for patients with pouch LGD. The prognosis for pouch adenocarcinoma was poor.

Early PQQ supplementation has persistent long-term protective effects on developmental programming of hepatic lipotoxicity and inflammation in obese mice.

PubMed

Jonscher, Karen R; Stewart, Michael S; Alfonso-Garcia, Alba; DeFelice, Brian C; Wang, Xiaoxin X; Luo, Yuhuan; Levi, Moshe; Heerwagen, Margaret J R; Janssen, Rachel C; de la Houssaye, Becky A; Wiitala, Ellen; Florey, Garrett; Jonscher, Raleigh L; Potma, Eric O; Fiehn, Oliver; Friedman, Jacob E

2017-04-01

Nonalcoholic fatty liver disease (NAFLD) is widespread in adults and children. Early exposure to maternal obesity or Western-style diet (WD) increases steatosis and oxidative stress in fetal liver and is associated with lifetime disease risk in the offspring. Pyrroloquinoline quinone (PQQ) is a natural antioxidant found in soil, enriched in human breast milk, and essential for development in mammals. We investigated whether a supplemental dose of PQQ, provided prenatally in a mouse model of diet-induced obesity during pregnancy, could protect obese offspring from progression of NAFLD. PQQ treatment given pre- and postnatally in WD-fed offspring had no effect on weight gain but increased metabolic flexibility while reducing body fat and liver lipids, compared with untreated obese offspring. Indices of NAFLD, including hepatic ceramide levels, oxidative stress, and expression of proinflammatory genes ( Nos2 , Nlrp3 , Il6 , and Ptgs2 ), were decreased in WD PQQ-fed mice, concomitant with increased expression of fatty acid oxidation genes and decreased Pparg expression. Notably, these changes persisted even after PQQ withdrawal at weaning. Our results suggest that supplementation with PQQ, particularly during pregnancy and lactation, protects offspring from WD-induced developmental programming of hepatic lipotoxicity and may help slow the advancing epidemic of NAFLD in the next generation.-Jonscher, K. R., Stewart, M. S., Alfonso-Garcia, A., DeFelice, B. C., Wang, X. X., Luo, Y., Levi, M., Heerwagen, M. J. R., Janssen, R. C., de la Houssaye, B. A., Wiitala, E., Florey, G., Jonscher, R. L., Potma, E. O., Fiehn, O. Friedman, J. E. Early PQQ supplementation has persistent long-term protective effects on developmental programming of hepatic lipotoxicity and inflammation in obese mice. © FASEB.

Molecular basis of alcoholism.

PubMed

Most, Dana; Ferguson, Laura; Harris, R Adron

2014-01-01

Acute alcohol intoxication causes cellular changes in the brain that last for hours, while chronic alcohol use induces widespread neuroadaptations in the nervous system that can last a lifetime. Chronic alcohol use and the progression into dependence involve the remodeling of synapses caused by changes in gene expression produced by alcohol. The progression of alcohol use, abuse, and dependence can be divided into stages, which include intoxication, withdrawal, and craving. Each stage is associated with specific changes in gene expression, cellular function, brain circuits, and ultimately behavior. What are the molecular mechanisms underlying the transition from recreational use (acute) to dependence (chronic)? What cellular adaptations result in drug memory retention, leading to the persistence of addictive behaviors, even after prolonged drug abstinence? Research into the neurobiology of alcoholism aims to answer these questions. This chapter will describe the molecular adaptations caused by alcohol use and dependence, and will outline key neurochemical participants in alcoholism at the molecular level, which are also potential targets for therapy. © 2014 Elsevier B.V. All rights reserved.

Evaluation of a Postoperative Pain-Like State on Motivated Behavior in Rats: Effects of Plantar Incision on Progressive-Ratio Food-Maintained Responding.

PubMed

Warner, Emily; Krivitsky, Rebecca; Cone, Katherine; Atherton, Phillip; Pitre, Travis; Lanpher, Janell; Giuvelis, Denise; Bergquist, Ivy; King, Tamara; Bilsky, Edward J; Stevenson, Glenn W

2015-12-01

There has been recent interest in characterizing the effects of pain-like states on motivated behaviors in order to quantify how pain modulates goal-directed behavior and the persistence of that behavior. The current set of experiments assessed the effects of an incisional postoperative pain manipulation on food-maintained responding under a progressive-ratio (PR) operant schedule. Independent variables included injury state (plantar incision or anesthesia control) and reinforcer type (grain pellet or sugar pellet); dependent variables were tactile sensory thresholds and response breakpoint. Once responding stabilized on the PR schedule, separate groups of rats received a single ventral hind paw incision or anesthesia (control condition). Incision significantly reduced breakpoints in rats responding for grain, but not sugar. In rats responding for sugar, tactile hypersensitivity recovered within 24 hr, indicating a faster recovery of incision-induced tactile hypersensitivity compared to rats responding for grain, which demonstrated recovery at PD2. The NSAID analgesic, diclofenac (5.6 mg/kg) completely restored incision-depressed PR operant responding and tactile sensitivity at 3 hr following incision. The PR schedule differentiated between sucrose and grain, suggesting that relative reinforcing efficacy may be an important determinant in detecting pain-induced changes in motivated behavior. © 2015 Wiley Periodicals, Inc.

Evaluation of a post-operative pain-like state on motivated behavior in rats: Effects of plantar incision on progressive-ratio food-maintained responding

PubMed Central

Warner, Emily; Krivitsky, Rebecca; Cone, Katherine; Atherton, Phillip; Pitre, Travis; Lanpher, Janell; Giuvelis, Denise; Bergquist, Ivy; King, Tamara; Bilsky, Edward J.; Stevenson, Glenn W.

2015-01-01

There has been recent interest in characterizing the effects of pain-like states on motivated behaviors in order to quantify how pain modulates goal-directed behavior and the persistence of that behavior. The current set of experiments assessed the effects of an incisional post-operative pain manipulation on food-maintained responding under a progressive-ratio (PR) operant schedule. Independent variables included injury state (plantar incision or anesthesia control) and reinforcer type (grain pellet or sugar pellet); dependent variables were tactile sensory thresholds and response breakpoint. Once responding stabilized on the PR schedule, separate groups of rats received a single ventral hind paw incision or anesthesia (control condition). Incision significantly reduced breakpoints in rats responding for grain, but not sugar. In rats responding for sugar, tactile hypersensitivity recovered within 24 hrs, indicating a faster recovery of incision-induced tactile hypersensitivity compared to rats responding for grain, which demonstrated recovery at PD2. The NSAID analgesic, diclofenac (5.6 mg/kg) completely restored incision-depressed PR operant responding and tactile sensitivity at 3 hr following incision. The PR schedule differentiated between sucrose and grain, suggesting that relative reinforcing efficacy may be an important determinant in detecting pain-induced changes in motivated behavior. PMID:26494422

Experimental neonatal hypoxia ischemia causes long lasting changes of oxidative stress parameters in the hippocampus and the spleen.

PubMed

Odorcyk, Felipe Kawa; Kolling, Janaína; Sanches, Eduardo Farias; Wyse, Angela T S; Netto, Carlos Alexandre

2018-05-24

Neonatal hypoxia ischemia (HI) is the main cause of mortality and morbidity in newborns. The mechanisms involved in its progression start immediately and persist for several days. Oxidative stress and inflammation are determinant factors of the severity of the final lesion. The spleen plays a major part in the inflammatory response to HI. This study assessed the temporal progression of HI-induced alterations in oxidative stress parameters in the hippocampus, the most affected brain structure, and in the spleen. HI was induced in Wistar rat pups in post-natal day 7. Production of reactive oxygen species (ROS), and the activity of the anti oxidant enzyme superoxide dismutase and catalase were assessed 24 h, 96 h and 38 days post-HI. Interestingly, both structures showed a similar pattern, with few alterations in the production of ROS species up to 96 h often combined with an increased activity of the anti oxidant enzymes. However, 38 days after the injury, ROS were at the highest in both structures, coupled with a decrease in the activity of the enzymes. Altogether, present results suggest that HI causes long lasting alterations in the hippocampus as well as in the spleen, suggesting a possible target for delayed treatments for HI.

Thioacetamide-induced cirrhosis in selenium-adequate mice displays rapid and persistent abnormity of hepatic selenoenzymes which are mute to selenium supplementation

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

Zhang Jinsong; Wang Huali; Yu Hanqing

2007-10-01

Selenium reduction in cirrhosis is frequently reported. The known beneficial effect of selenium supplementation on cirrhosis is probably obtained from nutritionally selenium-deficient subjects. Whether selenium supplementation truly improves cirrhosis in general needs additional experimental investigation. Thioacetamide was used to induce cirrhosis in selenium-adequate and -deficient mice. Selenoenzyme activity and selenium content were measured and the influence of selenium supplementation was evaluated. In Se-adequate mice, thioacetamide-mediated rapid onset of hepatic oxidative stress resulted in an increase in thioredoxin reductase activity and a decrease in both glutathione peroxidase activity and selenium content. The inverse activity of selenoenzymes (i.e. TrxR activity goes upmore » and GPx activity goes down) was persistent and mute to selenium supplementation during the progress of cirrhosis; accordingly, cirrhosis was not improved by selenium supplementation in any period. On the other hand, selenium supplementation to selenium-deficient mice always more efficiently increased hepatic glutathione peroxidase activity and selenium content compared with those treated with thioacetamide, indicating that thioacetamide impairs the liver bioavailability of selenium. Although thioacetamide profoundly affects hepatic selenium status in selenium-adequate mice, selenium supplementation does not modify the changes. Selenium supplementation to cirrhotic subjects with a background of nutritional selenium deficiency can improve selenium status but cannot restore hepatic glutathione peroxidase and selenium to normal levels.« less

Persistent increase in oxygen consumption and impaired neurovascular coupling after spreading depression in rat neocortex.

PubMed

Piilgaard, Henning; Lauritzen, Martin

2009-09-01

Cortical spreading depression (CSD) is associated with a dramatic failure of brain ion homeostasis and increased energy metabolism. There is strong clinical and experimental evidence to suggest that CSD is the mechanism of migraine, and involved in progressive neuronal injury in stroke and head trauma. Here we tested the hypothesis that single episodes of CSD induced acute hypoxia, and prolonged impairment of neurovascular and neurometabolic coupling. Cortical spreading depression was induced in rat frontal cortex, whereas cortical electrical activity and local field potentials (LFPs) were recorded by glass microelectrodes, cerebral blood flow (CBF) by laser-Doppler flowmetry, and tissue oxygen tension (tpO(2)) with polarographic microelectrodes. Cortical spreading depression increased cerebral metabolic rate of oxygen (CMRO(2)) by 71%+/-6.7% and CBF by 238%+/-48.1% for 1 to 2 mins. For the following 2 h, basal tpO(2) and CBF were reduced whereas basal CMRO(2) was persistently elevated by 8.1%+/-2.9%. In addition, within first hour after CSD we found impaired neurovascular coupling (LFP versus CBF), whereas neurometabolic coupling (LFP versus CMRO(2)) remained unaffected. Impaired neurovascular coupling was explained by both reduced vascular reactivity and suppressed function of cortical inhibitory interneurons. The protracted effects of CSD on basal CMRO(2) and neurovascular coupling may contribute to cellular dysfunction in patients with migraine and acutely injured cerebral cortex.

5-HT2C receptor involvement in the control of persistence in the reinforced spatial alternation animal model of obsessive-compulsive disorder.

PubMed

Papakosta, Vassiliki-Maria; Kalogerakou, Stamatina; Kontis, Dimitris; Anyfandi, Eleni; Theochari, Eirini; Boulougouris, Vasileios; Papadopoulos, Sokrates; Panagis, George; Tsaltas, Eleftheria

2013-04-15

The serotonergic system is implicated in the pathophysiology of obsessive-compulsive disorder (OCD). However, the distinct role of serotonin (5-HT) receptor subtypes remains unclear. This study investigates the contribution of 5-HT2A and 5-HT2C receptors in the modulation of persistence in the reinforced spatial alternation model of OCD. Male Wistar rats were assessed for spontaneous and pharmacologically induced (by m-chlorophenylpiperazine: mCPP) directional persistence in the reinforced alternation OCD model. Systemic administration of mCPP (non-specific 5-HT agonist, 2.5mg/kg), M100907 (selective 5-HT2A receptor antagonist, 0.08 mg/kg), SB242084 (selective 5-HT2C receptor antagonist, 0.5 mg/kg) and vehicle was used. Experiment 1 investigated M100907 and SB242084 effects in animals spontaneously exhibiting high and low persistence during the early stages of alternation training. Experiment 2 investigated M100900 and SB242084 effects on mCPP-induced persistence. Under the regime used in Experiment 1, 5-HT2A or 5-HT2C receptor antagonism did not affect spontaneous directional persistence in either high or low persistence groups. In Experiment 2, 5-HT2C but not 5-HT2A receptor antagonism significantly reduced, but did not abolish, mCPP-induced directional persistence. These findings suggest that 5-HT2C but not 5-HT2A receptors contribute to the modulation of mCPP-induced persistent behaviour, raising the possibility that the use of 5-HT2C antagonists may have a therapeutic value in OCD. Copyright © 2013 Elsevier B.V. All rights reserved.

Heart rate is associated with progression of atrial fibrillation, independent of rhythm.

PubMed

Holmqvist, Fredrik; Kim, Sunghee; Steinberg, Benjamin A; Reiffel, James A; Mahaffey, Kenneth W; Gersh, Bernard J; Fonarow, Gregg C; Naccarelli, Gerald V; Chang, Paul; Freeman, James V; Kowey, Peter R; Thomas, Laine; Peterson, Eric D; Piccini, Jonathan P

2015-06-01

Atrial fibrillation (AF) often progresses from paroxysmal or persistent to more sustained forms, but the rate and predictors of AF progression in clinical practice are not well described. Using the Outcomes Registry for Better Informed Treatment of AF, we analysed the incidence and predictors of progression and tested the discrimination and calibration of the HATCH (hypertension, age, TIA/stroke, chronic obstructive pulmonary disease, heart failure) and CHA₂DS₂VASc scores for identifying AF progression. Among 6235 patients with paroxysmal or persistent AF at baseline, 1479 progressed, during follow-up (median 18 (IQR 12-24) months). These patients were older and had more comorbidities than patients who did not progress (CHADS₂ 2.3±1.3 vs 2.1±1.3, p<0.0001). At baseline, patients with AF progression were more often on a rate control as opposed to a rhythm control strategy (66 vs 56%, p<0.0001) and had higher heart rate (72(64-80) vs 68(60-76) bpm, p<0.0001). The strongest predictors of AF progression were AF on the baseline ECG (OR 2.30, 95% CI 1.95 to 2.73, p<0.0001) and increasing age (OR 1.16, 95% CI1.09 to 1.24, p<0.0001, per 10 increase), while patients with lower heart rate (OR 0.84, 95% CI 0.79 to 0.89, p<0.0001, per 10 decrease ≤80) were less likely to progress. There was no significant interaction between rhythm on baseline ECG and heart rate (p=0.71). The HATCH and CHA₂DS₂VASc scores had modest discriminatory power for AF progression (C-indices 0.55 (95% CI 0.53 to 0.58) and 0.55 (95% CI 0.52 to 0.57)). Within 1.5 years, almost a quarter of the patients with paroxysmal or persistent AF progress to a more sustained form. Progression is strongly associated with heart rate, and age. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Pharmacological Targeting of Protease-Activated Receptor 2 Affords Protection from Bleomycin-Induced Pulmonary Fibrosis

PubMed Central

Lin, Cong; von der Thüsen, Jan; Daalhuisen, Joost; ten Brink, Marieke; Crestani, Bruno; van der Poll, Tom; Borensztajn, Keren; Spek, C Arnold

2015-01-01

Idiopathic pulmonary fibrosis is the most devastating diffuse fibrosing lung disease that remains refractory to therapy. Despite increasing evidence that protease-activated receptor 2 (PAR-2) contributes to fibrosis, its importance in pulmonary fibrosis is under debate. We addressed whether PAR-2 deficiency persistently reduces bleomycin-induced pulmonary fibrosis or merely delays disease progression and whether pharmacological PAR-2 inhibition limits experimental pulmonary fibrosis. Bleomycin was instilled intranasally into wild-type or PAR-2–deficient mice in the presence/absence of a specific PAR-2 antagonist (P2pal-18S). Pulmonary fibrosis was consistently reduced in PAR-2–deficient mice throughout the fibrotic phase, as evident from reduced Ashcroft scores (29%) and hydroxyproline levels (26%) at d 28. Moreover, P2pal-18S inhibited PAR-2–induced profibrotic responses in both murine and primary human pulmonary fibroblasts (p < 0.05). Once daily treatment with P2pal-18S reduced the severity and extent of fibrotic lesions in lungs of bleomycin-treated wild-type mice but did not further reduce fibrosis in PAR-2–deficient mice. Importantly, P2pal-18S treatment starting even 7 d after the onset of fibrosis limits pulmonary fibrosis as effectively as when treatment was started together with bleomycin instillation. Overall, PAR-2 contributes to the progression of pulmonary fibrosis, and targeting PAR-2 may be a promising therapeutic strategy for treating pulmonary fibrosis. PMID:26147947

Substance P Promotes Wound Healing in Diabetes by Modulating Inflammation and Macrophage Phenotype

PubMed Central

Leal, Ermelindo C.; Carvalho, Eugénia; Tellechea, Ana; Kafanas, Antonios; Tecilazich, Francesco; Kearney, Cathal; Kuchibhotla, Sarada; Auster, Michael E.; Kokkotou, Efi; Mooney, David J.; LoGerfo, Frank W.; Pradhan-Nabzdyk, Leena; Veves, Aristidis

2016-01-01

Diabetic foot ulceration is a major complication of diabetes. Substance P (SP) is involved in wound healing, but its effect in diabetic skin wounds is unclear. We examined the effect of exogenous SP delivery on diabetic mouse and rabbit wounds. We also studied the impact of deficiency in SP or its receptor, neurokinin-1 receptor, on wound healing in mouse models. SP treatment improved wound healing in mice and rabbits, whereas the absence of SP or its receptor impaired wound progression in mice. Moreover, SP bioavailability in diabetic skin was reduced as SP gene expression was decreased, whereas the gene expression and protein levels of the enzyme that degrades SP, neutral endopeptidase, were increased. Diabetes and SP deficiency were associated with absence of an acute inflammatory response important for wound healing progression and instead revealed a persistent inflammation throughout the healing process. SP treatment induced an acute inflammatory response, which enabled the progression to the proliferative phase and modulated macrophage activation toward the M2 phenotype that promotes wound healing. In conclusion, SP treatment reverses the chronic proinflammatory state in diabetic skin and promotes healing of diabetic wounds. PMID:25871534

High Risk Human Papillomavirus Persistence Among HIV-infected Young Women in South Africa

PubMed Central

Adler, David; Wallace, Melissa; Bennie, Thola; Abar, Beau; Sadeghi, Rokhsanna; Meiring, Tracy; Williamson, Anna-Lise; Bekker, Linda-Gail

2015-01-01

Objectives Persistence of infection with high-risk Human papillomaviruses (HR-HPV) increases the risk of incident and progressive precancerous lesions of the cervix. Rates of HR-HPV persistence have been shown to be increased among HIV-infected adult women, however there is a paucity of literature addressing HPV persistence in the young HIV-infected population. We compared rates of HR-HPV persistence between HIV-infected and HIV-uninfected young women. Methods We obtained self-collected vaginal swabs at six-month intervals from 50 HIV-uninfected and 33 HIV-infected young women recruited through a community youth center (age 17-21 years) and compared rates of HR-HPV persistence. HR-HPV testing was conducted using the Roche’s Linear Array® HPV Test. Results Eighty-three prevalent (upon baseline testing) and incident (upon subsequent testing) individual HR-HPV infections were identified among 43 members of the cohort (23 HIV-uninfected and 20 HIV-infected). At twelve months, 19% of baseline HR-HPV infections continued to be present with a statistically significant difference between HIV-uninfected and HIV-infected participants (4% versus 31%; p=0.01). Conclusions HIV-infected young women in our cohort had a seven-fold increased rate of persistence of HR-HPV overall at 12 months indicating an increased risk for incident and progressive precancerous lesions. Identification of persistent infection with HR-HPV may complement cytological findings in determining the need for colposcopy. PMID:25697074

Both Complexity and Location of DNA Damage Contribute to Cellular Senescence Induced by Ionizing Radiation

PubMed Central

Zhang, Xurui; Ye, Caiyong; Sun, Fang; Wei, Wenjun; Hu, Burong; Wang, Jufang

2016-01-01

Persistent DNA damage is considered as a main cause of cellular senescence induced by ionizing radiation. However, the molecular bases of the DNA damage and their contribution to cellular senescence are not completely clear. In this study, we found that both heavy ions and X-rays induced senescence in human uveal melanoma 92–1 cells. By measuring senescence associated-β-galactosidase and cell proliferation, we identified that heavy ions were more effective at inducing senescence than X-rays. We observed less efficient repair when DNA damage was induced by heavy ions compared with X-rays and most of the irreparable damage was complex of single strand breaks and double strand breaks, while DNA damage induced by X-rays was mostly repaired in 24 hours and the remained damage was preferentially associated with telomeric DNA. Our results suggest that DNA damage induced by heavy ion is often complex and difficult to repair, thus presents as persistent DNA damage and pushes the cell into senescence. In contrast, persistent DNA damage induced by X-rays is preferentially associated with telomeric DNA and the telomere-favored persistent DNA damage contributes to X-rays induced cellular senescence. These findings provide new insight into the understanding of high relative biological effectiveness of heavy ions relevant to cancer therapy and space radiation research. PMID:27187621

Toll-like receptor signaling and stages of addiction.

PubMed

Crews, Fulton T; Walter, T Jordan; Coleman, Leon G; Vetreno, Ryan P

2017-05-01

Athina Markou and her colleagues discovered persistent changes in adult behavior following adolescent exposure to ethanol or nicotine consistent with increased risk for developing addiction. Building on Dr. Markou's important work and that of others in the field, researchers at the Bowles Center for Alcohol Studies have found that persistent changes in behavior following adolescent stress or alcohol exposure may be linked to induction of immune signaling in brain. This study aims to illuminate the critical interrelationship of the innate immune system (e.g., toll-like receptors [TLRs], high-mobility group box 1 [HMGB1]) in the neurobiology of addiction. This study reviews the relevant research regarding the relationship between the innate immune system and addiction. Emerging evidence indicates that TLRs in brain, particularly those on microglia, respond to endogenous innate immune agonists such as HMGB1 and microRNAs (miRNAs). Multiple TLRs, HMGB1, and miRNAs are induced in the brain by stress, alcohol, and other drugs of abuse and are increased in the postmortem human alcoholic brain. Enhanced TLR-innate immune signaling in brain leads to epigenetic modifications, alterations in synaptic plasticity, and loss of neuronal cell populations, which contribute to cognitive and emotive dysfunctions. Addiction involves progressive stages of drug binges and intoxication, withdrawal-negative affect, and ultimately compulsive drug use and abuse. Toll-like receptor signaling within cortical-limbic circuits is modified by alcohol and stress in a manner consistent with promoting progression through the stages of addiction.

60 YEARS OF NEUROENDOCRINOLOGY: Acromegaly.

PubMed

Capatina, Cristina; Wass, John A H

2015-08-01

Acromegaly (ACM) is a chronic, progressive disorder caused by the persistent hypersecretion of GH, in the vast majority of cases secreted by a pituitary adenoma. The consequent increase in IGF1 (a GH-induced liver protein) is responsible for most clinical features and for the systemic complications associated with increased mortality. The clinical diagnosis, based on symptoms related to GH excess or the presence of a pituitary mass, is often delayed many years because of the slow progression of the disease. Initial testing relies on measuring the serum IGF1 concentration. The oral glucose tolerance test with concomitant GH measurement is the gold-standard diagnostic test. The therapeutic options for ACM are surgery, medical treatment, and radiotherapy (RT). The outcome of surgery is very good for microadenomas (80-90% cure rate), but at least half of the macroadenomas (most frequently encountered in ACM patients) are not cured surgically. Somatostatin analogs are mainly indicated after surgical failure. Currently their routine use as primary therapy is not recommended. Dopamine agonists are useful in a minority of cases. Pegvisomant is indicated for patients refractory to surgery and other medical treatments. RT is employed sparingly, in cases of persistent disease activity despite other treatments, due to its long-term side effects. With complex, combined treatment, at least three-quarters of the cases are controlled according to current criteria. With proper control of the disease, the specific complications are partially improved and the mortality rate is close to that of the background population. © 2015 Society for Endocrinology.

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

PubMed

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

2017-01-01

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

Real-time scratch assay reveals mechanisms of early calcium signaling in breast cancer cells in response to wounding

PubMed Central

Pratt, Stephen J.P.; Hernández-Ochoa, Erick O.; Lee, Rachel M.; Ory, Eleanor C.; Lyons, James S.; Joca, Humberto C.; Johnson, Ashley; Thompson, Keyata; Bailey, Patrick; Lee, Cornell J.; Mathias, Trevor; Vitolo, Michele I.; Trudeau, Matt; Stains, Joseph P.; Ward, Christopher W.; Schneider, Martin F.; Martin, Stuart S.

2018-01-01

Aggressive cellular phenotypes such as uncontrolled proliferation and increased migration capacity engender cellular transformation, malignancy and metastasis. While genetic mutations are undisputed drivers of cancer initiation and progression, it is increasingly accepted that external factors are also playing a major role. Two recently studied modulators of breast cancer are changes in the cellular mechanical microenvironment and alterations in calcium homeostasis. While many studies investigate these factors separately in breast cancer cells, very few do so in combination. This current work sets a foundation to explore mechano-calcium relationships driving malignant progression in breast cancer. Utilizing real-time imaging of an in vitro scratch assay, we were able to resolve mechanically-sensitive calcium signaling in human breast cancer cells. We observed rapid initiation of intracellular calcium elevations within seconds in cells at the immediate wound edge, followed by a time-dependent increase in calcium in cells at distances up to 500μm from the scratch wound. Calcium signaling to neighboring cells away from the wound edge returned to baseline within seconds. Calcium elevations at the wound edge however, persisted for up to 50 minutes. Rigorous quantification showed that extracellular calcium was necessary for persistent calcium elevation at the wound edge, but intercellular signal propagation was dependent on internal calcium stores. In addition, intercellular signaling required extracellular ATP and activation of P2Y2 receptors. Through comparison of scratch-induced signaling from multiple cell lines, we report drastic reductions in response from aggressively tumorigenic and metastatic cells. The real-time scratch assay established here provides quantitative data on the molecular mechanisms that support rapid scratch-induced calcium signaling in breast cancer cells. These mechanisms now provide a clear framework for investigating which short-term calcium signals promote long-term changes in cancer cell biology. PMID:29861849

Adverse Health Effects of Thirdhand Smoke: From Cell to Animal Models

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

Hang, Bo; Wang, Pin; Zhao, Yue

The newly identified smoke hazard, thirdhand smoke (THS), has gained public attention in recent years but its health impact and biological effects are largely unknown. THS may be defined by “the four Rs”: tobacco chemicals that remain, react, re-emit, and/or are resuspended long after active smoking has ceased. This review summarizes recent research progress in the effects of THS on genotoxicity, metabolism and early life development using cellular and animal models. We first reported that THS generated in laboratory systems caused significant DNA damage in human cell lines. Our finding that THS significantly induces oxidative base lesions has been confirmedmore » in skin wounds of mice models exposed to THS. THS also induced metabolomic changes in human reproductive cell lines. Furthermore, we demonstrated that early exposure to THS not only negatively impacts body weight in both male and female mice, but also induces persistent changes to immunological parameters in peripheral blood in these mice. These results indicate that THS is genotoxic at realistic experimental doses and that there may be a window of susceptibility for some forms of cellular damage induced by THS.« less

Adverse Health Effects of Thirdhand Smoke: From Cell to Animal Models

DOE PAGES

Hang, Bo; Wang, Pin; Zhao, Yue; ...

2017-04-28

The newly identified smoke hazard, thirdhand smoke (THS), has gained public attention in recent years but its health impact and biological effects are largely unknown. THS may be defined by “the four Rs”: tobacco chemicals that remain, react, re-emit, and/or are resuspended long after active smoking has ceased. This review summarizes recent research progress in the effects of THS on genotoxicity, metabolism and early life development using cellular and animal models. We first reported that THS generated in laboratory systems caused significant DNA damage in human cell lines. Our finding that THS significantly induces oxidative base lesions has been confirmedmore » in skin wounds of mice models exposed to THS. THS also induced metabolomic changes in human reproductive cell lines. Furthermore, we demonstrated that early exposure to THS not only negatively impacts body weight in both male and female mice, but also induces persistent changes to immunological parameters in peripheral blood in these mice. These results indicate that THS is genotoxic at realistic experimental doses and that there may be a window of susceptibility for some forms of cellular damage induced by THS.« less

Current hypotheses on the mechanisms of alcoholism.

PubMed

Vetreno, R P; Crews, F T

2014-01-01

Chronic use of alcohol results in progressive changes to brain and behavior that often lead to the development of alcohol dependence and alcoholism. Although the mechanisms underlying the development of alcoholism remain to be fully elucidated, diminished executive functioning due to hypoactive prefrontal cortex executive control and hyperactive limbic system anxiety and negative emotion might contribute mechanistically to the shift from experimental use to alcoholism and dependence. In the chapter that follows, behavioral deficits associated with cortical dysfunction and neurodegeneration will be related to the behavioral characteristics of alcoholism (e.g., diminished executive function, impulsivity, altered limbic modulation). We will provide evidence that alterations in cyclic AMP-responsive element binding protein (CREB: neurotrophic) and NF-κB (neuroimmune) signaling contribute to the development and persistence of alcoholism. In addition, genetic predispositions and an earlier age of drinking onset will be discussed as contributing factors to the development of alcohol dependence and alcoholism. Overall chronic ethanol-induced neuroimmune gene induction is proposed to alter limbic and frontal neuronal networks contributing to the development and persistence of alcoholism. © 2014 Elsevier B.V. All rights reserved.

Tertiary Excess of Fibroblast Growth Factor 23 and Hypophosphatemia Following Kidney Transplantation

PubMed Central

Seeherunvong, Wacharee; Wolf, Myles

2010-01-01

Hypophosphatemia due to inappropriate urinary phosphate wasting is a frequent metabolic complication of the early period following kidney transplantation. Although previously considered to be caused by tertiary hyperparathyroidism, recent evidence suggests a primary role for persistently elevated circulating levels of the phosphorus-regulating hormone, fibroblast growth factors 23 (FGF23). In the setting of a healthy renal allograft, markedly increased FGF23 levels from the dialysis period induce renal phosphate wasting and inhibition of calcitriol production, which contribute to hypophosphatemia. While such tertiary FGF23 excess and resultant hypophosphatemia typically abates within the first few weeks to months post-transplant, some recipients manifest persistent renal phosphate wasting. Furthermore, increased FGF23 levels have been associated with increased risk of kidney disease progression, cardiovascular disease and death outside of the transplant setting. Whether tertiary FGF23 excess is associated with adverse transplant outcomes is unknown. In this article, we review the physiology of FGF23, summarize its relationship with hypophosphatemia after kidney transplantation, and speculate on its potential impact on long term outcomes of renal allograft recipients. PMID:20946192

Progression is caused by angiotensin II-dependent persistent podocyte loss from destabilized glomeruli

PubMed Central

Fukuda, Akihiro; Wickman, Larysa T.; Venkatareddy, Madhusudan; Sato, Yuji; Chowdhury, Mahboob; Wang, Su Q; Shedden, Kerby; Dysko, Robert; Wiggins, Jocelyn E.; Wiggins, Roger C.

2013-01-01

Podocyte depletion is a major mechanism driving glomerulosclerosis. Progression is the process by which progressive glomerulosclerosis leads to End Stage Kidney Disease (ESKD). We therefore tested the hypothesis that progression to ESKD can be caused by persistent podocyte loss using the human diphtheria toxin transgenic rat model. After initial podocyte injury causing >30% loss of podocytes glomeruli became destabilized, resulting in continuous podocyte loss over time until global podocyte depletion (ESKD) occured. Similar patterns of podocyte depletion were observed in the puromycin aminonucleoside and 5/6 nephrectomy rat models of progression. Angiotensin II blockade prevented continuous podocyte loss and progression (restabilized glomeruli). Discontinuing angiotensin II blockade resulted in recurrent glomerular destabilization, podocyte loss and progression. Reduction in blood pressure alone did not reduce proteinuria or prevent podocyte loss from destabilized glomeruli. The protective effect of angiotensin II blockade could be entirely accounted for by reduction in podocyte loss. These data demonstrate that an initiating event that results in a critical degree of podocyte depletion can destabilize glomeruli by setting in train a superimposed angiotensin II-dependent podocyte loss cycle that accelerates the progression process and results in global podocyte depletion and progression to ESKD. These events can be monitored non-invasively through urine mRNA assays. PMID:21937979

Identifying the culprit lesion in tumor induced hypophosphatemia, the solution of a clinical enigma.

PubMed

Slot-Steenks, Mathilde M Bruins; Hamdy, Neveen A T; van de Sande, Michiel A J; Vriens, Dennis; Cleven, Arjen H G; Appelman-Dijkstra, Natasha M

2016-12-01

Tumor-induced osteomalacia is a rare acquired metabolic bone disorder characterized by isolated renal phosphate wasting due to abnormal tumor production of fibroblast growth factor 23. We report the case of a 59 year old woman referred to our department with a long history of progressive diffuse muscle weakness and pain, generalized bone pains and multiple insufficiency fractures of heels, ankles and hips due to a hypophosphatemic osteomalacia. A fibroblast growth factor 23-producing phosphaturic mesenchymal tumor localized in the left quadriceps femoris muscle was identified 7 years after onset of symptoms. Excision of the tumor resulted in normalization of serum phosphate and fibroblast growth factor 23 levels and in complete resolution of the clinical picture with disappearance of all musculoskeletal symptoms. This case illustrates the diagnostic difficulties in establishing a diagnosis tumor-induced osteomalacia and in identifying the responsible tumor. Our case underscores the clinical need to investigate all patients with persistent musculoskeletal symptoms for hypophosphatemia. A systematic approach is of pivotal importance because early recognition and treatment of the metabolic abnormality can prevent deleterious effects of osteomalacia on the skeleton.

Lesion bacterial communities in American lobsters with diet-induced shell disease.

PubMed

Quinn, Robert A; Metzler, Anita; Tlusty, Michael; Smolowitz, Roxanna M; Leberg, Paul; Chistoserdov, Andrei Y

2012-04-26

In southern New England, USA, shell disease affects the profitability of the American lobster Homarus americanus fishery. In laboratory trials using juvenile lobsters, exclusive feeding of herring Clupea harengus induces shell disease typified initially by small melanized spots that progress into distinct lesions. Amongst a cohabitated, but segregated, cohort of 11 juvenile lobsters fed exclusively herring, bacterial communities colonizing spots and lesions were investigated by denaturing gradient gel electrophoresis of 16S rDNA amplified using 1 group-specific and 2 universal primer sets. The Bacteroidetes and Proteobacteria predominated in both spots and lesions and included members of the orders Flavobacteriales (Bacteriodetes), Rhodobacterales, Rhodospirillales and Rhizobiales (Alphaproteobacteria), Xanthomonadales (Gammaproteobacteria) and unclassified Gammaproteobacteria. Bacterial communities in spot lesions displayed more diversity than communities with larger (older) lesions, indicating that the lesion communities stabilize over time. At least 8 bacterial types persisted as lesions developed from spots. Aquimarina 'homaria', a species commonly cultured from lesions present on wild lobsters with epizootic shell disease, was found ubiquitously in spots and lesions, as was the 'Candidatus Kopriimonas aquarianus', implicating putative roles of these species in diet-induced shell disease of captive lobsters.

Folate dietary insufficiency and folic acid supplementation similarly impair metabolism and compromise hematopoiesis

PubMed Central

Henry, Curtis J.; Nemkov, Travis; Casás-Selves, Matias; Bilousova, Ganna; Zaberezhnyy, Vadym; Higa, Kelly C.; Serkova, Natalie J.; Hansen, Kirk C.; D’Alessandro, Angelo; DeGregori, James

2017-01-01

While dietary folate deficiency is associated with increased risk for birth defects and other diseases, evidence suggests that supplementation with folic acid can contribute to predisposition to some diseases, including immune dysfunction and cancer. Herein, we show that diets supplemented with folic acid both below and above the recommended levels led to significantly altered metabolism in multiple tissues in mice. Surprisingly, both low and excessive dietary folate induced similar metabolic changes, which were particularly evident for nucleotide biosynthetic pathways in B-progenitor cells. Diet-induced metabolic changes in these cells partially phenocopied those observed in mice treated with anti-folate drugs, suggesting that both deficiency and excessive levels of dietary folic acid compromise folate-dependent biosynthetic pathways. Both folate deficiency and excessive dietary folate levels compromise hematopoiesis, resulting in defective cell cycle progression, persistent DNA damage, and impaired production of lymphocytes. These defects reduce the reconstitution potential in transplantation settings and increase radiation-induced mortality. We conclude that excessive folic acid supplementation can metabolically mimic dietary folate insufficiency, leading to similar functional impairment of hematopoiesis. PMID:28883079

The presence of anti-Tat antibodies is predictive of long-term nonprogression to AIDS or severe immunodeficiency: findings in a cohort of HIV-1 seroconverters.

PubMed

Rezza, Giovanni; Fiorelli, Valeria; Dorrucci, Maria; Ciccozzi, Massimo; Tripiciano, Antonella; Scoglio, Arianna; Collacchi, Barbara; Ruiz-Alvarez, Maria; Giannetto, Concettina; Caputo, Antonella; Tomasoni, Lina; Castelli, Francesco; Sciandra, Mauro; Sinicco, Alessandro; Ensoli, Fabrizio; Buttò, Stefano; Ensoli, Barbara

2005-04-15

The human immunodeficiency virus (HIV) type 1 Tat protein plays a key role in the life cycle of the virus and in pathogenesis and is highly conserved among HIV subtypes. On the basis of this and of safety, immunogenicity, and efficacy findings in monkeys, Tat is being tested as a vaccine in phase 1 trials. Here, we evaluated the incidence and risk of progression to advanced HIV disease by anti-Tat serostatus in a cohort of 252 HIV-1 seroconverters. The risk of progression was lower in the anti-Tat-positive subjects than in the anti-Tat-negative subjects. Progression was faster in the persistently anti-Tat-negative subjects than in the transiently anti-Tat-positive subjects, and no progression was observed in the persistently anti-Tat-positive subjects.

Matefin/SUN-1 Phosphorylation Is Part of a Surveillance Mechanism to Coordinate Chromosome Synapsis and Recombination with Meiotic Progression and Chromosome Movement

PubMed Central

Woglar, Alexander; Daryabeigi, Anahita; Adamo, Adele; Habacher, Cornelia; Machacek, Thomas; La Volpe, Adriana; Jantsch, Verena

2013-01-01

Faithful chromosome segregation during meiosis I depends on the establishment of a crossover between homologous chromosomes. This requires induction of DNA double-strand breaks (DSBs), alignment of homologs, homolog association by synapsis, and repair of DSBs via homologous recombination. The success of these events requires coordination between chromosomal events and meiotic progression. The conserved SUN/KASH nuclear envelope bridge establishes transient linkages between chromosome ends and cytoskeletal forces during meiosis. In Caenorhabditis elegans, this bridge is essential for bringing homologs together and preventing nonhomologous synapsis. Chromosome movement takes place during synapsis and recombination. Concomitant with the onset of chromosome movement, SUN-1 clusters at chromosome ends associated with the nuclear envelope, and it is phosphorylated in a chk-2- and plk-2-dependent manner. Identification of all SUN-1 phosphomodifications at its nuclear N terminus allowed us to address their role in prophase I. Failures in recombination and synapsis led to persistent phosphorylations, which are required to elicit a delay in progression. Unfinished meiotic tasks elicited sustained recruitment of PLK-2 to chromosome ends in a SUN-1 phosphorylation–dependent manner that is required for continued chromosome movement and characteristic of a zygotene arrest. Furthermore, SUN-1 phosphorylation supported efficient synapsis. We propose that signals emanating from a failure to successfully finish meiotic tasks are integrated at the nuclear periphery to regulate chromosome end–led movement and meiotic progression. The single unsynapsed X chromosome in male meiosis is precluded from inducing a progression delay, and we found it was devoid of a population of phosphorylated SUN-1. This suggests that SUN-1 phosphorylation is critical to delaying meiosis in response to perturbed synapsis. SUN-1 may be an integral part of a checkpoint system to monitor establishment of the obligate crossover, inducible only in leptotene/zygotene. Unrepaired DSBs and unsynapsed chromosomes maintain this checkpoint, but a crossover intermediate is necessary to shut it down. PMID:23505384

Imbalanced Oxidative Stress Causes Chlamydial Persistence during Non-Productive Human Herpes Virus Co-Infection

PubMed Central

Prusty, Bhupesh K.; Böhme, Linda; Bergmann, Birgit; Siegl, Christine; Krause, Eva; Mehlitz, Adrian; Rudel, Thomas

2012-01-01

Both human herpes viruses and Chlamydia are highly prevalent in the human population and are detected together in different human disorders. Here, we demonstrate that co-infection with human herpes virus 6 (HHV6) interferes with the developmental cycle of C. trachomatis and induces persistence. Induction of chlamydial persistence by HHV6 is independent of productive virus infection, but requires the interaction and uptake of the virus by the host cell. On the other hand, viral uptake is strongly promoted under co-infection conditions. Host cell glutathione reductase activity was suppressed by HHV6 causing NADPH accumulation, decreased formation of reduced glutathione and increased oxidative stress. Prevention of oxidative stress restored infectivity of Chlamydia after HHV6-induced persistence. We show that co-infection with Herpes simplex virus 1 or human Cytomegalovirus also induces chlamydial persistence by a similar mechanism suggesting that Chlamydia -human herpes virus co-infections are evolutionary shaped interactions with a thus far unrecognized broad significance. PMID:23077614

Prevalence of IL-28B and ITPA genotypes in Chinese Han population infected persistently with hepatitis C virus genotype 6 or HCV-1.

PubMed

Zhang, Xiao-Hong; Cai, Qing-Xian; Hong, Chun-Xia; Lin, Chao-Shuang; Zhao, Zhi-Xin

2013-07-01

The geographic distribution, demographics, epidemiology, host factors, and clinical characteristics of persistent HCV-6 infection in China need further characterization. This multicenter study enrolled 63 patients with persistent HCV-6 infection and 63 patients with persistent HCV-1 infection as controls. Blood biochemistry, quantitation of HCV RNA levels, and identification of host IL-28B genotypes (rs12979860, rs8099917, and rs12980275) and ITPA genotype (rs1127354) were performed to estimate potential variability in host factors that may affect response to treatment. The mean HCV-6 RNA level (3.8E6 IU/ml) was significantly higher than that in patients infected with HCV-1 (1.7E6 IU/ml; P < 0.001). Patients persistently infected with HCV-6 had a high prevalence of IL-28B rs12979860 CC genotype (92.1%), rs8099917 TT genotype (93.7%), and rs12980275 AA genotype (90.5%). Their prevalence in patients infected with HCV-1 was only modestly lower (82.5%, 84.1%, and 82.5%, respectively; P > 0.05). The inosine triphosphate pyrophosphatase (ITPA) SNP rs1127354 CC genotype was present in 66.7% of patients infected with HCV-6, comparable to that of patients infected with HCV-1 (65.1%; P > 0.05). There were no differences in the liver function, proportion of hepatic cirrhosis patients or patients with increased serum glucose between these two groups. Persistent HCV-6 infection in Chinese Han is found mainly in the southern China. Chinese Han with chronic HCV-1 or HCV-6 infection have IL-28B genotypes, suggesting responsiveness to interferon-based pharmacotherapy. Most patients (67%) possess the ITPA genotype associated with susceptibility to ribavirin-induced hemolysis. The routes of transmission for HCV-6 genotype were more diversified than HCV-1 genotype. The outbreak of HCV-6 infection through blood transfusion progressed faster than HCV-1. Copyright © 2013 Wiley Periodicals, Inc.

Modelling the role of Tax expression in HTLV-I persistence in vivo.

PubMed

Li, Michael Y; Lim, Aaron G

2011-12-01

Human T-lymphotropic virus type I (HTLV-I) is a persistent human retrovirus characterized by life-long infection and risk of developing HAM/TSP, a progressive neurological and inflammatory disease, and adult T-cell leukemia (ATL). Chronically infected individuals often harbor high proviral loads despite maintaining a persistently activated immune response. Based on a new hypothesis for the persistence of HTLV-I infection, a three-dimensional compartmental model is constructed that describes the dynamic interactions among latently infected target cells, target-cell activation, and immune responses to HTLV-I, with an emphasis on understanding the role of Tax expression in the persistence of HTLV-I.

Hypoxia, hypoxia-inducible factors and fibrogenesis in chronic liver diseases.

PubMed

Cannito, Stefania; Paternostro, Claudia; Busletta, Chiara; Bocca, Claudia; Colombatto, Sebastiano; Miglietta, Antonella; Novo, Erica; Parola, Maurizio

2014-01-01

Fibrogenic progression of chronic liver diseases (CLDs) towards the end-point of cirrhosis is currently regarded, whatever the aetiology, as a dynamic and highly integrated cellular response to chronic liver injury. Liver fibrogenesis (i.e., the process) is sustained by hepatic populations of highly proliferative, pro-fibrogenic and contractile myofibroblast-like cells (MFs) that mainly originate from hepatic stellate cells (HSC) or, to a less extent, from portal fibroblasts or bone marrow-derived cells. As is well known, liver fibrosis (i.e., the result) is accompanied by perpetuation of liver injury, chronic hepatitis and persisting activation of tissue repair mechanisms, leading eventually to excess deposition of extracellular matrix (ECM) components. In this scenario, hypoxic areas represent a very common and major feature of fibrotic and cirrhotic liver during the progression of CLDs. Cells exposed to hypoxia respond by means of heterodimeric hypoxia-inducible factors (HIFs) that translocate into the nucleus and binds to a specific core sequence defined hypoxia-responsive element (HRE), present in the promoter on several genes which are considered as hypoxia-regulated target genes. HIFs transcription factors can activate a complex genetic program designed to sustain several changes necessary to efficiently counteract the decrease in oxygen tension. Accordingly, hypoxia, through up-regulation of angiogenesis, is currently believed to significantly contribute to fibrogenic progression of CLDs, mostly by affecting the pro-fibrogenic and pro-angiogenic behaviour of hepatic MFs. In addition, experimental and clinical evidence generated in the last decade also indicates that angiogenesis and fibrogenesis in CLDs may also be sustained by HIF-dependent but hypoxia-independent mediators.

Treatment of phenothiazine induced bulbar persistent dyskinesia with deanol acetamidobenzoate.

PubMed

Curran, D J; Nagaswami, S; Mohan, K J

1975-02-01

The late manifestation of neuroleptic-induced dyskinesia (persistent dyskinesia) is an irreversible complication of long-term treatment that is poorly understood and difficult to treat. Recently, a theory of dopamine receptor hypersensitivity in the dopaminergic-cholinergic system has suggested an explanation of choreiform movements and, thus, an implication for the management of persistent dyskinesia. The case presented is that of bulbar persistent dyskinesia in a patient who had been prescribed a phenothiazine derivative for eleven years; his symptoms improved with the use of deanol, which probably converts to acetylcholine after crossing the blood brain barrier. This improvement suggests that deanol may shift the neuroleptic-induced dopaminergic-cholinergic system unbalance toward equilibrium by matching predominant dopaminergic effect or by enhancing deficient cholinergic action in the dopaminergic-cholinergic system. This isolated finding needs to be confirmed by more research in neuropharmacology.

ERK1/2 signalling protects against apoptosis following endoplasmic reticulum stress but cannot provide long-term protection against BAX/BAK-independent cell death.

PubMed

Darling, Nicola J; Balmanno, Kathryn; Cook, Simon J

2017-01-01

Disruption of protein folding in the endoplasmic reticulum (ER) causes ER stress. Activation of the unfolded protein response (UPR) acts to restore protein homeostasis or, if ER stress is severe or persistent, drive apoptosis, which is thought to proceed through the cell intrinsic, mitochondrial pathway. Indeed, cells that lack the key executioner proteins BAX and BAK are protected from ER stress-induced apoptosis. Here we show that chronic ER stress causes the progressive inhibition of the extracellular signal-regulated kinase (ERK1/2) signalling pathway. This is causally related to ER stress since reactivation of ERK1/2 can protect cells from ER stress-induced apoptosis whilst ERK1/2 pathway inhibition sensitises cells to ER stress. Furthermore, cancer cell lines harbouring constitutively active BRAFV600E are addicted to ERK1/2 signalling for protection against ER stress-induced cell death. ERK1/2 signalling normally represses the pro-death proteins BIM, BMF and PUMA and it has been proposed that ER stress induces BIM-dependent cell death. We found no evidence that ER stress increased the expression of these proteins; furthermore, BIM was not required for ER stress-induced death. Rather, ER stress caused the PERK-dependent inhibition of cap-dependent mRNA translation and the progressive loss of pro-survival proteins including BCL2, BCLXL and MCL1. Despite these observations, neither ERK1/2 activation nor loss of BAX/BAK could confer long-term clonogenic survival to cells exposed to ER stress. Thus, ER stress induces cell death by at least two biochemically and genetically distinct pathways: a classical BAX/BAK-dependent apoptotic response that can be inhibited by ERK1/2 signalling and an alternative ERK1/2- and BAX/BAK-independent cell death pathway.

Respiratory Syncytial Virus Infections Enhance Cigarette Smoke Induced COPD in Mice

PubMed Central

Foronjy, Robert F.; Dabo, Abdoulaye J.; Taggart, Clifford C.; Weldon, Sinead; Geraghty, Patrick

2014-01-01

Respiratory syncytial viral (RSV) infections are a frequent cause of chronic obstructive pulmonary disease (COPD) exacerbations, which are a major factor in disease progression and mortality. RSV is able to evade antiviral defenses to persist in the lungs of COPD patients. Though RSV infection has been identified in COPD, its contribution to cigarette smoke-induced airway inflammation and lung tissue destruction has not been established. Here we examine the long-term effects of cigarette smoke exposure, in combination with monthly RSV infections, on pulmonary inflammation, protease production and remodeling in mice. RSV exposures enhanced the influx of macrophages, neutrophils and lymphocytes to the airways of cigarette smoke exposed C57BL/6J mice. This infiltration of cells was most pronounced around the vasculature and bronchial airways. By itself, RSV caused significant airspace enlargement and fibrosis in mice and these effects were accentuated with concomitant smoke exposure. Combined stimulation with both smoke and RSV synergistically induced cytokine (IL-1α, IL-17, IFN-γ, KC, IL-13, CXCL9, RANTES, MIF and GM-CSF) and protease (MMP-2, -8, -12, -13, -16 and cathepsins E, S, W and Z) expression. In addition, RSV exposure caused marked apoptosis within the airways of infected mice, which was augmented by cigarette smoke exposure. RSV and smoke exposure also reduced protein phosphatase 2A (PP2A) and protein tyrosine phosphates (PTP1B) expression and activity. This is significant as these phosphatases counter smoke-induced inflammation and protease expression. Together, these findings show for the first time that recurrent RSV infection markedly enhances inflammation, apoptosis and tissue destruction in smoke-exposed mice. Indeed, these results indicate that preventing RSV transmission and infection has the potential to significantly impact on COPD severity and progression. PMID:24587397

Temporal dynamics of anxiety phenotypes in a dental pulp injury model.

PubMed

Shang, Lin; Xu, Tian-Le; Li, Fei; Su, Jiansheng; Li, Wei-Guang

2015-06-30

Accumulating clinical and preclinical evidence indicates that chronic pain is often comorbid with persistent low mood and anxiety. However, the mechanisms underlying pain-induced anxiety, such as its causality, temporal progression, and relevant neural networks are poorly understood, impeding the development of efficacious therapeutic approaches. Here, we have identified the sequential emergence of anxiety phenotypes in mice subjected to dental pulp injury (DPI), a prototypical model of orofacial pain that correlates with human toothache. Compared with sham controls, mice subjected to DPI by mechanically exposing the pulp to the oral environment exhibited significant signs of anxiogenic effects, specifically, altered behaviors on the elevated plus maze (EPM), novelty-suppressed feeding (NSF) tests at 1 but not 3 days after the surgery. Notably, at 7 and 14 days, the DPI mice again avoided the open arm, center area, and novelty environment in the EPM, open field, and NSF tests, respectively. In particular, DPI-induced social phobia and increased repetitive grooming did not occur until 14 days after surgery, suggesting that DPI-induced social anxiety requires a long time. Moreover, oral administration of an anti-inflammatory drug, ibuprofen, or an analgesic agent, ProTx-II, which is a selective inhibitor of NaV1.7 sodium channels, both significantly alleviated DPI-induced avoidance in mice. Finally, to investigate the underlying central mechanisms, we pharmacologically blocked a popular form of synaptic plasticity with a GluA2-derived peptide, long-term depression, as that treatment significantly prevented the development of anxiety phenotype upon DPI. Together, these results suggest a temporally progressive causal relationship between orofacial pain and anxiety, calling for more in-depth mechanistic studies on concomitant pain and anxiety disorders.

The Negative Sign and Exponential Expressions: Unveiling Students' Persistent Errors and Misconceptions

ERIC Educational Resources Information Center

Cangelosi, Richard; Madrid, Silvia; Cooper, Sandra; Olson, Jo; Hartter, Beverly

2013-01-01

The purpose of this study was to determine whether or not certain errors made when simplifying exponential expressions persist as students progress through their mathematical studies. College students enrolled in college algebra, pre-calculus, and first- and second-semester calculus mathematics courses were asked to simplify exponential…

New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections

USDA-ARS?s Scientific Manuscript database

Toxoplasma gondii, the most common parasitic infection of the human brain and eye, persists across lifetimes, can progressively damage sight, and is currently incurable. New, curative medicines are needed urgently. Herein, we developed novel models to facilitate drug development: EGS strain T. gondi...

Aldosterone and cardiovascular disease: the heart of the matter

PubMed Central

He, B. Julie; Anderson, Mark E.

2012-01-01

Aldosterone contributes to the endocrine basis of heart failure and studies on cardiac aldosterone signaling have reinforced its value as a therapeutic target. Recent focus has shifted to new roles of aldosterone that appear to depend on co-existing pathologic stimuli, cell type, and disease etiology. This review evaluates recent advances in mechanisms underlying aldosterone-induced cardiac disease and highlights the interplay between aldosterone and Ca2+ and calmodulin dependent protein kinase II, whose hyperactivity during heart failure contributes to disease progression. Increasing evidence implicates aldosterone in diastolic dysfunction, and there is need to develop more targeted therapeutics such as aldosterone synthase inhibitors and molecularly specific anti-oxidants. Despite accumulating knowledge, many questions still persist and will likely dictate areas of future research. PMID:23040074

Rituximab Restores IFN-γ-STAT1 Function and Ameliorates Disseminated Mycobacterium avium Infection in a Patient with Anti-Interferon-γ Autoantibody.

PubMed

Koizumi, Yusuke; Sakagami, Takuro; Nishiyama, Naoya; Hirai, Jun; Hayashi, Yuta; Asai, Nobuhiro; Yamagishi, Yuka; Kato, Hideo; Hagihara, Mao; Sakanashi, Daisuke; Suematsu, Hiroyuki; Ogawa, Kenji; Mikamo, Hiroshige

2017-10-01

A 67-year-old Japanese female with back pain and severe cachexia visited our hospital. The diagnosis was disseminated Mycobacterium avium complex infection (dMAC) with multiple bone involvement. Anti-mycobacterial chemotherapy was started, but fever persisted and dislocation of cervical vertebrae has made her bedridden. Because anti-interferon (IFN)-γ autoantibody was positive, four doses of rituximab 375 mg/m 2 , every 7 day, were administered. Soon after treatment, progression of osteolytic lesions and wasting has stopped. We proved that rituximab has recovered IFN-γ signaling as shown by IFN-γ-induced STAT1 phosphorylation. It can be a promising option for dMAC cases with anti-IFN-γ autoantibody.

Fe-induced enhancement of antiferromagnetic spin correlations in Mn2-xFexBO4

NASA Astrophysics Data System (ADS)

Kazak, N. V.; Platunov, M. S.; Knyazev, Yu. V.; Moshkina, E. M.; Gavrilkin, S. Yu.; Bayukov, O. A.; Gorev, M. V.; Pogoreltsev, E. I.; Zeer, G. M.; Zharkov, S. M.; Ovchinnikov, S. G.

2018-04-01

Fe substitution effect on the magnetic behavior of Mn2-xFexBO4 (x = 0.3, 0.5, 0.7) warwickites has been investigated combining Mössbauer spectroscopy, dc magnetization, ac magnetic susceptibility, and heat capacity measurements. The Fe3+ ions distribution over two crystallographic nonequivalent sites is studied. The Fe introduction breaks a long-range antiferromagnetic order and leads to onset of spin-glass ground state. The antiferromagnetic short-range-order spin correlations persist up to temperatures well above TSG reflecting in increasing deviations from the Curie-Weiss law, the reduced effective magnetic moment and "missing" entropy. The results are interpreted in the terms of the progressive increase of the frustration effect and the formation of spin-correlated regions.

Temporal Persistence of Attitudes Induced Through Required Training

ERIC Educational Resources Information Center

Tansik, David A.; Driskill, John D.

1977-01-01

A posttest-only control group design procedure was used with a semantic differential questionnaire to examine the persistence of changes in racial attitudes induced via a required training course for supervisors at a large military installation. There was an immediate, small, positive change which decayed, and a short "sleeper effect". (Author)

A TRANSPLANTABLE RABBIT CARCINOMA ORIGINATING IN A VIRUS-INDUCED PAPILLOMA AND CONTAINING THE VIRUS IN MASKED OR ALTERED FORM

PubMed Central

Kidd, John G.; Rous, Peyton

1940-01-01

A squamous cell carcinoma derived from a virus-induced rabbit papilloma has been propagated in fourteen successive groups of animals. It grows rapidly now in most individuals to which it is transplanted, killing early and metastasizing frequently. The original cancer was the outcome of alterations in epidermal cells already rendered neoplastic by the virus, and the latter, or an agent nearly related to it, has persisted and increased in the malignant tissue, as a study of the blood of the first ten groups of cancerous animals has shown. An antibody capable of specifically neutralizing the virus in vitro appeared in the blood of every new host in which the tumor enlarged progressively, and reached a titer comparable with that obtaining in animals which had long carried large papillomas. The antibody was absent from normal rabbits and those in which the cancer failed to grow. The implications of these facts are considered. PMID:19871000

Accumulation of methylglyoxal increases the advanced glycation end-product levels in DRG and contributes to lumbar disk herniation-induced persistent pain.

PubMed

Liu, Cui-Cui; Zhang, Xin-Sheng; Ruan, Yu-Ting; Huang, Zhu-Xi; Zhang, Su-Bo; Liu, Meng; Luo, Hai-Jie; Wu, Shao-Ling; Ma, Chao

2017-08-01

Lumbar disk herniation (LDH) with discogenic low back pain and sciatica is a common and complicated musculoskeletal disorder. The underlying mechanisms are poorly understood, and there are no effective therapies for LDH-induced pain. In the present study, we found that the patients who suffered from LDH-induced pain had elevated plasma methylglyoxal (MG) levels. In rats, implantation of autologous nucleus pulposus (NP) to the left lumbar 5 spinal nerve root, which mimicked LDH, induced mechanical allodynia, increased MG level in plasma and dorsal root ganglion (DRG), and enhanced the excitability of small DRG neurons (<30 μm in diameter). Intrathecal injection of MG also induced mechanical allodynia, and its application to DRG neurons ex vivo increased the number of action potentials evoked by depolarizing current pulses. Furthermore, inhibition of MG accumulation by aminoguanidine attenuated the enhanced excitability of small DRG neurons and the mechanical allodynia induced by NP implantation. In addition, NP implantation increased levels of advanced glycation end products (AGEs) in DRG, and intrathecal injection of MG-derived AGEs induced the mechanical allodynia and DRG neuronal hyperactivity. Intrathecal injection of MG also significantly increased the expression of AGEs in DRG. Importantly, scavenging of MG by aminoguanidine also attenuated the increase in AGEs induced by NP implantation. These results suggested that LDH-induced MG accumulation contributed to persistent pain by increasing AGE levels. Thus generation of AGEs from MG may represent a target for treatment of LDH-induced pain. NEW & NOTEWORTHY Our study demonstrates that methylglyoxal accumulation via increasing advanced glycation end-product levels in dorsal root ganglion contributes to the persistent pain induced by lumbar disk herniation, which proposed potential targets for the treatment of lumbar disk herniation-induced persistent pain. Copyright © 2017 the American Physiological Society.

Time course of polyhexamethyleneguanidine phosphate-induced lung inflammation and fibrosis in mice.

PubMed

Song, Jeongah; Kim, Woojin; Kim, Yong-Bum; Kim, Bumseok; Lee, Kyuhong

2018-04-15

Pulmonary fibrosis is a chronic progressive disease with unknown etiology and has poor prognosis. Polyhexamethyleneguanidine phosphate (PHMG-P) causes acute interstitial pneumonia and pulmonary fibrosis in humans when it exposed to the lung. In a previous study, when rats were exposed to PHMG-P through inhalation for 3 weeks, lung inflammation and fibrosis was observed even after 3 weeks of recovery. In this study, we aimed to determine the time course of PHMG-P-induced lung inflammation and fibrosis. We compared pathological action of PHMG-P with that of bleomycin (BLM) and investigated the mechanism underlying PHMG-P-induced lung inflammation and fibrosis. PHMG-P (0.9 mg/kg) or BLM (1.5 mg/kg) was intratracheally administered to mice. At weeks 1, 2, 4 and 10 after instillation, the levels of inflammatory and fibrotic markers and the expression of inflammasome proteins were measured. The inflammatory and fibrotic responses were upregulated until 10 and 4 weeks in the PHMG-P and BLM groups, respectively. Immune cell infiltration and considerable collagen deposition in the peribronchiolar and interstitial areas of the lungs, fibroblast proliferation, and hyperplasia of type II epithelial cells were observed. NALP3 inflammasome activation was detected in the PHMG-P group until 4 weeks, which is suspected to be the main reason for the persistent inflammatory response and exacerbation of fibrotic changes. Most importantly, the pathological changes in the PHMG-P group were similar to those observed in humidifier disinfectant-associated patients. A single exposure of PHMG-P led to persistent pulmonary inflammation and fibrosis for at least 10 weeks. Copyright © 2018. Published by Elsevier Inc.

Polygenic risk accelerates the developmental progression to heavy, persistent smoking and nicotine dependence: Evidence from a 4-Decade Longitudinal Study

PubMed Central

Moffitt, Terrie E; Baker, Timothy B; Biddle, Andrea K; Evans, James P; Harrington, HonaLee; Houts, Renate; Meier, Madeline; Sugden, Karen; Williams, Benjamin; Poulton, Richie; Caspi, Avshalom

2013-01-01

OBJECTIVE To test how genomic loci identified in genome-wide association studies (GWAS) influence the developmental progression of smoking behavior. DESIGN A 38-year prospective longitudinal study of a representative birth-cohort. SETTING The Dunedin Multidisciplinary Health and Development Study, New Zealand. PARTICIPANTS N=1037 male and female study members. MAIN EXPOSURES We assessed genetic risk with a multi-locus genetic risk score (GRS). The GRS was composed of single-nucleotide polymorphisms identified in three meta-analyses of GWAS of smoking quantity phenotypes. OUTCOME MEASURES Smoking initiation, conversion to daily smoking, progression to heavy smoking, nicotine dependence (Fagerstrom Test of Nicotine Dependence), and cessation difficulties were evaluated at eight assessments spanning ages 11-38 years. RESULTS Genetic risk score was unrelated to smoking initiation. However, individuals at higher genetic risk were more likely to convert to daily smoking as teenagers, progressed more rapidly from smoking initiation to heavy smoking, persisted longer in smoking heavily, developed nicotine dependence more frequently, were more reliant on smoking to cope with stress, and were more likely to fail in their cessation attempts. Further analysis revealed that two adolescent developmental phenotypes—early conversion to daily smoking and rapid progression to heavy smoking--mediated associations between the genetic risk score and mature phenotypes of persistent heavy smoking, nicotine dependence, and cessation failure. The genetic risk score predicted smoking risk over and above family history. CONCLUSIONS Initiatives that disrupt the developmental progression of smoking behavior among adolescents may mitigate genetic risks for developing adult smoking problems. Future genetic research may maximize discovery potential by focusing on smoking behavior soon after smoking initiation and by studying young smokers. PMID:23536134

Estimation of TiO₂ nanoparticle-induced genotoxicity persistence and possible chronic gastritis-induction in mice.

PubMed

Mohamed, Hanan Ramadan Hamad

2015-09-01

Titanium dioxide (TiO2) nanoparticles are widely used as a food additive and coloring agent in many consumer products however limited data is available on the nano-TiO2 induced genotoxicity persistence. Thus, this study investigated the persistence of nano-TiO2 induced genotoxicity and possible induction of chronic gastritis in mice. The mice were orally administered 5, 50 or 500 mg/kg body weight nano-TiO2 for five consecutive days, and then mice from each dosage group were sacrificed 24 h or one or two weeks after the last treatment. The administration of nano-TiO2 resulted in persistent apoptotic DNA fragmentation and mutations in p53 exons (5-8) as well as significant persistent elevations in malondialdehyde and nitric oxide levels and decreases in the reduced glutathione level and catalase activity compared with the control mice in a dose- and time-dependent manner. Necrosis and inflammation were evident upon histological examination. These findings could be attributed to the persistent accumulation of nano-TiO2 at the tested doses at all three time points. Based on these findings, we conclude that the administration of nano-TiO2, even at low doses, leads to persistent accumulation of nano-TiO2 in mice, resulting in persistent inflammation, apoptosis and oxidative stress, ultimately leading to the induction of chronic gastritis. Copyright © 2015 Elsevier Ltd. All rights reserved.

Examining a Grade-Level Math CBM Designed for Persistently Low-Performing Students

ERIC Educational Resources Information Center

Anderson, Daniel; Lai, Cheng-Fei; Alonzo, Julie; Tindal, Gerald

2011-01-01

Students with disabilities participate in two major measurement systems. The Individuals with Disabilities Education Act emphasizes working within a Response to Intervention (RTI) framework to identify and monitor the progress of low-performing students. Persistent low-performing students also may be eligible for some form of an alternate…

Semantic Dementia and Persisting Wernicke's Aphasia: Linguistic and Anatomical Profiles

ERIC Educational Resources Information Center

Ogar, J. M.; Baldo, J. V.; Wilson, S. M.; Brambati, S. M.; Miller, B. L.; Dronkers, N. F.; Gorno-Tempini, M. L.

2011-01-01

Few studies have directly compared the clinical and anatomical characteristics of patients with progressive aphasia to those of patients with aphasia caused by stroke. In the current study we examined fluent forms of aphasia in these two groups, specifically semantic dementia (SD) and persisting Wernicke's aphasia (WA) due to stroke. We compared…

History of Clinical Transplantation

PubMed Central

Starzl, Thomas E.

2010-01-01

The emergence of transplantation has seen the development of increasingly potent immunosuppressive agents, progressively better methods of tissue and organ preservation, refinements in histocompatibility matching, and numerous innovations in surgical techniques. Such efforts in combination ultimately made it possible to successfully engraft all of the organs and bone marrow cells in humans. At a more fundamental level, however, the transplantation enterprise hinged on two seminal turning points. The first was the recognition by Billingham, Brent, and Medawar in 1953 that it was possible to induce chimerism-associated neonatal tolerance deliberately. This discovery escalated over the next 15 years to the first successful bone marrow transplantations in humans in 1968. The second turning point was the demonstration during the early 1960s that canine and human organ allografts could self-induce tolerance with the aid of immunosuppression. By the end of 1962, however, it had been incorrectly concluded that turning points one and two involved different immune mechanisms. The error was not corrected until well into the 1990s. In this historical account, the vast literature that sprang up during the intervening 30 years has been summarized. Although admirably documenting empiric progress in clinical transplantation, its failure to explain organ allograft acceptance predestined organ recipients to lifetime immunosuppression and precluded fundamental changes in the treatment policies. After it was discovered in 1992 that long-surviving organ transplant recipients had persistent microchimerism, it was possible to see the mechanistic commonality of organ and bone marrow transplantation. A clarifying central principle of immunology could then be synthesized with which to guide efforts to induce tolerance systematically to human tissues and perhaps ultimately to xenografts. PMID:10833242

Obesity-Associated Alterations in Inflammation, Epigenetics, and Mammary Tumor Growth Persist in Formerly Obese Mice.

PubMed

Rossi, Emily L; de Angel, Rebecca E; Bowers, Laura W; Khatib, Subreen A; Smith, Laura A; Van Buren, Eric; Bhardwaj, Priya; Giri, Dilip; Estecio, Marcos R; Troester, Melissa A; Hair, Brionna Y; Kirk, Erin L; Gong, Ting; Shen, Jianjun; Dannenberg, Andrew J; Hursting, Stephen D

2016-05-01

Using a murine model of basal-like breast cancer, we tested the hypothesis that chronic obesity, an established breast cancer risk and progression factor in women, induces mammary gland epigenetic reprogramming and increases mammary tumor growth. Moreover, we assessed whether the obesity-induced epigenetic and protumor effects are reversed by weight normalization. Ovariectomized female C57BL/6 mice were fed a control diet or diet-induced obesity (DIO) regimen for 17 weeks, resulting in a normal weight or obese phenotype, respectively. Mice on the DIO regimen were then randomized to continue the DIO diet or were switched to the control diet, resulting in formerly obese (FOb) mice with weights comparable with control mice. At week 24, all mice were orthotopically injected with MMTV-Wnt-1 mouse mammary tumor cells. Mean tumor volume, serum IL6 levels, expression of proinflammatory genes in the mammary fat pad, and mammary DNA methylation profiles were similar in DIO and FOb mice and higher than in controls. Many of the genes found to have obesity-associated hypermethylation in mice were also found to be hypermethylated in the normal breast tissue of obese versus nonobese human subjects, and nearly all of these concordant genes remained hypermethylated after significant weight loss in the FOb mice. Our findings suggest that weight normalization may not be sufficient to reverse the effects of chronic obesity on epigenetic reprogramming and inflammatory signals in the microenvironment that are associated with breast cancer progression. Cancer Prev Res; 9(5); 339-48. ©2016 AACR. ©2016 American Association for Cancer Research.

A novel prostate cancer therapeutic strategy using icaritin-activated arylhydrocarbon-receptor to co-target androgen receptor and its splice variants

PubMed Central

Sun, Feng; Indran, Inthrani R.; Zhang, Zhi Wei; Tan, M.H.Eileen; Li, Yu; Lim, Z.L.Ryan; Hua, Rui; Yang, Chong; Soon, Fen-Fen; Li, Jun; Xu, H.Eric; Cheung, Edwin; Yong, Eu-Leong

2015-01-01

Persistent androgen receptor (AR) signaling is the key driving force behind progression and development of castration-resistant prostate cancer (CRPC). In many patients, AR COOH-terminal truncated splice variants (ARvs) play a critical role in contributing to the resistance against androgen depletion therapy. Unfortunately, clinically used antiandrogens like bicalutamide (BIC) and enzalutamide (MDV), which target the ligand binding domain, have failed to suppress these AR variants. Here, we report for the first time that a natural prenylflavonoid, icaritin (ICT), can co-target both persistent AR and ARvs. ICT was found to inhibit transcription of key AR-regulated genes, such as KLK3 [prostate-specific antigen (PSA)] and ARvs-regulated genes, such as UBE2C and induce apoptosis in AR-positive prostate cancer (PC) cells. Mechanistically, ICT promoted the degradation of both AR and ARvs by binding to arylhydrocarbon-receptor (AhR) to mediate ubiquitin-proteasomal degradation. Therefore, ICT impaired AR transactivation in PC cells. Knockdown of AhR gene restored AR stability and partially prevented ICT-induced growth suppression. In clinically relevant murine models orthotopically implanted with androgen-sensitive and CRPC cells, ICT was able to target AR and ARvs, to inhibit AR signaling and tumor growth with no apparent toxicity. Our results provide a mechanistic framework for the development of ICT, as a novel lead compound for AR-positive PC therapeutics, especially for those bearing AR splice variants. PMID:25908644

PERSISTENCE OF MESSENGER RNA THROUGH MITOSIS IN HELA CELLS

PubMed Central

Hodge, L. D.; Robbins, E.; Scharff, M. D.

1969-01-01

The decrease in protein synthesis which occurs in mammalian cells during cell division is associated with significant disaggregation of polyribosomes. For determining whether messenger RNA survives this disaggregation, the reformation of polyribosomes was investigated in synchronized HeLa cells as they progressed from metaphase into interphase in the presence of 2 µg/ml Actinomycin D. The persistence of messenger during cell division was evidenced by: (1) a progressive increase in the rate of protein synthesis in both treated and untreated cells for 45 min after metaphase; (2) reformation of polyribosomes, as determined by both sucrose gradients and electron microscopy, within 30 min after the addition of Actinomycin D to metaphase cells; (3) the persistence of approximately 50% of the rapidly labeled nonribosomal RNA which had associated with polyribosomes just before metaphase; (4) the resumption of synthesis, following cell division, of 6 selected peptides in Actinomycin-treated cells. PMID:5761922

The Impacts of Climate-Induced Drought on Biogeochemical Cycles

NASA Astrophysics Data System (ADS)

Peng, C.

2014-12-01

Terrestrial ecosystems and, in particular, forests exert strong controls on the global biogeochemical cycles and influence regional hydrology and climatology directly through water and surface energy budgets. Recent studies indicated that forest mortality caused by rising temperature and drought from around the world have unexpectedly increased in the past decade and they collectively illustrate the vulnerability of many forested ecosystems to rapid increases in tree mortality due to warmer temperatures and more severe drought. Persistent changes in tree mortality rates can alter forest structure, composition, and ecosystem services (such as albedo and carbon sequestration). Quantifying potential impacts of tree mortality on ecosystem processes requires research into mortality effects on carbon, energy, and water budgets at both site and regional levels. Despite recent progress, the uncertainty around mortality responses still limits our ability to predict the likelihood and anticipate the impacts of tree die-off. Studies are needed that explore tree death physiology for a wide variety of functional types, connect patterns of mortality with climate events, and quantify the impacts on carbon, energy, and water flux. In this presentation, I will highlight recent research progress, and identify key research needs and future challenges to predict the consequence and impacts of drought-induced large-scale forest mortality on biogeochemical cycles. I will focus on three main forest ecosystems (tropic rainforest in Amazon, temperate forest in Western USA, and boreal forest in Canada) as detailed case studies.

Nucleus accumbens core lesions induce sub-optimal choice and reduce sensitivity to magnitude and delay in impulsive choice tasks

PubMed Central

Steele, Catherine C.; Peterson, Jennifer R.; Marshall, Andrew T.; Stuebing, Sarah L.; Kirkpatrick, Kimberly

2017-01-01

The nucleus accumbens core (NAc) has long been recognized as an important contributor to the computation of reward value that is critical for impulsive choice behavior. Impulsive choice refers to choosing a smaller-sooner (SS) over a larger-later (LL) reward when the LL is more optimal in terms of the rate of reward delivery. Two experiments examined the role of the NAc in impulsive choice and its component processes of delay and magnitude processing. Experiment 1 delivered an impulsive choice task with manipulations of LL reward magnitude, followed by a reward magnitude discrimination task. Experiment 2 tested impulsive choice under manipulations of LL delay, followed by temporal bisection and progressive interval tasks. NAc lesions, in comparison to sham control lesions, produced suboptimal preferences that resulted in lower reward earning rates, and led to reduced sensitivity to magnitude and delay within the impulsive choice task. The secondary tasks revealed intact reward magnitude and delay discrimination abilities, but the lesion rats persisted in responding more as the progressive interval increased during the session. The results suggest that the NAc is most critical for demonstrating good sensitivity to magnitude and delay, and adjusting behavior accordingly. Ultimately, the NAc lesions induced suboptimal choice behavior rather than simply promoting impulsive choice, suggesting that an intact NAc is necessary for optimal decision making. PMID:29146281

Severe Depletion of Mucosal CD4+ T Cells in AIDS-Free Simian Immunodeficiency Virus-Infected Sooty Mangabeys1

PubMed Central

Gordon, Shari N.; Klatt, Nichole R.; Bosinger, Steven E.; Brenchley, Jason M.; Milush, Jeffrey M.; Engram, Jessica C.; Dunham, Richard M.; Paiardini, Mirko; Klucking, Sara; Danesh, Ali; Strobert, Elizabeth A.; Apetrei, Cristian; Pandrea, Ivona V.; Kelvin, David; Douek, Daniel C.; Staprans, Silvija I.; Sodora, Donald L.; Silvestri, Guido

2008-01-01

HIV-infected humans and SIV-infected rhesus macaques experience a rapid and dramatic loss of mucosal CD4+ T cells that is considered to be a key determinant of AIDS pathogenesis. In this study, we show that nonpathogenic SIV infection of sooty mangabeys (SMs), a natural host species for SIV, is also associated with an early, severe, and persistent depletion of memory CD4+ T cells from the intestinal and respiratory mucosa. Importantly, the kinetics of the loss of mucosal CD4+ T cells in SMs is similar to that of SIVmac239-infected rhesus macaques. Although the nonpathogenic SIV infection of SMs induces the same pattern of mucosal target cell depletion observed during pathogenic HIV/SIV infections, the depletion in SMs occurs in the context of limited local and systemic immune activation and can be reverted if virus replication is suppressed by antiretroviral treatment. These results indicate that a profound depletion of mucosal CD4+ T cells is not sufficient per se to induce loss of mucosal immunity and disease progression during a primate lentiviral infection. We propose that, in the disease-resistant SIV-infected SMs, evolutionary adaptation to both preserve immune function with fewer mucosal CD4+ T cells and attenuate the immune activation that follows acute viral infection protect these animals from progressing to AIDS. PMID:17709517

Severe depletion of mucosal CD4+ T cells in AIDS-free simian immunodeficiency virus-infected sooty mangabeys.

PubMed

Gordon, Shari N; Klatt, Nichole R; Bosinger, Steven E; Brenchley, Jason M; Milush, Jeffrey M; Engram, Jessica C; Dunham, Richard M; Paiardini, Mirko; Klucking, Sara; Danesh, Ali; Strobert, Elizabeth A; Apetrei, Cristian; Pandrea, Ivona V; Kelvin, David; Douek, Daniel C; Staprans, Silvija I; Sodora, Donald L; Silvestri, Guido

2007-09-01

HIV-infected humans and SIV-infected rhesus macaques experience a rapid and dramatic loss of mucosal CD4+ T cells that is considered to be a key determinant of AIDS pathogenesis. In this study, we show that nonpathogenic SIV infection of sooty mangabeys (SMs), a natural host species for SIV, is also associated with an early, severe, and persistent depletion of memory CD4+ T cells from the intestinal and respiratory mucosa. Importantly, the kinetics of the loss of mucosal CD4+ T cells in SMs is similar to that of SIVmac239-infected rhesus macaques. Although the nonpathogenic SIV infection of SMs induces the same pattern of mucosal target cell depletion observed during pathogenic HIV/SIV infections, the depletion in SMs occurs in the context of limited local and systemic immune activation and can be reverted if virus replication is suppressed by antiretroviral treatment. These results indicate that a profound depletion of mucosal CD4+ T cells is not sufficient per se to induce loss of mucosal immunity and disease progression during a primate lentiviral infection. We propose that, in the disease-resistant SIV-infected SMs, evolutionary adaptation to both preserve immune function with fewer mucosal CD4+ T cells and attenuate the immune activation that follows acute viral infection protect these animals from progressing to AIDS.

Nephrin is necessary for podocyte recovery following injury in an adult mature glomerulus.

PubMed

Verma, Rakesh; Venkatareddy, Madhusudan; Kalinowski, Anne; Li, Theodore; Kukla, Joanna; Mollin, Ashomathi; Cara-Fuentes, Gabriel; Patel, Sanjeevkumar R; Garg, Puneet

2018-01-01

Nephrin (Nphs1) is an adhesion protein that is expressed at the podocyte intercellular junction in the glomerulus. Nphs1 mutations in humans or deletion in animal genetic models results in a developmental failure of foot process formation. A number of studies have shown decrease in expression of nephrin in various proteinuric kidney diseases as well as in animal models of glomerular disease. Decrease in nephrin expression has been suggested to precede podocyte loss and linked to the progression of kidney disease. Whether the decrease in expression of nephrin is related to loss of podocytes or lead to podocyte detachment is unclear. To answer this central question we generated an inducible model of nephrin deletion (Nphs1Tam-Cre) in order to lower nephrin expression in healthy adult mice. Following tamoxifen-induction there was a 75% decrease in nephrin expression by 14 days. The Nphs1Tam-Cre mice had normal foot process ultrastructure and intact filtration barriers up to 4-6 weeks post-induction. Despite the loss of nephrin expression, the podocyte number and density remained unchanged during the initial period. Unexpectedly, nephrin expression, albeit at low levels persisted at the slit diaphragm up to 16-20 weeks post-tamoxifen induction. The mice became progressively proteinuric with glomerular hypertrophy and scarring reminiscent of focal and segmental glomerulosclerosis at 20 weeks. Four week-old Nphs1 knockout mice subjected to protamine sulfate model of podocyte injury demonstrated failure to recover from foot process effacement following heparin sulfate. Similarly, Nphs1 knockout mice failed to recover following nephrotoxic serum (NTS) with persistence of proteinuria and foot process effacement. Our results suggest that as in development, nephrin is necessary for maintenance of a healthy glomerular filter. In contrast to the developmental phenotype, lowering nephrin expression in a mature glomerulus resulted in a slowly progressive disease that histologically resembles FSGS a disease linked closely with podocyte depletion. Podocytes with low levels of nephrin expression are both susceptible and unable to recover following perturbation. Our results suggest that decreased nephrin expression independent of podocyte loss occurring as an early event in proteinuric kidney diseases might play a role in disease progression.

Considerations of persistence and security in CHOICES, an object-oriented operating system

NASA Technical Reports Server (NTRS)

Campbell, Roy H.; Madany, Peter W.

1990-01-01

The current design of the CHOICES persistent object implementation is summarized, and research in progress is outlined. CHOICES is implemented as an object-oriented system, and persistent objects appear to simplify and unify many functions of the system. It is demonstrated that persistent data can be accessed through an object-oriented file system model as efficiently as by an existing optimized commercial file system. The object-oriented file system can be specialized to provide an object store for persistent objects. The problems that arise in building an efficient persistent object scheme in a 32-bit virtual address space that only uses paging are described. Despite its limitations, the solution presented allows quite large numbers of objects to be active simultaneously, and permits sharing and efficient method calls.

Dendritic cells induce antigen-specific regulatory T cells that prevent graft versus host disease and persist in mice

PubMed Central

Olds, Peter; Park, Andrew; Schlesinger, Sarah J.

2011-01-01

Foxp3+ regulatory T cells (T reg cells) effectively suppress immunity, but it is not determined if antigen-induced T reg cells (iT reg cells) are able to persist under conditions of inflammation and to stably express the transcription factor Foxp3. We used spleen cells to stimulate the mixed leukocyte reaction (MLR) in the presence of transforming growth factor β (TGF-β) and retinoic acid. We found that the CD11chigh dendritic cell fraction was the most potent at inducing high numbers of alloreactive Foxp3+ cells. The induced CD4+CD25+Foxp3+ cells appeared after extensive proliferation. When purified from the MLR, iT reg cells suppressed both primary and secondary MLR in vitro in an antigen-specific manner. After transfer into allogeneic mice, iT reg cells persisted for 6 mo and prevented graft versus host disease (GVHD) caused by co-transferred CD45RBhi T cells. Similar findings were made when iT reg cells were transferred after onset of GVHD. The CNS2 intronic sequence of the Foxp3 gene in the persisting iT reg cells was as demethylated as the corresponding sequence of naturally occurring T reg cells. These results indicate that induced Foxp3+ T reg cells, after proliferating and differentiating into antigen-specific suppressive T cells, can persist for long periods while suppressing a powerful inflammatory disease. PMID:22084406

Association between neutrophilic airway inflammation and airflow limitation in adults with asthma.

PubMed

Shaw, Dominick E; Berry, Michael A; Hargadon, Bev; McKenna, Susan; Shelley, Maria J; Green, Ruth H; Brightling, Christopher E; Wardlaw, Andrew J; Pavord, Ian D

2007-12-01

There is debate about the mechanisms of persistent airflow limitation in patients with asthma. Chronic inflammation is assumed to be important, although there is limited and contradictory information about the relationship between airway inflammation and postbronchodilator FEV1. We have assessed the cross-sectional relationship between prebronchodilator and postbronchodilator FEV1 and measures of airway inflammation after allowing for the effects of potential confounding factors. Multivariate analysis was performed on data collected from 1,197 consecutive patients with asthma seen at the respiratory outpatient clinic at Glenfield Hospital between 1997 and 2004. Relationships between induced sputum total neutrophil and differential eosinophil cell counts, and prebronchodilator and postbronchodilator lung function were examined. Sputum total neutrophil but not differential eosinophil count was associated with lower postbronchodilator FEV1. Both differential eosinophil and total neutrophil count were associated with lower prebronchodilator FEV1. These effects were independent after adjustment for age, smoking, ethnicity, asthma duration, and inhaled corticosteroid use. A 10-fold increase in neutrophil count was associated with a 92 mL reduction (95% confidence interval, 29 to 158; p = 0.007) in postbronchodilator FEV1. In this large heterogeneous population of adults with asthma, we have shown that prebronchodilator FEV1 is associated with neutrophilic and eosinophilic airway inflammation, whereas sputum total neutrophil counts alone are associated with postbronchodilator FEV1. This supports the hypothesis that neutrophilic airway inflammation has a role in the progression of persistent airflow limitation in asthma and raises the possibility that this progression and the development of COPD share a common mechanism.

Substance P promotes wound healing in diabetes by modulating inflammation and macrophage phenotype.

PubMed

Leal, Ermelindo C; Carvalho, Eugénia; Tellechea, Ana; Kafanas, Antonios; Tecilazich, Francesco; Kearney, Cathal; Kuchibhotla, Sarada; Auster, Michael E; Kokkotou, Efi; Mooney, David J; LoGerfo, Frank W; Pradhan-Nabzdyk, Leena; Veves, Aristidis

2015-06-01

Diabetic foot ulceration is a major complication of diabetes. Substance P (SP) is involved in wound healing, but its effect in diabetic skin wounds is unclear. We examined the effect of exogenous SP delivery on diabetic mouse and rabbit wounds. We also studied the impact of deficiency in SP or its receptor, neurokinin-1 receptor, on wound healing in mouse models. SP treatment improved wound healing in mice and rabbits, whereas the absence of SP or its receptor impaired wound progression in mice. Moreover, SP bioavailability in diabetic skin was reduced as SP gene expression was decreased, whereas the gene expression and protein levels of the enzyme that degrades SP, neutral endopeptidase, were increased. Diabetes and SP deficiency were associated with absence of an acute inflammatory response important for wound healing progression and instead revealed a persistent inflammation throughout the healing process. SP treatment induced an acute inflammatory response, which enabled the progression to the proliferative phase and modulated macrophage activation toward the M2 phenotype that promotes wound healing. In conclusion, SP treatment reverses the chronic proinflammatory state in diabetic skin and promotes healing of diabetic wounds. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

The Deadbeat Paternal Effect of Uncapped Sperm Telomeres on Cell Cycle Progression and Chromosome Behavior in Drosophila melanogaster

PubMed Central

Yamaki, Takuo; Yasuda, Glenn K.; Wakimoto, Barbara T.

2016-01-01

Telomere-capping complexes (TCCs) protect the ends of linear chromosomes from illegitimate repair and end-to-end fusions and are required for genome stability. The identity and assembly of TCC components have been extensively studied, but whether TCCs require active maintenance in nondividing cells remains an open question. Here we show that Drosophila melanogaster requires Deadbeat (Ddbt), a sperm nuclear basic protein (SNBP) that is recruited to the telomere by the TCC and is required for TCC maintenance during genome-wide chromatin remodeling, which transforms spermatids to mature sperm. Ddbt-deficient males produce sperm lacking TCCs. Their offspring delay the initiation of anaphase as early as cycle 1 but progress through the first two cycles. Persistence of uncapped paternal chromosomes induces arrest at or around cycle 3. This early arrest can be rescued by selective elimination of paternal chromosomes and production of gynogenetic haploid or haploid mosaics. Progression past cycle 3 can also occur if embryos have reduced levels of the maternally provided checkpoint kinase Chk2. The findings provide insights into how telomere integrity affects the regulation of the earliest embryonic cell cycles. They also suggest that other SNBPs, including those in humans, may have analogous roles and manifest as paternal effects on embryo quality. PMID:27029731

Mind the Gap: 20 Years of Progress and Retrenchment in School Funding and Achievement Gaps. Policy Information Report. ETS RR-16-15

ERIC Educational Resources Information Center

Baker, Bruce D.; Farrie, Danielle; Sciarra, David G.

2016-01-01

Although there has been significant progress in the long term, achievement gaps among the nation's students persist.Many factors have contributed to the disparities in outcomes, and societal changes can explain progress, or lack thereof, over the past few decades.This is well documented in the 2010 Educational Testing Service (ETS) report…

Do HIV-1 non-B subtypes differentially impact resistance mutations and clinical disease progression in treated populations? Evidence from a systematic review

PubMed Central

Bhargava, Madhavi; Cajas, Jorge Martinez; Wainberg, Mark A; Klein, Marina B; Pai, Nitika Pant

2014-01-01

There are 31 million adults living with HIV-1 non-B subtypes globally, and about 10 million are on antiretroviral therapy (ART). Global evidence to guide clinical practice on ART response in HIV-1 non-B subtypes remains limited. We systematically searched 11 databases for the period 1996 to 2013 for evidence. Outcomes documented included time to development of AIDS and/or death, resistance mutations, opportunistic infections, and changes in CD4 cell counts and viral load. A lack of consistent reporting of all clinical end points precluded a meta-analysis. In sum, genetic diversity that precipitated differences in disease progression in ART-naïve populations was minimized in ART-experienced populations, although variability in resistance mutations persisted across non-B subtypes. To improve the quality of patient care in global settings, recording HIV genotypes at baseline and at virologic failure with targeted non-B subtype-based point-of-care resistance assays and timely phasing out of resistance-inducing ART regimens is recommended. PMID:24998532

Targeting Interleukin-17 signalling in cigarette smoke-induced lung disease: Mechanistic concepts and therapeutic opportunities.

PubMed

Roos, Abraham B; Stampfli, Martin R

2017-10-01

It is widely accepted that compromised lung function in chronic obstructive pulmonary disease (COPD) is, at least in part, a consequence of persistent airway inflammation caused by particles and noxious gases present in cigarette smoke and indoor air pollution from burning biomass fuel. Currently, the World Health Organization estimates that 80 million people have moderate or severe COPD worldwide. While there is a global need for effective medical treatment, current therapeutic interventions have shown limited success in preventing disease pathology and progression. This is, in large part, due to the complexity and heterogeneity of COPD, and an incomplete understanding of the molecular mechanisms governing inflammatory processes in individual patients. This review discusses recent discoveries related to the pro-inflammatory cytokine interleukin (IL)-17A, and its potential role in the pathogenesis of COPD. We propose that an intervention strategy targeting IL-17 signalling offers an exciting opportunity to mitigate inflammatory processes, and prevent the progression of tissue pathologies associated with COPD. Copyright © 2017 Elsevier Inc. All rights reserved.

Diabetes insipidus as a rare cause of acute cognitive impairment in multiple sclerosis.

PubMed

Tiedje, V; Schlamann, M; Führer, D; Moeller, L C

2013-10-01

Multiple sclerosis (MS) is a complex neurodegenerative disease presenting with a diversity of clinical symptoms including palsy and cognitive impairment. We present a 59-year-old woman with a history of secondary progressive MS since 1987, who was referred to our department because of recent onset of confusion and polydipsia. Initial lab tests showed mildly elevated serum sodium levels and low urine osmolality. Under water deprivation, diuresis and low urine osmolality persisted and serum sodium levels rose above 150 mmol/l. Oral desmopressin resulted in normalisation of serum sodium as well as urine osmolarity, confirming a diagnosis of central diabetes insipidus. As drug-induced diabetes could be excluded, pituitary magnetic resonance imaging (MRI) was performed. A demyelinating lesion was detected in the hypothalamus. The patient was started on oral desmopressin treatment (0.2 mg/day). Fluid intake and serum sodium levels have since remained normal. In summary, we report the rare case of a patient presenting with diabetes insipidus due to progressive MS. Diabetes insipidus should be considered in MS patients who develop new onset of polydipsia.

GPCR-autoantibodies in chronic heart failure.

PubMed

Boivin-Jahns, Valerie; Jahns, Roland

2018-06-01

Chronic heart failure (CHF) is a syndrome characterized by shortness of breath, fluid retention, and a progressive reduction in cardiac function. More than 60% of the cases are ischemic in origin (i.e., due to myo-cardial infarction) and about 30% are caused by non-ischemic myocardial damage (i.e., due to genetic or non-genetic causes like myocardial inflammation). Because of alterations in both cellular and humoral immunity patients with non-ischemic CHF often develop abnormal or misled immune responses, including cross-reacting antibodies and/or autoantibodies to various cardiac anti-gens. Non-ischemic myo-cardial damage was found to progress to CHF particularly, when associated (a) with the generation of autoantibodies directed against distinct myocyte membrane proteins critically involved in cardiac function - like G-protein coup-led membrane receptors (GPCRs), or (b) with virus persistence in the myocardium. This article will review current knowledge on the pathophysiological relevance of GPCR-autoreactivity in CHF by giving an overview on the so far available evidence from pre-clinical, clinical and epidemiological studies on the CHF-inducing potential of GPCR-autoantibodies and thereon based novel therapeutic approaches in GPCR autoantibody-associated CHF.

Chronic Chagas cardiomyopathy: a review of the main pathogenic mechanisms and the efficacy of aetiological treatment following the BENznidazole Evaluation for Interrupting Trypanosomiasis (BENEFIT) trial.

PubMed

Rassi, Anis; Marin, José Antonio; Rassi, Anis

2017-03-01

Chagas cardiomyopathy is the most frequent and most severe manifestation of chronic Chagas disease, and is one of the leading causes of morbidity and death in Latin America. Although the pathogenesis of Chagas cardiomyopathy is incompletely understood, it may involve several mechanisms, including parasite-dependent myocardial damage, immune-mediated myocardial injury (induced by the parasite itself and by self-antigens), and microvascular and neurogenic disturbances. In the past three decades, a consensus has emerged that parasite persistence is crucial to the development and progression of Chagas cardiomyopathy. In this context, antiparasitic treatment in the chronic phase of Chagas disease could prevent complications related to the disease. However, according to the results of the BENEFIT trial, benznidazole seems to have no benefit for arresting disease progression in patients with chronic Chagas cardiomyopathy. In this review, we give an update on the main pathogenic mechanisms of Chagas disease, and re-examine and discuss the results of the BENEFIT trial, together with its limitations and implications.

Effect of inhibitors of polyamine biosynthesis on gibberellin-induced internode growth in light-grown dwarf peas

NASA Technical Reports Server (NTRS)

Kaur-Sawhney, R.; Dai, Y. R.; Galston, A. W.

1986-01-01

When gibberellic acid (GA3) is sprayed on 9-day-old light-brown dwarf Progress pea (Pisum sativum) seedlings, arginine decarboxylase (ADC; EC 4.1.1.9) activity increases within 3 h and peaks at about 9 h after GA3 application. This is followed by a second lower peak at about 30 h; both peaks were higher than the corresponding peaks in the controls. In contrast, no appreciable effect of GA3 on internode length was observed until about 12 h, after which time a dramatic increase in growth rate occurred and persisted for about 12 h. Specific (DL-alpha-difluoromethylarginine) and non-specific (D-arginine and L-canavanine) inhibitors of ADC strongly inhibited ADC activity and to a lesser extent internode growth. The inhibition was reversed only slightly by the addition of polyamines. Actinomycin D and cycloheximide inhibited the rise in ADC activity induced by GA3. The half-life of the enzyme was increased by GA3 treatment. The results suggest that part of the GA3-induced increase in internode growth may result from enhanced polyamine biosynthesis through the ADC pathway. Furthermore, the GA3 induced increase in ADC activity probably requires de novo synthesis of both RNA and protein.

Chronic CNS oxytocin signaling preferentially induces fat loss in high-fat diet-fed rats by enhancing satiety responses and increasing lipid utilization

PubMed Central

Thompson, Benjamin W.; Anekonda, Vishwanath T.; Ho, Jacqueline M.; Graham, James L.; Roberts, Zachary S.; Hwang, Bang H.; Ogimoto, Kayoko; Wolden-Hanson, Tami; Nelson, Jarrell; Kaiyala, Karl J.; Havel, Peter J.; Bales, Karen L.; Morton, Gregory J.; Schwartz, Michael W.; Baskin, Denis G.

2016-01-01

Based largely on a number of short-term administration studies, growing evidence suggests that central oxytocin is important in the regulation of energy balance. The goal of the current work is to determine whether long-term third ventricular (3V) infusion of oxytocin into the central nervous system (CNS) is effective for obesity prevention and/or treatment in rat models. We found that chronic 3V oxytocin infusion between 21 and 26 days by osmotic minipumps both reduced weight gain associated with the progression of high-fat diet (HFD)-induced obesity and elicited a sustained reduction of fat mass with no decrease of lean mass in rats with established diet-induced obesity. We further demonstrated that these chronic oxytocin effects result from 1) maintenance of energy expenditure at preintervention levels despite ongoing weight loss, 2) a reduction in respiratory quotient, consistent with increased fat oxidation, and 3) an enhanced satiety response to cholecystokinin-8 and associated decrease of meal size. These weight-reducing effects persisted for approximately 10 days after termination of 3V oxytocin administration and occurred independently of whether sucrose was added to the HFD. We conclude that long-term 3V administration of oxytocin to rats can both prevent and treat diet-induced obesity. PMID:26791828

Chronic CNS oxytocin signaling preferentially induces fat loss in high-fat diet-fed rats by enhancing satiety responses and increasing lipid utilization.

PubMed

Blevins, James E; Thompson, Benjamin W; Anekonda, Vishwanath T; Ho, Jacqueline M; Graham, James L; Roberts, Zachary S; Hwang, Bang H; Ogimoto, Kayoko; Wolden-Hanson, Tami; Nelson, Jarrell; Kaiyala, Karl J; Havel, Peter J; Bales, Karen L; Morton, Gregory J; Schwartz, Michael W; Baskin, Denis G

2016-04-01

Based largely on a number of short-term administration studies, growing evidence suggests that central oxytocin is important in the regulation of energy balance. The goal of the current work is to determine whether long-term third ventricular (3V) infusion of oxytocin into the central nervous system (CNS) is effective for obesity prevention and/or treatment in rat models. We found that chronic 3V oxytocin infusion between 21 and 26 days by osmotic minipumps both reduced weight gain associated with the progression of high-fat diet (HFD)-induced obesity and elicited a sustained reduction of fat mass with no decrease of lean mass in rats with established diet-induced obesity. We further demonstrated that these chronic oxytocin effects result from 1) maintenance of energy expenditure at preintervention levels despite ongoing weight loss, 2) a reduction in respiratory quotient, consistent with increased fat oxidation, and 3) an enhanced satiety response to cholecystokinin-8 and associated decrease of meal size. These weight-reducing effects persisted for approximately 10 days after termination of 3V oxytocin administration and occurred independently of whether sucrose was added to the HFD. We conclude that long-term 3V administration of oxytocin to rats can both prevent and treat diet-induced obesity.

Down-regulation of Wild-type p53-induced Phosphatase 1 (Wip1) Plays a Critical Role in Regulating Several p53-dependent Functions in Premature Senescent Tumor Cells*

PubMed Central

Crescenzi, Elvira; Raia, Zelinda; Pacifico, Francesco; Mellone, Stefano; Moscato, Fortunato; Palumbo, Giuseppe; Leonardi, Antonio

2013-01-01

Premature or drug-induced senescence is a major cellular response to chemotherapy in solid tumors. The senescent phenotype develops slowly and is associated with chronic DNA damage response. We found that expression of wild-type p53-induced phosphatase 1 (Wip1) is markedly down-regulated during persistent DNA damage and after drug release during the acquisition of the senescent phenotype in carcinoma cells. We demonstrate that down-regulation of Wip1 is required for maintenance of permanent G2 arrest. In fact, we show that forced expression of Wip1 in premature senescent tumor cells induces inappropriate re-initiation of mitosis, uncontrolled polyploid progression, and cell death by mitotic failure. Most of the effects of Wip1 may be attributed to its ability to dephosphorylate p53 at Ser15 and to inhibit DNA damage response. However, we also uncover a regulatory pathway whereby suppression of p53 Ser15 phosphorylation is associated with enhanced phosphorylation at Ser46, increased p53 protein levels, and induction of Noxa expression. On the whole, our data indicate that down-regulation of Wip1 expression during premature senescence plays a pivotal role in regulating several p53-dependent aspects of the senescent phenotype. PMID:23612976

Progression and regression of cervical pap test lesions in an urban AIDS clinic in the combined antiretroviral therapy era: a longitudinal, retrospective study.

PubMed

Lofgren, Sarah M; Tadros, Talaat; Herring-Bailey, Gina; Birdsong, George; Mosunjac, Marina; Flowers, Lisa; Nguyen, Minh Ly

2015-05-01

Our objective was to evaluate the progression and regression of cervical dysplasia in human immunodeficiency virus (HIV)-positive women during the late antiretroviral era. Risk factors as well as outcomes after treatment of cancerous or precancerous lesions were examined. This is a longitudinal retrospective review of cervical Pap tests performed on HIV-infected women with an intact cervix between 2004 and 2011. Subjects needed over two Pap tests for at least 2 years of follow-up. Progression was defined as those who developed a squamous intraepithelial lesion (SIL), atypical glandular cells (AGC), had low-grade SIL (LSIL) followed by atypical squamous cells-cannot exclude high-grade SIL (ASC-H) or high-grade SIL (HSIL), or cancer. Regression was defined as an initial SIL with two or more subsequent normal Pap tests. Persistence was defined as having an SIL without progression or regression. High-risk human papillomavirus (HPV) testing started in 2006 on atypical squamous cells of undetermined significance (ASCUS) Pap tests. AGC at enrollment were excluded from progression analysis. Of 1,445 screened, 383 patients had over two Pap tests for a 2-year period. Of those, 309 had an intact cervix. The median age was 40 years and CD4+ cell count was 277 cells/mL. Four had AGC at enrollment. A quarter had persistently normal Pap tests, 64 (31%) regressed, and 50 (24%) progressed. Four developed cancer. The only risk factor associated with progression was CD4 count. In those with treated lesions, 24 (59%) had negative Pap tests at the end of follow-up. More studies are needed to evaluate follow-up strategies of LSIL patients, potentially combined with HPV testing. Guidelines for HIV-seropositive women who are in care, have improved CD4, and have persistently negative Pap tests could likely lengthen the follow-up interval.

Progression and Regression of Cervical Pap Test Lesions in an Urban AIDS Clinic in the Combined Antiretroviral Therapy Era: A Longitudinal, Retrospective Study

PubMed Central

Tadros, Talaat; Herring-Bailey, Gina; Birdsong, George; Mosunjac, Marina; Flowers, Lisa; Nguyen, Minh Ly

2015-01-01

Abstract Our objective was to evaluate the progression and regression of cervical dysplasia in human immunodeficiency virus (HIV)-positive women during the late antiretroviral era. Risk factors as well as outcomes after treatment of cancerous or precancerous lesions were examined. This is a longitudinal retrospective review of cervical Pap tests performed on HIV-infected women with an intact cervix between 2004 and 2011. Subjects needed over two Pap tests for at least 2 years of follow-up. Progression was defined as those who developed a squamous intraepithelial lesion (SIL), atypical glandular cells (AGC), had low-grade SIL (LSIL) followed by atypical squamous cells-cannot exclude high-grade SIL (ASC-H) or high-grade SIL (HSIL), or cancer. Regression was defined as an initial SIL with two or more subsequent normal Pap tests. Persistence was defined as having an SIL without progression or regression. High-risk human papillomavirus (HPV) testing started in 2006 on atypical squamous cells of undetermined significance (ASCUS) Pap tests. AGC at enrollment were excluded from progression analysis. Of 1,445 screened, 383 patients had over two Pap tests for a 2-year period. Of those, 309 had an intact cervix. The median age was 40 years and CD4+ cell count was 277 cells/mL. Four had AGC at enrollment. A quarter had persistently normal Pap tests, 64 (31%) regressed, and 50 (24%) progressed. Four developed cancer. The only risk factor associated with progression was CD4 count. In those with treated lesions, 24 (59%) had negative Pap tests at the end of follow-up. More studies are needed to evaluate follow-up strategies of LSIL patients, potentially combined with HPV testing. Guidelines for HIV-seropositive women who are in care, have improved CD4, and have persistently negative Pap tests could likely lengthen the follow-up interval. PMID:25693769

Salt stress-induced transcription of σB- and CtsR-regulated genes in persistent and non-persistent Listeria monocytogenes strains from food processing plants.

PubMed

Ringus, Daina L; Ivy, Reid A; Wiedmann, Martin; Boor, Kathryn J

2012-03-01

Listeria monocytogenes is a foodborne pathogen that can persist in food processing environments. Six persistent and six non-persistent strains from fish processing plants and one persistent strain from a meat plant were selected to determine if expression of genes in the regulons of two stress response regulators, σ(B) and CtsR, under salt stress conditions is associated with the ability of L. monocytogenes to persist in food processing environments. Subtype data were also used to categorize the strains into genetic lineages I or II. Quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was used to measure transcript levels for two σ(B)-regulated genes, inlA and gadD3, and two CtsR-regulated genes, lmo1138 and clpB, before and after (t=10 min) salt shock (i.e., exposure of exponential phase cells to BHI+6% NaCl for 10 min at 37°C). Exposure to salt stress induced higher transcript levels relative to levels under non-stress conditions for all four stress and virulence genes across all wildtype strains tested. Analysis of variance (ANOVA) of induction data revealed that transcript levels for one gene (clpB) were induced at significantly higher levels in non-persistent strains compared to persistent strains (p=0.020; two-way ANOVA). Significantly higher transcript levels of gadD3 (p=0.024; two-way ANOVA) and clpB (p=0.053; two-way ANOVA) were observed after salt shock in lineage I strains compared to lineage II strains. No clear association between stress gene transcript levels and persistence was detected. Our data are consistent with an emerging model that proposes that establishment of L. monocytogenes persistence in a specific environment occurs as a random, stochastic event, rather than as a consequence of specific bacterial strain characteristics.

Anticipating persistent infection

NASA Astrophysics Data System (ADS)

Moitra, Promit; Jain, Kanishk; Sinha, Sudeshna

2018-03-01

We explore the emergence of persistent infection in a closed region where the disease progression of the individuals is given by the SIRS model, with an individual becoming infected on contact with another infected individual within a given range. We focus on the role of synchronization in the persistence of contagion. Our key result is that higher degree of synchronization, both globally in the population and locally in the neighbourhoods, hinders persistence of infection. Importantly, we find that early short-time asynchrony appears to be a consistent precursor to future persistence of infection, and can potentially provide valuable early warnings for sustained contagion in a population patch. Thus, transient synchronization can help anticipate the long-term persistence of infection. Further we demonstrate that when the range of influence of an infected individual is wider, one obtains lower persistent infection. This counterintuitive observation can also be understood through the relation between synchronization and infection burn-out.

Worster-Drought Syndrome: Poorly Recognized despite Severe and Persistent Difficulties with Feeding and Speech

ERIC Educational Resources Information Center

Clark, Maria; Harris, Rebecca; Jolleff, Nicola; Price, Katie; Neville, Brian G. R.

2010-01-01

Aim: Worster-Drought syndrome (WDS), or congenital suprabulbar paresis, is a permanent movement disorder of the bulbar muscles causing persistent difficulties with swallowing, feeding, speech, and saliva control owing to a non-progressive disturbance in early brain development. As such, it falls within the cerebral palsies. The aim of this study…

Postsecondary Pathways and Persistence for STEM versus Non-STEM Majors: Among College Students with an Autism Spectrum Disorder

ERIC Educational Resources Information Center

Wei, Xin; Christiano, Elizabeth R. A.; Yu, Jennifer W.; Blackorby, Jose; Shattuck, Paul; Newman, Lynn A.

2014-01-01

Little is known about postsecondary pathways and persistence among college students with an autism spectrum disorder (ASD). This study analyzed data from the National Longitudinal Transition Study-2, 2001-2009, a nationally representative sample of students in special education with an ASD who progressed from high school to postsecondary…

Gamed by the System: Adequate Yearly Progress as an Indicator of Persistently Low-Achieving School Performance

ERIC Educational Resources Information Center

Hochbein, Craig; Mitchell, Amanda M.; Pollio, Martin

2013-01-01

The recent policy focus on the turnaround of persistently low-achieving schools has generated considerable debate about the reforms needed to dramatically and quickly increase school performance. The purpose of this article is not to focus on specific turnaround interventions, but rather on the identification of schools slated to receive these…

Postsecondary Pathways and Persistence for STEM versus Non-STEM Majors; Among College Students with an Autism Spectrum Disorder

ERIC Educational Resources Information Center

Wei, Xin; Christiano, Elizabeth R.; Yu, Jennifer W.; Blackorby, Jose; Shattuck, Paul; Newman, Lynn

2014-01-01

Little is known about postsecondary pathways and persistence among college students with an Autism Spectrum Disorder (ASD). This study analyzed data from the National Longitudinal Transition Study-2, 2001-2009, a nationally representative sample of students in special education with an ASD who progressed from high school to postsecondary…

Developmental programming of energy balance regulation: is physical activity more 'programmable' than food intake?

PubMed

Zhu, Shaoyu; Eclarinal, Jesse; Baker, Maria S; Li, Ge; Waterland, Robert A

2016-02-01

Extensive human and animal model data show that environmental influences during critical periods of prenatal and early postnatal development can cause persistent alterations in energy balance regulation. Although a potentially important factor in the worldwide obesity epidemic, the fundamental mechanisms underlying such developmental programming of energy balance are poorly understood, limiting our ability to intervene. Most studies of developmental programming of energy balance have focused on persistent alterations in the regulation of energy intake; energy expenditure has been relatively underemphasised. In particular, very few studies have evaluated developmental programming of physical activity. The aim of this review is to summarise recent evidence that early environment may have a profound impact on establishment of individual propensity for physical activity. Recently, we characterised two different mouse models of developmental programming of obesity; one models fetal growth restriction followed by catch-up growth, and the other models early postnatal overnutrition. In both studies, we observed alterations in body-weight regulation that persisted to adulthood, but no group differences in food intake. Rather, in both cases, programming of energy balance appeared to be due to persistent alterations in energy expenditure and spontaneous physical activity (SPA). These effects were stronger in female offspring. We are currently exploring the hypothesis that developmental programming of SPA occurs via induced sex-specific alterations in epigenetic regulation in the hypothalamus and other regions of the central nervous system. We will summarise the current progress towards testing this hypothesis. Early environmental influences on establishment of physical activity are likely an important factor in developmental programming of energy balance. Understanding the fundamental underlying mechanisms in appropriate animal models will help determine whether early life interventions may be a practical approach to promote physical activity in man.

Persistent inflammation in HIV infection: established concepts, new perspectives.

PubMed

Nasi, Milena; Pinti, Marcello; Mussini, Cristina; Cossarizza, Andrea

2014-10-01

Immune activation is now considered a main driving force for the progressive immune failure in HIV infection. During the early phases of infection, a rapid depletion of gastrointestinal CD4+ T cells occurs that is followed by a deterioration of the gut epithelium and by the subsequent translocation of microbial products into the blood. Activation of innate immunity results in massive production of proinflammatory cytokines, which can trigger activation induced cell death phenomena among T lymphocytes. Moreover, persistent antigenic stimulation and inflammatory status causes immune exhaustion. The chronic immune activation also damages lymphoid tissue architecture, so contributing to the impairment of immune reconstitution. Recently, new mechanisms were identified, so opening new perspective on the innate immune sensing in HIV-1 infection. Cell death is followed by the release of molecules containing "damage-associated molecular patterns", that trigger a potent innate immune response through the engagement of Toll-like receptors. Then, also different types of HIV-related nucleic acids can act as potent stimulators of innate immunity. All these events contribute to the loss of T cell homeostatic regulation and to the failure of adaptive immunity. Copyright © 2014 Elsevier B.V. All rights reserved.

Oxidation in the nucleotide pool, the DNA damage response and cellular senescence: Defective bricks build a defective house.

PubMed

Rai, Priyamvada

2010-11-28

Activation of persistent DNA damage response (DDR) signaling is associated with the induction of a permanent proliferative arrest known as cellular senescence, a phenomenon intrinsically linked to both tissue aging as well as tumor suppression. The DNA damage observed in senescent cells has been attributed to elevated levels of reactive oxygen species (ROS), failing DNA damage repair processes, and/or oncogenic activation. It is not clear how labile molecules such as ROS are able to damage chromatin-bound DNA to a sufficient extent to invoke persistent DNA damage and DDR signaling. Recent evidence suggests that the nucleotide pool is a significant target for oxidants and that oxidized nucleotides, once incorporated into genomic DNA, can lead to the induction of a DNA strand break-associated DDR that triggers senescence in normal cells and in cells sustaining oncogene activation. Evasion of this DDR and resulting senescence is a key step in tumor progression. This review will explore the role of oxidation in the nucleotide pool as a major effector of oxidative stress-induced genotoxic damage and DDR in the context of cellular senescence and tumorigenic transformation. 2010 Elsevier B.V. All rights reserved.

An origin-deficient yeast artificial chromosome triggers a cell cycle checkpoint.

PubMed

van Brabant, A J; Buchanan, C D; Charboneau, E; Fangman, W L; Brewer, B J

2001-04-01

Checkpoint controls coordinate entry into mitosis with the completion of DNA replication. Depletion of nucleotide precursors by treatment with the drug hydroxyurea triggers such a checkpoint response. However, it is not clear whether the signal for this hydroxyurea-induced checkpoint pathway is the presence of unreplicated DNA, or rather the persistence of single-stranded or damaged DNA. In a yeast artificial chromosome (YAC) we have engineered an approximately 170 kb region lacking efficient replication origins that allows us to explore the specific effects of unreplicated DNA on cell cycle progression. Replication of this YAC extends the length of S phase and causes cells to engage an S/M checkpoint. In the absence of Rad9 the YAC becomes unstable, undergoing deletions within the origin-free region.

Scribble Modulates the MAPK/Fra1 Pathway to Disrupt Luminal and Ductal Integrity and Suppress Tumour Formation in the Mammary Gland

PubMed Central

Godde, Nathan J.; Sheridan, Julie M.; Smith, Lorey K.; Pearson, Helen B.; Britt, Kara L.; Galea, Ryan C.; Yates, Laura L.; Visvader, Jane E.; Humbert, Patrick O.

2014-01-01

Polarity coordinates cell movement, differentiation, proliferation and apoptosis to build and maintain complex epithelial tissues such as the mammary gland. Loss of polarity and the deregulation of these processes are critical events in malignant progression but precisely how and at which stage polarity loss impacts on mammary development and tumourigenesis is unclear. Scrib is a core polarity regulator and tumour suppressor gene however to date our understanding of Scrib function in the mammary gland has been limited to cell culture and transplantation studies of cell lines. Utilizing a conditional mouse model of Scrib loss we report for the first time that Scrib is essential for mammary duct morphogenesis, mammary progenitor cell fate and maintenance, and we demonstrate a critical and specific role for Scribble in the control of the early steps of breast cancer progression. In particular, Scrib-deficiency significantly induced Fra1 expression and basal progenitor clonogenicity, which resulted in fully penetrant ductal hyperplasia characterized by high cell turnover, MAPK hyperactivity, frank polarity loss with mixing of apical and basolateral membrane constituents and expansion of atypical luminal cells. We also show for the first time a role for Scribble in mammalian spindle orientation with the onset of mammary hyperplasia being associated with aberrant luminal cell spindle orientation and a failure to apoptose during the final stage of duct tubulogenesis. Restoring MAPK/Fra1 to baseline levels prevented Scrib-hyperplasia, whereas persistent Scrib deficiency induced alveolar hyperplasia and increased the incidence, onset and grade of mammary tumours. These findings, based on a definitive genetic mouse model provide fundamental insights into mammary duct maturation and homeostasis and reveal that Scrib loss activates a MAPK/Fra1 pathway that alters mammary progenitor activity to drive premalignancy and accelerate tumour progression. PMID:24852022

Persistent luminescence of transition metal (Co, Ni...)-doped ZnGa2O4 phosphors for applications in the near-infrared range

NASA Astrophysics Data System (ADS)

Pellerin, Morgane; Castaing, Victor; Gourier, Didier; Chanéac, Corinne; Viana, Bruno

2018-02-01

Persistent luminescence materials present many applications including security lighting and bio-imaging. Many progresses have been made in the elaboration of persistent luminescent nanoparticles suitable for the first NIR partial transparency window (650 - 950 nm). Moving to the second and third near-infrared partial transparency windows (1000 nm - 1800 nm) allows further reducing of scattering, absorption and tissue autofluorescence effects. In this work, we present the synthesis of Co2+ and Ni2+ doped zinc-gallate nanoparticles with broad emission covering the NIR-II range. Site occupancy, energy levels, optical features and persistent phenomena are presented.

The novel compound Sul-121 inhibits airway inflammation and hyperresponsiveness in experimental models of chronic obstructive pulmonary disease

PubMed Central

Han, Bing; Poppinga, Wilfred J.; Zuo, Haoxiao; Zuidhof, Annet B.; Bos, I. Sophie T.; Smit, Marieke; Vogelaar, Pieter; Krenning, Guido; Henning, Robert H.; Maarsingh, Harm; Halayko, Andrew J.; van Vliet, Bernard; Stienstra, Stef; Graaf, Adrianus Cornelis van der; Meurs, Herman; Schmidt, Martina

2016-01-01

COPD is characterized by persistent airflow limitation, neutrophilia and oxidative stress from endogenous and exogenous insults. Current COPD therapy involving anticholinergics, β2-adrenoceptor agonists and/or corticosteroids, do not specifically target oxidative stress, nor do they reduce chronic pulmonary inflammation and disease progression in all patients. Here, we explore the effects of Sul-121, a novel compound with anti-oxidative capacity, on hyperresponsiveness (AHR) and inflammation in experimental models of COPD. Using a guinea pig model of lipopolysaccharide (LPS)-induced neutrophilia, we demonstrated that Sul-121 inhalation dose-dependently prevented LPS-induced airway neutrophilia (up to ~60%) and AHR (up to ~90%). Non-cartilaginous airways neutrophilia was inversely correlated with blood H2S, and LPS-induced attenuation of blood H2S (~60%) was prevented by Sul-121. Concomitantly, Sul-121 prevented LPS-induced production of the oxidative stress marker, malondialdehyde by ~80%. In immortalized human airway smooth muscle (ASM) cells, Sul-121 dose-dependently prevented cigarette smoke extract-induced IL-8 release parallel with inhibition of nuclear translocation of the NF-κB subunit, p65 (each ~90%). Sul-121 also diminished cellular reactive oxygen species production in ASM cells, and inhibited nuclear translocation of the anti-oxidative response regulator, Nrf2. Our data show that Sul-121 effectively inhibits airway inflammation and AHR in experimental COPD models, prospectively through inhibition of oxidative stress. PMID:27229886

Preventive effect of curcumin and its highly bioavailable preparation on hearing loss induced by single or repeated exposure to noise: A comparative and mechanistic study.

PubMed

Yamaguchi, Taro; Yoneyama, Masanori; Onaka, Yusuke; Imaizumi, Atsushi; Ogita, Kiyokazu

2017-08-01

We sought to determine the preventive effects of curcumin and its highly bioavailable preparation on noise-induced hearing loss in a novel murine model of permanent hearing loss developed by repeated exposure to noise. Upon exposure to noise (8-kHz octave band noise, 90 dB sound pressure level, 1 h), hearing ability was impaired in a temporary and reversible manner. During repeated noise exposure (1-h exposure per day, 5 days), there was a progressive increase in the auditory threshold shift at 12 and 20 kHz. The threshold shift persisted for at least 6 days after noise exposure. Oral administration of curcumin for 3 days before and each day during noise exposure significantly alleviated the hearing loss induced by repeated noise exposure. Curcumin abolished intranuclear translocation of nuclear factor-κB-p65 and generation of 4-hydroxynonenal-adducted proteins found in the cochlea after noise exposure. Theracurmin ® , a highly absorbable and bioavailable preparation of curcumin, had strong preventive effects on hearing loss induced by repeated noise exposure. Together, these data suggest that curcumin exerts a preventive effect on noise-induced hearing loss and is therefore a good therapeutic candidate for preventing sensorineural hearing loss. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

IDENTIFICATION OF SPONTANEOUS FELINE IDIOPATHIC PULMONARY FIBROSIS: MORPHOLOGY AND ULTRASTRUCTURAL EVIDENCE FOR A TYPE II PNEUMOCYTE DEFECT

EPA Science Inventory

Abstract
Idiopathic pulmonary fibrosis currently lacks an animal model that develops the persistent, progressive lung fibrosis characteristic of the disease. Sixteen domestic cats developed dyspnea that was not responsive to therapy and which rapidly progressed until death/eu...

Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism

PubMed Central

Vujkovic-Cvijin, Ivan; Dunham, Richard M.; Iwai, Shoko; Maher, M. Cyrus; Albright, Rebecca G.; Broadhurst, Mara J.; Hernandez, Ryan D.; Lederman, Michael M.; Huang, Yong; Somsouk, Ma; Deeks, Steven G.; Hunt, Peter W.; Lynch, Susan V.; McCune, Joseph M.

2014-01-01

Progressive HIV infection is characterized by dysregulation of the intestinal immune barrier, translocation of immunostimulatory microbial products, and chronic systemic inflammation that is thought to drive progression of disease to AIDS. Elements of this pathologic process persist despite viral suppression during highly active antiretroviral therapy (HAART) and drivers of these phenomena remain poorly understood. Disrupted intestinal immunity can precipitate dysbiosis that induces chronic inflammation in the mucosa and periphery of mice. However, putative microbial drivers of HIV-associated immunopathology versus recovery have not been identified in humans. Using high-resolution bacterial community profiling, we identified a dysbiotic mucosal-adherent community enriched in Proteobacteria and depleted of Bacteroidia members that was associated with markers of mucosal immune disruption, T cell activation, and chronic inflammation in HIV-infected subjects. Furthermore, this dysbiosis was evident among HIV-infected subjects undergoing HAART, and the extent of dysbiosis correlated with activity of the kynurenine pathway of tryptophan metabolism and plasma concentrations of the inflammatory cytokine interleukin-6 (IL-6), two established markers of disease progression. Gut-resident bacteria with capacity to metabolize tryptophan through the kynurenine pathway were found to be enriched in HIV-infected subjects, strongly correlated with kynurenine levels in HIV-infected subjects, and capable of kynurenine production in vitro. These observations demonstrate a link between mucosal-adherent colonic bacteria and immunopathogenesis during progressive HIV infection, which is apparent even in the setting of viral suppression during HAART. This link suggests that gut-resident microbial populations may influence intestinal homeostasis during HIV disease. PMID:23843452

Chronic proliferative hepatitis in A/JCr mice associated with persistent Helicobacter hepaticus infection: a model of helicobacter-induced carcinogenesis.

PubMed Central

Fox, J G; Li, X; Yan, L; Cahill, R J; Hurley, R; Lewis, R; Murphy, J C

1996-01-01

Helicobacter hepaticus causes hepatitis in selected strains of mice and in A/JCr mice is linked to liver cancer. To analyze whether H. hepaticus persists in specified ecological niches, to determine whether biomarkers of infection exist, and to analyze the influence of H. hepaticus on hepatocyte proliferation, a longitudinal study of H. hepaticus-infected A/JCr mice was undertaken. A/JCr mice were serially euthanatized from 3 through 18 months and surveyed by enzyme-linked immunosorbent assay; bacterial culture of liver, colon, and cecum; histology; electron microscopy; hepatocyte proliferation indices determined by using 5-bromo-2'-deoxyuridine; and measurement of the liver enzyme alanine aminotransferase. In infected animals throughout the 18-month study, H. hepaticus was consistently isolated from the lower bowel but only sporadically from the liver. By electron microscopy, H. hepaticus was noted infrequently and only in bile canaliculi. Infected mice, particularly males, showed chronic inflammation; oval cell, Kupffer cell, and Ito cell hyperplasia; hepatocytomegaly; and bile duct proliferation. The inflammatory and necrotizing lesion was progressive and involved the hepatic parenchyma, portal triads, and intralobular venules. Hepatic adenomas were noted only in male mice, whereas 5-bromo-2'-deoxyuridine proliferation indices were markedly increased in both sexes, but especially in males, compared to control A/J mice. Infected mice also developed sustained anti-H. hepaticus serum immunoglobulin G antibody responses and elevated alanine aminotransferase levels. H. hepaticus, which persists in the lower bowels and livers of A/JCr mice, is associated with a chronic proliferative hepatitis, and hepatomas in selected male mice indicate that this novel bacterium may cause an increased risk of hepatic cancer induction in susceptible strains of mice. This murine model should prove useful in dissecting the molecular events operable in the development of neoplasms induced by bacteria belonging to this expanding genera of pathogenic Helicobacter species. PMID:8613359

Persistent nature of alterations in cognition and neuronal circuit excitability after exposure to simulated cosmic radiation in mice.

PubMed

Parihar, Vipan K; Maroso, Mattia; Syage, Amber; Allen, Barrett D; Angulo, Maria C; Soltesz, Ivan; Limoli, Charles L

2018-07-01

Of the many perils associated with deep space travel to Mars, neurocognitive complications associated with cosmic radiation exposure are of particular concern. Despite these realizations, whether and how realistic doses of cosmic radiation cause cognitive deficits and neuronal circuitry alterations several months after exposure remains unclear. In addition, even less is known about the temporal progression of cosmic radiation-induced changes transpiring over the duration of a time period commensurate with a flight to Mars. Here we show that rodents exposed to the second most prevalent radiation type in space (i.e. helium ions) at low, realistic doses, exhibit significant hippocampal and cortical based cognitive decrements lasting 1 year after exposure. Cosmic-radiation-induced impairments in spatial, episodic and recognition memory were temporally coincident with deficits in cognitive flexibility and reduced rates of fear extinction, elevated anxiety and depression like behavior. At the circuit level, irradiation caused significant changes in the intrinsic properties (resting membrane potential, input resistance) of principal cells in the perirhinal cortex, a region of the brain implicated by our cognitive studies. Irradiation also resulted in persistent decreases in the frequency and amplitude of the spontaneous excitatory postsynaptic currents in principal cells of the perirhinal cortex, as well as a reduction in the functional connectivity between the CA1 of the hippocampus and the perirhinal cortex. Finally, increased numbers of activated microglia revealed significant elevations in neuroinflammation in the perirhinal cortex, in agreement with the persistent nature of the perturbations in key neuronal networks after cosmic radiation exposure. These data provide new insights into cosmic radiation exposure, and reveal that even sparsely ionizing particles can disrupt the neural circuitry of the brain to compromise cognitive function over surprisingly protracted post-irradiation intervals. Copyright © 2018 Elsevier Inc. All rights reserved.

Persistent Increase in Microglial RAGE Contributes to Chronic Stress-Induced Priming of Depressive-like Behavior.

PubMed

Franklin, Tina C; Wohleb, Eric S; Zhang, Yi; Fogaça, Manoela; Hare, Brendan; Duman, Ronald S

2018-01-01

Chronic stress-induced inflammatory responses occur in part via danger-associated molecular pattern (DAMP) molecules, such as high mobility group box 1 protein (HMGB1), but the receptor(s) underlying DAMP signaling have not been identified. Microglia morphology and DAMP signaling in enriched rat hippocampal microglia were examined during the development and expression of chronic unpredictable stress (CUS)-induced behavioral deficits, including long-term, persistent changes after CUS. The results show that CUS promotes significant morphological changes and causes robust upregulation of HMGB1 messenger RNA in enriched hippocampal microglia, an effect that persists for up to 6 weeks after CUS exposure. This coincides with robust and persistent upregulation of receptor for advanced glycation end products (RAGE) messenger RNA, but not toll-like receptor 4 in hippocampal microglia. CUS also increased surface expression of RAGE protein on hippocampal microglia as determined by flow cytometry and returned to basal levels 5 weeks after CUS. Importantly, exposure to short-term stress was sufficient to increase RAGE surface expression as well as anhedonic behavior, reflecting a primed state that results from a persistent increase in RAGE messenger RNA expression. Further evidence for DAMP signaling in behavioral responses is provided by evidence that HMGB1 infusion into the hippocampus was sufficient to cause anhedonic behavior and by evidence that RAGE knockout mice were resilient to stress-induced anhedonia. Together, the results provide evidence of persistent microglial HMGB1-RAGE expression that increases vulnerability to depressive-like behaviors long after chronic stress exposure. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Zika Virus Persistently Infects and Is Basolaterally Released from Primary Human Brain Microvascular Endothelial Cells.

PubMed

Mladinich, Megan C; Schwedes, John; Mackow, Erich R

2017-07-11

Zika virus (ZIKV) is a mosquito-borne Flavivirus that has emerged as the cause of encephalitis and fetal microencephaly in the Americas. ZIKV uniquely persists in human bodily fluids for up to 6 months, is sexually transmitted, and traverses the placenta and the blood-brain barrier (BBB) to damage neurons. Cells that support persistent ZIKV replication and mechanisms by which ZIKV establishes persistence remain enigmatic but central to ZIKV entry into protected neuronal compartments. The endothelial cell (EC) lining of capillaries normally constrains transplacental transmission and forms the BBB, which selectively restricts access of blood constituents to neurons. We found that ZIKV (strain PRVABC59) persistently infects and continuously replicates in primary human brain microvascular ECs (hBMECs), without cytopathology, for >9 days and following hBMEC passage. ZIKV did not permeabilize hBMECs but was released basolaterally from polarized hBMECs, suggesting a direct mechanism for ZIKV to cross the BBB. ZIKV-infected hBMECs were rapidly resistant to alpha interferon (IFN-α) and transiently induced, but failed to secrete, IFN-β and IFN-λ. Global transcriptome analysis determined that ZIKV constitutively induced IFN regulatory factor 7 (IRF7), IRF9, and IFN-stimulated genes (ISGs) 1 to 9 days postinfection, despite persistently replicating in hBMECs. ZIKV constitutively induced ISG15, HERC5, and USP18, which are linked to hepatitis C virus (HCV) persistence and IFN regulation, chemokine CCL5, which is associated with immunopathogenesis, as well as cell survival factors. Our results reveal that hBMECs act as a reservoir of persistent ZIKV replication, suggest routes for ZIKV to cross hBMECs into neuronal compartments, and define novel mechanisms of ZIKV persistence that can be targeted to restrict ZIKV spread. IMPORTANCE ZIKV persists in patients, crossing placental and neuronal barriers, damaging neurons, and causing fetal microencephaly. We found that ZIKV persistently infects brain endothelial cells that normally protect neurons from viral exposure. hBMECs are not damaged by ZIKV infection and, analogous to persistent HCV infection, ZIKV constitutively induces and evades antiviral ISG and IFN responses to continuously replicate in hBMECs. As a result, hBMECs provide a protective niche for systemic ZIKV spread and a viral reservoir localized in the normally protective blood-brain barrier. Consistent with the spread of ZIKV into neuronal compartments, ZIKV was released basolaterally from hBMECs. Our findings define hBMEC responses that contribute to persistent ZIKV infection and potential targets for clearing ZIKV infections from hBMECs. These results further suggest roles for additional ZIKV-infected ECs to facilitate viral spread and persistence in the protected placental, retinal, and testicular compartments. Copyright © 2017 Mladinich et al.

Persistent wind-induced enhancement of diffusive CO2 transport in a mountain forest snowpack

Treesearch

D. R. Bowling; W. J. Massman

2011-01-01

Diffusion dominates the transport of trace gases between soil and the atmosphere. Pressure gradients induced by atmospheric flow and wind interacting with topographical features cause a small but persistent bulk flow of air within soil or snow. This forcing, called pressure pumping or wind pumping, leads to a poorly quantified enhancement of gas transport beyond the...

Differences in cocaine-induced place preference persistence, locomotion and social behaviors between C57BL/6J and BALB/cJ mice

PubMed Central

WANG, Jian-Li; WANG, Bei; CHEN, Wen

2014-01-01

C57BL/6J and BALB/cJ mice display significant differences in sociability and response to drugs, but the phenotypic variability of their susceptibility to cocaine is still not well known. In this study, the differences between these two mice strains in the persistence of cocaine-induced conditioned place preference (CPP), as well as the locomotion and social behaviors after the 24-hour withdrawal from a four-day cocaine (20 mg/kg/day) administration were investigated. The results showed that the cocaine-induced CPP persisted over two weeks in C57BL/6J mice, while it diminished within one week among BALB/cJ mice. After 24-hours of cocaine withdrawal, high levels of locomotion as well as low levels of social interaction and aggressive behavior were found in C57BL/6J mice, but no significant changes were found in BALB/cJ mice, indicating that cocaine-induced CPP persistence, locomotion and social behavior are not consistent between these two strains, and that overall C57BL/6J mice are more susceptible to cocaine than BALB/cJ mice at the tested doses. PMID:25297083

Differences in cocaine-induced place preference persistence, locomotion and social behaviors between C57BL/6J and BALB/cJ mice.

PubMed

Wang, Jian-Li; Wang, Bei; Chen, Wen

2014-09-01

C57BL/6J and BALB/cJ mice display significant differences in sociability and response to drugs, but the phenotypic variability of their susceptibility to cocaine is still not well known. In this study, the differences between these two mice strains in the persistence of cocaine-induced conditioned place preference (CPP), as well as the locomotion and social behaviors after the 24-hour withdrawal from a four-day cocaine (20 mg/kg/day) administration were investigated. The results showed that the cocaine-induced CPP persisted over two weeks in C57BL/6J mice, while it diminished within one week among BALB/cJ mice. After 24-hours of cocaine withdrawal, high levels of locomotion as well as low levels of social interaction and aggressive behavior were found in C57BL/6J mice, but no significant changes were found in BALB/cJ mice, indicating that cocaine-induced CPP persistence, locomotion and social behavior are not consistent between these two strains, and that overall C57BL/6J mice are more susceptible to cocaine than BALB/cJ mice at the tested doses.

Sulfur mustard disrupts human α3β1-integrin receptors in concert with α6β4-integrin receptors and collapse of the keratin K5/K14 cytoskeleton

NASA Astrophysics Data System (ADS)

Werrlein, Robert J.; Braue, Catherine R.

2004-06-01

Sulfur mustard (SM; bis(2-chloroethyl) sulfide) is a chemical warfare agent that produces persistent, incapacitating blisters of the skin. The lesions inducing vesication remain elusive, and there is no completely effective treatment. Using mulitphoton microscopy and immunofluorescent staining, we found that exposing human epidermal keratinocytes (HEK) and intact epidermis to SM (400 μm for 5 min) caused progressive collapse of the keratin (K5/K14) cytoskeleton and depletion of α6β integrins. We now report that SM causes concomitant disruption nad collapse of the basal cell's α3β1-integrin receptors. At 1 h postexposure, images of Alexa488-conjugated HEK/α3β1 integrins showed almost complete withdrawal and disappearance of retraction fibers and a progressive loss of polarized mobility. With stero imaging, in vitro expression of this SM effect was characterized by collapse and abutment of adjacent cell membranes. At 2 h postexposure, there was an average 13% dorso-ventral collapse of HEK membranes that paralleled progressive collapse of the K5/K14 cytoskeleton. α3β1 integrin, like α6β4 integrin, is a regulator of cytoskeletal assembly, a receptor for laminin 5 and a mediator of HEK attachment to the basement membrane. Our images indicate that SM disrupts these receptors. We suggest that the progressive disruption destabilizes and potentiates blistering of the epidermal-dermal junction.

Parsing apart the persisters: Etiological mechanisms and criminal offense patterns of moderate- and high-level persistent offenders.

PubMed

Amemiya, Jamie; Vanderhei, Susan; Monahan, Kathryn C

2017-08-01

Longitudinal investigations that have applied Moffitt's dual taxonomic framework to criminal offending have provided support for the existence of adolescent-limited and life-course persistent antisocial individuals, but have also identified additional trajectories. For instance, rather than a single persistent trajectory, studies have found both high-level and moderate-level persistent offenders. To inform theory and progress our understanding of chronic antisocial behavior, the present study used a sample of serious adolescent offenders (N =1,088) followed from middle adolescence to early adulthood (14-25 years), and examined how moderate-level persistent offenders differed from low-rate, desisting, and high-level persistent offenders. Results indicated that moderate-level persisters' etiology and criminal offense patterns were most similar to high-level persisters, but there were notable differences. Specifically, increasing levels of contextual adversity characterized both moderate-level and high-level persisting trajectories, but moderate-level persisters reported consistently lower levels of environmental risk. While both high- and moderate-level persisters committed more drug-related offenses in early adulthood compared to adolescence, moderate-level persisters engaged in lower levels of antisocial behavior across all types of criminal offenses. Taken cumulatively, the findings of this study suggest that sociocontextual interventions may be powerful in reducing both moderate- and high-level persistence in crime.

Immune response of Staphylococcus aureus strains in a mouse mastitis model is linked to adaptive capacity and genotypic profiles.

PubMed

Pereyra, Elizabet A L; Sacco, Sofía C; Duré, Andrea; Baravalle, Celina; Renna, María S; Andreotti, Carolina S; Monecke, Stefan; Calvinho, Luis F; Dallard, Bibiana E

2017-05-01

Staphylococcus aureus is one of the most frequently isolated major pathogens from intramammary infections (IMI) worldwide. The mechanisms by which S. aureus IMI are established and maintained in dairy cows involve both bacterial escape strategies and modulation of the host immune response. Moreover, it was shown that different S. aureus strains have varying effects on the immune response. The aim of this study was to investigate the immune response in a mouse mastitis model of two S. aureus strains isolated from bovine IMI with different clinical manifestation (persistent-P or non-persistent-NP), phenotypic and genotypic profile. Both strains were capable of establishing an IMI after 264h post inoculation (pi). Strain A (NP) showed a more aggressive behaviour than strain B (P) at early stages of IMI, while strain B multiplied initially at a lower rate but increased its replication capacity from 120h pi to the end of the study (264h pi). Strain A triggered a stronger initial inflammatory response compared with strain B inducing higher gene and protein expression of TLR2, NF-κB activation and higher gene expression of IL-1α at initial stage of IMI (6-12h pi) but inducing extensive mammary tissue damage. Immune cells response was different for each S. aureus strain throughout the course of infection, showing mammary glands inoculated with strain A greater initial immune cells stimulation compared with strain B and then a second immune cells stimulation (from 120 to 264h pi) represented by monocytes-macrophages, T and B lymphocytes, mainly stimulated by strain B, consistent with inflammatory process becoming chronic. Strain-specific pathogenicity observed underscores the importance of pathogen factors in the progression of the infectious process. These results contribute to increase the available information on host-pathogen interaction and point out for the need of further research to expand the knowledge about these interactions for developing new strategies to intervene in the IMI progress. Copyright © 2017 Elsevier B.V. All rights reserved.

The Glass Ceiling: Progress and Persistent Challenges

ERIC Educational Resources Information Center

McLlwain, Wendy M.

2012-01-01

It has been written that since 2001, there has not been any significant progress and the glass ceiling is still intact. Women are still underrepresented in top positions (Anonymous, 2004). If this is true, the glass ceiling presents a major barrier between women and their desire to advance into executive or senior management positions. In addition…

Advising and Progress in the Community College STEM Transfer Pathway

ERIC Educational Resources Information Center

Packard, Becky Wai-Ling; Jeffers, Kimberly C.

2013-01-01

Community college students enrolled in science and technology fields face many challenges as they pursue transfer pathways to earn a 4-year degree. Despite clear links to student persistence, advising interactions that facilitate or inhibit transfer progress are not clearly understood. In this study, 82 community college students pursuing science…

Observation of long-lived persistent spin polarization in a topological insulator

NASA Astrophysics Data System (ADS)

Tian, Jifa; Hong, Seokmin; Miotkowski, Ireneusz; Datta, Supriyo; Chen, Yong P.

3D Topological insulators (TI), featuring helically spin-momentum-locked topological surface states (TSS), are considered promising for spintronics applications. Several recent experiments in TIs have demonstrated a current induced electronic spin polarization that may be used for all electrical spin generation and injection. Here, we report spin potentiometric measurements in TIs that have revealed a long-lived persistent electron spin polarization even at zero current. Unaffected by a small bias current and persisting for several days at low temperature, the spin polarization can be induced and reversed by a large ``writing'' current applied for an extended time. Such an electrically controlled persistent spin polarization with unprecedented long lifetime could enable a rechargeable spin battery and rewritable spin memory for potential applications in spintronics and quantum information.

TMJ inflammation increases Fos expression in the nucleus raphe magnus induced by subsequent formalin injection of the masseter or hindpaw of rats.

PubMed

Oh, Sang-Hoon; Imbe, Hiroki; Iwai-Liao, Yasutomo

2006-08-01

The study was designed to examine the effect of persistent temporomandibular joint (TMJ) inflammation on neuronal activation in the descending pain modulatory system in response to noxious stimulus. Formalin was injected into the left masseter muscle or hindpaw of rats 10 days after injection of the left TMJ with saline or complete Freund's adjuvant (CFA). The results showed that 10-day persistent TMJ inflammation (induced by CFA) alone did not induce a significant increase in Fos-like immunoreactive (Fos-LI) neurons in the rostral ventromedial medulla (RVM) or locus coeruleus (LC), but that formalin injection of the masseter muscle or hindpaw induced a significant increase in Fos-LI neurons in the RVM and LC of rats with and without TMJ inflammation (P < 0.05). However, persistent TMJ inflammation significantly increased Fos-LI neurons in the nucleus raphe magnus (NRM) induced by subsequent formalin injection of the masseter muscle and hindpaw (70.2% increase and 53.8% increase, respectively, over the control TMJ-saline-injected rats; P < 0.05). The results suggest that persistent TMJ inflammation increases neuronal activity, in particularly in the NRM, by the plastic change of the descending pain modulatory system after ipsilateral application of a noxious stimulus to either orofacial area or a spatially remote body area.

Persistent increased PKMζ in long-term and remote spatial memory.

PubMed

Hsieh, Changchi; Tsokas, Panayiotis; Serrano, Peter; Hernández, A Iván; Tian, Dezhi; Cottrell, James E; Shouval, Harel Z; Fenton, André Antonio; Sacktor, Todd Charlton

2017-02-01

PKMζ is an autonomously active PKC isoform that is thought to maintain both LTP and long-term memory. Whereas persistent increases in PKMζ protein sustain the kinase's action in LTP, the molecular mechanism for the persistent action of PKMζ during long-term memory has not been characterized. PKMζ inhibitors disrupt spatial memory when introduced into the dorsal hippocampus from 1day to 1month after training. Therefore, if the mechanisms of PKMζ's persistent action in LTP maintenance and long-term memory were similar, persistent increases in PKMζ would last for the duration of the memory, far longer than most other learning-induced gene products. Here we find that spatial conditioning by aversive active place avoidance or appetitive radial arm maze induces PKMζ increases in dorsal hippocampus that persist from 1day to 1month, coinciding with the strength and duration of memory retention. Suppressing the increase by intrahippocampal injections of PKMζ-antisense oligodeoxynucleotides prevents the formation of long-term memory. Thus, similar to LTP maintenance, the persistent increase in the amount of autonomously active PKMζ sustains the kinase's action during long-term and remote spatial memory maintenance. Copyright © 2016. Published by Elsevier Inc.

Catheterization alters bladder ecology to potentiate Staphylococcus aureus infection of the urinary tract.

PubMed

Walker, Jennifer N; Flores-Mireles, Ana L; Pinkner, Chloe L; Schreiber, Henry L; Joens, Matthew S; Park, Alyssa M; Potretzke, Aaron M; Bauman, Tyler M; Pinkner, Jerome S; Fitzpatrick, James A J; Desai, Alana; Caparon, Michael G; Hultgren, Scott J

2017-10-10

Methicillin-resistant Staphylococcus aureus (MRSA) is an emerging cause of catheter-associated urinary tract infection (CAUTI), which frequently progresses to more serious invasive infections. We adapted a mouse model of CAUTI to investigate how catheterization increases an individual's susceptibility to MRSA UTI. This analysis revealed that catheterization was required for MRSA to achieve high-level, persistent infection in the bladder. As shown previously, catheter placement induced an inflammatory response resulting in the release of the host protein fibrinogen (Fg), which coated the bladder and implant. Following infection, we showed that MRSA attached to the urothelium and implant in patterns that colocalized with deposited Fg. Furthermore, MRSA exacerbated the host inflammatory response to stimulate the additional release and accumulation of Fg in the urinary tract, which facilitated MRSA colonization. Consistent with this model, analysis of catheters from patients with S. aureus -positive cultures revealed colocalization of Fg, which was deposited on the catheter, with S. aureus Clumping Factors A and B (ClfA and ClfB) have been shown to contribute to MRSA-Fg interactions in other models of disease. We found that mutants in clfA had significantly greater Fg-binding defects than mutants in clfB in several in vitro assays. Paradoxically, only the ClfB - strain was significantly attenuated in the CAUTI model. Together, these data suggest that catheterization alters the urinary tract environment to promote MRSA CAUTI pathogenesis by inducing the release of Fg, which the pathogen enhances to persist in the urinary tract despite the host's robust immune response.

Catheterization alters bladder ecology to potentiate Staphylococcus aureus infection of the urinary tract

PubMed Central

Walker, Jennifer N.; Flores-Mireles, Ana L.; Pinkner, Chloe L.; Schreiber, Henry L.; Joens, Matthew S.; Park, Alyssa M.; Potretzke, Aaron M.; Bauman, Tyler M.; Pinkner, Jerome S.; Fitzpatrick, James A. J.; Desai, Alana; Caparon, Michael G.

2017-01-01

Methicillin-resistant Staphylococcus aureus (MRSA) is an emerging cause of catheter-associated urinary tract infection (CAUTI), which frequently progresses to more serious invasive infections. We adapted a mouse model of CAUTI to investigate how catheterization increases an individual’s susceptibility to MRSA UTI. This analysis revealed that catheterization was required for MRSA to achieve high-level, persistent infection in the bladder. As shown previously, catheter placement induced an inflammatory response resulting in the release of the host protein fibrinogen (Fg), which coated the bladder and implant. Following infection, we showed that MRSA attached to the urothelium and implant in patterns that colocalized with deposited Fg. Furthermore, MRSA exacerbated the host inflammatory response to stimulate the additional release and accumulation of Fg in the urinary tract, which facilitated MRSA colonization. Consistent with this model, analysis of catheters from patients with S. aureus-positive cultures revealed colocalization of Fg, which was deposited on the catheter, with S. aureus. Clumping Factors A and B (ClfA and ClfB) have been shown to contribute to MRSA–Fg interactions in other models of disease. We found that mutants in clfA had significantly greater Fg-binding defects than mutants in clfB in several in vitro assays. Paradoxically, only the ClfB− strain was significantly attenuated in the CAUTI model. Together, these data suggest that catheterization alters the urinary tract environment to promote MRSA CAUTI pathogenesis by inducing the release of Fg, which the pathogen enhances to persist in the urinary tract despite the host’s robust immune response. PMID:28973850

Targeting extinction and reconsolidation mechanisms to combat the impact of drug cues on addiction.

PubMed

Taylor, Jane R; Olausson, Peter; Quinn, Jennifer J; Torregrossa, Mary M

2009-01-01

Drug addiction is a progressive and compulsive disorder, where recurrent craving and relapse to drug-seeking occur even after long periods of abstinence. A major contributing factor to relapse is drug-associated cues. Here we review behavioral and pharmacological studies outlining novel methods of effective and persistent reductions in cue-induced relapse behavior in animal models. We focus on extinction and reconsolidation of cue-drug associations as the memory processes that are the most likely targets for interventions. Extinction involves the formation of new inhibitory memories rather than memory erasure; thus, it should be possible to facilitate the extinction of cue-drug memories to reduce relapse. We propose that context-dependency of extinction might be altered by mnemonic agents, thereby enhancing the efficacy of cue-exposure therapy as treatment strategy. In contrast, interfering with memory reconsolidation processes can disrupt the integrity or strength of specific cue-drug memories. Reconsolidation is argued to be a distinct process that occurs over a brief time period after memory is reactivated/retrieved - when the memory becomes labile and vulnerable to disruption. Reconsolidation is thought to be an independent, perhaps opposing, process to extinction and disruption of reconsolidation has recently been shown to directly affect subsequent cue-drug memory retrieval in an animal model of relapse. We hypothesize that a combined approach aimed at both enhancing the consolidation of cue-drug extinction and interfering with the reconsolidation of cue-drug memories will have a greater potential for persistently inhibiting cue-induced relapse than either treatment alone.

Difference Between Cryotherapy and Follow Up Low Grade Squamous Lesion of Cervix Uteri.

PubMed

Jahic, Mahira; Jahic, Elmir; Mulavdic, Mirsada; Hadzimehmedovic, Azra

2017-08-01

Cervical cancer can be successfully prevented by effective treatment. Analyse of success of cryotherapy in LSIL and ASCUS. In retrospective study between January 2016 to March 2017, 3244 PAP test were analysed. 257 patients who had been diagnosed with LSIL and ASCUS from PAP smear were divided in two groups: women who had HPV positive, colposcopic positive and cytologic finding of LSIL or ASCUS treathed with cryotherapy and women with LSIL, ASCUS and negative colposcopy. χ 2 test was used for statistical analysis of data. Analysis of 3244 PAP smears showed negative for intraepithelial lesion or malignancy (NILM) in 90,10% (N-2923), and abnormal in 9,8% (N-321) of women. ASCUS was found in 4,8% (N-156) and ASC-H in 0,2% (N-6), LSIL in 3,1% (N-101), HSIL in 0,64% (N-21). The average age of patients with ASCUS lesion was 41 ± 12 years. After cryotherapy, HSIL had progression in 1,5% (N-1), persistence in 6,3% (N-4) and regression in 91,7% (N-58). Progression occured in 10,5% (N-4) of HSIL, persistence in 52,6% (N-20) and regression in 36,7% (N-14) in 38 women with LSIL lesion after repeated PAP test. Progression occured in 8% (N-10) of LSIL and 4% HSIL (N-5), persistence in 58% (N-72) and regression in 29,8% (N-37) in 124 women with ASCUS lesion after treatment and repeated PAP test. Difference in progression lesions in HSIL between women with cryotherapy (1,5%) and follow-up (10,5%) after LSIL is not significant, but progression to CIN II occured after cryotherapy. CIN III or cervical cancer was not found. Cryotherapy prevents progression of LSIL in HSIL and in cervical cancer. Because of that cryotherapy is successful method in prevention of cervical cancer.

Difference Between Cryotherapy and Follow Up Low Grade Squamous Lesion of Cervix Uteri

PubMed Central

Jahic, Mahira; Jahic, Elmir; Mulavdic, Mirsada; Hadzimehmedovic, Azra

2017-01-01

Introduction: Cervical cancer can be successfully prevented by effective treatment. Aim: Analyse of success of cryotherapy in LSIL and ASCUS. Materials et methods: In retrospective study between January 2016 to March 2017, 3244 PAP test were analysed. 257 patients who had been diagnosed with LSIL and ASCUS from PAP smear were divided in two groups: women who had HPV positive, colposcopic positive and cytologic finding of LSIL or ASCUS treathed with cryotherapy and women with LSIL, ASCUS and negative colposcopy. χ2 test was used for statistical analysis of data. Results: Analysis of 3244 PAP smears showed negative for intraepithelial lesion or malignancy (NILM) in 90,10% (N-2923), and abnormal in 9,8% (N-321) of women. ASCUS was found in 4,8% (N-156) and ASC-H in 0,2% (N-6), LSIL in 3,1% (N-101), HSIL in 0,64% (N-21). The average age of patients with ASCUS lesion was 41 ± 12 years. After cryotherapy, HSIL had progression in 1,5% (N-1), persistence in 6,3% (N-4) and regression in 91,7% (N-58). Progression occured in 10,5% (N-4) of HSIL, persistence in 52,6% (N-20) and regression in 36,7% (N-14) in 38 women with LSIL lesion after repeated PAP test. Progression occured in 8% (N-10) of LSIL and 4% HSIL (N-5), persistence in 58% (N-72) and regression in 29,8% (N-37) in 124 women with ASCUS lesion after treatment and repeated PAP test. Difference in progression lesions in HSIL between women with cryotherapy (1,5%) and follow-up (10,5%) after LSIL is not significant, but progression to CIN II occured after cryotherapy. CIN III or cervical cancer was not found. Conclusion: Cryotherapy prevents progression of LSIL in HSIL and in cervical cancer. Because of that cryotherapy is successful method in prevention of cervical cancer. PMID:28974850

MazEF toxin-antitoxin proteins alter Escherichia coli cell morphology and infrastructure during persister formation and regrowth.

PubMed

Cho, Junho; Carr, Anita Nicole; Whitworth, Lisa; Johnson, Brent; Wilson, Kevin Scott

2017-03-01

When exposed to antibiotics, many bacteria respond by activating intracellular 'toxin' proteins, which arrest cell growth and induce formation of persister cells that survive antibiotics. After antibiotics are removed, persisters can regrow by synthesizing 'antitoxin' proteins that sequester toxin proteins. In Escherichia coli, MazE antitoxin sequesters the activity of MazF toxin, which extensively cleaves cellular RNAs. Although the functions of MazEF proteins are well characterized, there is surprisingly little known about their effects on cell structure. Here, using a combination of microscopy techniques, we visualized the effects of MazEF and three bactericidal antibiotics on E. coli cell morphology and infrastructure. When ectopically expressed in E. coli, MazF temporarily stalled cell growth and induced persister formation, but only mildly elevated DNA mutagenesis. Viewed by electron microscopy, MazF-expressing persister cells were arrested in cell growth and division. Their chromosomal DNAs were compacted into thread-like structures. Their ribosomes were excluded from their nucleoids. After exposure to ciprofloxacin, persister regrowth was activated by MazE. Cell division remained inhibited while cells became extraordinarily elongated, then divided multiple times during stationary growth phase. This extreme filamentation during persister regrowth was unique to ciprofloxacin-treated persisters, likely caused by inhibition of cell division during regrowth, and was not observed with kanamycin-treated persisters.

Spontaneously obese dogs exhibit greater postprandial glucose, triglyceride, and insulin concentrations than lean dogs.

PubMed

Verkest, K R; Rand, J S; Fleeman, L M; Morton, J M

2012-02-01

Dogs do not appear to progress from obesity-induced insulin resistance to type 2 diabetes mellitus. Both postprandial hyperglycemia and postprandial hypertriglyceridemia have been proposed to cause or maintain beta cell failure and progression to type 2 diabetes mellitus in other species. Postprandial glucose, triglyceride, and insulin concentrations have not been compared in lean and obese dogs. We measured serum glucose, triglyceride, and insulin concentrations in nine naturally occurring obese and nine age- and gender-matched lean dogs. After a 24-h fast, dogs were fed half their calculated daily energy requirement of a standardized diet that provided 37% and 40% of metabolizable energy as carbohydrate and fat, respectively. Fasting and postprandial glucose and triglyceride concentrations were greater in the obese dogs (P < 0.001), although the mean insulin concentration for this group was five times greater than that of the lean group (P < 0.001). Most of the 0.6 mM (11 mg/dL) difference in mean postprandial glucose concentrations between lean and obese dogs was attributable to a subset of persistently hyperglycemic obese dogs with mean postprandial glucose concentrations 1.0 mM (18 mg/dL) greater than that in lean dogs. Persistently hyperglycemic obese dogs had lower triglyceride (P = 0.02 to 0.04) and insulin (P < 0.02) concentrations than other obese dogs. None of the dogs developed clinical signs of diabetes mellitus during follow-up for a median of 2.6 yr. We conclude that pancreatic beta cells in dogs are either not sensitive to toxicity because of mild hyperglycemia or lack another component of the pathophysiology of beta cell failure in type 2 diabetes mellitus. Copyright © 2012 Elsevier Inc. All rights reserved.

A Quantitative Analysis of a Mandatory Student Success Course on First-Time Full-Time Student College Academic Progress and Persistence

ERIC Educational Resources Information Center

Klinkenberg, Laurel Beth

2013-01-01

In recent years, community colleges have come into the spotlight nationally in terms of their potential to assist in the revitalization of the economy. This has resulted in an increased need for community colleges to understand more fully the factors that influence student persistence. The purpose of this quasi-experimental study was to…

[Analysis of the etiological structure of sexually transmitted infections and immunological responsiveness in women with papillomavirus infection of the cervix uteri].

PubMed

Shevchenko, E A; Uspenskaia, O A

2009-01-01

Two sexually transmitted infections or more were more frequently encountered in persistent papillomavirus infection (PVI) than those in transient PVI. The found immunological parameters in PVI arrested further infection progression, suppressed the persistence of human papillomavirus infection types 16 and 18, and prevented related cancer. This might eliminate the virus from the body.

Magnesium ions and opioid agonists in vincristine-induced neuropathy.

PubMed

Bujalska, Magdalena; Makulska-Nowak, Helena; Gumułka, Stanisław W

2009-01-01

Neuropathic pain is difficult to treat. Classic analgesics (i.e., opioid receptor agonists) usually possess low activity. Therefore other agents such as antidepressants, anticonvulsants, and corticosteroids are used. It is commonly known that NMDA antagonists increase analgesic activity of opioids. Unfortunately, clinical use of NMDA antagonists is limited because of the relatively frequent occurrence of adverse effects e.g., memory impairment, psychomimetic effects, ataxia and motor in-coordination. Magnesium ions (Mg(2+)) are NMDA receptor blockers in physiological conditions. Therefore, in this study the effect of opioid receptor agonists and the influence of Mg(2+) on the action of opioid agonists in vincristine-induced hyperalgesia were examined. Opioid agonists such as morphine (5 mg/kg, ip), and fentanyl (0.0625 mg/kg, ip), as well as the partial agonist buprenorphine (0.075 mg/kg, ip) administered alone on 5 consecutives days did not modify the hyperalgesia in vincristine rats. In contrast, pretreatment with a low dose of magnesium sulfate (30 mg/kg, ip) resulted in a progressive increase of the analgesic action of all three investigated opioids. After discontinuation of drug administration, the effect persisted for several days.

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

Itoh, Masahiko; Nelson, Celeste M.; Myers, Connie A.

Maintenance of apico-basal polarity in normal breast epithelial acini requires a balance between cell proliferation, cell death, and proper cell-cell and cell-extracellular matrix signaling. Aberrations in any of these processes can disrupt tissue architecture and initiate tumor formation. Here we show that the small GTPase Rap1 is a crucial element in organizing acinar structure and inducing lumen formation. Rap1 activity in malignant HMT-3522 T4-2 cells is appreciably higher than in S1 cells, their non-malignant counterparts. Expression of dominant-negative Rap1 resulted in phenotypic reversion of T4-2 cells, led to formation of acinar structures with correct apico-basal polarity, and dramatically reduced tumormore » incidence despite the persistence of genomic abnormalities. The resulting acini contained prominent central lumina not observed when other reverting agents were used. Conversely, expression of dominant-active Rap1 in T4-2 cells inhibited phenotypic reversion and led to increased invasiveness and tumorigenicity. Thus, Rap1 acts as a central regulator of breast architecture, with normal levels of activation instructing apical polarity during acinar morphogenesis, and increased activation inducing tumor formation and progression to malignancy.« less

New Approaches to Immunotherapy for HPV Associated Cancers

PubMed Central

Bergot, Anne-Sophie; Kassianos, Andrew; Frazer, Ian H; Mittal, Deepak

2011-01-01

Cervical cancer is the second most common cancer of women worldwide and is the first cancer shown to be entirely induced by a virus, the human papillomavirus (HPV, major oncogenic genotypes HPV-16 and -18). Two recently developed prophylactic cervical cancer vaccines, using virus-like particles (VLP) technology, have the potential to prevent a large proportion of cervical cancer associated with HPV infection and to ensure long-term protection. However, prophylactic HPV vaccines do not have therapeutic effects against pre-existing HPV infections and do not prevent their progression to HPV-associated malignancy. In animal models, therapeutic vaccines for persisting HPV infection can eliminate transplantable tumors expressing HPV antigens, but are of limited efficacy in inducing rejection of skin grafts expressing the same antigens. In humans, clinical trials have reported successful immunotherapy of HPV lesions, providing hope and further interest. This review discusses possible new approaches to immunotherapy for HPV associated cancer, based on recent advances in our knowledge of the immunobiology of HPV infection, of epithelial immunology and of immunoregulation, with a brief overview on previous and current HPV vaccine clinical trials. PMID:24212964

Murine CMV-Induced Hearing Loss Is Associated with Inner Ear Inflammation and Loss of Spiral Ganglia Neurons

PubMed Central

Golemac, Mijo; Pugel, Ester Pernjak; Jonjic, Stipan; Britt, William J.

2015-01-01

Congenital human cytomegalovirus (HCMV) occurs in 0.5–1% of live births and approximately 10% of infected infants develop hearing loss. The mechanism(s) of hearing loss remain unknown. We developed a murine model of CMV induced hearing loss in which murine cytomegalovirus (MCMV) infection of newborn mice leads to hematogenous spread of virus to the inner ear, induction of inflammatory responses, and hearing loss. Characteristics of the hearing loss described in infants with congenital HCMV infection were observed including, delayed onset, progressive hearing loss, and unilateral hearing loss in this model and, these characteristics were viral inoculum dependent. Viral antigens were present in the inner ear as were CD3+ mononuclear cells in the spiral ganglion and stria vascularis. Spiral ganglion neuron density was decreased after infection, thus providing a mechanism for hearing loss. The lack of significant inner ear histopathology and persistence of inflammation in cochlea of mice with hearing loss raised the possibility that inflammation was a major component of the mechanism(s) of hearing loss in MCMV infected mice. PMID:25875183

RFWD3-Mediated Ubiquitination Promotes Timely Removal of Both RPA and RAD51 from DNA Damage Sites to Facilitate Homologous Recombination.

PubMed

Inano, Shojiro; Sato, Koichi; Katsuki, Yoko; Kobayashi, Wataru; Tanaka, Hiroki; Nakajima, Kazuhiro; Nakada, Shinichiro; Miyoshi, Hiroyuki; Knies, Kerstin; Takaori-Kondo, Akifumi; Schindler, Detlev; Ishiai, Masamichi; Kurumizaka, Hitoshi; Takata, Minoru

2017-06-01

RFWD3 is a recently identified Fanconi anemia protein FANCW whose E3 ligase activity toward RPA is essential in homologous recombination (HR) repair. However, how RPA ubiquitination promotes HR remained unknown. Here, we identified RAD51, the central HR protein, as another target of RFWD3. We show that RFWD3 polyubiquitinates both RPA and RAD51 in vitro and in vivo. Phosphorylation by ATR and ATM kinases is required for this activity in vivo. RFWD3 inhibits persistent mitomycin C (MMC)-induced RAD51 and RPA foci by promoting VCP/p97-mediated protein dynamics and subsequent degradation. Furthermore, MMC-induced chromatin loading of MCM8 and RAD54 is defective in cells with inactivated RFWD3 or expressing a ubiquitination-deficient mutant RAD51. Collectively, our data reveal a mechanism that facilitates timely removal of RPA and RAD51 from DNA damage sites, which is crucial for progression to the late-phase HR and suppression of the FA phenotype. Copyright © 2017 Elsevier Inc. All rights reserved.

The pharmacology of second-generation chimeric antigen receptors.

PubMed

van der Stegen, Sjoukje J C; Hamieh, Mohamad; Sadelain, Michel

2015-07-01

Second-generation chimeric antigen receptors (CARs) retarget and reprogramme T cells to augment their antitumour efficacy. The combined activating and co-stimulatory domains incorporated in these CARs critically determine the function, differentiation, metabolism and persistence of engineered T cells. CD19-targeted CARs that incorporate CD28 or 4-1BB signalling domains are the best known to date. Both have shown remarkable complete remission rates in patients with refractory B cell malignancies. Recent data indicate that CD28-based CARs direct a brisk proliferative response and boost effector functions, whereas 4-1BB-based CARs induce a more progressive T cell accumulation that may compensate for less immediate potency. These distinct kinetic features can be exploited to further develop CAR-based T cell therapies for a variety of cancers. A new field of immunopharmacology is emerging.

[Periodic oscillating respiration outside of comatous stages].

PubMed

Jammes, Y; Delpierre, S; Zwirn, P; Nicoli, M M

1977-04-01

A periodic oscillating breathing was observed in 11 subjects during study of their pulmonary function. All these patients were male and more than 50 years old. A cardiovascular disease was clinically evident in eight of them. Arterial hypoxemia was found in five subjects and a light hypocapnia in three. Analysis of oscillating rhythms first, revealed unexistence of ventilatory pauses between periods of deep breaths in some subjects and secondly, showed existence of permanent or discontinuous periodic rhythms. Breath by breath changes in ventilation were essentially induced by oscillations in tidal volume. Discontinuous oscillating breathing appeared after forced maximal inspiration and this periodic rhythm was frequently associated with sights. This periodic breathing began or persisted under progressive hypoxia but disappeared under normobaric hyperoxia. These data are discussed in terms of changes in the ventilatory control system and in central regulation of breathing patterns.

Metabolic memory and chronic diabetes complications: potential role for epigenetic mechanisms.

PubMed

Intine, Robert V; Sarras, Michael P

2012-10-01

Recent estimates indicate that diabetes mellitus currently affects more than 10 % of the world's population. Evidence from both the laboratory and large scale clinical trials has revealed that prolonged hyperglycemia induces chronic complications which persist and progress unimpeded even when glycemic control is pharmaceutically achieved via the phenomenon of metabolic memory. The epigenome is comprised of all chromatin modifications including post translational histone modification, expression control via miRNAs and the methylation of cytosine within DNA. Modifications of these epigenetic marks not only allow cells and organisms to quickly respond to changing environmental stimuli but also confer the ability of the cell to "memorize" these encounters. As such, these processes have gained much attention as potential molecular mechanisms underlying metabolic memory and chronic diabetic complications. Here we present a review of the very recent literature published pertaining to this subject.

Clonal evolution and progression of 20-methylcholanthrene-induced squamous cell carcinoma of mouse epidermis as revealed by DNA instability and other malignancy markers.

PubMed

Hirai, K; Kumakiri, M; Ueda, K; Imamura, Y; Noriki, S; Nishi, Y; Kato, H; Fukuda, M

2001-01-01

We examined the clonal evolution of skin malignant lesions by repeated topical applications of 20-methylcholanthrene (20-MC) to the skin, which induces hyperplastic epidermis, papillomatous lesion and invasive carcinoma in mice. The lesions were examined histologically and immunohistochemically with anti-single-stranded DNA after acid hydrolysis (DNA-instability test), p53, VEGF, DFF45, PCNA and AgNORs parameters analyses. Multiple clones with increased DNA instability comparable to that of invasive carcinoma were noted in early-stage (2-6 weeks) hyperplastic epidermis, and their number increased in middle (7-11 weeks), and late-stages (12-25 weeks) of hyperplastic epidermis, indicating that they belong to the malignancy category. All papillomatous lesions and invasive carcinomas showed a positive DNA-instability test. Positive immunostaining for various biomarkers and AgNORs parameters appeared in clones with a positive DNA-instability test in early-or middle-stage hyperplastic epidermis, and markedly increased in late-stage hyperplastic epidermis, papillomatous lesions and invasive carcinomas. The percentage of PCNA-positive vascular endothelial cells was significantly higher in VEGF-positive lesions with a positive DNA-instability test and became higher toward the late-stage of progression. Cut-woundings were made to papillomatous and invasive carcinoma lesions, and the regeneration activity of vascular endothelial cells was determined by using flash labeling with tritiated thymidine (3H-TdR). In small papillomatous lesions, vascular endothelial cells showed regenerative response, but the response was weak in large lesions. No such response was noted in invasive carcinomas; rather, cut-wounding induced collapse of blood vessels, which in turn induced massive coagulative necrosis of cancer cells. These responses can be interpreted to reflect exhausted vascular growth activity due to excessive stimulation by VEGF-overexpression, which was persistently seen from hyperplastic epidermis to invasive carcinoma.

Fundamental Research in Engineering Education. Identifying and Repairing Student Misconceptions in Thermal and Transport Science: Concept Inventories and Schema Training Studies

ERIC Educational Resources Information Center

Miller, Ronald L.; Streveler, Ruth A.; Yang, Dazhi; Roman, Aidsa I. Santiago

2011-01-01

This paper summarizes progress on two related lines of chemical engineering education research: 1) identifying persistent student misconceptions in thermal and transport science (fluid mechanics, heat transfer, and thermodynamics); and, 2) developing a method to help students repair these misconceptions. Progress on developing the Thermal and…

The Idea and Ideology of Progress in Social and Educational Thought.

ERIC Educational Resources Information Center

Popkewitz, Thomas S.

One of the most important myths in education is that of progress. The idea derives from a specifically Western messianic tradition and contains the belief in the growth and the development of an organism. That belief emerges from Greek and Hebraic thought, is modified in Christian theology, and then is secularized in science. The persistence and…

Characterization of Different Microbubbles in Assisting Focused Ultrasound-Induced Blood-Brain Barrier Opening

NASA Astrophysics Data System (ADS)

Wu, Sheng-Kai; Chu, Po-Chun; Chai, Wen-Yen; Kang, Shih-Tsung; Tsai, Chih-Hung; Fan, Ching-Hsiang; Yeh, Chih-Kuang; Liu, Hao-Li

2017-04-01

Microbubbles (MBs) serve as a critical catalyst to amplify local cavitation in CNS capillary lumen to facilitate focused ultrasound (FUS) to transiently open the blood-brain barrier (BBB). However, limited understanding is available regarding the effect of different microbubbles to induce BBB opening. The aim of this study is to characterize different MBs on their effect in FUS-induced BBB opening. Three MBs, SonoVue, Definity, and USphere, were tested, with 0.4-MHz FUS exposure at 0.62-1.38 of mechanical index (MI) on rats. Evans blue, dynamic contrast-enhanced (DCE) MRI and small-animal ultrasound imaging were used as surrogates to allow molecule-penetrated quantification, BBB-opened observation, and MBs circulation/persistence. Cavitation activity was measured via the passive cavitation detection (PCD) setup to correlate with the exposure level and the histological effect. Under given and identical MB concentrations, the three MBs induced similar and equivalent BBB-opening effects and persistence. In addition, a treatment paradigm by adapting exposure time is proposed to compensate MB decay to retain the persistence of BBB-opening efficiency in multiple FUS exposures. The results potentially improve understanding of the equivalence among MBs in focused ultrasound CNS drug delivery, and provide an effective strategy for securing persistence in this treatment modality.

Progression and recovery of Parkinsonism in a chronic progressive MPTP-induction model in the marmoset without persistent molecular and cellular damage.

PubMed

Franke, S K; van Kesteren, R E; Wubben, J A M; Hofman, S; Paliukhovich, I; van der Schors, R C; van Nierop, P; Smit, A B; Philippens, I H C H M

2016-01-15

Chronic exposure to low-dose 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in marmoset monkeys was used to model the prodromal stage of Parkinson's disease (PD), and to investigate mechanisms underlying disease progression and recovery. Marmosets were subcutaneously injected with MPTP for a period of 12weeks, 0.5mg/kg once per week, and clinical signs of Parkinsonism, motor- and non-motor behaviors were recorded before, during and after exposure. In addition, postmortem immunohistochemistry and proteomics analysis were performed. MPTP-induced parkinsonian clinical symptoms increased in severity during exposure, and recovered after MPTP administration was ended. Postmortem analyses, after the recovery period, revealed no alteration of the number and sizes of tyrosine hydroxylase (TH)-positive dopamine (DA) neurons in the substantia nigra. Also levels of TH in putamen and caudate nucleus were unaltered, no differences were observed in DA, serotonin or nor-adrenalin levels in the caudate nucleus, and proteomics analysis revealed no global changes in protein expression in these brain areas between treatment groups. Our findings indicate that parkinsonian symptoms can occur without detectable damage at the cellular or molecular level. Moreover, we show that parkinsonian symptoms may be reversible when diagnosed and treated early. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Induced sadness increases persistence in a simulated slot machine task among recreational gamblers.

PubMed

Devos, Gaëtan; Clark, Luke; Maurage, Pierre; Billieux, Joël

2018-05-01

Gambling may constitute a strategy for coping with depressive mood, but a direct influence of depressive mood on gambling behaviors has never been tested via realistic experimental designs in gamblers. The current study tested whether experimentally induced sadness increases persistence on a simulated slot machine task using real monetary reinforcement in recreational gamblers. Sixty participants were randomly assigned to an experimental (sadness induction) or control (no emotional induction) condition, and then performed a slot machine task consisting of a mandatory phase followed by a persistence phase. Potential confounding variables (problem gambling symptoms, impulsivity traits, gambling cognitions) were measured to ensure that the experimental and control groups were comparable. The study showed that participants in the sadness condition displayed greater gambling persistence than control participants (p = .011). These data support the causal role of negative affect in decisions to gamble and persistence, which bears important theoretical and clinical implications. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Nonalcoholic Fatty Liver Disease and Fibrosis in Youth Taking Psychotropic Medications: Literature Review, Case Reports, and Management.

PubMed

Gracious, Barbara L; Bhatt, Ramona; Potter, Carol

2015-10-01

Nonalcoholic fatty liver disease (NAFLD) has become a worldwide epidemic because of the greater prevalence of obesity. Despite implications for youth with severe mental disorders, little has been published in the psychiatric literature about this increasingly common medical comorbidity. The goals of this article are to: 1) provide an overview of the epidemiology and pathophysiology of NAFLD, including progression to nonalcoholic steatohepatitis (NASH); 2) describe two clinical cases illustrating difficulties faced in management; and 3) review screening recommendations, differential diagnosis, and monitoring and intervention approaches. A literature review was conducted, including guidelines and recommendations, with case presentations including case and control liver histology biopsy photographs. NAFLD in childhood and adolescence, as a precursor to NASH, progresses to fibrosis in a small percentage of youth, leading to risk for early onset cirrhosis and the need for transplantation. The cases presented raise concern that youth with severe mental health disorders, already at greater risk for obesity and its sequelae, may be at higher risk for progression to NASH, potentially because of greater rates of weight gain on top of overweight or obese status, and to liver metabolism changes from psychotropic medications favoring fat deposition. Patients with rapid weight gain into the overweight or obese categories, or who develop elevated liver transaminases that persist across 3-6 months, should be screened or referred for screening by their psychotropic-providing clinicians for early detection, diagnosis, and co-management by a pediatric gastroenterologist, to decrease risk of progression to NASH, which is reversible if early and sufficient lifestyle change results in significant weight loss. There is urgent need for controlled research on the relationships among weight gain, psychotropic medications, ultrasound and biopsy findings, and rates of progression to NAFLD and NASH in youth taking weight-gain-inducing psychotropic medications.

Promoting professional identity, motivation, and persistence: Benefits of an informal mentoring program for female undergraduate students

PubMed Central

Bloodhart, Brittany; Barnes, Rebecca T.; Adams, Amanda S.; Clinton, Sandra M.; Pollack, Ilana; Godfrey, Elaine; Burt, Melissa; Fischer, Emily V.

2017-01-01

Women are underrepresented in a number of science, technology, engineering, and mathematics (STEM) disciplines. Limited diversity in the development of the STEM workforce has negative implications for scientific innovation, creativity, and social relevance. The current study reports the first-year results of the PROmoting Geoscience Research, Education, and SuccesS (PROGRESS) program, a novel theory-driven informal mentoring program aimed at supporting first- and second-year female STEM majors. Using a prospective, longitudinal, multi-site (i.e., 7 universities in Colorado/Wyoming Front Range & Carolinas), propensity score matched design, we compare mentoring and persistence outcomes for women in and out of PROGRESS (N = 116). Women in PROGRESS attended an off-site weekend workshop and gained access to a network of volunteer female scientific mentors from on- and off-campus (i.e., university faculty, graduate students, and outside scientific professionals). The results indicate that women in PROGRESS had larger networks of developmental mentoring relationships and were more likely to be mentored by faculty members and peers than matched controls. Mentoring support from a faculty member benefited early-undergraduate women by strengthening their scientific identity and their interest in earth and environmental science career pathways. Further, support from a faculty mentor had a positive indirect impact on women’s scientific persistence intentions, through strengthened scientific identity development. These results imply that first- and second- year undergraduate women’s mentoring support networks can be enhanced through provision of protégé training and access to more senior women in the sciences willing to provide mentoring support. PMID:29091969

Promoting professional identity, motivation, and persistence: Benefits of an informal mentoring program for female undergraduate students.

PubMed

Hernandez, Paul R; Bloodhart, Brittany; Barnes, Rebecca T; Adams, Amanda S; Clinton, Sandra M; Pollack, Ilana; Godfrey, Elaine; Burt, Melissa; Fischer, Emily V

2017-01-01

Women are underrepresented in a number of science, technology, engineering, and mathematics (STEM) disciplines. Limited diversity in the development of the STEM workforce has negative implications for scientific innovation, creativity, and social relevance. The current study reports the first-year results of the PROmoting Geoscience Research, Education, and SuccesS (PROGRESS) program, a novel theory-driven informal mentoring program aimed at supporting first- and second-year female STEM majors. Using a prospective, longitudinal, multi-site (i.e., 7 universities in Colorado/Wyoming Front Range & Carolinas), propensity score matched design, we compare mentoring and persistence outcomes for women in and out of PROGRESS (N = 116). Women in PROGRESS attended an off-site weekend workshop and gained access to a network of volunteer female scientific mentors from on- and off-campus (i.e., university faculty, graduate students, and outside scientific professionals). The results indicate that women in PROGRESS had larger networks of developmental mentoring relationships and were more likely to be mentored by faculty members and peers than matched controls. Mentoring support from a faculty member benefited early-undergraduate women by strengthening their scientific identity and their interest in earth and environmental science career pathways. Further, support from a faculty mentor had a positive indirect impact on women's scientific persistence intentions, through strengthened scientific identity development. These results imply that first- and second- year undergraduate women's mentoring support networks can be enhanced through provision of protégé training and access to more senior women in the sciences willing to provide mentoring support.

Hippocampal activation of microglia may underlie the shared neurobiology of comorbid posttraumatic stress disorder and chronic pain.

PubMed

Sun, Rao; Zhang, Zuoxia; Lei, Yishan; Liu, Yue; Lu, Cui'e; Rong, Hui; Sun, Yu'e; Zhang, Wei; Ma, Zhengliang; Gu, Xiaoping

2016-01-01

The high comorbidity rates of posttraumatic stress disorder and chronic pain have been widely reported, but the underlying mechanisms remain unclear. Emerging evidence suggested that an excess of inflammatory immune activities in the hippocampus involved in the progression of both posttraumatic stress disorder and chronic pain. Considering that microglia are substrates underlying the initiation and propagation of the neuroimmune response, we hypothesized that stress-induced activation of hippocampal microglia may contribute to the pathogenesis of posttraumatic stress disorder-pain comorbidity. We showed that rats exposed to single prolonged stress, an established posttraumatic stress disorder model, exhibited persistent mechanical allodynia and anxiety-like behavior, which were accompanied by increased activation of microglia and secretion of pro-inflammatory cytokines in the hippocampus. Correlation analyses showed that hippocampal activation of microglia was significantly correlated with mechanical allodynia and anxiety-like behavior. Our data also showed that both intraperitoneal and intra-hippocampal injection of minocycline suppressed single prolonged stress-induced microglia activation and inflammatory cytokines accumulation in the hippocampus, and attenuated both single prolonged stress-induced mechanical allodynia and anxiety-like behavior. Taken together, the present study suggests that stress-induced microglia activation in the hippocampus may serve as a critical mechanistic link in the comorbid relationship between posttraumatic stress disorder and chronic pain. The novel concept introduces the possibility of cotreating chronic pain and posttraumatic stress disorder. © The Author(s) 2016.

HTLV-1 Tax upregulates early growth response protein 1 through nuclear factor-κB signaling.

PubMed

Huang, Qingsong; Niu, Zhiguo; Han, Jingxian; Liu, Xihong; Lv, Zhuangwei; Li, Huanhuan; Yuan, Lixiang; Li, Xiangping; Sun, Shuming; Wang, Hui; Huang, Xinxiang

2017-08-01

Human T cell leukemia virus type 1 (HTLV-1) is a complex retrovirus that causes adult T cell leukemia (ATL) in susceptible individuals. The HTLV-1-encoded oncoprotein Tax induces persistent activation of the nuclear factor-κB (NF-κB) pathway. Early growth response protein 1 (EGR1) is overexpressed in HTLV-1-infected T cell lines and ATL cells. Here, we showed that both Tax expression and HTLV-1 infection promoted EGR1 overexpression. Loss of the NF-κB binding site in the EGR1 promotor or inhibition of NF-κB activation reduced Tax-induced EGR1 upregulation. Tax mutants unable to activate NF-κB induced only slight EGR1 upregulation as compared with wild-type Tax, confirming NF-κB pathway involvement in EGR1 regulation. Tax also directly interacted with the EGR1 protein and increased endogenous EGR1 stability. Elevated EGR1 in turn promoted p65 nuclear translocation and increased NF-κB activation. These results demonstrate a positive feedback loop between EGR1 expression and NF-κB activation in HTLV-1-infected and Tax-expressing cells. Both NF-κB activation and Tax-induced EGR1 stability upregulated EGR1, which in turn enhanced constitutive NF-κB activation and facilitated ATL progression in HTLV-1-infected cells. These findings suggest EGR1 may be an effective anti-ATL therapeutic target.

NADPH oxidase mediates depressive behavior induced by chronic stress in mice.

PubMed

Seo, Ji-Seon; Park, Jin-Young; Choi, Juli; Kim, Tae-Kyung; Shin, Joo-Hyun; Lee, Ja-Kyeong; Han, Pyung-Lim

2012-07-11

Stress is a potent risk factor for depression, yet the underlying mechanism is not clearly understood. In the present study, we explored the mechanism of development and maintenance of depression in a stress-induced animal model. Mice restrained for 2 h daily for 14 d showed distinct depressive behavior, and the altered behavior persisted for >3 months in the absence of intervention. Acute restraint induced a surge of oxidative stress in the brain, and stress-induced oxidative stress progressively increased with repetition of stress. In vitro, the stress hormone glucocorticoid generated superoxide via upregulation of NADPH oxidase. Consistently, repeated restraints increased the expression of the key subunits of NADPH oxidase, p47phox and p67phox, in the brain. Moreover, stressed brains markedly upregulated the expression of p47phox to weak restress evoked in the poststress period, and this molecular response was reminiscent of amplified ROS surge to restress. Pharmacological inhibition of NADPH oxidase by the NADPH oxidase inhibitor apocynin during the stress or poststress period completely blocked depressive behavior. Consistently, heterozygous p47phox knock-out mice (p47phox(+/-)) or molecular inhibition of p47phox with Lenti shRNA-p47phox in the hippocampus suppressed depressive behavior. These results suggest that repeated stress promotes depressive behavior through the upregulation of NADPH oxidase and the resultant metabolic oxidative stress, and that the inhibition of NADPH oxidase provides beneficial antidepression effects.

Clinical progress of human papillomavirus genotypes and their persistent infection in subjects with atypical squamous cells of undetermined significance cytology: Statistical and latent Dirichlet allocation analysis

PubMed Central

Kim, Yee Suk; Lee, Sungin; Zong, Nansu; Kahng, Jimin

2017-01-01

The present study aimed to investigate differences in prognosis based on human papillomavirus (HPV) infection, persistent infection and genotype variations for patients exhibiting atypical squamous cells of undetermined significance (ASCUS) in their initial Papanicolaou (PAP) test results. A latent Dirichlet allocation (LDA)-based tool was developed that may offer a facilitated means of communication to be employed during patient-doctor consultations. The present study assessed 491 patients (139 HPV-positive and 352 HPV-negative cases) with a PAP test result of ASCUS with a follow-up period ≥2 years. Patients underwent PAP and HPV DNA chip tests between January 2006 and January 2009. The HPV-positive subjects were followed up with at least 2 instances of PAP and HPV DNA chip tests. The most common genotypes observed were HPV-16 (25.9%, 36/139), HPV-52 (14.4%, 20/139), HPV-58 (13.7%, 19/139), HPV-56 (11.5%, 16/139), HPV-51 (9.4%, 13/139) and HPV-18 (8.6%, 12/139). A total of 33.3% (12/36) patients positive for HPV-16 had cervical intraepithelial neoplasia (CIN)2 or a worse result, which was significantly higher than the prevalence of CIN2 of 1.8% (8/455) in patients negative for HPV-16 (P<0.001), while no significant association was identified for other genotypes in terms of genotype and clinical progress. There was a significant association between clearance and good prognosis (P<0.001). Persistent infection was higher in patients aged ≥51 years (38.7%) than in those aged ≤50 years (20.4%; P=0.036). Progression from persistent infection to CIN2 or worse (19/34, 55.9%) was higher than clearance (0/105, 0.0%; P<0.001). In the LDA analysis, using symmetric Dirichlet priors α=0.1 and β=0.01, and clusters (k)=5 or 10 provided the most meaningful groupings. Statistical and LDA analyses produced consistent results regarding the association between persistent infection of HPV-16, old age and long infection period with a clinical progression of CIN2 or worse. Therefore, LDA results may be presented as explanatory evidence during time-constrained patient-doctor consultations in order to deliver information regarding the patient's status. PMID:28587376

Hemorrhagic Tamponade as Initial Manifestation of Systemic Lupus with Subsequent Refractory and Progressive Lupus Myocarditis Resulting in Cardiomyopathy and Mitral Regurgitation.

PubMed

Marijanovich, Nicole; Halalau, Alexandra

2018-01-01

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a wide range of clinical and serological manifestations. Cardiac disease among patients with SLE is common and can involve the pericardium, myocardium, valves, conduction system, and coronary arteries. We are reporting a case of SLE in a young woman that is unique is unique in that initial symptoms consisted of pericarditis and hemorrhagic tamponade which remained progressive and resistant to aggressive immunosuppressive treatment and led to severe cardiomyopathy (ejection fraction of 25%) and severe (+4) mitral regurgitation. Her immunosuppressive treatment included hydroxychloroquine, high-dose steroids, intravenous immunoglobulins, azathioprine, and mycophenolate mofetil. Her disease progression was felt to be due to underlying uncontrolled SLE because the complement levels remained persistently low throughout the entire course and PET Myocardial Perfusion and Viability study showed stable persistent active inflammation. Eventually, she was treated with cyclophosphamide which led to improvement in ejection fraction to 55% with only mild mitral regurgitation.

Hemorrhagic Tamponade as Initial Manifestation of Systemic Lupus with Subsequent Refractory and Progressive Lupus Myocarditis Resulting in Cardiomyopathy and Mitral Regurgitation

PubMed Central

Marijanovich, Nicole

2018-01-01

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a wide range of clinical and serological manifestations. Cardiac disease among patients with SLE is common and can involve the pericardium, myocardium, valves, conduction system, and coronary arteries. We are reporting a case of SLE in a young woman that is unique is unique in that initial symptoms consisted of pericarditis and hemorrhagic tamponade which remained progressive and resistant to aggressive immunosuppressive treatment and led to severe cardiomyopathy (ejection fraction of 25%) and severe (+4) mitral regurgitation. Her immunosuppressive treatment included hydroxychloroquine, high-dose steroids, intravenous immunoglobulins, azathioprine, and mycophenolate mofetil. Her disease progression was felt to be due to underlying uncontrolled SLE because the complement levels remained persistently low throughout the entire course and PET Myocardial Perfusion and Viability study showed stable persistent active inflammation. Eventually, she was treated with cyclophosphamide which led to improvement in ejection fraction to 55% with only mild mitral regurgitation. PMID:29610699

Persistent positive metaiodobenzylguanidine scans after autologous peripheral blood stem cell transplantation may indicate maturation of stage 4 neuroblastoma.

PubMed

Okamoto, Yasuhiro; Kodama, Yuichi; Nishikawa, Takuro; Rindiarti, Almitra; Tanabe, Takayuki; Nakagawa, Shunsuke; Yoshioka, Takako; Takumi, Koji; Kaji, Tatsuru; Kawano, Yoshifumi

2017-04-01

Metaiodobenzylguanidine (MIBG) scans are sensitive testing tools for neuroblastoma. Persistent positive MIBG scans in patients with stage 3 neuroblastoma have previously been found to indicate maturation rather than regression. We assessed the significance of this finding in stage 4 neuroblastoma in the present study. Fifteen consecutive pediatric patients with stage 4 neuroblastoma treated between 2004 and 2014 at the Kagoshima University Hospital were retrospectively examined. Treatment involved a combination of multiagent chemotherapy, resection, autologous peripheral blood stem cell transplantation (PBSCT), radiotherapy, and maintenance therapy with retinoic acid. The MIBG uptake in each patient during treatment was assessed using a Curie score. The 5-year event-free and overall survival rates in 15 patients were 38.9% and 58.7%, respectively. Four patients with persistent positive MIBG scans who underwent autologous PBSCT but experienced decreased 123 I-MIBG uptake during the clinical course survived without progression, and their event-free survival (EFS) was significantly superior to that of patients who showed negative MIBG scans after PBSCT (5-year EFS rate: 18.2%, p = 0.0176). Therefore, persistent positive MIBG scans with gradually decreased uptake after PBSCT do not always indicate neuroblastoma progression, and may instead indicate tumor maturation in some selected cases, if not all cases, of stage 4 neuroblastoma.

Immune Evasion Strategies during Chronic Hepatitis B and C Virus Infection

PubMed Central

Ortega-Prieto, Ana Maria; Dorner, Marcus

2017-01-01

Both hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are a major global healthcare problem with more than 240 million and 70 million infected, respectively. Both viruses persist within the liver and result in progressive liver disease, resulting in liver fibrosis, cirrhosis and hepatocellular carcinoma. Strikingly, this pathogenesis is largely driven by immune responses, unable to clear an established infection, rather than by the viral pathogens themselves. Even though disease progression is very similar in both infections, HBV and HCV have evolved distinct mechanisms, by which they ensure persistence within the host. Whereas HCV utilizes a cloak-and-dagger approach, disguising itself as a lipid-like particle and immediately crippling essential pattern-recognition pathways, HBV has long been considered a “stealth” virus, due to the complete absence of innate immune responses during infection. Recent developments and access to improved model systems, however, revealed that even though it is among the smallest human-tropic viruses, HBV may, in addition to evading host responses, employ subtle immune evasion mechanisms directed at ensuring viral persistence in the absence of host responses. In this review, we compare the different strategies of both viruses to ensure viral persistence by actively interfering with viral recognition and innate immune responses. PMID:28862649

Lymphatic deletion of calcitonin receptor–like receptor exacerbates intestinal inflammation

PubMed Central

Davis, Reema B.; Kechele, Daniel O.; Blakeney, Elizabeth S.; Pawlak, John B.

2017-01-01

Lymphatics play a critical role in maintaining gastrointestinal homeostasis and in the absorption of dietary lipids, yet their roles in intestinal inflammation remain elusive. Given the increasing prevalence of inflammatory bowel disease, we investigated whether lymphatic vessels contribute to, or may be causative of, disease progression. We generated a mouse model with temporal and spatial deletion of the key lymphangiogenic receptor for the adrenomedullin peptide, calcitonin receptor–like receptor (Calcrl), and found that the loss of lymphatic Calcrl was sufficient to induce intestinal lymphangiectasia, characterized by dilated lacteals and protein-losing enteropathy. Upon indomethacin challenge, Calcrlfl/fl/Prox1-CreERT2 mice demonstrated persistent inflammation and failure to recover and thrive. The epithelium and crypts of Calcrlfl/fl/Prox1-CreERT2 mice exhibited exacerbated hallmarks of disease progression, and the lacteals demonstrated an inability to absorb lipids. Furthermore, we identified Calcrl/adrenomedullin signaling as an essential upstream regulator of the Notch pathway, previously shown to be critical for intestinal lacteal maintenance and junctional integrity. In conclusion, lymphatic insufficiency and lymphangiectasia caused by loss of lymphatic Calcrl exacerbates intestinal recovery following mucosal injury and underscores the importance of lymphatic function in promoting recovery from intestinal inflammation. PMID:28352669

Boron neutron capture therapy induces cell cycle arrest and cell apoptosis of glioma stem/progenitor cells in vitro.

PubMed

Sun, Ting; Zhang, Zizhu; Li, Bin; Chen, Guilin; Xie, Xueshun; Wei, Yongxin; Wu, Jie; Zhou, Youxin; Du, Ziwei

2013-08-06

Glioma stem cells in the quiescent state are resistant to clinical radiation therapy. An almost inevitable glioma recurrence is due to the persistence of these cells. The high linear energy transfer associated with boron neutron capture therapy (BNCT) could kill quiescent and proliferative cells. The present study aimed to evaluate the effects of BNCT on glioma stem/progenitor cells in vitro. The damage induced by BNCT was assessed using cell cycle progression, apoptotic cell ratio and apoptosis-associated proteins expression. The surviving fraction and cell viability of glioma stem/progenitor cells were decreased compared with differentiated glioma cells using the same boronophenylalanine pretreatment and the same dose of neutron flux. BNCT induced cell cycle arrest in the G2/M phase and cell apoptosis via the mitochondrial pathway, with changes in the expression of associated proteins. Glioma stem/progenitor cells, which are resistant to current clinical radiotherapy, could be effectively killed by BNCT in vitro via cell cycle arrest and apoptosis using a prolonged neutron irradiation, although radiosensitivity of glioma stem/progenitor cells was decreased compared with differentiated glioma cells when using the same dose of thermal neutron exposure and boronophenylalanine pretreatment. Thus, BNCT could offer an appreciable therapeutic advantage to prevent tumor recurrence, and may become a promising treatment in recurrent glioma.

Neonatal Systemic AAV Induces Tolerance to CNS Gene Therapy in MPS I Dogs and Nonhuman Primates

PubMed Central

Hinderer, Christian; Bell, Peter; Louboutin, Jean-Pierre; Zhu, Yanqing; Yu, Hongwei; Lin, Gloria; Choa, Ruth; Gurda, Brittney L; Bagel, Jessica; O'Donnell, Patricia; Sikora, Tracey; Ruane, Therese; Wang, Ping; Tarantal, Alice F; Casal, Margret L; Haskins, Mark E; Wilson, James M

2015-01-01

The potential host immune response to a nonself protein poses a fundamental challenge for gene therapies targeting recessive diseases. We demonstrate in both dogs and nonhuman primates that liver-directed gene transfer using an adeno-associated virus (AAV) vector in neonates induces a persistent state of immunological tolerance to the transgene product, substantially improving the efficacy of subsequent vector administration targeting the central nervous system (CNS). We applied this approach to a canine model of mucopolysaccharidosis type I (MPS I), a progressive neuropathic lysosomal storage disease caused by deficient activity of the enzyme α-l-iduronidase (IDUA). MPS I dogs treated systemically in the first week of life with a vector expressing canine IDUA did not develop antibodies against the enzyme and exhibited robust expression in the CNS upon intrathecal AAV delivery at 1 month of age, resulting in complete correction of brain storage lesions. Newborn rhesus monkeys treated systemically with AAV vector expressing human IDUA developed tolerance to the transgene, resulting in high cerebrospinal fluid (CSF) IDUA expression and no antibody induction after subsequent CNS gene therapy. These findings suggest that inducing tolerance to the transgene product during a critical period in immunological development can improve the efficacy and safety of gene therapy. PMID:26022732

Neonatal Systemic AAV Induces Tolerance to CNS Gene Therapy in MPS I Dogs and Nonhuman Primates.

PubMed

Hinderer, Christian; Bell, Peter; Louboutin, Jean-Pierre; Zhu, Yanqing; Yu, Hongwei; Lin, Gloria; Choa, Ruth; Gurda, Brittney L; Bagel, Jessica; O'Donnell, Patricia; Sikora, Tracey; Ruane, Therese; Wang, Ping; Tarantal, Alice F; Casal, Margret L; Haskins, Mark E; Wilson, James M

2015-08-01

The potential host immune response to a nonself protein poses a fundamental challenge for gene therapies targeting recessive diseases. We demonstrate in both dogs and nonhuman primates that liver-directed gene transfer using an adeno-associated virus (AAV) vector in neonates induces a persistent state of immunological tolerance to the transgene product, substantially improving the efficacy of subsequent vector administration targeting the central nervous system (CNS). We applied this approach to a canine model of mucopolysaccharidosis type I (MPS I), a progressive neuropathic lysosomal storage disease caused by deficient activity of the enzyme α-l-iduronidase (IDUA). MPS I dogs treated systemically in the first week of life with a vector expressing canine IDUA did not develop antibodies against the enzyme and exhibited robust expression in the CNS upon intrathecal AAV delivery at 1 month of age, resulting in complete correction of brain storage lesions. Newborn rhesus monkeys treated systemically with AAV vector expressing human IDUA developed tolerance to the transgene, resulting in high cerebrospinal fluid (CSF) IDUA expression and no antibody induction after subsequent CNS gene therapy. These findings suggest that inducing tolerance to the transgene product during a critical period in immunological development can improve the efficacy and safety of gene therapy.

The Role of Regulatory T Cell in Nontypeable Haemophilus influenzae-Induced Acute Exacerbation of Chronic Obstructive Pulmonary Disease

PubMed Central

Guan, Xuewa; Lu, Yanjiao; Wang, Guoqiang; Fang, Keyong; Wang, Ziyan; Pang, Zhiqiang; Guo, Yingqiao; Lu, Junying; Yuan, Yuze; Ran, Nan

2018-01-01

Chronic obstructive pulmonary disease (COPD) is associated with irreversible persistent airflow limitation and enhanced inflammation. The episodes of acute exacerbation (AECOPD) largely depend on the colonized pathogens such as nontypeable Haemophilus influenzae (NTHi), one of the most commonly isolated bacteria. Regulatory T cells (Tregs) are critical in controlling inflammatory immune responses and maintaining tolerance; however, their role in AECOPD is poorly understood. In this study, we hypothesized a regulatory role of Tregs, as NTHi participated in the progress of COPD. Immunological pathogenesis was investigated in a murine COPD model induced by cigarette smoke (CS). NTHi was administrated through intratracheal instillation for an acute exacerbation. Weight loss and lung function decline were observed in smoke-exposed mice. Mice in experimental groups exhibited serious inflammatory responses via histological and cytokine assessment. Expression levels of Tregs and Th17 cells with specific cytokines TGF-β1 and IL-17 were detected to assess the balance of pro-/anti-inflammatory influence partially. Our findings suggested an anti-inflammatory activity of Tregs in CS-induced model. But this activity was suppressed after NTHi administration. Collectively, these data suggested that NTHi might play a necessary role in downregulating Foxp3 to impair the function of Tregs, helping development into AECOPD. PMID:29725272

Reduction of Endoplasmic Reticulum Stress Improves Angiogenic Progenitor Cell function in a Mouse Model of Type 1 Diabetes.

PubMed

Bhatta, Maulasri; Chatpar, Krishna; Hu, Zihua; Wang, Joshua J; Zhang, Sarah X

2018-04-27

Persistent vascular injury and degeneration in diabetes are attributed in part to defective reparatory function of angiogenic cells. Our recent work implicates endoplasmic reticulum (ER) stress in high-glucose-induced bone marrow (BM) progenitor dysfunction. Herein, we investigated the in vivo role of ER stress in angiogenic abnormalities of streptozotocin-induced diabetic mice. Our data demonstrate that ER stress markers and inflammatory gene expression in BM mononuclear cells and hematopoietic progenitor cells increase dynamically with disease progression. Increased CHOP and cleaved caspase- 3 levels were observed in BM--derived early outgrowth cells (EOCs) after 3 months of diabetes. Inhibition of ER stress by ex vivo or in vivo chemical chaperone treatment significantly improved the generation and migration of diabetic EOCs while reducing apoptosis of these cells. Chemical chaperone treatment also increased the number of circulating angiogenic cells in peripheral blood, alleviated BM pathology, and enhanced retinal vascular repair following ischemia/reperfusion in diabetic mice. Mechanistically, knockdown of CHOP alleviated high-glucose-induced EOC dysfunction and mitigated apoptosis, suggesting a pivotal role of CHOP in mediating ER stress-associated angiogenic cell injury in diabetes. Together, our study suggests that targeting ER signaling may provide a promising and novel approach to enhancing angiogenic function in diabetes.

The role of macrophage mediators in respirable quartz-elicited inflammation

NASA Astrophysics Data System (ADS)

van Berlo, D.; Albrecht, C.; Knaapen, A. M.; van Schooten, F. J.; Schins, R. P. F.

2009-02-01

The instigation and persistence of an inflammatory response is widely considered to be critically important in quartz-induced lung cancer and fibrosis. Macrophages have been long recognised as a crucial player in pulmonary inflammation, but evidence for the role of type II epithelial cells is accumulating. Investigations were performed in the rat lung type II cell line RLE and the rat alveolar macrophage cell line NR8383 using Western blotting, NF-κB immunohistochemistry and qRT-PCR of the pro-inflammatory genes iNOS and COX-2, as well as the cellular stress gene HO-1. The direct effect of quartz on pro-inflammatory signalling cascades and gene expression in RLE cells was compared to the effect of conditioned media derived from quartz-treated NR8383 cells. Conditioned media activated the NF-κB signalling pathway and induced a far stronger upregulation of iNOS mRNA than quartz itself. Quartz elicited a stronger, progressive induction of COX-2 and HO-1 mRNA. Our results suggest a differentially mediated inflammatory response, in which reactive particles themselves induce oxidative stress and activation of COX-2, while mediators released from particle-activated macrophages trigger NF-κB activation and iNOS expression in type II cells.

Postsynaptic elevation of calcium induces persistent depression of developing neuromuscular synapses.

PubMed

Cash, S; Dan, Y; Poo, M M; Zucker, R

1996-04-01

Synaptic activity is known to modulate neuronal connectivity in the nervous system. At developing Xenopus neuromuscular synapses in culture, repetitive postsynaptic application of ACh near the synapse leads to immediate and persistent synaptic depression, which was shown to be caused by reduction of presynaptic evoked transmitter release. However, little depression was found when ACh was applied to the muscle 20 microns or further from the synapse. Fluorescence imaging of cytosolic Ca2+ ([Ca2+]i) showed that each ACh pulse induced a transient elevation of myocyte [Ca2+]i that spread approximately 20 microns. Local photoactivated release of Ca2+ from the caged Ca2+ chelators nitr-5 or nitrophen in the postsynaptic cell was sufficient to induce persistent synaptic depression. These results support a model in which localized Ca2+ influx into the postsynaptic myocyte initiates transsynaptic retrograde modulation of presynaptic secretion mechanisms.

Increased mitochondrial functions in human glioblastoma cells persistently infected with measles virus.

PubMed

Takahashi, Megumi; Wolf, Alexander M; Watari, Eiji; Norose, Yoshihiko; Ohta, Shigeo; Takahashi, Hidemi

2013-09-01

Measles virus (MV) is known for its ability to cause an acute infection with a potential of development of persistent infection. However, knowledge of how viral genes and cellular factors interact to cause or maintain the persistent infection has remained unclear. We have previously reported the possible involvement of mitochondrial short chain enoyl-CoA hydratase (ECHS), which is localized at mitochondria, in the regulation of MV replication. In this study we found increased functions of mitochondria in MV-persistently infected cells compared with uninfected or acutely infected cells. Furthermore, impairment of mitochondrial functions by treatment with mitochondrial inhibitors such as ethidium bromide (EtBr) or carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP) induced the cytopathic effects of extensive syncytial formation in persistently infected cells. These findings suggest that mitochondria are one of the subcellular organelles contributing to regulate persistent infection of MV. Recent studies showed mitochondria provide an integral platform for retinoic acid-inducible protein (RIG-I)-like cytosolic receptors (RLRs) signaling and participate in cellular innate antiviral immunity. Our findings not only reveal a role of mitochondria in RLR mediated antiviral signaling but also suggest that mitochondria contribute to the regulation of persistent viral infection. Copyright © 2013 Elsevier B.V. All rights reserved.

Secondary invasions of noxious weeds associated with control of invasive Tamarix are frequent, idiosyncratic and persistent

USGS Publications Warehouse

González, Eduardo; Sher, Anna A.; Anderson, Robert M.; Bay, Robin F.; Bean, Daniel W.; Bissonnete, Gabriel J.; Cooper, David J.; Dohrenwend, Kara; Eichhorst, Kim D.; El Waer, Hisham; Kennard, Deborah K.; Harms-Weissinger, Rebecca; Henry, Annie L.; Makarick, Lori J.; Ostoja, Steven M.; Reynolds, Lindsay V.; Robinson, W. Wright; Shafroth, Patrick B.; Tabacchi, Erich

2017-01-01

Control of invasive species within ecosystems may induce secondary invasions of non-target invaders replacing the first alien. We used four plant species listed as noxious by local authorities in riparian systems to discern whether 1) the severity of these secondary invasions was related to the control method applied to the first alien; and 2) which species that were secondary invaders persisted over time. In a collaborative study by 16 research institutions, we monitored plant species composition following control of non-native Tamarix trees along southwestern U.S. rivers using defoliation by an introduced biocontrol beetle, and three physical removal methods: mechanical using saws, heavy machinery, and burning in 244 treated and 79 untreated sites across six U.S. states. Physical removal favored secondary invasions immediately after Tamarix removal (0–3 yrs.), while in the biocontrol treatment, secondary invasions manifested later (> 5 yrs.). Within this general trend, the response of weeds to control was idiosyncratic; dependent on treatment type and invader. Two annual tumbleweeds that only reproduce by seed (Bassia scoparia and Salsola tragus) peaked immediately after physical Tamarix removal and persisted over time, even after herbicide application. Acroptilon repens, a perennial forb that vigorously reproduces by rhizomes, and Bromus tectorum, a very frequent annual grass before removal that only reproduces by seed, were most successful at biocontrol sites, and progressively spread as the canopy layer opened. These results demonstrate that strategies to control Tamarix affect secondary invasions differently among species and that time since disturbance is an important, generally overlooked, factor affecting response.

Continual renewal and replication of persistent Leishmania major parasites in concomitantly immune hosts

PubMed Central

Mandell, Michael A.

2017-01-01

In most natural infections or after recovery, small numbers of Leishmania parasites remain indefinitely in the host. Persistent parasites play a vital role in protective immunity against disease pathology upon reinfection through the process of concomitant immunity, as well as in transmission and reactivation, yet are poorly understood. A key question is whether persistent parasites undergo replication, and we devised several approaches to probe the small numbers in persistent infections. We find two populations of persistent Leishmania major: one rapidly replicating, similar to parasites in acute infections, and another showing little evidence of replication. Persistent Leishmania were not found in “safe” immunoprivileged cell types, instead residing in macrophages and DCs, ∼60% of which expressed inducible nitric oxide synthase (iNOS). Remarkably, parasites within iNOS+ cells showed normal morphology and genome integrity and labeled comparably with BrdU to parasites within iNOS− cells, suggesting that these parasites may be unexpectedly resistant to NO. Nonetheless, because persistent parasite numbers remain roughly constant over time, their replication implies that ongoing destruction likewise occurs. Similar results were obtained with the attenuated lpg2− mutant, a convenient model that rapidly enters a persistent state without inducing pathology due to loss of the Golgi GDP mannose transporter. These data shed light on Leishmania persistence and concomitant immunity, suggesting a model wherein a parasite reservoir repopulates itself indefinitely, whereas some progeny are terminated in antigen-presenting cells, thereby stimulating immunity. This model may be relevant to understanding immunity to other persistent pathogen infections. PMID:28096392

Depolarization- and transmitter-induced changes in intracellular Ca2+ of rat cerebellar granule cells in explant cultures.

PubMed

Connor, J A; Tseng, H Y; Hockberger, P E

1987-05-01

Digital imaging of the Ca indicator fura-2 has been used to study the responses of developing granule cells in culture to depolarization and transmitter action. Unstimulated cells bathed in Krebs saline exhibited cytoplasmic Ca ion concentrations, [Ca2+], that were generally in the 30-60 nM range. Exposure of cells to high-potassium (25 mM) saline depolarized the membrane potential and produced an immediate rise in [Ca2+] that recovered within 2-3 min in normal saline. The response grew progressively larger over the first 20 d in culture. Transient increases in [Ca2+] to levels greater than 1 microM were observed after 12-14 d in vitro, at which time the cells displayed intense electrical activity when exposed to high K. At this stage, the increases were attenuated by blocking action potential activity with TTX. In TTX-treated or immature cells, in which the transient phase of the Ca change was relatively small, a second exposure to high K typically produced a much larger Ca response that the initial exposure. The duration of this facilitation of the response persisted for periods longer than 5 min. Application of the neurotransmitter GABA induced a transient increase in membrane conductance, with a reversal potential near resting potential (approx. -60 mV), and caused an intracellular Ca2+ increase that outlasted the exposure to GABA by several minutes. Glutamate, or kainate, induced an increase in membrane conductance but with a reversal potential more positive than spike threshold. These agents also elevated intracellular Ca2+, but unlike the case with GABA, this Ca response reversed rapidly upon removal of the transmitter. The facilitatory effect of repeated exposures to high-K saline, as well as the persistent Ca elevation following a brief GABA application, suggests that granule cells possess the capability of displaying activity-dependent changes in Ca levels in culture.

Isoflurane anesthesia induced persistent, progressive memory impairment, caused a loss of neural stem cells, and reduced neurogenesis in young, but not adult, rodents.

PubMed

Zhu, Changlian; Gao, Jianfeng; Karlsson, Niklas; Li, Qian; Zhang, Yu; Huang, Zhiheng; Li, Hongfu; Kuhn, H Georg; Blomgren, Klas

2010-05-01

Isoflurane and related anesthetics are widely used to anesthetize children, ranging from premature babies to adolescents. Concerns have been raised about the safety of these anesthetics in pediatric patients, particularly regarding possible negative effects on cognition. The purpose of this study was to investigate the effects of repeated isoflurane exposure of juvenile and mature animals on cognition and neurogenesis. Postnatal day 14 (P14) rats and mice, as well as adult (P60) rats, were anesthetized with isoflurane for 35 mins daily for four successive days. Object recognition, place learning and reversal learning as well as cell death and cytogenesis were evaluated. Object recognition and reversal learning were significantly impaired in isoflurane-treated young rats and mice, whereas adult animals were unaffected, and these deficits became more pronounced as the animals grew older. The memory deficit was paralleled by a decrease in the hippocampal stem cell pool and persistently reduced neurogenesis, subsequently causing a reduction in the number of dentate gyrus granule cell neurons in isoflurane-treated rats. There were no signs of increased cell death of progenitors or neurons in the hippocampus. These findings show a previously unknown mechanism of neurotoxicity, causing cognitive deficits in a clearly age-dependent manner.

Urbanization Impacts on River Landscapes in a Global Context

NASA Astrophysics Data System (ADS)

Chin, A.

2005-12-01

A half century ago, Strahler (1956) and Leopold (1956) pointed attention to the reality of human impacts on river systems, outlining erosion and aggradation as system responses when steady state is disturbed by human activity, and linking river channel adjustments to changes in sediment yield owing to land use alterations. Significant advances have been made along these lines in the years since, with intensified research efforts producing a voluminous literature documenting a range of human impacts on fluvial geomorphology. This paper summarizes the progress made on understanding the impacts of urban development on river landscapes, with emphasis on the distribution of such impacts in a global context. Drawing from a database developed from published literature representing a range of world areas, the analysis quantifies the magnitude and direction of urban-induced change in a comparative context, evaluates how impacts vary with locale and scale, and assesses the persistence of such impacts across locales and scales. Results indicate high variability both in magnitude and persistence of impacts. The spatial distribution of research investigations has also been markedly uneven, with input to theory development having come from a limited number of sites. Substantial areas across the earth surface remain blind spots in this context; future investigations might serve the science best if they are conducted in some of these locations.

Persistent Epithelial Defects and Corneal Opacity After Collagen Cross-Linking With Substitution of Dextran (T-500) With Dextran Sulfate in Compounded Topical Riboflavin.

PubMed

Höllhumer, Roland; Watson, Stephanie; Beckingsale, Peter

2017-03-01

Collagen cross-linking (CXL) is a commonly performed procedure to prevent the progression of keratoconus. Riboflavin is an essential part of the procedure, which facilitates both the cross-linking process and protection of intraocular structures. Dextran can be added to riboflavin to create an isotonic solution. This case report highlights the importance of compounding riboflavin with the correct dextran solution. A retrospective case series. Six eyes of 4 male patients with keratoconus aged from 20 to 38 years underwent CXL with substitution of 20% dextran (T-500) with 20% dextran sulfate in a compounded riboflavin 0.1% solution. Postoperatively, persistent corneal epithelial defects, stromal haze, and then scarring occurred. Corneal transplantation was performed for visual rehabilitation but was complicated by graft rejection followed by failure (n = 1 eye), dehiscence (n = 4), cataract (n = 2), post-laser ablation haze (n = 1), and steroid-induced glaucoma (n = 2). The visual outcome was <6/18 in all 6 cases because of irregular astigmatism and stromal haze. Thinning, vascularization, and scarring of the residual host tissue were noted. Substitution of dextran (T-500) with dextran sulfate in riboflavin solutions during CXL results in loss of vision from permanent corneal opacity. Residual host changes may compromise the results of corneal transplantation.

Chronic hyperinsulinemia contributes to insulin resistance under dietary restriction in association with altered lipid metabolism in Zucker diabetic fatty rats.

PubMed

Morita, Ippei; Tanimoto, Keiichi; Akiyama, Nobuteru; Naya, Noriyuki; Fujieda, Kumiko; Iwasaki, Takanori; Yukioka, Hideo

2017-04-01

Hyperinsulinemia is widely thought to be a compensatory response to insulin resistance, whereas its potentially causal role in the progression of insulin resistance remains to be established. Here, we aimed to examine whether hyperinsulinemia could affect the progression of insulin resistance in Zucker fatty diabetic (ZDF) rats. Male ZDF rats at 8 wk of age were fed a diet ad libitum (AL) or dietary restriction (DR) of either 15 or 30% from AL feeding over 6 wk. Insulin sensitivity was determined by hyperinsulinemic euglycemic clamp. ZDF rats in the AL group progressively developed hyperglycemia and hyperinsulinemia by 10 wk of age, and then plasma insulin rapidly declined to nearly normal levels by 12 wk of age. Compared with AL group, DR groups showed delayed onset of hyperglycemia and persistent hyperinsulinemia, leading to weight gain and raised plasma triglycerides and free fatty acids by 14 wk of age. Notably, insulin sensitivity was significantly reduced in the DR group rather than the AL group and inversely correlated with plasma levels of insulin and triglyceride but not glucose. Moreover, enhanced lipid deposition and upregulation of genes involved in lipogenesis were detected in liver, skeletal muscle, and adipose tissues of the DR group rather than the AL group. Alternatively, continuous hyperinsulinemia induced by insulin pellet implantation produced a decrease in insulin sensitivity in ZDF rats. These results suggest that chronic hyperinsulinemia may lead to the progression of insulin resistance under DR conditions in association with altered lipid metabolism in peripheral tissues in ZDF rats. Copyright © 2017 the American Physiological Society.

Common variants in immune and DNA repair genes and risk for human papillomavirus persistence and progression to cervical cancer.

PubMed

Wang, Sophia S; Bratti, M Concepcion; Rodríguez, Ana Cecilia; Herrero, Rolando; Burk, Robert D; Porras, Carolina; González, Paula; Sherman, Mark E; Wacholder, Sholom; Lan, Z Elizabeth; Schiffman, Mark; Chanock, Stephen J; Hildesheim, Allan

2009-01-01

We examined host genetic factors to identify those more common in individuals whose human papillomavirus (HPV) infections were most likely to persist and progress to cervical intraepithelial neoplasia grade 3 (CIN3) and cancer. We genotyped 92 single-nucleotide polymorphisms (SNPs) from 49 candidate immune response and DNA repair genes obtained from 469 women with CIN3 or cancer, 390 women with persistent HPV infections (median duration, 25 months), and 452 random control subjects from the 10,049-woman Guanacaste Costa Rica Natural History Study. We calculated odds ratios and 95% confidence intervals (CIs) for the association of SNP and haplotypes in women with CIN3 or cancer and HPV persistence, compared with random control subjects. A SNP in the Fanconi anemia complementation group A gene (FANCA) (G501S) was associated with increased risk of CIN3 or cancer. The AG and GG genotypes had a 1.3-fold (95% CI, 0.95-1.8-fold) and 1.7-fold (95% CI, 1.1-2.6-fold) increased risk for CIN3 or cancer, respectively (P(trend) = .008; referent, AA). The FANCA haplotype that included G501S also conferred increased risk of CIN3 or cancer, as did a different haplotype that included 2 other FANCA SNPs (G809A and T266A). A SNP in the innate immune gene IRF3 (S427T) was associated with increased risk for HPV persistence (P(trend) = .009). Our results require replication but support the role of FANCA variants in cervical cancer susceptibility and of IRF3 in HPV persistence.

Prospective randomized study to assess the efficacy of site and rate of atrial pacing on long-term progression of atrial fibrillation in sick sinus syndrome: Septal Pacing for Atrial Fibrillation Suppression Evaluation (SAFE) Study.

PubMed

Lau, Chu-Pak; Tachapong, Ngarmukos; Wang, Chun-Chieh; Wang, Jing-Feng; Abe, Haruhiko; Kong, Chi-Woon; Liew, Reginald; Shin, Dong-Gu; Padeletti, Luigi; Kim, You-Ho; Omar, Razali; Jirarojanakorn, Kreingkrai; Kim, Yoon-Nyun; Chen, Mien-Cheng; Sriratanasathavorn, Charn; Munawar, Muhammad; Kam, Ruth; Chen, Jan-Yow; Cho, Yong-Keun; Li, Yi-Gang; Wu, Shu-Lin; Bailleul, Christophe; Tse, Hung-Fat

2013-08-13

Atrial-based pacing is associated with lower risk of atrial fibrillation (AF) in sick sinus syndrome compared with ventricular pacing; nevertheless, the impact of site and rate of atrial pacing on progression of AF remains unclear. We evaluated whether long-term atrial pacing at the right atrial (RA) appendage versus the low RA septum with (ON) or without (OFF) a continuous atrial overdrive pacing algorithm can prevent the development of persistent AF. We randomized 385 patients with paroxysmal AF and sick sinus syndrome in whom a pacemaker was indicated to pacing at RA appendage ON (n=98), RA appendage OFF (n=99), RA septum ON (n=92), or RA septum OFF (n=96). The primary outcome was the occurrence of persistent AF (AF documented at least 7 days apart or need for cardioversion). Demographic data were homogeneous across both pacing site (RA appendage/RA septum) and atrial overdrive pacing (ON/OFF). After a mean follow-up of 3.1 years, persistent AF occurred in 99 patients (25.8%; annual rate of persistent AF, 8.3%). Alternative site pacing at the RA septum versus conventional RA appendage (hazard ratio=1.18; 95% confidence interval, 0.79-1.75; P=0.65) or continuous atrial overdrive pacing ON versus OFF (hazard ratio=1.17; 95% confidence interval, 0.79-1.74; P=0.69) did not prevent the development of persistent AF. In patients with paroxysmal AF and sick sinus syndrome requiring pacemaker implantation, an alternative atrial pacing site at the RA septum or continuous atrial overdrive pacing did not prevent the development of persistent AF. URL: http://www.clinicaltrials.gov. UNIQUE IDENTIFIER: NCT00419640.

Whole Brain Radiation-Induced Impairments in Learning and Memory Are Time-Sensitive and Reversible by Systemic Hypoxia

PubMed Central

Warrington, Junie P.; Csiszar, Anna; Mitschelen, Matthew; Lee, Yong Woo; Sonntag, William E.

2012-01-01

Whole brain radiation therapy (WBRT) is commonly used for treatment of primary and metastatic brain tumors; however, cognitive impairment occurs in 40–50% of brain tumor survivors. The etiology of the cognitive impairment following WBRT remains elusive. We recently reported that radiation-induced cerebrovascular rarefaction within hippocampal subregions could be completely reversed by systemic hypoxia. However, the effects of this intervention on learning and memory have not been reported. In this study, we assessed the time-course for WBRT-induced impairments in contextual and spatial learning and the capacity of systemic hypoxia to reverse WBRT-induced deficits in spatial memory. A clinical fractionated series of 4.5Gy WBRT was administered to mice twice weekly for 4 weeks, and after various periods of recovery, behavioral analyses were performed. To study the effects of systemic hypoxia, mice were subjected to 11% (hypoxia) or 21% oxygen (normoxia) for 28 days, initiated 1 month after the completion of WBRT. Our results indicate that WBRT induces a transient deficit in contextual learning, disruption of working memory, and progressive impairment of spatial learning. Additionally, systemic hypoxia completely reversed WBRT-induced impairments in learning and these behavioral effects as well as increased vessel density persisted for at least 2 months following hypoxia treatment. Our results provide critical support for the hypothesis that cerebrovascular rarefaction is a key component of cognitive impairment post-WBRT and indicate that processes of learning and memory, once thought to be permanently impaired after WBRT, can be restored. PMID:22279591

Microtubule-Targeting Agents Eribulin and Paclitaxel Differentially Affect Neuronal Cell Bodies in Chemotherapy-Induced Peripheral Neuropathy.

PubMed

Benbow, Sarah J; Wozniak, Krystyna M; Kulesh, Bridget; Savage, April; Slusher, Barbara S; Littlefield, Bruce A; Jordan, Mary Ann; Wilson, Leslie; Feinstein, Stuart C

2017-07-01

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of anticancer treatment with microtubule-targeted agents (MTAs). The frequency of severe CIPN, which can be dose limiting and even life threatening, varies widely among different MTAs. For example, paclitaxel induces a higher frequency of severe CIPN than does eribulin. Different MTAs also possess distinct mechanisms of microtubule-targeted action. Recently, we demonstrated that paclitaxel and eribulin differentially affect sciatic nerve axons, with paclitaxel inducing more pronounced neurodegenerative effects and eribulin inducing greater microtubule stabilizing biochemical effects. Here, we complement and extend these axonal studies by assessing the effects of paclitaxel and eribulin in the cell bodies of sciatic nerve axons, housed in the dorsal root ganglia (DRG). Importantly, the microtubule network in cell bodies is known to be significantly more dynamic than in axons. Paclitaxel induced activating transcription factor 3 expression, a marker of neuronal stress/injury. Paclitaxel also increased expression levels of acetylated tubulin and end binding protein 1, markers of microtubule stability and growth, respectively. These effects are hypothesized to be detrimental to the dynamic microtubule network within the cell bodies. In contrast, eribulin had no significant effect on any of these parameters in the cell bodies. Taken together, DRG cell bodies and their axons, two distinct neuronal cell compartments, contain functionally distinct microtubule networks that exhibit unique biochemical responses to different MTA treatments. We hypothesize that these distinct mechanistic actions may underlie the variability seen in the initiation, progression, persistence, and recovery from CIPN.

Intraocular 6-hydroxydopamine prevents the persistent estrus induced by continuous light.

PubMed

Shimizu, K; Hokano, M

1985-01-15

Following the intraocular injection of 6-hydroxydopamine, which can destroy the retinal dopaminergic neurons, female rats showed a normal estrous cycle in LD 12:12 but not a persistent estrus in continuous light.

Inducing Sadness and Anxiousness through Visual Media: Measurement Techniques and Persistence

PubMed Central

Kuijsters, Andre; Redi, Judith; de Ruyter, Boris; Heynderickx, Ingrid

2016-01-01

The persistence of negative moods (sadness and anxiousness) induced by three visual Mood Induction Procedures (MIP) was investigated. The evolution of the mood after the MIP was monitored for a period of 8 min with the Self-Assessment Manikin (SAM; every 2 min) and with recordings of skin conductance level (SCL) and electrocardiography (ECG). The SAM pleasure ratings showed that short and longer film fragments were effective in inducing a longer lasting negative mood, whereas the negative mood induced by the IAPS slideshow was short lived. The induced arousal during the anxious MIPs diminished quickly after the mood induction; nevertheless, the SCL data suggest longer lasting arousal effects for both movies. The decay of the induced mood follows a logarithmic function; diminishing quickly in the first minutes, thereafter returning slowly back to baseline. These results reveal that caution is needed when investigating the effects of the induced mood on a task or the effect of interventions on induced moods, because the induced mood diminishes quickly after the mood induction. PMID:27536260

Conditioned medium from persistently RSV-infected macrophages alters transcriptional profile and inflammatory response of non-infected macrophages.

PubMed

Rivera-Toledo, Evelyn; Salido-Guadarrama, Iván; Rodríguez-Dorantes, Mauricio; Torres-González, Laura; Santiago-Olivares, Carlos; Gómez, Beatriz

2017-02-15

Cells susceptible to persistent viral infections undergo important changes in their biological functions as a consequence of the expression of viral gene products that are capable of altering the gene expression profile of the host cell. Previously, we reported that persistence of the RSV genome in a mouse macrophage cell line induces important alterations in cell homeostasis, including constitutive expression of IFN-β and other pro-inflammatory cytokines. Here, we postulated that changes in the homeostasis of non-infected macrophages could be induced by soluble factors secreted by persistently RSV- infected macrophages. To test this hypothesis, non-infected mouse macrophages were treated with conditioned medium (CM) collected from cultures of persistently RSV-infected macrophages. Total RNA was extracted and a microarray-based gene expression analysis was performed. Non-infected macrophages, treated under similar conditions with CM obtained from cultures of non-infected macrophages, were used as a control to establish differential gene expression between the two conditions. Results showed that CM from the persistently RSV-infected cultures altered expression of a total of 95 genes in non-infected macrophages, resulting in an antiviral gene-transcription profile along with inhibition of the inflammatory response, since some inflammatory genes were down-regulated, including Nlrp3 and Il-1 β, both related to the inflammasome pathway. However, down-regulation of Nlrp3 and Il-1 β was reversible upon acute RSV infection. Additionally, we observed that the inflammatory response, evaluated by secreted IL-1 β, a final product of the inflammasome activity, was enhanced during acute RSV infection in macrophages treated with CM from persistently RSV-infected cultures, compared to that in macrophages treated with the control CM. This suggests that soluble factors secreted during RSV persistence may induce an exacerbated inflammatory response in non-infected cells. Copyright © 2017 Elsevier B.V. All rights reserved.

Persistent and progressive long-term lung disease in survivors of preterm birth.

PubMed

Urs, Rhea; Kotecha, Sailesh; Hall, Graham L; Simpson, Shannon J

2018-04-13

Preterm birth accounts for approximately 11% of births globally, with rates increasing across many countries. Concurrent advances in neonatal care have led to increased survival of infants of lower gestational age (GA). However, infants born <32 weeks of GA experience adverse respiratory outcomes, manifesting with increased respiratory symptoms, hospitalisation and health care utilisation into early childhood. The development of bronchopulmonary dysplasia (BPD) - the chronic lung disease of prematurity - further increases the risk of poor respiratory outcomes throughout childhood, into adolescence and adulthood. Indeed, survivors of preterm birth have shown increased respiratory symptoms, altered lung structure, persistent and even declining lung function throughout childhood. The mechanisms behind this persistent and sometimes progressive lung disease are unclear, and the implications place those born preterm at increased risk of respiratory morbidity into adulthood. This review aims to summarise what is known about the long-term pulmonary outcomes of contemporary preterm birth, examine the possible mechanisms of long-term respiratory morbidity in those born preterm and discuss addressing the unknowns and potentials for targeted treatments. Copyright © 2018 Elsevier Ltd. All rights reserved.

Persistent parasites and immunologic memory in cutaneous leishmaniasis: implications for vaccine designs and vaccination strategies.

PubMed

Okwor, Ifeoma; Uzonna, Jude

2008-01-01

Despite a plethora of publications on the murine model of cutaneous leishmaniasis and their contribution to our understanding of the factors that regulate the development of CD4+ T cell immunity in vivo, there is still no effective vaccine against the human disease. While recovery from natural or experimental infection with Leishmania major, the causative agent of human cutaneous leishmaniasis, results in persistence of parasites at the primary infection site and the development of long-lasting immunity to reinfection, vaccination with killed parasites or recombinant proteins induces only short-term protection. The reasons for the difference in protective immunity following recovery from live infection and vaccination with heat-killed parasites are not known. This may in part be related to persistence of live parasites following healing of primary cutaneous lesions, because complete clearance of parasites leads to rapid loss of infection-induced immunity. Recent reports indicate that in addition to persistent parasites, IL-10-producing natural regulatory T cells may also play critical roles in the maintenance and loss of infection-induced immunity. This review focuses on current understanding of the factors that regulate the development, maintenance and loss of anti-Leishmania memory responses and highlights the role of persistent parasites and regulatory T cells in this process. Understanding these factors is crucial for designing effective vaccines and vaccination strategies against cutaneous leishmaniasis.

Electrostatic stiffening and induced persistence length for coassembled molecular bottlebrushes

NASA Astrophysics Data System (ADS)

Storm, Ingeborg M.; Stuart, Martien A. Cohen; de Vries, Renko; Leermakers, Frans A. M.

2018-03-01

A self-consistent field analysis for tunable contributions to the persistence length of isolated semiflexible polymer chains including electrostatically driven coassembled deoxyribonucleic acid (DNA) bottlebrushes is presented. When a chain is charged, i.e., for polyelectrolytes, there is, in addition to an intrinsic rigidity, an electrostatic stiffening effect, because the electric double layer resists bending. For molecular bottlebrushes, there is an induced contribution due to the grafts. We explore cases beyond the classical phantom main-chain approximation and elaborate molecularly more realistic models where the backbone has a finite volume, which is necessary for treating coassembled bottlebrushes. We find that the way in which the linear charge density or the grafting density is regulated is important. Typically, the stiffening effect is reduced when there is freedom for these quantities to adapt to the curvature stresses. Electrostatically driven coassembled bottlebrushes, however, are relatively stiff because the chains have a low tendency to escape from the compressed regions and the electrostatic binding force is largest in the convex part. For coassembled bottlebrushes, the induced persistence length is a nonmonotonic function of the polymer concentration: For low polymer concentrations, the stiffening grows quadratically with coverage; for semidilute polymer concentrations, the brush chains retract and regain their Gaussian size. When doing so, they lose their induced persistence length contribution. Our results correlate well with observed physical characteristics of electrostatically driven coassembled DNA-bioengineered protein-polymer bottlebrushes.

A Drug Combination Screen Identifies Drugs Active against Amoxicillin-Induced Round Bodies of In Vitro Borrelia burgdorferi Persisters from an FDA Drug Library

PubMed Central

Feng, Jie; Shi, Wanliang; Zhang, Shuo; Sullivan, David; Auwaerter, Paul G.; Zhang, Ying

2016-01-01

Although currently recommended antibiotics for Lyme disease such as doxycycline or amoxicillin cure the majority of the patients, about 10–20% of patients treated for Lyme disease may experience lingering symptoms including fatigue, pain, or joint and muscle aches. Under experimental stress conditions such as starvation or antibiotic exposure, Borrelia burgdorferi can develop round body forms, which are a type of persister bacteria that appear resistant in vitro to customary first-line antibiotics for Lyme disease. To identify more effective drugs with activity against the round body form of B. burgdorferi, we established a round body persister model induced by exposure to amoxicillin (50 μg/ml) and then screened the Food and Drug Administration drug library consisting of 1581 drug compounds and also 22 drug combinations using the SYBR Green I/propidium iodide viability assay. We identified 23 drug candidates that have higher activity against the round bodies of B. burgdorferi than either amoxicillin or doxycycline. Eleven individual drugs scored better than metronidazole and tinidazole which have been previously described to be active against round bodies. In this amoxicillin-induced round body model, some drug candidates such as daptomycin and clofazimine also displayed enhanced activity which was similar to a previous screen against stationary phase B. burgdorferi persisters not exposure to amoxicillin. Additional candidate drugs active against round bodies identified include artemisinin, ciprofloxacin, nifuroxime, fosfomycin, chlortetracycline, sulfacetamide, sulfamethoxypyridazine and sulfathiozole. Two triple drug combinations had the highest activity against amoxicillin-induced round bodies and stationary phase B. burgdorferi persisters: artemisinin/cefoperazone/doxycycline and sulfachlorpyridazine/daptomycin/doxycycline. These findings confirm and extend previous findings that certain drug combinations have superior activity against B. burgdorferi persisters in vitro, even when pre-treated with amoxicillin. These findings may have implications for improved treatment of Lyme disease. PMID:27242757

A Drug Combination Screen Identifies Drugs Active against Amoxicillin-Induced Round Bodies of In Vitro Borrelia burgdorferi Persisters from an FDA Drug Library.

PubMed

Feng, Jie; Shi, Wanliang; Zhang, Shuo; Sullivan, David; Auwaerter, Paul G; Zhang, Ying

2016-01-01

Although currently recommended antibiotics for Lyme disease such as doxycycline or amoxicillin cure the majority of the patients, about 10-20% of patients treated for Lyme disease may experience lingering symptoms including fatigue, pain, or joint and muscle aches. Under experimental stress conditions such as starvation or antibiotic exposure, Borrelia burgdorferi can develop round body forms, which are a type of persister bacteria that appear resistant in vitro to customary first-line antibiotics for Lyme disease. To identify more effective drugs with activity against the round body form of B. burgdorferi, we established a round body persister model induced by exposure to amoxicillin (50 μg/ml) and then screened the Food and Drug Administration drug library consisting of 1581 drug compounds and also 22 drug combinations using the SYBR Green I/propidium iodide viability assay. We identified 23 drug candidates that have higher activity against the round bodies of B. burgdorferi than either amoxicillin or doxycycline. Eleven individual drugs scored better than metronidazole and tinidazole which have been previously described to be active against round bodies. In this amoxicillin-induced round body model, some drug candidates such as daptomycin and clofazimine also displayed enhanced activity which was similar to a previous screen against stationary phase B. burgdorferi persisters not exposure to amoxicillin. Additional candidate drugs active against round bodies identified include artemisinin, ciprofloxacin, nifuroxime, fosfomycin, chlortetracycline, sulfacetamide, sulfamethoxypyridazine and sulfathiozole. Two triple drug combinations had the highest activity against amoxicillin-induced round bodies and stationary phase B. burgdorferi persisters: artemisinin/cefoperazone/doxycycline and sulfachlorpyridazine/daptomycin/doxycycline. These findings confirm and extend previous findings that certain drug combinations have superior activity against B. burgdorferi persisters in vitro, even when pre-treated with amoxicillin. These findings may have implications for improved treatment of Lyme disease.

Reproductive history and progression of lower urinary tract symptoms in women: results from a population-based cohort study.

PubMed

Maserejian, Nancy N; Curto, Teresa; Hall, Susan A; Wittert, Gary; McKinlay, John B

2014-04-01

To examine whether reproductive history and related conditions are associated with the development and persistence of lower urinary tract symptoms (LUTS) other than urinary incontinence in a racially and/or ethnically diverse population-based sample of women. The Boston Area Community Health Survey enrolled 3201 women aged 30-79 years of black, Hispanic, or white race and/or ethnicity. Baseline and 5-year follow-up interviews were completed by 2534 women (conditional response rate, 83.4%). The association between reproductive history factors and population-weighted estimates of LUTS progression and persistence was tested using multivariable logistic regression models. Between baseline and 5-year follow-up, 23.9% women had LUTS progression. In age-adjusted models, women who had delivered ≥2 childbirths had higher odds of LUTS progression, but the association was completely accounted for by vaginal child delivery (eg, 2 vaginal childbirths vs none, multivariable-adjusted odds ratio = 2.21; 95% CI, 1.46-3.35; P <.001). No increased odds of LUTS progression were found for women with only 1 vaginal delivery or who only had cesarean section(s). Uterine prolapse was associated with higher odds of LUTS progression (multivariable-adjusted odds ratio = 3.05; 95% CI, 1.43-6.50; P = .004). Gestational diabetes was associated with approximately twice the odds of LUTS progression, but only among younger women (interaction P = .003). In this cohort study, ≥2 vaginal child deliveries, uterine prolapse, and among younger women, gestational diabetes were robust predictors of LUTS progression. Clinicians should assess the presence of bothersome urinary frequency, urgency, and voiding symptoms among women who have had multiple vaginal childbirths or gestational diabetes. Copyright © 2014 Elsevier Inc. All rights reserved.

High risk of progression to NIDDM in South-African Indians with impaired glucose tolerance.

PubMed

Motala, A A; Omar, M A; Gouws, E

1993-04-01

A four-yr prospective study was undertaken to examine the natural history of IGT in 128 South-African Indians classified as such at year 0 of the study, based on WHO criteria. Subjects were reexamined at year 1 and year 4. Of the 113 subjects who completed the study, 50.4% progressed to NIDDM (rate of progression 12.6%/yr), 24.8% persisted with IGT, and 24.8%, reverted to NGT. The majority (72%) who progressed to NIDDM did so in year 1. At year 1, 47 subjects were still classified as IGT; of the 40 subjects completing the study, 16 subjects (40%) progressed to NIDDM, 17 subjects (42.5%) persisted with IGT, and 7 subjects (17.5%) reverted to NGT. Examination of risk factors predictive of subsequent progression to NIDDM was undertaken by analysis of baseline variables in two ways: When year 0 was used as baseline (in 113 IGT0 subjects), significant predictive risk factors were the FPG and 2-h plasma glucose concentrations. All subjects who at year 0 had 2-h plasma glucose > or = 10.2 and < 11.1 mM or FPG > or = 7.3 but < 7.8 mM, subsequently progressed to NIDDM. When year 1 was used as baseline (40 IGT1 subjects), 90-min plasma glucose concentration (midtest level) was found to be a significant risk factor for development of NIDDM. In conclusion, this study has demonstrated that in South-African Indians with IGT, the majority (50.4%) progress to NIDDM within 4 yr; significant predictors of subsequent diabetes are the baseline fasting and 2-h plasma glucose concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Solid waste containing persistent organic pollutants in Serbia: From precautionary measures to the final treatment (case study).

PubMed

Stevanovic-Carapina, Hristina; Milic, Jelena; Curcic, Marijana; Randjelovic, Jasminka; Krinulovic, Katarina; Jovovic, Aleksandar; Brnjas, Zvonko

2016-07-01

Sustainable solid waste management needs more dedicated attention in respect of environmental and human health protection. Solid waste containing persistent organic pollutants is of special concern, since persistent organic pollutants are persistent, toxic and of high risk to human health and the environment. The objective of this investigation was to identify critical points in the Serbian system of solid waste and persistent organic pollutants management, to assure the life cycle management of persistent organic pollutants and products containing these chemicals, including prevention and final destruction. Data were collected from the Serbian competent authorities, and led us to identify preventive actions for solid waste management that should reduce or minimise release of persistent organic pollutants into the environment, and to propose actions necessary for persistent organic pollutants solid waste. The adverse impact of persistent organic pollutants is multidimensional. Owing to the lack of treatment or disposal plants for hazardous waste in Serbia, the only option at the moment to manage persistent organic pollutants waste is to keep it in temporary storage and when conditions are created (primarily financial), such waste should be exported for destruction in hazardous waste incinerators. Meanwhile, it needs to be assured that any persistent organic pollutants management activity does not negatively impact recycling flows or disturb progress towards a more circular economy in Serbia. © The Author(s) 2016.

AN ANIMAL MODEL OF SCHIZOPHRENIA BASED ON CHRONIC LSD ADMINISTRATION: OLD IDEA, NEW RESULTS

PubMed Central

Marona-Lewicka, Danuta; Nichols, Charles D.; Nichols, David E.

2011-01-01

Many people who take LSD experience a second temporal phase of LSD intoxication that is qualitatively different, and was described by Daniel Freedman as “clearly a paranoid state.” We have previously shown that the discriminative stimulus effects of LSD in rats also occur in two temporal phases, with initial effects mediated by activation of 5-HT2A receptors (LSD30), and the later temporal phase mediated by dopamine D2-like receptors (LSD90). Surprisingly, we have now found that non-competitive NMDA antagonists produced full substitution in LSD90 rats, but only in older animals, whereas in LSD30, or in younger animals, these drugs did not mimic LSD. Chronic administration of low doses of LSD (>3 months, 0.16 mg/kg every other day) induces a behavioral state characterized by hyperactivity and hyperirritability, increased locomotor activity, anhedonia, and impairment in social interaction that persists at the same magnitude for at least three months after cessation of LSD treatment. These behaviors, which closely resemble those associated with psychosis in humans, are not induced by withdrawal from LSD; rather, they are the result of neuroadaptive changes occurring in the brain during the chronic administration of LSD. These persistent behaviors are transiently reversed by haloperidol and olanzapine, but are insensitive to MDL-100907. Gene expression analysis data show that chronic LSD treatment produced significant changes in multiple neurotransmitter system-related genes, including those for serotonin and dopamine. Thus, we propose that chronic treatment of rats with low doses of LSD can serve as a new animal model of psychosis that may mimic the development and progression of schizophrenia, as well as model the established disease better than current acute drug administration models utilizing amphetamine or NMDA antagonists such as PCP. PMID:21352832

Maternal protein restriction during pregnancy and lactation alters central leptin signalling, increases food intake, and decreases bone mass in 1 year old rat offspring.

PubMed

Qasem, Rani J; Li, Jing; Tang, Hee Man; Pontiggia, Laura; D'mello, Anil P

2016-04-01

The effects of perinatal nutrition on offspring physiology have mostly been examined in young adult animals. Aging constitutes a risk factor for the progressive loss of metabolic flexibility and development of disease. Few studies have examined whether the phenotype programmed by perinatal nutrition persists in aging offspring. Persistence of detrimental phenotypes and their accumulative metabolic effects are important for disease causality. This study determined the effects of maternal protein restriction during pregnancy and lactation on food consumption, central leptin sensitivity, bone health, and susceptibility to high fat diet-induced adiposity in 1-year-old male offspring. Sprague-Dawley rats received either a control or a protein restricted diet throughout pregnancy and lactation and pups were weaned onto laboratory chow. One-year-old low protein (LP) offspring exhibited hyperphagia. The inability of an intraperitoneal (i.p.) leptin injection to reduce food intake indicated that the hyperphagia was mediated by decreased central leptin sensitivity. Hyperphagia was accompanied by lower body weight suggesting increased energy expenditure in LP offspring. Bone density and bone mineral content that are negatively regulated by leptin acting via the sympathetic nervous system (SNS), were decreased in LP offspring. LP offspring did not exhibit increased susceptibility to high fat diet induced metabolic effects or adiposity. The results presented here indicate that the programming effects of perinatal protein restriction are mediated by specific decreases in central leptin signalling to pathways involved in the regulation of food intake along with possible enhancement of different CNS leptin signalling pathways acting via the SNS to regulate bone mass and energy expenditure. © 2016 John Wiley & Sons Australia, Ltd.

Repeated restraint stress exposure during early withdrawal accelerates incubation of cue-induced cocaine craving.

PubMed

Glynn, Ryan M; Rosenkranz, J Amiel; Wolf, Marina E; Caccamise, Aaron; Shroff, Freya; Smith, Alyssa B; Loweth, Jessica A

2018-01-01

A major challenge for treating cocaine addiction is the propensity for abstinent users to relapse. Two important triggers for relapse are cues associated with prior drug use and stressful life events. To study their interaction in promoting relapse during abstinence, we used the incubation model of craving and relapse in which cue-induced drug seeking progressively intensifies ('incubates') during withdrawal from extended-access cocaine self-administration. We tested rats for cue-induced cocaine seeking on withdrawal day (WD) 1. Rats were then subjected to repeated restraint stress or control conditions (seven sessions held between WD6 and WD14). All rats were tested again for cue-induced cocaine seeking on WD15, 1 day after the last stress or control session. Although controls showed a time-dependent increase in cue-induced cocaine seeking (incubation), rats exposed to repeated stress in early withdrawal exhibited a more robust increase in seeking behavior between WD1 and WD15. In separate stressed and control rats, equivalent cocaine seeking was observed on WD48. These results indicate that repeated stress in early withdrawal accelerates incubation of cocaine craving, although craving plateaus at the same level were observed in controls. However, 1 month after the WD48 test, rats subjected to repeated stress in early withdrawal showed enhanced cue-induced cocaine seeking following acute (24 hours) food deprivation stress. Together, these data indicate that chronic stress exposure enhances the initial rate of incubation of craving during early withdrawal, resulting in increased vulnerability to cue-induced relapse during this period, and may lead to a persistent increase in vulnerability to the relapse-promoting effects of stress. © 2016 Society for the Study of Addiction.

A role for the non-canonical Wnt-ß-Catenin and TGF-ß signaling pathways in the induction of tolerance during the establishment of a Salmonella enterica serovar Enteritidis persistent cecal infection in chickens

USDA-ARS?s Scientific Manuscript database

Non-typhoidal Salmonella enterica induce an early pro-inflammatory response in chickens. However, the response is short-lived, asymptomatic of disease, resulting in a persistent colonization of the ceca, and fecal shedding of bacteria. The underlying mechanisms that control this persistent infecti...

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

Holland, J.M.; Whitaker, M.S.; Wesley, J.W.

The relative carcinogenicities of coal and shale derived liquid crudes was compared with a composite blend of natural petroleum using discontinuous exposure of mouse skin. All of the syncrudes were carcinogenic while the natural crude composite was negative following three times weekly application of 50% w/v solutions for 22 wks followed by a 22 wk observation period. In addition to eliciting progressive squamous carcinomas the syncrudes were also capable of inducing persistent ulcerative dermatitis. This inflammatory or necrotizing potential appeared to be inversely proportional to the carcinogenicity of the material. A measure of the relative solubility of the materials inmore » mouse skin was obtained by quantitation of native fluorescence in frozen sections of skin. There appeared to be a general, although non-quantitative association between fluorescence intensity in sebaceous glands and carcinogenicity in epidermal cells, however it will be necessary to examine a greater number of samples to establish such a correlation.« less

Persistent rhinitis and epithelial remodeling induced by cyclic ozone exposure in the nasal airways of infant monkeys

PubMed Central

Ballinger, Carol A.; Plopper, Charles G.; McDonald, Ruth J.; Bartolucci, Alfred A.; Postlethwait, Edward M.; Harkema, Jack R.

2011-01-01

Children chronically exposed to high levels of ozone (O3), the principal oxidant pollutant in photochemical smog, are more vulnerable to respiratory illness and infections. The specific factors underlying this differential susceptibility are unknown but may be related to air pollutant-induced nasal alterations during postnatal development that impair the normal physiological functions (e.g., filtration and mucociliary clearance) serving to protect the more distal airways from inhaled xenobiotics. In adult animal models, chronic ozone exposure is associated with adaptations leading to a decrease in airway injury. The purpose of our study was to determine whether cyclic ozone exposure induces persistent morphological and biochemical effects on the developing nasal airways of infant monkeys early in life. Infant (180-day-old) rhesus macaques were exposed to 5 consecutive days of O3 [0.5 parts per million (ppm), 8 h/day; “1-cycle”] or filtered air (FA) or 11 biweekly cycles of O3 (FA days 1–9; 0.5 ppm, 8 h/day on days 10–14; “11-cycle”). The left nasal passage was processed for light microscopy and morphometric analysis. Mucosal samples from the right nasal passage were processed for GSH, GSSG, ascorbate (AH2), and uric acid (UA) concentration. Eleven-cycle O3 induced persistent rhinitis, squamous metaplasia, and epithelial hyperplasia in the anterior nasal airways of infant monkeys, resulting in a 39% increase in the numeric density of epithelial cells. Eleven-cycle O3 also induced a 65% increase in GSH concentrations at this site. The persistence of epithelial hyperplasia was positively correlated with changes in GSH. These results indicate that early life ozone exposure causes persistent nasal epithelial alterations in infant monkeys and provide a potential mechanism for the increased susceptibility to respiratory illness exhibited by children in polluted environments. PMID:21131400

Electroconvulsive therapy-induced persistent retrograde amnesia: could it be minimised by ketamine or other pharmacological approaches?

PubMed

Gregory-Roberts, Emily M; Naismith, Sharon L; Cullen, Karen M; Hickie, Ian B

2010-10-01

Certain pharmacological agents administered during electroconvulsive therapy may have the potential to prevent persistent retrograde amnesia induced during electroconvulsive therapy. This review examines mechanisms for electroconvulsive therapy-induced retrograde amnesia, and evaluates the suitability of the anaesthetic ketamine for preventing this amnestic outcome. A review of human studies, animal models and theoretical models in light of memory dysfunction following electroconvulsive therapy was conducted. MEDLINE was searched from 1950 to April 2009 using the MeSH terms "electroconvulsive therapy", "memory", "memory short term", "memory disorders", "excitatory amino acid antagonists", and "ketamine". PREMEDLINE was searched using the terms "electroconvulsive therapy", "amnesia" and "ketamine". Additional keyword and reference list searches were performed. No language, date constraints or article type constraints were used. Disruption of long term potentiation as a mechanism for electroconvulsive therapy-induced retrograde amnesia is well supported. Based on this putative mechanism, an N-methyl-D-aspartate receptor antagonist would appear suitable for preventing the retrograde amnesia. Available evidence in animals and humans supports the prediction that ketamine, an anaesthetic agent and N-methyl-D-aspartate receptor antagonist, could effectively prevent electroconvulsive therapy-induced persistent retrograde amnesia. Whilst there are concerns about the use of ketamine with electroconvulsive therapy, such as possible psychotomimetic effects, on balance this anaesthetic agent may improve or hasten clinical response to electroconvulsive therapy. A clinical trial is warranted to determine if ketamine anaesthesia during electroconvulsive therapy can lessen persistent retrograde amnesia and improve therapeutic response. Electroconvulsive therapy with ketamine anaesthesia may provide effective antidepressant action with minimal side effects. Copyright 2009 Elsevier B.V. All rights reserved.

Opposite Roles for p38MAPK-Driven Responses and Reactive Oxygen Species in the Persistence and Resolution of Radiation-Induced Genomic Instability

PubMed Central

Werner, Erica; Wang, Huichen; Doetsch, Paul W.

2014-01-01

We report the functional and temporal relationship between cellular phenotypes such as oxidative stress, p38MAPK-dependent responses and genomic instability persisting in the progeny of cells exposed to sparsely ionizing low-Linear Energy Transfer (LET) radiation such as X-rays or high-charge and high-energy (HZE) particle high-LET radiation such as 56Fe ions. We found that exposure to low and high-LET radiation increased reactive oxygen species (ROS) levels as a threshold-like response induced independently of radiation quality and dose. This response was sustained for two weeks, which is the period of time when genomic instability is evidenced by increased micronucleus formation frequency and DNA damage associated foci. Indicators for another persisting response sharing phenotypes with stress-induced senescence, including beta galactosidase induction, increased nuclear size, p38MAPK activation and IL-8 production, were induced in the absence of cell proliferation arrest during the first, but not the second week following exposure to high-LET radiation. This response was driven by a p38MAPK-dependent mechanism and was affected by radiation quality and dose. This stress response and elevation of ROS affected genomic instability by distinct pathways. Through interference with p38MAPK activity, we show that radiation-induced stress phenotypes promote genomic instability. In contrast, exposure to physiologically relevant doses of hydrogen peroxide or increasing endogenous ROS levels with a catalase inhibitor reduced the level of genomic instability. Our results implicate persistently elevated ROS following exposure to radiation as a factor contributing to genome stabilization. PMID:25271419

A slow progressor HIV-infected boy developing quadriplegia with evidence of Epstein-Barr virus associated smooth muscle tumour of the cervical spinal cord

PubMed Central

Wilaisakditipakorn, Tanaporn; Vilaisaktipakorn, Pitchamol; Bunupuradah, Torsak; Puthanakit, Thanyawee

2015-01-01

The authors report a case of slowly progressive HIV in an 11-year-old boy whose initial presenting AIDS-defining symptom was progressive quadriplegia with complete cord compression and pathological confirmation of Epstein-Barr virus associated smooth muscle tumour. Despite tumour removal, quadriplegia persisted as did ventilator dependence. PMID:26123466

Behavioral and monoamine perturbations in adult male mice with chronic inflammation induced by repeated peripheral lipopolysaccharide administration.

PubMed

Krishna, Saritha; Dodd, Celia A; Filipov, Nikolay M

2016-04-01

Considering the limited information on the ability of chronic peripheral inflammation to induce behavioral alterations, including on their persistence after inflammatory stimuli termination and on associated neurochemical perturbations, this study assessed the effects of chronic (0.25 mg/kg; i.p.; twice weekly) lipopolysaccharide (LPS) treatment on selected behavioral, neurochemical and molecular measures at different time points in adult male C57BL/6 mice. Behaviorally, LPS-treated mice were hypoactive after 6 weeks, whereas significant hyperactivity was observed after 12 weeks of LPS and 11 weeks after 13 week LPS treatment termination. Similar biphasic responses, i.e., early decrease followed by a delayed increase were observed in the open field test center time, suggestive of, respectively, increased and decreased anxiety. In a forced swim test, mice exhibited increased immobility (depressive behavior) at all times they were tested. Chronic LPS also produced persistent increase in splenic serotonin (5-HT) and time-dependent, brain region-specific alterations in striatal and prefrontocortical dopamine and 5-HT homeostasis. Microglia, but not astrocytes, were activated by LPS early and late, but their activation did not persist after LPS treatment termination. Above findings demonstrate that chronic peripheral inflammation initially causes hypoactivity and increased anxiety, followed by persistent hyperactivity and decreased anxiety. Notably, chronic LPS-induced depressive behavior appears early, persists long after LPS termination, and is associated with increased splenic 5-HT. Collectively, our data highlight the need for a greater focus on the peripheral/central monoamine alterations and lasting behavioral deficits induced by chronic peripheral inflammation as there are many pathological conditions where inflammation of a chronic nature is a hallmark feature. Copyright © 2016 Elsevier B.V. All rights reserved.

Correlates of aortic stiffness progression in patients with type 2 diabetes: importance of glycemic control: the Rio de Janeiro type 2 diabetes cohort study.

PubMed

Ferreira, Marcel T; Leite, Nathalie C; Cardoso, Claudia R L; Salles, Gil F

2015-05-01

The correlates of serial changes in aortic stiffness in patients with diabetes have never been investigated. We aimed to examine the importance of glycemic control on progression/regression of carotid-femoral pulse wave velocity (cf-PWV) in type 2 diabetes. In a prospective study, two cf-PWV measurements were performed with the Complior equipment in 417 patients with type 2 diabetes over a mean follow-up of 4.2 years. Clinical laboratory data were obtained at baseline and throughout follow-up. Multivariable linear/logistic regressions assessed the independent correlates of changes in cf-PWV. Median cf-PWV increase was 0.11 m/s per year (1.1% per year). Overall, 212 patients (51%) increased/persisted with high cf-PWV, while 205 (49%) reduced/persisted with low cf-PWV. Multivariate linear regression demonstrated direct associations between cf-PWV changes and mean HbA1c during follow-up (partial correlation 0.14, P = 0.005). On logistic regression, a mean HbA1c ≥7.5% (58 mmol/mol) was associated with twofold higher odds of having increased/persistently high cf-PWV during follow-up. Furthermore, the rate of HbA1c reduction relative to baseline levels was inversely associated with cf-PWV changes (partial correlation -0.11, P = 0.011) and associated with reduced risk of having increased/persistently high aortic stiffness (odds ratio 0.82 [95% CI 0.69-0.96]; P = 0.017). Other independent correlates of progression in aortic stiffness were increases in systolic blood pressure and heart rate between the two cf-PWV measurements, older age, female sex, and presence of dyslipidemia and retinopathy. Better glycemic control, together with reductions in blood pressure and heart rate, was the most important correlate to attenuate/prevent progression of aortic stiffness in patients with type 2 diabetes. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Familial factors responsible for persistent crying-induced asthma: a case report.

PubMed

Weinstein, A G

1987-10-01

Crying behavior of the asthmatic child may induce wheezing symptoms. This may be a clinical problem for families with asthmatic children who exhibit frequent and persistent crying behavior. This case report identifies behaviors by the child and parents that may be responsible for continual crying. Child factors include (1) "spoiled" personality, (2) poor self-image, (3) biologic sensitivity to foods, medication, and environmental allergens producing irritability. Parental factors include poor disciplinary practices secondary to (1) disrupted home life, (2) guilt, and (3) overprotective behavior. Identification of these factors may be helpful in establishing clinical management strategies to reduce crying-induced asthma.

The MqsRA Toxin-Antitoxin System from Xylella fastidiosa Plays a Key Role in Bacterial Fitness, Pathogenicity, and Persister Cell Formation.

PubMed

Merfa, Marcus V; Niza, Bárbara; Takita, Marco A; De Souza, Alessandra A

2016-01-01

Through the formation of persister cells, bacteria exhibit tolerance to multidrug and other environmental stresses without undergoing genetic changes. The toxin-antitoxin (TA) systems are involved in the formation of persister cells because they are able to induce cell dormancy. Among the TA systems, the MqsRA system has been observed to be highly induced in persister cells of Xylella fastidiosa (causal agent of citrus variegated chlorosis-CVC) activated by copper stress, and has been described in Escherichia coli as related to the formation of persister cells and biofilms. Thus, we evaluated the role of this TA system in X. fastidiosa by overexpressing the MqsR toxin, and verified that the toxin positively regulated biofilm formation and negatively cell movement, resulting in reduced pathogenicity in citrus plants. The overexpression of MqsR also increased the formation of persister cells under copper stress. Analysis of the gene and protein expression showed that this system likely has an autoregulation mechanism to express the toxin and antitoxin in the most beneficial ratio for the cell to oppose stress. Our results suggest that this TA system plays a key role in the adaptation and survival of X. fastidiosa and reveal new insights into the physiology of phytopathogen-host interactions.

The MqsRA Toxin-Antitoxin System from Xylella fastidiosa Plays a Key Role in Bacterial Fitness, Pathogenicity, and Persister Cell Formation

PubMed Central

Merfa, Marcus V.; Niza, Bárbara; Takita, Marco A.; De Souza, Alessandra A.

2016-01-01

Through the formation of persister cells, bacteria exhibit tolerance to multidrug and other environmental stresses without undergoing genetic changes. The toxin-antitoxin (TA) systems are involved in the formation of persister cells because they are able to induce cell dormancy. Among the TA systems, the MqsRA system has been observed to be highly induced in persister cells of Xylella fastidiosa (causal agent of citrus variegated chlorosis—CVC) activated by copper stress, and has been described in Escherichia coli as related to the formation of persister cells and biofilms. Thus, we evaluated the role of this TA system in X. fastidiosa by overexpressing the MqsR toxin, and verified that the toxin positively regulated biofilm formation and negatively cell movement, resulting in reduced pathogenicity in citrus plants. The overexpression of MqsR also increased the formation of persister cells under copper stress. Analysis of the gene and protein expression showed that this system likely has an autoregulation mechanism to express the toxin and antitoxin in the most beneficial ratio for the cell to oppose stress. Our results suggest that this TA system plays a key role in the adaptation and survival of X. fastidiosa and reveal new insights into the physiology of phytopathogen-host interactions. PMID:27375608

Abnormal cortical synaptic plasticity in primary motor area in progressive supranuclear palsy.

PubMed

Conte, Antonella; Belvisi, Daniele; Bologna, Matteo; Ottaviani, Donatella; Fabbrini, Giovanni; Colosimo, Carlo; Williams, David R; Berardelli, Alfredo

2012-03-01

No study has yet investigated whether cortical plasticity in primary motor area (M1) is abnormal in patients with progressive supranuclear palsy (PSP). We studied M1 plasticity in 15 PSP patients and 15 age-matched healthy subjects. We used intermittent theta-burst stimulation (iTBS) to investigate long-term potentiation (LTP) and continuous TBS (cTBS) to investigate long-term depression (LTD)-like cortical plasticity in M1. Ten patients underwent iTBS again 1 year later. We also investigated short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) in M1 with paired-pulse transcranial magnetic stimulation, tested H reflex from upper limb flexor muscles before and after iTBS, and measured motor evoked potential (MEP) input-output (I/O) curves before and after iTBS. iTBS elicited a significantly larger MEP facilitation after iTBS in patients than in healthy subjects. Whereas in healthy subjects, cTBS inhibited MEP, in patients it significantly facilitated MEPs. In patients, SICI was reduced, whereas ICF was normal. H reflex size remained unchanged after iTBS. Patients had steeper MEP I/O slopes than healthy subjects at baseline and became even more steeper after iTBS only in patients. The iTBS-induced abnormal MEP facilitation in PSP persisted at 1-year follow-up. In conclusion, patients with PSP have abnormal M1 LTP/LTD-like plasticity. The enhanced LTP-like cortical synaptic plasticity parallels disease progression.

Do seizures and epileptic activity worsen epilepsy and deteriorate cognitive function?

PubMed

Avanzini, Giuliano; Depaulis, Antoine; Tassinari, Alberto; de Curtis, Marco

2013-11-01

Relevant to the definition of epileptic encephalopathy (EE) is the concept that the epileptic activity itself may contribute to bad outcomes, both in terms of epilepsy and cognition, above and beyond what might be expected from the underlying pathology alone, and that these can worsen over time. The review of the clinical and experimental evidence that seizures or interictal electroencephalography (EEG) discharges themselves can induce a progression toward more severe epilepsy and a regression of brain function leads to the following conclusions: The possibility of seizure-dependent worsening is by no means a general one but is limited to some types of epilepsy, namely mesial temporal lobe epilepsy (MTLE) and EEs. Clinical and experimental data concur in indicating that prolonged seizures/status epilepticus (SE) are a risky initial event that can set in motion an epileptogenic process leading to persistent, possibly drug-refractory epilepsies. The mechanisms for SE-related epileptogenic process are incompletely known; they seem to involve inflammation and/or glutamatergic transmission. The evidence of the role of recurrent individual seizures in sustaining epilepsy progression is ambiguous. The correlation between high seizure frequency and bad outcome does not necessarily demonstrate a cause-effect relationship, rather high seizure frequency and bad outcome can both depend on a particularly aggressive epileptogenic process. The results of EE studies challenge the idea of a common seizure-dependent mechanism for epilepsy progression/intellectual deterioration. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

Multilevel lumbar fusion and postoperative physiotherapy rehabilitation in a patient with persistent pain.

PubMed

Pons, Tracey; Shipton, Edward A

2011-04-01

There are no comparative randomised controlled trials of physiotherapy modalities for chronic low back and radicular pain associated with multilevel fusion. Physiotherapy-based rehabilitation to control pain and improve activation levels for persistent pain following multilevel fusion can be challenging. This is a case report of a 68-year-old man who was referred for physiotherapy intervention 10 months after a multilevel spinal fusion for spinal stenosis. He reported high levels of persistent postoperative pain with minimal activity as a consequence of his pain following the surgery. The physiotherapy interventions consisted of three phases of rehabilitation starting with pool exercise that progressed to land-based walking. These were all combined with transcutaneous electrical nerve stimulation (TENS) that was used consistently for up to 8 hours per day. As outcome measures, daily pain levels and walking distances were charted once the pool programme was completed (in the third phase). Phase progression was determined by shuttle test results. The pain level was correlated with the distance walked using linear regression over a 5-day average. Over a 5-day moving average, the pain level reduced and walking distance increased. The chart of recorded pain level and walking distance showed a trend toward decreased pain with the increased distance walked. In a patient undergoing multilevel lumbar fusion, the combined use of TENS and a progressive walking programme (from pool to land) reduced pain and increased walking distance. This improvement was despite poor medication compliance and a reported high level of postsurgical pain.

Time-controlled fasting prevents aging-like mitochondrial changes induced by persistent dietary fat overload in skeletal muscle

PubMed Central

Lettieri-Barbato, Daniele; Cannata, Stefano Maria; Casagrande, Viviana; Ciriolo, Maria Rosa

2018-01-01

A large body of evidence suggests that persistent dietary fat overload causes mitochondrial dysfunction and systemic metabolic gridlock. Mitochondrial and lipid metabolism in skeletal muscle (SkM) are severely affected upon persistent high fat diet (HFD) leading to premature tissue aging. Here, we designed weekly cycles of fasting (called as time-controlled fasting, TCF) and showed that they were effective in limiting mitochondrial damage and metabolic disturbances induced by HFD. Specifically, TCF was able to prevent the decline of adipose triglyceride lipase (Atgl), maintain efficient mitochondrial respiration in SkM as well as improve blood glucose and lipid profile. Atgl was found to be the mediator of such preventive effects as its downregulation or up-regulation in C2C12 myotubes triggers mitochondrial alteration or protects against the deleterious effects of high fat levels respectively. In conclusion, TCF could represent an effective strategy to limit mitochondrial impairment and metabolic inflexibility that are typically induced by modern western diets or during aging. PMID:29742122

FXYD2, a γ subunit of Na+,K+-ATPase, maintains persistent mechanical allodynia induced by inflammation

PubMed Central

Wang, Feng; Cai, Bing; Li, Kai-Cheng; Hu, Xu-Ye; Lu, Ying-Jin; Wang, Qiong; Bao, Lan; Zhang, Xu

2015-01-01

Na+,K+-ATPase (NKA) is required to generate the resting membrane potential in neurons. Nociceptive afferent neurons express not only the α and β subunits of NKA but also the γ subunit FXYD2. However, the neural function of FXYD2 is unknown. The present study shows that FXYD2 in nociceptive neurons is necessary for maintaining the mechanical allodynia induced by peripheral inflammation. FXYD2 interacted with α1NKA and negatively regulated the NKA activity, depolarizing the membrane potential of nociceptive neurons. Mechanical allodynia initiated in FXYD2-deficient mice was abolished 4 days after inflammation, whereas it persisted for at least 3 weeks in wild-type mice. Importantly, the FXYD2/α1NKA interaction gradually increased after inflammation and peaked on day 4 post inflammation, resulting in reduction of NKA activity, depolarization of neuron membrane and facilitation of excitatory afferent neurotransmission. Thus, the increased FXYD2 activity may be a fundamental mechanism underlying the persistent hypersensitivity to pain induced by inflammation. PMID:25633594

Time-controlled fasting prevents aging-like mitochondrial changes induced by persistent dietary fat overload in skeletal muscle.

PubMed

Lettieri-Barbato, Daniele; Cannata, Stefano Maria; Casagrande, Viviana; Ciriolo, Maria Rosa; Aquilano, Katia

2018-01-01

A large body of evidence suggests that persistent dietary fat overload causes mitochondrial dysfunction and systemic metabolic gridlock. Mitochondrial and lipid metabolism in skeletal muscle (SkM) are severely affected upon persistent high fat diet (HFD) leading to premature tissue aging. Here, we designed weekly cycles of fasting (called as time-controlled fasting, TCF) and showed that they were effective in limiting mitochondrial damage and metabolic disturbances induced by HFD. Specifically, TCF was able to prevent the decline of adipose triglyceride lipase (Atgl), maintain efficient mitochondrial respiration in SkM as well as improve blood glucose and lipid profile. Atgl was found to be the mediator of such preventive effects as its downregulation or up-regulation in C2C12 myotubes triggers mitochondrial alteration or protects against the deleterious effects of high fat levels respectively. In conclusion, TCF could represent an effective strategy to limit mitochondrial impairment and metabolic inflexibility that are typically induced by modern western diets or during aging.

Control of stress-induced persistent anxiety by an extra-amygdala septohypothalamic circuit

PubMed Central

Anthony, Todd E.; Dee, Nick; Bernard, Amy; Lerchner, Walter; Heintz, Nathaniel; Anderson, David J.

2014-01-01

The extended amygdala has dominated research on the neural circuitry of fear and anxiety, but the septo-hippocampal axis plays an important role as well. The lateral septum (LS) is thought to suppress fear and anxiety, through its outputs to the hypothalamus. However, this structure has not yet been dissected using modern tools. The type 2 CRF receptor (Crfr2) marks a subset of LS neurons, whose functional connectivity we have investigated using optogenetics. Crfr2+ cells include GABAergic projection neurons that connect with the anterior hypothalamus. Surprisingly, we find that these LS outputs enhance stress-induced behavioral measures of anxiety. Furthermore, transient activation of Crfr2+ neurons promotes, while inhibition suppresses, persistent anxious behaviors. LS Crfr2+ outputs also positively regulate circulating corticosteroid levels. These data identify a subset of LS projection neurons that promote, rather than suppress, stress-induced behavioral and endocrinological dimensions of persistent anxiety states, and provide a cellular point-of-entry to LS circuitry. PMID:24485458

HTLV-1 Tax upregulates early growth response protein 1 through nuclear factor-κB signaling

PubMed Central

Han, Jingxian; Liu, Xihong; Lv, Zhuangwei; Li, Huanhuan; Yuan, Lixiang; Li, Xiangping; Sun, Shuming; Wang, Hui; Huang, Xinxiang

2017-01-01

Human T cell leukemia virus type 1 (HTLV-1) is a complex retrovirus that causes adult T cell leukemia (ATL) in susceptible individuals. The HTLV-1-encoded oncoprotein Tax induces persistent activation of the nuclear factor-κB (NF-κB) pathway. Early growth response protein 1 (EGR1) is overexpressed in HTLV-1-infected T cell lines and ATL cells. Here, we showed that both Tax expression and HTLV-1 infection promoted EGR1 overexpression. Loss of the NF-κB binding site in the EGR1 promotor or inhibition of NF-κB activation reduced Tax-induced EGR1 upregulation. Tax mutants unable to activate NF-κB induced only slight EGR1 upregulation as compared with wild-type Tax, confirming NF-κB pathway involvement in EGR1 regulation. Tax also directly interacted with the EGR1 protein and increased endogenous EGR1 stability. Elevated EGR1 in turn promoted p65 nuclear translocation and increased NF-κB activation. These results demonstrate a positive feedback loop between EGR1 expression and NF-κB activation in HTLV-1-infected and Tax-expressing cells. Both NF-κB activation and Tax-induced EGR1 stability upregulated EGR1, which in turn enhanced constitutive NF-κB activation and facilitated ATL progression in HTLV-1-infected cells. These findings suggest EGR1 may be an effective anti-ATL therapeutic target. PMID:28881635

Inferring biomarkers for Mycobacterium avium subsp. paratuberculosis infection and disease progression in cattle using experimental data

NASA Astrophysics Data System (ADS)

Magombedze, Gesham; Shiri, Tinevimbo; Eda, Shigetoshi; Stabel, Judy R.

2017-03-01

Available diagnostic assays for Mycobacterium avium subsp. paratuberculosis (MAP) have poor sensitivities and cannot detect early stages of infection, therefore, there is need to find new diagnostic markers for early infection detection and disease stages. We analyzed longitudinal IFN-γ, ELISA-antibody and fecal shedding experimental sensitivity scores for MAP infection detection and disease progression. We used both statistical methods and dynamic mathematical models to (i) evaluate the empirical assays (ii) infer and explain biological mechanisms that affect the time evolution of the biomarkers, and (iii) predict disease stages of 57 animals that were naturally infected with MAP. This analysis confirms that the fecal test is the best marker for disease progression and illustrates that Th1/Th2 (IFN-γ/ELISA antibodies) assays are important for infection detection, but cannot reliably predict persistent infections. Our results show that the theoretical simulated macrophage-based assay is a potential good diagnostic marker for MAP persistent infections and predictor of disease specific stages. We therefore recommend specifically designed experiments to test the use of a based assay in the diagnosis of MAP infections.

Drosophila Insulin receptor regulates the persistence of injury-induced nociceptive sensitization

PubMed Central

Patel, Atit A.

2018-01-01

ABSTRACT Diabetes-associated nociceptive hypersensitivity affects diabetic patients with hard-to-treat chronic pain. Because multiple tissues are affected by systemic alterations in insulin signaling, the functional locus of insulin signaling in diabetes-associated hypersensitivity remains obscure. Here, we used Drosophila nociception/nociceptive sensitization assays to investigate the role of Insulin receptor (Insulin-like receptor, InR) in nociceptive hypersensitivity. InR mutant larvae exhibited mostly normal baseline thermal nociception (absence of injury) and normal acute thermal hypersensitivity following UV-induced injury. However, their acute thermal hypersensitivity persists and fails to return to baseline, unlike in controls. Remarkably, injury-induced persistent hypersensitivity is also observed in larvae that exhibit either type 1 or type 2 diabetes. Cell type-specific genetic analysis indicates that InR function is required in multidendritic sensory neurons including nociceptive class IV neurons. In these same nociceptive sensory neurons, only modest changes in dendritic morphology were observed in the InRRNAi-expressing and diabetic larvae. At the cellular level, InR-deficient nociceptive sensory neurons show elevated calcium responses after injury. Sensory neuron-specific expression of InR rescues the persistent thermal hypersensitivity of InR mutants and constitutive activation of InR in sensory neurons ameliorates the hypersensitivity observed with a type 2-like diabetic state. Our results suggest that a sensory neuron-specific function of InR regulates the persistence of injury-associated hypersensitivity. It is likely that this new system will be an informative genetically tractable model of diabetes-associated hypersensitivity. PMID:29752280

Human papilloma virus, DNA methylation and microRNA expression in cervical cancer (Review).

PubMed

Jiménez-Wences, Hilda; Peralta-Zaragoza, Oscar; Fernández-Tilapa, Gloria

2014-06-01

Cancer is a complex disease caused by genetic and epigenetic abnormalities that affect gene expression. The progression from precursor lesions to invasive cervical cancer is influenced by persistent human papilloma virus (HPV) infection, which induces changes in the host genome and epigenome. Epigenetic alterations, such as aberrant miRNA expression and changes in DNA methylation status, favor the expression of oncogenes and the silencing of tumor-suppressor genes. Given that some miRNA genes can be regulated through epigenetic mechanisms, it has been proposed that alterations in the methylation status of miRNA promoters could be the driving mechanism behind their aberrant expression in cervical cancer. For these reasons, we assessed the relationship among HPV infection, cellular DNA methylation and miRNA expression. We conclude that alterations in the methylation status of protein-coding genes and various miRNA genes are influenced by HPV infection, the viral genotype, the physical state of the viral DNA, and viral oncogenic risk. Furthermore, HPV induces deregulation of miRNA expression, particularly at loci near fragile sites. This deregulation occurs through the E6 and E7 proteins, which target miRNA transcription factors such as p53.

Colloidal chromic phosphate /sup 32/P synovectomy in antigen-induced arthritis in the rabbit

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

Howson, M.P.; Shepard, N.L.; Mitchell, N.S.

1988-04-01

Radioisotopes have been employed in the therapy of chronic arthritis, in particular, rheumatoid arthritis for many years. A variety of isotopes have been popularized, and in the last ten years a colloidal solution of radioactive chromic phosphate /sup 32/P has been in use apparently with equivalent efficacy to others such as /sup 169/erbium, /sup 90/yttrium, and /sup 165/dysprosium. No controlled studies on this modality have been reported and few animal studies were found. The efficacy of therapeutic doses of /sup 32/P as a medical synovectomy and its effect on rabbit joints with antigen-induced arthritis were observed in 62 arthritic kneemore » joints in 31 adult rabbits treated on one side with 0.1 microCi of /sup 32/P, the opposite serving as control. The animals were observed over a period of 11 months and examined by histologic and biochemical means. The synovium showed no evidence of radiation necrosis in treated joints. Cartilage of treated and control joints showed similar changes consistent with chronic arthritis, persistent synovitis, progressive chondrocyte degeneration, and decreased matrix metachromasia. The radiosynovectomy had neither removed synovium nor protected the cartilage. Its efficacy in humans is therefore questionable.« less

Magnetic resonance imaging indicators of blood-brain barrier and brain water changes in young rats with kaolin-induced hydrocephalus.

PubMed

Del Bigio, Marc R; Slobodian, Ili; Schellenberg, Angela E; Buist, Richard J; Kemp-Buors, Tanya L

2011-08-11

Hydrocephalus is associated with enlargement of cerebral ventricles. We hypothesized that magnetic resonance (MR) imaging parameters known to be influenced by tissue water content would change in parallel with ventricle size in young rats and that changes in blood-brain barrier (BBB) permeability would be detected. Hydrocephalus was induced by injection of kaolin into the cisterna magna of 4-week-old rats, which were studied 1 or 3 weeks later. MR was used to measure longitudinal and transverse relaxation times (T1 and T2) and apparent diffusion coefficients in several regions. Brain tissue water content was measured by the wet-dry weight method, and tissue density was measured in Percoll gradient columns. BBB permeability was measured by quantitative imaging of changes on T1-weighted images following injection of gadolinium diethylenetriamine penta-acetate (Gd-DTPA) tracer and microscopically by detection of fluorescent dextran conjugates. In nonhydrocephalic rats, water content decreased progressively from age 3 to 7 weeks. T1 and T2 and apparent diffusion coefficients did not exhibit parallel changes and there was no evidence of BBB permeability to tracers. The cerebral ventricles enlarged progressively in the weeks following kaolin injection. In hydrocephalic rats, the dorsal cortex was more dense and the white matter less so, indicating that the increased water content was largely confined to white matter. Hydrocephalus was associated with transient elevation of T1 in gray and white matter and persistent elevation of T2 in white matter. Changes in the apparent diffusion coefficients were significant only in white matter. Ventricle size correlated significantly with dorsal water content, T1, T2, and apparent diffusion coefficients. MR imaging showed evidence of Gd-DTPA leakage in periventricular tissue foci but not diffusely. These correlated with microscopic leak of larger dextran tracers. MR characteristics cannot be used as direct surrogates for water content in the immature rat model of hydrocephalus, probably because they are also influenced by other changes in tissue composition that occur during brain maturation. There is no evidence for widespread persistent opening of BBB as a consequence of hydrocephalus in young rats. However, increase in focal BBB permeability suggests that periventricular blood vessels may be disrupted.

Sustained, neuron-specific IKK/NF-κB activation generates a selective neuroinflammatory response promoting local neurodegeneration with aging

PubMed Central

2013-01-01

Background Increasing evidence indicates that neuroinflammation is a critical factor contributing to the progression of various neurodegenerative diseases. The IKK/NF-κB signalling system is a central regulator of inflammation, but it also affects neuronal survival and differentiation. A complex interplay between different CNS resident cells and infiltrating immune cells, which produce and respond to various inflammatory mediators, determines whether neuroinflammation is beneficial or detrimental. The IKK/NF-κB system is involved in both production of and responses to these mediators, although the precise contribution depends on the cell type as well as the cellular context, and is only partially understood. Here we investigated the specific contribution of neuronal IKK/NF-κB signalling on the regulation of neuroinflammatory processes and its consequences. To address this issue, we established and analysed a conditional gain-of-function mouse model that expresses a constitutively active allele of IKK2 in principal forebrain neurons (IKK2nCA). Proinflammatory gene and growth factor expression, histopathology, microgliosis, astrogliosis, immune cell infiltration and spatial learning were assessed at different timepoints after persistent canonical IKK2/NF-κB activation. Results In contrast to other cell types and organ systems, chronic IKK2/NF-κB signalling in forebrain neurons of adult IKK2nCA animals did not cause a full-blown inflammatory response including infiltration of immune cells. Instead, we found a selective inflammatory response in the dentate gyrus characterized by astrogliosis, microgliosis and Tnf-α upregulation. Furthermore, downregulation of the neurotrophic factor Bdnf correlated with a selective and progressive atrophy of the dentate gyrus and a decline in hippocampus-dependent spatial learning. Neuronal degeneration was associated with increased Fluoro-jade staining, but lacked activation of apoptosis. Remarkably, neuronal loss could be partially reversed when chronic IKK2/NF-κB signalling was turned off and Bdnf expression was restored. Conclusion Our results demonstrate that persistent IKK2/NF-κB signalling in forebrain neurons does not induce overall neuroinflammation, but elicits a selective inflammatory response in the dentate gyrus accompanied by decreased neuronal survival and impaired learning and memory. Our findings further suggest that chronic activation of neuronal IKK2/NF-κB signalling, possibly as a consequence of neuroinflammatory conditions, is able to induce apoptosis-independent neurodegeneration via paracrine suppression of Bdnf synthesis. PMID:24119288

Are there mechanistic differences between ultraviolet and visible radiation induced skin pigmentation?

PubMed

Ramasubramaniam, Rajagopal; Roy, Arindam; Sharma, Bharati; Nagalakshmi, Surendra

2011-12-01

Most of the studies on sunlight-induced pigmentation of skin are mainly focused on ultraviolet (UV) radiation-induced pigmentation and ways to prevent it. Recent studies have shown that the visible component of sunlight can also cause significant skin pigmentation. In the current study, the extent of pigmentation induced by UV and visible regions of sunlight in subjects with Fitzpatrick skin type IV-V was measured and compared with pigmentation induced by total sunlight. The immediate pigment darkening (IPD) induced by the visible fraction of sunlight is not significantly different from that induced by the UV fraction. However, the persistent pigment darkening (PPD) induced by visible fraction of sunlight in significantly lower than that induced by the UV fraction. The dose responses of IPD induced by UV, visible light and total sunlight suggest that both UV and visible light interact with the same precursor although UV is 25 times more efficient in inducing pigmentation per J cm(-2) of irradiation compared to visible radiation. The measured diffused reflection spectra and decay kinetics of UV and visible radiation-induced pigmentation are very similar, indicating that the nature of the transient and persistent species involved in both the processes are also likely to be same.

A slow progressor HIV-infected boy developing quadriplegia with evidence of Epstein-Barr virus associated smooth muscle tumour of the cervical spinal cord.

PubMed

Wilaisakditipakorn, Tanaporn; Vilaisaktipakorn, Pitchamol; Bunupuradah, Torsak; Puthanakit, Thanyawee

2015-06-29

The authors report a case of slowly progressive HIV in an 11-year-old boy whose initial presenting AIDS-defining symptom was progressive quadriplegia with complete cord compression and pathological confirmation of Epstein-Barr virus associated smooth muscle tumour. Despite tumour removal, quadriplegia persisted as did ventilator dependence. 2015 BMJ Publishing Group Ltd.

Influence of N incorporation on persistent photoconductivity in GaAsN alloys

NASA Astrophysics Data System (ADS)

Field, R. L., III; Jin, Y.; Cheng, H.; Dannecker, T.; Jock, R. M.; Wang, Y. Q.; Kurdak, C.; Goldman, R. S.

2013-04-01

We examine the role of N environment on persistent photoconductivity (PPC) in GaAs1-xNx films. For x > 0.006, significant PPC is observed at cryogenic temperatures, with the PPC magnitude increasing with increasing x due to an increase in the density of N-induced levels. Interestingly, rapid thermal annealing suppresses the PPC magnitude and reduces the N interstitial fraction; thus, the N-induced level is likely associated with N interstitials. PPC is attributed to the photogeneration of carriers from N-induced levels to the conduction-band edge, leading to a modified N molecular bond configuration. With the addition of thermal energy, the ground state configuration is restored; the N-induced level is then able to accept carriers and the conductivity decays to its preillumination value.

Evaluation of the persistence of vaccine-induced protection with human vaccines.

PubMed

Vidor, E

2010-01-01

The persistence of protection induced by vaccines is a key aspect of the implementation of human vaccination policies, particularly for ageing populations. At the time of initial licensure, the duration of protection induced by a vaccine is generally only documented by longitudinal follow up of cohorts of subjects enrolled in the pre-licensure trials over a period of 1-5 years. The follow up of these cohorts provides two types of data: antibody kinetics (or another clinically relevant immunological parameter) over time and the disease incidence. Generally, the latter trials, if implemented during the pre-licensure period, are designed to follow-up cohorts in order to demonstrate vaccine efficacy above the minimal level required for the license. For vaccines already licensed, additional tools exist. The use of immunological surrogate markers of protection is a practical way to monitor the duration of protection. Measuring the persistence of circulating antibodies is widely used in human vaccines. For several vaccines, observed data have allowed the creation of mathematical models to predict the antibody persistence over periods of time longer than those effectively documented. Clinical trials assessing the capacity of the immune system to mount a quick anamnestic response upon re-stimulation a long time after initial priming (measurement of immune memory) is also a tool employed to document the duration of protection. The waning of protection can also be demonstrated by an increase of disease incidence in the subsequent 'time-to-last-vaccine administration' age segments. Seroprevalence studies in a given age group of people that were vaccinated under real-life conditions are another way to document the persistence of protection. Finally, case-control studies in outbreak situations or in situations of persisting endemicity can also be used to document the persistence of the vaccine efficacy. All of these tools are used in the development of new vaccines, and also during their use in the field, in order to develop the best (re)vaccination policies. Copyright 2009 Elsevier Ltd. All rights reserved.

Physical Exercise Counteracts Stress-induced Upregulation of Melanin-concentrating Hormone in the Brain and Stress-induced Persisting Anxiety-like Behaviors.

PubMed

Kim, Tae-Kyung; Han, Pyung-Lim

2016-08-01

Chronic stress induces anxiety disorders, whereas physical exercise is believed to help people with clinical anxiety. In the present study, we investigated the mechanisms underlying stress-induced anxiety and its counteraction by exercise using an established animal model of anxiety. Mice treated with restraint for 2 h daily for 14 days exhibited anxiety-like behaviors, including social and nonsocial behavioral symptoms, and these behavioral impairments lasted for more than 12 weeks after the stress treatment was removed. Despite these lasting behavioral changes, wheel-running exercise treatment for 1 h daily from post-stress days 1 - 21 counteracted anxiety-like behaviors, and these anxiolytic effects of exercise persisted for more than 2 months, suggesting that anxiolytic effects of exercise stably induced. Repeated restraint treatment up-regulated the expression of the neuropeptide, melanin-concentrating hormone (MCH), in the lateral hypothalamus, hippocampus, and basolateral amygdala, the brain regions important for emotional behaviors. In an in vitro study, treatment of HT22 hippocampal cells with glucocorticoid increased MCH expression, suggesting that MCH upregulation can be initially triggered by the stress hormone, corticosterone. In contrast, post-stress treatment with wheel-running exercise reduced the stress-induced increase in MCH expression to control levels in the lateral hypothalamus, hippocampus and basolateral amygdala. Administration of an MCH receptor antagonist (SNAP94847) to stress-treated mice was therapeutic against stress-induced anxiety-like behaviors. These results suggest that repeated stress produces long-lasting anxiety-like behaviors and upregulates MCH in the brain, while exercise counteracts stress-induced MCH expression and persisting anxiety-like behaviors.

[Strategy for choosing antibiotics for treating bacterial infections associated with chronic tick-borne encephalitis].

PubMed

Malenko, G V; Pogodina, V V; Frolova, M P; Ivannikova, T A

1996-01-01

The capacity of wide-spectrum antibiotics kefzol and ristomycin to activate the persisting tick-borne encephalitis (TBE) virus and cause an exacerbation of chronic process was investigated in Syrian hamsters in whom a prolonged (77 to 270 days) persistent TBE infection was induced by three TBE strains: Vasilchenko, V-383, and 205. The degree of antibiotic-induced activation was assessed using the criteria characterizing the reproduction and peculiarities of persisting TBE virus, immunodepression, and morphologic changes in the central nervous system. Effects of kefzol and ristomycin were compared with those of 8 antibiotics studied previously. Ristomycin, levomycetin (chloramphycin), penicillin, ampicillin (ampital), and levoridan were referred to drugs devoid of evident provoking effect. Kefzol (cefamezin), florimycin (viomycin), and kanamycin (kanamytrex) were characterized as weak activators and streptomycin and tetracycline as potent activators of the persisting TBE virus. These data may be used when selecting alternative agents for therapy of secondary bacterial infections concomitant with TBE.

SIRT1 overexpression protects non-small cell lung cancer cells against osteopontin-induced epithelial-mesenchymal transition by suppressing NF-κB signaling.

PubMed

Li, Xuejiao; Jiang, Zhongxiu; Li, Xiangmin; Zhang, Xiaoye

2018-01-01

Osteopontin (OPN) is a promoter for tumor progression. It has been reported to promote non-small cell lung cancer (NSCLC) progression via the activation of nuclear factor-κB (NF-κB) signaling. As the increased acetylation of NF-κB p65 is linked to NF-κB activation, the regulation of NF-κB p65 acetylation could be a potential treatment target for OPN-induced NSCLC progression. Sirtuin 1 (SIRT1) is a deacetylase, and the role of SIRT1 in tumor progression is still controversial. The effect and mechanism of SIRT1 on OPN-induced tumor progression remains unknown. The results presented in this research demonstrated that OPN inhibited SIRT1 expression and promoted NF-κB p65 acetylation in NSCLC cell lines (A549 and NCI-H358). In this article, overexpression of SIRT1 was induced by infection of SIRT1-overexpressing lentiviral vectors. The overexpression of SIRT1 protected NSCLC cells against OPN-induced NF-κB p65 acetylation and epithelial-mesenchymal transition (EMT), as indicated by the reduction of OPN-induced changes in the expression levels of EMT-related markers and cellular morphology. Furthermore, SIRT1 overexpression significantly attenuated OPN-induced cell proliferation, migration and invasion. Moreover, overexpression of SIRT1 inhibited OPN-induced NF-κB activation. As OPN induced NSCLC cell EMT through activation of NF-κB signaling, OPN-induced SIRT1 downregulation may play an important role in NSCLC cell EMT via NF-κB signaling. The results suggest that SIRT1 could be a tumor suppressor to attenuate OPN-induced NSCLC progression through the regulation of NF-κB signaling.

Prolonged feeding with guanidinoacetate, a methyl group consumer, exacerbates ethanol-induced liver injury.

PubMed

Osna, Natalia A; Feng, Dan; Ganesan, Murali; Maillacheruvu, Priya F; Orlicky, David J; French, Samuel W; Tuma, Dean J; Kharbanda, Kusum K

2016-10-14

To investigate the hypothesis that exposure to guanidinoacetate (GAA, a potent methyl-group consumer) either alone or combined with ethanol intake for a prolonged period of time would cause more advanced liver pathology thus identifying methylation defects as the initiator and stimulator for progressive liver damage. Adult male Wistar rats were fed the control or ethanol Lieber DeCarli diet in the absence or presence of GAA supplementation. At the end of 6 wk of the feeding regimen, various biochemical and histological analyses were conducted. Contrary to our expectations, we observed that GAA treatment alone resulted in a histologically normal liver without evidence of hepatosteatosis despite persistence of some abnormal biochemical parameters. This protection could result from the generation of creatine from the ingested GAA. Ethanol treatment for 6 wk exhibited changes in liver methionine metabolism and persistence of histological and biochemical defects as reported before. Further, when the rats were fed the GAA-supplemented ethanol diet, similar histological and biochemical changes as observed after 2 wk of combined treatment, including inflammation, macro- and micro-vesicular steatosis and a marked decrease in the methylation index were noted. In addition, rats on the combined treatment exhibited increased liver toxicity and even early fibrotic changes in a subset of animals in this group. The worsening liver pathology could be related to the profound reduction in the hepatic methylation index, an increased accumulation of GAA and the inability of creatine generated to exert its hepato-protective effects in the setting of ethanol. To conclude, prolonged exposure to a methyl consumer superimposed on chronic ethanol consumption causes persistent and pronounced liver damage.

A novel single-cell method provides direct evidence of persistent DNA damage in senescent cells and aged mammalian tissues.

PubMed

Galbiati, Alessandro; Beauséjour, Christian; d'Adda di Fagagna, Fabrizio

2017-04-01

The DNA damage response (DDR) arrests cell cycle progression until DNA lesions, like DNA double-strand breaks (DSBs), are repaired. The presence of DSBs in cells is usually detected by indirect techniques that rely on the accumulation of proteins at DSBs, as part of the DDR. Such detection may be biased, as some factors and their modifications may not reflect physical DNA damage. The dependency on DDR markers of DSB detection tools has left questions unanswered. In particular, it is known that senescent cells display persistent DDR foci, that we and others have proposed to be persistent DSBs, resistant to endogenous DNA repair activities. Others have proposed that these peculiar DDR foci might not be sites of damaged DNA per se but instead stable chromatin modifications, termed DNA-SCARS. Here, we developed a method, named 'DNA damage in situ ligation followed by proximity ligation assay' (DI-PLA) for the detection and imaging of DSBs in cells. DI-PLA is based on the capture of free DNA ends in fixed cells in situ, by ligation to biotinylated double-stranded DNA oligonucleotides, which are next recognized by antibiotin anti-bodies. Detection is enhanced by PLA with a partner DDR marker at the DSB. We validated DI-PLA by demonstrating its ability to detect DSBs induced by various genotoxic insults in cultured cells and tissues. Most importantly, by DI-PLA, we demonstrated that both senescent cells in culture and tissues from aged mammals retain true unrepaired DSBs associated with DDR markers. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Prolonged feeding with guanidinoacetate, a methyl group consumer, exacerbates ethanol-induced liver injury

PubMed Central

Osna, Natalia A; Feng, Dan; Ganesan, Murali; Maillacheruvu, Priya F; Orlicky, David J; French, Samuel W; Tuma, Dean J; Kharbanda, Kusum K

2016-01-01

AIM To investigate the hypothesis that exposure to guanidinoacetate (GAA, a potent methyl-group consumer) either alone or combined with ethanol intake for a prolonged period of time would cause more advanced liver pathology thus identifying methylation defects as the initiator and stimulator for progressive liver damage. METHODS Adult male Wistar rats were fed the control or ethanol Lieber DeCarli diet in the absence or presence of GAA supplementation. At the end of 6 wk of the feeding regimen, various biochemical and histological analyses were conducted. RESULTS Contrary to our expectations, we observed that GAA treatment alone resulted in a histologically normal liver without evidence of hepatosteatosis despite persistence of some abnormal biochemical parameters. This protection could result from the generation of creatine from the ingested GAA. Ethanol treatment for 6 wk exhibited changes in liver methionine metabolism and persistence of histological and biochemical defects as reported before. Further, when the rats were fed the GAA-supplemented ethanol diet, similar histological and biochemical changes as observed after 2 wk of combined treatment, including inflammation, macro- and micro-vesicular steatosis and a marked decrease in the methylation index were noted. In addition, rats on the combined treatment exhibited increased liver toxicity and even early fibrotic changes in a subset of animals in this group. The worsening liver pathology could be related to the profound reduction in the hepatic methylation index, an increased accumulation of GAA and the inability of creatine generated to exert its hepato-protective effects in the setting of ethanol. CONCLUSION To conclude, prolonged exposure to a methyl consumer superimposed on chronic ethanol consumption causes persistent and pronounced liver damage. PMID:27784962

Familial exudative vitreoretinopathy mimicking persistent hyperplastic primary vitreous.

PubMed

Chang-Godinich, A; Paysse, E A; Coats, D K; Holz, E R

1999-04-01

To report an unusual case of familial exudative vitreoretinopathy in an infant. Case report. A 6-day-old girl had unilateral microphthalmia in the right eye, with a retrolental plaque initially diagnosed as persistent hyperplastic primary vitreous. Three months later, peripheral retinal vascular changes and a fibrovascular ridge were noted in the left eye, suggesting familial exudative vitreoretinopathy as the cause in both eyes. The microphthalmic right eye was unsalvageable. The left eye developed an exudative retinal detachment despite photocoagulation of the peripheral avascular retina. Additional cryotherapy resulted in resolution of the detachment and regression of the vascular changes. With highly asymmetric involvement, neonatal familial exudative vitreoretinopathy can mimic persistent hyperplastic primary vitreous. Fellow eye involvement can progress rapidly.

Increased S-Nitrosylation and Proteasomal Degradation of Caspase-3 during Infection Contribute to the Persistence of Adherent Invasive Escherichia coli (AIEC) in Immune Cells

PubMed Central

Dunne, Karl A.; Allam, Amr; McIntosh, Anne; Houston, Stephanie A.; Cerovic, Vuk; Goodyear, Carl S.; Roe, Andrew J.; Beatson, Scott A.; Milling, Simon W.; Walker, Daniel; Wall, Daniel M.

2013-01-01

Adherent invasive Escherichia coli (AIEC) have been implicated as a causative agent of Crohn’s disease (CD) due to their isolation from the intestines of CD sufferers and their ability to persist in macrophages inducing granulomas. The rapid intracellular multiplication of AIEC sets it apart from other enteric pathogens such as Salmonella Typhimurium which after limited replication induce programmed cell death (PCD). Understanding the response of infected cells to the increased AIEC bacterial load and associated metabolic stress may offer insights into AIEC pathogenesis and its association with CD. Here we show that AIEC persistence within macrophages and dendritic cells is facilitated by increased proteasomal degradation of caspase-3. In addition S-nitrosylation of pro- and active forms of caspase-3, which can inhibit the enzymes activity, is increased in AIEC infected macrophages. This S-nitrosylated caspase-3 was seen to accumulate upon inhibition of the proteasome indicating an additional role for S-nitrosylation in inducing caspase-3 degradation in a manner independent of ubiquitination. In addition to the autophagic genetic defects that are linked to CD, this delay in apoptosis mediated in AIEC infected cells through increased degradation of caspase-3, may be an essential factor in its prolonged persistence in CD patients. PMID:23861899

Down-regulation of NR2B receptors partially contributes to analgesic effects of Gentiopicroside in persistent inflammatory pain.

PubMed

Chen, Lei; Liu, Jin-cheng; Zhang, Xiao-nan; Guo, Yan-yan; Xu, Zhao-hui; Cao, Wei; Sun, Xiao-li; Sun, Wen-ji; Zhao, Ming-Gao

2008-06-01

Gentiopicroside is one of the secoiridoid compound isolated from Gentiana lutea. It exhibits analgesic activities in the mice. The anterior cingulate cortex (ACC) is a forebrain structure known for its roles in pain transmission and modulation. Painful stimuli potentiate the prefrontal synaptic transmission and induce glutamate NMDA NR2B receptor expression in the ACC. But little is known about Gentiopicroside on the persistent inflammatory pain and chronic pain-induced synaptic transmission changes in the ACC. The present study was undertaken to investigate its analgesic activities and central synaptic modulation to the peripheral painful inflammation. Gentiopicroside produced significant analgesic effects against persistent inflammatory pain stimuli in mice. Systemic administration of Gentiopicroside significantly reversed NR2B over-expression during the chronic phases of persistent inflammation caused by hind-paw administration of complete Freunds adjuvant (CFA) in mice. Whole-cell patch clamp recordings revealed that Gentiopicroside significantly reduced NR2B receptors mediated postsynaptic currents in the ACC. Our findings provide strong evidence that analgesic effects of Gentiopicroside involve down-regulation of NR2B receptors in the ACC to persistent inflammatory pain.

Longitudinal study of the effects of chronic hypothyroidism on skeletal muscle in dogs.

PubMed

Rossmeisl, John H; Duncan, Robert B; Inzana, Karen D; Panciera, David L; Shelton, G Diane

2009-07-01

To study the effects of experimentally induced hypothyroidism on skeletal muscle and characterize any observed myopathic abnormalities in dogs. 9 female, adult mixed-breed dogs; 6 with hypothyroidism induced with irradiation with 131 iodine and 3 untreated control dogs. Clinical examinations were performed monthly. Electromyographic examinations; measurement of plasma creatine kinase, alanine aminotransferase, aspartate aminotransferase, lactate, and lactate dehydrogenase isoenzyme activities; and skeletal muscle morphologic-morphometric examinations were performed prior to and every 6 months for 18 months after induction of hypothyroidism. Baseline, 6-month, and 18-month assessments of plasma, urine, and skeletal muscle carnitine concentrations were also performed. Hypothyroid dogs developed electromyographic and morphologic evidence of myopathy by 6 months after treatment, which persisted throughout the study, although these changes were subclinical at all times. Hypothyroid myopathy was associated with significant increases in plasma creatine kinase, aspartate aminotransferase, and lactate dehydrogenase 5 isoenzyme activities and was characterized by nemaline rod inclusions, substantial and progressive predominance of type I myofibers, decrease in mean type II fiber area, subsarcolemmal accumulations of abnormal mitochondria, and myofiber degeneration. Chronic hypothyroidism was associated with substantial depletion in skeletal muscle free carnitine. Chronic, experimentally induced hypothyroidism resulted in substantial but subclinical phenotypic myopathic changes indicative of altered muscle energy metabolism and depletion of skeletal muscle carnitine. These abnormalities may contribute to nonspecific clinical signs, such as lethargy and exercise intolerance, often reported in hypothyroid dogs.

Boron neutron capture therapy induces cell cycle arrest and cell apoptosis of glioma stem/progenitor cells in vitro

PubMed Central

2013-01-01

Background Glioma stem cells in the quiescent state are resistant to clinical radiation therapy. An almost inevitable glioma recurrence is due to the persistence of these cells. The high linear energy transfer associated with boron neutron capture therapy (BNCT) could kill quiescent and proliferative cells. Methods The present study aimed to evaluate the effects of BNCT on glioma stem/progenitor cells in vitro. The damage induced by BNCT was assessed using cell cycle progression, apoptotic cell ratio and apoptosis-associated proteins expression. Results The surviving fraction and cell viability of glioma stem/progenitor cells were decreased compared with differentiated glioma cells using the same boronophenylalanine pretreatment and the same dose of neutron flux. BNCT induced cell cycle arrest in the G2/M phase and cell apoptosis via the mitochondrial pathway, with changes in the expression of associated proteins. Conclusions Glioma stem/progenitor cells, which are resistant to current clinical radiotherapy, could be effectively killed by BNCT in vitro via cell cycle arrest and apoptosis using a prolonged neutron irradiation, although radiosensitivity of glioma stem/progenitor cells was decreased compared with differentiated glioma cells when using the same dose of thermal neutron exposure and boronophenylalanine pretreatment. Thus, BNCT could offer an appreciable therapeutic advantage to prevent tumor recurrence, and may become a promising treatment in recurrent glioma. PMID:23915425

Genome-wide gene expression changes associated with exposure of rat liver, heart, and kidney cells to endosulfan.

PubMed

Liu, Ruifeng; Printz, Richard L; Jenkins, Erin C; O'Brien, Tracy P; Te, Jerez A; Shiota, Masakazu; Wallqvist, Anders

2018-04-01

Endosulfan was once the most commonly used pesticide in agriculture and horticulture. It is an environmentally persistent organochlorine compound with the potential to bioaccumulate as it progresses through the food chain. Its acute and chronic toxicity to mammals, including humans, is well known, but the molecular mechanisms of its toxicity are not fully understood. To gain insight to these mechanisms, we examined genome-wide gene expression changes of rat liver, heart, and kidney cells induced by endosulfan exposure. We found that among the cell types examined, kidney and liver cells were the most sensitive and most resilient, respectively, to endosulfan insult. We acquired RNA sequencing information from cells exposed to endosulfan to identify differentially expressed genes, which we further examined to determine the cellular pathways that were affected. In kidney cells, exposure to endosulfan was uniquely associated with altered expression levels of genes constituting the hypoxia-inducible factor-1 (HIF-1) signaling pathway. In heart and liver cells, exposure to endosulfan altered the expression levels of genes for many members of the extracellular matrix (ECM)-receptor interaction pathway. Because both HIF-1 signaling and ECM-receptor interaction pathways directly or indirectly control cell growth, differentiation, proliferation, and apoptosis, our findings suggest that dysregulation of these pathways is responsible for endosulfan-induced cell death. Copyright © 2018 Elsevier Ltd. All rights reserved.

Early postnatal nutrition determines adult physical activity and energy expenditure in female mice

USDA-ARS?s Scientific Manuscript database

Decades of research in rodent models has shown that early postnatal overnutrition induces excess adiposity and other components of metabolic syndrome that persist into adulthood. The specific biologic mechanisms explaining the persistence of these effects, however, remain unknown. On postnatal day 1...

Squamous cell hyperplastic foci: precursors of cutaneous papillomas induced in SENCAR mice by a two-stage carcinogenesis regimen.

PubMed

Binder, R L; Johnson, G R; Gallagher, P M; Stockman, S L; Sundberg, J P; Conti, C J

1998-10-01

We have conducted a series of experiments to characterize the lesions that are precursors of cutaneous papillomas in SENCAR mice initiated with 7,12-dimethylbenz(a)anthracene (DMBA) and promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA). The first grossly detectable lesions at sites where papillomas subsequently developed were papules, slightly raised areas of skin ranging in diameter from 0.25 to approximately 1.5 mm. Papules were first detected in DMBA-initiated mice 21 days after the start of dosing with TPA. Of 78 DMBA/TPA-induced papules tracked during 15 weeks of TPA treatments, 68% progressed to papillomas, 9% persisted as papules, and 22% completely regressed. Histological evaluation of serial sections of 69 DMBA/TPA-induced papules revealed that they were focal hyperplastic lesions that we refer to as squamous cell hyperplastic foci (SCHF). These hyperproliferative lesions appeared to progress through two distinct stages. Stage I SCHF were characterized as regular hyperplastic foci involving the interfollicular epidermis and the outer root sheaths of 1 or more hair follicles down to the level of the sebaceous glands. Stage II SCHF were foci of irregular epithelial hyperplasia with increased fibrovascular stroma and involved from 3 to >10 hair follicles. Prominent dilated capillaries and inflammatory cell infiltrates were frequently associated with both stage I and II SCHF. Ha-ras gene codon 61 mutations were detected in 7 of 10 stage I SCHF and 13 of 14 stage II SCHF microdissected from histological sections and 7 of 7 of whole papules by mutation-specific PCR analysis. These data provide molecular evidence that SCHF are foci of initiated cells. Further study of these lesions may contribute to more fully defining the sequence of molecular and cellular changes necessary for tumorigenesis in mouse skin. SCHF may also have utility as early indicators of potential skin tumorigenicity in cancer bioassays.

Understanding Lymphangiogenesis in Knockout Models, the Cornea, and Ocular Diseases for the Development of Therapeutic Interventions

PubMed Central

Yang, Jessica F.; Walia, Amit; Huang, Yu-hui; Han, Kyu-yeon; Rosenblatt, Mark I; Azar, Dimitri T.; Chang, Jin-Hong

2015-01-01

A major focus of cancer research for several decades has been understanding the ability of tumors to induce new blood vessel formation, a process known as angiogenesis. Unfortunately, only limited success has been achieved in the clinical application of angiogenesis inhibitors. We now know that lymphangiogenesis, the growth of lymphatic vessels, likely also plays a major role in tumor progression. Thus, therapeutic strategies targeting lymphangiogenesis or both lymphangiogenesis and angiogenesis may represent promising approaches for treating cancer and other diseases. Importantly, research progress toward understanding lymphangiogenesis is significantly behind that related to angiogenesis. A PubMed search of ‘angiogenesis’ returns nearly 80,000 articles, whereas a search of ‘lymphangiogenesis’ returns approximately 2,635 articles. This stark contrast can be explained by the lack of molecular markers for identifying the invisible lymphatic vasculature that persisted until less than two decades ago combined with the intensity of research interest in angiogenesis during the past half-century. Still, significant strides have been made in developing strategies to modulate lymphangiogenesis, largely using ocular disease models. Here, we review the current knowledge of lymphangiogenesis in the context of knockout models, ocular diseases, the biology of activators and inhibitors, and the potential for therapeutic interventions targeting this process. PMID:26706194

Physics and application of persistent spin helix state in semiconductor heterostructures

NASA Astrophysics Data System (ADS)

Kohda, Makoto; Salis, Gian

2017-07-01

In order to utilize the spin degree of freedom in semiconductors, control of spin states and transfer of the spin information are fundamental requirements for future spintronic devices and quantum computing. Spin orbit (SO) interaction generates an effective magnetic field for moving electrons and enables spin generation, spin manipulation and spin detection without using external magnetic field and magnetic materials. However, spin relaxation also takes place due to a momentum dependent SO-induced effective magnetic field. As a result, SO interaction is considered to be a double-edged sword facilitating spin control but preventing spin transport over long distances. The persistent spin helix (PSH) state solves this problem since uniaxial alignment of the SO field with SU(2) symmetry enables the suppression of spin relaxation while spin precession can still be controlled. Consequently, understanding the PSH becomes an important step towards future spintronic technologies for classical and quantum applications. Here, we review recent progress of PSH in semiconductor heterostructures and its device application. Fundamental physics of SO interaction and the conditions of a PSH state in semiconductor heterostructures are discussed. We introduce experimental techniques to observe a PSH and explain both optical and electrical measurements for detecting a long spin relaxation time and the formation of a helical spin texture. After emphasizing the bulk Dresselhaus SO coefficient γ, the application of PSH states for spin transistors and logic circuits are discussed.

STAT1-Regulated Lung MDSC-like Cells Produce IL-10 and Efferocytose Apoptotic Neutrophils With Relevance In Resolution of Bacterial Pneumonia

PubMed Central

Poe, Stephanie L.; Arora, Meenakshi; Oriss, Timothy B.; Yarlagadda, Manohar; Isse, Kumiko; Khare, Anupriya; Levy, David E.; Lee, Janet S.; Mallampalli, Rama; Ray, Anuradha; Ray, Prabir

2012-01-01

Bacterial pneumonia remains a significant burden worldwide. Although an inflammatory response in the lung is required to fight the causative agent, persistent tissue-resident neutrophils in non-resolving pneumonia can induce collateral tissue damage and precipitate acute lung injury. However, little is known about mechanisms orchestrated in the lung tissue that remove apoptotic neutrophils to restore tissue homeostasis. In mice infected with Klebsiella pneumoniae, a bacterium commonly associated with hospital-acquired pneumonia, we show that interleukin-10 is essential for resolution of lung inflammation and recovery of mice after infection. Although IL-10−/− mice cleared bacteria, they displayed increased morbidity with progressive weight loss and persistent lung inflammation in the later phase after infection. A source of tissue IL-10 was found to be resident CD11b+Gr1intF4/80+ cells resembling myeloid-derived suppressor cells that appeared with a delayed kinetics after infection. These cells efficiently efferocytosed apoptotic neutrophils, which was aided by IL-10. The lung neutrophil burden was attenuated in infected STAT1−/− mice with concomitant increase in the frequency of the MDSC-like cells and lung IL-10 levels. Thus, inhibiting STAT1 in combination with antibiotics may be a novel therapeutic strategy to address inefficient resolution of bacterial pneumonia. PMID:22785228

Chronic Noise Exposure Acts Cumulatively to Exacerbate Alzheimer’s Disease-Like Amyloid-β Pathology and Neuroinflammation in the Rat Hippocampus

PubMed Central

Cui, Bo; Li, Kang; Gai, Zhihui; She, Xiaojun; Zhang, Na; Xu, Chuanxiang; Chen, Xuewei; An, Gaihong; Ma, Qiang; Wang, Rui

2015-01-01

A putative etiological association exists between noise exposure and Alzheimer’s disease (AD). Amyloid-β (Aβ) pathology is thought to be one of the primary initiating factors in AD. It has been further suggested that subsequent dysregulation of Aβ may play a mechanistic role in the AD-like pathophysiology associated with noise exposure. Here, we used ELISA, immunoblotting, cytokine arrays, and RT-PCR, to examine both hippocampal Aβ pathology and neuroinflammation in rats at different time points after noise exposure. We found that chronic noise exposure significantly accelerated the progressive overproduction of Aβ, which persisted for 7 to 14 days after the cessation of exposure. This effect was accompanied by up-regulated expression of amyloid precursor protein (APP) and its cleavage enzymes, β- and γ-secretases. Cytokine analysis revealed that chronic noise exposure increased levels of tumor necrosis factor-α and the receptor for advanced glycation end products, while decreasing the expression of activin A and platelet-derived growth factor- AA. Furthermore, we found persistent elevations of glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1 expression that closely corresponded to the noise-induced increases in Aβ and neuroinflammation. These studies suggest that lifelong environmental noise exposure may have cumulative effects on the onset and development of AD. PMID:26251361

Persistent activation of interlinked type 2 airway epithelial gene networks in sputum-derived cells from aeroallergen-sensitized symptomatic asthmatics.

PubMed

Jones, Anya C; Troy, Niamh M; White, Elisha; Hollams, Elysia M; Gout, Alexander M; Ling, Kak-Ming; Kicic, Anthony; Stick, Stephen M; Sly, Peter D; Holt, Patrick G; Hall, Graham L; Bosco, Anthony

2018-01-24

Atopic asthma is a persistent disease characterized by intermittent wheeze and progressive loss of lung function. The disease is thought to be driven primarily by chronic aeroallergen-induced type 2-associated inflammation. However, the vast majority of atopics do not develop asthma despite ongoing aeroallergen exposure, suggesting additional mechanisms operate in conjunction with type 2 immunity to drive asthma pathogenesis. We employed RNA-Seq profiling of sputum-derived cells to identify gene networks operative at baseline in house dust mite-sensitized (HDM S ) subjects with/without wheezing history that are characteristic of the ongoing asthmatic state. The expression of type 2 effectors (IL-5, IL-13) was equivalent in both cohorts of subjects. However, in HDM S -wheezers they were associated with upregulation of two coexpression modules comprising multiple type 2- and epithelial-associated genes. The first module was interlinked by the hubs EGFR, ERBB2, CDH1 and IL-13. The second module was associated with CDHR3 and mucociliary clearance genes. Our findings provide new insight into the molecular mechanisms operative at baseline in the airway mucosa in atopic asthmatics undergoing natural aeroallergen exposure, and suggest that susceptibility to asthma amongst these subjects involves complex interactions between type 2- and epithelial-associated gene networks, which are not operative in equivalently sensitized/exposed atopic non-asthmatics.

A -819 C/T polymorphism in the interleukin-10 promoter is associated with persistent HBV infection, but -1082 A/G and -592A/C polymorphisms are not: a meta-analysis.

PubMed

Ren, Hong; Zhang, Ting-Ting; Hu, Wen-Long

2015-03-01

Single-nucleotide polymorphisms (SNPs) in the interleukin-10 (IL10) gene promoter have been associated with persistent hepatitis B virus (HBV) infection. In particular, the -1082A/G, -819 C/T and -592 A/C polymorphisms have most often been implicated. We performed a meta-analysis of available data to determine the relative importance of these SNPs in persistent HBV infection. We searched available articles in NCBI PubMed, EMBASE, the Chinese National Knowledge Infrastructure (CNKI), and the Chinese Biomedical Literature Database (CBM) and identified 24 studies for inclusion in our meta-analysis. Our results indicated that the presence of the IL10 -819 C allele significantly increased the risk for persistent HBV infection (CC+CT vs. TT: OR = 1.283, 95 % CI 1.023-1.610, P = 0.031; C vs. T: OR = 1.183, 95 % CI 1.001-1.399, P = 0.049). Meanwhile, the -1082A/-819T/-592A haplotype (OR = 0.751, 95 % CI 0.640-0.881, P = 0.000) and the -1082A/-819C/-592C haplotype (OR = 1.568, 95 % CI 1.304-1.884, P = 0.000) were observed to be significantly associated with HBV disease progression in Asians. In contrast, the IL10 -1082A/G and -592A/C polymorphisms were not associated with an increased susceptibility to or outcome of HBV infection. Our meta-analysis supports the growing body of evidence that the presence of the IL10 -819 C/T polymorphism is associated with persistent HBV infection and that the -1082A/-819T/-592A haplotype and the -1082A/-819C/-592C haplotype are associated with HBV disease progression in Asians.

Whole-Genome Sequencing and Variant Analysis of Human Papillomavirus 16 Infections.

PubMed

van der Weele, Pascal; Meijer, Chris J L M; King, Audrey J

2017-10-01

Human papillomavirus (HPV) is a strongly conserved DNA virus, high-risk types of which can cause cervical cancer in persistent infections. The most common type found in HPV-attributable cancer is HPV16, which can be subdivided into four lineages (A to D) with different carcinogenic properties. Studies have shown HPV16 sequence diversity in different geographical areas, but only limited information is available regarding HPV16 diversity within a population, especially at the whole-genome level. We analyzed HPV16 major variant diversity and conservation in persistent infections and performed a single nucleotide polymorphism (SNP) comparison between persistent and clearing infections. Materials were obtained in the Netherlands from a cohort study with longitudinal follow-up for up to 3 years. Our analysis shows a remarkably large variant diversity in the population. Whole-genome sequences were obtained for 57 persistent and 59 clearing HPV16 infections, resulting in 109 unique variants. Interestingly, persistent infections were completely conserved through time. One reinfection event was identified where the initial and follow-up samples clustered differently. Non-A1/A2 variants seemed to clear preferentially ( P = 0.02). Our analysis shows that population-wide HPV16 sequence diversity is very large. In persistent infections, the HPV16 sequence was fully conserved. Sequencing can identify HPV16 reinfections, although occurrence is rare. SNP comparison identified no strongly acting effect of the viral genome affecting HPV16 infection clearance or persistence in up to 3 years of follow-up. These findings suggest the progression of an early HPV16 infection could be host related. IMPORTANCE Human papillomavirus 16 (HPV16) is the predominant type found in cervical cancer. Progression of initial infection to cervical cancer has been linked to sequence properties; however, knowledge of variants circulating in European populations, especially with longitudinal follow-up, is limited. By sequencing a number of infections with known follow-up for up to 3 years, we gained initial insights into the genetic diversity of HPV16 and the effects of the viral genome on the persistence of infections. A SNP comparison between sequences obtained from clearing and persistent infections did not identify strongly acting DNA variations responsible for these infection outcomes. In addition, we identified an HPV16 reinfection event where sequencing of initial and follow-up samples showed different HPV16 variants. Based on conventional genotyping, this infection would incorrectly be considered a persistent HPV16 infection. In the context of vaccine efficacy and monitoring studies, such infections could potentially cause reduced reported efficacy or efficiency. Copyright © 2017 van der Weele et al.

Severe Pleuropulmonary Paragonimiasis Caused by Paragonimus mexicanus Treated as Tuberculosis in Ecuador.

PubMed

Calvopina, Manuel; Romero-Alvarez, Daniel; Macias, Rubén; Sugiyama, Hiromu

2017-01-11

A 30-year-old male, from a subtropical region of Ecuador, was hospitalized with a 5-year history of persistent cough with rusty brown sputum, chest pain, and progressive dyspnea. The patient underwent thoracic surgery 3 years ago for pleural effusion and subsequently received a 9-month regimen treatment of tuberculosis. However, there was no clinical resolution and symptoms became progressively worse. A chest radiograph and computerized tomography scan showed several small nodules in both lungs. Eggs of Paragonimus spp. were observed in sputum smears, but the smears were negative for acid-fast bacilli. Molecular characterization of eggs by the internal transcribed spacer-2 regions identified them as Paragonimus mexicanus The patient was treated with praziquantel and tested negative parasitologically for 12 months. There was clinical resolution of the cough and expectoration, but dyspnea and chest pain persisted. © The American Society of Tropical Medicine and Hygiene.

Severe Pleuropulmonary Paragonimiasis Caused by Paragonimus mexicanus Treated as Tuberculosis in Ecuador

PubMed Central

Calvopina, Manuel; Romero-Alvarez, Daniel; Macias, Rubén; Sugiyama, Hiromu

2017-01-01

A 30-year-old male, from a subtropical region of Ecuador, was hospitalized with a 5-year history of persistent cough with rusty brown sputum, chest pain, and progressive dyspnea. The patient underwent thoracic surgery 3 years ago for pleural effusion and subsequently received a 9-month regimen treatment of tuberculosis. However, there was no clinical resolution and symptoms became progressively worse. A chest radiograph and computerized tomography scan showed several small nodules in both lungs. Eggs of Paragonimus spp. were observed in sputum smears, but the smears were negative for acid-fast bacilli. Molecular characterization of eggs by the internal transcribed spacer-2 regions identified them as Paragonimus mexicanus. The patient was treated with praziquantel and tested negative parasitologically for 12 months. There was clinical resolution of the cough and expectoration, but dyspnea and chest pain persisted. PMID:27879464

Childhood Stuttering – Where are we and Where are we going?

PubMed Central

Smith, Anne; Weber, Christine

2017-01-01

Remarkable progress has been made over the past two decades in expanding our understanding of the behavioral, peripheral physiological, and central neurophysiological bases of stuttering in early childhood. It is clear that stuttering is a neurodevelopmental disorder characterized by atypical development of speech motor planning and execution networks. The speech motor system must interact in complex ways with neural systems mediating language, other cognitive, and emotional processes. During the time window when stuttering typically appears and follows its path to either recovery or persistence, all of these neurobehavioral systems are undergoing rapid and dramatic developmental changes. We summarize our current understanding of the various developmental trajectories relevant for the understanding of stuttering in early childhood. We also present theoretical and experimental approaches that we believe will be optimal for even more rapid progress toward developing better and more targeted treatment for stuttering in the preschool children who are more likely to persist in stuttering. PMID:27701705

Influence of N incorporation on persistent photoconductivity in GaAsN alloys

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

Field III, R. L.; Jin, Y.; Cheng, H.

2013-04-08

We examine the role of N environment on persistent photoconductivity (PPC) in GaAs 1-xN x films. For x > 0.006, significant PPC is observed at cryogenic temperatures, with the PPC magnitude increasing with increasing x due to an increase in the density of N-induced levels. Interestingly, rapid thermal annealing suppresses the PPC magnitude and reduces the N interstitial fraction; thus, the N-induced level is likely associated with N interstitials. PPC is attributed to the photogeneration of carriers from N-induced levels to the conduction-band edge, leading to a modified N molecular bond configuration. With the addition of thermal energy, the groundmore » state configuration is restored; the N-induced level is then able to accept carriers and the conductivity decays to its preillumination value.« less

Current therapies and future perspectives in subacute sclerosing panencephalitis.

PubMed

Tatli, Burak; Ekici, Bariş; Ozmen, Meral

2012-04-01

Subacute sclerosing panencephalitis is a progressive neurological disorder of children and young adults caused by a measles virus that became defective by persisting in the host. According to the results of clinical trials, antiviral and/or immunomodulatory therapy can slow the progression of the disease and improve life expectancy in patients. However, its long-term effects and eventual outcome remain debatable due to conflicting results and its lack of effect on the rapidly progressive form of the disease. Possible future therapies for subacute sclerosing panencephalitis are RNAi and antiapoptotic agents, which are currently in the hypothetical and experimental stages of research.

Hyperbaric Oxygen Therapy in the Treatment of Chronic Mild-Moderate Blast-Induced Traumatic Brain Injury PCS and PTSD

DTIC Science & Technology

2015-10-01

hyperbaric oxygen therapy; TBI: traumatic brain injury; PPCS: persistent post- concussion syndrome 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF...persistent post- concussion syndrome (PPCS). Evidence-based medicine exists for PTSD, but there is no effective treatment for the persistent post... concussion syndrome (PPCS) of mild-moderate TBI nor the combined diagnoses of PPCS and PTSD. Between the Fall of 2008 and end of 2010, the P.I

Postsecondary pathways and persistence for STEM versus non-STEM majors: among college students with an autism spectrum disorder.

PubMed

Wei, Xin; Christiano, Elizabeth R A; Yu, Jennifer W; Blackorby, Jose; Shattuck, Paul; Newman, Lynn A

2014-05-01

Little is known about postsecondary pathways and persistence among college students with an autism spectrum disorder (ASD). This study analyzed data from the National Longitudinal Transition Study-2, 2001-2009, a nationally representative sample of students in special education with an ASD who progressed from high school to postsecondary education. Findings suggest that most college students with an ASD enrolled in a 2-year community college at some point in the postsecondary careers (81%). Those in science, technology, engineering and mathematics (STEM) fields were more likely to persist in a 2-year community college and were twice as likely to transfer from a 2-year community college to a 4-year university than their peers in the non-STEM fields. College persistence rates varied by gender, race, parent education level, and college pathway and major. Educational policy implications are discussed.

Postsecondary Pathways and Persistence for STEM versus non-STEM Majors: Among College Students with an Autism Spectrum Disorder

PubMed Central

Wei, Xin; Christiano, Elizabeth R. A.; Yu, Jennifer W.; Blackorby, Jose; Shattuck, Paul; Newman, Lynn

2014-01-01

Little is known about postsecondary pathways and persistence among college students with an Autism Spectrum Disorder (ASD). This study analyzed data from the National Longitudinal Transition Study-2, 2001–2009, a nationally representative sample of students in special education with an ASD who progressed from high school to postsecondary education. Findings suggest that most college students with an ASD enrolled in a 2-year community college at some point in their postsecondary careers (81%). Those in science, technology, engineering and mathematics (STEM) fields were more likely to persist in a 2-year community college and were twice as likely to transfer from a 2-year community college to a 4-year university than their peers in the non-STEM fields. College persistence rates varied by gender, race, parent education level, and college pathway and major. Educational policy implications are discussed. PMID:24158680

Spatial and Temporal Resolution of Global Protein Synthesis during HSV Infection Using Bioorthogonal Precursors and Click Chemistry

PubMed Central

Serwa, Remigiusz A.; O’Hare, Peter

2016-01-01

We used pulse-labeling with the methionine analogue homopropargylglycine (HPG) to investigate spatiotemporal aspects of protein synthesis during herpes simplex virus (HSV) infection. In vivo incorporation of HPG enables subsequent selective coupling of fluorochrome-capture reagents to newly synthesised proteins. We demonstrate that HPG labeling had no effect on cell viability, on accumulation of test early or late viral proteins, or on overall virus yields. HPG pulse-labeling followed by SDS-PAGE analysis confirmed incorporation into newly synthesised proteins, while parallel processing by in situ cycloaddition revealed new insight into spatiotemporal aspects of protein localisation during infection. A striking feature was the rapid accumulation of newly synthesised proteins not only in a general nuclear pattern but additionally in newly forming sub-compartments represented by small discrete foci. These newly synthesised protein domains (NPDs) were similar in size and morphology to PML domains but were more numerous, and whereas PML domains were progressively disrupted, NPDs were progressively induced and persisted. Immediate-early proteins ICP4 and ICP0 were excluded from NPDs, but using an ICP0 mutant defective in PML disruption, we show a clear spatial relationship between NPDs and PML domains with NPDs frequently forming immediately adjacent and co-joining persisting PML domains. Further analysis of location of the chaperone Hsc70 demonstrated that while NPDs formed early in infection without overt Hsc70 recruitment, later in infection Hsc70 showed pronounced recruitment frequently in a coat-like fashion around NPDs. Moreover, while ICP4 and ICP0 were excluded from NPDs, ICP22 showed selective recruitment. Our data indicate that NPDs represent early recruitment of host and viral de novo translated protein to distinct structural entities which are precursors to the previously described VICE domains involved in protein quality control in the nucleus, and reveal new features from which we propose spatially linked platforms of newly synthesised protein processing after nuclear import. PMID:27706239

Prevention of plasticity of endocannabinoid signaling inhibits persistent limbic hyperexcitability caused by developmental seizures.

PubMed

Chen, Kang; Neu, Axel; Howard, Allyson L; Földy, Csaba; Echegoyen, Julio; Hilgenberg, Lutz; Smith, Martin; Mackie, Ken; Soltesz, Ivan

2007-01-03

Depolarization-induced suppression of inhibition (DSI) is an endocannabinoid-mediated short-term plasticity mechanism that couples postsynaptic Ca2+ rises to decreased presynaptic GABA release. Whether the gain of this retrograde synaptic mechanism is subject to long-term modulation by glutamatergic excitatory inputs is not known. Here, we demonstrate that activity-dependent long-term DSI potentiation takes place in hippocampal slices after tetanic stimulation of Schaffer collateral synapses. This activity-dependent, long-term plasticity of endocannabinoid signaling was specific to GABAergic synapses, as it occurred without increases in the depolarization-induced suppression of excitation. Induction of tetanus-induced DSI potentiation in vitro required a complex pathway involving AMPA/kainate and metabotropic glutamate receptor as well as CB1 receptor activation. Because DSI potentiation has been suggested to play a role in persistent limbic hyperexcitability after prolonged seizures in the developing brain, we used these mechanistic insights into activity-dependent DSI potentiation to test whether interference with the induction of DSI potentiation prevents seizure-induced long-term hyperexcitability. The results showed that the in vitro, tetanus-induced DSI potentiation was occluded by previous in vivo fever-induced (febrile) seizures, indicating a common pathway. Accordingly, application of CB1 receptor antagonists during febrile seizures in vivo blocked the seizure-induced persistent DSI potentiation, abolished the seizure-induced upregulation of CB1 receptors, and prevented the emergence of long-term limbic hyperexcitability. These results reveal a new form of activity-dependent, long-term plasticity of endocannabinoid signaling at perisomatic GABAergic synapses, and demonstrate that blocking the induction of this plasticity abolishes the long-term effects of prolonged febrile seizures in the developing brain.

Juvenile social defeat stress exposure persistently impairs social behaviors and neurogenesis.

PubMed

Mouri, Akihiro; Ukai, Mayu; Uchida, Mizuki; Hasegawa, Sho; Taniguchi, Masayuki; Ito, Takahiro; Hida, Hirotake; Yoshimi, Akira; Yamada, Kiyofumi; Kunimoto, Shohko; Ozaki, Norio; Nabeshima, Toshitaka; Noda, Yukihiro

2018-05-01

Adverse juvenile experiences, including physical abuse, often have negative health consequences later in life. We investigated the influence of social defeat stress exposure as juveniles on neuropsychological behaviors, and the causal role of glucocorticoids in abnormal behaviors and impairment of neurogenesis in mice exposed to the stress. The juvenile (24-day-old) and adult (70-day-old) male C57BL/6J mice were exposed to social defeat stress induced by an aggressive ICR mouse. Social defeat stress exposure as juveniles, even for 1 day, induced persistent social avoidance to the unfamiliar ICR mouse in the social interaction test, but that was not observed in mice exposed to the stress as adults. Social avoidance by the stress exposure as juveniles for 10 consecutive days was observed, when the target mouse was not only unfamiliar ICR but also another C57BL/J mouse, but not an absent or an anesthetized ICR mouse. The stress exposure did not induce anxiety- and depression-like behaviors in spontaneous locomotor activity, elevated plus-maze test, marble-burying test, forced swimming test, or sucrose preference test. Serum corticosterone levels increased immediately after the stress exposure. The hippocampal neurogenesis was suppressed 1 day and 4 weeks after the stress exposure. Administration of mifepristone, a glucocorticoid receptor antagonist, prior to each stress exposure, blocked the persistent social avoidance and suppression of neurogenesis. In conclusion, social avoidance induced by social defeat stress exposure as juveniles are more persistent than that as adults. These social avoidances are associated with suppression of hippocampal neurogenesis via glucocorticoid receptors. Copyright © 2018 Elsevier Ltd. All rights reserved.

Induction of immunity following vaccination with a chemically attenuated malaria vaccine correlates with persistent antigenic stimulation.

PubMed

Reiman, Jennifer M; Kumar, Sanjai; Rodriguez, Ingrid B; Gnidehou, Sedami; Ito, Koichi; Stanisic, Danielle I; Lee, Moses; McPhun, Virginia; Majam, Victoria; Willemsen, Nicole M; Batzloff, Michael R; Raja, Amber I; Dooley, Brad; Hoffman, Stephen L; Yanow, Stephanie K; Good, Michael F

2018-01-01

Blood stage malaria parasites attenuated with seco-cyclopropyl pyrrolo indole (CPI) analogues induce robust immunity in mice to homologous and heterologous malaria parasites and are being considered for the development of a human vaccine. However, it is not understood how attenuated parasites induce immunity. We showed that following vaccination, parasite DNA persisted in blood for several months, raising the possibility that ongoing immune stimulation may be critical. However, parasites were not seen microscopically beyond 24 h postvaccination. We aimed to provide a mechanistic understanding of immune induction. Mice were vaccinated with chemically attenuated Plasmodium chabaudi parasites. PCR and adoptive transfer studies were used to determine the presence of parasites and antigen in vivo . In other experiments, Plasmodium falciparum parasitised red blood cells were attenuated in vitro and RNA and antigen expression studied. We show that blood transferred from vaccinated mice into naïve mice activates T cells and induces complete protective immunity in the recipient mice strongly suggesting that there is persistence of parasite antigen postvaccination. This is supported by the presence of parasite RNA in vaccinated mice and both RNA and antigen expression in P. falciparum cultures treated with CPI drugs in vitro . In addition, drugs that block parasite growth also prevent the induction of immunity in vaccinated mice, indicating that some growth of attenuated parasites is required for immune induction. Attenuated parasites persist at submicroscopic levels in the blood of mice postvaccination with the ability to activate T cells and induce ongoing protective immune responses.

Modeling the environmental growth of Pseudogymnoascus destructans and its impact on the white-nose syndrome epidemic.

PubMed

Reynolds, Hannah T; Ingersoll, Tom; Barton, Hazel A

2015-04-01

White-nose syndrome (WNS) has had a devastating effect on North American bat populations. The causal agent of WNS is the fungal pathogen, Pseudogymnoascus destructans (Pd), which has been shown to persist in caves after the eradication of host populations. As nonpathogenic Pseudogymnoascus spp. display saprophytic growth and are among the most commonly isolated fungi from caves, we examined whether Pd could grow in cave sediments and the contribution such growth could have to WNS disease progression. We inoculated a range of diverse cave sediments and demonstrated the growth of Pd in all sediments tested. These data indicate that environmental growth of Pd could lead to the accumulation of spores above the estimated infection threshold for WNS, allowing environment-to-bat infection. The obtained growth parameters were then used in a susceptible-infected-susceptible mathematic model to determine the possible contribution of environmental Pd growth to WNS disease progression in a colony of little brown bats (Myotis lucifugus). This model suggests that the environmental growth of Pd would increase WNS infection rates, particularly in colonies experiencing longer hibernation periods or in hibernacula with high levels of organic detritus. The model also suggests that once introduced, environmental Pd growth would allow the persistence of this pathogen within infected hibernacula for decades, greatly compromising the success of bat reintroduction strategies. Together these data suggest that Pd is not reliant on its host for survival and is capable of environmental growth and amplification that could contribute to the rapid progression and long-term persistence of WNS in the hibernacula of threatened North American bats.

Predictive validity of cannabis consumption measures: Results from a national longitudinal study.

PubMed

Buu, Anne; Hu, Yi-Han; Pampati, Sanjana; Arterberry, Brooke J; Lin, Hsien-Chang

2017-10-01

Validating the utility of cannabis consumption measures for predicting later cannabis related symptomatology or progression to cannabis use disorder (CUD) is crucial for prevention and intervention work that may use consumption measures for quick screening. This study examined whether cannabis use quantity and frequency predicted CUD symptom counts, progression to onset of CUD, and persistence of CUD. Data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) at Wave 1 (2001-2002) and Wave 2 (2004-2005) were used to identify three risk samples: (1) current cannabis users at Wave 1 who were at risk for having CUD symptoms at Wave 2; (2) current users without lifetime CUD who were at risk for incident CUD; and (3) current users with past-year CUD who were at risk for persistent CUD. Logistic regression and zero-inflated Poisson models were used to examine the longitudinal effect of cannabis consumption on CUD outcomes. Higher frequency of cannabis use predicted lower likelihood of being symptom-free but it did not predict the severity of CUD symptomatology. Higher frequency of cannabis use also predicted higher likelihood of progression to onset of CUD and persistence of CUD. Cannabis use quantity, however, did not predict any of the developmental stages of CUD symptomatology examined in this study. This study has provided a new piece of evidence to support the predictive validity of cannabis use frequency based on national longitudinal data. The result supports the common practice of including frequency items in cannabis screening tools. Copyright © 2017 Elsevier Ltd. All rights reserved.

Pre-treatment anxiety is associated with persistent chemotherapy-induced peripheral neuropathy in women treated with neoadjuvant chemotherapy for breast cancer.

PubMed

Lee, Kwang-Min; Jung, Dooyoung; Hwang, Heesung; Son, Kyung-Lak; Kim, Tae-Yong; Im, Seock-Ah; Lee, Kyung-Hun; Hahm, Bong-Jin

2018-05-01

Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent adverse reaction caused by chemotherapeutic agents, especially the taxanes. CIPN can persist from months to years after completion of chemotherapy, decreasing quality of life for cancer survivors. The aim of this study was to explore the incidence and risk factors of persistent CIPN among women with breast cancer receiving neoadjuvant chemotherapy. In this prospective study, we recruited women with breast cancer receiving neoadjuvant chemotherapy, including four cycles of docetaxel. Participants reported neuropathic symptoms of tingling/numbness at baseline, at the end of chemotherapy treatment, and at 8 months after completion of chemotherapy. Candidate factors associated with CIPN were assessed before chemotherapy. Among 111 participants, 50 (45.0%) experienced CIPN during chemotherapy, and 21 (18.9%) reported persistent CIPN after chemotherapy. Univariate logistic regression analysis revealed that development of CIPN was significantly associated with pre-treatment numbness (odds ratio [OR], 4.02; 95% confidence interval [CI], 1.09-7.40; p = .033), and persistent CIPN was significantly associated with pre-treatment numbness (OR, 3.60; 95% CI, 1.12-11.61; p = .032) and pre-treatment anxiety (OR, 5.02; 95% CI, 1.84-13.70; p = .002). Multivariate analysis indicated that pre-treatment anxiety remained significantly associated with persistent CIPN (OR, 4.01; 95% CI, 1.25-12.87; p = .020). Our results suggested that pre-treatment anxiety might be related to a patient's risk for persistent CIPN in women with breast cancer undergoing neoadjuvant chemotherapy. Further research is required to investigate if interventions targeting pre-treatment anxiety could provide prevention and management for persistent CIPN. Copyright © 2018. Published by Elsevier Inc.

Progressive myopia or hyperopia can be induced in chicks and reversed by manipulation of the chromaticity of ambient light.

PubMed

Foulds, Wallace S; Barathi, Veluchamy A; Luu, Chi D

2013-12-09

To determine whether progressive ametropia can be induced in chicks and reversed by manipulation of the chromaticity of ambient light. One-day-old chicks were raised in red light (90% red, 10% yellow-green) or in blue light (85% blue, 15% green) with a 12 hour on/off cycle for 14 to 42 days. Refraction was determined by streak retinoscopy, and by automated infrared photoretinoscopy and ocular biometry by A-scan ultrasonography. Red light induced progressive myopia (mean refraction ± SD at 28 days, -2.83 ± 0.25 diopters [D]). Progressive hyperopia was induced by blue light (mean refraction at 28 days, +4.55 ± 0.21 D). The difference in refraction between the groups was highly significant at P < 0.001. Induced myopia or hyperopia was axial as confirmed by ultrasound biometry. Myopia induced by 21 days of red light (-2.21 ± 0.21 D) was reversed to hyperopia (+2.50 ± 0.29 D) by subsequent 21 days of blue light. Hyperopia induced by 21 days of blue light (+4.21 ± 0.19 D) was reversed to myopia (-1.23 ± 0.12 D) by 21 days of red light. Rearing chicks in red light caused progressive myopia, while rearing in blue light caused progressive hyperopia. Light-induced myopia or hyperopia in chicks can be reversed to hyperopia or myopia, respectively, by an alteration in the chromaticity of ambient light. Manipulation of chromaticity may be applicable to the management of human childhood myopia.

Protein Translation in the Nucleus Accumbens Is Dysregulated during Cocaine Withdrawal and Required for Expression of Incubation of Cocaine Craving.

PubMed

Werner, Craig T; Stefanik, Michael T; Milovanovic, Mike; Caccamise, Aaron; Wolf, Marina E

2018-03-14

Exposure to drug-associated cues can induce drug craving and relapse in abstinent addicts. Cue-induced craving that progressively intensifies ("incubates") during withdrawal from cocaine has been observed in both rats and humans. Building on recent evidence that aberrant protein translation underlies incubation-related adaptations in the NAc, we used male rats to test the hypothesis that translation is dysregulated during cocaine withdrawal and/or when rats express incubated cocaine craving. We found that intra-NAc infusion of anisomycin, a general protein translation inhibitor, or rapamycin, an inhibitor of mammalian target of rapamycin, reduced the expression of incubated cocaine craving, consistent with previous results showing that inhibition of translation in slices normalized the adaptations that maintain incubation. We then examined signaling pathways involved in protein translation using NAc synaptoneurosomes prepared after >47 d of withdrawal from cocaine or saline self-administration, or after withdrawal plus a cue-induced seeking test. The most robust changes were observed following seeking tests. Most notably, we found that eukaryotic elongation factor 2 (eEF2) and eukaryotic initiation factor 2α (eIF2α) are dephosphorylated when cocaine rats undergo a cue-induced seeking test; both effects are consistent with increased translation during the test. Blocking eIF2α dephosphorylation and thereby restoring its inhibitory influence on translation, via intra-NAc injection of Sal003 just before the test, substantially reduced cocaine seeking. These results are consistent with dysregulation of protein translation in the NAc during cocaine withdrawal, enabling cocaine cues to elicit an aberrant increase in translation that is required for the expression of incubated cocaine craving. SIGNIFICANCE STATEMENT Cue-induced cocaine craving progressively intensifies (incubates) during withdrawal in both humans and rats. This may contribute to persistent vulnerability to relapse. We previously demonstrated a role for protein translation in synaptic adaptations in the NAc closely linked to incubation. Here, we tested the hypothesis that translation is dysregulated during cocaine withdrawal, and this contributes to incubated craving. Analysis of signaling pathways regulating translation suggested that translation is enhanced when "incubated" rats undergo a cue-induced seeking test. Furthermore, intra-NAc infusions of drugs that inhibit protein translation through different mechanisms reduced expression of incubated cue-induced cocaine seeking. These results demonstrate that the expression of incubation depends on an acute increase in translation that may result from dysregulation of several pathways. Copyright © 2018 the authors 0270-6474/18/382683-15$15.00/0.

Estrogens and Progesterone Promote Persistent CCND1 Gene Activation during G1 by Inducing Transcriptional Derepression via c-Jun/c-Fos/Estrogen Receptor (Progesterone Receptor) Complex Assembly to a Distal Regulatory Element and Recruitment of Cyclin D1 to Its Own Gene Promoter

PubMed Central

Cicatiello, Luigi; Addeo, Raffaele; Sasso, Annarita; Altucci, Lucia; Petrizzi, Valeria Belsito; Borgo, Raphaelle; Cancemi, Massimo; Caporali, Simona; Caristi, Silvana; Scafoglio, Claudio; Teti, Diana; Bresciani, Francesco; Perillo, Bruno; Weisz, Alessandro

2004-01-01

Transcriptional activation of the cyclin D1 gene (CCND1) plays a pivotal role in G1-phase progression, which is thereby controlled by multiple regulatory factors, including nuclear receptors (NRs). Appropriate CCND1 gene activity is essential for normal development and physiology of the mammary gland, where it is regulated by ovarian steroids through a mechanism(s) that is not fully elucidated. We report here that CCND1 promoter activation by estrogens in human breast cancer cells is mediated by recruitment of a c-Jun/c-Fos/estrogen receptor α complex to the tetradecanoyl phorbol acetate-responsive element of the gene, together with Oct-1 to a site immediately adjacent. This process coincides with the release from the same DNA region of a transcriptional repressor complex including Yin-Yang 1 (YY1) and histone deacetylase 1 and is sufficient to induce the assembly of the basal transcription machinery on the promoter and to lead to initial cyclin D1 accumulation in the cell. Later on in estrogen stimulation, the cyclin D1/Cdk4 holoenzyme associates with the CCND1 promoter, where E2F and pRb can also be found, contributing to the long-lasting gene enhancement required to drive G1-phase completion. Interestingly, progesterone triggers similar regulatory events through its own NRs, suggesting that the gene regulation cascade described here represents a crossroad for the transcriptional control of G1-phase progression by different classes of NRs. PMID:15282324

Cocaine-induced midline destructive lesions - an autoimmune disease?

PubMed

Trimarchi, M; Bussi, M; Sinico, R A; Meroni, Pierluigi; Specks, U

2013-02-01

In Europe it is estimated that around 13million of adults (15-64years) have used cocaine at least once in their lifetime. The most frequently used route of administration for the drug is intranasal inhalation, or "snorting", and thus the adverse effects of cocaine on the nasal tract are very common. Habitual nasal insufflations of cocaine may cause mucosal lesions, and if cocaine use becomes chronic and compulsive, progressive damage of the mucosa and perichondrium leads to ischemic necrosis of septal cartilage and perforation of the nasal septum. Occasionally, cocaine-induced lesions cause extensive destruction of the osteocartilaginous structures of nose, sinuses and palate that can mimic other diseases such as tumors, infections, and immunological diseases. Thorough diagnostic workup, including endoscopic, radiologic, histopathologic and serologic testing is imperative to arrive at the proper diagnosis and to initiate appropriate local and systemic treatment. Positive antineutrophil cytoplasmic antibody (ANCA) test results may be found in an unexpectedly large proportion of patients with CIMDL. In several instances their lesions are clinically indistinguishable from granulomatosis with polyangiitis (Wegener's) limited to the upper respiratory tract. CIMDL seem to be the result of a necrotizing inflammatory tissue response triggered by cocaine abuse in a subset of patients predisposed to produce ANCA, particularly those reacting with HNE. The presence of these HNE-ANCA seems to promote or define the disease phenotype. CIMDL do not respond well to immunosuppressive therapy. Only the consistent removal of persistent stimuli of autoantibody production (cocaine, bacterial superinfections) can halt the disease process, prevent the progression of the lesions and promise success of surgical repair procedures. Copyright © 2012 Elsevier B.V. All rights reserved.

Experimental progressive emphysema in BALB/cJ mice as a model for chronic alveolar destruction in humans

PubMed Central

Limjunyawong, Nathachit; Craig, John M.; Lagassé, H. A. Daniel; Scott, Alan L.

2015-01-01

Emphysema, one of the major components of chronic obstructive pulmonary disease (COPD), is characterized by the progressive and irreversible loss of alveolar lung tissue. Even though >80% of COPD cases are associated with cigarette smoking, only a relatively small proportion of smokers develop emphysema, suggesting a potential role for genetic factors in determining individual susceptibility to emphysema. Although strain-dependent effects have been shown in animal models of emphysema, the molecular basis underlying this intrinsic susceptibility is not fully understood. In this present study, we investigated emphysema development using the elastase-induced experimental emphysema model in two commonly used mouse strains, C57BL/6J and BALB/cJ. The results demonstrate that mice with different genetic backgrounds show disparate susceptibility to the development of emphysema. BALB/cJ mice were found to be much more sensitive than C57BL/6J to elastase injury in both a dose-dependent and time-dependent manner, as measured by significantly higher mortality, greater body weight loss, greater decline in lung function, and a greater loss of alveolar tissue. The more susceptible BALB/cJ strain also showed the persistence of inflammatory cells in the lung, especially macrophages and lymphocytes. A comparative gene expression analysis following elastase-induced injury showed BALB/cJ mice had elevated levels of il17A mRNA and a number of classically (M1) and alternatively (M2) activated macrophage genes, whereas the C57BL/6J mice demonstrated augmented levels of interferon-γ. These findings suggest a possible role for these cellular and molecular mediators in modulating the severity of emphysema and highlight the possibility that they might contribute to the heterogeneity observed in clinical emphysema outcomes. PMID:26232300

Experimental progressive emphysema in BALB/cJ mice as a model for chronic alveolar destruction in humans.

PubMed

Limjunyawong, Nathachit; Craig, John M; Lagassé, H A Daniel; Scott, Alan L; Mitzner, Wayne

2015-10-01

Emphysema, one of the major components of chronic obstructive pulmonary disease (COPD), is characterized by the progressive and irreversible loss of alveolar lung tissue. Even though >80% of COPD cases are associated with cigarette smoking, only a relatively small proportion of smokers develop emphysema, suggesting a potential role for genetic factors in determining individual susceptibility to emphysema. Although strain-dependent effects have been shown in animal models of emphysema, the molecular basis underlying this intrinsic susceptibility is not fully understood. In this present study, we investigated emphysema development using the elastase-induced experimental emphysema model in two commonly used mouse strains, C57BL/6J and BALB/cJ. The results demonstrate that mice with different genetic backgrounds show disparate susceptibility to the development of emphysema. BALB/cJ mice were found to be much more sensitive than C57BL/6J to elastase injury in both a dose-dependent and time-dependent manner, as measured by significantly higher mortality, greater body weight loss, greater decline in lung function, and a greater loss of alveolar tissue. The more susceptible BALB/cJ strain also showed the persistence of inflammatory cells in the lung, especially macrophages and lymphocytes. A comparative gene expression analysis following elastase-induced injury showed BALB/cJ mice had elevated levels of il17A mRNA and a number of classically (M1) and alternatively (M2) activated macrophage genes, whereas the C57BL/6J mice demonstrated augmented levels of interferon-γ. These findings suggest a possible role for these cellular and molecular mediators in modulating the severity of emphysema and highlight the possibility that they might contribute to the heterogeneity observed in clinical emphysema outcomes. Copyright © 2015 the American Physiological Society.

Neuroimmune Basis of Alcoholic Brain Damage

PubMed Central

Crews, Fulton T.; Vetreno, Ryan P.

2017-01-01

Alcohol-induced brain damage likely contributes to the dysfunctional poor decisions associated with alcohol dependence. Human alcoholics have a global loss of brain volume that is most severe in the frontal cortex. Neuroimmune gene induction by binge drinking increases neurodegeneration through increased oxidative stress, particularly NADPH oxidase-induced oxidative stress. In addition, HMGB1-TLR4 and innate immune NF-κB target genes are increased leading to persistent and sensitized neuroimmune responses to ethanol and other agents that release HMGB1 or directly stimulate TLR receptors and/or NMDA receptors. Neuroimmune signaling and glutamate excitotoxicity are linked to alcoholic neurodegeneration. Models of adolescent alcohol abuse lead to significant frontal cortical degeneration and show the most severe loss of hippocampal neurogenesis. Adolescence is a period of high risk for ethanol-induced neurodegeneration and alterations in brain structure, gene expression, and maturation of adult phenotypes. Together, these findings support the hypothesis that adolescence is a period of risk for persistent and long-lasting increases in brain neuroimmune gene expression that promote persistent and long-term increases in alcohol consumption, neuroimmune gene induction, and neurodegeneration that we find associated with alcohol use disorders. PMID:25175868

Can re-cTURBT be useful in pT1HG disease as a risk indicator of recurrence and progression? A single centre experience.

PubMed

Giulianelli, Roberto; Gentile, Barbara Cristina; Mirabile, Gabriella; Albanesi, Luca; Tariciotti, Paola; Rizzo, Giorgio; Buscarini, Maurizio; Vermiglio, Mauro

2017-12-31

Understaging after initial transurethral resection is common in patients with high-risk non muscle infiltrating bladder cancer (NMIBC) and can delay accurate diagnosis and definitive treatment. The rate of upstaging from T1 to T2 disease after repeated transurethral resection ranges from 0 to 28%, although the rate of upstaging may be even higher up to 49% when muscularis propria is absent in the first specimen. A restaging classic transurethral resection of bladder tumour (re-cTURBT) is the better predictor of early stage progression. According to some reports, the rate of positivity for tumor in re-cTURBT performed within eight weeks after initial cTURBT was as high as 18-77%, and in about 40% of the patients a change in tumor stage was reported. We aimed to investigate, in high risk group, the presence of residual tumor following white light classical transurethral resection of bladder tumor (WLre-cTURBT) and the different recurrence and progression rate between patients with persistent or negative (pT0) oncological disease after WLre-cTURBT. A cohort of 285 patients presenting with primitive bladder cancer underwent to WLcTURBT from January 2011 to December 2015; out of them 92 (32.28%) were T1HG. In according to EAU guidelines 2011, after 4-6 weeks all HG bladder cancer patients underwent a WL recTURBT . All patients were submitted to a subsequent followup including cystoscopy every 3 months with multiple biopsies, randomly and in the previous zone of resection; urinary citology on 3 specimens and kidney/bladder ultrasound every 6 months. The average follow-up was 48 months. Following WLre-cTURBT we observed a persistent disease in 18 (15.2%) patients: 14 (77.7%) with a HG-NMIBC and 4 (22.2%) with a high grade (HG) muscle invasive bladder cancer (pT2HG). After follow up of all 92 patients according to the guidelines EAU, we observed recurrence in 36/92 (39.1%) and progression in 14/92 (15.2%). Of 14 NMIBC with persistent disease, 10 patients (71.4%) showed recurrence: 4 patients (40%) were pT1HG with concomitant carcinoma in situ (CIS), 3 patients (30%) multifocal pTaHG, 2 (20%) patients CIS and one patient (10%) a muscle invasive neoplasm (pT2HG). Instead of the group of 48 patients pT0 following WL recTURBT, we observed recurrence in 26 patients (54.1%) and in two patients (4.1%) progressions, who presented after 3 months in association with CIS. The remaining 22 patients (45.9%) with initial pT1HG are still progression free. Multivariate analysis showed that the most important variable of early progression were persistent neoplasm and histopathological findings at WLre-cTURBt (p = 0.01), followed by the Summary No conflict of interest declared. INTRODUCTION Bladder cancer is a common genito-urinary malignancy, with transitional cell carcinoma comprising nearly 90% of all primary bladder tumours. At the first diagnosis 70% to 80% of urothelial tumours are confined to the epithelium, the remainder is characterized by muscle invasion. A significant number of patients with high risk non-muscle invasive bladder tumours (HG-NMIBT) treated with white light classic transurethral resection of bladder tumours (WLcTURBT) and intravesical BCG will progress to invasive disease (1-3). Progression to muscle invasion (pT2) mandates immediate radical cystectomy (4). WLcTURBT is the standard initial therapy for NMIBT, but the high percentage of recurrence after surgery is still an unresolved problem (5). High grade pT1 bladder neoplasm (pT1HG) really represents a therapeutic challenge due to the high risk of progression (about 15-30%) to muscle-invasive disease, usually within 5 years (6). However, no consensus exists regarding the treatment of patients with recurrent bladder tumours that invade the lamina propria (pT1) (7-9). Recent studies suggested that the first cTURBT may be incomplete in a significant number of cases (10). Understaging at the time of the initial transurethral resection is common for patients with high-risk NMIBC and can delay accurate diagnosis and definitive treatment. It is therefore recommended for patients with high-risk disease and in those with large or multiple tumors or when the initial transurethral resection is incomplete, to repeat WLre-cTURBT within 2-6 DOI: 10.4081/aiua.2017.4.272 result of the first cystoscopy (p = 0.002) and presence of CIS (p = 0.02). Following WLre-cTURBt in HG-NMIBC patients we identified in 15% of cases a persistent disease with a 4.3% of MIBC. In the high risk persistent bladder neoplasms group we observed recurrent and progression rate higher than in T0 bladder tumours group (Δ = + 17.3% and = Δ + 62.5%, p < 0.05.

Control of Uncertain Systems under Constraints: Switching Horizon Predictive Control of Persistently Disturbed Input-Saturated Plants

DTIC Science & Technology

2006-12-01

on at any time from a family of candidate feedback-gains so as to control a discrete- time input-saturated LTI system possibly subject to persistent... times robustness Mosca, E. (2006) Control of Uncertain Systems under Constraints: Switching Horizon Predictive Control of Persistently Disturbed...feedback controls u = f(x̂) (3) so as to ensure, under suitable conditions, stability in the noiseless case as well as finite l∞-induced gain of the

World food and agriculture: outlook for the medium and longer term.

PubMed

Alexandratos, N

1999-05-25

The world has been making progress in improving food security, as measured by the per person availability of food for direct human consumption. However, progress has been very uneven, and many developing countries have failed to participate in such progress. In some countries, the food security situation is today worse than 20 years ago. The persistence of food insecurity does not reflect so much a lack of capacity of the world as a whole to increase food production to whatever level would be required for everyone to have consumption levels assuring satisfactory nutrition. The world already produces sufficient food. The undernourished and the food-insecure persons are in these conditions because they are poor in terms of income with which to purchase food or in terms of access to agricultural resources, education, technology, infrastructure, credit, etc., to produce their own food. Economic development failures account for the persistence of poverty and food insecurity. In the majority of countries with severe food-security problems, the greatest part of the poor and food-insecure population depend greatly on local agriculture for a living. In such cases, development failures are often tantamount to failures of agricultural development. Development of agriculture is seen as the first crucial step toward broader development, reduction of poverty and food insecurity, and eventually freedom from excessive economic dependence on poor agricultural resources. Projections indicate that progress would continue, but at a pace and pattern that would be insufficient for the incidence of undernutrition to be reduced significantly in the medium-term future. As in the past, world agricultural production is likely to keep up with, and perhaps tend to exceed, the growth of the effective demand for food. The problem will continue to be one of persistence of poverty, leading to growth of the effective demand for food on the part of the poor that would fall short of that required for them to attain levels of consumption compatible with freedom from undernutrition.

World food and agriculture: Outlook for the medium and longer term

PubMed Central

Alexandratos, Nikos

1999-01-01

The world has been making progress in improving food security, as measured by the per person availability of food for direct human consumption. However, progress has been very uneven, and many developing countries have failed to participate in such progress. In some countries, the food security situation is today worse than 20 years ago. The persistence of food insecurity does not reflect so much a lack of capacity of the world as a whole to increase food production to whatever level would be required for everyone to have consumption levels assuring satisfactory nutrition. The world already produces sufficient food. The undernourished and the food-insecure persons are in these conditions because they are poor in terms of income with which to purchase food or in terms of access to agricultural resources, education, technology, infrastructure, credit, etc., to produce their own food. Economic development failures account for the persistence of poverty and food insecurity. In the majority of countries with severe food-security problems, the greatest part of the poor and food-insecure population depend greatly on local agriculture for a living. In such cases, development failures are often tantamount to failures of agricultural development. Development of agriculture is seen as the first crucial step toward broader development, reduction of poverty and food insecurity, and eventually freedom from excessive economic dependence on poor agricultural resources. Projections indicate that progress would continue, but at a pace and pattern that would be insufficient for the incidence of undernutrition to be reduced significantly in the medium-term future. As in the past, world agricultural production is likely to keep up with, and perhaps tend to exceed, the growth of the effective demand for food. The problem will continue to be one of persistence of poverty, leading to growth of the effective demand for food on the part of the poor that would fall short of that required for them to attain levels of consumption compatible with freedom from undernutrition. PMID:10339517

Fluidity of HIV-1-Specific T-Cell Responses during Acute and Early Subtype C HIV-1 Infection and Associations with Early Disease Progression ▿

PubMed Central

Mlotshwa, Mandla; Riou, Catherine; Chopera, Denis; de Assis Rosa, Debra; Ntale, Roman; Treunicht, Florette; Woodman, Zenda; Werner, Lise; van Loggerenberg, Francois; Mlisana, Koleka; Abdool Karim, Salim; Williamson, Carolyn; Gray, Clive M.

2010-01-01

Deciphering immune events during early stages of human immunodeficiency virus type 1 (HIV-1) infection is critical for understanding the course of disease. We characterized the hierarchy of HIV-1-specific T-cell gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay responses during acute subtype C infection in 53 individuals and associated temporal patterns of responses with disease progression in the first 12 months. There was a diverse pattern of T-cell recognition across the proteome, with the recognition of Nef being immunodominant as early as 3 weeks postinfection. Over the first 6 months, we found that there was a 23% chance of an increased response to Nef for every week postinfection (P = 0.0024), followed by a nonsignificant increase to Pol (4.6%) and Gag (3.2%). Responses to Env and regulatory proteins appeared to remain stable. Three temporal patterns of HIV-specific T-cell responses could be distinguished: persistent, lost, or new. The proportion of persistent T-cell responses was significantly lower (P = 0.0037) in individuals defined as rapid progressors than in those progressing slowly and who controlled viremia. Almost 90% of lost T-cell responses were coincidental with autologous viral epitope escape. Regression analysis between the time to fixed viral escape and lost T-cell responses (r = 0.61; P = 0.019) showed a mean delay of 14 weeks after viral escape. Collectively, T-cell epitope recognition is not a static event, and temporal patterns of IFN-γ-based responses exist. This is due partly to viral sequence variation but also to the recognition of invariant viral epitopes that leads to waves of persistent T-cell immunity, which appears to associate with slower disease progression in the first year of infection. PMID:20826686

Predictors of Progression From the Appearance of Islet Autoantibodies to Early Childhood Diabetes: The Environmental Determinants of Diabetes in the Young (TEDDY).

PubMed

Steck, Andrea K; Vehik, Kendra; Bonifacio, Ezio; Lernmark, Ake; Ziegler, Anette-G; Hagopian, William A; She, JinXiong; Simell, Olli; Akolkar, Beena; Krischer, Jeffrey; Schatz, Desmond; Rewers, Marian J

2015-05-01

While it is known that there is progression to diabetes in <10 years in 70% of children with two or more islet autoantibodies, predictors of the progression to diabetes are only partially defined. The Environmental Determinants of Diabetes in the Young (TEDDY) study has observed 8,503 children who were at increased genetic risk for autoimmune diabetes. Insulin autoantibodies (IAAs), GAD65 autoantibodies (GADAs), and insulinoma-associated protein 2 autoantibodies (IA-2As) were measured every 3 months until 4 years of age and every 6 months thereafter; if results were positive, the autoantibodies were measured every 3 months. Life table analysis revealed that the cumulative incidence of diabetes by 5 years since the appearance of the first autoantibody differed significantly by the number of positive autoantibodies (47%, 36%, and 11%, respectively, in those with three autoantibodies, two autoantibodies, and one autoantibody, P < 0.001). In time-varying survival models adjusted for first-degree relative status, number of autoantibodies, age at first persistent confirmed autoantibodies, and HLA genotypes, higher mean IAA and IA-2A levels were associated with an increased risk of type 1 diabetes in children who were persistently autoantibody positive (IAAs: hazard ratio [HR] 8.1 [95% CI 4.6-14.2]; IA-2A: HR 7.4 [95% CI 4.3-12.6]; P < 0.0001]). The mean GADA level did not significantly affect the risk of diabetes. In the TEDDY study, children who have progressed to diabetes usually expressed two or more autoantibodies. Higher IAA and IA-2A levels, but not GADA levels, increased the risk of diabetes in those children who were persistently autoantibody positive. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

A Link between Meiotic Prophase Progression and CrossoverControl

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

Carlton, Peter M.; Farruggio, Alfonso P.; Dernburg, Abby F.

2005-07-06

During meiosis, most organisms ensure that homologous chromosomes undergo at least one exchange of DNA, or crossover, to link chromosomes together and accomplish proper segregation. How each chromosome receives a minimum of one crossover is unknown. During early meiosis in Caenorhabditis elegans and many other species, chromosomes adopt a polarized organization within the nucleus, which normally disappears upon completion of homolog synapsis. Mutations that impair synapsis even between a single pair of chromosomes in C. elegans delay this nuclear reorganization. We quantified this delay by developing a classification scheme for discrete stages of meiosis. Immunofluorescence localization of RAD-51 protein revealedmore » that delayed meiotic cells also contained persistent recombination intermediates. Through genetic analysis, we found that this cytological delay in meiotic progression requires double-strand breaks and the function of the crossover-promoting heteroduplex HIM-14 (Msh4) and MSH-5. Failure of X chromosome synapsis also resulted in impaired crossover control on autosomes, which may result from greater numbers and persistence of recombination intermediates in the delayed nuclei. We conclude that maturation of recombination events on chromosomes promotes meiotic progression, and is coupled to the regulation of crossover number and placement. Our results have broad implications for the interpretation of meiotic mutants, as we have shown that asynapsis of a single chromosome pair can exert global effects on meiotic progression and recombination frequency.« less

Vulvar Intraepithelial Neoplasia 3 in Women Less Than 35 Years

PubMed Central

Kesterson, Joshua P.; Lele, Shashikant

2016-01-01

Objective To examine the outcome of women diagnosed with vulvar intraepithelial neoplasia (VIN) 3 at less than 35 years. Materials and Methods All cases of VIN 3 treated in women less than 35 years treated at Roswell Park Cancer Institute between January 1973 and January 2008 were reviewed. Medical records were reviewed for year of diagnosis, treatment modality, recurrence and/or progression, associated medical conditions, history of genital condyloma, smoking status, history of cervical pathology, and treatment. Results Thirty-one women were identified. The mean age at diagnosis was 29 years. Smoking status was available in 28 patients, of which 82% (23/28) were current or former smokers. Eighty-one percent (25/31) of the women had cervical disease. Fifty-two percent (16/31) had a history of genital condyloma. Ten of the 31 women (32%) were diagnosed with persistence or recurrence of VIN 3. Three women (9.7%) progressed to invasive carcinoma. Conclusions Women diagnosed with VIN 3 at less than 35 years are at risk for persistence and/or recurrence of their disease as well as progression to carcinoma, warranting frequent and prolonged follow-up with liberal utilization of directed biopsies of suspicious lesions. PMID:27942201

Vulvar Intraepithelial Neoplasia 3 in Women Less Than 35 Years.

PubMed

Kesterson, Joshua P; Lele, Shashikant

2009-10-01

To examine the outcome of women diagnosed with vulvar intraepithelial neoplasia (VIN) 3 at less than 35 years. All cases of VIN 3 treated in women less than 35 years treated at Roswell Park Cancer Institute between January 1973 and January 2008 were reviewed. Medical records were reviewed for year of diagnosis, treatment modality, recurrence and/or progression, associated medical conditions, history of genital condyloma, smoking status, history of cervical pathology, and treatment. Thirty-one women were identified. The mean age at diagnosis was 29 years. Smoking status was available in 28 patients, of which 82% (23/28) were current or former smokers. Eighty-one percent (25/31) of the women had cervical disease. Fifty-two percent (16/31) had a history of genital condyloma. Ten of the 31 women (32%) were diagnosed with persistence or recurrence of VIN 3. Three women (9.7%) progressed to invasive carcinoma. Women diagnosed with VIN 3 at less than 35 years are at risk for persistence and/or recurrence of their disease as well as progression to carcinoma, warranting frequent and prolonged follow-up with liberal utilization of directed biopsies of suspicious lesions.

Coxsackievirus B4 Can Infect Human Peripheral Blood-Derived Macrophages

PubMed Central

Alidjinou, Enagnon Kazali; Sané, Famara; Trauet, Jacques; Copin, Marie-Christine; Hober, Didier

2015-01-01

Beyond acute infections, group B coxsackieviruses (CVB) are also reported to play a role in the development of chronic diseases, like type 1 diabetes. The viral pathogenesis mainly relies on the interplay between the viruses and innate immune response in genetically-susceptible individuals. We investigated the interaction between CVB4 and macrophages considered as major players in immune response. Monocyte-derived macrophages (MDM) generated with either M-CSF or GM-CSF were inoculated with CVB4, and infection, inflammation, viral replication and persistence were assessed. M-CSF-induced MDM, but not GM-CSF-induced MDM, can be infected by CVB4. In addition, enhancing serum was not needed to infect MDM in contrast with parental monocytes. The expression of viral receptor (CAR) mRNA was similar in both M-CSF and GM-CSF MDM. CVB4 induced high levels of pro-inflammatory cytokines (IL-6 and TNFα) in both MDM populations. CVB4 effectively replicated and persisted in M-CSF MDM, but IFNα was produced in the early phase of infection only. Our results demonstrate that CVB4 can replicate and persist in MDM. Further investigations are required to determine whether the interaction between the virus and MDM plays a role in the pathogenesis of CVB-induced chronic diseases. PMID:26610550

Coxsackievirus B4 Can Infect Human Peripheral Blood-Derived Macrophages.

PubMed

Alidjinou, Enagnon Kazali; Sané, Famara; Trauet, Jacques; Copin, Marie-Christine; Hober, Didier

2015-11-24

Beyond acute infections, group B coxsackieviruses (CVB) are also reported to play a role in the development of chronic diseases, like type 1 diabetes. The viral pathogenesis mainly relies on the interplay between the viruses and innate immune response in genetically-susceptible individuals. We investigated the interaction between CVB4 and macrophages considered as major players in immune response. Monocyte-derived macrophages (MDM) generated with either M-CSF or GM-CSF were inoculated with CVB4, and infection, inflammation, viral replication and persistence were assessed. M-CSF-induced MDM, but not GM-CSF-induced MDM, can be infected by CVB4. In addition, enhancing serum was not needed to infect MDM in contrast with parental monocytes. The expression of viral receptor (CAR) mRNA was similar in both M-CSF and GM-CSF MDM. CVB4 induced high levels of pro-inflammatory cytokines (IL-6 and TNFα) in both MDM populations. CVB4 effectively replicated and persisted in M-CSF MDM, but IFNα was produced in the early phase of infection only. Our results demonstrate that CVB4 can replicate and persist in MDM. Further investigations are required to determine whether the interaction between the virus and MDM plays a role in the pathogenesis of CVB-induced chronic diseases.

Persistence of T-cell immune response induced by two acellular pertussis vaccines in children five years after primary vaccination.

PubMed

Palazzo, Raffaella; Carollo, Maria; Bianco, Manuela; Fedele, Giorgio; Schiavoni, Ilaria; Pandolfi, Elisabetta; Villani, Alberto; Tozzi, Alberto E; Mascart, Françoise; Ausiello, Clara M

2016-01-01

The resurgence of pertussis suggests the need for greater efforts to understand the long-lasting protective responses induced by vaccination. In this paper we dissect the persistence of T memory responses induced by primary vaccination with two different acellular pertussis (aP) vaccines, hexavalent Hexavac® vaccine (Hexavac) (Sanofi Pasteur MSD) and Infanrix hexa® (Infanrix) (Glaxo-SmithKline Biologicals). We evaluated magnitude and duration of T-cell responses to pertussis toxin (PT) by measuring T-cell proliferation, cytokines (IL-2 and IFNγ) production and memory subsets in two groups of children 5 years after primary vaccination. Some of the enrolled children received only primary vaccination, while others had the pre-school boost dose. Positive T-cell responses to PT were detected in 36% of children. Percentage of responsive children, T-cell proliferation and CD4IL-2+ cells were significantly higher in the children primed with Hexavac than in those who received Infanrix vaccine. No major effects of the boost on PT-specific proliferation were observed. Overall, our data documented a persistence of T-cell memory against PT in a minor fraction of children 5 years after primary vaccination. The different responses induced by Hexavac and Infanrix vaccine could rely on differences in PT inactivation process or excipients/adjuvants formulations.

Long-term Persistence of Innate Lymphoid Cells in the Gut After Intestinal Transplantation.

PubMed

Weiner, Joshua; Zuber, Julien; Shonts, Brittany; Yang, Suxiao; Fu, Jianing; Martinez, Mercedes; Farber, Donna L; Kato, Tomoaki; Sykes, Megan

2017-10-01

Little is known about innate lymphoid cell (ILC) populations in the human gut, and the turnover of these cells and their subsets after transplantation has not been described. Intestinal samples were taken from 4 isolated intestine and 3 multivisceral transplant recipients at the time of any operative resection, such as stoma closure or revision. ILCs were isolated and analyzed by flow cytometry. The target population was defined as being negative for lineage markers and double-positive for CD45/CD127. Cells were further stained to define ILC subsets and a donor-specific or recipient-specific HLA marker to analyze chimerism. Donor-derived ILCs were found to persist greater than 8 years after transplantation. Additionally, the percentage of cells thought to be lymphoid tissue inducer cells among donor ILCs was far higher than that among recipient ILCs. Our findings demonstrate that donor-derived ILCs persist long-term after transplantation and support the notion that human lymphoid tissue inducer cells may form in the fetus and persist throughout life, as hypothesized in rodents. Correlation between chimerism and rejection, graft failure, and patient survival requires further study.

Methamphetamine treatment during development attenuates the dopaminergic deficits caused by subsequent high-dose methamphetamine administration.

PubMed

McFadden, Lisa M; Hoonakker, Amanda J; Vieira-Brock, Paula L; Stout, Kristen A; Sawada, Nicole M; Ellis, Jonathan D; Allen, Scott C; Walters, Elliot T; Nielsen, Shannon M; Gibb, James W; Alburges, Mario E; Wilkins, Diana G; Hanson, Glen R; Fleckenstein, Annette E

2011-08-01

Administration of high doses of methamphetamine (METH) causes persistent dopaminergic deficits in both nonhuman preclinical models and METH-dependent persons. Noteworthy, adolescent [i.e., postnatal day (PND) 40] rats are less susceptible to this damage than young adult (PND90) rats. In addition, biweekly treatment with METH, beginning at PND40 and continuing throughout development, prevents the persistent dopaminergic deficits caused by a "challenge" high-dose METH regimen when administered at PND90. Mechanisms underlying this "resistance" were thus investigated. Results revealed that biweekly METH treatment throughout development attenuated both the acute and persistent deficits in VMAT2 function, as well as the acute hyperthermia, caused by a challenge METH treatment. Pharmacokinetic alterations did not appear to contribute to the protection afforded by the biweekly treatment. Maintenance of METH-induced hyperthermia abolished the protection against both the acute and persistent VMAT2-associated deficits suggesting that alterations in thermoregulation were caused by exposure of rats to METH during development. These findings suggest METH during development prevents METH-induced hyperthermia and the consequent METH-related neurotoxicity. Copyright © 2011 Wiley-Liss, Inc.

Abnormal-induced theta activity supports early directed-attention network deficits in progressive MCI.

PubMed

Deiber, Marie-Pierre; Ibañez, Vicente; Missonnier, Pascal; Herrmann, François; Fazio-Costa, Lara; Gold, Gabriel; Giannakopoulos, Panteleimon

2009-09-01

The electroencephalography (EEG) theta frequency band reacts to memory and selective attention paradigms. Global theta oscillatory activity includes a posterior phase-locked component related to stimulus processing and a frontal-induced component modulated by directed attention. To investigate the presence of early deficits in the directed attention-related network in elderly individuals with mild cognitive impairment (MCI), time-frequency analysis at baseline was used to assess global and induced theta oscillatory activity (4-6Hz) during n-back working memory tasks in 29 individuals with MCI and 24 elderly controls (EC). At 1-year follow-up, 13 MCI patients were still stable and 16 had progressed. Baseline task performance was similar in stable and progressive MCI cases. Induced theta activity at baseline was significantly reduced in progressive MCI as compared to EC and stable MCI in all n-back tasks, which were similar in terms of directed attention requirements. While performance is maintained, the decrease of induced theta activity suggests early deficits in the directed-attention network in progressive MCI, whereas this network is functionally preserved in stable MCI.

The BCGΔBCG1419c strain, which produces more pellicle in vitro, improves control of chronic tuberculosis in vivo.

PubMed

Pedroza-Roldán, César; Guapillo, Carolina; Barrios-Payán, Jorge; Mata-Espinosa, Dulce; Aceves-Sánchez, Michel de Jesús; Marquina-Castillo, Brenda; Hernández-Pando, Rogelio; Flores-Valdez, Mario Alberto

2016-09-14

Mycobacterium tuberculosis (Mtb) has been a threat to humans since ancient times, and it is the main causative agent of tuberculosis (TB). Until today, the only licensed vaccine against Mtb is the live attenuated M. bovis Bacillus Calmette-Guérin (BCG), which has variable levels of protection against the pulmonary form of infection. The quest for a new vaccine is a priority given the rise of multidrug-resistant Mtb around the world, as well as the tremendous burden imposed by latent TB. The objective of this study was to evaluate the immunogenicity and capacity of protection of a modified BCG strain (BCGΔBCG1419c) lacking the c-di-GMP phosphodiesterase gene BCG1419c, in diverse mice models. In a previous report, we have shown that BCGΔBCG1419c was capable of increasing biofilm production and after intravenous infection of immunocompetent mice; this strain persisted longer in lungs than parental BCG Pasteur. This led us to hypothesize that BCGΔBCG1419c might therefore possess some advantage as vaccine candidate. Our results in this report indicate that compared to conventional BCG, vaccination with BCGΔBCG1419c induced a better activation of specific T-lymphocytes population, was equally effective in preventing weight loss despite being used at lower dose, reduced tissue damage (pneumonic scores), increased local IFNγ(+) T cells, and diminished bacterial burden in lungs of BALB/c mice infected intratracheally with high dose Mtb H37Rv to induce progressive TB. Moreover, vaccination with BCGΔBCG1419c improved resistance to reactivation after immunosuppression induced by corticosterone in a murine model of chronic infection similar to latent TB. Furthermore, despite showing increased persistence in immunocompetent mice, BCGΔBCG1419c was as attenuated as parental BCG in nude mice. To our knowledge, this is the first demonstration that a modified BCG vaccine candidate with increased pellicle/biofilm production has the capacity to protect against Mtb challenge in chronic and reactivation models of infection. Copyright © 2016 Elsevier Ltd. All rights reserved.

Clear lens extraction for the treatment of persistent accommodative spasm after head trauma.

PubMed

McMurray, Catherine J; Burley, Celeste D; Elder, Mark J

2004-12-01

We report the case of a 28-year-old man with decreased visual acuity after closed head trauma sustained in a motor vehicle accident 16 weeks earlier. Several structures thought to be associated with the control of accommodation were injured. The patient had a persistent accommodative spasm causing up to 7.0 diopters of pseudomyopia. We present the patient's progress through the clinic, including manifest and cycloplegic refractions and results of a trial with atropine drops, and successful transition to bilateral pseudophakia 2 years and 9 months after the accident.

Cholesterol catabolism as a therapeutic target in Mycobacterium tuberculosis

PubMed Central

Ouellet, Hugues; Johnston, Jonathan B.; Ortiz de Montellano, Paul R.

2011-01-01

Mycobacterium tuberculosis (Mtb) is an intracellular pathogen that infects 10 million worldwide and kills 2 million people every year. The uptake and utilization of nutrients by Mtb within the host cell is still poorly understood, although lipids play an important role in Mtb persistence. The recent identification of a large regulon of cholesterol catabolic genes suggests that Mtb can use host sterol for infection and persistence. In this review, we report on recent progress in elucidation of the Mtb cholesterol catabolic reactions and their potential utility as targets for tuberculosis therapeutic agents. PMID:21924910

Complement inhibition decreases early fibrogenic events in the lung of septic baboons.

PubMed

Silasi-Mansat, Robert; Zhu, Hua; Georgescu, Constantin; Popescu, Narcis; Keshari, Ravi S; Peer, Glenn; Lupu, Cristina; Taylor, Fletcher B; Pereira, Heloise Anne; Kinasewitz, Gary; Lambris, John D; Lupu, Florea

2015-11-01

Acute respiratory distress syndrome (ARDS) induced by severe sepsis can trigger persistent inflammation and fibrosis. We have shown that experimental sepsis in baboons recapitulates ARDS progression in humans, including chronic inflammation and long-lasting fibrosis in the lung. Complement activation products may contribute to the fibroproliferative response, suggesting that complement inhibitors are potential therapeutic agents. We have been suggested that treatment of septic baboons with compstatin, a C3 convertase inhibitor protects against ARDS-induced fibroproliferation. Baboons challenged with 10(9) cfu/kg (LD50) live E. coli by intravenous infusion were treated or not with compstatin at the time of challenge or 5 hrs thereafter. Changes in the fibroproliferative response at 24 hrs post-challenge were analysed at both transcript and protein levels. Gene expression analysis showed that sepsis induced fibrotic responses in the lung as early as 24 hrs post-bacterial challenge. Immunochemical and biochemical analysis revealed enhanced collagen synthesis, induction of profibrotic factors and increased cell recruitment and proliferation. Specific inhibition of complement with compstatin down-regulated sepsis-induced fibrosis genes, including transforming growth factor-beta (TGF-β), connective tissue growth factor (CTGF), tissue inhibitor of metalloproteinase 1 (TIMP1), various collagens and chemokines responsible for fibrocyte recruitment (e.g. chemokine (C-C motif) ligand 2 (CCL2) and 12 (CCL12)). Compstatin decreased the accumulation of myofibroblasts and proliferating cells, reduced the production of fibrosis mediators (TGF-β, phospho-Smad-2 and CTGF) and inhibited collagen deposition. Our data demonstrate that complement inhibition effectively attenuates collagen deposition and fibrotic responses in the lung after severe sepsis. Inhibiting complement could prove an attractive strategy for preventing sepsis-induced fibrosis of the lung. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Photo-induced persistent inversion of germanium in a 200-nm-deep surface region.

PubMed

Prokscha, T; Chow, K H; Stilp, E; Suter, A; Luetkens, H; Morenzoni, E; Nieuwenhuys, G J; Salman, Z; Scheuermann, R

2013-01-01

The controlled manipulation of the charge carrier concentration in nanometer thin layers is the basis of current semiconductor technology and of fundamental importance for device applications. Here we show that it is possible to induce a persistent inversion from n- to p-type in a 200-nm-thick surface layer of a germanium wafer by illumination with white and blue light. We induce the inversion with a half-life of ~12 hours at a temperature of 220 K which disappears above 280 K. The photo-induced inversion is absent for a sample with a 20-nm-thick gold capping layer providing a Schottky barrier at the interface. This indicates that charge accumulation at the surface is essential to explain the observed inversion. The contactless change of carrier concentration is potentially interesting for device applications in opto-electronics where the gate electrode and gate oxide could be replaced by the semiconductor surface.

Pattern-Recognition Receptor Signaling Regulator mRNA Expression in Humans and Mice, and in Transient Inflammation or Progressive Fibrosis

PubMed Central

Günthner, Roman; Kumar, Vankayala Ramaiah Santhosh; Lorenz, Georg; Anders, Hans-Joachim; Lech, Maciej

2013-01-01

The cell type-, organ-, and species-specific expression of the pattern-recognition receptors (PRRs) are well described but little is known about the respective expression profiles of their negative regulators. We therefore determined the mRNA expression levels of A20, CYLD, DUBA, ST2, CD180, SIGIRR, TANK, SOCS1, SOCS3, SHIP, IRAK-M, DOK1, DOK2, SHP1, SHP2, TOLLIP, IRF4, SIKE, NLRX1, ERBIN, CENTB1, and Clec4a2 in human and mouse solid organs. Humans and mice displayed significant differences between their respective mRNA expression patterns of these factors. Additionally, we characterized their expression profiles in mononuclear blood cells upon bacterial endotoxin, which showed a consistent induction of A20, SOCS3, IRAK-M, and Clec4a2 in human and murine cells. Furthermore, we studied the expression pattern in transient kidney ischemia-reperfusion injury versus post-ischemic atrophy and fibrosis in mice. A20, CD180, ST2, SOCS1, SOCS3, SHIP, IRAK-M, DOK1, DOK2, IRF4, CENTB1, and Clec4a2 were all induced, albeit at different times of injury and repair. Progressive fibrosis was associated with a persistent induction of these factors. Thus, the organ- and species-specific expression patterns need to be considered in the design and interpretation of studies related to PRR-mediated innate immunity, which seems to be involved in tissue injury, tissue regeneration and in progressive tissue scarring. PMID:24009023

Roxithromycin inhibits VEGF-induced human airway smooth muscle cell proliferation: Opportunities for the treatment of asthma

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

Pei, Qing-Mei, E-mail: 34713316@qq.com; Jiang, Ping, E-mail: jiangping@163.com; Yang, Min, E-mail: YangMin@163.com

Asthma is a chronic respiratory disease characterized by reversible airway obstruction with persistent airway inflammation and airway remodelling, which is associated with increased airway smooth muscle (ASM) mass. Roxithromycin (RXM) has been widely used in asthma treatment; however, its mechanism of action is poorly understood. Vascular endothelial growth factor (VEGF) has been implicated in inflammatory and airway blood vessel remodelling in patients with asthma, and shown to promote ASM cell proliferation. Here, we investigated the effect of RXM on VEGF-induced ASM cell proliferation and attempted to elucidate the underlying mechanisms of action. We tested the effect of RXM on proliferationmore » and cell cycle progression, as well as on the expression of phospho-VEGF receptor 2 (VEGFR2), phospho-extracellular signal-regulated kinase 1/2 (ERK1/2), phospho-Akt, and caveolin-1 in VEGF-stimulated ASM cells. RXM inhibited VEGF-induced ASM cell proliferation and induced cell cycle arrest. Additionally, VEGF-induced ASM cell proliferation was suppressed by inhibiting the activity of ERK1/2, but not that of Akt. Furthermore, RXM treatment inhibits VEGF-induced activation of VEGFR2 and ERK and downregulation of caveolin-1 in a dose-dependent manner. RXM also inhibited TGF-β-induced VEGF secretion by ASM cells and BEAS-2B cells. Collectively, our findings suggest that RXM inhibits VEGF-induced ASM cell proliferation by suppression of VEGFR2 and ERK1/2 activation and caveolin-1 down-regulation, which may be involved in airway remodelling. Further elucidation of the mechanisms underlying these observations should enable the development of treatments for smooth muscle hyperplasia-associated diseases of the airway such as asthma. - Highlights: • RXM inhibited VEGF-induced ASM cell proliferation and induced cell cycle arrest. • VEGF-induced cell proliferation was suppressed by inhibiting the activity of ERK1/2. • RXM inhibits activation of VEGFR2 and ERK and downregulation of caveolin-1. • RXM inhibited TGF-β-induced VEGF secretion by ASM cells and BEAS-2B cells. • Our findings expand our knowledge of the role of RXM in airway remodelling.« less

Bombardment-induced segregation and redistribution

NASA Astrophysics Data System (ADS)

Lam, N. Q.; Wiedersich, H.

During ion bombardment, a number of processes can alter the compositional distribution and microstructure in near-surface regions of alloys. The relative importance of each process depends principally on the target composition, temperature, and ion characteristics. In addition to displacement mixing leading to a randomization of atomic locations, and preferential loss of alloying elements by sputtering, which are dominant at relatively low temperatures, several thermally-activated processes, including radiation-enhanced diffusion, radiation-induced segregation and Gibbsian adsorption, also play important roles. At elevated temperatures, nonequilibrium point defects induced by ion impacts become mobile and tend to anneal out by recombination and diffusion to extended sinks, such as dislocations, grain boundaries and free surfaces. The high defect concentrations, far exceeding the thermodynamic equilibrium values, can enhance diffusion-controlled processes, while persistent defect fluxes, originating from the spatial non-uniformity in defect production and annihilation, give rise to local redistribution of alloy constituents because of radiation-induced segregation. Moreover, when the alloy is maintained at high temperature, Gibbsian adsorption, driven by the reduction in free energy of the system, occurs even without irradiation; it involves a compositional perturbation in a few atom layers near the alloy surface. The combination of these processes leads to the complex development of a compositionally-modified layer in the subsurface region. Considerable progress has been made recently in identifying and understanding the relative contributions from the individual processes under various irradiation conditions. In the present paper, selected examples of these different phenomena and their synergistic effects on the evolution of the near-surface compositions of alloys during sputtering and ion implantation at elevated temperatures are discussed.

Reno-Cerebral Reflex Activates the Renin-Angiotensin System, Promoting Oxidative Stress and Renal Damage After Ischemia-Reperfusion Injury.

PubMed

Cao, Wei; Li, Aiqing; Li, Jiawen; Wu, Chunyi; Cui, Shuang; Zhou, Zhanmei; Liu, Youhua; Wilcox, Christopher S; Hou, Fan Fan

2017-09-01

A kidney-brain interaction has been described in acute kidney injury, but the mechanisms are uncertain. Since we recently described a reno-cerebral reflex, we tested the hypothesis that renal ischemia-reperfusion injury (IRI) activates a sympathetic reflex that interlinks the renal and cerebral renin-angiotensin axis to promote oxidative stress and progression of the injury. Bilateral ischemia-reperfusion activated the intrarenal and cerebral, but not the circulating, renin-angiotensin system (RAS), increased sympathetic activity in the kidney and the cerebral sympathetic regulatory regions, and induced brain inflammation and kidney injury. Selective renal afferent denervation with capsaicin or renal denervation significantly attenuated IRI-induced activation of central RAS and brain inflammation. Central blockade of RAS or oxidative stress by intracerebroventricular (ICV) losartan or tempol reduced the renal ischemic injury score by 65% or 58%, respectively, and selective renal afferent denervation or reduction of sympathetic tone by ICV clonidine decreased the score by 42% or 52%, respectively (all p < 0.05). Ischemia-reperfusion-induced renal damage and dysfunction persisted after controlling blood pressure with hydralazine. This study uncovered a novel reflex pathway between ischemic kidney and the brain that sustains renal oxidative stress and local RAS activation to promote ongoing renal damage. These data suggest that the renal and cerebral renin-angiotensin axes are interlinked by a reno-cerebral sympathetic reflex that is activated by ischemia-reperfusion, which contributes to ischemia-reperfusion-induced brain inflammation and worsening of the acute renal injury. Antioxid. Redox Signal. 27, 415-432.

BDNF and VEGF in the pathogenesis of stress-induced affective diseases: an insight from experimental studies.

PubMed

Nowacka, Marta; Obuchowicz, Ewa

2013-01-01

Stress is known to play an important role in etiology, development and progression of affective diseases. Especially, chronic stress, by initiating changes in the hypothalamic-pituitary-adrenal axis (HPA), neurotransmission and the immune system, acts as a trigger for affective diseases. It has been reported that the rise in the concentration of pro-inflammatory cytokines and persistent up-regulation of glucocorticoid expression in the brain and periphery increases the excitotoxic effect on CA3 pyramidal neurons in the hippocampus resulting in dendritic atrophy, apoptosis of neurons and possibly inhibition of neurogenesis in adult brain. Stress was observed to disrupt neuroplasticity in the brain, and growing evidence demonstrates its role in the pathomechanism of affective disorders. Experimental studies indicate that a well-known brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) which have recently focused increasing attention of neuroscientists, promote cell survival, positively modulate neuroplasticity and hippocampal neurogenesis. In this paper, we review the alterations in BDNF and VEGF pathways induced by chronic and acute stress, and their relationships with HPA axis activity. Moreover, behavioral effects evoked in rodents by both above-mentioned factors and the effects consequent to their deficit are presented. Biochemical as well as behavioral findings suggest that BDNF and VEGF play an important role as components of cascade of changes in the pathomechanism of stress-induced affective diseases. Further studies on the mechanisms regulating their expression in stress conditions are needed to better understand the significance of trophic hypothesis of stress-induced affective diseases.

Investigating the relationship between persistent reflux flow on the first postoperative day and recurrent varicocele in varicocelectomy patients.

PubMed

Cil, Ahmet Said; Bozkurt, Murat; Kara Bozkurt, Duygu; Gok, Mustafa

2015-01-01

The aim of this study was to investigate the presence of persistent reflux flow on the first postoperative day using color Doppler sonography (CDS) in patients who had undergone sub-inguinal varicocelectomy, and to research the relationship between persistent reflux flow and recurrent varicocele. A total of 54 patients were included in the study. Ages of the patients were between 21 and 38 years (mean 27.3 ± 7.6). All patients were evaluated four times with CDS: preoperatively, first postoperative day, 3 months postoperative, and finally 6 months after the operation. Preoperative venous diameters were measured between 3 and 5.5 mm; mean vein diameters were 3.8 ± 0.7 mm for the left side and 3.4 ± 0.4 mm for the right side. Mean duration of reflux was 3.5 ± 0.3 seconds on the left side and 2.9 ± 0.7 seconds on the right side. First postoperative day persistent Valsalva-induced reflux flow was seen in 10 patients (18%). Mean venous diameter was measured 1.8 ± 0.9 mm. Three months after the operation, Valsalva-induced reflux flow was seen in two patients (3%) in whom reflux was not seen on the first postoperative day. After 6 months, venous diameters larger than 2 mm at rest and the occurrence of reflux during the Valsalva maneuver were considered to be a recurrence. Six months after the operation, 12 patients had recurrent varicocele. Detecting persistent reflux with CDS on the first postoperative day was found to be 85% sensitive and 100% specific for showing recurrence. Valsalva-induced persistent reflux flow investigated with CDS on the first postoperative day can be used to show success of the surgery and is also an indicator of recurrence in varicocelectomy patients.

Gender Equity Matters!

ERIC Educational Resources Information Center

Thorius, Kathleen King

2010-01-01

Despite remarkable progress along many indicators of equitable access, participation, and outcomes of schooling, there are still persistent, pervasive issues that must be addresses, including continued disparities in access to athletics and academic programs, sexual harassment, hate crimes, and discriminatory treatment of girls and women. This…

Relaxation-Induced Anxiety: Paradoxical Anxiety Enhancement Due to Relaxation Training.

ERIC Educational Resources Information Center

Heide, Frederick J.; Borkovec, T. D.

1983-01-01

Documented relaxation-induced anxiety in 14 subjects suffering from tension who were given training in progressive relaxation and mantra meditation. Four of the subjects displayed clinical evidence of an anxiety reaction during a preliminary practice period. Progressive relaxation produced less evidence of relaxation-induced anxiety. (Author/JAC)

Cumulative Inequality and Racial Disparities in Health: Private Insurance Coverage and Black/White Differences in Functional Limitations

PubMed Central

Taylor, Miles G.

2014-01-01

Objectives. To test different forms of private insurance coverage as mediators for racial disparities in onset, persistent level, and acceleration of functional limitations among Medicare age-eligible Americans. Method. Data come from 7 waves of the Health and Retirement Study (1996–2008). Onset and progression latent growth models were used to estimate racial differences in onset, level, and growth of functional limitations among a sample of 5,755 people aged 65 and older in 1996. Employer-provided insurance, spousal insurance, and market insurance were next added to the model to test how differences in private insurance mediated the racial gap in physical limitations. Results. In baseline models, African Americans had larger persistent level of limitations over time. Although employer-provided, spousal provided, and market insurances were directly associated with lower persistent levels of limitation, only differences in market insurance accounted for the racial disparities in persistent level of limitations. Discussion. Results suggest private insurance is important for reducing functional limitations, but market insurance is an important mediator of the persistently larger level of limitations observed among African Americans. PMID:24569001

Identification of oxalic acid and tartaric acid as major persistent pain-inducing toxins in the stinging hairs of the nettle, Urtica thunbergiana.

PubMed

Fu, Han Yi; Chen, Shiang Jiuun; Chen, Ruei Feng; Ding, Wang Hsien; Kuo-Huang, Ling Long; Huang, Rong Nan

2006-07-01

Once human skin contacts stinging hairs of Urtica spp. (stinging nettles), the irritant is released and produces pain, wheals or a stinging sensation which may last for >12 h. However, the existence of pain-inducing toxins in the stinging hairs of Urtica thunbergiana has never been systematically demonstrated. Experiments were therefore conducted to identify the persistent pain-inducing agents in the stinging hairs of U. thunbergiana. The stinging hairs of U. thunbergiana were removed and immersed in deionized water. After centrifugation, the clear supernatants were then subjected to high-performance liquid chromatography (HPLC), enzymatic analysis and/or behavioural bioassays. The HPLC results showed that the major constituents in the stinging hairs of U. thunbergiana were histamine, oxalic acid and tartaric acid. However, the well-recognized pain-inducing agents, serotonin and formic acid, existed at a low concentration as estimated by HPLC and/or enzymatic analyses. The behavioural tests showed that 2% oxalic acid and 10% tartaric acid dramatically elicited persistent pain sensations in rats. In contrast, 10% formic acid and 2% serotonin only elicited moderate pain sensation in the first 10 min. Moreover, no significant pain-related behavioural response was observed after injecting 10% acetylcholine and histamine in rats. Oxalic acid and tartaric acid were identified, for the first time, as major long-lasting pain-inducing toxins in the stinging hairs of U. thunbergiana. The general view that formic acid, histamine and serotonin are the pain-inducing agents in the stinging hairs of U. dioica may require updating, since their concentrations in U. thunbergiana were too low to induce significant pain sensation in behavioural bioassays.

DNA vaccination protects mice against Zika virus-induced damage to the testes

PubMed Central

Griffin, Bryan D.; Muthumani, Kar; Warner, Bryce M.; Majer, Anna; Hagan, Mable; Audet, Jonathan; Stein, Derek R.; Ranadheera, Charlene; Racine, Trina; De La Vega, Marc-Antoine; Piret, Jocelyne; Kucas, Stephanie; Tran, Kaylie N.; Frost, Kathy L.; De Graff, Christine; Soule, Geoff; Scharikow, Leanne; Scott, Jennifer; McTavish, Gordon; Smid, Valerie; Park, Young K.; Maslow, Joel N.; Sardesai, Niranjan Y.; Kim, J. Joseph; Yao, Xiao-jian; Bello, Alexander; Lindsay, Robbin; Boivin, Guy; Booth, Stephanie A.; Kobasa, Darwyn; Embury-Hyatt, Carissa; Safronetz, David; Weiner, David B.; Kobinger, Gary P.

2017-01-01

Zika virus (ZIKV) is an emerging pathogen causally associated with serious sequelae in fetuses, inducing fetal microcephaly and other neurodevelopment defects. ZIKV is primarily transmitted by mosquitoes, but can persist in human semen and sperm, and sexual transmission has been documented. Moreover, exposure of type-I interferon knockout mice to ZIKV results in severe damage to the testes, epididymis and sperm. Candidate ZIKV vaccines have shown protective efficacy in preclinical studies carried out in animal models, and several vaccines have entered clinical trials. Here, we report that administration of a synthetic DNA vaccine encoding ZIKV pre-membrane and envelope (prME) completely protects mice against ZIKV-associated damage to the testes and sperm and prevents viral persistence in the testes following challenge with a contemporary strain of ZIKV. These data suggest that DNA vaccination merits further investigation as a potential means to reduce ZIKV persistence in the male reproductive tract. PMID:28589934

PPARγ-mediated increase in glucose availability sustains chronic Brucella abortus infection in alternatively activated macrophages

PubMed Central

Xavier, Mariana N.; Winter, Maria G.; Spees, Alanna M.; den Hartigh, Andreas B.; Nguyen, Kim; Roux, Christelle M.; Silva, Teane M. A.; Atluri, Vidya L.; Kerrinnes, Tobias; Keestra, A. Marijke; Monack, Denise M.; Luciw, Paul A.; Eigenheer, Richard A.; Bäumler, Andreas J.; Santos, Renato L.; Tsolis, Renée M.

2013-01-01

SUMMARY Eradication of persistent intracellular bacterial pathogens with antibiotic therapy is often slow or incomplete. However, strategies to augment antibiotics are hampered by our poor understanding of the nutritional environment that sustains chronic infection. Here we show that the intracellular pathogen Brucella abortus survives and replicates preferentially in alternatively activated macrophages (AAM), which are more abundant during chronic infection. A metabolic shift induced by peroxisome proliferator activated receptor γ (PPARγ), which increases intracellular glucose availability, is identified as a causal mechanism promoting enhanced bacterial survival in AAM. Glucose uptake was crucial for increased replication of B. abortus in AAM, and chronic infection, as inactivation of the bacterial glucose transporter gluP reduced both intracellular survival in AAM and persistence in mice. Thus, a shift in intracellular nutrient availability induced by PPARγ promotes chronic persistence of B. abortus within AAM and targeting this pathway may aid in eradicating chronic infection. PMID:23954155

Human central nervous system astrocytes support survival and activation of B cells: implications for MS pathogenesis.

PubMed

Touil, Hanane; Kobert, Antonia; Lebeurrier, Nathalie; Rieger, Aja; Saikali, Philippe; Lambert, Caroline; Fawaz, Lama; Moore, Craig S; Prat, Alexandre; Gommerman, Jennifer; Antel, Jack P; Itoyama, Yasuto; Nakashima, Ichiro; Bar-Or, Amit

2018-04-19

The success of clinical trials of selective B cell depletion in patients with relapsing multiple sclerosis (MS) indicates B cells are important contributors to peripheral immune responses involved in the development of new relapses. Such B cell contribution to peripheral inflammation likely involves antibody-independent mechanisms. Of growing interest is the potential that B cells, within the MS central nervous system (CNS), may also contribute to the propagation of CNS-compartmentalized inflammation in progressive (non-relapsing) disease. B cells are known to persist in the inflamed MS CNS and are more recently described as concentrated in meningeal immune-cell aggregates, adjacent to the subpial cortical injury which has been associated with progressive disease. How B cells are fostered within the MS CNS and how they may contribute locally to the propagation of CNS-compartmentalized inflammation remain to be elucidated. We considered whether activated human astrocytes might contribute to B cell survival and function through soluble factors. B cells from healthy controls (HC) and untreated MS patients were exposed to primary human astrocytes that were either maintained under basal culture conditions (non-activated) or pre-activated with standard inflammatory signals. B cell exposure to astrocytes included direct co-culture, co-culture in transwells, or exposure to astrocyte-conditioned medium. Following the different exposures, B cell survival and expression of T cell co-stimulatory molecules were assessed by flow cytometry, as was the ability of differentially exposed B cells to induce activation of allogeneic T cells. Secreted factors from both non-activated and activated human astrocytes robustly supported human B cell survival. Soluble products of pre-activated astrocytes also induced B cell upregulation of antigen-presenting cell machinery, and these B cells, in turn, were more efficient activators of T cells. Astrocyte-soluble factors could support survival and activation of B cell subsets implicated in MS, including memory B cells from patients with both relapsing and progressive forms of disease. Our findings point to a potential mechanism whereby activated astrocytes in the inflamed MS CNS not only promote a B cell fostering environment, but also actively support the ability of B cells to contribute to the propagation of CNS-compartmentalized inflammation, now thought to play key roles in progressive disease.

Type I and Type II Interferon Coordinately Regulate Suppressive Dendritic Cell Fate and Function during Viral Persistence

PubMed Central

Cunningham, Cameron R.; Champhekar, Ameya; Tullius, Michael V.; Dillon, Barbara Jane; Zhen, Anjie; de la Fuente, Justin Rafael; Herskovitz, Jonathan; Elsaesser, Heidi; Snell, Laura M.; Wilson, Elizabeth B.; de la Torre, Juan Carlos; Kitchen, Scott G.; Horwitz, Marcus A.; Bensinger, Steven J.; Smale, Stephen T.; Brooks, David G.

2016-01-01

Persistent viral infections are simultaneously associated with chronic inflammation and highly potent immunosuppressive programs mediated by IL-10 and PDL1 that attenuate antiviral T cell responses. Inhibiting these suppressive signals enhances T cell function to control persistent infection; yet, the underlying signals and mechanisms that program immunosuppressive cell fates and functions are not well understood. Herein, we use lymphocytic choriomeningitis virus infection (LCMV) to demonstrate that the induction and functional programming of immunosuppressive dendritic cells (DCs) during viral persistence are separable mechanisms programmed by factors primarily considered pro-inflammatory. IFNγ first induces the de novo development of naive monocytes into DCs with immunosuppressive potential. Type I interferon (IFN-I) then directly targets these newly generated DCs to program their potent T cell immunosuppressive functions while simultaneously inhibiting conventional DCs with T cell stimulating capacity. These mechanisms of monocyte conversion are constant throughout persistent infection, establishing a system to continuously interpret and shape the immunologic environment. MyD88 signaling was required for the differentiation of suppressive DCs, whereas inhibition of stimulatory DCs was dependent on MAVS signaling, demonstrating a bifurcation in the pathogen recognition pathways that promote distinct elements of IFN-I mediated immunosuppression. Further, a similar suppressive DC origin and differentiation was also observed in Mycobacterium tuberculosis infection, HIV infection and cancer. Ultimately, targeting the underlying mechanisms that induce immunosuppression could simultaneously prevent multiple suppressive signals to further restore T cell function and control persistent infections. PMID:26808628

Atrial fibrillation induced and converted by domestic supply electric shock.

PubMed

Rao, Usha; Agarwal, Ajit

2012-11-01

We present a case of persistent atrial fibrillation induced by a low-voltage electric shock reverting back to sinus rhythm after a similar repeat shock. ©2011, The Authors. Journal compilation ©2012 Wiley Periodicals, Inc.

Systems-wide analyses of mucosal immune responses to Helicobacter pylori at the interface between pathogenicity and symbiosis

PubMed Central

Kronsteiner, Barbara; Bassaganya-Riera, Josep; Philipson, Casandra; Viladomiu, Monica; Carbo, Adria; Abedi, Vida; Hontecillas, Raquel

2016-01-01

Abstract Helicobacter pylori is the dominant member of the gastric microbiota in over half of the human population of which 5–15% develop gastritis or gastric malignancies. Immune responses to H. pylori are characterized by mixed T helper cell, cytotoxic T cell and NK cell responses. The presence of Tregs is essential for the control of gastritis and together with regulatory CX3CR1+ mononuclear phagocytes and immune-evasion strategies they enable life-long persistence of H. pylori. This H. pylori-induced regulatory environment might contribute to its cross-protective effect in inflammatory bowel disease and obesity. Here we review host-microbe interactions, the development of pro- and anti-inflammatory immune responses and how the latter contribute to H. pylori's role as beneficial member of the gut microbiota. Furthermore, we present the integration of existing and new data into a computational/mathematical model and its use for the investigation of immunological mechanisms underlying initiation, progression and outcomes of H. pylori infection. PMID:26939848

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

PubMed

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

2016-06-01

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

Topical anesthesia-induced keratopathy after laser-assisted subepithelial keratectomy.

PubMed

Rao, Srinivas K; Wong, Victoria W Y; Cheng, Arthur C K; Lam, Philip T H; Lam, Dennis S C

2007-08-01

A 42-year-old woman had uneventful bilateral laser-assisted subepithelial keratectomy (LASEK) to correct myopia. She experienced intense pain in the first postoperative week and obtained topical oxybuprocaine for pain relief. Subsequently, she developed bilateral persistent corneal epithelial defects, epithelial edema, and bullae that failed to heal with bandage contact lens and topical lubricants. Over the next 4 months, there was progressive corneal stromal thinning and descemetocele formation in 1 eye, requiring application of cyanoacrylate glue, and stromal edema and scarring in the other eye, which resulted in a visual acuity of counting fingers. Investigations did not reveal associated infection or an underlying immunological disorder; however, the patient admitted to excessive use of topical anesthetic eyedrops in the post-LASEK period. She subsequently had penetrating keratoplasty and lens extraction with IOL implantation in the right eye. The left eye healed with central corneal scarring. This case illustrates that serious sight-threatening complications may occur after LASEK due to abuse of topical anesthetic agents.

Influence of anesthesia on cerebral blood flow, cerebral metabolic rate, and brain functional connectivity.

PubMed

Bonhomme, Vincent; Boveroux, Pierre; Hans, Pol; Brichant, Jean François; Vanhaudenhuyse, Audrey; Boly, Melanie; Laureys, Steven

2011-10-01

To describe recent studies exploring brain function under the influence of hypnotic anesthetic agents, and their implications on the understanding of consciousness physiology and anesthesia-induced alteration of consciousness. Cerebral cortex is the primary target of the hypnotic effect of anesthetic agents, and higher-order association areas are more sensitive to this effect than lower-order processing regions. Increasing concentration of anesthetic agents progressively attenuates connectivity in the consciousness networks, while connectivity in lower-order sensory and motor networks is preserved. Alteration of thalamic sub-cortical regulation could compromise the cortical integration of information despite preserved thalamic activation by external stimuli. At concentrations producing unresponsiveness, the activity of consciousness networks becomes anticorrelated with thalamic activity, while connectivity in lower-order sensory networks persists, although with cross-modal interaction alterations. Accumulating evidence suggests that hypnotic anesthetic agents disrupt large-scale cerebral connectivity. This would result in an inability of the brain to generate and integrate information, while external sensory information is still processed at a lower order of complexity.

Chronic lymphadenopathic toxoplasmosis. A case with marked hyperglobulinemia and impaired delayed hypersensitivity responses during active infection.

PubMed

Sheagren, J N; Lunde, M N; Simon, H B

1976-02-01

A patient with lymphadenopathic toxoplasmosis characterized by prolonged symptoms and repeated relapses with isolation of toxoplasma from lymph nodes is described. As the disease persisted and progressed, striking immunologic changes occurred that ultimately resulted in a state of extreme hyperglobulinemia associated with impaired delayed hypersensitivity responses. The case in question illustrates that progressive infection may occur in the face of high antibody levels of all immunoglobulin types whereas the only demonstrable immunologic impairment was of delayed hypersensitivity.

Persistent effects of pre-weaning in piglets on composition of fecal microbiota are diet-, genus-, and time-specific

USDA-ARS?s Scientific Manuscript database

The effects of diet on gut microbiota composition in the pre-weaning period have been characterized, but it is unknown whether differences in composition are sustained after weaning. The objective of this study was to determine if post-natal diet-induced differences in microbiota persist after weani...

Associative, Bidirectional Changes in Neural Signaling Utilizing NMDA Receptor- and Endocannabinoid-Dependent Mechanisms

ERIC Educational Resources Information Center

Li, Qin; Burrell, Brian D.

2011-01-01

Persistent, bidirectional changes in synaptic signaling (that is, potentiation and depression of the synapse) can be induced by the precise timing of individual pre- and postsynaptic action potentials. However, far less attention has been paid to the ability of paired trains of action potentials to elicit persistent potentiation or depression. We…

Biological impact of low dose-rate simulated solar particle event radiation in vivo.

PubMed

Chang, P Y; Doppalapudi, R; Bakke, J; Wang, A; Menda, S; Davis, Z

2010-08-01

C57Bl6-lacZ animals were exposed to a range of low dose-rate simulated solar particle event (sSPE) radiation at the NASA-sponsored Research Laboratory (NSRL) at Brookhaven National Laboratory (BNL). Peripheral blood was harvested from animals from 1 to 12 days after total body irradiation (TBI) to quantify the level of circulating reticulocytes (RET) and micronucleated reticulocytes (MN-RET) as an early indicator of radiation-induced genotoxicity. Bone marrow lymphocytes and hippocampal tissues from each animal were collected at 12 days and up to two months, to evaluate dose-dependent late effects after sSPE exposure. Early hematopoietic changes show that the % RET was reduced up to 3 days in response to radiation exposure but recovered at 12 days postirradiation. The % MN-RET in peripheral blood was temporally regulated and dependant on the total accumulated dose. Total chromosome aberrations in lymphocytes increased linearly with dose within a week after radiation and remained significantly higher than the control values at 4 weeks after exposure. The level of aberrations in the irradiated animals returned to control levels by 8 weeks postirradiation. Measurements of chromosome 2 and 8 specific aberrations indicate that, consistent with conventional giemsa-staining methods, the level of aberrations is also not significantly higher than in control animals at 8 weeks postirradiation. The hippocampus was surveyed for differential transcriptional regulation of genes known to be associated with neurogenesis. Our results showed differential expression of neurotrophin and their associated receptor genes within 1 week after sSPE exposure. Progressive changes in the profile of expressed genes known to be involved in neurogenic signaling pathways were dependent on the sSPE dose. Our results to date suggest that radiation-induced changes in the hematopoietic system, i.e., chromosome aberrations in lymphocytes, are transient and do not persist past 4 weeks after radiation. On the other hand, alteration in the profile of genes known to be involved in neurotrophic functions in the hippocampal tissue appears to persist for up to 8 weeks after radiation exposure. Such temporal changes confirm that, although cytogenetic changes after a single dose of low-dose and low-dose-rate protons appear to be transient, the impact of this exposure is sufficient to lead to persistent dynamic changes in neuronal tissues long after the initial radiation exposure.

Safety and persistence of the humoral and cellular immune responses induced by 2 doses of an AS03-adjuvanted A(H1N1)pdm09 pandemic influenza vaccine administered to infants, children and adolescents: Two open, uncontrolled studies.

PubMed

Garcia-Sicilia, José; Arístegui, Javier; Omeñaca, Félix; Carmona, Alfonso; Tejedor, Juan C; Merino, José M; García-Corbeira, Pilar; Walravens, Karl; Bambure, Vinod; Moris, Philippe; Caplanusi, Adrian; Gillard, Paul; Dieussaert, Ilse

2015-01-01

In children, 2 AS03-adjuvanted A(H1N1)pdm09 vaccine doses given 21 days apart were previously shown to induce a high humoral immune response and to have an acceptable safety profile up to 42 days following the first vaccination. Here, we analyzed the persistence data from 2 open-label studies, which assessed the safety, and humoral and cell-mediated immune responses induced by 2 doses of this vaccine. The first study was a phase II, randomized trial conducted in 104 children aged 6-35 months vaccinated with the A(H1N1)pdm09 vaccine containing 1.9 µg haemagglutinin antigen (HA) and AS03B (5.93 mg tocopherol) and the second study, a phase III, non-randomized trial conducted in 210 children and adolescents aged 3-17 years vaccinated with the A(H1N1)pdm09 vaccine containing 3.75 µg HA and AS03A (11.86 mg tocopherol). Approximately one year after the first dose, all children with available data were seropositive for haemagglutinin inhibition and neutralising antibody titres, but a decline in geometric mean antibody titres was noted. The vaccine induced a cell-mediated immune response in terms of antigen-specific CD4(+) T-cells, which persisted up to one year post-vaccination. The vaccine did not raise any safety concern, though these trials were not designed to detect rare events. In conclusion, 2 doses of the AS03-adjuvanted A(H1N1)pdm09 vaccine at 2 different dosages had a clinically acceptable safety profile, and induced high and persistent humoral and cell-mediated immune responses in children aged 6-35 months and 3-17 years. These studies have been registered at www.clinicaltrials.gov NCT00971321 and NCT00964158.

Hypoxia-independent upregulation of placental hypoxia inducible factor-1α gene expression contributes to the pathogenesis of preeclampsia.

PubMed

Iriyama, Takayuki; Wang, Wei; Parchim, Nicholas F; Song, Anren; Blackwell, Sean C; Sibai, Baha M; Kellems, Rodney E; Xia, Yang

2015-06-01

Accumulation of hypoxia inducible factor-1α (HIF-1α) is commonly an acute and beneficial response to hypoxia, whereas chronically elevated HIF-1α is associated with multiple disease conditions, including preeclampsia, a serious hypertensive disease of pregnancy. However, the molecular basis underlying the persistent elevation of placental HIF-1α in preeclampsia and its role in the pathogenesis of preeclampsia are poorly understood. Here we report that Hif-1α mRNA and HIF-1α protein were elevated in the placentas of pregnant mice infused with angiotensin II type I receptor agonistic autoantibody, a pathogenic factor in preeclampsia. Knockdown of placental Hif-1α mRNA by specific siRNA significantly attenuated hallmark features of preeclampsia induced by angiotensin II type I receptor agonistic autoantibody in pregnant mice, including hypertension, proteinuria, kidney damage, impaired placental vasculature, and elevated maternal circulating soluble fms-like tyrosine kinase-1 levels. Next, we discovered that Hif-1α mRNA levels and HIF-1α protein levels were induced in an independent preeclampsia model with infusion of the inflammatory cytokine tumor necrosis factor superfamily member 14 (LIGHT). SiRNA knockdown experiments also demonstrated that elevated HIF-1α contributed to LIGHT-induced preeclampsia features. Translational studies with human placentas showed that angiotensin II type I receptor agonistic autoantibody or LIGHT is capable of inducing HIF-1α in a hypoxia-independent manner. Moreover, increased HIF-1α was found to be responsible for angiotensin II type I receptor agonistic autoantibody or LIGHT-induced elevation of Flt-1 gene expression and production of soluble fms-like tyrosine kinase-1 in human villous explants. Overall, we demonstrated that hypoxia-independent stimulation of HIF-1α gene expression in the placenta is a common pathogenic mechanism promoting disease progression. Our findings reveal new insight to preeclampsia and highlight novel therapeutic possibilities for the disease. © 2015 American Heart Association, Inc.

Student continuation in high school chemistry

NASA Astrophysics Data System (ADS)

Bowen, James Iddon

2006-12-01

This investigation originally intended to uncover teacher behaviors that encourage students to persist in AP Chemistry in a typical urban Texas high school. As the investigation progressed, however, alternative reasons were sought for the persistence of some students when it became apparent that teacher behaviors might not be a factor in the decision to select AP Chemistry at the school under observation. In response to this, "Branding", a business theory which suggests certain attractive aspects of a product are promoted as a way to improve sales, is introduced as an alternative way of thinking about persistence in chemistry. "Branding" can explain why some students continue to select chemistry in the face of disappointing teaching. It is also argued here that "Branding" can encourage more students to take chemistry in the future.

PERSISTENT ORGANIC POLLUTANTS IN THE ENVIRONMENT: CHLORDANE RESIDUES IN COMPOST. (R828174)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

Persistent, circulative transmission of begomoviruses by whitefly vectors

USDA-ARS?s Scientific Manuscript database

Begomoviruses comprise an emerging and economically important group of plant viruses exclusively transmitted by the sweetpotato whitefly Bemisia tabaci in many regions of the world. The past twenty years have witnessed significant progress in studying the molecular interactions between members of th...

d-Aspartate oxidase influences glutamatergic system homeostasis in mammalian brain.

PubMed

Cristino, Luigia; Luongo, Livio; Squillace, Marta; Paolone, Giovanna; Mango, Dalila; Piccinin, Sonia; Zianni, Elisa; Imperatore, Roberta; Iannotta, Monica; Longo, Francesco; Errico, Francesco; Vescovi, Angelo Luigi; Morari, Michele; Maione, Sabatino; Gardoni, Fabrizio; Nisticò, Robert; Usiello, Alessandro

2015-05-01

We have investigated the relevance of d-aspartate oxidase, the only enzyme known to selectively degrade d-aspartate (d-Asp), in modulating glutamatergic system homeostasis. Interestingly, the lack of the Ddo gene, by raising d-Asp content, induces a substantial increase in extracellular glutamate (Glu) levels in Ddo-mutant brains. Consistent with an exaggerated and persistent N-methyl-d-aspartate receptor (NMDAR) stimulation, we documented in Ddo knockouts severe age-dependent structural and functional alterations mirrored by expression of active caspases 3 and 7 along with appearance of dystrophic microglia and reactive astrocytes. In addition, prolonged elevation of d-Asp triggered in mutants alterations of NMDAR-dependent synaptic plasticity associated to reduction of hippocampal GluN1 and GluN2B subunits selectively located at synaptic sites and to increase in the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-to-N-methyl-d-aspartate ratio. These effects, all of which converged on a progressive hyporesponsiveness at NMDAR sites, functionally resulted in a greater vulnerability to phencyclidine-induced prepulse inhibition deficits in mutants. In conclusion, our results indicate that d-aspartate oxidase, by strictly regulating d-Asp levels, impacts on the homeostasis of glutamatergic system, thus preventing accelerated neurodegenerative processes. Copyright © 2015 Elsevier Inc. All rights reserved.

Systemic PPARγ deletion causes severe disturbance in fluid homeostasis in mice

PubMed Central

Zhou, Li; Panasiuk, Alexandra; Downton, Maicy; Zhao, Daqiang; Yang, Baoxue; Jia, Zhanjun

2015-01-01

The pharmacological action of peroxisome proliferator-activated receptor (PPAR)γ in promoting sodium and water retention is well documented as highlighted by the major side-effect of body weight gain and edema associated with thiazolidinedione use. However, a possible physiological role of PPARγ in regulation of fluid metabolism has not been reported by previous studies. Here we analyzed fluid metabolism in inducible whole-body PPARγ knockout mice. The null mice developed severe polydipsia and polyuria, reduced urine osmolality, and modest hyperphagia. The phenomenon persisted during 3 days of pair feeding and pair drinking, accompanied by progressive weight loss. After 24 h water deprivation, the null mice had a lower urine osmolality, a higher urine volume, a greater weight loss, and a greater rise in hematocrit than the floxed control. Urinary vasopressin (AVP) excretion was not different between the genotypes under basal condition or after WD. The response of urine osmolality to acute and chronic 1-desamino-8-d-arginine vasopressin treatment was attenuated in the null mice, but the total abundance or phosphorylation of aquaporin 2 (AQP2) in the kidney or AVP-induced cAMP production in inner medullary collecting duct suspensions was unaffected. Overall, PPARγ participates in physiological control of fluid homeostasis through an unknown mechanism involving cAMP/AQP2-independent enhancement of AVP response. PMID:26330489

FAT10 IS AN EPIGENETIC MARKER FOR LIVER PRENEOPLASIA IN A DRUG-PRIMED MOUSE MODEL OF TUMORIGENESIS

PubMed Central

Oliva, Joan; Bardag-Gorce, Fawzia; French, Barbara A; Li, Jun; McPhaul, Laron; Amidi, Fataneh; Dedes, Jeniffer; Habibi, Amir; Nguyen, Sheila; French, Samuel W

2010-01-01

There is clinical evidence that chronic liver diseases in which MDBs (Mallory Denk Bodies) form progress to hepatocellular carcinoma. The present study provides evidence that links MDB formation induced by chronic drug injury, with preneoplasia and later to the formation of tumors, which develop long after drug withdrawal. Evidence indicated that this link was due to an epigenetic cellular memory induced by chronic drug ingestion. Microarray analysis showed that the expressions of many markers of preneoplasia (UBD, Alpha Fetoprotein, KLF6 and Glutathione-S-Transferase mu2) were increased together when the drug DDC was refed. These changes were suppressed by S-adenosylmethionine feeding, indicating that the drug was affecting DNA and histones methylation in an epigenetic manner. The link between MDB formation and neoplasia formation was likely due to the over expression of UBD (also called FAT10), which is up regulated in 90% of human hepatocellular carcinomas. Immunohistochemical staining of drug primed mouse livers showed that FAT10 positive liver cells persisted up to 4 months after drug withdrawal and they were still found in the livers of mice, 14 months after drug withdrawal. The refeeding of DDC increased the percent of FAT10 hepatocytes. PMID:18280469

Survival of bactericidal antibiotic treatment by tolerant persister cells of Klebsiella pneumoniae.

PubMed

Li, Ying; Zhang, Luhua; Zhou, Yingshun; Zhang, Zhikun; Zhang, Xinzhuo

2018-03-01

Persister cells, a subpopulation of tolerant cells within the bacterial culture, are commonly thought to be responsible for antibiotic therapy failure and infection recurrence. Klebsiella pneumoniae is a notorious human pathogen for its increasing resistance to antibiotics and wide involvement in severe infections. In this study, we aimed to investigate the persister subpopulation of K. pneumoniae. The presence of persisters in K. pneumoniae was determined by treatment with high concentrations of antibiotics, used alone or in combination. The effect of low level of antibiotics on persister formation was investigated by pre-exposure of cells to antibiotics with low concentrations followed by higher doses. The dependence of persister levels on growth phase was determined by measuring the survival ability of cells along the growth stages upon exposure to a high concentration of antibiotic. Analysis on persister type was carried out by persister elimination assays.Results/Key findings. We show that K. pneumoniae produces high levels of tolerant persister cells to survive treatment by a variety of high concentrations of bactericidal antibiotics and persister formation is prevalent among K. pneumoniae clinical strains. Besides, we find that persister cells can be induced by low concentrations of antibiotics. Finally, we provide evidence that persister formation is growth phase-dependent and Type II persisters dominate the persister subpopulation during the entire exponential phase of K. pneumoniae. Our study describes the formation of tolerant persister cells that allow survival of treatment by high concentrations of antibiotics in K. pneumoniae.

[Progress in stem cells and regenerative medicine].

PubMed

Wang, Libin; Zhu, He; Hao, Jie; Zhou, Qi

2015-06-01

Stem cells have the ability to differentiate into all types of cells in the body and therefore have great application potential in regenerative medicine, in vitro disease modelling and drug screening. In recent years, stem cell technology has made great progress, and induced pluripotent stem cell technology revolutionizes the whole stem cell field. At the same time, stem cell research in our country has also achieved great progress and becomes an indispensable power in the worldwide stem cell research field. This review mainly focuses on the research progress in stem cells and regenerative medicine in our country since the advent of induced pluripotent stem cell technology, including induced pluripotent stem cells, transdifferentiation, haploid stem cells, and new gene editing tools.

Pathogenicity of exopolysaccharide-producing Actinomyces oris isolated from an apical abscess lesion

PubMed Central

Yamane, K; Nambu, T; Yamanaka, T; Ishihara, K; Tatami, T; Mashimo, C; Walker, C B; Leung, K-P; Fukushima, H

2013-01-01

Aim To demonstrate a capacity for producing exopolysaccharides (EPSs) and an ability to form biofilm on abiotic materials of Actinomyces oris strain K20. Methodology The productivity of EPSs and the ability to form biofilm of strain K20 were evaluated by measuring viscosity of spent culture media and by scanning electron microscopy (SEM) and the biofilm assay on microtitre plates, respectively. High-performance liquid chromatography was used to determine the chemical composition of the viscous materials. To examine the role of the viscous materials attributable to the pathogenicity in this organism, the ability of strain K20 to induce abscess formation was compared in mice to that of ATCC 27044. Results The viscosity of the spent culture media of K20 was significantly higher than that of ATCC 27044. Strain K20 showed dense meshwork structures around the cells and formed biofilms on microtitre plates, whereas ATCC 27044 did not. Chemical analysis of the viscous materials revealed that they were mainly composed of neutral sugars with mannose constituting 77.5% of the polysaccharides. Strain K20 induced persistent abscesses in mice lasting at least 5 days at a concentration of 108 cells mL−1, whereas abscesses induced by ATCC 27044 healed and disappeared or decreased in size at day 5. Conclusions Strain K20 produced EPSs, mainly consisting of mannose, and formed biofilms. This phenotype might play an important role for A. oris to express virulence through the progression of apical periodontitis. PMID:22900599

Pathogenicity of exopolysaccharide-producing Actinomyces oris isolated from an apical abscess lesion.

PubMed

Yamane, K; Nambu, T; Yamanaka, T; Ishihara, K; Tatami, T; Mashimo, C; Walker, C B; Leung, K-P; Fukushima, H

2013-02-01

To demonstrate a capacity for producing exopolysaccharides (EPSs) and an ability to form biofilm on abiotic materials of Actinomyces oris strain K20. The productivity of EPSs and the ability to form biofilm of strain K20 were evaluated by measuring viscosity of spent culture media and by scanning electron microscopy (SEM) and the biofilm assay on microtitre plates, respectively. High-performance liquid chromatography was used to determine the chemical composition of the viscous materials. To examine the role of the viscous materials attributable to the pathogenicity in this organism, the ability of strain K20 to induce abscess formation was compared in mice to that of ATCC 27044. The viscosity of the spent culture media of K20 was significantly higher than that of ATCC 27044. Strain K20 showed dense meshwork structures around the cells and formed biofilms on microtitre plates, whereas ATCC 27044 did not. Chemical analysis of the viscous materials revealed that they were mainly composed of neutral sugars with mannose constituting 77.5% of the polysaccharides. Strain K20 induced persistent abscesses in mice lasting at least 5 days at a concentration of 10(8) cells mL(-1), whereas abscesses induced by ATCC 27044 healed and disappeared or decreased in size at day 5. Strain K20 produced EPSs, mainly consisting of mannose, and formed biofilms. This phenotype might play an important role for A. oris to express virulence through the progression of apical periodontitis. © 2012 International Endodontic Journal.

LUNG INJURY, INFLAMMATION AND AKT SIGNALING FOLLOWING INHALATION OF PARTICULATE HEXAVALENT CHROMIUM

PubMed Central

Beaver, Laura M.; Stemmy, Erik J.; Constant, Stephanie L.; Schwartz, Arnold; Little, Laura G.; Gigley, Jason P.; Chun, Gina; Sugden, Kent D.; Ceryak, Susan M.; Patierno, Steven R.

2013-01-01

Certain particulate hexavalent chromium [Cr(VI)] compounds are human respiratory carcinogens that release genotoxic soluble chromate, and are associated with fibrosis, fibrosarcomas, adenocarcinomas and squamous cell carcinomas of the lung. We postulate that inflammatory processes and mediators may contribute to the etiology of Cr(VI) carcinogenesis, however the immediate (0–24 hours) pathologic injury and immune responses after exposure to particulate chromates have not been adequately investigated. Our aim was to determine the nature of the lung injury, inflammatory response, and survival signaling responses following intranasal exposure of BALB/c mice to particulate basic zinc chromate. Factors associated with lung injury, inflammation and survival signaling were measured in airway lavage fluid and in lung tissue. A single chromate exposure induced an acute immune response in the lung, characterized by a rapid and significant increase in IL-6 and GRO-α levels, an influx of neutrophils, and a decline in macrophages in lung airways. Histological examination of lung tissue in animals challenged with a single chromate exposure revealed an increase in bronchiolar cell apoptosis and mucosal injury. Furthermore, chromate exposure induced injury and inflammation that progressed to alveolar and interstitial pneumonitis. Finally, a single Cr(VI) challenge resulted in a rapid and persistent increase in the number of airways immunoreactive for phosphorylation of the survival signaling protein Akt, on serine 473. These data illustrate that chromate induces both survival signaling and an inflammatory response in the lung, which we postulate may contribute to early oncogenesis. PMID:19109987

Emerging Role of Probiotics in the Management of Helicobacter pylori Infection: Histopathologic Perspectives.

PubMed

Emara, Mohamed H; Elhawari, Soha A; Yousef, Salem; Radwan, Mohamed I; Abdel-Aziz, Hesham R

2016-02-01

There is growing evidence from preclinical and clinical studies that emphasizes the efficacy of probiotics in the management of Helicobacter (H) pylori infection; it increased the eradication rate, improved patient clinical manifestations and lowered treatment associated side effects. In this review we documented the potential ability of probiotics to ameliorate H. pylori induced histological features. We searched the available literature for full length articles focusing the role of probiotics on H. pylori induced gastritis from histologic perspectives. Probiotics lowered H. pylori density at the luminal side of epithelium, improved histological inflammatory and activity scores both in the gastric corpus and antrum. This effect persists for long period of time after discontinuation of probiotic supplementation and this is probably through an immune mechanism. The current evidence support the promising role of probiotics in improving H. pylori induced histopathological features both in gastric antrum and corpus and for long periods of time. Because increased density of H. pylori on the gastric mucosa is linked to more severe gastritis and increased incidence of peptic ulcers, we can infer that a reduction of the density might help to decrease the risk of developing pathologies, probably the progression toward atrophic gastritis and gastric adenocarcinoma. These effects together with improving the H. pylori eradication rates and amelioration of treatment related side effects might open the door for probiotics to be added to H. pylori eradication regimens. © 2015 John Wiley & Sons Ltd.

Persistence of Yellow Fever vaccine-induced antibodies after cord blood stem cell transplant.

PubMed

Avelino-Silva, Vivian Iida; Freire, Marcos da Silva; Rocha, Vanderson; Rodrigues, Celso Arrais; Novis, Yana Sarkis; Sabino, Ester C; Kallas, Esper Georges

2016-04-02

We report the case of a cord blood haematopoietic stem cell transplant recipient who was vaccinated for Yellow Fever (YF) 7 days before initiating chemotherapy and had persistent YF antibodies more than 3 years after vaccination. Since the stem cell donor was never exposed to wild YF or to the YF vaccine, and our patient was not exposed to YF or revaccinated, this finding strongly suggests the persistence of recipient immunity. We briefly discuss potential consequences of incomplete elimination of recipient's leukocytes following existing haematopoietic cancer treatments.

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse.

PubMed

Korpi, Esa R; den Hollander, Bjørnar; Farooq, Usman; Vashchinkina, Elena; Rajkumar, Ramamoorthy; Nutt, David J; Hyytiä, Petri; Dawe, Gavin S

2015-10-01

Adaptation of the nervous system to different chemical and physiologic conditions is important for the homeostasis of brain processes and for learning and remembering appropriate responses to challenges. Although processes such as tolerance and dependence to various drugs of abuse have been known for a long time, it was recently discovered that even a single pharmacologically relevant dose of various drugs of abuse induces neuroplasticity in selected neuronal populations, such as the dopamine neurons of the ventral tegmental area, which persist long after the drug has been excreted. Prolonged (self-) administration of drugs induces gene expression, neurochemical, neurophysiological, and structural changes in many brain cell populations. These region-specific changes correlate with addiction, drug intake, and conditioned drugs effects, such as cue- or stress-induced reinstatement of drug seeking. In rodents, adolescent drug exposure often causes significantly more behavioral changes later in adulthood than a corresponding exposure in adults. Clinically the most impairing and devastating effects on the brain are produced by alcohol during fetal development. In adult recreational drug users or in medicated patients, it has been difficult to find persistent functional or behavioral changes, suggesting that heavy exposure to drugs of abuse is needed for neurotoxicity and for persistent emotional and cognitive alterations. This review describes recent advances in this important area of research, which harbors the aim of translating this knowledge to better treatments for addictions and related neuropsychiatric illnesses. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Improving Underrepresented Minority Student Persistence in STEM

PubMed Central

Estrada, Mica; Burnett, Myra; Campbell, Andrew G.; Campbell, Patricia B.; Denetclaw, Wilfred F.; Gutiérrez, Carlos G.; Hurtado, Sylvia; John, Gilbert H.; Matsui, John; McGee, Richard; Okpodu, Camellia Moses; Robinson, T. Joan; Summers, Michael F.; Werner-Washburne, Maggie; Zavala, MariaElena

2016-01-01

Members of the Joint Working Group on Improving Underrepresented Minorities (URMs) Persistence in Science, Technology, Engineering, and Mathematics (STEM)—convened by the National Institute of General Medical Sciences and the Howard Hughes Medical Institute—review current data and propose deliberation about why the academic “pathways” leak more for URM than white or Asian STEM students. They suggest expanding to include a stronger focus on the institutional barriers that need to be removed and the types of interventions that “lift” students’ interests, commitment, and ability to persist in STEM fields. Using Kurt Lewin’s planned approach to change, the committee describes five recommendations to increase URM persistence in STEM at the undergraduate level. These recommendations capitalize on known successes, recognize the need for accountability, and are framed to facilitate greater progress in the future. The impact of these recommendations rests upon enacting the first recommendation: to track successes and failures at the institutional level and collect data that help explain the existing trends. PMID:27543633

An animal model of schizophrenia based on chronic LSD administration: old idea, new results.

PubMed

Marona-Lewicka, Danuta; Nichols, Charles D; Nichols, David E

2011-09-01

Many people who take LSD experience a second temporal phase of LSD intoxication that is qualitatively different, and was described by Daniel Freedman as "clearly a paranoid state." We have previously shown that the discriminative stimulus effects of LSD in rats also occur in two temporal phases, with initial effects mediated by activation of 5-HT(2A) receptors (LSD30), and the later temporal phase mediated by dopamine D2-like receptors (LSD90). Surprisingly, we have now found that non-competitive NMDA antagonists produced full substitution in LSD90 rats, but only in older animals, whereas in LSD30, or in younger animals, these drugs did not mimic LSD. Chronic administration of low doses of LSD (>3 months, 0.16 mg/kg every other day) induces a behavioral state characterized by hyperactivity and hyperirritability, increased locomotor activity, anhedonia, and impairment in social interaction that persists at the same magnitude for at least three months after cessation of LSD treatment. These behaviors, which closely resemble those associated with psychosis in humans, are not induced by withdrawal from LSD; rather, they are the result of neuroadaptive changes occurring in the brain during the chronic administration of LSD. These persistent behaviors are transiently reversed by haloperidol and olanzapine, but are insensitive to MDL-100907. Gene expression analysis data show that chronic LSD treatment produced significant changes in multiple neurotransmitter system-related genes, including those for serotonin and dopamine. Thus, we propose that chronic treatment of rats with low doses of LSD can serve as a new animal model of psychosis that may mimic the development and progression of schizophrenia, as well as model the established disease better than current acute drug administration models utilizing amphetamine or NMDA antagonists such as PCP. Copyright © 2011 Elsevier Ltd. All rights reserved.

Characterisation of palatal dysfunction after laryngoplasty.

PubMed

Barnett, T P; O'Leary, J M; Dixon, P M; Barakzai, S Z

2014-01-01

Dorsal displacement of the soft palate (DDSP) in the horse has been previously described as intermittent, typically occurring at fast exercise; or persistent, seen at rest. Dorsal displacement of the soft palate has recently been reported following laryngoplasty (LP) and can be associated with continued poor performance and respiratory noise. The current study aimed to characterise the DDSP diagnosed post LP. Cross-sectional study. Owners/trainers of horses undergoing LP at one institution over 6 years were contacted to determine the horse's progress and willingness for re-examination. The horses were examined at the rest, walk, trot and canter with an overground exercising endoscope. A GPS-equipped watch was carried to obtain maximal exercising speeds. Videos of horses with DDSP were reviewed to determine frequency and duration of DDSP and swallowing events at the various gaits. Exercising endoscopy was performed in 41 of the 89 horses that had undergone LP. Nineteen of the 41 horses were diagnosed with DDSP at exercise, of which 7/41 also had DDSP at rest. No difference was detected in the percentage of total time spent displaced at each gait (P = 0.67), or in the frequency of new DDSP events per minute between each gait (P = 0.10), or in the frequency of swallowing events per minute between each gait (P = 0.52). The majority of horses displaced at various times throughout each gait. Dorsal displacement of the soft palate was most commonly solely induced spontaneously and always corrected with a swallow. The maximum speed achieved was 8.3 m/s. Dorsal displacement of the soft palate was common following LP and it appears to be induced at slower gaits than DDSP that has previously been described. It also occurred at various times throughout each gait and did not always occur persistently at rest. These findings suggest horses undergoing LP may be more prone to DDSP and further investigations into the aetiology of post LP palatal dysfunction are warranted. © 2013 EVJ Ltd.

Persistent photoconductivity due to trapping of induced charges in Sn/ZnO thin film based UV photodetector

NASA Astrophysics Data System (ADS)

Yadav, Harish Kumar; Sreenivas, K.; Gupta, Vinay

2010-05-01

Photoconductivity relaxation in rf magnetron sputtered ZnO thin films integrated with ultrathin tin metal overlayer is investigated. Charge carriers induced at the ZnO-metal interface by the tin metal overlayer compensates the surface lying trap centers and leads to the enhanced photoresponse. On termination of ultraviolet radiation, recombination of the photoexcited electrons with the valence band holes leaves the excess carriers deeply trapped at the recombination center and holds the dark conductivity level at a higher value. Equilibrium between the recombination centers and valence band, due to trapped charges, eventually stimulates the persistent photoconductivity in the Sn/ZnO photodetectors.

Model-based estimates of long-term persistence of induced HPV antibodies: a flexible subject-specific approach.

PubMed

Aregay, Mehreteab; Shkedy, Ziv; Molenberghs, Geert; David, Marie-Pierre; Tibaldi, Fabián

2013-01-01

In infectious diseases, it is important to predict the long-term persistence of vaccine-induced antibodies and to estimate the time points where the individual titers are below the threshold value for protection. This article focuses on HPV-16/18, and uses a so-called fractional-polynomial model to this effect, derived in a data-driven fashion. Initially, model selection was done from among the second- and first-order fractional polynomials on the one hand and from the linear mixed model on the other. According to a functional selection procedure, the first-order fractional polynomial was selected. Apart from the fractional polynomial model, we also fitted a power-law model, which is a special case of the fractional polynomial model. Both models were compared using Akaike's information criterion. Over the observation period, the fractional polynomials fitted the data better than the power-law model; this, of course, does not imply that it fits best over the long run, and hence, caution ought to be used when prediction is of interest. Therefore, we point out that the persistence of the anti-HPV responses induced by these vaccines can only be ascertained empirically by long-term follow-up analysis.

Persistent inhibition of hippocampal long-term potentiation in vivo by learned helplessness stress.

PubMed

Ryan, Benedict K; Vollmayr, Barbara; Klyubin, Igor; Gass, Peter; Rowan, Michael J

2010-06-01

The persistent cognitive disruptive effects of stress have been strongly implicated in the pathophysiology of depression and post-traumatic stress disorder. Here we examined factors influencing the time course of recovery from the inhibitory effect of acute inescapable stressors on the ability to induce long-term potentiation (LTP) in the dorsal hippocampus in vivo. We tested different forms of LTP, different stressors and different inbred strains of rats. Acute elevated platform stress completely, but transiently (<3 h), inhibited induction of both NMDA receptor-dependent LTP induced by a standard high frequency (200 Hz) conditioning stimulus and an additional LTP that required voltage-dependent Ca(2+) channel activation triggered by strong (400 Hz) conditioning stimulation. In contrast, acute inescapable footshock stress, used to study learned helplessness, inhibited LTP for at least 4 weeks. Contrary to expectations, there was no clear relationship between the ability of the footshock to trigger helpless behavior, a model of stress-induced depression, and the magnitude of LTP inhibition. Moreover, LTP did not appear to be affected by genetic susceptibility to learned helplessness, a model of genetic vulnerability to depression. This long-lasting synaptic plasticity disruption may underlie persistent impairment of hippocampus-dependent cognition by excessive acute inescapable stress.

An OX40/OX40L interaction directs successful immunity to hepatitis B virus

PubMed Central

Publicover, Jean; Gaggar, Anuj; Jespersen, Jillian M.; Halac, Ugur; Johnson, Audra J.; Goodsell, Amanda; Avanesyan, Lia; Nishimura, Stephen L.; Holdorf, Meghan; Mansfield, Keith G.; Judge, Joyce Bousquet; Koshti, Arya; Croft, Michael; Wakil, Adil E.; Rosenthal, Philip; Pai, Eric; Cooper, Stewart; Baron, Jody L.

2018-01-01

Depending on age of acquisition, hepatitis B virus (HBV) can induce a cell-mediated immune response that results in either cure or progressive liver injury. In adult-acquired infection, HBV antigens are usually cleared, whereas in infancy-acquired infection, they persist. Individuals infected during infancy therefore represent the majority of patients chronically infected with HBV (CHB). A therapy that can promote viral antigen clearance in most CHB patients has not been developed and would represent a major health care advance and cost mitigator. Using an age-dependent mouse model of HBV clearance and persistence in conjunction with human blood and liver tissue, we studied mechanisms of viral clearance to identify new therapeutic targets. We demonstrate that age-dependent expression of the costimulatory molecule OX40 ligand (OX40L) by hepatic innate immune cells is pivotal in determining HBV immunity, and that treatment with OX40 agonists leads to improved HBV antigen clearance in young mice, as well as increased strength of T cell responses in young mice and adult mice that were exposed to HBV when they were young and developed a CHB serological profile. Similarly, in humans, we show that hepatic OX40L transcript expression is age-dependent and that increased OX40 expression on peripheral CD4+ T cells in adults is associated with HBV clearance. These findings provide new mechanistic understanding of the immune pathways and cells necessary for HBV immunity and identify potential therapeutic targets for resolving CHB. PMID:29563320

Decoupling activation and exhaustion of B cells in spontaneous controllers of HIV infection

PubMed Central

Sciaranghella, Gaia; Tong, Neath; Mahan, Alison E.; Suscovich, Todd J.; Alter, Galit

2013-01-01

Objective To define the impact of chronic viremia and associated immune activation on B-cell exhaustion in HIV infection. Design Progressive HIV infection is marked by B-cell anergy and exhaustion coupled with dramatic hypergammaglobulinemia. Although both upregulation of CD95 and loss of CD21 have been used as markers of infection-associated B-cell dysfunction, little is known regarding the specific profiles of dysfunctional B cells and whether persistent viral replication and its associated immune activation play a central role in driving B-cell dysfunction. Methods Multiparameter flow cytometry was used to define the profile of dysfunctional B cells. The changes in the expression of CD21 and CD95 were tracked on B-cell subpopulations in patients with differential control of viral replication. Results Although the emergence of exhausted, CD21low tissue-like memory B cells followed similar patterns in both progressors and controllers, the frequency of CD21low activated memory B cells was lower in spontaneous controllers. Conclusion Our results suggest that the loss of CD21 and the upregulation of CD95 occur as separate events during the development of B-cell dysfunction. The loss of CD21 is a marker of B-cell exhaustion induced in the absence of appreciable viral replication, whereas the upregulation of CD95 is tightly linked to persistent viral replication and its associated immune activation. Thus, these dysfunctional profiles potentially represent two functionally distinct states within the B-cell compartment. PMID:23135171

Ironing Out the Unconventional Mechanisms of Iron Acquisition and Gene Regulation in Chlamydia

PubMed Central

Pokorzynski, Nick D.; Thompson, Christopher C.; Carabeo, Rey A.

2017-01-01

The obligate intracellular pathogen Chlamydia trachomatis, along with its close species relatives, is known to be strictly dependent upon the availability of iron. Deprivation of iron in vitro induces an aberrant morphological phenotype termed “persistence.” This persistent phenotype develops in response to various immunological and nutritional insults and may contribute to the development of sub-acute Chlamydia-associated chronic diseases in susceptible populations. Given the importance of iron to Chlamydia, relatively little is understood about its acquisition and its role in gene regulation in comparison to other iron-dependent bacteria. Analysis of the genome sequences of a variety of chlamydial species hinted at the involvement of unconventional mechanisms, being that Chlamydia lack many conventional systems of iron homeostasis that are highly conserved in other bacteria. Herein we detail past and current research regarding chlamydial iron biology in an attempt to provide context to the rapid progress of the field in recent years. We aim to highlight recent discoveries and innovations that illuminate the strategies involved in chlamydial iron homeostasis, including the vesicular mode of acquiring iron from the intracellular environment, and the identification of a putative iron-dependent transcriptional regulator that is synthesized as a fusion with a ABC-type transporter subunit. These recent findings, along with the noted absence of iron-related homologs, indicate that Chlamydia have evolved atypical approaches to the problem of iron homeostasis, reinvigorating research into the iron biology of this pathogen. PMID:28951853

3 CFR 8773 - Proclamation 8773 of January 13, 2012. Martin Luther King, Jr., Federal Holiday, 2012

Code of Federal Regulations, 2013 CFR

2013-01-01

..., sharing his dream of an America that ensured the true equality of all our people. From the steps of the... remarkable dream is unending, with persistence, progress is within our reach. On the Martin Luther King, Jr...

The State of Race Relations.

ERIC Educational Resources Information Center

Hatchett, David

1989-01-01

Despite advances in civil rights in the 1950s and 1960s, racial and ethnic prejudice and discrimination remain deeply entrenched in American society. Chronicles political and social trends, including White backlash and the perpetuation of socioeconomic stratification, that have undercut progress toward equality. Examines the persistence of…

"Eureka, Eureka!" Discoveries in Science

ERIC Educational Resources Information Center

Agarwal, Pankaj

2011-01-01

Accidental discoveries have been of significant value in the progress of science. Although accidental discoveries are more common in pharmacology and chemistry, other branches of science have also benefited from such discoveries. While most discoveries are the result of persistent research, famous accidental discoveries provide a fascinating…

Workplace Discrimination, A Picture of Hope and Concern. Global Report.

ERIC Educational Resources Information Center

World of Work, 2003

2003-01-01

An International Labour Organisation report finds that workplace discrimination is a persistent global problem. Although sex discrimination is most prevalent, discrimination in racial, HIV/AIDS, disability, religious, and age categories is rising. Progress is uneven, and inequalities within groups are widening. (SK)

Scaling Watershed Models: Modern Approaches to Science Computation with MapReduce, Parallelization, and Cloud Optimization

EPA Science Inventory

Environmental models are products of the computer architecture and software tools available at the time of development. Scientifically sound algorithms may persist in their original state even as system architectures and software development approaches evolve and progress. Dating...

Addressing Student Diversity and Equity

ERIC Educational Resources Information Center

Januszyk, Rita; Miller, Emily C.; Lee, Okhee

2016-01-01

While student demographics continue to change nationwide, science achievement gaps persist, as measured by the National Assessment of Educational Progress (NCES 2012). As traditional racial and ethnic minority students have become the numeric majority (NCES 2013), teaching science for all increasingly means addressing diverse student populations.…

The role of neuroimmune signaling in alcoholism.

PubMed

Crews, Fulton T; Lawrimore, Colleen J; Walter, T Jordan; Coleman, Leon G

2017-08-01

Alcohol consumption and stress increase brain levels of known innate immune signaling molecules. Microglia, the innate immune cells of the brain, and neurons respond to alcohol, signaling through Toll-like receptors (TLRs), high-mobility group box 1 (HMGB1), miRNAs, pro-inflammatory cytokines and their associated receptors involved in signaling between microglia, other glia and neurons. Repeated cycles of alcohol and stress cause a progressive, persistent induction of HMGB1, miRNA and TLR receptors in brain that appear to underlie the progressive and persistent loss of behavioral control, increased impulsivity and anxiety, as well as craving, coupled with increasing ventral striatal responses that promote reward seeking behavior and increase risk of developing alcohol use disorders. Studies employing anti-oxidant, anti-inflammatory, anti-depressant, and innate immune antagonists further link innate immune gene expression to addiction-like behaviors. Innate immune molecules are novel targets for addiction and affective disorders therapies. This article is part of the Special Issue entitled "Alcoholism". Copyright © 2017 Elsevier Ltd. All rights reserved.

Childhood Stuttering: Where Are We and Where Are We Going?

PubMed

Smith, Anne; Weber, Christine

2016-11-01

Remarkable progress has been made over the past two decades in expanding our understanding of the behavioral, peripheral physiologic, and central neurophysiologic bases of stuttering in early childhood. It is clear that stuttering is a neurodevelopmental disorder characterized by atypical development of speech motor planning and execution networks. The speech motor system must interact in complex ways with neural systems mediating language and other cognitive and emotional processes. During the time when stuttering typically appears and follows its path to either recovery or persistence, all of these neurobehavioral systems are undergoing rapid and dramatic developmental changes. We summarize our current understanding of the various developmental trajectories relevant for the understanding of stuttering in early childhood. We also present theoretical and experimental approaches that we believe will be optimal for even more rapid progress toward developing better and more targeted treatment for stuttering in the preschool children who are more likely to persist in stuttering. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

DNA damage in cells exhibiting radiation-induced genomic instability

DOE PAGES

Keszenman, Deborah J.; Kolodiuk, Lucia; Baulch, Janet E.

2015-02-22

Cells exhibiting radiation induced genomic instability exhibit varied spectra of genetic and chromosomal aberrations. Even so, oxidative stress remains a common theme in the initiation and/or perpetuation of this phenomenon. Isolated oxidatively modified bases, abasic sites, DNA single strand breaks and clustered DNA damage are induced in normal mammalian cultured cells and tissues due to endogenous reactive oxygen species generated during normal cellular metabolism in an aerobic environment. While sparse DNA damage may be easily repaired, clustered DNA damage may lead to persistent cytotoxic or mutagenic events that can lead to genomic instability. In this study, we tested the hypothesismore » that DNA damage signatures characterised by altered levels of endogenous, potentially mutagenic, types of DNA damage and chromosomal breakage are related to radiation-induced genomic instability and persistent oxidative stress phenotypes observed in the chromosomally unstable progeny of irradiated cells. The measurement of oxypurine, oxypyrimidine and abasic site endogenous DNA damage showed differences in non-double-strand breaks (DSB) clusters among the three of the four unstable clones evaluated as compared to genomically stable clones and the parental cell line. These three unstable clones also had increased levels of DSB clusters. The results of this study demonstrate that each unstable cell line has a unique spectrum of persistent damage and lead us to speculate that alterations in DNA damage signaling and repair may be related to the perpetuation of genomic instability.« less

Persistent induction of c-fos and c-jun expression by asbestos

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

Heintz, N.H.; Mossman, B.T.; Janssen, Y.M.

To investigate the mechanisms of asbestos-induced carcinogenesis, expression of c-fos and c-jun protooncogenes was examined in rat pleural mesothelial cells and hamster tracheal epithelial cells after exposure to crocidolite or chrysotile asbestos. In contrast to phorbol 12-myristate 13-acetate, which induces rapid and transient increases in c-fos and c-jun mRNA, asbestos causes 2- to 5-fold increases in c-fos and c-jun mRNA that persist for at least 24 hr in mesothelial cells. The induction of c-fos and c-jun mRNA by asbestos in mesothelial cells is dose-dependent and is most pronounced with crocidolite, the type of asbestos most pathogenic in the causation ofmore » pleural mesothelioma. Induction of c-jun gene expression by asbestos occurs in tracheal epithelial cells but is not accompanied by a corresponding induction of c-fos gene expression. In both cell types, asbestos induces increases in protein factors that bind specifically to the DNA sites that mediate gene expression by the AP-1 family of transcription factors. The persistent induction of AP-1 transcription factors by asbestos suggests a model of asbestos-induced carcinogenesis involving chronic stimulation of cell proliferation through activation of the early response gene pathway that includes c-jun and/or c-fos. 30 refs., 5 figs.« less

Pulmonary Vein Antral Isolation and Nonpulmonary Vein Trigger Ablation Are Sufficient to Achieve Favorable Long-Term Outcomes Including Transformation to Paroxysmal Arrhythmias in Patients With Persistent and Long-Standing Persistent Atrial Fibrillation.

PubMed

Liang, Jackson J; Elafros, Melissa A; Muser, Daniele; Pathak, Rajeev K; Santangeli, Pasquale; Zado, Erica S; Frankel, David S; Supple, Gregory E; Schaller, Robert D; Deo, Rajat; Garcia, Fermin C; Lin, David; Hutchinson, Mathew D; Riley, Michael P; Callans, David J; Marchlinski, Francis E; Dixit, Sanjay

2016-11-01

Transformation from persistent to paroxysmal atrial fibrillation (AF) after ablation suggests modification of the underlying substrate. We examined the nature of initial arrhythmia recurrence in patients with nonparoxysmal AF undergoing antral pulmonary vein isolation and nonpulmonary vein trigger ablation and correlated recurrence type with long-term ablation efficacy after the last procedure. Three hundred and seventeen consecutive patients with persistent (n=200) and long-standing persistent (n=117) AF undergoing first ablation were included. AF recurrence was defined as early (≤6 weeks) or late (>6 weeks after ablation) and paroxysmal (either spontaneous conversion or treated with cardioversion ≤7 days) or persistent (lasting >7 days). During median follow-up of 29.8 (interquartile range: 14.8-49.9) months, 221 patients had ≥1 recurrence. Initial recurrence was paroxysmal in 169 patients (76%) and persistent in 52 patients (24%). Patients experiencing paroxysmal (versus persistent) initial recurrence were more likely to achieve long-term freedom off antiarrhythmic drugs (hazard ratio, 2.2; 95% confidence interval, 1.5-3.2; P<0.0001), freedom on/off antiarrhythmic drugs (hazard ratio, 2.5; 95% confidence interval, 1.6-3.8; P<0.0001), and arrhythmia control (hazard ratio, 5.2; 95% confidence interval, 2.9-9.2; P<0.0001) after last ablation. In patients with persistent and long-standing persistent AF, limited ablation targeting pulmonary veins and documented nonpulmonary vein triggers improves the maintenance of sinus rhythm and reverses disease progression. Transformation to paroxysmal AF after initial ablation may be a step toward long-term freedom from recurrent arrhythmia. © 2016 American Heart Association, Inc.

Crosstalk between the Unfolded Protein Response and NF-κB-Mediated Inflammation in the Progression of Chronic Kidney Disease

PubMed Central

Cruz, Gaile L.; Dickhout, Jeffrey G.

2015-01-01

The chronic inflammatory response is emerging as an important therapeutic target in progressive chronic kidney disease. A key transcription factor in the induction of chronic inflammation is NF-κB. Recent studies have demonstrated that sustained activation of the unfolded protein response (UPR) can initiate this NF-κB signaling phenomenon and thereby induce chronic kidney disease progression. A key factor influencing chronic kidney disease progression is proteinuria and this condition has now been demonstrated to induce sustained UPR activation. This review details the crosstalk between the UPR and NF-κB pathways as pertinent to chronic kidney disease. We present potential tools to study this phenomenon as well as potential therapeutics that are emerging to regulate the UPR. These therapeutics may prevent inflammation specifically induced in the kidney due to proteinuria-induced sustained UPR activation. PMID:25977931

Persistent Salmonellosis Causes Pancreatitis in a Murine Model of Infection

PubMed Central

Hall, Jason C.; Thotakura, Gangadaar; Crawford, Howard C.; van der Velden, Adrianus W. M.

2014-01-01

Pancreatitis, a known risk factor for the development of pancreatic ductal adenocarcinoma, is a serious, widespread medical condition usually caused by alcohol abuse or gallstone-mediated ductal obstruction. However, many cases of pancreatitis are of an unknown etiology. Pancreatitis has been linked to bacterial infection, but causality has yet to be established. Here, we found that persistent infection of mice with the bacterial pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) was sufficient to induce pancreatitis reminiscent of the human disease. Specifically, we found that pancreatitis induced by persistent S. Typhimurium infection was characterized by a loss of pancreatic acinar cells, acinar-to-ductal metaplasia, fibrosis and accumulation of inflammatory cells, including CD11b+ F4/80+, CD11b+ Ly6Cint Ly6G+ and CD11b+ Ly6Chi Ly6G− cells. Furthermore, we found that S. Typhimurium colonized and persisted in the pancreas, associated with pancreatic acinar cells in vivo, and could invade cultured pancreatic acinar cells in vitro. Thus, persistent infection of mice with S. Typhimurium may serve as a useful model for the study of pancreatitis as it relates to bacterial infection. Increased knowledge of how pathogenic bacteria can cause pancreatitis will provide a more integrated picture of the etiology of the disease and could lead to the development of new therapeutic approaches for treatment and prevention of pancreatitis and pancreatic ductal adenocarcinoma. PMID:24717768

Hyperinsulinemia and hyperfiltration in renal transplantation.

PubMed

Porrini, Esteban; Bayes, Beatriz; Diaz, Juan M; Ibernon, Meritxell; Benitez, Rocio; Domínguez, Rosa; Moreno, Juan Manuel; Delgado, Patricia; Lauzurica, Ricardo; Silva, Irene; Moreso, Francisco; Lampreabe, Ildefonso; Arias, Manuel; Osuna, Antonio; Torres, Armando

2009-01-27

Insulin-resistance hyperinsulinemia is a novel risk factor for renal disease in the general population. Glomerular hyperfiltration has been proposed as an early consequence of hyperinsulinemia. In this multicenter cohort study, we analyzed 202 patients without diabetes before or after renal transplantation during the first posttransplant year. Insulin was measured at 3 and 12 months. The majority of patients (91%) were on calcineurin inhibitors. Patients were classified as with persistent normo or hyperinsulinemia when situated below or above the median value of insulin (3 months: 9 muU/mL; 12 months: 8.74 muU/mL) at both periods. The 3 to 12 months percent change in calculated creatinine clearance (3-12 months DeltaCrCL) was calculated. Patients with persistent hyperinsulinemia showed a higher increase in 3 to 12 months DeltaCrCL compared with those with persistent normoinsulinemia (12% [-20/40] vs. -0.03% [-12/18], P=0.035). We performed a multivariate linear regression analysis with the 3 to 12 months DeltaCrCL as the dependent variable and different factors that may induce hyperfiltration, including persistent hyperinsulinemia, as covariates. Persistent hyperinsulinemia was a risk factor for increased CrCL (beta 0.09, 95% CI 0.07/0.12, P=0.035). In nondiabetic recipients during the first posttransplant year, hyperinsulinemia induced increments in CrCL. As this may herald future renal dysfunction, hyperinsulinemia should not be ignored as a potential target in this population.

The role of hepatocyte nuclear factor 4-alpha in perfluorooctanoic and perfluorooctanesulfonic acid-induced hepatocellular dysfunction

EPA Science Inventory

Perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), chemicals present in a multitude of consumer products, are persistent organic pollutants. Both compounds induce hepatotoxic effects in rodents, including steatosis, hepatomegaly and liver cancer. The mechani...

A Novel Model of Asymptomatic Plasmodium Parasitemia That Recapitulates Elements of the Human Immune Response to Chronic Infection

PubMed Central

Baccarella, Alyssa; Craft, Joshua F.; Boyle, Michelle J.; McIntyre, Tara I.; Wood, Matthew D.; Thorn, Kurt S.; Anidi, Chioma; Bayat, Aqieda; Chung, Me Ree; Hamburger, Rebecca; Kim, Chris Y.; Pearman, Emily; Pham, Jennifer; Tang, Jia J.; Boon, Louis; Kamya, Moses R.; Dorsey, Grant; Feeney, Margaret E.; Kim, Charles C.

2016-01-01

In humans, immunity to Plasmodium sp. generally takes the form of protection from symptomatic malaria (i.e., 'clinical immunity') rather than infection ('sterilizing immunity'). In contrast, mice infected with Plasmodium develop sterilizing immunity, hindering progress in understanding the mechanistic basis of clinical immunity. Here we present a novel model in which mice persistently infected with P. chabaudi exhibit limited clinical symptoms despite sustaining patent parasite burdens for many months. Characterization of immune responses in persistently infected mice revealed development of CD4+ T cell exhaustion, increased production of IL-10, and expansion of B cells with an atypical surface phenotype. Additionally, persistently infected mice displayed a dramatic increase in circulating nonclassical monocytes, a phenomenon that we also observed in humans with both chronic Plasmodium exposure and asymptomatic infection. Following pharmacological clearance of infection, previously persistently infected mice could not control a secondary challenge, indicating that persistent infection disrupts the sterilizing immunity that typically develops in mouse models of acute infection. This study establishes an animal model of asymptomatic, persistent Plasmodium infection that recapitulates several central aspects of the immune response in chronically exposed humans. As such, it provides a novel tool for dissection of immune responses that may prevent development of sterilizing immunity and limit pathology during infection. PMID:27583554

Chemically engineered persistent luminescence nanoprobes for bioimaging

PubMed Central

Lécuyer, Thomas; Teston, Eliott; Ramirez-Garcia, Gonzalo; Maldiney, Thomas; Viana, Bruno; Seguin, Johanne; Mignet, Nathalie; Scherman, Daniel; Richard, Cyrille

2016-01-01

Imaging nanoprobes are a group of nanosized agents developed for providing improved contrast for bioimaging. Among various imaging probes, optical sensors capable of following biological events or progresses at the cellular and molecular levels are actually actively developed for early detection, accurate diagnosis, and monitoring of the treatment of diseases. The optical activities of nanoprobes can be tuned on demand by chemists by engineering their composition, size and surface nature. This review will focus on researches devoted to the conception of nanoprobes with particular optical properties, called persistent luminescence, and their use as new powerful bioimaging agents in preclinical assays. PMID:27877248

Chicken-specific kinome array reveals that Salmonella enterica serovar Enteritidis modulates host immune signaling pathways in the cecum to establish a persistence infection

USDA-ARS?s Scientific Manuscript database

Non-typhoidal Salmonella enterica induce an early, short-lived, pro-inflammatory response in chickens that is asymptomatic of clinical disease and results in a persistent colonization of the gastrointestinal (GI) tract that transmits infections to naïve hosts via fecal shedding of bacteria. The und...

Inflammatory Asthma Phenotype Discrimination Using an Electronic Nose Breath Analyzer.

PubMed

Plaza, V; Crespo, A; Giner, J; Merino, J L; Ramos-Barbón, D; Mateus, E F; Torrego, A; Cosio, B G; Agustí, A; Sibila, O

2015-01-01

Patients with persistent asthma have different inflammatory phenotypes. The electronic nose is a new technology capable of distinguishing volatile organic compound (VOC) breath-prints in exhaled breath. The aim of the study was to investigate the capacity of electronic nose breath-print analysis to discriminate between different inflammatory asthma phenotypes (eosinophilic, neutrophilic, paucigranulocytic) determined by induced sputum in patients with persistent asthma. Fifty-two patients with persistent asthma were consecutively included in a cross-sectional proof-of-concept study. Inflammatory asthma phenotypes (eosinophilic, neutrophilic and paucigranulocytic) were recognized by inflammatory cell counts in induced sputum. VOC breath-prints were analyzed using the electronic nose Cyranose 320 and assessed by discriminant analysis on principal component reduction, resulting in cross-validated accuracy values. Receiver operating characteristic (ROC) curves were calculated. VOC breath-prints were different in eosinophilic asthmatics compared with both neutrophilic asthmatics (accuracy 73%; P=.008; area under ROC, 0.92) and paucigranulocytic asthmatics (accuracy 74%; P=.004; area under ROC, 0.79). Likewise, neutrophilic and paucigranulocytic breath-prints were also different (accuracy 89%; P=.001; area under ROC, 0.88). An electronic nose can discriminate inflammatory phenotypes in patients with persistent asthma in a regular clinical setting. ClinicalTrials.gov identifier: NCT02026336.

Persistent structural adaptation in the lungs of guinea pigs raised at high altitude.

PubMed

Ravikumar, Priya; Bellotto, Dennis J; Hsia, Connie C W

2015-03-01

Laboratory guinea pigs raised at high altitude (HA, 3800 m) for up to 6 mo exhibit enhanced alveolar growth and remodeling (Hsia et al., 2005. Resp. Physiol. Neurobiol. 147, 105-115). To determine whether initial HA-induced structural enhancement persists following return to intermediate altitude (IA), we raised weanling guinea pigs at (a) HA for 11-12 mo, (b) IA (1200 m) for 11-12 mo, and (c) HA for 4 mo followed by IA for 7-8 mo (HA-to-IA). Morphometric analysis was performed under light and electron microscopy. Body weight and lung volume were similar among groups. Prolonged HA residence increased alveolar epithelium and interstitium volumes while reducing alveolar-capillary blood volume. The HA-induced gains in type-1 epithelium volume and alveolar surface area were no longer present following return to IA whereas volume increases in type-2 epithelium and interstitium and the reduction in alveolar duct volume persisted. Results demonstrate persistent augmentation of some but not all aspects of lung structure throughout prolonged HA residence, with partial reversibility following re-acclimatization to IA. Copyright © 2014 Elsevier B.V. All rights reserved.

A demonstration of athermal effects of continuous microwave irradiation on the growth and antibiotic sensitivity of Pseudomonas aeruginosa PAO1.

PubMed

Nakouti, Ismini; Hobbs, Glyn; Teethaisong, Yothin; Phipps, David

2017-01-01

Stress, caused by exposure to microwaves (2.45 GHz) at constant temperature (37 ± 0.5°C), alters the growth profile of Pseudomonas aeruginosa PAO1. In the absence of microwave treatment a simple, highly reproducible growth curve was observed over 24 h or more. Microwave treatment caused no reduction in growth during the first 6 h, but at a later stage (>12 h) the growth was markedly different to the controls. Secondary growth, typical of the presence of persisters clearly became apparent, as judged by both the dissolved oxygen and the cell density profiles. These treated cells showed distinct morphological changes, but on regrowth these cells reverted to normal. The microwave induced persisters were subject to antibiotic challenge (tobramycin) and showed increased sensitivity when compared to the unstressed planktonic cells. This is in marked contrast to antibiotic induced persisters which show increased resistance. This provides evidence for both a nonthermal effect of microwaves and a previously undescribed route to a novel form of antibiotic susceptible persister cells. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 33:37-44, 2017. © 2016 American Institute of Chemical Engineers.

The Transition of Acute Postoperative Pain to Chronic Pain: An Integrative Overview of Research on Mechanisms.

PubMed

Chapman, C Richard; Vierck, Charles J

2017-04-01

The nature of the transition from acute to chronic pain still eludes explanation, but chronic pain resulting from surgery provides a natural experiment that invites clinical epidemiological investigation and basic scientific inquiry into the mechanisms of this transition. The primary purpose of this article is to review current knowledge and hypotheses on the transition from acute to persistent postsurgical pain, summarizing literature on clinical epidemiological studies of persistent postsurgical pain development, as well as basic neurophysiological studies targeting mechanisms in the periphery, spinal cord, and brain. The second purpose of this article is to integrate theory, information, and causal reasoning in these areas. Conceptual mapping reveals 5 classes of hypotheses pertaining to pain. These propose that chronic pain results from: 1) persistent noxious signaling in the periphery; 2) enduring maladaptive neuroplastic changes at the spinal dorsal horn and/or higher central nervous system structures reflecting a multiplicity of factors, including peripherally released neurotrophic factors and interactions between neurons and microglia; 3) compromised inhibitory modulation of noxious signaling in medullary-spinal pathways; 4) descending facilitatory modulation; and 5) maladaptive brain remodeling in function, structure, and connectivity. The third purpose of this article is to identify barriers to progress and review opportunities for advancing the field. This review reveals a need for a concerted, strategic effort toward integrating clinical epidemiology, basic science research, and current theory about pain mechanisms to hasten progress toward understanding, managing, and preventing persistent postsurgical pain. The development of chronic pain after surgery is a major clinical problem that provides an opportunity to study the transition from acute to chronic pain at epidemiologic and basic science levels. Strategic, coordinated, multidisciplinary research efforts targeting mechanisms of pain chronification can to help minimize or eliminate persistent postsurgical pain. Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.

Magnitude of increase in QTc interval after initiation of dofetilide in patients with persistent atrial fibrillation is associated with increased rates of pharmacological cardioversion and long-term freedom from recurrent atrial fibrillation.

PubMed

Huang, Henry D; Waks, Jonathan W; Steinhaus, Daniel A; Zimetbaum, Peter

2016-07-01

Dofetilide is a class III antiarrhythmic drug approved for the treatment of atrial fibrillation (AF). Dofetilide-induced corrected QT (QTc) interval prolongation is a surrogate for the degree of drug effect, but the relationships between drug-induced QTc interval prolongation, pharmacological cardioversion (PCV), and freedom from recurrent AF are unclear. The purpose of this study was to assess associations between QTc interval change during dofetilide initiation and PCV and long-term AF recurrence. We performed retrospective analyses of a prospective cohort of patients with AF admitted for dofetilide initiation between 2001 and 2014. Clinical characteristics and electrocardiographic variables were assessed. We evaluated outcomes of successful PCV in patients with persistent AF and time to recurrence of AF in patients with paroxysmal and persistent AF. During the study, 243 patients with persistent AF and 176 patients with paroxysmal AF initiated dofetilide. PCV occurred in 93/243 (41.7%) patients with persistent AF. After multivariable adjustment, QTc interval change was associated with PCV (adjusted odds ratio 1.21; P = .003 per 10-ms QTc increase). Inhospital QTc interval change was associated with long-term freedom from AF in patients with persistent AF (adjusted hazard ratio 0.92; P = .011 at 4 years per 10-ms QTc increase), but not in patients with paroxysmal AF. In patients with persistent AF, PCV was also associated with long-term freedom from recurrent AF (adjusted hazard ratio 0.62; P = .009 at 4 years). The magnitude of QTc interval prolongation during dofetilide initiation is an independent predictor of successful PCV and long-term freedom from arrhythmia in patients with persistent AF. QTc interval change had no association with AF recurrence in patients with paroxysmal AF, suggesting that different mechanisms of arrhythmogenesis may be operant in different AF types. Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Persistent in vivo cytogenetic effects of radioiodine therapy: a 21-year follow-up study using multicolor FISH.

PubMed

Livingston, Gordon K; Escalona, Maria; Foster, Alvis; Balajee, Adayabalam S

2018-01-01

Our previous studies demonstrated the cytogenetic effects in the peripheral blood lymphocytes of a 34-year-old male patient who received ablative radioactive 131iodine therapy (RIT) on two different occasions in 1992 and 1994. Assessment of RIT-induced chromosomal damage by the cytokinesis-blocked micronucleus assay (CBMN) showed the persistence of elevated micronucleus frequency in this patient for more than two decades since the first RIT. Subsequent cytogenetic analysis performed in 2012 revealed both stable and unstable aberrations, whose frequencies were higher than the baseline reported in the literature. Here, we report the findings of our recent cytogenetic analysis peformed in 2015 on this patient using the multicolor fluorescence in situ hybridization (mFISH) technique. Our results showed that both reciprocal and non-reciprocal translocations persisted at higher frequencies in the patient than those reported in 2012. Persistence of structural aberrations for more than two decades indicate that these aberrations might have originated from long-lived T-lymphocytes or hematopoietic stem cells. Our study suggests that the long-term persistence of chromosome translocations in circulating lymphocytes can be useful for monitoring the extent of RIT-induced chromosomal instability several years after exposure and for estimating the cumulative absorbed dose after multiple RITs for retrospective biodosimetry purposes. This is perhaps the first and longest follow-up study documenting the persistence of cytogenetic damage for 21 years after internal radiation exposure. © The Author 2017. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

HABITAT SELECTION MODELS TO ACCOUNT FOR SEASONAL PERSISTENCE IN RADIO TELEMETRY DATA. (R829095C001)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

Reframing Retention Strategy: A Focus on Progress

ERIC Educational Resources Information Center

Spittle, Brian

2013-01-01

Few words have dominated the vocabulary of college retention as has the word "persistence." Many institutions still struggle to engage faculty and administrators in building campuswide retention efforts, to find the organizational levers that translate the abstractions and complexities of retention theory into scalable and durable initiatives, and…

Authentic Engagement for Promoting a College-Going Culture

ERIC Educational Resources Information Center

Collins, William

2011-01-01

The United States has lost ground internationally as a leader in educational attainment. Personal empowerment, national economic progress, and democratic ideals are enhanced through education, yet inequalities persist in the educational attainment of certain groups, such as low-income families or underrepresented minorities. Because the evolving…

High Impact Practices: Student Engagement and Retention

ERIC Educational Resources Information Center

Bonet, Giselle; Walters, Barbara R.

2016-01-01

Community college students face special challenges that can impede their academic progress, resulting in lower grades and persistence than students in selective four-year colleges. Kingsborough Community College in Brooklyn, New York, successfully addresses these challenges with learning communities: small cohorts of students in a blocked program…

PERSISTENCE OF TETRACHLORODIBENZO-P-DIOXIN IN SOIL: TIMES BEACH CASE STUDY. (R825549C032)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

Decisions, Decisions, Decisions: Using Data to Make Instructional Decisions for Struggling Readers

ERIC Educational Resources Information Center

Filderman, Marissa J.; Toste, Jessica R.

2018-01-01

Reading proficiency is fundamental to school success. However, up to 50% of students with reading disabilities are not making adequate progress. Students who demonstrate persistent and severe reading difficulties require increasingly intensive instruction individualized to meet their instructional needs Individualizing instruction with…

Expression of cyclin D{sub 1} during endotoxin-induced aleveolar type II cell hyperplasia in rat lung and the detection of apoptotic cells during the remodeling process

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

Tesfaigzi, J.; Wood, M.B.; Johnson, N.F.

Our studies have shown that endotoxin intratracheally instilled into the rat lung induces proliferation of alveolar type II cells. In that study, the alveolar type II cells. In that study, the alveolar type II cell hyperplasia occurred 2 d after instillation of endotoxin and persisted for a further 2 d. After hyperplasia, the lung remodeled and returned to a normal state within 24-48 h. Understanding the mechanisms involved in the remodeling process of this transient hyperplasia may be useful to identify molecular changes that are altered in neoplasia. The purpose of the present study was to corroborate induction of epithelialmore » cell hyperplasia by endotoxin and to delineate mechanisms involved in tissue remodeling after endotoxin-induced alveolar type II cell hyperplasia. In conclusion, immonostaining with cyclin D1 and cytokeratin shows that endotoxin induced epithelial cell proliferation and resulted in hyperplasia in the lung which persisted through 4 d post-instillation.« less

Economic impact of disease progression in follicular non-Hodgkin lymphoma

PubMed Central

Beveridge, Roy; Satram-Hoang, Sacha; Sail, Kavita; Darragh, Joseph; Chen, Clara; Forsyth, Michael; Reyes, Carolina

2011-01-01

Using a retrospective claims database, we estimated the economic costs of progression among patients with follicular non-Hodgkin lymphoma (f-NHL) treated in an outpatient community-based setting. Patients with f-NHL who received care between 1 July 2006 and 31 December 2009 were categorized into two cohorts based on whether they experienced progressive disease (PD) or not. Costs per patient per month (PPPM) were compared between patients with PD versus non-PD. Follow-up time was censored at the last entry for disease status or 6 months after the date of remission/stable disease or progression. Of the 1002 patients with f-NHL identified, 268 progressed and 734 did not. The mean overall costs PPPM over the 6-month follow-up period were significantly higher for patients with PD versus non-PD ($3527 vs. $860; difference = $2667; p < 0.001). This cost difference persisted within all resource categories evaluated. Results of this study indicate that therapies which delay progression for patients with f-NHL may result in potential cost savings. PMID:21745172

Caffeine stabilizes Cdc25 independently of Rad3 in S chizosaccharomyces pombe contributing to checkpoint override

PubMed Central

Alao, John P; Sjölander, Johanna J; Baar, Juliane; Özbaki-Yagan, Nejla; Kakoschky, Bianca; Sunnerhagen, Per

2014-01-01

Cdc25 is required for Cdc2 dephosphorylation and is thus essential for cell cycle progression. Checkpoint activation requires dual inhibition of Cdc25 and Cdc2 in a Rad3-dependent manner. Caffeine is believed to override activation of the replication and DNA damage checkpoints by inhibiting Rad3-related proteins in both S chizosaccharomyces pombe and mammalian cells. In this study, we have investigated the impact of caffeine on Cdc25 stability, cell cycle progression and checkpoint override. Caffeine induced Cdc25 accumulation in S . pombe independently of Rad3. Caffeine delayed cell cycle progression under normal conditions but advanced mitosis in cells treated with replication inhibitors and DNA-damaging agents. In the absence of Cdc25, caffeine inhibited cell cycle progression even in the presence of hydroxyurea or phleomycin. Caffeine induces Cdc25 accumulation in S . pombe by suppressing its degradation independently of Rad3. The induction of Cdc25 accumulation was not associated with accelerated progression through mitosis, but rather with delayed progression through cytokinesis. Caffeine-induced Cdc25 accumulation appears to underlie its ability to override cell cycle checkpoints. The impact of Cdc25 accumulation on cell cycle progression is attenuated by Srk1 and Mad2. Together our findings suggest that caffeine overrides checkpoint enforcement by inducing the inappropriate nuclear localization of Cdc25. PMID:24666325

Sporadic on/off switching of HTLV-1 Tax expression is crucial to maintain the whole population of virus-induced leukemic cells

PubMed Central

Mahgoub, Mohamed; Iwami, Shingo; Nakaoka, Shinji; Koizumi, Yoshiki; Shimura, Kazuya; Matsuoka, Masao

2018-01-01

Viruses causing chronic infection artfully manipulate infected cells to enable viral persistence in vivo under the pressure of immunity. Human T-cell leukemia virus type 1 (HTLV-1) establishes persistent infection mainly in CD4+ T cells in vivo and induces leukemia in this subset. HTLV-1–encoded Tax is a critical transactivator of viral replication and a potent oncoprotein, but its significance in pathogenesis remains obscure due to its very low level of expression in vivo. Here, we show that Tax is expressed in a minor fraction of leukemic cells at any given time, and importantly, its expression spontaneously switches between on and off states. Live cell imaging revealed that the average duration of one episode of Tax expression is ∼19 hours. Knockdown of Tax rapidly induced apoptosis in most cells, indicating that Tax is critical for maintaining the population, even if its short-term expression is limited to a small subpopulation. Single-cell analysis and computational simulation suggest that transient Tax expression triggers antiapoptotic machinery, and this effect continues even after Tax expression is diminished; this activation of the antiapoptotic machinery is the critical event for maintaining the population. In addition, Tax is induced by various cytotoxic stresses and also promotes HTLV-1 replication. Thus, it seems that Tax protects infected cells from apoptosis and increases the chance of viral transmission at a critical moment. Keeping the expression of Tax minimal but inducible on demand is, therefore, a fundamental strategy of HTLV-1 to promote persistent infection and leukemogenesis. PMID:29358408

PKMζ Inhibition Reverses Learning-Induced Increases in Hippocampal Synaptic Strength and Memory during Trace Eyeblink Conditioning

PubMed Central

Madroñal, Noelia; Gruart, Agnès; Sacktor, Todd C.; Delgado-García, José M.

2010-01-01

A leading candidate in the process of memory formation is hippocampal long-term potentiation (LTP), a persistent enhancement in synaptic strength evoked by the repetitive activation of excitatory synapses, either by experimental high-frequency stimulation (HFS) or, as recently shown, during actual learning. But are the molecular mechanisms for maintaining synaptic potentiation induced by HFS and by experience the same? Protein kinase Mzeta (PKMζ), an autonomously active atypical protein kinase C isoform, plays a key role in the maintenance of LTP induced by tetanic stimulation and the storage of long-term memory. To test whether the persistent action of PKMζ is necessary for the maintenance of synaptic potentiation induced after learning, the effects of ZIP (zeta inhibitory peptide), a PKMζ inhibitor, on eyeblink-conditioned mice were studied. PKMζ inhibition in the hippocampus disrupted both the correct retrieval of conditioned responses (CRs) and the experience-dependent persistent increase in synaptic strength observed at CA3-CA1 synapses. In addition, the effects of ZIP on the same associative test were examined when tetanic LTP was induced at the hippocampal CA3-CA1 synapse before conditioning. In this case, PKMζ inhibition both reversed tetanic LTP and prevented the expected LTP-mediated deleterious effects on eyeblink conditioning. Thus, PKMζ inhibition in the CA1 area is able to reverse both the expression of trace eyeblink conditioned memories and the underlying changes in CA3-CA1 synaptic strength, as well as the anterograde effects of LTP on associative learning. PMID:20454458

Multiple rare opportunistic and pathogenic fungi in persistent foot skin infection.

PubMed

Chan, Giek Far; Sinniah, Sivaranjini; Idris, Tengku Idzzan Nadzirah Tengku; Puad, Mohamad Safwan Ahmad; Abd Rahman, Ahmad Zuhairi

2013-03-01

Persistent superficial skin infection caused by multiple fungi is rarely reported. Recently, a number of fungi, both opportunistic and persistent in nature were isolated from the foot skin of a 24-year old male in Malaysia. The fungi were identified as Candida parapsilosis, Rhodotorula mucilaginosa, Phoma spp., Debaryomyces hansenii, Acremonium spp., Aureobasidium pullulans and Aspergillus spp., This is the first report on these opportunistic strains were co-isolated from a healthy individual who suffered from persistent foot skin infection which was diagnosed as athlete's foot for more than 12 years. Among the isolated fungi, C. parapsilosis has been an increasingly common cause of skin infections. R. mucilaginosa and D. hansenii were rarely reported in cases of skin infection. A. pullulans, an emerging fungal pathogen was also being isolated in this case. Interestingly, it was noted that C. parapsilosis, R. mucilaginosa, D. hansenii and A. pullulans are among the common halophiles and this suggests the association of halotolerant fungi in causing persistent superficial skin infection. This discovery will shed light on future research to explore on effective treatment for inhibition of pathogenic halophiles as well as to understand the interaction of multiple fungi in the progress of skin infection.

Long persistence of rigor mortis at constant low temperature.

PubMed

Varetto, Lorenzo; Curto, Ombretta

2005-01-06

We studied the persistence of rigor mortis by using physical manipulation. We tested the mobility of the knee on 146 corpses kept under refrigeration at Torino's city mortuary at a constant temperature of +4 degrees C. We found a persistence of complete rigor lasting for 10 days in all the cadavers we kept under observation; and in one case, rigor lasted for 16 days. Between the 11th and the 17th days, a progressively increasing number of corpses showed a change from complete into partial rigor (characterized by partial bending of the articulation). After the 17th day, all the remaining corpses showed partial rigor and in the two cadavers that were kept under observation "à outrance" we found the absolute resolution of rigor mortis occurred on the 28th day. Our results prove that it is possible to find a persistence of rigor mortis that is much longer than the expected when environmental conditions resemble average outdoor winter temperatures in temperate zones. Therefore, this datum must be considered when a corpse is found in those environmental conditions so that when estimating the time of death, we are not misled by the long persistence of rigor mortis.

Insights on persistent airway infection by non-typeable Haemophilus influenzae in chronic obstructive pulmonary disease

PubMed Central

Ahearn, Christian P.; Gallo, Mary C.

2017-01-01

Abstract Non-typeable Haemophilus influenzae (NTHi) is the most common bacterial cause of infection of the lower airways in adults with chronic obstructive pulmonary disease (COPD). Infection of the COPD airways causes acute exacerbations, resulting in substantial morbidity and mortality. NTHi has evolved multiple mechanisms to establish infection in the hostile environment of the COPD airways, allowing the pathogen to persist in the airways for months to years. Persistent infection of the COPD airways contributes to chronic airway inflammation that increases symptoms and accelerates the progressive loss of pulmonary function, which is a hallmark of the disease. Persistence mechanisms of NTHi include the expression of multiple redundant adhesins that mediate binding to host cellular and extracellular matrix components. NTHi evades host immune recognition and clearance by invading host epithelial cells, forming biofilms, altering gene expression and displaying surface antigenic variation. NTHi also binds host serum factors that confer serum resistance. Here we discuss the burden of COPD and the role of NTHi infections in the course of the disease. We provide an overview of NTHi mechanisms of persistence that allow the pathogen to establish a niche in the hostile COPD airways. PMID:28449098

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

Malaviya, Rama; Venosa, Alessandro; Hall, LeRoy

Nitrogen mustard (NM) is a toxic vesicant known to cause damage to the respiratory tract. Injury is associated with increased expression of inducible nitric oxide synthase (iNOS). In these studies we analyzed the effects of transient inhibition of iNOS using aminoguanidine (AG) on NM-induced pulmonary toxicity. Rats were treated intratracheally with 0.125 mg/kg NM or control. Bronchoalveolar lavage fluid (BAL) and lung tissue were collected 1 d–28 d later and lung injury, oxidative stress and fibrosis assessed. NM exposure resulted in progressive histopathological changes in the lung including multifocal lesions, perivascular and peribronchial edema, inflammatory cell accumulation, alveolar fibrin deposition,more » bronchiolization of alveolar septal walls, and fibrosis. This was correlated with trichrome staining and expression of proliferating cell nuclear antigen (PCNA). Expression of heme oxygenase (HO)-1 and manganese superoxide dismutase (Mn-SOD) was also increased in the lung following NM exposure, along with levels of protein and inflammatory cells in BAL, consistent with oxidative stress and alveolar-epithelial injury. Both classically activated proinflammatory (iNOS{sup +} and cyclooxygenase-2{sup +}) and alternatively activated profibrotic (YM-1{sup +} and galectin-3{sup +}) macrophages appeared in the lung following NM administration; this was evident within 1 d, and persisted for 28 d. AG administration (50 mg/kg, 2 ×/day, 1 d–3 d) abrogated NM-induced injury, oxidative stress and inflammation at 1 d and 3 d post exposure, with no effects at 7 d or 28 d. These findings indicate that nitric oxide generated via iNOS contributes to acute NM-induced lung toxicity, however, transient inhibition of iNOS is not sufficient to protect against pulmonary fibrosis. -- Highlights: ► Nitrogen mustard (NM) induces acute lung injury and fibrosis. ► Pulmonary toxicity is associated with increased expression of iNOS. ► Transient inhibition of iNOS attenuates acute lung injury induced by NM.« less

Decrease in fruit moisture content heralds and might launch the onset of ripening processes.

PubMed

Frenkel, Chaim; Hartman, Thomas G

2012-10-01

It is known that fruit ripening is a genetically programmed event but it is not entirely clear what metabolic cue(s) stimulate the onset of ripening, ethylene action notwithstanding. Here, we examined the conjecture that fruit ripening might be evoked by an autonomously induced decrease in tissue water status. We found decline in water content occurring at the onset of ripening in climacteric and nonclimacteric fruit, suggesting that this phenomenon might be universal. This decline in water content persisted throughout the ripening process in some fruit, whereas in others it reversed during the progression of the ripening process. Applied ethylene also induced a decrease in water content in potato (Solanum tuberosum) tubers. In ethylene-mutant tomato (Solanum lycopersicum) fruit (antisense to1-aminocyclopropane carboxylate synthase), cold-induced decline in water content stimulated onset of ripening processes apparently independently of ethylene action, suggesting cause-and-effect relationship between decreasing water content and onset of ripening. The decline in tissue water content, occurring naturally or induced by ethylene, was strongly correlated with a decrease in hydration (swelling) efficacy of cell wall preparations suggesting that hydration dynamics of cell walls might account for changes in tissue moisture content. Extent of cell wall swelling was, in turn, related to the degree of oxidative cross-linking of wall-bound phenolic acids, suggesting that oxidant-induced wall restructuring might mediate cell wall and, thus, fruit tissue hydration status. We propose that oxidant-induced cell wall remodeling and consequent wall dehydration might evoke stress signaling for the onset of ripening processes. This study suggests that decline in fruit water content is an early event in fruit ripening. This information may be used to gauge fruit maturity for appropriate harvest date and for processing. Control of fruit hydration state might be used to regulate the onset of fruit ripening. © 2012 Institute of Food Technologists®

Cytisine modulates chronic voluntary ethanol consumption and ethanol-induced striatal up-regulation of ΔFosB in mice.

PubMed

Sajja, Ravi Kiran; Rahman, Shafiqur

2013-06-01

Chronic administration of ethanol induces persistent accumulation of ΔFosB, an important transcription factor, in the midbrain dopamine system. This process underlies the progression to addiction. Previously, we have shown that cytisine, a neuronal nicotinic acetylcholine receptor (nAChR) partial agonist, reduces various ethanol-drinking behaviors and ethanol-induced striatal dopamine function. However, the effects of cytisine on chronic ethanol drinking and ethanol-induced up-regulation of striatal ΔFosB are not known. Therefore, we examined the effects of cytisine on chronic voluntary ethanol consumption and associated striatal ΔFosB up-regulation in C57BL/6J mice using behavioral and biochemical methods. Following the chronic voluntary consumption of 15% (v/v) ethanol under a 24-h two-bottle choice intermittent access (IA; 3 sessions/week) or continuous access (CA; 24 h/d and 7 d/week) paradigm, mice received repeated intraperitoneal injections of saline or cytisine (0.5 or 3.0 mg/kg). Ethanol and water intake were monitored for 24 h post-treatment. Pretreatment with cytisine (0.5 or 1.5 mg/kg) significantly reduced ethanol consumption and preference in both paradigms at 2 h and 24 h post-treatment. The ΔFosB levels in the ventral and dorsal striatum were determined by Western blotting 18-24 h after the last point of ethanol access. In addition, cytisine (0.5 mg/kg) significantly attenuated up-regulation of ΔFosB in the ventral and dorsal striatum following chronic ethanol consumption in IA and CA paradigms. The results indicate that cytisine modulates chronic voluntary ethanol consumption and reduces ethanol-induced up-regulation of striatal ΔFosB. Further, the data suggest a critical role of nAChRs in chronic ethanol-induced neurochemical adaptations associated with ethanol addiction. Copyright © 2013 Elsevier Inc. All rights reserved.

Increasing Optimism Protects Against Pain-Induced Impairment in Task-Shifting Performance.

PubMed

Boselie, Jantine J L M; Vancleef, Linda M G; Peters, Madelon L

2017-04-01

Persistent pain can lead to difficulties in executive task performance. Three core executive functions that are often postulated are inhibition, updating, and shifting. Optimism, the tendency to expect that good things happen in the future, has been shown to protect against pain-induced performance deterioration in executive function updating. This study tested whether this protective effect of a temporary optimistic state by means of a writing and visualization exercise extended to executive function shifting. A 2 (optimism: optimism vs no optimism) × 2 (pain: pain vs no pain) mixed factorial design was conducted. Participants (N = 61) completed a shifting task once with and once without concurrent painful heat stimulation after an optimism or neutral manipulation. Results showed that shifting performance was impaired when experimental heat pain was applied during task execution, and that optimism counteracted pain-induced deterioration in task-shifting performance. Experimentally-induced heat pain impairs shifting task performance and manipulated optimism or induced optimism counteracted this pain-induced performance deterioration. Identifying psychological factors that may diminish the negative effect of persistent pain on the ability to function in daily life is imperative. Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.

The effect of radiation dose on the onset and progression of radiation-induced brain necrosis in the rat model.

PubMed

Hartl, Brad A; Ma, Htet S W; Hansen, Katherine S; Perks, Julian; Kent, Michael S; Fragoso, Ruben C; Marcu, Laura

2017-07-01

To provide a comprehensive understanding of how the selection of radiation dose affects the temporal and spatial progression of radiation-induced necrosis in the rat model. Necrosis was induced with a single fraction of radiation exposure, at doses ranging between 20 and 60 Gy, to the right hemisphere of 8-week-old Fischer rats from a linear accelerator. The development and progression of necrosis in the rats was monitored and quantified every other week with T1- and T2-weighted gadolinium contrast-enhanced MRI studies. The time to onset of necrosis was found to be dose-dependent, but after the initial onset, the necrosis progression rate and total volume generated was constant across different doses ranging between 30 and 60 Gy. Radiation doses less than 30 Gy did not develop necrosis within 33 weeks after treatment, indicating a dose threshold existing between 20 and 30 Gy. The highest dose used in this study led to the shortest time to onset of radiation-induced necrosis, while producing comparable disease progression dynamics after the onset. Therefore, for the radiation-induced necrosis rat model using a linear accelerator, the most optimum results were generated from a dose of 60 Gy.

Prolonged Effect of Intensive Therapy on the Risk of Retinopathy Complications in Patients With Type 1 Diabetes Mellitus

PubMed Central

2009-01-01

Objective To examine the persistence of the original treatment effects 10 years after the Diabetes Control and Complications Trial (DCCT) in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. In the DCCT, intensive therapy aimed at near-normal glycemia reduced the risk of microvascular complications of type 1 diabetes mellitus compared with conventional therapy. Methods Retinopathy was evaluated by fundus photography in 1211 subjects at EDIC year 10. Further 3-step progression on the Early Treatment Diabetic Retinopathy Study scale from DCCT closeout was the primary outcome. Results After 10 years of EDIC follow-up, there was no significant difference in mean glycated hemoglobin levels (8.07% vs 7.98%) between the original treatment groups. Nevertheless, compared with the former conventional treatment group, the former intensive group had significantly lower incidences from DCCT close of further retinopathy progression and proliferative retinopathy or worse (hazard reductions, 53%-56%; P<.001). The risk (hazard) reductions at 10 years of EDIC were attenuated compared with the 70% to 71% over the first 4 years of EDIC (P<.001). The persistent beneficial effects of former intensive therapy were largely explained by the difference in glycated hemoglobin levels during DCCT. Conclusion The persistent difference in diabetic retinopathy between former intensive and conventional therapy (“metabolic memory”) continues for at least 10 years but may be waning. PMID:19064853

The Durability of Endoscopic Therapy for Treatment of Barrett's Metaplasia, Dysplasia, and Mucosal Cancer After Nissen Fundoplication.

PubMed

Johnson, Corey S; Louie, Brian E; Wille, Aaron; Dunst, Christy M; Worrell, Stephanie G; DeMeester, Steven R; Reynolds, Jessica; Dixon, Joe; Lipham, John C; Lada, Michal; Peters, Jeffrey H; Watson, Thomas J; Farivar, Alexander S; Aye, Ralph W

2015-05-01

Radiofrequency ablation (RFA) ± endoscopic resection (EMR) is an established treatment strategy for neoplastic Barrett's and intramucosal cancer. Most patients are managed with proton pump inhibitors. The incidence of recurrent Barrett's metaplasia, dysplasia, or cancer after complete eradication is up to 43 % using this strategy. We hypothesize the addition of fundoplication should result in a lower recurrence rates after complete eradication. Multi-institutional retrospective review of patients undergoing endotherapy followed by Nissen fundoplication A total of 49 patients underwent RFA ± EMR followed by Nissen fundoplication. Complete remission of intestinal metaplasia (CR-IM) was achieved in 26 (53 %) patients, complete remission of dysplasia (CR-D) in 16 (33 %) patients, and 7 (14 %) had persistent neoplastic Barrett's. After fundoplication, 18/26 (70 %) remained in CR-IM. An additional 10/16 CR-D achieved CR-IM and 4/7 with persistent dysplasia achieved CR-IM. One patient progressed to LGD while no patient developed HGD or cancer. Endoscopic therapy for Barrett's dysplasia and/or intramucosal cancer followed by fundoplication results in similar durability of CR-IM to patients being managed with PPIs alone after endoscopic therapy. However, fundoplication may be superior in preventing further progression of disease and the development of cancer. Fundoplication is an important strategy to achieve and maintain CR-IM, and facilitate eradication of persistent dysplasia.

Obg and Membrane Depolarization Are Part of a Microbial Bet-Hedging Strategy that Leads to Antibiotic Tolerance.

PubMed

Verstraeten, Natalie; Knapen, Wouter Joris; Kint, Cyrielle Ines; Liebens, Veerle; Van den Bergh, Bram; Dewachter, Liselot; Michiels, Joran Elie; Fu, Qiang; David, Charlotte Claudia; Fierro, Ana Carolina; Marchal, Kathleen; Beirlant, Jan; Versées, Wim; Hofkens, Johan; Jansen, Maarten; Fauvart, Maarten; Michiels, Jan

2015-07-02

Within bacterial populations, a small fraction of persister cells is transiently capable of surviving exposure to lethal doses of antibiotics. As a bet-hedging strategy, persistence levels are determined both by stochastic induction and by environmental stimuli called responsive diversification. Little is known about the mechanisms that link the low frequency of persisters to environmental signals. Our results support a central role for the conserved GTPase Obg in determining persistence in Escherichia coli in response to nutrient starvation. Obg-mediated persistence requires the stringent response alarmone (p)ppGpp and proceeds through transcriptional control of the hokB-sokB type I toxin-antitoxin module. In individual cells, increased Obg levels induce HokB expression, which in turn results in a collapse of the membrane potential, leading to dormancy. Obg also controls persistence in Pseudomonas aeruginosa and thus constitutes a conserved regulator of antibiotic tolerance. Combined, our findings signify an important step toward unraveling shared genetic mechanisms underlying persistence. Copyright © 2015 Elsevier Inc. All rights reserved.

A Small Molecule Polyamine Oxidase Inhibitor Blocks Androgen-Induced Oxidative Stress and Delays Prostate Cancer Progression in the TRAMP Mouse Model

PubMed Central

Basu, Hirak S.; Thompson, Todd A.; Church, Dawn R.; Clower, Cynthia C.; Mehraein-Ghomi, Farideh; Amlong, Corey A.; Martin, Christopher T.; Woster, Patrick M.; Lindstrom, Mary J.; Wilding, George

2009-01-01

High levels of reactive oxygen species (ROS) present in human prostate epithelia are an important etiological factor in prostate cancer (CaP) occurrence, recurrence and progression. Androgen induces ROS production in the prostate by a yet unknown mechanism. Here, to the best of our knowledge, we report for the first time that androgen induces an overexpression of spermidine/spermine N1-acetyltransferase (SSAT), the rate-limiting enzyme in the polyamine oxidation pathway. As prostatic epithelia produce a large excess of polyamines, the androgen-induced polyamine oxidation that produces H2O2 could be a major reason for the high ROS levels in the prostate epithelia. A small molecule polyamine oxidase inhibitor N,N'-butanedienyl butanediamine (MDL 72,527 or CPC-200) effectively blocks androgen-induced ROS production in human CaP cells as well as significantly delays CaP progression and death in animals developing spontaneous CaP. These data demonstrate that polyamine oxidation is not only a major pathway for ROS production in prostate, but inhibiting this pathway also successfully delays prostate cancer progression. PMID:19773450

Chronic Cocaine-Induced H3 Acetylation and Transcriptional Activation of CaMKIIα in the Nucleus Accumbens Is Critical for Motivation for Drug Reinforcement

PubMed Central

Wang, Lei; Lv, Zhigang; Hu, Zhaoyang; Sheng, Jian; Hui, Bin; Sun, Jie; Ma, Lan

2010-01-01

The regulation of gene expression in the brain reward regions is known to contribute to the pathogenesis and persistence of drug addiction. Increasing evidence suggests that the regulation of gene transcription is mediated by epigenetic mechanisms that alter the chromatin structure at specific gene promoters. To better understand the involvement of epigenetic regulation in drug reinforcement properties, rats were subjected to cocaine self-administration paradigm. Daily histone deacetylase (HDAC) inhibitor infusions in the shell of the nucleus accumbens (NAc) caused an upward shift in the dose-response curve under fixed-ratio schedule and increased the break point under progressive-ratio schedule, indicating enhanced motivation for self-administered drug. The effect of the HDAC inhibitor is attributed to the increased elevation of histone acetylation induced by chronic, but not acute, cocaine experience. In contrast, neutralizing the chronic cocaine-induced increase in histone modification by the bilateral overexpression of HDAC4 in the NAc shell reduced drug motivation. The association between the motivation for cocaine and the transcriptional activation of addiction-related genes by H3 acetylation in the NAc shell was analyzed. Among the genes activated by chronic cocaine experiences, the expression of CaMKIIα, but not CaMKIIβ, correlated positively with motivation for the drug. Lentivirus-mediated shRNA knockdown experiments showed that CaMKIIα, but not CaMKIIβ, in the NAc shell is essential for the maintenance of motivation to self-administered cocaine. These findings suggest that chronic drug-use-induced transcriptional activation of genes, such as CaMKIIα, modulated by H3 acetylation in the NAc is a critical regulatory mechanism underlying motivation for drug reinforcement. PMID:20010550

HMGB1 promotes the starvation-induced autophagic degradation of α-synuclein in SH-SY5Y cells Atg 5-dependently.

PubMed

Guan, Yi; Li, Yiping; Zhao, Gang; Li, Yunqian

2018-06-01

Impaired autophagic clearance of aggregated α-synuclein is considered as one of key mechanisms underlining Parkinson disease (PD). High-mobility group protein B1 (HMGB1) has recently been demonstrated to mediate persistent neuroinflammation and consequent progressive neurodegeneration by promoting multiple inflammatory and neurotoxic factors. In this study, we examined the influence of the overexpression of wild-type (WT) and mutant-type (MT, A53T and A30P) α-synuclein on the autophagy in neuroblastoma SH-SY5Y cells under starvation, and then investigated the regulation of endogenous HMGB1 on the α-synuclein degradation and on the starvation-induced autophagy in the α-synuclein-overexpressed SH-SY5Y cells. It was demonstrated that the overexpression of WT or MT α-synuclein significantly downregulated the starvation-induced conversion of LC3I to LC3II and autophagy protein (Atg) 5 expression, whereas markedly inhibited the starvation-downregulated mTOR in SH-SY5Y cells. On the other side, the lentivirus-mediated upregulation of endogenous HMGB1 promoted the degradation of WT or MT α-synuclein in SH-SY5Y cells autophagy-dependently via promoting Atg 5, but not mTOR, the Atg 5 knockdown downregulated the HMGB1-mediated promotion to α-synuclein degeneration. Thus, we concluded that α-synuclein inhibited the starvation-induced autophagy in neuroblastoma SH-SY5Y cells via inhibiting the mTOR/Atg 5 signaling. However, the endogenous HMGB1 promoted the autophagic degradation of α-synuclein via the Atg 5-dependent autophagy-initiation pathway, implying the protective role of endogenous HMGB1 in the neuroblastoma cells against the α-synuclein accumulation. Copyright © 2018. Published by Elsevier Inc.

The hemodynamic effects of prolonged respiratory alkalosis in anesthetized newborn piglets.

PubMed

Jundi, K; Barrington, K J; Henderson, C; Allen, R G; Finer, N N

2000-04-01

To test the hypothesis that prolonged alkalosis decreases cardiac output and, furthermore, exacerbates hypoxic pulmonary vasoconstriction, as respiratory alkalosis is frequently induced as a therapy for persistent pulmonary hypertension of the newborn despite a lack of controlled evidence of improved outcomes. Potential adverse effects of prolonged alkalosis have been demonstrated. Two groups (control, n = 6, and hypocapnic alkalosis, n = 6) of 1-3 day old fentanyl-anesthetized, vecuronium-paralyzed piglets were instrumented to measure cardiac index (CI) and mean systemic (MAP) and pulmonary (PAP) arterial pressures. Baseline values were recorded. Alveolar hypoxia was then induced to achieve an arterial oxygen saturation of between 50 and 60% for 15 min. Respiratory alkalosis was then induced, by increasing ventilation to achieve a pH between 7.55-7.60, and was continued for 240 min. Inspired carbon dioxide was used with hyperventilation in the control group to maintain pressure of arterial carbon dioxide (PaCO2) at 35-45 mmHg and pH of 7.35-7.45. Hypoxia was induced again at 15 and 240 min. Pulmonary and systemic vascular resistances (PVR and SVR) were calculated. Prolonged alkalosis led to a significant and progressive fall in mean MAP from 61 (SD 7) mmHg at the start of the study falling to 50 (SD 6.9, p = 0.043), with no effect on CI. Calculated SVR decreased (0.45 SD 0.03 vs 0.36 SD 0.05). There were no statistically significant changes in any of the variables in the control group. Neither acute nor prolonged respiratory alkalosis had a significant effect on hypoxic pulmonary vasoconstriction. Prolonged hyperventilation leads to systemic hypotension, however it does not exacerbate hypoxic pulmonary vasoconstriction.

[Protective immunity against Mycobacterium tuberculosis].

PubMed

Kawamura, Ikuo

2006-11-01

Mycobacterium tuberculosis (MTB) is a facultative intracellular pathogen with which over a billion people have been infected and 3 million people die annually. The bacterium induces vigorous immune responses, yet evades host immunity, persisting within phagosomes of the infected macrophages. Thus, it is necessary to delineate that the virulence-related intracellular survival mechanism and the host immune responses to eradicate M. tuberculosis on the molecular basis. In this regard, recent findings clearly indicated that Toll-like receptors (TLRs) play an essential role in the recognition of MTB components by macrophages and dendritic cells, resulting in not only activation of innate immunity but also development of antigen-specific adaptive immunity. It has been also reported that induction of early death of the infected cells may be one of the strategy of host defense against MTB because macrophages go into apoptosis upon infection with MTB, resulting in suppression of the intracellular replication. Furthermore, recent report has shown that autophagy is induced by IFN-gamma and suppress intracellular survival of mycobacteria, suggesting that activation of autophagy pathway is required to overcome phagosome maturation arrest induced by MTB. In addition, it is known that IFN-gamma plays an important role in protection. The cytokine that is produced from NK cells and dendritic cells at the early period of infection strongly induces not only macrophage activation but also development of antigen-specific IFN-gamma-producing CD4+T cells. Since antigen-specific CD8+ T cells and CD1-restricted T cells are also reported to contribute to the protective immunity, cooperation of these T cells is essential for the host resistance. In this paper, I am going to summarize the recent progress of the understanding of protective immunity against MTB.

N2O emission from plant surfaces - light stimulated and a global phenomenon.

NASA Astrophysics Data System (ADS)

Mikkelsen, Teis; Bruhn, Dan; Ambus, Per

2017-04-01

Nitrous oxide (N2O) is an important long-lived greenhouse gas and precursor of stratospheric ozone depleting mono-nitrogen oxides. The atmospheric concentration of N2O is persistently increasing; however, large uncertainties are associated with the distinct source strengths. Here we investigate for the first time N2O emission from terrestrial vegetation in response to natural solar ultra violet radiation. We conducted field site measurements to investigate N2O atmosphere exchange from grass vegetation exposed to solar irradiance with and without UV-screening. Further laboratory tests were conducted with a range of species to study the controls and possible loci of UV-induced N2O emission from plants. Plants released N2O in response to natural sunlight at rates of c. 20-50 nmol m-2 h-1, mostly due to the UV component. The emission rate is temperature dependent with a rather high activation energy indicative for an abiotic process. The prevailing zone for the N2O formation appears to be at the very surface of leaves. However, only c. 26% of the UV-induced N2O appears to originate from plant-N. Further, the process is dependent on atmospheric oxygen concentration. Our work demonstrates that ecosystem emission of the important greenhouse gas, N2O, may be up to c. 30% higher than hitherto assumed. Literature: Mikkelsen TN, Bruhn D & Ambus P. (2016). Solar UV Irradiation-Induced Production of Greenhouse Gases from Plant Surfaces: From Leaf to Earth. Progress in Botany, DOI 10.1007/124_2016_10. Bruhn D, Albert KR, Mikkelsen TN & Ambus P. (2014). UV-induced N2O emission from plants. Atmospheric Environment 99, 206-214.

Soman increases neuronal COX-2 levels: possible link between seizures and protracted neuronal damage.

PubMed

Angoa-Pérez, Mariana; Kreipke, Christian W; Thomas, David M; Van Shura, Kerry E; Lyman, Megan; McDonough, John H; Kuhn, Donald M

2010-12-01

Nerve agent-induced seizures cause neuronal damage in brain limbic and cortical circuits leading to persistent behavioral and cognitive deficits. Without aggressive anticholinergic and benzodiazepine therapy, seizures can be prolonged and neuronal damage progresses for extended periods of time. The objective of this study was to determine the effects of the nerve agent soman on expression of cyclooxygenase-2 (COX-2), the initial enzyme in the biosynthetic pathway of the proinflammatory prostaglandins and a factor that has been implicated in seizure initiation and propagation. Rats were exposed to a toxic dose of soman and scored behaviorally for seizure intensity. Expression of COX-2 was determined throughout brain from 4h to 7 days after exposure by immunohistochemistry and immunoblotting. Microglial activation and astrogliosis were assessed microscopically over the same time-course. Soman increased COX-2 expression in brain regions known to be damaged by nerve agents (e.g., hippocampus, amygdala, piriform cortex and thalamus). COX-2 expression was induced in neurons, and not in microglia or astrocytes, and remained elevated through 7 days. The magnitude of COX-2 induction was correlated with seizure intensity. COX-1 expression was not changed by soman. Increased expression of neuronal COX-2 by soman is a late-developing response relative to other signs of acute physiological distress caused by nerve agents. COX-2-mediated production of prostaglandins is a consequence of the seizure-induced neuronal damage, even after survival of the initial cholinergic crisis is assured. COX-2 inhibitors should be considered as adjunct therapy in nerve agent poisoning to minimize nerve agent-induced seizure activity. Published by Elsevier B.V.

The effect of the leukotriene antagonist pranlukast on pediatric acute otitis media.

PubMed

Nakamura, Yoshihisa; Hamajima, Yuki; Suzuki, Motohiko; Esaki, Shinichi; Yokota, Makoto; Oshika, Masanori; Takagi, Ippei; Yasui, Keiko; Miyamoto, Naoya; Sugiyama, Kazuko; Nakayama, Meiho; Murakami, Shingo

2016-08-01

Conventional treatment for acute otitis media mainly targets bacteria with antibiotics, neglecting to control for mediators of inflammation. Mediators of inflammation, such as leukotrienes, have been identified in patients with acute otitis media (AOM) or subsequent secretory otitis media (SOM). They can cause functional eustachian tube dysfunction or increase mucous in the middle ear, causing persistent SOM following AOM. The objective of the present study was to evaluate whether or not administration of pranlukast, a widely used leukotriene C4, D4, and E4 antagonist, together with antibiotics could inhibit the progression to SOM. Children with AOM, who were from two to 12 years old, were randomly divided into two groups as follows: a control group in which 50 patients received antibiotic-based conventional treatment according to guidelines for treating AOM proposed by the Japan Otological Society (version 2006); and a pranlukast group, in which 52 patients were administered pranlukast for up to 28 days as well as given conventional treatment. Cases were regarded as persistent SOM when a tympanogram was type B or C2 four weeks after treatment was initiated. Two patients in the pranlukast group and 3 patients in the control group were excluded because they relapsed AOM within 28 days after initial treatment. Therefore, the analysis included 50 and 47 subjects in the pranlukast and control groups, respectively. The percentage of patients diagnosed with persistent SOM (22.0%) was significantly smaller in the pranlukast group compared with the control group (44.7%) (p = 0.018, chi-squared test). The results indicate that combined treatment of AOM with antibiotics and a leukotriene antagonist to control inflammation is useful for preventing progression to persistent SOM. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Asymptomatic Hepadnaviral Persistence and Its Consequences in the Woodchuck Model of Occult Hepatitis B Virus Infection

PubMed Central

Mulrooney-Cousins, Patricia M.; Michalak, Tomasz I.

2015-01-01

Woodchuck hepatitis virus (WHV) is molecularly and pathogenically closely related to hepatitis B virus (HBV). Both viruses display tropism towards hepatocytes and cells of the immune system and cause similar liver pathology, where acute hepatitis can progress to chronic hepatitis and to hepatocellular carcinoma (HCC). Two forms of occult hepadnaviral persistence were identified in the woodchuck-WHV model: secondary occult infection (SOI) and primary occult infection (POI). SOI occurs after resolution of a serologically apparent infection with hepatitis or after subclinical serologically evident virus exposure. POI is caused by small amounts of virus and progresses without serological infection markers, but the virus genome and its replication are detectable in the immune system and with time in the liver. SOI can be accompanied by minimal hepatitis, while the hallmark of POI is normal liver morphology. Nonetheless, HCC develops in about 20% of animals with SOI or POI within 3 to 5 years. The virus persists throughout the lifespan in both SOI and POI at serum levels rarely greater than 100 copies/mL, causes hepatitis and HCC when concentrated and administered to virus-naïve woodchucks. SOI is accompanied by virus-specific T and B cell immune responses, while only virus-specific T cells are detected in POI. SOI coincides with protection against reinfection, while POI does not and hepatitis develops after challenge with liver pathogenic doses >1000 virions. Both SOI and POI are associated with virus DNA integration into the liver and the immune system genomes. Overall, SOI and POI are two distinct forms of silent hepadnaviral persistence that share common characteristics. Here, we review findings from the woodchuck model and discuss the relevant observations made in human occult HBV infection (OBI). PMID:26623268

Asymptomatic Hepadnaviral Persistence and Its Consequences in the Woodchuck Model of Occult Hepatitis B Virus Infection.

PubMed

Mulrooney-Cousins, Patricia M; Michalak, Tomasz I

2015-09-28

Woodchuck hepatitis virus (WHV) is molecularly and pathogenically closely related to hepatitis B virus (HBV). Both viruses display tropism towards hepatocytes and cells of the immune system and cause similar liver pathology, where acute hepatitis can progress to chronic hepatitis and to hepatocellular carcinoma (HCC). Two forms of occult hepadnaviral persistence were identified in the woodchuck-WHV model: secondary occult infection (SOI) and primary occult infection (POI). SOI occurs after resolution of a serologically apparent infection with hepatitis or after subclinical serologically evident virus exposure. POI is caused by small amounts of virus and progresses without serological infection markers, but the virus genome and its replication are detectable in the immune system and with time in the liver. SOI can be accompanied by minimal hepatitis, while the hallmark of POI is normal liver morphology. Nonetheless, HCC develops in about 20% of animals with SOI or POI within 3 to 5 years. The virus persists throughout the lifespan in both SOI and POI at serum levels rarely greater than 100 copies/mL, causes hepatitis and HCC when concentrated and administered to virus-naïve woodchucks. SOI is accompanied by virus-specific T and B cell immune responses, while only virus-specific T cells are detected in POI. SOI coincides with protection against reinfection, while POI does not and hepatitis develops after challenge with liver pathogenic doses >1000 virions. Both SOI and POI are associated with virus DNA integration into the liver and the immune system genomes. Overall, SOI and POI are two distinct forms of silent hepadnaviral persistence that share common characteristics. Here, we review findings from the woodchuck model and discuss the relevant observations made in human occult HBV infection (OBI).

Climatology of summer midtropospheric perturbations in the U.S. northern plains. Part I: Influence on northwest flow severe weather outbreaks

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

Wang, Shih-Yu; Chen, Tsing-Chang; Correia, James

Northwest flow severe weather outbreaks (NWF outbreaks) describe a type of summer convective storm that occurs in areas of mid-level NWF in the central United States. Convective storms associated with NWF outbreaks are often progressive (i.e. traveling a long distance) along systematic, northwestsoutheast oriented tracks throughout the northern plains. Previous studies have observed that progressive convective storms under NWF are often coupled with subsynoptic-scale midtropospheric perturbations (MPs) coming from the Rocky Mountains. This study traces such MPs for the decade of 1997-2006 using the North American Regional Reanalysis to examine their climatology and possible influence on NWF outbreaks. MPs initiatedmore » over the Rocky Mountains have a maximum frequency in July when the North American anticyclone fully develops and forms prevailing NWF over the northern plains. MPs developed under this anticyclone appear restricted in their vertical extension. Nevertheless, persistent upward motion is apparent in the leading edge (east) of MPs soon after their genesis subsequently inducing or intensifying convective storms. MPs propagate along systematic tracks similar to those of NWF outbreaks. The propagation of MPs also synchronizes with the progressive behavior of the associated convective storms. When encountering strong low-level jets (LLJs), upward motion and convergence of water vapor flux associated with MPs intensify substantially, resulting in strongly enhanced convection and precipitation. Convective wind and hail frequencies associated with MPs in strong LLJs reveal a pattern and magnitude very similar to that of NWF outbreaks. While about 60% of summer rainfall in the northern plains is linked to MPs, 75% of these instances occur in strong LLJs.« less

Stromal Fibroblasts Induce CCL20 through IL6/C/EBPβ to Support the Recruitment of Th17 Cells during Cervical Cancer Progression.

PubMed

Walch-Rückheim, Barbara; Mavrova, Russalina; Henning, Melanie; Vicinus, Benjamin; Kim, Yoo-Jin; Bohle, Rainer Maria; Juhasz-Böss, Ingolf; Solomayer, Erich-Franz; Smola, Sigrun

2015-12-15

Cervical cancer is a consequence of persistent infection with human papillomaviruses (HPV). Progression to malignancy is linked to an inflammatory microenvironment comprising T-helper-17 (Th17) cells, a T-cell subset with protumorigenic properties. Neoplastic cells express only low endogenous levels of the Th17 chemoattractant CCL20, and therefore, it is unclear how Th17 cells are recruited to the cervical cancer tissue. In this study, we demonstrate that CCL20 was predominantly expressed in the stroma of cervical squamous cell carcinomas in situ. This correlated with stromal infiltration of CD4(+)/IL17(+) cells and with advancing International Federation of Gynecology and Obstetrics (FIGO) stage. Furthermore, we show that cervical cancer cells instructed primary cervical fibroblasts to produce high levels of CCL20 and to attract CD4/IL17/CCR6-positive cells, generated in vitro, in a CCL20/CCR6-dependent manner. Further mechanistic investigations identified cervical cancer cell-derived IL6 as an important mediator of paracrine CCL20 induction at the promoter, mRNA, and protein level in fibroblasts. CCL20 was upregulated through the recently described CCAAT/enhancer-binding protein β (C/EBPβ) pathway as shown with a dominant-negative version of C/EBPβ and through siRNA-mediated knockdown. In summary, our study defines a novel molecular mechanism by which cervical neoplastic cells shape their local microenvironment by instructing fibroblasts to support Th17 cell infiltration in a paracrine IL6/C/EBPβ-dependent manner. Th17 cells may in turn maintain chronic inflammation within high-grade cervical lesions to further promote cancer progression. ©2015 American Association for Cancer Research.

Serial measurement of type-specific human papillomavirus load enables classification of cervical intraepithelial neoplasia lesions according to occurring human papillomavirus-induced pathway.

PubMed

Verhelst, Stefanie; Poppe, Willy A J; Bogers, Johannes J; Depuydt, Christophe E

2017-03-01

This retrospective study examined whether human papillomavirus (HPV) type-specific viral load changes measured in two or three serial cervical smears are predictive for the natural evolution of HPV infections and correlate with histological grades of cervical intraepithelial neoplasia (CIN), allowing triage of HPV-positive women. A cervical histology database was used to select consecutive women with biopsy-proven CIN in 2012 who had at least two liquid-based cytology samples before the diagnosis of CIN. Before performing cytology, 18 different quantitative PCRs allowed HPV type-specific viral load measurement. Changes in HPV-specific load between measurements were assessed by linear regression, with calculation of coefficient of determination (R) and slope. All infections could be classified into one of five categories: (i) clonal progressing process (R≥0.85; positive slope), (ii) simultaneously occurring clonal progressive and transient infection, (iii) clonal regressing process (R≥0.85; negative slope), (iv) serial transient infection with latency [R<0.85; slopes (two points) between 0.0010 and -0.0010 HPV copies/cell/day], and (v) transient productive infection (R<0.85; slope: ±0.0099 HPV copies/cell/day). Three hundred and seven women with CIN were included; 124 had single-type infections and 183 had multiple HPV types. Only with three consecutive measurements could a clonal process be identified in all CIN3 cases. We could clearly demonstrate clonal regressing lesions with a persistent linear decrease in viral load (R≥0.85; -0.003 HPV copies/cell/day) in all CIN categories. Type-specific viral load increase/decrease in three consecutive measurements enabled classification of CIN lesions in clonal HPV-driven transformation (progression/regression) and nonclonal virion-productive (serial transient/transient) processes.

Evaluation of the effects of hyaluronic acid-carboxymethyl cellulose barrier on ovarian tumor progression

PubMed Central

2014-01-01

Background Hyaluronic acid is a prognostic factor in ovarian cancers. It is also a component of Hyaluronic Acid-Carboxymethyl Cellulose (HA-CMC) barrier, an anti-adhesion membrane widely used during abdominal surgeries in particular for ovarian carcinosis. 70% of patients who undergo ovarian surgery will relapse due to the persistence of cancer cells. This study’s objective was to determine the oncological risk from use of this material, in the presence of residual disease, despite the benefit gained by it decreasing post-surgical adhesions in order to provide an unambiguous assessment of its appropriateness for use in ovarian surgical management. Methods We assessed the effects of HA-CMC barrier on the in vitro proliferation of human ovarian tumor cell lines (OVCAR-3, IGROV-1 and SKOV-3). We next evaluated, in vivo in nude mice, the capacity of this biomaterial to regulate the tumor progression of subcutaneous and intraperitoneal models of ovarian tumor xenografts. Results We showed that HA-CMC barrier does not increase in vitro proliferation of ovarian cancer cell lines compared to control. In vivo, HA-CMC barrier presence with subcutaneous xenografts induced neither an increase in tumor volume nor cell proliferation (Ki67 and mitotic index). With the exception of an increased murine carcinosis score in peritoneum, the presence of HA-CMC barrier with intraperitoneal xenografts modified neither macro nor microscopic tumor growth. Finally, protein analysis of survival (Akt), proliferation (ERK) and adhesion (FAK) pathways highlighted no activation on the xenografts imputable to HA-CMC barrier. Conclusions For the most part, our results support the lack of tumor progression activation due to HA-CMC barrier. We conclude that the benefits gained from using HA-CMC barrier membrane during ovarian cancer surgeries seem to outweigh the potential oncological risks. PMID:24739440

Iron-Hepcidin Dysmetabolism, Anemia and Renal Hypoxia, Inflammation and Fibrosis in the Remnant Kidney Rat Model

PubMed Central

Garrido, Patrícia; Ribeiro, Sandra; Fernandes, João; Vala, Helena; Bronze-da-Rocha, Elsa; Rocha-Pereira, Petronila; Belo, Luís; Costa, Elísio; Santos-Silva, Alice; Reis, Flávio

2015-01-01

Anemia is a common complication of chronic kidney disease (CKD) that develops early and its severity increases as renal function declines. It is mainly due to a reduced production of erythropoietin (EPO) by the kidneys; however, there are evidences that iron metabolism disturbances increase as CKD progresses. Our aim was to study the mechanisms underlying the development of anemia of CKD, as well as renal damage, in the remnant kidney rat model of CKD induced by 5/6 nephrectomy. This model of CKD presented a sustained degree of renal dysfunction, with mild and advanced glomerular and tubulointerstitial lesions. Anemia developed 3 weeks after nephrectomy and persisted throughout the protocol. The remnant kidney was still able to produce EPO and the liver showed an increased EPO gene expression. In spite of the increased EPO blood levels, anemia persisted and was linked to low serum iron and transferrin levels, while serum interleukin (IL)-6 and high sensitivity C-reactive protein (hs-CRP) levels showed the absence of systemic inflammation. The increased expression of duodenal ferroportin favours iron absorption; however, serum iron is reduced which might be due to iron leakage through advanced kidney lesions, as showed by tubular iron accumulation. Our data suggest that the persistence of anemia may result from disturbances in iron metabolism and by an altered activity/function of EPO as a result of kidney cell damage and a local inflammatory milieu, as showed by the increased gene expression of different inflammatory proteins in the remnant kidney. In addition, this anemia and the associated kidney hypoxia favour the development of fibrosis, angiogenesis and inflammation that may underlie a resistance to EPO stimuli and reduced iron availability. These findings might contribute to open new windows to identify putative therapeutic targets for this condition, as well as for recombinant human EPO (rHuEPO) resistance, which occurs in a considerable percentage of CKD patients. PMID:25867633

Revolutionizing Child Welfare with Outcomes Management

PubMed Central

Toche-Manley, Linda L.; Dietzen, Laura; Nankin, Jesse; Beigel, Astrid

2013-01-01

Outcomes management technology holds great promise for improving the quality of services provided to youth in the child welfare system. Advantages include better detection of behavioral health and trauma-related issues, early indicators of case progress or risk of failure and program- and system-level learning. Yet organizational barriers to implementation persist. Attention is spent in this paper on addressing these barriers so the use of outcomes management technology becomes a common practice. A model for predicting resiliency is presented, along with case examples demonstrating its potential use for treatment planning and monitoring progress. PMID:23460130

Progress and pitfalls in Shigella vaccine research

PubMed Central

Barry, Eileen M.; Pasetti, Marcela F.; Sztein, Marcelo B.; Fasano, Alessio; Kotloff, Karen L.; Levine, Myron M.

2013-01-01

Renewed awareness of the significant morbidity and mortality that Shigella causes among young children in developing countries combined with technological innovations in vaccinology has led to the development of novel vaccine strategies in the past five years. Along with advancement of classical vaccines in clinical trials and new sophisticated measurements of immunological responses, much new data has been produced lending promise to the potential for production of safe and effective Shigella vaccines. Herein we review the recent progress in Shigella vaccine development within the framework of persistent obstacles. PMID:23419287

tRNA-mediated codon-biased translation in mycobacterial hypoxic persistence

NASA Astrophysics Data System (ADS)

Chionh, Yok Hian; McBee, Megan; Babu, I. Ramesh; Hia, Fabian; Lin, Wenwei; Zhao, Wei; Cao, Jianshu; Dziergowska, Agnieszka; Malkiewicz, Andrzej; Begley, Thomas J.; Alonso, Sylvie; Dedon, Peter C.

2016-11-01

Microbial pathogens adapt to the stress of infection by regulating transcription, translation and protein modification. We report that changes in gene expression in hypoxia-induced non-replicating persistence in mycobacteria--which models tuberculous granulomas--are partly determined by a mechanism of tRNA reprogramming and codon-biased translation. Mycobacterium bovis BCG responded to each stage of hypoxia and aerobic resuscitation by uniquely reprogramming 40 modified ribonucleosides in tRNA, which correlate with selective translation of mRNAs from families of codon-biased persistence genes. For example, early hypoxia increases wobble cmo5U in tRNAThr(UGU), which parallels translation of transcripts enriched in its cognate codon, ACG, including the DosR master regulator of hypoxic bacteriostasis. Codon re-engineering of dosR exaggerates hypoxia-induced changes in codon-biased DosR translation, with altered dosR expression revealing unanticipated effects on bacterial survival during hypoxia. These results reveal a coordinated system of tRNA modifications and translation of codon-biased transcripts that enhance expression of stress response proteins in mycobacteria.

tRNA-mediated codon-biased translation in mycobacterial hypoxic persistence

PubMed Central

Chionh, Yok Hian; McBee, Megan; Babu, I. Ramesh; Hia, Fabian; Lin, Wenwei; Zhao, Wei; Cao, Jianshu; Dziergowska, Agnieszka; Malkiewicz, Andrzej; Begley, Thomas J.; Alonso, Sylvie; Dedon, Peter C.

2016-01-01

Microbial pathogens adapt to the stress of infection by regulating transcription, translation and protein modification. We report that changes in gene expression in hypoxia-induced non-replicating persistence in mycobacteria—which models tuberculous granulomas—are partly determined by a mechanism of tRNA reprogramming and codon-biased translation. Mycobacterium bovis BCG responded to each stage of hypoxia and aerobic resuscitation by uniquely reprogramming 40 modified ribonucleosides in tRNA, which correlate with selective translation of mRNAs from families of codon-biased persistence genes. For example, early hypoxia increases wobble cmo5U in tRNAThr(UGU), which parallels translation of transcripts enriched in its cognate codon, ACG, including the DosR master regulator of hypoxic bacteriostasis. Codon re-engineering of dosR exaggerates hypoxia-induced changes in codon-biased DosR translation, with altered dosR expression revealing unanticipated effects on bacterial survival during hypoxia. These results reveal a coordinated system of tRNA modifications and translation of codon-biased transcripts that enhance expression of stress response proteins in mycobacteria. PMID:27834374

Persistent kallikrein 5 activation induces atopic dermatitis-like skin architecture independent of PAR2 activity.

PubMed

Zhu, Yanan; Underwood, Joanne; Macmillan, Derek; Shariff, Leila; O'Shaughnessy, Ryan; Harper, John I; Pickard, Chris; Friedmann, Peter S; Healy, Eugene; Di, Wei-Li

2017-11-01

Upregulation of kallikreins (KLKs) including KLK5 has been reported in atopic dermatitis (AD). KLK5 has biological functions that include degrading desmosomal proteins and inducing proinflammatory cytokine secretion through protease-activated receptor 2 (PAR2). However, due to the complex interactions between various cells in AD inflamed skin, it is difficult to dissect the precise and multiple roles of upregulated KLK5 in AD skin. We investigated the effect of upregulated KLK5 on the expression of epidermal-related proteins and cytokines in keratinocytes and on skin architecture. Lesional and nonlesional AD skin biopsies were collected for analysis of morphology and protein expression. The relationship between KLK5 and barrier-related molecules was investigated using an ex vivo dermatitis skin model with transient KLK5 expression and a cell model with persistent KLK5 expression. The influence of upregulated KLK5 on epidermal morphology was investigated using an in vivo skin graft model. Upregulation of KLK5 and abnormal expression of desmoglein 1 (DSG1) and filaggrin, but not PAR2 were identified in AD skin. PAR2 was increased in response to transient upregulation of KLK5, whereas persistently upregulated KLK5 did not show this effect. Persistently upregulated KLK5 degraded DSG1 and stimulated secretion of IL-8, IL-10, and thymic stromal lymphopoietin independent of PAR2 activity. With control of higher KLK5 activity by the inhibitor sunflower trypsin inhibitor G, restoration of DSG1 expression and a reduction in AD-related cytokine IL-8, thymic stromal lymphopoietin, and IL-10 secretion were observed. Furthermore, persistently elevated KLK5 could induce AD-like skin architecture in an in vivo skin graft model. Persistently upregulated KLK5 resulted in AD-like skin architecture and secretion of AD-related cytokines from keratinocytes in a PAR2 independent manner. Inhibition of KLK5-mediated effects may offer potential as a therapeutic approach in AD. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Persistent Skin Reactions and Aluminium Hypersensitivity Induced by Childhood Vaccines.

PubMed

Salik, Elaha; Løvik, Ida; Andersen, Klaus E; Bygum, Anette

2016-11-02

There is increasing awareness of reactions to vaccination that include persistent skin reactions. We present here a retrospective investigation of long-lasting skin reactions and aluminium hypersensitivity in children, based on medical records and questionnaires sent to the parents. In the 10-year period 2003 to 2013 we identified 47 children with persistent skin reactions caused by childhood vaccinations. Most patients had a typical presentation of persisting pruritic subcutaneous nodules. Five children had a complex diagnostic process involving paediatricians, orthopaedics and plastic surgeons. Two patients had skin biopsies performed from their skin lesions, and 2 patients had the nodules surgically removed. Forty-two children had a patch-test performed with 2% aluminium chloride hexahydrate in petrolatum and 39 of them (92%) had a positive reaction. The persistent skin reactions were treated with potent topical corticosteroids and disappeared slowly. Although we advised families to continue vaccination of their children, one-third of parents omitted or postponed further vaccinations.

Delay of constant light-induced persistent vaginal estrus by 24-hour time cues in rats.

PubMed

Weber, A L; Adler, N T

1979-04-20

The normal ovarian cycle of female rats is typically replaced by persistent estrus when these animals are housed under constant light. Evidence presented here shows that the maintenance of periodicity in the environment can at least delay (if not prevent) the photic induction of persistent vaginal estrus. Female rats in constant light were exposed to vaginal smearing at random times or at the same time every day. In another experiment, female rats were exposed to either constant bright light, constant dim light, or a 24-hour photic cycle of bright and dim light. The onset of persistent vaginal estrus was delayed in rats exposed to 24-hour time cues even though the light intensities were the same as or greater than those for the aperiodic control groups. The results suggest that the absence of 24-hour time cues in constant light contributes to the induction of persistent estrus.

STEM Gets a Boost from Business

ERIC Educational Resources Information Center

Rosen, Linda

2012-01-01

STEM--science, technology, engineering, and mathematics--has become a fixture of the education debate, and much effort already has been put toward improving student performance. Yet troubling statistics persist: On the latest round of testing for the National Assessment of Educational Progress (NAEP), only 40 percent of fourth graders nationwide…

DETECTING PERSISTENT CHANGE IN THE HABITAT OF SALMON-BEARING STREAMS IN THE PACIFIC NORTHWEST. (R829095C003)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

The Racial School-Climate Gap

ERIC Educational Resources Information Center

Voight, Adam

2013-01-01

Education inequity is a persistent reality of American culture. As early as kindergarten, there are marked differences in academic performance between racial minority students and their peers. These differences are sustained as students progress through school. One aspect of students' social experience that may help to explain the gap is school…

Space fabrication demonstration system

NASA Technical Reports Server (NTRS)

1978-01-01

The lower right aluminum beam cap roll forming mill was delivered and installed in the beam builder. The beam was brought to full operational status and beams of one to six bay lengths were produced to demonstrate full system capability. Although the cap flange waviness problem persists, work is progressing within cost and schedule.

Bubonic lymphogranuloma venereum with multidrug treatment failure.

PubMed

Vall-Mayans, Martí; Isaksson, Jenny; Caballero, Estrella; Sallés, Beatriz; Herrmann, Björn

2014-03-01

A patient with proctitis and inguinal buboes diagnosed with lymphogranuloma venereum (LGV) was treated with doxycycline 21 days, azithromycin 20 days and moxifloxacin for a further 12 days because of progressive worsening of inguinal symptoms. Despite extensive antibiotic treatment, the inguinal LGV lesions persisted; however, the patient recovered spontaneously after three months.

Reduced lentivirus susceptibility in sheep with TMEM154 mutations

USDA-ARS?s Scientific Manuscript database

Visna/Maedi, or ovine progressive pneumonia (OPP) as it is known in the U.S., is an incurable slow-acting disease of sheep caused by persistent lentivirus infection. This disease affects multiple tissues, including those of the respiratory and central nervous systems. Our aim was to identify ovine g...

Educational Attainment as Process: Using Hierarchical Discrete-Time Event History Analysis to Model Rate of Progress

ERIC Educational Resources Information Center

Bahr, Peter Riley

2009-01-01

Variables that address student enrollment patterns (e.g., persistence, enrollment inconsistency, completed credit hours, course credit load, course completion rate, procrastination) constitute a longstanding fixture of analytical strategies in educational research, particularly research that focuses on explaining variation in academic outcomes.…

Beyond Testing: Social and Psychological Considerations in Recruiting and Retaining Gifted Black Students

ERIC Educational Resources Information Center

Ford, Donna Y.; Whiting, Gilman W.

2011-01-01

For more than a half century, concerns have existed about the persistent underrepresentation of African American students in gifted education and advanced Placement classes. Various recommendations to reverse underrepresentation have been proposed, with the majority focusing on testing and assessment instruments. Nonetheless, progress has been…

Progress in Literacy Coaching Success--A Dozen Years On

ERIC Educational Resources Information Center

Toll, Cathy A.

2018-01-01

Literacy coaches are most successful when they: develop strong, trusting relationships; provide clarity about their roles; communicate well; spend much of their time in coaching conversations; and monitor their perspectives about their work and those with whom they work. However, challenges still persist for literacy coaches, particularly in…

PERSISTENT ORGANIC POLLUTANTS IN THE DUSTS THAT SETTLED ACROSS LOWER MANHATTAN AFTER SEPTEMBER 11, 2001. (R827351)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

Perceptions of Community College Students and Faculty on Persistence in Developmental Reading

ERIC Educational Resources Information Center

Aofrate, Lisa H.

2016-01-01

Attrition for entry-level, non-traditional college students taking developmental reading courses is a concern for higher education institutions. Students need to complete basic developmental reading courses in order to progress in their vocational or collegiate studies. This phenomenological study followed a social constructivist approach to…

Turkish Students' Science Performance and Related Factors in PISA 2006 and 2009

ERIC Educational Resources Information Center

Topçu, Mustafa Sami; Arikan, Serkan; Erbilgin, Evrim

2015-01-01

The OECD's Programme for International Student Assessment (PISA) enables participating countries to monitor 15-year old students' progress in reading, mathematics, and science literacy. The present study investigates persistent factors that contribute to science performance of Turkish students in PISA 2006 and PISA 2009. Additionally, the study…

Cooling out Undergraduates with Health Impairments: The Freshman Experience

ERIC Educational Resources Information Center

Carroll, Jamie M.; Muller, Chandra; Pattison, Evangeleen

2016-01-01

Students with health impairments represent a growing sector of the college population, but health-based disparities in bachelor's degree completion persist. The classes students pass and the grades they receive during the first year of college provides signals of degree progress and academic fit that shape educational expectations, potentially…

Addressing Language Variety in Educational Settings: Toward a Policy and Research Agenda

ERIC Educational Resources Information Center

Miciak, Jeremy; Wilkinson, Cheryl; Alexander, Celeste; Reyes, Pedro

2016-01-01

Improving minority academic achievement is a primary goal for education policy makers. Despite resource allocations, gaps in minority accomplishments persist. Emerging research suggests language variety may hinder minority students, thereby slowing academic progress. This article synthesizes suggestions from a panel composed of experts in the…

Responding to the Challenges of Inclusion in Irish Schools

ERIC Educational Resources Information Center

Day, Thérèse; Prunty, Anita

2015-01-01

While much progress has been made in relation to including students in mainstream education in Ireland, significant challenges remain. Despite positive attitudes, the implementation of effective inclusive practice at school level persists as one of the most pervasive challenges. This study investigated how six Irish schools, three primary and…