WorldWideScience

Sample records for susceptibility increased significantly

  1. Alcohol increases hypnotic susceptibility.

    Science.gov (United States)

    Semmens-Wheeler, Rebecca; Dienes, Zoltán; Duka, Theodora

    2013-09-01

    One approach to hypnosis suggests that for hypnotic experience to occur frontal lobe activity must be attenuated. For example, cold control theory posits that a lack of awareness of intentions is responsible for the experience of involuntariness and/or the subjective reality of hypnotic suggestions. The mid-dorso-lateral prefrontal cortex and the ACC are candidate regions for such awareness. Alcohol impairs frontal lobe executive function. This study examined whether alcohol affects hypnotisability. We administered 0.8 mg/kg of alcohol or a placebo to 32 medium susceptible participants. They were subsequently hypnotised and given hypnotic suggestions. All participants believed they had received some alcohol. Participants in the alcohol condition were more susceptible to hypnotic suggestions than participants in the placebo condition. Impaired frontal lobe activity facilitates hypnotic responding, which supports theories postulating that attenuation of executive function facilitates hypnotic response, and contradicts theories postulating that hypnotic response involves enhanced inhibitory, attentional or other executive function. Copyright © 2013. Published by Elsevier Inc.

  2. Hyperglycemia Increases Susceptibility to Ischemic Necrosis

    Directory of Open Access Journals (Sweden)

    D. Lévigne

    2013-01-01

    Full Text Available Diabetic patients are at risk for spontaneous foot ulcers, chronic wounds, infections, and tissue necrosis. Current theories suggest that the development and progression of diabetic foot ulcers are mainly caused by arteriosclerosis and peripheral neuropathy. Tissue necrosis plays a primordial role in the progression of diabetic foot ulcers but the underlying mechanisms are poorly understood. The aim of the present study was to investigate the effects of hyperglycemia per se on the susceptibility of ischemic tissue to necrosis, using a critical ischemic hind limb animal model. We inflicted the same degree of ischemia in both euglycemic and streptozotocin-induced hyperglycemic rats by resecting the external iliac, the femoral, and the saphenous arteries. Postoperative laser Doppler flowmetry of the ischemic feet showed the same degree of reduction in skin perfusion in both hyperglycemic and euglycemic animals. Nevertheless, we found a significantly higher rate of limb necrosis in hyperglycemic rats compared to euglycemic rats (71% versus 29%, resp.. In this study, we revealed that hyperglycemia per se increases the susceptibility to limb necrosis in ischemic conditions. Our results may help to better understand the physiopathology of progressive diabetic wounds and underline the importance of strict glycemic control in patients with critical limb ischemia.

  3. Obesity is a significant susceptibility factor for idiopathic AA amyloidosis.

    Science.gov (United States)

    Blank, Norbert; Hegenbart, Ute; Dietrich, Sascha; Brune, Maik; Beimler, Jörg; Röcken, Christoph; Müller-Tidow, Carsten; Lorenz, Hanns-Martin; Schönland, Stefan O

    2018-01-24

    To investigate obesity as susceptibility factor in patients with idiopathic AA amyloidosis. Clinical, biochemical and genetic data were obtained from 146 patients with AA amyloidosis. Control groups comprised 40 patients with long-standing inflammatory diseases without AA amyloidosis and 56 controls without any inflammatory disease. Patients with AA amyloidosis had either familial Mediterranean fever (FMF) or long-standing rheumatic diseases as underlying inflammatory disease (n = 111, median age 46 years). However, in a significant proportion of patients with AA amyloidosis no primary disease was identified (idiopathic AA; n = 37, median age 60 years). Patients with idiopathic AA amyloidosis were more obese and older than patients with AA amyloidosis secondary to FMF or rheumatic diseases. Serum leptin levels correlated with the body mass index (BMI) in all types of AA amyloidosis. Elevated leptin levels of more than 30 µg/l were detected in 18% of FMF/rheumatic + AA amyloidosis and in 40% of patients with idiopathic AA amyloidosis (p = .018). Finally, the SAA1 polymorphism was confirmed as a susceptibility factor for AA amyloidosis irrespective of the type of the disease. Obesity, age and the SAA1 polymorphism are susceptibility factors for idiopathic AA amyloidosis. Recent advances in treatment of FMF and rheumatic disorders will decrease the incidence of AA amyloidosis due to these diseases. Idiopathic AA, however, might be an emerging problem in the ageing and increasingly obese population.

  4. The Aging Kidney: Increased Susceptibility to Nephrotoxicity

    Directory of Open Access Journals (Sweden)

    Xinhui Wang

    2014-09-01

    Full Text Available Three decades have passed since a series of studies indicated that the aging kidney was characterized by increased susceptibility to nephrotoxic injury. Data from these experimental models is strengthened by clinical data demonstrating that the aging population has an increased incidence and severity of acute kidney injury (AKI. Since then a number of studies have focused on age-dependent alterations in pathways that predispose the kidney to acute insult. This review will focus on the mechanisms that are altered by aging in the kidney that may increase susceptibility to injury, including hemodynamics, oxidative stress, apoptosis, autophagy, inflammation and decreased repair.

  5. Tobacco use increases susceptibility to bacterial infection

    Directory of Open Access Journals (Sweden)

    Demuth Donald R

    2008-12-01

    Full Text Available Abstract Active smokers and those exposed to secondhand smoke are at increased risk of bacterial infection. Tobacco smoke exposure increases susceptibility to respiratory tract infections, including tuberculosis, pneumonia and Legionnaires disease; bacterial vaginosis and sexually transmitted diseases, such as chlamydia and gonorrhoea; Helicobacter pylori infection; periodontitis; meningitis; otitis media; and post-surgical and nosocomial infections. Tobacco smoke compromises the anti-bacterial function of leukocytes, including neutrophils, monocytes, T cells and B cells, providing a mechanistic explanation for increased infection risk. Further epidemiological, clinical and mechanistic research into this important area is warranted.

  6. Chlorine gas exposure increases susceptibility to invasive lung fungal infection.

    Science.gov (United States)

    Gessner, Melissa A; Doran, Stephen F; Yu, Zhihong; Dunaway, Chad W; Matalon, Sadis; Steele, Chad

    2013-06-01

    Chlorine (Cl₂) is a highly irritating and reactive gas with potential occupational and environmental hazards. Acute exposure to Cl₂ induces severe epithelial damage, airway hyperreactivity, impaired alveolar fluid clearance, and pulmonary edema in the presence of heightened inflammation and significant neutrophil accumulation in the lungs. Herein, we investigated whether Cl₂ exposure affected the lung antimicrobial immune response leading to increased susceptibility to opportunistic infections. Mice exposed to Cl₂ and challenged intratracheally 24 h thereafter with the opportunistic mold Aspergillus fumigatus demonstrated an >500-fold increase in A. fumigatus lung burden 72 h postchallenge compared with A. fumigatus mice exposed to room air. Cl₂-exposed A. fumigatus challenged mice also demonstrated significantly higher lung resistance following methacholine challenge and increased levels of plasma proteins (albumin and IgG) in the bronchoalveolar lavage fluid. Despite enhanced recruitment of inflammatory cells to the lungs of Cl₂-exposed A. fumigatus challenged mice, these cells (>60% of which were neutrophils) demonstrated a profound impairment in generating superoxide. Significantly higher A. fumigatus burden in the lungs of Cl₂ exposed mice correlated with enhanced production of IL-6, TNF-α, CXCL1, CCL2, and CCL3. Surprisingly, however, Cl₂-exposed A. fumigatus challenged mice had a specific impairment in the production of IL-17A and IL-22 in the lungs compared with mice exposed to room air and challenged with A. fumigatus. In summary, our results indicate that Cl₂ exposure markedly impairs the antimicrobial activity and inflammatory reactivity of myeloid cells in the lung leading to increased susceptibility to opportunistic pathogens.

  7. Microbicide excipients can greatly increase susceptibility to genital herpes transmission in the mouse

    Directory of Open Access Journals (Sweden)

    Sun Mianmian

    2010-11-01

    Full Text Available Abstract Background Several active ingredients proposed as vaginal microbicides have been shown paradoxically to increase susceptibility to infection in mouse genital herpes (HSV-2 vaginal susceptibility models and in clinical trials. In addition, "inactive ingredients" (or excipients used in topical products to formulate and deliver the active ingredient might also cause epithelial toxicities that increase viral susceptibility. However, excipients have not previously been tested in susceptibility models. Methods Excipients commonly used in topical products were formulated in a non-toxic vehicle (the "HEC universal placebo", or other formulations as specified. Twelve hours after exposure to the excipient or a control treatment, mice were challenged with a vaginal dose of HSV-2, and three days later were assessed for infection by vaginal lavage culture to assess susceptibility. Results The following excipients markedly increased susceptibility to HSV-2 after a single exposure: 5% glycerol monolaurate (GML formulated in K-Y® Warming Jelly, 5% GML as a colloidal suspension in phosphate buffered saline, K-Y Warming Jelly alone, and both of its humectant/solvent ingredients (neat propylene glycol and neat PEG-8. For excipients formulated in the HEC vehicle, 30% glycerin significantly increased susceptibility, and a trend toward increased HSV-2 susceptibility was observed after 10% glycerin, and 0.1% disodium EDTA, but not after 0.0186% disodium EDTA. The following excipients did not increase susceptibility: 10% propylene glycol, 0.18%, methylparaben plus 0.02% propylparaben, and 1% benzyl alcohol. Conclusions As reported with other surfactants, the surfactant/emulsifier GML markedly increased susceptibility to HSV-2. Glycerin at 30% significantly increased susceptibility, and, undiluted propylene glycol and PEG-8 greatly increased susceptibility.

  8. Ozone increases susceptibility to antigen inhalation in allergic dogs

    Energy Technology Data Exchange (ETDEWEB)

    Yanai, M.; Ohrui, T.; Aikawa, T.; Okayama, H.; Sekizawa, K.; Maeyama, K.; Sasaki, H.; Takishima, T. (Tohoku Univ., Sendai (Japan))

    1990-06-01

    To determine whether O3 exposure increased airway responsiveness to antigen inhalation, we studied airway responsiveness to acetylcholine (ACh) and Ascaris suum antigen (AA) before and after O3 in dogs both sensitive and insensitive to AA. Airway responsiveness was assessed by determining the provocative concentration of ACh and AA aerosols that increased respiratory resistance (Rrs) to twice the base-line value. O3 (3 parts per million) increased airway responsiveness to ACh in dogs both sensitive and insensitive to AA, and it significantly decreased the ACh provocation concentration from 0.541 +/- 0.095 to 0.102 +/- 0.047 (SE) mg/ml (P less than 0.01; n = 10). AA aerosols, even at the highest concentration in combination with O3, did not increase Rrs in dogs insensitive to AA. However, O3 increased airway responsiveness to AA in AA-sensitive dogs and significantly decreased log AA provocation concentration from 2.34 +/- 0.22 to 0.50 +/- 0.17 (SE) log protein nitrogen units/ml (P less than 0.01; n = 7). O3-induced hyperresponsiveness to ACh returned to the base-line level within 2 wk, but hyperresponsiveness to AA continued for greater than 2 wk. The plasma histamine concentration after AA challenge was significantly higher after than before O3 (P less than 0.01). Intravenous infusion of OKY-046 (100 micrograms.kg-1.min-1), an inhibitor of thromboxane synthesis, inhibited the O3-induced increase in responsiveness to ACh, but it had no effects on the O3-induced increase in responsiveness to AA and the increase in the plasma histamine concentration. These results suggest that O3 increases susceptibility to the antigen in sensitized dogs via a different mechanism from that of O3-induced muscarinic hyperresponsiveness.

  9. Toluene exposure increases aminophylline-induced seizure susceptibility in mice.

    Science.gov (United States)

    Chan, Ming-Huan; Chen, Hwei-Hsien

    2003-12-01

    The effects of toluene on the sensitivity to seizures induced by aminophylline were investigated. Mice were pretreated with an ip injection of corn oil or toluene (100-500 mg/kg) followed by a timed intravenous infusion of aminophylline at various time intervals to assess the seizure thresholds and lethal doses. Toluene increased seizure susceptibility to aminophylline in a dose- and time-dependent manner. Toluene-induced enhancement of seizure susceptibility to aminophylline occurred as early as 30 min and persisted for at least 3 days after a single administration of toluene (500 mg/kg). Treatment of benzaldehyde, one of toluene's metabolites, also showed an increase in the susceptibility to aminophylline. The enhancing effect was also observed in caffeine-induced seizures 1 h, but not 1 day after toluene treatment. These results suggest that individuals with toluene exposure may increase the risk for convulsive and even lethal complications associated with the therapeutic use of aminophylline.

  10. Significantly increased visceral adiposity index in prehypertension.

    Directory of Open Access Journals (Sweden)

    Yanan Ding

    Full Text Available The prevalence of prehypertension has increased in China, and prehypertension frequently progress to hypertension over a short time period; both have become public health problems. Therefore, this study was conducted to determine the relationship between the Visceral Adiposity Index (VAI and blood pressure (BP in China.A cross-sectional epidemiological survey was conducted in China using a stratified random cluster sampling method. Sex-specific VAI quartile cut-off points were used as follows: 0.88, 1.41, 2.45 in males and 0.85, 1.33, 2.22 in females. Prehypertension and hypertension were each defined according to The Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7 guidelines. A multivariate logistic analysis was conducted to analyze the relationship among VAI, prehypertension and hypertension.The ORs for prehypertension and hypertension in the upper quartiles of the VAI were 1.514 (1.074-2.133, P=0.018 and 1.660 (1.084-2.542, P=0.020, in males, after adjusting for age, education, smoking habits, alcohol consumption, physical activity, serum creatinine, fasting glucose, and plasma insulin. Following further adjustments for the above confounders, chronic kidney disease, and diabetes, the ORs for prehypertension and hypertension in the upper quartile of the VAI were 1.660 1.533 (1.086-2.165, P=0.015, and 1.743 (1.133-2.680, P=0.011, in males. The ORs for prehypertension and hypertension in the upper quartile of the VAI were 1.691 (1.223-2.338, P=0.001, and 1.682 (1.162-2.435, P=0.006, in females, after adjusting for age, education, smoking habits, alcohol consumption, physical activity, serum creatinine, fasting glucose, and plasma insulin. Following further adjustments for the above confounders, chronic kidney disease, and diabetes, the ORs for prehypertension and hypertension in the upper quartile of the VAI were 1.688 (1.220-2.334, P=0.002, and 1.657 (1

  11. Wolbachia increases susceptibility to Plasmodium infection in a natural system

    Science.gov (United States)

    Zélé, F.; Nicot, A.; Berthomieu, A.; Weill, M.; Duron, O.; Rivero, A.

    2014-01-01

    Current views about the impact of Wolbachia on Plasmodium infections are almost entirely based on data regarding artificially transfected mosquitoes. This work has shown that Wolbachia reduces the intensity of Plasmodium infections in mosquitoes, raising the exciting possibility of using Wolbachia to control or limit the spread of malaria. Whether natural Wolbachia infections have the same parasite-inhibiting properties is not yet clear. Wolbachia–mosquito combinations with a long evolutionary history are, however, key for understanding what may happen with Wolbachia-transfected mosquitoes after several generations of coevolution. We investigate this issue using an entirely natural mosquito–Wolbachia–Plasmodium combination. In contrast to most previous studies, which have been centred on the quantification of the midgut stages of Plasmodium, we obtain a measurement of parasitaemia that relates directly to transmission by following infections to the salivary gland stages. We show that Wolbachia increases the susceptibility of Culex pipiens mosquitoes to Plasmodium relictum, significantly increasing the prevalence of salivary gland stage infections. This effect is independent of the density of Wolbachia in the mosquito. These results suggest that naturally Wolbachia-infected mosquitoes may, in fact, be better vectors of malaria than Wolbachia-free ones. PMID:24500167

  12. Increased LDL susceptibility to oxidation accelerates future carotid artery atherosclerosis

    Directory of Open Access Journals (Sweden)

    Aoki Toshinari

    2012-01-01

    Full Text Available Abstract Background We analyzed the causal relationship between LDL susceptibility to oxidation and the development of new carotid artery atherosclerosis over a period of 5 years. We previously described the determinants related to a risk of cardiovascular changes determined in a Japanese population participating in the Niigata Study, which is an ongoing epidemiological investigation of the prevention of cardiovascular diseases. Methods We selected 394 individuals (169 males and 225 females who underwent a second carotid artery ultrasonographic examination in 2001 - 2002 for the present study. The susceptibility of LDL to oxidation was determined as the photometric absorbance and electrophoretic mobility of samples that had been collected in 1996 - 1997. The measurements were compared with ultrasonographic findings obtained in 2001 - 2002. Results The multivariate-adjusted model showed that age (odds ratio (OR, 1.034; 95% confidence interval (95%CI, 1.010 - 1.059, HbA1c (OR, 1.477; 95%CI, 0.980 - 2.225, and photometric O/N (OR, 2.012; 95%CI, 1.000 - 4.051 were significant variables that could independently predict the risk of new carotid artery atherosclerosis. Conclusion The susceptibility of LDL to oxidation was a significant parameter that could predict new carotid artery atherosclerosis over a 5-year period, and higher susceptibility was associated with a higher incidence of new carotid artery atherosclerosis.

  13. RHD maternal-fetal genotype incompatibility increases schizophrenia susceptibility.

    Science.gov (United States)

    Palmer, Christina G S; Turunen, Joni A; Sinsheimer, Janet S; Minassian, Sonia; Paunio, Tiina; Lönnqvist, Jouko; Peltonen, Leena; Woodward, J Arthur

    2002-12-01

    Fetal events and obstetric complications are associated with schizophrenia. Here we report the results of a family-based candidate-gene study that assesses the role of maternal-fetal genotype incompatibility at the RHD locus in schizophrenia. We adapted the case-parent-trio log-linear modeling approach to test for RHD maternal-fetal genotype incompatibility and to distinguish this effect from a high-risk allele at or near the RHD locus and from a direct maternal effect alone. Eighty-eight patient-parent trios, 72 patient-mother pairs, and 21 patient-father pairs were genotyped at the RHD locus. Of the 181 patients, 62% were male and 81% were second born or later. Only three patients were born after prophylaxis against maternal isoimmunization had become common practice. There was significant evidence for an RHD maternal-fetal genotype incompatibility, and the incompatibility parameter was estimated at 2.6. There was no evidence to support linkage/association with schizophrenia at or near the RHD locus nor any evidence to support the role of maternal genotype effect alone. Our results replicate previous findings that implicate the RHD locus in schizophrenia, and the candidate-gene design of this study allows the elimination of alternative explanations for the role of this locus in disease. Thus, the present study provides increasing evidence that the RHD locus increases schizophrenia risk through a maternal-fetal genotype incompatibility mechanism that increases risk of an adverse prenatal environment (e.g., Rh incompatibility) rather than through linkage/association with the disorder, linkage disequilibrium with an unknown nearby susceptibility locus, or a direct maternal effect alone. This is the first candidate-gene study to explicitly test for and provide evidence of a maternal-fetal genotype incompatibility mechanism in schizophrenia.

  14. Polytrauma Increases Susceptibility to Pseudomonas Pneumonia in Mature Mice.

    Science.gov (United States)

    Turnbull, Isaiah R; Ghosh, Sarbani; Fuchs, Anja; Hilliard, Julia; Davis, Christopher G; Bochicchio, Grant V; Southard, Robert E

    2016-05-01

    Pneumonia is the most common complication observed in patients with severe injuries. Although the average age of injured patients is 47 years, existing studies of the effect of injury on the susceptibility to infectious complications have focused on young animals, equivalent to a late adolescent human. We hypothesized that mature adult animals are more susceptible to infection after injury than younger counterparts. To test this hypothesis, we challenged 6 to 8-month-old mature mice to a polytrauma injury followed by Pseudomonas aeruginosa pneumonia and compared them to young (8-10-week-old) animals. We demonstrate that polytrauma injury increases mortality from pneumonia in mature animals (sham-pneumonia 21% vs. polytrauma-pneumonia 62%) but not younger counterparts. After polytrauma, pneumonia in mature mice is associated with higher bacterial burden in lung, increased incidence of bacteremia, and elevated levels of bacteria in the blood, demonstrating that injury decreases the ability to control the infectious challenge. We further find that polytrauma did not induce elevations in circulating cytokine levels (TNF-alpha, IL-6, KC, and IL-10) 24  h after injury. However, mature mice subjected to polytrauma demonstrated an exaggerated circulating inflammatory cytokine response to subsequent Pseudomonas pneumonia. Additionally, whereas prior injury increases LPS-stimulated IL-6 production by peripheral blood leukocytes from young (8-10-week-old) mice, injury does not prime IL-6 production by cell from mature adult mice. We conclude that in mature mice polytrauma results in increased susceptibility to Pseudomonas pneumonia while priming an exaggerated but ineffective inflammatory response.

  15. Species belonging to the "Streptococcus milleri" group: antimicrobial susceptibility and comparative prevalence in significant clinical specimens.

    Science.gov (United States)

    Bantar, C; Fernandez Canigia, L; Relloso, S; Lanza, A; Bianchini, H; Smayevsky, J

    1996-01-01

    The association between the three species belonging to the "Streptococcus milleri" group and different sites of isolation was examined for 73 successive strains recovered from clinically significant, purulent infections. Susceptibility testing was performed on 64 of these strains. The present study supports the association of particular species with different clinical sources. Susceptibility data suggest that emerging penicillin resistance among Streptococcus anginosus and Streptococcus intermedius isolates may represent a potential clinical problem in the therapeutic management of infections caused by these species. PMID:8818904

  16. Air pollution increases forest susceptibility to wildfires: a case study for the San Bernardino Mountains in southern California

    Science.gov (United States)

    N.E. Grulke; R.A. Minnich; T. Paine; P. Riggan

    2010-01-01

    Many factors increase susceptibility of forests to wildfire. Among them are increases in human population, changes in land use, fire suppression, and frequent droughts. These factors have been exacerbating forest susceptibility to wildfires over the last century in southern California. Here we report on the significant role that air pollution has on increasing forest...

  17. Clinical significance, antimicrobial susceptibility and molecular identification of Nocardia species isolated from children with cystic fibrosis.

    Science.gov (United States)

    Betrán, Ana; Villuendas, M Cruz; Rezusta, Antonio; Pereira, Javier; Revillo, M José; Rodríguez-Nava, Verónica

    2016-01-01

    Nocardia is an opportunistic pathogen that causes respiratory infections in immunocompromised patients. The aim of this study was to analyze the epidemiology, clinical significance and antimicrobial susceptibility of Nocardia species isolated from eight children with cystic fibrosis. The isolated species were identified as Nocardia farcinica, Nocardia transvalensis, Nocardia pneumoniae, Nocardia veterana and Nocardia wallacei. N. farcinica was isolated in three patients and all of them presented lung affectation with a chronic colonization and pneumonia. N. farcinica showed resistance against gentamicin, tobramycin, cefotaxime, but was susceptible to trimethoprim-sulfamethoxazole and amikacin. N. transvalensis, which was isolated from two patients, showed an association with chronic colonization. N. transvalensis was resistant to tobramycin and amikacin, but susceptible to ciprofloxacin, trimethoprim-sulfamethoxazole and cefotaxime. N. veterana, N. pneumoniae and N. wallacei were isolated from three different patients and appeared in transitory lung colonization. N. veterana and N. pneumoniae were susceptible to imipenem, trimethoprim-sulfamethoxazole, amikacin, tobramycin, and cefotaxime. N. wallacei was resistant to amikacin, tobramycin, imipenem, and trimethoprim-sulfamethoxazole and susceptible to ciprofloxacin and cefotaxime. All the isolates were identified up to species level by 16S rRNA gene sequencing. The presence of Nocardia in the sputum of patients with cystic fibrosis is not always an indication of an active infection; therefore, the need for a treatment should be evaluated on an individual basis. The detection of multidrug-resistant species needs molecular identification and susceptibility testing, and should be performed for all Nocardia infections. Copyright © 2016 Sociedade Brasileira de Microbiologia. Published by Elsevier Editora Ltda. All rights reserved.

  18. Increased False-Memory Susceptibility After Mindfulness Meditation.

    Science.gov (United States)

    Wilson, Brent M; Mickes, Laura; Stolarz-Fantino, Stephanie; Evrard, Matthew; Fantino, Edmund

    2015-10-01

    The effect of mindfulness meditation on false-memory susceptibility was examined in three experiments. Because mindfulness meditation encourages judgment-free thoughts and feelings, we predicted that participants in the mindfulness condition would be especially likely to form false memories. In two experiments, participants were randomly assigned to either a mindfulness induction, in which they were instructed to focus attention on their breathing, or a mind-wandering induction, in which they were instructed to think about whatever came to mind. The overall number of words from the Deese-Roediger-McDermott paradigm that were correctly recalled did not differ between conditions. However, participants in the mindfulness condition were significantly more likely to report critical nonstudied items than participants in the control condition. In a third experiment, which tested recognition and used a reality-monitoring paradigm, participants had reduced reality-monitoring accuracy after completing the mindfulness induction. These results demonstrate a potential unintended consequence of mindfulness meditation in which memories become less reliable. © The Author(s) 2015.

  19. Analysis of significance of environmental factors in landslide susceptibility modeling: Case study Jemma drainage network, Ethiopia

    Directory of Open Access Journals (Sweden)

    Vít Maca

    2017-06-01

    Full Text Available Aim of the paper is to describe methodology for calculating significance of environmental factors in landslide susceptibility modeling and present result of selected one. As a study area part of a Jemma basin in Ethiopian Highland is used. This locality is highly affected by mass movement processes. In the first part all major factors and their influence are described briefly. Majority of the work focuses on research of other methodologies used in susceptibility models and design of own methodology. This method is unlike most of the methods used completely objective, therefore it is not possible to intervene in the results. In article all inputs and outputs of the method are described as well as all stages of calculations. Results are illustrated on specific examples. In study area most important factor for landslide susceptibility is slope, on the other hand least important is land cover. At the end of article landslide susceptibility map is created. Part of the article is discussion of results and possible improvements of the methodology.

  20. Magnetic susceptibility of surface soils in the Mu Us Desert and its environmental significance

    Science.gov (United States)

    Liu, Xiaokang; Lu, Ruijie; Lü, Zhiqiang; Du, Jing; Jia, Feifei; Li, Tengfei; Chen, Lu; Wu, Yongqiu

    2017-04-01

    Magnetic susceptibility has been widely used as a climatic proxy in paleoclimatic research. In arid and semi-arid regions, the magnetic properties of modern surface soil are significantly influenced by precipitation. This is demonstrated by observed positive correlations between percentage frequency-dependent magnetic susceptibility (χfd%), which reflects the presence of fine-grained (superparamagnetic, SP) grains produced during weathering and pedogenesis, and regional mean annual precipitation (MAP). To further investigate this relationship, we measured the magnetic properties of 104 surface soil samples collected along two transects (AA and BB) spanning a rainfall gradient across the Mu Us Desert in northern China. There were no systematic trends in magnetic properties along transect BB; the χfd% values remained relatively low and stable, probably reflecting weak pedogenesis and the domination of the magnetic properties by lithology. In contrast, along transect AA there was a significant positive correlation (p modern Mu Us Desert. The results show that the variations of reconstructed precipitation are consistent with those of lithological properties, and they also confirm previous conclusions that paleosol development in the study area is dominated by precipitation. Overall the results further demonstrate the feasibility of using frequency-dependent magnetic susceptibility to quantitatively reconstruct regional paleo-precipitation, including within a geographically diverse desert area. In addition, they provide an improved understanding of the main sand provenance in Mu Us Desert.

  1. Sidestream smoke exposure increases the susceptibility of airway epithelia to adenoviral infection.

    Directory of Open Access Journals (Sweden)

    Priyanka Sharma

    Full Text Available Although significant epidemiological evidence indicates that cigarette smoke exposure increases the incidence and severity of viral infection, the molecular mechanisms behind the increased susceptibility of the respiratory tract to viral pathogens are unclear. Adenoviruses are non-enveloped DNA viruses and important causative agents of acute respiratory disease. The Coxsackievirus and adenovirus receptor (CAR is the primary receptor for many adenoviruses. We hypothesized that cigarette smoke exposure increases epithelial susceptibility to adenovirus infection by increasing the abundance of apical CAR.Cultured human airway epithelial cells (CaLu-3 were used as a model to investigate the effect of sidestream cigarette smoke (SSS, mainstream cigarette smoke (MSS, or control air exposure on the susceptibility of polarized respiratory epithelia to adenoviral infection. Using a Cultex air-liquid interface exposure system, we have discovered novel differences in epithelial susceptibility between SSS and MSS exposures. SSS exposure upregulates an eight-exon isoform of CAR and increases adenoviral entry from the apical surface whilst MSS exposure is similar to control air exposure. Additionally, the level of cellular glycogen synthase kinase 3β (GSK3β is downregulated by SSS exposure and treatment with a specific GSK3β inhibitor recapitulates the effects of SSS exposure on CAR expression and viral infection.This is the first time that SSS exposure has been shown to directly enhance the susceptibility of a polarized epithelium to infection by a common respiratory viral pathogen. This work provides a novel understanding of the impact of SSS on the burden of respiratory viral infections and may lead to new strategies to alter viral infections. Moreover, since GSK3β inhibitors are under intense clinical investigation as therapeutics for a diverse range of diseases, studies such as these might provide insight to extend the use of clinically relevant

  2. Sidestream smoke exposure increases the susceptibility of airway epithelia to adenoviral infection.

    Science.gov (United States)

    Sharma, Priyanka; Kolawole, Abimbola O; Core, Susan B; Kajon, Adriana E; Excoffon, Katherine J D A

    2012-01-01

    Although significant epidemiological evidence indicates that cigarette smoke exposure increases the incidence and severity of viral infection, the molecular mechanisms behind the increased susceptibility of the respiratory tract to viral pathogens are unclear. Adenoviruses are non-enveloped DNA viruses and important causative agents of acute respiratory disease. The Coxsackievirus and adenovirus receptor (CAR) is the primary receptor for many adenoviruses. We hypothesized that cigarette smoke exposure increases epithelial susceptibility to adenovirus infection by increasing the abundance of apical CAR. Cultured human airway epithelial cells (CaLu-3) were used as a model to investigate the effect of sidestream cigarette smoke (SSS), mainstream cigarette smoke (MSS), or control air exposure on the susceptibility of polarized respiratory epithelia to adenoviral infection. Using a Cultex air-liquid interface exposure system, we have discovered novel differences in epithelial susceptibility between SSS and MSS exposures. SSS exposure upregulates an eight-exon isoform of CAR and increases adenoviral entry from the apical surface whilst MSS exposure is similar to control air exposure. Additionally, the level of cellular glycogen synthase kinase 3β (GSK3β) is downregulated by SSS exposure and treatment with a specific GSK3β inhibitor recapitulates the effects of SSS exposure on CAR expression and viral infection. This is the first time that SSS exposure has been shown to directly enhance the susceptibility of a polarized epithelium to infection by a common respiratory viral pathogen. This work provides a novel understanding of the impact of SSS on the burden of respiratory viral infections and may lead to new strategies to alter viral infections. Moreover, since GSK3β inhibitors are under intense clinical investigation as therapeutics for a diverse range of diseases, studies such as these might provide insight to extend the use of clinically relevant therapeutics and

  3. Increasing trend of fluconazole-non-susceptible Cryptococcus neoformans in patients with invasive cryptococcosis: a 12-year longitudinal study.

    Science.gov (United States)

    Chen, Yi-Chun; Chang, Tzu-Yao; Liu, Jien-Wei; Chen, Fang-Ju; Chien, Chun-Chih; Lee, Chen-Hsiang; Lu, Cheng-Hsien

    2015-07-22

    This study aimed to investigate the rate of fluconazole-non-susceptible Cryptococcus neoformans in Southern Taiwan for the period 2001-2012 and analyze the risk factors for acquiring it among patients with invasive cryptococcosis. All enrolled strains were isolated from blood or cerebrospinal fluid samples of the included patients. If a patient had multiple positive results for C. neoformans, only the first instance was enrolled. Susceptibility testing was performed using the Clinical and Laboratory Standards Institutes M27-A3 broth micro-dilution method. The MIC interpretative criteria for susceptibility to fluconazole were ≤ 8 μg/ml. A total of 89 patients were included. Patients (n = 59) infected by fluconazole-susceptible strains were compared with those (n = 30) infected by non-susceptible strains. The patients' demographic and clinical characteristics were analyzed. The rate of fluconazole-non-susceptible C. neoformans in the study period significantly increased over time (p fluconazole-non-susceptible C. neoformans. The rate of fluconazole-non-susceptible C. neoformans has significantly increased recently. Continuous and large-scale anti-fungal susceptibility tests for C. neoformans are warranted to confirm this trend.

  4. Alzheimer skin fibroblasts show increased susceptibility to free radicals.

    Science.gov (United States)

    Tesco, G; Latorraca, S; Piersanti, P; Piacentini, S; Amaducci, L; Sorbi, S

    1992-11-01

    We have studied the response to toxic oxygen metabolites of fibroblasts derived from skin biopsies of 5 patients with familial (FAD) and 4 with sporadic (AD) Alzheimer's disease compared with those derived from 4 normal controls. Fibroblasts were damaged by the generation of oxygen metabolites during the enzymatic oxidation of acetaldehyde by 50 munits of xanthine-oxidase (Xo). To quantify cell damage we measured lactate dehydrogenase (LDH) activity in the culture medium and cell viability in fibroblast cultures. We found a significant increase in LDH activity in the FAD vs. controls and also in the AD vs. controls.

  5. The association of genome-wide significant spirometric loci with chronic obstructive pulmonary disease susceptibility.

    Science.gov (United States)

    Castaldi, Peter J; Cho, Michael H; Litonjua, Augusto A; Bakke, Per; Gulsvik, Amund; Lomas, David A; Anderson, Wayne; Beaty, Terri H; Hokanson, John E; Crapo, James D; Laird, Nan; Silverman, Edwin K

    2011-12-01

    Two recent metaanalyses of genome-wide association studies conducted by the CHARGE and SpiroMeta consortia identified novel loci yielding evidence of association at or near genome-wide significance (GWS) with FEV(1) and FEV(1)/FVC. We hypothesized that a subset of these markers would also be associated with chronic obstructive pulmonary disease (COPD) susceptibility. Thirty-two single-nucleotide polymorphisms (SNPs) in or near 17 genes in 11 previously identified GWS spirometric genomic regions were tested for association with COPD status in four COPD case-control study samples (NETT/NAS, the Norway case-control study, ECLIPSE, and the first 1,000 subjects in COPDGene; total sample size, 3,456 cases and 1,906 controls). In addition to testing the 32 spirometric GWS SNPs, we tested a dense panel of imputed HapMap2 SNP markers from the 17 genes located near the 32 GWS SNPs and in a set of 21 well studied COPD candidate genes. Of the previously identified GWS spirometric genomic regions, three loci harbored SNPs associated with COPD susceptibility at a 5% false discovery rate: the 4q24 locus including FLJ20184/INTS12/GSTCD/NPNT, the 6p21 locus including AGER and PPT2, and the 5q33 locus including ADAM19. In conclusion, markers previously associated at or near GWS with spirometric measures were tested for association with COPD status in data from four COPD case-control studies, and three loci showed evidence of association with COPD susceptibility at a 5% false discovery rate.

  6. The incidence of melanoma is increasing in the susceptible young Australian population.

    Science.gov (United States)

    Czarnecki, Douglas

    2014-09-01

    The number of melanomas removed from Australians is increasing. Despite this, it has been reported that the incidence of melanoma is decreasing in the young Australian population. However, the denominator for these estimates includes individuals at low risk of melanoma, and the proportion of such individuals has changed over recent decades due to immigration. In this study, the incidence was calculated for the susceptible young population. Data from the Australian Bureau of Statistics were analysed to determine the number of people younger than 30 years at low risk of developing melanoma in 1982 and 2009. Low risk people were defined as those born in Asia, the Pacific Islands, The Middle East, or Sub-Saharan Africa, or had parents born in these regions. There was a significant increase in the number of young Australians at low risk for melanoma. If these people are not included when calculating the crude rate of melanoma, the rate increased from 5.9 per 100,000 in 1982 to 6.3 in 2009. If the estimated number of young Maoris and young Aborigines is excluded from the susceptible population, the crude rate increased from 6.0 per 100,000 in 1982 to 6.8 in 2009. This is the first calculation of the rate of melanoma for the susceptible young Australian population.

  7. Aire deficiency causes increased susceptibility to streptozotocin-induced murine type 1 diabetes.

    Science.gov (United States)

    Hässler, S; Peltonen, L; Sandler, S; Winqvist, O

    2008-06-01

    Aire-deficient mice are a model of the human monogenic disorder autoimmune polyendocrine syndrome type I (APS I) characterized by a progressive autoimmune destruction of multiple endocrine glands such as the adrenal cortex, the parathyroids and the beta-cells of the pancreas. The disease is caused by mutations in the autoimmune regulator (AIRE) gene, a putative transcription factor expressed in thymic medullary epithelial cells and in antigen-presenting cells of the myeloid lineage in peripheral lymphoid organs. As Aire(-/-) mice do not spontaneously develop endocrinopathies, we wanted to evaluate the autoimmune multiple low-dose streptozotocin (MLDSTZ) diabetes model in Aire(-/-) mice. Surprisingly, Aire heterozygote mice were most susceptible to MLDSTZ-induced diabetes, whereas Aire(-/-) mice displayed an intermediate sensitivity to diabetes. Furthermore, Aire(-/-) macrophages produced higher levels of TNF-alpha and lower levels of IL-10 following streptozotocin stimulation, and Aire(-/-) mice developed a higher frequency of islet cells autoantibodies as a sign of increased activation. However, the number of islet infiltrating F4/80(+) Aire(-/-) macrophages was significantly decreased which was attributed to an increased susceptibility to streptozotocin cytotoxicity of Aire(-/-) macrophages. In conclusion, Aire(-/-) macrophages display an increased activation after STZ stimuli, but suffer from increased susceptibility to STZ cytotoxicity. These results support an important function of Aire in the control of peripheral tolerance through myeloid antigen-presenting cells.

  8. Protection of susceptible potato cultivars against late blight in mixtures increases with decreasing disease pressure.

    Science.gov (United States)

    Pilet, F; Chacón, G; Forbes, G A; Andrivon, D

    2006-07-01

    ABSTRACT Cultivar mixtures can reduce potato late blight severity on susceptible cultivars. While alternating rows of susceptible and resistant cultivars would be more acceptable than random mixtures for commercial use, they increase the genotype unit area, which is an unfavorable factor for mixture efficiency, and have been minimally efficient when disease pressure is high. The effects of disease pressure on the performance of alternating rows of cultivars possessing various types and levels of resistance were investigated in 2000 and 2001 near Quito, Ecuador, where natural pressure of late blight is high. The experiments included the highly susceptible cvs. Cecilia in 2000 and LBr37 in 2001, as well as C114 (moderately resistant) and PAN (highly resistant), planted as pure stands and as the three possible two-way combinations. Different disease pressures were obtained with three spraying schedules of a contact fungicide: nontreated, one spray every second week, and one spray weekly. The area under the disease progress curve (AUDPC) on the susceptible cultivar was 0 to 20% less in mixed than in pure plots when no fungicide was applied, 13 to 26% less with a biweekly application of fungicide, and 32 to 53% less with a weekly application. These values are comparable to those obtained in previous experiments in smaller plots with designs maximizing the distance between susceptible plants. No significant differences in mixture performance were observed according to the resistant cultivar included. Effects on yield were minimal, because of the impact of factors other than late blight. Disease pressure therefore appears as a major factor conditioning the efficiency of potato cultivar mixtures against late blight.

  9. Significant association of methylenetetrahydrofolate reductase single nucleotide polymorphisms with prostate cancer susceptibility in taiwan.

    Science.gov (United States)

    Wu, Hsi-Chin; Chang, Chao-Hsiang; Tsai, Ru-Yin; Lin, Chih-Hsueh; Wang, Rou-Fen; Tsai, Chia-Wen; Chen, Kuen-Bao; Yao, Chun-Hsu; Chiu, Chang-Fang; Bau, Da-Tian; Lin, Cheng-Chieh

    2010-09-01

    Prostate cancer is the most common cause of cancer death in men and is a major health problem worldwide. Methylene tetrahydrofolate reductase (MTHFR) plays an important role in folate metabolism and is also an important source of DNA methylation and DNA synthesis (nucleotide synthesis). To assess the association and interaction of genotypic polymorphisms in MTHFR and lifestyle factors with prostate cancer in Taiwan, we investigated two well-known polymorphic variants of MTHFR, C677T (rs1801133) and A1298C (rs1801131), analyzed the association of specific genotypes with prostate cancer susceptibility, and discussed their joint effects with individual habits on prostate cancer risk. In total, 218 patients with prostate cancer and 436 healthy controls recruited from the China Medical Hospital in central Taiwan were genotyped for these polymorphisms with prostate cancer susceptibility. We found the MTHFR C677T but not the A1298C genotype was differently distributed between the prostate cancer and control groups. The T allele of MTHFR C677T conferred a significantly (p=0.0011) decreased risk of prostate cancer. As for the A1298C polymorphism, there was no difference in distribution between the prostate cancer and control groups. Gene interactions with smoking were significant for MTHFR C677T polymorphism. The MTHFR C677T CT and TT genotypes in association with smoking conferred a decreased risk of 0.501 (95% confidence interval=0.344-0.731) for prostate cancer. Our results provide the first evidence that the C allele of MTHFR C677T may be associated with the development of prostate cancer and may be a novel useful marker for primary prevention and anticancer intervention.

  10. Climate impacts of oil extraction increase significantly with oilfield age

    Science.gov (United States)

    Masnadi, Mohammad S.; Brandt, Adam R.

    2017-08-01

    Record-breaking temperatures have induced governments to implement targets for reducing future greenhouse gas (GHG) emissions. Use of oil products contributes ~35% of global GHG emissions, and the oil industry itself consumes 3-4% of global primary energy. Because oil resources are becoming increasingly heterogeneous, requiring different extraction and processing methods, GHG studies should evaluate oil sources using detailed project-specific data. Unfortunately, prior oil-sector GHG analysis has largely neglected the fact that the energy intensity of producing oil can change significantly over the life of a particular oil project. Here we use decades-long time-series data from twenty-five globally significant oil fields (>1 billion barrels ultimate recovery) to model GHG emissions from oil production as a function of time. We find that volumetric oil production declines with depletion, but this depletion is accompanied by significant growth--in some cases over tenfold--in per-MJ GHG emissions. Depletion requires increased energy expenditures in drilling, oil recovery, and oil processing. Using probabilistic simulation, we derive a relationship for estimating GHG increases over time, showing an expected doubling in average emissions over 25 years. These trends have implications for long-term emissions and climate modelling, as well as for climate policy.

  11. Significant Impacts of Increasing Aridity on the Arid Soil Microbiome.

    Science.gov (United States)

    Neilson, Julia W; Califf, Katy; Cardona, Cesar; Copeland, Audrey; van Treuren, Will; Josephson, Karen L; Knight, Rob; Gilbert, Jack A; Quade, Jay; Caporaso, J Gregory; Maier, Raina M

    2017-01-01

    Global deserts occupy one-third of the Earth's surface and contribute significantly to organic carbon storage, a process at risk in dryland ecosystems that are highly vulnerable to climate-driven ecosystem degradation. The forces controlling desert ecosystem degradation rates are poorly understood, particularly with respect to the relevance of the arid-soil microbiome. Here we document correlations between increasing aridity and soil bacterial and archaeal microbiome composition along arid to hyperarid transects traversing the Atacama Desert, Chile. A meta-analysis reveals that Atacama soil microbiomes exhibit a gradient in composition, are distinct from a broad cross-section of nondesert soils, and yet are similar to three deserts from different continents. Community richness and diversity were significantly positively correlated with soil relative humidity (SoilRH). Phylogenetic composition was strongly correlated with SoilRH, temperature, and electrical conductivity. The strongest and most significant correlations between SoilRH and phylum relative abundance were observed for Acidobacteria, Proteobacteria, Planctomycetes, Verrucomicrobia, and Euryarchaeota (Spearman's rank correlation [rs] = >0.81; false-discovery rate [q] = ≤0.005), characterized by 10- to 300-fold decreases in the relative abundance of each taxon. In addition, network analysis revealed a deterioration in the density of significant associations between taxa along the arid to hyperarid gradient, a pattern that may compromise the resilience of hyperarid communities because they lack properties associated with communities that are more integrated. In summary, results suggest that arid-soil microbiome stability is sensitive to aridity as demonstrated by decreased community connectivity associated with the transition from the arid class to the hyperarid class and the significant correlations observed between soilRH and both diversity and the relative abundances of key microbial phyla typically

  12. Bark Beetles as Significant Forest Disturbances: Estimating Susceptibility Based On Stand Structure

    Science.gov (United States)

    Hicke, J. A.; Jenkins, J. C.

    2007-12-01

    In the western United States, bark beetle outbreaks affect millions of hectares of forests. These disturbances have multiple effects on ecosystems, including modifications to biogeochemical cycles, interactions with fire, and changes in land cover type and species composition. In recent years, extensive outbreaks have occurred in multiple forest ecosystems in the West, thought to be caused by climate variability and stand structure. In this study, we focus on epidemics of mountain pine beetle. We used USDA Forest Service inventories and a model to estimate lodgepole pine susceptibility to mountain pine beetle attack in the West. The model considers stand age, stem density, and percentage of large lodgepole pine to estimate stand susceptibility. Over 150,000 trees in 4454 plots across the western United States were used to compute susceptibility at the plot scale as well as map susceptibility at the county scale. We found that regional susceptibility was high (estimated potential of losses of 34% of stand basal area) for 2.8 Mha, or 46%, of lodgepole pine forests. The highest susceptibility occurred in the Rocky Mountains, with lower susceptibility in coastal states. This study reveals that a substantial fraction of lodgepole pine forest could be subjected to bark beetle outbreaks under current climate conditions. Because climate and weather affect beetle populations, projected future warming will influence outbreak regimes. Thus, forest ecosystems in the West may experience more frequent, extensive, and/or severe disturbances than in recent decades due to current stand structure, and these disturbances may be intensified under climate change.

  13. Beta defensin-1 gene polymorphisms and susceptibility to atypical squamous cells of undetermined significance lesions in Italian gynecological patients.

    Science.gov (United States)

    Casalicchio, Giorgia; Freato, Nadia; Maestri, Iva; Comar, Manola; Crovella, Sergio; Segat, Ludovica

    2014-12-01

    The role of the human beta-defensin 1 (hBD-1) in the susceptibility to the onset of the Atypical Squamous Cells of Undetermined Significance (ASCUS) lesion, in the presence or not of HPV infection, is still unknown. In the current study, the three functional single nucleotide polymorphisms (SNPs) -52G > A, -44C > G, and -20G > A at the 5' un-translated region (UTR) of DEFB1 gene, encoding hBD-1, were analyzed in ASCUS lesion gynecological patients and healthy women from the north-east of Italy (Trieste). Cervical samples from 249 European-Caucasian women were collected, screened for HPV and cytologically evaluated; DEFB1 genotyping has been performed by direct sequencing. No significant differences were found for -52G > A, -44C > G, and -20G > A SNPs allele and genotype frequencies between women with and without ASCUS lesions. DEFB1 minor haplotypes were significantly more frequent in ASCUS lesion positive than negative women, associating with an increased risk of this type of lesion. When women were stratified according to HPV infection status, significant differences in the distribution of -52G > A SNP genotype frequencies were found: the presence of the A allele in the homozygous genotype A/A associated with a lower risk of developing ASCUS lesions in HPV negative women. DEFB1 minor haplotypes were also associated with an increased risk of developing ASCUS lesions, being significantly more frequent in HPV negative women with lesions, than without lesions. Although these results highlight the possible involvement of DEFB1, further studies are needed to support the role of DEFB1 in the modulation of the susceptibility to ASCUS lesions. © 2014 Wiley Periodicals, Inc.

  14. Significance of increased leptin expression in osteoarthritis patients.

    Directory of Open Access Journals (Sweden)

    Ping Zhang

    Full Text Available Alterations in leptin expression contributes to the progression of various diseases, including cancers. This meta-analysis investigated the clinical significance of leptin levels in osteoarthritis (OA patients, with the goal of building a leptin-based diagnostic criterion for OA.Multiple scientific databases in English and Chinese languages, such as the Cochrane Library Database, CINAHL, Chinese Biomedical (CBM, EMBASE, PubMed, and Web of Science, were exhaustively searched, without any language restrictions, to identify high-quality studies relevant to leptin and OA. Version 12.0 STATA software was used for data analysis. We used odds ratios (OR and 95% confidence intervals (CI to test the correlation between serum leptin levels and OA progression.A total of 11 clinical studies were finally selected for their high quality and relevance to the topic in this meta-analysis. The 11 case-control studies contained a combined total of 3,625 subjects. The meta-analysis results showed that leptin expression was significantly increased in OA patients, compared with the controls (SMD = 0.87, 95%CI: 0.72-1.02, P < 0.001, and there was also a strong association between leptin expression levels and gender (SMD = 8.55, 95%CI: 4.74-12.35, P < 0.001. In ethnicity-stratified subgroup analysis, all the study populations, irrespective of ethnicity, showed remarkably high leptin expression levels in females and in OA patients (all P < 0.05, compared to their respective counterparts.The present study revealed that increased leptin expression levels are associated with disease severity in OA patients, especially among the female OA patients. Based on our results, we propose that leptin level may be a useful biomarker for the assessment of the clinical status in OA patients.

  15. Significance of increased leptin expression in osteoarthritis patients.

    Science.gov (United States)

    Zhang, Ping; Zhong, Zhi-Hong; Yu, Hao-Tao; Liu, Bin

    2015-01-01

    Alterations in leptin expression contributes to the progression of various diseases, including cancers. This meta-analysis investigated the clinical significance of leptin levels in osteoarthritis (OA) patients, with the goal of building a leptin-based diagnostic criterion for OA. Multiple scientific databases in English and Chinese languages, such as the Cochrane Library Database, CINAHL, Chinese Biomedical (CBM), EMBASE, PubMed, and Web of Science, were exhaustively searched, without any language restrictions, to identify high-quality studies relevant to leptin and OA. Version 12.0 STATA software was used for data analysis. We used odds ratios (OR) and 95% confidence intervals (CI) to test the correlation between serum leptin levels and OA progression. A total of 11 clinical studies were finally selected for their high quality and relevance to the topic in this meta-analysis. The 11 case-control studies contained a combined total of 3,625 subjects. The meta-analysis results showed that leptin expression was significantly increased in OA patients, compared with the controls (SMD = 0.87, 95%CI: 0.72-1.02, P leptin expression levels and gender (SMD = 8.55, 95%CI: 4.74-12.35, P leptin expression levels in females and in OA patients (all P leptin expression levels are associated with disease severity in OA patients, especially among the female OA patients. Based on our results, we propose that leptin level may be a useful biomarker for the assessment of the clinical status in OA patients.

  16. Increased susceptibility to Pseudomonas aeruginosa infection under hindlimb-unloading conditions

    Science.gov (United States)

    Aviles, Hernan; Belay, Tesfaye; Fountain, Kimberly; Vance, Monique; Sonnenfeld, Gerald

    2003-01-01

    It has been reported that spaceflight conditions alter the immune system and resistance to infection [Belay T, Aviles H, Vance M, Fountain K, and Sonnenfeld G. J Allergy Clin Immunol 170: 262-268, 2002; Hankins WR and Ziegelschmid JF. In: Biomedical Results of Apollo. Washington, DC: NASA, 1975, p. 43-81. (NASA Spec. Rep. SP-368)]. Ground-based models, including the hindlimb-unloading model, have become important tools for increasing understanding of how spaceflight conditions can influence physiology. The objective of the present study was to determine the effect of hindlimb unloading on the susceptibility of mice to Pseudomonas aeruginosa infection. Hindlimb-unloaded and control mice were subcutaneously infected with 1 LD50 of P. aeruginosa. Survival, bacterial organ load, and antibody and corticosterone levels were compared among the groups. Hindlimb unloading had detrimental effects for infected mice. Animals in the hindlimb-unloaded group, compared with controls, 1). showed significantly increased mortality and reduced time to death, 2). had increased levels of corticosterone, and 3). were much less able to clear bacteria from the organs. These results suggest that hindlimb unloading may induce the production of corticosterone, which may play a critical role in the modulation of the immune system leading to increased susceptibility to P. aeruginosa infection.

  17. Decreased Polysaccharide Feruloylation Compromises Plant Cell Wall Integrity and Increases Susceptibility to Necrotrophic Fungal Pathogens

    Directory of Open Access Journals (Sweden)

    Nathan T Reem

    2016-05-01

    Full Text Available The complexity of cell wall composition and structure determines the strength, flexibility, and function of the primary cell wall in plants. However, the contribution of the various components to cell wall integrity and function remains unclear. Modifications of cell wall composition can induce plant responses known as Cell Wall Integrity control. In this study, we used transgenic expression of the fungal feruloyl esterase AnFAE to examine the effect of post-synthetic modification of Arabidopsis and Brachypodium cell walls. Transgenic Arabidopsis plants expressing AnFAE showed a significant reduction of monomeric ferulic acid, increased amounts of wall-associated extensins, and increased susceptibility to Botrytis cinerea, compared with wild type. Transgenic Brachypodium showed reductions in monomeric and dimeric ferulic acids and increased susceptibility to Bipolaris sorokiniana. Upon infection, transgenic Arabidopsis and Brachypodium plants also showed increased expression of several defense-related genes compared with wild type. These results demonstrate a role, in both monocot and dicot plants, of polysaccharide feruloylation in plant cell wall integrity, which contributes to plant resistance to necrotrophic pathogens.

  18. MicroRNA gene polymorphisms and environmental factors increase patient susceptibility to hepatocellular carcinoma.

    Directory of Open Access Journals (Sweden)

    Yin-Hung Chu

    Full Text Available BACKGROUND: Micro RNAs (miRNAs are small RNA fragments that naturally exist in the human body. Through various physiological mechanisms, miRNAs can generate different functions for regulating RNA protein levels and balancing abnormalities. Abnormal miRNA expression has been reported to be highly related to several diseases and cancers. Single-nucleotide polymorphisms (SNPs in miRNAs have been reported to increase patient susceptibility and affect patient prognosis and survival. We adopted a case-control research design to verify the relationship between miRNAs and hepatocellular carcinoma. METHODOLOGY/PRINCIPAL FINDINGS: A total of 525 subjects, including 377 controls and 188 hepatocellular carcinoma patients, were selected. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP and real-time PCR were used to analyze miRNA146a (rs2910164, miRNA149 (rs2292832, miRNA196 (rs11614913, and miRNA499 (rs3746444 genetic polymorphisms between the control group and the case group. The results indicate that people who carry the rs3746444 CT or CC genotypes may have a significantly increased susceptibility to hepatocellular carcinoma (adjusted odds ratio [AOR] = 2.84, 95% confidence interval [CI] = 1.88-4.30. In addition, when combined with environmental risk factors, such as smoking and alcohol consumption, interaction effects were observed between gene polymorphisms and environmental factors (odds ratio [OR] = 4.69, 95% CI = 2.52-8.70; AOR = 3.38, 95% CI = 1.68-6.80. CONCLUSIONS: These results suggest that a significant association exists between miRNA499 SNPs and hepatocellular carcinoma. Gene-environment interactions of miRNA499 polymorphisms, smoking, and alcohol consumption might alter hepatocellular carcinoma susceptibility.

  19. Elevated fasting insulin level significantly increases the risk of microalbuminuria.

    Science.gov (United States)

    Ryoo, Jae-Hong; Park, Sung Keun; Jung, Ju Young

    2015-01-01

    Microalbuminuria is significantly associated with long-term prognosis in the general population as well as in diabetic patients. It is well known that insulin resistance (IR) can induce microalbuminuria, but an elevated fasting insulin level, which is an early clinical manifestation of IR, as a risk factor for microalbuminuria has not been clarified, so we investigated the association between fasting insulin level and the development of microalbuminuria in a general population. A total of 1,192 non-diabetic Korean men without microalbuminuria in 2005 were followed until 2010. They were categorized into 3 groups according to their fasting insulin levels and monitored for the development of microalbuminuria. The incidence of microalbuminuria was compared among groups, and Cox proportional hazards models were used to calculate the hazard ratios for microalbuminuria according to the fasting insulin levels. During 4,013.0 person-years of follow-up, 51 incident cases of microalbuminuria developed between 2006 and 2010. The incidence of microalbuminuria increased in proportion to the fasting insulin levels (tertile 1: 1.8%, tertile 2: 4.5%, tertile 3: 6.5%, Pfasting insulin levels [tertile 1: reference, tertile 2: 2.44 (1.01-5.89), tertile 3: 3.30 (1.40-7.78), respectively, P for trend 0.013]. Elevated fasting insulin level was associated with the future development of microalbuminuria.

  20. Inadequate Brain Glycogen or Sleep Increases Spreading Depression Susceptibility

    KAUST Repository

    Kilic, Kivilcim

    2017-12-16

    Glycogen in astrocyte endfeet contributes to maintenance of low extracellular glutamate and K+ concentrations around synapses. Sleep deprivation (SD), a common migraine trigger induces transcriptional changes in astrocytes reducing glycogen breakdown. We hypothesize that when glycogen utilization cannot match synaptic energy demand, extracellular K+ can rise to levels that activate neuronal pannexin-1 channels and downstream inflammatory pathway, which might be one of the mechanisms initiating migraine headaches.We suppressed glycogen breakdown by inhibiting glycogen phosphorylation with 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) and by SD.DAB caused neuronal pannexin-1 large-pore opening and activation of the downstream inflammatory pathway as shown by procaspase-1 cleavage and HMGB1 release from neurons. Six-hour SD induced pannexin-1 mRNA. DAB and SD also lowered the cortical spreading depression (CSD) induction threshold, which was reversed by glucose or lactate supplement, suggesting that glycogen-derived energy substrates are needed to prevent CSD generation. Supporting this, knocking-down neuronal lactate transporter, MCT2 with an anti-sense oligonucleotide or inhibiting glucose transport from vessels to astrocytes with intracerebroventricularly given phloretin reduced the CSD threshold. In vivo recordings with a K+ -sensitive/selective fluoroprobe, APG-4 disclosed that DAB treatment or SD caused significant rise in extracellular K+ during whisker-stimulation, illustrating the critical role of glycogen in extracellular K+ clearance.Synaptic metabolic stress caused by insufficient glycogen-derived energy substrate supply can activate neuronal pannexin-1 channels as well as lowering the CSD threshold. Therefore, conditions that limit energy supply to synapse (e.g. SD) may predispose to migraine attacks as suggested by genetic studies associating glucose or lactate transporter deficiency with migraine. This article is protected by copyright. All rights reserved.

  1. Inventory and recently increasing GLOF susceptibility of glacial lakes in Sikkim, Eastern Himalaya

    Science.gov (United States)

    Aggarwal, Suruchi; Rai, S. C.; Thakur, P. K.; Emmer, Adam

    2017-10-01

    Climatic changes alter the climate system, leading to a decrease of glacier mass volumes and swelling glacial lakes. This study provides a new inventory of glacial and high-altitude lakes for Sikkim, Eastern Himalaya, and evaluates the susceptibility of lakes to Glacial Lake Outburst Flood (GLOF). By using satellite data of high spatial resolution (5 m), we obtain 1104 glacial and high-altitude lakes with total area 30.498 km2, of which 472 have an area > 0.01 km2. Applying pre-defined GLOF susceptibility criteria on these 472 lakes yields 21 lakes susceptible to GLOF, which all increased in area from 1972-2015. Using Analytic Hierarchy Processes (AHP), the pairwise comparison matrix further reveals that 5 of these glacial lakes have low, 14 have medium and 2 have high GLOF susceptibility. Especially these 16 glacial lakes with high and medium GLOF susceptibility may threaten downstream communities and infrastructure and need further attention.

  2. Tumor Necrosis Factor B (TNFB) Genetic Variants and Its Increased Expression Are Associated with Vitiligo Susceptibility

    Science.gov (United States)

    Laddha, Naresh C.; Dwivedi, Mitesh; Gani, Amina R.; Mansuri, Mohmmad Shoab; Begum, Rasheedunnisa

    2013-01-01

    Genetic polymorphisms in TNFB are involved in the regulation of its expression and are found to be associated with various autoimmune diseases. The aim of the present study was to determine whether TNFB +252A/G (rs909253) and exon 3 C/A (rs1041981) polymorphisms are associated with vitiligo susceptibility, and expression of TNFB and ICAM1 affects the disease onset and progression. We have earlier reported the role of TNFA in autoimmune pathogenesis of vitiligo, and we now show the involvement of TNFB in vitiligo pathogenesis. The two polymorphisms investigated in the TNFB were in strong linkage disequilibrium and significantly associated with vitiligo. TNFB and ICAM1 transcripts were significantly increased in patients compared to controls. Active vitiligo patients showed significant increase in TNFB transcripts compared to stable vitiligo. The genotype-phenotype analysis revealed that TNFB expression levels were higher in patients with GG and AA genotypes as compared to controls. Patients with the early age of onset and female patients showed higher TNFB and ICAM1 expression. Overall, our findings suggest that the increased TNFB transcript levels in vitiligo patients could result, at least in part, from variations at the genetic level which in turn leads to increased ICAM1 expression. For the first time, we show that TNFB +252A/G and exon 3 C/A polymorphisms are associated with vitiligo susceptibility and influence the TNFB and ICAM1 expression. Moreover, the study also emphasizes influence of TNFB and ICAM1 on the disease progression, onset and gender bias for developing vitiligo. PMID:24312346

  3. Increased susceptibility to cardiovascular effects of dihydrocapcaicin in resuscitated rats. Cardiovascular effects of dihydrocapsaicin

    DEFF Research Database (Denmark)

    Fosgerau, Keld; Ristagno, Giuseppe; Jayatissa, Magdalena Niepsuj

    2010-01-01

    Survivors of a cardiac arrest often have persistent cardiovascular derangements following cardiopulmonary resuscitation including decreased cardiac output, arrhythmias and morphological myocardial damage. These cardiovascular derangements may lead to an increased susceptibility towards the extern...... and internal environment of the cardiovascular system as compared to the healthy situation.......Survivors of a cardiac arrest often have persistent cardiovascular derangements following cardiopulmonary resuscitation including decreased cardiac output, arrhythmias and morphological myocardial damage. These cardiovascular derangements may lead to an increased susceptibility towards the external...

  4. The Wildland-Urban Interface: Increasing Significance, Complexity and Contribution

    Science.gov (United States)

    John F. Dwyer; Sarah M. McCaffrey

    2002-01-01

    During the past two decades, presentations at International Symposia on Society and Resource Management (ISSRM) have covered an increasingly broad scope of topics on natural resource issues. The wildland-urban interface (WUI) was a key topic of discussion at the ninth ISSRM in 2002: a reflection of the response by social scientists to increasing residential development...

  5. Increased rate of penicillin non-susceptible strains of N. meningitidis in Naples, Italy.

    Science.gov (United States)

    Di Caprio, Giovanni; Carannante, Novella; Bernardo, Mariano; Cuccurullo, Susanna; Pallotto, Carlo; Tascini, Carlo

    2017-07-20

    Neisseria meningitidis is a causative agent of community-acquired sepsis and meningitis in humans. These diseases are associated with high mortality and morbidity if treatment is not started promptly. The empiric antibiotic treatment depends on patient factors and local epidemiology. In the past years, an increased number meningococcal strain with reduced susceptibility to penicillin has also been described. We analysed the susceptibility pattern of 11 N. meningitidis strains isolated between 2013 and 2016. Only three (27%) strains were fully susceptible to penicillin, suggesting that a third-generation cephalosporin, instead of penicillin, as empiric therapy is more reliable when an invasive meningococcal disease is suspected.

  6. CONTINUING THE REFORMS IN MAJOR SIGNIFICANCE FIELDS FOR ECONOMIC INCREASE

    Directory of Open Access Journals (Sweden)

    CECILIA ELENA VĂDUVA

    2008-01-01

    Full Text Available The macroeconomic framework has to focus on structural reforms, tax and budgetary policy, agriculture and rural development, and the macroeconomic framework has to follow IMMs preservation. Form the convergence view the macroeconomic framework supports the durability of the economic increase including by financing the development of physical infrastructures of the human capital.

  7. Natural killer cells in obesity: impaired function and increased susceptibility to the effects of cigarette smoke.

    LENUS (Irish Health Repository)

    O'Shea, Donal

    2012-02-01

    BACKGROUND: Obese individuals who smoke have a 14 year reduction in life expectancy. Both obesity and smoking are independently associated with increased risk of malignancy. Natural killer cells (NK) are critical mediators of anti-tumour immunity and are compromised in obese patients and smokers. We examined whether NK cell function was differentially affected by cigarette smoke in obese and lean subjects. METHODOLOGY AND PRINCIPAL FINDINGS: Clinical data and blood were collected from 40 severely obese subjects (BMI>40 kg\\/m(2)) and 20 lean healthy subjects. NK cell levels and function were assessed using flow cytometry and cytotoxicity assays. The effect of cigarette smoke on NK cell ability to kill K562 tumour cells was assessed in the presence or absence of the adipokines leptin and adiponectin. NK cell levels were significantly decreased in obese subjects compared to lean controls (7.6 vs 16.6%, p = 0.0008). NK function was also significantly compromised in obese patients (30% +\\/- 13% vs 42% +\\/-12%, p = 0.04). Cigarette smoke inhibited NK cell ability to kill tumour cell lines (p<0.0001). NK cells from obese subjects were even more susceptible to the inhibitory effects of smoke compared to lean subjects (33% vs 28%, p = 0.01). Cigarette smoke prevented NK cell activation, as well as perforin and interferon-gamma secretion upon tumour challenge. Adiponectin but not leptin partially reversed the effects of smoke on NK cell function in both obese (p = 0.002) and lean controls (p = 0.01). CONCLUSIONS\\/SIGNIFICANCE: Obese subjects have impaired NK cell activity that is more susceptible to the detrimental effects of cigarette smoke compared to lean subjects. This may play a role in the increase of cancer and infection seen in this population. Adiponectin is capable of restoring NK cell activity and may have therapeutic potential for immunity in obese subjects and smokers.

  8. Natural killer cells in obesity: impaired function and increased susceptibility to the effects of cigarette smoke.

    LENUS (Irish Health Repository)

    O'Shea, Donal

    2010-01-01

    BACKGROUND: Obese individuals who smoke have a 14 year reduction in life expectancy. Both obesity and smoking are independently associated with increased risk of malignancy. Natural killer cells (NK) are critical mediators of anti-tumour immunity and are compromised in obese patients and smokers. We examined whether NK cell function was differentially affected by cigarette smoke in obese and lean subjects. METHODOLOGY AND PRINCIPAL FINDINGS: Clinical data and blood were collected from 40 severely obese subjects (BMI>40 kg\\/m(2)) and 20 lean healthy subjects. NK cell levels and function were assessed using flow cytometry and cytotoxicity assays. The effect of cigarette smoke on NK cell ability to kill K562 tumour cells was assessed in the presence or absence of the adipokines leptin and adiponectin. NK cell levels were significantly decreased in obese subjects compared to lean controls (7.6 vs 16.6%, p = 0.0008). NK function was also significantly compromised in obese patients (30% +\\/- 13% vs 42% +\\/-12%, p = 0.04). Cigarette smoke inhibited NK cell ability to kill tumour cell lines (p<0.0001). NK cells from obese subjects were even more susceptible to the inhibitory effects of smoke compared to lean subjects (33% vs 28%, p = 0.01). Cigarette smoke prevented NK cell activation, as well as perforin and interferon-gamma secretion upon tumour challenge. Adiponectin but not leptin partially reversed the effects of smoke on NK cell function in both obese (p = 0.002) and lean controls (p = 0.01). CONCLUSIONS\\/SIGNIFICANCE: Obese subjects have impaired NK cell activity that is more susceptible to the detrimental effects of cigarette smoke compared to lean subjects. This may play a role in the increase of cancer and infection seen in this population. Adiponectin is capable of restoring NK cell activity and may have therapeutic potential for immunity in obese subjects and smokers.

  9. Heterogeneity of aquatic sediment significantly increases nitrogen removal

    Science.gov (United States)

    Sawyer, A. H.

    2014-12-01

    In recent decades, nitrate loads to rivers and coasts have increased dramatically and contributed to eutrophication and hypoxia in coastal waters. A major sink for nitrate in the environment is denitrification in aquatic sediments. Here, I show that nitrate removal rates are as much as 100 times more efficient in heterogeneous than equivalent homogeneous aquatic sediments. Numerical experiments quantify nitrate removal from groundwater discharging through shallow columns of heterogeneous aquatic sediment. The steady groundwater flow equation was coupled to the advection-dispersion-reaction equations for dissolved oxygen, nitrate, and dissolved organic carbon (DOC). Bimodal sediments composed of sand and clay were simulated using TPROGS for a wide range of clay fractions. Small (centimeter-scale) sedimentary structures were intended to represent infilled burrows or clay rip-up clasts. Clay structures were assigned a relatively high organic carbon content (2%). The local source of DOC fuels oxygen consumption in clay structures and promotes restricted zones of denitrification in otherwise aerobic sediments. As a result, redox transformations do not strictly depend on residence times but rather on distributions of organic carbon in aquatic sediments. Furthermore, bimodal sand and clay deposits are more efficient than either clean sand or homogeneous sandy-clay at removing nitrate. These results help explain observations of efficient nitrate removal in relatively sandy, oxygenated aquatic sediments when small organic-rich structures are present. The results also suggest that models of reactive transport in homogeneous sediment underestimate biogeochemical transformation rates relative to heterogeneous sediment. Similarly, laboratory-derived denitrification rates on homogenized cores are likely underestimated relative to intact cores.

  10. Placing Antismoking Graphic Warning Posters at Retail Point-of-Sale Locations Increases Some Adolescents' Susceptibility to Future Smoking.

    Science.gov (United States)

    Shadel, William G; Martino, Steven C; Setodji, Claude; Dunbar, Michael; Kusuke, Daniela; Lanna, Serafina; Meyer, Amanda

    2017-12-13

    This experiment tested whether introducing graphic antitobacco posters at point-of-sale (POS) had any effect on adolescents' susceptibility to future cigarette smoking and whether these effects were moderated by adolescents' baseline risk of cigarette smoking. The study was conducted in the RAND StoreLab, a life-sized replica of a convenience store that was developed to experimentally evaluate how changing aspects of tobacco advertising displays in retail POS environments influence tobacco use risk and behavior during simulated shopping experiences. In this study, 441 adolescents were randomized to one of the four conditions in a 2 (graphic antismoking poster placed near the tobacco power wall: no, yes) × 2 (graphic antismoking poster placed near the cash register: no, yes) experimental design. The outcome of interest was susceptibility to future cigarette smoking. The addition of antismoking posters at POS led to a significant increase in future smoking susceptibility among those adolescents who already were at high risk for smoking in the future (p graphic antismoking posters had no impact on committed never smokers, regardless of poster location; never smokers' susceptibility to future smoking was uniformly low across experimental conditions. Introducing graphic antismoking posters at POS may have the unintended effect of further increasing cigarette smoking susceptibility among adolescents already at risk.

  11. Diabetes Mellitus and Increased Tuberculosis Susceptibility: The Role of Short-Chain Fatty Acids

    NARCIS (Netherlands)

    Lachmandas, E.L.; Heuvel, C.N.A.M. van den; Damen, M.S.M.A.; Cleophas, M.C.P.; Netea, M.G.; Crevel, R. van

    2016-01-01

    Type 2 diabetes mellitus confers a threefold increased risk for tuberculosis, but the underlying immunological mechanisms are still largely unknown. Possible mediators of this increased susceptibility are short-chain fatty acids, levels of which have been shown to be altered in individuals with

  12. SU-E-I-62: Reduction of Susceptibility Artifacts by Increasing the Bandwidth (BW) and Echo Train Length (ETL)

    Energy Technology Data Exchange (ETDEWEB)

    Mavroidis, P [University of North Carolina, Chapel Hill, NC (United States); Boci, N; Kostopoulos, S; Ninos, C; Glotsos, D; Oikonomou, G; Bakas, A; Roka, V; Cavouras, D; Lavdas, E [Technological Education Institute of Athens, Athens, Attika (Greece); Sakkas, G; Tsagkalis, A [Animus Kyanoys Larissas Hospital, Larissa, Thessaly (Greece); Chatzivasileiou, V; Batsikas, G [IASO Thessalias Hospital, Larissa, Thessaly (Greece); Papanikolaou, N [University of Texas HSC SA, San Antonio, TX (United States); Stathakis, S [Cancer Therapy and Research Center, San Antonio, TX (United States)

    2015-06-15

    Purpose: The aim of this present study is to increase bandwidth (BW) and echo train length (ETL) in Proton Density Turbo Spin Echo (PD TSE) sequences with and without fat saturation (FS) as well as in Turbo Inversion Recovery Magnitude sequences (TIRM) in order to assess whether these sequences are capable of reducing susceptibility artifacts. Methods: We compared 1) TIRM coronal (COR) with the same sequence with increased both BW and ETL 2) Conventional PD TSE sagittal (SAG) with FS with an increased BW 3) Conventional PD TSE SAG without FS with an increased BW 4) Conventional PD TSE SAG without FS with increased both BW and ETL. A quantitative analysis was performed to measure the extent of the susceptibility artifacts. Furthermore, a qualitative analysis was performed by two radiologists in order to evaluate the susceptibility artifacts, image distortion and fat suppression. The depiction of cartilage, menisci, muscles, tendons and bone marrow were also qualitatively analyzed. Results: The quantitative analysis found that the modified TIRM sequence is significantly superior to the conventional one regarding the extent of the susceptibility artifacts. In the qualitative analysis, the modified TIRM sequence was superior to the corresponding conventional one in eight characteristics out of ten that were analyzed. The modified PD TSE with FS was superior to the corresponding conventional one regarding the susceptibility artifacts, image distortion and depiction of bone marrow and cartilage while achieving effective fat saturation. The modified PD TSE sequence without FS with a high (H) BW was found to be superior corresponding to the conventional one in the case of cartilage. Conclusion: Consequently, TIRM sequence with an increased BW and ETL is proposed for producing images of high quality and modified PD TSE with H BW for smaller metals, especially when FS is used.

  13. Increased susceptibility to infectious salmon anemia virus (ISAv) in Lepeophtheirus salmonis – infected Atlantic salmon

    Science.gov (United States)

    The salmon louse and infectious salmon anemia virus (ISAv) are the two most significant pathogens of concern to the Atlantic salmon (Salmo salar) aquaculture industry. However, the interactions between sea lice and ISAv, as well as the impact of a prior sea lice infection on the susceptibility of th...

  14. Pulmonary exposure to particles during pregnancy causes increased neonatal asthma susceptibility

    DEFF Research Database (Denmark)

    Fedulov, Alexey V; Leme, Adriana; Yang, Zhiping

    2008-01-01

    Maternal immune responses can promote allergy development in offspring, as shown in a model of increased susceptibility to asthma in babies of ovalbumin (OVA)-sensitized and -challenged mother mice. We investigated whether inflammatory responses to air pollution particles (diesel exhaust particles...

  15. Significant linkage to chromosome 12q24.32-q24.33 and identification of SFRS8 as a possible asthma susceptibility gene

    DEFF Research Database (Denmark)

    brasch-andersen, c; Tan, Q; Børglum, A D

    2006-01-01

    BACKGROUND: Asthma is a complex genetic disorder. Many studies have suggested that chromosome 12q harbours a susceptibility gene for asthma and atopy. Linkage on chromosome 12q24.21-q24.33 was investigated in 167 Danish families with asthma. METHODS: A two step procedure was used: (1) a genome...... in a family based transmission disequilibrium test. RESULTS: An MLS of 3.27 was obtained at 12q24.33. The significance of this result was tested by simulation, resulting in a significant empirical genome-wide p value of 0.018. To our Knowledge, this is the first significant evidence for linkage on chromosome...... part of chromosome 12q contains a gene that increases the susceptibility to asthma. SFRS8 could act as a weak predisposing gene for asthma in our sample....

  16. Significantly increased risk of carotid atherosclerosis with arsenic exposure and polymorphisms in arsenic metabolism genes

    Energy Technology Data Exchange (ETDEWEB)

    Hsieh, Yi-Chen [School of Public Health, College of Public Health and Nutrition, Taipei Medical University, 250 Wusing St., Taipei 11031, Taiwan (China); Lien, Li-Ming [Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (China); School of Medicine, Taipei Medical University, Taipei, Taiwan (China); Department of Neurology, Shin Kong WHS Memorial Hospital, Taipei, Taiwan (China); Chung, Wen-Ting [Department of Neurology, Wanfang Hospital, Taipei Medical University, Taipei, Taiwan (China); Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan (China); Hsieh, Fang-I; Hsieh, Pei-Fan [School of Public Health, College of Public Health and Nutrition, Taipei Medical University, 250 Wusing St., Taipei 11031, Taiwan (China); Wu, Meei-Maan [School of Public Health, College of Public Health and Nutrition, Taipei Medical University, 250 Wusing St., Taipei 11031, Taiwan (China); Graduate Institute of Basic Medicine, College of Medicine, Fu-Jen Catholic University, Taipei, Taiwan (China); Tseng, Hung-Pin [Department of Neurology, Lotung Poh-Ai Hospital, I-Lan, Taiwan (China); Chiou, Hung-Yi, E-mail: hychiou@tmu.edu.tw [School of Public Health, College of Public Health and Nutrition, Taipei Medical University, 250 Wusing St., Taipei 11031, Taiwan (China); Chen, Chien-Jen [Genomics Research Center, Academia Sinica, Taipei, Taiwan (China)

    2011-08-15

    Individual susceptibility to arsenic-induced carotid atherosclerosis might be associated with genetic variations in arsenic metabolism. The purpose of this study is to explore the interaction effect on risk of carotid atherosclerosis between arsenic exposure and risk genotypes of purine nucleoside phosphorylase (PNP), arsenic (+3) methyltransferase (As3MT), and glutathione S-transferase omega 1 (GSTO1) and omega 2 (GSTO2). A community-based case-control study was conducted in northeastern Taiwan to investigate the arsenic metabolic-related genetic susceptibility to carotid atherosclerosis. In total, 863 subjects, who had been genotyped and for whom the severity of carotid atherosclerosis had been determined, were included in the present study. Individual well water was collected and arsenic concentration determined using hydride generation combined with flame atomic absorption spectrometry. The result showed that a significant dose-response trend (P=0.04) of carotid atherosclerosis risk associated with increasing arsenic concentration. Non-significant association between genetic polymorphisms of PNP Gly51Ser, Pro57Pro, As3MT Met287Thr, GSTO1 Ala140Asp, and GSTO2 A-183G and the risk for development of carotid atherosclerosis were observed. However, the significant interaction effect on carotid atherosclerosis risk was found for arsenic exposure (>50 {mu}g/l) and the haplotypes of PNP (p=0.0115). A marked elevated risk of carotid atherosclerosis was observed in subjects with arsenic exposure of >50 {mu}g/l in drinking water and those who carried the PNP A-T haplotype and at least either of the As3MT risk polymorphism or GSTO risk haplotypes (OR, 6.43; 95% CI, 1.79-23.19). In conclusion, arsenic metabolic genes, PNP, As3MT, and GSTO, may exacerbate the formation of atherosclerosis in individuals with high levels of arsenic concentration in well water (>50 {mu}g/l). - Highlights: {yields}Arsenic metabolic genes might be associated with carotid atherosclerosis. {yields

  17. Seizure-induced disinhibition of the HPA axis increases seizure susceptibility.

    Science.gov (United States)

    O'Toole, Kate K; Hooper, Andrew; Wakefield, Seth; Maguire, Jamie

    2014-01-01

    Stress is the most commonly reported precipitating factor for seizures. The proconvulsant actions of stress hormones are thought to mediate the effects of stress on seizure susceptibility. Interestingly, epileptic patients have increased basal levels of stress hormones, including corticotropin-releasing hormone (CRH) and corticosterone, which are further increased following seizures. Given the proconvulsant actions of stress hormones, we proposed that seizure-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis may contribute to future seizure susceptibility. Consistent with this hypothesis, our data demonstrate that pharmacological induction of seizures in mice with kainic acid or pilocarpine increases circulating levels of the stress hormone, corticosterone, and exogenous corticosterone administration is sufficient to increase seizure susceptibility. However, the mechanism(s) whereby seizures activate the HPA axis remain unknown. Here we demonstrate that seizure-induced activation of the HPA axis involves compromised GABAergic control of CRH neurons, which govern HPA axis function. Following seizure activity, there is a collapse of the chloride gradient due to changes in NKCC1 and KCC2 expression, resulting in reduced amplitude of sIPSPs and even depolarizing effects of GABA on CRH neurons. Seizure-induced activation of the HPA axis results in future seizure susceptibility which can be blocked by treatment with an NKCC1 inhibitor, bumetanide, or blocking the CRH signaling with Antalarmin. These data suggest that compromised GABAergic control of CRH neurons following an initial seizure event may cause hyperexcitability of the HPA axis and increase future seizure susceptibility. Copyright © 2013 Elsevier B.V. All rights reserved.

  18. Hypoxia increases susceptibility of Pacific white shrimp to whitespot syndrome virus (WSSV

    Directory of Open Access Journals (Sweden)

    M. Lehmann

    2016-04-01

    Full Text Available The present study aimed to evaluate the mortality, reactive oxygen species production (ROS and total hemocyte counts (THC of the marine shrimp Litopenaeus vannamei infected with the white spot syndrome virus (WSSV at three levels of oxygen saturation. For this, 360 shrimp (20±2g were distributed in 24 tanks (60L, divided in two groups (infected and non-infected, which were subjected to 30, 60 and 100% of dissolved oxygen saturation (in quadruplicate. During 96 hours after infection, daily hemolymph samples were collected for hemato-immunological parameter evaluation (THC and ROS and dead animals were removed and computed to assess cumulative mortality rates. In the infected group, animals subjected to 100% saturation showed higher ROS production (P<0.05 after 48 hours, while THC was significantly reduced (P<0.05, regardless of oxygen saturation. The hypoxia resulted in high mortality when compared to 100% saturation condition. In the uninfected group, no significant differences were observed in all evaluated parameters. Thus, the hypoxia condition increased the susceptibility of shrimp to the infection of WSSV, which may be partly related to the low ROS production showed by the animals subjected to 30% oxygen saturation.

  19. Significant increase of Echinococcus multilocularis prevalence in foxes, but no increased predicted risk for humans.

    Science.gov (United States)

    Maas, M; Dam-Deisz, W D C; van Roon, A M; Takumi, K; van der Giessen, J W B

    2014-12-15

    The emergence of the zoonotic tapeworm Echinococcus multilocularis, causative agent of alveolar echinococcosis (AE), poses a public health risk. A previously designed risk map model predicted a spread of E. multilocularis and increasing numbers of alveolar echinococcosis patients in the province of Limburg, The Netherlands. This study was designed to determine trends in the prevalence and worm burden of E. multilocularis in foxes in a popular recreational area in the southern part of Limburg to assess the risk of infection for humans and to study the prevalence of E. multilocularis in dogs in the adjacent city of Maastricht. Thirty-seven hunted red foxes were tested by the intestinal scraping technique and nested PCR on colon content. Additionally, 142 fecal samples of domestic dogs from Maastricht were analyzed by qPCR for the presence of E. multilocularis. In foxes, a significantly increased prevalence of 59% (95% confidence interval 43-74%) was found, compared to the prevalence of 11% (95% CI 7-18%) in 2005-2006. Average worm burden increased to 37 worms per fox, the highest since the first detection, but consistent with the prediction about the parasite population for this region. Updated prediction on the number of AE cases did not lead to an increase in previous estimates of human AE cases up to 2018. No dogs in the city of Maastricht tested positive, but results of questionnaires showed that deworming schemes were inadequate, especially in dogs that were considered at risk for infection. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. Diabetes Mellitus and Increased Tuberculosis Susceptibility: The Role of Short-Chain Fatty Acids.

    Science.gov (United States)

    Lachmandas, Ekta; van den Heuvel, Corina N A M; Damen, Michelle S M A; Cleophas, Maartje C P; Netea, Mihai G; van Crevel, Reinout

    2016-01-01

    Type 2 diabetes mellitus confers a threefold increased risk for tuberculosis, but the underlying immunological mechanisms are still largely unknown. Possible mediators of this increased susceptibility are short-chain fatty acids, levels of which have been shown to be altered in individuals with diabetes. We examined the influence of physiological concentrations of butyrate on cytokine responses to Mycobacterium tuberculosis (Mtb) in human peripheral blood mononuclear cells (PBMCs). Butyrate decreased Mtb-induced proinflammatory cytokine responses, while it increased production of IL-10. This anti-inflammatory effect was independent of butyrate's well-characterised inhibition of HDAC activity and was not accompanied by changes in Toll-like receptor signalling pathways, the eicosanoid pathway, or cellular metabolism. In contrast blocking IL-10 activity reversed the effects of butyrate on Mtb-induced inflammation. Alteration of the gut microbiota, thereby increasing butyrate concentrations, can reduce insulin resistance and obesity, but further studies are needed to determine how this affects susceptibility to tuberculosis.

  1. Prenatal ethanol exposure programs an increased susceptibility of non-alcoholic fatty liver disease in female adult offspring rats

    Energy Technology Data Exchange (ETDEWEB)

    Shen, Lang; Liu, Zhongfen; Gong, Jun; Zhang, Li [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Wang, Linlong [Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China); Magdalou, Jacques [UMR 7561 CNRS-Nancy Université, Faculté de Médicine, Vandoeuvre-lès-Nancy (France); Chen, Liaobin [Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China); Wang, Hui, E-mail: wanghui19@whu.edu.cn [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Research Center of Food and Drug Evaluation, Wuhan University, Wuhan 430071 (China)

    2014-01-15

    Prenatal ethanol exposure (PEE) induces dyslipidemia and hyperglycemia in fetus and adult offspring. However, whether PEE increases the susceptibility to non-alcoholic fatty liver disease (NAFLD) in offspring and its underlying mechanism remain unknown. This study aimed to demonstrate an increased susceptibility to high-fat diet (HFD)-induced NAFLD and its intrauterine programming mechanisms in female rat offspring with PEE. Rat model of intrauterine growth retardation (IUGR) was established by PEE, the female fetus and adult offspring that fed normal diet (ND) or HFD were sacrificed. The results showed that, in PEE + ND group, serum corticosterone (CORT) slightly decreased and insulin-like growth factor-1 (IGF-1) and glucose increased with partial catch-up growth; In PEE + HFD group, serum CORT decreased, while serum IGF-1, glucose and triglyceride (TG) increased, with notable catch-up growth, higher metabolic status and NAFLD formation. Enhanced liver expression of the IGF-1 pathway, gluconeogenesis, and lipid synthesis as well as reduced expression of lipid output were accompanied in PEE + HFD group. In PEE fetus, serum CORT increased while IGF-1 decreased, with low body weight, hyperglycemia, and hepatocyte ultrastructural changes. Hepatic IGF-1 expression as well as lipid output was down-regulated, while lipid synthesis significantly increased. Based on these findings, we propose a “two-programming” hypothesis for an increased susceptibility to HFD-induced NAFLD in female offspring of PEE. That is, the intrauterine programming of liver glucose and lipid metabolic function is “the first programming”, and postnatal adaptive catch-up growth triggered by intrauterine programming of GC-IGF1 axis acts as “the second programming”. - Highlights: • Prenatal ethanol exposure increase the susceptibility of NAFLD in female offspring. • Prenatal ethanol exposure reprograms fetal liver’s glucose and lipid metabolism . • Prenatal ethanol exposure cause

  2. Heterozygote loss of ACE2 is sufficient to increase the susceptibility to heart disease.

    Science.gov (United States)

    Wang, Wang; Patel, Vaibhav B; Parajuli, Nirmal; Fan, Dong; Basu, Ratnadeep; Wang, Zuocheng; Ramprasath, Tharmarajan; Kassiri, Zamaneh; Penninger, Josef M; Oudit, Gavin Y

    2014-08-01

    Angiotensin-converting enzyme 2 (ACE2) metabolizes Ang II into Ang 1-7 thereby negatively regulating the renin-angiotensin system. However, heart disease in humans and in animal models is associated with only a partial loss of ACE2. ACE2 is an X-linked gene; and as such, we tested the clinical relevance of a partial loss of ACE2 by using female ACE2(+/+) (wildtype) and ACE2(+/-) (heterozygote) mice. Pressure overload in ACE2(+/-) mice resulted in greater LV dilation and worsening systolic and diastolic dysfunction. These changes were associated with increased myocardial fibrosis, hypertrophy, and upregulation of pathological gene expression. In response to Ang II infusion, there was increased NADPH oxidase activity and myocardial fibrosis resulting in the worsening of Ang II-induced diastolic dysfunction with a preserved systolic function. Ang II-mediated cellular effects in cultured adult ACE2(+/-) cardiomyocytes and cardiofibroblasts were exacerbated. Ang II-mediated pathological signaling worsened in ACE2(+/-) hearts characterized by an increase in the phosphorylation of ERK1/2 and JNK1/2 and STAT-3 pathways. The ACE2(+/-) mice showed an exacerbated pressor response with increased vascular fibrosis and stiffness. Vascular superoxide and nitrotyrosine levels were increased in ACE2(+/-) vessels consistent with increased vascular oxidative stress. These changes occurred with increased renal fibrosis and superoxide production. Partial heterozygote loss of ACE2 is sufficient to increase the susceptibility to heart disease secondary to pressure overload and Ang II infusion. Heart disease in humans with idiopathic dilated cardiomyopathy is associated with a partial loss of ACE2. Heterozygote female ACE2 mutant mice showed enhanced susceptibility to pressure overload-induced heart disease. Heterozygote female ACE2 mutant mice showed enhanced susceptibility to Ang II-induced heart and vascular diseases. Partial loss of ACE2 is sufficient to enhance the susceptibility to

  3. Ciliary neurotrophic factor (CNTF) activation of astrocytes decreases spreading depolarization susceptibility and increases potassium clearance.

    Science.gov (United States)

    Seidel, Jessica L; Faideau, Mathilde; Aiba, Isamu; Pannasch, Ulrike; Escartin, Carole; Rouach, Nathalie; Bonvento, Gilles; Shuttleworth, C William

    2015-01-01

    Waves of spreading depolarization (SD) have been implicated in the progressive expansion of acute brain injuries. SD can persist over several days, coincident with the time course of astrocyte activation, but little is known about how astrocyte activation may influence SD susceptibility. We examined whether activation of astrocytes modified SD threshold in hippocampal slices. Injection of a lentiviral vector encoding Ciliary neurotrophic factor (CNTF) into the hippocampus in vivo, led to sustained astrocyte activation, verified by up-regulation of glial fibrillary acidic protein (GFAP) at the mRNA and protein levels, as compared to controls injected with vector encoding LacZ. In acute brain slices from LacZ controls, localized 1M KCl microinjections invariably generated SD in CA1 hippocampus, but SD was never induced with this stimulus in CNTF tissues. No significant change in intrinsic excitability was observed in CA1 neurons, but excitatory synaptic transmission was significantly reduced in CNTF samples. mRNA levels of the predominantly astrocytic Na(+) /K(+) -ATPase pump α2 subunit were higher in CNTF samples, and the kinetics of extracellular K(+) transients during matched synaptic activation were consistent with increased K(+) uptake in CNTF tissues. Supporting a role for the Na(+) /K(+) -ATPase pump in increased SD threshold, ouabain, an inhibitor of the pump, was able to generate SD in CNTF tissues. These data support the hypothesis that activated astrocytes can limit SD onset via increased K(+) clearance and suggest that therapeutic strategies targeting these glial cells could improve the outcome following acute brain injuries associated with SD. © 2014 Wiley Periodicals, Inc.

  4. Increased susceptibility of aging gastric mucosa to injury: the mechanisms and clinical implications.

    Science.gov (United States)

    Tarnawski, Andrzej S; Ahluwalia, Amrita; Jones, Michael K

    2014-04-28

    This review updates the current views on aging gastric mucosa and the mechanisms of its increased susceptibility to injury. Experimental and clinical studies indicate that gastric mucosa of aging individuals-"aging gastropathy"-has prominent structural and functional abnormalities vs young gastric mucosa. Some of these abnormalities include a partial atrophy of gastric glands, impaired mucosal defense (reduced bicarbonate and prostaglandin generation, decreased sensory innervation), increased susceptibility to injury by a variety of damaging agents such as ethanol, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), impaired healing of injury and reduced therapeutic efficacy of ulcer-healing drugs. Detailed analysis of the above changes indicates that the following events occur in aging gastric mucosa: reduced mucosal blood flow and impaired oxygen delivery cause hypoxia, which leads to activation of the early growth response-1 (egr-1) transcription factor. Activation of egr-1, in turn, upregulates the dual specificity phosphatase, phosphatase and tensin homologue deleted on chromosome ten (PTEN) resulting in activation of pro-apoptotic caspase-3 and caspase-9 and reduced expression of the anti-apoptosis protein, survivin. The imbalance between pro- and anti-apoptosis mediators results in increased apoptosis and increased susceptibility to injury. This paradigm has human relevance since increased expression of PTEN and reduced expression of survivin were demonstrated in gastric mucosa of aging individuals. Other potential mechanisms operating in aging gastric mucosa include reduced telomerase activity, increase in replicative cellular senescence, and reduced expression of vascular endothelial growth factor and importin-α-a nuclear transport protein essential for transport of transcription factors to nucleus. Aging gastropathy is an important and clinically relevant issue because of: (1) an aging world population due to prolonged life span; (2) older

  5. RCAN1 Regulates Mitochondrial Function and Increases Susceptibility to Oxidative Stress in Mammalian Cells

    Science.gov (United States)

    Peiris, Heshan; Dubach, Daphne; Jessup, Claire F.; Raghupathi, Ravinarayan; Muyderman, Hakan; Zanin, Mark P.; Mackenzie, Kimberly; Pritchard, Melanie A.; Keating, Damien J.

    2014-01-01

    Mitochondria are the primary site of cellular energy generation and reactive oxygen species (ROS) accumulation. Elevated ROS levels are detrimental to normal cell function and have been linked to the pathogenesis of neurodegenerative disorders such as Down's syndrome (DS) and Alzheimer's disease (AD). RCAN1 is abundantly expressed in the brain and overexpressed in brain of DS and AD patients. Data from nonmammalian species indicates that increased RCAN1 expression results in altered mitochondrial function and that RCAN1 may itself regulate neuronal ROS production. In this study, we have utilized mice overexpressing RCAN1 (RCAN1ox) and demonstrate an increased susceptibility of neurons from these mice to oxidative stress. Mitochondria from these mice are more numerous and smaller, indicative of mitochondrial dysfunction, and mitochondrial membrane potential is altered under conditions of oxidative stress. We also generated a PC12 cell line overexpressing RCAN1 (PC12RCAN1). Similar to RCAN1ox neurons, PC12RCAN1 cells have an increased susceptibility to oxidative stress and produce more mitochondrial ROS. This study demonstrates that increasing RCAN1 expression alters mitochondrial function and increases the susceptibility of neurons to oxidative stress in mammalian cells. These findings further contribute to our understanding of RCAN1 and its potential role in the pathogenesis of neurodegenerative disorders such as AD and DS. PMID:25009690

  6. Synergistic interaction between UVB radiation and temperature increases susceptibility to parasitic infection in a fish.

    Science.gov (United States)

    Cramp, Rebecca L; Reid, Stefanie; Seebacher, Frank; Franklin, Craig E

    2014-09-01

    Levels of UVB radiation (UVB) and mean temperatures have increased substantially over recent decades in many regions of the world. Both stressors independently can compromise immune function, disease resistance and fitness in fish. The impact of UVB can also be exacerbated by interactions with environmental temperatures. In this paper, we test the hypothesis that UVB and temperature act synergistically to influence patterns of energy consumption and susceptibility to disease. We exposed mosquitofish, Gambusia holbrooki, to a factorial design of low and high UVB levels and low (18°C) and high (25°C) temperatures. The combination of high UVB and high temperature interacted synergistically to suppress metabolism and exacerbate infection intensity by the fish pathogen whitespot (Ichtyhophthirius multifiliis). Given the rapid changes in the thermal environment globally, the interaction between UVB and temperatures on energy use and disease resistance could pose significant problems for aquatic animal health in the context of both pre-existing and emerging diseases. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

  7. Genetic variants and increased expression of Parascaris equorum P-glycoprotein-11 in populations with decreased ivermectin susceptibility.

    Directory of Open Access Journals (Sweden)

    I Jana I Janssen

    Full Text Available Macrocyclic lactones (MLs represent the major drug class for control of parasitic infections in humans and animals. However, recently reports of treatment failures became more frequent. In addition to human and ruminant parasitic nematodes this also is the case for the horse-nematode Parascaris equorum. Nevertheless, to date the molecular basis of ML resistance is still not understood. Unspecific resistance mechanisms involving transporters such as P-glycoproteins (Pgps are expected to contribute to ML resistance in nematodes. Here, complete sequences of two P. equorum Pgps were cloned and identified as orthologs of Caenorhabditis elegans Ppg-11 and an unnamed Caenorhabditis briggsae Pgp designated as Pgp-16 using phylogenetic analysis. Quantitative real-time PCR was used to compare expression between tissues. Significantly higher PeqPgp-11 expression was found in the gut for both genders, whereas for PeqPgp-16 the body wall was identified as predominant expression site. Furthermore, Pgps were analyzed regarding their participation in resistance development. Using SeqDoC analyses, Pgp-sequences of P. equorum populations with different ML susceptibility were compared. This approach revealed three single nucleotide polymorphisms (SNPs causing missense mutations in the PeqPgp-11 sequence which correlated with decreased ML susceptibility. However, no resistance associated differences in mRNA expression levels were detected between embryonated eggs of these populations. In contrast, comparison of two pre-adult groups with different ivermectin (IVM susceptibility revealed the presence of the three SNPs and in addition statistically significant PeqPgp-11 overexpression in the group of worms with reduced susceptibility. These results indicate that Pgp-11 might be involved in IVM resistance in P. equorum as it shows increased expression in an IVM exposed life-cycle stage of an IVM resistant population as well as occurrence of putatively resistance

  8. Exposure to the Paralytic Shellfish Toxin Producer Alexandrium catenella Increases the Susceptibility of the Oyster Crassostrea gigas to Pathogenic Vibrios

    Directory of Open Access Journals (Sweden)

    Celina Abi-Khalil

    2016-01-01

    Full Text Available The multifactorial etiology of massive Crassostrea gigas summer mortalities results from complex interactions between oysters, opportunistic pathogens and environmental factors. In a field survey conducted in 2014 in the Mediterranean Thau Lagoon (France, we evidenced that the development of the toxic dinoflagellate Alexandrium catenella, which produces paralytic shellfish toxins (PSTs, was concomitant with the accumulation of PSTs in oyster flesh and the occurrence of C. gigas mortalities. In order to investigate the possible role of toxic algae in this complex disease, we experimentally infected C. gigas oyster juveniles with Vibrio tasmaniensis strain LGP32, a strain associated with oyster summer mortalities, after oysters were exposed to Alexandrium catenella. Exposure of oysters to A. catenella significantly increased the susceptibility of oysters to V. tasmaniensis LGP32. On the contrary, exposure to the non-toxic dinoflagellate Alexandrium tamarense or to the haptophyte Tisochrysis lutea used as a foraging alga did not increase susceptibility to V. tasmaniensis LGP32. This study shows for the first time that A. catenella increases the susceptibility of Crassostrea gigas to pathogenic vibrios. Therefore, in addition to complex environmental factors explaining the mass mortalities of bivalve mollusks, feeding on neurotoxic dinoflagellates should now be considered as an environmental factor that potentially increases the severity of oyster mortality events.

  9. Exposure to the Paralytic Shellfish Toxin Producer Alexandrium catenella Increases the Susceptibility of the Oyster Crassostrea gigas to Pathogenic Vibrios.

    Science.gov (United States)

    Abi-Khalil, Celina; Lopez-Joven, Carmen; Abadie, Eric; Savar, Veronique; Amzil, Zouher; Laabir, Mohamed; Rolland, Jean-Luc

    2016-01-15

    The multifactorial etiology of massive Crassostrea gigas summer mortalities results from complex interactions between oysters, opportunistic pathogens and environmental factors. In a field survey conducted in 2014 in the Mediterranean Thau Lagoon (France), we evidenced that the development of the toxic dinoflagellate Alexandrium catenella, which produces paralytic shellfish toxins (PSTs), was concomitant with the accumulation of PSTs in oyster flesh and the occurrence of C. gigas mortalities. In order to investigate the possible role of toxic algae in this complex disease, we experimentally infected C. gigas oyster juveniles with Vibrio tasmaniensis strain LGP32, a strain associated with oyster summer mortalities, after oysters were exposed to Alexandrium catenella. Exposure of oysters to A. catenella significantly increased the susceptibility of oysters to V. tasmaniensis LGP32. On the contrary, exposure to the non-toxic dinoflagellate Alexandrium tamarense or to the haptophyte Tisochrysis lutea used as a foraging alga did not increase susceptibility to V. tasmaniensis LGP32. This study shows for the first time that A. catenella increases the susceptibility of Crassostrea gigas to pathogenic vibrios. Therefore, in addition to complex environmental factors explaining the mass mortalities of bivalve mollusks, feeding on neurotoxic dinoflagellates should now be considered as an environmental factor that potentially increases the severity of oyster mortality events.

  10. Crude oil impairs immune function and increases susceptibility to pathogenic bacteria in southern flounder.

    Directory of Open Access Journals (Sweden)

    Keith M Bayha

    Full Text Available Exposure to crude oil or its individual constituents can have detrimental impacts on fish species, including impairment of the immune response. Increased observations of skin lesions in northern Gulf of Mexico fish during the 2010 Deepwater Horizon oil spill indicated the possibility of oil-induced immunocompromisation resulting in bacterial or viral infection. This study used a full factorial design of oil exposure and bacterial challenge to examine how oil exposure impairs southern flounder (Paralichthys lethostigma immune function and increases susceptibility to the bacteria Vibrio anguillarum, a causative agent of vibriosis. Fish exposed to oil prior to bacterial challenge exhibited 94.4% mortality within 48 hours of bacterial exposure. Flounder challenged with V. anguillarum without prior oil exposure had <10% mortality. Exposure resulted in taxonomically distinct gill and intestine bacterial communities. Mortality strongly correlated with V. anguillarum levels, where it comprised a significantly higher percentage of the microbiome in Oil/Pathogen challenged fish and was nearly non-existent in the No Oil/Pathogen challenged fish bacterial community. Elevated V. anguillarum levels were a direct result of oil exposure-induced immunosuppression. Oil-exposure reduced expression of immunoglobulin M, the major systemic fish antibody, and resulted in an overall downregulation in transcriptome response, particularly in genes related to immune function, response to stimulus and hemostasis. Ultimately, sediment-borne oil exposure impairs immune function, leading to increased incidences of bacterial infections. This type of sediment-borne exposure may result in long-term marine ecosystem effects, as oil-bound sediment in the northern Gulf of Mexico will likely remain a contamination source for years to come.

  11. Abrupt suspension of probiotics administration may increase host pathogen susceptibility by inducing gut dysbiosis

    OpenAIRE

    Zhi Liu; Wenshu Liu; Chao Ran; Jun Hu; Zhigang Zhou

    2016-01-01

    In this study, we investigated the risk associated with suspension of probiotics administration in tilapia, an animal model that may mimic immune-compromised conditions in humans. Tilapias were fed for 14 days using a probiotics-supplemented diet, followed by a three-day suspension of probiotics treatment and a subsequent challenge by Aeromonas hydrophila. Unexpectedly, the suspension of a probiotic strain Lactobacillus plantarum JCM1149 significantly triggered susceptibility of the host to A...

  12. Propofol Increases Host Susceptibility to Microbial Infection by Reducing Subpopulations of Mature Immune Effector Cells at Sites of Infection

    Science.gov (United States)

    Visvabharathy, Lavanya; Xayarath, Bobbi; Weinberg, Guy; Shilling, Rebecca A.; Freitag, Nancy E.

    2015-01-01

    Anesthetics are known to modulate host immune responses, but separating the variables of surgery from anesthesia when analyzing hospital acquired infections is often difficult. Here, the bacterial pathogen Listeria monocytogenes (Lm) was used to assess the impact of the common anesthetic propofol on host susceptibility to infection. Brief sedation of mice with physiologically relevant concentrations of propofol increased bacterial burdens in target organs by more than 10,000-fold relative to infected control animals. The adverse effects of propofol sedation on immune clearance of Lm persisted after recovery from sedation, as animals given the drug remained susceptible to infection for days following anesthesia. In contrast to propofol, sedation with alternative anesthetics such as ketamine/xylazine or pentobarbital did not increase susceptibility to systemic Lm infection. Propofol altered systemic cytokine and chemokine expression during infection, and prevented effective bacterial clearance by inhibiting the recruitment and/or activity of immune effector cells at sites of infection. Propofol exposure induced a marked reduction in marginal zone macrophages in the spleens of Lm infected mice, resulting in bacterial dissemination into deep tissue. Propofol also significantly increased mouse kidney abscess formation following infection with the common nosocomial pathogen Staphylococcus aureus. Taken together, these data indicate that even brief exposure to propofol severely compromises host resistance to microbial infection for days after recovery from sedation. PMID:26381144

  13. Claudin 2 deficiency reduces bile flow and increases susceptibility to cholesterol gallstone disease in mice.

    Science.gov (United States)

    Matsumoto, Kengo; Imasato, Mitsunobu; Yamazaki, Yuji; Tanaka, Hiroo; Watanabe, Mitsuhiro; Eguchi, Hidetoshi; Nagano, Hiroaki; Hikita, Hayato; Tatsumi, Tomohide; Takehara, Tetsuo; Tamura, Atsushi; Tsukita, Sachiko

    2014-11-01

    Bile formation and secretion are essential functions of the hepatobiliary system. Bile flow is generated by transepithelial transport of water and ionic/nonionic solutes via transcellular and paracellular pathways that is mainly driven by osmotic pressure. We examined the role of tight junction-based paracellular transport in bile secretion. Claudins are cell-cell adhesion molecules in tight junctions that create the paracellular barrier. The claudin family has 27 reported members, some of which have paracellular ion- and/or water-channel-like functions. Claudin 2 is a paracellular channel-forming protein that is highly expressed in hepatocytes and cholangiocytes; we examined the hepatobiliary system of claudin 2 knockout (Cldn2(-/-)) mice. We collected liver and biliary tissues from Cldn2(-/-) and Cldn2(+/+) mice and performed histologic, biochemical, and electrophysiologic analyses. We measured osmotic movement of water and/or ions in Cldn2(-/-) and Cldn2(+/+) hepatocytes and bile ducts. Mice were placed on lithogenic diets for 4 weeks and development of gallstone disease was assessed. The rate of bile flow in Cldn2(-/-) mice was half that of Cldn2(+/+) mice, resulting in significantly more concentrated bile in livers of Cldn2(-/-) mice. Consistent with these findings, osmotic gradient-driven water flow was significantly reduced in hepatocyte bile canaliculi and bile ducts isolated from Cldn2(-/-) mice, compared with Cldn2(+/+) mice. After 4 weeks on lithogenic diets, all Cldn2(-/-) mice developed macroscopically visible gallstones; the main component of the gallstones was cholesterol (>98%). In contrast, none of the Cldn2(+/+) mice placed on lithogenic diets developed gallstones. Based on studies of Cldn2(-/-) mice, claudin 2 regulates paracellular ion and water flow required for proper regulation of bile composition and flow. Dysregulation of this process increases susceptibility to cholesterol gallstone disease in mice. Copyright © 2014 AGA Institute

  14. Downregulation of FoxC2 Increased Susceptibility to Experimental Colitis: Influence of Lymphatic Drainage Function?

    Science.gov (United States)

    Becker, Felix; Potepalov, Sergey; Shehzahdi, Romana; Bernas, Michael; Witte, Marlys; Abreo, Fleurette; Traylor, James; Orr, Wayne A.; Tsunoda, Ikuo

    2015-01-01

    Background: Although inflammation-induced expansion of the intestinal lymphatic vasculature (lymphangiogenesis) is known to be a crucial event in limiting inflammatory processes, through clearance of interstitial fluid and immune cells, considerably less is known about the impact of an impaired lymphatic clearance function (as seen in inflammatory bowel diseases) on this cascade. We aimed to investigate whether the impaired intestinal lymphatic drainage function observed in FoxC2(+/−) mice would influence the course of disease in a model of experimental colitis. Methods: Acute dextran sodium sulfate colitis was induced in wild-type and haploinsufficient FoxC2(+/−) mice, and survival, disease activity, colonic histopathological injury, neutrophil, T-cell, and macrophage infiltration were evaluated. Functional and structural changes in the intestinal lymphatic vessel network were analyzed, including submucosal edema, vessel morphology, and lymphatic vessel density. Results: We found that FoxC2 downregulation in FoxC2(+/−) mice significantly increased the severity and susceptibility to experimental colitis, as displayed by lower survival rates, increased disease activity, greater histopathological injury, and elevated colonic neutrophil, T-cell, and macrophage infiltration. These findings were accompanied by structural (dilated torturous lymphatic vessels) and functional (greater submucosal edema, higher immune cell burden) changes in the intestinal lymphatic vasculature. Conclusions: These results indicate that sufficient lymphatic clearance plays a crucial role in limiting the initiation and perpetuation of experimental colitis and those disturbances in the integrity of the intestinal lymphatic vessel network could intensify intestinal inflammation. Future therapies might be able to exploit these processes to restore and maintain adequate lymphatic clearance function in inflammatory bowel disease. PMID:25822012

  15. Downregulation of FoxC2 Increased Susceptibility to Experimental Colitis: Influence of Lymphatic Drainage Function?

    Science.gov (United States)

    Becker, Felix; Potepalov, Sergey; Shehzahdi, Romana; Bernas, Michael; Witte, Marlys; Abreo, Fleurette; Traylor, James; Orr, Wayne A; Tsunoda, Ikuo; Alexander, Jonathan Steven

    2015-06-01

    Although inflammation-induced expansion of the intestinal lymphatic vasculature (lymphangiogenesis) is known to be a crucial event in limiting inflammatory processes, through clearance of interstitial fluid and immune cells, considerably less is known about the impact of an impaired lymphatic clearance function (as seen in inflammatory bowel diseases) on this cascade. We aimed to investigate whether the impaired intestinal lymphatic drainage function observed in FoxC2 mice would influence the course of disease in a model of experimental colitis. Acute dextran sodium sulfate colitis was induced in wild-type and haploinsufficient FoxC2 mice, and survival, disease activity, colonic histopathological injury, neutrophil, T-cell, and macrophage infiltration were evaluated. Functional and structural changes in the intestinal lymphatic vessel network were analyzed, including submucosal edema, vessel morphology, and lymphatic vessel density. We found that FoxC2 downregulation in FoxC2 mice significantly increased the severity and susceptibility to experimental colitis, as displayed by lower survival rates, increased disease activity, greater histopathological injury, and elevated colonic neutrophil, T-cell, and macrophage infiltration. These findings were accompanied by structural (dilated torturous lymphatic vessels) and functional (greater submucosal edema, higher immune cell burden) changes in the intestinal lymphatic vasculature. These results indicate that sufficient lymphatic clearance plays a crucial role in limiting the initiation and perpetuation of experimental colitis and those disturbances in the integrity of the intestinal lymphatic vessel network could intensify intestinal inflammation. Future therapies might be able to exploit these processes to restore and maintain adequate lymphatic clearance function in inflammatory bowel disease.

  16. Prolonged pre-incubation increases the susceptibility of Galleria mellonella larvae to bacterial and fungal infection

    Science.gov (United States)

    Browne, Niall; Surlis, Carla; Maher, Amie; Gallagher, Clair; Carolan, James C; Clynes, Martin; Kavanagh, Kevin

    2015-01-01

    Galleria mellonella larvae are widely used for assessing the virulence of microbial pathogens and for measuring the in vivo activity of antimicrobial agents and produce results comparable to those that can be obtained using mammals. The aim of the work described here was to ascertain the effect of pre-incubation at 15°C for 1, 3, 6 or 10 weeks on the susceptibility of larvae to infection with Candida albicans and Staphylococcus aureus. Larvae infected with C. albicans after 1 week pre-incubation at 15°C showed 73.3 ± 3.3% survival at 24 hours post-infection while those infected after 10 weeks pre-incubation showed 30 ± 3.3% survival (P mellonella larvae are a useful in vivo model system but the duration of the pre-incubation stage significantly affects their susceptibility to microbial pathogens possibly as a result of altered metabolism. PMID:25785635

  17. Alginate microencapsulation of human islets does not increase susceptibility to acute hypoxia.

    Science.gov (United States)

    Hals, I K; Rokstad, A M; Strand, B L; Oberholzer, J; Grill, V

    2013-01-01

    Islet transplantation in diabetes is hampered by the need of life-long immunosuppression. Encapsulation provides partial immunoprotection but could possibly limit oxygen supply, a factor that may enhance hypoxia-induced beta cell death in the early posttransplantation period. Here we tested susceptibility of alginate microencapsulated human islets to experimental hypoxia (0.1-0.3% O2 for 8 h, followed by reoxygenation) on viability and functional parameters. Hypoxia reduced viability as measured by MTT by 33.8 ± 3.5% in encapsulated and 42.9 ± 5.2% in nonencapsulated islets (P microencapsulation of human islets does not increase susceptibility to acute hypoxia. This is a positive finding in relation to potential use of encapsulation for islet transplantation.

  18. Alginate Microencapsulation of Human Islets Does Not Increase Susceptibility to Acute Hypoxia

    Science.gov (United States)

    Hals, I. K.; Rokstad, A. M.; Strand, B. L.; Oberholzer, J.; Grill, V.

    2013-01-01

    Islet transplantation in diabetes is hampered by the need of life-long immunosuppression. Encapsulation provides partial immunoprotection but could possibly limit oxygen supply, a factor that may enhance hypoxia-induced beta cell death in the early posttransplantation period. Here we tested susceptibility of alginate microencapsulated human islets to experimental hypoxia (0.1–0.3% O2 for 8 h, followed by reoxygenation) on viability and functional parameters. Hypoxia reduced viability as measured by MTT by 33.8 ± 3.5% in encapsulated and 42.9 ± 5.2% in nonencapsulated islets (P microencapsulation of human islets does not increase susceptibility to acute hypoxia. This is a positive finding in relation to potential use of encapsulation for islet transplantation. PMID:24364039

  19. Does precipitation susceptibility vary with increasing cloud thickness in marine stratocumulus?

    Directory of Open Access Journals (Sweden)

    C. R. Terai

    2012-05-01

    Full Text Available The relationship between precipitation rate and accumulation mode aerosol concentration in marine stratocumulus-topped boundary layers is investigated by applying the precipitation susceptibility metric to aircraft data obtained during the VOCALS Regional Experiment. A new method to calculate the precipitation susceptibility that incorporates non-precipitating clouds is introduced. The mean precipitation rate R over a segment of the data is expressed as the product of a drizzle fraction f and a drizzle intensity I (mean rate for drizzling columns. The susceptibility Sx is then defined as the fractional decrease in precipitation variable x = {R, f, I} per fractional increase in the concentration of aerosols with dry diameter >0.1 μm, with cloud thickness h held fixed. The precipitation susceptibility SR is calculated using data from both precipitating and non-precipitating cloudy columns to quantify how aerosol concentrations affect the mean precipitation rate of all clouds of a given h range and not just the mean precipitation of clouds that are precipitating. SR systematically decreases with increasing h, and this is largely because Sf decreases with h while SI is approximately independent of h. In a general sense, Sf can be thought of as the effect of aerosols on the probability of precipitation, while SI can be thought of as the effect of aerosols on the intensity of precipitation. Since thicker clouds are likely to precipitate regardless of ambient aerosol concentration, we expect Sf to decrease with increasing h. The results are broadly insensitive to the choice of horizontal averaging scale. Similar susceptibilities are found for both cloud base and near-surface drizzle rates. The analysis is repeated with cloud

  20. Lack of a Functioning P2X7 Receptor Leads to Increased Susceptibility to Toxoplasmic Ileitis.

    Directory of Open Access Journals (Sweden)

    Catherine M Miller

    Full Text Available Oral infection of C57BL/6J mice with the protozoan parasite Toxoplasma gondii leads to a lethal inflammatory ileitis.Mice lacking the purinergic receptor P2X7R are acutely susceptible to toxoplasmic ileitis, losing significantly more weight than C57BL/6J mice and exhibiting much greater intestinal inflammatory pathology in response to infection with only 10 cysts of T. gondii. This susceptibility is not dependent on the ability of P2X7R-deficient mice to control the parasite, which they accomplish just as efficiently as C57BL/6J mice. Rather, susceptibility is associated with elevated ileal concentrations of pro-inflammatory cytokines, reactive nitrogen intermediates and altered regulation of elements of NFκB activation in P2X7R-deficient mice.Our data support the thesis that P2X7R, a well-documented activator of pro-inflammatory cytokine production, also plays an important role in the regulation of intestinal inflammation.

  1. Significant increase of Echinococcus multilocularis prevalencein foxes, but no increased predicted risk for humans

    NARCIS (Netherlands)

    Maas, M.; Dam-Deisz, W.D.C.; Roon, van A.M.; Takumi, K.; Giessen, van der J.W.B.

    2014-01-01

    The emergence of the zoonotic tapeworm Echinococcus multilocularis, causative agent ofalveolar echinococcosis (AE), poses a public health risk. A previously designed risk mapmodel predicted a spread of E. multilocularis and increasing numbers of alveolar echinococ-cosis patients in the province of

  2. Excess algal symbionts increase the susceptibility of reef corals to bleaching

    Science.gov (United States)

    Cunning, Ross; Baker, Andrew C.

    2013-03-01

    Rising ocean temperatures associated with global climate change are causing mass coral bleaching and mortality worldwide. Understanding the genetic and environmental factors that mitigate coral bleaching susceptibility may aid local management efforts to help coral reefs survive climate change. Although bleaching susceptibility depends partly on the genetic identity of a coral's algal symbionts, the effect of symbiont density, and the factors controlling it, remain poorly understood. By applying a new metric of symbiont density to study the coral Pocillopora damicornis during seasonal warming and acute bleaching, we show that symbiont cell ratio density is a function of both symbiont type and environmental conditions, and that corals with high densities are more susceptible to bleaching. Higher vulnerability of corals with more symbionts establishes a quantitative mechanistic link between symbiont density and the molecular basis for coral bleaching, and indicates that high densities do not buffer corals from thermal stress, as has been previously suggested. These results indicate that environmental conditions that increase symbiont densities, such as nutrient pollution, will exacerbate climate-change-induced coral bleaching, providing a mechanistic explanation for why local management to reduce these stressors will help coral reefs survive future warming.

  3. Deuterium content of water increases depression susceptibility: the potential role of a serotonin-related mechanism.

    Science.gov (United States)

    Strekalova, Tatyana; Evans, Matthew; Chernopiatko, Anton; Couch, Yvonne; Costa-Nunes, João; Cespuglio, Raymond; Chesson, Lesley; Vignisse, Julie; Steinbusch, Harry W; Anthony, Daniel C; Pomytkin, Igor; Lesch, Klaus-Peter

    2015-01-15

    Environmental factors can significantly affect disease prevalence, including neuropsychiatric disorders such as depression. The ratio of deuterium to protium in water shows substantial geographical variation, which could affect disease susceptibility. Thus the link between deuterium content of water and depression was investigated, both epidemiologically, and in a mouse model of chronic mild stress. We performed a correlation analysis between deuterium content of tap water and rates of depression in regions of the USA. Next, we used a 10-day chronic stress paradigm to test whether 2-week deuterium-depleted water treatment (91 ppm) affects depressive-like behavior and hippocampal SERT. The effect of deuterium-depletion on sleep electrophysiology was also evaluated in naïve mice. There was a geographic correlation between a content of deuterium and the prevalence of depression across the USA. In the chronic stress model, depressive-like features were reduced in mice fed with deuterium-depleted water, and SERT expression was decreased in mice treated with deuterium-treated water compared with regular water. Five days of predator stress also suppressed proliferation in the dentate gyrus; this effect was attenuated in mice fed with deuterium-depleted water. Finally, in naïve mice, deuterium-depleted water treatment increased EEG indices of wakefulness, and decreased duration of REM sleep, phenomena that have been shown to result from the administration of selective serotonin reuptake inhibitors (SSRI). Our data suggest that the deuterium content of water may influence the incidence of affective disorder-related pathophysiology and major depression, which might be mediated by the serotoninergic mechanisms. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

  4. Genetic susceptibility to viral exposure may increase the risk of cerebral palsy.

    Science.gov (United States)

    Djukic, Michael; Gibson, Catherine S; Maclennan, Alastair H; Goldwater, Paul N; Haan, Eric A; McMichael, Gai; Priest, Kevin; Dekker, Gustaaf A; Hague, William M; Chan, Annabelle; Rudzki, Zbigniew; VAN Essen, Phillipa; Khong, T Yee; Morton, Mark R; Ranieri, Enzo; Scott, Heather; Tapp, Heather; Casey, Graeme

    2009-06-01

    Cytokine polymorphisms may alter the fetal inflammatory response, increasing susceptibility to cerebral palsy (CP). This study investigates associations between selected inflammatory mediator and cytokine gene polymorphisms (Toll-like receptor-4 (TLR-4) Asp299Gly, interleukin-6 G-174C and interleukin-4 C-589T) and CP from 443 CP infants and 883 control infants. Results were correlated with viral nucleic acids in the same samples. At all gestational ages (GA), TLR-4 was associated with a decreased risk of developing CP (homozygous/heterozygous odds ratio (OR) 0.70, 95% confidence interval (CI) 0.50-0.98) and interleukin (IL)-6 was associated with an increased risk of developing hemiplegia (OR 1.38, 95% CI 1.05-1.83). For infants born 32-36 weeks GA, there was a tenfold increase in the risk of quadriplegic CP with homozygous/heterozygous IL-6 (OR 10.42, 95% CI 1.34-80.82). Viral exposure in combination with IL-4 in preterm infants was associated with a fourfold increased risk of quadriplegia (homozygous/heterozygous OR 4.25, 95% CI 1.21-14.95). In very preterm infants, the absence of detectable viral exposure in combination with IL-4 decreased the risk of developing CP (homozygous/heterozygous OR 0.31, 95% CI 0.13-0.76). Polymorphisms in TLR-4 may be associated with a decreased risk of CP. Polymorphisms in IL-6 or IL-4 may act as susceptibility genes, in the presence of viral exposure, for the development of hemiplegic and quadriplegic CP. These associations require confirmation but they suggest a hypothesis for CP causation due to double jeopardy from neurotropic viral exposure and genetic susceptibility to infection.

  5. Modelling increased landslide susceptibility near highways in the Andes of southern Ecuador

    Science.gov (United States)

    Brenning, Alexander; Muenchow, Jannes

    2016-04-01

    Modelling increased landslide susceptibility near highways in the Andes of southern Ecuador A. Brenning (1), J. Muenchow (1) (1) Department of Geography, Friedrich Schiller University Jena, Loebdergraben 32, 07743 Jena, Germany Mountain roads are affected by and also affect themselves landslide suceptibility. Especially in developing countries, inadequate drainage systems and mechanical destabilization of hillslopes by undercutting and overloading are known processes through which road construction and maintenance can enhance landslide activity within the immediate surroundings of road infrastructure. In the Andes of southern Ecuador, strong precipitation gradients as well as lithological differences provide an excellent study site in which the relationship between highways and landslide susceptibility and its regional differentiation can be studied. This study uses Generalized Additive Models (GAM) to investigate patterns of landslide susceptibility along two paved interurban highways in the tropical Andes of southern Ecuador. The relationship of landslides to distance from road is modeled while accounting for topographic, climatic and lithological predictors as possible confounders and modifiers, focusing on the odds ratio of landslide occurrence at 25 m versus 200 m distance from the highway. Spatial attention is given to uncertainties in estimated odds ratios of landslide occurrence using spatial block bootstrap techniques. The GAM is able to represent nonlinear additive terms as well as bivariate smooth interaction terms, providing a good tradeoff between model complexity and interpretability. The estimated odds of landslide occurrence were 18-21 times higher near the highway than at 200 m distance, based on different analyses, with lower 95% confidence limits always >13. (Semi-) parametric estimates confirmed this general range of values but suggests slightly higher odds ratios (95% confidence interval: 15.5-25.3). Highway-related effects were observed to

  6. [Significant increase in the colonisation of Staphylococcus aureus among medical students during their hospital practices].

    Science.gov (United States)

    Rodríguez-Avial, Carmen; Alvarez-Novoa, Andrea; Losa, Azucena; Picazo, Juan J

    2013-10-01

    Staphylococcus aureus is a pathogen of major concern. The emergence of methicillin-resistant S. aureus (MRSA) has increasingly complicated the therapeutic approach of hospital-acquired infections. Surveillance of MRSA and control measures must be implemented in different healthcare settings, including screening programs for carriers. Our first aim was to determine the prevalence of methicillin-susceptible S. aureus (MSSA) and MRSA nasal carriage in medical students from the Clínico San Carlos Hospital (Madrid). As the MRSA carrier rate in healthcare workers is higher than in the general population, we hypothesised that carrier rate could be increased during their clinical practice in their last three years. We performed an epidemiologic al study of the prevalence of S. aureus colonisation among a group of medical students, who were sampled in 2008 in their third-year, and in 2012 when this class was in its sixth year. We have found a significant increase in MSSA carriage, from 27% to 46%. There were no MRSA colonisations in the third-year, but one was found in the sixth-year group. The large majority of strains (89%) of strains were resistant to penicillin, and 27% to erythromycin and clindamycin. As 19 coagulase-negative Staphylococcus MR were also identified, a horizontal transfer of genes, such as mecA gene to S. aureus, could have occurred. Medical students are both, at risk for acquiring, and a potential source of nosocomial pathogens, mainly MSSA. Therefore, they should take special care for hygienic precautions, such as frequent and proper hand washing, while working in the hospital. Copyright © 2012 Elsevier España, S.L. All rights reserved.

  7. Simulated microgravity increases myocardial susceptibility to ischemia-reperfusion injury via a deficiency of AMP-activated protein kinase.

    Science.gov (United States)

    Lu, Yuan-Ming; Jiao, Bo; Lee, Jun; Zhang, Lin; Yu, Zhi-Bin

    2017-01-01

    Gravitation is an important factor in maintaining cardiac contractility. Our study investigated whether simulated microgravity increases myocardial susceptibility to ischemia-reperfusion (IR) injury. Using the Langendorff-perfused heart model with 300 beats/min pacing, 4-week tail suspension (SUS) and control (CON) male Sprague-Dawley rats (n = 10 rats/group) were subjected to 60 min of left anterior descending coronary artery (LAD) occlusion followed by 120 min of reperfusion. Left ventricular end-systolic pressure (LVESP), left ventricular end-diastolic pressure (LVEDP), creatine kinase (CK) and lactate dehydrogenase (LDH) activity, and infarct size were assessed. Data demonstrated that there were significantly increased LVEDP, CK, LDH, and infarct size in SUS compared with CON (P < 0.05), accompanied by decreased LVESP (P < 0.05). Furthermore, TUNEL-positive cardiomyocytes were higher in SUS than that in CON (P < 0.01), and AMP-activated protein kinase (AMPK) phosphorylation and Bcl-2/Bax in SUS were less compared with CON (P < 0.05). Similarly, isolated hearts pre-treated with A-769662 exhibited better recovery of cardiac function, increased AMPK phosphorylation, and reduced necrosis and apoptosis. Furthermore, AMPKα protein showed a significant suppression in 4-week hindlimb unweighting rats. These results suggest that AMPK deficiency increases myocardial susceptibility to IR injury in rats subjected to simulated microgravity.

  8. Increasing vaginal progesterone gel supplementation after frozen-thawed embryo transfer significantly increases the delivery rate

    DEFF Research Database (Denmark)

    Alsbjerg, Birgit; Polyzos, Nikolaos P; Elbaek, Helle Olesen

    2013-01-01

    The aim of this study was to evaluate the reproductive outcome in patients receiving frozen-thawed embryo transfer before and after doubling of the vaginal progesterone gel supplementation. The study was a retrospective study performed in The Fertility Clinic, Skive Regional Hospital, Denmark....... A total of 346 infertility patients with oligoamenorrhoea undergoing frozen-thawed embryo transfer after priming with oestradiol and vaginal progesterone gel were included. The vaginal progesterone dose was changed from 90mg (Crinone) once a day to twice a day and the reproductive outcome during the two...... rate (8.7% versus 20.5%, respectively; P=0.002). Doubling of the vaginal progesterone gel supplementation during frozen-thawed embryo transfer cycles decreased the early pregnancy loss rate, resulting in a significantly higher delivery rate. This study evaluated the reproductive outcome of 346 women...

  9. Alginate Microencapsulation of Human Islets Does Not Increase Susceptibility to Acute Hypoxia

    Directory of Open Access Journals (Sweden)

    I. K. Hals

    2013-01-01

    Full Text Available Islet transplantation in diabetes is hampered by the need of life-long immunosuppression. Encapsulation provides partial immunoprotection but could possibly limit oxygen supply, a factor that may enhance hypoxia-induced beta cell death in the early posttransplantation period. Here we tested susceptibility of alginate microencapsulated human islets to experimental hypoxia (0.1–0.3% O2 for 8 h, followed by reoxygenation on viability and functional parameters. Hypoxia reduced viability as measured by MTT by 33.8±3.5% in encapsulated and 42.9±5.2% in nonencapsulated islets (P<0.2. Nonencapsulated islets released 37.7% (median more HMGB1 compared to encapsulated islets after hypoxic culture conditions (P<0.001. Glucose-induced insulin release was marginally affected by hypoxia. Basal oxygen consumption was equally reduced in encapsulated and nonencapsulated islets, by 22.0±6.1% versus 24.8±5.7%. Among 27 tested cytokines/chemokines, hypoxia increased the secretion of IL-6 and IL-8/CXCL8 in both groups of islets, whereas an increase of MCP-1/CCL2 was seen only with nonencapsulated islets. Conclusion. Alginate microencapsulation of human islets does not increase susceptibility to acute hypoxia. This is a positive finding in relation to potential use of encapsulation for islet transplantation.

  10. Susceptibility to hippocampal kindling seizures is increased in aging C57 black mice

    Directory of Open Access Journals (Sweden)

    Kurt R. Stover

    2017-12-01

    Full Text Available The incidence of seizures increases with old age. Stroke, dementia and brain tumors are recognized risk factors for new-onset seizures in the aging populations and the incidence of these conditions also increased with age. Whether aging is associated with higher seizure susceptibility in the absence of the above pathologies remains unclear. We used classic kindling to explore this issue as the kindling model is highly reproducible and allows close monitoring of electrographic and motor seizure activities in individual animals. We kindled male young and aging mice (C57BL/6 strain, 2–3 and 18–22 months of age via daily hippocampal CA3 stimulation and monitored seizure activity via video and electroencephalographic recordings. The aging mice needed fewer stimuli to evoke stage-5 motor seizures and exhibited longer hippocampal afterdischarges and more frequent hippocampal spikes relative to the young mice, but afterdischarge thresholds and cumulative afterdischarge durations to stage 5 motor seizures were not different between the two age groups. While hippocampal injury and structural alterations at cellular and micro-circuitry levels remain to be examined in the kindled mice, our present observations suggest that susceptibility to hippocampal CA3 kindling seizures is increased with aging in male C57 black mice.

  11. Does abnormal glycogen structure contribute to increased susceptibility to seizures in epilepsy?

    Science.gov (United States)

    DiNuzzo, Mauro; Mangia, Silvia; Maraviglia, Bruno; Giove, Federico

    2014-01-01

    Epilepsy is a family of brain disorders with a largely unknown etiology and high percentage of pharmacoresistance. The clinical manifestations of epilepsy are seizures, which originate from aberrant neuronal synchronization and hyperexcitability. Reactive astrocytosis, a hallmark of the epileptic tissue, develops into loss-of-function of glutamine synthetase, impairment of glutamate-glutamine cycle and increase in extracellular and astrocytic glutamate concentration. Here, we argue that chronically elevated intracellular glutamate level in astrocytes is instrumental to alterations in the metabolism of glycogen and leads to the synthesis of polyglucosans. Unaccessibility of glycogen-degrading enzymes to these insoluble molecules compromises the glycogenolysis-dependent reuptake of extracellular K+ by astrocytes, thereby leading to increased extracellular K+ and associated membrane depolarization. Based on current knowledge, we propose that the deterioration in structural homogeneity of glycogen particles is relevant to disruption of brain K+ homeostasis and increased susceptibility to seizures in epilepsy. PMID:24643875

  12. Perinatal Nicotine Exposure Increases Obesity Susceptibility in Adult Male Rat Offspring by Altering Early Adipogenesis.

    Science.gov (United States)

    Fan, Jie; Zhang, Wan-Xia; Rao, Yi-Song; Xue, Jing-Ling; Wang, Fei-Fei; Zhang, Li; Yan, You-E

    2016-11-01

    The present study aims to evaluate whether perinatal nicotine (NIC) exposure increases obesity susceptibility in adult male rat offspring by altering early adipogenesis. NIC was sc administered (2.0 mg/kg per day) to pregnant rats from gestational day 9 to the time of weaning (postnatal day 28). At weaning, NIC-exposed male pups had an increased body weight and inguinal sc fat mass and a decreased average cell area of adipocyte, which was accompanied by an overexpression of adipogenic and lipogenic genes in the epididymal white adipose tissue. Additionally, the hepatic lipogenic gene levels from NIC-exposed male pups were also affected. At 12 and 26 weeks of age, body weight and fat mass were increased, whereas there was no change in food intake in NIC-exposed male offspring. Adipogenic and lipogenic genes, glucose transporter 4, and leptin mRNA levels were increased, whereas adiponectin mRNA levels were decreased in the epididymal white adipose tissue of NIC-exposed males. The hepatic lipogenic gene expression of NIC-exposed males was increased. NIC-exposed male offspring showed normal glycemia and a higher serum insulin level, homeostasis model assessment of insulin resistance, and homeostasis model assessment of β-cell function. Furthermore, the NIC-exposed male offspring showed higher serum lipids and Castelli index I and lower nonesterified fatty acid. At 26 weeks, in the ip glucose and insulin tolerance tests, the glucose clearance was delayed, and the area under the curve was higher in the NIC-exposed male offspring. In conclusion, perinatal NIC exposure increased obesity susceptibility in adult male rat offspring by altering early adipogenesis.

  13. Telling true from false: cannabis users show increased susceptibility to false memories.

    Science.gov (United States)

    Riba, J; Valle, M; Sampedro, F; Rodríguez-Pujadas, A; Martínez-Horta, S; Kulisevsky, J; Rodríguez-Fornells, A

    2015-06-01

    Previous studies on the neurocognitive impact of cannabis use have found working and declarative memory deficits that tend to normalize with abstinence. An unexplored aspect of cognitive function in chronic cannabis users is the ability to distinguish between veridical and illusory memories, a crucial aspect of reality monitoring that relies on adequate memory function and cognitive control. Using functional magnetic resonance imaging, we show that abstinent cannabis users have an increased susceptibility to false memories, failing to identify lure stimuli as events that never occurred. In addition to impaired performance, cannabis users display reduced activation in areas associated with memory processing within the lateral and medial temporal lobe (MTL), and in parietal and frontal brain regions involved in attention and performance monitoring. Furthermore, cannabis consumption was inversely correlated with MTL activity, suggesting that the drug is especially detrimental to the episodic aspects of memory. These findings indicate that cannabis users have an increased susceptibility to memory distortions even when abstinent and drug-free, suggesting a long-lasting compromise of memory and cognitive control mechanisms involved in reality monitoring.

  14. The MspA porin promotes growth and increases antibiotic susceptibility of both Mycobacterium bovis BCG and Mycobacterium tuberculosis.

    Science.gov (United States)

    Mailaender, Claudia; Reiling, Norbert; Engelhardt, Harald; Bossmann, Stefan; Ehlers, Stefan; Niederweis, Michael

    2004-04-01

    Porins mediate the diffusion of hydrophilic solutes across the outer membrane of mycobacteria, but the efficiency of this pathway is very low compared to Gram-negative bacteria. To examine the importance of porins in slow-growing mycobacteria, the major porin MspA of Mycobacterium smegmatis was expressed in Mycobacterium tuberculosis and Mycobacterium bovis. Approximately 20 and 35 MspA molecules per microm(2) cell wall were observed in M. tuberculosis and M. bovis BCG, respectively, by electron microscopy and quantitative immunoblot experiments. Surface accessibility of MspA in M. tuberculosis was demonstrated by flow cytometry. Glucose uptake was twofold faster, indicating that the outer membrane permeability of M. bovis BCG to small and hydrophilic solutes was increased by MspA. This significantly accelerated the growth of M. bovis BCG, identifying very slow nutrient uptake as one of the determinants of slow growth in mycobacteria. The susceptibility of both M. bovis BCG and M. tuberculosis to zwitterionic beta-lactam antibiotics was substantially enhanced by MspA, decreasing the minimal inhibitory concentration up to 16-fold. Furthermore, M. tuberculosis became significantly more susceptible to isoniazid, ethambutol and streptomycin. Fluorescence with the nucleic acid binding dye SYTO 9 was 10-fold increased upon expression of mspA. These results indicated that MspA not only enhanced the efficiency of the porin pathway, but also that of pathways mediating access to large and/or hydrophobic agents. This study provides the first experimental evidence that porins are important for drug susceptibility of M. tuberculosis.

  15. Projections of climate conditions that increase coral disease susceptibility and pathogen abundance and virulence

    Science.gov (United States)

    Maynard, Jeffrey; van Hooidonk, Ruben; Eakin, C. Mark; Puotinen, Marjetta; Garren, Melissa; Williams, Gareth; Heron, Scott F.; Lamb, Joleah; Weil, Ernesto; Willis, Bette; Harvell, C. Drew

    2015-07-01

    Rising sea temperatures are likely to increase the frequency of disease outbreaks affecting reef-building corals through impacts on coral hosts and pathogens. We present and compare climate model projections of temperature conditions that will increase coral susceptibility to disease, pathogen abundance and pathogen virulence. Both moderate (RCP 4.5) and fossil fuel aggressive (RCP 8.5) emissions scenarios are examined. We also compare projections for the onset of disease-conducive conditions and severe annual coral bleaching, and produce a disease risk summary that combines climate stress with stress caused by local human activities. There is great spatial variation in the projections, both among and within the major ocean basins, in conditions favouring disease development. Our results indicate that disease is as likely to cause coral mortality as bleaching in the coming decades. These projections identify priority locations to reduce stress caused by local human activities and test management interventions to reduce disease impacts.

  16. Changes in human dendritic cell number and function in severe obesity may contribute to increased susceptibility to viral infection.

    LENUS (Irish Health Repository)

    O'Shea, D

    2013-02-26

    Dendritic cells (DCs) are key immune sentinels linking the innate and adaptive immune systems. DCs recognise danger signals and initiate T-cell tolerance, memory and polarisation. They are critical cells in responding to a viral illness. Obese individuals have been shown to have an impaired response to vaccinations against virally mediated conditions and to have an increased susceptibility to multi-organ failure in response to viral illness. We investigated if DCs are altered in an obese cohort (mean body mass index 51.7±7.3 kg m(-2)), ultimately resulting in differential T-cell responses. Circulating DCs were found to be significantly decreased in the obese compared with the lean cohort (0.82% vs 2.53%). Following Toll-like receptor stimulation, compared with lean controls, DCs generated from the obese cohort upregulated significantly less CD83 (40% vs 17% mean fluorescence intensity), a molecule implicated in the elicitation of T-cell responses, particularly viral responses. Obese DCs produced twofold more of the immunosuppressive cytokine interleukin (IL)-10 than lean controls, and in turn stimulated fourfold more IL-4-production from allogenic naive T cells. We conclude that obesity negatively impacts the ability of DCs to mature and elicit appropriate T-cell responses to a general stimulus. This may contribute to the increased susceptibility to viral infection observed in severe obesity.International Journal of Obesity advance online publication, 26 February 2013; doi:10.1038\\/ijo.2013.16.

  17. Perinatal hypoxia increases susceptibility to high-altitude polycythemia and attendant pulmonary vascular dysfunction.

    Science.gov (United States)

    Julian, Colleen Glyde; Gonzales, Marcelino; Rodriguez, Armando; Bellido, Diva; Salmon, Carlos Salinas; Ladenburger, Anne; Reardon, Lindsay; Vargas, Enrique; Moore, Lorna G

    2015-08-15

    Perinatal exposures exert a profound influence on physiological function, including developmental processes vital for efficient pulmonary gas transfer throughout the lifespan. We extend the concept of developmental programming to chronic mountain sickness (CMS), a debilitating syndrome marked by polycythemia, ventilatory impairment, and pulmonary hypertension that affects ∼10% of male high-altitude residents. We hypothesized that adverse perinatal oxygenation caused abnormalities of ventilatory and/or pulmonary vascular function that increased susceptibility to CMS in adulthood. Subjects were 67 male high-altitude (3,600-4,100 m) residents aged 18-25 yr with excessive erythrocytosis (EE, Hb concentration ≥18.3 g/dl), a preclinical form of CMS, and 66 controls identified from a community-based survey (n = 981). EE subjects not only had higher Hb concentrations and erythrocyte counts, but also lower alveolar ventilation, impaired pulmonary diffusion capacity, higher systolic pulmonary artery pressure, lower pulmonary artery acceleration time, and more frequent right ventricular hypertrophy, than controls. Compared with controls, EE subjects were more often born to mothers experiencing hypertensive complications of pregnancy and hypoxia during the perinatal period, with each increasing the risk of developing EE (odds ratio = 5.25, P = 0.05 and odds ratio = 6.44, P = 0.04, respectively) after other factors known to influence EE status were taken into account. Adverse perinatal oxygenation is associated with increased susceptibility to EE accompanied by modest abnormalities of the pulmonary circulation that are independent of increased blood viscosity. The association between perinatal hypoxia and EE may be due to disrupted alveolarization and microvascular development, leading to impaired gas exchange and/or pulmonary hypertension. Copyright © 2015 the American Physiological Society.

  18. Abrupt suspension of probiotics administration may increase host pathogen susceptibility by inducing gut dysbiosis

    Science.gov (United States)

    Liu, Zhi; Liu, Wenshu; Ran, Chao; Hu, Jun; Zhou, Zhigang

    2016-01-01

    In this study, we investigated the risk associated with suspension of probiotics administration in tilapia, an animal model that may mimic immune-compromised conditions in humans. Tilapias were fed for 14 days using a probiotics-supplemented diet, followed by a three-day suspension of probiotics treatment and a subsequent challenge by Aeromonas hydrophila. Unexpectedly, the suspension of a probiotic strain Lactobacillus plantarum JCM1149 significantly triggered susceptibility of the host to A. hydrophila. We further observed that suspension of JCM1149 resulted in host gut microbiota dysbiosis and the subsequent disorder in the intestinal metabolites (bile acids, amino acids, and glucose) and damage in the intestinal epithelium, giving rise to a condition similar to antibiotics-induced gut dysbiosis, which collectively impaired tilapia’s gut health and resistance to pathogenic challenges. Additionally, we determined that JCM1149 adhered relatively poorly to tilapia intestinal mucosa and was rapidly released from the gastrointestinal tract (GIT) after suspension, with the rapid loss of probiotic strain probably being the direct cause of gut dysbiosis. Finally, three other probiotic Lactobacillus strains with low intestinal mucosa binding activity showed similar rapid loss phenotype following administration suspension, and induced higher host susceptibility to infection, indicating that the risk is a generic phenomenon in Lactobacillus. PMID:26983596

  19. Antimicrobial susceptibility testing for Helicobacter pylori in times of increasing antibiotic resistance.

    Science.gov (United States)

    Smith, Sinéad M; O'Morain, Colm; McNamara, Deirdre

    2014-08-07

    The gram-negative bacterium Helicobacter pylori (H. pylori) causes chronic gastritis, gastric and duodenal ulcers, gastric cancer and mucosa-associated lymphoid tissue lymphoma. Treatment is recommended in all symptomatic patients. The current treatment options for H. pylori infection are outlined in this review in light of the recent challenges in eradication success, largely due to the rapid emergence of antibiotic resistant strains of H. pylori. Antibiotic resistance is a constantly evolving process and numerous studies have shown that the prevalence of H. pylori antibiotic resistance varies significantly from country to country, and even between regions within the same country. In addition, recent data has shown that previous antibiotic use is associated with harbouring antibiotic resistant H. pylori. Local surveillance of antibiotic resistance is warranted to guide clinicians in their choice of therapy. Antimicrobial resistance is assessed by H. pylori culture and antimicrobial susceptibility testing. Recently developed molecular tests offer an attractive alternative to culture and allow for the rapid molecular genetic identification of H. pylori and resistance-associated mutations directly from biopsy samples or bacterial culture material. Accumulating evidence indicates that surveillance of antimicrobial resistance by susceptibility testing is feasible and necessary to inform clinicians in their choice of therapy for management of H. pylori infection.

  20. Loss of Cannabinoid CB1 Receptors Induces Cortical Migration Malformations and Increases Seizure Susceptibility.

    Science.gov (United States)

    Díaz-Alonso, Javier; de Salas-Quiroga, Adán; Paraíso-Luna, Juan; García-Rincón, Daniel; Garcez, Patricia P; Parsons, Maddy; Andradas, Clara; Sánchez, Cristina; Guillemot, François; Guzmán, Manuel; Galve-Roperh, Ismael

    2017-11-01

    Neuronal migration is a fundamental process of brain development, and its disruption underlies devastating neurodevelopmental disorders. The transcriptional programs governing this process are relatively well characterized. However, how environmental cues instruct neuronal migration remains poorly understood. Here, we demonstrate that the cannabinoid CB1 receptor is strictly required for appropriate pyramidal neuron migration in the developing cortex. Acute silencing of the CB1 receptor alters neuronal morphology and impairs radial migration. Consequently, CB1 siRNA-electroporated mice display cortical malformations mimicking subcortical band heterotopias and increased seizure susceptibility in adulthood. Importantly, rescuing the CB1 deficiency-induced radial migration arrest by knockdown of the GTPase protein RhoA restored the hyperexcitable neuronal network and seizure susceptibility. Our findings show that CB1 receptor/RhoA signaling regulates pyramidal neuron migration, and that deficient CB1 receptor signaling may contribute to cortical development malformations leading to refractory epilepsy independently of its canonical neuromodulatory role in the adult brain. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  1. Dystrophin-deficiency increases the susceptibility to doxorubicin-induced cardiotoxicity.

    Science.gov (United States)

    Deng, Shiwei; Kulle, Bettina; Hosseini, Mehdi; Schlüter, Gregor; Hasenfuss, Gerd; Wojnowski, Leszek; Schmidt, Albrecht

    2007-10-01

    The clinical use of doxorubicin (DOX) and other anthracyclines is limited by a dosage-dependent cardiotoxicity, which can lead to cardiomyopathy. The role of the individual genetic makeup in this disorder is poorly understood. Alterations in genes encoding cardiac cytoskeleton or sarcolemma proteins may increase the susceptibility to doxorubicin-related cardiotoxicity. Female dystrophin-deficient mice (MDX) and age-matched wild-type mice underwent chronic treatment with doxorubicin. Cardiac function and tissue damage were assessed by echocardiography and histopathology, respectively. Gene expression changes were investigated using microarrays. DOX treatment resulted in mortality, cardiac insufficiency, and cardiac interstitial fibrosis. These alterations were more pronounced in DOX-treated MDX mice than in DOX-treated wild-type mice. Changes in gene expression were more numerous in MDX mice, including genes involved in cell adhesion, oxidative stress, cytoskeleton organization, inflammatory and immune response and cell death. Dystrophin deficiency facilitates the development and progression of doxorubicin-induced cardiac injury. The underlying mechanisms may involve changes in cell adhesion, in cytoskeleton, as well as in inflammatory and immune responses. Genetic variants of cytoskeletal proteins in humans may affect the individual susceptibility to doxorubicin. Cardiotoxic drugs may accelerate the manifestation of pre-clinical cardiomyopathies caused by deficiencies in cytoskeletal or sarcolemma proteins.

  2. Interleukin-10: Role in increasing susceptibility and pathogenesis of rheumatic fever/rheumatic heart disease.

    Science.gov (United States)

    Sharma, Neha; Toor, Devinder

    2017-02-01

    Streptococcus pyogenes (group A streptococcus) causes rheumatic fever (RF) which later progresses towards rheumatic heart disease (RHD) in the susceptible individuals. RF and RHD both contribute towards increasing global burden of disease, especially in developing countries. RHD is one of the most common acquired heart diseases causing permanent damage to heart valves which ultimately leads to heart failure. In RHD, heart valve lesions are formed which are mediated by autoimmune reaction between streptococcal antigens (M protein and group A carbohydrate epitope GlcNAc) and heart tissues. On the other hand, inflammatory response generated by cytokines promotes chronicity of the disease. Varying concentrations of interleukin-10 (IL-10) in patients and controls are reported and are also found to be associated with IL-10 gene polymorphism in RF/RHD patients. Although the effect of IL-10 gene polymorphism on the functionality of IL-10 is unknown, many investigations suggest an important role of IL-10 and its polymorphism in immune regulation and progression of disease in RF/RHD. This review summarizes the studies based on association of interleukin-10 with RHD in different populations to understand the role of IL-10 in susceptibility and pathogenesis of the disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Interleukin-13–Induced Mucous Metaplasia Increases Susceptibility of Human Airway Epithelium to Rhinovirus Infection

    Science.gov (United States)

    Lachowicz-Scroggins, Marrah E.; Boushey, Homer A.; Finkbeiner, Walter E.; Widdicombe, Jonathan H.

    2010-01-01

    Infection of airway epithelium by rhinovirus is the most common cause of asthma exacerbations. Even in mild asthma, airway epithelium exhibits mucous metaplasia, which increases with increasing severity of the disease. We previously showed that squamous cultures of human airway epithelium manifest rhinoviral infection at levels many times higher than in well-differentiated cultures of a mucociliary phenotype. Here we tested the hypothesis that mucous metaplasia is also associated with increased levels of rhinoviral infection. Mucous metaplasia was induced with IL-13, which doubled the numbers of goblet cells. In both control (mucociliary) and IL-13– treated (mucous metaplastic) cultures, goblet cells were preferentially infected by rhinovirus. IL-13 doubled the numbers of infected cells by increasing the numbers of infected goblet cells. Furthermore, IL-13 increased both the maturity of goblet cells and the probability that a goblet cell would be infected. The infection of cells other than goblet cells was unaltered by IL-13. Treatment with IL-13 did not alter the levels of rhinovirus receptor ICAM-1, nor did the proliferative effects of IL-13 enhance infection, because rhinovirus did not colocalize with dividing cells. However, the induction of mucous metaplasia caused changes in the apical membrane structure, notably a marked decrease in overall ciliation, and an increase in the overall flatness of the apical surface. We conclude that mucous metaplasia in asthma increases the susceptibility of airway epithelium to infection by rhinovirus because of changes in the overall architecture of the apical surface. PMID:20081054

  4. Reduced erythrocyte susceptibility and increased host clearance of young parasites slows Plasmodium growth in a murine model of severe malaria

    Science.gov (United States)

    Khoury, David S.; Cromer, Deborah; Best, Shannon E.; James, Kylie R.; Sebina, Ismail; Haque, Ashraful; Davenport, Miles P.

    2015-05-01

    The best correlate of malaria severity in human Plasmodium falciparum (Pf) infection is the total parasite load. Pf-infected humans could control parasite loads by two mechanisms, either decreasing parasite multiplication, or increasing parasite clearance. However, few studies have directly measured these two mechanisms in vivo. Here, we have directly quantified host clearance of parasites during Plasmodium infection in mice. We transferred labelled red blood cells (RBCs) from Plasmodium infected donors into uninfected and infected recipients, and tracked the fate of donor parasites by frequent blood sampling. We then applied age-based mathematical models to characterise parasite clearance in the recipient mice. Our analyses revealed an increased clearance of parasites in infected animals, particularly parasites of a younger developmental stage. However, the major decrease in parasite multiplication in infected mice was not mediated by increased clearance alone, but was accompanied by a significant reduction in the susceptibility of RBCs to parasitisation.

  5. Antepartum Antibiotic Treatment Increases Offspring Susceptibility to Experimental Colitis: A Role of the Gut Microbiota.

    Directory of Open Access Journals (Sweden)

    Peris Mumbi Munyaka

    Full Text Available Postnatal maturation of the immune system is largely driven by exposure to microbes, and thus the nature of intestinal colonization may be associated with development of childhood diseases that may persist into adulthood. We investigated whether antepartum antibiotic (ATB therapy can increase offspring susceptibility to experimental colitis through alteration of the gut microbiota.Pregnant C57Bl/6 mice were treated with cefazolin at 160 mg/kg body weight or with saline starting six days before due date. At 7 weeks, fecal samples were collected from male offspring after which they received 4% dextran sulfate sodium (DSS in drinking water for 5 days. Disease activity index, histology, colonic IL-6, IL-1β and serum C-reactive protein (CRP were determined. The V3-V4 region of colonic and fecal bacterial 16S rRNA was sequenced. Alpha-, beta-diversity and differences at the phylum and genus levels were determined, while functional pathways of classified bacteria were predicted.ATB influenced fecal bacterial composition and hence bacterial functional pathways before induction of colitis. After induction of colitis, ATB increased onset of clinical disease, histologic score, and colonic IL-6. In addition, ATB decreased fecal microbial richness, changed fecal and colon microbial composition, which was accompanied by a modification of microbial functional pathways. Also, several taxa were associated with ATB at lower taxonomical levels.The results support the hypothesis that antepartum antibiotics modulate offspring intestinal bacterial colonization and increase susceptibility to develop colonic inflammation in a murine model of colitis, and may guide future interventions to restore physiologic intestinal colonization in offspring born by antibiotic-exposed mothers.

  6. Increased susceptibility to diet-induced obesity in GPRC6A receptor knockout mice

    DEFF Research Database (Denmark)

    Clemmensen, Christoffer; Smajilovic, Sanela; Madsen, Andreas N

    2013-01-01

    complications is still elusive. In the present study, we investigated the impact of GPRC6A deficiency in a murine model of diet-induced obesity (DIO). Male Gprc6a knockout (KO) mice and WT littermates were subjected to a high-fat diet (HFD) for 25 weeks and exposed to comprehensive metabolic phenotyping...... in glucose metabolism showing that Gprc6a KO mice on an HFD display increased susceptibility to develop metabolic-related disorders. Altogether, these data suggest that the amino acid sensing receptor GPRC6A plays an important role in resistance to DIO and metabolic complications. Future studies......The recently identified G protein-coupled receptor GPRC6A is activated by dietary amino acids and expressed in multiple tissues. Although the receptor is hypothesised to exert biological impact on metabolic and endocrine-related parameters, the role of the receptor in obesity and metabolic...

  7. Working memory deficits, increased anxiety-like traits, and seizure susceptibility in BDNF overexpressing mice

    Science.gov (United States)

    Papaleo, Francesco; Silverman, Jill L.; Aney, Jordan; Tian, Qingjun; Barkan, Charlotte L.; Chadman, Kathryn K.; Crawley, Jacqueline N.

    2011-01-01

    BDNF regulates components of cognitive processes and has been implicated in psychiatric disorders. Here we report that genetic overexpression of the BDNF mature isoform (BDNF-tg) in female mice impaired working memory functions while sparing components of fear conditioning. BDNF-tg mice also displayed reduced breeding efficiency, higher anxiety-like scores, high self-grooming, impaired prepulse inhibition, and higher susceptibility to seizures when placed in a new empty cage, as compared with wild-type (WT) littermate controls. Control measures of general health, locomotor activity, motor coordination, depression-related behaviors, and sociability did not differ between genotypes. The present findings, indicating detrimental effects of life-long increased BDNF in mice, may inform human studies evaluating the role of BDNF functional genetic variations on cognitive abilities and vulnerability to psychiatric disorders. PMID:21791566

  8. Increasing Susceptibility of the Global Network of Food Trade to Climate Disturbances

    Science.gov (United States)

    Puma, M. J.; Bose, S.; Chon, S.; Cook, B.

    2013-12-01

    Globalization of agriculture through trade liberalization has led to a dramatic transformation of the global network of food trade. The many benefits of this globalization include greater and more efficient global agricultural production, reduced variability of regional and global food supplies, and savings in global water resources. However, a potential hidden cost is an increasingly fragile network that is more susceptible to shocks or disruptions. Recent studies suggest that complex systems, like the global food trade network, may have architectural features typically associated with the existence of tipping points and susceptibility to collapse. Here we present evidence that this global agricultural network is increasingly connected, homogeneous, and in a state where network nodes (here countries) can flip between alternate states. We use production and trade data from 1986 to 2009 to identify shifts in national self sufficiency and to quantify changes in connectivity and homogeneity of the wheat, maize and rice trade. We then simulate the possible impacts of climate and crop-disease disruptions, which could potentially trigger a global food crisis through an export-restriction-induced domino effect. Changes in self-sufficiency ratio (SSR) over time for various country groups. The SSR is computed based on production and trade of cereals and starchy roots. (Top row) Time series of SSR for the Group of Eight + Five (G8+5) countries. The '+ Five' refers to the five leading emerging economies in the world. (Bottom row) Boxplots of average SSR over two periods (1986-1990 and 2005-2009) for countries designated as 'Annex I' and 'Least Developed Countries' (LDC) by the United Nations.

  9. Lysozyme M deficiency leads to an increased susceptibility to Streptococcus pneumoniae-induced otitis media

    Directory of Open Access Journals (Sweden)

    Woo Jeong-Im

    2008-10-01

    Full Text Available Abstract Background Lysozyme is an antimicrobial innate immune molecule degrading peptidoglycan of the bacterial cell wall. Lysozyme shows the ubiquitous expression in wide varieties of species and tissues including the tubotympanum of mammals. We aim to investigate the effects of lysozyme depletion on pneumococcal clearance from the middle ear cavity. Methods Immunohistochemistry was performed to localize lysozyme in the Eustachian tube. Lysozyme expression was compared between the wild type and the lysozyme M-/- mice using real time quantitative RT-PCR and western blotting. Muramidase activity and bactericidal activity of lysozyme was measured using a lysoplate radial diffusion assay and a liquid broth assay, respectively. To determine if depletion of lysozyme M increases a susceptibility to pneumococal otitis media, 50 CFU of S. pneumoniae 6B were transtympanically inoculated to the middle ear and viable bacteria were counted at day 3 and 7 with clinical grading of middle ear inflammation. Results Immunolabeling revealed that localization of lysozyme M and lysozyme P is specific to some/particular cell types of the Eustachian tube. Lysozyme P of lysozyme M-/- mice was mainly expressed in the submucosal gland but not in the tubal epithelium. Although lysozyme M-/- mice showed compensatory up-regulation of lysozyme P, lysozyme M depletion resulted in a decrease in both muramidase and antimicrobial activities. Deficiency in lysozyme M led to an increased susceptibility to middle ear infection with S. pneumoniae 6B and resulted in severe middle ear inflammation, compared to wild type mice. Conclusion The results suggest that lysozyme M plays an important role in protecting the middle ear from invading pathogens, particularly in the early phase. We suggest a possibility of the exogenous lysozyme as an adjuvant therapeutic agent for otitis media, but further studies are necessary.

  10. I171V germline mutation in the NBS1 gene significantly increases risk of breast cancer.

    Science.gov (United States)

    Roznowski, Krzysztof; Januszkiewicz-Lewandowska, Danuta; Mosor, Maria; Pernak, Monika; Litwiniuk, Maria; Nowak, Jerzy

    2008-07-01

    Nijmegen Breakage Syndrome (NBS) is a rare autosomal, recessive disease caused by homozygous mutations in the NBS1 gene. The most common deletion of 5 bp (657del5) in exon 6, which affects mostly the population of Central Europe is observed. Among the typical features of this disorder is that NBS patients experience a high incidence of lymphoid malignancies as well. An increased risk of solid tumors development for 657del5 carriers was the reason to investigate the role of NBS1 gene as a susceptible one for the breast cancer. The purpose of this work is to identify mutations in all 16 exons of the NBS1 gene in the group of the patients with diagnosed breast cancer and the control group of healthy individuals. In the group of 270 women with breast cancer, seven cases of mutated NBS1 gene were revealed. In the subgroup presenting mutated NBS1 gene, the mutation I171V in 5th exon occurred in five cases. It is the first such a discovery concerning breast cancer patients because this mutation had been previously observed only in the course of lymphoid or hematological malignancies. The rate of I171V mutation in the group of breast cancer patients was significantly higher than in the controls (OR: 9.42; 95% CI: 1.09-81.05; P = 0.02). The conclusion is that heterozygous germline mutation I171V in NBS1 gene is a significant risk factor for breast cancer development. It concerns especially the women whose first degree relatives had a previously diagnosed breast cancer (OR: 6.00; 95% CI: 0.98-38.07; P = 0.04). The histopathological and clinical features of breast cancer with I171V mutation suggest accumulation of the negative prognostic factors. The treatment's results however were unexpectedly satisfactory, that is why further investigations are necessary to assess the role of I171V mutation in NBS1 gene as a prognostic and predictive factor for breast cancer.

  11. Increased susceptibility of Cantagalo virus to the antiviral effect of ST-246®.

    Science.gov (United States)

    Santos-Fernandes, Élida; Beltrame, Cristiana O; Byrd, Chelsea M; Cardwell, Kara B; Schnellrath, Laila C; Medaglia, Maria Luiza G; Hruby, Dennis E; Jordan, Robert; Damaso, Clarissa R

    2013-03-01

    Cantagalo virus (CTGV) is the etiologic agent of a pustular disease in dairy cows and dairy workers in Brazil with important economical and occupational impacts. Nevertheless, no antiviral therapy is currently available. ST-246 is a potent inhibitor of orthopoxvirus egress from cells and has proved its efficacy in cell culture and in animal models. In this work, we evaluated the effect of ST-246 on CTGV replication. Plaque reduction assays indicated that CTGV is 6-38 times more susceptible to the drug than VACV-WR and cowpox virus, respectively, with an EC50 of 0.0086μM and a selective index of >11,600. The analysis of β-gal activity expressed by recombinant viruses in the presence of ST-246 confirmed these results. In addition, ST-246 had a greater effect on the reduction of CTGV spread in comet tail assays and on the production of extracellular virus relative to VACV-WR. Infection of mice with CTGV by tail scarification generated primary lesions at the site of scarification that appeared less severe than those induced by VACV-WR. Animals infected with CTGV and treated with ST-246 at 100mg/kg for 5days did not develop primary lesions and virus yields were inhibited by nearly 98%. In contrast, primary lesions induced by VACV-WR were not affected by ST-246. The analysis of F13 (p37) protein from CTGV revealed a unique substitution in residue 217 (D217N) not found in other orthopoxviruses. Construction of recombinant VACV-WR containing the D217N polymorphism did not lead to an increase in the susceptibility to ST-246. Therefore, it is still unknown why CTGV is more susceptible to the antiviral effects of ST-246 compared to VACV-WR. Nonetheless, our data demonstrates that ST-246 is a potent inhibitor of CTGV replication that should be further evaluated as a promising anti-CTGV therapy. Copyright © 2012 Elsevier B.V. All rights reserved.

  12. Increased susceptibility to amyloid-β toxicity in rat brain microvascular endothelial cells under hyperglycemic conditions.

    Science.gov (United States)

    Carvalho, Cristina; Katz, Paige S; Dutta, Somhrita; Katakam, Prasad V G; Moreira, Paula I; Busija, David W

    2014-01-01

    We hypothesized that hyperglycemia-induced mitochondrial dysfunction and oxidative stress are closely associated with amyloid-β peptide (Aβ) toxicity in endothelial cells. Brain microvascular endothelial cells from rat (RBMEC) and mice (MBMEC) were isolated from adult Sprague-Dawley rats and homozygous db/db (Leprdb/Leprdb) and heterozygous (Dock7m/Leprdb) mice, and cultured under normo- and hyperglycemic conditions for 7 d followed by 24 h exposure to Aβ1-40. Some experiments were also performed with two mitochondrial superoxide (O2•-) scavengers, MitoTempo and Peg-SOD. Cell viability was measured by the Alamar blue assay and mitochondrial membrane potential (ΔΨm) by confocal microscopy. Mitochondrial O2•- and hydrogen peroxide (H2O2) production was assessed by fluorescence microscopy and H2O2 production was confirmed by microplate reader. Hyperglycemia or Aβ1-40 alone did not affect cell viability in RBMEC. However, the simultaneous presence of high glucose and Aβ1-40 reduced cell viability and ΔΨm, and enhanced mitochondrial O2•- and H2O2 production. MitoTempo and PEG-SOD prevented Aβ1-40 toxicity. Interestingly, MBMEC presented a similar pattern of alterations with db/db cultures presenting higher susceptibility to Aβ1-40. Overall, our results show that high glucose levels increase the susceptibility of brain microvascular endothelial cells to Aβ toxicity supporting the idea that hyperglycemia is a major risk factor for vascular injury associated with AD.

  13. Interleukin-15 promotes intestinal dysbiosis with butyrate deficiency associated with increased susceptibility to colitis.

    Science.gov (United States)

    Meisel, Marlies; Mayassi, Toufic; Fehlner-Peach, Hannah; Koval, Jason C; O'Brien, Sarah L; Hinterleitner, Reinhard; Lesko, Kathryn; Kim, Sangman; Bouziat, Romain; Chen, Li; Weber, Christopher R; Mazmanian, Sarkis K; Jabri, Bana; Antonopoulos, Dionysios A

    2017-01-01

    Dysbiosis resulting in gut-microbiome alterations with reduced butyrate production are thought to disrupt intestinal immune homeostasis and promote complex immune disorders. However, whether and how dysbiosis develops before the onset of overt pathology remains poorly defined. Interleukin-15 (IL-15) is upregulated in distressed tissue and its overexpression is thought to predispose susceptible individuals to and have a role in the pathogenesis of celiac disease and inflammatory bowel disease (IBD). Although the immunological roles of IL-15 have been largely studied, its potential impact on the microbiota remains unexplored. Analysis of 16S ribosomal RNA-based inventories of bacterial communities in mice overexpressing IL-15 in the intestinal epithelium (villin-IL-15 transgenic (v-IL-15tg) mice) shows distinct changes in the composition of the intestinal bacteria. Although some alterations are specific to individual intestinal compartments, others are found across the ileum, cecum and feces. In particular, IL-15 overexpression restructures the composition of the microbiota with a decrease in butyrate-producing bacteria that is associated with a reduction in luminal butyrate levels across all intestinal compartments. Fecal microbiota transplant experiments of wild-type and v-IL-15tg microbiota into germ-free mice further indicate that diminishing butyrate concentration observed in the intestinal lumen of v-IL-15tg mice is the result of intrinsic alterations in the microbiota induced by IL-15. This reconfiguration of the microbiota is associated with increased susceptibility to dextran sodium sulfate-induced colitis. Altogether, this study reveals that IL-15 impacts butyrate-producing bacteria and lowers butyrate levels in the absence of overt pathology, which represent events that precede and promote intestinal inflammatory diseases.

  14. Crude oil impairs immune function and increases susceptibility to pathogenic bacteria in southern flounder.

    Science.gov (United States)

    Bayha, Keith M; Ortell, Natalie; Ryan, Caitlin N; Griffitt, Kimberly J; Krasnec, Michelle; Sena, Johnny; Ramaraj, Thiruvarangan; Takeshita, Ryan; Mayer, Gregory D; Schilkey, Faye; Griffitt, Robert J

    2017-01-01

    Exposure to crude oil or its individual constituents can have detrimental impacts on fish species, including impairment of the immune response. Increased observations of skin lesions in northern Gulf of Mexico fish during the 2010 Deepwater Horizon oil spill indicated the possibility of oil-induced immunocompromisation resulting in bacterial or viral infection. This study used a full factorial design of oil exposure and bacterial challenge to examine how oil exposure impairs southern flounder (Paralichthys lethostigma) immune function and increases susceptibility to the bacteria Vibrio anguillarum, a causative agent of vibriosis. Fish exposed to oil prior to bacterial challenge exhibited 94.4% mortality within 48 hours of bacterial exposure. Flounder challenged with V. anguillarum without prior oil exposure had Oil/Pathogen challenged fish and was nearly non-existent in the No Oil/Pathogen challenged fish bacterial community. Elevated V. anguillarum levels were a direct result of oil exposure-induced immunosuppression. Oil-exposure reduced expression of immunoglobulin M, the major systemic fish antibody, and resulted in an overall downregulation in transcriptome response, particularly in genes related to immune function, response to stimulus and hemostasis. Ultimately, sediment-borne oil exposure impairs immune function, leading to increased incidences of bacterial infections. This type of sediment-borne exposure may result in long-term marine ecosystem effects, as oil-bound sediment in the northern Gulf of Mexico will likely remain a contamination source for years to come.

  15. Acidosis increases the susceptibility of respiratory epithelial cells to Pseudomonas aeruginosa-induced cytotoxicity.

    Science.gov (United States)

    Torres, Iviana M; Demirdjian, Sally; Vargas, Jennifer; Goodale, Britton C; Berwin, Brent

    2017-07-01

    Bacterial infection can lead to acidosis of the local microenvironment, which is believed to exacerbate disease pathogenesis; however, the mechanisms by which changes in pH alter disease progression are poorly understood. We test the hypothesis that acidosis enhances respiratory epithelial cell death in response to infection with Pseudomonas aeruginosa Our findings support the idea that acidosis in the context of P. aeruginosa infection results in increased epithelial cell cytotoxicity due to ExoU intoxication. Importantly, enforced maintenance of neutral pH during P. aeruginosa infection demonstrates that cytotoxicity is dependent on the acidosis. Investigation of the underlying mechanisms revealed that host cell cytotoxicity correlated with increased bacterial survival during an acidic infection that was due to reduced bactericidal activity of host-derived antimicrobial peptides. These findings extend previous reports that the activities of antimicrobial peptides are pH-dependent and provide novel insights into the consequences of acidosis on infection-derived pathology. Therefore, this report provides the first evidence that physiological levels of acidosis increase the susceptibility of epithelial cells to acute Pseudomonas infection and demonstrates the benefit of maintaining pH homeostasis during a bacterial infection. Copyright © 2017 the American Physiological Society.

  16. Prolactin increases the susceptibility of primary leukemia cells to NK and LAK effectors.

    Science.gov (United States)

    Oberholtzer, E; Contarini, M; Veglia, F; Cossarizza, A; Franceschi, C; Geuna, M; Provinciali, M; Di Stefano, G; Sissom, J; Brizzi, M F; Pegoraro, L; Matera, L

    1996-01-01

    Our previous studies have shown that prolactin (PRL), a pituitary and lymphocyte hormone and a ligand of the cytokine/hemopoietin receptors (R) superfamily, acts synergistically with interleukin (IL)-2 on the development of lymphokine activated killer (LAK) cells and enhances the effects of GM-CSF and IL-3 on myeloid progenitors' proliferation and differentiation. More recently, we have demonstrated that GM-CSF and IL-3 increase the sensitivity of acute myeloid leukemic (AML) cells to LAK activity. Together, these findings have prompted us to study the role of PRL on the target arm of the LAK response. We show here that CD33+ blasts from AML patients express membrane PRL-R and that the PRL/PRL-R interaction is followed by increased susceptibility to natural killer (NK) (p < 0.02) and LAK (p < 0.001) cells. As predicted from the dimerization model of PRL-R and in agreement with previous reports, the response of AML blasts to PRL was bell-shaped with a trend peak at 25 ng/ml. Although enhanced lysis occurred at the target recognition level, it was not accompanied by changes in the MHC class I, cellular adhesion molecules, or myeloid differentiation antigens. Cell cycle recruitment and lysis increased concurrently in three cases studied, suggesting a modulatory action of PRL on the expression of putative cycle-related NK/LAK-target structures. Together, these data strengthen the role of PRL in the LAK response.

  17. Age-Associated Changes in Estrogen Receptor Ratios Correlate with Increased Female Susceptibility to Coxsackievirus B3-Induced Myocarditis

    Directory of Open Access Journals (Sweden)

    Andreas Koenig

    2017-11-01

    Full Text Available Sexual bias is a hallmark in various diseases. This review evaluates sexual dimorphism in clinical and experimental coxsackievirus B3 (CVB3 myocarditis, and how sex bias in the experimental disease changes with increased age. Coxsackieviruses are major causes of viral myocarditis, an inflammation of the heart muscle, which is more frequent and severe in men than women. Young male mice infected with CVB3 develop heart-specific autoimmunity and severe myocarditis. Females infected during estrus (high estradiol develop T-regulatory cells and when infected during diestrus (low estradiol develop autoimmunity similar to males. During estrus, protection depends on estrogen receptor alpha (ERα, which promotes type I interferon, activation of natural killer/natural killer T cells and suppressor cell responses. Estrogen receptor beta has opposing effects to ERα and supports pro-inflammatory immunity. However, the sexual dimorphism of the disease is significantly ameliorated in aged animals when old females become as susceptible as males. This correlates to a selective loss of the ERα that is required for immunosuppression. Therefore, sex-associated hormones control susceptibility in the virus-mediated disease, but their impact can alter with the age and physiological stage of the individual.

  18. RCAN1 (DSCR1) increases neuronal susceptibility to oxidative stress: a potential pathogenic process in neurodegeneration.

    Science.gov (United States)

    Porta, Sílvia; Serra, Selma A; Huch, Meritxell; Valverde, Miguel A; Llorens, Franc; Estivill, Xavier; Arbonés, Maria L; Martí, Eulàlia

    2007-05-01

    Oxidative stress (OS) underlies neuronal dysfunction in many neurodegenerative disorders. Regulator of Calcineurin 1 (RCAN1 or DSCR1) is a dose-sensitive gene whose overexpression has been linked to Down syndrome (DS) and Alzheimer's disease (AD) neuropathology and to the response of cells to stress stimuli. Here, we show that RCAN1 mRNA and protein expression are sensitive to OS in primary neurons, and we evaluate the involvement of RCAN1 dosage in neuronal death induced by OS. We find that Rcan1(-/-) neurons display an increased resistance to damage by H(2)O(2), which can be reverted by RCAN1 overexpression or by exogenous inhibitors of calcineurin. Although increased intracellular Ca(2+) concentration is an important factor in OS-mediated cell death, our results show that Ca(2+) loading after exposure to H(2)O(2) was similar in Rcan1(+/+) and Rcan1(-/-) neurons. Our data further suggest that CaN and NFAT signaling protect against OS in both Rcan1(+/+) and Rcan1(-/-) neurons. To explain the observed differential vulnerability, we therefore propose a mechanism downstream of H(2)O(2)-mediated Ca(2+) entry, involving calcineurin-NFAT signaling. These findings highlight the importance of RCAN1 gene dosage in the modulation of cell survival and death pathways and suggest that changes in the amount of RCAN1 could represent an important mechanism for regulating susceptibility to neurodegeneration, especially in DS and AD.

  19. Manipulation of the Xanthophyll Cycle Increases Plant Susceptibility to Sclerotinia sclerotiorum.

    Science.gov (United States)

    Zhou, Jun; Zeng, Lizhang; Liu, Jian; Xing, Da

    2015-05-01

    The xanthophyll cycle is involved in dissipating excess light energy to protect the photosynthetic apparatus in a process commonly assessed from non-photochemical quenching (NPQ) of chlorophyll fluorescence. Here, it is shown that the xanthophyll cycle is modulated by the necrotrophic pathogen Sclerotinia sclerotiorum at the early stage of infection. Incubation of Sclerotinia led to a localized increase in NPQ even at low light intensity. Further studies showed that this abnormal change in NPQ was closely correlated with a decreased pH caused by Sclerotinia-secreted oxalate, which might decrease the ATP synthase activity and lead to a deepening of thylakoid lumen acidification under continuous illumination. Furthermore, suppression (with dithiothreitol) or a defect (in the npq1-2 mutant) of violaxanthin de-epoxidase (VDE) abolished the Sclerotinia-induced NPQ increase. HPLC analysis showed that the Sclerotinia-inoculated tissue accumulated substantial quantities of zeaxanthin at the expense of violaxanthin, with a corresponding decrease in neoxanthin content. Immunoassays revealed that the decrease in these xanthophyll precursors reduced de novo abscisic acid (ABA) biosynthesis and apparently weakened tissue defense responses, including ROS induction and callose deposition, resulting in enhanced plant susceptibility to Sclerotinia. We thus propose that Sclerotinia antagonizes ABA biosynthesis to suppress host defense by manipulating the xanthophyll cycle in early pathogenesis. These findings provide a model of how photoprotective metabolites integrate into the defense responses, and expand the current knowledge of early plant-Sclerotinia interactions at infection sites.

  20. Manipulation of the Xanthophyll Cycle Increases Plant Susceptibility to Sclerotinia sclerotiorum.

    Directory of Open Access Journals (Sweden)

    Jun Zhou

    2015-05-01

    Full Text Available The xanthophyll cycle is involved in dissipating excess light energy to protect the photosynthetic apparatus in a process commonly assessed from non-photochemical quenching (NPQ of chlorophyll fluorescence. Here, it is shown that the xanthophyll cycle is modulated by the necrotrophic pathogen Sclerotinia sclerotiorum at the early stage of infection. Incubation of Sclerotinia led to a localized increase in NPQ even at low light intensity. Further studies showed that this abnormal change in NPQ was closely correlated with a decreased pH caused by Sclerotinia-secreted oxalate, which might decrease the ATP synthase activity and lead to a deepening of thylakoid lumen acidification under continuous illumination. Furthermore, suppression (with dithiothreitol or a defect (in the npq1-2 mutant of violaxanthin de-epoxidase (VDE abolished the Sclerotinia-induced NPQ increase. HPLC analysis showed that the Sclerotinia-inoculated tissue accumulated substantial quantities of zeaxanthin at the expense of violaxanthin, with a corresponding decrease in neoxanthin content. Immunoassays revealed that the decrease in these xanthophyll precursors reduced de novo abscisic acid (ABA biosynthesis and apparently weakened tissue defense responses, including ROS induction and callose deposition, resulting in enhanced plant susceptibility to Sclerotinia. We thus propose that Sclerotinia antagonizes ABA biosynthesis to suppress host defense by manipulating the xanthophyll cycle in early pathogenesis. These findings provide a model of how photoprotective metabolites integrate into the defense responses, and expand the current knowledge of early plant-Sclerotinia interactions at infection sites.

  1. Increased susceptibility to structural acute kidney injury in a mouse model of presymptomatic cardiomyopathy.

    Science.gov (United States)

    Pleasant, LaTawnya; Ma, Qing; Devarajan, Mahima; Parameswaran, Priyanka; Drake, Keri; Siroky, Brian; Shay-Winkler, Kritton; Robbins, Jeffrey; Devarajan, Prasad

    2017-09-01

    The early events that signal renal dysfunction in presymptomatic heart failure are unclear. We tested the hypothesis that functional and mechanistic changes occur in the kidney that precede the development of symptomatic heart failure. We employed a transgenic mouse model with cardiomyocyte-specific overexpression of mutant α-B-crystallin that develops slowly progressive cardiomyopathy. Presymptomatic transgenic mice displayed an increase in serum creatinine (1.17 ± 0.34 vs. wild type 0.65 ± 0.16 mg/dl, P kidneys exhibited a twofold upregulation of the Ren1 gene, marked overexpression of renin protein in the tubules, and a worsened response to ischemia-reperfusion injury based on serum creatinine (2.77 ± 0.66 in transgenic mice vs. 2.01 ± 0.58 mg/dl in wild type, P kidney that occur in early presymptomatic heart failure, which increase the susceptibility to subsequent acute kidney injury. Copyright © 2017 the American Physiological Society.

  2. Induction of Rhizopus oryzae germination under starvation using host metabolites increases spore susceptibility to heat stress.

    Science.gov (United States)

    Turgeman, Tidhar; Kakongi, Nathan; Schneider, Avishai; Vinokur, Yakov; Teper-Bamnolker, Paula; Carmeli, Shmuel; Levy, Maggie; Skory, Christopher D; Lichter, Amnon; Eshel, Dani

    2014-03-01

    Sweetpotato is a nutritional source worldwide. Soft rot caused by Rhizopus spp. is a major limiting factor in the storage of produce, rendering it potentially unsafe for human consumption. In this study, Rhizopus oryzae was used to develop a concept of postharvest disease control by weakening the pathogen through induction of spore germination under starvation conditions. We isolated the sweetpotato active fractions (SPAFs) that induce spore germination and used them at a low dose to enhance spore weakening caused by starvation. Germination in SPAF at 1 mg/ml weakened the pathogen spores by delaying their ability to form colonies on rich media and by increasing their sensitivity to heat stress. The weakening effect was also supported by reduced metabolic activity, as detected by Alarmar Blue fluorescent dye assays. Spores incubated with SPAF at 1 mg/ml showed DNA fragmentation in some of their nuclei, as observed by TUNEL assay. In addition, these spores exhibited changes in ultrastructural morphology (i.e., shrinkage of germ tubes, nucleus deformation, and vacuole formation) which are hallmarks of programmed cell death. We suggest that induction of spore germination under starvation conditions increases their susceptibility to stress and, therefore, might be considered a new strategy for pathogen control.

  3. Increased Tumor Necrosis Factor (TNF)-α and its promoter polymorphisms correlate with disease progression and higher susceptibility towards vitiligo.

    Science.gov (United States)

    Laddha, Naresh C; Dwivedi, Mitesh; Begum, Rasheedunnisa

    2012-12-20

    Tumor Necrosis Factor (TNF)-α, is a paracrine inhibitor of melanocytes, which plays a critical role in the pathogenesis of several autoimmune diseases including vitiligo, as abnormal immune responses have frequently been observed in vitiligo patients. Moreover, vitiligo patients show higher lesion levels of TNF-α. Genetic polymorphisms in the promoter region of TNF-α are involved in the regulation of its expression. The present study explores TNF-α promoter polymorphisms and correlates them with TNF-α transcript and protein levels in vitiligo patients and controls of Gujarat along with its effect on disease onset and progression. PCR-RFLP technique was used for genotyping of these polymorphisms in 977 vitiligo patients and 990 controls. TNF-α transcript and protein levels were measured by Real time PCR and ELISA respectively. The genotype and allele frequencies for the investigated polymorphisms were significantly associated with vitiligo patients. The study revealed significant increase in TNF-α transcript and protein levels in vitiligo patients compared to controls. In particular, haplotypes: AATCC, AACCT, AGTCT, GATCT, GATCC and AGCCT were found to increase the TNF-α levels in vitiligo patients. Analysis of TNF-α levels based on the gender and disease progression suggests that female patients and patients with active vitiligo had higher levels of TNF-α. Also, the TNF-α levels were high in patients with generalized vitiligo as compared to localized vitiligo. Age of onset analysis of the disease suggests that the haplotypes: AACAT, AACCT, AATCC and AATCT had a profound effect in the early onset of the disease. Moreover, the analysis suggests that female patients had an early onset of vitiligo. Overall, our results suggest that TNF-α promoter polymorphisms may be genetic risk factors for susceptibility and progression of the disease. The up-regulation of TNF-α transcript and protein levels in individuals with susceptible haplotypes advocates the

  4. Increased Tumor Necrosis Factor (TNF-α and its promoter polymorphisms correlate with disease progression and higher susceptibility towards vitiligo.

    Directory of Open Access Journals (Sweden)

    Naresh C Laddha

    2012-12-01

    Full Text Available Tumor Necrosis Factor (TNF-α, is a paracrine inhibitor of melanocytes, which plays a critical role in the pathogenesis of several autoimmune diseases including vitiligo, as abnormal immune responses have frequently been observed in vitiligo patients. Moreover, vitiligo patients show higher lesion levels of TNF-α. Genetic polymorphisms in the promoter region of TNF-α are involved in the regulation of its expression. The present study explores TNF-α promoter polymorphisms and correlates them with TNF-α transcript and protein levels in vitiligo patients and controls of Gujarat along with its effect on disease onset and progression. PCR-RFLP technique was used for genotyping of these polymorphisms in 977 vitiligo patients and 990 controls. TNF-α transcript and protein levels were measured by Real time PCR and ELISA respectively. The genotype and allele frequencies for the investigated polymorphisms were significantly associated with vitiligo patients. The study revealed significant increase in TNF-α transcript and protein levels in vitiligo patients compared to controls. In particular, haplotypes: AATCC, AACCT, AGTCT, GATCT, GATCC and AGCCT were found to increase the TNF-α levels in vitiligo patients. Analysis of TNF-α levels based on the gender and disease progression suggests that female patients and patients with active vitiligo had higher levels of TNF-α. Also, the TNF-α levels were high in patients with generalized vitiligo as compared to localized vitiligo. Age of onset analysis of the disease suggests that the haplotypes: AACAT, AACCT, AATCC and AATCT had a profound effect in the early onset of the disease. Moreover, the analysis suggests that female patients had an early onset of vitiligo. Overall, our results suggest that TNF-α promoter polymorphisms may be genetic risk factors for susceptibility and progression of the disease. The up-regulation of TNF-α transcript and protein levels in individuals with susceptible haplotypes

  5. Increased Tumor Necrosis Factor (TNF)-α and Its Promoter Polymorphisms Correlate with Disease Progression and Higher Susceptibility towards Vitiligo

    Science.gov (United States)

    Laddha, Naresh C.; Dwivedi, Mitesh; Begum, Rasheedunnisa

    2012-01-01

    Abstract Tumor Necrosis Factor (TNF)-α, is a paracrine inhibitor of melanocytes, which plays a critical role in the pathogenesis of several autoimmune diseases including vitiligo, as abnormal immune responses have frequently been observed in vitiligo patients. Moreover, vitiligo patients show higher lesion levels of TNF-α. Genetic polymorphisms in the promoter region of TNF-α are involved in the regulation of its expression. The present study explores TNF-α promoter polymorphisms and correlates them with TNF-α transcript and protein levels in vitiligo patients and controls of Gujarat along with its effect on disease onset and progression. PCR-RFLP technique was used for genotyping of these polymorphisms in 977 vitiligo patients and 990 controls. TNF-α transcript and protein levels were measured by Real time PCR and ELISA respectively. The genotype and allele frequencies for the investigated polymorphisms were significantly associated with vitiligo patients. The study revealed significant increase in TNF-α transcript and protein levels in vitiligo patients compared to controls. In particular, haplotypes: AATCC, AACCT, AGTCT, GATCT, GATCC and AGCCT were found to increase the TNF-α levels in vitiligo patients. Analysis of TNF-α levels based on the gender and disease progression suggests that female patients and patients with active vitiligo had higher levels of TNF-α. Also, the TNF-α levels were high in patients with generalized vitiligo as compared to localized vitiligo. Age of onset analysis of the disease suggests that the haplotypes: AACAT, AACCT, AATCC and AATCT had a profound effect in the early onset of the disease. Moreover, the analysis suggests that female patients had an early onset of vitiligo. Overall, our results suggest that TNF-α promoter polymorphisms may be genetic risk factors for susceptibility and progression of the disease. The up-regulation of TNF-α transcript and protein levels in individuals with susceptible haplotypes advocates

  6. Increased susceptibility for white spot lesions by surplus orthodontic etching exceeding bracket base area.

    Science.gov (United States)

    Knösel, Michael; Bojes, Mariana; Jung, Klaus; Ziebolz, Dirk

    2012-05-01

    There is a paucity of information with regard to the susceptibility of iatrogenic white spot lesion formation after inattentive, surplus orthodontic etching with 30% phosphoric acid and the subsequent provision or absence of adequate oral hygiene. Ninety sound enamel specimens were randomly allocated to 6 trial groups (n = 15 each) for etching with 30% phosphoric acid for either 15 seconds and standardized daily enamel brushing or no brushing, etching for 30 seconds with daily brushing or no brushing, or nonetched controls with brushing or no brushing. Nutritive acidic assaults were simulated by demineralization cycles 3 times per day for 1 hour with interim storage in artificial saliva. Lesion depths in terms of percentage of fluorescence loss (delta F, delta Q) and lesion extension compared with the baseline were assessed by using quantitative light-induced fluorescence after 2, 7, 14, 21, and 42 days. Etching duration, trial time elapse, and oral hygiene, as well as the significance of factor interactions, were analyzed with 3-way analysis of variance (α = 5%). The impact of the factors of enamel brushing, trial time elapse, and etching each had a comparably significant effect on lesion progression. The effect of surplus etching on white spot lesion formation was significantly enhanced by the simultaneous absence of enamel brushing and also the progression of trial time. The combination of 30 seconds of surplus etching with inadequate oral hygiene was especially detrimental. Excessive surplus orthodontic etching of the complete labial enamel surface, instead of the bracket bases only, must be avoided to prevent iatrogenic white spot lesions. Etching times not exceeding 15 seconds are favorable. Copyright © 2012 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.

  7. [Increased susceptibility for white spot lesions by surplus orthodontic etching exceeding bracket base area].

    Science.gov (United States)

    Knösel, Michael; Bojes, Mariana; Jung, Klaus; Ziebolz, Dirk; Renger, Stéphane

    2015-09-01

    There is a paucity of information with regard to the susceptibility of iatrogenic white spot lesion formation after inattentive, surplus orthodontic etching with 30% phosphoric acid and the subsequent provision or absence of adequate oral hygiene. Ninety sound enamel specimens were randomly allocated to 6 trial groups (N = 15 each) for etching with 30% phosphoric acid for either 15 seconds and standardized daily enamel brushing or no brushing, etching for 30 seconds with daily brushing or no brushing, or nonetched controls with brushing or no brushing. Nutritive acidic assaults were simulated by demineralization cycles 3 times per day for 1 hour with interim storage in artificial saliva. Lesion depths in terms of percentage of fluorescence loss (delta F, delta Q) and lesion extension compared with the baseline were assessed by using quantitative light-induced fluorescence after 2, 7, 14, 21, and 42 days. Etching duration, trial time elapse, and oral hygiene, as well as the significance of factor interactions, were analyzed with 3-way analysis of variance (α=5%). The impact of the factors of enamel brushing, trial time elapse, and etching each had a comparably significant effect on lesion progression. The effect of surplus etching on white spot lesion formation was significantly enhanced by the simultaneous absence of enamel brushing and also the progression of trial time. The combination of 30 seconds of surplus etching with inadequate oral hygiene was especially detrimental. Excessive surplus orthodontic etching of the complete labial enamel surface, instead of the bracket bases only, must be avoided to prevent iatrogenic white spot lesions. Etching times not exceeding 15 seconds are favorable. © EDP Sciences, SFODF, 2015.

  8. Changing Epidemiological Characteristics of Hepatitis A in Zhejiang Province, China: Increased Susceptibility in Adults.

    Science.gov (United States)

    Wang, Zhifang; Chen, Yaping; Xie, Shuyun; Lv, Huakun

    2016-01-01

    Hepatitis A is a common acute hepatitis caused by hepatitis A virus (HAV). Annually, it affects 1.4 million people worldwide. Between 1991 and 1994, HAV infections were highly endemic in Zhejiang Province (China), with 78,720 reported HAV infections per year. Hepatitis A vaccine came on the market in 1995 and was implemented for voluntary immunization. Since 2008, hepatitis A vaccine has been integrated into the national childhood routine immunization program. To understand the current epidemiological profile of hepatitis A in Zhejiang Province since hepatitis A vaccine has been available for nearly two decades. This study used the 2005-2014 National Notifiable Diseases Reporting System data to evaluate the incidence rate of notified hepatitis A cases in Zhejiang Province. The overall trend of incidence rate of notified hepatitis A cases significantly decreased from 2005 to 2014 (Phepatitis A vaccine seemed to be effective in decreasing notified hepatitis A incidence rate in individuals aged ≤19 years. Those aged ≥20 years were observed to be the most susceptible population. The vast majority of hepatitis A cases were notified among Laborers. Therefore, we strongly suggest that future preventive and control measures should focus more on adults, particularly Laborers, in addition to the current childhood hepatitis A vaccination programme.

  9. Low dose chronic Schistosoma mansoni infection increases susceptibility to Mycobacterium bovis BCG infection in mice.

    Science.gov (United States)

    Elias, D; Akuffo, H; Thors, C; Pawlowski, A; Britton, S

    2005-03-01

    The incidence of mycobacterial diseases is high and the efficacy of Bacillus Calmette Guerin (BCG) is low in most areas of the world where chronic worm infections are common. However, if and how concurrent worm infections could affect immunity to mycobacterial infections has not been elucidated. In this study we investigated whether infection of mice with Schistosoma mansoni could affect the ability of the animals to control Mycobacterium bovis BCG infection and the immune response to mycobacterial antigens. BALB/c mice subclinically infected with S. mansoni were challenged with M. bovis BCG via the intravenous route. The ability of the animals to contain the replication of M. bovis BCG in their organs, lung pathology as well as the in vitro mycobacterial and worm antigen induced immune responses were evaluated. The results showed that S. mansoni coinfected mice had significantly higher levels of BCG bacilli in their organs and sustained greater lung pathology compared to Schistosoma uninfected controls. Moreover, Schistosoma infected mice show depressed mycobacterial antigen specific Th1 type responses. This is an indication that chronic worm infection could affect resistance/susceptibility to mycobacterial infections by impairing mycobacteria antigen specific Th1 type responses. This finding is potentially important in the control of TB in helminth endemic parts of the world.

  10. Reduced salinity increases susceptibility of zooxanthellate jellyfish to herbicide toxicity during a simulated rainfall event.

    Science.gov (United States)

    Klein, Shannon G; Pitt, Kylie A; Carroll, Anthony R

    2016-02-01

    Accurately predicting how marine biota are likely to respond to changing ocean conditions requires accurate simulation of interacting stressors, exposure regimes and recovery periods. Jellyfish populations have increased in some parts of the world and, despite few direct empirical tests, are hypothesised to be increasing because they are robust to a range of environmental stressors. Here, we investigated the effects of contaminated runoff on a zooxanthellate jellyfish by exposing juvenile Cassiopea sp. medusae to a photosystem II (PSII) herbicide, atrazine and reduced salinity conditions that occur following rainfall. Four levels of atrazine (0ngL(-1), 10ngL(-1), 2μgL(-1), 20μgL(-1)) and three levels of salinity (35 ppt, 25 ppt, 17 ppt) were varied, mimicking the timeline of light, moderate and heavy rainfall events. Normal conditions were then slowly re-established over four days to mimic the recovery of the ecosystem post-rain and the experiment continued for a further 7 days to observe potential recovery of the medusae. Pulse-amplitude modulated (PAM) chlorophyll fluorescence, growth and bell contraction rates of medusae were measured. Medusae exposed to the combination of high atrazine and lowest salinity died. After 3 days of exposure, bell contraction rates were reduced by 88% and medusae were 16% smaller in the lowest salinity treatments. By Day 5 of the experiment, all medusae that survived the initial pulse event began to recover quickly. Although atrazine decreased YII under normal salinity conditions, YII was further reduced when medusae were exposed to both low salinity and atrazine simultaneously. Atrazine breakdown products were more concentrated in jellyfish tissues than atrazine at the end of the experiment, suggesting that although bioaccumulation occurred, atrazine was metabolised. Our results suggest that reduced salinity may increase the susceptibility of medusae to herbicide exposure during heavy rainfall events. Copyright © 2015 Elsevier

  11. Voluntary wheel running attenuates ethanol withdrawal-induced increases in seizure susceptibility in male and female rats

    Science.gov (United States)

    Devaud, Leslie L.; Walls, Shawn A.; McCulley, Walter D.; Rosenwasser, Alan M.

    2012-01-01

    We recently found that voluntary wheel running attenuated ethanol withdrawal-induced increased susceptibility to chemoconvulsant-induced seizures in male rats. Since female rats recover from ethanol withdrawal (EW) more quickly than male rats across several behavioral measures, this study was designed to determine whether the effects of exercise on EW seizures also exhibited sex differences. Animals were maintained under No-Wheel, Locked-Wheel or Free-Wheel conditions and ethanol was administered by liquid diet for 14 days with control animals pair-fed an isocaloric diet, after which seizure thresholds were determined at 1 day or 3 days of EW. Consistent with previous reports, females ran significantly more than males, regardless of diet condition. Introduction of the ethanol-containing liquid diet dramatically increased running for females during the day (rest) phase, with little impact on night phase activity. Consistent with previous reports, EW increased seizure susceptibility at 1 day in non-exercising males and females and at 3 days in males. These effects were attenuated by access to running wheels in both sexes. We also assessed the effects of sex, ethanol diet and exercise on ethanol clearance following an acute ethanol administration at 1 day EW in a separate set of animals. Blood ethanol concentrations at 30 min post-injection were lower in males, ethanol-exposed animals, and runners, but no interactions among these factors were detected. Interestingly, females displayed more rapid ethanol clearance than males and there were no effects of either diet or wheel access on clearance rates. Taken together, these data suggest that voluntary wheel running during ethanol administration provides protective effects against EW seizures in both males and females. This effect may be mediated, in part, in male, but not female rat, by effects of exercise on early pharmacokinetic contributions. This supports the idea that encouraging alcoholics to exercise may benefit

  12. Increased susceptibility to otitis media in a Splunc1-deficient mouse model

    Science.gov (United States)

    Bartlett, Jennifer A.; Meyerholz, David K.; Wohlford-Lenane, Christine L.; Naumann, Paul W.; Salzman, Nita H.; McCray, Paul B.

    2015-01-01

    ABSTRACT Otitis media (inflammation of the middle ear) is one of the most common diseases of early childhood. Susceptibility to otitis is influenced by a number of factors, including the actions of innate immune molecules secreted by the epithelia lining the nasopharynx, middle ear and Eustachian tube. The SPLUNC1 (short palate, lung, nasal epithelial clone 1) protein is a highly abundant secretory product of the mammalian nasal, oral and respiratory mucosa that is thought to play a multifunctional role in host defense. In this study we investigated Splunc1 expression in the ear of the mouse, and examined whether this protein contributes to overall host defense in the middle ear and/or Eustachian tube. We found that Splunc1 is highly expressed in both the surface epithelium and in submucosal glands in these regions in wild-type mice. In mice lacking Splunc1, we noted histologically an increased frequency of otitis media, characterized by the accumulation of leukocytes (neutrophils with scattered macrophages), proteinaceous fluid and mucus in the middle ear lumens. Furthermore, many of these mice had extensive remodeling of the middle ear wall, suggesting a chronic course of disease. From these observations, we conclude that loss of Splunc1 predisposes mice to the development of otitis media. The Splunc1−/− mouse model should help investigators to better understand both the biological role of Splunc1 as well as host defense mechanisms in the middle ear. PMID:25765466

  13. Implications of increased susceptibility to predation for management of the sylvatic cycle of Echinococcus multilocularis

    DEFF Research Database (Denmark)

    Vervaeke, V; Davis, S; Leirs, Herwig

    2006-01-01

    The ability to increase the chances that infectious prey are taken by predators is an observed feature of many parasites that rely on one or more predator-prey relationships to complete their life-cycle. In the sylvatic life-cycle of Echinococcus multilocularis - the causative agent of human...... alveolar echinococcosis - foxes are the final host, with voles acting as intermediate hosts. Here we review the evidence that E. multilocularis causes increased susceptibility to predation and present a general mathematical model for the sylvatic life-cycle. The ability to increase susceptibility...... susceptibility to predation is a plausible explanation for the observed resilience of E. multilocularis during and following field trials of praziquantel baiting....

  14. Acute Schistosoma mansoni infection increases susceptibility to systemic SHIV clade C infection in rhesus macaques after mucosal virus exposure.

    Directory of Open Access Journals (Sweden)

    Agnès-Laurence Chenine

    2008-07-01

    Full Text Available Individuals living in sub-Saharan Africa represent 10% of the world's population but almost 2/3 of all HIV-1/AIDS cases. The disproportionate HIV-1 infection rates in this region may be linked to helminthic parasite infections that affect many individuals in the developing world. However, the hypothesis that parasite infection increases an individual's susceptibility to HIV-1 has never been prospectively tested in a relevant in vivo model.We measured whether pre-existing infection of rhesus monkeys with a parasitic worm would facilitate systemic infection after mucosal AIDS virus exposure. Two groups of animals, one consisting of normal monkeys and the other harboring Schistosoma mansoni, were challenged intrarectally with decreasing doses of R5-tropic clade C simian-human immunodeficiency virus (SHIV-C. Systemic infection occurred in parasitized monkeys at viral doses that remained sub-infectious in normal hosts. In fact, the 50% animal infectious (AID(50 SHIV-C dose was 17-fold lower in parasitized animals compared to controls (P<0.001. Coinfected animals also had significantly higher peak viral RNA loads than controls (P<0.001, as well as increased viral replication in CD4(+ central memory cells (P = 0.03.Our data provide the first direct evidence that acute schistosomiasis significantly increases the risk of de novo AIDS virus acquisition, and the magnitude of the effect suggests that control of helminth infections may be a useful public health intervention to help decrease the spread of HIV-1.

  15. Female Nur77-deficient mice show increased susceptibility to diet-induced obesity.

    Directory of Open Access Journals (Sweden)

    Sonia Perez-Sieira

    Full Text Available Adipose tissue is essential in the regulation of body weight. The key process in fat catabolism and the provision of energy substrate during times of nutrient deprivation or enhanced energy demand is the hydrolysis of triglycerides and the release of fatty acids and glycerol. Nur77 is a member of the NR4A subfamily of nuclear receptors that plays an important metabolic role, modulating hepatic glucose metabolism and lipolysis in muscle. However, its endogenous role on white adipose tissue, as well as the gender dependency of these mechanisms, remains largely unknown. Male and female wild type and Nur77 deficient mice were fed with a high fat diet (45% calories from fat for 4 months. Mice were analyzed in vivo with the indirect calorimetry system, and tissues were analyzed by real-time PCR and Western blot analysis. Female, but not male Nur77 deficient mice, gained more weight and fat mass when compared to wild type mice fed with high fat diet, which can be explained by decreased energy expenditure. The lack of Nur77 also led to a decreased pHSL/HSL ratio in white adipose tissue and increased expression of CIDEA in brown adipose tissue of female Nur77 deficient mice. Overall, these findings suggest that Nur77 is an important physiological modulator of lipid metabolism in adipose tissue and that there are gender differences in the sensitivity to deletion of the Nur77 signaling. The decreased energy expenditure and the actions of Nur77 on liver, muscle, brown and white adipose tissue contribute to the increased susceptibility to diet-induced obesity in females lacking Nur77.

  16. Human apolipoprotein E4 targeted replacement in mice reveals increased susceptibility to sleep disruption and intermittent hypoxia

    Science.gov (United States)

    Kaushal, Navita; Ramesh, Vijay

    2012-01-01

    Intermittent hypoxia (IH) and sleep fragmentation (SF) are major manifestations of sleep apnea, a frequent condition in aging humans. Sleep perturbations are frequent in Alzheimer's disease (AD) and may underlie the progression of disease. We hypothesized that acute short-term IH, SF, and their combination (IH+SF) may reveal unique susceptibility in sleep integrity in a murine model of AD. The effects of acute IH, SF, and IH+SF on sleep architecture, delta power, sleep latency, and core body temperature were assessed in adult male human ApoE4-targeted replacement mice (hApoE4) and wild-type (WT) controls. Slow wave sleep (SWS) was significantly reduced, and rapid eye movement (REM) sleep was almost abolished during acute exposure to IH alone and IH+SF for 6 h in hApoE4, with milder effects in WT controls. Decreased delta power during SWS did not show postexposure rebound in hApoE4 unlike WT controls. IH and IH+SF induced hypothermia, which was more prominent in hApoE4 than WT controls. Mice subjected to SF also showed sleep deficits but without hypothermia. hApoE4 mice, unlike WT controls, exhibited increased sleep propensity, especially following IH and IH+SF, suggesting limited ability for sleep recovery in hApoE4 mice. These findings substantiate the potential impact of IH and SF in modulating sleep architecture and sleep homeostasis including maintenance of body temperature. Furthermore, the increased susceptibility and limited recovery ability of hApoE4 mice to sleep apnea suggests that early recognition and treatment of the latter in AD patients may restrict the progression and clinical manifestations of this frequent neurodegenerative disorder. PMID:22573105

  17. Identification of Variants in Breast Cancer Susceptibility Genes and Determination of Functional and Clinical Significance of Novel Mutations

    Science.gov (United States)

    2014-10-01

    Zheng Y, Ogundiran TO, Falusi AG, et al. Fine mapping of breast cancer genome-wide association studies loci in women of African ancestry identifies...and ovarian cancer susceptibility genes, BRCA1 and BRCA2, are found in 10-20% of women with early-onset breast cancer (defined as breast cancer...diagnosed under age 40)1. In comparison to women with postmenopausal breast cancer, women with early-onset breast cancer have a worse prognosis with

  18. Updates on breast cancer genetics: Clinical implications of detecting syndromes of inherited increased susceptibility to breast cancer.

    Science.gov (United States)

    Cobain, Erin F; Milliron, Kara J; Merajver, Sofia D

    2016-10-01

    Since the initial discovery that pathogenic germline alterations in BRCA 1/2 increase susceptibility to breast and ovarian cancer, many additional genes have now been discovered that also increase breast cancer risk. Given that several more genes have now been implicated in hereditary breast cancer syndromes, there is increased clinical use of multigene panel testing to evaluate patients with a suspected genetic predisposition to breast cancer. While this is most certainly a cost-effective approach, broader testing strategies have resulted in a higher likelihood of identifying moderate-penetrance genes, for which management guidelines regarding breast cancer risk reduction have not been firmly established. In addition, the testing of more genes has led to increased detection of variants of uncertain significance. We review the current knowledge regarding both high- and moderate-risk hereditary breast cancer syndromes, as well as additional genes implicated in hereditary breast cancer for which there is limited data. Furthermore, strategies for cancer risk reduction in mutation carriers as well as therapeutic implications for those patients who harbor pathogenic germline alterations are discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Systemic Inflammatory Responses and Lung Injury following Hip Fracture Surgery Increases Susceptibility to Infection in Aged Rats

    Directory of Open Access Journals (Sweden)

    Hao Zhang

    2013-01-01

    Full Text Available Pulmonary infections frequently occur following hip fracture surgery in aged patients. However, the underlying reasons are not fully understood. The present study investigates the systemic inflammatory response and pulmonary conditions following hip fracture surgery as a means of identifying risk factors for lung infections using an aged rodent model. Aged, male Sprague-Dawley rats (8 animals per group underwent a sham procedure or hip fracture plus femoral intramedullary pinning. Animals were sacrificed 1, 3, and 7 days after the injury. Markers of systemic inflammation and pulmonary injury were analyzed. Both sham-operated and injured/surgical group animals underwent intratracheal inoculation with Pseudomonas aeruginosa 1, 3, and 7 days after surgery. P. aeruginosa counts in blood and bronchoalveolar lavage (BAL fluid and survival rates were recorded. Serum TNF-α, IL-6, IL-1β, and IL-10 levels and markers of pulmonary injury were significantly increased at 1 and 3 days following hip fracture and surgery. Animals challenged with P. aeruginosa at 1 and 3 days after injury had a significantly decreased survival rate and more P. aeruginosa recovered from blood and BAL fluid. This study shows that hip fracture and surgery in aged rats induced a systemic inflammatory response and lung injury associated with increased susceptibility to infection during the acute phase after injury and surgery.

  20. Increased susceptibility of vault poly(ADP-ribose) polymerase-deficient mice to carcinogen-induced tumorigenesis.

    Science.gov (United States)

    Raval-Fernandes, Sujna; Kickhoefer, Valerie A; Kitchen, Christina; Rome, Leonard H

    2005-10-01

    Vault poly(ADP-ribose) polymerase (VPARP) and telomerase-associated protein 1 (TEP1) are components of the vault ribonucleoprotein complex. Vaults have been implicated in multidrug resistance of human tumors and are thought to be involved in macromolecular assembly and/or transport. Previous studies showed that VPARP-deficient mice were viable, fertile, and did not display any vault-related or telomerase-related phenotype, whereas disruption of telomerase-associated protein 1 in mice led to reduced stability of the vault RNA and affected its stable association with vaults, although there were no telomerase-related changes. In this study, we evaluated the susceptibility of Vparp-/- and Tep1-/- mice to dimethylhydrazine-induced colon tumorigenesis and urethane-induced lung tumorigenesis. Mice received i.p. injections of either 1 g/kg body weight of urethane twice a week for 2 weeks or 20 mg/kg body weight of dimethylhydrazine once a week for 10 weeks and were analyzed after 10 and 60 weeks, respectively. The colon tumor incidence and multiplicity were significantly higher and colon tumor latency was significantly shorter in Vparp-/- mice compared with wild-type mice. Increased colon tumor incidence, multiplicity, and reduced tumor latency were also seen in Tep1-/- mice, however, these results were statistically not significant. Lung tumor multiplicities were increased in both Vparp-/- and Tep1-/- mice but were not significant. The increase in carcinogen-induced tumors in VPARP-deficient mice is the only phenotype observed to date, and suggests a possible role for VPARP, directly or indirectly, in chemically induced neoplasia.

  1. Re-evaluation of the significance of penicillin binding protein 3 in the susceptibility of Listeria monocytogenes to β-lactam antibiotics

    Directory of Open Access Journals (Sweden)

    Krawczyk-Balska Agata

    2012-04-01

    Full Text Available Abstract Background Penicillin binding protein 3 (PBP3 of L. monocytogenes has long been thought of as the primary lethal target for β-lactam antibiotics due to the excellent correlation between the MICs of different β-lactams and their affinity for this protein. The gene encoding PBP3 has not yet been directly identified in this gram-positive bacterium, but based on in silico analysis, this protein is likely to be encoded by lmo1438. However, studies examining the effects of mutations in genes encoding known and putative L. monocytogenes PBPs have demonstrated that inactivation of lmo1438 does not affect sensitivity to β-lactams. Results In this study, overexpression of lmo1438 was achieved using an inducible (nisin-controlled expression system. This permitted the direct demonstration that lmo1438 encodes PBP3. PBP3 overexpression was accompanied by slightly elevated PBP4 expression. The recombinant strain overexpressing PBP3 displayed significant growth retardation and greatly reduced cell length in the stationary phase of growth in culture. In antibiotic susceptibility assays, the strain overexpressing PBP3 displayed increased sensitivity to subinhibitory concentrations of several β-lactams and decreased survival in the presence of a lethal dose of penicillin G. However, the MIC values of the tested β-lactams for this recombinant strain were unchanged compared to the parent strain. Conclusions The present study allows a reevaluation of the importance of PBP3 in the susceptibility of L. monocytogenes to β-lactams. It is clear that PBP3 is not the primary lethal target for β-lactams, since neither the absence nor an excess of this protein affect the susceptibility of L. monocytogenes to these antibiotics. The elevated level of PBP4 expression observed in the recombinant strain overexpressing PBP3 demonstrates that the composition of the L. monocytogenes cell wall is subject to tight regulation. The observed changes in the morphology of

  2. Susceptibility to hyperosmotic stress-induced phosphatidylserine exposure increases during red blood cell storage

    NARCIS (Netherlands)

    Bosman, G.J.C.G.M.; Cluitmans, J.C.A.; Groenen, Y.A.; Werre, J.M.; Willekens, F.L.A.; Novotny, V.M.J.

    2011-01-01

    BACKGROUND: During storage of red blood cell (RBCs) before transfusion, RBCs undergo a series of structural and functional changes that include the exposure of phosphatidylserine (PS), a potent removal signal. It was postulated that, during blood bank storage, the susceptibility to stress-induced PS

  3. Does obesity increase susceptibility to ozone? Respiratory, behavioral, and metabolic assessments in Brown Norway rats

    Science.gov (United States)

    There may be a link between obesity and susceptibility to the respiratory, cardiovascular, and other health effects of air pollutants. Furthermore, it has been proposed that some air pollutants are obesogenic and may contribute to obesity. In view of the epidemic growth of obesit...

  4. Does Reactivating a Witnessed Memory Increase Its Susceptibility to Impairment by Subsequent Misinformation?

    Science.gov (United States)

    Rindal, Eric J.; DeFranco, Rachel M.; Rich, Patrick R.; Zaragoza, Maria S.

    2016-01-01

    In a recent PNAS article, Chan and LaPaglia (2013) provided arguments and evidence to support the claim that reactivating a witnessed memory (by taking a test) renders the memory labile and susceptible to impairment by subsequent misinformation. In the current article, we argue that Chan and LaPaglia's (2013) findings are open to alternative…

  5. Interleukin 1 alpha increases the susceptibility of rabbits to experimental viridans streptococcal endocarditis

    NARCIS (Netherlands)

    Dankert, J; Joldersma, W; Zaat, SAJ; van der Werff, J.

    Major predisposing conditions for infective endocarditis (IE) are the presence of a cardiac platelet-fibrin vegetation and of circulating bacteria with relatively low susceptibility to microbicidal activity of blood platelets. The influence of proinflammatory conditions on development of IE is

  6. Cost of wound treatment to increase significantly in Denmark over the next decade

    DEFF Research Database (Denmark)

    Hjort, Anne Mette; Gottrup, F

    2010-01-01

    To demonstrate that changes in demography, life expectancy and incidence of background diseases (including type 2 diabetes mellitus) during the period 2009-2020 will significantly increase the costs of wound care in Denmark.......To demonstrate that changes in demography, life expectancy and incidence of background diseases (including type 2 diabetes mellitus) during the period 2009-2020 will significantly increase the costs of wound care in Denmark....

  7. Reduced Antioxidant Potential of LDL Is Associated With Increased Susceptibility to LDL Peroxidation in Type II Diabetic Patients

    Science.gov (United States)

    Singh, Nivedita; Singh, Neelima; Kumar Singh, Sanjeev; Kumar Singh, Ajay; kafle, Deepak; Agrawal, Navneet

    2012-01-01

    Background Type II diabetes mellitus is a complex heterogeneous group of metabolic conditions characterized by an increased level of blood glucose, due to impairment in insulin action and/or insulin secretion. Hyperglycemia is a major factor in the pathogenesis of atherosclerosis in diabetes. Oxidative modification of low density lipoprotein (LDL) is recognized as one of the major processes involved in the early stages of atherosclerosis in type II diabetes. LDL contains different antioxidants, which increase LDL resistance against oxidative modification, this is known as its antioxidant potential (AOP). Objectives The present study has been carried out to investigate the sensitivity of LDL to oxidation, AOP of LDL and to assess whether hyperglycemia in diabetes mellitus is associated with increased LDL oxidizability, and whether these relationships are related to diabetic complications. Patients and Methods This study was carried out on 100 diabetic subjects, divided into two groups according to their glycosylated hemoglobin (HbA1c) values, either regulated ( 0.50 M hexose/ M Hb.) A further 50 healthy subjects were included to determine the sensitivity of LDL oxidation and measurement of LDL AOP. LDL from the serum sample was precipitated by the heparin-citrate precipitation method. The LDL fractions were exposed to oxidation with copper sulphate and their sensitivity to oxidation was evaluated. AOP was measured by taking measurements from 30 subjects in each group. Results The sensitivity of LDL oxidation was significantly higher in both diabetic groups compared to the control group. AOP was significantly decreased in all diabetic groups compared to the control group. Conclusions In type II diabetes, the increased susceptibility of LDL to oxidation is related to hyperglycemia and low AOP. PMID:23843827

  8. Stress response differences and disease susceptibility reflected by heterophil to lymphocyte ratio in turkeys selected for increased body weight.

    Science.gov (United States)

    Huff, G R; Huff, W E; Balog, J M; Rath, N C; Anthony, N B; Nestor, K E

    2005-05-01

    Three genetic lines of turkeys were compared for their responses to Escherichia coli challenge following dexamethasone injection (Dex) or E. coli challenge preceding transport stress (TS). The turkey lines were a slow growing line selected for increased egg production (Egg line), a fast growing line selected for increased 16-wk BW (F line), and a commercial line (Comm line). At 14 wk of age, the Dex group was treated with 3 injections of 2 mg of Dex/kg of BW followed by airsac challenge with 100 cfu of E. coli. The TS group was given the same E. coli challenge at 1 x 10(4) cfu/bird without Dex treatment, and was subjected to transport stress, including 12 h of holding time in a transport vehicle, 8 d after the challenge. All treated birds and untreated control birds were bled at the same time, which was 1 d after transport and 9 d after challenge with E. coli. The main effect mean (MEM) total leukocyte counts (WBC) and the percentages of eosinophils (Eos) and basophils (Baso) were the same for all 3 lines; however, the MEM percentages of heterophils (Het) and monocytes (Mono) and the heterophil/lymphocyte ratio (H/L) were lower and the percentage of lymphocytes (Lym) was higher in the Egg line compared with the 2 fast-growing lines. Both stress treatments increased WBC, Het, and H/L and decreased Lym in all 3 lines; however, these effects were significantly greater in both fast growing lines compared with the Egg line. Sixteen-week BW was unaffected by either treatment in the Egg line and was decreased by both treatments in the Comm line and by the Dex treatment in the F line. Main effect mean airsacculitis score (AS) was not affected by line and was significantly increased by TS and Dex treatments. Neither treatment affected AS of the Egg line birds, whereas Dex treatment increased AS of the F line, and both Dex and TS increased AS of the Comm line. Mortality was significantly higher in the Comm line compared with the Egg line and was intermediate in the F line

  9. Pyrethroid resistance in Anopheles gambiae leads to increased susceptibility to the entomopathogenic fungi Metarhizium anisopliae and Beauveria bassiana.

    Science.gov (United States)

    Howard, Annabel F V; Koenraadt, Constantianus J M; Farenhorst, Marit; Knols, Bart G J; Takken, Willem

    2010-06-16

    Entomopathogenic fungi are being investigated as a new mosquito control tool because insecticide resistance is preventing successful mosquito control in many countries, and new methods are required that can target insecticide-resistant malaria vectors. Although laboratory studies have previously examined the effects of entomopathogenic fungi against adult mosquitoes, most application methods used cannot be readily deployed in the field. Because the fungi are biological organisms it is important to test potential field application methods that will not adversely affect them. The two objectives of this study were to investigate any differences in fungal susceptibility between an insecticide-resistant and insecticide-susceptible strain of Anopheles gambiae sensu stricto, and to test a potential field application method with respect to the viability and virulence of two fungal species Pieces of white polyester netting were dipped in Metarhizium anisopliae ICIPE-30 or Beauveria bassiana IMI391510 mineral oil suspensions. These were kept at 27 +/- 1 degrees C, 80 +/- 10% RH and the viability of the fungal conidia was recorded at different time points. Tube bioassays were used to infect insecticide-resistant (VKPER) and insecticide-susceptible (SKK) strains of An. gambiae s.s., and survival analysis was used to determine effects of mosquito strain, fungus species or time since fungal treatment of the net. The resistant VKPER strain was significantly more susceptible to fungal infection than the insecticide-susceptible SKK strain. Furthermore, B. bassiana was significantly more virulent than M. anisopliae for both mosquito strains, although this may be linked to the different viabilities of these fungal species. The viability of both fungal species decreased significantly one day after application onto polyester netting when compared to the viability of conidia remaining in suspension. The insecticide-resistant mosquito strain was susceptible to both species of fungus

  10. Pyrethroid resistance in Anopheles gambiae leads to increased susceptibility to the entomopathogenic fungi Metarhizium anisopliae and Beauveria bassiana

    Directory of Open Access Journals (Sweden)

    Knols Bart GJ

    2010-06-01

    Full Text Available Abstract Background Entomopathogenic fungi are being investigated as a new mosquito control tool because insecticide resistance is preventing successful mosquito control in many countries, and new methods are required that can target insecticide-resistant malaria vectors. Although laboratory studies have previously examined the effects of entomopathogenic fungi against adult mosquitoes, most application methods used cannot be readily deployed in the field. Because the fungi are biological organisms it is important to test potential field application methods that will not adversely affect them. The two objectives of this study were to investigate any differences in fungal susceptibility between an insecticide-resistant and insecticide-susceptible strain of Anopheles gambiae sensu stricto, and to test a potential field application method with respect to the viability and virulence of two fungal species Methods Pieces of white polyester netting were dipped in Metarhizium anisopliae ICIPE-30 or Beauveria bassiana IMI391510 mineral oil suspensions. These were kept at 27 ± 1°C, 80 ± 10% RH and the viability of the fungal conidia was recorded at different time points. Tube bioassays were used to infect insecticide-resistant (VKPER and insecticide-susceptible (SKK strains of An. gambiae s.s., and survival analysis was used to determine effects of mosquito strain, fungus species or time since fungal treatment of the net. Results The resistant VKPER strain was significantly more susceptible to fungal infection than the insecticide-susceptible SKK strain. Furthermore, B. bassiana was significantly more virulent than M. anisopliae for both mosquito strains, although this may be linked to the different viabilities of these fungal species. The viability of both fungal species decreased significantly one day after application onto polyester netting when compared to the viability of conidia remaining in suspension. Conclusions The insecticide

  11. Proanthocyanidins inhibit Ascaris suum glutathione-S-transferase activity and increase susceptibility of larvae to levamisole in vitro.

    Science.gov (United States)

    Hansen, Tina V A; Fryganas, Christos; Acevedo, Nathalie; Caraballo, Luis; Thamsborg, Stig M; Mueller-Harvey, Irene; Williams, Andrew R

    2016-08-01

    Proanthocyanidins (PAC) are a class of plant secondary metabolites commonly found in the diet that have shown potential to control gastrointestinal nematode infections. The anti-parasitic mechanism(s) of PAC remain obscure, however the protein-binding properties of PAC suggest that disturbance of key enzyme functions may be a potential mode of action. Glutathione-S-transferases (GSTs) are essential for parasite detoxification and have been investigated as drug and vaccine targets. Here, we show that purified PAC strongly inhibit the activity of both recombinant and native GSTs from the parasitic nematode Ascaris suum. As GSTs are involved in detoxifying xenobiotic substances within the parasite, we hypothesised that this inhibition may render parasites hyper-susceptible to anthelmintic drugs. Migration inhibition assays with A. suum larvae demonstrated that the potency of levamisole (LEV) and ivermectin (IVM) were significantly increased in the presence of PAC purified from pine bark (4.6-fold and 3.2-fold reduction in IC50 value for LEV and IVM, respectively). Synergy analysis revealed that the relationship between PAC and LEV appeared to be synergistic in nature, suggesting a specific enhancement of LEV activity, whilst the relationship between PAC and IVM was additive rather than synergistic, suggesting independent actions. Our results demonstrate that these common dietary compounds may increase the efficacy of synthetic anthelmintic drugs in vitro, and also suggest one possible mechanism for their well-known anti-parasitic activity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  12. Increasing age is a major risk factor for susceptibility to heat stress during physical activity.

    Science.gov (United States)

    McGinn, Ryan; Poirier, Martin P; Louie, Jeffrey C; Sigal, Ronald J; Boulay, Pierre; Flouris, Andreas D; Kenny, Glen P

    2017-11-01

    We evaluated the extent to which age, cardiorespiratory fitness, and body fat can independently determine whole-body heat loss (WBHL) in 87 otherwise healthy adults. We show that increasing age is a major predictor for decreasing WBHL in otherwise healthy adults (aged 20-70 years), accounting for 40% of the variation in the largest study to date. While greater body fat also had a minor detrimental impact on WBHL, there was no significant role for cardiorespiratory fitness.

  13. Collateral damage: rapid exposure-induced evolution of pesticide resistance leads to increased susceptibility to parasites.

    Science.gov (United States)

    Jansen, Mieke; Stoks, Robby; Coors, Anja; van Doorslaer, Wendy; de Meester, Luc

    2011-09-01

    Although natural populations may evolve resistance to anthropogenic stressors such as pollutants, this evolved resistance may carry costs. Using an experimental evolution approach, we exposed different Daphnia magna populations in outdoor containers to the carbamate pesticide carbaryl and control conditions, and assessed the resulting populations for both their resistance to carbaryl as well as their susceptibility to infection by the widespread bacterial microparasite Pasteuria ramosa. Our results show that carbaryl selection led to rapid evolution of carbaryl resistance with seemingly no cost when assessed in a benign environment. However, carbaryl-resistant populations were more susceptible to parasite infection than control populations. Exposure to both stressors reveals a synergistic effect on sterilization rate by P. ramosa, but this synergism did not evolve under pesticide selection. Assessing costs of rapid adaptive evolution to anthropogenic stress in a semi-natural context may be crucial to avoid too optimistic predictions for the fitness of the evolving populations. © 2011 The Author(s).

  14. Remarkable increase of Neisseria gonorrhoeae with decreased susceptibility of azithromycin and increase in the failure of azithromycin therapy in male gonococcal urethritis in Sendai in 2015.

    Science.gov (United States)

    Yasuda, Mitsuru; Ito, Shin; Hatazaki, Kyoko; Deguchi, Takashi

    2016-12-01

    The antimicrobial resistance of Neisseria gonorrhoeae is a serious problem worldwide. In this study, we examined the susceptibility of N. gonorrhoeae isolated from male gonococcal urethritis in Sendai in 2014 and 2015. Furthermore, of all cases, we investigated the clinical efficacy of a single 2-g dose of extended-release azithromycin (AZM-SR) in the treatment of male gonococcal urethritis retrospectively. Sixty N. gonorrhoeae strains in 2014 and 54 strains in 2015 were isolated from male gonococcal urethritis and stored each year. The MIC of AZM was ≥1 mg/L in 4 strains (6.7%) in 2014 and in 13 strains (24.1%) in 2015 and the number of strains having ≥1 mg/L MIC increased significantly (P = 0.016). Microbiological efficacy was evaluated in 32 and 29 of these patients, and the rates of treatment success were 93.8% and 79.3%, respectively. All of the treatment failures were caused by strains having a MIC of AZM of ≥0.5 mg/L. In particular, the increase in the isolates having a MIC of AZM of ≥1 mg/L was remarkable. Therefore, it was thought that the increase in these strains was the reason for the increase in treatment failures in 2015. Because no other drug is effective, it is currently necessary to use AZM-SR to treat gonococcal infections caused by ceftriaxone-resistant strains or patients allergic to ceftriaxone. To prevent a further increase in resistance to AZM, we should not use AZM-SR to treat normal cases of gonococcal infection. Copyright © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  15. Mycobacterial Cultures Contain Cell Size and Density Specific Sub-populations of Cells with Significant Differential Susceptibility to Antibiotics, Oxidative and Nitrite Stress

    Science.gov (United States)

    Vijay, Srinivasan; Nair, Rashmi Ravindran; Sharan, Deepti; Jakkala, Kishor; Mukkayyan, Nagaraja; Swaminath, Sharmada; Pradhan, Atul; Joshi, Niranjan V.; Ajitkumar, Parthasarathi

    2017-01-01

    The present study shows the existence of two specific sub-populations of Mycobacterium smegmatis and Mycobacterium tuberculosis cells differing in size and density, in the mid-log phase (MLP) cultures, with significant differential susceptibility to antibiotic, oxidative, and nitrite stress. One of these sub-populations (~10% of the total population), contained short-sized cells (SCs) generated through highly-deviated asymmetric cell division (ACD) of normal/long-sized mother cells and symmetric cell divisions (SCD) of short-sized mother cells. The other sub-population (~90% of the total population) contained normal/long-sized cells (NCs). The SCs were acid-fast stainable and heat-susceptible, and contained high density of membrane vesicles (MVs, known to be lipid-rich) on their surface, while the NCs possessed negligible density of MVs on the surface, as revealed by scanning and transmission electron microscopy. Percoll density gradient fractionation of MLP cultures showed the SCs-enriched fraction (SCF) at lower density (probably indicating lipid-richness) and the NCs-enriched fraction (NCF) at higher density of percoll fractions. While live cell imaging showed that the SCs and the NCs could grow and divide to form colony on agarose pads, the SCF, and NCF cells could independently regenerate MLP populations in liquid and solid media, indicating their full genomic content and population regeneration potential. CFU based assays showed the SCF cells to be significantly more susceptible than NCF cells to a range of concentrations of rifampicin and isoniazid (antibiotic stress), H2O2 (oxidative stress),and acidified NaNO2 (nitrite stress). Live cell imaging showed significantly higher susceptibility of the SCs of SC-NC sister daughter cell pairs, formed from highly-deviated ACD of normal/long-sized mother cells, to rifampicin and H2O2, as compared to the sister daughter NCs, irrespective of their comparable growth rates. The SC-SC sister daughter cell pairs, formed

  16. Significant overlap between human genome-wide association-study nominated breast cancer risk alleles and rat mammary cancer susceptibility loci.

    Science.gov (United States)

    Sanders, Jennifer; Samuelson, David J

    2014-01-27

    Human population-based genome-wide association (GWA) studies identify low penetrance breast cancer risk alleles; however, GWA studies alone do not definitively determine causative genes or mechanisms. Stringent genome- wide statistical significance level requirements, set to avoid false-positive associations, yield many false-negative associations. Laboratory rats (Rattus norvegicus) are useful to study many aspects of breast cancer, including genetic susceptibility. Several rat mammary cancer associated loci have been identified using genetic linkage and congenic strain based-approaches. Here, we sought to determine the amount of overlap between GWA study nominated human breast and rat mammary cancer susceptibility loci. We queried published GWA studies to identify two groups of SNPs, one that reached genome-wide significance and one comprised of SNPs failing a validation step and not reaching genome- wide significance. Human genome locations of these SNPs were compared to known rat mammary carcinoma susceptibility loci to determine if risk alleles existed in both species. Rat genome regions not known to associate with mammary cancer risk were randomly selected as control regions. Significantly more human breast cancer risk GWA study nominated SNPs mapped at orthologs of rat mammary cancer loci than to regions not known to contain rat mammary cancer loci. The rat genome was useful to predict associations that had met human genome-wide significance criteria and weaker associations that had not. Integration of human and rat comparative genomics may be useful to parse out false-negative associations in GWA studies of breast cancer risk.

  17. Continuous background light significantly increases flashing-light enhancement of photosynthesis and growth of microalgae.

    Science.gov (United States)

    Abu-Ghosh, Said; Fixler, Dror; Dubinsky, Zvy; Iluz, David

    2015-01-01

    Under specific conditions, flashing light enhances the photosynthesis rate in comparison to continuous illumination. Here we show that a combination of flashing light and continuous background light with the same integrated photon dose as continuous or flashing light alone can be used to significantly enhance photosynthesis and increase microalgae growth. To test this hypothesis, the green microalga Dunaliella salina was exposed to three different light regimes: continuous light, flashing light, and concomitant application of both. Algal growth was compared under three different integrated light quantities; low, intermediate, and moderately high. Under the combined light regime, there was a substantial increase in all algal growth parameters, with an enhanced photosynthesis rate, within 3days. Our strategy demonstrates a hitherto undescribed significant increase in photosynthesis and algal growth rates, which is beyond the increase by flashing light alone. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. Lack of the pattern recognition molecule mannose-binding lectin increases susceptibility to influenza A virus infection

    Directory of Open Access Journals (Sweden)

    Hartshorn Kevan L

    2010-12-01

    Full Text Available Abstract Background Mannose-binding lectin (MBL, a pattern recognition innate immune molecule, inhibits influenza A virus infection in vitro. MBL deficiency due to gene polymorphism in humans has been associated with infection susceptibility. These clinical observations were confirmed by animal model studies, in which mice genetically lacking MBL were susceptible to certain pathogens, including herpes simplex virus 2. Results We demonstrate that MBL is present in the lung of naïve healthy wild type (WT mice and that MBL null mice are more susceptible to IAV infection. Administration of recombinant human MBL (rhMBL reverses the infection phenotype, confirming that the infection susceptibility is MBL-mediated. The anti-viral mechanisms of MBL include activation of the lectin complement pathway and coagulation, requiring serum factors. White blood cells (WBCs in the lung increase in WT mice compared with MBL null mice on day 1 post-infection. In contrast, apoptotic macrophages (MΦs are two-fold higher in the lung of MBL null mice compared with WT mice. Furthermore, MBL deficient macrophages appear to be susceptible to apoptosis in vitro. Lastly, soluble factors, which are associated with lung injury, are increased in the lungs of MBL null mice during IAV infection. These results suggest that MBL plays a key role against IAV infection. Conclusion MBL plays a key role in clearing IAV and maintaining lung homeostasis. In addition, our findings also suggest that MBL deficiency maybe a risk factor in IAV infection and MBL may be a useful adjunctive therapy for IAV infection.

  19. Mechanism of cold-induced increase in susceptibility to enterotoxigenic Escherichia coli-induced diarrhea of the newborn pig

    Energy Technology Data Exchange (ETDEWEB)

    Sarmiento Mendoza, J.I.

    1986-01-01

    These experiments studied the susceptibility to enterotoxigenic Escherichia coli (ETEC) in piglets kept at 25/sup 0/C (cold) or 35/sup 0/C (warm) from birth and infected at 18 h of age. When infected with ETEC strain M431 cold piglets had greater incidence and severity of diarrhea, fluid secretion, dehydration and intestinal colonization than warm littermates. In contrast, when piglets were challenged with ETEC strain O926-B-9C, which lacks the pilus antigens K99, K88, 987P but is able to produce heat stable enterotoxin (ST), increases influidity of feces and colonic and fecal contents in cold piglets were not consistent and there was no significant difference in bacterial counts between temperature groups. Cold piglets given /sup 14/C-polyethylene glycol had the bulk of radiolabelled contents in the cranial small intestinal segments indicating prolonged retention or decreased propulsion in comparison to warm littermates. No difference, however, was found in xylose absorption between temperature groups. It was investigated if insulin administration reduces the net propulsion of contents in newborn piglets as cold stress does. The segments containing the greater percentages of radioactivity were always more cranial in insulin injected piglets than in control piglets. There was, however, no differences in severity of disease or bacterial numbers between insulin injected and control piglets infected with M431 ETEC.

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

    Science.gov (United States)

    Morley, Wendy A; Seneff, Stephanie

    2014-01-01

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

  1. Interactions among genes in the ErbB-Neuregulin signalling network are associated with increased susceptibility to schizophrenia

    Directory of Open Access Journals (Sweden)

    McGinnis Ralph

    2007-06-01

    Full Text Available Abstract Background Evidence of genetic association between the NRG1 (Neuregulin-1 gene and schizophrenia is now well-documented. Furthermore, several recent reports suggest association between schizophrenia and single-nucleotide polymorphisms (SNPs in ERBB4, one of the receptors for Neuregulin-1. In this study, we have extended the previously published associations by investigating the involvement of all eight genes from the ERBB and NRG families for association with schizophrenia. Methods Eight genes from the ERBB and NRG families were tested for association to schizophrenia using a collection of 396 cases and 1,342 blood bank controls ascertained from Aberdeen, UK. A total of 365 SNPs were tested. Association testing of both alleles and genotypes was carried out using the fast Fisher's Exact Test (FET. To understand better the nature of the associations, all pairs of SNPs separated by ≥ 0.5 cM with at least nominal evidence of association (P Results 42 out of 365 tested SNPs in the eight genes from the ERBB and NRG gene families were significantly associated with schizophrenia (P Conclusion These new findings suggest that observed associations between NRG1 and schizophrenia may be mediated through functional interaction not just with ERBB4, but with other members of the NRG and ERBB families. There is evidence that genetic interaction among these loci may increase susceptibility to schizophrenia.

  2. Increased iron accumulation occurs in the earliest stages of demyelinating disease: an ultra-high field susceptibility mapping study in Clinically Isolated Syndrome.

    Science.gov (United States)

    Al-Radaideh, Ali M; Wharton, Samuel J; Lim, Su-Yin; Tench, Christopher R; Morgan, Paul S; Bowtell, Richard W; Constantinescu, Cris S; Gowland, Penny A

    2013-06-01

    To determine, using ultra-high field magnetic resonance imaging (MRI), whether changes in iron content occur in the earliest phases of demyelinating disease, by quantifying the magnetic susceptibility of deep grey matter structures in patients with Clinically Isolated Syndrome (CIS) that is suggestive of multiple sclerosis (MS), as compared with age-matched healthy subjects. We compared 19 CIS patients to 20 age-matched, healthy controls. Scanning of the study subjects was performed on a 7T Philips Achieva system, using a 3-dimensional, T2*-weighted gradient echo acquisition. Phase data were first high-pass filtered, using a dipole fitting method, and then inverted to produce magnetic susceptibility maps. Region of interest (ROI) analysis was used to estimate magnetic susceptibility values for deep grey matter structures (caudate nucleus, putamen, globus pallidus, the thalamus and its pulvinar). Significantly increased relative susceptibilities were found in the CIS group, compared with controls, for the caudate nucleus (p = 0.05). In CIS patients, the time elapsed since the clinical event and the Expanded Disability Status Scale (EDSS) scores were not correlated with iron levels in any ROI (r(2) 0.05); however, a moderate correlation (r(2) = 0.3; p disease.

  3. p.Asn176Lys and p.Met137Thr dimorphisms of the PRNP gene significantly decrease the susceptibility to classical scrapie in ARQ/ARQ sheep.

    Science.gov (United States)

    Maestrale, C; Carta, A; Attene, S; Galistu, A; Santucciu, C; Cancedda, M G; Saba, M; Sechi, S; Patta, C; Bandino, E; Ligios, C

    2009-12-01

    In this study, we investigated the susceptibility to scrapie of Sarda breed sheep carrying the genotype ARQ/ARQ with additional polymorphisms at the PRNP gene. To do this, we examined 256 scrapie-affected sheep and 320 flock-mate negative controls from 24 flocks. Logistic regression analysis demonstrated that sheep carrying the ARQ/ARQ genotype with additional dimorphisms had lower risk of becoming scrapie affected when compared with those with ARQ/ARQ(wildtype) genotype. ARQ/ARQ genotypes that were detected with heterozygous or homozygous p.Asn176Lys and p.Met137Thr dimorphisms were associated with the lowest susceptibility to the disease. A significant lower risk was also associated with the p.Arg154His dimorphism, while p.Leu141Phe had a protective effect that was not statistically significant.

  4. Allele-specific up-regulation of FGFR2 increases susceptibility to breast cancer.

    Directory of Open Access Journals (Sweden)

    Kerstin B Meyer

    2008-05-01

    Full Text Available The recent whole-genome scan for breast cancer has revealed the FGFR2 (fibroblast growth factor receptor 2 gene as a locus associated with a small, but highly significant, increase in the risk of developing breast cancer. Using fine-scale genetic mapping of the region, it has been possible to narrow the causative locus to a haplotype of eight strongly linked single nucleotide polymorphisms (SNPs spanning a region of 7.5 kilobases (kb in the second intron of the FGFR2 gene. Here we describe a functional analysis to define the causative SNP, and we propose a model for a disease mechanism. Using gene expression microarray data, we observed a trend of increased FGFR2 expression in the rare homozygotes. This trend was confirmed using real-time (RT PCR, with the difference between the rare and the common homozygotes yielding a Wilcox p-value of 0.028. To elucidate which SNPs might be responsible for this difference, we examined protein-DNA interactions for the eight most strongly disease-associated SNPs in different breast cell lines. We identify two cis-regulatory SNPs that alter binding affinity for transcription factors Oct-1/Runx2 and C/EBPbeta, and we demonstrate that both sites are occupied in vivo. In transient transfection experiments, the two SNPs can synergize giving rise to increased FGFR2 expression. We propose a model in which the Oct-1/Runx2 and C/EBPbeta binding sites in the disease-associated allele are able to lead to an increase in FGFR2 gene expression, thereby increasing the propensity for tumour formation.

  5. Apoplastic nucleoside accumulation in Arabidopsis leads to reduced photosynthetic performance and increased susceptibility against Botrytis cinerea

    Directory of Open Access Journals (Sweden)

    Manuel eDaumann

    2015-12-01

    Full Text Available ABSTRACT Interactions between plant and pathogen often occur in the extracellular space and especially nucleotides like ATP and NAD have been identified as key players in this scenario. Arabidopsis mutants accumulating nucleosides in the extracellular space were generated and studied with respect to susceptibility against Botrytis cinerea infection and general plant fitness determined as photosynthetic performance. The mutants used are deficient in the main nucleoside uptake system ENT3 and the extracellular nucleoside hydrolase NSH3. When grown on soil but not in hydroponic culture, these plants markedly accumulate adenosine and uridine in leaves. This nucleoside accumulation was accpmpanied by reduced photosystem II efficiency and altered expression of photosynthesis related genes. Moreover, a higher susceptibility towards Botrytis cinerea infection and a reduced induction of pathogen related genes PR1 and WRKY33 was observed. All these effects did not occur in hydroponically grown plants substantiating a contribution of extracellular nucleosides to these effects. Whether reduced general plant fitness, altered pathogen response capability or more direct interactions with the pathogen are responsible for these observations is discussed.

  6. IDH2 deficiency increases the liver susceptibility to ischemia-reperfusion injury via increased mitochondrial oxidative injury

    Directory of Open Access Journals (Sweden)

    Sang Jun Han

    2018-04-01

    Full Text Available Mitochondrial NADP+-dependent isocitrate dehydrogenase 2 (IDH2 is a major producer of mitochondrial NADPH, required for glutathione (GSH-associated mitochondrial antioxidant systems including glutathione peroxidase (GPx and glutathione reductase (GR. Here, we investigated the role of IDH2 in hepatic ischemia-reperfusion (HIR-associated mitochondrial injury using Idh2-knockout (Idh2-/- mice and wild-type (Idh2+/+ littermates. Mice were subjected to either 60 min of partial liver ischemia or sham-operation. Some mice were administered with 2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino-2-oxoethyl triphenylphosphonium chloride (mito-TEMPO, a mitochondria-targeting antioxidant. HIR induced severe histological and functional damages of liver in both Idh2+/+ mice and Idh2-/- mice and those damages were more severe in Idh2-/- mice than in wild-type littermates. HIR induces dysfunction of IDH2, leading to the decreases of NADPH level and mitochondrial GR and GPx functions, consequently resulting in mitochondrial and cellular oxidative injury as reflected by mitochondrial cristae loss, mitochondrial fragmentation, shift in mitochondrial fission, cytochrome c release, and cell death. These HIR-induced changes were greater in Idh2-/- mice than wild-type mice. The mito-TEMPO supplement significantly attenuated the aforementioned changes, and these attenuations were much greater in Idh2-/- mice when compared with wild-type littermates. Taken together, results have demonstrated that HIR impairs in the IDH2-NADPH-GSH mitochondrial antioxidant system, resulting in increased mitochondrial oxidative damage and dysfunction, suggesting that IDH2 plays a critical role in mitochondrial redox balance and HIR-induced impairment of IDH2 function is associated with the pathogenesis of ischemia-reperfusion-induced liver failure. Keywords: Liver ischemia, Mitochondria, Oxidative stress, Apoptosis, IDH2

  7. IDH2 deficiency increases the liver susceptibility to ischemia-reperfusion injury via increased mitochondrial oxidative injury.

    Science.gov (United States)

    Han, Sang Jun; Choi, Hong Seok; Kim, Jee In; Park, Jeen-Woo; Park, Kwon Moo

    2017-09-08

    Mitochondrial NADP(+)-dependent isocitrate dehydrogenase 2 (IDH2) is a major producer of mitochondrial NADPH, required for glutathione (GSH)-associated mitochondrial antioxidant systems including glutathione peroxidase (GPx) and glutathione reductase (GR). Here, we investigated the role of IDH2 in hepatic ischemia-reperfusion (HIR)-associated mitochondrial injury using Idh2-knockout (Idh2(-/-)) mice and wild-type (Idh2(+/+)) littermates. Mice were subjected to either 60min of partial liver ischemia or sham-operation. Some mice were administered with 2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl) triphenylphosphonium chloride (mito-TEMPO, a mitochondria-targeting antioxidant). HIR induced severe histological and functional damages of liver in both Idh2(+/+) mice and Idh2(-/-) mice and those damages were more severe in Idh2(-/-) mice than in wild-type littermates. HIR induces dysfunction of IDH2, leading to the decreases of NADPH level and mitochondrial GR and GPx functions, consequently resulting in mitochondrial and cellular oxidative injury as reflected by mitochondrial cristae loss, mitochondrial fragmentation, shift in mitochondrial fission, cytochrome c release, and cell death. These HIR-induced changes were greater in Idh2(-/-) mice than wild-type mice. The mito-TEMPO supplement significantly attenuated the aforementioned changes, and these attenuations were much greater in Idh2(-/-) mice when compared with wild-type littermates. Taken together, results have demonstrated that HIR impairs in the IDH2-NADPH-GSH mitochondrial antioxidant system, resulting in increased mitochondrial oxidative damage and dysfunction, suggesting that IDH2 plays a critical role in mitochondrial redox balance and HIR-induced impairment of IDH2 function is associated with the pathogenesis of ischemia-reperfusion-induced liver failure. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  8. Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain.

    Science.gov (United States)

    Volkow, N D; Wang, G; Fowler, J S; Logan, J; Gerasimov, M; Maynard, L; Ding, Y; Gatley, S J; Gifford, A; Franceschi, D

    2001-01-15

    Methylphenidate (Ritalin) is the most commonly prescribed psychoactive drug in children for the treatment of attention deficit hyperactivity disorder (ADHD), yet the mechanisms responsible for its therapeutic effects are poorly understood. Whereas methylphenidate blocks the dopamine transporter (main mechanism for removal of extracellular dopamine), it is unclear whether at doses used therapeutically it significantly changes extracellular dopamine (DA) concentration. Here we used positron emission tomography and [(11)C]raclopride (D2 receptor radioligand that competes with endogenous DA for binding to the receptor) to evaluate whether oral methylphenidate changes extracellular DA in the human brain in 11 healthy controls. We showed that oral methylphenidate (average dose 0.8 +/- 0.11 mg/kg) significantly increased extracellular DA in brain, as evidenced by a significant reduction in B(max)/K(d) (measure of D2 receptor availability) in striatum (20 +/- 12%; p methylphenidate at doses within the therapeutic range significantly increases extracellular DA in human brain. This result coupled with recent findings of increased dopamine transporters in ADHD patients (which is expected to result in reductions in extracellular DA) provides a mechanistic framework for the therapeutic efficacy of methylphenidate. The increase in DA caused by the blockade of dopamine transporters by methylphenidate predominantly reflects an amplification of spontaneously released DA, which in turn is responsive to environmental stimulation. Because DA decreases background firing rates and increases signal-to-noise in target neurons, we postulate that the amplification of weak DA signals in subjects with ADHD by methylphenidate would enhance task-specific signaling, improving attention and decreasing distractibility. Alternatively methylphenidate-induced increases in DA, a neurotransmitter involved with motivation and reward, could enhance the salience of the task facilitating the "interest that

  9. Significant alterations in reported clinical practice associated with increased oversight of organ transplant center performance.

    Science.gov (United States)

    Schold, Jesse D; Arrington, Charlotte J; Levine, Greg

    2010-09-01

    In the past several years, emphasis on quality metrics in the field of organ transplantation has increased significantly, largely because of the new conditions of participation issued by the Centers for Medicare and Medicaid Services. These regulations directly associate patients' outcomes and measured performance of centers with the distribution of public funding to institutions. Moreover, insurers and marketing ventures have used publicly available outcomes data from transplant centers for business decision making and advertisement purposes. We gave a 10-question survey to attendees of the Transplant Management Forum at the 2009 meeting of the United Network for Organ Sharing to ascertain how centers have responded to the increased oversight of performance. Of 63 responses, 55% indicated a low or near low performance rating at their center in the past 3 years. Respondents from low-performing centers were significantly more likely to indicate increased selection criteria for candidates (81% vs 38%, P = .001) and donors (77% vs 31%, P vs 52%, P = .007). Among respondents indicating lost insurance contracts (31%), these differences were also highly significant. Based on respondents' perceptions, outcomes of performance evaluations are associated with significant changes in clinical practice at transplant centers. The transplant community and policy makers should practice vigilance that performance evaluations and regulatory oversight do not inadvertently lead to diminished access to care among viable candidates or decreased transplant volume.

  10. Denosumab significantly increases DXA BMD at both trabecular and cortical sites: results from the FREEDOM study.

    Science.gov (United States)

    Bolognese, Michael A; Teglbjærg, Christence Stubbe; Zanchetta, Jose R; Lippuner, Kurt; McClung, Michael R; Brandi, Maria Luisa; Høiseth, Arne; Lakatos, Péter; Moffett, Alfred H; Lorenc, Roman S; Wang, Andrea; Libanati, Cesar

    2013-01-01

    Denosumab is an approved therapy for postmenopausal women with osteoporosis at high or increased risk for fracture. In the FREEDOM study, denosumab reduced fracture risk and increased bone mineral density (BMD). We report the spine and hip dual-energy X-ray absorptiometry (DXA) BMD responses from the overall study of 7808 women and from a substudy of 441 participants in which more extensive spine and hip assessments as well as additional skeletal sites were evaluated. Significant BMD improvements were observed as early as 1 mo at the lumbar spine, total hip, and trochanter (all p<0.005 vs placebo and baseline). BMD increased progressively at the lumbar spine, total hip, femoral neck, trochanter, 1/3 radius, and total body from baseline to months 12, 24, and 36 (all p<0.005 vs placebo and baseline). BMD gains above the least significant change of more than 3% at 36 months were observed in 90% of denosumab-treated subjects at the lumbar spine and 74% at the total hip, and gains more than 6% occurred in 77% and 38%, respectively. In conclusion, denosumab treatment resulted in significant, early, and continued BMD increases at both trabecular and cortical sites throughout the skeleton over 36 mo with important gains observed in most subjects. Copyright © 2013 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.

  11. Application of artificial photoperiod in fish: a factor that increases susceptibility to infectious diseases?

    Science.gov (United States)

    Valenzuela, Ariel; Campos, Victor; Yañez, Francisco; Alveal, Katherine; Gutiérrez, Pamela; Rivas, Meyling; Contreras, Nancy; Klempau, Alfredo; Fernandez, Italo; Oyarzun, Ciro

    2012-08-01

    This paper describes and evaluates the mortality associated with the potential stressor effect induced by application of artificial photoperiods in rainbow trout (Oncorhynchus mykiss). After application of artificial photoperiods, high mortalities of trout subjected to this management were recorded (36% in LD 14:10 and 25% in LD 24:0) as compared to controls (7%). The recorded signology related to diseased trout included darkening, lethargy and erratic swimming. Among the morphological changes, skin lesions and ulcerative-type necrosis could be observed. Blood tests, histopathology and isolation of pathogens identified as Flavobacterium psychrophilum, associated with Aeromonas, Pseudomonas and Saprolegnia sp., were performed. The application of artificial photoperiods suggests that fish may be more susceptible to opportunistic diseases; thus, it is advisable to emphasize preventive measures in fish subjected to this management.

  12. Increased dermal mast cell prevalence and susceptibility to development of basal cell carcinoma in humans

    DEFF Research Database (Denmark)

    Grimbaldeston, Michele A; Skov, Lone; Finlay-Jones, John J

    2002-01-01

    eliminate them. Studies in a range of inbred mouse strains as well as mast cell-depleted mice reconstituted with mast cell precursors support a functional link between histamine-staining dermal mast cells and the extent of susceptibility to UVB-induced systemic immunomodulation. Humans, like mouse strains......, display variations in dermal mast cell prevalence. In a study of Danish and South Australian BCC patients and control subjects, one 4-mm punch biopsy of non-sun-exposed buttock skin was sampled from each participant. This skin site was investigated to avoid any changes in mast cell prevalence caused...... by sun exposure. Two sections (4 microm) per biopsy were immunohistochemically stained for detection of histamine-containing dermal mast cells. Computer-generated image analysis evaluated dermal mast cell prevalence in both sections by quantifying the total number of mast cells according to the total...

  13. Functional polymorphisms of the CCL2 and MBL genes cumulatively increase susceptibility to severe acute respiratory syndrome coronavirus infection.

    Science.gov (United States)

    Tu, Xinyi; Chong, Wai Po; Zhai, Yun; Zhang, Hongxing; Zhang, Fang; Wang, Shixin; Liu, Wei; Wei, Maoti; Siu, Nora Ho On; Yang, Hao; Yang, Wanling; Cao, Wuchun; Lau, Yu Lung; He, Fuchu; Zhou, Gangqiao

    2015-07-01

    To assess associations between the functional polymorphisms G-2518A at the chemokine (C-C motif) ligand 2 gene (CCL2) and mannose binding lectin (MBL) codon 54 variant (A/B) and susceptibility to SARS. We genotyped the CCL2 G-2518A and MBL codon 54 variant (A/B) in 4 case-control populations of Chinese descent, totally consisting of 932 patients with SARS and 982 control subjects. Both the high-CCL2-producing GG genotype and the low-MBL-producing B allele were consistently associated with increased risks of SARS-CoV infection in all 4 case-control populations (joint P = 1.6 × 10(-4) and 4.9 × 10(-8), for CCL2 and MBL respectively), with no interaction between polymorphisms could be detected. Furthermore, all the 4 case-control studies demonstrated a cumulative effect on risk of SARS-CoV infection for the combination of polymorphisms (joint P = 1.3 × 10(-10)). However, tests using the area under the curve (AUC) indicated that at this stage, the polymorphisms were unlikely to be appropriate for risk prediction testing because of low AUC values (all <66%). Additionally, no association was observed between the polymorphisms and severity of SARS. The CCL2 G-2518A and MBL codon 54 variant have a significantly cumulative effect on increased risk of SARS-CoV infection. Copyright © 2015 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

  14. CD33: increased inclusion of exon 2 implicates the Ig V-set domain in Alzheimer's disease susceptibility

    Science.gov (United States)

    Raj, Towfique; Ryan, Katie J.; Replogle, Joseph M.; Chibnik, Lori B.; Rosenkrantz, Laura; Tang, Anna; Rothamel, Katie; Stranger, Barbara E.; Bennett, David A.; Evans, Denis A.; De Jager, Philip L.; Bradshaw, Elizabeth M.

    2014-01-01

    We previously demonstrated that the Alzheimer's disease (AD) associated risk allele, rs3865444C, results in a higher surface density of CD33 on monocytes. Here, we find alternative splicing of exon 2 to be the primary mechanism of the genetically driven differential expression of CD33 protein. We report that the risk allele, rs3865444C, is associated with greater cell surface expression of CD33 in both subjects of European and African–American ancestry and that there is a single haplotype influencing CD33 surface expression. A meta-analysis of the two populations narrowed the number of significant SNPs in high linkage disequilibrium (LD) (r2 > 0.8) with rs3865444 to just five putative causal variants associated with increased protein expression. Using gene expression data from flow-sorted CD14+CD16− monocytes from 398 healthy subjects of three populations, we show that the rs3865444C risk allele is strongly associated with greater expression of CD33 exon 2 (pMETA = 2.36 × 10−60). Western blotting confirms increased protein expression of the full-length CD33 isoform containing exon 2 relative to the rs3865444C allele (P < 0.0001). Of the variants in strong LD with rs3865444, rs12459419, which is located in a putative SRSF2 splice site of exon 2, is the most likely candidate to mediate the altered alternative splicing of CD33's Immunoglobulin V-set domain 2 and ultimately influence AD susceptibility. PMID:24381305

  15. Intrauterine Growth Retardation Increases the Susceptibility of Pigs to High-Fat Diet-Induced Mitochondrial Dysfunction in Skeletal Muscle

    Science.gov (United States)

    Liu, Jingbo; Chen, Daiwen; Yao, Ying; Yu, Bing; Mao, Xiangbing; He, Jun; Huang, Zhiqing; Zheng, Ping

    2012-01-01

    It has been recognized that there is a relationship between prenatal growth restriction and the development of metabolic-related diseases in later life, a process involved in mitochondrial dysfunction. In addition, intrauterine growth retardation (IUGR) increases the susceptibility of offspring to high-fat (HF) diet-induced metabolic syndrome. Recent findings suggested that HF feeding decreased mitochondrial oxidative capacity and impaired mitochondrial function in skeletal muscle. Therefore, we hypothesized that the long-term consequences of IUGR on mitochondrial biogenesis and function make the offspring more susceptible to HF diet-induced mitochondrial dysfunction. Normal birth weight (NBW), and IUGR pigs were allotted to control or HF diet in a completely randomized design, individually. After 4 weeks of feeding, growth performance and molecular pathways related to mitochondrial function were determined. The results showed that IUGR decreased growth performance and plasma insulin concentrations. In offspring fed a HF diet, IUGR was associated with enhanced plasma leptin levels, increased concentrations of triglyceride and malondialdehyde (MDA), and reduced glycogen and ATP contents in skeletal muscle. High fat diet-fed IUGR offspring exhibited decreased activities of lactate dehydrogenase (LDH) and glucose-6-phosphate dehydrogenase (G6PD). These alterations in metabolic traits of IUGR pigs were accompanied by impaired mitochondrial respiration function, reduced mitochondrial DNA (mtDNA) contents, and down-regulated mRNA expression levels of genes responsible for mitochondrial biogenesis and function. In conclusion, our results suggest that IUGR make the offspring more susceptible to HF diet-induced mitochondrial dysfunction. PMID:22523560

  16. Defects in early cell recruitment contribute to the increased susceptibility to respiratory Klebsiella pneumoniae infection in diabetic mice.

    Science.gov (United States)

    Martinez, Nuria; Ketheesan, Natkunam; Martens, Gregory W; West, Kim; Lien, Egil; Kornfeld, Hardy

    2016-10-01

    Diabetes is associated with increased susceptibility to Klebsiella pneumoniae and poor prognosis with infection. We demonstrate accelerated mortality in mice with streptozotocin-induced diabetes following tracheal instillation of K. pneumoniae. Diabetic mice recruited fewer granulocytes to the alveolar airspace and had reduced early production of CXCL1, CXCL2, IL-1β and TNF-α following tracheal instillation of K. pneumoniae-lipopolysaccharide. Additionally, TLR2 and TIRAP expression following K. pneumoniae-lipopolysaccharide exposure was decreased in hyperglycemic mice. These findings indicate that impaired innate sensing and failure to rapidly recruit granulocytes to the site of infection is a mechanism for diabetic susceptibility to respiratory K. pneumoniae infection. Copyright © 2016 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

  17. Exam anxiety induces significant blood pressure and heart rate increase in college students.

    Science.gov (United States)

    Zhang, Zhihong; Su, Hai; Peng, Qiang; Yang, Qing; Cheng, Xiaoshu

    2011-01-01

    To investigate the relationship between the anxiety and blood pressure (BP) and heart rate (HR) increase in peri-exam period. Sixty-four college students(20.0 ± 0.1 year old) were included in this study. The BP and HR were measured in the morning and in the evening for 3 days during the prereview (ba), review, and exam periods. The BP and HR increase amplitudes (HRIA) of review and exam periods were from the difference of corresponding values and basic values, and the BPIA/baBP and HRIA/baHR were calculated. All of the students completed the Self-Rating Anxiety score (SAS) questionnaire the first day of the exam period. Scores over 50 points were used as the standard for anxiety. From the prereview to exam periods, the BP and HR increased gradually. The exam SBPIA (4.3 ± 1.3 vs. 0.3 ± 0.5 mmHg, P anxiety group than in the no-anxiety group. The SBPIA/DBPIA and HRIA showed a similar profile also(9.7 ± 2.1 vs. 1.9 ± 0.9 bpm, P anxiety score; meanwhile, their exam BPIAs and HRIAs were significantly higher than their corresponding group. The BP and HR increase in the review and exam period, anxiety is an important factor of BP and HR increase.

  18. Increase in susceptibility to insecticides with aging of wild Anopheles gambiae mosquitoes from Côte d’Ivoire

    Directory of Open Access Journals (Sweden)

    Chouaibou Mouhamadou S

    2012-09-01

    Full Text Available Abstract Background Appropriate monitoring of vector insecticide susceptibility is required to provide the rationale for optimal insecticide selection in vector control programs. Methods In order to assess the influence of mosquito age on susceptibility to various insecticides, field-collected larvae of An. gambiae s.l. from Tiassalé were reared to adults. Females aged 1, 2, 3, 5 and 10 days were exposed to 5 insecticides (deltamethrin, permethrin, DDT, malathion and propoxur using WHO susceptibility test kits. Outcome measures included the LT50 (exposure time required to achieve 50% knockdown, the RR (resistance ratio, i.e. a calculation of how much more resistant the wild population is compared with a standard susceptible strain and the mortality rate following 1 hour exposure, for each insecticide and each mosquito age group. Results There was a positive correlation between the rate of knockdown and mortality for all the age groups and for all insecticides tested. For deltamethrin, the RR50 was highest for 2 day old and lowest for 10 day old individuals. Overall, mortality was lowest for 2 and 3 day old individuals and significantly higher for 10 day old individuals (P 50 was highest for 1 to 3 day old individuals and lowest for 10 day old individuals and mortality was lowest for 1 to 3 day old individuals, intermediate for 5 day old and highest for 10 day old individuals. DDT did not display any knockdown effect and mortality was low for all mosquito age groups (50 was low (1.54 - 2.77 and mortality was high (>93% for all age groups. With propoxur, no knockdown effect was observed for 1, 2 and 3 day old individuals and a very low level of mortality was observed ( Conclusion Results indicate that for An. gambiae s.l. adults derived from wild-collected larvae, there was an influence of age on insecticide susceptibility status, with younger individuals (1 to 3 days old more resistant than older mosquitoes. This

  19. Endurance training significantly increases serum endocan but not osteoprotegerin levels: a prospective observational study.

    Science.gov (United States)

    Sponder, Michael; Campean, Ioana-Alexandra; Emich, Michael; Fritzer-Szekeres, Monika; Litschauer, Brigitte; Bergler-Klein, Jutta; Graf, Senta; Strametz-Juranek, Jeanette

    2017-01-05

    Endocan (EN) was suggested a potential inflammatory and cardiovascular disease (CVD) marker which might also be involved in renal failure and/or renal failure-associated vascular events. It is not clear whether osteoprotegerin (OPG) is a pro- or anti-atherogenic factor, however, it is agreed upon that OPG is elevated in subjects with increased calcification status. The aim of the study was to investigate the influence of long-term physical activity on serum endocan (EN) and osteoprotegerin-levels. One hundred nine subjects were told to increase their amount of physical activity for 8 months by performing 150min/week moderate or 75min/week vigorous exercise. Incremental cycle ergometer tests were performed at the beginning and the end of the study to prove and quantify the performance gain. Blood samples were drawn at baseline and every 2 months for the determination of EN and OPG. To investigate the difference between baseline and 8 months levels of EN and OPG we used a paired sample t-test. To investigate the significance of the tendency of the progression (baseline/2 months/4 months/6 months/8 months) we used a Friedman test. Thirty-eight female and 60 male subjects completed the study. In the group of 61 subjects who had a performance gain by >4,9% EN-levels increased from 146 ± 110 to 196 ± 238 pg/ml (p = 0,036) equivalent to an increase of 33,5% but there was no significant change in OPG (4,4 ± 2,4 pmol/l vs. 4,3 ± 2,1 pmol/l; p = 0,668). Physical activity increases significantly EN-levels relativizing the status of EN as proinflammatory factor. EN should rather be considered as a mediator which is involved in several physiological (e.g., angiogenesis) but also pathological processes (e.g., CVD, tumour progression or endothelium-dependent inflammation) and whose expression can be significantly influenced by long term endurance training. Clinical trial registration number: NCT02097199 Date of trial registration at Clinical Trials

  20. Increased susceptibility of blood type O individuals to develop anemia in Plasmodium vivax infection.

    Science.gov (United States)

    Resende, Sarah Stela; Milagres, Vanessa Gonçalves; Chaves, Daniel Gonçalves; Fontes, Cor Jesus Fernandes; Carvalho, Luzia Helena; Sousa, Tais Nobrega; Brito, Cristiana Ferreira Alves de

    2017-06-01

    Plasmodium vivax has been reported to cause severe malaria, and one of the main resulting complications is anemia. Considering that P. vivax infects only young erythrocytes, anemia has been associated with the destruction of infected and non-infected erythrocytes. However, few studies have focused on understanding the relationship between the pathogenesis of P. vivax malaria and human genetic polymorphisms. Although ABO groups seem to influence the outcome of Plasmodium falciparum malaria, the association between P. vivax and ABO blood groups has been minimally investigated. Thus, we investigate the correlation between ABO blood groups and anemia induced by P. vivax infection. Five single nucleotide polymorphisms at the ABO gene were genotyped by PCR-RFLP and Real-Time PCR in P. vivax-infected subjects. The ABO blood types were associated with the hematological data of the patients. Our main finding was that type O infected-individuals showed lower levels of hemoglobin and hematocrit compared to type A-infected individuals. The correlation between ABO blood groups and hemoglobin levels remained significant when a multiple linear regression was applied with the possible confounding effects of clinical-epidemiologic variables taken into account. The finding that type O individuals have a higher frequency of anemia is a first step to understand the mechanisms involved in malaria anemia, which could be associated to increased destruction of type O erythrocytes. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Increased susceptibility to Kuru of carriers of the PRNP 129 methionine/methionine genotype.

    Science.gov (United States)

    Lee, H S; Brown, P; Cervenáková, L; Garruto, R M; Alpers, M P; Gajdusek, D C; Goldfarb, L G

    2001-01-15

    Kuru reached epidemic proportions by the mid-twentieth century among the Fore people of New Guinea and disappeared after the abolition of cannibalistic rituals. To determine susceptibility to kuru and its role in the spread and elimination of the epidemic, we analyzed the PRNP gene coding sequences in 5 kuru patients; no germline mutations were found. Analysis of the PRNP 129 methionine (M)/valine (V) polymorphism in 80 patients and 95 unaffected controls demonstrated that the kuru epidemic preferentially affected individuals with the M/M genotype. A higher representation of M/M carriers was observed among the affected young Fore males entering the age of risk, whereas a lower frequency of M/M homozygotes was found among the survivors. M/V and V/V genotypes predisposed to a lower risk of disease development and longer incubation times. These findings are relevant to the current outbreak of variant Creutzfeldt-Jakob disease (vCJD) in the United Kingdom, because all vCJD patients tested thus far have been M/M carriers.

  2. Clinicopathological significance of increased ZIC1 expression in human endometrial cancer.

    Science.gov (United States)

    Gu, Xing; Liu, Qin; Yang, Ning; Shen, Jian-fang; Zhang, Xue-gang; Cao, Fang; Ding, Hou-zhong

    2015-12-01

    Zinc finger of the cerebellum (ZIC1), one of ZIC family genes, has been shown to play important roles in many cancers such as gastric cancer and breast cancer. However, there is little known about the expression and significance of ZIC1 in endometrial cancer. The aim of this study was to determine the expression pattern and clinicopathological significance of ZIC1 in endometrial cancer. The mRNA and protein expression of ZIC1 in endometrial cancer tissues was detected using the reverse-transcription polymerase chain reaction and Western blotting, respectively. Immunostaining of ZIC1 in 99 endometrial cancer samples was examined and its associations with clinicopathological parameters were analyzed. Hec-1-B cells were transfected with ZIC1-shRNA or sc-shRNA, and cell proliferation was assayed. Hec-1-B cells stably transfected with ZIC1-shRNA or sc-shRNA were subcutaneously inoculated into nude mice, and the tumor weight was measured. A significantly increased expression of ZIC1 mRNA and protein was observed in endometrial cancer tissues compared to that in normal endometrial tissues (Pendometrial cancer samples (90/99) while light and moderate immunostaining of ZIC1 was only detected in 17 of 30 (56.7%) normal tissues. Moreover, up-regulation of ZIC1 was significantly correlated with age, disease stage, TNM stage and FIGO stage (Pendometrial cancer tissue but not in normal tissue, and positively correlated to the malignant biological behavior of endometrial carcinogenesis.

  3. Activated T cells exhibit increased uptake of silicon phthalocyanine Pc 4 and increased susceptibility to Pc 4-photodynamic therapy-mediated cell death

    Science.gov (United States)

    Soler, David C.; Ohtola, Jennifer; Sugiyama, Hideaki; Rodriguez, Myriam E.; Han, Ling; Oleinick, Nancy L.; Lam, Minh; Baron, Elma D.; Cooper, Kevin D.; McCormick, Thomas S.

    2016-01-01

    Photodynamic therapy (PDT) is an emerging treatment for malignant and inflammatory dermal disorders. Photoirradiation of the silicon phthalocyanine (Pc) 4 photosensitizer with red light generates singlet oxygen and other reactive oxygen species to induce cell death. We previously reported that Pc 4-PDT elicited cell death in lymphoid-derived (Jurkat) and epithelial-derived (A431) cell lines in vitro, and furthermore that Jurkat cells were more sensitive than A431 cells to treatment. In this study, we examined the effectiveness of Pc 4-PDT on primary human CD3+ T cells in vitro. Fluorometric analyses of lysed T cells confirmed the dose-dependent uptake of Pc 4 in non-stimulated and stimulated T cells. Flow cytometric analyses measuring annexin V and propidium iodide (PI) demonstrated a dose-dependent increase of T cell apoptosis (6.6–59.9%) at Pc 4 doses ranging from 0–300 nM. Following T cell stimulation through the T cell receptor using a combination of anti-CD3 and anti-CD28 antibodies, activated T cells exhibited increased susceptibility to Pc 4-PDT-induced apoptosis (10.6–81.2%) as determined by Pc 4 fluorescence in each cell, in both non-stimulated and stimulated T cells, Pc 4 uptake increased with Pc 4 dose up to 300 nM as assessed by flow cytometry. The mean fluorescence intensity (MFI) of Pc 4 uptake measured in stimulated T cells was significantly increased over the uptake of resting T cells at each dose of Pc 4 tested (50, 100, 150 and 300nM, p<0.001 between 50 and 150nM, n=8). Treg uptake was diminished relative to other T cells. Cutaneous T cell lymphoma (CTCL) T cells appeared to take up somewhat more Pc 4 than normal resting T cells at 100 and 150nm Pc 4. Confocal imaging revealed that Pc 4 localized in cytoplasmic organelles, with approximately half of the Pc 4 co-localized with mitochondria in T cells. Thus, Pc 4-PDT exerts an enhanced apoptotic effect on activated CD3+ T cells that may be exploited in targeting T cell-mediated skin diseases

  4. Head and neck cooling decreases tympanic and skin temperature, but significantly increases blood pressure.

    Science.gov (United States)

    Koehn, Julia; Kollmar, Rainer; Cimpianu, Camelia-Lucia; Kallmünzer, Bernd; Moeller, Sebastian; Schwab, Stefan; Hilz, Max J

    2012-08-01

    Localized head and neck cooling might be suited to induce therapeutic hypothermia in acute brain injury such as stroke. Safety issues of head and neck cooling are undetermined and may include cardiovascular autonomic side effects that were identified in this study. Ten healthy men (age 35±13 years) underwent 120 minutes of combined head and neck cooling (Sovika, HVM Medical). Before and after onset of cooling, after 60 and 120 minutes, we determined rectal, tympanic, and forehead skin temperatures, RR intervals, systolic and diastolic blood pressures (BP), laser-Doppler skin blood flow at the index finger and cheek, and spectral powers of mainly sympathetic low-frequency (0.04-0.15 Hz) and parasympathetic high-frequency (0.15-0.5 Hz) RR interval oscillations and sympathetic low-frequency oscillations of BP. We compared values before and during cooling using analysis of variance with post hoc analysis; (significance, Pskin temperature dropped by 5.5±2.2°C with cooling onset and by 12.4±3.2°C after 20 minutes. Tympanic temperature decreased by 4.7±0.7°C within 40 minutes, and rectal temperature by only 0.3±0.3°C after 120 minutes. Systolic and diastolic BP increased immediately on cooling onset and rose by 15.3±20.8 mm Hg and 16.5±13.4 mm Hg (P=0.004) after 120 minutes, whereas skin blood flow fell significantly during cooling. RR intervals and parasympathetic RR interval high-frequency powers increased with cooling onset and were significantly higher after 60 and 120 minutes than they were before cooling. Head and neck cooling prominently reduced tympanic temperature and thus might also induce intracerebral hypothermia; however, it did not significantly lower body core temperature. Profound skin temperature decrease induced sympathetically mediated peripheral vasoconstriction and prominent BP increases that are not offset by simultaneous parasympathetic heart rate slowing. Prominent peripheral vasoconstriction and BP increase must be considered as

  5. Kinematic and Microphysical Significance of Lightning Jumps versus Non-Jump Increases in Total Flash Rate.

    Science.gov (United States)

    Schultz, Christopher J; Carey, Lawrence D; Schultz, Elise V; Blakeslee, Richard J

    2017-02-01

    Thirty-nine thunderstorms are examined using multiple-Doppler, polarimetric and total lightning observations to understand the role of mixed phase kinematics and microphysics in the development of lightning jumps. This sample size is larger than those of previous studies on this topic. The principal result of this study is that lightning jumps are a result of mixed phase updraft intensification. Larger increases in intense updraft volume (≥ 10 m s-1) and larger changes in peak updraft speed are observed prior to lightning jump occurrence when compared to other non-jump increases in total flash rate. Wilcoxon-Mann-Whitney Rank Sum testing yields p-values ≤0.05, indicating statistical independence between lightning jump and non-jump distributions for these two parameters. Similar changes in mixed phase graupel mass magnitude are observed prior to lightning jumps and non-jump increases in total flash rate. The p-value for graupel mass change is p=0.096, so jump and non-jump distributions for graupel mass change are not found statistically independent using the p=0.05 significance level. Timing of updraft volume, speed and graupel mass increases are found to be 4 to 13 minutes in advance of lightning jump occurrence. Also, severe storms without lightning jumps lack robust mixed phase updrafts, demonstrating that mixed phase updrafts are not always a requirement for severe weather occurrence. Therefore, the results of this study show that lightning jump occurrences are coincident with larger increases in intense mixed phase updraft volume and peak updraft speed than smaller non-jump increases in total flash rate.

  6. Aging increases the susceptibility to motor memory interference and reduces off-line gains in motor skill learning.

    Science.gov (United States)

    Roig, Marc; Ritterband-Rosenbaum, Anina; Lundbye-Jensen, Jesper; Nielsen, Jens Bo

    2014-08-01

    Declines in the ability to learn motor skills in older adults are commonly attributed to deficits in the encoding of sensorimotor information during motor practice. We investigated whether aging also impairs motor memory consolidation by assessing the susceptibility to memory interference and off-line gains in motor skill learning after practice in children, young, and older adults. Subjects performed a ballistic task (A) followed by an accuracy-tracking task (B) designed to disrupt the consolidation of A. Retention tests of A were performed immediately and 24 hours after B. Older adults showed greater susceptibility to memory interference and no off-line gains in motor skill learning. Performing B produced memory interference and reduced off-line gains only in the older group. However, older adults also showed deficits in memory consolidation independent of the interfering effects of B. Age-related declines in motor skill learning are not produced exclusively by deficits in the encoding of sensorimotor information during practice. Aging also increases the susceptibility to memory interference and reduces off-line gains in motor skill learning after practice. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Mortality of acute mesenteric ischemia remains unchanged despite significant increase in utilization of endovascular techniques.

    Science.gov (United States)

    Eslami, Mohammad H; Rybin, Denis; Doros, Gheorghe; McPhee, James T; Farber, Alik

    2016-02-01

    In this study, we evaluated if increase in utilization of endovascular surgery has affected in-hospital mortality rates among patients with acute mesenteric ischemia. The National Inpatient Sample (2003-2011) was queried for acute mesenteric ischemia using ICD-9 code for acute mesenteric ischemia (557.1). This cohort was divided into patients treated with open vascular surgery (open vascular group) and by endovascular therapies (endovascular group) based on the ICD-9CM procedure codes. Multivariable logistic regression was used to determine temporal trend for mortality while adjusting for confounding variables. There was 1.45-fold increase in utilization of endovascular techniques in this study. In-hospital mortality rate, total median charges and length of stay were significantly lower among the endovascular group than the open vascular group despite having significantly higher Elixhauser comorbidities index (3 ± 0.1 vs. 2.7 ± 0.1, p = .003). Over the course of the study period, there was no change in the overall mortality rate despite higher endovascular utilization. Factors associated with increased mortality included age, open surgical repair (Odds ratio: 1.45, 95% Confidence Interval: 1.10-1.91, p = .016) and bowel resection Odds ratio: 2.88, 95% Confidence Interval: 2.01-4.12). The mortality rate for acute mesenteric ischemia remains unchanged throughout this contemporary study. Open surgical intervention, bowel resection and age were associated with increased mortality. Endovascular group patients had better survival despite higher morbidity indices. © The Author(s) 2015.

  8. Increased seizure susceptibility and other toxicity symptoms following acute sulforaphane treatment in mice.

    Science.gov (United States)

    Socała, Katarzyna; Nieoczym, Dorota; Kowalczuk-Vasilev, Edyta; Wyska, Elżbieta; Wlaź, Piotr

    2017-07-01

    Activation of Nrf2 with sulforaphane has recently gained attention as a new therapeutic approach in the treatment of many diseases, including epilepsy. As a plant-derived compound, sulforaphane is considered to be safe and well-tolerated. It is widely consumed, also by patients suffering from seizure and taking antiepileptic drugs, but no toxicity profile of sulforaphane exists. Since many natural remedies and dietary supplements may increase seizure risk and potentially interact with antiepileptic drugs, the aim of our study was to investigate the acute effects of sulforaphane on seizure thresholds and activity of some first- and second-generation antiepileptic drugs in mice. In addition, some preliminary toxicity profile of sulforaphane in mice after intraperitoneal injection was evaluated. The LD50 value of sulforaphane in mice was estimated at 212.67mg/kg, while the TD50 value - at 191.58mg/kg. In seizure tests, sulforaphane at the highest dose tested (200mg/kg) significantly decreased the thresholds for the onset of the first myoclonic twitch and generalized clonic seizure in the iv PTZ test as well as the threshold for the 6Hz-induced psychomotor seizure. At doses of 10-200mg/kg, sulforaphane did not affect the threshold for the iv PTZ-induced forelimb tonus or the threshold for maximal electroshock-induced hindlimb tonus. Interestingly, sulforaphane (at 100mg/kg) potentiated the anticonvulsant efficacy of carbamazepine in the maximal electroshock seizure test. This interaction could have been pharmacokinetic in nature, as sulforaphane increased concentrations of carbamazepine in both serum and brain tissue. The toxicity study showed that high doses of sulforaphane produced marked sedation (at 150-300mg/kg), hypothermia (at 150-300mg/kg), impairment of motor coordination (at 200-300mg/kg), decrease in skeletal muscle strength (at 250-300mg/kg), and deaths (at 200-300mg/kg). Moreover, blood analysis showed leucopenia in mice injected with sulforaphane at 200mg

  9. Processes involved in assisted reproduction technologies significantly increase sperm DNA fragmentation and phosphatidylserine translocation.

    Science.gov (United States)

    Balasuriya, A; Serhal, P; Doshi, A; Harper, J C

    2014-03-01

    Sperm preparation techniques in assisted reproduction technologies (ART) are potential generators of exogenous stresses that cause additional DNA damage. DNA fragmentation tests, such as the sperm chromatin structure assay, involve freezing sperm samples in the absence of cryoprotectant. Thermal, oxidative stress (OS) and freezing are detrimental to sperm DNA fragmentation and phosphatidylserine (PS) translocation. The primary aim of this study was to subject mature sperm to environmental insults that normally occur during ART. We tested the hypotheses that OS, thermal stress and freeze-thawing caused sperm nuclear and membrane damage and that a positive correlation exists between PS translocation and DNA fragmentation. Sperm DNA integrity deteriorates in semen samples from men with advancing age and a sperm concentration of <15 m ml(-1) . The significant increase in sperm DNA fragmentation at 37 °C after merely 1 h is important clinically as semen liquefaction and short-term sperm storage in an ART cycle involve incubating samples at this temperature. Freezing without a cryoprotectant significantly increases the level of sperm nuclear damage, so it is important not to freeze neat semen prior to DNA fragmentation testing. This study highlights the importance of minimising the production of exogenous stresses during sperm preparation in ART. © 2012 Blackwell Verlag GmbH.

  10. Significant increase in ecosystem C can be achieved with sustainable forest management in subtropical plantation forests.

    Science.gov (United States)

    Wei, Xiaohua; Blanco, Juan A

    2014-01-01

    Subtropical planted forests are rapidly expanding. They are traditionally managed for intensive, short-term goals that often lead to long-term yield decline and reduced carbon sequestration capacity. Here we show how it is possible to increase and sustain carbon stored in subtropical forest plantations if management is switched towards more sustainable forestry. We first conducted a literature review to explore possible management factors that contribute to the potentials in ecosystem C in tropical and subtropical plantations. We found that broadleaves plantations have significantly higher ecosystem C than conifer plantations. In addition, ecosystem C increases with plantation age, and reaches a peak with intermediate stand densities of 1500-2500 trees ha⁻¹. We then used the FORECAST model to simulate the regional implications of switching from traditional to sustainable management regimes, using Chinese fir (Cunninghamia lanceolata) plantations in subtropical China as a study case. We randomly simulated 200 traditional short-rotation pure stands and 200 sustainably-managed mixed Chinese fir--Phoebe bournei plantations, for 120 years. Our results showed that mixed, sustainably-managed plantations have on average 67.5% more ecosystem C than traditional pure conifer plantations. If all pure plantations were gradually transformed into mixed plantations during the next 10 years, carbon stocks could rise in 2050 by 260.22 TgC in east-central China. Assuming similar differences for temperate and boreal plantations, if sustainable forestry practices were applied to all new forest plantation types in China, stored carbon could increase by 1,482.80 TgC in 2050. Such an increase would be equivalent to a yearly sequestration rate of 40.08 TgC yr⁻¹, offsetting 1.9% of China's annual emissions in 2010. More importantly, this C increase can be sustained in the long term through the maintenance of higher amounts of soil organic carbon and the production of timber products

  11. Significant increase in ecosystem C can be achieved with sustainable forest management in subtropical plantation forests.

    Directory of Open Access Journals (Sweden)

    Xiaohua Wei

    Full Text Available Subtropical planted forests are rapidly expanding. They are traditionally managed for intensive, short-term goals that often lead to long-term yield decline and reduced carbon sequestration capacity. Here we show how it is possible to increase and sustain carbon stored in subtropical forest plantations if management is switched towards more sustainable forestry. We first conducted a literature review to explore possible management factors that contribute to the potentials in ecosystem C in tropical and subtropical plantations. We found that broadleaves plantations have significantly higher ecosystem C than conifer plantations. In addition, ecosystem C increases with plantation age, and reaches a peak with intermediate stand densities of 1500-2500 trees ha⁻¹. We then used the FORECAST model to simulate the regional implications of switching from traditional to sustainable management regimes, using Chinese fir (Cunninghamia lanceolata plantations in subtropical China as a study case. We randomly simulated 200 traditional short-rotation pure stands and 200 sustainably-managed mixed Chinese fir--Phoebe bournei plantations, for 120 years. Our results showed that mixed, sustainably-managed plantations have on average 67.5% more ecosystem C than traditional pure conifer plantations. If all pure plantations were gradually transformed into mixed plantations during the next 10 years, carbon stocks could rise in 2050 by 260.22 TgC in east-central China. Assuming similar differences for temperate and boreal plantations, if sustainable forestry practices were applied to all new forest plantation types in China, stored carbon could increase by 1,482.80 TgC in 2050. Such an increase would be equivalent to a yearly sequestration rate of 40.08 TgC yr⁻¹, offsetting 1.9% of China's annual emissions in 2010. More importantly, this C increase can be sustained in the long term through the maintenance of higher amounts of soil organic carbon and the production

  12. Brief overdose education can significantly increase accurate recognition of opioid overdose among heroin users.

    Science.gov (United States)

    Jones, Jermaine D; Roux, Perrine; Stancliff, Sharon; Matthews, William; Comer, Sandra D

    2014-01-01

    In an effort to increase effective intervention following opioid overdose, the New York State Department of Health (NYSDOH) has implemented programs where bystanders are given brief education in recognizing the signs of opioid overdose and how to provide intervention, including the use of naloxone. The current study sought to assess the ability of NYSDOH training to increase accurate identification of opioid and non-opioid overdose, and naloxone use among heroin users. Eighty-four participants completed a test on overdose knowledge comprised of 16 putative overdose scenarios. Forty-four individuals completed the questionnaire immediately prior to and following standard overdose prevention training. A control group (n=40), who opted out of training, completed the questionnaire just once. Overdose training significantly increased participants' ability to accurately identify opioid overdose (pnaloxone administration was indicated (poverdose or non-overdose situations where naloxone should not be administered. The data indicate that overdose prevention training improves participants' knowledge of opioid overdose and naloxone use, but naloxone may be administered in some situations where it is not warranted. Training curriculum could be improved by teaching individuals to recognize symptoms of non-opioid drug over-intoxication. Copyright © 2013 Elsevier B.V. All rights reserved.

  13. Exposure to AT1 Receptor Autoantibodies during Pregnancy Increases Susceptibility of the Maternal Heart to Postpartum Ischemia-Reperfusion Injury in Rats

    Directory of Open Access Journals (Sweden)

    Hui-Ping Wang

    2014-06-01

    Full Text Available Epidemiological studies have demonstrated that women with a history of preeclampsia have a two-fold increased risk of developing cardiovascular diseases in later life. It is not known whether or not this risk is associated with angiotensin II receptor type 1 autoantibody (AT1-AA, an agonist acting via activation of AT1 receptor (AT1R, which is believed to be involved in the pathogenesis of preeclampsia. The objective of the present study was to confirm the hypothesis that AT1-AA exposure during pregnancy may change the maternal cardiac structure and increase the susceptibility of the postpartum heart to ischemia/reperfusion injury (IRI. In the present study, we first established a preeclampsia rat model by intravenous injection of AT1-AA extracted from the plasma of rats immunized with AT1R, observed the susceptibility of the postpartum maternal heart to IRI at 16 weeks postpartum using the Langendorff preparation, and examined the cardiac structure using light and transmission electron microscopy. The modeled animals presented with symptoms very similar to the clinical symptoms of human preeclampsia during pregnancy, including hypertension and proteinuria. The left ventricular weight (LVW and left ventricular mass index (LVMI in AT1-AA treatment group were significantly increased as compared with those of the control group (p < 0.01, although there was no significant difference in final weight between the two groups. AT1-AA acting on AT1R not only induced myocardial cell hypertrophy, mitochondrial swelling, cristae disorganization and collagen accumulation in the interstitium but affected the left ventricular (LV function and delayed recovery from IRI. In contrast, co-treatment with AT1-AA + losartan completely blocked AT1-AA-induced changes in cardiac structure and function. These data indicate that the presence of AT1-AA during pregnancy was strongly associated with the markers of LV geometry changes and remodeling, and increased the cardiac

  14. Pre-Existing Diseases of Patients Increase Susceptibility to Hypoxemia during Gastrointestinal Endoscopy

    Science.gov (United States)

    Yu, Changhong; Tian, Xia; Yang, Yi-Ran; Wang, Cheng; Pan, Yajuan

    2012-01-01

    Hypoxemia is the most common adverse event that happened during gastrointestinal endoscopy. To estimate risk of hypoxemia prior to endoscopy, American Society of Anesthesiology (ASA) classification scores were used as a major predictive factor. But the accuracy of ASA scores for predicting hypoxemia incidence was doubted here, considering that the classification system ignores much information about general health status and fitness of patient that may contribute to hypoxemia. In this retrospective review of clinical data collected prospectively, the data on 4904 procedures were analyzed. The Pearson’s chi-square test or the Fisher exact test was employed to analyze variance of categorical factors. Continuous variables were statistically evaluated using t-tests or Analysis of variance (ANOVA). As a result, only 245 (5.0%) of the enrolled 4904 patients were found to present hypoxemia during endoscopy. Multivariable logistic regressions revealed that independent risk factors for hypoxemia include high BMI (BMI 30 versus 20, Odd ratio: 1.52, 95% CI: 1.13–2.05; P = 0.0098), hypertension (Odd ratio: 2.28, 95% CI: 1.44–3.60; P = 0.0004), diabetes (Odd ratio: 2.37, 95% CI: 1.30–4.34; P = 0.005), gastrointestinal diseases (Odd ratio: 1.77, 95% CI: 1.21–2.60; P = 0.0033), heart diseases (Odd ratio: 1.97, 95% CI: 1.06–3.68; P = 0.0325) and the procedures that combined esophagogastroduodenoscopy (EGD) and colonoscopy (Odd ratio: 4.84, 95% CI: 1.61–15.51; P = 0.0292; EGD as reference). It is noteworthy that ASA classification scores were not included as an independent predictive factor, and susceptibility of youth to hypoxemia during endoscopy was as high as old subjects. In conclusion, some certain pre-existing diseases of patients were newly identified as independent risk factors for hypoxemia during GI endoscopy. High ASA scores are a confounding predictive factor of pre-existing diseases. We thus recommend that youth (≤18 yrs), obese

  15. Application of Bioorganic Fertilizer Significantly Increased Apple Yields and Shaped Bacterial Community Structure in Orchard Soil.

    Science.gov (United States)

    Wang, Lei; Li, Jing; Yang, Fang; E, Yaoyao; Raza, Waseem; Huang, Qiwei; Shen, Qirong

    2017-02-01

    and Rhodospirillaceae, were found to be the significantly increased by the BOF addition and the genus Lysobacter may identify members of this group effective in biological control-based plant disease management and the members of family Rhodospirillaceae had an important role in fixing molecular nitrogen. These results strengthen the understanding of responses to the BOF and possible interactions within bacterial communities in soil that can be associated with disease suppression and the accumulation of carbon and nitrogen. The increase of apple yields after the application of BOF might be attributed to the fact that the application of BOF increased SOM, and soil total nitrogen, and changed the bacterial community by enriching Rhodospirillaceae, Alphaprotreobateria, and Proteobacteria.

  16. Maternal geohelminth infections are associated with an increased susceptibility to geohelminth infection in children: a case-control study.

    Directory of Open Access Journals (Sweden)

    Raaj S Mehta

    Full Text Available Children of mothers infected with soil-transmitted helminths (STH may have an increased susceptibility to STH infection.We did a case-control study nested in a birth cohort in Ecuador. Data from 1,004 children aged 7 months to 3 years were analyzed. Cases were defined as children with Ascaris lumbricoides and/or Trichuris trichiura, controls without. Exposure was defined as maternal infection with A. lumbricoides and/or T. trichiura, detected during the third trimester of pregnancy. The analysis was restricted to households with a documented infection to control for infection risk. Children of mothers with STH infections had a greater risk of infection compared to children of uninfected mothers (adjusted OR 2.61, 95% CI: 1.88-3.63, p<0.001. This effect was particularly strong in children of mothers with both STH infections (adjusted OR: 5.91, 95% CI: 3.55-9.81, p<0.001. Newborns of infected mothers had greater levels of plasma IL-10 than those of uninfected mothers (p=0.033, and there was evidence that cord blood IL-10 was increased among newborns who became infected later in childhood (p=0.060.Our data suggest that maternal STH infections increase susceptibility to infection during early childhood, an effect that was associated with elevated IL-10 in cord plasma.

  17. Medroxyprogesterone acetate and levonorgestrel increase genital mucosal permeability and enhance susceptibility to genital herpes simplex virus type 2 infection.

    Science.gov (United States)

    Quispe Calla, N E; Vicetti Miguel, R D; Boyaka, P N; Hall-Stoodley, L; Kaur, B; Trout, W; Pavelko, S D; Cherpes, T L

    2016-11-01

    Depot-medroxyprogesterone acetate (DMPA) is a hormonal contraceptive especially popular in areas with high prevalence of HIV and other sexually transmitted infections (STI). Although observational studies identify DMPA as an important STI risk factor, mechanisms underlying this connection are undefined. Levonorgestrel (LNG) is another progestin used for hormonal contraception, but its effect on STI susceptibility is much less explored. Using a mouse model of genital herpes simplex virus type 2 (HSV-2) infection, we herein found that DMPA and LNG similarly reduced genital expression of the desmosomal cadherin desmoglein-1α (DSG1α), enhanced access of inflammatory cells to genital tissue by increasing mucosal epithelial permeability, and increased susceptibility to viral infection. Additional studies with uninfected mice revealed that DMPA-mediated increases in mucosal permeability promoted tissue inflammation by facilitating endogenous vaginal microbiota invasion. Conversely, concomitant treatment of mice with DMPA and intravaginal estrogen restored mucosal barrier function and prevented HSV-2 infection. Evaluating ectocervical biopsy tissue from women before and 1 month after initiating DMPA remarkably revealed that inflammation and barrier protection were altered by treatment identically to changes seen in progestin-treated mice. Together, our work reveals DMPA and LNG diminish the genital mucosal barrier; a first-line defense against all STI, but may offer foundation for new contraceptive strategies less compromising of barrier protection.

  18. Deletion of the DNA Ligase IV Gene in Candida glabrata Significantly Increases Gene-Targeting Efficiency.

    Science.gov (United States)

    Cen, Yuke; Fiori, Alessandro; Van Dijck, Patrick

    2015-08-01

    Candida glabrata is reported as the second most prevalent human opportunistic fungal pathogen in the United States. Over the last decades, its incidence increased, whereas that of Candida albicans decreased slightly. One of the main reasons for this shift is attributed to the inherent tolerance of C. glabrata toward the commonly used azole antifungal drugs. Despite a close phylogenetic distance to Saccharomyces cerevisiae, homologous recombination works with poor efficiency in C. glabrata compared to baker's yeast, in fact limiting targeted genetic alterations of the pathogen's genome. It has been shown that nonhomologous DNA end joining is dominant over specific gene targeting in C. glabrata. To improve the homologous recombination efficiency, we have generated a strain in which the LIG4 gene has been deleted, which resulted in a significant increase in correct gene targeting. The very specific function of Lig4 in mediating nonhomologous end joining is the reason for the absence of clear side effects, some of which affect the ku80 mutant, another mutant with reduced nonhomologous end joining. We also generated a LIG4 reintegration cassette. Our results show that the lig4 mutant strain may be a valuable tool for the C. glabrata research community. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  19. Intrauterine growth retardation increases the susceptibility of pigs to high-fat diet-induced mitochondrial dysfunction in skeletal muscle.

    Directory of Open Access Journals (Sweden)

    Jingbo Liu

    Full Text Available It has been recognized that there is a relationship between prenatal growth restriction and the development of metabolic-related diseases in later life, a process involved in mitochondrial dysfunction. In addition, intrauterine growth retardation (IUGR increases the susceptibility of offspring to high-fat (HF diet-induced metabolic syndrome. Recent findings suggested that HF feeding decreased mitochondrial oxidative capacity and impaired mitochondrial function in skeletal muscle. Therefore, we hypothesized that the long-term consequences of IUGR on mitochondrial biogenesis and function make the offspring more susceptible to HF diet-induced mitochondrial dysfunction. Normal birth weight (NBW, and IUGR pigs were allotted to control or HF diet in a completely randomized design, individually. After 4 weeks of feeding, growth performance and molecular pathways related to mitochondrial function were determined. The results showed that IUGR decreased growth performance and plasma insulin concentrations. In offspring fed a HF diet, IUGR was associated with enhanced plasma leptin levels, increased concentrations of triglyceride and malondialdehyde (MDA, and reduced glycogen and ATP contents in skeletal muscle. High fat diet-fed IUGR offspring exhibited decreased activities of lactate dehydrogenase (LDH and glucose-6-phosphate dehydrogenase (G6PD. These alterations in metabolic traits of IUGR pigs were accompanied by impaired mitochondrial respiration function, reduced mitochondrial DNA (mtDNA contents, and down-regulated mRNA expression levels of genes responsible for mitochondrial biogenesis and function. In conclusion, our results suggest that IUGR make the offspring more susceptible to HF diet-induced mitochondrial dysfunction.

  20. Forkhead box C2 promoter variant c.-512C>T is associated with increased susceptibility to chronic venous diseases.

    Directory of Open Access Journals (Sweden)

    Sumi Surendran

    Full Text Available Chronic venous disease (CVD is one of the most prevalent yet underrated disorders worldwide. High heritability estimates of CVD indicate prominent genetic components in its etiology and pathology. Mutations in human forkhead box C2 (FoxC2 gene are strongly associated with valve failure in saphenous and deep veins of lower extremities. We explored the association of genetic variants of FoxC2 as well as FoxC2 mRNA and protein expression levels with CVD of lower limbs. We systematically sequenced the single coding exon, 5' and 3' flanking regions of FoxC2 gene in 754 study subjects which includes 382 patients with CVD and 372 healthy subjects. Four novel and three reported polymorphisms were identified in our cohort. Three variants in 5' flanking region and one in 3' flanking region of FoxC2 gene were significantly associated with CVD risk. FoxC2 mRNA in vein tissues from 22 patients was 4±1.42 fold increased compared to saphenous veins from 20 normal subjects (pT (rs34221221: C>T variant which is located in the FoxC2 putative promoter region was further analyzed. Functional analysis of c.-512C>T revealed increased mRNA and protein expression in patients with homozygous TT genotype compared to heterozygous CT and wild CC genotypes. Luciferase assay indicated higher transcriptional activity of mutant compared to wild genotype of this variant. These findings suggested that c.-512C>T variant of FoxC2 was strongly associated with susceptibility to CVD and also that this variant resulted in FoxC2 overexpression. To obtain a mechanistic insight into the role of upregulated FoxC2 in varicosities, we overexpressed FoxC2 in venous endothelial cells and observed elevated expression of arterial markers Dll4 and Hey2 and downregulation of venous marker COUP-TFII. Our study indicates altered FoxC2-Notch signaling in saphenous vein wall remodeling in patients with varicose veins.

  1. Serological evidence of increased susceptibility to varicella-zoster virus reactivation or reinfection in natalizumab-treated patients with multiple sclerosis.

    Science.gov (United States)

    Kohlmann, Rebekka; Salmen, Anke; Chan, Andrew; Knabbe, Cornelius; Diekmann, Jürgen; Brockmeyer, Norbert; Skaletz-Rorowski, Adriane; Michalik, Claudia; Gold, Ralf; Überla, Klaus

    2015-12-01

    Serious adverse drug reactions of disease-modifying drugs in multiple sclerosis (MS) therapy may include enhanced susceptibility to reactivation of neurotropic herpes viruses like varicella-zoster virus (VZV) and the John Cunningham (JC) polyomavirus. Because symptomatic reactivation of these viruses are rare events, we determined the incidence of rises in anti-VZV IgG antibody levels as a potential marker for enhanced susceptibility to subclinical and symptomatic reactivation of neurotropic viruses. Anti-VZV IgG levels were measured in paired serum samples taken 6-8 months apart from natalizumab-treated MS patients, healthy blood donors and human immunodeficiency virus (HIV) infected patients. The incidence of significant rises in anti-VZV IgG levels in natalizumab-treated MS patients was 4.26 per 100 person-years, which was significantly higher than in healthy blood donors. Retrospective evaluation of the available medical records of patients with rises of anti-VZV IgG levels did not reveal herpes zoster (i.e. shingles) manifestations. The increased incidence of significant rises of anti-VZV IgG levels in natalizumab-treated MS patients might indicate an association of natalizumab treatment of MS with an elevated risk of a subclinical VZV reactivation and/or reinfection events. Whether this is predictive of an increased risk of herpes zoster or even symptomatic reactivation of other neurotropic viruses remains to be determined in larger prospective studies. © The Author(s), 2015.

  2. A 5-year Survey Reveals Increased Susceptibility to Glycopeptides for Methicillin-Resistant Staphylococcus aureus Isolates from Staphylococcus aureus Bacteremia Patients in a Chinese Burn Center

    Directory of Open Access Journals (Sweden)

    Bei Jiang

    2017-12-01

    Full Text Available Methicillin-resistant Staphylococcus aureus (MRSA infections are prevalent in burn wards, and are especially serious in S. aureus bacteremia (SAB patients. Glycopeptides and daptomycin are effective against MRSA infections, but MIC creeps can reduce their efficacy. Our object was to perform a molecular epidemiological investigation of S. aureus isolates in our burn center and to evaluate MICs for antimicrobials against SAB-associated MRSA isolates. A total of 259 S. aureus isolates, obtained from August 2011 to July 2016, were used in this study. Multiple molecular typing was used for molecular epidemiological analysis. E-tests were used to determine MICs of vancomycin, teicoplanin, and daptomycin for SAB-associated MRSA isolates. MIC values were stratified by collection date or source and compared. Spearman's test was used to analyze MICs correlations amongst tested antimicrobials. ST239-MRSA-III-t030-agrI clone was found to be dominant in both SAB and non-SAB patients, and significantly more in SAB patients (P < 0.0001. SAB-MRSA isolates exhibited decreased MICs for vancomycin, teicoplanin, and daptomycin during the 5-year period. Compared to those isolated from catheters or wounds, SAB-MRSA isolates from the bloodstream were less susceptible to vancomycin and daptomycin, but more susceptible to teicoplanin. MICs Correlation was found only between vancomycin and daptomycin in MRSA isolates from the bloodstream (rho = 0.250, P = 0.024. In conclusion, our results suggest that MRSA infections are still serious problems in burn centers. In contrast to most other studies, we observed increased susceptibility to glycopeptides and daptomycin against SAB-associated MRSA in our center from 2011 to 2016, suggesting the use of glycopeptides does not lead to MIC creeps. Isolates from different sites of the body may exhibit different levels of susceptibility and change trend over time for different antimicrobials, antimicrobials selection for MRSA

  3. Glutathione S-Transferase P1 (GSTP1 gene polymorphism increases age-related susceptibility to hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Kuo Wu-Hsien

    2010-03-01

    Full Text Available Abstract Background Hepatocellular carcinoma (HCC is one of the most frequent malignant neoplasms in the world. Genetic polymorphism has been reported to be a factor increasing the risk of HCC. Phase II enzymes such as glutathione s-transferases (GSTP1, GSTA1 play important roles in protecting cells against damage induced by carcinogens. The aim of this study was to estimate the relationship of the GSTP1 and GSTA1 gene polymorphisms to HCC risk and clinico-pathological status. Methods Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP was used to measure GSTP1 (A→G and GSTA1 (C→T gene polymorphisms in 386 healthy controls and 177 patients with HCC. Results Neither gene polymorphism was associated with the clinico-pathological status of HCC and serum expression of liver-related clinico-pathological markers. No association between the GSTA1 gene polymorphism and HCC susceptibility was found. However, in the younger group, aged ≤ 57 years, individuals with AG or GG alleles of GSTP1 had a 2.18-fold (95%CI = 1.09-4.36; p = 0.02 and 5.64-fold (95%CI = 1.02-31.18; p = 0.04 risk, respectively, of developing HCC compared to individuals with AA alleles, after adjusting for other confounders. Conclusion AG and GG alleles of GSTP1 gene polymorphisms may be considered as factors increasing the susceptibility to and risk of HCC in Taiwanese aged ≤ 57 years.

  4. Upregulated HSP27 in human breast cancer cells reduces Herceptin susceptibility by increasing Her2 protein stability

    Directory of Open Access Journals (Sweden)

    Kong Sun-Young

    2008-10-01

    Full Text Available Abstract Background Elucidating the molecular mechanisms by which tumors become resistant to Herceptin is critical for the treatment of Her2-overexpressed metastatic breast cancer. Methods To further understand Herceptin resistance mechanisms at the molecular level, we used comparative proteome approaches to analyze two human breast cancer cell lines; Her2-positive SK-BR-3 cells and its Herceptin-resistant SK-BR-3 (SK-BR-3 HR cells. Results Heat-shock protein 27 (HSP27 expression was shown to be upregulated in SK-BR-3 HR cells. Suppression of HSP27 by specific siRNA transfection increased the susceptibility of SK-BR-3 HR cells to Herceptin. In the presence of Herceptin, Her2 was downregulated in both cell lines. However, Her2 expression was reduced by a greater amount in SK-BR-3 parent cells than in SK-BR-3 HR cells. Interestingly, co-immunoprecipitation analysis showed that HSP27 can bind to Her2. In the absence of Herceptin, HSP27 expression is suppressed and Her2 expression is reduced, indicating that downregulation of Her2 by Herceptin can be obstructed by the formation of a Her2-HSP27 complex. Conclusion Our present study demonstrates that upregulated HSP27 in human breast cancer cells can reduce Herceptin susceptibility by increasing Her2 protein stability.

  5. Defense against dermal exposures is only skin deep: significantly increased penetration through slightly damaged skin.

    Science.gov (United States)

    Nielsen, Jesper Bo; Nielsen, Flemming; Sørensen, Jens Ahm

    2007-11-01

    The OECD guideline for studies on percutaneous penetration to be used in hazard and risk evaluations prescribes experimental conditions with optimal barrier integrity of the skin, which in many occupational settings probably is not true. Thus, workers may have compromised skin due to chemical or mechanical damage, due to different medical conditions (eczema, dermatitis, skin irritation) or related to occupational scenarios involving prolonged wet work. The present study used the OECD guideline procedures to study the in vitro percutaneous penetration through human skin of a number of model substances (glyphosat, caffeine, benzoic acid, malathion) covering a range of solubilities. Further, we studied the extent to which a slightly damaged skin would change the rate, the amount absorbed during dermal exposure and the distribution of chemical deposition between epidermis and dermis. The present study demonstrates that a limited damage to the skin significantly increases the permeability coefficient (K (p)) as well as total percutaneous penetration of chemicals, and most significantly for those compounds that due to their physicochemical characteristics (the most hydrophilic as well as the most lipophilic) have low penetration rates through intact skin. The present experiment not only confirms the proportionality between lipophilicity and potential for percutaneous penetration, but also illustrates that at a certain degree of lipophilicity of a model compound, the different skin compartments become more attractive for temporary deposition of model compounds. Moreover, a clear change from epidermal deposition towards a dominating dermis deposition of chemicals temporarily deposited within the skin is seen following damage to the skin barrier. Thus, the distribution of chemicals within the skin compartments is affected by the physicochemical characteristics of the chemicals as well as by the integrity of the skin. This observation may have implications when evaluating

  6. Improved bowel preparation increases polyp detection and unmasks significant polyp miss rate

    Science.gov (United States)

    Papanikolaou, Ioannis S; Sioulas, Athanasios D; Magdalinos, Nektarios; Beintaris, Iosif; Lazaridis, Lazaros-Dimitrios; Polymeros, Dimitrios; Malli, Chrysoula; Dimitriadis, George D; Triantafyllou, Konstantinos

    2015-01-01

    AIM: To retrospectively compare previous-day vs split-dose preparation in terms of bowel cleanliness and polyp detection in patients referred for polypectomy. METHODS: Fifty patients underwent two colonoscopies: one diagnostic in a private clinic and a second for polypectomy in a University Hospital. The latter procedures were performed within 12 wk of the index ones. Examinations were accomplished by two experienced endoscopists, different in each facility. Twenty-seven patients underwent screening/surveillance colonoscopy, while the rest were symptomatic. Previous day bowel preparation was utilized initially and split-dose for polypectomy. Colon cleansing was evaluated using the Aronchick scale. We measured the number of detected polyps, and the polyp miss rates per-polyp. RESULTS: Excellent/good preparation was reported in 38 cases with previous-day preparation (76%) vs 46 with split-dose (92%), respectively (P = 0.03). One hundred and twenty-six polyps were detected initially and 169 subsequently (P < 0.0001); 88 vs 126 polyps were diminutive (P < 0.0001), 25 vs 29 small (P = 0.048) and 13 vs 14 equal or larger than 10 mm. The miss rates for total, diminutive, small and large polyps were 25.4%, 30.1%, 13.7% and 6.6%, respectively. Multivariate analysis revealed that split-dose preparation was significantly associated (OR, P) with increased number of polyps detected overall (0.869, P < 0.001), in the right (0.418, P = 0.008) and in the left colon (0.452, P = 0.02). CONCLUSION: Split-dose preparation improved colon cleansing, enhanced polyp detection and unmasked significant polyp miss rates. PMID:26488024

  7. Revisiting the agentic shift : Weakening personal control increases susceptibility to social influence

    NARCIS (Netherlands)

    Fennis, B.M.; Aarts, H.

    2012-01-01

    What happens when people experience a reduced sense of personal control? Among the various strategies to defend against a perception of randomness, people may show an increased acceptance of external sources of control. Indeed, in one of the most classic studies in social psychology, Stanley Milgram

  8. Myriocin Significantly Increases the Mortality of a Non-Mammalian Model Host during Candida Pathogenesis

    Science.gov (United States)

    de Melo, Nadja Rodrigues; Abdrahman, Ahmed; Greig, Carolyn; Mukherjee, Krishnendu; Thornton, Catherine; Ratcliffe, Norman A.; Vilcinskas, Andreas; Butt, Tariq M.

    2013-01-01

    Candida albicans is a major human pathogen whose treatment is challenging due to antifungal drug toxicity, drug resistance and paucity of antifungal agents available. Myrocin (MYR) inhibits sphingosine synthesis, a precursor of sphingolipids, an important cell membrane and signaling molecule component. MYR also has dual immune suppressive and antifungal properties, potentially modulating mammalian immunity and simultaneously reducing fungal infection risk. Wax moth (Galleria mellonella) larvae, alternatives to mice, were used to establish if MYR suppressed insect immunity and increased survival of C. albicans-infected insects. MYR effects were studied in vivo and in vitro, and compared alone and combined with those of approved antifungal drugs, fluconazole (FLC) and amphotericin B (AMPH). Insect immune defenses failed to inhibit C. albicans with high mortalities. In insects pretreated with the drug followed by C. albicans inoculation, MYR+C. albicans significantly increased mortality to 93% from 67% with C. albicans alone 48 h post-infection whilst AMPH+C. albicans and FLC+C. albicans only showed 26% and 0% mortalities, respectively. MYR combinations with other antifungal drugs in vivo also enhanced larval mortalities, contrasting the synergistic antifungal effect of the MYR+AMPH combination in vitro. MYR treatment influenced immunity and stress management gene expression during C. albicans pathogenesis, modulating transcripts putatively associated with signal transduction/regulation of cytokines, I-kappaB kinase/NF-kappaB cascade, G-protein coupled receptor and inflammation. In contrast, all stress management gene expression was down-regulated in FLC and AMPH pretreated C. albicans -infected insects. Results are discussed with their implications for clinical use of MYR to treat sphingolipid-associated disorders. PMID:24260135

  9. Myriocin significantly increases the mortality of a non-mammalian model host during Candida pathogenesis.

    Directory of Open Access Journals (Sweden)

    Nadja Rodrigues de Melo

    Full Text Available Candida albicans is a major human pathogen whose treatment is challenging due to antifungal drug toxicity, drug resistance and paucity of antifungal agents available. Myrocin (MYR inhibits sphingosine synthesis, a precursor of sphingolipids, an important cell membrane and signaling molecule component. MYR also has dual immune suppressive and antifungal properties, potentially modulating mammalian immunity and simultaneously reducing fungal infection risk. Wax moth (Galleria mellonella larvae, alternatives to mice, were used to establish if MYR suppressed insect immunity and increased survival of C. albicans-infected insects. MYR effects were studied in vivo and in vitro, and compared alone and combined with those of approved antifungal drugs, fluconazole (FLC and amphotericin B (AMPH. Insect immune defenses failed to inhibit C. albicans with high mortalities. In insects pretreated with the drug followed by C. albicans inoculation, MYR+C. albicans significantly increased mortality to 93% from 67% with C. albicans alone 48 h post-infection whilst AMPH+C. albicans and FLC+C. albicans only showed 26% and 0% mortalities, respectively. MYR combinations with other antifungal drugs in vivo also enhanced larval mortalities, contrasting the synergistic antifungal effect of the MYR+AMPH combination in vitro. MYR treatment influenced immunity and stress management gene expression during C. albicans pathogenesis, modulating transcripts putatively associated with signal transduction/regulation of cytokines, I-kappaB kinase/NF-kappaB cascade, G-protein coupled receptor and inflammation. In contrast, all stress management gene expression was down-regulated in FLC and AMPH pretreated C. albicans-infected insects. Results are discussed with their implications for clinical use of MYR to treat sphingolipid-associated disorders.

  10. Effect of sludge retention on UF membrane fouling: The significance of sludge crystallization and EPS increase.

    Science.gov (United States)

    Yu, Wenzheng; Graham, Nigel; Yang, Yunjia; Zhou, Zhiqi; Campos, Luiza C

    2015-10-15

    This paper concerns a previously unreported mechanism of membrane ultrafiltration (UF) fouling when a UF process with coagulation pre-treatment is used in drinking water treatment. The significance of settled coagulant solids (sludge) with different age within the membrane tank on UF fouling has been investigated at laboratory-scale, using model micro-polluted surface water. The process of floc crystallization and increasing bacterial EPS with solids (sludge) retention time may be detrimental to UF operation by causing an increased rate of membrane fouling. In this study the performance of two alum pre-treated hollow-fibre UF units, operated in parallel but with different settled sludge retention times (1 and 7 days), was compared. The results showed that over 34 days of operation the extent of reversible and irreversible fouling was much greater for the 7-day solids retention time. This was attributed to the greater extent of bacterial activity and the presence of Al-nanoparticles, arising from sludge crystallization, at the longer retention time. In particular, greater quantities of organic matter, particularly EPS (proteins and polysaccharides), were found in the UF cake layer and pores for the 7-day retention time. The addition of chlorine later in the membrane run substantially reduced the rate of membrane fouling for both sludge retention times, and this corresponded to reduced quantities of organic substances, including EPS, in the cake layer and pores of both membranes. The results suggest that bacterial activity (and EPS production) is more important than the production of Al-nanoparticles from solids crystallization in causing membrane fouling. However, it is likely that both phenomena are interactive and possibly synergistic. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Templated assembly of photoswitches significantly increases the energy-storage capacity of solar thermal fuels.

    Science.gov (United States)

    Kucharski, Timothy J; Ferralis, Nicola; Kolpak, Alexie M; Zheng, Jennie O; Nocera, Daniel G; Grossman, Jeffrey C

    2014-05-01

    Large-scale utilization of solar-energy resources will require considerable advances in energy-storage technologies to meet ever-increasing global energy demands. Other than liquid fuels, existing energy-storage materials do not provide the requisite combination of high energy density, high stability, easy handling, transportability and low cost. New hybrid solar thermal fuels, composed of photoswitchable molecules on rigid, low-mass nanostructures, transcend the physical limitations of molecular solar thermal fuels by introducing local sterically constrained environments in which interactions between chromophores can be tuned. We demonstrate this principle of a hybrid solar thermal fuel using azobenzene-functionalized carbon nanotubes. We show that, on composite bundling, the amount of energy stored per azobenzene more than doubles from 58 to 120 kJ mol(-1), and the material also maintains robust cyclability and stability. Our results demonstrate that solar thermal fuels composed of molecule-nanostructure hybrids can exhibit significantly enhanced energy-storage capabilities through the generation of template-enforced steric strain.

  12. Templated assembly of photoswitches significantly increases the energy-storage capacity of solar thermal fuels

    Science.gov (United States)

    Kucharski, Timothy J.; Ferralis, Nicola; Kolpak, Alexie M.; Zheng, Jennie O.; Nocera, Daniel G.; Grossman, Jeffrey C.

    2014-05-01

    Large-scale utilization of solar-energy resources will require considerable advances in energy-storage technologies to meet ever-increasing global energy demands. Other than liquid fuels, existing energy-storage materials do not provide the requisite combination of high energy density, high stability, easy handling, transportability and low cost. New hybrid solar thermal fuels, composed of photoswitchable molecules on rigid, low-mass nanostructures, transcend the physical limitations of molecular solar thermal fuels by introducing local sterically constrained environments in which interactions between chromophores can be tuned. We demonstrate this principle of a hybrid solar thermal fuel using azobenzene-functionalized carbon nanotubes. We show that, on composite bundling, the amount of energy stored per azobenzene more than doubles from 58 to 120 kJ mol-1, and the material also maintains robust cyclability and stability. Our results demonstrate that solar thermal fuels composed of molecule-nanostructure hybrids can exhibit significantly enhanced energy-storage capabilities through the generation of template-enforced steric strain.

  13. Increased Mortality in Diabetic Foot Ulcer Patients: The Significance of Ulcer Type.

    Science.gov (United States)

    Chammas, N K; Hill, R L R; Edmonds, M E

    2016-01-01

    Diabetic foot ulcer (DFU) patients have a greater than twofold increase in mortality compared with nonulcerated diabetic patients. We investigated (a) cause of death in DFU patients, (b) age at death, and (c) relationship between cause of death and ulcer type. This was an eleven-year retrospective study on DFU patients who attended King's College Hospital Foot Clinic and subsequently died. A control group of nonulcerated diabetic patients was matched for age and type of diabetes mellitus. The cause of death was identified from death certificates (DC) and postmortem (PM) examinations. There were 243 DFU patient deaths during this period. Ischaemic heart disease (IHD) was the major cause of death in 62.5% on PM compared to 45.7% on DC. Mean age at death from IHD on PM was 5 years lower in DFU patients compared to controls (68.2 ± 8.7 years versus 73.1 ± 8.0 years, P = 0.015). IHD as a cause of death at PM was significantly linked to neuropathic foot ulcers (OR 3.064, 95% CI 1.003-9.366, and P = 0.049). Conclusions. IHD is the major cause of premature mortality in DFU patients with the neuropathic foot ulcer patients being at a greater risk.

  14. RCAN1 Regulates Mitochondrial Function and Increases Susceptibility to Oxidative Stress in Mammalian Cells

    OpenAIRE

    Heshan Peiris; Daphne Dubach; Jessup, Claire F.; Petra Unterweger; Ravinarayan Raghupathi; Hakan Muyderman; Zanin, Mark P.; Kimberly Mackenzie; Pritchard, Melanie A.; Keating, Damien J.

    2014-01-01

    Mitochondria are the primary site of cellular energy generation and reactive oxygen species (ROS) accumulation. Elevated ROS levels are detrimental to normal cell function and have been linked to the pathogenesis of neurodegenerative disorders such as Down's syndrome (DS) and Alzheimer's disease (AD). RCAN1 is abundantly expressed in the brain and overexpressed in brain of DS and AD patients. Data from nonmammalian species indicates that increased RCAN1 expression results in altered mitochond...

  15. Crude oil impairs immune function and increases susceptibility to pathogenic bacteria in southern flounder

    OpenAIRE

    Bayha, Keith M.; Ortell, Natalie; Ryan, Caitlin N.; Griffitt, Kimberly J.; Krasnec, Michelle; Sena, Johnny; Ramaraj, Thiruvarangan; Takeshita, Ryan; Gregory D Mayer; Schilkey, Faye; Griffitt, Robert J.

    2017-01-01

    Exposure to crude oil or its individual constituents can have detrimental impacts on fish species, including impairment of the immune response. Increased observations of skin lesions in northern Gulf of Mexico fish during the 2010 Deepwater Horizon oil spill indicated the possibility of oil-induced immunocompromisation resulting in bacterial or viral infection. This study used a full factorial design of oil exposure and bacterial challenge to examine how oil exposure impairs southern flounder...

  16. Telling true from false: cannabis users show increased susceptibility to false memories

    OpenAIRE

    Riba, J; Valle, M.; Sampedro, F; Rodr?guez-Pujadas, A; Mart?nez-Horta, S; Kulisevsky, J; Rodr?guez-Fornells, A

    2015-01-01

    Previous studies on the neurocognitive impact of cannabis use have found working and declarative memory deficits that tend to normalize with abstinence. An unexplored aspect of cognitive function in chronic cannabis users is the ability to distinguish between veridical and illusory memories, a crucial aspect of reality monitoring that relies on adequate memory function and cognitive control. Using functional magnetic resonance imaging, we show that abstinent cannabis users have an increased s...

  17. Increased susceptibility of spinal muscular atrophy fibroblasts to camptothecin is p53-independent

    Directory of Open Access Journals (Sweden)

    Funanage Vicky L

    2009-05-01

    Full Text Available Abstract Background Deletion or mutation(s of the survival motor neuron 1 (SMN1 gene causes spinal muscular atrophy (SMA. The SMN protein is known to play a role in RNA metabolism, neurite outgrowth, and cell survival. Yet, it remains unclear how SMN deficiency causes selective motor neuron death and muscle atrophy seen in SMA. Previously, we have shown that skin fibroblasts from SMA patients are more sensitive to the DNA topoisomerase I inhibitor camptothecin, supporting a role for SMN in cell survival. Here, we examine the potential mechanism of camptothecin sensitivity in SMA fibroblasts. Results Camptothecin treatment reduced the DNA relaxation activity of DNA topoisomerase I in human fibroblasts. In contrast, kinase activity of DNA topoisomerase I was not affected by camptothecin, because levels of phosphorylated SR proteins were not decreased. Upon camptothecin treatment, levels of p53 were markedly increased. To determine if p53 plays a role in the increased sensitivity of SMA fibroblasts to camptothecin, we analyzed the sensitivity of SMA fibroblasts to another DNA topoisomerase I inhibitor, β-lapachone. This compound is known to induce death via a p53-independent pathway in several cancer cell lines. We found that β-lapachone did not induce p53 activation in human fibroblasts. In addition, SMA and control fibroblasts showed essentially identical sensitivity to this compound. By immunofluorescence staining, SMN and p53 co-localized in gems within the nucleus, and this co-localization was overall reduced in SMA fibroblasts. However, depletion of p53 by siRNA did not lessen the camptothecin sensitivity in SMA fibroblasts. Conclusion Even though p53 and SMN are associated, the increased sensitivity of SMA fibroblasts to camptothecin does not occur through a p53-dependent mechanism.

  18. Decreased NLRP3 inflammasome expression in aged lung may contribute to increased susceptibility to secondary Streptococcus pneumoniae infection.

    Science.gov (United States)

    Cho, Soo Jung; Plataki, Maria; Mitzel, Dana; Lowry, Gena; Rooney, Kristen; Stout-Delgado, Heather

    2017-12-07

    Post-viral pneumococcal pneumonia is a leading morbidity and mortality in older patients (≥65years of age). The goal of our current study is to understand the impact of chronological aging on innate immune responses to a secondary, post viral infection with Streptococcus pneumoniae, a causative agent of bacterial pneumonia. Using aged murine models of infection, our findings demonstrate increased morbidity and mortality in aged mice within 48h post-secondary S. pneumoniae infection. Increased susceptibility of aged mice was associated with decreased TLR1, TLR6, and TLR9 mRNA expression and diminished IL1β mRNA expression. Examination of NLRP3 inflammasome expression illustrated decreased NLRP3 mRNA expression and decreased IL1β production in aged lung in response to secondary S. pneumoniae infection. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Fluorescent lighting enhances chemically induced papilloma formation and increases susceptibility to tumor challenge in mice.

    Science.gov (United States)

    Wiskemann, A; Sturm, E; Klehr, N W

    1986-01-01

    To study whether fluorescent lighting at work might increase carcinogenesis, hairless mice were exposed to a bank of six 36 W standard fluorescent lamps (neutral-white) every workday for 8 h at an illuminance level of 1,000 lx. For comparison, other mice were exposed to UVB radiation or to simulated solar radiation. In experiment A the animals were irradiated for 6 weeks prior to the application of 7,12-dimethyl-benzanthracene once and--following an interval of 2 days--for 10 weeks after DMBA application. The number of blue nevi and papillomas was enhanced by exposure to all spectra 10 weeks after chemical tumor induction. In experiment B the animals were irradiated for 6 weeks prior to the transplantation of UV-induced fibrosarcoma cells from syngeneic mice into the dorsal and ventral skin. Within the following 4 months fibrosarcoma developed in the dorsal skin exposed to the fluorescent lighting and to the UVB radiation, as well as in the non-irradiated ventral skin of 10-20% of the mice. The results suggest that fluorescent lighting as used in certain work environments may increase carcinogenesis caused by other factors.

  20. Increased susceptibility to Yersinia enterocolitica Infection of Tff2 deficient mice.

    Science.gov (United States)

    Shah, Aftab A; Mihalj, Martina; Ratkay, Ivana; Lubka-Pathak, Maria; Balogh, Peter; Klingel, Karin; Bohn, Erwin; Blin, Nikolaus; Baus-Loncar, Mirela

    2012-01-01

    TFF2 is one of the members of the trefoil factor family, known for its role in protection of gastrointestinal epithelia upon injury; however, recent studies suggest that TFF2 could also play an important role in the immune system. In the present study Tff2 deficient and wild type mice were infected by Y. enterocolitica which resulted in a lethal outcome in all Tff2 deficient mice, but not in WT animals. Yersinia invaded Peyer's patches more efficiently as shown by high bacterial titers in the KO mice while wild type mice displayed lower titers and a visible bacterial accumulation in the intestine. Bacterial accumulation in Peyer's patches of Tff2 deficient mice was accompanied by increased recruitment of macrophages. While an increased level of MAC-1 positive cells was observed in the spleens of both Tff2 deficient and WT mice at third day post infection, bacterial dissemination to liver, lung and kidneys was observed only in Tff2 knock-out mice. Analysis of the cellular composition of spleen did not reveal any substantial alteration to WT animals, suggesting possible disregulation of hemopoietic cells involved in immune response to Y. enterocolitica. These new data indicate that Tff2 plays an important role in immune response by protecting the organism from consequences of infection and that Tff2 knock-out mice react adversely to bacterial infections, in this case specifically to Y. enterocolitica. Copyright © 2012 S. Karger AG, Basel.

  1. Ethanol and reactive species increase basal sequence heterogeneity of hepatitis C virus and produce variants with reduced susceptibility to antivirals.

    Directory of Open Access Journals (Sweden)

    Scott Seronello

    Full Text Available Hepatitis C virus (HCV exhibits a high level of genetic variability, and variants with reduced susceptibility to antivirals can occur even before treatment begins. In addition, alcohol decreases efficacy of antiviral therapy and increases sequence heterogeneity of HCV RNA but how ethanol affects HCV sequence is unknown. Ethanol metabolism and HCV infection increase the level of reactive species that can alter cell metabolism, modify signaling, and potentially act as mutagen to the viral RNA. Therefore, we investigated whether ethanol and reactive species affected the basal sequence variability of HCV RNA in hepatocytes. Human hepatoma cells supporting a continuous replication of genotype 1b HCV RNA (Con1, AJ242652 were exposed to ethanol, acetaldehyde, hydrogen peroxide, or L-buthionine-S,R-sulfoximine (BSO that decreases intracellular glutathione as seen in patients. Then, NS5A region was sequenced and compared with genotype 1b HCV sequences in the database. Ethanol and BSO elevated nucleotide and amino acid substitution rates of HCV RNA by 4-18 folds within 48 hrs which were accompanied by oxidative RNA damage. Iron chelator and glutathione ester decreased both RNA damage and mutation rates. Furthermore, infectious HCV and HCV core gene were sufficient to induce oxidative RNA damage even in the absence of ethanol or BSO. Interestingly, the dn/ds ratio and percentage of sites undergoing positive selection increased with ethanol and BSO, resulting in an increased detection of NS5A variants with reduced susceptibility to interferon alpha, cyclosporine, and ribavirin and others implicated in immune tolerance and modulation of viral replication. Therefore, alcohol is likely to synergize with virus-induced oxidative/nitrosative stress to modulate the basal mutation rate of HCV. Positive selection induced by alcohol and reactive species may contribute to antiviral resistance.

  2. Low dose chronic Schistosoma mansoni infection increases susceptibility to Mycobacterium bovis BCG infection in mice

    DEFF Research Database (Denmark)

    Elias, D; Akuffo, H; Thors, C

    2005-01-01

    The incidence of mycobacterial diseases is high and the efficacy of Bacillus Calmette Guerin (BCG) is low in most areas of the world where chronic worm infections are common. However, if and how concurrent worm infections could affect immunity to mycobacterial infections has not been elucidated....... In this study we investigated whether infection of mice with Schistosoma mansoni could affect the ability of the animals to control Mycobacterium bovis BCG infection and the immune response to mycobacterial antigens. BALB/c mice subclinically infected with S. mansoni were challenged with M. bovis BCG via...... the intravenous route. The ability of the animals to contain the replication of M. bovis BCG in their organs, lung pathology as well as the in vitro mycobacterial and worm antigen induced immune responses were evaluated. The results showed that S. mansoni coinfected mice had significantly higher levels of BCG...

  3. Polymyalgia rheumatica without significantly increased erythrocyte sedimentation rate. A more benign syndrome.

    Science.gov (United States)

    González-Gay, M A; Rodríguez-Valverde, V; Blanco, R; Fernández-Sueiro, J L; Armona, J; Figueroa, M; Martínez-Taboada, V M

    1997-02-10

    An erythrocyte sedimentation rate (ESR) of at least 40 mm/h is considered an important requisite for the diagnosis of polymyalgia rheumatica (PMR). However, the relative frequency and clinical features of PMR in patients without a significantly increased ESR are unclear. We performed a retrospective study of patients diagnosed as having PMR at the rheumatology divisions of 3 teaching hospitals. The diagnosis of PMR was established, regardless of the ESR, in 201 consecutive patients fulfilling the following criteria: (1) age 50 years or older, (2) severe proximal pain for more than 1 month in at least 2 of 3 areas: neck, shoulder, and/or pelvic girdles, and (3) rapid resolution of the syndrome while taking low-dose prednisone. Patients with giant cell arteritis were previously excluded from the study. The frequency and clinical features of patients with PMR and an ESR lower than 40 mm/h were analyzed. A comparative study between these patients and those with high ESRs was performed. An ESR lower than 40 mm/h was found in 41 patients (20.4%). These patients were younger (P = .02), were more frequently men (P = .006), and experienced a lower frequency of fever (P = .003) and weight loss (P = .07). Furthermore, these patients were characterized by an absence of anemia (P = .002) and a lower frequency of abnormal protein electrophoresis results (P fever, weight loss, and laboratory test result abnormalities, but it was unrelated to the duration of the illness prior to diagnosis. It is not uncommon to find a patient with PMR with an ESR lower than 40 mm/h. This syndrome is more frequent in men and it is clinically less severe than the classic form of PMR. Its recognition will allow these patients to benefit from an effective treatment with low-dose corticosteroids.

  4. Is an Early Age at Illness Onset in Schizophrenia Associated With Increased Genetic Susceptibility?

    DEFF Research Database (Denmark)

    Hilker, Rikke Warming; Helenius, Dorte; Fagerlund, Birgitte

    2017-01-01

    BACKGROUND: Early age at illness onset has been viewed as an important liability marker for schizophrenia, which may be associated with an increased genetic vulnerability. A twin approach can be valuable, because it allows for the investigation of specific illness markers in individuals...... with schizophrenia spectrum) and a subsample of N=448 (affected with schizophrenia). Survival analysis was applied to investigate the effect of age at illness onset. FINDINGS: We found that early age at illness onset compared to later onset in the first diagnosed twin can be considered a major risk factor...... for developing schizophrenia in the second twin. Additionally, we found that the stronger genetic component in MZ twins compared to DZ twins is manifested in the proximity of assigned diagnosis within pairs. DISCUSSION: Early onset schizophrenia could be linked to a more severe genetic predisposition, indicating...

  5. Neonicotinoid insecticides alter induced defenses and increase susceptibility to spider mites in distantly related crop plants.

    Directory of Open Access Journals (Sweden)

    Adrianna Szczepaniec

    Full Text Available Chemical suppression of arthropod herbivores is the most common approach to plant protection. Insecticides, however, can cause unintended, adverse consequences for non-target organisms. Previous studies focused on the effects of pesticides on target and non-target pests, predatory arthropods, and concomitant ecological disruptions. Little research, however, has focused on the direct effects of insecticides on plants. Here we demonstrate that applications of neonicotinoid insecticides, one of the most important insecticide classes worldwide, suppress expression of important plant defense genes, alter levels of phytohormones involved in plant defense, and decrease plant resistance to unsusceptible herbivores, spider mites Tetranychus urticae (Acari: Tetranychidae, in multiple, distantly related crop plants.Using cotton (Gossypium hirsutum, corn (Zea mays and tomato (Solanum lycopersicum plants, we show that transcription of phenylalanine ammonia lyase, coenzyme A ligase, trypsin protease inhibitor and chitinase are suppressed and concentrations of the phytohormone OPDA and salicylic acid were altered by neonicotinoid insecticides. Consequently, the population growth of spider mites increased from 30% to over 100% on neonicotinoid-treated plants in the greenhouse and by nearly 200% in the field experiment.Our findings are important because applications of neonicotinoid insecticides have been associated with outbreaks of spider mites in several unrelated plant species. More importantly, this is the first study to document insecticide-mediated disruption of plant defenses and link it to increased population growth of a non-target herbivore. This study adds to growing evidence that bioactive agrochemicals can have unanticipated ecological effects and suggests that the direct effects of insecticides on plant defenses should be considered when the ecological costs of insecticides are evaluated.

  6. Neonicotinoid insecticides alter induced defenses and increase susceptibility to spider mites in distantly related crop plants.

    Science.gov (United States)

    Szczepaniec, Adrianna; Raupp, Michael J; Parker, Roy D; Kerns, David; Eubanks, Micky D

    2013-01-01

    Chemical suppression of arthropod herbivores is the most common approach to plant protection. Insecticides, however, can cause unintended, adverse consequences for non-target organisms. Previous studies focused on the effects of pesticides on target and non-target pests, predatory arthropods, and concomitant ecological disruptions. Little research, however, has focused on the direct effects of insecticides on plants. Here we demonstrate that applications of neonicotinoid insecticides, one of the most important insecticide classes worldwide, suppress expression of important plant defense genes, alter levels of phytohormones involved in plant defense, and decrease plant resistance to unsusceptible herbivores, spider mites Tetranychus urticae (Acari: Tetranychidae), in multiple, distantly related crop plants. Using cotton (Gossypium hirsutum), corn (Zea mays) and tomato (Solanum lycopersicum) plants, we show that transcription of phenylalanine ammonia lyase, coenzyme A ligase, trypsin protease inhibitor and chitinase are suppressed and concentrations of the phytohormone OPDA and salicylic acid were altered by neonicotinoid insecticides. Consequently, the population growth of spider mites increased from 30% to over 100% on neonicotinoid-treated plants in the greenhouse and by nearly 200% in the field experiment. Our findings are important because applications of neonicotinoid insecticides have been associated with outbreaks of spider mites in several unrelated plant species. More importantly, this is the first study to document insecticide-mediated disruption of plant defenses and link it to increased population growth of a non-target herbivore. This study adds to growing evidence that bioactive agrochemicals can have unanticipated ecological effects and suggests that the direct effects of insecticides on plant defenses should be considered when the ecological costs of insecticides are evaluated.

  7. Increased susceptibility of post-weaning rats on high-fat diet to metabolic syndrome.

    Science.gov (United States)

    Cheng, Hong Sheng; Ton, So Ha; Phang, Sonia Chew Wen; Tan, Joash Ban Lee; Abdul Kadir, Khalid

    2017-11-01

    The present study aimed to examine the effects of the types of high-calorie diets (high-fat and high-fat-high-sucrose diets) and two different developmental stages (post-weaning and young adult) on the induction of metabolic syndrome. Male, post-weaning and adult (3- and 8-week old, respectively) Sprague Dawley rats were given control, high-fat (60% kcal), and high-fat-high-sucrose (60% kcal fat + 30% sucrose water) diets for eight weeks (n = 6 to 7 per group). Physical, biochemical, and transcriptional changes as well as liver histology were noted. Post-weaning rats had higher weight gain, abdominal fat mass, fasting glucose, high density lipoprotein cholesterol, faster hypertension onset, but lower circulating advanced glycation end products compared to adult rats. This is accompanied by upregulation of peroxisome proliferator-activated receptor (PPAR) α and γ in the liver and receptor for advanced glycation end products (RAGE) in the visceral adipose tissue. Post-weaning rats on high-fat diet manifested all phenotypes of metabolic syndrome and increased hepatic steatosis, which are linked to increased hepatic and adipocyte PPARγ expression. Adult rats on high-fat-high-sucrose diet merely became obese and hypertensive within the same treatment duration. Thus, it is more effective and less time-consuming to induce metabolic syndrome in male post-weaning rats with high-fat diet compared to young adult rats. As male rats were selectively included into the study, the results may not be generalisable to all post-weaning rats and further investigation on female rats is required.

  8. Prenatal ethanol exposure increases osteoarthritis susceptibility in female rat offspring by programming a low-functioning IGF-1 signaling pathway

    Science.gov (United States)

    Ni, Qubo; Tan, Yang; Zhang, Xianrong; Luo, Hanwen; Deng, Yu; Magdalou, Jacques; Chen, Liaobin; Wang, Hui

    2015-10-01

    Epidemiological evidence indicates that osteoarthritis (OA) and prenatal ethanol exposure (PEE) are both associated with low birth weight but possible causal interrelationships have not been investigated. To investigate the effects of PEE on the susceptibility to OA in adult rats that experienced intrauterine growth retardation (IUGR), and to explore potential intrauterine mechanisms, we established the rat model of IUGR by PEE and dexamethasone, and the female fetus and 24-week-old adult offspring subjected to strenuous running for 6 weeks were sacrificed. Knee joints were collected from fetuses and adult offspring for histochemistry, immunohistochemistry and qPCR assays. Histological analyses and the Mankin score revealed increased cartilage destruction and accelerated OA progression in adult offspring from the PEE group compared to the control group. Immunohistochemistry showed reduced expression of insulin-like growth factor-1 (IGF-1) signaling pathway components. Furthermore, fetuses in the PEE group experienced IUGR but exhibited a higher postnatal growth rate. The expression of many IGF-1 signaling components was downregulated, which coincided with reduced amounts of type II collagen in the epiphyseal cartilage of fetuses in the PEE group. These results suggest that PEE enhances the susceptibility to OA in female adult rat offspring by down-regulating IGF-1 signaling and retarding articular cartilage development.

  9. A trade off between mlo resistance to powdery mildew and increased susceptibility of barley to a newly important disease, Ramularia leaf spot.

    Science.gov (United States)

    McGrann, Graham R D; Stavrinides, Anna; Russell, Joanne; Corbitt, Margaret M; Booth, Allan; Chartrain, Laetitia; Thomas, William T B; Brown, James K M

    2014-03-01

    Ramularia leaf spot (RLS), caused by the fungus Ramularia collo-cygni, is a serious, recently emerged disease of barley in Europe and other temperate regions. This study investigated the trade off between strong resistance to powdery mildew conferred by mlo mutant alleles and increased susceptibility to RLS. In field trials and seedling tests, the presence of mlo alleles increased severity of RLS. Genetic analysis of a doubled-haploid population identified one quantitative trait locus for susceptibility to RLS, colocalizing with the mlo-11 allele for mildew resistance. The effect of mlo-11 on RLS severity was environmentally sensitive. Analysis of near-isogenic lines of different mlo mutations in various genetic backgrounds confirmed that mlo alleles increased RLS severity in seedlings and adult plants. For mlo resistance to mildew to be fully effective, the genes ROR1 and ROR2 are required. RLS symptoms were significantly reduced on mlo-5 ror double mutants but fungal DNA levels remained as high as in mlo-5 single mutants, implying that ror alleles modify the transition of the fungus from endophytism to necrotrophy. These results indicate that the widespread use of mlo resistance to control mildew may have inadvertently stimulated the emergence of RLS as a major disease of barley.

  10. Deficiency of mannose-binding lectin greatly increases susceptibility to postburn infection with Pseudomonas aeruignosa

    DEFF Research Database (Denmark)

    Møller-Kristensen, Mette; Ip, WK; Shi, L

    2006-01-01

    % total body surface area burn alone or s.c. infection with P. aeruginosa alone. However, when mice were burned then inoculated s.c. with P. aeruginosa at the burn site, all MBL null mice died by 42 h from septicemia, whereas only one-third of wild-type mice succumbed (p = 0.0005). This result indicates...... injury of the skin. This activity is followed by an inflammatory response that includes influx of phagocytes and serum factors, such as complement and mannose-binding lectin (MBL), which is a broad-spectrum pattern recognition molecule that plays a key role in innate immunity. A growing consensus from...... studies in humans and mice suggests that lack of MBL together with other comorbid factors predisposes the host to infection. In this study we examined whether MBL deficiency increases the risk of P. aeruginosa infection in a burned host. We found that both wild-type and MBL null mice were resistant to a 5...

  11. Biogenic acidification reduces sea urchin gonad growth and increases susceptibility of aquaculture to ocean acidification.

    Science.gov (United States)

    Mos, Benjamin; Byrne, Maria; Dworjanyn, Symon A

    2016-02-01

    Decreasing oceanic pH (ocean acidification) has emphasised the influence of carbonate chemistry on growth of calcifying marine organisms. However, calcifiers can also change carbonate chemistry of surrounding seawater through respiration and calcification, a potential limitation for aquaculture. This study examined how seawater exchange rate and stocking density of the sea urchin Tripneustes gratilla that were reproductively mature affected carbonate system parameters of their culture water, which in turn influenced growth, gonad production and gonad condition. Growth, relative spine length, gonad production and consumption rates were reduced by up to 67% by increased density (9-43 individuals.m(-2)) and reduced exchange rates (3.0-0.3 exchanges.hr(-1)), but survival and food conversion efficiency were unaffected. Analysis of the influence of seawater parameters indicated that reduced pH and calcite saturation state (ΩCa) were the primary factors limiting gonad production and growth. Uptake of bicarbonate and release of respiratory CO2 by T. gratilla changed the carbonate chemistry of surrounding water. Importantly total alkalinity (AT) was reduced, likely due to calcification by the urchins. Low AT limits the capacity of culture water to buffer against acidification. Direct management to counter biogenic acidification will be required to maintain productivity and reproductive output of marine calcifiers, especially as the ocean carbonate system is altered by climate driven ocean acidification. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Increased susceptibility of IDH2-deficient mice to dextran sodium sulfate-induced colitis

    Directory of Open Access Journals (Sweden)

    Hanvit Cha

    2017-10-01

    Full Text Available Inflammatory bowel disease (IBD is a group of chronic, relapsing, immunological, inflammatory disorders of the gastrointestinal tract including ulcerative colitis (UC and Crohn's disease (CD. It has been reported that UC, which is studied using a dextran sodium sulfate (DSS-induced colitis model, is associated with the production of reactive oxygen species (ROS and the apoptosis of intestine epithelial cells (IEC. Mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2 has been reported as an essential enzyme in the mitochondrial antioxidant system via generation of NADPH. Therefore, we evaluated the role of IDH2 in DSS-induced colitis using IDH2-deficient (IDH2-/- mice. We observed that DSS-induced colitis in IDH2-/- mice was more severe than that in wild-type IDH2+/+ mice. Our results also suggest that IDH2 deficiency exacerbates PUMA-mediated apoptosis, resulting from NF-κB activation regulated by histone deacetylase (HDAC activity. In addition, DSS-induced colitis is ameliorated by an antioxidant N-acetylcysteine (NAC through attenuation of oxidative stress, resulting from deficiency of the IDH2 gene. In conclusion, deficiency of IDH2 leads to increased mitochondrial ROS levels, which inhibits HDAC activity, and the activation of NF-κB via acetylation is enhanced by attenuated HDAC activity, which causes PUMA-mediated apoptosis of IEC in DSS-induced colitis. The present study supported the rationale for targeting IDH2 as an important cancer chemoprevention strategy, particularly in the prevention of colorectal cancer.

  13. Inactivation of MarR gene homologs increases susceptibility to antimicrobials in Bacteroides fragilis.

    Science.gov (United States)

    Silva, Clara Maria Guimarães; Silva, Déborah Nascimento Dos Santos; Costa, Scarlathe Bezerra da; Almeida, Juliana Soares de Sá; Boente, Renata Ferreira; Teixeira, Felipe Lopes; Domingues, Regina Maria Cavalcanti Pilotto; Lobo, Leandro Araujo

    Bacteroides fragilis is the strict anaerobic bacteria most commonly found in human infections, and has a high mortality rate. Among other virulence factors, the remarkable ability to acquire resistance to a variety of antimicrobial agents and to tolerate nanomolar concentrations of oxygen explains in part their success in causing infection and colonizing the mucosa. Much attention has been given to genes related to multiple drug resistance derived from plasmids, integrons or transposon, but such genes are also detected in chromosomal systems, like the mar (multiple antibiotic resistance) locus, that confer resistance to a range of drugs. Regulators like MarR, that control expression of the locus mar, also regulate resistance to organic solvents, disinfectants and oxygen reactive species are important players in these events. Strains derived from the parental strain 638R, with mutations in the genes hereby known as marRI (BF638R_3159) and marRII (BF638R_3706) were constructed by gene disruption using a suicide plasmid. Phenotypic response of the mutant strains to hydrogen peroxide, cell survival assay against exposure to oxygen, biofilm formation, resistance to bile salts and resistance to antibiotics was evaluated. The results showed that the mutant strains exhibit statistically significant differences in their response to oxygen stress, but no changes were observed in survival when exposed to bile salts. Biofilm formation was not affected by either gene disruption. Both mutant strains however, became more sensitive to multiple antimicrobial drugs tested. This indicates that as observed in other bacterial species, MarR are an important resistance mechanism in B. fragilis. Copyright © 2017 Sociedade Brasileira de Microbiologia. Published by Elsevier Editora Ltda. All rights reserved.

  14. PARP-1 and p53 Regulate the Increased Susceptibility to Oxidative Death of Lymphocytes from MCI and AD Patients.

    Science.gov (United States)

    Salech, Felipe; Ponce, Daniela P; SanMartín, Carol D; Rogers, Nicole K; Chacón, Carlos; Henríquez, Mauricio; Behrens, Maria I

    2017-01-01

    Mild cognitive impairment (MCI) is a clinically detectable initial stage of cognitive deterioration with a high conversion rate to dementia. There is increasing evidence that some of the cerebral alterations present in Alzheimer type dementia can be found in peripheral tissues. We have previously shown that lymphocytes from Alzheimer's disease (AD) patients have increased susceptibility to hydrogen peroxide (H2O2)-induced death that depends on dementia severity. We here investigated whether lymphocytes from MCI patients show increased vulnerability to death, and explored the involvement of Poly [ADP-ribose] polymerase (PARP-1) and p53 in the regulation of this process. Lymphocytes from 16 MCI and 10 AD patients, and 15 healthy controls (HCs) were submitted to increasing concentrations of H2O2 for 20 h. Cell death was determined by flow cytometry, in the presence or absence of PARP-1 inhibitors (3-aminobenzamide (3-ABA) or Nicotinamide (NAM)), or the p53 inhibitor (nutlin-3) or stabilizer (pifithrin-α). PARP-1 and p53 mRNA levels were determined by quantitative PCR (qPCR). Lymphocytes from MCI patients showed increased susceptibility to death, attaining intermediate values between AD and controls. PARP inhibitors -3-ABA and NAM- markedly protected from H2O2-induced death, making the difference between MCI and controls disappear, but not the difference between AD and controls. PARP-1 mRNA expression was increased in MCI lymphocytes. Modulation of p53 with Nutlin-3 or pifithrin-α did not modify the H2O2-induced death of lymphocytes from MCI or AD patients, but augmented the death in control lymphocytes attaining levels similar to MCI and AD. Accordingly, p53 mRNA expression was increased in AD and MCI lymphocytes compared to controls. In all, these results show that increased oxidative death is present in lymphocytes at the MCI stage. PARP-1 has a preponderant role, with complete death protection achieved with PARP inhibition in MCI lymphocytes, but not in AD

  15. Cooler temperatures destabilize RNA interference and increase susceptibility of disease vector mosquitoes to viral infection.

    Directory of Open Access Journals (Sweden)

    Zach N Adelman

    Full Text Available The impact of global climate change on the transmission dynamics of infectious diseases is the subject of extensive debate. The transmission of mosquito-borne viral diseases is particularly complex, with climatic variables directly affecting many parameters associated with the prevalence of disease vectors. While evidence shows that warmer temperatures often decrease the extrinsic incubation period of an arthropod-borne virus (arbovirus, exposure to cooler temperatures often predisposes disease vector mosquitoes to higher infection rates. RNA interference (RNAi pathways are essential to antiviral immunity in the mosquito; however, few experiments have explored the effects of temperature on the RNAi machinery.We utilized transgenic "sensor" strains of Aedes aegypti to examine the role of temperature on RNA silencing. These "sensor" strains express EGFP only when RNAi is inhibited; for example, after knockdown of the effector proteins Dicer-2 (DCR-2 or Argonaute-2 (AGO-2. We observed an increase in EGFP expression in transgenic sensor mosquitoes reared at 18°C as compared with 28°C. Changes in expression were dependent on the presence of an inverted repeat with homology to a portion of the EGFP sequence, as transgenic strains lacking this sequence, the double stranded RNA (dsRNA trigger for RNAi, showed no change in EGFP expression when reared at 18°C. Sequencing small RNAs in sensor mosquitoes reared at low temperature revealed normal processing of dsRNA substrates, suggesting the observed deficiency in RNAi occurs downstream of DCR-2. Rearing at cooler temperatures also predisposed mosquitoes to higher levels of infection with both chikungunya and yellow fever viruses.This data suggest that microclimates, such as those present in mosquito breeding sites, as well as more general climactic variables may influence the dynamics of mosquito-borne viral diseases by affecting the antiviral immunity of disease vectors.

  16. Brain pericytes from stress-susceptible pigs increase blood-brain barrier permeability in vitro

    Directory of Open Access Journals (Sweden)

    Vandenhaute Elodie

    2012-06-01

    Full Text Available Abstract Background The function of pericytes remains questionable but with improved cultured technique and the use of genetically modified animals, it has become increasingly clear that pericytes are an integral part of blood–brain barrier (BBB function, and the involvement of pericyte dysfunction in certain cerebrovascular diseases is now emerging. The porcine stress syndrome (PSS is the only confirmed, homologous model of malignant hyperthermia (MH in veterinary medicine. Affected animals can experience upon slaughter a range of symptoms, including skeletal muscle rigidity, metabolic acidosis, tachycardia and fever, similar to the human syndrome. Symptoms are due to an enhanced calcium release from intracellular stores. These conditions are associated with a point mutation in ryr1/hal gene, encoding the ryanodine receptor, a calcium channel. Important blood vessel wall muscle modifications have been described in PSS, but potential brain vessel changes have never been documented in this syndrome. Methods In the present work, histological and ultrastructural analyses of brain capillaries from wild type and ryr1 mutated pigs were conducted to investigate the potential impairment of pericytes, in this pathology. In addition, brain pericytes were isolated from the three porcine genotypes (wild-type NN pigs; Nn and nn pigs, bearing one or two (n mutant ryr1/hal alleles, respectively, and tested in vitro for their influence on the permeability of BBB endothelial monolayers. Results Enlarged perivascular spaces were observed in ryr1-mutant samples, corresponding to a partial or total detachment of the astrocytic endfeet. These spaces were electron lucent and sometimes filled with lipid deposits and swollen astrocytic feet. At the ultrastructural level, brain pericytes did not seem to be affected because they showed regular morphology and characteristics, so we aimed to check their ability to maintain BBB properties in vitro. Our results indicated

  17. Significant Historical and Projected Increases in Evaporative Demand in the United States

    Science.gov (United States)

    Ficklin, D. L.; Novick, K. A.

    2016-12-01

    Climate change will modify vapor pressure deficit (VPD) via increases in air temperature and changes in relative humidity. VPD is the difference between the water vapor the air can hold at saturation (es) and the actual amount of water vapor (ea) and is a critical determinant for the exchange of water vapor and CO2 between the land surface and the atmosphere. Over non-vegetated surfaces, increases in VPD will increase the evapotranspiration (ET) rate; however, over vegetated ecosystems, stomata close when VPD is high, modifying the rates of ET and reducing carbon uptake. This work assesses how VPD, es, ea, and their underlying climatic components (maximum and minimum air temperature, relative humidity) have been changing in the United States for the recent, observed past (1979-2013) and how these components may change in the future (2065-2099) using 18 downscaled General Circulation Models (GCMs). An increase in historic VPD was observed for all seasons, and was especially apparent in the southwestern United States. The increases in VPD are a result of directional or divergent changes in es and ea, where es is increasing for a large portion of the United States from increases in air temperature while ea is decreasing from decreases in relative humidity. GCM projections indicate similar, but stronger patterns into future. There is GCM agreement that VPD will increase compared to the historical time period due to temperature-driven increases in es that are not matched by concomitant increases in ea, reflecting a general pattern of declining relative humidity moving forward.

  18. Clinical significance of coryneform Gram-positive rods from blood identified by MALDI-TOF mass spectrometry and their susceptibility profiles - a retrospective chart review.

    Science.gov (United States)

    Mushtaq, Ammara; Chen, Derrick J; Strand, Gregory J; Dylla, Brenda L; Cole, Nicolynn C; Mandrekar, Jayawant; Patel, Robin

    2016-07-01

    With the advent of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), most Gram-positive rods (GPRs) are readily identified; however, their clinical relevance in blood cultures remains unclear. Herein, we assessed the clinical significance of GPRs isolated from blood and identified in the era of MALDI-TOF MS. A retrospective chart review of patients presenting to the Mayo Clinic, Rochester, MN, from January 1, 2013, to October 13, 2015, was performed. Any episode of a positive blood culture for a GPR was included. We assessed the number of bottles positive for a given isolate, time to positivity of blood cultures, patient age, medical history, interpretation of culture results by the healthcare team and whether infectious diseases consultation was obtained. We also evaluated the susceptibility profiles of a larger collection of GPRs tested in the clinical microbiology laboratory of the Mayo Clinic, Rochester, MN from January 1, 2013, to October 31, 2015. There were a total of 246 GPRs isolated from the blood of 181 patients during the study period. 56% (n = 101) were deemed contaminants by the healthcare team and were not treated; 33% (n = 59) were clinically determined to represent true bacteremia and were treated; and 8% (n = 14) were considered of uncertain significance, with patients prescribed treatment regardless. Patient characteristics associated with an isolate being treated on univariate analysis included younger age (P = 0.02), identification to the species level (P = 0.02), higher number of positive blood culture sets (P blood culture sets (P = 0.0005) and lower time to positivity (P = 0.03) were associated with an isolate being treated. 100, 83, 48 and 34% of GPRs were susceptible to vancomycin, meropenem, penicillin and ceftriaxone, respectively. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Additional evidence supports association of common genetic variants in VTI1A and ETFA with increased risk of glioma susceptibility.

    Science.gov (United States)

    Wang, Ning; Deng, Zhong; Wang, Maode; Li, Ruichun; Xu, Gaofeng; Bao, Gang

    2017-04-15

    VTI1A and ETFA were identified recently as susceptibility genes for non-glioblastoma (GBM) of glioma risk in European populations, but the genetic etiology and pathogenesis of glioma have not been fully elucidated. Here, we aimed to investigate whether common genetic variants in VTI1A and ETFA predispose Han Chinese individuals to glioma. The association of thirteen common tagging single nucleotide polymorphisms (SNPs) in VTI1A and ETFA genes with glioma were assessed in a hospital-based case-control study including 473 non-GBM of glioma patients and 1046 cancer-free controls. Two SNPs (rs11196067 in VTI1A and rs1801591 in ETFA) were found to be significantly associated with non-GBM of glioma risk (rs11196067, adjusted P=0.00018, adjusted odds ratio (OR)=1.37, 95% confidence interval (CI)=1.16-1.61; rs1801591, adjusted P=0.000022, adjusted OR=1.72, 95% CI=1.34-2.20). In further stratified analysis, they were both more pronounced in the adult subgroup. In haplotype-based analysis, two haplotypes were identified to be significant association with glioma. The haplotype "TGA" (P=0.002) in VTI1A and the haplotype "ACA" (Pglioma risk respectively, compared with corresponding non-carriers. In summary, our results indicate that genetic variants in VTI1A and ETFA may modify individual susceptibility to non-GBM of glioma in the Han Chinese population and support the role of the VTI1A and ETFA genes in the occurrence of glioma. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Increment of late sodium currents in the left atrial myocytes and its potential contribution to increased susceptibility of atrial fibrillation in castrated male mice.

    Science.gov (United States)

    Zhang, Yang; Wang, Hui-Min; Wang, Ying-Zhe; Zhang, Yi-Yuan; Jin, Xue-Xin; Zhao, Yue; Wang, Jin; Sun, Yi-Lin; Xue, Gen-Long; Li, Peng-Hui; Huang, Qi-He; Yang, Bao-Feng; Pan, Zhen-Wei

    2017-07-01

    The incidence of atrial fibrillation (AF) is correlated with decreased levels of testosterone in elderly men. Late sodium current may exert a role in AF pathogenesis. The purpose of this study was to explore the effect of testosterone deficiency on AF susceptibility and the therapeutic effect of late sodium current inhibitors in mice. Male ICR mice (5 weeks old) were castrated to establish a testosterone deficiency model. One month after castration, dihydrotestosterone 5 mg/kg was administered subcutaneously for 2 months. Serum total testosterone level was assessed by enzyme-linked immunosorbent assay. High-frequency electrical stimulation was used to induce atrial arrhythmias. Whole-cell patch-clamp technique was used to for single-cell electrophysiologic study. Serum dihydrotestosterone levels of castration mice declined significantly but recovered with administration of exogenous dihydrotestosterone. In comparison with sham mice, the number of AF episodes significantly increased by 13.5-fold, AF rate increased by 3.75-fold, and AF duration prolonged in castrated mice. Dihydrotestosterone administration alleviated the occurrence of AF. Action potential duration at both 50% and 90% repolarization were markedly increased in castrated mice compared to sham controls. The late sodium current was enhanced in castrated male mice. These alterations were alleviated by treatment with dihydrotestosterone. Systemic application of the INa-L inhibitors ranolazine, eleclazine, and GS967 inhibited the occurrence of AF in castrated mice. Testosterone deficiency contributed to the increased late sodium current, prolonged action potential repolarization, and increased susceptibility to AF. Blocking of late sodium current is beneficial against the occurrence of AF in castrated mice. Copyright © 2017. Published by Elsevier Inc.

  1. Mitochondrial vulnerability and increased susceptibility to nutrient-induced cytotoxicity in fibroblasts from leigh syndrome French canadian patients.

    Directory of Open Access Journals (Sweden)

    Yan Burelle

    Full Text Available Mutations in LRPPRC are responsible for the French Canadian variant of Leigh Syndrome (LSFC, a severe disorder characterized biochemically by a tissue-specific deficiency of cytochrome c oxidase (COX and clinically by the occurrence of severe and deadly acidotic crises. Factors that precipitate these crises remain unclear. To better understand the physiopathology and identify potential treatments, we performed a comprehensive analysis of mitochondrial function in LSFC and control fibroblasts. Furthermore, we have used this cell-based model to screen for conditions that promote premature cell death in LSFC cells and test the protective effect of ten interventions targeting well-defined aspects of mitochondrial function. We show that, despite maintaining normal ATP levels, LSFC fibroblasts present several mitochondrial functional abnormalities under normal baseline conditions, which likely impair their capacity to respond to stress. This includes mitochondrial network fragmentation, impaired oxidative phosphorylation capacity, lower membrane potential, increased sensitivity to Ca2+-induced permeability transition, but no changes in reactive oxygen species production. We also show that LSFC fibroblasts display enhanced susceptibility to cell death when exposed to palmitate, an effect that is potentiated by high lactate, while high glucose or acidosis alone or in combination were neutral. Furthermore, we demonstrate that compounds that are known to promote flux through the electron transport chain independent of phosphorylation (methylene blue, dinitrophenol, or modulate fatty acid (L-carnitine or Krebs cycle metabolism (propionate are protective, while antioxidants (idebenone, N-acetyl cysteine, resveratrol exacerbate palmitate plus lactate-induced cell death. Collectively, beyond highlighting multiple alterations in mitochondrial function and increased susceptibility to nutrient-induced cytotoxicity in LSFC fibroblasts, these results raise

  2. Presence of gingivitis and periodontitis significantly increases hospital charges in patients undergoing heart valve surgery.

    Science.gov (United States)

    Allareddy, Veerasathpurush; Elangovan, Satheesh; Rampa, Sankeerth; Shin, Kyungsup; Nalliah, Romesh P; Allareddy, Veerajalandhar

    2015-01-01

    To examine the prevalence and impact of gingivitis and periodontitis in patients having heart valve surgical procedures. Nationwide Inpatient Sample for the years 2004-2010 was used. All patients who had heart valve surgical procedures were selected. Prevalence of gingivitis/periodontitis was examined in these patients. Impact of gingivitis/periodontitis on hospital charges, length of stay, and infectious complications was examined. 596,190 patients had heart valve surgical procedures. Gingivitis/periodontitis was present in 0.2 percent. Outcomes included: median hospital charges ($175,418 with gingivitis/ periodontitis versus $149,353 without gingivitis/periodontitis) and median length of stay (14 days with gingivitis/periodontitis versus 8 days without gingivitis/periodontitis). After adjusting for the effects of patient- and hospital-level confounding factors, hospital charges and length of stay were significantly higher (p gingivitis/periodontitis compared to their counterparts. Further, patients with gingivitis/periodontitis had significantly higher odds for having bacterial infections (OR = 3.41, 95% CI = 2.33-4.98, p gingivitis/periodontitis. Presence of gingivitis and periodontitis is associated with higher risk for bacterial infections and significant hospital resource utilization.

  3. Transglutaminase 2 expression is significantly increased in cyclosporine-induced gingival overgrowth

    OpenAIRE

    Asioli, Sofia; Righi, Alberto; Cardone, Pietro; Aimetti, Mario; Maletta, Francesca; Coda, Renato; Carossa, Stefano; Navone, Roberto; Cassoni, Paola

    2011-01-01

    Cyclosporine A is a potent immunosuppressant used to prevent organ transplant rejection and treat various autoimmune diseases. However, cyclosporine A can also induce gingival overgrowth, which is characterized by increased extracellular matrix due to an altered balance between collagen synthesis and degradation. This study proposed to verify whether trans-glutaminase 2, an enzyme thought to be responsible for the assembly and remodelling of extracellular matrix, plays any role in the path...

  4. ABA Suppresses Botrytis cinerea Elicited NO Production in Tomato to Influence H2O2 Generation and Increase Host Susceptibility

    Science.gov (United States)

    Sivakumaran, Anushen; Akinyemi, Aderemi; Mandon, Julian; Cristescu, Simona M.; Hall, Michael A.; Harren, Frans J. M.; Mur, Luis A. J.

    2016-01-01

    Abscisic acid (ABA) production has emerged a susceptibility factor in plant-pathogen interactions. This work examined the interaction of ABA with nitric oxide (NO) in tomato following challenge with the ABA-synthesizing pathogen, Botrytis cinerea. Trace gas detection using a quantum cascade laser detected NO production within minutes of challenge with B. cinerea whilst photoacoustic laser detection detected ethylene production – an established mediator of defense against this pathogen – occurring after 6 h. Application of the NO generation inhibitor N-Nitro-L-arginine methyl ester (L-NAME) suppressed both NO and ethylene production and resistance against B. cinerea. The tomato mutant sitiens fails to accumulate ABA, shows increased resistance to B. cinerea and we noted exhibited elevated NO and ethylene production. Exogenous application of L-NAME or ABA reduced NO production in sitiens and reduced resistance to B. cinerea. Increased resistance to B. cinerea in sitiens have previously been linked to increased reactive oxygen species (ROS) generation but this was reduced in both L-NAME and ABA-treated sitiens. Taken together, our data suggests that ABA can decreases resistance to B. cinerea via reduction of NO production which also suppresses both ROS and ethylene production. PMID:27252724

  5. ABA suppresses Botrytis cinerea elicited NO production in tomato to influence H2O2 generation and increase host susceptibility

    Directory of Open Access Journals (Sweden)

    Anushen eSivakumaran

    2016-05-01

    Full Text Available Abscisic acid (ABA production has emerged a susceptibility factor in plant-pathogen interactions. This work examined the interaction of ABA with NO in tomato following challenge with the ABA-synthesising pathogen, Botrytis cinerea. Trace gas detection using a quantum cascade laser detected NO production within minutes of challenge with B. cinerea whilst photoacoustic laser detection detected ethylene production – an established mediator of defence against this pathogen - occurring after 6 h. Application of the NO generation inhibitor N-Nitro-L-arginine methyl ester (L-NAME suppressed both NO and ethylene production and resistance against B. cinerea. The tomato mutant sitiens fails to accumulate ABA (abscisic acid, shows increased resistance to B. cinerea and we noted exhibited elevated NO and ethylene production. Exogenous application of L-NAME or ABA reduced NO production in sitiens and reduced resistance to B. cinerea. Increased resistance to B. cinerea in sitiens have previously been linked to increased reactive oxygen species (ROS generation but this was reduced in both L-NAME and ABA treated sitiens. Taken together, our data suggests that ABA can decreases resistance to B. cinerea via reduction of NO production which also suppresses both ROS and ethylene production.

  6. ABA Suppresses Botrytis cinerea Elicited NO Production in Tomato to Influence H2O2 Generation and Increase Host Susceptibility.

    Science.gov (United States)

    Sivakumaran, Anushen; Akinyemi, Aderemi; Mandon, Julian; Cristescu, Simona M; Hall, Michael A; Harren, Frans J M; Mur, Luis A J

    2016-01-01

    Abscisic acid (ABA) production has emerged a susceptibility factor in plant-pathogen interactions. This work examined the interaction of ABA with nitric oxide (NO) in tomato following challenge with the ABA-synthesizing pathogen, Botrytis cinerea. Trace gas detection using a quantum cascade laser detected NO production within minutes of challenge with B. cinerea whilst photoacoustic laser detection detected ethylene production - an established mediator of defense against this pathogen - occurring after 6 h. Application of the NO generation inhibitor N-Nitro-L-arginine methyl ester (L-NAME) suppressed both NO and ethylene production and resistance against B. cinerea. The tomato mutant sitiens fails to accumulate ABA, shows increased resistance to B. cinerea and we noted exhibited elevated NO and ethylene production. Exogenous application of L-NAME or ABA reduced NO production in sitiens and reduced resistance to B. cinerea. Increased resistance to B. cinerea in sitiens have previously been linked to increased reactive oxygen species (ROS) generation but this was reduced in both L-NAME and ABA-treated sitiens. Taken together, our data suggests that ABA can decreases resistance to B. cinerea via reduction of NO production which also suppresses both ROS and ethylene production.

  7. CR1 exon variants are associated with lowered CR1 expression and increased susceptibility to SLE in a Plasmodium falciparum endemic population.

    Science.gov (United States)

    Panda, Aditya K; Ravindran, Balachandran; Das, Bidyut K

    2016-01-01

    Complement receptor 1 (CR1) plays an important role in immune complex clearance by opsonisation and possibly protects subjects from development of autoantibodies. Lower CR1 expression has been associated with susceptibility to systemic lupus erythematosus (SLE). In contrast, subjects displaying lower CR1 expression are protected against severe manifestations of falciparum malaria. This study is the first of its kind to investigate the association of CR1 variants with development of SLE in a P. falciparum endemic population from Odisha, India. CR1 polymorphisms (intron 27 (A>T), exon 22 (A>G) and exon 33 (G>C)) were typed by PCR and restriction length polymorphism in 297 cases of female patients with SLE and 300 age-matched and sex-matched healthy controls from malaria endemic areas in Odisha, India. CR1 expression on monocytes was quantified by flow cytometry. The homozygous mutants of CR1 exon 22 (GG) and exon 33 (GG) and their minor alleles were associated with susceptibility to SLE. Furthermore, patients with SLE who harboured the GG genotype of the exon 33 polymorphism had a 3.12-fold higher chance of developing lupus nephritis. CR1 exon (22 and 33) variants were associated with lowered CR1 expression on monocytes in patients with SLE and in healthy controls. Patients with lupus nephritis showed significantly diminished CR1 expression than those without renal involvement (p=0.01). The results of the present study demonstrate that common CR1 exon variants are associated with diminished CR1 expression on monocytes and increased susceptibility to development of SLE and lupus nephritis in a malaria endemic area.

  8. Significant yield increases from control of leaf diseases in maize - an overlooked problem?!

    DEFF Research Database (Denmark)

    Jørgensen, Lise Nistrup

    2012-01-01

    maize have often grown maize consecutively for several years. This leads to significant amounts of debris building up in the fields, which serves as an important source of inoculum for diseases when new crops are grown. In recent years, leaf diseases have caused production problems over several seasons....... Two major diseases have been identified: Eyespot (Kabatiella zeae) and Northern leaf blotch (Exserohilum turcicum). Other diseases, including Southern maize leaf blight or maydis leaf blight, caused by Bipolaris maydis, and Northern corn leaf spot, caused by Bipolaris zeicola, may potentially play...

  9. Investigation of potential non-HLA rheumatoid arthritis susceptibility loci in a European cohort increases the evidence for nine markers

    DEFF Research Database (Denmark)

    Plant, Darren; Flynn, Edward; Mbarek, Hamdi

    2010-01-01

    Genetic factors have a substantial role in determining development of rheumatoid arthritis (RA), and are likely to account for 50-60% of disease susceptibility. Genome-wide association studies have identified non-human leucocyte antigen RA susceptibility loci which associate with RA with low...

  10. Strong Selection Significantly Increases Epistatic Interactions in the Long-Term Evolution of a Protein.

    Directory of Open Access Journals (Sweden)

    Aditi Gupta

    2016-03-01

    Full Text Available Epistatic interactions between residues determine a protein's adaptability and shape its evolutionary trajectory. When a protein experiences a changed environment, it is under strong selection to find a peak in the new fitness landscape. It has been shown that strong selection increases epistatic interactions as well as the ruggedness of the fitness landscape, but little is known about how the epistatic interactions change under selection in the long-term evolution of a protein. Here we analyze the evolution of epistasis in the protease of the human immunodeficiency virus type 1 (HIV-1 using protease sequences collected for almost a decade from both treated and untreated patients, to understand how epistasis changes and how those changes impact the long-term evolvability of a protein. We use an information-theoretic proxy for epistasis that quantifies the co-variation between sites, and show that positive information is a necessary (but not sufficient condition that detects epistasis in most cases. We analyze the "fossils" of the evolutionary trajectories of the protein contained in the sequence data, and show that epistasis continues to enrich under strong selection, but not for proteins whose environment is unchanged. The increase in epistasis compensates for the information loss due to sequence variability brought about by treatment, and facilitates adaptation in the increasingly rugged fitness landscape of treatment. While epistasis is thought to enhance evolvability via valley-crossing early-on in adaptation, it can hinder adaptation later when the landscape has turned rugged. However, we find no evidence that the HIV-1 protease has reached its potential for evolution after 9 years of adapting to a drug environment that itself is constantly changing. We suggest that the mechanism of encoding new information into pairwise interactions is central to protein evolution not just in HIV-1 protease, but for any protein adapting to a changing

  11. Modern environmental health hazards: a public health issue of increasing significance in Africa.

    Science.gov (United States)

    Nweke, Onyemaechi C; Sanders, William H

    2009-06-01

    Traditional hazards such as poor sanitation currently account for most of Africa's environmentally related disease burden. However, with rapid development absent appropriate safeguards for environment and health, modern environmental health hazards (MEHHs) may emerge as critical contributors to the continent's disease burden. We review recent evidence of human exposure to and health effects from MEHHs, and their occurrence in environmental media and consumer products. Our purpose is to highlight the growing significance of these hazards as African countries experience urbanization, industrial growth, and development. We reviewed published epidemiologic, exposure, and environmental studies of chemical agents such as heavy metals and pesticides. The body of evidence demonstrates ongoing environmental releases of MEHHs and human exposures sometimes at toxicologically relevant levels. Several sources of MEHHs in environmental media have been identified, including natural resource mining and processing and automobile exhaust. Biomonitoring studies provided direct evidence of human exposure to metals such as mercury and lead and pesticides such as p,p'-dichlorodiphenyltrichloroethane (DDT) and organophosphates. Land and water resource pollution and industrial air toxics are areas of significant data gaps, notwithstanding the presence of several emitting sources. Unmitigated MEHH releases and human exposure have implications for Africa's disease burden. For Africans encumbered by conditions such as malnutrition that impair resilience to toxicologic challenges, the burden may be higher. A shift in public health policy toward accommodating the emerging diversity in Africa's environmental health issues is necessary to successfully alleviate the burden of avoidable ill health and premature death for all its communities now and in the future.

  12. Longer duration of asthma is significantly associated with increased RV/TLC ratio.

    Science.gov (United States)

    Tiwari, Anupama; Rahman, Kazi; Abejie, Belayneh; Jain, Vipul V; Vempilly, Jose Joseph

    2017-03-01

    Although FEV1/FVC ratio has been shown to be negatively associated with longer duration of asthma; an association between RV/TLC ratio and longer duration of asthma has not been explored. Patients with established asthma for more than a year and met inclusion and exclusion criteria were recruited. Data obtained by questionnaire after informed consent was obtained, Pulmonary function tests and laboratory results were collected through chart review. Correlation and multiple linear regressions were used to analyze the data. Among the 93 subjects, 61 were women. The mean age of patients was 58 ± 15 years, and the mean duration of asthma was 21 ± 18 years. The ethnic composition included: Caucasians 64%, Hispanics 28% and other groups 8%. The FEV1/FVC ratio was not significantly associated with duration of asthma (R2 = 0.15, p = 0.05). However, the RV/TLC ratio was significantly associated with duration of asthma (R2 = 0.46, p TLC ratio may be a better indicator than FEV1/FVC ratio to detect airway obstruction related to longer duration of asthma. Lung volume measurements should be done in addition to spirometry to detect changes related to airway obstruction in patients with longer duration of asthma. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Combining modularity, conservation, and interactions of proteins significantly increases precision and coverage of protein function prediction.

    Science.gov (United States)

    Jaeger, Samira; Sers, Christine T; Leser, Ulf

    2010-12-20

    While the number of newly sequenced genomes and genes is constantly increasing, elucidation of their function still is a laborious and time-consuming task. This has led to the development of a wide range of methods for predicting protein functions in silico. We report on a new method that predicts function based on a combination of information about protein interactions, orthology, and the conservation of protein networks in different species. We show that aggregation of these independent sources of evidence leads to a drastic increase in number and quality of predictions when compared to baselines and other methods reported in the literature. For instance, our method generates more than 12,000 novel protein functions for human with an estimated precision of ~76%, among which are 7,500 new functional annotations for 1,973 human proteins that previously had zero or only one function annotated. We also verified our predictions on a set of genes that play an important role in colorectal cancer (MLH1, PMS2, EPHB4 ) and could confirm more than 73% of them based on evidence in the literature. The combination of different methods into a single, comprehensive prediction method infers thousands of protein functions for every species included in the analysis at varying, yet always high levels of precision and very good coverage.

  14. Dietary phosphorus is associated with a significant increase in left ventricular mass

    Science.gov (United States)

    Yamamoto, Kalani T.; Robinson-Cohen, Cassianne; de Oliveira, Marcia C.; Kostina, Alina; Nettleton, Jennifer A.; Ix, Joachim H.; Nguyen, Ha; Eng, John; Lima, Joao A.C.; Siscovick, David; Weiss, Noel S.; Kestenbaum, Bryan

    2012-01-01

    Dietary phosphorus consumption has risen steadily in the United States. Oral phosphorus loading alters key regulatory hormones and impairs vascular endothelial function which may lead to an increase in left ventricular mass (LVM). We investigated the association of dietary phosphorus with LVM in 4,494 participants from the Multi-Ethnic Study of Atherosclerosis, a community-based study of individuals free of known cardiovascular disease. The intake of dietary phosphorus was estimated using a 120-item food frequency questionnaire and the LVM was measured using magnetic resonance imaging. Regression models were used to determine associations of estimated dietary phosphorus with LVM and left ventricular hypertrophy (LVH). Mean estimated dietary phosphorus intake was 1,167 mg/day in men and 1,017 mg/day in women. After adjustment for demographics, dietary sodium, total calories, lifestyle factors, comorbidities, and established LVH risk factors, each quintile increase in the estimated dietary phosphate intake was associated with an estimated 1.1 gram greater LVM. The highest gender-specific dietary phosphorus quintile was associated with an estimated 6.1 gram greater LVM compared to the lowest quintile. Higher dietary phosphorus intake was associated with greater odds of LVH among women, but not men. These associations require confirmation in other studies. PMID:23283134

  15. Up-regulation of TRPV1 in mononuclear cells of end-stage kidney disease patients increases susceptibility to N-arachidonoyl-dopamine (NADA)-induced cell death.

    Science.gov (United States)

    Saunders, Cassandra I; Fassett, Robert G; Geraghty, Dominic P

    2009-10-01

    Transient receptor potential vanilloid (TRPV) 1 channels function as sensors for a variety of noxious and inflammatory signals, including capsaicin, heat and protons, and are up-regulated under inflammatory conditions. As end-stage kidney disease (ESKD) is associated with chronic inflammation, impaired immunity and depressed lymphocyte numbers, we sought to determine whether altered TRPV1 (and related TRPV2) expression in immune cells might be a contributing factor. TRPV1 and TRPV2 mRNA expression in peripheral blood mononuclear cells (PBMC) was similar in controls and ESKD patients by quantitative real-time RT-PCR. However, using immunocytochemistry, TRPV1-immunoreactivity was significantly higher and TRPV2-immunoreactivity was significantly lower in PBMC from ESKD patients compared to controls. The plant-derived TRPV1 agonists, capsaicin and resiniferatoxin (RTX) and the putative endovanilloid/endocannabinoids, N-arachidonoyl-dopamine (NADA) and N-oleoyl-dopamine (OLDA), induced concentration-dependent death of PBMC from healthy donors with a rank order of potency of RTX>NADA>OLDA>capsaicin. TRPV1 (5'-iodoresiniferatoxin) and cannabinoid (CB2; AM630) receptor antagonists blocked the cytotoxic effect of NADA. In subsequent experiments, PBMC from ESKD patients exhibited significantly increased susceptibility to NADA-induced death compared to PBMC from controls. The apparent up-regulation of TRPV1 may be a response to the inflammatory milieu in which PBMC exist in ESKD and may be responsible for the increased susceptibility of these cells to NADA-induced death, providing a possible explanation as to why ESKD patients have reduced lymphocyte counts and impaired immune function. Thus, TRPV1 (and possibly CB2) antagonists may have potential for the treatment of immune dysfunction in ESKD.

  16. Current and past cigarette smoking significantly increase risk for microscopic colitis.

    Science.gov (United States)

    Yen, Eugene F; Pokhrel, Bhupesh; Du, Hongyan; Nwe, Steven; Bianchi, Laura; Witt, Benjamin; Hall, Curtis

    2012-10-01

    Cigarette smoking is an important environmental factor affecting inflammatory bowel disease. The role of smoking has not been rigorously studied in microscopic colitis (MC). The aim of this study was to compare the association of cigarette smoking in individuals with MC compared to a control population without MC. We reviewed the records of patients with a clinical and histologic diagnosis of collagenous colitis (CC) or lymphocytic colitis (LC). Clinical history, including alcohol and smoking status at the time of diagnosis of MC, were reviewed. In this case-control study, age- and gender-matched patients without diarrhea presenting for outpatient colonoscopy served as the control population. We analyzed a total of 340 patients with MC: 124 with CC and 216 with LC. Overall, any smoking status (former or current) was associated with MC (odds ratio [OR] 2.12, 95% confidence interval [CI]: 1.56-2.88). This risk was more prominent in current smokers (adjusted OR 5.36, 3.81, and 4.37 for CC, LC, and all MC, respectively, 95% CI all greater than 1). The association of smoking was not significantly affected by gender or average alcohol consumption. In our study population, cigarette smoking is a risk factor for the development of both forms of microscopic colitis. There were no significant differences between LC and CC, and current smoking and the development of microscopic colitis affected men and women similarly. We feel that these data are sufficient to discuss the potential risks of tobacco use in patients with microscopic colitis. Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.

  17. Memory T Cells Are Significantly Increased in Rejecting Liver Allografts of Rhesus Monkeys.

    Science.gov (United States)

    Kim, Hwajung; Kim, Hyeyoung; Lee, Sun-Kyung; Jin, Xue-Li; Kim, Tae Jin; Park, Chanho; Lee, Jae-Il; Kim, Hyo-Sin; Hong, Suk Kyun; Yoon, Kyung Chul; Ahn, Sung Woo; Lee, Kyoung-Bun; Yi, Nam-Joon; Yang, Jaeseok; Lee, Kwang-Woong; Hawthorne, Wayne J; Suh, Kyung-Suk

    2017-11-18

    The Rhesus monkey (RM) is an excellent preclinical model in kidney, heart and islet transplantation that has provided the basis for new immunosuppressive protocols for clinical studies. However, there remain relatively few liver transplantation (LT) models in nonhuman primates. In this study, we analyzed the immune cell populations of PBMCs and secondary lymphoid organs along with livers of normal rhesus monkeys and compared them to those of rejecting liver transplanted recipient's following withdrawal of immunosuppression. We undertook five allogeneic ABO compatible orthotopic LT in monkeys using five normal donor monkey livers. We collected tissues including lymph nodes, spleens, blood, recipient livers and performed flow cytometric analysis using isolated immune cells. We found that CD4 or CD8 naïve T cells were normally seen at low levels and memory T cells were seen at high levels in the liver rather than lymphoid organs or PBMC. However, regulatory cells such as CD4+FoxP-3(+)T cells and CD8+CD28- cells remained in high numbers in the liver, but not in lymph node or PBMC. The comparison of CD4/8 T sub-populations in normal and rejected livers and the various tissues showed that naïve cells were dramatically decreased in spleen, lymph node and PBMC of rejected liver transplanted monkeys, but rather memory CD4/8 T cells were increased in all tissues and PBMC. The normal liver has large numbers of CD4 Tregs, CD8+CD28- and myeloid-derived suppressor cells, which are known immunosuppressive cells occurring at much higher levels than those seen in lymph node or peripheral blood. Memory T cells are dramatically increased in rejecting liver allografts of rhesus monkeys compared to those seen in normal RM tissues. This article is protected by copyright. All rights reserved. © 2017 by the American Association for the Study of Liver Diseases.

  18. Nanospray FAIMS Fractionation Provides Significant Increases in Proteome Coverage of Unfractionated Complex Protein Digests*

    Science.gov (United States)

    Swearingen, Kristian E.; Hoopmann, Michael R.; Johnson, Richard S.; Saleem, Ramsey A.; Aitchison, John D.; Moritz, Robert L.

    2012-01-01

    High-field asymmetric waveform ion mobility spectrometry (FAIMS) is an atmospheric pressure ion mobility technique that can be used to reduce sample complexity and increase dynamic range in tandem mass spectrometry experiments. FAIMS fractionates ions in the gas-phase according to characteristic differences in mobilities in electric fields of different strengths. Undesired ion species such as solvated clusters and singly charged chemical background ions can be prevented from reaching the mass analyzer, thus decreasing chemical noise. To date, there has been limited success using the commercially available Thermo Fisher FAIMS device with both standard ESI and nanoLC-MS. We have modified a Thermo Fisher electrospray source to accommodate a fused silica pulled tip capillary column for nanospray ionization, which will enable standard laboratories access to FAIMS technology. Our modified source allows easily obtainable stable spray at flow rates of 300 nL/min when coupled with FAIMS. The modified electrospray source allows the use of sheath gas, which provides a fivefold increase in signal obtained when nanoLC is coupled to FAIMS. In this work, nanoLC-FAIMS-MS and nanoLC-MS were compared by analyzing a tryptic digest of a 1:1 mixture of SILAC-labeled haploid and diploid yeast to demonstrate the performance of nanoLC-FAIMS-MS, at different compensation voltages, for post-column fractionation of complex protein digests. The effective dynamic range more than doubled when FAIMS was used. In total, 10,377 unique stripped peptides and 1649 unique proteins with SILAC ratios were identified from the combined nanoLC-FAIMS-MS experiments, compared with 6908 unique stripped peptides and 1003 unique proteins with SILAC ratios identified from the combined nanoLC-MS experiments. This work demonstrates how a commercially available FAIMS device can be combined with nanoLC to improve proteome coverage in shotgun and targeted type proteomics experiments. PMID:22186714

  19. Loss of Myh14 Increases Susceptibility to Noise-Induced Hearing Loss in CBA/CaJ Mice

    Directory of Open Access Journals (Sweden)

    Xiaolong Fu

    2016-01-01

    Full Text Available MYH14 is a member of the myosin family, which has been implicated in many motile processes such as ion-channel gating, organelle translocation, and the cytoskeleton rearrangement. Mutations in MYH14 lead to a DFNA4-type hearing impairment. Further evidence also shows that MYH14 is a candidate noise-induced hearing loss (NIHL susceptible gene. However, the specific roles of MYH14 in auditory function and NIHL are not fully understood. In the present study, we used CRISPR/Cas9 technology to establish a Myh14 knockout mice line in CBA/CaJ background (now referred to as Myh14−/− mice and clarify the role of MYH14 in the cochlea and NIHL. We found that Myh14−/− mice did not exhibit significant hearing loss until five months of age. In addition, Myh14−/− mice were more vulnerable to high intensity noise compared to control mice. More significant outer hair cell loss was observed in Myh14−/− mice than in wild type controls after acoustic trauma. Our findings suggest that Myh14 may play a beneficial role in the protection of the cochlea after acoustic overstimulation in CBA/CaJ mice.

  20. CCL2-driven inflammation increases mammary gland stromal density and cancer susceptibility in a transgenic mouse model.

    Science.gov (United States)

    Sun, Xuan; Glynn, Danielle J; Hodson, Leigh J; Huo, Cecilia; Britt, Kara; Thompson, Erik W; Woolford, Lucy; Evdokiou, Andreas; Pollard, Jeffrey W; Robertson, Sarah A; Ingman, Wendy V

    2017-01-11

    Macrophages play diverse roles in mammary gland development and breast cancer. CC-chemokine ligand 2 (CCL2) is an inflammatory cytokine that recruits macrophages to sites of injury. Although CCL2 has been detected in human and mouse mammary epithelium, its role in regulating mammary gland development and cancer risk has not been explored. Transgenic mice were generated wherein CCL2 is driven by the mammary epithelial cell-specific mouse mammary tumour virus 206 (MMTV) promoter. Estrous cycles were tracked in adult transgenic and non-transgenic FVB mice, and mammary glands collected at the four different stages of the cycle. Dissected mammary glands were assessed for cyclical morphological changes, proliferation and apoptosis of epithelium, macrophage abundance and collagen deposition, and mRNA encoding matrix remodelling enzymes. Another cohort of control and transgenic mice received carcinogen 7,12-Dimethylbenz(a)anthracene (DMBA) and tumour development was monitored weekly. CCL2 protein was also quantified in paired samples of human breast tissue with high and low mammographic density. Overexpression of CCL2 in the mammary epithelium resulted in an increased number of macrophages, increased density of stroma and collagen and elevated mRNA encoding matrix remodelling enzymes lysyl oxidase (LOX) and tissue inhibitor of matrix metalloproteinases (TIMP)3 compared to non-transgenic controls. Transgenic mice also exhibited increased susceptibility to development of DMBA-induced mammary tumours. In a paired sample cohort of human breast tissue, abundance of epithelial-cell-associated CCL2 was higher in breast tissue of high mammographic density compared to tissue of low mammographic density. Constitutive expression of CCL2 by the mouse mammary epithelium induces a state of low level chronic inflammation that increases stromal density and elevates cancer risk. We propose that CCL2-driven inflammation contributes to the increased risk of breast cancer observed in women

  1. Hypoxia-Induced Intrauterine Growth Restriction Increases the Susceptibility of Rats to High-Fat Diet–Induced Metabolic Syndrome

    Science.gov (United States)

    Rueda-Clausen, Christian F.; Dolinsky, Vernon W.; Morton, Jude S.; Proctor, Spencer D.; Dyck, Jason R.B.; Davidge, Sandra T.

    2011-01-01

    OBJECTIVE It is recognized that there is a remarkable variability in the systemic response to high-fat (HF) diets that cannot be completely explained by genetic factors. In addition, pregnancy complications leading to intrauterine growth restriction (IUGR) have been associated with an increased risk of developing metabolic syndrome (MetS) later in life. Thus, we hypothesized that offspring born with IUGR exhibit permanent metabolic changes that make them more susceptible to HF diet–induced MetS. RESEARCH DESIGN AND METHODS SD rats born normal (control) or with hypoxia-induced IUGR were randomized to low-fat (10% fat) or HF (45% fat) diets. After 9 weeks of feeding, physiological and molecular pathways involved in the MetS were evaluated. RESULTS IUGR offspring exhibited decreased energy intake and physical activity relative to controls. In offspring fed a HF diet, IUGR was associated with decreased total body fat content, a relative increase in intra-abdominal fat deposition and adipocyte size, an increase in fasting plasma concentrations of leptin, triglyceride and free fatty acids, and an increased concentration of triglycerides and ceramides in both liver and skeletal muscle. These changes in lipid homeostasis were accompanied by in vivo insulin resistance and impaired glucose tolerance and associated with increased phosphorylation of protein kinase C θ, inhibition of insulin receptor substrate 1, and a decreased activation of protein kinase B (PKB; also known as Akt) in liver and skeletal muscle in response to insulin. CONCLUSIONS IUGR enhances specific deleterious metabolic responses to a HF diet. Our results suggest that offspring born with IUGR may require special attention and follow-up to prevent the early onset of MetS. PMID:21270262

  2. Droughts may increase susceptibility of prairie dogs to fleas: Incongruity with hypothesized mechanisms of plague cycles in rodents

    Science.gov (United States)

    Eads, David A.; Biggins, Dean E.; Long, Dustin H.; Gage, Kenneth L.; Antolin, Michael F.

    2016-01-01

    Plague is a reemerging, rodent-associated zoonosis caused by the flea-borne bacterium Yersinia pestis. As a vector-borne disease, rates of plague transmission may increase when fleas are abundant. Fleas are highly susceptible to desiccation under hot-dry conditions; we posited that their densities decline during droughts. We evaluated this hypothesis with black-tailed prairie dogs (Cynomys ludovicianus) in New Mexico, June–August 2010–2012. Precipitation was relatively plentiful during 2010 and 2012 but scarce during 2011, the driest spring–summer on record for the northeastern grasslands of New Mexico. Unexpectedly, fleas were 200% more abundant in 2011 than in 2010 and 2012. Prairie dogs were in 27% better condition during 2010 and 2012, and they devoted 287% more time to grooming in 2012 than in 2011. During 2012, prairie dogs provided with supplemental food and water were in 23% better condition and carried 40% fewer fleas. Collectively, these results suggest that during dry years, prairie dogs are limited by food and water, and they exhibit weakened defenses against fleas. Long-term data are needed to evaluate the generality of whether droughts increase flea densities and how changes in flea abundance during sequences of dry and wet years might affect plague cycles in mammalian hosts.

  3. Continues administration of Nano-PSO significantly increased survival of genetic CJD mice.

    Science.gov (United States)

    Binyamin, Orli; Keller, Guy; Frid, Kati; Larush, Liraz; Magdassi, Shlomo; Gabizon, Ruth

    2017-12-01

    We have shown previously that Nano-PSO, a nanodroplet formulation of pomegranate seed oil, delayed progression of neurodegeneration signs when administered for a designated period of time to TgMHu2ME199K mice, modeling for genetic prion disease. In the present work, we treated these mice with a self-emulsion formulation of Nano-PSO or a parallel Soybean oil formulation from their day of birth until a terminal disease stage. We found that long term Nano-PSO administration resulted in increased survival of TgMHu2ME199K lines by several months. Interestingly, initiation of treatment at day 1 had no clinical advantage over initiation at day 70, however cessation of treatment at 9months of age resulted in the rapid loss of the beneficial clinical effect. Pathological studies revealed that treatment with Nano-PSO resulted in the reduction of GAG accumulation and lipid oxidation, indicating a strong neuroprotective effect. Contrarily, the clinical effect of Nano-PSO did not correlate with reduction in the levels of disease related PrP, the main prion marker. We conclude that long term administration of Nano-PSO is safe and may be effective in the prevention/delay of onset of neurodegenerative conditions such as genetic CJD. Copyright © 2017. Published by Elsevier Inc.

  4. Gangrenous cholecystitis: Deceiving ultrasounds, significant delay in surgical consult, and increased postoperative morbidity!

    Science.gov (United States)

    Yeh, Daniel Dante; Cropano, Catrina; Fagenholz, Peter; King, David R; Chang, Yuchiao; Klein, Eric N; DeMoya, Marc; Kaafarani, Haytham; Velmahos, George

    2015-11-01

    Gangrenous cholecystitis (GC) is difficult to diagnose preoperatively in the patient with suspected acute cholecystitis. We sought to characterize preoperative risk factors and post-operative complications. Pathology reports of all patients undergoing cholecystectomy for suspected acute cholecystitis from June 2010 to January 2014 and admitted through the emergency department were examined. Patients with GC were compared with those with acute/chronic cholecystitis (AC/CC). Data collected included demographics, preoperative signs and symptoms, radiologic studies, operative details, and clinical outcomes. Thirty-eight cases of GC were identified and compared with 171 cases of AC/CC. Compared with AC/CC, GC patients were more likely to be older (57 years vs. 41 years, p < 0.001), of male sex (63% vs. 31%, p < 0.001), hypertensive (47% vs. 22%, p = 0.002), hyperlipidemic (29% vs. 14%, p = 0.026), and diabetic (24% vs. 8%, p = 0.006). GC patients were more likely to have a fever (29% vs. 12%, p = 0.007) and less likely to have nausea/vomiting (61% vs. 80%, p = 0.019) or an impacted gallstone on ultrasound (US) (8% vs. 26%, p = 0.017). Otherwise, there was no significant difference in clinical or US findings. Among GC patients, US findings were absent (8%, n = 3) or minimal (42%, n = 16). Median time from emergency department registration to US (3.3 hours vs. 2.8 hours, p = 0.28) was similar, but US to operation was longer (41.2 hours vs. 18.4 hours, p < 0.001), conversion to open cholecystectomy was more common (37% vs. 10%, p < 0.001), and hospital stay was longer (median, 4 days vs. 2 days, p < 0.0001). Delay in surgical consultation occurred in 16% of GC patients compared with 1% of AC patients (p < 0.001). Demographic features may be predictive of GC. Absent or minimal US signs occur in 50%, and delay in surgical consultation is common. Postoperative morbidity is greater for patients with GC compared with those with AC/CC. Epidemiologic study, level III; therapeutic

  5. Sustained Ex Vivo Susceptibility of Plasmodium falciparum to Artemisinin Derivatives but Increasing Tolerance to Artemisinin Combination Therapy Partner Quinolines in The Gambia.

    Science.gov (United States)

    Amambua-Ngwa, Alfred; Okebe, Joseph; Mbye, Haddijatou; Ceesay, Sukai; El-Fatouri, Fatima; Joof, Fatou; Nyang, Haddy; Janha, Ramatoulie; Affara, Muna; Ahmad, Abdullahi; Kolly, Olimatou; Nwakanma, Davis; D'Alessandro, Umberto

    2017-12-01

    Antimalarial interventions have yielded a significant decline in malaria prevalence in The Gambia, where artemether-lumefantrine (AL) has been used as a first-line antimalarial for a decade. Clinical Plasmodium falciparum isolates collected from 2012 to 2015 were analyzed ex vivo for antimalarial susceptibility and genotyped for drug resistance markers (pfcrt K76T, pfmdr1 codons 86, 184, and 1246, and pfk13) and microsatellite variation. Additionally, allele frequencies of single nucleotide polymorphisms (SNPs) from other drug resistance-associated genes were compared from genomic sequence data sets from 2008 (n = 79) and 2014 (n = 168). No artemisinin resistance-associated pfk13 mutation was found, and only 4% of the isolates tested in 2015 showed significant growth after exposure to dihydroartemisinin. Conversely, the 50% inhibitory concentrations (IC50s) of amodiaquine and lumefantrine increased within this period. pfcrt 76T and pfmdr1 184F mutants remained at a prevalence above 80%. pfcrt 76T was positively associated with higher IC50s to chloroquine. pfmdr1 NYD increased in frequency between 2012 and 2015 due to lumefantrine selection. The TNYD (pfcrt 76T and pfmdr1 NYD wild-type haplotype) also increased in frequency following AL implementation in 2008. These results suggest selection for pfcrt and pfmdr1 genotypes that enable tolerance to lumefantrine. Increased tolerance to lumefantrine calls for sustained chemotherapeutic monitoring in The Gambia to minimize complete artemisinin combination therapy (ACT) failure in the future. Copyright © 2017 Amambua-Ngwa et al.

  6. Capreomycin susceptibility is increased by TlyA-directed 2'-O-methylation on both ribosomal subunits

    DEFF Research Database (Denmark)

    Monshupanee, Tanakarn; Johansen, Shanna K; Dahlberg, Albert E

    2012-01-01

    of these methylations through inactivation of TlyA confers resistance to capreomycin and viomycin. We report here that TlyA orthologues occur in diverse bacteria and fall into two distinct groups. One group, now termed TlyA(I) , has shorter N- and C-termini and methylates only C1920; the second group (now TlyA(II......) ) includes the mycobacterial enzyme, and these longer orthologues methylate at both C1409 and C1920. Ribosomal subunits are the preferred substrates for both groups of orthologues. Amino acid substitutions at the N-terminus of TlyA(II) reduce its ability to methylate these substrates. Growing pairs...... of recombinant TlyA(II) Escherichia coli strains in competition shows that even subtle changes in the level of rRNA methylation lead to significant differences in susceptibility to sub-inhibitory concentrations of capreomycin. The findings reveal that 2'-O-methyls at both C1409 and C1920 play a role...

  7. Glucose-6-phosphate dehydrogenase deficiency does not increase the susceptibility of sperm to oxidative stress induced by H2O2.

    Science.gov (United States)

    Roshankhah, Shiva; Rostami-Far, Zahra; Shaveisi-Zadeh, Farhad; Movafagh, Abolfazl; Bakhtiari, Mitra; Shaveisi-Zadeh, Jila

    2016-12-01

    Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme defect. G6PD plays a key role in the pentose phosphate pathway, which is a major source of nicotinamide adenine dinucleotide phosphate (NADPH). NADPH provides the reducing equivalents for oxidation-reduction reductions involved in protecting against the toxicity of reactive oxygen species such as H2O2. We hypothesized that G6PD deficiency may reduce the amount of NADPH in sperms, thereby inhibiting the detoxification of H2O2, which could potentially affect their motility and viability, resulting in an increased susceptibility to infertility. Semen samples were obtained from four males with G6PD deficiency and eight healthy males as a control. In both groups, motile sperms were isolated from the seminal fluid and incubated with 0, 10, 20, 40, 60, 80, and 120 µM concentrations of H2O2. After 1 hour incubation at 37℃, sperms were evaluated for motility and viability. Incubation of sperms with 10 and 20 µM H2O2 led to very little decrease in motility and viability, but motility decreased notably in both groups in 40, 60, and 80 µM H2O2, and viability decreased in both groups in 40, 60, 80, and 120 µM H2O2. However, no statistically significant differences were found between the G6PD-deficient group and controls. G6PD deficiency does not increase the susceptibility of sperm to oxidative stress induced by H2O2, and the reducing equivalents necessary for protection against H2O2 are most likely produced by other pathways. Therefore, G6PD deficiency cannot be considered as major risk factor for male infertility.

  8. Gain-of-function mutations of Ptpn11 (Shp2) cause aberrant mitosis and increase susceptibility to DNA damage-induced malignancies.

    Science.gov (United States)

    Liu, Xia; Zheng, Hong; Li, Xiaobo; Wang, Siying; Meyerson, Howard J; Yang, Wentian; Neel, Benjamin G; Qu, Cheng-Kui

    2016-01-26

    Gain-of-function (GOF) mutations of protein tyrosine phosphatase nonreceptor type 11 Ptpn11 (Shp2), a protein tyrosine phosphatase implicated in multiple cell signaling pathways, are associated with childhood leukemias and solid tumors. The underlying mechanisms are not fully understood. Here, we report that Ptpn11 GOF mutations disturb mitosis and cytokinesis, causing chromosomal instability and greatly increased susceptibility to DNA damage-induced malignancies. We find that Shp2 is distributed to the kinetochore, centrosome, spindle midzone, and midbody, all of which are known to play critical roles in chromosome segregation and cytokinesis. Mouse embryonic fibroblasts with Ptpn11 GOF mutations show a compromised mitotic checkpoint. Centrosome amplification and aberrant mitosis with misaligned or lagging chromosomes are significantly increased in Ptpn11-mutated mouse and patient cells. Abnormal cytokinesis is also markedly increased in these cells. Further mechanistic analyses reveal that GOF mutant Shp2 hyperactivates the Polo-like kinase 1 (Plk1) kinase by enhancing c-Src kinase-mediated tyrosine phosphorylation of Plk1. This study provides novel insights into the tumorigenesis associated with Ptpn11 GOF mutations and cautions that DNA-damaging treatments in Noonan syndrome patients with germ-line Ptpn11 GOF mutations could increase the risk of therapy-induced malignancies.

  9. Pgc-1α overexpression downregulates Pitx3 and increases susceptibility to MPTP toxicity associated with decreased Bdnf.

    Directory of Open Access Journals (Sweden)

    Joanne Clark

    Full Text Available Multiple mechanisms likely contribute to neuronal death in Parkinson's disease (PD, including mitochondrial dysfunction and oxidative stress. Peroxisome proliferator-activated receptor gamma co-activator-1 alpha (PGC-1α positively regulates the expression of genes required for mitochondrial biogenesis and the cell's antioxidant responses. Also, expression of PGC-1α-regulated genes is low in substantia nigra (SN neurons in early PD. Thus upregulation of PGC-1α is a candidate neuroprotective strategy in PD. Here, an adeno-associated virus (AAV was used to induce unilateral overexpression of Pgc-1α, or a control gene, in the SN of wild-type C57BL/6CR mice. Three weeks after AAV administration, mice were treated with saline or MPTP. Overexpression of Pgc-1α in the SN induced expression of target genes, but unexpectedly it also greatly reduced the expression of tyrosine hydroxylase (Th and other markers of the dopaminergic phenotype with resultant severe loss of striatal dopamine. Reduced Th expression was associated with loss of Pitx3, a transcription factor that is critical for the development and maintenance of dopaminergic cells. Expression of the neurotrophic factor Bdnf, which also is regulated by Pitx3, similarly was reduced. Overexpression of Pgc-1α also led to increased sensitivity to MPTP-induced death of Th+ neurons. Pgc-1α overexpression alone, in the absence of MPTP treatment, did not lead to cell loss in the SN or to loss of dopaminergic terminals. These data demonstrate that overexpression of Pgc-1α results in dopamine depletion associated with lower levels of Pitx3 and enhances susceptibility to MPTP. These data may have ramifications for neuroprotective strategies targeting overexpression of PGC-1α in PD.

  10. Pgc-1α overexpression downregulates Pitx3 and increases susceptibility to MPTP toxicity associated with decreased Bdnf.

    Science.gov (United States)

    Clark, Joanne; Silvaggi, Jessica M; Kiselak, Tomas; Zheng, Kangni; Clore, Elizabeth L; Dai, Ying; Bass, Caroline E; Simon, David K

    2012-01-01

    Multiple mechanisms likely contribute to neuronal death in Parkinson's disease (PD), including mitochondrial dysfunction and oxidative stress. Peroxisome proliferator-activated receptor gamma co-activator-1 alpha (PGC-1α) positively regulates the expression of genes required for mitochondrial biogenesis and the cell's antioxidant responses. Also, expression of PGC-1α-regulated genes is low in substantia nigra (SN) neurons in early PD. Thus upregulation of PGC-1α is a candidate neuroprotective strategy in PD. Here, an adeno-associated virus (AAV) was used to induce unilateral overexpression of Pgc-1α, or a control gene, in the SN of wild-type C57BL/6CR mice. Three weeks after AAV administration, mice were treated with saline or MPTP. Overexpression of Pgc-1α in the SN induced expression of target genes, but unexpectedly it also greatly reduced the expression of tyrosine hydroxylase (Th) and other markers of the dopaminergic phenotype with resultant severe loss of striatal dopamine. Reduced Th expression was associated with loss of Pitx3, a transcription factor that is critical for the development and maintenance of dopaminergic cells. Expression of the neurotrophic factor Bdnf, which also is regulated by Pitx3, similarly was reduced. Overexpression of Pgc-1α also led to increased sensitivity to MPTP-induced death of Th+ neurons. Pgc-1α overexpression alone, in the absence of MPTP treatment, did not lead to cell loss in the SN or to loss of dopaminergic terminals. These data demonstrate that overexpression of Pgc-1α results in dopamine depletion associated with lower levels of Pitx3 and enhances susceptibility to MPTP. These data may have ramifications for neuroprotective strategies targeting overexpression of PGC-1α in PD.

  11. Multimodal Fundus Imaging of Sodium Iodate-Treated Mice Informs RPE Susceptibility and Origins of Increased Fundus Autofluorescence.

    Science.gov (United States)

    Zhao, Jin; Kim, Hye Jin; Sparrow, Janet R

    2017-04-01

    By multimodal imaging, and the use of mouse and in vitro models, we have addressed changes in fundus autofluorescence (488 and 790 nm) and observed interactions between the photooxidative stress imposed by RPE bisretinoid lipofuscin and the oxidative impact of systemic sodium iodate (NaIO3). Abca4-/-, wild-type, and Rpe65rd12 mice were given systemic injections of NaIO3 (30 mg/kg). Analysis included noninvasive imaging of fundus autofluorescence (short-wavelength [SW-AF]; near-infrared excitation [NIR-AF]), quantitative fundus AF (qAF; 488 nm); light microscopy, RPE flat-mounts and measurements of outer nuclear layer (ONL) thickness. NaIO3 also was studied by using in vitro assays. In SW-AF and NIR-AF images, fundus mottling was visible 3 and 7 days after NaIO3 injection with changes being more pronounced in Abca4-/- mice that are characterized by an abundance of RPE bisretinoid lipofuscin. In Abca4-/- mice, qAF was elevated 3 and 7 days after NaIO3 administration. In light micrographs and RPE flat-mounts stained to reveal tight junctions (ZO-1) and nuclei, the RPE monolayer was disorganized, and clumping and loss of RPE was visible. ONL thinning was most pronounced in Abca4-/- mice. Treatment of ARPE-19 cells with NaIO3 together with the photooxidation of the bisretinoid A2E by exposure to 430-nm light produced an additive effect whereby loss of cell viability was greater than with either perturbation alone. Elevations in SW-AF intensity can occur due to photoreceptor cell dysfunction as induced secondarily by NaIO3. Photooxidative stress associated with RPE cell bisretinoid lipofuscin may confer increased susceptibility to the oxidant NaIO3.

  12. Mice lacking Tbk1 activity exhibit immune cell infiltrates in multiple tissues and increased susceptibility to LPS-induced lethality.

    Science.gov (United States)

    Marchlik, Erica; Thakker, Paresh; Carlson, Thaddeus; Jiang, Zhaozhao; Ryan, Mark; Marusic, Suzana; Goutagny, Nadege; Kuang, Wen; Askew, G Roger; Roberts, Victoria; Benoit, Stephen; Zhou, Tianhui; Ling, Vincent; Pfeifer, Richard; Stedman, Nancy; Fitzgerald, Katherine A; Lin, Lih-Ling; Hall, J Perry

    2010-12-01

    TBK1 is critical for immunity against microbial pathogens that activate TLR4- and TLR3-dependent signaling pathways. To address the role of TBK1 in inflammation, mice were generated that harbor two copies of a mutant Tbk1 allele. This Tbk1(Δ) allele encodes a truncated Tbk1(Δ) protein that is catalytically inactive and expressed at very low levels. Upon LPS stimulation, macrophages from Tbk1(Δ/Δ) mice produce normal levels of proinflammatory cytokines (e.g., TNF-α), but IFN-β and RANTES expression and IRF3 DNA-binding activity are ablated. Three-month-old Tbk1(Δ/Δ) mice exhibit mononuclear and granulomatous cell infiltrates in multiple organs and inflammatory cell infiltrates in their skin, and they harbor a 2-fold greater amount of circulating monocytes than their Tbk1(+/+) and Tbk1(+/Δ) littermates. Skin from 2-week-old Tbk1(Δ/Δ) mice is characterized by reactive changes, including hyperkeratosis, hyperplasia, necrosis, inflammatory cell infiltrates, and edema. In response to LPS challenge, 3-month-old Tbk1(Δ/Δ) mice die more quickly and in greater numbers than their Tbk1(+/+) and Tbk1(+/Δ) counterparts. This lethality is accompanied by an overproduction of several proinflammatory cytokines in the serum of Tbk1(Δ/Δ) mice, including TNF-α, GM-CSF, IL-6, and KC. This overproduction of serum cytokines in Tbk1(Δ/Δ) mice following LPS challenge and their increased susceptibility to LPS-induced lethality may result from the reactions of their larger circulating monocyte compartment and their greater numbers of extravasated immune cells.

  13. Acute Ethanol Exposure Increases the Susceptibility of the Donor Hearts to Ischemia/Reperfusion Injury after Transplantation in Rats

    Science.gov (United States)

    Loganathan, Sivakkanan; Weymann, Alexander; Radovits, Tamás; Barnucz, Enikő; Hirschberg, Kristóf; Hegedüs, Peter; Zhou, Yan; Tao, Liang; Páli, Szabolcs; Veres, Gábor; Karck, Matthias; Szabó, Gábor

    2012-01-01

    , oxidative stress and altered protein expression were observed. Conclusions These results demonstrate acute alcohol abuse increases the susceptibility of donor hearts to ischemia/reperfusion in a rat heart transplant model even though the global contractile function recovers 6 h after ethanol-administration. PMID:23155471

  14. Acute ethanol exposure increases the susceptibility of the donor hearts to ischemia/reperfusion injury after transplantation in rats.

    Directory of Open Access Journals (Sweden)

    Shiliang Li

    contractility and relaxation, oxidative stress and altered protein expression were observed. CONCLUSIONS: These results demonstrate acute alcohol abuse increases the susceptibility of donor hearts to ischemia/reperfusion in a rat heart transplant model even though the global contractile function recovers 6 h after ethanol-administration.

  15. Clinical Significance of Long Non-Coding RNA CASC8 rs10505477 Polymorphism in Lung Cancer Susceptibility, Platinum-Based Chemotherapy Response, and Toxicity

    Directory of Open Access Journals (Sweden)

    Lei Hu

    2016-05-01

    Full Text Available Long non-coding RNA (lncRNA CASC8 rs10505477 polymorphism has been identified to be related to risk of many kinds of cancers, such as colorectal cancer, gastric cancer, and invasive ovarian cancer, and it may be involved in the prognosis of gastric cancer patients who have received platinum-based chemotherapy after surgical treatment. So far, there is no study investigating the clinical significance of lncRNA CASC8 rs10505477 in lung cancer susceptibility and treatment. In this study, we genotyped 498 lung cancer patients and 213 healthy control subjects to explore the correlation between the rs10505477 polymorphism and lung cancer risk in a Chinese population. Among the 498 patients, 467 were selected for the chemotherapy response and toxicity study. We found that the single nucleotide polymorphisms (SNP rs10505477 was greatly related to lung cancer risk in male and adenocarcinoma subgroups in recessive model (adjusted OR = 0.51, 95%CI = 0.29–0.90, p = 0.02; adjusted OR = 0.52, 95%CI = 0.30–0.89, p = 0.02, respectively. It was also closely correlated with platinum-based chemotherapy response in dominant model (adjusted OR = 1.58, 95%CI = 1.05–2.39, p = 0.03. Additionally, we observed that CASC8 rs10505477 polymorphism was significantly relevant to severe hematologic toxicity in non-small-cell lung cancer (NSCLC subgroup in dominant model (adjusted OR = 0.59, 95%CI = 0.35–0.98, p = 0.04 and in additive model (adjusted OR = 0.62, 95%CI = 0.43–0.90, p = 0.01. Furthermore, it was found that rs10505477 polymorphism was greatly associated with gastrointestinal toxicity in SCLC and cisplatin subgroups in dominant model (adjusted OR = 7.82, 95%CI = 1.36–45.07, p = 0.02; adjusted OR = 1.94, 95%CI = 1.07–3.53, p = 0.03, respectively. Thus, lncRNA CASC8 rs10505477 could serve as a possible risk marker for diagnosing lung cancer, and could be used to forecast the response and toxicity of platinum-based treatment in lung cancer patients.

  16. Significant linkage to chromosome 12q24.32-q24.33 and identification of SFRS8 as a possible asthma susceptibility gene

    DEFF Research Database (Denmark)

    brasch-andersen, c; Tan, Q; Børglum, A D

    2006-01-01

    BACKGROUND: Asthma is a complex genetic disorder. Many studies have suggested that chromosome 12q harbours a susceptibility gene for asthma and atopy. Linkage on chromosome 12q24.21-q24.33 was investigated in 167 Danish families with asthma. METHODS: A two step procedure was used: (1) a genome-wi...

  17. Aging increases the susceptibility to motor memory interference and reduces off-line gains in motor skill learning

    DEFF Research Database (Denmark)

    Roig, Marc; Ritterband-Rosenbaum, Anina; Jensen, Jesper Lundbye

    2014-01-01

    Declines in the ability to learn motor skills in older adults are commonly attributed to deficits in the encoding of sensorimotor information during motor practice. We investigated whether aging also impairs motor memory consolidation by assessing the susceptibility to memory interference and off...

  18. PIRIN2 stabilizes cysteine protease XCP2 and increases susceptibility to the vascular pathogen Ralstonia solanacearum in Arabidopsis

    NARCIS (Netherlands)

    Zhang, B.; Tremousaygue, D.; Denancé, N.; Esse, van H.P.; Hörger, A.C.; Dabos, P.; Goffner, D.; Thomma, B.P.H.J.; Hoorn, van der R.A.L.; Tuominen, H.

    2014-01-01

    PIRIN (PRN) is a member of the functionally diverse cupin protein superfamily. There are four members of the Arabidopsis thaliana PRN family, but the roles of these proteins are largely unknown. Here we describe a function of the Arabidopsis PIRIN2 (PRN2) that is related to susceptibility to the

  19. Proanthocyanidins inhibit Ascaris suum glutathione-S-transferase activity and increase susceptibility of larvae to levamisole in vitro

    DEFF Research Database (Denmark)

    Hansen, Tina Vicky Alstrup; Fryganas, Christos; Acevedo, Nathalie

    2016-01-01

    the parasitic nematode Ascaris suum. As GSTs are involved in detoxifying xenobiotic substances within the parasite, we hypothesised that this inhibition may render parasites hyper-susceptible to anthelmintic drugs. Migration inhibition assays with A. suum larvae demonstrated that the potency of levamisole (LEV...

  20. Deficiency in macrophage-stimulating protein results in spontaneous intestinal inflammation and increased susceptibility toward epithelial damage in zebrafish

    NARCIS (Netherlands)

    Witte, Merlijn; Huitema, Leonie F. A.; Nieuwenhuis, Edward E. S.; Brugman, Sylvia

    2014-01-01

    Abstract Several genome-wide association studies have identified the genes encoding for macrophage-stimulating protein (MSP) and its receptor RON (Recepteur d'Origine Nantais) as possible susceptibility factors in inflammatory bowel disease. While it has been shown that the MSP-RON signaling pathway

  1. Noninherited maternal antigens do not increase the susceptibility for familial rheumatoid arthritis. European Consortium on Rheumatoid Arthritis Families (ECRAF).

    NARCIS (Netherlands)

    Barrera Rico, P.; Balsa, A.; Alves, H.; Westhovens, R.; Maenaut, K.; Cornelis, F.; Fritz, P.; Bardin, T.; Ceu Maia, M.; Lopes-Vaz, A.; Pascual-Salcedo, D.; Concha, E. de la; Radstake, T.R.D.J.; Putte, L.B.A. van de; Migliorini, P.; Prudhomme, J.F.; Charron, D.; Spyropoulou, M.; Mendes, A.; Spaepen, M.; Martinez, M.; Stavropoulos, C.

    2001-01-01

    OBJECTIVE: It has been proposed that noninherited maternal HLA-DR antigens (NIMA) might play a role in the susceptibility for rheumatoid arthritis (RA). This hypothesis has not been thoroughly tested in patients with familial RA, in whom genetic factors, either inherited or not, might have stronger

  2. Diabetes increases the susceptibility to acute kidney injury after myocardial infarction through augmented activation of renal Toll-like receptors in rats.

    Science.gov (United States)

    Ohno, Kouhei; Kuno, Atsushi; Murase, Hiromichi; Muratsubaki, Shingo; Miki, Takayuki; Tanno, Masaya; Yano, Toshiyuki; Ishikawa, Satoko; Yamashita, Tomohisa; Miura, Tetsuji

    2017-12-01

    Acute kidney injury (AKI) after acute myocardial infarction (MI) worsens the prognosis of MI patients. Although type 2 diabetes mellitus (DM) is a major risk factor of AKI after MI, the underlying mechanism remains unclear. Here, we examined the roles of renal Toll-like receptors (TLRs) in the impact of DM on AKI after MI. MI was induced by coronary artery ligation in Otsuka-Long-Evans-Tokushima fatty (OLETF) rats, a rat DM model, and Long-Evans-Tokushima-Otsuka (LETO) rats, nondiabetic controls. Sham-operated rats served as no-MI controls. Renal mRNA levels of TLR2 and myeloid differentiation factor 88 (MyD88) were significantly higher in sham-operated OLETF rats than in sham-operated LETO rats, although levels of TLR1, TLR3, and TLR4 were similar. At 12 h after MI, protein levels of kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) in the kidney were elevated by 5.3- and 4.0-fold, respectively, and their mRNA levels were increased in OLETF but not LETO rats. The increased KIM-1 and NGAL expression levels after MI in the OLETF kidney were associated with upregulated expression of TLR1, TLR2, TLR4, MyD88, IL-6, TNF-α, chemokine (C-C motif) ligand 2, and transforming growth factor-β1 and also with activation of p38 MAPK, JNK, and NF-κB. Cu-CPT22, a TLR1/TLR2 antagonist, administered before MI significantly suppressed MI-induced upregulation of KIM-1, TLR2, TLR4, MyD88, and chemokine (C-C motif) ligand 2 levels and activation of NF-κB, whereas NGAL levels and IL-6 and TNF-α expression levels were unchanged. The results suggest that DM increases the susceptibility to AKI after acute MI by augmented activation of renal TLRs and that TLR1/TLR2-mediated signaling mediates KIM-1 upregulation after MI.NEW & NOTEWORTHY This is the first report to demonstrate the involvement of Toll-like recpetors (TLRs) in diabetes-induced susceptibility to acute kidney injury after acute myocardial infarction. We propose that the TLR1/TLR2

  3. Increased susceptibility to metabolic dysregulation in a mouse model of Alzheimer's disease is associated with impaired hypothalamic insulin signaling and elevated BCAA levels.

    Science.gov (United States)

    Ruiz, Henry H; Chi, Tiffany; Shin, Andrew C; Lindtner, Claudia; Hsieh, Wilson; Ehrlich, Michelle; Gandy, Sam; Buettner, Christoph

    2016-08-01

    Epidemiologic studies have demonstrated an association between diabetes and dementia. Insulin signaling within the brain, in particular within the hypothalamus regulates carbohydrate, lipid, and branched chain amino acid (BCAA) metabolism in peripheral organs such as the liver and adipose tissue. We hypothesized that cerebral amyloidosis impairs central nervous system control of metabolism through disruption of insulin signaling in the hypothalamus, which dysregulates glucose and BCAA homeostasis resulting in increased susceptibility to diabetes. We examined whether APP/PS1 mice exhibit increased susceptibility to aging or high-fat diet (HFD)-induced metabolic impairment using metabolic phenotyping and insulin-signaling studies. APP/PS1 mice were more susceptible to high-fat feeding and aging-induced metabolic dysregulation including disrupted BCAA homeostasis and exhibited impaired hypothalamic insulin signaling. Our data suggest that AD pathology increases susceptibility to diabetes due to impaired hypothalamic insulin signaling, and that plasma BCAA levels could serve as a biomarker of hypothalamic insulin action in patients with AD. Copyright © 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  4. Apolipoprotein A5-1131T>C polymorphism, but not APOE genotypes, increases susceptibility for dyslipidemia in children and adolescents.

    Science.gov (United States)

    Brito, D D V; Fernandes, A P; Gomes, K B; Coelho, F F; Cruz, N G; Sabino, A P; Cardoso, J E; Figueiredo-Filho, P P; Diamante, R; Norton, C R; Sousa, M O

    2011-10-01

    Apolipoprotein A5 (APOA5) and apolipoprotein E (APOE) play important roles in the metabolism of cholesterol and triglycerides. The aim of this study was to determine the allelic and genotypic distributions of the APOA5-1131T>C (rs 662799) and the APOE HhaI polymorphisms and to identify the association of both individual and combined APOA5-APOE genetic variants and the risk for dyslipidemia in children and adolescents. We genotyped 53 dyslipidemic and 77 normolipidemic individuals. The total cholesterol, triglycerides and HDL cholesterol were determined enzymatically. For APOA5 polymorphism, the presence of the allele C confers an individual risk for dyslipidemia (OR = 2.38, 95% CI = 1.15-4.89; P = 0.018). No significant differences were observed for lipid parameters among the APOA5 groups, except for a higher value of HDLc (P = 0.024) in C-carriers. The allelic and genotypic frequencies of APOE polymorphism were similar between groups and did not increase the susceptibility for dyslipidemia. None of the combined APOA5-APOE polymorphisms increased risk for dyslipidemia. We demonstrated an association between APOA5-1131T>C polymorphism and dyslipidemia in children and adolescents. This finding may be useful to guide new studies with genetic markers down a path toward a better characterization of the genetic risk factors for dyslipidemia and atherosclerotic diseases.

  5. Gender-specific increase in susceptibility to metabolic syndrome of offspring rats after prenatal caffeine exposure with post-weaning high-fat diet

    Energy Technology Data Exchange (ETDEWEB)

    Li, Jing [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Luo, Hanwen [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China); Wu, Yimeng; He, Zheng; Zhang, Li; Guo, Yu [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Ma, Lu [Department of Epidemiology & Health Statistics, Public Health School of Wuhan University, Wuhan 430071 (China); Magdalou, Jacques [UMR 7561 CNRS-NancyUniversité, Faculté de Médicine, Vandoeuvre-lès-Nancy (France); Chen, Liaobin [Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China); Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071 (China); Wang, Hui, E-mail: wanghui19@whu.edu.cn [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071 (China)

    2015-05-01

    Prenatal caffeine exposure (PCE) alters the hypothalamic–pituitary–adrenocortical (HPA) axis-associated neuroendocrine metabolic programming and induces an increased susceptibility to metabolic syndrome (MS) in intrauterine growth retardation (IUGR) offspring rats. High-fat diet (HFD) is one of the main environmental factors accounting for the incidence of MS. In this study, we aimed to clarify the gender-specific increase in susceptibility to MS in offspring rats after PCE with post-weaning HFD. Maternal Wistar rats were administered with caffeine (120 mg/kg·d) from gestational day 11 until delivery. The offspring rats with normal diet or HFD were euthanized at postnatal week 24, and blood samples were collected. Results showed that PCE not only reduced serum adrenocorticotropic hormone (ACTH) and corticosterone levels, but also enhanced serum glucose, triglyceride and total cholesterol (TCH) concentrations in the offspring rats. Moreover, several interactions among PCE, HFD and gender were observed by a three-way ANOVA analysis. In PCE offspring, HFD could aggravate the degree of increased serum triglyceride level. Meanwhile, serum corticosterone levels of females were decreased more obviously than those of males in PCE offspring. The results also revealed interactions between HFD and gender in the levels of serum ACTH, triglyceride and TCH, which were changed more evidently in female HFD offspring. These results indicate that HFD could exacerbate the dysfunction of lipid metabolism and the susceptibility to MS induced by PCE, and the female offspring are more sensitive to HFD-induced neuroendocrine metabolic dysfunction than their male counterparts. - Highlights: • Caffeine induced HPA axis dysfunction in offspring rats fed by high-fat diet (HFD). • Caffeine induced an increased susceptibility to metabolic syndrome. • HFD aggravated susceptibility to metabolic syndrome induced by caffeine. • Female was more sensitive to HFD-induced neuroendocrine

  6. Increased susceptibility of skin from HERDA (Hereditary Equine Regional Dermal Asthenia)-affected horses to bacterial collagenase degradation: a potential contributing factor to the clinical signs of HERDA.

    Science.gov (United States)

    Rashmir-Raven, Ann; Lavagnino, Michael; Sedlak, Aleksa; Gardner, Keri; Arnoczky, Steven

    2015-12-01

    Hereditary equine regional dermal asthenia (HERDA) is a genetic disorder of collagen resulting in fragile, hyper-extensible skin and ulcerative lesions. The predominance of skin lesions have been shown to occur on the dorsum of HERDA-affected horses. While this has been postulated to be due to increased exposure to sunlight of these areas, the precise pathological mechanism which causes this to occur is unclear. We hypothesized that an increase in collagenase activity, that has been associated with the exposure of dermal fibroblasts to sunlight, will significantly degrade the material properties of skin from HERDA-affected horses when compared to unaffected controls. Six unaffected and seven HERDA-affected horses, all euthanized for other reasons. Full-thickness skin samples from similar locations on each horse were collected and cut into uniform strips and their material properties (tensile modulus) determined by mechanical testing before (n = 12 samples/horse) or after (n = 12 samples/horse) incubation in bacterial collagenase at 37°C for 6 h. The change in modulus following treatment was then compared between HERDA-affected and unaffected horses using a Student's t-test. The modulus of skin from HERDA-affected horses decreased significantly more than that from unaffected horses following collagenase treatment (54 ± 7% versus 30 ± 16%, P = 0.004). The significant decrease in the modulus of skin from HERDA-affected horses following collagenase exposure suggests that their altered collagen microarchitecture is more susceptible to enzymatic degradation and may explain the localization of skin lesions in HERDA-affected horses to those areas of the body most exposed to sunlight. These findings appear to support the previously reported benefits of sunlight restriction in HERDA-affected horses. © 2015 ESVD and ACVD.

  7. Maternal treatment with agonistic autoantibodies against type-1 angiotensin II receptor in late pregnancy increases apoptosis of myocardial cells and myocardial susceptibility to ischemia-reperfusion injury in offspring rats.

    Directory of Open Access Journals (Sweden)

    Zhu Jin

    Full Text Available Epidemiological studies have demonstrated that offspring born to mothers preeclampsia (PE are at increased risk for developing cardiovascular diseases after birth, but the underlying mechanism is unknown. Angiotensin II receptor type 1 autoantibody (AT1-AA, an agonist acting via activation of the AT1 receptor, is believed to be involved in the pathogenesis of both PE and fetal growth restriction. The aim of the present study was to confirm the hypothesis that prenatal AT1-AA exposure increases the heart susceptibility to ischemia/reperfusion injury (IRI in the offspring in an AT1-AA-induced animal model of PE, and determine whether or not the increase of maternal AT1-AA level is a factor contributing to sustained abnormalities of the heart structure during infancy. The hearts of 45-day-old offspring rats were studied using Langendorff preparation to determine the susceptibility of the heart to IRI. The results showed that the body weight of the maternal rats was not significantly different between the study and control groups, but the body weight of their offspring in AT1-AA group was decreased slightly at day 21 of gestational age, and at day 3 after birth. Although the heart weight index was not significantly affected at all ages examined, AT1-AA significantly increased the size of myocardial cells of the left ventricle (LV at the age of 45 days. AT1-AA gained access to fetal circulation via the placenta and induced apoptosis of fetal myocardial cells. AT1-AA also significantly delayed recovery from IRI and affected the LV function of 45-day-old offspring. This was associated with a significant increase in IRI-induced LV myocardial infarct size. These results suggest that AT1-AA induced abnormal apoptosis of fetal myocardial cells during the fetal period and increased the cardiac susceptibility to IRI in adult offspring.

  8. Maternal treatment with agonistic autoantibodies against type-1 angiotensin II receptor in late pregnancy increases apoptosis of myocardial cells and myocardial susceptibility to ischemia-reperfusion injury in offspring rats.

    Science.gov (United States)

    Jin, Zhu; Zhang, Wenhui; Yang, Hailiang; Wang, Xiaofang; Zheng, Yanqian; Zhang, Qiaoyan; Zhi, Jianming

    2013-01-01

    Epidemiological studies have demonstrated that offspring born to mothers preeclampsia (PE) are at increased risk for developing cardiovascular diseases after birth, but the underlying mechanism is unknown. Angiotensin II receptor type 1 autoantibody (AT1-AA), an agonist acting via activation of the AT1 receptor, is believed to be involved in the pathogenesis of both PE and fetal growth restriction. The aim of the present study was to confirm the hypothesis that prenatal AT1-AA exposure increases the heart susceptibility to ischemia/reperfusion injury (IRI) in the offspring in an AT1-AA-induced animal model of PE, and determine whether or not the increase of maternal AT1-AA level is a factor contributing to sustained abnormalities of the heart structure during infancy. The hearts of 45-day-old offspring rats were studied using Langendorff preparation to determine the susceptibility of the heart to IRI. The results showed that the body weight of the maternal rats was not significantly different between the study and control groups, but the body weight of their offspring in AT1-AA group was decreased slightly at day 21 of gestational age, and at day 3 after birth. Although the heart weight index was not significantly affected at all ages examined, AT1-AA significantly increased the size of myocardial cells of the left ventricle (LV) at the age of 45 days. AT1-AA gained access to fetal circulation via the placenta and induced apoptosis of fetal myocardial cells. AT1-AA also significantly delayed recovery from IRI and affected the LV function of 45-day-old offspring. This was associated with a significant increase in IRI-induced LV myocardial infarct size. These results suggest that AT1-AA induced abnormal apoptosis of fetal myocardial cells during the fetal period and increased the cardiac susceptibility to IRI in adult offspring.

  9. Colonization by nitrogen-fixing Frankia bacteria causes short-term increases in herbivore susceptibility in red alder (Alnus rubra) seedlings.

    Science.gov (United States)

    Ballhorn, Daniel J; Elias, Jacob D; Balkan, M A; Fordyce, Rachel F; Kennedy, Peter G

    2017-06-01

    Carbon allocation demands from root-nodulating nitrogen-fixing bacteria (NFB) can modulate the host plant's chemical phenotype, with strong bottom-up effects on herbivores. In contrast to well-studied rhizobia, the effects of other important NFB on plant chemistry and herbivory are much less understood. Here, combining field surveys in the Oregon Coast Range, USA with laboratory experiments, we analyzed how N2-fixing Frankia bacteria influenced plant growth, chemistry, and herbivory on Alnus rubra (red alder) seedlings. In the field, we quantified Frankia nodulation, herbivore damage, and plant size. In the laboratory, we grew seedlings with Frankia (F+), Frankia-free but nitrogen-fertilized (N+), or both uncolonized and unfertilized (F-N-) and assessed growth and leaf chemistry. We further conducted choice trials with black slugs, Arion rufus, a natural red alder herbivore. In the field, Frankia nodulation was significantly positively correlated with herbivory and negatively with seedling height. In contrast, in the lab, F+ as well as N+ seedlings were significantly taller than the F-N- controls. Seedlings from both treatments also had significantly increased leaf protein concentration compared to controls, whereas carbon-based nutritive compounds (carbohydrates) as well as leaf palatability-decreasing condensed tannins, lignin, and fiber were decreased in F+ but not in N+ treatments. In the choice assays, slugs preferred leaf material from F+ seedlings, but the effects were only significant in young leaves. Our study indicates that colonization by Frankia causes short-term ecological costs in terms of susceptibility to herbivory. However, the ubiquity of this symbiosis in natural settings suggests that these costs are outweighed by benefits beyond the seedling stage.

  10. Increased susceptibility to bladder inflammation in smokers: targeting the PAF-PAF receptor interaction to manage inflammatory cell recruitment.

    Science.gov (United States)

    Marentette, John; Kolar, Grant; McHowat, Jane

    2015-12-01

    Chronic bladder inflammation can result in a significant reduction in quality of life. Smoking remains a leading preventable risk factor in many diseases. Despite the large amount of evidence supporting the risks of smoking, roughly 45 million people in the United States remain smokers. The impact of cigarette smoking on inflammation is well established, but how smoking promotes bladder inflammation is currently unknown. The aim of this study was to determine if cigarette smoke exposure impacts inflammatory cell adherence to bladder endothelial cells and if targeting the platelet-activating factor (PAF)-PAF receptor (PAFR) interaction could be beneficial in managing bladder inflammation. In response to cigarette smoke extract (CSE) incubation, bladder endothelial cells from human or mouse displayed increased PAF accumulation, decreased PAF-AH activity, and increased inflammatory cell adherence. Inhibition of endothelial cell calcium-independent phospholipase A2β (iPLA2β) with (S)-BEL, to block PAF production, prevented adherence of inflammatory cells. Pretreatment of inflammatory cells with PAFR antagonists, ginkgolide B or WEB2086 significantly reduced the number of adhered cells to bladder endothelium. Wild-type mice exposed to cigarette smoke displayed increased presence of inflammatory infiltration which was absent in iPLA2β(-/-) mice and those exposed to room air. In conclusion, cigarette smoke exposure increases endothelial cell PAF accumulation and increased inflammatory cell adherence. Inhibition of PAF accumulation or PAFR antagonism markedly attenuated inflammatory cell adherence to bladder endothelial cells. The results detailed in this study highlight to potential therapeutic targets for managing bladder inflammation. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  11. A diet with 3% of energy from a mixture of Omega-3 fatty acids significantly increases in vivo lipid peroxidation in postmenopausal women

    Science.gov (United States)

    Dietary omega-3 polyunsaturated fatty acids (n-3 PUFA) are recommended by public health organizations to reduce the risk of disease. However, n-3 PUFA are susceptible to an increase in lipid peroxidation in the human body. As part of a crossover dietary intervention study of a diet (20% of energy ...

  12. Light Fractionation Significantly Increases the Efficacy of Photodynamic Therapy Using BF-200 ALA in Normal Mouse Skin.

    NARCIS (Netherlands)

    H.S. de Bruijn (Riette); S. Brooks (Sander); A. van der Ploeg-van den Heuvel (Angélique); T.L.M. ten Hagen (Timo); E.R.M. de Haas (Ellen); D.J. Robinson (Dominic)

    2016-01-01

    markdownabstractBACKGROUND: Light fractionation significantly increases the efficacy of 5-aminolevulinic acid (ALA) based photodynamic therapy (PDT) using the nano-emulsion based gel formulation BF-200. PDT using BF-200 ALA has recently been clinically approved and is under investigation in several

  13. Aging Increases Susceptibility to High Fat Diet-Induced Metabolic Syndrome in C57BL/6 Mice: Improvement in Glycemic and Lipid Profile after Antioxidant Therapy

    Directory of Open Access Journals (Sweden)

    Valéria Nunes-Souza

    2016-01-01

    Full Text Available Nonalcoholic fatty liver disease (NAFLD has been considered a novel component of the metabolic syndrome (MetS, with the oxidative stress participating in its progression. This study aimed to evaluate the metabolic profile in young and old mice with MetS, and the effects of apocynin and tempol on glycemic and lipid parameters. Young and old C57BL/6 mice with high fat diet- (HFD- induced MetS received apocynin and tempol 50 mg·kg−1/day in their drinking water for 10 weeks. After HFD, the young group showed elevated fasting glucose, worsened lipid profile in plasma, steatosis, and hepatic lipid peroxidation. Nevertheless, the old group presented significant increase in fasting insulin levels, insulin resistance, plasma and hepatic lipid peroxidation, and pronounced steatosis. The hepatic superoxide dismutase and catalase activity did not differ between the groups. Tempol and apocynin seemed to prevent hepatic lipid deposition in both groups. Furthermore, apocynin improved glucose tolerance and insulin sensitivity in old mice. In summary, old mice are more susceptible to HFD-induced metabolic changes than their young counterparts. Also, the antioxidant therapy improved insulin sensitivity and glucose tolerance, and in addition, apocynin seemed to prevent the HFD-induced hepatic fat deposition, suggesting an important role of oxidative stress in the induction of NAFLD.

  14. Aging Increases Susceptibility to High Fat Diet-Induced Metabolic Syndrome in C57BL/6 Mice: Improvement in Glycemic and Lipid Profile after Antioxidant Therapy.

    Science.gov (United States)

    Nunes-Souza, Valéria; César-Gomes, Cheila Juliana; Da Fonseca, Lucas José Sá; Guedes, Glaucevane Da Silva; Smaniotto, Salete; Rabelo, Luíza Antas

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) has been considered a novel component of the metabolic syndrome (MetS), with the oxidative stress participating in its progression. This study aimed to evaluate the metabolic profile in young and old mice with MetS, and the effects of apocynin and tempol on glycemic and lipid parameters. Young and old C57BL/6 mice with high fat diet- (HFD-) induced MetS received apocynin and tempol 50 mg·kg(-1)/day in their drinking water for 10 weeks. After HFD, the young group showed elevated fasting glucose, worsened lipid profile in plasma, steatosis, and hepatic lipid peroxidation. Nevertheless, the old group presented significant increase in fasting insulin levels, insulin resistance, plasma and hepatic lipid peroxidation, and pronounced steatosis. The hepatic superoxide dismutase and catalase activity did not differ between the groups. Tempol and apocynin seemed to prevent hepatic lipid deposition in both groups. Furthermore, apocynin improved glucose tolerance and insulin sensitivity in old mice. In summary, old mice are more susceptible to HFD-induced metabolic changes than their young counterparts. Also, the antioxidant therapy improved insulin sensitivity and glucose tolerance, and in addition, apocynin seemed to prevent the HFD-induced hepatic fat deposition, suggesting an important role of oxidative stress in the induction of NAFLD.

  15. Genotype GG of rs895819 Functional Polymorphism Within miR-27a Might Increase Genetic Susceptibility to Colorectal Cancer in Han Chinese Population.

    Science.gov (United States)

    Jiang, Yu; Lin, Dong-Hong; Xu, Jian-Ping; Chen, Wen-Xu; Zheng, Shu-Jian; Song, Lin

    2016-07-01

    MicroRNA-27a (miR-27a) is supposed to be an oncogene in various types of cancers, and genetic variation of miR-27a might result in aberrant expression and abnormal second structure of mature-miR-27a, contributing to elevated genetic risk and poor prognosis for colorectal cancer (CRC). In order to explore the possible association between rs895819 within miR-27a and CRC in Han Chinese population, we investigated the genotype distributions of rs895819 in 508 CRC cases and 562 healthy check-up controls using TaqMan genotype discrimination system, and analyzed the possible association between them. Odds ratio (OR) and 95% confidential interval (95% CI) were used to assess the strength between allele and genotype of the locus and risk of CRC. In our study, we found that genotype GG of rs895819 was significantly associated with an increased risk for CRC (17.1% vs. 11.6%, adjusted OR = 1.546, 95% CI = 1.070-2.236), and allele A carrier (AA/AG) was significantly associated with a decreased risk for CRC (82.9% vs. 89.4%, adjusted OR = 0.63, 95% CI = 0.446-0.893). In addition, a significant association was observed between genotype GG and larger tumor size (>5 cm; P GG within rs895819 might be a genetic susceptible factor for CRC. Further multicentral, large sample size, and well-designed epidemiological study as well as functional study are warrant to verify our findings. © 2015 Wiley Periodicals, Inc.

  16. Knockdown of NADPH-cytochrome P450 reductase increases the susceptibility to carbaryl in the migratory locust, Locusta migratoria.

    Science.gov (United States)

    Zhang, Xueyao; Wang, Junxiu; Liu, Jiao; Li, Yahong; Liu, Xiaojian; Wu, Haihua; Ma, Enbo; Zhang, Jianzhen

    2017-12-01

    NADPH-cytochrome P450 reductase (CPR) plays important roles in cytochrome P450-mediated metabolism of endogenous and exogenous compounds, and participates in cytochrome P450-related detoxification of insecticides. However, the CPR from Locusta migratoria has not been well characterized and its function is still undescribed. The full-length of CPR gene from Locusta migratoria (LmCPR) was cloned by RT-PCR based on transcriptome information. The membrane anchor region, and 3 conserved domains (FMN binding domain, connecting domain, FAD/NADPH binding domain) were analyzed by bioinformatics analysis. Phylogenetic analysis showed that LmCPR was grouped in the Orthoptera branch and was more closely related to the CPRs from hemimetabolous insects. The LmCPR gene was ubiquitously expressed at all developmental stages and was the most abundant in the fourth-instar nymphs and the lowest in the egg stage. Tissue-specific expression analysis showed that LmCPR was higher expressed in ovary, hindgut, and integument. The CPR activity was relatively higher in Malpighian tubules and integument. Silencing of LmCPR obviously reduced the enzymatic activity of LmCPR, and enhanced the susceptibility of Locusta migratoria to carbaryl. These results suggest that LmCPR contributes to the susceptibility of L. migratoria to carbaryl and could be considered as a novel target for pest control. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Triglyceride content in remnant lipoproteins is significantly increased after food intake and is associated with plasma lipoprotein lipase.

    Science.gov (United States)

    Nakajima, Katsuyuki; Tokita, Yoshiharu; Sakamaki, Koji; Shimomura, Younosuke; Kobayashi, Junji; Kamachi, Keiko; Tanaka, Akira; Stanhope, Kimber L; Havel, Peter J; Wang, Tao; Machida, Tetsuo; Murakami, Masami

    2017-02-01

    Previous large population studies reported that non-fasting plasma triglyceride (TG) reflect a higher risk for cardiovascular disease than TG in the fasting plasma. This is suggestive of the presence of higher concentration of remnant lipoproteins (RLP) in postprandial plasma. TG and RLP-TG together with other lipids, lipoproteins and lipoprotein lipase (LPL) in both fasting and postprandial plasma were determined in generally healthy volunteers and in patients with coronary artery disease (CAD) after consuming a fat load or a more typical moderate meal. RLP-TG/TG ratio (concentration) and RLP-TG/RLP-C ratio (particle size) were significantly increased in the postprandial plasma of both healthy controls and CAD patients compared with those in fasting plasma. LPL/RLP-TG ratio demonstrated the interaction correlation between RLP concentration and LPL activity The increased RLP-TG after fat consumption contributed to approximately 90% of the increased plasma TG, while approximately 60% after a typical meal. Plasma LPL in postprandial plasma was not significantly altered after either type of meal. Concentrations of RLP-TG found in the TG along with its particle size are significantly increased in postprandial plasma compared with fasting plasma. Therefore, non-fasting TG determination better reflects the presence of higher RLP concentrations in plasma. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  18. High-fat/fructose feeding during prenatal and postnatal development in female rats increases susceptibility to renal and metabolic injury later in life

    OpenAIRE

    Flynn, Elizabeth R.; Alexander, Barbara T.; Lee, Jonathan; Hutchens, Zachary M.; Maric-Bilkan, Christine

    2012-01-01

    Accumulating evidence suggests that both an adverse prenatal and early postnatal environment increase susceptibility to renal and metabolic dysfunction later in life; however, whether exposure to adverse conditions during both prenatal and postnatal development act synergistically to potentiate the severity of renal and metabolic injury remains unknown. Sprague-Dawley rats were fed either a standard diet or a diet high in fat/fructose throughout pregnancy and lactation. After being weaned, fe...

  19. Significant social events and increasing use of life-sustaining treatment: trend analysis using extracorporeal membrane oxygenation as an example.

    Science.gov (United States)

    Chen, Yen-Yuan; Chen, Likwang; Huang, Tien-Shang; Ko, Wen-Je; Chu, Tzong-Shinn; Ni, Yen-Hsuan; Chang, Shan-Chwen

    2014-03-04

    Most studies have examined the outcomes of patients supported by extracorporeal membrane oxygenation as a life-sustaining treatment. It is unclear whether significant social events are associated with the use of life-sustaining treatment. This study aimed to compare the trend of extracorporeal membrane oxygenation use in Taiwan with that in the world, and to examine the influence of significant social events on the trend of extracorporeal membrane oxygenation use in Taiwan. Taiwan's extracorporeal membrane oxygenation uses from 2000 to 2009 were collected from National Health Insurance Research Dataset. The number of the worldwide extracorporeal membrane oxygenation cases was mainly estimated using Extracorporeal Life Support Registry Report International Summary July 2012. The trend of Taiwan's crude annual incidence rate of extracorporeal membrane oxygenation use was compared with that of the rest of the world. Each trend of extracorporeal membrane oxygenation use was examined using joinpoint regression. The measurement was the crude annual incidence rate of extracorporeal membrane oxygenation use. Each of the Taiwan's crude annual incidence rates was much higher than the worldwide one in the same year. Both the trends of Taiwan's and worldwide crude annual incidence rates have significantly increased since 2000. Joinpoint regression selected the model of the Taiwan's trend with one joinpoint in 2006 as the best-fitted model, implying that the significant social events in 2006 were significantly associated with the trend change of extracorporeal membrane oxygenation use following 2006. In addition, significantly social events highlighted by the media are more likely to be associated with the increase of extracorporeal membrane oxygenation use than being fully covered by National Health Insurance. Significant social events, such as a well-known person's successful extracorporeal membrane oxygenation use highlighted by the mass media, are associated with the use of

  20. Placental-mediated increased cytokine response to lipopolysaccharides: a potential mechanism for enhanced inflammation susceptibility of the preterm fetus

    Directory of Open Access Journals (Sweden)

    Ross MG

    2012-07-01

    vehicle. Conversely, interleukin-6 release from e20 explants was not significantly different compared with vehicle, and tumor necrosis alpha release was only 2-fold higher (P < 0.05 versus vehicle following exposure to lipopolysaccharide. Phosphorylated NFκB protein expression was significantly increased in the nuclear fraction from placental explants exposed to lipopolysaccharide at both e16 and e20, although TLR4 protein expression was unaffected.Conclusion: Lipopolysaccharide induces higher interleukin-6 and tumor necrosis alpha expression at e16 versus e20, suggesting that preterm placentas may have a greater placental cytokine response to lipopolysaccharide infection. Furthermore, increased phosphorylated NFκB indicates that placental cytokine induction may occur by activation of the TLR4 pathway.Keywords: cytokines, lipopolysaccharide, NFκB, placenta, rat pregnancy

  1. Polymorphisms of the CRP gene inhibit inflammatory response and increase susceptibility to depression: the Health in Men Study.

    Science.gov (United States)

    Almeida, Osvaldo P; Norman, Paul E; Allcock, Richard; van Bockxmeer, Frank; Hankey, Graeme J; Jamrozik, Konrad; Flicker, Leon

    2009-08-01

    Depression has been associated with chronic changes in the serum concentration of C-reactive protein (CRP) in observational studies, but it is unclear if this association is causal or is due to confounding and bias. Genetic studies are less subject to this type of error and offer an opportunity to investigate if CRP is causally linked to depression, particularly because known polymorphisms of the CRP gene have been associated with high- and low-basal serum concentrations of CRP [single nucleotide polymorphisms (SNPs) rs1130864 and rs1205, respectively]. The aim of this study is to determine if polymorphisms of SNPs rs1130864 and rs1205 are associated with prevalent depression. We completed a cross-sectional study of a community sample of 3700 men aged > or = 70 years, and used the 15-item Geriatric Depression Scale (GDS-15) to assess depressive symptoms. A GDS-15 score 7 or more indicates the presence of clinically significant depressive symptoms. Physical morbidity was assessed with the physical component summary score (PCS) of the SF-36 Health Survey. We collected fasting blood samples to measure high sensitivity CRP and to extract DNA for the genotyping of SNPs rs1130864 and rs1205 of the CRP gene. One hundred and eighty-two men were depressed (4.9%). The odds of depression increased by 2% (95% CI = 1-4%) for every unit (mg/l) increase of CRP and nearly doubled for men with CRP > or = 3 mg/l vs or = 3 mg/l) and depression was no longer significant after the analyses were adjusted for smoking, age, body mass index (BMI) and PCS. Men with the CT and TT genotypes of rs1130864 had 1.36 (95% CI = 1.13-1.63) and 2.31 (95% CI = 1.65-3.24) greater odds of CRP > or = 3 mg/l than CC carriers, but there was no association between this polymorphism and the presence of prevalent depression. The G > A polymorphism of SNP rs1205 was associated with 24% (95% CI = 16-32%) lower concentration of CRP compared with other genotypes. Men with the rs1205 AA genotype had 1.66 (95% CI

  2. Children born by women with rheumatoid arthritis have increased susceptibility for selected chronic diseases – a nationwide cohort study

    DEFF Research Database (Denmark)

    Jølving, Line Riis; Nielsen, Jan; Kesmodel, Ulrik Schiøler

    2018-01-01

    on the Danish health registries and included data on all children born alive in Denmark from January 1st 1989 to December 31st 2013. The cohort comprised 2106 children born by women with RA (exposed), and 1 378 539 children born by women without RA (unexposed). Cox proportional hazard regression models were.......89 (95% CI, 2.06 - 4.05). The HR's for anxiety and personality disorders and chronic lung disease including asthma were in the range of 1.15 - 1.16, but these were not statistically significant. CONCLUSIONS: Our results suggest that in utero exposure to maternal RA is associated with an increased risk......OBJECTIVE: Fetal exposure to maternal rheumatoid arthritis (RA) might impact the long-term risk of disease in the offspring. We examined a possible association between maternal RA and 15 selected groups of chronic diseases in the offspring. METHODS: This nationwide cohort study was based...

  3. A standing posture is associated with increased susceptibility to the sound-induced flash illusion in fall-prone older adults.

    Science.gov (United States)

    Stapleton, John; Setti, Annalisa; Doheny, Emer P; Kenny, Rose Anne; Newell, Fiona N

    2014-02-01

    Recent research has provided evidence suggesting a link between inefficient processing of multisensory information and incidence of falling in older adults. Specifically, Setti et al. (Exp Brain Res 209:375-384, 2011) reported that older adults with a history of falling were more susceptible than their healthy, age-matched counterparts to the sound-induced flash illusion. Here, we investigated whether balance control in fall-prone older adults was directly associated with multisensory integration by testing susceptibility to the illusion under two postural conditions: sitting and standing. Whilst standing, fall-prone older adults had a greater body sway than the age-matched healthy older adults and their body sway increased when presented with the audio-visual illusory but not the audio-visual congruent conditions. We also found an increase in susceptibility to the sound-induced flash illusion during standing relative to sitting for fall-prone older adults only. Importantly, no performance differences were found across groups in either the unisensory or non-illusory multisensory conditions across the two postures. These results suggest an important link between multisensory integration and balance control in older adults and have important implications for understanding why some older adults are prone to falling.

  4. Testosterone depletion increases the susceptibility of brain tissue to oxidative damage in a restraint stress mouse model.

    Science.gov (United States)

    Son, Seung-Wan; Lee, Jin-Seok; Kim, Hyeong-Geug; Kim, Dong-Woon; Ahn, Yo-Chan; Son, Chang-Gue

    2016-01-01

    Among sex hormones, estrogen is particularly well known to act as neuroprotective agent. Unlike estrogen, testosterone has not been well investigated in regard to its effects on the brain, especially under psychological stress. To investigate the role of testosterone in oxidative brain injuries under psychological stress, we adapted an orchiectomy and restraint stress model. BALB/c mice were subjected to either an orchiectomy or sham operation. After allowing 15 days for recovery, mice were re-divided into four groups according to exposure of restraint stress: sham, sham plus stress, orchiectomy, and orchiectomy plus stress. Serum testosterone was undetectable in orchiectomized groups and restraint-induced stress significantly reduced testosterone levels in sham plus stress group. The serum levels of corticosterone and adrenaline were notably elevated by restraint stress, and these elevated hormones were markedly augmented by orchiectomy. Two oxidative stressors and biomarkers for lipid and protein peroxidation were significantly increased in the cerebral cortex and hippocampus by restraint stress, while the reverse pattern was observed in antioxidant enzymes. These results were supported by histopathological findings, with 4-hydroxynonenal staining for oxidative injury and Fluoro-Jade B staining showing the degenerating neurons. The aforementioned patterns of oxidative injury were accelerated by orchiectomy. These findings strongly suggest the conclusion that testosterone exerts a protective effect against oxidative brain damage, especially under stressed conditions. Unlike estrogen, the effects of testosterone on the brain have not been thoroughly investigated. In order to investigate the role of testosterone in oxidative brain injuries under psychological stress, we adapted an orchiectomy and restraint stress model. Orchiectomy markedly augmented the restraint stress-induced elevation of serum corticosterone and adrenaline levels as well as oxidative alterations

  5. Hen's egg allergen in house and bed dust is significantly increased after hen's egg consumption-A pilot study.

    Science.gov (United States)

    Trendelenburg, V; Tschirner, S; Niggemann, B; Beyer, K

    2017-09-02

    Environmental exposure to food allergens may be a risk factor for cutaneous sensitization. Previous studies could detect peanut allergen in house dust. In this pilot study, we wanted to investigate whether hen's egg allergen is detectable in house dust collected from different household areas and whether levels are increased after intentional hen's egg consumption. Hen's egg protein levels of dust samples were measured using ELISA. In 8 of 8 households, hen's egg was detectable in dust samples of eating area and bed. Forty-eight hours after intentional hen's egg consumption, hen's egg protein levels were significantly increased in both. Still, further research is necessary to investigate whether hen's egg allergen in house and bed dust plays a role in sensitization via skin. © 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

  6. A significant increase in the frequency of hand-foot-mouth disease in İstanbul in June 2012

    Directory of Open Access Journals (Sweden)

    Algün Polat Ekinci

    2013-12-01

    Full Text Available We have reviwed that there is a dramatic increase in the frequency of hand-foot-mouth disease at Dermatovenerology Department of İstanbul Medical Faculty in June 2013 compared to previous years. When we compared these data with those of June 2011, we have determined a significant difference statistically. We have learned from the authorities of City Health Administrative that they had not been reported about this issue. Although it is difficult to comment based on the data of a single clinic, we want to draw attention that there is a possibility for epidemic disease and a need for national data about this disease.

  7. Thymoquinone inhibits the CXCL12-induced chemotaxis of multiple myeloma cells and increases their susceptibility to Fas-mediated apoptosis.

    Directory of Open Access Journals (Sweden)

    Gamal Badr

    Full Text Available In multiple myeloma (MM, malignant plasma cells reside in the bone marrow, where they accumulate in close contact with stromal cells. The mechanisms responsible for the chemotaxis of malignant plasma cells are still poorly understood. Thus, we investigated the mechanisms involved in the chemotaxis of MDN and XG2 MM cell lines. Both cell lines strongly expressed CCR9, CXCR3 and CXCR4 chemokine receptors but only migrated toward CXCL12. Activation of CXCR4 by CXCL12 resulted in the association of CXCR4 with CD45 and activation of PLCβ3, AKT, RhoA, IκBα and ERK1/2. Using siRNA-silencing techniques, we showed CD45/CXCR4 association is essential for CXCL12-induced migration of MM cells. Thymoquinone (TQ, the major active component of the medicinal herb Nigella sativa Linn, has been described as a chemopreventive and chemotherapeutic compound. TQ treatment strongly inhibited CXCL12-mediated chemotaxis in MM cell lines as well as primary cells isolated from MM patients, but not normal PBMCs. Moreover, TQ significantly down-regulated CXCR4 expression and CXCL12-mediated CXCR4/CD45 association in MM cells. Finally, TQ also induced the relocalization of cytoplasmic Fas/CD95 to the membrane of MM cells and increased CD95-mediated apoptosis by 80%. In conclusion, we demonstrate the potent anti-myeloma activity of TQ, providing a rationale for further clinical evaluation.

  8. Analysis of a large dataset of mycorrhiza inoculation field trials on potato shows highly significant increases in yield.

    Science.gov (United States)

    Hijri, Mohamed

    2016-04-01

    An increasing human population requires more food production in nutrient-efficient systems in order to simultaneously meet global food needs while reducing the environmental footprint of agriculture. Arbuscular mycorrhizal fungi (AMF) have the potential to enhance crop yield, but their efficiency has yet to be demonstrated in large-scale crop production systems. This study reports an analysis of a dataset consisting of 231 field trials in which the same AMF inoculant (Rhizophagus irregularis DAOM 197198) was applied to potato over a 4-year period in North America and Europe under authentic field conditions. The inoculation was performed using a liquid suspension of AMF spores that was sprayed onto potato seed pieces, yielding a calculated 71 spores per seed piece. Statistical analysis showed a highly significant increase in marketable potato yield (ANOVA, P < 0.0001) for inoculated fields (42.2 tons/ha) compared with non-inoculated controls (38.3 tons/ha), irrespective of trial year. The average yield increase was 3.9 tons/ha, representing 9.5 % of total crop yield. Inoculation was profitable with a 0.67-tons/ha increase in yield, a threshold reached in almost 79 % of all trials. This finding clearly demonstrates the benefits of mycorrhizal-based inoculation on crop yield, using potato as a case study. Further improvements of these beneficial inoculants will help compensate for crop production deficits, both now and in the future.

  9. Infection of host plants by Cucumber mosaic virus increases the susceptibility of Myzus persicae aphids to the parasitoid Aphidius colemani.

    Science.gov (United States)

    Mauck, Kerry E; De Moraes, Consuelo M; Mescher, Mark C

    2015-06-04

    Plant viruses can profoundly alter the phenotypes of their host plants, with potentially far-reaching implications for ecology. Yet few studies have explored the indirect, host-mediated, effects of plant viruses on non-vector insects. We examined how infection of Cucurbita pepo plants by Cucumber mosaic virus (CMV) impacted the susceptibility of aphids (Myzus persicae) to attack by the parasitoid wasp Aphidius colemani. In semi-natural foraging assays, we observed higher rates of aphid parasitism on infected plants compared to healthy plants. Subsequent experiments revealed that this difference is not explained by different attack rates on plants differing in infection status, but rather by the fact that parasitoid larvae successfully complete their development more often when aphid hosts feed on infected plants. This suggests that the reduced nutritional quality of infected plants as host for aphids--documented in previous studies--compromises their ability to mount effective defenses against parasitism. Furthermore, our current findings indicate that the aphid diet during parasitoid development (rather than prior to wasp oviposition) is a key factor influencing resistance. These findings complement our previous work showing that CMV-induced changes in host plant chemistry alter patterns of aphid recruitment and dispersal in ways conducive to virus transmission.

  10. Susceptibility of experimental faults to pore pressure increase: insights from load-controlled experiments on calcite-bearing rocks

    Science.gov (United States)

    Spagnuolo, Elena; Violay, Marie; Nielsen, Stefan; Cornelio, Chiara; Di Toro, Giulio

    2017-04-01

    Fluid pressure has been indicated as a major factor controlling natural (e.g., L'Aquila, Italy, 2009 Mw 6.3) and induced seismicity (e.g., Wilzetta, Oklahoma, 2011 Mw 5.7). Terzaghi's principle states that the effective normal stress is linearly reduced by a pore pressure (Pf) increase σeff=σn(1 - αPf), where the effective stress parameter α, may be related to the fraction of the fault area that is flooded. A value of α =1 is often used by default, with Pf shifting the Mohr circle towards lower normal effective stresses and anticipating failure on pre-existing faults. However, within a complex fault core of inhomogeneous permeability, α may vary in a yet poorly understood way. To shed light on this problem, we conducted experiments on calcite-bearing rock samples (Carrara marble) at room humidity conditions and in the presence of pore fluids (drained conditions) using a rotary apparatus (SHIVA). A pre-cut fault is loaded by constant shear stress τ under constant normal stress σn=15 MPa until a target value corresponding roughly to the 80 % of the frictional fault strength. The pore pressure Pf is then raised with regular pressure and time steps to induce fault instability. Assuming α=1 and a threshold for instability τp_eff=μp σeff, the experiments reveal that an increase of Pf does not necessarily induce an instability even when the effective strength threshold is largely surpassed (e.g., τp_eff=1.3 μpσeff). This result may indicate that the Pf increase did not instantly diffuse throughout the slip zone, but took a finite time to equilibrate with the external imposed pressure increase due to finite permeability. Under our experimental conditions, a significant departure from α=1 is observed provided that the Pf step is shorter than about < 20s. We interpret this delay as indicative of the diffusion time (td), which is related to fluid penetration length l by l = √ κtd-, where κ is the hydraulic diffusivity on the fault plane. We show that a

  11. Expression of a bacterial catalase in a strictly anaerobic methanogen significantly increases tolerance to hydrogen peroxide but not oxygen

    Science.gov (United States)

    Jennings, Matthew E.; Schaff, Cody W.; Horne, Alexandra J.; Lessner, Faith H.

    2014-01-01

    Haem-dependent catalase is an antioxidant enzyme that degrades H2O2, producing H2O and O2, and is common in aerobes. Catalase is present in some strictly anaerobic methane-producing archaea (methanogens), but the importance of catalase to the antioxidant system of methanogens is poorly understood. We report here that a survey of the sequenced genomes of methanogens revealed that the majority of species lack genes encoding catalase. Moreover, Methanosarcina acetivorans is a methanogen capable of synthesizing haem and encodes haem-dependent catalase in its genome; yet, Methanosarcina acetivorans cells lack detectable catalase activity. However, inducible expression of the haem-dependent catalase from Escherichia coli (EcKatG) in the chromosome of Methanosarcina acetivorans resulted in a 100-fold increase in the endogenous catalase activity compared with uninduced cells. The increased catalase activity conferred a 10-fold increase in the resistance of EcKatG-induced cells to H2O2 compared with uninduced cells. The EcKatG-induced cells were also able to grow when exposed to levels of H2O2 that inhibited or killed uninduced cells. However, despite the significant increase in catalase activity, growth studies revealed that EcKatG-induced cells did not exhibit increased tolerance to O2 compared with uninduced cells. These results support the lack of catalase in the majority of methanogens, since methanogens are more likely to encounter O2 rather than high concentrations of H2O2 in the natural environment. Catalase appears to be a minor component of the antioxidant system in methanogens, even those that are aerotolerant, including Methanosarcina acetivorans. Importantly, the experimental approach used here demonstrated the feasibility of engineering beneficial traits, such as H2O2 tolerance, in methanogens. PMID:24222618

  12. The adipokine leptin increases skeletal muscle mass and significantly alters skeletal muscle miRNA expression profile in aged mice

    Energy Technology Data Exchange (ETDEWEB)

    Hamrick, Mark W., E-mail: mhamrick@mail.mcg.edu [Department of Cellular Biology and Anatomy, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); Department of Orthopaedic Surgery, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); Herberg, Samuel; Arounleut, Phonepasong [Department of Cellular Biology and Anatomy, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); Department of Orthopaedic Surgery, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); He, Hong-Zhi [Henry Ford Immunology Program, Henry Ford Health System, Detroit, MI (United States); Department of Dermatology, Henry Ford Health System, Detroit, MI (United States); Shiver, Austin [Department of Cellular Biology and Anatomy, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); Department of Orthopaedic Surgery, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); Qi, Rui-Qun [Henry Ford Immunology Program, Henry Ford Health System, Detroit, MI (United States); Department of Dermatology, Henry Ford Health System, Detroit, MI (United States); Zhou, Li [Henry Ford Immunology Program, Henry Ford Health System, Detroit, MI (United States); Department of Dermatology, Henry Ford Health System, Detroit, MI (United States); Department of Internal Medicine, Henry Ford Health System, Detroit, MI (United States); Isales, Carlos M. [Department of Cellular Biology and Anatomy, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); Department of Orthopaedic Surgery, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); and others

    2010-09-24

    Research highlights: {yields} Aging is associated with muscle atrophy and loss of muscle mass, known as the sarcopenia of aging. {yields} We demonstrate that age-related muscle atrophy is associated with marked changes in miRNA expression in muscle. {yields} Treating aged mice with the adipokine leptin significantly increased muscle mass and the expression of miRNAs involved in muscle repair. {yields} Recombinant leptin therapy may therefore be a novel approach for treating age-related muscle atrophy. -- Abstract: Age-associated loss of muscle mass, or sarcopenia, contributes directly to frailty and an increased risk of falls and fractures among the elderly. Aged mice and elderly adults both show decreased muscle mass as well as relatively low levels of the fat-derived hormone leptin. Here we demonstrate that loss of muscle mass and myofiber size with aging in mice is associated with significant changes in the expression of specific miRNAs. Aging altered the expression of 57 miRNAs in mouse skeletal muscle, and many of these miRNAs are now reported to be associated specifically with age-related muscle atrophy. These include miR-221, previously identified in studies of myogenesis and muscle development as playing a role in the proliferation and terminal differentiation of myogenic precursors. We also treated aged mice with recombinant leptin, to determine whether leptin therapy could improve muscle mass and alter the miRNA expression profile of aging skeletal muscle. Leptin treatment significantly increased hindlimb muscle mass and extensor digitorum longus fiber size in aged mice. Furthermore, the expression of 37 miRNAs was altered in muscles of leptin-treated mice. In particular, leptin treatment increased the expression of miR-31 and miR-223, miRNAs known to be elevated during muscle regeneration and repair. These findings suggest that aging in skeletal muscle is associated with marked changes in the expression of specific miRNAs, and that nutrient

  13. Prognostic significance of increased bone marrow microcirculation in newly diagnosed multiple myeloma: results of a prospective DCE-MRI study

    Energy Technology Data Exchange (ETDEWEB)

    Merz, Maximilian; Hillengass, Jens [Department of Radiology, German Cancer Research Center, Heidelberg (Germany); University of Heidelberg, Department of Hematology, Oncology and Rheumatology, Heidelberg (Germany); Moehler, Thomas M.; Ritsch, Judith; Delorme, Stefan [Department of Radiology, German Cancer Research Center, Heidelberg (Germany); Baeuerle, Tobias [University of Erlangen-Nuremberg, Department of Radiology, Erlangen (Germany); Zechmann, Christian M. [Rinecker Proton Therapy, Muenchen (Germany); Wagner, Barbara; Hose, Dirk [University of Heidelberg, Department of Hematology, Oncology and Rheumatology, Heidelberg (Germany); Jauch, Anna [University of Heidelberg, Institute of Human Genetics, Heidelberg (Germany); Kunz, Christina; Hielscher, Thomas [German Cancer Research Center, Department of Biostatistics, Heidelberg (Germany); Laue, Hendrik [Fraunhofer MEVIS, Bremen (Germany); Goldschmidt, Hartmut [University of Heidelberg, Department of Hematology, Oncology and Rheumatology, Heidelberg (Germany); National Center for Tumor Diseases, Heidelberg (Germany)

    2016-05-15

    Aim of this prospective study was to investigate prognostic significance of increased bone marrow microcirculation as detected by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for survival and local complications in patients with multiple myeloma (MM). We performed DCE-MRI of the lumbar spine in 131 patients with newly diagnosed MM and analysed data according to the Brix model to acquire amplitude A and exchange rate constant k{sub ep}. In 61 patients a second MRI performed after therapy was evaluated to assess changes in vertebral height and identify vertebral fractures. Correlation analysis revealed significant positive association between beta2-microglobulin as well as immunoparesis with DCE-MRI parameters A and k{sub ep}. Additionally, A was negatively correlated with haemoglobin levels and k{sub ep} was positively correlated with LDH levels. Higher baseline k{sub ep} values were associated with decreased vertebral height in a second MRI (P = 0.007) and A values were associated with new vertebral fractures in the lower lumbar spine (P = 0.03 for L4). Pre-existing lytic bone lesions or remission after therapy had no impact on the occurrence of vertebral fractures. Multivariate analysis revealed that amplitude A is an independent adverse risk factor for overall survival. DCE-MRI is a non-invasive tool with significance for systemic prognosis and vertebral complications. (orig.)

  14. The contribution of human agricultural activities to increasing evapotranspiration is significantly greater than climate change effect over Heihe agricultural region.

    Science.gov (United States)

    Zou, Minzhong; Niu, Jun; Kang, Shaozhong; Li, Xiaolin; Lu, Hongna

    2017-08-18

    Evapotranspiration (ET) is a major component linking the water, energy, and carbon cycles. Understanding changes in ET and the relative contribution rates of human activity and of climate change at the basin scale is important for sound water resources management. In this study, changes in ET in the Heihe agricultural region in northwest China during 1984-2014 were examined using remotely-sensed ET data with the Soil and Water Assessment Tool (SWAT). Correlation analysis identified the dominant factors that influence change in ET per unit area and those that influence change in total ET. Factor analysis identified the relative contribution rates of the dominant factors in each case. The results show that human activity, which includes factors for agronomy and irrigation, and climate change, including factors for precipitation and relative humidity, both contribute to increases in ET per unit area at rates of 60.93% and 28.01%, respectively. Human activity, including the same factors, and climate change, including factors for relative humidity and wind speed, contribute to increases in total ET at rates of 53.86% and 35.68%, respectively. Overall, in the Heihe agricultural region, the contribution of human agricultural activities to increased ET was significantly greater than that of climate change.

  15. HIV-1 Structural Proteins Serve as PAMPs for TLR2 Heterodimers Significantly Increasing Infection and Innate Immune Activation.

    Science.gov (United States)

    Henrick, Bethany M; Yao, Xiao-Dan; Rosenthal, Kenneth Lee

    2015-01-01

    Immune activation is critical to HIV infection and pathogenesis; however, our understanding of HIV innate immune activation remains incomplete. Recently we demonstrated that soluble TLR2 (sTLR2) physically inhibited HIV-induced NFκB activation and inflammation, as well as HIV-1 infection. In light of these findings, we hypothesized that HIV-1 structural proteins may serve as pathogen-associated molecular patterns (PAMPs) for cellular TLR2 heterodimers. These studies made use of primary human T cells and TZMbl cells stably transformed to express TLR2 (TZMbl-2). Our results demonstrated that cells expressing TLR2 showed significantly increased proviral DNA compared to cells lacking TLR2, and mechanistically this may be due to a TLR2-mediated increased CCR5 expression. Importantly, we show that HIV-1 structural proteins, p17, p24, and gp41, act as viral PAMPs signaling through TLR2 and its heterodimers leading to significantly increased immune activation via the NFκB signaling pathway. Using co-immunoprecipitation and a dot blot method, we demonstrated direct protein interactions between these viral PAMPs and TLR2, while only p17 and gp41 bound to TLR1. Specifically, TLR2/1 heterodimer recognized p17 and gp41, while p24 lead to immune activation through TLR2/6. These results were confirmed using TLR2/1 siRNA knock down assays which ablated p17 and gp41-induced cellular activation and through studies of HEK293 cells expressing selected TLRs. Interestingly, our results show in the absence of TLR6, p24 bound to TLR2 and blocked p17 and gp41-induced activation, thus providing a novel mechanism by which HIV-1 can manipulate innate sensing. Taken together, our results identified, for the first time, novel HIV-1 PAMPs that play a role in TLR2-mediated cellular activation and increased proviral DNA. These findings have important implications for our fundamental understanding of HIV-1 immune activation and pathogenesis, as well as HIV-1 vaccine development.

  16. Little evidence for significant increases of methane emissions from oil and gas operations in the U.S.

    Science.gov (United States)

    Lan, X.; Tans, P. P.; Sweeney, C.; Andrews, A. E.; Dlugokencky, E. J.; Lang, P. M.; Crotwell, M.; Miller, B.; Kofler, J.; Newberger, T.; McKain, K.; Wolter, S.; Montzka, S. A.

    2016-12-01

    Recent studies on whether methane (CH4) emissions from oil and natural gas (ONG) operations in the U.S. have increased are still inconclusive. To provide observational evidence we carefully analyzed the in-situ CH4 measurements from the NOAA/ESRL Global Greenhouse Gas Reference Network (GGGRN) for the best estimates of CH4 trends for 2006-2016. Methane data from more than 20 surface and aircraft sites across the U.S. were included in this study. Variations of sampling frequencies in different seasons were taken into account for accurate trend detection. Correlations among measurements within short sampling intervals were also considered for uncertainty estimates. We found that most of our sites had similar CH4 trends of 6 ppb/yr, which was comparable with the recent global background CH4 trend. Substantially higher growth rates were found at the Southern Great Plain site in Oklahoma (SGP, downwind of the Eagle Ford, Barnett Shale and Woodford ONG fields) and the Dahlen sites in North Dakota (DND, downwind of the Bakken ONG field), which indicated influences from regional ONG activities. Ethane (C2H6) measurements from SGP (C2H6 measurements were not available from DND) and propane (C3H8) measurements from both SPG and DND exhibited significant increasing trends, while trends at other sites were either non-significant (trend ONG emissions) on CH4 trend estimates, we would infer much larger surface CH4 trends than what we actually observed at these two sites. This discrepancy suggests that using enhancement ratios of C3H8 /CH4 is not likely a reliable approach to compute CH4 emission trends.

  17. High-risk human papillomavirus E7 expression reduces cell-surface MHC class I molecules and increases susceptibility to natural killer cells

    DEFF Research Database (Denmark)

    Bottley, G; Watherston, O G; Hiew, Y-L

    2007-01-01

    High-risk human papillomavirus (HPV) is a major causative agent of cervical cancer and the E6 and E7 genes encode the major HPV oncoproteins. The E7 protein from high-risk HPV types alters cell cycle progression and represses genes encoding components of the antigen-presentation pathway, suggesting...... a role for E7 in tumour immune evasion. We show that knockdown of E7 expression in HPV16- and HPV18-transformed cervical carcinoma cells by RNA interference increased expression of major histocompatibility complex (MHC) class I at the cell surface and reduced susceptibility of these cells to natural...

  18. A Prolonged Time Interval Between Trauma and Prophylactic Radiation Therapy Significantly Increases the Risk of Heterotopic Ossification

    Energy Technology Data Exchange (ETDEWEB)

    Mourad, Waleed F., E-mail: Waleed246@gmail.com [Department of Radiation Oncology, University of Mississippi Medical Center, Jackson, MS (United States); Department of Radiation Oncology, Beth Israel Medical Center, New York, NY (Israel); Packianathan, Satyaseelan [Department of Radiation Oncology, University of Mississippi Medical Center, Jackson, MS (United States); Shourbaji, Rania A. [Department of Epidemiology and Biostatistics, Jackson State University, Jackson, MS (United States); Zhang Zhen; Graves, Mathew [Department of Orthopedic Surgery, University of Mississippi Medical Center, Jackson, MS (United States); Khan, Majid A. [Department of Radiology, University of Mississippi Medical Center, Jackson, MS (United States); Baird, Michael C. [Department of Radiation Oncology, University of Mississippi Medical Center, Jackson, MS (United States); Russell, George [Department of Orthopedic Surgery, University of Mississippi Medical Center, Jackson, MS (United States); Vijayakumar, Srinivasan [Department of Radiation Oncology, University of Mississippi Medical Center, Jackson, MS (United States)

    2012-03-01

    Purpose: To ascertain whether the time from injury to prophylactic radiation therapy (RT) influences the rate of heterotopic ossification (HO) after operative treatment of displaced acetabular fractures. Methods and Materials: This is a single-institution, retrospective analysis of patients referred for RT for the prevention of HO. Between January 2000 and January 2009, 585 patients with displaced acetabular fractures were treated surgically followed by RT for HO prevention. We analyzed the effect of time from injury on prevention of HO by RT. In all patients, 700 cGy was prescribed in a single fraction and delivered within 72 hours postsurgery. The patients were stratified into five groups according to time interval (in days) from the date of their accident to the date of RT: Groups A {<=}3, B {<=}7, C {<=}14, D {<=}21, and E >21days. Results: Of the 585 patients with displaced acetabular fractures treated with RT, (18%) 106 patients developed HO within the irradiated field. The risk of HO after RT increased from 10% for RT delivered {<=}3 days to 92% for treatment delivered >21 days after the initial injury. Wilcoxon test showed a significant correlation between the risk of HO and the length of time from injury to RT (p < 0.0001). Chi-square test and multiple logistic regression analysis showed no significant association between all other factors and the risk of HO (race, gender, cause and type of fracture, surgical approach, or the use of indomethacin). Conclusions: Our data suggest that there is higher incidence and risk of HO if prophylactic RT is significantly delayed after a displaced acetabular fracture. Thus, RT should be administered as early as clinically possible after the trauma. Patients undergoing RT >3 weeks from their displaced acetabular fracture should be informed of the higher risk (>90%) of developing HO despite prophylaxis.

  19. Student Acceptance of Plain Milk Increases Significantly 2 Years after Flavored Milk Is Removed from School Cafeterias: An Observational Study.

    Science.gov (United States)

    Schwartz, Marlene B; Henderson, Kathryn E; Read, Margaret; Cornelius, Talea

    2017-07-13

    Previous studies document decreases in lunchtime milk consumption immediately after flavored milk is removed. Less is known about longer-term effects. Plain milk selection and consumption were measured the first year flavored milk was removed in a school district (2010 to 2011 [Time 1]) and 2 years later (2012 to 2013 [Time 2]). Four behavioral economic interventions to promote milk were tested in one school at Time 2. This was a longitudinal, observational study. Participants were kindergarten through grade 8 students in two schools in an urban district. Primary data were collected 10 times per school year at Time 1 and Time 2, yielding 40 days of data and 13,883 student observations. The milk promotion interventions were tested on 6 additional days. Outcomes were the percentage of students selecting milk at lunch, the ounces of milk consumed per carton, and the ounces of milk consumed school-wide per student. Logistic regressions were used to assess how sex, grade, time, availability of 100% juice, and behavioral interventions affected milk selection and consumption. At Time One, 51.5% of students selected milk and drank 4 oz (standard deviation=3.2 oz) per carton, indicating school-wide per-student consumption of 2.1 oz (standard deviation=3.0 oz). At Time Two, 72% of students selected milk and consumed 3.4 oz per carton (standard deviation=3.2 oz), significantly increasing the school-wide per-student consumption to 2.5 oz (standard deviation=3.1 oz). Older students and boys consumed significantly more milk. Availability of 100% fruit juice was associated with a 16-percentage point decrease in milk selection. None of the behavioral economic interventions significantly influenced selection. These data suggest that after flavored milk is removed from school cafeterias, school-wide per-student consumption of plain milk increases over time. In addition, the presence of 100% juice is associated with lower milk selection. Copyright © 2017 Academy of Nutrition and

  20. Unequivocal detection of ozone recovery in the Antarctic Ozone Hole through significant increases in atmospheric layers with minimum ozone

    Science.gov (United States)

    de Laat, Jos; van Weele, Michiel; van der A, Ronald

    2015-04-01

    An important new landmark in present day ozone research is presented through MLS satellite observations of significant ozone increases during the ozone hole season that are attributed unequivocally to declining ozone depleting substances. For many decades the Antarctic ozone hole has been the prime example of both the detrimental effects of human activities on our environment as well as how to construct effective and successful environmental policies. Nowadays atmospheric concentrations of ozone depleting substances are on the decline and first signs of recovery of stratospheric ozone and ozone in the Antarctic ozone hole have been observed. The claimed detection of significant recovery, however, is still subject of debate. In this talk we will discuss first current uncertainties in the assessment of ozone recovery in the Antarctic ozone hole by using multi-variate regression methods, and, secondly present an alternative approach to identify ozone hole recovery unequivocally. Even though multi-variate regression methods help to reduce uncertainties in estimates of ozone recovery, great care has to be taken in their application due to the existence of uncertainties and degrees of freedom in the choice of independent variables. We show that taking all uncertainties into account in the regressions the formal recovery of ozone in the Antarctic ozone hole cannot be established yet, though is likely before the end of the decade (before 2020). Rather than focusing on time and area averages of total ozone columns or ozone profiles, we argue that the time evolution of the probability distribution of vertically resolved ozone in the Antarctic ozone hole contains a better fingerprint for the detection of ozone recovery in the Antarctic ozone hole. The advantages of this method over more tradition methods of trend analyses based on spatio-temporal average ozone are discussed. The 10-year record of MLS satellite measurements of ozone in the Antarctic ozone hole shows a

  1. Early life exposure to chronic intermittent Hypoxia Primes Increased Susceptibility to Hypoxia-Induced Weakness in Rat Sternohyoid Muscle during adulthood.

    LENUS (Irish Health Repository)

    McDonald, Fiona B

    2016-03-01

    Intermittent hypoxia is a feature of apnea of prematurity (AOP), chronic lung disease, and sleep apnea. Despite the clinical relevance, the long-term effects of hypoxic exposure in early life on respiratory control are not well defined. We recently reported that exposure to chronic intermittent hypoxia (CIH) during postnatal development (pCIH) causes upper airway muscle weakness in both sexes, which persists for several weeks. We sought to examine if there are persistent sex-dependent effects of pCIH on respiratory muscle function into adulthood and\\/or increased susceptibility to re-exposure to CIH in adulthood in animals previously exposed to CIH during postnatal development. We hypothesized that pCIH would cause long-lasting muscle impairment and increased susceptibility to subsequent hypoxia. Within 24 h of delivery, pups and their respective dams were exposed to CIH: 90 s of hypoxia reaching 5% O2 at nadir; once every 5 min, 8 h per day for 3 weeks. Sham groups were exposed to normoxia in parallel. Three groups were studied: sham; pCIH; and pCIH combined with adult CIH (p+aCIH), where a subset of the pCIH-exposed pups were re-exposed to the same CIH paradigm beginning at 13 weeks. Following gas exposures, sternohyoid and diaphragm muscle isometric contractile and endurance properties were examined ex vivo. There was no apparent lasting effect of pCIH on respiratory muscle function in adults. However, in both males and females, re-exposure to CIH in adulthood in pCIH-exposed animals caused sternohyoid (but not diaphragm) weakness. Exposure to this paradigm of CIH in adulthood alone had no effect on muscle function. Persistent susceptibility in pCIH-exposed airway dilator muscle to subsequent hypoxic insult may have implications for the control of airway patency in adult humans exposed to intermittent hypoxic stress during early life.

  2. Chimpanzees show a developmental increase in susceptibility to contagious yawning: a test of the effect of ontogeny and emotional closeness on yawn contagion.

    Directory of Open Access Journals (Sweden)

    Elainie Alenkær Madsen

    Full Text Available Contagious yawning has been reported for humans, dogs and several non-human primate species, and associated with empathy in humans and other primates. Still, the function, development and underlying mechanisms of contagious yawning remain unclear. Humans and dogs show a developmental increase in susceptibility to yawn contagion, with children showing an increase around the age of four, when also empathy-related behaviours and accurate identification of others' emotions begin to clearly evince. Explicit tests of yawn contagion in non-human apes have only involved adult individuals and examined the existence of conspecific yawn contagion. Here we report the first study of heterospecific contagious yawning in primates, and the ontogeny of susceptibility thereto in chimpanzees, Pan troglodytes verus. We examined whether emotional closeness, defined as attachment history with the yawning model, affected the strength of contagion, and compared the contagiousness of yawning to nose-wiping. Thirty-three orphaned chimpanzees observed an unfamiliar and familiar human (their surrogate human mother yawn, gape and nose-wipe. Yawning, but not nose-wiping, was contagious for juvenile chimpanzees, while infants were immune to contagion. Like humans and dogs, chimpanzees are subject to a developmental trend in susceptibility to contagious yawning, and respond to heterospecific yawn stimuli. Emotional closeness with the model did not affect contagion. The familiarity-biased social modulatory effect on yawn contagion previously found among some adult primates, seem to only emerge later in development, or be limited to interactions with conspecifics. The influence of the 'chameleon effect', targeted vs. generalised empathy, perspective-taking and visual attention on contagious yawning is discussed.

  3. Early Life Exposure to Chronic Intermittent Hypoxia Primes Increased Susceptibility to Hypoxia-Induced Weakness in Rat Sternohyoid Muscle During Adulthood

    Directory of Open Access Journals (Sweden)

    Fiona B Mcdonald

    2016-03-01

    Full Text Available Intermittent hypoxia is a feature of apnea of prematurity, chronic lung disease and sleep apnea. Despite the clinical relevance, the long-term effects of hypoxic exposure in early life on respiratory control are not well defined. We recently reported that exposure to chronic intermittent hypoxia (CIH during postnatal development (pCIH causes upper airway muscle weakness in both sexes, which persists for several weeks. We sought to examine if there are persistent sex-dependent effects of pCIH on respiratory muscle function into adulthood and/or increased susceptibility to re-exposure to CIH in adulthood in animals previously exposed to CIH during postnatal development. We hypothesized that pCIH would cause long-lasting muscle impairment and increased susceptibility to subsequent hypoxia. Within 24 hours of delivery, pups and their respective dams were exposed to CIH: 90s of hypoxia reaching 5% O2 at nadir; once every 5 min, 8 hrs per day for 3 weeks. Sham groups were exposed to normoxia in parallel. Three groups were studied: sham; pCIH; and pCIH combined with adult CIH (p+aCIH, where a subset of the pCIH-exposed pups were re-exposed to the same CIH paradigm beginning at 13 weeks. Following gas exposures, sternohyoid and diaphragm muscle isometric contractile and endurance properties were examined ex vivo. There was no apparent lasting effect of pCIH on respiratory muscle function in adults. However, in both males and females, re-exposure to CIH in adulthood in pCIH-exposed animals caused sternohyoid (but not diaphragm weakness. Exposure to this paradigm of CIH in adulthood alone had no effect on muscle function. Persistent susceptibility in pCIH-exposed airway dilator muscle to subsequent hypoxic insult may have implications for the control of airway patency in adult humans exposed to intermittent hypoxic stress during early life.

  4. Chimpanzees show a developmental increase in susceptibility to contagious yawning: a test of the effect of ontogeny and emotional closeness on yawn contagion.

    Science.gov (United States)

    Madsen, Elainie Alenkær; Persson, Tomas; Sayehli, Susan; Lenninger, Sara; Sonesson, Göran

    2013-01-01

    Contagious yawning has been reported for humans, dogs and several non-human primate species, and associated with empathy in humans and other primates. Still, the function, development and underlying mechanisms of contagious yawning remain unclear. Humans and dogs show a developmental increase in susceptibility to yawn contagion, with children showing an increase around the age of four, when also empathy-related behaviours and accurate identification of others' emotions begin to clearly evince. Explicit tests of yawn contagion in non-human apes have only involved adult individuals and examined the existence of conspecific yawn contagion. Here we report the first study of heterospecific contagious yawning in primates, and the ontogeny of susceptibility thereto in chimpanzees, Pan troglodytes verus. We examined whether emotional closeness, defined as attachment history with the yawning model, affected the strength of contagion, and compared the contagiousness of yawning to nose-wiping. Thirty-three orphaned chimpanzees observed an unfamiliar and familiar human (their surrogate human mother) yawn, gape and nose-wipe. Yawning, but not nose-wiping, was contagious for juvenile chimpanzees, while infants were immune to contagion. Like humans and dogs, chimpanzees are subject to a developmental trend in susceptibility to contagious yawning, and respond to heterospecific yawn stimuli. Emotional closeness with the model did not affect contagion. The familiarity-biased social modulatory effect on yawn contagion previously found among some adult primates, seem to only emerge later in development, or be limited to interactions with conspecifics. The influence of the 'chameleon effect', targeted vs. generalised empathy, perspective-taking and visual attention on contagious yawning is discussed.

  5. Induction of peritoneal sepsis increases the susceptibility of isolated hearts to a calcium paradox-mediated injury.

    Science.gov (United States)

    Omachi, Akira; Sharma, Avadhesh C; Alden, Kris J; Sam, Albert D; Ferguson, James L

    2002-03-01

    experiments. With sham hearts, 32% of CK release was inhibited by sucrose, while 68% of the CK release was attributed to stress associated with surgery performed in the sham-septic group. In septic hearts, only 8% of the CK release was inhibited by sucrose, suggesting that more severe myocardial injury occurs when septic hearts are subjected to a calcium paradox as compared to other groups. It is evident that sucrose can inhibit a small fraction of the CK release from septic hearts during the calcium paradox as compared to the large CK loss associated with sham sepsis. We have concluded that induction of sepsis made the heart more susceptible to a calcium paradox-mediated myocardial injury.

  6. 10'(Z),13'(E)-heptadecadienylhydroquinone inhibits swarming and virulence factors and increases polymyxin B susceptibility in Proteus mirabilis

    National Research Council Canada - National Science Library

    Liu, Ming-Che; Lin, Shwu-Bin; Chien, Hsiung-Fei; Wang, Won-Bo; Yuan, Yu-Han; Hsueh, Po-Ren; Liaw, Shwu-Jen

    2012-01-01

    In this study, we demonstrated that 10'(Z), 13'(E)-heptadecadienylhydroquinone (HQ17-2), isolated from the lacquer tree, could decrease swarming motility and hemolysin activity but increase polymyxin B...

  7. The significance of increased fluid signal on magnetic resonance imaging in lumbar facets in relationship to degenerative spondylolisthesis.

    Science.gov (United States)

    Chaput, Christopher; Padon, Derek; Rush, Jeremy; Lenehan, Eric; Rahm, Mark

    2007-08-01

    Retrospective radiographic review of consecutive patients with universally applied standard. To define MRI findings at the facet joints that may suggest abnormal sagittal plane translation seen on standing lateral flexion-extension (SLFE) radiographs. MRI findings, including facet joint orientation, facet joint osteoarthritis, and the presence of synovial cysts, have all been linked with degenerative spondylolisthesis (DS). MRI can also detect facet joint effusion; however, there has not been a study specifically addressing the association of facet fluid signal to degenerative spondylolisthesis (DS). MRI and SLFE films of all patients seen at a single institution for an orthopedic spine consultation over a 2-year period were analyzed. The presence of facet effusions, synovial cysts, increased intensity within the interspinous ligament, degenerative changes at the facets, and anterior sagittal plane translation were all recorded. The data were analyzed to determine if there was a significant association between the presence of DS and the following: facet effusion, degenerative changes of the facets, synovial cysts, increased signal in the interspinous ligament, age, and gender. There were 139 patients without DS at (NegDS) and 54 with DS (PosDS) on SLFE films at L4-L5 (n = 193). PosDS patients were more likely to be older (P 1.5 mm) facet effusions are highly predictive of degenerative spondylolisthesis at L4-L5 in the absence of measurable anterolisthesis on supine MRI. A clinically measurable facet effusion (> or = 1 mm) suggests the need for SLFE films to diagnose degenerative spondylolisthesis that can be missed with supine positioning on MRI.

  8. High-fat/fructose feeding during prenatal and postnatal development in female rats increases susceptibility to renal and metabolic injury later in life.

    Science.gov (United States)

    Flynn, Elizabeth R; Alexander, Barbara T; Lee, Jonathan; Hutchens, Zachary M; Maric-Bilkan, Christine

    2013-02-15

    Accumulating evidence suggests that both an adverse prenatal and early postnatal environment increase susceptibility to renal and metabolic dysfunction later in life; however, whether exposure to adverse conditions during both prenatal and postnatal development act synergistically to potentiate the severity of renal and metabolic injury remains unknown. Sprague-Dawley rats were fed either a standard diet or a diet high in fat/fructose throughout pregnancy and lactation. After being weaned, female offspring were randomized to either standard diet or the high-fat/high-fructose diet, resulting in the following treatment groups: NF-NF, offspring of mothers fed a standard diet and fed a standard diet postnatally; NF-HF, offspring of mothers fed a standard diet and fed a high-fat/fructose diet postnatally; HF-NF, offspring of mothers fed a high-fat/fructose diet and fed a standard diet postnatally; HF-HF, offspring of mothers fed a high-fat/fructose diet and fed a high-fat/fructose diet postnatally. At the time of euthanasia (17 wk of age), HF-HF offspring weighed 30% more and had 110% more visceral fat than NF-NF offspring. The HF-HF offspring also had elevated blood glucose levels, glucose intolerance, 286% increase in urine albumin excretion, and 60% increase in glomerulosclerosis compared with NF-NF. In addition, HF-HF offspring exhibited a 100% increase in transforming growth factor-β protein expression and 116% increase in the abundance of infiltrated macrophages compared with the NF-NF offspring. These observations suggest that high-fat/fructose feeding during prenatal and throughout postnatal life increases the susceptibility to renal and metabolic injury later in life.

  9. Increased susceptibility to atrial fibrillation secondary to atrial fibrosis in transgenic goats expressing transforming growth factor - B1

    Science.gov (United States)

    Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in people with significant morbidity and mortality. There is a strong association between atrial fibrosis and AF. Transforming growth factor B1 (TGF-B1) is an essential mediator of atrial fibrosis in animal models and human pat...

  10. Tunicamycins, a class of nucleoside antibiotics similar to corynetoxins of the Rathayibactor toxicus, increase susceptibility of mice to Neospora caninum

    Science.gov (United States)

    Neosporosis is the leading cause of abortion in cattle. Neospora caninum-associated abortion may exhibit both endemic and epidemic patterns. It was reported that the epidemic outbreaks took place in the form of “abortion storms” and were not significantly correlated with seasonal changes or consumpt...

  11. Trauma-induced coagulopathy upon emergency room arrival: still a significant problem despite increased awareness and management?

    Science.gov (United States)

    Fröhlich, Matthias; Mutschler, Manuel; Caspers, Michael; Nienaber, Ulrike; Jäcker, Vera; Driessen, Arne; Bouillon, Bertil; Maegele, Marc

    2017-11-23

    Over the last decade, the pivotal role of trauma-induced coagulopathy has been described and principal drivers have been identified. We hypothesized that the increased knowledge on coagulopathy of trauma would translate into a more cautious treatment, and therefore, into a reduced overall incidence rate of coagulopathy upon ER admission. Between 2002 and 2013, 61,212 trauma patients derived from the TraumaRegister DGU® had a full record of coagulation parameters and were assessed for the presence of coagulopathy. Coagulopathy was defined by a Quick's value  50), the incidence of coagulopathy was reduced by 7%. Regardless of the injury severity, the amount of pre-hospital i.v.-fluids declined during the observed period by 51%. Simultaneously, morbidity and mortality of severely injured patients were on the decrease. During the 12 years observed, a substantial decline of coagulopathy has been observed. This was paralleled by a significant decrease of i.v.-fluids administered in the pre-hospital treatment. The reduced presence of coagulopathy translated into decreased transfusion requirements and mortality. Nevertheless, especially in the most severely injured patients, posttraumatic coagulopathy remains a frequent and life-threatening syndrome.

  12. Remodelling of myocardial intercalated disc protein connexin 43 causes increased susceptibility to malignant arrhythmias in ARVC/D patients.

    Science.gov (United States)

    Chen, Xiao; Chen, Liang; Chen, Zhenglian; Chen, Xinshan; Song, Jiangping

    2017-06-01

    Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a primary cardiomyopathy characterised by fibrofatty replacement and ventricular arrhythmias. The occurrence of malignant arrhythmias may be associated with fatty infiltration and intercalated disk remodelling, but the specific pathological remodelling pattern is not yet clear. Twelve explanted hearts from patients diagnosed with ARVC/D according to the 2010 Task Force Criteria and pathology examination were divided into two groups with (SVT, n=6) or without (non-SVT, n=6) recurrent sustained ventricular tachycardia (SVT) before heart transplantation. Six ARVC autopsy hearts and six normal donor hearts were also collected. We evaluated the fibrofatty infiltration by Masson staining and the expression of intercalated disc proteins through immunohistochemistry staining combined with western blot using the ventricular tissue of ARVC as well as normal hearts. There was significant fatty replacement in the right ventricles of both the SVT and the non-SVT groups compared to normal hearts, but no significant differences were found in fibre, fatty and residual myocardium components between these two groups. Immunohistochemistry and western blot further showed disturbed distribution and significantly reduced expression of Connexin 43 (Cx43) in the SVT group (SVT vs. Normal P=0.010, SVT vs. non-SVT P=0.012). No significantly diminished expression was found in the non-SVT group. The cardiac histology of ARVC/D patients with sudden death verified by forensic pathology confirmed a similar phenomenon. Our pathology study on explanted and autopsied hearts indicates that the expression of Cx43 was significantly reduced and disturbed in distribution in ARVC/D myocardium with sustained ventricular tachycardia, but not in patients without malignant ventricular arrhythmias. This implies a correlation between Cx43 remodelling and malignant arrhythmias in ARVC/D patients. Copyright © 2017 Elsevier B.V. All rights

  13. TNF-α and TLR agonists increase susceptibility to HIV-1 transmission by human Langerhans cells ex vivo

    NARCIS (Netherlands)

    de Jong, M.A.W.P.; de Witte, L.; Oudhoff, M.J.; Gringhuis, S.I.; Gallay, P.; Geijtenbeek, T.B.H.

    2008-01-01

    Genital coinfections increase an individual’s risk of becoming infected with HIV-1 by sexual contact. Several mechanisms have been proposed to explain this, such as the presence of ulceration and bleeding caused by the coinfecting pathogen. Here we demonstrate that Langerhans cells (LCs) are

  14. Six Year Refractive Change among White Children and Young Adults: Evidence for Significant Increase in Myopia among White UK Children.

    Directory of Open Access Journals (Sweden)

    Sara J McCullough

    Full Text Available To determine six-year spherical refractive error change among white children and young adults in the UK and evaluate differences in refractive profiles between contemporary Australian children and historical UK data.Population-based prospective study.The Northern Ireland Childhood Errors of Refraction (NICER study Phase 1 examined 1068 children in two cohorts aged 6-7 years and 12-13 years. Prospective data for six-year follow-up (Phase 3 are available for 212 12-13 year olds and 226 18-20 year olds in each cohort respectively.Cycloplegic refractive error was determined using binocular open-field autorefraction (Shin-Nippon NVision-K 5001, cyclopentolate 1%. Participants were defined by spherical equivalent refraction (SER as myopic SER ≤-0.50D, emmetropic -0.50Dsignificantly increased between 6-7 years (1.9% and 12-13 years (14.6% (p<0.001 but not between 12-13 and 18-20 years (16.4% to 18.6%, p = 0.51. The estimated annual incidence of myopia was 2.2% and 0.7% for the younger and older cohorts respectively. There were significantly more myopic children in the UK at age 12-13 years in the NICER study (16.4% than reported in Australia (4.4% (p<0.001. However by 17 years the proportion of myopia neared equivalence in the two populations (NICER 18.6%, Australia 17.7%, p = 0.75. The proportion of myopic children aged 12-13 years in the present study (2006-2008 was 16.4%, significantly greater than that reported for children aged 10-16 years in the 1960's (7.2%, p = 0.01. The proportion of hyperopes in the younger NICER cohort decreased significantly over the six year period (from 21.7% to 14.2%, p = 0.04. Hyperopes with SER ≥+3.50D in both NICER age cohorts demonstrated persistent hyperopia.The incidence and proportion of myopia are relatively low in this contemporary white UK population in comparison to other worldwide studies. The proportion of

  15. Genetic Susceptibility to Atherosclerosis

    Directory of Open Access Journals (Sweden)

    Sanja Kovacic

    2012-01-01

    Full Text Available Atherosclerosis is a complex multifocal arterial disease involving interactions of multiple genetic and environmental factors. Advances in techniques of molecular genetics have revealed that genetic ground significantly influences susceptibility to atherosclerotic vascular diseases. Besides further investigations of monogenetic diseases, candidate genes, genetic polymorphisms, and susceptibility loci associated with atherosclerotic diseases have been identified in recent years, and their number is rapidly increasing. This paper discusses main genetic investigations fields associated with human atherosclerotic vascular diseases. The paper concludes with a discussion of the directions and implications of future genetic research in arteriosclerosis with an emphasis on prospective prediction from an early age of individuals who are predisposed to develop premature atherosclerosis as well as to facilitate the discovery of novel drug targets.

  16. Leukotriene C4 increases the susceptibility of adult mice to Shiga toxin-producing Escherichia coli infection.

    Science.gov (United States)

    Cabrera, Gabriel; Fernández-Brando, Romina J; Mejías, María Pilar; Ramos, María Victoria; Abrey-Recalde, María Jimena; Vanzulli, Silvia; Vermeulen, Mónica; Palermo, Marina S

    2015-12-01

    Shiga toxin-producing Escherichia coli (STEC) is a food-borne pathogen that causes hemorrhagic colitis. Under some circumstances, Shiga toxin (Stx) produced within the intestinal tract enters the bloodstream, leading to systemic complications that may cause the potentially fatal hemolytic-uremic syndrome (HUS). Despite STEC human infection is characterized by acute inflammation of the colonic mucosa, little is known regarding the role of proinflammatory mediators like cysteine leukotrienes (cysLTs) in this pathology. Thus, the aim of this work was to analyze whether leukotriene C4 (LTC4) influences STEC pathogenesis in mice. We report that exogenous LTC4 pretreatment severely affected the outcome of STEC gastrointestinal infection. LTC4-pretreated (LTC4+) and STEC-infected (STEC+) mice showed an increased intestinal damage by histological studies, and a decreased survival compared to LTC4-non-pretreated (LTC4-) and STEC+ mice. LTC4+/STEC+ mice that died after the infection displayed neutrophilia and high urea levels, indicating that the cause of death was related to Stx2-toxicity. Despite the differences observed in the survival between LTC4+ and LTC4- mice after STEC infection, both groups showed the same survival after Stx2-intravenous inoculation. In addition, LTC4 pretreatment increased the permeability of mucosal intestinal barrier, as assessed by FITC-dextran absorption experiments. Altogether these results suggest that LTC4 detrimental effect on STEC infection is related to the increased passage of pathogenic factors to the bloodstream. Finally, we showed that STEC infection per se increases the endogenous LTC4 levels in the gut, suggesting that this inflammatory mediator plays a role in the pathogenicity of STEC infection in mice, mainly by disrupting the mucosal epithelial barrier. Copyright © 2015 Elsevier GmbH. All rights reserved.

  17. Increased susceptibility to collagen-induced arthritis in female mice carrying congenic Cia40/Pregq2 fragments

    DEFF Research Database (Denmark)

    Liljander, Maria; Andersson, Åsa Inga Maria; Holmdahl, Rikard

    2008-01-01

    of the B10.Q strain. The major polymorphic candidate genes for the effects on CIA are Cd79b, Abca8a, and Map2k6. The congenic fragment also contains polymorphic genes that affect reproductive behavior and reproductive success. The Sox9 gene, known to influence sex reversal, is a candidate gene...... effects on onset, incidence, severity, and anti-CII antibody titers were observed in female mice carrying a heterozygous congenic Cia40/Pregq2 fragment of NFR/N origin, containing one or more polymorphic genes. Congenic male mice did not show increased incidence of CIA, but males carrying a heterozygous...

  18. Neonatal Lipopolysaccharide Exposure Gender-Dependently Increases Heart Susceptibility to Ischemia/Reperfusion Injury in Male Rats.

    Science.gov (United States)

    Zhang, Peng; Lv, Juanxiu; Li, Yong; Zhang, Lubo; Xiao, Daliao

    2017-01-01

    Background: Adverse stress exposure during the early neonatal period has been shown to cause aberrant development, resulting in an increased risk of adult disease. We tested the hypothesis that neonatal exposure to lipopolysaccharide (LPS) does not alter heart function at rest condition but causes heart dysfunction under stress stimulation later in life. Methods: Saline control or LPS were administered to neonatal rats via intraperitoneal injection. Experiments were conducted in 6 week-old male and female rats. Isolated hearts were perfused in a Langendorff preparation. Results: Neonatal LPS exposure exhibited no effects on the body weight of the developing rats, but induced decreases in the left ventricle (LV) to the body weight ratio in male rats. Neonatal LPS exposure showed no effects on the baseline heart function determined by in vivo and ex vivo experiments, but caused decreases in the post-ischemic recovery of the LV function in male but not female rats. Neonatal LPS-mediated LV dysfunction was associated with an increase in myocardial infarct size and the LDH release in the male rats. Conclusion: The present study provides novel evidence that neonatal immune challenges could induce gender-dependent long-term effects on cardiac development and heart function, which reinforces the notion that adverse stress exposure during the early neonatal period can aggravate heart functions and the development of a heart ischemia-sensitive phenotype later in life.

  19. Transgenic apple plants overexpressing the chalcone 3-hydroxylase gene of Cosmos sulphureus show increased levels of 3-hydroxyphloridzin and reduced susceptibility to apple scab and fire blight.

    Science.gov (United States)

    Hutabarat, Olly Sanny; Flachowsky, Henryk; Regos, Ionela; Miosic, Silvija; Kaufmann, Christine; Faramarzi, Shadab; Alam, Mohammed Zobayer; Gosch, Christian; Peil, Andreas; Richter, Klaus; Hanke, Magda-Viola; Treutter, Dieter; Stich, Karl; Halbwirth, Heidi

    2016-05-01

    Overexpression of chalcone-3-hydroxylase provokes increased accumulation of 3-hydroxyphloridzin in Malus . Decreased flavonoid concentrations but unchanged flavonoid class composition were observed. The increased 3-hydroxyphlorizin contents correlate well with reduced susceptibility to fire blight and scab. The involvement of dihydrochalcones in the apple defence mechanism against pathogens is discussed but unknown biosynthetic steps in their formation hamper studies on their physiological relevance. The formation of 3-hydroxyphloretin is one of the gaps in the pathway. Polyphenol oxidases and cytochrome P450 dependent enzymes could be involved. Hydroxylation of phloretin in position 3 has high similarity to the B-ring hydroxylation of flavonoids catalysed by the well-known flavonoid 3'-hydroxylase (F3'H). Using recombinant F3'H and chalcone 3-hydroxylase (CH3H) from Cosmos sulphureus we show that F3'H and CH3H accept phloretin to some extent but higher conversion rates are obtained with CH3H. To test whether CH3H catalyzes the hydroxylation of dihydrochalcones in planta and if this could be of physiological relevance, we created transgenic apple trees harbouring CH3H from C. sulphureus. The three transgenic lines obtained showed lower polyphenol concentrations but no shift between the main polyphenol classes dihydrochalcones, flavonols, hydroxycinnamic acids and flavan 3-ols. Increase of 3-hydroxyphloridzin within the dihydrochalcones and of epicatechin/catechin within soluble flavan 3-ols were observed. Decreased activity of dihydroflavonol 4-reductase and chalcone synthase/chalcone isomerase could partially explain the lower polyphenol concentrations. In comparison to the parent line, the transgenic CH3H-lines showed a lower disease susceptibility to fire blight and apple scab that correlated with the increased 3-hydroxyphlorizin contents.

  20. NKCC1 up-regulation contributes to early post-traumatic seizures and increased post-traumatic seizure susceptibility.

    Science.gov (United States)

    Wang, Fushun; Wang, Xiaowei; Shapiro, Lee A; Cotrina, Maria L; Liu, Weimin; Wang, Ernest W; Gu, Simeng; Wang, Wei; He, Xiaosheng; Nedergaard, Maiken; Huang, Jason H

    2017-04-01

    Traumatic brain injury (TBI) is not only a leading cause for morbidity and mortality in young adults (Bruns and Hauser, Epilepsia 44(Suppl 10):210, 2003), but also a leading cause of seizures. Understanding the seizure-inducing mechanisms of TBI is of the utmost importance, because these seizures are often resistant to traditional first- and second-line anti-seizure treatments. The early post-traumatic seizures, in turn, are a contributing factor to ongoing neuropathology, and it is critically important to control these seizures. Many of the available anti-seizure drugs target gamma-aminobutyric acid (GABAA) receptors. The inhibitory activity of GABAA receptor activation depends on low intracellular Cl(-), which is achieved by the opposing regulation of Na(+)-K(+)-Cl(-) cotransporter 1 (NKCC1) and K(+)-Cl(-)-cotransporter 2 (KCC2). Up-regulation of NKCC1 in neurons has been shown to be involved in neonatal seizures and in ammonia toxicity-induced seizures. Here, we report that TBI-induced up-regulation of NKCC1 and increased intracellular Cl(-) concentration. Genetic deletion of NKCC1 or pharmacological inhibition of NKCC1 with bumetanide suppresses TBI-induced seizures. TGFβ expression was also increased after TBI and competitive antagonism of TGFβ reduced NKKC1 expression, ameliorated reactive astrocytosis, and inhibited seizures. Thus, TGFβ might be an important pathway involved in NKCC1 up-regulation after TBI. Our findings identify neuronal up-regulation of NKCC1 and its mediation by TGFβ, as a potential and important mechanism in the early post-traumatic seizures, and demonstrate the therapeutic potential of blocking this pathway.

  1. Cellular Hypertrophy and Increased Susceptibility to Spontaneous Calcium-Release of Rat Left Atrial Myocytes Due to Elevated Afterload.

    Directory of Open Access Journals (Sweden)

    Haifei Zhang

    Full Text Available Atrial remodeling due to elevated arterial pressure predisposes the heart to atrial fibrillation (AF. Although abnormal sarcoplasmic reticulum (SR function has been associated with AF, there is little information on the effects of elevated afterload on atrial Ca2+-handling. We investigated the effects of ascending aortic banding (AoB on Ca2+-handling in rat isolated atrial myocytes in comparison to age-matched sham-operated animals (Sham. Myocytes were either labelled for ryanodine receptor (RyR or loaded with fluo-3-AM and imaged by confocal microscopy. AoB myocytes were hypertrophied in comparison to Sham controls (P<0.0001. RyR labeling was localized to the z-lines and to the cell edge. There were no differences between AoB and Sham in the intensity or pattern of RyR-staining. In both AoB and Sham, electrical stimulation evoked robust SR Ca2+-release at the cell edge whereas Ca2+ transients at the cell center were much smaller. Western blotting showed a decreased L-type Ca channel expression but no significant changes in RyR or RyR phosphorylation or in expression of Na+/Ca2+ exchanger, SR Ca2+ ATPase or phospholamban. Mathematical modeling indicated that [Ca2+]i transients at the cell center were accounted for by simple centripetal diffusion of Ca2+ released at the cell edge. In contrast, caffeine (10 mM induced Ca2+ release was uniform across the cell. The caffeine-induced transient was smaller in AoB than in Sham, suggesting a reduced SR Ca2+-load in hypertrophied cells. There were no significant differences between AoB and Sham cells in the rate of Ca2+ extrusion during recovery of electrically-stimulated or caffeine-induced transients. The incidence and frequency of spontaneous Ca2+-transients following rapid-pacing (4 Hz was greater in AoB than in Sham myocytes. In conclusion, elevated afterload causes cellular hypertrophy and remodeling of atrial SR Ca2+-release.

  2. Increased susceptibility to delayed genetic effects of low dose X-irradiation in DNA repair deficient cells.

    Science.gov (United States)

    Kashino, Genro; Suzuki, Keiji; Kodama, Seiji; Watanabe, Masami; Prise, Kevin M

    2013-04-01

    To examine whether the levels of micronuclei induction, as a marker for genomic instability in the progeny of X-irradiated cells, correlates with DNA repair function. Two repair deficient cell lines (X-ray repair cross-complementing 1 [XRCC1] deficient cell line [EM9] and X-ray repair cross complementing 5 [XRCC5; Ku80] deficient X-ray sensitive Chinese hamster ovary [CHO] cell line [xrs5]) were used in addition to wild-type CHO cells. These cells were irradiated with low doses of X-rays (up to 1 Gy). Seven days after irradiation, micronuclei formed in binucleated cells were counted. To assess the contribution of the bystander effect micronuclei induction was measured in progeny of non-irradiated cells co-cultured with cells that had been irradiated with 1Gy. The delayed induction of micronuclei in 1 Gy-irradiated cells was observed in normal CHO and EM9 but not in xrs5. In the clone analysis, progenies of xrs5 under bystander conditions showed significantly higher levels of micronuclei, while CHO and EM9 did not. Genomic instability induced by X-irradiation is associated with DSB (double-strand break) repair, even at low doses. It is also suggested that bystander signals, which lead to genomic instability, may be enhanced when DSB repair is compromised.

  3. Structural determinants of increased susceptibility to dehydration-induced cavitation in post-fire resprouting chaparral shrubs.

    Science.gov (United States)

    Jacobsen, Anna L; Tobin, Michael F; Toschi, Hayden S; Percolla, Marta I; Pratt, R Brandon

    2016-11-01

    It is well established that transpiration and photosynthetic rates generally increase in resprouting shoots after fire in chaparral shrublands. By contrast, little is known about how plant hydraulic function varies during this same recovery period. We hypothesized that vascular traits, both functional and structural, would also shift in order to support this heightened level of gas exchange and growth. We examined stem xylem-specific hydraulic conductivity (Ks ) and resistance to cavitation (P50 ) for eight chaparral shrub species as well as several potential xylem structural determinants of hydraulic function and compared established unburned plants and co-occurring post-fire resprouting plants. Unburned plants were generally more resistant to cavitation than resprouting plants, but the two groups did not differ in Ks . Resprouting plants had altered vessel structure compared with unburned plants, with resprouting plants having both wider diameter vessels and higher inter-vessel pit density. For biomechanics, unburned plants had both stronger and denser stem xylem tissue than resprouting plants. Shifts in hydraulic structure and function resulted in resprouting plants being more vulnerable to dehydration. The interaction between time since disturbance (i.e. resprouting versus established stands) and drought may complicate attempts to predict mortality risk of resprouting plants. © 2016 John Wiley & Sons Ltd.

  4. Distractibility during Retrieval of Long-Term Memory: Domain-General Interference, Neural Networks and Increased Susceptibility in Normal Aging

    Directory of Open Access Journals (Sweden)

    Peter Edward Wais

    2014-04-01

    Full Text Available The mere presence of irrelevant external stimuli results in interference with the fidelity of details retrieved from long-term memory (LTM. Recent studies suggest that distractibility during LTM retrieval occurs when the focus of resource-limited, top-down mechanisms that guide the selection of relevant mnemonic details is disrupted by representations of external distractors. We review findings from four studies that reveal distractibility during episodic retrieval. The approach cued participants to recall previously studied visual details when their eyes were closed, or were open and irrelevant visual information was present. The results showed a negative impact of the distractors on the fidelity of details retrieved from LTM. An fMRI experiment using the same paradigm replicated the behavioral results and found that diminished episodic memory was associated with the disruption of functional connectivity in whole-brain networks. Specifically, network connectivity supported recollection of details based on visual imagery when eyes were closed, but connectivity declined in the presence of visual distractors. Another experiment using auditory distractors found equivalent effects for auditory and visual distraction during cued recall, suggesting that the negative impact of distractibility is a domain-general phenomenon in LTM. Comparisons between older and younger adults revealed an aging-related increase in the negative impact of distractibility on retrieval of LTM. Finally, a new study that compared categorization abilities between younger and older adults suggests a cause underlying age-related decline of visual details in LTM. The sum of our findings suggests that cognitive control resources, although limited, have the capability to resolve interference from distractors during tasks of moderate effort, but these resources are overwhelmed when additional processes associated with episodic retrieval, or categorization of complex prototypes, are

  5. Epithelial-to-Mesenchymal Transition of RPE Cells In Vitro Confers Increased β1,6-N-Glycosylation and Increased Susceptibility to Galectin-3 Binding.

    Science.gov (United States)

    Priglinger, Claudia S; Obermann, Jara; Szober, Christoph M; Merl-Pham, Juliane; Ohmayer, Uli; Behler, Jennifer; Gruhn, Fabian; Kreutzer, Thomas C; Wertheimer, Christian; Geerlof, Arie; Priglinger, Siegfried G; Hauck, Stefanie M

    2016-01-01

    Epithelial-to-mesenchymal transition (EMT) of retinal pigment epithelial cells is a crucial event in the onset of proliferative vitreoretinopathy (PVR), the most common reason for treatment failure in retinal detachment surgery. We studied alterations in the cell surface glycan expression profile upon EMT of RPE cells and focused on its relevance for the interaction with galectin-3 (Gal-3), a carbohydrate binding protein, which can inhibit attachment and spreading of human RPE cells in a dose- and carbohydrate-dependent manner, and thus bares the potential to counteract PVR-associated cellular events. Lectin blot analysis revealed that EMT of RPE cells in vitro confers a glycomic shift towards an abundance of Thomsen-Friedenreich antigen, poly-N-acetyllactosamine chains, and complex-type branched N-glycans. Using inhibitors of glycosylation we found that both, binding of Gal-3 to the RPE cell surface and Gal-3-mediated inhibition of RPE attachment and spreading, strongly depend on the interaction of Gal-3 with tri- or tetra-antennary complex type N-glycans and sialylation of glycans but not on complex-type O-glycans. Importantly, we found that β1,6 N-acetylglucosaminyltransferase V (Mgat5), the key enzyme catalyzing the synthesis of tetra- or tri-antennary complex type N-glycans, is increased upon EMT of RPE cells. Silencing of Mgat5 by siRNA and CRISPR-Cas9 genome editing resulted in reduced Gal-3 binding. We conclude from these data that binding of recombinant Gal-3 to the RPE cell surface and inhibitory effects on RPE attachment and spreading largely dependent on interaction with Mgat5 modified N-glycans, which are more abundant on dedifferentiated than on the healthy, native RPE cells. Based on these findings we hypothesize that EMT of RPE cells in vitro confers glycomic changes, which account for high affinity binding of recombinant Gal-3, particularly to the cell surface of myofibroblastic RPE. From a future perspective recombinant Gal-3 may disclose a

  6. Epithelial-to-Mesenchymal Transition of RPE Cells In Vitro Confers Increased β1,6-N-Glycosylation and Increased Susceptibility to Galectin-3 Binding.

    Directory of Open Access Journals (Sweden)

    Claudia S Priglinger

    Full Text Available Epithelial-to-mesenchymal transition (EMT of retinal pigment epithelial cells is a crucial event in the onset of proliferative vitreoretinopathy (PVR, the most common reason for treatment failure in retinal detachment surgery. We studied alterations in the cell surface glycan expression profile upon EMT of RPE cells and focused on its relevance for the interaction with galectin-3 (Gal-3, a carbohydrate binding protein, which can inhibit attachment and spreading of human RPE cells in a dose- and carbohydrate-dependent manner, and thus bares the potential to counteract PVR-associated cellular events. Lectin blot analysis revealed that EMT of RPE cells in vitro confers a glycomic shift towards an abundance of Thomsen-Friedenreich antigen, poly-N-acetyllactosamine chains, and complex-type branched N-glycans. Using inhibitors of glycosylation we found that both, binding of Gal-3 to the RPE cell surface and Gal-3-mediated inhibition of RPE attachment and spreading, strongly depend on the interaction of Gal-3 with tri- or tetra-antennary complex type N-glycans and sialylation of glycans but not on complex-type O-glycans. Importantly, we found that β1,6 N-acetylglucosaminyltransferase V (Mgat5, the key enzyme catalyzing the synthesis of tetra- or tri-antennary complex type N-glycans, is increased upon EMT of RPE cells. Silencing of Mgat5 by siRNA and CRISPR-Cas9 genome editing resulted in reduced Gal-3 binding. We conclude from these data that binding of recombinant Gal-3 to the RPE cell surface and inhibitory effects on RPE attachment and spreading largely dependent on interaction with Mgat5 modified N-glycans, which are more abundant on dedifferentiated than on the healthy, native RPE cells. Based on these findings we hypothesize that EMT of RPE cells in vitro confers glycomic changes, which account for high affinity binding of recombinant Gal-3, particularly to the cell surface of myofibroblastic RPE. From a future perspective recombinant Gal-3 may

  7. Increased susceptibility to fundus camera-delivered light-induced retinal degeneration in mice deficient in oxidative stress response proteins.

    Science.gov (United States)

    Ding, Yi; Aredo, Bogale; Zhong, Xin; Zhao, Cynthia X; Ufret-Vincenty, Rafael L

    2017-06-01

    Oxidative stress is an important contributor to the pathogenesis of many retinal diseases including age-related macular degeneration and retinal dystrophies. Light-induced retinal degeneration (LIRD) can serve as a model in which to study the response of the retina to stress. Of note, many genetic mutant mice are in a C57BL/6 J background and are thus resistant to the usual LIRD models. We recently developed a new model of fundus camera-delivered light-induced retinal degeneration (FCD-LIRD) which is effective in strains of mice expressing the light-resistant variant of RPE65 (450Met), including C57BL/6 J. In this work we investigated whether FCD-LIRD would be useful as a model in which to test the effect of genetic mutations on the response of the retina to stress. Furthermore, we tested whether oxidative stress plays an important role in the setting of this new FCD-LIRD model. FCD-LIRD was applied to C57BL/6 J mice and to mice simultaneously deficient in three proteins that are important in the response of the retina to oxidative stress (SOD1, DJ-1 and Parkin). Using fundus photography, we found that retinal damage was dramatically increased in the SOD1/DJ-1/Parkin deficient mice compared to C57BL/6 J. Outer retinal OCT volume and RPE cell morphology analysis in ZO-1-stained flat mounts added support to these findings. Gene expression analysis confirmed a strong oxidative stress response after FCD-LIRD, which was differentially altered in the SOD1/DJ1/Parkin deficient mice. We conclude that FCD-LIRD is useful to study the effect of genetic mutations on the response of the retina to light stress in light-resistant strains of mice. Furthermore, oxidative stress seems to be an important component of FCD-LIRD. Finally, we have established protocols to quantify the effect of FCD-LIRD on the retina and RPE which will be useful for future studies. Further dissection of the mechanisms by which the retina responds to light-induced oxidative stress may result in new

  8. Was there significant tax evasion after the 1999 50 cent per pack cigarette tax increase in California?

    OpenAIRE

    Emery, S.; White, M.; Gilpin, E; Pierce, J.

    2002-01-01

    Objectives: Several states, including California, have implemented large cigarette excise tax increases, which may encourage smokers to purchase their cigarettes in other lower taxed states, or from other lower or non-taxed sources. Such tax evasion thwarts tobacco control objectives and may cost the state substantial tax revenues. Thus, this study investigates the extent of tax evasion in the 6–12 months after the implementation of California's $0.50/pack excise tax increase.

  9. Susceptibility for Lupus Nephritis by Low Copy Number of the FCGR3B Gene Is Linked to Increased Levels of Pathogenic Autoantibodies

    Directory of Open Access Journals (Sweden)

    Johannes C. Nossent

    2013-01-01

    Full Text Available Low copy number (CN of the FCGR3B gene reduces FCGR3B membrane expression on neutrophils and results in clearance of a smaller amount of immune complex. We investigated FCGR3B CN in relation to the clinical phenotype in a Caucasian SLE cohort (. FCGR3B CN was determined by three different qPCR parameter estimations (Ct−, Cy0, and cpD1 and confirmed by the FCGR2C/FCGR2A paralog ratio test. Clinical and serological data were then analyzed for their association with FCGR3B CN. Low FCGR3B CN (2. In multivariate analyses, LN was independently associated with anti-C1q-Ab levels ( and low FCGR3B CN (. We conclude that the susceptibility for LN in patients with low FCGR3B CN is linked to increased levels of pathogenic autoantibodies.

  10. Increasing significance of advanced physical/chemical processes in the development and application of sustainable wastewater treatment systems

    NARCIS (Netherlands)

    Rulkens, W.H.

    2008-01-01

    The awareness of the problem of the scarcity of water of high quality has strongly changed the approach of wastewater treatment. Currently, there is an increasing need for the beneficial reuse of treated wastewater and to recover valuable products and energy from the wastewater. Because

  11. Simulation of Jack-Up Overturning Using the Monte Carlo Method with Artificially Increased Significant Wave Height

    DEFF Research Database (Denmark)

    Jensen, Jørgen Juncher

    2010-01-01

    It is well known from linear analyses in stochastic seaway that the mean out-crossing rate of a level r is given through the reliability index, defined as r divided by the standard deviation. Hence, the reliability index becomes inversely proportional to the significant wave height. For non......-linear processes the mean out-crossing rate depends non-linearly on the response level r and a good estimate can be found using the First Order Reliability Method (FORM), see e.g. Jensen and Capul (2006). The FORM analysis also shows that the reliability index is strictly inversely proportional to the significant...... wave height irrespectively of the non-linearity in the system. However, the FORM analysis only gives an approximation to the mean out-crossing rate. A more exact result can be obtained by Monte Carlo simulations, but the necessary length of the time domain simulations for very low out-crossing rates...

  12. Increased Risk of Clinically Significant Gallstones following an Appendectomy: A Five-Year Follow-Up Study.

    Directory of Open Access Journals (Sweden)

    Shiu-Dong Chung

    Full Text Available Although the vermiform appendix is commonly considered a vestigial organ, adverse health consequences after an appendectomy have garnered increasing attention. In this study, we investigated the risks of gallstone occurrence during a 5-year follow-up period after an appendectomy, using a population-based dataset. We used data from the Taiwan Longitudinal Health Insurance Database 2005. The exposed cohort included 4916 patients who underwent an appendectomy. The unexposed cohort was retrieved by randomly selecting 4916 patients matched with the exposed cohort in terms of sex, age, and year. We individually tracked each patient for a 5-year period to identify those who received a diagnosis of gallstones during the follow-up period. Cox proportional hazard regressions were performed for the analysis. During the 5-year follow-up period, the incidence rate per 1000 person-years was 4.71 for patients who had undergone an appendectomy, compared to a rate of 2.59 for patients in the unexposed cohort (p<0.001. Patients who had undergone an appendectomy were independently associated with a 1.79 (95% CI = 1.29~2.48-fold increased risk of being diagnosed with gallstones during the 5-year follow-up period. We found that among female patients, the adjusted hazard ratio of gallstones was 2.25 (95% CI = 1.41~3.59 for patients who underwent an appendectomy compared to unexposed patients. However, for male patients, we failed to observe an increased hazard for gallstones among patients who underwent an appendectomy compared to unexposed patients. We found an increased risk of a subsequent gallstone diagnosis within 5 years after an appendectomy.

  13. Love is the triumph of the imagination: Daydreams about significant others are associated with increased happiness, love and connection.

    Science.gov (United States)

    Poerio, Giulia L; Totterdell, Peter; Emerson, Lisa-Marie; Miles, Eleanor

    2015-05-01

    Social relationships and interactions contribute to daily emotional well-being. The emotional benefits that come from engaging with others are known to arise from real events, but do they also come from the imagination during daydreaming activity? Using experience sampling methodology with 101 participants, we obtained 371 reports of naturally occurring daydreams with social and non-social content and self-reported feelings before and after daydreaming. Social, but not non-social, daydreams were associated with increased happiness, love and connection and this effect was not solely attributable to the emotional content of the daydreams. These effects were only present when participants were lacking in these feelings before daydreaming and when the daydream involved imagining others with whom the daydreamer had a high quality relationship. Findings are consistent with the idea that social daydreams may function to regulate emotion: imagining close others may serve the current emotional needs of daydreamers by increasing positive feelings towards themselves and others. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  14. Serum Leukocyte Immunoglobulin-Like Receptor A3 (LILRA3 Is Increased in Patients with Multiple Sclerosis and Is a Strong Independent Indicator of Disease Severity; 6.7kbp LILRA3 Gene Deletion Is Not Associated with Diseases Susceptibility.

    Directory of Open Access Journals (Sweden)

    Hongyan An

    Full Text Available Leukocyte immunoglobulin-like receptor A3 (LILRA3 is a soluble immune regulatory molecule primarily expressed by monocytes and macrophages. A homozygous 6.7kbp LILRA3 gene deletion that removes the first seven of its eight exons is predicted to lead to lack of LILRA3 protein, although this has not been experimentally confirmed. Moreover, there are conflicting results with regards to the link between the LILRA3 homozygous genetic deletion and susceptibility to multiple sclerosis (MS in different European populations. The aim of this study was to investigate whether LILRA3 gene deletion is associated with MS susceptibility in a North American cohort of European ancestry and assess if serum LILRA3 protein level is a marker of clinical subtype and/or disease severity in MS. A total of 456 patients with MS and 99 unrelated healthy controls were genotyped for the 6.7kbp LILRA3 gene deletion and levels of LILRA3 protein in sera determined by in-house sandwich ELISA. We showed that LILRA3 gene deletion was not associated with MS susceptibility and did not affect the age of disease onset, clinical subtype or disease severity. However, we discovered for the first time that homozygous LILRA3 gene deletion results in lack of production of LILRA3 protein. Importantly, LILRA3 protein level was significantly increased in sera of patients with MS when compared with control subjects, particularly in more severe type primary progressive MS. Multiple regression analysis showed that LILRA3 level in serum was one of the strongest independent markers of disease severity in MS, which potentially can be used as a diagnostic marker.

  15. 'Knowledge for better health' revisited - the increasing significance of health research systems: a review by departing Editors-in-Chief.

    Science.gov (United States)

    Hanney, Stephen R; González-Block, Miguel A

    2017-10-02

    How can nations organise research investments to obtain the best bundle of knowledge and the maximum level of improved health, spread as equitably as possible? This question was the central focus of a major initiative from WHO led by Prof Tikki Pang, which resulted in a range of developments, including the publication of a conceptual framework for national health research systems - Knowledge for better health - in 2003, and in the founding of the journal Health Research Policy and Systems (HARPS). As Editors-in-Chief of the journal since 2006, we mark our retirement by tracking both the progress of the journal and the development of national health research systems. HARPS has maintained its focus on a range of central themes that are key components of a national health research system in any country. These include building capacity to conduct and use health research, identifying appropriate priorities, securing funds and allocating them accountably, producing scientifically valid research outputs, promoting the use of research in polices and practice in order to improve health, and monitoring and evaluating the health research system. Some of the themes covered in HARPS are now receiving increased attention and, for example, with the assessment of research impact and development of knowledge translation platforms, the journal has covered their progress throughout that expansion of interest. In addition, there is increasing recognition of new imperatives, including the importance of promoting gender equality in health research if benefits are to be maximised. In this Editorial, we outline some of the diverse and developing perspectives considered within each theme, as well as considering how they are held together by the growing desire to build effective health research systems in all countries.From 2003 until mid-June 2017, HARPS published 590 articles on the above and related themes, with authors being located in 76 countries. We present quantitative data tracing

  16. No increased susceptibility to breast cancer from combined CHEK2 1100delC genotype and the HLA class III region risk factors

    NARCIS (Netherlands)

    de Jong, Mirjam; Nolte, Ilja; te Meerman, Gerhardus; van der Graaf, WTA; Oosterom, E; Bruinenberg, M; van der Steege, G; Oosterwijk, JC; van der Hout, Annemarie; Boezen, HM; Schaapveld, M; Kleibeuker, JH; de Vries, EGE

    CHEK2 is low-penetrance breast cancer susceptibility gene. The 1100delC mutation may interact with variants/mutations in other breast cancer susceptibility loci. We identified a risk haplotype in the HLA class III region in breast cancer patients [de Jong MM, Nolte IM, de Vries EGE, et al. The HLA

  17. Functional significance of extent and timing of muscle activation during double poling on-snow with increasing speed.

    Science.gov (United States)

    Zoppirolli, Chiara; Boccia, Gennaro; Bortolan, Lorenzo; Schena, Federico; Pellegrini, Barbara

    2017-11-01

    To evaluate the level of activation and timing of upper- and lower-body muscles during double poling at different speeds on snow. Nineteen well-trained cross-country skiers volunteered to double pole on a flat snowy track at different speeds (15, 18, 21 km h -1 ). The target speeds could be maintained by the skiers thanks to the use of an audio-pace system in combination with cones spaced equally alongside the track. Only 11 subjects were finally included in the analysis, since their actual speeds, calculated through a photocell system, were within ±0.5 km h -1 from those requested. Cycle and poling durations were measured from the recordings of an accelerometer attached to a wrist, while the pattern and the level of muscle activation were evaluated from electromyographyc signals. Double poling speed did not alter the sequence of muscle activation that started with hip flexors, continued with trunk flexors, shoulder, elbow and trunk extensors and ended with ankle plantar-flexors. However, higher speeds required an increasing involvement of thigh, trunk and shoulder muscles (P < 0.05) as well as an anticipation of their activation before pole plant (P < 0.05). A progressively earlier activation of trunk and lower limb muscles is a coordinative strategy that allows rapid achievement of optimal body posture prior to the exertion of poling phase. Moreover, earlier activation of these muscles as the speed increases provides adequate muscle stiffness in the shoulder and core regions for the acceptance of the poling load.

  18. Downregulation of miR-151-5p contributes to increased susceptibility to arrhythmogenesis during myocardial infarction with estrogen deprivation.

    Directory of Open Access Journals (Sweden)

    Ying Zhang

    Full Text Available Estrogen deficiency is associated with increased incidence of cardiovascular diseases. But merely estrogen supplementary treatment can induce many severe complications such as breast cancer. The present study was designed to elucidate molecular mechanisms underlying increased susceptibility of arrhythmogenesis during myocardial infarction with estrogen deprivation, which provides us a new target to cure cardiac disease accompanied with estrogen deprivation. We successfully established a rat model of myocardial ischemia (MI accompanied with estrogen deprivation by coronary artery ligation and ovariectomy (OVX. Vulnerability and mortality of ventricular arrhythmias increased in estrogen deficiency rats compared to non estrogen deficiency rats when suffered MI, which was associated with down-regulation of microRNA-151-5p (miR-151-5p. Luciferase Reporter Assay demonstrated that miR-151-5p can bind to the 3'-UTR of FXYD1 (coding gene of phospholemman, PLM and inhibit its expression. We found that the expression of PLM was increased in (OVX+MI group compared with MI group. More changes such as down-regulation of Kir2.1/IK1, calcium overload had emerged in (OVX+MI group compared to MI group merely. Transfection of miR-151-5p into primary cultured myocytes decreased PLM levels and [Ca(2+]i, however, increased Kir2.1 levels. These effects were abolished by the antisense oligonucleotides against miR-151-5p. Co-immunoprecipitation and immunofluorescent experiments confirmed the co-localization between Kir2.1 and PLM in rat ventricular tissue. We conclude that the increased ventricular arrhythmias vulnerability in response to acute myocardial ischemia in rat is critically dependent upon down-regulation of miR-151-5p. These findings support the proposal that miR-151-5p could be a potential therapeutic target for the prevention of ischemic arrhythmias in the subjects with estrogen deficiency.

  19. Growth hormone significantly increases the adult height of children with idiopathic short stature: comparison of subgroups and benefit

    Science.gov (United States)

    2014-01-01

    Background Children with Idiopathic Short Stature do not attain a normal adult height. The improvement of adult height with treatment with recombinant human growth hormone (rhGH), at doses of 0.16 to 0.28 mg/kg/week is modest, usually less that 4 cm, and they remain short as adults. The benefit obtained seems dose dependent and benefits of 7.0 to 8.0 cm have been reported with higher doses of 0.32 to 0.4 mg/kg/week, but the number of studies is limited. The topic has remained controversial. Objective The objective was to conduct a retrospective analysis of our experience with 123 children with ISS treated with 0.32 ± 0.03 mg/kg/week of rhGH, with the aim of comparing the different subgroups of non-familial short stature, familial short stature, normal puberty, and delayed puberty and to assess the benefit by comparison with 305 untreated historical controls, from nine different randomized and nonrandomized controlled studies. Results Eighty eight of our children (68 males and 20 females) attained an adult height or near adult height of -0.71 SDS (0.74 SD) (95% CI, -0.87 to -0.55) with a benefit over untreated controls of 9.5 cm (7.4 to 11.6 cm) for males and 8.6 cm (6.7 to 10.5 cm) for females. In the analysis of the subgroups, the adult height and adult height gain of children with non-familial short stature were significantly higher than of familial short stature. No difference was found in the cohorts with normal or delayed puberty in any of the subgroups, except between the non-familial short stature and familial short stature puberty cohorts. This has implications for the interpretation of the benefit of treatment in studies where the number of children with familial short stature in the controls or treated subjects is not known. The treatment was safe. There were no significant adverse events. The IGF-1 values were essentially within the levels expected for the stages of puberty. Conclusion Our experience was quite positive with normalization of

  20. Plant Explants Grown on Medium Supplemented with Fe3O4 Nanoparticles Have a Significant Increase in Embryogenesis

    Directory of Open Access Journals (Sweden)

    Inese Kokina

    2017-01-01

    Full Text Available Development of nanotechnology leads to the increasing release of nanoparticles in the environment that results in accumulation of different NPs in living organisms including plants. This can lead to serious changes in plant cultures which leads to genotoxicity. The aims of the present study were to detect if iron oxide NPs pass through the flax cell wall, to compare callus morphology, and to estimate the genotoxicity in Linum usitatissimum L. callus cultures induced by different concentrations of Fe3O4 nanoparticles. Two parallel experiments were performed: experiment A, where flax explants were grown on medium supplemented with 0.5 mg/l, 1 mg/l, and 1.5 mg/l Fe3O4 NPs for callus culture obtaining, and experiment B, where calluses obtained from basal MS medium were transported into medium supplemented with concentrations of NPs identical to experiment A. Obtained results demonstrate similarly in both experiments that 25 nm Fe3O4 NPs pass into callus cells and induce low toxicity level in the callus cultures. Nevertheless, calluses from experiment A showed 100% embryogenesis in comparison with experiment B where 100% rhizogenesis was noticed. It could be associated with different stress levels and adaptation time for explants and calluses that were transported into medium with Fe3O4 NPs supplementation.

  1. High Dose Atorvastatin Associated with Increased Risk of Significant Hepatotoxicity in Comparison to Simvastatin in UK GPRD Cohort.

    Directory of Open Access Journals (Sweden)

    Alan T Clarke

    Full Text Available Occasional risk of serious liver dysfunction and autoimmune hepatitis during atorvastatin therapy has been reported. We compared the risk of hepatotoxicity in atorvastatin relative to simvastatin treatment.The UK GPRD identified patients with a first prescription for simvastatin [164,407] or atorvastatin [76,411] between 1997 and 2006, but with no prior record of liver disease, alcohol-related diagnosis, or liver dysfunction. Incident liver dysfunction in the following six months was identified by biochemical value and compared between statin groups by Cox regression model adjusting for age, sex, year treatment started, dose, alcohol consumption, smoking, body mass index and comorbid conditions.Moderate to severe hepatotoxicity [bilirubin >60μmol/L, AST or ALT >200U/L or alkaline phosphatase >1200U/L] developed in 71 patients on atorvastatin versus 101 on simvastatin. Adjusted hazard ratio [AHR] for all atorvastatin relative to simvastatin was 1.9 [95% confidence interval 1.4-2.6]. High dose was classified as 40-80mg daily and low dose 10-20mg daily. Hepatotoxicity occurred in 0.44% of 4075 patients on high dose atorvastatin [HDA], 0.07% of 72,336 on low dose atorvastatin [LDA], 0.09% of 44,675 on high dose simvastatin [HDS] and 0.05% of 119,732 on low dose simvastatin [LDS]. AHRs compared to LDS were 7.3 [4.2-12.7] for HDA, 1.4 [0.9-2.0] for LDA and 1.5 [1.0-2.2] for HDS.The risk of hepatotoxicity was increased in the first six months of atorvastatin compared to simvastatin treatment, with the greatest difference between high dose atorvastatin and low dose simvastatin. The numbers of events in the analyses were small.

  2. A significant increase in the pepsinogen I/II ratio is a reliable biomarker for successful Helicobacter pylori eradication.

    Directory of Open Access Journals (Sweden)

    Hiroki Osumi

    Full Text Available Helicobacter pylori (H. pylori eradication is usually assessed using the 13C-urea breath test (UBT, anti-H. pylori antibody and the H. pylori stool antigen test. However, a few reports have used pepsinogen (PG, in particular, the percentage change in the PG I/II ratio. Here, we evaluated the usefulness of the percentage changes in serum PG I/II ratios for determining the success of eradication therapy for H. pylori.In total, 650 patients received eradication therapy from October 2008 to March 2013 in our Cancer Institute Hospital. We evaluated the relationship between H. pylori eradication and percentage changes in serum PG I/II ratios before and 3 months after treatment with CLEIA® (FUJIREBIO Inc, Tokyo, Japan. The gold standard of H. pylori eradication was defined as negative by the UBT performed 3 months after completion of eradication treatment. Cut-off values for percentage changes in serum PG I/II ratios were set as +40, +25 and +10% when the serum PG I/II ratio before treatment was below 3.0, above 3.0 but below 5.0 and 5.0 or above, respectively.Serum PG I and PG II levels were measured in 562 patients with H. pylori infection before and after eradication therapy. Eradication of H. pylori was achieved in 433 patients studied (77.0%. The ratios of first, second, third-line and penicillin allergy eradication treatment were 73.8% (317/429, 88.3% (99/112, 75% (12/16 and 100% (5/5, respectively. An increasing percentage in the serum levels of the PG I/II ratios after treatment compared with the values before treatment clearly distinguished success from failure of eradication (108.2±57.2 vs. 6.8±30.7, p<0.05. Using the above cut-off values, the sensitivity, specificity and validity for determination of H. pylori were 93.1, 93.8 and 93.2%, respectively.In conclusion, the percentage changes in serum PG I/II ratios are useful as evaluation criteria for assessing the success of eradication therapy for H. pylori.

  3. Old Fashioned vs. Ultra-Processed-Based Current Diets: Possible Implication in the Increased Susceptibility to Type 1 Diabetes and Celiac Disease in Childhood

    Science.gov (United States)

    Aguayo-Patrón, Sandra V.; Calderón de la Barca, Ana M.

    2017-01-01

    Ultra-processed foods are ready-to-heat and ready-to-eat products created to replace traditional homemade meals and dishes due to convenience and accessibility. Because of their low-fiber and high-fat and sugar composition, these foodstuffs could induce a negative impact on health. They are partially responsible for obesity and chronic non-transmissible diseases; additionally, they could impact in the prevalence of autoimmune diseases such as type 1 diabetes and celiac disease. The rationale is that the nutritional composition of ultra-processed foodstuffs can induce gut dysbiosis, promoting a pro-inflammatory response and consequently, a “leaky gut”. These factors have been associated with increased risk of autoimmunity in genetically predisposed children. In addition, food emulsifiers, commonly used in ultra-processed products could modify the gut microbiota and intestinal permeability, which could increase the risk of autoimmunity. In contrast, unprocessed and minimally processed food-based diets have shown the capacity to promote gut microbiota eubiosis, anti-inflammatory response, and epithelial integrity, through bacterial butyrate production. Thus, to decrease the susceptibility to autoimmunity, genetically predisposed children should avoid ultra-processed food products and encourage the consumption of fresh and minimally processed foods. PMID:29140275

  4. Old Fashioned vs. Ultra-Processed-Based Current Diets: Possible Implication in the Increased Susceptibility to Type 1 Diabetes and Celiac Disease in Childhood

    Directory of Open Access Journals (Sweden)

    Sandra V. Aguayo-Patrón

    2017-11-01

    Full Text Available Ultra-processed foods are ready-to-heat and ready-to-eat products created to replace traditional homemade meals and dishes due to convenience and accessibility. Because of their low-fiber and high-fat and sugar composition, these foodstuffs could induce a negative impact on health. They are partially responsible for obesity and chronic non-transmissible diseases; additionally, they could impact in the prevalence of autoimmune diseases such as type 1 diabetes and celiac disease. The rationale is that the nutritional composition of ultra-processed foodstuffs can induce gut dysbiosis, promoting a pro-inflammatory response and consequently, a “leaky gut”. These factors have been associated with increased risk of autoimmunity in genetically predisposed children. In addition, food emulsifiers, commonly used in ultra-processed products could modify the gut microbiota and intestinal permeability, which could increase the risk of autoimmunity. In contrast, unprocessed and minimally processed food-based diets have shown the capacity to promote gut microbiota eubiosis, anti-inflammatory response, and epithelial integrity, through bacterial butyrate production. Thus, to decrease the susceptibility to autoimmunity, genetically predisposed children should avoid ultra-processed food products and encourage the consumption of fresh and minimally processed foods.

  5. Finding of coagulase negative staphylococci in the herd with an increased number of somatic cells in milk and their antimicrobial susceptibility

    Directory of Open Access Journals (Sweden)

    Katić Vera

    2013-01-01

    Full Text Available Coagulase-negative staphylococci (CNS are generally considered to be opportunistic pathogens. Controlling CNS mastitis is difficult because the epidemiology is not clear, and the CNS group consists of about 40 different Staphylococcus species. Therefore, the aim of this study was to determine the prevalence of coagulasenegative staphylococci in milk of the cows with subclinical mastitis, as well as to determine different CNS species isolated from quarter milk samples for their susceptibility to antimicrobials used commonly for mastitis therapy. On the farm where there was found an increase of somatic cells in bulk milk, 112 dairy cows were examined by mastitis test. From 52 udder quarters where mastitis test showed an increase of somatic cells, milk samples were taken for bacteriological examination. For isolating the causes of mastitis there was used blood agar. Identification of the causative agents of mastitis was carried out on the basis of colony appearance on blood agar and their physiological characteristics. Coagulasepositive staphylococci sensitivity which cause mastitis was tested by Kirby Bauer method. For susceptibility testing there were used commercially produced discs containing: 10 IU penicillin, amoxicillin/clavulanic acid (20 +10 μg, cloxacillin 25 μg, 30 μg amoxicillin, cephalexin 30 μg, ceftiofur 30 μg, 15 μg lincomycin, gentamicin and tetracycline 30 μg. The sensitivity of microorganisms was evaluated on the basis of inhibition zone diameter recommended by the manufacturer and was labeled as sensitive (S moderately sensitive (I or resistant (R. Coagulase-negative staphylococci were isolated from 61.53% of samples from cows with subclinical mastitis, making them the most common cause of subclinical mastitis. The highest resistance of coagulase-negative staphylococci was found to penicillin G (58.33% of isolates. Full sensitivity of coagulase-negative staphylococci was found to amoxicillin / clavulanic acid (100% of

  6. Increased In Vitro Phenol-Soluble Modulin Production is Associated with Soft Tissue Infection Source in Clinical Isolates of Methicillin-Susceptible Staphylococcus aureus

    Science.gov (United States)

    Qi, Robert; Joo, Hwang-Soo; Sharma-Kuinkel, Batu; Berlon, Nicholas R.; Park, Lawrence; Fu, Chih-lung; Messina, Julia A.; Thaden, Joshua T.; Yan, Qin; Ruffin, Felicia; Maskarinec, Stacey; Warren, Bobby; Chu, Vivian H.; Fortes, Claudio Q.; Giannitsioti, Efthymia; Durante-Mangoni, Emanuele; Kanafani, Zeina A.; Otto, Michael; Fowler, Vance G.

    2016-01-01

    Background Phenol-soluble modulins (PSM) are amphipathic proteins produced by Staphylococcus aureus that promote virulence, inflammatory response, and biofilm formation. We previously showed that MRSA isolates from soft tissue infection (SSTI) produced significantly higher levels of PSM than MRSA isolates from hospital-acquired pneumonia (HAP) or infective endocarditis (IE). In this investigation, we sought to validate this finding in methicillin-susceptible S. aureus (MSSA) isolates. Methods MSSA isolates (n=162) from patients with SSTI, HAP, and IE were matched 1:1:1 based on geographic origin of the infection to form 54 triplets (North America n=27, Europe n=25, Australia n=2). All isolates underwent spa-typing and were classified using eGenomics. In vitro PSM production was quantified by high performance liquid chromatography/mass spectrometry. Fischer’s Exact Test and the Kruskal-Wallis test were used for statistical analysis. Results Spa1 was more common in SSTI (14.81% SSTI, 3.70% HAP, 1.85% IE) (p<0.03). Spa2 was more common in HAP (0% SSTI, 12.96% HAP, 3.70% IE) (p<0.01). Levels of PSMα1-4 all differed significantly among the three clinical groups, with SSTI isolates producing the highest levels and IE producing the lowest levels of PSMα1-4. Spa1 isolates produced significantly more delta-toxin (p<0.03) than non-Spa1 isolates. No associations between PSM levels and clinical outcome of SSTI, HAP, or IE were identified. Conclusion Production of PSMα1-4 is highest in SSTI MSSA isolates, supporting the hypothesis that these peptides are important for SSTI pathogenesis. These findings are similar to those described in MRSA, and demonstrate that associations between PSM levels and type of infection are independent of the methicillin resistance status of the isolate. PMID:26778460

  7. Increased in vitro phenol-soluble modulin production is associated with soft tissue infection source in clinical isolates of methicillin-susceptible Staphylococcus aureus.

    Science.gov (United States)

    Qi, Robert; Joo, Hwang-Soo; Sharma-Kuinkel, Batu; Berlon, Nicholas R; Park, Lawrence; Fu, Chih-Lung; Messina, Julia A; Thaden, Joshua T; Yan, Qin; Ruffin, Felicia; Maskarinec, Stacey; Warren, Bobby; Chu, Vivian H; Fortes, Claudio Q; Giannitsioti, Efthymia; Durante-Mangoni, Emanuele; Kanafani, Zeina A; Otto, Michael; Fowler, Vance G

    2016-03-01

    Phenol-soluble modulins (PSM) are amphipathic proteins produced by Staphylococcus aureus that promote virulence, inflammatory response, and biofilm formation. We previously showed that MRSA isolates from soft tissue infection (SSTI) produced significantly higher levels of PSM than MRSA isolates from hospital-acquired pneumonia (HAP) or infective endocarditis (IE). In this investigation, we sought to validate this finding in methicillin-susceptible S. aureus (MSSA) isolates. MSSA isolates (n = 162) from patients with SSTI, HAP, and IE were matched 1:1:1 based on geographic origin of the infection to form 54 triplets (North America n = 27, Europe n = 25, Australia n = 2). All isolates underwent spa typing and were classified using eGenomics. In vitro PSM production was quantified by high-performance liquid chromatography/mass spectrometry. Fischer's Exact Test and the Kruskal-Wallis test were used for statistical analysis. Spa1 was more common in SSTI (14.81% SSTI, 3.70% HAP, 1.85% IE) (p < 0.03). Spa2 was more common in HAP (0% SSTI, 12.96% HAP, 3.70% IE) (p < 0.01). Levels of PSMα1-4 all differed significantly among the three clinical groups, with SSTI isolates producing the highest levels and IE producing the lowest levels of PSMα1-4. Spa1 isolates produced significantly more delta-toxin (p < 0.03) than non-Spa1 isolates. No associations between PSM levels and clinical outcome of SSTI, HAP, or IE were identified. Production of PSMα1-4 is highest in SSTI MSSA isolates, supporting the hypothesis that these peptides are important for SSTI pathogenesis. These findings are similar to those described in MRSA, and demonstrate that associations between PSM levels and type of infection are independent of the methicillin-resistance status of the isolate. Copyright © 2015 The British Infection Association. All rights reserved.

  8. Pemetrexed had significantly better clinical efficacy in patients with stage IV lung adenocarcinoma with susceptible EGFR mutations receiving platinum-based chemotherapy after developing resistance to the first-line gefitinib treatment

    Directory of Open Access Journals (Sweden)

    Yang CJ

    2016-03-01

    Full Text Available Chih-Jen Yang,1–4 Ming-Ju Tsai,2,4 Jen-Yu Hung,2,3 Ta-Chih Liu,3,5 Shah-Hwa Chou,3,6 Jui-Ying Lee,6 Jui-Sheng Hsu,3,7 Ying-Ming Tsai,1,2,4 Ming-Shyan Huang,2–4 Inn-Wen Chong2,3 1Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, 3Faculty of Medicine, College of Medicine, 4Graduate Institute of Medicine, College of Medicine, 5Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, 6Division of Chest Surgery, Department of Surgery, Kaohsiung Medical University Hospital, 7Department of Medical Imaging, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan Background: Increased evidences show that epidermal growth factor receptor (EGFR-tyrosine kinase inhibitors such as gefitinib could prolong progression-free survival (PFS compared with cytotoxic chemotherapy for metastatic lung nonsquamous cell carcinoma harboring susceptible EGFR mutation, and gefitinib was served as the first-line therapy. However, acquired resistance is inevitable, but the salvage therapies are still unclear.Patients and methods: We designed a retrospective study of the salvage therapy and enrolled patients with stage IV lung adenocarcinoma who had mutated EGFR and developed an acquired resistance to the first-line gefitinib in two university-affiliated hospitals in Taiwan during June 2011 to December 2014. Age, sex, smoking history, EGFR gene mutation, performance statuses, response rate, PFS2 (the PFS in salvage therapy, and overall survival (OS2, the OS in salvage therapy were recorded.Results: Two hundred and nine patients with mutated EGFR and who took gefitinib as first-line therapy were identified in the period, and a total of 98 patients who had been treated with salvage therapy with cytotoxic chemotherapy or erlotinib were eligible for this

  9. Slice-accelerated gradient-echo echo planar imaging dynamic susceptibility contrast-enhanced MRI with blipped CAIPI: effect of increasing temporal resolution.

    Science.gov (United States)

    Takamura, Tomohiro; Hori, Masaaki; Kamagata, Koji; Kumamaru, Kanako K; Irie, Ryusuke; Hagiwara, Akifumi; Hamasaki, Nozomi; Aoki, Shigeki

    2018-01-01

    To assess the influence of high temporal resolution on the perfusion measurements and image quality of perfusion maps, by applying simultaneous-multi-slice acquisition (SMS) dynamic susceptibility contrast-enhanced (DSC) magnetic resonance imaging (MRI). DSC-MRI data using SMS gradient-echo echo planar imaging sequences in 10 subjects with no intracranial abnormalities were retrospectively analyzed. Three additional data sets with temporal resolution of 1.0, 1.5, and 2.0 s were created from the raw data sets of 0.5 s. Cerebral blood flow (CBF), cerebral blood volume, mean transit time (MTT), time to peak (TTP), and time to maximum tissue residue function (T max ) measurements were performed, as was visual perfusion map analysis. The perfusion parameter for temporal resolution of 0.5 s (reference) was compared with each synthesized perfusion parameter. CBF, MTT, and TTP values at temporal resolutions of 1.5 and 2.0 s differed significantly from the reference. The image quality of MTT, TTP, and T max maps deteriorated with decreasing temporal resolution. The temporal resolution of DSC-MRI influences perfusion parameters and SMS DSC-MRI provides better image quality for MTT, TTP, and T max maps.

  10. Increased susceptibility to Strongyloides venezuelensis infection is related to the parasite load and absence of major histocompatibility complex (MHC) class II molecules.

    Science.gov (United States)

    Rodrigues, Rosângela Maria; Cardoso, Cristina Ribeiro; Gonçalves, Ana Lúcia Ribeiro; Silva, Neide Maria; Massa, Virgínia; Alves, Ronaldo; Ueta, Marlene Tiduko; Silva, João Santana; Costa-Cruz, Julia Maria

    2013-11-01

    In human and murine models strongyloidiasis induce a Th2 type response. In the current study we investigated the role of different loads of Strongyloides venezuelensis in the immune response raised against the parasite and the participation of the major histocompatibility complex (MHC) class II molecule in the disease outcome in face of the different parasite burden. The C57BL/6 wild type (WT) and MHC II(-/-) mice were individually inoculated by subcutaneous injection with 500 or 3000 S. venezuelensis L3. The MHC II(-/-) mice infected with 3000L3 were more susceptible to S. venezuelensis infection when compared with WT groups, in which the parasite was completely eliminated. The production of Th2 cytokines and specific IgG1 or IgE antibodies against parasite were significantly lowered in MHC II(-/-) infected mice with different larvae inoculums. The infection of MHC II(-/-) mice with S. venezuelensis induced slight inflammatory alterations in the small intestine, and these lesions were lower when compared with WT mice, irrespective of the parasite load utilized to infect animals. Finally, we concluded that MHC class II molecules are essential in the immune response against S. venezuelensis mainly when infection occurs with high parasite inoculum. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. Inherited variant on chromosome 11q23 increases susceptibility to IDH-mutated but not IDH-normal gliomas regardless of grade or histology.

    Science.gov (United States)

    Rice, Terri; Zheng, Shichun; Decker, Paul A; Walsh, Kyle M; Bracci, Paige; Xiao, Yuanyuan; McCoy, Lucie S; Smirnov, Ivan; Patoka, Joseph S; Hansen, Helen M; Hsuang, George; Wiemels, Joe L; Tihan, Tarik; Pico, Alexander R; Prados, Michael D; Chang, Susan M; Berger, Mitchel S; Caron, Alissa; Fink, Stephanie; Kollmeyer, Thomas; Rynearson, Amanda; Voss, Jesse; Kosel, Matthew L; Fridley, Brooke L; Lachance, Daniel H; Eckel-Passow, Jeanette E; Sicotte, Hugues; O'Neill, Brian Patrick; Giannini, Caterina; Wiencke, John K; Jenkins, Robert B; Wrensch, Margaret R

    2013-05-01

    Recent discoveries of inherited glioma risk loci and acquired IDH mutations are providing new insights into glioma etiology. IDH mutations are common in lower grade gliomas and secondary glioblastomas and uncommon in primary glioblastomas. Because the inherited variant in 11q23 has been associated with risk of lower grade glioma and not with glioblastomas, we hypothesized that this variant increases susceptibility to IDH-mutated gliomas, but not to IDH-wild-type gliomas. We tested this hypothesis in patients with glioma and controls from the San Francisco Adult Glioma Study, the Mayo Clinic, and Illumina controls (1102 total patients, 5299 total controls). Case-control additive associations of 11q23 risk alleles (rs498872, T allele) were calculated using logistic regression, stratified by tumor IDH status (mutated or wild-type) and by histology and grade. We also adjusted for the recently discovered 8q24 glioma risk locus rs55705857 G allele. The 11q23 glioma risk locus was associated with increased risk of IDH-mutated gliomas of all histologies and grades (odds ratio [OR] = 1.50; 95% confidence interval [CI] = 1.29-1.74; P = 1.3X10(-7)) but not with IDH-wild-type gliomas of any histology or grade (OR = 0.91; 95% CI = 0.81-1.03; P = 0.14). The associations were independent of the rs55705857 G allele. A variant at the 11q23 locus increases risk for IDH-mutated but not IDH-wild-type gliomas, regardless of grade or histology.

  12. Increased seizure susceptibility and up-regulation of nNOS expression in hippocampus following recurrent early-life seizures in rats.

    Science.gov (United States)

    Kim, Doo-Kwun

    2010-06-01

    This study aimed to determine the long-term change of seizure susceptibility and the role of nNOS on brain development following recurrent early-life seizures in rats. Video-EEG recordings were conducted between postnatal days 50 and 60. Alterations in seizure susceptibility were assayed on day 22 or 50 using the flurothyl method. Changes in nNOS expression were determined by quantitative immunoblotting on day 50. On average, rats had 8.4+/-2.7 seizures during 10 daily 1 hr behavioral monitoring sessions. As adults (days 50-60), all rats displayed interictal spikes in the hippocampus and/or overlying cortex. Brief electrographic seizures were recorded in only one of five animals. Rats appeared to progress from a period of marked seizure susceptibility (day 22) to one of lessened seizure susceptibility (day 50). Up-regulation of nNOS expression following early-life recurrent seizures was observed on day 50. In conclusion, these data suggested that recurrent early-life seizures had the long-term effects on seizure susceptibility late in life and up-regulatory nNOS expression on the hippocampus during brain development, and nNOS appeared to contribute to the persistent changes in seizure susceptibility, and epileptogenesis.

  13. Increasing Resistance to Extended-Spectrum Cephalosporins, Fluoroquinolone, and Carbapenem in Gram-Negative Bacilli and the Emergence of Carbapenem Non-Susceptibility in Klebsiella pneumoniae: Analysis of Korean Antimicrobial Resistance Monitoring System (KARMS) Data From 2013 to 2015.

    Science.gov (United States)

    Kim, Dokyun; Ahn, Ji Young; Lee, Chae Hoon; Jang, Sook Jin; Lee, Hyukmin; Yong, Dongeun; Jeong, Seok Hoon; Lee, Kyungwon

    2017-05-01

    National surveillance of antimicrobial resistance becomes more important for the control of antimicrobial resistance and determination of treatment guidelines. We analyzed Korean Antimicrobial Resistance Monitoring System (KARMS) data collected from 2013 to 2015. Of the KARMS participants, 16 secondary or tertiary hospitals consecutively reported antimicrobial resistance rates from 2013 to 2015. Data from duplicate isolates and institutions with fewer than 20 isolates were excluded. To determine the long-term trends, previous KARMS data from 2004 to 2012 were also considered. The prevalence of methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium from 2013 to 2015 was 66-72% and 29-31%, respectively. The resistance rates of Escherichia coli to cefotaxime and cefepime gradually increased to 35% and 31%, respectively, and fluoroquinolone resistance reached 48% in 2015. The resistance rates of Klebsiella pneumoniae to cefotaxime, cefepime, and carbapenem were 38-41%, 33-41%, and resistance rate of Pseudomonas aeruginosa to carbapenem increased to 35% and the prevalence of carbapenem-resistant Acinetobacter baumannii increased from 77% in 2013 to 85% in 2015. Between 2013 and 2015, the resistance rates of E. coli to third- and fourth-generation cephalosporins increased continuously, while carbapenem-susceptibility gradually decreased, particularly in K. pneumoniae. The prevalence of carbapenem-resistant P. aeruginosa and A. baumannii increased significantly; therefore, few treatment options remain for these resistant strains.

  14. Changes in rocket salad phytochemicals within the commercial supply chain: Glucosinolates, isothiocyanates, amino acids and bacterial load increase significantly after processing.

    Science.gov (United States)

    Bell, Luke; Yahya, Hanis Nadia; Oloyede, Omobolanle Oluwadamilola; Methven, Lisa; Wagstaff, Carol

    2017-04-15

    Five cultivars of Eruca sativa and a commercial variety of Diplotaxis tenuifolia were grown in the UK (summer) and subjected to commercial growth, harvesting and processing, with subsequent shelf life storage. Glucosinolates (GSL), isothiocyanates (ITC), amino acids (AA), free sugars, and bacterial loads were analysed throughout the supply chain to determine the effects on phytochemical compositions. Bacterial load of leaves increased significantly over time and peaked during shelf life storage. Significant correlations were observed with GSL and AA concentrations, suggesting a previously unknown relationship between plants and endemic leaf bacteria. GSLs, ITCs and AAs increased significantly after processing and during shelf life. The supply chain did not significantly affect glucoraphanin concentrations, and its ITC sulforaphane significantly increased during shelf life in E. sativa cultivars. We hypothesise that commercial processing may increase the nutritional value of the crop, and have added health benefits for the consumer. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  15. IL-10 gene polymorphism c.-592C>A increases HPV infection susceptibility and influences IL-10 levels in HPV infected women.

    Science.gov (United States)

    Berti, Fernanda Costa Brandão; Pereira, Ana Paula Lombardi; Trugilo, Kleber Paiva; Cebinelli, Guilherme Cesar Martelossi; Silva, Lorena Flor da Rosa Santos; Lozovoy, Marcell Alysson Batisti; Simão, Andréa Name Colado; Watanabe, Maria Angelica Ehara; de Oliveira, Karen Brajão

    2017-09-01

    Interleukin-10 (IL-10) influences HPV infection and viral persistence, favoring cervical immunosuppression and cervical carcinogenesis. IL-10 levels may be influenced by HPV itself and by IL-10 polymorphisms, including rs1800872 (c.-592C>A). Therefore, we evaluated the influence of IL-10 c.-592C>A polymorphism in HPV infection and in IL-10 plasmatic/cervical levels in HPV infected and non-infected women. The study included 174 infected and 186 non-infected patients. Cervical epithelial scrapings were obtained to determine HPV DNA presence PCR. Peripheral blood samples were obtained to determine IL-10 polymorphism by PCR-RFLP, while IL-10 levels were assessed by ELISA. HPV was more prevalent among allele A carriers (pA polymorphism being associated with HPV infection. As demonstrated by binary logistic regression analysis, heterozygotes [ORadj=2.081 95% CI (1.222-3.544), p=0.007] and homozygotes [ORadj=3.745 95% CI (1.695-8.271), p=0.001] showed approximately 2 and 4 time's greater odds, respectively, of presenting HPV when compared to CC patients. Moreover, HPV infected patients carrying polymorphic allele A showed higher IL-10 cervical levels (p=0.039). Binary logistic regression analysis demonstrated that IL-10 cervical levels were not independently associated to CA+AA genotypes (p=0.162), neither to HPV's presence (p=0.061), thus IL-10 cervical levels are possibly increased because of both HPV and allele A presence. Taken together, these findings suggest that IL-10 c.-592C>A polymorphism is independently associated with HPV infection susceptibility exerting influence on IL-10 cervical levels in HPV infected women, thus contributing to cervical carcinogenesis. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Short communication: SDF1-3'A gene mutation is correlated with increased susceptibility to HIV type 1 infection by sexual transmission in Han Chinese.

    Science.gov (United States)

    Wang, Yueyun; Wang, Xiaohui; Peng, Ji; Chen, Lin; Cheng, Jinquan; Nie, Shaofa; Feng, Tiejian; Zhao, Guanglu; Zhao, Jin; Shi, Xiangdong

    2008-11-01

    Limited information is available on host genetic polymorphisms that confer resistance to HIV-1 infection in Han Chinese who persistently remain seronegative (HEPS) despite high exposure to HIV-1 through unprotected sexual activity with known HIV-1-seropositive spouses or long-term sexual partners. The aim of this study was to investigate the correlation of CCR5-Delta32, CCR2b-64I, and SDF1-3'A polymorphisms with susceptibility to HIV-1 infection through sexual transmission in Han Chinese. A cross-sectional study was used to analyze the differences in allelic frequencies of CCR5-Delta32, CCR2b-64I, and SDF1-3'A among HEPS, healthy HIV-unexposed individuals, and HIV-1-seropositive individuals. Restriction fragment length polymorphism (RFLP) analysis was used for genotype determination. The CCR5-Delta32 mutation was not detected in the three groups (n = 260). The allelic frequencies of CCR2b-64I were 21.57%, 21.63%, and 22.12% in the three groups, respectively. There was no significant difference among the three groups in CCR2b-64I distribution. The allelic frequencies of SDF1-3'A were 20.19%, 28.37%, and 29.33% in the three groups, respectively. There was a significant difference in the allelic distribution of SDF1-3'A between HEPS and healthy HIV-unexposed individuals (p = 0.023), as well as between HEPS and HIV-1-seropositive individuals (p = 0.049). Statistical analysis showed that the allelic distributions on CCR2b-64I and SDF1-3'A were in equilibrium according to the Hardy-Weinberg equation. The mutant genotypes of CCR5-Delta32 and CCR2b-64I were not correlated with HIV-1 infection through sexual transmission in Han Chinese. SDF1- 3'A was associated with a high risk of HIV-1 infection through sexual transmission in Han Chinese.

  17. Serum Antioxidant Parameters are Significantly Increased in Patients with Type 2 Diabetes Mellitus after Consumption of Chinese Propolis: A Randomized Controlled Trial Based on Fasting Serum Glucose Level.

    Science.gov (United States)

    Gao, Weina; Pu, Lingling; Wei, Jingyu; Yao, Zhanxin; Wang, Yawen; Shi, Tala; Zhao, Liting; Jiao, Changya; Guo, Changjiang

    2018-02-01

    Propolis is a natural product with many biological activities. The present study was designed to evaluate the effects of Chinese propolis on glucose metabolism, antioxidant function, and inflammatory cytokines in patients with type 2 diabetes mellitus (T2DM). In the 18-week study, recruited T2DM patients were randomly divided into a Chinese propolis group (900 mg/day) (n = 31) and a control group (n = 30) according to fasting serum glucose levels at baseline. At the end of the study, no significant difference was found between the groups in serum glucose, glycosylated hemoglobin, insulin, aldose reductase, or adiponectin. However, serum GSH, flavonoids, and polyphenols were significantly increased, and serum lactate dehydrogenase activity was significantly reduced in the Chinese propolis group. Meanwhile, serum IL-6 was significantly increased in the Chinese propolis group. Chinese propolis is effective at improving antioxidant function in T2DM patients, partly by increasing serum antioxidant parameters.

  18. Increase in serotype 19A prevalence and amoxicillin non-susceptibility among paediatric Streptococcus pneumoniae isolates from middle ear fluid in a passive laboratory-based surveillance in Spain, 1997-2009

    Directory of Open Access Journals (Sweden)

    Robledo Olga

    2011-09-01

    Full Text Available Abstract Background Conjugate vaccines, such as the 7-valent conjugate vaccine (PCV7, alter serotype nasopharyngeal carriage, potentially increasing cases of otitis media by non-vaccine serotypes. Methods All paediatric middle ear fluid (MEF isolates received in the Spanish Reference Laboratory for Pneumococci through a passive, laboratory-based surveillance system from January 1997 to June 2009 were analysed. Data from 1997 to 2000 were pooled as pre-vaccination period. Trends over time were explored by linear regression analysis. Results A total of 2,077 isolates were analysed: 855 belonging to PCV7 serotypes, 466 to serotype 19A, 215 to serotype 3, 89 to serotype 6A and 452 to other serotypes (2 = 0.944; p 2 = 0.901; p 2 = 0.463; p = 0.030 and other non-PCV7 serotypes (R2 = 0.877; p 2 = 0.311; p = 0.094. Considering all isolates, amoxicillin non-susceptibility showed an increasing trend (R2 = 0.528; p = 0.017. Regarding serotype 19A, increasing trends in non-susceptibility to penicillin (R2 = 0.726; p = 0.001, amoxicillin (R2 = 0.804; p 2 = 0.546; p = 0.005 and erythromycin (R2 = 0.546; p = 0.009 were found, with amoxicillin non-susceptibility firstly detected in 2003 (7.4% and increasing up to 38.0% in 2009. In PCV7 serotypes (which prevalence decreased from 70.7% during 1997-2000 to 10.6% in 2009 amoxicillin non-susceptibility rates showed an increasing trend (R2 = 0.702; p = 0.002. However, overall, amoxicillin non-susceptibility (≈25% in 2008-9 could be mainly attributed to serotype 19A (> 35% isolates since PCV7 strains represented Conclusions In contrast to reports on invasive pneumococcal strains, in MEF isolates the reduction in the prevalence of PCV7 serotypes was not associated with decreases in penicillin/erythromycin non-susceptibility. The high prevalence of serotype 19A among paediatric MEF isolates and the amoxicillin non-susceptibility found in this serotype are worrisome since amoxicillin is the most common antibiotic used

  19. Semi-national surveillance of fungaemia in Denmark 2004-2006: increasing incidence of fungaemia and numbers of isolates with reduced azole susceptibility

    DEFF Research Database (Denmark)

    Arendrup, M.C.; Fuursted, K.; Gahrn-Hansen, B.

    2008-01-01

    .2% to 6.4% (p 0.06). MIC distributions of amphotericin B and caspofungin were in close agreement with the patterns predicted by species identification; however, decreased susceptibility to voriconazole, defined as an MIC of >1 mg/L, was detected in one (2.5%) C. glabrata isolate in 2004 and in 12 (14......, and a new trend towards C. glabrata isolates with elevated voriconazole MICs was observed Udgivelsesdato: 2008/5...

  20. TNF-α/IL-10 ratio correlates with burn severity and may serve as a risk predictor of increased susceptibility to infections

    Directory of Open Access Journals (Sweden)

    Amy Tsurumi

    2016-10-01

    Full Text Available Severe burn injury renders patients susceptible to multiple infection episodes, however identifying specific patient groups at high risk remains challenging. Burn-induced inflammatory response dramatically modifies the levels of various cytokines. Whether these changes could predict susceptibility to infections remains unknown. The aim of this study was to determine the early changes in the pro- to anti-inflammatory cytokine ratio and investigate its ability to predict susceptibility to repeated infections after severe burn trauma. The patient population consisted of 34 adult patients having early (≤48 hours since injury blood draws following severe (≥20% total burn surface area (TBSA burn injury, and suffering from a first infection episode at least one day after blood collection. Plasma TNF-α and IL-10 levels were measured to explore the association between the TNF-α/IL-10 ratio, hypersusceptibility to infections, burn size (TBSA, and common severity scores (Acute Physiology and Chronic Health Evaluation (APACHEII, Baux, modified Baux (R-Baux, Ryan Score, Abbreviated Burn Severity Index (ABSI. TNF-α/IL10 plasma ratio measured shortly after burn trauma was inversely correlated with burn size and the injury severity scores investigated, and was predictive of repeated infections (≥3 infection episodes outcome (AUROC [95%CI] of 0.80 [0.63–0.93]. Early measures of circulating TNF-α/IL10 ratio may be a previously unidentified biomarker associated with burn injury severity and predictive of the risk of hypersusceptibility to repeated infections.

  1. Graphene susceptibility in Holstein model

    Energy Technology Data Exchange (ETDEWEB)

    Mousavi, Hamze, E-mail: hamze.mousavi@gmail.co [Department of Physics, Razi University, Kermanshah (Iran, Islamic Republic of); Nano Science and Nano Technology Research Center, Razi University, Kermanshah (Iran, Islamic Republic of)

    2011-06-15

    We study the effects of the electron-phonon interaction on the temperature dependence of the orbital magnetic susceptibility of monolayer graphene. We use the linear response theory and Green's function formalism within the Holstein Hamiltonian model. The results show that the effects of the electron-phonon interaction on the susceptibility of graphene sheet have different behaviors in two temperature regions. In the low temperature region, susceptibility increases when the electron-phonon coupling strength increases. On the other hand, the susceptibility reduces with increasing the electron-phonon coupling strength in the high temperature region. - Highlights: Effect of electron-phonon interaction on the susceptibility of graphene is studied. Linear response theory and Green's function technique in Holstein model are used. Effect of electron-phonon on susceptibility has different behaviors in two temperature regions.

  2. Increased μ-Calpain Activity in Blasts of Common B-Precursor Childhood Acute Lymphoblastic Leukemia Correlates with Their Lower Susceptibility to Apoptosis.

    Directory of Open Access Journals (Sweden)

    Anna Mikosik

    Full Text Available Childhood acute lymphoblastic leukemia (ALL blasts are characterized by inhibited apoptosis promoting fast disease progress. It is known that in chronic lymphocytic and acute myeloid leukemias the reduced apoptosis is strongly related with the activity of calpain-calpastatin system (CCS composed of cytoplasmic proteases--calpains--performing the modulatory proteolysis of key proteins involved in cell proliferation and apoptosis, and of their endogenous inhibitor--calpastatin. Here, the CCS protein abundance and activity was for the first time studied in childhood ALL blasts and in control bone marrow CD19+ B cells by semi-quantitative flow cytometry and western blotting of calpastatin fragments resulting from endogenous calpain activity. Significantly higher μ-calpain (CAPN1 gene transcription, protein amounts and activity (but not those of m-calpain, with calpastatin amount and transcription of its gene (CAST greatly varying were observed in CD19(+ ALL blasts compared to control cells. Significant inverse relation between the amount/activity of calpain and spontaneous apoptosis was noted. Patients older than 10 years (considered at higher risk displayed increased amounts and activities of blast calpain. Finally, treatment of blasts with the tripeptide calpain inhibitors II and IV significantly and in dose-dependent fashion increased the percentage of blasts entering apoptosis. Together, these findings make the CCS a potential new predictive tool and therapeutic target in childhood ALL.

  3. Over-expression in the nucleotide-binding site-leucine rich repeat gene DEPG1 increases susceptibility to bacterial leaf streak disease in transgenic rice plants.

    Science.gov (United States)

    Guo, Lijia; Li, Min; Wang, Wujing; Wang, Lijuan; Hao, Guojing; Guo, Chiming; Chen, Liang

    2012-04-01

    Bacterial leaf streak of rice (BLS) caused by Xanthomonas oryzae pv. oryzicola (Xoc) is a widely-spread disease in the main rice-producing areas of the world. Investigating the genes that play roles in rice-Xoc interactions helps us to understand the defense signaling pathway in rice. Here we report a differentially expressed protein gene (DEPG1), which regulates susceptibility to BLS. DEPG1 is a nucleotide-binding site (NBS)-leucine rich repeat (LRR) gene, and the deduced protein sequence of DEPG1 has approximately 64% identity with that of the disease resistance gene Pi37. Phylogenetic analysis of DEPG1 and the 18 characterized NBS-LRR genes revealed that DEPG1 is more closely related to Pi37. DEPG1 protein is located to the cytoplasm, which was confirmed by transient expression of DEPG1-GFP (green fluorescent protein) fusion construct in onion epidermal cells. Semi-quantitative PCR assays showed that DEPG1 is widely expressed in rice, and is preferentially expressed in internodes, leaf blades, leaf sheaths and flag leaves. Observation of cross sections of leaves from the transgenic plants with a DEPG1-promoter::glucuronidase (GUS) fusion gene revealed that DEPG1 is also highly expressed in mesophyll tissues where Xoc mainly colonizes. Additionally, Xoc negatively regulates expression of DEPG1 at the early stage of the pathogen infection, and so do the three defense-signal compounds including salicylic acid (SA), methyl jasmonate (MeJA) and 1-aminocyclopropane-1-carboxylic-acid (ACC). Transgenic rice plants overexpressing DEPG1 exhibit enhanced susceptibility to Xoc compared to the wild-type controls. Moreover, enhanced susceptibility to Xoc may be mediated by inhibition of the expression of some SA biosynthesis-related genes and pathogenesis-related genes that may contribute to the disease resistance. Taken together, DEPG1 plays roles in the interactions between rice and BLS pathogen Xoc.

  4. The interferon-induced gene Ifi27l2a is active in lung macrophages and lymphocytes after influenza A infection but deletion of Ifi27l2a in mice does not increase susceptibility to infection.

    Science.gov (United States)

    Tantawy, Mohamed A; Hatesuer, Bastian; Wilk, Esther; Dengler, Leonie; Kasnitz, Nadine; Weiß, Siegfried; Schughart, Klaus

    2014-01-01

    Interferons represent one of the first and essential host defense mechanisms after infection, and the activation of the IFN-pathway results in the transcriptional activation of hundreds of interferon-stimulated genes. The alpha-inducible protein 27 like 2A (Ifi27l2a) gene (human synonym: ISG12) is strongly up-regulated in the lung after influenza A infection in mice and has been shown in gene expression studies to be highly correlated to other activated genes. Therefore, we investigated the role of Ifi27l2a for the host defense to influenza A infections in more detail. RT-PCR analyses in non-infected mice demonstrated that Ifi27l2a was expressed in several tissues, including the lung. Detailed analyses of reporter gene expression in lungs from Ifi27l2a-LacZ mice revealed that Ifi27l2a was expressed in macrophages and lymphocytes but not in alveolar cells or bronchiolar epithelium cells. The number of macrophages and lymphocyte strongly increased in the lung after infection, but no significant increase in expression levels of the LacZ reporter gene was found within individual immune cells. Also, no reporter gene expression was found in bronchiolar epithelial cells, alveolar cells or infiltrating neutrophils after infection. Thus, up-regulation of Ifi27l2a in infected lungs is mainly due to the infiltration of macrophages and lymphocytes. Most surprisingly, deletion of Ifi27l2a in mouse knock-out lines did not result in increased susceptibility to infections with H1N1 or H7N7 influenza A virus compared to wild type C57BL/6N mice, suggesting a less important role of the gene for the host response to influenza infections than for bacterial infections.

  5. The Impact of Agricultural Bank Advertisement and Identification of the Most Significant Factors in Increasing Impact of Advertisement in Mazandaran Province

    OpenAIRE

    Seyed Reza Mousavizadeh; Vahid Esmailpour Souteh

    2016-01-01

    The aim of this study is a survey about the impact of Agricultural bank advertisement and identification of the most significant factors in increasing impact of advertisement in Mazandaran province. The fundamental hypothesis of this study consists the commercial advertisement of Agricultural bank in Mazandaran province is influential. The applied model in order to assay the impact of advertisement is A.I.D.A model that includes 4 aspects of attracting attention, making interest, making tende...

  6. Significant increases in pulping efficiency in C4H-F5H-transformed poplars: improved chemical savings and reduced environmental toxins.

    Science.gov (United States)

    Huntley, Shannon K; Ellis, Dave; Gilbert, Margarita; Chapple, Clint; Mansfield, Shawn D

    2003-10-08

    The gene encoding ferulate 5-hydroxylase (F5H) was overexpressed in poplar (Populus tremula x Populus alba) using the cinnamate-4-hydroxylase (C4H) promoter to drive expression specifically in cells involved in the lignin biosynthetic pathway and was shown to significantly alter the mole percentage of syringyl subunits in the lignin, as determined by thioacidolysis. Analysis of poplar transformed with a C4H-F5H construct demonstrated significant increases in chemical (kraft) pulping efficiency from greenhouse-grown trees. Compared to wild-type wood, decreases of 23 kappa units and increases of >20 ISO brightness units were observed in trees exhibiting high syringyl monomer concentrations. These changes were associated with no significant modification in total lignin content and no observed phenotypic differences. C4H-F5H-transformed trees could increase pulp throughputs at mills by >60% while concurrently decreasing chemicals employed during processing (chemical pulping and bleaching) and, consequently, the amount of deleterious byproducts released into the environment.

  7. Liver-Specific Deletion of Phosphatase and Tensin Homolog Deleted on Chromosome 10 Significantly Ameliorates Chronic EtOH-Induced Increases in Hepatocellular Damage.

    Directory of Open Access Journals (Sweden)

    Colin T Shearn

    Full Text Available Alcoholic liver disease is a significant contributor to global liver failure. In murine models, chronic ethanol consumption dysregulates PTEN/Akt signaling. Hepatospecific deletion of phosphatase and tensin homolog deleted on chromosome 10 (PTENLKO mice possess constitutive activation of Akt(s and increased de novo lipogenesis resulting in increased hepatocellular steatosis. This makes PTENLKO a viable model to examine the effects of ethanol in an environment of preexisting steatosis. The aim of this study was to determine the impact of chronic ethanol consumption and the absence of PTEN (PTENLKO compared to Alb-Cre control mice (PTENf/f on hepatocellular damage as evidenced by changes in lipid accumulation, protein carbonylation and alanine amino transferase (ALT. In the control PTENf/f animals, ethanol significantly increased ALT, liver triglycerides and steatosis. In contrast, chronic ethanol consumption in PTENLKO mice decreased hepatocellular damage when compared to PTENLKO pair-fed controls. Consumption of ethanol elevated protein carbonylation in PTENf/f animals but had no effect in PTENLKO animals. In PTENLKO mice, overall hepatic mRNA expression of genes that contribute to GSH homeostasis as well as reduced glutathione (GSH and oxidized glutathione (GSSG concentrations were significantly elevated compared to respective PTENf/f counterparts. These data indicate that during conditions of constitutive Akt activation and steatosis, increased GSH homeostasis assists in mitigation of ethanol-dependent induction of oxidative stress and hepatocellular damage. Furthermore, data herein suggest a divergence in EtOH-induced hepatocellular damage and increases in steatosis due to polyunsaturated fatty acids downstream of PTEN.

  8. A Point Mutation in Suppressor of Cytokine Signalling 2 (Socs2) Increases the Susceptibility to Inflammation of the Mammary Gland while Associated with Higher Body Weight and Size and Higher Milk Production in a Sheep Model.

    Science.gov (United States)

    Rupp, Rachel; Senin, Pavel; Sarry, Julien; Allain, Charlotte; Tasca, Christian; Ligat, Laeticia; Portes, David; Woloszyn, Florent; Bouchez, Olivier; Tabouret, Guillaume; Lebastard, Mathieu; Caubet, Cécile; Foucras, Gilles; Tosser-Klopp, Gwenola

    2015-12-01

    Mastitis is an infectious disease mainly caused by bacteria invading the mammary gland. Genetic control of susceptibility to mastitis has been widely evidenced in dairy ruminants, but the genetic basis and underlying mechanisms are still largely unknown. We describe the discovery, fine mapping and functional characterization of a genetic variant associated with elevated milk leukocytes count, or SCC, as a proxy for mastitis. After implementing genome-wide association studies, we identified a major QTL associated with SCC on ovine chromosome 3. Fine mapping of the region, using full sequencing with 12X coverage in three animals, provided one strong candidate SNP that mapped to the coding sequence of a highly conserved gene, suppressor of cytokine signalling 2 (Socs2). The frequency of the SNP associated with increased SCC was 21.7% and the Socs2 genotype explained 12% of the variance of the trait. The point mutation induces the p.R96C substitution in the SH2 functional domain of SOCS2 i.e. the binding site of the protein to various ligands, as well-established for the growth hormone receptor GHR. Using surface plasmon resonance we showed that the p.R96C point mutation completely abrogates SOCS2 binding affinity for the phosphopeptide of GHR. Additionally, the size, weight and milk production in p.R96C homozygote sheep, were significantly increased by 24%, 18%, and 4.4%, respectively, when compared to wild type sheep, supporting the view that the point mutation causes a loss of SOCS2 functional activity. Altogether these results provide strong evidence for a causal mutation controlling SCC in sheep and highlight the major role of SOCS2 as a tradeoff between the host's inflammatory response to mammary infections, and body growth and milk production, which are all mediated by the JAK/STAT signaling pathway.

  9. A Point Mutation in Suppressor of Cytokine Signalling 2 (Socs2 Increases the Susceptibility to Inflammation of the Mammary Gland while Associated with Higher Body Weight and Size and Higher Milk Production in a Sheep Model.

    Directory of Open Access Journals (Sweden)

    Rachel Rupp

    2015-12-01

    Full Text Available Mastitis is an infectious disease mainly caused by bacteria invading the mammary gland. Genetic control of susceptibility to mastitis has been widely evidenced in dairy ruminants, but the genetic basis and underlying mechanisms are still largely unknown. We describe the discovery, fine mapping and functional characterization of a genetic variant associated with elevated milk leukocytes count, or SCC, as a proxy for mastitis. After implementing genome-wide association studies, we identified a major QTL associated with SCC on ovine chromosome 3. Fine mapping of the region, using full sequencing with 12X coverage in three animals, provided one strong candidate SNP that mapped to the coding sequence of a highly conserved gene, suppressor of cytokine signalling 2 (Socs2. The frequency of the SNP associated with increased SCC was 21.7% and the Socs2 genotype explained 12% of the variance of the trait. The point mutation induces the p.R96C substitution in the SH2 functional domain of SOCS2 i.e. the binding site of the protein to various ligands, as well-established for the growth hormone receptor GHR. Using surface plasmon resonance we showed that the p.R96C point mutation completely abrogates SOCS2 binding affinity for the phosphopeptide of GHR. Additionally, the size, weight and milk production in p.R96C homozygote sheep, were significantly increased by 24%, 18%, and 4.4%, respectively, when compared to wild type sheep, supporting the view that the point mutation causes a loss of SOCS2 functional activity. Altogether these results provide strong evidence for a causal mutation controlling SCC in sheep and highlight the major role of SOCS2 as a tradeoff between the host's inflammatory response to mammary infections, and body growth and milk production, which are all mediated by the JAK/STAT signaling pathway.

  10. Increased expression of interleukin-21 along colorectal adenoma-carcinoma sequence and its predicating significance in patients with sporadic colorectal cancer.

    Science.gov (United States)

    Cui, Guanglin; Yuan, Aping; Zhu, Li; Florholmen, Jon; Goll, Rasmus

    2017-10-01

    The role and significance of interleukin (IL)-21 in the development of sporadic CRC have not been well defined. The aim of this study is therefore to investigate the dynamics of the IL-21 along colorectal adenoma-carcinoma sequence and to evaluate the impact of IL-21 on clinicopathological parameters and CRC prognosis. The real-time PCR results showed that the level of IL-21 in adenomas (n=50) and sporadic CRC (n=50) were significantly higher than that in normal controls (n=18), which were predominately observed in the adenoma/CRC stroma. Analysis revealed that IL-21 level was correlated with the overall survival time in CRC patients. Double immunofluorescence observations confirmed that IL-21 positive cells were mostly natural killer cells and T lymphocytes in the tumor stroma. These results indicate that significant increased IL-21 expression present within the adenoma/CRC microenvironment might have a potential predicating significance for survival time in patients with CRC. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Prognostic significance of repeat biopsy in lupus nephritis: Histopathologic worsening and a short time between biopsies is associated with significantly increased risk for end stage renal disease and death.

    Science.gov (United States)

    Arriens, Cristina; Chen, Sixia; Karp, David R; Saxena, Ramesh; Sambandam, Kamalanathan; Chakravarty, Eliza; James, Judith A; Merrill, Joan T

    2017-12-01

    histopathology had died compared to 2 (3.2%) of non-worsening patients. Biopsy worsening was associated with a significantly greater 15-year risk of ESRD (Hazard Ratio 4.2, p=0.0001) and death (Hazard Ratio 4.3, p=0.022), adjusting for age, gender, race, biopsy class, and treatment. Time between first and second biopsies was 5years in 28. Over a 15-year period, those with biopsies (presumably enriched for patients with early clinical signs of progression) had a significantly greater risk of ESRD (Hazard Ratio 13.7, pbiopsy class, and treatment. A repeat renal biopsy demonstrating worsening pathology increases the risk of ESRD and death more than four-fold compared to non-worsening patients. Given known potential mismatch between biopsy and clinical data, repeat biopsies may add important information and justify changes in treatment not considered on clinical grounds. Earlier detection of poor prognostic signs in those without early clinical deterioration might improve outcomes in enough patients to reconsider cost effectiveness of routine repeat biopsy. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Prenatal prochloraz treatment significantly increases pregnancy length and reduces offspring weight but does not affect social-olfactory memory in rats

    DEFF Research Database (Denmark)

    Dmytriyeva, Oksana; Klementiev, Boris; Berezin, Vladimir

    2013-01-01

    the perinatal period. Pregnant Wistar rats were administered a 200mg/kg dose of prochloraz on gestational day (GD) 7, GD11, and GD15. The social recognition test (SRT) was performed on 7-week-old male rat offspring. We found an increase in pregnancy length and a significantly reduced pup weight on PND15 and PND......Metabolites of the commonly used imidazole fungicide prochloraz are androgen receptor antagonists. They have been shown to block androgen-driven development and compromise reproductive function. We tested the effect of prochloraz on cognitive behavior following exposure to this fungicide during...

  13. Variants within MECP2, a key transcription regulator, are associated with increased susceptibility to lupus and differential gene expression in patients with systemic lupus erythematosus.

    Science.gov (United States)

    Webb, Ryan; Wren, Jonathan D; Jeffries, Matlock; Kelly, Jennifer A; Kaufman, Kenneth M; Tang, Yuhong; Frank, Mark Barton; Merrill, Joan; Kimberly, Robert P; Edberg, Jeffrey C; Ramsey-Goldman, Rosalind; Petri, Michelle; Reveille, John D; Alarcón, Graciela S; Vilá, Luis M; Alarcón-Riquelme, Marta E; James, Judith A; Vyse, Timothy J; Moser, Kathy L; Gaffney, Patrick M; Gilkeson, Gary S; Harley, John B; Sawalha, Amr H

    2009-04-01

    Both genetic and epigenetic factors play an important role in the pathogenesis of lupus. The aim of this study was to examine methyl-CpG-binding protein 2 gene (MECP2) polymorphisms in a large cohort of patients with lupus and control subjects, and to determine the functional consequences of the lupus-associated MECP2 haplotype. We genotyped 18 single-nucleotide polymorphisms within MECP2, located on chromosome Xq28, in a large cohort of patients with lupus and control subjects of European descent. We studied the functional effects of the lupus-associated MECP2 haplotype by determining gene expression profiles in B cell lines in female lupus patients with and those without the lupus-associated MECP2 risk haplotype. We confirmed, replicated, and extended the genetic association between lupus and genetic markers within MECP2 in a large independent cohort of lupus patients and control subjects of European descent (odds ratio 1.35, P = 6.65 x 10(-11)). MECP2 is a dichotomous transcription regulator that either activates or represses gene expression. We identified 128 genes that are differentially expressed in lupus patients with the disease-associated MECP2 haplotype; most ( approximately 81%) were up-regulated. Genes that were up-regulated had significantly more CpG islands in their promoter regions compared with genes that were down-regulated. Gene ontology analysis using the differentially expressed genes revealed significant association with epigenetic regulatory mechanisms, suggesting that these genes are targets for MECP2 regulation in B cells. Furthermore, at least 13 of the 104 up-regulated genes are regulated by interferon. The disease-risk MECP2 haplotype was associated with increased expression of the MECP2 transcription coactivator CREB1 and decreased expression of the corepressor histone deacetylase 1. Polymorphism in the MECP2 locus is associated with lupus and, at least in part, contributes to the interferon signature observed in lupus patients.

  14. CaMKII Activation Promotes Cardiac Electrical Remodeling and Increases the Susceptibility to Arrhythmia Induction in High-fat Diet-Fed Mice With Hyperlipidemia Conditions.

    Science.gov (United States)

    Zhong, Peng; Quan, Dajun; Huang, Yan; Huang, He

    2017-10-01

    Obesity/hyperlipidemia is closely related to both atrial and ventricular arrhythmias. CaMKII, a multifunctional serine/threonine kinase, has been involved in cardiac arrhythmias of different etiologies. However, its role in obesity/hyperlipidemia-related cardiac arrhythmia is unexplored. The aim of this was to determine the involvement of CaMKII in the process. Adult male APOE mice were fed a high-fat diet (HFD), administrated with KN93 (10 mg·kg·2d), a specific inhibitor of CaMKII. Serum lipid and glucose profile, cardiac function, and surface electrocardiogram were determined. Electrophysiological study and epicardial activation mapping were performed in Langendorff-perfused heart. Expression of cardiac ion channels, gap junction proteins, Ca handling proteins, and CaMKII were evaluated, coupled with histological analysis. A hyperlipidemia condition was induced by HFD in the APOE mice, which was associated with increased expression and activity of CaMKII in the hearts. In Langendorff-perfused hearts, HFD-induced heart showed increased arrhythmia inducibility, prolonged action potential duration, and decreased action potential duration alternans thresholds, coupled with slow ventricular conduction, connexin-43 upregulation, and interstitial fibrosis. Downregulation of ion channels including Cav1.2 and Kv4.2/Kv4.3 and disturbed Ca handling proteins were also observed in HFD-induced heart. Interestingly, all these alterations were significantly inhibited by KN93 treatment. Our results demonstrated an adverse effect of metabolic components on cardiac electrophysiology and implicated an important role of CaMKII underlying this process.

  15. The rs4846049 polymorphism in the 3’UTR region of the MTHFR gene increases the migraine susceptibility in an Iranian population

    Directory of Open Access Journals (Sweden)

    Salehi M

    2018-01-01

    Full Text Available Mohaddeseh Salehi,1,* Mona Amin-Beidokhti,2,* Behnam Safarpour Lima,3 Milad Gholami,2 Gholam-Reza Javadi,1 Reza Mirfakhraie2,4 1Department of Biology, Islamic Azad University, Science and Research Branch, 2Department of Medical Genetics, 3Department of Neurology, School of Medicine, 4Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran *These authors contributed equally to this work Introduction: Migraine is a painful complex neurovascular disease characterized by recurrent moderate-to-severe headaches. Increased level of homocysteine is related to dilation of cerebral vessels and endothelial injury that could trigger migraine attacks. Functional polymorphisms in the MTHFR gene affect homocysteine metabolism and, therefore, play an important role in the etiology of the disease. Objectives: We aimed to investigate the possible association between MTHFR gene rs4846049, C677T, and A1298C polymorphisms and the risk of migraine in Iranian population. Methods: In this genetic association study, 498 individuals were enrolled, including 223 migraine patients and 275 healthy controls. Genotyping was performed using tetra-primer ARMS-PCR for rs4846049 and PCR-restriction fragment length polymorphism for C677T and A1298C polymorphisms. Results: The association between rs4846049 and C677T polymorphisms and migraine was observed. For the rs4846049 polymorphism, the association was detected under a dominant model (P=0.007; odds ratio [OR] =0.60; 95% confidence interval [CI], 0.41–0.87, and for the C677T polymorphism, the TT genotype frequency was significantly different in the studied groups (P=0.009; OR =2.48; 95% CI, 1.25–4.92. No significant differences in the genotype or allele frequencies were found for the A1298C polymorphism between the migraineurs and controls. Conclusion: Present data provide evidence for the association of rs4846049 and C677T polymorphisms in the MTHFR gene and migraine. Further studies are

  16. Decidual Macrophages Are Significantly Increased in Spontaneous Miscarriages and Over-Express FasL: A Potential Role for Macrophages in Trophoblast Apoptosis

    Directory of Open Access Journals (Sweden)

    Antonis Makrigiannakis

    2012-07-01

    Full Text Available Decidual macrophages (DM are the second most abundant population in the fetal-maternal interface. Their role has been so far identified as being local immuno-modulators favoring the maternal tolerance to the fetus. Herein we investigated tissue samples from 11 cases of spontaneous miscarriages and from 9 cases of elective terminations of pregnancy. Using immunohistochemistry and dual immunofluorescence we have demonstrated that in spontaneous miscarriages the DM are significantly increased. Additionally, we noted a significant up-regulation of macrophage FasL expression. Our results further support a dual role for DM during pregnancy and miscarriages. We hypothesize that the baseline DM population in normal pregnancy is in line with an M2 phenotype supporting the ongoing gestation. In contrast, during spontaneous miscarriages, the increased FasL-expressing population could be a part of an M1 phenotype participating in Fas/FasL-related apoptosis. Our results highlight a new aspect of macrophage biology in pregnancy physiology and pathophysiology. Further studies with larger samples are needed to verify the current results and evaluate their clinical impact.

  17. MyD88-, but not Nod1- and/or Nod2-deficient mice, show increased susceptibility to polymicrobial sepsis due to impaired local inflammatory response.

    Directory of Open Access Journals (Sweden)

    Fabiane Sônego

    Full Text Available Pathogen recognition and triggering of the inflammatory response following infection in mammals depend mainly on Toll-like and Nod-like receptors. Here, we evaluated the role of Nod1, Nod2 and MyD88-dependent signaling in the chemokine production and neutrophil recruitment to the infectious site during sepsis induced by cecal ligation and puncture (CLP in C57Bl/6 mice. We demonstrate that Nod1 and Nod2 are not involved in the release of chemokines and recruitment of neutrophils to the infectious site during CLP-induced septic peritonitis because these events were similar in wild-type, Nod1-, Nod2-, Nod1/Nod2- and Rip2-deficient mice. Consequently, the local and systemic bacterial loads were not altered. Accordingly, neither Nod1 nor Nod2 was involved in the production of the circulating cytokines and in the accumulation of leukocytes in the lungs. By contrast, we showed that MyD88-dependent signaling is crucial for the establishment of the local inflammatory response during CLP-induced sepsis. MyD88-deficient mice were susceptible to sepsis because of an impaired local production of chemokines and defective neutrophil recruitment to the infection site. Altogether, these data show that Nod1, Nod2 and Rip2 are not required for local chemokine production and neutrophil recruitment during CLP-induced sepsis, and they reinforce the importance of MyD88-dependent signaling for initiation of a protective host response.

  18. Susceptibility to COPD: differential proteomic profiling after acute smoking.

    Directory of Open Access Journals (Sweden)

    Lorenza Franciosi

    Full Text Available Cigarette smoking is the main risk factor for COPD (Chronic Obstructive Pulmonary Disease, yet only a subset of smokers develops COPD. Family members of patients with severe early-onset COPD have an increased risk to develop COPD and are therefore defined as "susceptible individuals". Here we perform unbiased analyses of proteomic profiles to assess how "susceptible individuals" differ from age-matched "non-susceptible individuals" in response to cigarette smoking. Epithelial lining fluid (ELF was collected at baseline and 24 hours after smoking 3 cigarettes in young individuals susceptible or non-susceptible to develop COPD and older subjects with established COPD. Controls at baseline were older healthy smoking and non-smoking individuals. Five samples per group were pooled and analysed by stable isotope labelling (iTRAQ in duplicate. Six proteins were selected and validated by ELISA or immunohistochemistry. After smoking, 23 proteins increased or decreased in young susceptible individuals, 7 in young non-susceptible individuals, and 13 in COPD in the first experiment; 23 proteins increased or decreased in young susceptible individuals, 32 in young non-susceptible individuals, and 11 in COPD in the second experiment. SerpinB3 and Uteroglobin decreased after acute smoke exposure in young non-susceptible individuals exclusively, whereas Peroxiredoxin I, S100A9, S100A8, ALDH3A1 (Aldehyde dehydrogenase 3A1 decreased both in young susceptible and non-susceptible individuals, changes being significantly different between groups for Uteroglobin with iTRAQ and for Serpin B3 with iTRAQ and ELISA measures. Peroxiredoxin I, SerpinB3 and ALDH3A1 increased in COPD patients after smoking. We conclude that smoking induces a differential protein response in ELF of susceptible and non-susceptible young individuals, which differs from patients with established COPD. This is the first study applying unbiased proteomic profiling to unravel the underlying

  19. Effect of repetitive daily ethanol intoxication on adult rat brain: significant changes in phospholipase A2 enzyme levels in association with increased PARP-1 indicate neuroinflammatory pathway activation.

    Science.gov (United States)

    Tajuddin, Nuzhath F; Przybycien-Szymanska, Magdalena M; Pak, Toni R; Neafsey, Edward J; Collins, Michael A

    2013-02-01

    Collaborating on studies of subchronic daily intoxication in juvenile and adult rats, we examined whether the repetitive ethanol treatments at these two life stages altered levels of key neuroinflammation-associated proteins-aquaporin-4 (AQP4), certain phospholipase A2 (PLA2) enzymes, PARP-1 and caspase-3-in hippocampus (HC) and entorhinal cortex (EC). Significant changes in the proteins could implicate activation of specific neuroinflammatory signaling pathways in these rats as well as in severely binge-intoxicated adult animals that are reported to incur degeneration of vulnerable neurons in HC and EC. Male Wistar rats, ethanol-intoxicated (3 g/kg i.p.) once daily for 6 days over an 8-day interval beginning at 37 days old and repeated at age 68-75 days, were sacrificed 1 h after the day 75 dose (blood ethanol, 200- 230 mg/dl). Analysis of HC with an immunoblot technique showed that AQP4, Ca(+2)-dependent PLA2 (cPLA2 IVA), phosphorylated (activated) p-cPLA2, cleaved (89 kD) PARP (c-PARP), and caspase-3 levels were significantly elevated over controls, whereas Ca(+2)-independent PLA2 (iPLA2 VIA) was reduced ∼70%; however, cleaved caspase-3 was undetectable. In the EC, AQP4 was unchanged, but cPLA2 and p-cPLA2 were significantly increased while iPLA2 levels were diminished (∼40%) similar to HC, although just outside statistical significance (p = 0.06). In addition, EC levels of PARP-1 and c-PARP were significantly increased. The ethanol-induced activation of cPLA2 in association with reduced iPLA2 mirrors PLA2 changes in reports of neurotrauma and also of dietary omega-3 fatty acid depletion. Furthermore, the robust PARP-1 elevations accompanied by negligible caspase-3 activation indicate that repetitive ethanol intoxication may be potentiating non-apoptotic neurodegenerative processes such as parthanatos. Overall, the repetitive ethanol treatments appeared to instigate previously unappreciated neuroinflammatory pathways in vivo. The data provide insights

  20. Addition of a third field significantly increases dose to the brachial plexus for patients undergoing tangential whole-breast therapy after lumpectomy

    Energy Technology Data Exchange (ETDEWEB)

    Stanic, Sinisa; Mathai, Mathew; Mayadev, Jyoti S.; Do, Ly V.; Purdy, James A. [Department of Radiation Oncology, University of California, Davis, Sacramento, CA (United States); Chen, Allen M., E-mail: allen.chen@ucdmc.ucdavis.edu [Department of Radiation Oncology, University of California, Davis, Sacramento, CA (United States)

    2012-07-01

    Our goal was to evaluate brachial plexus (BP) dose with and without the use of supraclavicular (SCL) irradiation in patients undergoing breast-conserving therapy with whole-breast radiation therapy (RT) after lumpectomy. Using the standardized Radiation Therapy Oncology Group (RTOG)-endorsed guidelines delineation, we contoured the BP for 10 postlumpectomy breast cancer patients. The radiation dose to the whole breast was 50.4 Gy using tangential fields in 1.8-Gy fractions, followed by a conedown to the operative bed using electrons (10 Gy). The prescription dose to the SCL field was 50.4 Gy, delivered to 3-cm depth. The mean BP volume was 14.5 {+-} 1.5 cm{sup 3}. With tangential fields alone, the median mean dose to the BP was 0.57 Gy, the median maximum dose was 1.93 Gy, and the irradiated volume of the BP receiving 40, 45, and 50 Gy was 0%. When the third (SCL field) was added, the dose to the BP was significantly increased (P = .01): the median mean dose to the BP was 40.60 Gy, and the median maximum dose was 52.22 Gy. With 3-field RT, the median irradiated volume of the BP receiving 40, 45, and 50 Gy was 83.5%, 68.5%, and 24.6%, respectively. The addition of the SCL field significantly increases dose to the BP. The possibility of increasing the risk of BP morbidity should be considered in the context of clinical decision making.

  1. Clinical significance of increased cerebellar default-mode network connectivity in resting-state patients with drug-naive somatization disorder.

    Science.gov (United States)

    Wang, Houliang; Guo, Wenbin; Liu, Feng; Chen, Jindong; Wu, Renrong; Zhang, Zhikun; Yu, Miaoyu; Li, Lehua; Zhao, Jingping

    2016-07-01

    The cerebellum has been proven to be connected to the brain network, as in the default-mode network (DMN), among healthy subjects and patients with psychiatric disorders. However, whether or not abnormal cerebellar DMN connectivity exists and what its clinical significance is among drug-naive patients with somatization disorder (SD) at rest remain unclear.A total of 25 drug-naive patients with SD and 28 healthy controls were enrolled for a resting-state scan. The imaging data were analyzed using the seed-based functional connectivity (FC) method.Compared with the controls, patients with SD showed increased left/right Crus I-left/right angular gyrus (AG) connectivity and Lobule IX-left superior medial prefrontal cortex (MPFC) connectivity. The FC values of the left/right Crus I-right AG connectivity of the patients were positively correlated with their scores in the somatization subscale of the symptom checklist-90 (Scl-90). A trend level of correlations was observed between the FC values of the left Crus I-left AG connectivity of the patients and their scores for the somatization subscale of Scl-90, as well as between the FC values of their Lobule IX-left superior MPFC connectivity and their scores for the Eysenck personality questionnaire (EPQ) extraversion.Our findings show the increased cerebellar DMN connectivity in patients with SD and therefore highlight the importance of the DMN in the neurobiology of SD. Increased cerebellar DMN connectivities are also correlated with their somatization severity and personality, both of which bear clinical significance.

  2. Impact of MTHFR rs1801133, MTHFR rs1801131 and ABCB1 rs1045642 polymorphisms with increased susceptibility of rheumatoid arthritis in the West Algerian population: A case-control study.

    Directory of Open Access Journals (Sweden)

    Wefa BOUGHRARA

    2015-10-01

    Full Text Available Rheumatoid arthritis (RA is an autoimmune disease that results in a chronic systemic inflammation. A few genetic epidemiologic studies found a potential association between genetic polymorphisms C677T (rs1801133 and A1298C (rs1801131 of methylenetatrahydrofolate reductase (MTHFR gene and C3435T (rs1045642 of ATP-Binding cassette (ABCB1 gene and the increased risk for RA. The aim of this case-control study was to determine the relationship between these polymorphisms and RA susceptibility in West Algerian population. The dataset of the current study is composed of 110 RA patients and 101 healthy controls. All samples were genotyped for theses polymorphisms by TaqMan® allelic discrimination assay. Data were compared between cases and controls by the calculation of the odds ratio (OR with a confidence interval at 95%. After age and RA erosion-stratified analyzes, no differences in genotypes or alleles frequencies distribution were found for MTHFR C677T (rs1801133 and ABCB1 C3435T (rs1045642 polymorphisms between RA cases and controls. However, the MTHFR A1298C (rs1801131 polymorphism presented a significant distribution in RA with age ≥ 40 (Genotypic data: p=0.007, OR=13.53[1.44-63.31], Allelic data: p=0.001, OR=2.39[1.39-4.1], and in RA erosive form (Genotypic data: p=0.002, OR=6.92[1.68-30.23], Allelic data: p=0.0001, OR=2.43[1.54-3.85].These results were confirmed after the Bonferroni correction. In this study we have showed, for the first time in the West Algerian population, that the MTHFR A1298C (rs1801131 polymorphism can be associated with rheumatoid arthritis.

  3. MaquiBright™ standardized maqui berry extract significantly increases tear fluid production and ameliorates dry eye-related symptoms in a clinical pilot trial.

    Science.gov (United States)

    Hitoe, S; Tanaka, J; Shimoda, H

    2014-09-01

    Dry eye symptoms, resulting from insufficient tear fluid generation, represent a considerable burden for a largely underestimated number of people. We concluded from earlier pre-clinical investigations that the etiology of dry eyes encompasses oxidative stress burden to lachrymal glands and that antioxidant MaquiBright™ Aristotelia chilensis berry extract helps restore glandular activity. In this pilot trial we investigated 13 healthy volunteers with moderately dry eyes using Schirmer test, as well as a questionnaire which allows for estimating the impact of dry eyes on daily routines. Study participants were assigned to one of two groups, receiving MaquiBright™ at daily dosage of either 30 mg (N.=7) or 60 mg (N.=6) over a period of 60 days. Both groups presented with significantly (PDry Eye-related Quality of life Score" (DEQS), with values spanning from zero (impact) to a maximum score of 60. Participants had comparable baseline values of 41.0±7.7 (30 mg) and 40.2±6.3 (60 mg). With 30 mg treatment the score significantly decreased to 21.8±3.9 and 18.9±3.9, after 30 and 60 days, respectively. With 60 mg treatment the DEQS significantly decreased to 26.9±5.3 and 11.1±2.7, after 30 and 60 days, respectively. Blood was drawn for safety analyses (complete blood rheology and -chemistry) at all three investigative time points without negative findings. In conclusion, while daily supplementation with 30 mg MaquiBright™ is effective, the dosage of 60 significantly increased tear fluid volume at all investigative time points and decreased dry eye symptoms to almost a quarter from initial values after two months treatment.

  4. The in vitro mass-produced model mycorrhizal fungus, Rhizophagus irregularis, significantly increases yields of the globally important food security crop cassava.

    Directory of Open Access Journals (Sweden)

    Isabel Ceballos

    Full Text Available The arbuscular mycorrhizal symbiosis is formed between arbuscular mycorrhizal fungi (AMF and plant roots. The fungi provide the plant with inorganic phosphate (P. The symbiosis can result in increased plant growth. Although most global food crops naturally form this symbiosis, very few studies have shown that their practical application can lead to large-scale increases in food production. Application of AMF to crops in the tropics is potentially effective for improving yields. However, a main problem of using AMF on a large-scale is producing cheap inoculum in a clean sterile carrier and sufficiently concentrated to cheaply transport. Recently, mass-produced in vitro inoculum of the model mycorrhizal fungus Rhizophagus irregularis became available, potentially making its use viable in tropical agriculture. One of the most globally important food plants in the tropics is cassava. We evaluated the effect of in vitro mass-produced R. irregularis inoculum on the yield of cassava crops at two locations in Colombia. A significant effect of R. irregularis inoculation on yield occurred at both sites. At one site, yield increases were observed irrespective of P fertilization. At the other site, inoculation with AMF and 50% of the normally applied P gave the highest yield. Despite that AMF inoculation resulted in greater food production, economic analyses revealed that AMF inoculation did not give greater return on investment than with conventional cultivation. However, the amount of AMF inoculum used was double the recommended dose and was calculated with European, not Colombian, inoculum prices. R. irregularis can also be manipulated genetically in vitro, leading to improved plant growth. We conclude that application of in vitro R. irregularis is currently a way of increasing cassava yields, that there is a strong potential for it to be economically profitable and that there is enormous potential to improve this efficiency further in the future.

  5. Long-term use of amiodarone before heart transplantation significantly reduces early post-transplant atrial fibrillation and is not associated with increased mortality after heart transplantation.

    Science.gov (United States)

    Rivinius, Rasmus; Helmschrott, Matthias; Ruhparwar, Arjang; Schmack, Bastian; Erbel, Christian; Gleissner, Christian A; Akhavanpoor, Mohammadreza; Frankenstein, Lutz; Darche, Fabrice F; Schweizer, Patrick A; Thomas, Dierk; Ehlermann, Philipp; Bruckner, Tom; Katus, Hugo A; Doesch, Andreas O

    2016-01-01

    Amiodarone is a frequently used antiarrhythmic drug in patients with end-stage heart failure. Given its long half-life, pre-transplant use of amiodarone has been controversially discussed, with divergent results regarding morbidity and mortality after heart transplantation (HTX). The aim of this study was to investigate the effects of long-term use of amiodarone before HTX on early post-transplant atrial fibrillation (AF) and mortality after HTX. Five hundred and thirty patients (age ≥18 years) receiving HTX between June 1989 and December 2012 were included in this retrospective single-center study. Patients with long-term use of amiodarone before HTX (≥1 year) were compared to those without long-term use (none or amiodarone). Primary outcomes were early post-transplant AF and mortality after HTX. The Kaplan-Meier estimator using log-rank tests was applied for freedom from early post-transplant AF and survival. Of the 530 patients, 74 (14.0%) received long-term amiodarone therapy, with a mean duration of 32.3±26.3 months. Mean daily dose was 223.0±75.0 mg. Indications included AF, Wolff-Parkinson-White syndrome, ventricular tachycardia, and ventricular fibrillation. Patients with long-term use of amiodarone before HTX had significantly lower rates of early post-transplant AF (P=0.0105). Further, Kaplan-Meier analysis of freedom from early post-transplant AF showed significantly lower rates of AF in this group (P=0.0123). There was no statistically significant difference between patients with and without long-term use of amiodarone prior to HTX in 1-year (P=0.8596), 2-year (P=0.8620), 5-year (P=0.2737), or overall follow-up mortality after HTX (P=0.1049). Moreover, Kaplan-Meier survival analysis showed no statistically significant difference in overall survival (P=0.1786). Long-term use of amiodarone in patients before HTX significantly reduces early post-transplant AF and is not associated with increased mortality after HTX.

  6. Exercise significantly increases plasma adrenaline and oxidized low-density lipoprotein in normal healthy subjects but not in persons with spinal cord injury.

    Science.gov (United States)

    Mitsui, Toshihito; Nakamura, Takeshi; Ito, Tomoyuki; Umemoto, Yasunori; Sakamoto, Keiko; Kinoshita, Tokio; Nakagawa, Masafumi; Tajima, Fumihiro

    2012-04-01

    To compare plasma concentrations of oxidized low-density lipoprotein (oxLDL) and adrenaline during exercise between persons with spinal cord injury (SCI) and able-bodied (AB) individuals. Randomized controlled study. Human laboratory at a medical university. Persons with SCI (n=7) and AB individuals (n=9). Two-hour arm crank ergometer exercise at 60% maximum oxygen consumption. Plasma oxLDL and adrenaline levels. Exercise significantly increased plasma adrenaline levels in AB persons (mean ± SD: rest, 45.4±32.2 pg/mL; exercise, 200.9±113.7 pg/mL; Pplasma oxLDL levels in AB persons (mean ± SD: rest, 102.2±30.2 U/L; exercise, 179.7±60.0 U/L; Pplasma adrenaline levels during exercise contribute to the increase in plasma oxLDL levels. Copyright © 2012 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

  7. Changes in epidemiologic features of testicular germ cell cancer: age at diagnosis and relative frequency of seminoma are constantly and significantly increasing.

    Science.gov (United States)

    Ruf, Christian G; Isbarn, Hendrik; Wagner, Walter; Fisch, Margit; Matthies, Cord; Dieckmann, Klaus-Peter

    2014-01-01

    Testicular germ cell tumors (GCTs) have their incidence peak in the third and fourth decades of life. Histologically, GCTs comprise of seminoma and nonseminoma at almost equal proportions with a slight preponderance of nonseminoma in most of the major series. Since decades, there is a shift toward decreasing age at presentation. Recently, there are suggestions of a reversal of the age trend, and also, the histologic subtype ratio appears to shift toward seminoma. We retrospectively looked to our patient populations to verify these recent trends. A total of 2,482 patients with histologically proven GCT diagnosed between 1976 and 2010 were retrospectively evaluated regarding the year of diagnosis, histology of primary tumor, and age at presentation. Patients were categorized according to the following time periods of treatment: before 1990, 1990 to 1994, 1995 to 1999, 2000 to 2004, and 2005 to 2010. Mean age and relative proportion of seminoma were compared among patient categories by employing the chi-square test and analysis of variance, respectively. The mean age significantly increased from 28 to 36 years. The age difference between the 2 histologic subtypes remained constant between 6 and 8 years during the entire observation period. The relative proportion of seminoma continuously increased from 30.9% to 56% (P theories regarding the pathogenesis of GCT may receive support from our results: first, the theory of divergent pathogenetic pathways of seminoma and nonseminoma and second, the involvement of postnatal environmental factors in the pathogenesis of GCTs. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. Symmetric dimeric bisbenzimidazoles DBP(n reduce methylation of RARB and PTEN while significantly increase methylation of rRNA genes in MCF-7 cancer cells.

    Directory of Open Access Journals (Sweden)

    Svetlana V Kostyuk

    Full Text Available Hypermethylation is observed in the promoter regions of suppressor genes in the tumor cancer cells. Reactivation of these genes by demethylation of their promoters is a prospective strategy of the anticancer therapy. Previous experiments have shown that symmetric dimeric bisbenzimidazoles DBP(n are able to block DNA methyltransferase activities. It was also found that DBP(n produces a moderate effect on the activation of total gene expression in HeLa-TI population containing epigenetically repressed avian sarcoma genome.It is shown that DBP(n are able to penetrate the cellular membranes and accumulate in breast carcinoma cell MCF-7, mainly in the mitochondria and in the nucleus, excluding the nucleolus. The DBP(n are non-toxic to the cells and have a weak overall demethylation effect on genomic DNA. DBP(n demethylate the promoter regions of the tumor suppressor genes PTEN and RARB. DBP(n promotes expression of the genes RARB, PTEN, CDKN2A, RUNX3, Apaf-1 and APC "silent" in the MCF-7 because of the hypermethylation of their promoter regions. Simultaneously with the demethylation of the DNA in the nucleus a significant increase in the methylation level of rRNA genes in the nucleolus was detected. Increased rDNA methylation correlated with a reduction of the rRNA amount in the cells by 20-30%. It is assumed that during DNA methyltransferase activity inhibition by the DBP(n in the nucleus, the enzyme is sequestered in the nucleolus and provides additional methylation of the rDNA that are not shielded by DBP(n.It is concluded that DBP (n are able to accumulate in the nucleus (excluding the nucleolus area and in the mitochondria of cancer cells, reducing mitochondrial potential. The DBP (n induce the demethylation of a cancer cell's genome, including the demethylation of the promoters of tumor suppressor genes. DBP (n significantly increase the methylation of ribosomal RNA genes in the nucleoli. Therefore the further study of these compounds is needed

  9. Gut microbiota are linked to increased susceptibility to hepatic steatosis in low aerobic capacity rats fed an acute high fat diet

    Science.gov (United States)

    Poor aerobic fitness is linked to nonalcoholic fatty liver disease and increased all-cause mortality. We previously found that low capacity running (LCR) rats fed acute high fat diet (HFD; 45% kcal from fat) for 3 days resulted in positive energy balance and increased hepatic steatosis compared with...

  10. Efficacy of phosphatidylcholine in the modulation of motion sickness susceptibility

    Science.gov (United States)

    Kohl, R. L.; Ryan, P.; Homick, J. L.

    1985-01-01

    This study evaluated the efficacy of pharmacological doses of phosphatidylcholine (lecithin) in the modulation of motion sickness induced by exposure to coriolis stimulation in a rotating chair. Subjects received daily dietary supplements of 25 grams of lecithin (90 percent phosphatidylcholine) and were tested for their susceptibility to motion sickness after 4 h, 2 d, and 21 d. A small but statistically significant increase in susceptibility (+15 percent) was noted 4 h after supplemental phosphatidylcholine, with four of nine subjects demonstrating a marked increase in susceptibility. This finding was attributed to choline's stimulatory action on cholinergic systems, an action which opposes that of the classical antimotion sickness drug scopolamine. Chronic lecithin loading revealed a trend towards reduced susceptibility, possibly indicating the occurrence of adaptive mechanisms such as receptor down-regulation. Withdrawal from lecithin loading, perhaps coupled with anticholinergic treatment, might prove to be a potent prophylactic regimen and ought to be tested.

  11. Emerged HA and NA mutants of the pandemic influenza H1N1 viruses with increasing epidemiological significance in Taipei and Kaohsiung, Taiwan, 2009-10.

    Directory of Open Access Journals (Sweden)

    Chuan-Liang Kao

    Full Text Available The 2009 influenza pandemic provided an opportunity to observe dynamic changes of the hemagglutinin (HA and neuraminidase (NA of pH1N1 strains that spread in two metropolitan areas--Taipei and Kaohsiung. We observed cumulative increases of amino acid substitutions of both HA and NA that were higher in the post-peak than in the pre-peak period of the epidemic. About 14.94% and 3.44% of 174 isolates had one and two amino acids changes, respective, in the four antigenic sites. One unique adaptive mutation of HA2 (E374K was first detected three weeks before the epidemic peak. This mutation evolved through the epidemic, and finally emerged as the major circulated strain, with significantly higher frequency in the post-peak period than in the pre-peak (64.65% vs 9.28%, p<0.0001. E374K persisted until ten months post-nationwide vaccination without further antigenic changes (e.g. prior to the highest selective pressure. In public health measures, the epidemic peaked at seven weeks after oseltamivir treatment was initiated. The emerging E374K mutants spread before the first peak of school class suspension, extended their survival in high-density population areas before vaccination, dominated in the second wave of class suspension, and were fixed as herd immunity developed. The tempo-spatial spreading of E374K mutants was more concentrated during the post-peak (p = 0.000004 in seven districts with higher spatial clusters (p<0.001. This is the first study examining viral changes during the naïve phase of a pandemic of influenza through integrated virological/serological/clinical surveillance, tempo-spatial analysis, and intervention policies. The vaccination increased the percentage of E374K mutants (22.86% vs 72.34%, p<0.001 and significantly elevated the frequency of mutations in Sa antigenic site (2.36% vs 23.40%, p<0.001. Future pre-vaccination public health efforts should monitor amino acids of HA and NA of pandemic influenza viruses isolated at

  12. N- and C-terminal truncations of a GH10 xylanase significantly increase its activity and thermostability but decrease its SDS resistance.

    Science.gov (United States)

    Zheng, Fei; Huang, Jingxuan; Liu, Xingchen; Hu, Hang; Long, Liangkun; Chen, Kaixiang; Ding, Shaojun

    2016-04-01

    XynII from Volvariella volvacea has high sodium dodecyl sulfate (SDS) resistance, with the potential for industrial applications under harsh conditions. It consists of a single glycoside hydrolase family 10 (GH10) catalytic domain but contains an additional unique 10 and 4 amino acid residues at the N- and C-terminus, respectively. In this study, five XynII derivatives with N- and/or C-terminus deletions were constructed to determine the effects of these regions on enzyme activity, substrate specificity, thermostability, and SDS resistance. Our results revealed that N- and/or C-terminal truncations significantly increased enzyme activity and thermostability, but reduced SDS resistance. Specifically, the XynIIΔNC4 mutant had 2.53-fold more catalytic efficiency (k cat/K m) towards beechwood xylan than wild-type and 3.0-fold more thermostability (t 1/2 [55°C]). XynIIΔNC4 displayed 3.33-, 4.38-, 1.37-, and 1.98-fold more activity against xylotriose, xylotetraose, xylopentaose, and xylohexaose, respectively, than XynII did. However, its half-life (t 1/2) in 4 % SDS was only 1.72 h, while that of XynII was 4.65 h. Circular dichroism analysis revealed that deletion of N- and C-terminal segments caused minor changes in secondary structure. Our observations suggest that the extra N- and C-terminal segments in wild-type XynII evolved to strengthen the interaction between these regions of the protein, making the local structure more rigid and reducing structural flexibility. In this way, N- and C-terminal truncations increased the thermostability and activity of XynII on different xylans and linear xylooligosaccharides, but reduced its resistance to SDS.

  13. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report.

    Science.gov (United States)

    Gómez-Reino, Juan J; Carmona, Loreto; Valverde, Vicente Rodríguez; Mola, Emilio Martín; Montero, Maria Dolores

    2003-08-01

    The long-term safety of therapeutic agents that neutralize tumor necrosis factor (TNF) is uncertain. Recent evidence based on spontaneous reporting shows an association with active tuberculosis (TB). We undertook this study to determine and describe the long-term safety of 2 of these agents, infliximab and etanercept, in rheumatic diseases based on a national active-surveillance system following the commercialization of the drugs. We analyzed the safety data actively collected in the BIOBADASER (Base de Datos de Productos Biológicos de la Sociedad Española de Reumatología) database, which was launched in February 2000 by the Spanish Society of Rheumatology. For the estimation of TB risk, the annual incidence rate in patients treated with these agents was compared with the background rate and with the rate in a cohort of patients with rheumatoid arthritis (RA) assembled before the era of anti-TNF treatment. Seventy-one participating centers sent data on 1,578 treatments with infliximab (86%) or etanercept (14%) in 1,540 patients. Drug survival rates (reported as the cumulative percentage of patients still receiving medication) for infliximab and etanercept pooled together were 85% and 81% at 1 year and 2 years, respectively. Instances of discontinuation were essentially due to adverse events. Seventeen cases of TB were found in patients treated with infliximab. The estimated incidence of TB associated with infliximab in RA patients was 1,893 per 100,000 in the year 2000 and 1,113 per 100,000 in the year 2001. These findings represent a significant increased risk compared with background rates. In the first 5 months of 2002, after official guidelines were established for TB prevention in patients treated with biologics, only 1 new TB case was registered (in January). Therapy with infliximab is associated with an increased risk of active TB. Proper measures are needed to prevent and manage this adverse event.

  14. Epilepsy by the Numbers: Epilepsy deaths by age, race/ethnicity, and gender in the United States significantly increased from 2005 to 2014.

    Science.gov (United States)

    Greenlund, Sujay F; Croft, Janet B; Kobau, Rosemarie

    2017-04-01

    To inform public health efforts to prevent epilepsy-related deaths, we used the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (WONDER; Wonder.cdc.gov) to examine any-listed epilepsy deaths for the period 2005-2014 by age groups (≤24, 25-44, 45-64, 65-84, ≥85years), sex, and race/ethnicity (non-Hispanic White, non-Hispanic African American, Hispanic, Asian/Pacific Islander, or American Indian/Alaska Native). Epilepsy deaths were defined by the International Classification of Diseases, Tenth Revision (ICD-10) codes G40.0-G40.9. The total number of deaths per year with epilepsy as any listed cause ranged from 1760 in 2005 to 2962 in 2014. Epilepsy was listed as the underlying cause of death for about 54% of all deaths with any mention of epilepsy in 2005 and for 43% of such deaths in 2014. Age-adjusted epilepsy mortality rates (as any-listed cause of death) per 100,000 significantly increased from 0.58 in 2005 to 0.85 in 2014 (47% increase). In 2014, deaths among the non-Hispanic Black population (1.42 deaths per 100,000) were higher than among non-Hispanic White (0.86 deaths per 100,000) and Hispanic populations (0.70 deaths per 100,000). Males had a higher mortality rate than females (1.01 per 100,000 versus 0.74 per 100,000 in 2014), and those aged 85years or older had the highest mortality among age groups. Results highlight the need for heightened action to prevent and monitor epilepsy-associated mortality. Published by Elsevier Inc.

  15. Significant increase in factual knowledge with web-assisted problem-based learning as part of an undergraduate cardio-respiratory curriculum.

    Science.gov (United States)

    Raupach, T; Münscher, C; Pukrop, T; Anders, S; Harendza, S

    2010-08-01

    In recent years, increasing attention has been paid to web-based learning although the advantages of computer-aided instruction over traditional teaching formats still need to be confirmed. This study examined whether participation in an online module on the differential diagnosis of dyspnoea impacts on student performance in a multiple choice examination of factual knowledge in cardiology and pneumology. A virtual problem-based learning environment for medical students supervised by postgraduate teachers was created. Seventy-four out of 183 fourth-year medical students volunteered to use the online module while attending a 6-week cardio-respiratory curriculum in summer 2007. Of these, 40 were randomly selected to be included (intervention group); the remaining 34 served as an internal control group. Analysis of all written exams taken during the preceding term showed that both groups were comparable (86.4 ± 1.1 vs. 85.9 ± 1.1%; p = 0.751). Students in the intervention group scored significantly higher in the final course assessment than students allocated to the control group (84.8 ± 1.3 vs. 79.5 ± 1.4%; p = 0.006; effect size 0.67). Thus, additional problem-based learning with an online module as part of an undergraduate cardio-respiratory curriculum lead to higher students' scores in an exam testing factual knowledge. Whether using this teaching format increases overall student motivation to engage in the learning process needs to be further investigated.

  16. Precision intrauterine contraception may significantly increase continuation of use: a review of long-term clinical experience with frameless copper-releasing intrauterine contraception devices

    Directory of Open Access Journals (Sweden)

    Wildemeersch D

    2013-04-01

    Full Text Available Dirk Wildemeersch,1 Ansgar Pett,2 Sohela Jandi,2 Thomas Hasskamp,3 Patrick Rowe,4 Marc Vrijens5 1Gynecological Outpatient Clinic and IUD Training Center, Ghent, Belgium; 2Gynecological Outpatient Clinic, Berlin, Germany; 3Gynecological Outpatient Clinic, Münster, Germany; 4Formely IUD Research Group at the UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, World Health Organization, Geneva, Switzerland; 5Gynecological Outpatient Clinic, Ghent, Belgium Objective: The purpose of this paper is to review the experience with the frameless, anchored, GyneFix copper-releasing intrauterine contraceptive devices (IUCDs/IUDs (Contrel Europe, Belgium, and to demonstrate their high acceptability and low rate of discontinuation of use, which could contribute to current efforts that aim to reduce radically the high number of unintended pregnancies and induced abortions, particularly in young women. Materials and methods: This paper is based on studies that examined the differences in uterine volume and cavity size, related to age and parity, and on original clinical research data and practical experience with frameless copper IUDs, as well as on literature data on the IUD–endometrial cavity relationship of conventional IUDs, with special reference to side effects and user discontinuation. Results: The mean transverse diameter in nulliparous and parous women is significantly less than the length of the transverse arm of the TCu380A IUD (ParaGard, Duramed, NY, USA or the levonorgestrel intrauterine system (Mirena, Bayer, Germany. Small, frameless, flexible, and unidimensional copper IUDs appear to be well tolerated, with less impact on menstrual bleeding, resulting in low discontinuation rates when compared with standard-size conventional IUDs, which often result in increased expulsion rates, complaints of pain and erratic or increased menstrual bleeding, and subsequent high rates of

  17. The Clinical Significance of Increased Serum Proinflammatory Cytokines, C-Reactive Protein, and Erythrocyte Sedimentation Rate in Patients with Hidradenitis Suppurativa

    Directory of Open Access Journals (Sweden)

    D. Jiménez-Gallo

    2017-01-01

    Full Text Available Objectives. To assess inflammatory serum markers including serum proinflammatory cytokines, C-reactive protein (CRP, and erythrocyte sedimentation rate (ESR according to the clinical inflammatory activity of patients with hidradenitis suppurativa (HS. Patients and Methods. Seventy-four patients with HS were studied based on the Hidradenitis Suppurativa-Physician Global Assessment (HS-PGA score and Hurley staging system. Proinflammatory cytokines were measured using a multiplex cytokine assay. Twenty-two healthy volunteers were recruited. Results. Serum interleukin- (IL- 6, IL-23, soluble tumour necrosis factor alpha (TNF-α receptor I (sTNF-RI, CRP, and ESR were different in the patients with HS compared with those in the healthy controls (P0.25, P<0.05. The levels of IL-6 (r=0.53, P<0.001, CRP (r=0.54, P<0.001, and ESR (r=0.60, P<0.001 were especially well correlated with clinical inflammatory activity based on HS-PGA scores. The levels of IL-6, IL-8, sTNF-RI, sTNF-RII, CRP, and ESR were significantly elevated according to Hurley staging system. Conclusions. Serum proinflammatory cytokines, CRP, and ESR are increased in relation to the clinical inflammatory activity of patients with HS compared with healthy controls. Serum IL-6, CRP, and ESR are effective biomarkers for evaluating the severity of HS.

  18. Significantly increased detection rate of drugs of abuse in urine following the introduction of new German driving licence re-granting guidelines.

    Science.gov (United States)

    Agius, Ronald; Nadulski, Thomas; Kahl, Hans-Gerhard; Dufaux, Bertin

    2012-02-10

    In this paper we present the first assessment of the new German driving licence re-granting medical and psychological assessment (MPA) guidelines by comparing over 3500 urine samples tested under the old MPA cut-offs to over 5000 samples tested under the new MPA cut-offs. Since the enzyme multiplied immunoassay technique (EMIT) technology used previously was not sensitive enough to screen for drugs at such low concentrations, as suggested by the new MPA guidelines, enzyme-linked immunosorbent assay (ELISA) screening kits were used to screen for the drugs of abuse at the new MPA cut-offs. The above comparison revealed significantly increased detection rates of drug use or exposure during the rehabilitation period as follows: 1.61, 2.33, 3.33, and 7 times higher for 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH), morphine, benzoylecgonine and amphetamine respectively. The present MPA guidelines seem to be more effective to detect non-abstinence from drugs of abuse and hence to detecting drivers who do not yet fulfil the MPA requirements to regain their revoked driving licence. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  19. Context-dependent codon partition models provide significant increases in model fit in atpB and rbcL protein-coding genes.

    Science.gov (United States)

    Baele, Guy; Van de Peer, Yves; Vansteelandt, Stijn

    2011-05-27

    Accurate modelling of substitution processes in protein-coding sequences is often hampered by the computational burdens associated with full codon models. Lately, codon partition models have been proposed as a viable alternative, mimicking the substitution behaviour of codon models at a low computational cost. Such codon partition models however impose independent evolution of the different codon positions, which is overly restrictive from a biological point of view. Given that empirical research has provided indications of context-dependent substitution patterns at four-fold degenerate sites, we take those indications into account in this paper. We present so-called context-dependent codon partition models to assess previous empirical claims that the evolution of four-fold degenerate sites is strongly dependent on the composition of its two flanking bases. To this end, we have estimated and compared various existing independent models, codon models, codon partition models and context-dependent codon partition models for the atpB and rbcL genes of the chloroplast genome, which are frequently used in plant systematics. Such context-dependent codon partition models employ a full dependency scheme for four-fold degenerate sites, whilst maintaining the independence assumption for the first and second codon positions. We show that, both in the atpB and rbcL alignments of a collection of land plants, these context-dependent codon partition models significantly improve model fit over existing codon partition models. Using Bayes factors based on thermodynamic integration, we show that in both datasets the same context-dependent codon partition model yields the largest increase in model fit compared to an independent evolutionary model. Context-dependent codon partition models hence perform closer to codon models, which remain the best performing models at a drastically increased computational cost, compared to codon partition models, but remain computationally interesting

  20. Biologic Effects of Microwave Exposure. 2. Studies on the Mechanisms Controlling Susceptibility to Microwave-Induced Increases in Complement Receptor-Positive Spleen Cells

    Science.gov (United States)

    1980-01-01

    George- town University School of Medicine, Washington, DC (K.S., J.N.W.), and Bureau of Radiological Health, Food and Drug Administration...located outside of the H-2 complex. In a previous paper [Sulek et al, 1980], we have shown that the increase in CR+ spleen cells was not a thermogenic ...Department, the naval service at large, or the Bureau of Radiological Health, Food and Drug Administration. The experimncts reported herein were conducted

  1. [Antimicrobial susceptibility in Chile 2012].

    Science.gov (United States)

    Cifuentes-D, Marcela; Silva, Francisco; García, Patricia; Bello, Helia; Briceño, Isabel; Calvo-A, Mario; Labarca, Jaime

    2014-04-01

    Bacteria antimicrobial resistance is an uncontrolled public health problem that progressively increases its magnitude and complexity. The Grupo Colaborativo de Resistencia, formed by a join of experts that represent 39 Chilean health institutions has been concerned with bacteria antimicrobial susceptibility in our country since 2008. In this document we present in vitro bacterial susceptibility accumulated during year 2012 belonging to 28 national health institutions that represent about 36% of hospital discharges in Chile. We consider of major importance to report periodically bacteria susceptibility so to keep the medical community updated to achieve target the empirical antimicrobial therapies and the control measures and prevention of the dissemination of multiresistant strains.

  2. Hypnotic susceptibility and dream characteristics.

    Science.gov (United States)

    Zamore, N; Barrett, D

    1989-11-01

    This study examined the relationship of hypnotic susceptibility to a variety of dream characteristics and types of dream content. A Dream Questionnaire was constructed synthesizing Gibson's dream inventory and Hilgard's theoretical conceptions of hypnosis. Employing the Harvard Group Scale of Hypnotic Susceptibility and the Field Inventory for evaluating hypnotic response, several dream dimensions correlated significantly with hypnotizability. For subjects as a whole, the strongest correlates were the frequency of dreams which they believed to be precognitive and out-of-body dreams. Ability to dream on a chosen topic also correlated significantly with hypnotic susceptibility for both genders. For females only, there was a negative correlation of hypnotic susceptibility to flying dreams. Absorption correlated positively with dream recall, ability to dream on a chosen topic, reports of conflict resolution in dreams, creative ideas occurring in dreams, amount of color in dreams, pleasantness of dreams, bizarreness of dreams, flying dreams and precognitive dreams.

  3. Is an Early Age at Illness Onset in Schizophrenia Associated With Increased Genetic Susceptibility?:Analysis of Data From the Nationwide Danish Twin Register

    OpenAIRE

    Rikke Hilker; Dorte Helenius; Birgitte Fagerlund; Axel Skytthe; Kaare Christensen; Werge, Thomas M.; Merete Nordentoft; Birte Glenthøj

    2017-01-01

    BACKGROUND: Early age at illness onset has been viewed as an important liability marker for schizophrenia, which may be associated with an increased genetic vulnerability. A twin approach can be valuable, because it allows for the investigation of specific illness markers in individuals with a shared genetic background.METHODS: We linked nationwide registers to identify a cohort of twin pairs born in Denmark from 1951 to 2000 (N=31,524 pairs), where one or both twins had a diagnosis in the sc...

  4. Blocking miRNA Biogenesis in Adult Forebrain Neurons Enhances Seizure Susceptibility, Fear Memory, and Food Intake by Increasing Neuronal Responsiveness.

    Science.gov (United States)

    Fiorenza, Anna; Lopez-Atalaya, Jose P; Rovira, Victor; Scandaglia, Marilyn; Geijo-Barrientos, Emilio; Barco, Angel

    2016-04-01

    The RNase Dicer is essential for the maturation of most microRNAs, a molecular system that plays an essential role in fine-tuning gene expression. To gain molecular insight into the role of Dicer and the microRNA system in brain function, we conducted 2 complementary RNA-seq screens in the hippocampus of inducible forebrain-restricted Dicer1 mutants aimed at identifying the microRNAs primarily affected by Dicer loss and their targets, respectively. Functional genomics analyses predicted the main biological processes and phenotypes associated with impaired microRNA maturation, including categories related to microRNA biology, signal transduction, seizures, and synaptic transmission and plasticity. Consistent with these predictions, we found that, soon after recombination, Dicer-deficient mice exhibited an exaggerated seizure response, enhanced induction of immediate early genes in response to different stimuli, stronger and more stable fear memory, hyperphagia, and increased excitability of CA1 pyramidal neurons. In the long term, we also observed slow and progressive excitotoxic neurodegeneration. Overall, our results indicate that interfering with microRNA biogenesis causes an increase in neuronal responsiveness and disrupts homeostatic mechanisms that protect the neuron against overactivation, which may explain both the initial and late phenotypes associated with the loss of Dicer in excitatory neurons. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  5. Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma.

    Directory of Open Access Journals (Sweden)

    Janey L Wiggs

    Full Text Available Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP less than 22 mmHg subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63-0.75], p = 1.86×10⁻¹⁸, and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21-1.43], p = 3.87×10⁻¹¹. In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50-0.67], p = 1.17×10⁻¹² and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53-0.72], p = 8.88×10⁻¹⁰. Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41-0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54-1.06], p = 0.021, suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009. These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for

  6. ACAT-1 gene polymorphism is associated with increased susceptibility to coronary artery disease in Chinese Han population: a case-control study.

    Science.gov (United States)

    Wang, Yong-Tao; Wang, Ying-Hong; Ma, Yi-Tong; Fu, Zhen-Yan; Yang, Yi-Ning; Ma, Xiang; Li, Xiao-Mei; Adi, Dilare; Liu, Fen; Chen, Bang-Dang

    2017-10-24

    Several studies suggest an important role of Acyl-CoA: cholesterol acyltransferase-1(ACAT-1) in the development of atherosclerosis. The aim of present study was to investigate whether there exists a possible correlation between genetic variations in ACAT-1 genes and coronary artery disease (CAD) risk. Four polymorphisms (rs1044925, rs11545566, rs12121758 and rs10913733) were finally selected and genotyped in 750 CAD patients and 580 health controls, using the improved multiplex ligation detection reaction (iMLDR) method. We found that the rs11545566 G allele was associated with a significantly elevated CAD risk [GG vs. AA: adjusted odds ratio (AOR) = 1.62, 95% confidence interval (CI) = 1.13-2.32, P = 0.008; GA/GG vs. AA: AOR = 1.67, 95% CI = 1.22-2.29, P = 0.001]. The rs10913733 G allele was also associated with a significantly elevated CAD risk (GG vs. TT: AOR = 1.57, 95% CI = 1.08-2.28, P = 0.018; GT/GG vs. TT: AOR = 1.39, 95% CI = 1.07-1.79, P = 0.013). Multivariate linear regression analysis showed that the rs11545566 polymorphism was independently associated with the Gensini scores (P = 0.005). The Gensini score of subjects in the variant GG genotype group and the GG/GA genotype group were higher than the score of subjects in the AA genotype group (32.49 ± 26.60 and 31.26 ± 26.96 vs. 23.45 ± 21.64; P = 0.001 and 0.002, respectively). Our results demonstrate that ACAT-1 rs1154556 and rs10913733 polymorphism are novel genetic factors in the development of CAD. Rs11545566 was also associated with the severity of CAD.

  7. Cigarette design and marketing features are associated with increased smoking susceptibility and perception of reduced harm among smokers in 27 EU countries.

    Science.gov (United States)

    Agaku, Israel T; Omaduvie, Uyoyo T; Filippidis, Filippos T; Vardavas, Constantine I

    2015-12-01

    This study assessed the role of cigarette design and marketing characteristics in initial smoking, cigarette brand choice and the perception of reduced harm of cigarette brands among adults in the European Union in 2012. Data were from the Eurobarometer 385 (V.77.1) survey conducted in 2012 (n=26 566). Multivariate logistic regression was used to assess associations between cigarette design/marketing features with aspects of initial smoking (among current and former smokers), cigarette brand choice and perception of reduced harm of cigarette brands (among current smokers; pmarketing strategies that may increase the attractiveness of tobacco products or promote perceptions of harm reduction. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  8. Adult-onset deletion of the Prader-Willi syndrome susceptibility gene Snord116 in mice results in reduced feeding and increased fat mass.

    Science.gov (United States)

    Purtell, Louise; Qi, Yue; Campbell, Lesley; Sainsbury, Amanda; Herzog, Herbert

    2017-04-01

    The imprinted small nucleolar RNA (snoRNA) Snord116 is implicated in the aetiology of Prader-Willi syndrome (PWS), a disease associated with hyperphagia and obesity. Germline deletion of Snord116 in mice has been found to lead to increased food intake but not to the development of obesity. To determine the role of Snord116 independent of potential compensatory developmental factors, we investigated the effects of conditional adult-onset deletion of Snord116 in mice. Deletion of Snord116 was induced at 8 weeks of age by oral administration of tamoxifen to male Snordlox/lox; ROSAcre/+ mice, with vehicle-treated mice used as controls. Body weight (BW) was monitored weekly and body composition was measured by dual-energy X-ray absorptiometry and tissue dissection. Non-fasted and fasting-induced food intake was determined, and glucose and insulin tolerance tests were performed. Twenty-four-hour energy expenditure and physical activity were assessed by indirect calorimetry. Adult-onset deletion of Snord116 led to reduced food intake and increased adiposity, albeit with no concomitant change in BW or lean mass compared to controls. Adult onset Snord116 deletion was also associated with worsened glucose tolerance and insulin sensitivity. This study identified a key role for Snord116 in feeding behaviour and growth. Further, it is likely that the effects of this gene are modulated by developmental stage, as mice with adult-onset deletion showed an opposite phenotype, with respect to food intake and body composition, to previously published data on mice with germline deletion.

  9. Haemophilus influenzae bla(ROB-1) mutations in hypermutagenic deltaampC Escherichia coli conferring resistance to cefotaxime and beta-lactamase inhibitors and increased susceptibility to cefaclor.

    Science.gov (United States)

    Galán, Juan-Carlos; Morosini, María-Isabel; Baquero, María-Rosario; Reig, Milagro; Baquero, Fernando

    2003-08-01

    The clinical use of cefaclor has been shown to enrich Haemophilus influenzae populations harboring cefaclor-hydrolyzing ROB-1 beta-lactamase. Such a selective process may lead to the increased use of extended-spectrum cephalosporins or beta-lactams plus beta-lactamase inhibitors and, eventually, resistance to these agents, which has not previously been observed in H. influenzae. In order to establish which bla(ROB-1) mutations, if any, could confer resistance to extended-spectrum cephalosporins and/or to beta-lactamase inhibitors, a plasmid harboring bla(ROB-1) was transformed into hypermutagenic strain Escherichia coli GB20 (DeltaampC mutS::Tn10), and this construct was used in place of H. influenzae bla(ROB-1). Strain GB20 with the cloned gene was submitted to serial passages in tubes containing broth with increasing concentrations of selected beta-lactams (cefotaxime or amoxicillin-clavulanate). Different mutations in the bla(ROB-1) gene were obtained during the passages in the presence of the different concentrations of the selective agents. Mutants resistant to extended-spectrum cephalosporins harbored either the Leu169-->Ser169 or the Arg164-->Trp164 substitution or the double amino acid change Arg164-->Trp164 and Ala237-->Thr237. ROB-1 mutants that were resistant to beta-lactams plus beta-lactamase inhibitors and that harbored the Arg244-->Cys244 or the Ser130-->Gly130 replacement were also obtained. The cefaclor-hydrolyzing efficiencies of the ROB-1 variants were strongly decreased in all mutants, suggesting that if bla(ROB-1) mutants were selected by cefaclor, this drug would prevent the further evolution of this beta-lactamase toward molecular forms able to resist extended-spectrum cephalosporins or beta-lactamase inhibitors.

  10. Increase in serotype 19A prevalence and amoxicillin non-susceptibility among paediatric Streptococcus pneumoniae isolates from middle ear fluid in a passive laboratory-based surveillance in Spain, 1997-2009.

    Science.gov (United States)

    Fenoll, Asunción; Aguilar, Lorenzo; Vicioso, Maria-Dolores; Gimenez, Maria-Jose; Robledo, Olga; Granizo, Juan-Jose

    2011-09-12

    Conjugate vaccines, such as the 7-valent conjugate vaccine (PCV7), alter serotype nasopharyngeal carriage, potentially increasing cases of otitis media by non-vaccine serotypes. All paediatric middle ear fluid (MEF) isolates received in the Spanish Reference Laboratory for Pneumococci through a passive, laboratory-based surveillance system from January 1997 to June 2009 were analysed. Data from 1997 to 2000 were pooled as pre-vaccination period. Trends over time were explored by linear regression analysis. A total of 2,077 isolates were analysed: 855 belonging to PCV7 serotypes, 466 to serotype 19A, 215 to serotype 3, 89 to serotype 6A and 452 to other serotypes ( 35% isolates) since PCV7 strains represented < 11% of total clinical isolates. In contrast to reports on invasive pneumococcal strains, in MEF isolates the reduction in the prevalence of PCV7 serotypes was not associated with decreases in penicillin/erythromycin non-susceptibility. The high prevalence of serotype 19A among paediatric MEF isolates and the amoxicillin non-susceptibility found in this serotype are worrisome since amoxicillin is the most common antibiotic used in the treatment of acute otitis media. These data suggest that non-PCV7 serotypes (mainly serotype 19A followed by serotypes 3 and 6A) are important etiological agents of acute otitis media and support the added value of the broader coverage of the new 13-valent conjugate vaccine.

  11. Silencing of a Germin-Like Protein Gene (CchGLP in Geminivirus-Resistant Pepper (Capsicum chinense Jacq. BG-3821 Increases Susceptibility to Single and Mixed Infections by Geminiviruses PHYVV and PepGMV

    Directory of Open Access Journals (Sweden)

    Laura Mejía-Teniente

    2015-11-01

    Full Text Available Germin-like proteins (GLPs are encoded by a family of genes found in all plants, and in terms of function, the GLPs are implicated in the response of plants to biotic and abiotic stresses. CchGLP is a gene encoding a GLP identified in a geminivirus-resistant Capsicum chinense Jacq accession named BG-3821, and it is important in geminivirus resistance when transferred to susceptible tobacco in transgenic experiments. To characterize the role of this GLP in geminivirus resistance in the original accession from which this gene was identified, this work aimed at demonstrating the possible role of CchGLP in resistance to geminiviruses in Capsicum chinense Jacq. BG-3821. Virus-induced gene silencing studies using a geminiviral vector based in PHYVV component A, displaying that silencing of CchGLP in accession BG-3821, increased susceptibility to geminivirus single and mixed infections. These results suggested that CchGLP is an important factor for geminivirus resistance in C. chinense BG-3821 accession.

  12. Variants in KCNQ1 increase type II diabetes susceptibility in South Asians: A study of 3,310 subjects from India and the US

    Directory of Open Access Journals (Sweden)

    Aston Christopher E

    2011-01-01

    Full Text Available Abstract Background Polymorphisms in intron 15 of potassium voltage-gated channel, KQT-like subfamily member 1 (KCNQ1 gene have been associated with type II diabetes (T2D in Japanese genome-wide association studies (GWAS. More recently a meta-analysis of European GWAS has detected a new independent signal associated with T2D in intron 11 of the KCNQ1 gene. The purpose of this investigation is to examine the role of these variants with T2D in populations of Asian Indian descent from India and the US. Methods We examined the association between four variants in the KCNQ1 gene with T2D and related quantitative traits in a total of 3,310 Asian Indian participants from two different cohorts comprising 2,431 individuals of the Punjabi case-control cohort from the Sikh Diabetes Study and 879 migrant Asian Indians living in the US. Results Our data confirmed the association of a new signal at the KCNQ1 locus (rs231362 with T2D showing an allelic odds ratio (OR of 1.24 95%CI [1.08-1.43], p = 0.002 in the Punjabi cohort. A moderate association with T2D was also seen for rs2237895 in the Punjabi (OR 1.14; p = 0.036 and combined cohorts (meta-analysis OR 1.14; p = 0.018. Three-site haplotype analysis of rs231362, rs2237892, rs2237895 exhibited considerably stronger evidence of association of the GCC haplotype with T2D showing OR of 1.24 95%CI [1.00-1.53], p = 0.001, permutation p = 8 × 10-4 in combined cohorts. The 'C' risk allele carriers of rs2237895 had significantly reduced measures of HOMA-B in the US cohort (p = 0.008 as well as in combined cohort in meta-analysis (p = 0.009. Conclusions Our investigation has confirmed that the variation within the KCNQ1 locus confers a significant risk to T2D among Asian Indians. Haplotype analysis further suggested that the T2D risk associated with KCNQ1 SNPs may be derived from 'G' allele of rs231362 and 'C' allele of rs2237895 and this appears to be mediated through β cell function.

  13. Is an Early Age at Illness Onset in Schizophrenia Associated With Increased Genetic Susceptibility? Analysis of Data From the Nationwide Danish Twin Register.

    Science.gov (United States)

    Hilker, Rikke; Helenius, Dorte; Fagerlund, Birgitte; Skytthe, Axel; Christensen, Kaare; Werge, Thomas M; Nordentoft, Merete; Glenthøj, Birte

    2017-04-01

    Early age at illness onset has been viewed as an important liability marker for schizophrenia, which may be associated with an increased genetic vulnerability. A twin approach can be valuable, because it allows for the investigation of specific illness markers in individuals with a shared genetic background. We linked nationwide registers to identify a cohort of twin pairs born in Denmark from 1951 to 2000 (N=31,524 pairs), where one or both twins had a diagnosis in the schizophrenia spectrum. We defined two groups consisting of; N=788 twin pairs (affected with schizophrenia spectrum) and a subsample of N=448 (affected with schizophrenia). Survival analysis was applied to investigate the effect of age at illness onset. We found that early age at illness onset compared to later onset in the first diagnosed twin can be considered a major risk factor for developing schizophrenia in the second twin. Additionally, we found that the stronger genetic component in MZ twins compared to DZ twins is manifested in the proximity of assigned diagnosis within pairs. Early onset schizophrenia could be linked to a more severe genetic predisposition, indicating that age might be perceived as a clinical marker for genetic vulnerability for the illness. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.