The role of endogenous free radical signalling in human endometrium

Differentiation of human endometrial stromal cells (HESCs) into specialized decidual cells is critical for embryo implantation and maintenance of a successful pregnancy. Initiation of this differentiation process, termed decidualization, is strictly dependent on elevated cAMP levels, whereas its maintenance requires continuous progesterone signalling. Here I show that NADPH oxidase-dependent reactive oxygen species (ROS) play a critical role in initiating and maintaining the decidual process. I first show that cAMP-dependent induction of decidual marker genes can be attenuated or enhanced upon inhibition or activation of the NADPH oxidase complex, respectively. Time-course analysis demonstrated that cAMP enhances endogenous ROS production, apparent after 12 hours of stimulation, which coincides with a marked induction of differentiation markers. By a process of elimination, I identified NOX4 as the main catalytic subunit involved in decidualization. Silencing of NOX4, or its cofactor p22PHOX, impaired the decidual process. I then show that the NOX4/p22PHOX complex regulates the transcriptional activity of CCAAT/enhancer binding protein β, a key regulator of HESC differentiation. Furthermore, microarray analysis revealed that the NOX4/p22PHOX complex functions downstream FOXO1, a multifaceted transcription factor involved in antioxidant defences, DNA repair and cell cycle regulation. In agreement, knockdown of NOX4/p22PHOX complex disrupted endogenous ROS production and resulted in a paradoxical prooxidant stress response further characterized by activation of the DNA repair pathway in the absence of primary DNA damage or cell death. Finally, I provide preliminary data that p22PHOX is downregulated at the transcript and protein level in the eutopic endometrium of patients with endometriosis. In summary, endogenous ROS signalling is critical for the differentiation and redox homeostasis of HESCs. Furthermore, deregulation of endometrial NADPH oxidase-dependent ROS production and signalling may be a hallmark of endometriosis, a prevalent and debilitating reproductive disorder

Incidence of hypomagnesemia on proton pump inhibitors at the Huntington Veterans Affairs Medical Center – IHOP

Abstract Title: Incidence of hypomagnesemia on proton pump inhibitors at the Huntington Veterans Affairs Medical Center – IHOP Purpose: Proton pump inhibitors (PPIs), both prescription and over-the-counter, are widely used for the treatment of acid-related disease states such as dyspepsia, gastroesophageal reflex disease, esophagitis, and peptic ulcers. These medications are generally considered safe in most patient populations; however, there are several adverse effects that may occur with long-term use. Hypomagnesemia is a newer complication arising in the literature following multiple case reports over the past several years, although the true incidence of hypomagnesemia associated with PPI use remains unclear at this time. Methods: A retrospective chart review was performed on patients enrolled at the Huntington VAMC who are receiving or have received long-term PPI therapy (considered \u3e 3 months). Magnesium levels were reviewed to determine the incidence of hypomagnesemia with PPI use. Other data analyzed included age, PPI prescribed, calcium level, potassium level, and diuretic use (both Loop and thiazide). Results: Three hundred thirty one patients were identified and reviewed that had a prescription for a PPI for 3 months or longer. Of the 331 patient charts reviewed, 192 met the study inclusion criteria and were analyzed for hypomagnesemia while on PPI therapy. There was a total of 51 out of 192 patients (26.6%) with hypomagnesemia reported at least 3 months after starting PPI therapy. The decline in magnesium levels over time while on PPI therapy resulted in a Pearson’s Correlation of -0.24 which was statistically significant (p Conclusion: In conclusion, hypomagnesemia may result in patients on long-term PPI therapy regardless of age and diuretics may further contribute to this issue. Low magnesium does not appear to be correlated with hypokalemia or hypocalcemia in this patient population. Baseline and routine monitoring of magnesium should be considered in patients that are being started on PPI therapy or are continued on therapy long-term. Additional studies would be helpful in determining the incidence of hypomagnesemia with the addition of a PPI in patients already prone to this problem. The use and effectiveness of magnesium supplementation in those with hypomagnesemia while on a PPI should be evaluated to determine if patients should be on long-term supplementation or if alternative antacid therapy should be considered

Hybrid Models Identified a 12-Gene Signature for Lung Cancer Prognosis and Chemoresponse Prediction

Lung cancer remains the leading cause of cancer-related deaths worldwide. The recurrence rate ranges from 35-50% among early stage non-small cell lung cancer patients. To date, there is no fully-validated and clinically applied prognostic gene signature for personalized treatment.From genome-wide mRNA expression profiles generated on 256 lung adenocarcinoma patients, a 12-gene signature was identified using combinatorial gene selection methods, and a risk score algorithm was developed with Naïve Bayes. The 12-gene model generates significant patient stratification in the training cohort HLM & UM (n = 256; log-rank P = 6.96e-7) and two independent validation sets, MSK (n = 104; log-rank P = 9.88e-4) and DFCI (n = 82; log-rank P = 2.57e-4), using Kaplan-Meier analyses. This gene signature also stratifies stage I and IB lung adenocarcinoma patients into two distinct survival groups (log-rank P<0.04). The 12-gene risk score is more significant (hazard ratio = 4.19, 95% CI: [2.08, 8.46]) than other commonly used clinical factors except tumor stage (III vs. I) in multivariate Cox analyses. The 12-gene model is more accurate than previously published lung cancer gene signatures on the same datasets. Furthermore, this signature accurately predicts chemoresistance/chemosensitivity to Cisplatin, Carboplatin, Paclitaxel, Etoposide, Erlotinib, and Gefitinib in NCI-60 cancer cell lines (P<0.017). The identified 12 genes exhibit curated interactions with major lung cancer signaling hallmarks in functional pathway analysis. The expression patterns of the signature genes have been confirmed in RT-PCR analyses of independent tumor samples.The results demonstrate the clinical utility of the identified gene signature in prognostic categorization. With this 12-gene risk score algorithm, early stage patients at high risk for tumor recurrence could be identified for adjuvant chemotherapy; whereas stage I and II patients at low risk could be spared the toxic side effects of chemotherapeutic drugs

Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-Adjusted life-years for 29 cancer groups, 1990 to 2017 : A systematic analysis for the global burden of disease study

Importance: Cancer and other noncommunicable diseases (NCDs) are now widely recognized as a threat to global development. The latest United Nations high-level meeting on NCDs reaffirmed this observation and also highlighted the slow progress in meeting the 2011 Political Declaration on the Prevention and Control of Noncommunicable Diseases and the third Sustainable Development Goal. Lack of situational analyses, priority setting, and budgeting have been identified as major obstacles in achieving these goals. All of these have in common that they require information on the local cancer epidemiology. The Global Burden of Disease (GBD) study is uniquely poised to provide these crucial data. Objective: To describe cancer burden for 29 cancer groups in 195 countries from 1990 through 2017 to provide data needed for cancer control planning. Evidence Review: We used the GBD study estimation methods to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-Adjusted life-years (DALYs). Results are presented at the national level as well as by Socio-demographic Index (SDI), a composite indicator of income, educational attainment, and total fertility rate. We also analyzed the influence of the epidemiological vs the demographic transition on cancer incidence. Findings: In 2017, there were 24.5 million incident cancer cases worldwide (16.8 million without nonmelanoma skin cancer [NMSC]) and 9.6 million cancer deaths. The majority of cancer DALYs came from years of life lost (97%), and only 3% came from years lived with disability. The odds of developing cancer were the lowest in the low SDI quintile (1 in 7) and the highest in the high SDI quintile (1 in 2) for both sexes. In 2017, the most common incident cancers in men were NMSC (4.3 million incident cases); tracheal, bronchus, and lung (TBL) cancer (1.5 million incident cases); and prostate cancer (1.3 million incident cases). The most common causes of cancer deaths and DALYs for men were TBL cancer (1.3 million deaths and 28.4 million DALYs), liver cancer (572000 deaths and 15.2 million DALYs), and stomach cancer (542000 deaths and 12.2 million DALYs). For women in 2017, the most common incident cancers were NMSC (3.3 million incident cases), breast cancer (1.9 million incident cases), and colorectal cancer (819000 incident cases). The leading causes of cancer deaths and DALYs for women were breast cancer (601000 deaths and 17.4 million DALYs), TBL cancer (596000 deaths and 12.6 million DALYs), and colorectal cancer (414000 deaths and 8.3 million DALYs). Conclusions and Relevance: The national epidemiological profiles of cancer burden in the GBD study show large heterogeneities, which are a reflection of different exposures to risk factors, economic settings, lifestyles, and access to care and screening. The GBD study can be used by policy makers and other stakeholders to develop and improve national and local cancer control in order to achieve the global targets and improve equity in cancer care. © 2019 American Medical Association. All rights reserved.Peer reviewe

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Jasmonic Acid Induced Systemic Resistance in Infected Cucumber by Pythium aphanidermatum

Damping-off disease of cucumber is one of the most destructive diseases of cucumber in worldwide. In this work, the potential of jasmonic acid (JA) for induce resistant against damping off disease was investigated. The effect of JA on activity of Polyphenol oxidase (PPO), Peroxidase (PO) and Catalase (CAT) enzymes and total phenol was assayed by spectrophotometric method. Expression level of three plant defense genes as Lipoxygenase, Cupi4 and Phenylalanine ammonia-lyase genes was analyzed using qRT-PCR method. Drop-plate method was used to assay inhibitory effect of JA on radial growth of fungi. Exogenic application of JA decreased disease severity in the infected plants but did not inhibit mycelia growth on solid medium compared to control. Our results showed that JA application substantially increased the activity of oxidative enzymes at different concentration. The highest enzyme activity was recorded after 48 hours post infection (hpi) at a concentration of 400 mg L-1 of JA. Gene expression analysis revealed that JA is differentially able to increase the mRNA transcripts of all tested genes at 48 hpi. The expression level of Cupi4 gene was higher than the other genes in treated plants. Induced systemic resistance by JA was mediated through an enhanced expression of ISR marker genes and increase of antioxidant enzymes activity. Based on these results, we suggest that exogenic application of JA could be considered as plant resistance inducer.&nbsp

The role of endogenous free radical signalling in human endometrium

Differentiation of human endometrial stromal cells (HESCs) into specialized decidual cells is critical for embryo implantation and maintenance of a successful pregnancy. Initiation of this differentiation process, termed decidualization, is strictly dependent on elevated cAMP levels, whereas its maintenance requires continuous progesterone signalling. Here I show that NADPH oxidase-dependent reactive oxygen species (ROS) play a critical role in initiating and maintaining the decidual process. I first show that cAMP-dependent induction of decidual marker genes can be attenuated or enhanced upon inhibition or activation of the NADPH oxidase complex, respectively. Time-course analysis demonstrated that cAMP enhances endogenous ROS production, apparent after 12 hours of stimulation, which coincides with a marked induction of differentiation markers. By a process of elimination, I identified NOX4 as the main catalytic subunit involved in decidualization. Silencing of NOX4, or its cofactor p22PHOX, impaired the decidual process. I then show that the NOX4/p22PHOX complex regulates the transcriptional activity of CCAAT/enhancer binding protein β, a key regulator of HESC differentiation. Furthermore, microarray analysis revealed that the NOX4/p22PHOX complex functions downstream FOXO1, a multifaceted transcription factor involved in antioxidant defences, DNA repair and cell cycle regulation. In agreement, knockdown of NOX4/p22PHOX complex disrupted endogenous ROS production and resulted in a paradoxical prooxidant stress response further characterized by activation of the DNA repair pathway in the absence of primary DNA damage or cell death. Finally, I provide preliminary data that p22PHOX is downregulated at the transcript and protein level in the eutopic endometrium of patients with endometriosis. In summary, endogenous ROS signalling is critical for the differentiation and redox homeostasis of HESCs. Furthermore, deregulation of endometrial NADPH oxidase-dependent ROS production and signalling may be a hallmark of endometriosis, a prevalent and debilitating reproductive disorder.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

The Effect of Chitosan on the Induction Systemic Resistance against Pythium aphanidermatum in Cucumber

Introduction: Land use change, deforestation, grazing, intentional and unintentional fire and invasive pests and diseases are all the major cause of damage to the Zagros forest ecosystem. The green oak leaf roller (Tortrix viridana L.) is one of the important pests of Zagros forests. Larvae of the pest significantly damage the oak forests with feeding on leaves and buds of different species of oaks each year. Larvae enter 2'd instar after eating the internal contents of oak buds, then the third and 4th instars larvae consume whole buds and even oak leaves. After development to the 5th larval instar, they roll the leaves and enter the pupal stage. The attacked trees revitalize by creating new leaves from early May onwards. New leaves, pale green and are smaller than normal leaves. Continuation of the pest activity on Quercus species causes gradual weakness the trees and readiness to accept a variety of secondary pests and diseases in later years. Based on the status of Zagros forests and their importance in the conservation of soil and water sources, the nutritional indices of Tortrix viridana larvae of two species of Oak i.e. Quercus infectoria and Q. libani were determined to get a better understanding of this pest. Materials and Methods: Since early April, with regular visits, last instar larvae (5th instar) of T. viridana in oak forests in Perdanan areas (around the village Ghabr Hossein) were collected and transferred to the laboratory chamber. The larvae were fed on the two oak species. The leaves of these species were collected and transported to the laboratory in a room at a temperature of 25°C and suitable photoperiod conditions. The larvae were fed individually or in a group. In a grouping method, 10 larvae in two replicates and in individually method 40 larvae (one larva per replicate) for each host were considered. Larval weight, amount of consumed food and weight of feces were estimated by using a sensitive digital Carriage scale (0.001 gr). Relative consumption rate (RCR), relative growth rate (RGR), the efficiency of conversion of ingested food (ECI), the efficiency of conversion of digested food (ECD) and approximate digestibility (AD) were also calculated. For statistical analysis t-test and SPSS17 software were used to compare the mean of the data. Results and Discussion: Results of t-test (α=5%) indicated that the larval biomass, RGR, ECI, and AD were significantly different among the hosts in both methods of grouping and individually rearing of the larvae. In this study, Q. libani showed the lowest rate of digestibility. The larvae fed on Q. infectoria have the higher rate of AD than Q. libani because of high RCR, RGR, ECD and ECI. Also, the results related to the comparison of two methods (grouping and individually rearing of the larvae), on nutritional indices were significantly different and in both host trees, the rate of RGR, ECI and ECD in grouping method was more than individually rearing method. RCR is the indication of the insect's exploitation speed of food. In the other words, it shows feeding rate regarding insect's weight at the specific point of time depending on the amount of water and other nutrition physicochemical characteristics in insects. The result showed that this index rate in group rearing method on two host species is equal, but in individual rearing method on Q. infectoria, it is more than Q. libani. The possible reasons are more feeding of larvae in individual rearing method due to the lack of competition stress, the more likelihood of the desirability of Q. infectoria compared to Q. libani, the probability of the existence of antixenosis in Q. libani. The similar study investigating individual and group rearing methods in one insect species is not available. This result confirms that T. viridana larvae’s has a tendency toward social life and in the group situation, they eat effectively. In fact, although larvae in individual form feed more because of lack of competition stress, but in the group they make use of that little food in the best way. Conclusion: In this study, Q. libani had low food quality. As a result, its relative consumption rate, relative growth rate, the efficiency of conversion of ingested food and efficiency of conversion of digested food was less than Q. infectoria. According to the results, Q. infectoria is an appropriate host for this pest. Also, it shows that the larvae were more considering the rate of larval biomass, RCR, RGR, ECI and ECD in grouping method than the single method