Dokuz Eylül University

autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

The pathogenesis of frailty and the role of inflammation is poorly understood. We examined the evidence considering the relationship between inflammation and frailty through a systematic review and meta-analysis. A systematic literature search of papers providing data on inflammatory biomarkers and frailty was carried out in major electronic databases from inception until May 2016. From 1856 initial hits, 35 studies (32 cross-sectional studies n=3232 frail, n=11,483 pre-frail and n=8522 robust, and 563 pre-frail+robust; 3 longitudinal studies n=3402 participants without frailty at baseline) were meta-analyzed. Cross-sectional studies reported that compared to 6757 robust participants, both 1698 frail (SMD=1.00, 95%CI: 0.40-1.61) and 8568 pre-frail (SMD=0.33, 95%CI: 0.04-0.62) participants had significantly higher levels of C-reactive protein (CRP). Frailty (n=1057; SMD=1.12, 95%CI: 0.27-2.13) and pre-frailty (n=4467; SMD=0.56, 95%CI: 0.00-1.11) were associated with higher serum levels of interleukin-6 compared to people who were robust (n=2392). Frailty and pre-frailty were also significantly associated with elevated white blood cell and fibrinogen levels. In three longitudinal studies, higher serum CRP (OR=1.06, 95%CI: 0.78-1.44,) and IL-6 (OR=1.19, 95%CI: 0.87-1.62) were not associated with frailty. In conclusion, frailty and pre-frailty are associated with higher inflammatory parameters and in particular CRP and IL-6. Further longitudinal studies are needed.

We assessed the risk factors and causes of death in patients with familial Mediterranean fever (FMF) in an era when colchicine is the standard therapy for all patients.This study included all FMF patients who had presented to any of the internal medicine, rheumatology, or nephrology clinics at Dokuz Eylul University Hospital between 1992 and 2009. Of the 650 patients with FMF identified, 587 (90.3%) had either a face-to-face (n = 380) or telephone (n = 193) interview, or were confirmed as deceased. A structured questionnaire was used to obtain socioeconomic and demographic data, presenting and cumulative clinical features, and disease severity scores.During the follow-up period mortality was analyzed by calculating age- and sex-standardized mortality ratio (SMR) according to the mortality statistics of the Turkish population. Factors predictive of mortality were evaluated using Kaplan-Meier and Cox proportional hazard models. Sixty-three (9.7%) patients whose initial demographic and major clinical characteristics were similar to the rest of the group could not be contacted during the study period.Most (94.2%) patients were on colchicine at the time of the study. Thirty-seven (6.3%) patients had biopsy-verified amyloidosis, and 44 (7.5%) had renal disease. During a median follow-up of 6 years, 14 patients (9 women) died, and amyloidosis and its related complications were the leading causes of death in 7 patients. Univariate analysis revealed that increasing age, coronary heart disease, hypertension, renal disease, and amyloidosis were associated with mortality. However, Cox regression analysis showed amyloidosis as the only significant predictor of mortality (p < 0.001). The overall patient survival rate was not significantly different from the age- and sex-matched Turkish general population (SMR, 1.48; 95% confidence interval, 0.817-2.49).Our findings suggest that although the survival of FMF patients in the colchicine era is comparable to that of the general population, renal involvement still predicts mortality.

A warming climate is expected to have an impact on the magnitude and timing of river floods; however, no consistent large-scale climate change signal in observed flood magnitudes has been identified so far. We analyzed the timing of river floods in Europe over the past five decades, using a pan-European database from 4262 observational hydrometric stations, and found clear patterns of change in flood timing. Warmer temperatures have led to earlier spring snowmelt floods throughout northeastern Europe; delayed winter storms associated with polar warming have led to later winter floods around the North Sea and some sectors of the Mediterranean coast; and earlier soil moisture maxima have led to earlier winter floods in western Europe. Our results highlight the existence of a clear climate signal in flood observations at the continental scale.

Abstract Multicollinearity refers to the linear relation among two or more variables. It is a data problem which may cause serious difficulty with the reliability of the estimates of the model parameters. In this article, multicollinearity among the explanatory variables in the multiple linear regression model is considered. Its effects on the linear regression model and some multicollinearity diagnostics for this model are presented. Copyright © 2010 John Wiley &amp; Sons, Inc. This article is categorized under: Statistical Models &gt; Linear Models Statistical Models &gt; Multivariate Models

Purpose The 2019 novel coronavirus (COVID-19) outbreak is projected to have adverse consequences on the global tourism and hospitality industry. This paper aims to examine how the outbreak may alter Chinese tourists’ lifestyle choices, travel behaviour and tourism preferences in the short and long term. Design/methodology/approach This paper is based on the synthesis of news broadcasted by several media outlets to be supported by an overview of the related literature on tourism marketing, tourism management and tourist behaviour. The authors’ experiences investigating trends in tourism and hospitality at the local and international level have also contributed to the study. Findings This paper predicts that COVID-19 will likely affect Chinese travellers’ consumption patterns, such as the growing popularity of free and independent travel, luxury trips and health and wellness tourism. New forms of tourism including slow tourism and smart tourism may also drive future tourism activities. Such changes are likely to force businesses to reconsider their service designs and distribution channels. Research limitations/implications While Chinese and other potential visitors rethink how they travel, professionals, too, should reflect upon how to bring positive or negative changes to the tourism industry following this pandemic. Subsequent research should also consider how to mitigate the effects of similar public health crises in the future. Practical implications Recommendations for industry practitioners and policymakers focus on tailoring travel arrangements to tourists’ backgrounds. The suggestions may help to alleviate outbreak-related stress, offer travellers newly enriching experiences and partially mitigate the effects of COVID-19 on the tourism and hospitality industry. These recommendations can also apply more broadly to global tourist markets. Social implications The COVID-19 outbreak has already brought significant impacts to nearly every society and industry. Tourism scholars and practitioners should carefully consider this tragedy and how it may inform industry and social practices. This and other public health crises represent sterling opportunities to view the industry holistically in terms of its effects on the environment, climate and travellers themselves. Originality/value This paper presumably represents a frontier study, critically examining the possible impacts of COVID-19 on Chinese travellers’ consumption patterns and how the tourism and hospitality industry may respond to such changes in the future.

Erythropoietin (EPO) is both hematopoietic and tissue protective, putatively through interaction with different receptors. We generated receptor subtype-selective ligands allowing the separation of EPO's bioactivities at the cellular level and in animals. Carbamylated EPO (CEPO) or certain EPO mutants did not bind to the classical EPO receptor (EPOR) and did not show any hematopoietic activity in human cell signaling assays or upon chronic dosing in different animal species. Nevertheless, CEPO and various nonhematopoietic mutants were cytoprotective in vitro and conferred neuroprotection against stroke, spinal cord compression, diabetic neuropathy, and experimental autoimmune encephalomyelitis at a potency and efficacy comparable to EPO.

Familial Mediterranean fever (FMF) is an autosomal recessive disease that is prevalent among eastern Mediterranean populations, mainly non-Ashkenazi Jews, Armenians, Turks, and Arabs. Since a large proportion of all the FMF patients in the world live in Turkey, the Turkish FMF Study Group (FMF-TR) was founded to develop a patient registry database and analyze demographic, clinical, and genetic features. The cohort was composed of 2838 patients (mean age, 23.0 +/- 13.33 yr; range, 2-87 yr), with a male:female ratio of 1.2:1. There was a mean period of 6.9 +/- 7.65 years from disease onset to diagnosis; the period was about 2 years shorter for each decade since 1981. Ninety-four percent of patients were living in the central-western parts of the country; however, their familial origins (70% from the central-eastern and Black Sea regions) reflected not only the ongoing east to west migration, but also the historical roots of FMF in Turkey. Patients' clinical features included peritonitis (93.7%), fever (92.5%), arthritis (47.4%), pleuritis (31.2%), myalgia (39.6%), and erysipelas-like erythema (20.9%). Arthritis, arthralgia, myalgia, and erysipelas-like erythema were significantly more frequent (p < 0.001) among patients with disease onset before the age of 18 years. Genetic analysis of 1090 patients revealed that M694V was the most frequent mutation (51.4%), followed by M680I (14.4%) and V726A (8.6%). Patients with the M694V/M694V genotype were found to have an earlier age of onset and higher frequencies of arthritis and arthralgia compared with the other groups (both p < 0.001). In contrast to other reported studies, there was no correlation between amyloidosis and M694V homozygosity in this cohort. However, amyloidosis was still remarkably frequent in our patients (12.9%), and it was prevalent (27.8%) even among the 18 patients with a disease onset after age 40 years. Twenty-two patients (0.8%) had nonamyloid glomerular diseases. The high prevalence of vasculitides (0.9% for polyarteritis nodosa and 2.7% for Henoch-Schonlein purpura) and high frequency of pericarditis (1.4%) were striking findings in the cohort. Phenotype II cases (those patients with amyloidosis as the presenting or only manifestation of disease) were rare (0.3% or less). There was a high rate of a past diagnosis of acute rheumatic fever, which suggested a possible misdiagnosis in children with FMF presenting with recurrent arthritis. To our knowledge, this is the largest series of patients with FMF reported from 1 country. We describe the features of the disease in the Turkish population and show that amyloidosis is still a substantial problem.

BACKGROUND: Coronary heart disease mortality rates have been decreasing in the United Kingdom since the 1970s. Our study aimed to examine how much of the decrease in England and Wales between 1981 and 2000 could be attributed to medical and surgical treatments and how much to changes in cardiovascular risk factors. METHODS AND RESULTS: The IMPACT mortality model was used to combine and analyze data on uptake and effectiveness of cardiological treatments and risk factor trends in England and Wales. The main data sources were published trials and meta-analyses, official statistics, clinical audits, and national surveys. Between 1981 and 2000, coronary heart disease mortality rates in England and Wales decreased by 62% in men and 45% in women 25 to 84 years old. This resulted in 68 230 fewer deaths in 2000. Some 42% of this decrease was attributed to treatments in individuals (including 11% to secondary prevention, 13% to heart failure treatments, 8% to initial treatments of acute myocardial infarction, and 3% to hypertension treatments) and 58% to population risk factor reductions (principally smoking, 48%; blood pressure, 9.5%; and cholesterol, 9.5%). Adverse trends were seen for physical activity, obesity and diabetes. CONCLUSIONS: More than half the coronary heart disease mortality decrease in Britain between 1981 and 2000 was attributable to reductions in major risk factors, principally smoking. This emphasizes the importance of a comprehensive strategy that promotes primary prevention, particularly for tobacco and diet, and that maximizes population coverage of effective treatments, especially for secondary prevention and heart failure. These findings may be cautiously generalizable to the United States and other developed countries.

Abstract Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities 1,2 . This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity 3–6 . Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017—and more than 80% in some low- and middle-income regions—was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing—and in some countries reversal—of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.

Exposure to ambient air pollution is a serious and common public health concern associated with growing morbidity and mortality worldwide. In the last decades, the adverse effects of air pollution on the pulmonary and cardiovascular systems have been well established in a series of major epidemiological and observational studies. In the recent past, air pollution has also been associated with diseases of the central nervous system (CNS), including stroke, Alzheimer's disease, Parkinson's disease, and neurodevelopmental disorders. It has been demonstrated that various components of air pollution, such as nanosized particles, can easily translocate to the CNS where they can activate innate immune responses. Furthermore, systemic inflammation arising from the pulmonary or cardiovascular system can affect CNS health. Despite intense studies on the health effects of ambient air pollution, the underlying molecular mechanisms of susceptibility and disease remain largely elusive. However, emerging evidence suggests that air pollution-induced neuroinflammation, oxidative stress, microglial activation, cerebrovascular dysfunction, and alterations in the blood-brain barrier contribute to CNS pathology. A better understanding of the mediators and mechanisms will enable the development of new strategies to protect individuals at risk and to reduce detrimental effects of air pollution on the nervous system and mental health.

BACKGROUND: The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown. METHODS: We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes. RESULTS: During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups. CONCLUSIONS: Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329; EudraCT number, 2016-002299-28.).

The number of immunosuppressive patients has increased significantly in recent years. These patients are at risk for opportunistic infections, especially fungal infections. Candidiasis is one of the most frequent fungal infections determined in these immunosuppressive patients and its epidemiology has changed over the last two decades. Recently, new antifungal agents and new therapy strategies such as antifungal prophylaxis, secondary prophylaxis, and preemptive therapy have come into use. These changes resulted in the alteration of Candida species causing invasive infections. The incidence of Candida albicans was decreased in many countries, especially among patients with immunosuppressive disorders, while the incidence of species other than C. albicans was increased. In this review, incidence, risk factors, and species distribution of invasive candidiasis are discussed.

BACKGROUND: Unfractionated heparin is often used as adjunctive therapy with fibrinolysis in patients with ST-elevation myocardial infarction. We compared a low-molecular-weight heparin, enoxaparin, with unfractionated heparin for this purpose. METHODS: We randomly assigned 20,506 patients with ST-elevation myocardial infarction who were scheduled to undergo fibrinolysis to receive enoxaparin throughout the index hospitalization or weight-based unfractionated heparin for at least 48 hours. The primary efficacy end point was death or nonfatal recurrent myocardial infarction through 30 days. RESULTS: The primary end point occurred in 12.0 percent of patients in the unfractionated heparin group and 9.9 percent of those in the enoxaparin group (17 percent reduction in relative risk, P<0.001). Nonfatal reinfarction occurred in 4.5 percent of the patients receiving unfractionated heparin and 3.0 percent of those receiving enoxaparin (33 percent reduction in relative risk, P<0.001); 7.5 percent of patients given unfractionated heparin died, as did 6.9 percent of those given enoxaparin (P=0.11). The composite of death, nonfatal reinfarction, or urgent revascularization occurred in 14.5 percent of patients given unfractionated heparin and 11.7 percent of those given enoxaparin (P<0.001); major bleeding occurred in 1.4 percent and 2.1 percent, respectively (P<0.001). The composite of death, nonfatal reinfarction, or nonfatal intracranial hemorrhage (a measure of net clinical benefit) occurred in 12.2 percent of patients given unfractionated heparin and 10.1 percent of those given enoxaparin (P<0.001). CONCLUSIONS: In patients receiving fibrinolysis for ST-elevation myocardial infarction, treatment with enoxaparin throughout the index hospitalization is superior to treatment with unfractionated heparin for 48 hours but is associated with an increase in major bleeding episodes. These findings should be interpreted in the context of net clinical benefit. (ClinicalTrials.gov number, NCT00077792.).

Two previous pan-European consensus meetings, the 1995 and 2006 Helsingborg meetings, were convened to review the scientific evidence and the state of current services to identify priorities for research and development and to set targets for the development of stroke care for the decade to follow. Adhering to the same format, the European Stroke Organisation (ESO) prepared a European Stroke Action Plan (ESAP) for the years 2018 to 2030, in cooperation with the Stroke Alliance for Europe (SAFE). The ESAP included seven domains: primary prevention, organisation of stroke services, management of acute stroke, secondary prevention, rehabilitation, evaluation of stroke outcome and quality assessment and life after stroke. Research priorities for translational stroke research were also identified. Documents were prepared by a working group and were open to public comments. The final document was prepared after a workshop in Munich on 21-23 March 2018. Four overarching targets for 2030 were identified: (1) to reduce the absolute number of strokes in Europe by 10%, (2) to treat 90% or more of all patients with stroke in Europe in a dedicated stroke unit as the first level of care, (3) to have national plans for stroke encompassing the entire chain of care, (4) to fully implement national strategies for multisector public health interventions. Overall, 30 targets and 72 research priorities were identified for the seven domains. The ESAP provides a basic road map and sets targets for the implementation of evidence-based preventive actions and stroke services to 2030.

About 20 years have passed since the discovery of the first microRNA (miRNA) and by now microRNAs are implicated in a variety of physiological and pathological processes. Since the discovery of the powerful effect miRNAs have on biological processes, it has been suggested that mutations affecting miRNA function may play a role in the pathogenesis of human diseases. Over the past several years microRNAs have been found to play a major role in various human diseases. In addition, many studies aim to apply miRNAs for diagnostic and therapeutic applications in human diseases. In this chapter, we summarize the role of miRNAs in pathological processes and discuss how miRNAs could be used as disease biomarkers.

Colorectal cancer is the third most common cancer worldwide with a high mortality rate at the advanced stages. However, colorectal cancer is not a single type of tumor; its pathogenesis depends on the anatomical location of the tumor and differs between right side and left side of the colon. Tumors in the proximal colon (right side) and distal colon (left side) exhibit different molecular characteristics and histology. In the right-sided tumors, mutations in the DNA mismatch repair pathway are commonly observed; and these tumors generally have a flat histology. In the left-sided tumors, chromosomal instability pathway-related mutations, such as KRAS, APC, PIK3CA, p53 mutations are observed and these tumors demonstrate polypoid-like morphology. Therapy responses are totally different between these tumor entities. Left-sided colorectal cancer (LCRC) patients benefit more from adjuvant chemotherapies such as 5-fluorouracil (5-FU)-based regimes, and targeted therapies such as anti- epidermal growth factor receptor (EGFR) therapy, and have a better prognosis. Right-sided colorectal cancer (RCRC) patients do not respond well to conventional chemotherapies, but demonstrate more promising results with immunotherapies because these tumors have high antigenic load. For the development of effective therapy regimes and better treatment options, it is essential to evaluate right-sided and left-sided tumors as separate entities, and design the therapy regime considering the differences between these tumors. Gastroenterol Res. 2018;11(4):264-273 doi: https://doi.org/10.14740/gr1062w

Biochemical markers have a central position in the diagnosis and management of patients in clinical medicine, and also in clinical research and drug development, also for brain disorders, such as Alzheimer's disease. The enzyme-linked immunosorbent assay (ELISA) is frequently used for measurement of low-abundance biomarkers. However, the quality of ELISA methods varies, which may introduce both systematic and random errors. This urges the need for more rigorous control of assay performance, regardless of its use in a research setting, in clinical routine, or drug development. The aim of a method validation is to present objective evidence that a method fulfills the requirements for its intended use. Although much has been published on which parameters to investigate in a method validation, less is available on a detailed level on how to perform the corresponding experiments. To remedy this, standard operating procedures (SOPs) with step-by-step instructions for a number of different validation parameters is included in the present work together with a validation report template, which allow for a well-ordered presentation of the results. Even though the SOPs were developed with the intended use for immunochemical methods and to be used for multicenter evaluations, most of them are generic and can be used for other technologies as well.

Inflammation is a crucial component of various stress-induced responses that contributes to the pathogenesis of major depressive disorder (MDD). Depressive-like behavior (DLB) is characterized by decreased mobility and depressive behavior that occurs in systemic infection induced by Lipopolysaccharide (LPS) in experimental animals and is considered as a model of exacerbation of MDD. We assessed the effects of melatonin on behavioral changes and inflammatory cytokine expression in hippocampus of mice in LPS-induced DLB, as well as its effects on NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome activation, oxidative stress and pyroptotic cell death in murine microglia in vitro. Intraperitoneal 5 mg/kg dose of LPS was used to mimic depressive-like behaviors and melatonin was given at a dose of 500 mg / kg for 4 times with 6 hour intervals, starting at 2 hours before LPS administration. Behavioral assessment was carried out at 24 hours post-LPS injection by tail suspension and forced swimming tests. Additionally, hippocampal cytokine and NLRP3 protein levels were estimated. Melatonin increased mobility time of LPS-induced DLB mice and suppressed NLRP3 expression and interleukin-1 (IL-1) cleavage in the hippocampus. Immunofluorescence staining of hippocampal tissue showed that NLRP3 is mainly expressed in ionized calcium-binding adapter molecule 1 (Iba1) -positive microglia. Our results show that melatonin prevents LPS and Adenosine triphosphate (ATP) induced NLRP3 inflammasome activation in murine microglia in vitro, evidenced by inhibition of NLRP3 expression, Apoptosis-associated speck-like protein containing a CARD (ASC) speck formation, caspase-1 cleavage and interleukin-1 (IL-1) maturation and secretion. Additionally, melatonin inhibits pyroptosis, production of mitochondrial and cytosolic reactive oxygen species (ROS) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. The beneficial effects of melatonin on NLRP3 inflammasome activation were associated with nuclear factor erythroid 2–related factor 2 (Nrf2) and Silent information regulator 2 homolog 1 (SIRT1) activation, which were reversed by Nrf2 siRNA and SIRT1 inhibitor treatment.

INTRODUCTION: A new third version of the Copenhagen Psychosocial Questionnaire (COPSOQ III) has been developed in response to trends in working life, theoretical concepts, and international experience. A key component of the COPSOQ III is a defined set of mandatory core items to be included in national short, middle, and long versions of the questionnaire. The aim of the present article is to present and test the reliability of the new international middle version of the COPSOQ III. METHODS: The questionnaire was tested among 23,361 employees during 2016-2017 in Canada, Spain, France, Germany, Sweden, and Turkey. A total of 26 dimensions (measured through scales or single items) of the middle version and two from the long version were tested. Psychometric properties of the dimensions were assessed regarding reliability (Cronbach α), ceiling and floor effects (fractions with extreme answers), and distinctiveness (correlations with other dimensions). RESULTS: Most international middle dimensions had satisfactory reliability in most countries, though some ceiling and floor effects were present. Dimensions with missing values were rare. Most dimensions had low to medium intercorrelations. CONCLUSIONS: The COPSOQ III offers reliable and distinct measures of a wide range of psychosocial dimensions of modern working life in different countries; although a few measures could be improved. Future testing should focus on validation of the COPSOQ items and dimensions using both qualitative and quantitative approaches. Such investigations would enhance the basis for recommendations using the COPSOQ III.