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Background Epstein-Barr virus (EBV) is an oncogenic virus implicated in the pathogenesis of a number of human malignancies of both lymphoid and epithelial origin. Thus, a comprehensive and up-to-date analysis focused on the global burden of EBV-attributable malignancies is of significant interest. Methods Based on published studies, we estimated the proportion of Burkitt’s lymphoma (BL), Hodgkin’s lymphoma (HL), nasopharyngeal carcinoma NPC), gastric carcinoma (GC) and post-transplant lymphoproliferative disease (PTLD) attributable to EBV, taking into consideration age, sex and geographical variations. This proportion was then imputed into the Global Burden of Disease 2010 dataset to determine the global burden of each EBV-attributable malignancy in males and females in 20 different age groups and 21 world regions from 1990 to 2010. Results The analysis showed that the combined global burden of deaths in 2010 from all EBV-attributable malignancies was 142,979, representing 1.8% of all cancer deaths. This burden has increased by 14.6% over a period of 20 years. All 5 EBV-attributable malignancies were more common in males in all geographical regions (ratio of 2.6:1). Gastric cancer and NPC accounted for 92% of all EBV-attributable cancer deaths. Almost 50% of EBV-attributed malignancies occurred in East Asia. This region also had the highest age-standardized death rates for both NPC and GC. Conclusions Approximately 143,000 deaths in 2010 were attributed to EBV-associated malignancies. This figure is likely to be an underestimate since some of the less prevalent EBV-associated malignancies have not been included. Moreover, the global increase in population and life-expectancy will further increase the overall burden of EBV-associated cancer deaths. Development of a suitable vaccine could have a substantial impact on reducing this burden.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) with no definitive trigger. However, epidemiological studies indicate that environmental factors, such as infection with Epstein-Barr virus (EBV) and low vitamin D (Vit D) levels in genetically predisposed individuals, are important risk factors. One leading proposal is that EBV triggers MS via mechanisms such as molecular mimicry, where activated autoreactive B and T lymphocytes mistakenly target self-antigens. In line with other risk factors, low serum Vit D level, genetic polymorphism of Vit D receptor, and higher incidence of MS in countries in the northern hemisphere, suggest that Vit D also plays a role in MS pathology. Vitamin D, known for its neuroprotective and immunomodulatory effects, helps maintain a balance between pro-inflammatory and anti-inflammatory immune cells. Studies and ongoing clinical trials indicate that hypovitaminosis D is associated with an increased risk of MS, and Vit D supplement can help to reduce the disease severity. Moreover, hypovitaminosis D has also been associated with a dysregulated immune system and an increased risk of developing MS. This review explores how these three well-recognized risk factors - EBV infection, hypovitaminosis D, and dysregulated immune system - interact in the pathogenesis of MS. Understanding these interactions and their consequences could provide new insights into novel therapeutic approaches for treating this devastating disease.

ObjectiveTo determine the global and regional burden of Epstein-Barr virus (EBV)-attributed malignancies.DesignAn international comparative study based on the Global Burden of Disease (GBD) Study estimates.SettingGlobal population by age, sex, region, demographic index and time.Methods and outcome measuresThe burden of EBV-attributed Burkitt lymphoma (BL), Hodgkin lymphoma (HL), nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC) was estimated in a two-step process. In the first step, the fraction of each malignancy attributable to EBV was estimated based on published studies; this was then applied to the GBD estimates to determine the global and regional incidence, mortality and disability-adjusted life-years (DALYs) for each malignancy by age, sex, geographical region and social demographic index (SDI) from 1990 to 2017.ResultsThe combined global incidence of BL, HL, NPC and GC in 2017 was 1.442 million cases, with over 973 000 deaths. An estimated 265 000 (18%) incident cases and 164 000 (17%) deaths were due to the EBV-attributed fraction. This is an increase of 36% in incidence and 19% in mortality from 1990. In 2017, EBV-attributed malignancies caused 4.604 million DALYs, of which 82% was due to NPC and GC alone. The incidence of both of these malignancies was higher in high and middle-high SDI regions and peaked in adults aged between 50 and 70 years. All four malignancies were more common in males and the highest burden was observed in East Asia.ConclusionsThis study provides comprehensive estimates of the burden of EBV-attributed BL, HL, NPC and GC. The overall burden of EBV-related malignancies is likely to be higher since EBV is aetiologically linked to several other malignancies not included in this analysis. Increasing global population and life expectancy is expected to further raise this burden in the future. The urgency for developing an effective vaccine to prevent these malignancies cannot be overstated.

We aimed to assess global trends in Human Immunodeficiency Virus (HIV)/Acquired Immune Deficiency Syndrome (AIDS) and evaluate progress toward eradication since the inception of the pandemic. Data were extracted from the Global Burden of Disease 2019 update and the UNAIDS Data 2019. The datasets included annual figures from 1990 to 2019 for HIV/AIDS in 204 countries and all world regions. We analyzed rates and trends for prevalence, incidence, mortality and disability adjusted life years. Analysis of age and gender distribution in different regions was used to assess demographic changes. Forecasting was used to estimate disease burden up to 2040. Although many countries have witnessed a decrease in the incidence, for Russia, Ukraine, Portugal, Brazil, Spain and the United States, the rates of new cases are rising since 2010. This trend is present even in age-standardized analysis, indicating a rise in excess of population growth. Over 0.5% of the world’s population is infected. About 5000 new infections occur daily, of which 500 are children. Mortality rates are falling globally; currently at 11 deaths per 100,000 population, forecasted to decrease to 8.5 deaths by 2040. Prevalence continues to increase, with South Africa, Nigeria, Mozambique, India, Kenya and the United States having the highest burden. The total number as well as the rates of new HIV infections are rising every year in Europe, South America, North America and other regions over the last decade. Maternal-to-child transmission continues at high rates despite effective preventive regimens. There is an urgent need to develop programs to curb the rising incidence of HIV.

Multiple sclerosis (MS) is a chronic neuroinflammatory condition of the central nervous system (CNS). It is a major cause of neurological disability in young adults, particularly women. What triggers the destruction of myelin sheaths covering nerve fibres is unknown. Both genetic and infectious agents have been implicated. Of the infectious agents, Epstein-Barr virus (EBV), a common herpesvirus, has the strongest epidemiological and serological evidence. However, the presence of EBV in the CNS and demonstration of the underlying mechanism(s) linking EBV to the pathogenesis of MS remain to be elucidated. We aimed at understanding the contribution of EBV infection in the pathology of MS. We examined 1055 specimens (440 DNA samples and 615 brain tissues) from 101 MS and 21 non-MS cases for the presence of EBV using PCR and EBER-in situ hybridization (EBER-ISH). EBV was detected by PCR and/or EBER-ISH in 91/101 (90%) of MS cases compared to only 5/21 (24%) of non-MS cases with other neuropathologies. None of the samples were PCR positive for other common herpesviruses (HSV-1, CMV, HHV-6). By quantitative PCR, EBV viral load in MS brain was mainly low to moderate in most cases. However, in 18/101 (18%) of MS cases, widespread but scattered presence of EBV infected cells was noted in the affected tissues by EBER-ISH. Immunohistochemical analysis of EBV gene expression in the 18 heavily infected cases, revealed that the EBV latent protein EBNA1, and to a lesser extent the early lytic protein BZLF1 were expressed. Furthermore, using double-staining we show for the first time that astrocytes and microglia, in addition to B-cells can also be infected. To the best of our knowledge, this is the most comprehensive study demonstrating that EBV is present and transcriptionally active in the brain of most cases of MS and supports a role for the virus in MS pathogenesis. Further studies are required to address the mechanism of EBV involvement in MS pathology.

Epstein-Barr virus (EBV) is an oncogenic herpesvirus implicated in the pathogenesis of several malignant and non-malignant conditions. However, a number of fundamental aspects about the biology of EBV and the mechanism(s) by which this virus induces pathology remain unknown. One major obstacle has been the lack of a suitable animal model for EBV infection. In this study, using our recently established rabbit model of EBV infection, we examined the early events following primary EBV infection. We show that, both immunocompetent and immunosuppressed animals were readily susceptible to EBV infection. However, immunosuppressed animals showed marked splenomegaly and widespread infection. Following EBV infection , the virus primarily targeted naïve IgM + , CD20 + , CD21 + and CD79a + B cells. Infected cells expressed varying sets of viral latent/lytic gene products. Notably, co-expression of latent and lytic proteins in the same cell was not observed. Infected cells in type 0/1 latency (EBERs + ), were small and proliferating (Ki67 + ). By contrast, cells in type 2/3 latency (LMP1 + ), were large, non-proliferating (Ki-67 − ) and p53 + . Although infected B-cells were widely present in splenic follicles, they did not express germinal center marker, BCL-6. Taken together, this study shows for the first time, some of the early events following primary EBV infection.

Death rates due to COVID-19 pandemic vary considerably across regions and countries. Case Mortality Rates (CMR) per 100,000 population are more reliable than case-fatality rates per 100 test-positive cases, which are heavily dependent on the extent of viral case testing carried out in a country. We aimed to study the variations in CMR against population risk factors such as aging, underlying chronic diseases and social determinants such as poverty and overcrowding. Data on COVID-19 CMR in 93 countries was analyzed for associations with preexisting prevalence rates of eight diseases [asthma, lung cancer, Chronic Obstructive Pulmonary Disease (COPD), Alzheimer’s Disease (AD), hypertension, ischemic heart disease, depression and diabetes], and six socio-demographic factors [Gross Domestic Product (GDP) per capita, unemployment, age over 65 years, urbanization, population density, and socio-demographic index]. These data were analyzed in three steps: correlation analysis, bivariate comparison of countries, and multivariate modelling. Bivariate analysis revealed that COVID-19 CMR were higher in countries that had high prevalence of population risk factors such as AD, lung cancer, asthma and COPD. On multivariate modeling however, AD, COPD, depression and higher GDP predicted increased death rates. Comorbid illnesses such as AD and lung diseases may be more influential than aging alone.

Epstein-Barr virus (EBV) is an oncogenic herpesvirus associated with a number of human malignancies of epithelial and lymphoid origin. However, the mechanism of oncogenesis is unclear. A number of viral products, including EBV latent proteins and non-protein coding RNAs have been implicated. Recently it was reported that EBV-encoded small RNAs (EBERs) are released from EBV infected cells and they can induce biological changes in cells via signaling from toll-like receptor 3. Here, we investigated if these abundantly expressed non-protein coding EBV RNAs (EBER-1 and EBER-2) are excreted from infected cells in exosomal fractions. Using differential ultracentrifugation we isolated exosomes from three EBV positive cell lines (B95-8, EBV-LCL, BL30-B95-8), one EBER-1 transfected cell line (293T-pHEBo-E1) and two EBV-negative cell lines (BL30, 293T-pHEBo). The identity of purified exosomes was determined by electron microscopy and western blotting for CD63. The presence of EBERs in cells, culture supernatants and purified exosomal fractions was determined using RT-PCR and confirmed by sequencing. Purified exosomal fractions were also tested for the presence of the EBER-1-binding protein La, using western blotting. Both EBER-1 and EBER-2 were found to be present not only in the culture supernatants, but also in the purified exosome fractions of all EBV-infected cell lines. EBER-1 could also be detected in exosomal fractions from EBER-1 transfected 293T cells whilst the fractions from vector only transfectants were clearly negative. Furthermore, purified exosomal fractions also contained the EBER-binding protein (La), supporting the notion that EBERs are most probably released from EBV infected cells in the form of EBER-La complex in exosomes.

Results showed that 78% of shEGFP +ve cells were positive for excitatory neurons which contain Vglut2 (vesicular glutamate transporter) whereas 22% were positive for inhibitory neurons which contain GAD65/67 (glutamate decarboxylase 65/67) (Figures 1G,H, in Wang et al., 2022). [...]following noxious heat, 33% of c-Fos +ve neurons also expressed ErbB4 (Figures 1M,N, in Wang et al., 2022). The medial part of the dorsal horn receives the termination of the primary afferents from the limbs through the ventral ramus, while the lateral part receives the termination of the primary afferents from the skin of the back through the dorsal ramus (Figure 1A). [...]exposing the hind paw of mice to noxious heat stimuli, as carried out by Wang et al. Scale bar = 250 [mu]m. Localization of c-Fos expression in response to noxious heat stimulation of the hind paw We used two methods to localize the distribution of c-Fos expression in response to noxious heat stimulation in adult male mice (C57BL/6): (1) Intraplantar injection of resiniferatoxin (45 μl of 0.001%), as an agonist of heat receptor TRPV1 (transient receptor potential vanilloid type 1, Caterina et al., 2000) into the left hind paw. All experimental procedures were approved by the Animal Ethics Committee of the CMHS, UAE University, and were performed in accordance with the guidelines of the European Communities Council Directive of November 24, 1986 (86/609/EEC).