Systematic Review and Meta-Analysis of the Sero-Epidemiological Association between Epstein Barr Virus and Multiple Sclerosis

Background

A role for Epstein Barr virus (EBV) in multiple sclerosis (MS) has been postulated. Previous systematic reviews found higher prevalences of anti-EBV antibodies in MS patients compared to controls, but many studies have since been published, and there is a need to apply more rigorous systematic review methods.

Methodology/Principal Findings

We examined the link between EBV and MS by conducting a systematic review and meta-analysis of case-control and cohort studies that examined the prevalence of anti-EBV antibodies in the serum of cases and controls. We searched Medline and Embase databases from 1960 to 2012, with no language restriction. The Mantel-Haenszel odds ratios (OR) for anti-EBV antibodies sero-positivity were calculated, and meta-analysis conducted. Quality assessment was performed using a modified version of the Newcastle Ottawa scale. Thirty-nine studies were included. Quality assessment found most studies reported acceptable selection and comparability of cases and controls. However the majority had poor reporting of ascertainment of exposure. Most studies found a higher sero-prevalence of anti-EBNA IgG and anti-VCA IgG in cases compared to controls. The results for anti-EA IgG were mixed with only half the studies finding a higher sero-prevalence in cases. The meta-analysis showed a significant OR for sero-positivity to anti-EBNA IgG and anti-VCA IgG in MS cases (4.5 [95% confidence interval (CI) 3.3 to 6.6, p<0.00001] and 4.5 [95% CI 2.8 to 7.2, p<0.00001] respectively). However, funnel plot examination suggested publication bias for the reporting of the anti-EBNA IgG. No significant difference in the OR for sero-positivity to anti-EA IgG was found (1.4 [95% CI 0.9 to 2.1, p = 0.09]).

Conclusion/Significance

These findings support previous systematic reviews, however publication bias cannot be excluded. The methodological conduct of studies could be improved, particularly with regard to reporting and conduct of laboratory analyses.     

The Tumor Suppressor Gene,RASSF1A,Is Essential for Protection against Inflammation -Induced Injury

Ras association domain family protein 1A (RASSF1A) is a tumor suppressor gene silenced in cancer. Here we report that RASSF1A is a novel regulator of intestinal inflammation as Rassf1a^+/−, Rassf1a^−/− and an intestinal epithelial cell specific knockout mouse (Rassf1a ^IEC-KO) rapidly became sick following dextran sulphate sodium (DSS) administration, a chemical inducer of colitis. Rassf1a knockout mice displayed clinical symptoms of inflammatory bowel disease including: increased intestinal permeability, enhanced cytokine/chemokine production, elevated nuclear factor of kappa light polypeptide gene enhancer in B-cells (NFκB) activity, elevated colonic cell death and epithelial cell injury. Furthermore, epithelial restitution/repair was inhibited in DSS-treated Rassf1a^−/− mice with reduction of several makers of proliferation including Yes associated protein (YAP)-driven proliferation. Surprisingly, tyrosine phosphorylation of YAP was detected which coincided with increased nuclear p73 association, Bax-driven epithelial cell death and p53 accumulation resulting in enhanced apoptosis and poor survival of DSS-treated Rassf1a knockout mice. We can inhibit these events and promote the survival of DSS-treated Rassf1a knockout mice with intraperitoneal injection of the c-Abl and c-Abl related protein tyrosine kinase inhibitor, imatinib/gleevec. However, p53 accumulation was not inhibited by imatinib/gleevec in the Rassf1a^−/− background which revealed the importance of p53-dependent cell death during intestinal inflammation. These observations suggest that tyrosine phosphorylation of YAP (to drive p73 association and up-regulation of pro-apoptotic genes such as Bax) and accumulation of p53 are consequences of inflammation-induced injury in DSS-treated Rassf1a^−/− mice. Mechanistically, we can detect robust associations of RASSF1A with membrane proximal Toll-like receptor (TLR) components to suggest that RASSF1A may function to interfere and restrict TLR-driven activation of NFκB. Failure to restrict NFκB resulted in the inflammation-induced DNA damage driven tyrosine phosphorylation of YAP, subsequent p53 accumulation and loss of intestinal epithelial homeostasis.     

First Dinosaurs from Saudi Arabia

Dinosaur remains from the Arabian subcontinent are exceedingly rare, and those that have been documented manifest indeterminate affinities. Consequently the discovery of a small, but diagnostic, accumulation of elements from Campanian-Maastrichtian (∼75 Ma) deposits in northwestern Saudi Arabia is significant because it constitutes the first taxonomically identifiable dinosaur material described from the Arabian Peninsula. The fossils include a series of possible lithostrotian titanosaur caudal vertebrae, and some isolated theropod marginal teeth that share unique character states and metric parameters (analyzed using multivariate statistical methods) with derived abelisaurids – this is the first justifiable example of a non-avian carnivorous dinosaur clade from Arabia. The recognition of titanosaurians and abelisaurids from Saudi Arabia extends the palaeogeographical range of these groups along the entire northern Gondwanan margin during the latest Cretaceous. Moreover, given the extreme paucity of coeval occurrences elsewhere, the Saudi Arabian fossils provide a tantalizing glimpse into dinosaurian assemblage diversity within the region.     

Levels of Heavy Metals and Essential Minerals in Hair Samples of Children with Autism in Oman: a Case–Control Study

Toxic levels of heavy metals and low levels of essential minerals have been suggested to play a critical role in the pathogenesis of autism spectrum disorders (ASD). This study documents the levels of heavy metals and essential minerals in hair samples of children with ASD in Muscat, the urbanized capital of Oman, Muscat. The study included 27 children with ASD and 27 matched non-ASD controls. Parental interviews were held and dietary intake questionnaires completed in conjunction with the collection of hair samples. Analysis of heavy metals and essential minerals was carried out by inductively coupled plasma mass spectrometry. Chi-square analysis and non-parametric Fisher’s exact tests were used to assess statistical significance. Children with ASD had significantly higher levels of all 11 analyzed heavy metals in their hair samples (P?<?0.05), ranging from 150 to 365 % of control levels. ASD children also had significantly higher levels of essential minerals sulfur, sodium, magnesium, potassium, zinc, and iron, but lower levels of calcium and copper in their hair samples. This study corroborates data from previous studies in different parts of the world indicating the presence of elevated levels of heavy metals and selective depletion of essential minerals in the hair of children with ASD.     

Zebrafish as a model for systems biology

Zebrafish offer a unique vertebrate model for research areas such as drug development, disease modeling and other biological exploration. There is significant conservation of genetics and other cellular networks among zebrafish and other vertebrate models, including humans. Here we discuss the recent work and efforts made in different fields of biology to explore the potential of zebrafish. Along with this, we also reviewed the concept of systems biology. A biological system is made up of a large number of components that interact in a huge variety of combinations. To understand completely the behavior of a system, it is important to know its components and interactions, and this can be achieved through a systems biology approach. At the end of the paper we present a concept of integrating zebrafish into the systems biology approach.     

Phylotype classification of Ralstonia solanacearum biovar 1 strains isolated from banana (Musa spp) in Malaysia

During 2011–2012, 15 bacterial isolates were obtained from wilting banana plants from seven locations in Malaysia. Characterisation of the Malaysian isolates was determined by biovar determination, pathogenicity test, phylotype-specific multiplex PCR (Pmx-PCR) and endoglucanase (egl) gene amplification. Based on the genotype, phenotype and pathogenic characteristics, all isolates were identified as Ralstonia solanacearum. Pmx- and egl-PCRs indicated that all isolates belong to phylotype II of Ralstonia species complex hierarchical classification. The neighbour joining phylogenetic tree of egl sequences also verified the results where the isolates were all clustered into phylotype II, together with the reference sequences strains, UW070 and UW162. Therefore, the results of our study may provide a better understanding on the taxonomy of R. solanacearum species occupying banana plantations in Malaysia. This study is indeed the first report of phylotype II classification of R. solanacearum biovar 1 strains isolated from banana plants in Malaysia.     

The Relationship Between Serum Levels of Zn and Cu and Severity of Coronary Atherosclerosis

The essential trace elements play important roles in the maintainance of the normal structure and physiology of cells. Several research groups have demonstrated that they also play important roles in states of cardiovascular diseases. Our aim is to investigate whether there is a relationship between trace elements (Zn and Cu) and the degree of atherosclerosis. The sample consisted of 67 patients with coronary artery disease and 26 clinically healthy individuals. Ninety-three subjects were separated into four groups according to their Gensini scores, the number of diseased vessels, the presence of acute coronary syndrome, and ejection fraction. Each group was divided into three subgroups, and serum zinc and copper levels were measured for each individual. The serum levels of zinc and copper were found to be significantly lower in patients with atherosclerosis than in the control group, but there were no significant differences in the serum levels of Cu and Zn between severe atherosclerosis and mild atherosclerosis. In Spearman's rank correlation, the zinc and copper levels were correlated with the Gensini score and the number of diseased vessels. The present study revealed a relationship between the serum levels of zinc and copper and atherosclerosis, but not between these levels and the severity of the disease.     

Metabolomic profiling of the effects of allopurinol on Drosophila melanogaster

Metabolomic profiling using hydrophilic interaction chromatography in combination with Fourier transform mass spectrometry was used to study the effects of the xanthine oxidase inhibitor allopurinol on wild type Drosophila melanogaster. Allopurinol treatment phenocopied the rosy mutation causing an elevation in the levels of xanthine and hypoxanthine and a fall in the levels of uric acid and allantoin. However, in addition there were some unexpected metabolic changes after treatment. Ascorbic acid levels were undetectable, glutathione levels fell and glutathione disulphide levels rose, methionine S-oxide levels rose and riboflavin levels fell. The origin of this oxidative stress was not immediately apparent; however, there was a strong suggestion that it might be related to a fall in NADPH levels linked to a reduction in glucose-6-phosphate dehydrogenase activity, resulting in reduced levels of some metabolites in the pentose phosphate pathway. In addition to producing oxidative stress there were marked effects on tryptophan metabolism with most of the metabolites in the kynurenine pathway being lowered by allopurinol treatment. The effects on the kynurenine pathway could be related to the established use of allopurinol in treating schizophrenia.     

Rhamnolipid produced by Pseudomonas aeruginosa USM-AR2 facilitates crude oil distillation

A biosurfactant-producing and hydrocarbon-utilizing bacterium, Pseudomonas aeruginosa USM-AR2, was used to assist conventional distillation. Batch cultivation in a bioreactor gave a biomass of 9.4 g L(-1) and rhamnolipid concentration of 2.4 g L(-1) achieved after 72 h. Biosurfactant activity (rhamnolipid) was detected by the orcinol assay, emulsification index and drop collapse test. Pretreatment of crude oil TK-1 and AG-2 with a culture of P. aeruginosa USM-AR2 that contains rhamnolipid was proven to facilitate the distillation process by reducing the duration without reducing the quality of petroleum distillate. It showed a potential in reducing the duration of the distillation process, with at least 2- to 3-fold decreases in distillation time. This is supported by GC-MS analysis of the distillate where there was no difference between compounds detected in distillate obtained from treated or untreated crude oil. Calorimetric tests showed the calorie value of the distillate remained the same with or without treatment. These two factors confirmed that the quality of the distillate was not compromised and the incubation process by the microbial culture did not over-degrade the oil. The rhamnolipid produced by this culture was the main factor that enhanced the distillation performance, which is related to the emulsification of hydrocarbon chains in the crude oil. This biotreatment may play an important role to improve the existing conventional refinery and distillation process. Reducing the distillation times by pretreating the crude oil with a natural biosynthetic product translates to energy and cost savings in producing petroleum products.     

Orally Administered Therapeutic Peptide Delivery: Enhanced Absorption Through the Small Intestine Using Permeation Enhancers

Peptide therapeutics (PTs) is generally regarded as highly effective macromolecule therapeutics at very low concentrations. The main issues surrounding the administration of PTs is guaranteeing that they are bioavailable, reach the desired therapeutic index and distribute throughout the body effectively. The oral administration, a non-invasive route, of PTs is considered a major complication due to inadequate oral absorption through biological membranes such as the small intestine epithelium due to presystemic proteolytic enzymatic activity. PTs bioavailability is further diminished in the systemic circulation due to low stability in the plasma and rapid excretion from the body. Many alternative routes can be considered non-invasive such as transdermal and nasal routes, but this review focuses on the oral route, specifically the small intestine region of the gastrointestinal tract. Although this region has the highest density of proteolytic enzymes, it contains tight junctions which have the lowest trans-epithelial electrical resistance throughout the body; thus paracellular transport of these large PTs can be achieved more readily. The use of a natural polysaccharide polymer, such as trimethyl chitosan (TMC), which enhances the bioavailability of these PTs through the small intestine, will also be discussed in great detail. TMC has been considered because it could potentially solve many of the mechanistic and chemical problems associated with oral therapeutic peptide administration. The safety of orally administered PTs through the small intestinal epithelium employing a polymer such as TMC is also discussed as this is a significant issue for regulatory bodies.