Epstein-Barr virus: clinical and epidemiological revisits and genetic basis of oncogenesis

Epstein-Barr virus (EBV) is classified as a member in the order herpesvirales, family herpesviridae, subfamily gammaherpesvirinae and the genus lymphocytovirus. The virus is an exclusively human pathogen and thus also termed as human herpesvirus 4 (HHV4). It was the first oncogenic virus recognized and has been incriminated in the causation of tumors of both lymphatic and epithelial nature. It was reported in some previous studies that 95% of the population worldwide are serologically positive to the virus. Clinically, EBV primary infection is almost silent, persisting as a life-long asymptomatic latent infection in B cells although it may be responsible for a transient clinical syndrome called infectious mononucleosis. Following reactivation of the virus from latency due to immunocompromised status, EBV was found to be associated with several tumors. EBV linked to oncogenesis as detected in lymphoid tumors such as Burkitt's lymphoma (BL), Hodgkin's disease (HD), post-transplant lymphoproliferative disorders (PTLD) and T-cell lymphomas (e.g. Peripheral T-cell lymphomas; PTCL and Anaplastic large cell lymphomas; ALCL). It is also linked to epithelial tumors such as nasopharyngeal carcinoma (NPC), gastric carcinomas and oral hairy leukoplakia (OHL). In vitro, EBV many studies have demonstrated its ability to transform B cells into lymphoblastoid cell lines (LCLs). Despite these malignancies showing different clinical and epidemiological patterns when studied, genetic studies have suggested that these EBV- associated transformations were characterized generally by low level of virus gene expression with only the latent virus proteins (LVPs) upregulated in both tumors and LCLs. In this review, we summarize some clinical and epidemiological features of EBV- associated tumors. We also discuss how EBV latent genes may lead to oncogenesis in the different clinical malignancies

Omega-3 fatty acids, cardiovascular disease and stability of atherosclerotic plaques

Long-chain n-3 polyunsaturated fatty acids are found in oily fish and in fish oils and similar preparations. Substantial evidence from epidemiological and case-control studies indicates that consumption of fish, oily fish and long-chain n-3 fatty acids reduces risk of cardiovascular mortality. Secondary prevention studies using long-chain n-3 fatty acids in patients post-myocardial infarction have shown a reduction in total and cardiovascular mortality with an especially potent effect on sudden death. Long-chain n-3 fatty acids have been shown to beneficially modify a range of cardiovascular risk factors, which may result in primary cardiovascular prevention. However, reduced non-fatal and fatal events and a reduction in sudden death probably involve other mechanisms. Reduced thrombosis following long-chain n-3 fatty acids may play a role. A decrease in arrhythmias is a favoured mechanism of action of long-chain n-3 fatty acids and is supported by cell culture and animal studies. However human trials using implantable cardiac defibrillators have produced inconsistent findings and a recent meta-analysis does not support this mechanism of action. An alternative mechanism of action may be stabilisation of atherosclerotic plaques by long-chain n-3 fatty acids. This is suggested by one published human study which showed that incorporation of long-chain n-3 fatty acids into plaques collected at carotid endarterectomy resulted in fewer macrophages in the plaque and a morphology indicative of increased stability. These findings are supported from observations in an animal model and suggest that the primary effect of long-chain n-3 fatty acids might be on macrophages within the plaque.

Fungicide and cultivar affect post-anthesis patterns of nitrogen uptake, remobilization and utilization efficiency in wheat

Three successive field experiments (2000/01-2002/03) assessed the effect of wheat cultivar (Consort.. Hereward and Shamrock) and fungicide (epoxiconazole and azoxystrobin) applied at and after flag leaf emergence on the nitrogen in the above-ground crop (Total N) and grain (Grain N), net nitrogen remobilization from non-grain tissues (Remobilized N). grain dry matter (Grain Dill), and nitrogen utilization efficiency (NUtE(g) = Grain DM/Total N). Ordinary logistic curves were fitted to the accumulation of Grain N, Grain DM and Remobilized N against thermal time after anthesis and used to simultaneously derive fits for Total N and NUtE(g). When disease was controlled, Consort achieved the greatest Grain DM, Total N, Grain N and NUtEg; in each case due mostly to longer durations, rather than quicker rates, of accumulation. Fungicide application increased final Grain Dill.. Grant N, Total N and Remobilized N, also mostly through effects on duration rather than rate of accumulation. Completely senesced leaf laminas retained less nitrogen when fungicide had been applied compared with leaf laminas previously infected severely with brown rust (Puccinia recondita) and Septoria tritici, or with just S. tritici. Late movement of nitrogen out of fungicide-treated laminas contributed to extended duration of both nitrogen remobilization and grain N filling, and meant that increases in NUtE(g) could occur without simultaneous reductions in grain N concentration.

Use of essential and molecular dynamics to study gamma B-crystallin unfolding after non-enzymic post-translational modifications

Essential and Molecular Dynamics (ED/MD) have been used to model the conformational changes of a protein implicated in a conformational disease-cataract, the largest cause of blindness in the world-after non-enzymic post-translational modification. Cyanate modification did not significantly alter flexibility, while the Schiff's base adduct produced a more flexible N-terminal domain, and intra-secondary structure regions, than either the cyanate adduct or the native structure. Glycation also increased linker flexibility and disrupted the charge network. A number of post-translational adducts showed structural disruption around Cys15 and increased linker flexibility; this may be important in subsequent protein aggregation. Our modelling results are in accord with experimental evidence, and show that ED/MD is a useful tool in modelling conformational changes in proteins implicated in disease processes. (C) 2003 Published by Elsevier Ltd.

Exaggerated postprandial lipaemia and lower post-heparin lipoprotein lipase activity in middle-aged men

An exaggerated postprandial lipaemic response is thought to play a central role in the development of an atherogenic lipoprotein phenotype, a recognized lipid risk factor for coronary heart disease. A small number of limited studies have compared postprandial lipaemia in subjects of varying age, but have not investigated mechanisms underlying age-associated changes in postprandial lipaemia. In order to test the hypothesis that impaired lipaemia in older subjects is associated with loss of insulin sensitivity, the present study compared the postprandial lipaemic and hormone responses for 9 h following a standard mixed meal in normolipidaemic healthy young and middle-aged men. Lipoprotein lipase (LPL) and hepatic lipase (HL) activities were determined in post-heparin plasma 9 h postprandially and on another occasion under fasting conditions. Postprandial plasma glucose (P < 0.02), retinyl ester (indirect marker for chylomicron particles; P < 0.005) and triacylglycerol (TAG)-rich lipoprotein (density < 1.006 g/ml fraction of plasma) TAG (P < 0.05) and retinyl ester (P < 0.005) responses were higher in middle-aged men, whereas plasma insulin responses were lower in this group (P < 0.001). Fasting and 9 h postprandial LPL and HL activities were also significantly lower in the middle-aged men compared with the young men (P < 0.006). In conclusion, the higher incremental postprandial TAG response in middle-aged men than young men was attributed to the accumulation of dietary-derived TAG-rich lipoproteins (density < 1.006 g/ml fraction of plasma) and occurred in the absence of marked differences in fasting TAG levels between the two groups. Fasting and postprandial LPL and HL activities were markedly lower in middle-aged men, but lack of statistical associations between measures of insulin response and post-heparin lipase activities, as well as between insulin and measures of postprandial lipaemia, suggest that this lower activity cannot be attributed to lack of sensitivity of lipases to activation by insulin. Alternatively, post-heparin lipase activities may not be good markers for the insulin-sensitive component of lipase that is activated postprandially.

The use of proteomics to identify novel therapeutic targets for the treatment of disease

The completion of the Human Genome Project has revealed a multitude of potential avenues for the identification of therapeutic targets. Extensive sequence information enables the identification of novel genes but does not facilitate a thorough understanding of how changes in gene expression control the molecular mechanisms underlying the development and regulation of a cell or the progression of disease. Proteomics encompasses the study of proteins expressed by a population of cells, and evaluates changes in protein expression, post-translational modifications, protein interactions, protein structure and splice variants, all of which are imperative for a complete understanding of protein function within the cell. From the outset, proteomics has been used to compare the protein profiles of cells in healthy and diseased states and as such can be used to identify proteins associated with disease development and progression. These candidate proteins might provide novel targets for new therapeutic agents or aid the development of assays for disease biomarkers. This review provides an overview of the current proteomic techniques available and focuses on their application in the search for novel therapeutic targets for the treatment of disease.

For better or worse: the effect of levodopa on speech in Parkinson's disease

While the beneficial effect of levodopa on traditional motor control tasks have been well documented over the decades. its effect on speech motor control has rarely been objectively examined and the existing literature remains inconclusive. This paper aims to examine the effect of levodopa on speech in patients with Parkinson's disease. It was hypothesized that levodopa would improve preparatory motor set related activity and alleviate hypophonia. Patients fasted and abstained from levodopa overnight. Motor examination and speech testing was performed the following day, pre-levodopa during their "off' state, then at hourly intervals post-medication to obtain the best "on" state. All speech stimuli showed a consistent tendency for increased loudness and faster rate during the "on" state, but this was accompanied by a greater extent of intensity decay. Pitch and articulation remained unchanged. Levodopa effectively upscaled the overall gain setting of vocal amplitude and tempo, similar to its well-known effect on limb movement. However, unlike limb movement, this effect on the final acoustic product of speech may or may not be advantageous, depending on the existing speech profile of individual patients. (C) 2007 Movement Disorder Society.

Cognitive follow up of a small cohort of Huntington's disease patients over a 5 year period

A small group of patients with manifest Huntington's disease (HD) were followed longitudinally to assess cognitive decline in relation to time from disease diagnosis. This article looks at performance on a range of computerised and pencil and paper cognitive tasks in patients 5 years post diagnosis, who were assessed annually for a 5 year follow up period. The almost universal cognitive decline reported in other longitudinal studies of HD was not replicated in this study. It was proposed that longitudinal follow up in HD is complicated by the varying degree to which different tasks are able to withstand repeated administration; a finding which would have significant implications on study design in future trials of cognitive enhansing interventions.

Animal disease and the limits of local knowledge: dealing with ticks and tick-borne diseases in South Africa

Some proponents of local knowledge, such as Sillitoe (2010), have expressed second thoughts about its capacity to effect development on the ‘revolutionary’ scale once predicted. Our argument in this article follows a similar route. Recent research into the management of livestock in South Africa makes clear that rural African livestock farmers experience uncertainty in relation to the control of stock diseases. State provision of veterinary services has been significantly reduced over the past decade. Both white and African livestock owners are to a greater extent left to their own devices. In some areas of animal disease management, African livestock owners have recourse to tried-and-tested local remedies, which are largely plant-based. But especially in the critical sphere of tick control, efficacious treatments are less evident, and livestock owners struggle to find adequate solutions to high tickloads. This is particularly important in South Africa in the early twenty-first century because land reform and the freedom to purchase land in the post-apartheid context affords African stockowners opportunities to expand livestock holdings. Our research suggests that the limits of local knowledge in dealing with ticks is one of the central problems faced by African livestock owners. We judge this not only in relation to efficacy but also the perceptions of livestock owners themselves. While confidence and practice varies, and there is increasing resort of chemical acaricides we were struck by the uncertainty of livestock owners over the best strategies.

Orange juice–derived flavanone and phenolic metabolites do not acutely affect cardiovascular risk biomarkers: a randomized, placebo-controlled, crossover trial in men at moderate risk of cardiovascular disease

Background: Epidemiological data suggest inverse associations between citrus flavanone intake and cardiovascular disease (CVD) risk. However, insufficient randomized controlled trial (RCT) data limit our understanding of mechanisms by which flavanones and their metabolites potentially reduce cardiovascular (CV) risk factors. Objective: We examined the effects of orange juice or a dose-matched hesperidin supplement on plasma concentrations of established and novel flavanone metabolites and their effects on CV risk biomarkers in men at moderate CVD risk. Methods: In an acute, randomized, placebo-controlled crossover trial, 16 fasted participants (aged 51-69 y) received orange juice or a hesperidin supplement (both providing 320 mg hesperidin) or control (all matched for sugar and vitamin C content). At baseline and 5 h post-intake, endothelial function (primary outcome), further CV risk biomarkers (i.e. blood pressure, arterial stiffness, cardiac autonomic function, platelet activation and NADPH oxidase gene expression) and plasma flavanone metabolites were assessed. Prior to each intervention, a diet low in flavonoids, nitrate/nitrite, alcohol and caffeine was followed and a standardized low-flavonoid evening meal was consumed. Results: Orange juice intake significantly elevated mean (± SEM) plasma concentrations of 8 flavanone (1.75 ± 0.35 µmol/L, P < 0.0001) and 15 phenolic metabolites (13.27 ± 2.22 µmol/L, P < 0.0001) compared with control at 5 h post-consumption. Despite increased plasma flavanone and phenolic metabolite concentrations, CV risk biomarkers were unaltered. Following hesperidin supplement intake, flavanone metabolites were not different to control, suggesting altered absorption/metabolism compared with the orange juice matrix. Conclusions: Following single-dose flavanone intake within orange juice, we detected circulating flavanone and phenolic metabolites collectively reaching a concentration of 15.20 ± 2.15 µmol/L but observed no effect on CV risk biomarkers. Longer-duration RCTs are required to further examine the previous associations between higher flavanone intakes and improved cardiovascular health and to ascertain the relative importance of food matrix and flavanone-derived phenolic metabolites.

The nature of impairments of memory in patients with end-stage renal disease (ESRD)

Possible impairments of memory in end-stage renal disease (ESRD) were investigated in two experiments. In Experiment 1, in which stimulus words were presented visually, participants were tested on conceptual or perceptual memory tasks, with retrieval being either explicit or implicit. Compared with healthy controls, ESRD patients were impaired when memory required conceptual but not when it required perceptual processing, regardless of whether retrieval was explicit or implicit. An impairment of conceptual implicit memory (priming) in the ESRD group represented a previously unreported deficit compared to healthy aging. There were no significant differences between pre- and immediate post-dialysis memory performance in ESRD patients on any of the tasks. In Experiment 2, in which presentation was auditory, patients again performed worse than controls on an explicit conceptual memory task. We conclude that the type of processing required by the task (conceptual vs. perceptual) is more important than the type of retrieval (explicit vs. implicit) in memory failures in ESRD patients, perhaps because temporal brain regions are more susceptible to the effects of the illness than are posterior regions.

An entirely new land? Italy’s post-war culture and its fascist past

Scholarship has for decades emphasised the significant continuities in Italian culture and society after Fascism, calling into question the rhetoric of post-war renewal. This essay proposes a reassessment of that rhetoric through the analysis of five key metaphors with which Italian intellectuals represented national recovery after 1945: parenthesis, disease, flood, childhood, and discovery. While the current critical consensus would lead us to expect a cultural conversation characterised by repression and evasion, an analysis of these five post-war metaphors instead reveals both a penetrating re-assessment of Italian culture after Fascism and an earnest adherence to the cause of national re-vitalisation. Foregrounding the inter-relation of Italy’s prospects for change and its continuities with Fascism, these metaphors suggest that post-war Italian intellectuals conceived of their country’s hopes for renewal, as well as its connections to the recent past, in terms that transcend the binary division favoured in many historical accounts.

SUMOylation: novel neuroprotective approach for Alzheimer's disease?

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized in the brain by the formation of amyloid-beta (Aβ)-containing plaques and neurofibrillary tangles containing the microtubule-associated protein tau. Neuroinflammation is another feature of AD and astrocytes are receiving increasing attention as key contributors. Although some progress has been made, the molecular mechanisms underlying the pathophysiology of AD remain unclear. Interestingly, some of the main proteins involved in AD, including amyloid precursor protein (APP) and tau, have recently been shown to be SUMOylated. The post-translational modification by SUMO (small ubiquitin-like modifier) has been shown to regulate APP and tau and may modulate other proteins implicated in AD. Here we present an overview of recent studies suggesting that protein SUMOylation might be involved in the underlying pathogenic mechanisms of AD and discuss how this could be exploited for therapeutic intervention.