Extracellular vesicles and viruses: Are they close relatives?

Extracellular vesicles (EVs) released by various cells are small phospholipid membrane-enclosed entities that can carry miRNA. They are now central to research in many fields of biology because they seem to constitute a new system of cell–cell communication. Physical and chemical characteristics of many EVs, as well as their biogenesis pathways, resemble those of retroviruses. Moreover, EVs generated by virus-infected cells can incorporate viral proteins and fragments of viral RNA, being thus indistinguishable from defective (noninfectious) retroviruses. EVs, depending on the proteins and genetic material incorporated in them, play a significant role in viral infection, both facilitating and suppressing it. Deciphering the mechanisms of EV-cell interactions may facilitate the design of EVs that inhibit viral infection and can be used as vehicles for targeted drug delivery.     

Malaria-treatment policies: when and how should they be changed?

There appears to be a large a gap in the literature between primary work on malaria control and policy on the one hand and the interpretation of such work in making real policy decisions on the other. The focus of the present review is policy formulation for treatment of uncomplicated falciparum malaria, rather than prophylaxis in travellers or the treatment of severe disease. The World Health Organization has formulated guidelines addressing the issue of changing from one recommended drug for treating malaria to another, but there does not appear to have been a comprehensive attempt to describe how and when such a decision on drug policy should be made. Issues of drug availability, both to countries and to communities within them, are discussed, as well as the acceptability of drug regimens and compliance with them. It emerges that the cost of treatment has a disproportionate influence on the decision-making process, and that the indirect costs of drug failure are often not considered properly. Brief mention is made of the indicators of overall disease burden. There is some discussion about the usefulness of one recently introduced economic indicator: the disability-adjusted life-year (DALY). Also examined are the difficulties that arise within the context of drug-policy changes, such as a regimen's appropriateness to all target groups, and the strong influence of the private sector on decision-making that affects its own financing. The consensus seems to be that a policy change is urgent when high-level resistance occurs in 40% or more of treated cases, when parasitological response is poor, and when the costs of treatment failures are higher than those of treatments with a newer drug. It also emerges that much remains to be done regarding co-operation between public and private sectors; considering the importance of private-sector provision of health care, this needs to be addressed.     

Asymptomatic adult patients with aortic stenosis: should they ever have aortic valve replacement?

Presently, conventional wisdom is that an asymptomatic patient, even with severe aortic stenosis (AS), can be followed medically. The basis for this recommendation is that sudden death as the first "symptom" in an asymptomatic patient is rare. Unfortunately, symptoms are subjective and can be ignored or explained away by both patient and physician, and once symptoms are recognized, sudden death accounts for at least one third of the deaths from AS in unoperated patients. There is evidence that once AS becomes severe, ischemia and fibrosis occur rapidly, setting up the possibility of heart failure and sudden death even after successful valve replacement. Aortic valve replacement should be performed before extensive fibrosis occurs. Multiple studies have shown that in severe AS, symptoms will occur rapidly when there is heavy valve calcification, an aortic valve area <0.8 cm, an annual rate of progression of aortic valve velocity of >/=0.3 m/sec, or a positive exercise stress test. These findings are excellent evidence that asymptomatic patients with severe AS and any of the above findings should be considered for aortic valve replacement.     

Nutraceuticals: do they work and when should we use them?

There are numerous biological mechanisms by which nutritional factors might be expected to exert favorable influences on pathophysiological processes in osteoarthritis. Such processes include oxidative damage, cartilage matrix degradation and repair, and chondrocyte function and responses in adjacent bone. Micronutrients for which preliminary evidence of benefit exists include vitamin C and vitamin D. In addition, numerous nutraceuticals that may influence osteoarthritis pathophysiology--including glucosamine, chondroitin, S-adenosylmethionine, ginger and avocado/soybean unsaponifiables--have been tested in clinical trials. These products are safe and well tolerated, but interpretation of the collective results is hampered by heterogeneity of the studies, inconsistent results, and the conundrum of how to reconcile an apparent structural benefit with absence or modest effect on symptoms.     

Achalasia: should we or should we not follow the bag?

This article concerns the long-term therapeutic effect of pneumatic dilations (PDs) in achalasia. Specifically, it is a retrospective study that follows a large cohort of achalasia patients treated with PD. Efficacy and need for repeat PDs were determined utilizing a score obtained from measuring symptoms after PD. After PDs that resulted in symptomatic improvement, patients were followed at 6-month intervals to determine the need for repeat PD. The major point of this article is that exacerbations of symptoms may occur in 35% of patients undergoing PD; however, follow-up at specific intervals using a symptom score to determine the need for repeat PD resulted in excellent long-term success. This article emphasizes the need for continued follow-up of achalasia patients following initial successful therapy.     

Insulin analogues: have they changed insulin treatment and improved glycaemic control?

To improve insulin therapy, new insulin analogues have been developed. Two fast-acting analogues with a more rapid onset of effect and a shorter duration of action combined with a low day-to-day variation in absorption rate are now available. Despite this favourable time-action profile most studies have not been able to show any improvement in overall glycaemic control with the fast-acting analogues. A reduced post-prandial increase in blood glucose has been found in all studies, whereas between 3 and 5 h after the meal and during the night an increased blood glucose level is the normal course. This is probably the main explanation for the absence of improvement in overall glycaemic control when compared with regular human insulin. A tendency to a reduction in hypoglycaemic events during treatment with fast-acting analogues has been observed in most studies. Recent studies have indicated that NPH insulin administered several times daily at mealtimes can improve glycaemic control without increasing the risk of hypoglycaemia. The fast-acting analogues are now also available as insulin mixed with NPH. Insulin glargine is a new long-acting insulin which is soluble and precipitates after injection, resulting in a long half-life with a residual activity of about 50% 24 h after injection. Insulin glargine is a peakless insulin and studies in both type 1 and type 2 diabetic patients indicate that glargine improves fasting blood glucose control and reduces the incidence of nocturnal hypoglycaemia. Surprisingly, the new fast-acting analogues have not achieved the expected commercial success, which emphasises the need for new strategies for basal insulin supplementation, exercise, diet and blood glucose monitoring.     

Simplified composite disease activity measures in rheumatoid arthritis: should they be used in standard care?

OBJECTIVE: To examine the validity, reliability, and predictive value of two recently developed composite disease activity measures, the Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI) in rheumatoid arthritis (RA) patients. METHODS: A systematic review of the published literature was performed between February 2003 and November 2007. Data was extracted regarding correlations of the SDAI and CDAI with standard clinical trial measures, the predictive ability of the measures and correlations with changes in radiographic scores. The ability of the measures to categorize patients according to their disease activity status compared to standard categories was also examined. RESULTS: Among 17 studies initially identified, 12 provided information on the validity and reliability of the SDAI and CDAI. These measures were found to be strongly correlated with the Disease Activity Score (DAS28) with correlation coefficients ranging from 0.80 to 0.93. Areas under the curve (AUC), from receiver operating characteristic (ROC) curve analysis predicting physician responses, varied from 0.821 to 0.923. Moderate association with changes in the HAQ and radiographic scores was found with correlation coefficients ranging from 0.30 to 0.59. Several studies reported mixed results between the measures when categorizing patients according to disease severity with the SDAI and CDAI the more stringent at remission. CONCLUSION: The SDAI and the CDAI were found to have concurrent validity and were highly predictive of a change in therapy, but not predictive of future functional capacity or joint damage. Differences were found when categorizing patients according to disease activity level. Further studies should be conducted, especially at remission and low disease activity status, before these measures are used independently in a clinical setting.     

Physiological determinants of walking effort in older adults: should they be targets for physical activity intervention?

Older adults do not get enough physical activity increasing risk for chronic disease and loss of physical function. The purpose of this study was to determine whether neuromuscular, metabolic, and cardiorespiratory indicators of walking effort explain daily activity in community-dwelling older adults. Sixteen women and fourteen men, 78?±?8 years, performed a steady-state walk on a treadmill at 1.25 m s^?1 while muscle activation, heart rate, lactate, respiratory exchange ratio, oxygen consumption (VO₂), ventilation, and rating of perceived exertion (RPE) were recorded as markers of Walking Effort. Daily walking time, sitting/lying time, energy expenditure, and up-down transitions were recorded by accelerometers as markers of Daily Activity. Structural equation modeling was used to explore the relationship between the latent variables Walking Effort and Daily Activity controlling for age and BMI. Participants spent 9.4?±?1.9 h of the waking day sedentary and 1.9?±?0.6 h walking. In the structural equation model, the latent variable Walking Effort explained 64% of the variance in the Daily Activity latent variable (β?=?0.80, p?=?0.004). Walking Effort was identified by heart rate (β?=?0.64), ventilation (β?=?0.88), vastus lateralis activation (β?=?0.49), and lactate (β?=?0.58), all p?<?0.05, but not RPE or VO₂. Daily Activity was identified by stepping time (β?=?0.75) and up-down transitions (β?=?0.52), all p?<?0.05. Walking effort mediated the effects of age and BMI on older adults’ daily activity making physiological determinants of walking effort potential points of intervention.