Do we use a priori knowledge of gravity when making elbow rotations?

In this study, we aim to investigate whether motor commands, emanating from movement planning, are customized to movement orientation relative to gravity from the first trial on. Participants made fast point-to-point elbow flexions and extensions in the transverse plane. We compared movements that had been practiced in reclined orientation either against or with gravity with the same movement relative to the body axis made in the upright orientation (neutral compared to gravity). For each movement type, five rotations from reclined to upright orientation were made. For each rotation, we analyzed the first trial in upright orientation and the directly preceding trial in reclined orientation. Additionally, we analyzed the last five trials of a 30-trial block in upright position and compared these trials with the first trials in upright orientation. Although participants moved fast, gravitational torques were substantial. The change in body orientation affected movement planning: we found a decrease in peak angular velocity and a decrease in amplitude for the first trials made in the upright orientation, regardless of whether the previous movements in reclined orientation were made against or with gravity. We found that these decreases disappeared after participants familiarized themselves with moving in upright position in a 30-trial block. These results indicate that participants used a general strategy, corresponding to the strategy observed in situations with unreliable or limited information on external conditions. From this, we conclude that during movement planning, a priori knowledge of gravity was not used to specifically customize motor commands for the neutral gravity condition.     

Cathepsins B and L activate Ebola but not Marburg virus glycoproteins for efficient entry into cell lines and macrophages independent of TMPRSS2 expression

Ebola (EBOV) and Marburg virus (MARV) cause severe hemorrhagic fever. The host cell proteases cathepsin B and L activate the Zaire ebolavirus glycoprotein (GP) for cellular entry and constitute potential targets for antiviral intervention. However, it is unclear if different EBOV species and MARV equally depend on cathepsin B/L activity for infection of cell lines and macrophages, important viral target cells. Here, we show that cathepsin B/L inhibitors markedly reduce 293T cell infection driven by the GPs of all EBOV species, independent of the type II transmembrane serine protease TMPRSS2, which cleaved but failed to activate EBOV-GPs. Similarly, a cathepsin B/L inhibitor blocked macrophage infection mediated by different EBOV-GPs. In contrast, MARV-GP-driven entry exhibited little dependence on cathepsin B/L activity. Still, MARV-GP-mediated entry was efficiently blocked by leupeptin. These results suggest that cathepsins B/L promote entry of EBOV while MARV might employ so far unidentified proteases for GP activation.     

Fluvastatin-induced alterations of skeletal muscle function in hypercholesterolaemic rats

Although statins, the most widely used drugs in the treatment of hyperlipidaemia, are generally accepted as efficient and safe drugs their side-effects on skeletal muscle have been reported with increasing frequency. The lack of an animal model in which these side effects would consistently be observed is one of the important drawbacks in studying statin associated myopathy. To overcome this and enable the studying of the effects of fluvastatin on skeletal muscles an animal model with high blood cholesterol levels was developed. In these animals cholesterol levels rose more than seven fold (from 1.5 ± 0.1 to 10.7 ± 2.0 mmol/l; n = 15 and 16) with a dramatic increase in low density lipoprotein/high density lipoprotein ratio (from 0.29 ± 0.02 to 1.56 ± 0.17). While the latter was reversed by statin treatment, an elevation in blood creatine kinase (CK) level indicated the presence of muscle wasting. Fibers from m. extensor digitorum longus (EDL) showed significant reduction in cross sectional area in the statin treated groups. Statin treatment also decreased the proliferation and fusion of skeletal myotubes in culture. In line with this, resting intracellular calcium concentration ([Ca(2+)](i)) was reduced in statin treated satellite cells and myotubes. On the other hand, in adult skeletal muscle fibers statin treatment increased resting [Ca(2+)](i) (116 ± 4 nM vs. 151 ± 5 nM; n = 33 and 34) and decreased both twitch and tetanic force both in EDL and m. soleus. In addition, in m. soleus the duration of twitch and tetanic force was shortened. These results clearly indicate that statin administration in these animals results in a myopathy characterized by decreased muscle force and elevated plasma CK level.     

Verbal fluency and awareness of functional deficits in early-stage dementia

Assessment of activities of daily living is an important element in the diagnosis of dementia, with research suggesting a link between functional ability and cognition. We investigated the relationship between self- and informant ratings of instrumental activities of daily living (iADL) and verbal executive functioning in early-stage dementia. A total of 96 people with early-stage Alzheimer's disease or vascular or mixed dementia and their carers completed the Functional Activities Questionnaire; people with dementia also completed a test of letter fluency. Letter fluency was associated with self-ratings of iADL, while informant ratings of iADL were associated with the age and Mini-Mental State Examination score of the person with dementia. Self-ratings of perceived functioning suggested significantly less impairment than informant ratings. Those with impaired letter fluency rated themselves as having greater difficulties in iADLs than those who performed better. People with early-stage dementia vary in their subjective level of awareness of their iADL functioning, and difficulties with language production may contribute to better awareness of iADL impairments.     

Novel insights into proteolytic cleavage of influenza virus hemagglutinin

The influenza virus hemagglutinin (HA) mediates the first essential step in the viral life cycle, virus entry into target cells. Influenza virus HA is synthesised as a precursor protein in infected cells and requires cleavage by host cell proteases to transit into an active form. Cleavage is essential for influenza virus infectivity and the HA‐processing proteases are attractive targets for therapeutic intervention. It is well established that cleavage by ubiquitously expressed subtilisin‐like proteases is a hallmark of highly pathogenic avian influenza viruses (HPAIV). In contrast, the nature of the proteases responsible for cleavage of HA of human influenza viruses and low pathogenic avian influenza viruses (LPAIV) is not well understood. Recent studies suggest that cleavage of HA of human influenza viruses might be a cell‐associated event and might be facilitated by the type II transmembrane serine proteases (TTSPs) TMPRSS2, TMPRSS4 and human airway trypsin‐like protease (HAT). Here, we will introduce the different concepts established for proteolytic activation of influenza virus HA, with a particular focus on the role of TTSPs, and we will discuss their implications for viral tropism, pathogenicity and antiviral intervention. Copyright © 2010 John Wiley & Sons, Ltd.     

The effect of altitude on parasite density case definitions for malaria in northeastern Tanzania

OBJECTIVES: Malaria clinical trials need precise endpoints to measure efficacy. In endemic areas where asymptomatic parasitaemia is common, 'fever plus parasitaemia' may not differentiate between malaria cases and non-cases. Case definitions based on parasite cut-off densities may be more appropriate but may vary with age and transmission intensity. This study examines appropriate case definitions from parasitological surveys conducted over a broad range of transmission intensities, using altitude as a proxy for transmission intensity. METHODS: Cross-sectional data collected from 24 villages at different altitudes in an endemic area of northeastern Tanzania were used to calculate malaria-attributable fractions using a modified Poisson regression method. We modelled fever as a function of parasite density and determined the optimum cut-off densities of parasites to cause fever using sensitivity and specificity analyses. RESULTS: The optimum cut-off density varied by altitude in children aged under 5 years: a case definition of 4,000 parasites per mul at altitudes <600 m (high transmission intensity) was most appropriate, compared with 1,000 parasites per mul at altitudes >600 m (low transmission intensity). In children aged over 5 years and adults, there was little variation by altitude and a case definition of any parasites plus fever was the most appropriate. CONCLUSIONS: Locally appropriate case definitions of malaria should be used for research purposes. In our setting, these varied independently with age and transmission intensity.