Identification of a new chemical class of antimalarials

The increasing spread of drug-resistant malaria strains underscores the need for new antimalarial agents with novel modes of action (MOAs). Here, we describe a compound representative of a new class of antimalarials. This molecule, ACT-213615, potently inhibits in vitro erythrocytic growth of all tested Plasmodium falciparum strains, irrespective of their drug resistance properties, with half-maximal inhibitory concentration (IC(50)) values in the low single-digit nanomolar range. Like the clinically used artemisinins, the compound equally and very rapidly affects all 3 asexual erythrocytic parasite stages. In contrast, microarray studies suggest that the MOA of ACT-213615 is different from that of the artemisinins and other known antimalarials. ACT-213615 is orally bioavailable in mice, exhibits activity in the murine Plasmodium berghei model and efficacy comparable to that of the reference drug chloroquine in the recently established P. falciparum SCID mouse model. ACT-213615 represents a new class of potent antimalarials that merits further investigation for its clinical potential.     

Context and dating of Aurignacian vulvar representations from Abri Castanet, France

We report here on the 2007 discovery, in perfect archaeological context, of part of the engraved and ocre-stained undersurface of the collapsed rockshelter ceiling from Abri Castanet, Dordogne, France. The decorated surface of the 1.5-t roof-collapse block was in direct contact with the exposed archaeological surface onto which it fell. Because there was no sedimentation between the engraved surface and the archaeological layer upon which it collapsed, it is clear that the Early Aurignacian occupants of the shelter were the authors of the ceiling imagery. This discovery contributes an important dimension to our understanding of the earliest graphic representation in southwestern France, almost all of which was discovered before modern methods of archaeological excavation and analysis. Comparison of the dates for the Castanet ceiling and those directly obtained from the Chauvet paintings reveal that the "vulvar" representations from southwestern France are as old or older than the very different wall images from Chauvet.     

Antigen stored in dendritic cells after macropinocytosis is released unprocessed from late endosomes to target B cells

B lymphocytes can be triggered in lymph nodes by nonopsonized antigens (Ag), potentially in their native form. However, the mechanisms that promote encounter of B lymphocytes with unprocessed antigens in lymph nodes are still elusive. We show here that antigens are detected in B cells in the draining lymph nodes of mice injected with live, but not fixed, dendritic cells (DCs) loaded with antigens. This highlights active processes in DCs to promote Ag transfer to B lymphocytes. In addition, antigen-loaded DCs found in the draining lymph node were CD103+. Using 3 different model Ag, we then show that immature DCs efficiently take up Ag by macropinocytosis and store the internalized material in late endocytic compartments. We find that DCs have a unique ability to release antigens from these compartments in the extracellular medium, which is controlled by Rab27. B cells take up the regurgitated Ag and the chemokine CXCL13, essential to attract B cells in lymph nodes, enhances this transfer. Our results reveal a unique property of DCs to regurgitate unprocessed Ag that could play an important role in B-cell activation.     

Indications for and results of arthroscopy in the arthritic knee: a European survey

Purpose

The place of arthroscopic treatment in osteoarthritis of the knee has generated much controversy. A survey was initiated to collect the opinion of experienced surgeons.

Methods

Of the 211 surgeons interviewed, 170 (80.6 %) replied to the electronic questionnaire. Respondents had at least ten years of experience in arthroscopy and currently perform more than 100 arthroscopies per year. Various indications and treatment modalities for arthroscopy in osteoarthritis of the knee had to be evaluated on a scale from “excellent” to “no indication”.

Results

The respondents generally believe that an improvement is more likely in low-grade osteoarthritis (p < 0.001) and in neutral leg axis (p < 0.001). The outcome was rated better if symptoms had persisted for less than six months (p < 0.001) and for patients that were younger than 60 years (p < 0.001). Partial meniscectomy and notchplasty in cases of extension deficit were considered as successful treatment options. Debridement was an accepted indication, with an outcome mainly rated as fair. A majority saw no indication for joint lavage, arthroscopic treatment of arthrofibrosis and removal of osteophytes. The outcome appears to be poor if a bone edema is diagnosed on magnetic resonance imaging prior to arthroscopy. Only 55.9 % of respondents were comfortable with the current definition of osteoarthritis.

Conclusions

Experienced arthroscopic surgeons all over Europe believe arthroscopy in osteoarthritis is appropriate, under certain conditions. The major task for surgeons is to select the right patients who are likely to benefit from this intervention.