Inhibitors of the Hepatitis C Virus Polymerase; Mode of Action and Resistance

The hepatitis C virus (HCV) is a pandemic human pathogen posing a substantial health and economic burden in both developing and developed countries. Controlling the spread of HCV through behavioural prevention strategies has met with limited success and vaccine development remains slow. The development of antiviral therapeutic agents has also been challenging, primarily due to the lack of efficient cell culture and animal models for all HCV genotypes, as well as the large genetic diversity between HCV strains. On the other hand, the use of interferon-α-based treatments in combination with the guanosine analogue, ribavirin, achieved limited success, and widespread use of these therapies has been hampered by prevalent side effects. For more than a decade, the HCV RNA-dependent RNA polymerase (RdRp) has been targeted for antiviral development. Direct acting antivirals (DAA) have been identified which bind to one of at least six RdRp inhibitor-binding sites, and are now becoming a mainstay of highly effective and well tolerated antiviral treatment for HCV infection. Here we review the different classes of RdRp inhibitors and their mode of action against HCV. Furthermore, the mechanism of antiviral resistance to each class is described, including naturally occurring resistance-associated variants (RAVs) in different viral strains and genotypes. Finally, we review the impact of these RAVs on treatment outcomes with the newly developed regimens.     

Statistical clues to postoperative blood loss: Moving averages applied to medical data

With the advent of computerized databases, medical data has become easy to accumulate; however, effective use of this data continues to pose significant problems. In other circumstances, smoothing algorithms have been used to uncover non-obvious correlations, trends and relationships in noisy data. We have applied four such algorithms to a large dataset of postoperative blood replacement in cardiopulmonary bypass patients. When applied to this dataset, one of the algorithms proved surprisingly effective. It confirmed several previously observed correlations, and also provided an additional series of counterintuitive and apparently unrelated associations. These associations have been explored in an accompanying paper.     

Copper-containing IUDs are not associated with an increase of malondialdehyde levels in cervical mucus

The malondialdehyde (MDA) content of cervical mucus from 23 healthy adult females was measured using an ion-pairing HPLC method capable of detecting 10 pmol MDA. Ten of the women were wearing copper IUDs, four were wearing plastic IUDs, and nine controls were not wearing an IUD. Cervical mucus was sampled during the follicular, periovulatory, luteal, and menstrual phases. The study was designed to determine if there is a relationship between MDA formation and the use of a copper IUD. A total of 79 samples were analyzed. Only 16 of the samples had sufficient MDA for reliable quantitation with the level ranging from 0.1 nmol/g to 2.32 nmol/g. In 19 of the samples, trace levels (less than 0.06 nmol/g) were detected but could not be reliably quantitated. In the remaining 44 samples, no MDA was detectable. There was no correlation between the presence of copper- or non-copper-containing IUDs and the level of MDA. These results are contrary to a previously published report that used a less specific method for MDA analysis.     

Public health capacity building in southeastern Europe: a partnership between the Open Society Institute and the US Centers for Disease Control and Prevention.

The political disintegration of former Yugoslavia inaugurated in 1991 resulted in the decentralization of health systems in the federation's successor nation-states. Efforts by the Open Society Institute improved public health planning and management needs consequent to health sector changes. Beginning in Croatia in 2001, the Institute developed ongoing collaborations between Andrija Stampar School of Public Health and the US Centers for Disease Control and Prevention. In 2003 and 2004, it expanded its project to include the republics of Macedonia and of Serbia and Montenegro.     

The attachments of the anteromedial and posterolateral fibre bundles of the anterior cruciate ligament

The tibial attachments of the individual anteromedial (AM) and posterolateral (PL) fibre bundles and the entire attachment of the anterior cruciate ligament are described, relating them to consistent bony landmarks; 55 fresh-frozen specimens were measured. The fibre bundles were separated and excised at their attachments and their peripheries marked with a pen. High-resolution scaled digital photographs were taken of each dissected specimen and transferred onto a computer for analysis. A wide variation was found when using the posterior tibial axis, the anterior tibial surface and the medial tibial spine as reference points. The most consistent measurements used the tibial interspinous “over-the-back” ridge as a datum. The attachments of the PL and AM bundles were centred 10 ± 1 mm (mean ± SD) and 17 ± 2 mm anterior to the over-the-back ridge. They were 4 ± 1 and 5 ± 1 mm, respectively, lateral to the medial tibial spine border. The positions of 6 mm circles in the posterior-medial limits of the fibre bundles (representing tunnels in a double-tunnel reconstruction) were measured. The overall dimensions of the tibial plateaux correlated significantly with many measurements. The results from this study could be used to guide ACL reconstruction techniques.