Silent soft tissue pathology is common with a modern metal-on-metal hip arthroplasty: Early detection with routine metal artifact-reduction MRI scanning

Adverse reactions to metal debris have been reported to be a cause of pain in metal-on-metal hip arthroplasty. We assessed the incidence of both symptomatic and asymptomatic adverse reactions in a consecutive series of patients with a modern large-head metal-on-metal hip arthroplasty

Settler state apologies and the elusiveness of forgiveness : The purification ritual that does not purify

Peer reviewedPostprin

Intragenic deletions and a deep intronic mutation affecting pre-mRNA splicing in the dihydropyrimidine dehydrogenase gene as novel mechanisms causing 5-fluorouracil toxicity

Dihydropyrimidine dehydrogenase (DPD) is the initial enzyme acting in the catabolism of the widely used antineoplastic agent 5-fluorouracil (5FU). DPD deficiency is known to cause a potentially lethal toxicity following administration of 5FU. Here, we report novel genetic mechanisms underlying DPD deficiency in patients presenting with grade III/IV 5FU-associated toxicity. In one patient a genomic DPYD deletion of exons 21–23 was observed. In five patients a deep intronic mutation c.1129–5923C>G was identified creating a cryptic splice donor site. As a consequence, a 44 bp fragment corresponding to nucleotides c.1129–5967 to c.1129–5924 of intron 10 was inserted in the mature DPD mRNA. The deleterious c.1129–5923C>G mutation proved to be in cis with three intronic polymorphisms (c.483 + 18G>A, c.959–51T>G, c.680 + 139G>A) and the synonymous mutation c.1236G>A of a previously identified haplotype. Retrospective analysis of 203 cancer patients showed that the c.1129–5923C>G mutation was significantly enriched in patients with severe 5FU-associated toxicity (9.1%) compared to patients without toxicity (2.2%). In addition, a high prevalence was observed for the c.1129–5923C>G mutation in the normal Dutch (2.6%) and German (3.3%) population. Our study demonstrates that a genomic deletion affecting DPYD and a deep intronic mutation affecting pre-mRNA splicing can cause severe 5FU-associated toxicity. We conclude that screening for DPD deficiency should include a search for genomic rearrangements and aberrant splicing

Listeria monocytogenes Internalin B Activates Junctional Endocytosis to Accelerate Intestinal Invasion

Listeria monocytogenes (Lm) uses InlA to invade the tips of the intestinal villi, a location at which cell extrusion generates a transient defect in epithelial polarity that exposes the receptor for InlA, E-cadherin, on the cell surface. As the dying cell is removed from the epithelium, the surrounding cells reorganize to form a multicellular junction (MCJ) that Lm exploits to find its basolateral receptor and invade. By examining individual infected villi using 3D-confocal imaging, we uncovered a novel role for the second major invasin, InlB, during invasion of the intestine. We infected mice intragastrically with isogenic strains of Lm that express or lack InlB and that have a modified InlA capable of binding murine E-cadherin and found that Lm lacking InlB invade the same number of villi but have decreased numbers of bacteria within each infected villus tip. We studied the mechanism of InlB action at the MCJs of polarized MDCK monolayers and find that InlB does not act as an adhesin, but instead accelerates bacterial internalization after attachment. InlB locally activates its receptor, c-Met, and increases endocytosis of junctional components, including E-cadherin. We show that MCJs are naturally more endocytic than other sites of the apical membrane, that endocytosis and Lm invasion of MCJs depends on functional dynamin, and that c-Met activation by soluble InlB or hepatocyte growth factor (HGF) increases MCJ endocytosis. Also, in vivo, InlB applied through the intestinal lumen increases endocytosis at the villus tips. Our findings demonstrate a two-step mechanism of synergy between Lm's invasins: InlA provides the specificity of Lm adhesion to MCJs at the villus tips and InlB locally activates c-Met to accelerate junctional endocytosis and bacterial invasion of the intestine

Virus Movements on the Plasma Membrane Support Infection and Transmission between Cells

How viruses are transmitted across the mucosal epithelia of the respiratory, digestive, or excretory tracts, and how they spread from cell to cell and cause systemic infections, is incompletely understood. Recent advances from single virus tracking experiments have revealed conserved patterns of virus movements on the plasma membrane, including diffusive motions, drifting motions depending on retrograde flow of actin filaments or actin tail formation by polymerization, and confinement to submicrometer areas. Here, we discuss how viruses take advantage of cellular mechanisms that normally drive the movements of proteins and lipids on the cell surface. A concept emerges where short periods of fast diffusive motions allow viruses to rapidly move over several micrometers. Coupling to actin flow supports directional transport of virus particles during entry and cell-cell transmission, and local confinement coincides with either nonproductive stalling or infectious endocytic uptake. These conserved features of virus–host interactions upstream of infectious entry offer new perspectives for anti-viral interference

A bovine low molecular weight bone morphogenetic protein (BMP) fraction.

A low MW bone morphogenetic protein fraction (BMP) is quantitatively extracted from bovine bone matrix by an inorganic-organic CaCl2-urea solvent mixture and fractionated by ion exchange and gel chromatography. The BMP fraction induces differentiation of perivascular mesenchymal type cells into cartilage and bone inside the mouse's thigh, outside of double walled diffusion chamber, in muscle pouches in the rabbit anterior abdominal wall, and in 0.8 cm trephine defects in the rat's skull. Bovine BMP may consist of electrophoretic components ranging from 12 K to 30 K in MW. The main components correspond to a MW of 23 K, 18 K and 12 K when they are compared with the mobilities of standard proteins. Because it was invariably present in all of the fractions with osteoinductive activity, circumstantial evidence leads to a 17 to 18 K component for a BMP. The possibility of a diameter monomer system for BMP activity also warrants consideration. The polypeptide portion constitutes only about 80% to 85% of the dry weight of the mixture of the three electrophoretic components, and suggests that the BMP fraction contains glycoproteins. Characteristically, glycoproteins migrate anomalously on SDS gels and create doubt about whether the major bands represent true MW. Nevertheless, the data clearly point to the low MW protein fractions for the direction of future work on BMP

Two-year migration results of the ReCap hip resurfacing system—a radiostereometric follow-up study of 23 hips

There has been renewed interest for metal-on-metal hip resurfacing due to improved design and manufacturing of implants, better materials, and enhanced implant fixation. In contrast to conventional total hip replacements, only a few clinical hip resurfacing trials using radiostereometry (RSA) have been reported, and solely for the Birmingham hip resurfacing arthroplasty. The purpose of this RSA trial was to describe the migration pattern of a new hip resurfacing system (ReCap) within the first two years after primary surgery. Twenty-six patients underwent total hip replacement. The patients were followed-up for up to 24 months and were evaluated with the use of radiostereometric measurements. The prosthesis showed mean translations and rotation close to zero. Maximum translation was seen along the transverse axis in the medial direction (0.13 mm). No statistically significant translation or rotation was seen at two-years follow-up, (t-test, p <0.05, translation or rotation)