Effects of implant design parameters on fluid convection, potentiating third-body debris ingress into the bearing surface during THA impingement/subluxation

Aseptic loosening from polyethylene wear debris is the leading cause of failure for metal-on-polyethylene total hip implants. Third-body debris ingress to the bearing space results in femoral head roughening and acceleration of polyethylene wear. How third-body particles manage to enter the bearing space between the closely conforming articulating surfaces of the joint is not well understood. We hypothesize that one such mechanism is from convective fluid transport during subluxation of the total hip joint. To test this hypothesis, a three-dimensional (3D) computational fluid dynamics (CFD) model was developed and validated, to quantify fluid ingress into the bearing space during a leg-cross subluxation event. The results indicated that extra-articular joint fluid could be drawn nearly to the pole of the cup with even very small separations of the femoral head (<0.60mm). Debris suspended near the equator of the cup at the site of maximum fluid velocity just before the subluxation began could be transported to within 11 degrees from the cup pole. Larger head diameters resulted in increased fluid velocity at all sites around the entrance to the gap compared to smaller head sizes, with fluid velocity being greatest along the anterosuperolateral cup edge, for all head sizes. Fluid pathlines indicated that suspended debris would reach similar angular positions in the bearing space regardless of head size. Increased inset of the femoral head into the acetabular cup resulted both in higher fluid velocity and in transport of third-body debris further into the bearing space.     

Release of hepatic Plasmodium yoelii merozoites into the pulmonary microvasculature

Plasmodium undergoes one round of multiplication in the liver prior to invading erythrocytes and initiating the symptomatic blood phase of the malaria infection. Productive hepatocyte infection by sporozoites leads to the generation of thousands of merozoites capable of erythrocyte invasion. Merozoites are released from infected hepatocytes as merosomes, packets of hundreds of parasites surrounded by host cell membrane. Intravital microscopy of green fluorescent protein-expressing P. yoelii parasites showed that the majority of merosomes exit the liver intact, adapt a relatively uniform size of 12-18 microm, and contain 100-200 merozoites. Merosomes survived the subsequent passage through the right heart undamaged and accumulated in the lungs. Merosomes were absent from blood harvested from the left ventricle and from tail vein blood, indicating that the lungs effectively cleared the blood from all large parasite aggregates. Accordingly, merosomes were not detectable in major organs such as brain, kidney, and spleen. The failure of annexin V to label merosomes collected from hepatic effluent indicates that phosphatidylserine is not exposed on the surface of the merosome membrane suggesting the infected hepatocyte did not undergo apoptosis prior to merosome release. Merosomal merozoites continued to express green fluorescent protein and did not incorporate propidium iodide or YO-PRO-1 indicating parasite viability and an intact merosome membrane. Evidence of merosomal merozoite infectivity was provided by hepatic effluent containing merosomes being significantly more infective than blood with an identical low-level parasitemia. Ex vivo analysis showed that merosomes eventually disintegrate inside pulmonary capillaries, thus liberating merozoites into the bloodstream. We conclude that merosome packaging protects hepatic merozoites from phagocytic attack by sinusoidal Kupffer cells, and that release into the lung microvasculature enhances the chance of successful erythrocyte invasion. We believe this previously unknown part of the plasmodial life cycle ensures an effective transition from the liver to the blood phase of the malaria infection.     

A two-phase finite element model of the diastolic left ventricle

A porous medium finite element model of the passive left ventricle is presented. The model is axisymmetric and allows for finite deformation, including torsion about the axis of symmetry. An anisotropic quasi-linear viscoelastic constitutive relation is implemented in the model. The model accounts for changing fibre orientation across the myocardial wall. During passive filling, the apex rotates in a clockwise direction relative to the base for an observer looking from apex to base. Within an intraventricular pressure range of 0-3 kPa the rotation angle of all nodes remained below 0.1 rad. Diastolic viscoelasticity of myocardial tissue is shown to reduce transmural differences of preload-induced sarcomere stretch and to generate residual stresses in an unloaded ventricular wall, consistent with the observation of opening angles seen when the heart is slit open. It is shown that the ventricular model stiffens following an increase of the intracoronary blood volume. At a given left ventricular volume, left ventricular pressure increases from 1.5 to 2.0 kPa when raising the intracoronary blood volume from 9 to 14 ml (100 g)-1 left ventricle.     

Relation between left ventricular cavity pressure and volume and systolic fiber stress and strain in the wall.

Pumping power as delivered by the heart is generated by the cells in the myocardial wall. In the present model study global left-ventricular pump function as expressed in terms of cavity pressure and volume is related to local wall tissue function as expressed in terms of myocardial fiber stress and strain. On the basis of earlier studies in our laboratory, it may be concluded that in the normal left ventricle muscle fiber stress and strain are homogeneously distributed. So, fiber stress and strain may be approximated by single values, being valid for the whole wall. When assuming rotational symmetry and homogeneity of mechanical load in the wall, the dimensionless ratio of muscle fiber stress (sigma f) to left-ventricular pressure (Plv) appears to depend mainly on the dimensionless ratio of cavity volume (Vlv) to wall volume (Vw) and is quite independent of other geometric parameters. A good (+/- 10%) and simple approximation of this relation is sigma f/Plv = 1 + 3 Vlv/Vw. Natural fiber strain is defined by ef = In (lf/lf,ref), where lf,ref indicates fiber length (lf) in a reference situation. Using the principle of conservation of energy for a change in ef, it holds delta ef = (1/3)delta In (1 + 3Vlv/Vw).     

Enhancement of gamma-glutamylcysteine synthetase mRNA in rat kidney by methyl mercury.

Glutathione (GSH), a major cellular antioxidant, is elevated 2- to 3-fold in kidneys of rats during prolonged treatment with mercury as methyl mercury hydroxide (MMH). Increased renal GSH is accompanied by a dose- and time-related elevation in the relative abundance of mRNA hybridizable to a cDNA probe which encodes renal gamma-glutamylcysteine synthetase (GCS), the rate-limiting enzyme in GSH synthesis. Renal GCS mRNA is maximally elevated 4.4-fold at 3 weeks following initiation of MMH treatment. Enhancement of GSH and GCS mRNA content corresponds to a relative sparing of renal cells from oxidative tissue damage during MMH exposure. These observations suggest that increased synthesis of GSH at the genetic level occurs as an initial adaptive response to mercury-induced oxidative stress in kidney cells.     

Natural variation in the V3 crown of human immunodeficiency virus type 1 affects replicative fitness and entry inhibitor sensitivity

Natural polymorphisms in the heterogeneous human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein may have an impact on both sensitivity to entry inhibitors and viral replicative fitness. Of significant interest is variation in the V3 crown due to its involvement in direct engagement with the coreceptor. Two positions in the crown (318 and 319) appear to be important in determining intrinsic susceptibility to multiple entry inhibitors. Thus, we evaluated a series of natural polymorphisms at positions 318 and 319 in three distinct CCR5-tropic envelope genetic backgrounds to address their role in replicative fitness and sensitivity to entry inhibitors. Change at position 319 to each of the three major consensus amino acids (A, T, and R) resulted in variation in sensitivity to entry inhibitors and altered replicative fitness, but the effects of any one amino acid depended on the envelope context. Change of the nearly invariant tyrosine at position 318 to a rare arginine resulted in increased sensitivity to entry inhibitors and decreased replicative fitness independent of envelope context. Polymorphisms in the V3 crown that showed increased susceptibility to entry inhibitors also exhibited decreased entry efficiency, replicative fitness in primary peripheral blood mononuclear cells, and ability to replicate in primary macrophages. These findings suggest that differences in coreceptor affinity and/or avidity may underlie these phenotypic characteristics.     

Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence

Cell-cycle arrest, apoptosis, and senescence are widely accepted as the major mechanisms by which p53 inhibits tumor formation. Nevertheless, it remains unclear whether they are the rate-limiting steps in tumor suppression. Here, we have generated mice bearing lysine to arginine mutations at one (p53(K117R)) or three (p53(3KR); K117R+K161R+K162R) of p53 acetylation sites. Although p53(K117R/K117R) cells are competent for p53-mediated cell-cycle arrest and senescence, but not apoptosis, all three of these processes are ablated in p53(3KR/3KR) cells. Surprisingly, unlike p53 null mice, which rapidly succumb to spontaneous thymic lymphomas, early-onset tumor formation does not occur in either p53(K117R/K117R) or p53(3KR/3KR) animals. Notably, p53(3KR) retains the ability to regulate energy metabolism and reactive oxygen species production. These findings underscore the crucial role of acetylation in differentially modulating p53 responses and suggest that unconventional activities of p53, such as metabolic regulation and antioxidant function, are critical for suppression of early-onset spontaneous tumorigenesis.     

Ecological tracers reveal resource convergence among prey fish species in a large lake ecosystem

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