Posterior capsular release is a biomechanically safe procedure to perform in total knee arthroplasty

Purpose Surgeons may attempt to strip the posterior capsule from its femoral attachment to overcome flexion contracture in total knee arthroplasty (TKA); however, it is unclear if this impacts anterior–posterior (AP) laxity of the implanted knee. The aim of the study was to investigate the effect of posterior capsular release on AP laxity in TKA, and compare this to the restraint from the posterior cruciate ligament (PCL). Methods Eight cadaveric knees were mounted in a six degree of freedom testing rig and tested at 0°, 30°, 60° and 90° flexion with ± 150 N AP force, with and without a 710 N axial compressive load. After the native knee was tested, a deep dished cruciate-retaining TKA was implanted and the tests were repeated. The PCL was then cut, followed by releasing the posterior capsule using a curved osteotome. Results With 0 N axial load applied, cutting the PCL as well as releasing the posterior capsule significantly increased posterior laxity compared to the native knee at all flexion angles, and CR TKA states at 30°, 60° and 90° (p < 0.05). However, no significant increase in laxity was found between cutting the PCL and subsequent PostCap release (n.s.). In anterior drawer, there was a significant increase of 1.4 mm between cutting the PCL and PostCap release at 0°, but not at any other flexion angles (p = 0.021). When a 710 N axial load was applied, there was no significant difference in anterior or posterior translation across the different knee states (n.s.). Conclusions Posterior capsular release only caused a small change in AP laxity compared to cutting the PCL and, therefore, may not be considered detrimental to overall AP stability if performed during TKA surgery. Level of evidence Controlled laboratory study

Recent tectonic reorganization of the Nubia-Eurasia convergent 2 boundary heading for the closure of the western Mediterranean

: In the western Mediterranean area, after a long period (late Paleogene-Neogene) of Nubian northward subduction beneath Eurasia, subduction is almost ceased as well as convergence accommodation in the subduction zone. With the progression of Nubia-Eurasia convergence, a tectonic reorganization is therefore necessary to accommodate future contraction. Previously-published tectonic, seismological, geodetic, tomographic, and seismic reflection data (integrated by some new GPS velocity data) are reviewed to understand the reorganization of the convergent boundary in the western Mediterranean. Between northern Morocco, to the west, and northern Sicily, to the east, contractional deformation has shifted from the former subduction zone to the margins of the two backarc oceanic basins (Algerian-Liguro-Provençal and Tyrrhenian basins) and it is now active in the south-Tyrrhenian (northern Sicily), northern Liguro-Provençal, Algerian, and Alboran (partly) margins. Compression and basin inversion has propagated in a scissor-like manner from the Alboran (c. 8 Ma) to the Tyrrhenian (younger than c. 2 Ma) basins following a similar propagation of the subduction cessation and slab breakoff, i.e., older to the west and younger to the east. It follows that basin inversion is rather advanced in the Algerian margin, where a new southward subduction seems to be in its very infant stage, while it has still to properly start in the Tyrrhenian margin, where contraction has resumed at the rear of the fold-thrust belt and may soon invert the Marsili oceanic basin. GPS-derived strain rates higher in the Tyrrhenian margin than in the Algerian boundary suggest that this latter manner of contraction accommodation (contraction resumption at the rear of the orogenic wedge) is more efficient than subduction inception and basin inversion along newly-generated reverse faults (Algeria), but the differential strain rates may also be explained with the heterogeneous distribution of GPS stations. Part of the contractional deformation may have shifted toward the north in the Liguro-Provençal basin possibly because of its weak rheological properties compared with the area between Tunisia and Sardinia, where no oceanic crust occurs and seismic deformation is absent or limited compared with the adjacent strands of the Nubia-Eurasia boundary. The tectonic reorganization of the Nubia-Eurasia boundary in the study area is still strongly controlled by the inherited tectonic fabric and rheological attributes, which are both discontinuous and non-cylindrical along the boundary. These features prevent, at present, the development of long and continuous thrust faults. In an extreme and approximate synthesis, the evolution of the western Mediterranean is inferred as being similar to a Wilson Cycle in the following main steps: (1) northward Nubian subduction with Mediterranean backarc extension (since ~35 Ma); (2) progressive cessation, from west to east, of Nubian main subduction (since ~15 Ma); (3) progressive compression, from west to east, in the former backarc domain and consequent basin inversion (since ~8-10 Ma); (4) possible future subduction of former backarc basins

Characterization of lysosomal proteins Progranulin and Prosaposin and their interactions in Alzheimer\u27s disease and aged brains: increased levels correlate with neuropathology.

Progranulin (PGRN) is a protein encoded by the GRN gene with multiple identified functions including as a neurotrophic factor, tumorigenic growth factor, anti-inflammatory cytokine and regulator of lysosomal function. A single mutation in the human GRN gene resulting in reduced PGRN expression causes types of frontotemporal lobar degeneration resulting in frontotemporal dementia. Prosaposin (PSAP) is also a multifunctional neuroprotective secreted protein and regulator of lysosomal function. Interactions of PGRN and PSAP affect their functional properties. Their roles in Alzheimer\u27s disease (AD), the leading cause of dementia, have not been defined. In this report, we examined in detail the cellular expression of PGRN in middle temporal gyrus samples of a series of human brain cases (n = 45) staged for increasing plaque pathology. Immunohistochemistry showed PGRN expression in cortical neurons, microglia, cerebral vessels and amyloid beta (Aβ) plaques, while PSAP expression was mainly detected in neurons and Aβ plaques, and to a limited extent in astrocytes. We showed that there were increased levels of PGRN protein in AD cases and corresponding increased levels of PSAP. Levels of PGRN and PSAP protein positively correlated with amyloid beta (Aβ), with PGRN levels correlating with phosphorylated tau (serine 205) levels in these samples. Although PGRN colocalized with lysosomal-associated membrane protein-1 in neurons, most PGRN associated with Aβ plaques did not. Aβ plaques with PGRN and PSAP deposits were identified in the low plaque non-demented cases suggesting this was an early event in plaque formation. We did not observe PGRN-positive neurofibrillary tangles. Co-immunoprecipitation studies of PGRN from brain samples identified only PSAP associated with PGRN, not sortilin or other known PGRN-binding proteins, under conditions used. Most PGRN associated with Aβ plaques were immunoreactive for PSAP showing a high degree of colocalization of these proteins that did not change between disease groups. As PGRN supplementation has been considered as a therapeutic approach for AD, the possible involvement of PGRN and PSAP interactions in AD pathology needs to be further considered

Effect of different weaning age (21, 28 or 35 days) on production, growth and certain parameters of the digestive tract in rabbits

The effect of different weaning ages, that is, 21 (G21), 28 (G28) or 35 (G35) days, on growth and certain parameters of the digestive tract was examined in rabbits to assess the risk of early weaning attributable to the less-developed digestive system. On days 35 and 42, G35 rabbits had 10% to 14% and 10% higher BW, respectively ( P,0.05), than those weaned at days 21 and 28. In the 4th week of life, early weaned animals had 75% higher feed intake than G28 and G35 rabbits ( P,0.05). The relative weight of the liver increased by 62% between 21 and 28 days of age, and thereafter it decreased by 76% between 35 and 42 days of age ( P,0.05), with G21 rabbits having 29% higher weight compared with G35 animals on day 35 ( P,0.05). The relative weight of the whole gastrointestinal (GI) tract increased by 49% and 22% after weaning in G21 and G28 rabbits, respectively ( P,0.05). On day 28, the relative weight of the GI tract was 19% higher in G21 than in G28 rabbits, whereas on day 35 G21 and G28 animals had a 12% heavier GI tract compared with G35 rabbits ( P,0.05). Age influenced the ratio of stomach, small intestine and caecum within the GI tract; however, no effect of different weaning age was demonstrated. The pH value of the stomach and caecum decreased from 5.7 to 1.6 and from 7.1 to 6.3, respectively, whereas that of the small intestine increased from 6.8 to 8.4 ( P,0.05); the differences between groups were not statistically significant. Strictly anaerobic culturable bacteria were present in the caecum in high amounts (108), already at 14 days of age; no significant difference attributable to weaning age was demonstrable. The concentration of total volatile fatty acids (tVFA) was higher in G21 than in G28 and G35 throughout the experimental period ( P,0.05). The proportion of acetic and butyric acid within tVFA increased, whereas that of propionic acid decreased, resulting in a C3 : C4 ratio decreasing with age. Early weaning (G21) resulted in higher butyric acid and lower propionic acid proportions on day 28 ( P,0.05). No interaction between age and treatment was found, except in relative weight of the GI tract and caecal content. In conclusion, early weaning did not cause considerable changes in the digestive physiological parameters measured, but it resulted in 10% lower growth in rabbits

The Grosmarin experiment

The GROSMARIN (which stands for GrandROSMARIN) cruise is proposed by UMR Géosciences Azur (with fellow french and italian research groups). Its goals are to better characterize active structures along this zone and to assess the resulting seismic hazard in a sort of continuation with respect to the MALISAR experiment, which has already surveyed some active structures through shallow observations. The GROSMARIN cruise is in fact the necessary counterpart to characterize them at depth

Characterization of a Clp Protease Gene Regulator and the Reaeration Response in Mycobacterium tuberculosis

Mycobacterium tuberculosis (MTB) enters a non-replicating state when exposed to low oxygen tension, a condition the bacillus encounters in granulomas during infection. Determining how mycobacteria enter and maintain this state is a major focus of research. However, from a public health standpoint the importance of latent TB is its ability to reactivate. The mechanism by which mycobacteria return to a replicating state upon re-exposure to favorable conditions is not understood. In this study, we utilized reaeration from a defined hypoxia model to characterize the adaptive response of MTB following a return to favorable growth conditions. Global transcriptional analysis identified the ∼100 gene Reaeration Response, induced relative to both log-phase and hypoxic MTB. This response includes chaperones and proteases, as well as the transcription factor Rv2745c, which we characterize as a Clp protease gene regulator (ClgR) orthologue. During reaeration, genes repressed during hypoxia are also upregulated in a wave of transcription that includes genes crucial to transcription, translation and oxidative phosphorylation and culminates in bacterial replication. In sum, this study defines a new transcriptional response of MTB with potential relevance to disease, and implicates ClgR as a regulator involved in resumption of replication following hypoxia

Inhibiting mevalonate pathway enzymes increases stromal cell resilience to a cholesterol-dependent cytolysin

Animal health depends on the ability of immune cells to kill invading pathogens, and on the resilience of tissues to tolerate the presence of pathogens. Trueperella pyogenes causes tissue pathology in many mammals by secreting a cholesterol-dependent cytolysin, pyolysin (PLO), which targets stromal cells. Cellular cholesterol is derived from squalene, which is synthesized via the mevalonate pathway enzymes, including HMGCR, FDPS and FDFT1. The present study tested the hypothesis that inhibiting enzymes in the mevalonate pathway to reduce cellular cholesterol increases the resilience of stromal cells to PLO. We first verified that depleting cellular cholesterol with methyl-β-cyclodextrin increased the resilience of stromal cells to PLO. We then used siRNA to deplete mevalonate pathway enzyme gene expression, and used pharmaceutical inhibitors, atorvastatin, alendronate or zaragozic acid to inhibit the activity of HMGCR, FDPS and FDFT1, respectively. These approaches successfully reduced cellular cholesterol abundance, but mevalonate pathway enzymes did not affect cellular resilience equally. Inhibiting FDFT1 was most effective, with zaragozic acid reducing the impact of PLO on cell viability. The present study provides evidence that inhibiting FDFT1 increases stromal cell resilience to a cholesterol-dependent cytolysin

Global Functional Analyses of Cellular Responses to Pore-Forming Toxins

Here we present the first global functional analysis of cellular responses to pore-forming toxins (PFTs). PFTs are uniquely important bacterial virulence factors, comprising the single largest class of bacterial protein toxins and being important for the pathogenesis in humans of many Gram positive and Gram negative bacteria. Their mode of action is deceptively simple, poking holes in the plasma membrane of cells. The scattered studies to date of PFT-host cell interactions indicate a handful of genes are involved in cellular defenses to PFTs. How many genes are involved in cellular defenses against PFTs and how cellular defenses are coordinated are unknown. To address these questions, we performed the first genome-wide RNA interference (RNAi) screen for genes that, when knocked down, result in hypersensitivity to a PFT. This screen identifies 106 genes (∼0.5% of genome) in seven functional groups that protect Caenorhabditis elegans from PFT attack. Interactome analyses of these 106 genes suggest that two previously identified mitogen-activated protein kinase (MAPK) pathways, one (p38) studied in detail and the other (JNK) not, form a core PFT defense network. Additional microarray, real-time PCR, and functional studies reveal that the JNK MAPK pathway, but not the p38 MAPK pathway, is a key central regulator of PFT-induced transcriptional and functional responses. We find C. elegans activator protein 1 (AP-1; c-jun, c-fos) is a downstream target of the JNK-mediated PFT protection pathway, protects C. elegans against both small-pore and large-pore PFTs and protects human cells against a large-pore PFT. This in vivo RNAi genomic study of PFT responses proves that cellular commitment to PFT defenses is enormous, demonstrates the JNK MAPK pathway as a key regulator of transcriptionally-induced PFT defenses, and identifies AP-1 as the first cellular component broadly important for defense against large- and small-pore PFTs

Evolution of major milk proteins in Mus musculus and Mus spretus mouse species: a genoproteomic analysis

<p>Abstract</p> <p>Background</p> <p>Due to their high level of genotypic and phenotypic variability, <it>Mus spretus </it>strains were introduced in laboratories to investigate the genetic determinism of complex phenotypes including quantitative trait loci. <it>Mus spretus </it>diverged from <it>Mus musculus </it>around 2.5 million years ago and exhibits on average a single nucleotide polymorphism (SNP) in every 100 base pairs when compared with any of the classical laboratory strains. A genoproteomic approach was used to assess polymorphism of the major milk proteins between SEG/Pas and C57BL/6J, two inbred strains of mice representative of <it>Mus spretus </it>and <it>Mus musculus </it>species, respectively.</p> <p>Results</p> <p>The milk protein concentration was dramatically reduced in the SEG/Pas strain by comparison with the C57BL/6J strain (34 ± 9 g/L <it>vs</it>. 125 ± 12 g/L, respectively). Nine major proteins were identified in both milks using RP-HPLC, bi-dimensional electrophoresis and MALDI-Tof mass spectrometry. Two caseins (β and α_s1) and the whey acidic protein (WAP), showed distinct chromatographic and electrophoresis behaviours. These differences were partly explained by the occurrence of amino acid substitutions and splicing variants revealed by cDNA sequencing. A total of 34 SNPs were identified in the coding and 3'untranslated regions of the SEG/Pas <it>Csn1s1 </it>(11), <it>Csn2 </it>(7) and <it>Wap </it>(8) genes. In addition, a 3 nucleotide deletion leading to the loss of a serine residue at position 93 was found in the SEG/Pas <it>Wap </it>gene.</p> <p>Conclusion</p> <p>SNP frequencies found in three milk protein-encoding genes between <it>Mus spretus </it>and <it>Mus musculus </it>is twice the values previously reported at the whole genome level. However, the protein structure and post-translational modifications seem not to be affected by SNPs characterized in our study. Splicing mechanisms (cryptic splice site usage, exon skipping, error-prone junction sequence), already identified in casein genes from other species, likely explain the existence of multiple α_s1-casein isoforms both in SEG/Pas and C57BL/6J strains. Finally, we propose a possible mechanism by which the hallmark tandem duplication of a 18-nt exon (14 copies) may have occurred in the mouse genome.</p

Description of the attachment geometry of the anteromedial and posterolateral bundles of the ACL from arthroscopic perspective for anatomical tunnel placement

The anterior cruciate ligament (ACL) consists of an anteromedial bundle (AMB) and a posterolateral bundle (PLB). A reconstruction restoring the functional two-bundled nature should be able to approximate normal ACL function better than the most commonly used single-bundle reconstructions. Accurate tunnel positioning is important, but difficult. The purpose of this study was to provide a geometric description of the centre of the attachments relative to arthroscopically visible landmarks. The AMB and PLB attachment sites in 35 dissected cadaver knees were measured with a 3D system, as were anatomical landmarks of femur and tibia. At the femur, the mean ACL centre is positioned 7.9 ± 1.4 mm (mean ± 1 SD) shallow, along the notch roof, from the most lateral over-the-top position at the posterior edge of the intercondylar notch and from that point 4.0 ± 1.3 mm from the notch roof, low on the surface of the lateral condyle wall. The mean AMB centre is at 7.2 ± 1.8 and 1.4 ± 1.7 mm, and the mean PLB centre at 8.8 ± 1.6 and 6.7 ± 2.0 mm. At the tibia, the mean ACL centre is positioned 5.1 ± 1.7 mm lateral of the medial tibial spine and from that point 9.8 ± 2.1 mm anterior. The mean AMB centre is at 3.0 ± 1.6 and 9.4 ± 2.2 mm, and the mean PLB centre at 7.2 ± 1.8 and 10.1 ± 2.1 mm. The ACL attachment geometry is well defined relative to arthroscopically visible landmarks with respect to the AMB and PLB. With simple guidelines for the surgeon, the attachments centres can be found during arthroscopic single-bundle or double-bundle reconstructions