Mitochondrial GSH replenishment as a potential therapeutic approach for Niemann Pick type C disease.

Niemann Pick type C (NPC) disease is a progressive lysosomal storage disorder caused by mutations in genes encoding NPC1/NPC2 proteins, characterized by neurological defects, hepatosplenomegaly and premature death. While the primary biochemical feature of NPC disease is the intracellular accumulation of cholesterol and gangliosides, predominantly in endolysosomes, mitochondrial cholesterol accumulation has also been reported. As accumulation of cholesterol in mitochondria is known to impair the transport of GSH into mitochondria, resulting in mitochondrial GSH (mGSH) depletion, we investigated the impact of mGSH recovery in NPC disease. We show that GSH ethyl ester (GSH-EE), but not N-acetylcysteine (NAC), restored the mGSH pool in liver and brain of Npc1-/- mice and in fibroblasts from NPC patients, while both GSH-EE and NAC increased total GSH levels. GSH-EE but not NAC increased the median survival and maximal life span of Npc1-/- mice. Moreover, intraperitoneal therapy with GSH-EE protected against oxidative stress and oxidant-induced cell death, restored calbindin levels in cerebellar Purkinje cells and reversed locomotor impairment in Npc1-/- mice. High-resolution respirometry analyses revealed that GSH-EE improved oxidative phosphorylation, coupled respiration and maximal electron transfer in cerebellum of Npc1-/- mice. Lipidomic analyses showed that GSH-EE treatment had not effect in the profile of most sphingolipids in liver and brain, except for some particular species in brain of Npc1-/- mice. These findings indicate that the specific replenishment of mGSH may be a potential promising therapy for NPC disease, worth exploring alone or in combination with other options.

On the Two-Dimensional Simplification of Three-Dimensional Cementless Hip Stem Numerical Models.

Three-dimensional (3D) finite element (FE) models are commonly used to analyze the mechanical behavior of the bone under different conditions (i.e., before and after arthroplasty). They can provide detailed information but they are numerically expensive and this limits their use in cases where large or numerous simulations are required. On the other hand, 2D models show less computational cost, but the precision of results depends on the approach used for the simplification. Two main questions arise: Are the 3D results adequately represented by a 2D section of the model? Which approach should be used to build a 2D model that provides reliable results compared to the 3D model? In this paper, we first evaluate if the stem symmetry plane used for generating the 2D models of bone-implant systems adequately represents the results of the full 3D model for stair climbing activity. Then, we explore three different approaches that have been used in the past for creating 2D models: (1) without side-plate (WOSP), (2) with variable thickness side-plate and constant cortical thickness (SPCT), and (3) with variable thickness side-plate and variable cortical thickness (SPVT). From the different approaches investigated, a 2D model including a side-plate best represents the results obtained with the full 3D model with much less computational cost. The side-plate needs to have variable thickness, while the cortical bone thickness can be kept constant.

Effects of Prosthetic Mismatch and Subscapularis Tear on Glenohumeral Contact Patterns in Total Shoulder Arthroplasty: A Numerical Musculoskeletal Analysis.

Prosthetic components' mismatch and subscapularis (SC) tear are determining factors for glenoid failure complication in nonconforming total shoulder arthroplasty (NC-TSA). Risk factors are linked to glenoid prosthetic loading. However, the mechanisms underlying the clinical observations remain unclear. This study assessed the combined impact of mismatch and subscapularis tear on glenoid loading. It was assumed that adequate glenoid loading was associated with minimal, but non-null, humeral head translations and contact pressure, as well as with maximal glenoid contact area, and that the center of pressure (COP) on the glenoid would have a centered displacement pattern. A numerical model was used to achieve two objectives. The first was to verify whether an optimum mismatch existed, for which failure risk would be minimal. The second was to explore the effect of subscapularis tear on the position of applied forces on the glenoid. A shoulder AnyBody musculoskeletal model was adapted to the arthroplasty context by introducing humeral head translations and contact between implants. Ten simulations were computed to compare combinations of varying mismatches (1.4 mm, 3.4 mm, 6.4 mm, 8.6 mm, and 9 mm) with two shoulder conditions (intact-muscle or subscapularis tear). Humeral head translations, center-of-pressure, contact area, contact pressure, and glenohumeral joint contact forces were numerically estimated. Mismatches between 3.4 mm and 6.4 mm were associated with the most minimal humeral translations and contact pressure, as well as with maximal contact area. Center of pressure displacement pattern differed according to shoulder condition, with an outward anterior tendency in presence of tear.

Finite element modelling approaches for well-ordered porous metallic materials for orthopaedic applications: cost effectiveness and geometrical considerations.

The mechanical properties of well-ordered porous materials are related to their geometrical parameters at the mesoscale. Finite element (FE) analysis is a powerful tool to design well-ordered porous materials by analysing the mechanical behaviour. However, FE models are often computationally expensive. This article aims to develop a cost-effective FE model to simulate well-ordered porous metallic materials for orthopaedic applications. Solid and beam FE modelling approaches are compared, using finite size and infinite media models considering cubic unit cell geometry. The model is then applied to compare two unit cell geometries: cubic and diamond. Models having finite size provide similar results than the infinite media model approach for large sample sizes. In addition, these finite size models also capture the influence of the boundary conditions on the mechanical response for small sample sizes. The beam FE modelling approach showed little computational cost and similar results to the solid FE modelling approach. Diamond unit cell geometry appeared to be more suitable for orthopaedic applications than the cubic unit cell geometry.

Adaptation of the AnyBody™ Musculoskeletal Shoulder Model to the Nonconforming Total Shoulder Arthroplasty Context.

Current musculoskeletal inverse dynamics shoulder models have two limitations to use in the context of nonconforming total shoulder arthroplasty (NC-TSA). First, the ball and socket glenohumeral (GH) joint simplification avoids any humeral head translations. Second, there is no contact at the GH joint to compute the contact area and the center of pressure (COP) between the two components of NC-TSA. In this paper, we adapted the AnyBody™ shoulder model by introducing humeral head translations and contact between the two components of an NC-TSA. Abduction in the scapular plane was considered. The main objective of this study was to adapt the AnyBody™ shoulder model to a NC-TSA context and to compare the results of our model (translations, COP, contact area, GH joint reaction forces (GH-JRFs), and muscular forces) with previous numerical, experimental, and clinical studies. Humeral head translations and contact were successfully introduced in our adapted shoulder model with strong support for our findings by previous studies.

Acetaldehyde targets superoxide dismutase 2 in liver cancer cells inducing transient enzyme impairment and a rapid transcriptional recovery.

Alcohol is undoubtedly, the main toxic agent that people consume by recreation and the abuse is associated with liver damage, mainly by the overproduction of reactive oxygen species and the toxic effects of its first metabolite acetaldehyde. It is known that acetaldehyde targets mitochondria inducing redox imbalance and oxidative stress. Mitochondrial superoxide dismutase transforms superoxide radical into hydrogen peroxide, which in addition, is transformed in water by other enzymes. In the present study we demonstrate that acetaldehyde transiently impairs SOD2 activity in HepG2 cells, the decrease in the enzyme activity was associated to a reduction in the protein content, which was rapidly recovered, to basal values, by synthesis de novo in a mechanism mediated by NF-κB and PKC. The SOD2 impairment was not associated with adduct formation. The recovery on SOD2 activity in HepG2 cells can represent survival advantage for cancer cells, the results shown that SOD2 could be considered a therapeutic target in liver cancer.

Hepatocyte growth factor protects against isoniazid/rifampicin-induced oxidative liver damage.

The worldwide increment of multidrug- and extensively drug-resistant tuberculosis has emphasized the importance of looking for new options in therapeutics. Long-time usage or higher doses of isoniazid and rifampicin have been considered for the treatment of multidrug-resistant tuberculosis; however, the risk of liver failure is proportionally increased. Hepatocyte growth factor (HGF) is a multitask growth factor that stimulates both antiapoptotic and antioxidant responses that counteract the toxic effects of drug metabolism in the liver. The present work was focused to address the antioxidant and antiapoptotic effects of HGF on isoniazid- and rifampicin-induced hepatotoxicity. BALB/c mice were subjected to rifampicin (150mg/kg, intragavage [ig]) plus isoniazid (75mg/kg, ig) for 7 days. Increments in alanine aminotransferase activity, steatosis, apoptosis, and oxidative stress markers were found in animals. Recombinant HGF (iv) prevented all the harmful effects by increasing the activation of Erk1/2 and PKCδ signaling pathways and glutathione (GSH) synthesis. Furthermore, inhibition of endogenous HGF with anti-HGF antibody (iv) enhanced the isoniazid- and rifampicin-induced oxidative stress damage and decreased the GSH content, aggravating liver damage. In conclusion, HGF demonstrated to be a good protective factor against antituberculosis drug-induced hepatotoxicity and could be considered a good adjuvant factor for the use of high doses of or the reintroduction of these antituberculosis drugs.

ASMase is required for chronic alcohol induced hepatic endoplasmic reticulum stress and mitochondrial cholesterol loading.

BACKGROUND & AIMS: The pathogenesis of alcohol-induced liver disease (ALD) is poorly understood. Here, we examined the role of acid sphingomyelinase (ASMase) in alcohol induced hepatic endoplasmic reticulum (ER) stress, a key mechanism of ALD. METHODS: We examined ER stress, lipogenesis, hyperhomocysteinemia, mitochondrial cholesterol (mChol) trafficking and susceptibility to LPS and concanavalin-A in ASMase(-)(/-) mice fed alcohol. RESULTS: Alcohol feeding increased SREBP-1c, DGAT-2, and FAS mRNA in ASMase(+/+) but not in ASMase(-/-) mice. Compared to ASMase(+/+) mice, ASMase(-/-) mice exhibited decreased expression of ER stress markers induced by alcohol, but the level of tunicamycin-mediated upregulation of ER stress markers and steatosis was similar in both types of mice. The increase in homocysteine levels induced by alcohol feeding was comparable in both ASMase(+/+) and ASMase(-/-) mice. Exogenous ASMase, but not neutral SMase, induced ER stress by perturbing ER Ca(2+) homeostasis. Moreover, alcohol-induced mChol loading and StARD1 overexpression were blunted in ASMase(-/-) mice. Tunicamycin upregulated StARD1 expression and this outcome was abrogated by tauroursodeoxycholic acid. Alcohol-induced liver injury and sensitization to LPS and concanavalin-A were prevented in ASMase(-/-) mice. These effects were reproduced in alcohol-fed TNFR1/R2(-/-) mice. Moreover, ASMase does not impair hepatic regeneration following partial hepatectomy. Of relevance, liver samples from patients with alcoholic hepatitis exhibited increased expression of ASMase, StARD1, and ER stress markers. CONCLUSIONS: Our data indicate that ASMase is critical for alcohol-induced ER stress, and provide a rationale for further clinical investigation in ALD.

A new interface element with progressive damage and osseointegration for modeling of interfaces in hip resurfacing.

Finite element models of orthopedic implants such as hip resurfacing femoral components usually rely on contact elements to model the load-bearing interfaces that connect bone, cement and implant. However, contact elements cannot simulate progressive degradation of bone-cement interfaces or osseointegration. A new interface element is developed to alleviate these shortcomings. This element is capable of simulating the nonlinear progression of bone-cement interface debonding or bone-implant interface osseointegration, based on mechanical stimuli in normal and tangential directions. The new element is applied to a hip resurfacing femoral component with a stem made of a novel biomimetic composite material. Three load cases are applied sequentially to simulate the 6-month period required for osseointegration of the stem. The effect of interdigitation depth of the bone-cement interface is found to be negligible, with only minor variations of micromotions. Numerical results show that the biomimetic stem progressively osseointegrates (alpha averages 0.7 on the stem surface, with spot-welds) and that bone-stem micromotions decrease below 10 microm. Osseointegration also changes the load path within the femoral bone: a decrease of 300 microepsilon was observed in the femoral head, and the inferomedial part of the femoral neck showed a slight increase of 165 microepsilon. There was also increased stress in the implant stem (from 7 to 11 MPa after osseointegration), indicating that part of the load is supported through the stem. The use of the new osseointegratable interface element has shown the osseointegration potential of the biomimetic stem. Its ability to model partially osseointegrated interfaces based on the mechanical conditions at the interface means that the new element could be used to study load transfer and osseointegration patterns on other models of uncemented hip resurfacing femoral components.

Biphasic regulation of the NADPH oxidase by HGF/c-Met signaling pathway in primary mouse hepatocytes.

Redox signaling is emerging as an essential mechanism in the regulation of biological activities of the cell. The HGF/c-Met signaling pathway has been implicated as a key regulator of the cellular redox homeostasis and oxidative stress. We previously demonstrated that genetic deletion of c-Met in hepatocytes disrupts redox homeostasis by a mechanism involving NADPH oxidase. Here, we were focused to address the mechanism of NADPH oxidase regulation by HGF/c-Met signaling in primary mouse hepatocytes and its relevance. HGF induced a biphasic mechanism of NADPH oxidase regulation. The first phase employed the rapid increase in production of ROS as signaling effectors to activate the Nrf2-mediated protective response resulting in up-regulation of the antioxidant proteins, such as NAD(P)H quinone oxidoreductase and γ-glutamylcysteine synthetase. The second phase operated under a prolonged HGF exposure, caused a suppression of the NADPH oxidase components, including NOX2, NOX4, p22 and p67, and was able to abrogate the TGFß-induced ROS production and improve cell viability. In conclusion, HGF/c-Met induces a Nrf2-mediated protective response by a double mechanism driven by NADPH oxidase.

Mechanical analysis of cuff tear arthropathy during multiplanar elevation with the AnyBody shoulder model.

BACKGROUND: This numerical study analysed the mechanics of cuff tear arthropathy with the AnyBody shoulder model. METHODS: The model simulated three frequent characteristics of cuff tear arthropathy: A supero-posterior massive rotator cuff tear, a proximal and static migration of the humeral head, and a contact between the humeral head and the scapula (glenoid & acromion) with friction. The mechanics of the cuff tear arthropathy with and without friction were studied by analysing: the mechanics of the deltoid (i.e. length & strength), the gleno-humeral and acromio-humeral contact forces, the friction moment, and the maximum elevation angle. Elevations in the frontal, scapular and sagittal planes were simulated. FINDINGS: Compared to an intact condition, the cuff tear arthropathy model without friction estimated a deltoid strength of -18% (frontal=-13%, scapular=-17%, sagittal=-25%), a gleno-humeral contact force of -34% (frontal=-60%, scapular=-46%, sagittal=+5%), estimated an acromio-humeral contact force of 240 N (frontal=213 N, scapular=184 N, sagittal=324 N) and a maximum elevation angle of 77° (frontal=80°, scapular=87°, sagittal=65°). Contact friction enhanced this behaviour, decreasing even more the gleno-humeral contact force and the maximum elevation angle, while increasing the acromio-humeral contact force. INTERPRETATION: This novel cuff tear arthropathy model suggests that friction and plane of elevation greatly influence the mechanics of the shoulder with cuff tear arthropathy. It also shows that the AnyBody simulation tool may be useful to study musculoskeletal pathologies and not only normal conditions.

Effect of glenoid implant design on glenohumeral stability: an experimental study.

BACKGROUND: Though several glenoid implants were developed over the past years, a high rate of glenoid loosening remains. This complication is linked to the glenohumeral stability, defined as humeral head translation. In an intact shoulder, this concept is ensured by all active and passive elements, particularly the labrum. Two features of a glenoid implant can be adjusted to improve the stability, or, in other words, to decrease the translations: the first is the mismatch, defined as the difference of curvature between the prosthetic head and glenoid; the second is the shape of the glenoid component. Therefore, the objective of this study was to compare the performance of 2 glenoid components (Ceraver, Roissy, France): (1) a standard design and (2) a design named "labrum design" with a superior part simulating the anatomic labrum. METHODS: An experimental device was developed to evaluate forces and kinematics. The device simulated active, dynamic and continuous abduction of an entire arm. It reproduced the Scapulo-Humeral Rhythm. The labrum design was installed first. To evaluate the effect of mismatch on the glenohumeral stability, 3 humeral heads were tested, corresponding to the ones recommended by the company. The experiment was repeated for the standard design. FINDINGS: The results obtained show a general decrease of the prosthetic head translation with the labrum design compared to the standard design. No noticeable effect of mismatch was found. INTERPRETATION: A proof of concept of the interest of the artificial labrum was provided since it improved the glenohumeral stability.

Passive contribution of the rotator cuff to abduction and joint stability.

PURPOSE: The purpose of this study is to compare shoulder joint biomechanics during abduction with and without intact non-functioning rotator cuff tissue. METHODS: A cadaver model was devised to simulate the clinical findings seen in patients with a massive cuff tear. Eight full upper limb shoulder specimens were studied. Initially, the rotator cuff tendons were left intact, representing a non-functional rotator cuff, as seen in suprascapular nerve paralysis or in cuff repair with a patch. Subsequently, a massive rotator cuff tear was re-created. Three-dimensional kinematics and force requirements for shoulder abduction were analyzed for each condition using ten abduction cycles in the plane of the scapula. RESULTS: Mediolateral displacements of the glenohumeral rotation center (GHRC) during abduction with an intact non-functioning cuff were minimal, but massive cuff tear resulted in significant lateral displacement of the GHRC (p < 0.013). Similarly, massive cuff tear caused increased superior migration of the GHRC during abduction compared with intact non-functional cuff (p < 0.01). From 5 to 30° of abduction, force requirements were significantly less with an intact non-functioning cuff than with massive cuff tear (p < 0.009). CONCLUSION: During abduction, an intact but non-functioning rotator cuff resulted in decreased GHRC displacement in two axes as well as lowered the force requirement for abduction from 5 to 30° as compared with the results following a massive rotator cuff tear. This provides insight into the potential biomechanical effect of repairing massive rotator cuff tears with a biological or synthetic "patch," which is a new treatment for massive cuff tear.

Factors affecting acetabular bone loss during primary hip arthroplasty--a quantitative analysis using computer simulation.

BACKGROUND: Although, various factors may affect the degree of acetabular bone loss during primary hip arthroplasty, they have not been quantified previously. METHODS: We assessed the influence of using various reamer diameters, designs and reaming depth on the amount of bone removed during acetabular preparation by simulated reaming in a three-dimensional pelvic model, using computer software. FINDINGS: The least amount of bone loss (6185 mm3) providing optimal bone contact with the acetabular articular surface occurred with a 165 degrees reamer design. Increase in reamer diameter, reaming depth and subtending angle of the reamer resulted in disproportionately large increase in the amount of bone resected compared to the relatively small increase in the reamer-bone contact area. INTERPRETATION: Surgeons must be aware of the relative influence of the reaming technique and the implant design on the amount of acetabular bone resection to optimize acetabular bone preservation during primary hip arthroplasty.

Factors affecting hip range of motion in surface replacement arthroplasty.

BACKGROUND: Surface replacement arthroplasty aims to re-create normal hip biomechanics; however the pathoanathomy of the hip, prosthetic component design, surgical technique and other factors may have a significant impact on the range of motion restoration attained following surface replacement arthroplasty. However, there is paucity of information on the effect of such factors. METHODS: A computerized three-dimensional hip model was created from preoperative computerized tomography images of a patient who was scheduled for a surface replacement arthroplasty. The effects of the femoral component size, translation and orientation on the range of motion were analysed as was the effect of increasing the seating depth and modification of the version of the acetabular component. FINDINGS: Increasing the femoral component size led to global improvement in range of motion while translation increased range of motion in one direction but reduced it in the opposite direction. Change in the femoral component orientation had minimal effects on range of motion in comparison to the effect of changes in the version of the acetabular component. Increasing the seating depth of the acetabulum only caused reduced range of motion in internal rotation in 90 degrees flexion. INTERPRETATION: To restore hip range of motion, surgeons performing surface replacement arthroplasty should aim to reproduce the natural femoral head-neck offset. Although increasing the femoral component size may achieve this, more acetabular bone will be resected. Knowing the specific zones of impingement of each arc of movement, selective translation of the femoral component or femoral neck osteoplasty can restore femoral neck offset in more critical areas without affecting acetabular bone stock. Over deepening of the acetabulum or leaving rim osteophytes should also be avoided to prevent impingement.

The effect of axis alignment on shoulder joint kinematics analysis during arm abduction.

BACKGROUND: A joint coordinate system allows coherence between the performed movement, its mathematical representation and the clinical interpretation of the kinematics of joint motion. In 2005, the International Society of Biomechanics (ISB) defined a joint coordinate system for the shoulder. To improve kinematics interpretation, the ISB suggested aligning the coordinate systems of the humerus and the scapula. Therefore, the aim of this research project was to determine how the alignment of the joint coordinate system axes can influence the interpretation of shoulder joint kinematics. More precisely, we wanted to investigate if mathematical alignment of the reference and moving coordinate system axes could facilitate the kinematic interpretation of a simple abduction movement without introducing additional coupled motion. METHODS: An experiment was carried out on eight shoulder cadaveric specimens. Elevation of the arm in the scapular plane (abduction) was recorded using an electromagnetic tracking device. Three-dimensional angular displacements of the arm during elevation in the scapular plane were described using the standard ISB joint coordinate system, and using a modified joint coordinate system for which the axes were mathematically aligned. FINDINGS: The results obtained revealed a difference in the interpretation of the starting angles between the ISB joint coordinate system and the aligned coordinate system. No difference was found in the interpretation of the angular range of motion (P<0.01). INTERPRETATION: The aligned coordinate system provided a standardized starting angle of elevation that allows an easier clinical interpretation of shoulder kinematics.