vendex and Necrosis

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle wasting secondary to repeated muscle damage and inadequate repair. Elevations in intracellular free Ca²⁺ have been implicated in disease progression, and sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase 1 (SERCA1) overexpression has been shown to ameliorate the dystrophic phenotype in mdx mice. The purpose of this study was to assess the effects of SERCA1 overexpression in the more severe mdx/Utr(-/-) mouse model of DMD. Mice overexpressing SERCA1 were crossed with mdx/Utr ± mice to generate mdx/Utr(-/-)/+SERCA1 mice and compared with wild-type (WT), WT/+SERCA1, mdx/+SERCA1, and genotype controls. Mice were assessed at ∼12 wk of age for changes in Ca²⁺ handling, muscle mass, quadriceps torque, markers of muscle damage, and response to repeated eccentric contractions. SERCA1-overexpressing mice had a two- to threefold increase in maximal sarcoplasmic reticulum Ca²⁺-ATPase activity compared with WT which was associated with normalization in body mass for both mdx/+SERCA1 and mdx/Utr(-/-)/+SERCA1. Torque deficit in the quadriceps after eccentric injury was 2.7-fold greater in mdx/Utr(-/-) vs. WT mice, but only 1.5-fold greater in mdx/Utr(-/-)/+SERCA1 vs. WT mice, an attenuation of 44%. Markers of muscle damage (% centrally nucleated fibers, necrotic area, and serum creatine kinase levels) were higher in both mdx and mdx/Utr(-/-) vs. WT, and all were attenuated by overexpression of SERCA1. These data indicate that SERCA1 overexpression ameliorates functional impairments and cellular markers of damage in a more severe mouse model of DMD. These findings support targeting intracellular Ca²⁺ control as a therapeutic approach for DMD.

Topics: Animals; Biomarkers; Biomechanical Phenomena; Calcium Signaling; Creatine Kinase, MM Form; Disease Models, Animal; Genotype; Hypertrophy; Mice, Inbred mdx; Mice, Transgenic; Muscle Contraction; Muscle Strength; Muscular Dystrophy, Duchenne; Necrosis; Organ Size; Phenotype; Quadriceps Muscle; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Severity of Illness Index; Torque; Up-Regulation; Utrophin

The influence of the wear rate of drills used in bone surgery on the temperature distribution in the femur models (Sawbones) is presented in the paper. Surgical drills of diameter d = 4.5 mm and diverse edge geometry (90° and 120°) were selected for the study. In order to carry out thermal analysis with the use of finite element, experimental studies of wear process were necessary. These studies, among others, consisted in determination of average values of axial forces and cutting torques as a function of the number of drilled holes. The study showed an impact of the drill geometry on values that describe cutting process. It was found that the greatest values of torques and axial cutting forces occur in drills of point angle of 120°. Next, in order to determine the effect of wear rate on the generation of temperature in the cutting zone, thermal analysis of the drilling process using the finite element method was carried out. It was found that higher temperatures in the bone are observed for drilling with the use of the drill of point angle equal to 120°, as in the experimental study. For the tools of such edge geometry the wear of cutting edge is more intensive and the generated temperature in femur for the wear land VBB = 0.32 mm has reached the critical value associated with the process of thermal necrosis.

Topics: Femur; Friction; Hot Temperature; Models, Theoretical; Necrosis; Stress, Mechanical; Surgical Instruments; Torque

Primary stability has been regarded as a key factor to ensure uneventful osseointegration of dental implants. Such stability is often achieved by placing implants in undersized drilled bone. The present study evaluated the effect of drilling dimensions in insertion torque and early implant osseointegration stages in a beagle dog model.. Six beagle dogs were acquired and subjected to bilateral surgeries in the radii 1 and 3 weeks before death. During surgery, 3 implants, 4 mm in diameter by 10 mm in length, were placed in bone sites drilled to 3.2 mm, 3.5 mm, and 3.8 mm in diameter. The insertion torque was recorded for all samples. After death, the implants in bone were nondecalcified processed and morphologically and morphometrically (bone-to-implant contact and bone area fraction occupancy) evaluated. Statistical analyses were performed using the Kruskal-Wallis test followed by Dunn's post hoc test for multiple comparisons at the 95% level of significance.. The insertion torque levels obtained were inversely proportional to the drilling dimension, with a significant difference detected between the 3.2-mm and 3.8-mm groups (P = .003). Despite a significant increase in the bone-to-implant contact over time in vivo for all groups (P = .007), no effect for the drilling dimension was observed. Additionally, no effect of the drilling dimension and time was observed for the bone area fraction occupancy parameter (P = .31). The initial healing pathways differed between implants placed in bone drilled to different dimensions.. Although different degrees of torque were observed with different drilling dimensions and these resulted in different healing patterns, no differences in the histometrically evaluated parameters were observed.

Topics: Acid Etching, Dental; Animals; Bone Remodeling; Coloring Agents; Dental Etching; Dental Implantation, Endosseous; Dental Implants; Dental Prosthesis Design; Dental Prosthesis Retention; Dogs; Image Processing, Computer-Assisted; Male; Necrosis; Osseointegration; Osteogenesis; Osteotomy; Radius; Surface Properties; Time Factors; Tolonium Chloride; Torque

Mutations in the DYSF gene, encoding dysferlin, cause muscular dystrophies in man. We compared 4 dysferlinopathic mouse strains: SJL/J and B10.SJL-Dysf(im)/AwaJ (B10.SJL), and A/J and B6.A-Dysf(prmd)/GeneJ (B6.A/J). The former but not the latter two are overtly myopathic and weaker at 3 months of age. Following repetitive large-strain injury (LSI) caused by lengthening contractions, all except B6.A/J showed ~40% loss in contractile torque. Three days later, torque in SJL/J, B10.SJL and controls, but not A/J, recovered nearly completely. B6.A/J showed ~30% torque loss post-LSI and more variable recovery. Pre-injury, all dysferlinopathic strains had more centrally nucleated fibers (CNFs) and all but A/J showed more inflammation than controls. At D3, all dysferlinopathic strains showed increased necrosis and inflammation, but not more CNFs; controls were unchanged. Dystrophin-null DMD(mdx) mice showed more necrosis and inflammation than all dysferlin-nulls. Torque loss and inflammation on D3 across all strains were linearly related to necrosis. Our results suggest that (1) dysferlin is not required for functional recovery 3 days after LSI; (2) B6.A/J mice recover from LSI erratically; (3) SJL/J and B10.SJL muscles recover rapidly, perhaps due to ongoing myopathy; (4) although they recover function to different levels, all 4 dysferlinopathic strains show increased inflammation and necrosis 3 days after LSI.

Topics: Animals; Disease Models, Animal; Dysferlin; Histocytochemistry; Inflammation; Macrophages; Membrane Proteins; Mice; Mice, Inbred Strains; Mice, Transgenic; Muscle Contraction; Muscle Fibers, Skeletal; Muscle, Skeletal; Muscular Dystrophies, Limb-Girdle; Necrosis; Torque

We studied the response of dysferlin-null and control skeletal muscle to large- and small-strain injuries to the ankle dorsiflexors in mice. We measured contractile torque and counted fibers retaining 10-kDa fluorescein dextran, necrotic fibers, macrophages, and fibers with central nuclei and expressing developmental myosin heavy chain to assess contractile function, membrane resealing, necrosis, inflammation, and myogenesis. We also studied recovery after blunting myogenesis with X-irradiation. We report that dysferlin-null myofibers retain 10-kDa dextran for 3 days after large-strain injury but are lost thereafter, following necrosis and inflammation. Recovery of dysferlin-null muscle requires myogenesis, which delays the return of contractile function compared with controls, which recover from large-strain injury by repairing damaged myofibers without significant inflammation, necrosis, or myogenesis. Recovery of control and dysferlin-null muscles from small-strain injury involved inflammation and necrosis followed by myogenesis, all of which were more pronounced in the dysferlin-null muscles, which recovered more slowly. Both control and dysferlin-null muscles also retained 10-kDa dextran for 3 days after small-strain injury. We conclude that dysferlin-null myofibers can survive contraction-induced injury for at least 3 days but are subsequently eliminated by necrosis and inflammation. Myogenesis to replace lost fibers does not appear to be significantly compromised in dysferlin-null mice.

Topics: Animals; Cumulative Trauma Disorders; Dextrans; Disease Models, Animal; Dysferlin; Fluoresceins; Inflammation; Macrophages; Male; Membrane Proteins; Mice; Mice, Knockout; Muscle Contraction; Muscle Development; Muscle Fibers, Skeletal; Muscle, Skeletal; Muscular Dystrophies, Limb-Girdle; Necrosis; Recovery of Function; Time Factors; Torque

Large diaphyseal bone defects often are reconstructed with large structural allografts but these are prone to major complications. We therefore asked whether impacted morselized bone graft could be an alternative for a massive structural graft in reconstructing large diaphyseal bone defects. Defects in the femora of goats were reconstructed using a cage filled with firmly impacted morselized allograft or with a structural cortical autograft (n = 6 in both groups). All reconstructions were stabilized with an intramedullary nail. The goats were allowed full weightbearing. In all reconstructions, the grafts united radiographically. Mechanical torsion strength of the femur with the cage and structural cortical graft reconstructions were 66.6% and 60.3%, respectively, as compared with the contralateral femurs after 6 months. Histologically, the impacted morselized graft was replaced completely by new viable bone. In the structural graft group, a mixture of new and necrotic bone was present. Incorporation of the impacted graft into new viable bone suggests this type of reconstruction may be safer than reconstruction with a structural graft in which creeping substitution results in a mixture of viable and necrotic bone that can fracture. The data suggest that a cage filled with a loaded morselized graft could be an alternative for the massive cortical graft in reconstruction of large diaphyseal defects in an animal model.

Topics: Animals; Bone Nails; Bone Transplantation; Diaphyses; Female; Femur; Goats; Models, Animal; Necrosis; Osseointegration; Osteotomy; Range of Motion, Articular; Recovery of Function; Surgical Mesh; Time Factors; Torque; Transplantation, Autologous; Walking; Weight-Bearing

The purpose of this study was to test the hypothesis that an increase in plasma creatine kinase (CK) activity after eccentric contractions (ECC) would be attenuated in regenerated muscle fibres. Adult male Wistar rats (aged 12-14 weeks) were randomly assigned to a treatment group (n = 14) or a control group (n = 10). In the treatment group, 1.2% barium chloride solution (BaCl2) was injected into the tibialis anterior (TA) and extensor digitorum longus (EDL) muscles to induce degeneration and subsequent regeneration. The same amount of isotonic saline solution was injected into TA and EDL for the control group. Histological observation showed that approximately 50% of the fibres in the transverse sections of both muscles underwent necrosis 2 days after BaCl2 injection. The CK activity increased about tenfold at 2-4 h after BaCl2 injection. At 4 weeks after BaCl2 injection, when the regeneration process was almost complete, the TA and EDL of anaesthetized rats from both groups were subjected to ECC in which maximal dorsiflexion was caused by nerve electrical stimulation and the flexed foot was forcibly extended by a lever arm connected to a motor. This action was performed in 2 sets of 30 repetitions. Maximal isometric torque of the dorsiflexors decreased to about 15% (P < 0.01) of the pre-ECC value immediately after the exercise. Blood samples were collected before and 2, 4, 12, 24, 48 h after ECC. The CK activity increased significantly (P < 0.01) and peaked at 2-4 h after ECC, and there was no significant difference in the amount of CK increase between the treatment [1007 (SEM 120) IU.l-1] and the control [1064 (SEM 120) IU.l-1] group. Contrary to the hypothesis, CK release after ECC was not attenuated in muscle regenerated from BaCl2-induced myonecrosis.

Topics: Animals; Barium Compounds; Chlorides; Creatine Kinase; Isometric Contraction; Male; Muscle Contraction; Muscle, Skeletal; Necrosis; Rats; Rats, Wistar; Regeneration; Torque