Simon C. Mears

Inhibition of TGF-β signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis

Osteoarthritis is a highly prevalent and debilitating joint disorder. There is no effective medical therapy for the condition because of limited understanding of its pathogenesis. We show that transforming growth factor β1 (TGF-β1) is activated in subchondral bone in response to altered mechanical loading in an anterior cruciate ligament transection (ACLT) mouse model of osteoarthritis. TGF-β1 concentrations are also high in subchondral bone from humans with osteoarthritis. High concentrations of TGF-β1 induced formation of nestin-positive mesenchymal stem cell (MSC) clusters, leading to formation of marrow osteoid islets accompanied by high levels of angiogenesis. We found that transgenic expression of active TGF-β1 in osteoblastic cells induced osteoarthritis, whereas inhibition of TGF-β activity in subchondral bone attenuated the degeneration of articular cartilage. In particular, knockout of the TGF-β type II receptor (TβRII) in nestin-positive MSCs led to less development of osteoarthritis relative to wild-type mice after ACLT. Thus, high concentrations of active TGF-β1 in subchondral bone seem to initiate the pathological changes of osteoarthritis, and inhibition of this process could be a potential therapeutic approach to treating this disease.Osteoarthritis is a highly prevalent and debilitating joint disorder. There is no effective medical therapy for osteoarthritis due to limited understanding of osteoarthritis pathogenesis. We show that TGF–β1 is activated in the subchondral bone in response to altered mechanical loading in an anterior cruciate ligament transection (ACLT) osteoarthritis mouse model. TGF–β1 concentrations also increased in human osteoarthritis subchondral bone. High concentrations of TGF–β1 induced formation of nestin+ mesenchymal stem cell (MSC) clusters leading to aberrant bone formation accompanied by increased angiogenesis. Transgenic expression of active TGF–β1 in osteoblastic cells induced osteoarthritis. Inhibition of TGF–β activity in subchondral bone attenuated degeneration of osteoarthritis articular cartilage. Notably, knockout of the TGF–β type II receptor (TβRII) in nestin+ MSCs reduced development of osteoarthritis in ACLT mice. Thus, high concentrations of active TGF–β1 in the subchondral bone initiated the pathological changes of osteoarthritis, inhibition of which could be a potential therapeutic approach.

Sedation Depth During Spinal Anesthesia and the Development of Postoperative Delirium in Elderly Patients Undergoing Hip Fracture Repair

OBJECTIVE To determine whether limiting intraoperative sedation depth during spinal anesthesia for hip fracture repair in elderly patients can decrease the prevalence of postoperative delirium. PATIENTS AND METHODS We performed a double-blind, randomized controlled trial at an academic medical center of elderly patients (>or=65 years) without preoperative delirium or severe dementia who underwent hip fracture repair under spinal anesthesia with propofol sedation. Sedation depth was titrated using processed electroencephalography with the bispectral index (BIS), and patients were randomized to receive either deep (BIS, approximately 50) or light (BIS, >or=80) sedation. Postoperative delirium was assessed as defined by Diagnostic and Statistical Manual of Mental Disorders (Third Edition Revised) criteria using the Confusion Assessment Method beginning at any time from the second day after surgery. RESULTS From April 2, 2005, through October 30, 2008, a total of 114 patients were randomized. The prevalence of postoperative delirium was significantly lower in the light sedation group (11/57 [19%] vs 23/57 [40%] in the deep sedation group; P=.02), indicating that 1 incident of delirium will be prevented for every 4.7 patients treated with light sedation. The mean +/- SD number of days of delirium during hospitalization was lower in the light sedation group than in the deep sedation group (0.5+/-1.5 days vs 1.4+/-4.0 days; P=.01). CONCLUSION The use of light propofol sedation decreased the prevalence of postoperative delirium by 50% compared with deep sedation. Limiting depth of sedation during spinal anesthesia is a simple, safe, and cost-effective intervention for preventing postoperative delirium in elderly patients that could be widely and readily adopted.

Predisposing factors for postoperative delirium after hip fracture repair in individuals with and without dementia.

Based on a multifactorial model of delirium, to compare the types and magnitude of pre‐ and intraoperative predisposing factors for incident delirium in a stratified sample of individuals with and without preoperative dementia undergoing acute hip fracture repair.

Antibodies to myelin-associated glycoprotein accelerate preferential motor reinnervation.

Abstract  Predegeneration of nerve enhances its ability to support axon regeneration. Trophic factors are upregulated by reactive Schwann cells while potentially inhibitory molecules are removed. These experiments isolate the effects of one such inhibitory molecule, the myelin‐associated glycoprotein (MAG), to determine its role in modifying regeneration after nerve repair. Suture of the mouse femoral nerve was followed by daily intraperitoneal injection of antibodies to MAG, antibodies to HNK‐1, a specific muscle pathway marker, or no further treatment. Regeneration was assayed by double‐labeling the femoral cutaneous and muscle branches with horseradish peroxidase and fluoro‐gold after 4 weeks or 6 weeks of regeneration. Four weeks after nerve repair, selective reinnervation of the muscle branch by motoneurons, or preferential motor reinnervation (PMR), was not seen in either controls or L2‐antibody‐treated animals. In contrast, treatment with MAG antibodies resulted in dramatic PMR. By 6 weeks, the controls had achieved borderline specificity, substantial PMR developed in the L2 antibody group and the MAG group changed little. Blocking access to MAG in the distal nerve stump thus accelerated and enhanced PMR. Sensory regeneration was depressed by both antibody treatments at 4 weeks but recovered by 6 weeks. Antibody administration has a generalized effect on sensory regeneration that is unrelated to the behavior of motoneurons in the same nerve.

Postoperative Opioid Consumption and Its Relationship to Cognitive Function in Older Adults with Hip Fracture

To determine the relationship between opioid consumption and cognitive impairment after hip fracture repair.

Suture-Button versus Screw Fixation in a Syndesmosis Rupture Model: A Biomechanical Comparison

Background: Flexible suture-button devices are used to stabilize the distal tibiofibular joint after syndesmotic rupture, but little is known about how they affect fibular motion during cyclic physiological loading. This study examined how much fibular motion occurs during cyclic loading of ankles repaired with suture-buttons or screws relative to one with intact ligaments. Materials and Methods: Ten pairs of cadaveric legs with intact ligaments were tested in axial compression (750 N), external rotational torque (7.5 Nm), and a combination thereof. Fibular rotation and translation in the sagittal and frontal planes were measured with linear variable displacement transducers. Then we sectioned the anterior tibiofibular, posterior tibiofibular, deltoid, and interosseous ligaments. Ankles were repaired with suture-buttons or a 3.5-mm screw through four-cortices. The ankles were tested for 10,000 cycles using the same loading protocol. Surviving ankles were brought to failure by increasing external rotation (1 degree/sec). Data from the linear variable differential transducers were used to calculate fibular motion at 100, 1,000, 5,000, and 10,000 cycles. Results: There was no significant difference in the effect of the suture-button or screw for translation in the sagittal or coronal plane or for rotation about the fibular axis. The screw repair had a significantly greater (p = 0.02) failure torque (median, 26.5 Nm; inner quartile range, 25.7 to 35.2 Nm) than did the suture-button repair (median, 23.6 Nm; inner quartile range, 16.5 to 25.6 Nm). Conclusion: The fibular motion that occurs during cyclic loading appears to be similar for the suture-button and syndesmotic screw. Motion in both constructs was similar, but neither restored native ankle motion. Clinical Relevance: It appears the suture-button behaves similarly to the syndesmotic screw in the syndesmotic rupture injury model tested. Clinical trials are needed to determine how the device performs in vivo.

Design of a new cable-driven manipulator with a large open lumen: Preliminary applications in the minimally-invasive removal of osteolysis

A dexterous manipulator (DM) with a large open lumen is presented. The manipulator is designed for surgical applications with a preliminary focus on the removal of osteolysis formed behind the acetabular shell of primary total hip arthroplasties (THAs). The manipulator is constructed from two nested superelastic nitinol tubes enabling lengthwise channels for drive cables. Notches in the nested assembly provide reliable bending under applied cable tension producing kinematics that can be effectively modeled as a series of rigid vertebrae connected using pin joints. The manipulator is controlled in plane with two independently actuated cables in a pull-pull configuration. For the purpose of the procedure, the manipulator is mounted on a Z-θ stage adding a translational and rotational degree of freedom (DOF) along the axis of the manipulator. Preliminary experimental results demonstrate the initial modeling and control of the manipulator.

Knee arthrotomy repair with a continuous barbed suture: a biomechanical study.

We compared knee arthrotomy closures using interrupted biodegradable sutures and running bidirectionally barbed sutures in cadaveric specimens subjected to cyclic loading. During the initial 2000 flexion cycles, both groups maintained closure and no suture ruptured. Suture throws were then sequentially cut to weaken the repairs, and the knees were cyclically flexed after each cut. Both types of suture repairs survived the cutting of the first throw or stitch and subsequent cyclical testing. However, there was a significant difference in the repairs after multiple cuts (log-rank test, P < .003). None of the knees in the interrupted suture group survived more than 3 cuts, whereas in the barbed repair group, it took the severing of as many as 7 throws for failure to occur.

Analysis of published evidence on minimally invasive total hip arthroplasty.

Minimally invasive surgery has become a popular method of total hip arthroplasty. This study reviewed the literature to determine the number and quality of scientific publications analyzing different types of minimally invasive surgery approaches. The miniposterior approach has been studied the most and to our knowledge is the only approach with good quality randomized control study evidence. The overall length of follow-up and quality of reports for minimally invasive total hip arthroplasty is low.

Three-dimensional mechanical evaluation of joint contact pressure in 12 periacetabular osteotomy patients with 10-year follow-up

Background and purpose Because of the varying structure of dysplastic hips, the optimal realignment of the joint during periacetabular osteotomy (PAO) may differ between patients. Three-dimensional (3D) mechanical and radiological analysis possibly accounts better for patient-specific morphology, and may improve and automate optimal joint realignment. Patients and methods We evaluated the 10-year outcomes of 12 patients following PAO. We compared 3D mechanical analysis results to both radiological and clinical measurements. A 3D discrete-element analysis algorithm was used to calculate the pre- and postoperative contact pressure profile within the hip. Radiological angles describing the coverage of the joint were measured using a computerized approach at actual and theoretical orientations of the acetabular cup. Quantitative results were compared using postoperative clinical evaluation scores (Harris score), and patient-completed outcome surveys (q-score) done at 2 and 10 years. Results The 3D mechanical analysis indicated that peak joint contact pressure was reduced by an average factor of 1.7 subsequent to PAO. Lateral coverage of the femoral head increased in all patients; however, it did not proportionally reduce the maximum contact pressure and, in 1 case, the pressure increased. This patient had the lowest 10-year q-score (70 out of 100) of the cohort. Another hip was converted to hip arthroplasty after 3 years because of increasing osteoarthritis. Interpretation The 3D analysis showed that a reduction in contact pressure was theoretically possible for all patients in this cohort, but this could not be achieved in every case during surgery. While intraoperative factors may affect the actual surgical outcome, the results show that 3D contact pressure analysis is consistent with traditional PAO planning techniques (more so than 2D analysis) and may be a valuable addition to preoperative planning and intraoperative assessment of joint realignment.