LXRs regulate features of age-related macular degeneration and may be a potential therapeutic target.

Effective treatments and animal models for the most prevalent neurodegenerative form of blindness in elderly people, called age-related macular degeneration (AMD), are lacking. Genome-wide association studies have identified lipid metabolism and inflammation as AMD-associated pathogenic pathways. Given liver X receptors (LXRs), encoded by the nuclear receptor subfamily 1 group H members 2 and 3 (NR1H3 and NR1H2), are master regulators of these pathways, herein we investigated the role of LXR in human and mouse eyes as a function of age and disease and tested the therapeutic potential of targeting LXR. We identified immunopositive LXR fragments in human extracellular early dry AMD lesions and a decrease in LXR expression within the retinal pigment epithelium (RPE) as a function of age. Aged mice lacking LXR presented with isoform-dependent ocular pathologies. Specifically, loss of the Nr1h3 isoform resulted in pathobiologies aligned with AMD, supported by compromised visual function, accumulation of native and oxidized lipids in the outer retina, and upregulation of ocular inflammatory cytokines, while absence of Nr1h2 was associated with ocular lipoidal degeneration. LXR activation not only ameliorated lipid accumulation and oxidant-induced injury in RPE cells but also decreased ocular inflammatory markers and lipid deposition in a mouse model, thereby providing translational support for pursuing LXR-active pharmaceuticals as potential therapies for dry AMD.

Compartment Syndrome of the Flexor Compartment of the Arm Secondary to Pectoralis Major Tendon Rupture.

Case. Compartment syndrome following muscle rupture is a rare entity with few mentions in the literature. We present a case of pectoralis major rupture in a 38-year-old male that evolved into compartment syndrome of the anterior compartment of the arm. Rupture of the pectoralis is uncommon and most often occurs during weight lifting. Compartment syndrome secondary to this injury is extremely uncommon, with only one reported case in the pectoralis major itself and several cases of biceps compartment syndrome. Due to the potentially devastating consequences of a missed compartment syndrome, it is imperative that physicians maintain a high level of suspicion in patients with these unusual injuries presenting with severe swelling and pain.

Quick-freeze/deep-etch electron microscopy visualization of the mouse posterior pole.

The mouse is one of the most commonly used mammalian systems to study human diseases. In particular it has been an invaluable tool to model a multitude of ocular pathologies affecting the posterior pole. The aim of this study was to create a comprehensive map of the ultrastructure of the mouse posterior pole using the quick-freeze/deep-etch method (QFDE). QFDE can produce detailed three-dimensional images of tissue structure and macromolecular moieties, without many of the artifacts introduced by structure-altering post-processing methods necessary to perform conventional transmission electron microscopy (cTEM). A total of 18 eyes from aged C57BL6/J mice were enucleated and the posterior poles were processed, either intact or with the retinal pigment epithelium (RPE) cell layer removed, for imaging by either QFDE or cTEM. QFDE images were correlated with cTEM cross-sections and en face images through the outer retina. Nicely preserved outer retinal architecture was observed with both methods, however, QFDE provided excellent high magnification imaging, with greater detail, of the apical, central, and basal planes of the RPE. Furthermore, key landmarks within Bruch's membrane, choriocapillaris, choroid and sclera were characterized and identified. In this study we developed methods for preparing the outer retina of the mouse for evaluation with QFDE and provide a map of the ultrastructure and cellular composition of the outer posterior pole. This technique should be applicable for morphological evaluation of mouse models, in which detailed visualization of subtle ocular structural changes is needed or in cases where post-processing methods introduce unacceptable artifacts.

Flow-Induced Crystallization of Collagen: A Potentially Critical Mechanism in Early Tissue Formation.

The type I collagen monomer is one of nature's most exquisite and prevalent structural tools. Its 300 nm triple-helical motifs assemble into tough extracellular fibers that transition seamlessly across tissue boundaries and exceed cell dimensions by up to 4 orders of magnitude. In spite of extensive investigation, no existing model satisfactorily explains how such continuous structures are generated and grown precisely where they are needed (aligned in the path of force) by discrete, microscale cells using materials with nanoscale dimensions. We present a simple fiber drawing experiment, which demonstrates that slightly concentrated type I collagen monomers can be "flow-crystallized" to form highly oriented, continuous, hierarchical fibers at cell-achievable strain rates (<1 s(-1)) and physiologically relevant concentrations (∼50 µM). We also show that application of tension following the drawing process maintains the structural integrity of the fibers. While mechanical tension has been shown to be a critical factor driving collagen fibril formation during tissue morphogenesis in developing animals, the precise role of force in the process of building tissue is not well understood. Our data directly couple mechanical tension, specifically the extensional strain rate, to collagen fibril assembly. We further derive a "growth equation" which predicts that application of extensional strains, either globally by developing muscles or locally by fibroblasts, can rapidly drive the fusion of already formed short fibrils to produce long-range, continuous fibers. The results provide a pathway to scalable connective tissue manufacturing and support a mechano-biological model of collagen fibril deposition and growth in vivo.

Spinal cord injuries without radiologic abnormality in children: a systematic review.

STUDY DESIGN: Systematic review. OBJECTIVES: The objective of this study is to systematically review the literature for pediatric cases of spinal cord injuries without radiologic abnormality (SCIWORA) to investigate any possible relationship between initial neurologic impairment and eventual neurologic status. SETTING: A university department of orthopedics. METHODS: Following the preferred reporting items for systemic reviews and meta-analysis (PRISMA) guidelines for systematic review, the databases of PubMed and OvidSP were electronically searched for articles that use individuals under 18 years old, have trauma resulting in spinal cord injury and have no fractures or dislocations on radiographs. When available, the patients' age, sex, mechanism of injury and spinal cord level were recorded. Individuals with cervical injury, who had specific information on cervical level and mechanism of injury, were recorded as well. Patients who reported specific magnetic resonance imaging findings and the time from the injury were also reported. When possible, the American Spinal Injury Association Impairment Scale (AIS) was determined initially after the injury and then at last follow-up. RESULTS: A total of 433 pediatric patients were identified with SCIWORA. The most prevalent mechanism of injury was sports-related injury cases (39.83%) followed by fall (24.18%) and motor vehicle-related (23.18%) injuries. The mean improvement recorded for all patients was 0.89 AIS grades. CONCLUSION: The most common mechanism of injury was sports-related and cervical injury, which occurred more frequently than other levels. Initial AIS grade A showed poorer outcomes in the pediatric population compared with the adult population. Initial presentation of D showed the highest likelihood of no permanent neurologic impairment (AIS of E).

Spondylolysis originates in the ventral aspect of the pars interarticularis: a clinical and biomechanical study.

Lumbar spondylolysis is a stress fracture of the pars interarticularis. We have evaluated the site of origin of the fracture clinically and biomechanically. Ten adolescents with incomplete stress fractures of the pars (four bilateral) were included in our study. There were seven boys and three girls aged between 11 and 17 years. The site of the fracture was confirmed by axial and sagittal reconstructed CT. The maximum principal tensile stresses and their locations in the L5 pars during lumbar movement were calculated using a three-dimensional finite-element model of the L3-S1 segment. In all ten patients the fracture line was seen only at the caudal-ventral aspect of the pars and did not spread completely to the craniodorsal aspect. According to the finite-element analysis, the higher stresses were found at the caudal-ventral aspect in all loading modes. In extension, the stress was twofold higher in the ventral than in the dorsal aspect. Our radiological and biomechanical results were in agreement with our clinical observations.

Decreased osteoclastogenesis and high bone mass in mice with impaired insulin clearance due to liver-specific inactivation to CEACAM1.

Type 2 diabetes is associated with normal-to-higher bone mineral density (BMD) and increased rate of fracture. Hyperinsulinemia and hyperglycemia may affect bone mass and quality in the diabetic skeleton. In order to dissect the effect of hyperinsulinemia from the hyperglycemic impact on bone homeostasis, we have analyzed L-SACC1 mice, a murine model of impaired insulin clearance in liver causing hyperinsulinemia and insulin resistance without fasting hyperglycemia. Adult L-SACC1 mice exhibit significantly higher trabecular and cortical bone mass, attenuated bone formation as measured by dynamic histomorphometry, and reduced number of osteoclasts. Serum levels of bone formation (BALP) and bone resorption markers (TRAP5b and CTX) are decreased by approximately 50%. The L-SACC1 mutation in the liver affects myeloid cell lineage allocation in the bone marrow: the (CD3(-)CD11b(-)CD45R(-)) population of osteoclast progenitors is decreased by 40% and the number of (CD3(-)CD11b(-)CD45R(+)) B-cell progenitors is increased by 60%. L-SACC1 osteoclasts express lower levels of c-fos and RANK and their differentiation is impaired. In vitro analysis corroborated a negative effect of insulin on osteoclast recruitment, maturation and the expression levels of c-fos and RANK transcripts. Although bone formation is decreased in L-SACC1 mice, the differentiation potential and expression of the osteoblast-specific gene markers in L-SACC1-derived mesenchymal stem cells (MSC) remain unchanged as compared to the WT. Interestingly, however, MSC from L-SACC1 mice exhibit increased PPARgamma2 and decreased IGF-1 transcript levels. These data suggest that high bone mass in L-SACC1 animals results, at least in part, from a negative regulatory effect of insulin on bone resorption and formation, which leads to decreased bone turnover. Because low bone turnover contributes to decreased bone quality and an increased incidence of fractures, studies on L-SACC1 mice may advance our understanding of altered bone homeostasis in type 2 diabetes.

Minimally invasive decompression for lumbar spinal canal stenosis in younger age patients could lead to higher stresses in the remaining neural arch -- a finite element investigation.

BACKGROUND AND PURPOSE: A young patient group with the symptoms of acquired spinal stenosis has been identified recently in the literature. The patients between 25-50 years of age were found to have signs of lumbar spinal stenosis because of degenerative spinal changes. Some of them were operated on using the same limited decompression approaches as the older patients. However, this group differs from the geriatric population due to the scarcity of remodeling degenerative signs at the spine. Therefore, the possible ligamentous laxity, facet joint degeneration or only the removal of some spinal structures could lead to the increased stresses in the remaining spinal arch and could have an unfavorable course of events after the procedure. A biomechanical study has been done using an experimentally validated finite element model (FEM) of the intact L3-S1 lumbar spine to elucidate the influence of the limited decompression on range of motion (ROM) and stress distribution on the neural arch in this patient group. METHODS: We simulated unilateral laminotomy L4 and medial facetectomy L4-5, medial facetectomy L4-5 and lateral fenestration of L5 pars interarticularis, combined transarticular lateral and medial approach with partial facetectomy L4-5, "port-hole" decompression at the L4 level, and hemilaminectomy L4 with medial facetectomy L4-5. The ROM and maximum von Mises stresses were analyzed in flexion, extension, lateral bending, and axial rotation in response to a 10.6 Nm moment with 400 N axial compression. The data were compared with the intact spine and hemilaminectomy L4 with medial facetectomy L4-5 models. RESULTS AND CONCLUSION: The investigation revealed almost the same ROM after simulation but a considerable increase in stresses at both the pars interarticularis and the inferior facet after limited decompressions, especially in extension and rotation to the contralateral side. Stresses at the contralateral L4 pedicle were highest after L4 hemilaminectomy and medial facetectomy L4-5. Due to the observed increases in stresses, the surgeon should be aware of the possibilities of stress-fractures in this patient group.

Three-dimensional volume rendering of tibiofibular joint space and quantitative analysis of change in volume due to tibiofibular syndesmosis diastases.

OBJECTIVE: The diagnosis of ankle syndesmosis injuries is made by various imaging techniques. The present study was undertaken to examine whether the three-dimensional reconstruction of axial CT images and calculation of the volume of tibiofibular joint space enhances the sensitivity of diastases diagnoses or not. DESIGN: Six adult cadaveric ankle specimens were used for spiral CT-scan assessment of tibiofibular syndesmosis. After the specimens were dissected, external fixation was performed and diastases of 1, 2, and 3 mm was simulated by a precalibrated device. Helical CT scans were obtained with 1.0-mm slice thickness. The data was transferred to the computer software AcquariusNET. Then the contours of the tibiofibular syndesmosis joint space were outlined on each axial CT slice and the collection of these slices were stacked using the computer software AutoCAD 2005, according to the spatial arrangement and geometrical coordinates between each slice, to produce a three-dimensional reconstruction of the joint space. The area of each slice and the volume of the entire tibiofibular joint space were calculated. The tibiofibular joint space at the 10th-mm slice level was also measured on axial CT scan images at normal, 1, 2 and 3-mm joint space diastases. RESULTS: The three-dimensional volume-rendering of the tibiofibular syndesmosis joint space from the spiral CT data demonstrated the shape of the joint space and has been found to be a sensitive method for calculating joint space volume. We found that, from normal to 1 mm, a 1-mm diastasis increases approximately 43% of the joint space volume, while from 1 to 3 mm, there is about a 20% increase for each 1-mm increase. CONCLUSIONS: Volume calculation using this method can be performed in cases of syndesmotic instability after ankle injuries and for preoperative and postoperative evaluation of the integrity of the tibiofibular syndesmosis.

Biomechanical comparison of lumbar spine with or without spina bifida occulta. A finite element analysis.

STUDY DESIGN: Biomechanical study using finite element model (FEM) of lumbar spine. OBJECTIVES: Very high coincidence of spina bifida occulta (SBO) has been reported more than in 60% of lumbar spondylolysis. The altered biomechanics due to SBO is one considerable factor for this coincidence. Thus, in this study, the biomechanical changes in the lumbar spine due to the presence of SBO were evaluated. SETTING: United States of America (USA). METHODS: An experimentally validated three-dimensional nonlinear FEM of the intact ligamentous L3-S1 segment was used and modified to simulate two kinds of SBO at L5. One model had SBO with no change in the length of the spinous process and the other had a small dysplastic spinous process. Von Mises stresses at pars interarticularis were analyzed in the six degrees of lumbar motion with 400 N axial compression, which simulates the standing position. The range of motion at L4/5 and L5/S1 were also calculated. RESULTS: It was observed that the stresses in all the models were similar, and there was no change in the highest stress value when compared to the intact model. The range of motion was also similar in all the models. The lumbar kinematics of SBO was thus shown to be similar to the intact model. CONCLUSION: SBO does not alter lumbar biomechanics with respect to stress and range of motion. The high coincidence of spondylolysis in spines with SBO may not be due to the mechanical factors.

Biomechanical rationale of endoscopic decompression for lumbar spondylolysis as an effective minimally invasive procedure - a study based on the finite element analysis.

We evaluated the biomechanical behavior of the endoscopic decompression for lumbar spondylolysis using the finite element technique. An experimentally validated, 3-dimensional, non-linear finite element model of the intact L3 - 5 segment was modified to create the L4 bilateral spondylolysis and left-sided endoscopic decompression. The model of Gill's laminectomy (conventional decompression surgery of the spondylolysis) was also created. The stress distributions in the disc and endplate regions were analyzed in response to 400 N compression and 10.6 Nm moment in clinically relevant modes. The results were compared among three models. During the flexion motion, the pressure in the L4/5 nucleus pulposus was 0.09, 0.09 and 0.16 (MPa) for spondylolysis, endoscopic decompression and Gill's procedure, respectively. The corresponding stresses in the annulus fibrosus were 0.65, 0.65 and 1.25 (MPa), respectively. The stress at the adjoining endplates showed an about 2-fold increase in the Gill's procedure compared to the other two models. The stress values for the endoscopic and spondylolysis models were of similar magnitudes. In the other motions, i. e., extension, lateral bending, or axial rotation, the results were similar among all of the models. These results indicate that the Gill's procedure may lead to an increase in intradiscal pressure (IDP) and other biomechanical parameters after the surgery during flexion, whereas the endoscopic decompression did not change the segment mechanics after the surgery, as compared to the spondylolysis alone case. In conclusion, endoscopic decompression of the spondylolysis, as a minimally invasive surgery, does not alert mechanical stability by itself.

Role of mechanical factors in the evaluation of pedicle screw type spinal fixation devices.

Prior to implantation, spinal implants are subjected to rigorous testing to ensure safety and efficacy. A full battery of tests for the devices may include many steps ranging from biocompatibility tests to in vivo animal studies. This paper describes some of the essential tests from a mechanical engineering perspective (e.g., motion, load sharing, bench type tests, and finite element model analyses). These protocols reflect the research experience of the past decade or so.

Kinematics of the human pelvis following open book injury.

The objective of this study is to determine the three dimensional kinematics of the human pelvis including both sacroiliac joints following a simulated open book injury induced on cadavers by applying anterior-posterior compressive loads to the pelvis. An electromagnetic digitizing and motion tracking system was utilized to measure the morphology of the pelvis and the relative movements of its bones during this simulated open book fracture. The screw displacement axis method was used to describe the relative motion between the sacrum and each hipbone. Morphologically, it was found that the articular surfaces forming the sacroiliac joints could be approximated with planar surfaces directed from proximal and lateral to distal and medial and from posteromedial to anterolateral. The kinematic data obtained from this study indicate that there is a direct correlation between the opening of the symphysis pubis and the opening of the sacroiliac joint (SIJ) during open book injury. This suggests that the extent of injury of the SIJ maybe estimated from the degree of opening of the symphysis pubis as demonstrated on anteroposterior (A-P) x-rays. The results obtained from this study also indicate that the motion of the hipbone with respect to the sacrum on the side of the sacroiliac joint opening is almost a pure rotation, which translates clinically on the A-P x-rays as pure opening of the SIJ without vertical displacement. The average axis of rotation was found to be almost parallel to the SIJ planar articular surface. Furthermore, the pubic bone on the side of SIJ opening was found to displace inferiorly and posteriorly. One can thus conclude that in open book pelvic injuries, the pubic bone on the side of injury displaces inferiorly on the outlet projection x-rays with no vertical displacement of the SIJ. This is important since the initial assessment of the open book injury in the emergency room includes outlet projection x-rays. From this study, the relative vertical positions of the pubic bones on these x-rays can help the surgeon in differentiating open book fracture injury from other pelvic injuries.

Identification of the anterior and posterior portions of the lateral pedicle cortex by roentgenograms in pedicle screw fixation.

Forty lumbar pedicles and pedicle screws in four cadavers were used to identify the anterior and posterior portions of the lumbar pedicle cortex by roentgenograms in order to evaluate the penetration of the pedicle cortex by pedicle screws intraoperatively. Firstly, the transverse pedicle angles were measured on roentgenograms. Three roentgenograms were taken on each pedicle in three different directions: (1). medial to the pedicle axis; (2). pedicle axis; (3). lateral to the pedicle axis. They revealed that the anterior portion of the lateral pedicle cortex was demonstrated by the pedicle lateral outline on the roentgenogram medial to the pedicle axis, and the posterior portion by the pedicle lateral outline on the roentgenogram lateral to the pedicle axis. Wire markers were used to confirm these data. Finally, anterior and/or posterior penetrations on the lateral pedicle cortex in pedicle screw fixation were studied by roentgenograms in these cadavers and showed that anterior penetration of lateral cortex was demonstrated by the view medial to the pedicle axis, and posterior penetration by the view lateral to the pedicle axis. It is concluded that projections medical and lateral to the pedicle axis are necessary to identify lateral screw penetration intraoperatively when X-ray checking is used.

Radiographic evaluation of transverse sacral fractures.

This study clarifies the pattern of fracture lines and facilitates diagnosis of transverse sacral fracture on plain radiographic images. Eight cadaveric sacra were used in this study. A U-shaped transverse sacral fracture at the S2-S3 level was created in all specimens. The fracture line was marked by painting with radio-opaque material and solder metal wires. The following radiographic views were taken: anteroposterior, lateral, AP with 35 degrees cephalad orientation, and inlet view. A double shadow in the upper sacral area can be identified in the plain AP view. As a consequence of the fracture, there are changes in the orientation of the planes of the foramina from the coronal to, more or less, axial plane. Anteroposterior with 35 degrees cephalad orientation radiographs provide good assessment for evaluation of the transverse sacral fracture.

Tosic external fixator in the management of proximal tibial fractures in adults.

This retrospective clinical study assessed proximal tibial fractures managed with the Tosic external fixator. Nineteen patients with 21 proximal tibial fractures treated with the Tosic external fixator between July 1997 and October 1998 comprised the study population. Eleven fractures were graded as 41A2, 3 fractures as 41 A3, 4 fractures as 41C1, and 3 fractures as 41 C2. Fourteen fractures were closed, and 7 fractures were open. Average time to healing was 1 7 weeks. No revision of fixation was needed. There were five cases of pin tract infection. Average range of knee motion was 2 degrees-135 degrees. These results indicate the Tosic external fixator is an efficient and simple way to treat proximal tibial metaphyseal fractures.

Bone-graft harvesting from iliac and fibular donor sites: techniques and complications.

The ilium and the fibula are the most common sites for bone-graft harvesting. The different methods for harvesting iliac bone graft include curettage, trapdoor or splitting techniques for cancellous bone, and the subcrestal-window technique for bicortical graft. A tricortical graft from the anterior ilium should be taken at least 3 cm posterior to the anterior superior iliac spine (ASIS). Iliac donor-site complications include pain, neurovascular injury, avulsion fractures of the ASIS, hematoma, infection, herniation of abdominal contents, gait disturbance, cosmetic deformity, violation of the sacroiliac joint, and ureteral injury. The neurovascular structures at risk for injury during iliac bone-graft harvesting include the lateral femoral cutaneous, iliohypogastric, and ilioinguinal nerves anteriorly and the superior cluneal nerves and superior gluteal neurovascular bundle posteriorly. Violation of the sacroiliac joint can be avoided by limiting the harvested area to 4 cm from the posterior superior iliac spine (PSIS) and by not penetrating the inner cortex. The caudal limit for bone harvesting should be the inferior margin of the roughened area anterior to the PSIS on the outer table to keep from injuring the superior gluteal artery. Potential complications of fibular graft harvesting include neurovascular injury, compartment syndrome, extensor hallucis longus weakness, and ankle instability. The neurovascular structures at risk for injury during fibular bone-graft harvesting include the peroneal nerves and their muscular branches in the proximal third of the fibular shaft and the peroneal vessels in the middle third.

Bone density of the first sacral vertebra in relation to sacral screw placement: a computed tomography study.

A visual three-dimensional image of the first sacral vertebra was constructed using computer software to predict the sites of strong density for better screw purchase of upper sacrum. Forty dry sacrum specimens were scanned in the prone position. An axial section, 10 mm below the S1 end plate, was selected for determining density at the region of interest. All images were stored on an optic disc and studied using the NIH Image 1.61 program. Plot analysis assessed the bone density in different regions. Also, three-dimensional pictures of the different screw paths and the related bone density in the upper sacrum were analyzed. Bone density in the anterolateral part of S1 was 115.1 +/- 10.4 pixel. Bone density for males (-99.7 +/- 11.3) was greater than for females (-131.4 +/- 9.6). Bone density in the anterolateral alar region was -108 +/- 10.6. The bone density for males (-95.6 +/- 9.8) and females (121.4 +/- 11.7) was more than the body region. Bone density in the middle anterior cortex of the ala was 759.8 +/- 11.6. Bone density for males (878.2 +/- 10.7) was greater than for females (637.6 +/- 11.9). Using surface plot, the midanterior cortex of the ala had high cortical density compared with other areas. The midanterior cortex of the sacral ala had the highest bone density. Sacral screw purchase in the midanterior cortex provides better mechanical fixation.

Intramedullary fibular graft for tibiotalocalcaneal arthrodesis.

The intramedullary fibular graft was used in four patients for tibiotalocalcaneal fusion. There were three men and one woman. The average age was 49.7 years (range, 35-73 years). The initial injuries were three pilon fractures and one ankle fracture. Tibiotalocalneal arthrodesis was performed as a salvage procedure for patients with significant posttraumatic arthritis of the ankle, concomitant subtalar arthritis, and severe osteopenia. The average followup was 28 months (range, 24-31 months). All the patients had successful arthrodesis and were satisfied with the outcome results. The average preoperative American Orthopaedic Foot And Ankle Society ankle-hindfoot score for the whole group was 49.5 (range, 44-54) and improved postoperatively to 78.5 (range, 71-81). Three patients had a good score and one patient had a fair score. There was no postoperative infection or fracture of the graft.