Mechanically-induced osteophyte in the rat knee.

OBJECTIVES: Osteophytes are common anatomical signs of advanced osteoarthritis. It remains unclear whether they develop from physio-molecular, and/or mechanical stimuli. This study examined the effects of mechanical impact on the knee joint periosteum leading to osteophyte formation. DESIGN: Eighteen mature rats received one single impact load of 53 N (30 MPa) to the periosteum of the experimental medial femoral condyles. Contralateral knees were used as controls. Animals were sacrificed at 24 h, 3, 6 and 9 weeks post-impact. Distal femurs were harvested and prepared for histology. Hematoxylin and Eosin, and Masson's trichrome stained slides were examined by light microscopy. Nuclear density was quantified to assess the tissue reaction. RESULTS: 24 h: The synovium membrane, fibrous and cambium periosteum were damaged. Blood infiltration pooled in the impacted medial collateral ligament (MCL) region. Week 3: A cartilaginous tissue spur, chondrophyte, was found in every rat at the impacted site of the MCL. Chondrophytes were composed of fibrocartilage and cartilage matrix, with signs of cartilage mineralization and remodelling activity. Week 6: Chondrophytes presented signs of more advanced mineralisation, recognized as osteophytes. Week 9: Osteophytes appeared to be more mineralized with almost no cartilage tissue. CONCLUSIONS: Osteophytes can be induced with a single mechanical impact applied to the periosteum in rat knees. These data indicate that a moderate trauma to the periosteal layer of the joint may play a role in osteophyte development.

Negative regulators of programed cell death.

During animal development many cells undergo programed deaths. Recently, genes that suppress the cell-death program have been described in both vertebrates and invertebrates. These genes play a vital role in regulation of the molecules that kill cells, and disruption of this regulatory process can contribute to disease.

Spectrin maintains the lateral order in phosphatidylserine monolayers.

We investigate the effect of the skeletal protein spectrin on the lateral order in dipalmitoyl phosphatidylserine monolayers spread on aqueous surfaces using grazing incidence X-ray diffraction. Without spectrin, the condensed lipid monolayer exhibits two-dimensional hexagonal packing, characterized by monotonic decrease in the d-spacing and increase in the degree of order with increasing surface pressure between 17 and 36 mN/m. Addition of spectrin to the aqueous subphase at high pressures preserves the monolayers structural parameters unchanged from 36 to 25 mN/m. These results demonstrate for the first time that spectrin could participate in sustaining the two-dimensional order in lipid domains through a direct interaction with phosphatidylserine species.

Dynamic simulation of a displacement-controlled total knee replacement wear tester.

This paper presents a dynamic finite element method (FEM) model of a commercial displacement-controlled total knee replacement (TKR) wear tester. The first goal of the study was to validate the model, which included both the wear tester and the TKR components. Convergence simulations and experimental testing were performed. These included a novel experimental determination of the coefficient of friction and an evaluation of predicted joint contact areas by comparing simulation results with experimental data collected using pressure-sensitive film. The second goal of this study was to develop a procedure for implementing force-based testing protocols on a displacement-controlled TKR wear tester. A standard force-based cyclic wear-testing protocol was simulated using the FEM model and resulting displacement waveforms were extracted. These were used as control inputs to the physical wear tester and an experimental wear test was performed. Reaction loads on the tibial components were measured and compared with the simulated results. The model was capable of accurately predicting the tibial loads throughout the test cycle, verifying the model's contact mechanics. The study demonstrated the use of computational modelling to convert a force-based testing protocol into displacement-based control parameters for use in a displacement-controlled mechanical testing system.

A navigation system for shoulder arthroscopic surgery.

The general framework and experimental validation of a novel navigation system designed for shoulder arthroscopy are presented. The system was designed to improve the surgeon's perception of the three-dimensional space within the human shoulder. Prior to surgery, a surface model of the shoulder was created from computed tomography images. Intraoperatively, optically tracked arthroscopic instruments were calibrated. The surface model was then registered to the patient using tracked freehand ultrasound images taken from predefined landmark regions on the scapula. Three-dimensional models of the surgical instruments were displayed, in real time, relative to the surface model in a user interface. Laboratory experiments revealed only small registration and calibration errors, with minimal time needed to complete the intraoperative tasks.

Patellofemoral joint kinematics in individuals with and without patellofemoral pain syndrome.

BACKGROUND: Patellofemoral pain syndrome is a prevalent condition in young people. While it is widely believed that abnormal patellar tracking plays a role in the development of patellofemoral pain syndrome, this link has not been established. The purpose of this cross-sectional case-control study was to test the hypothesis that patterns of patellar spin, tilt, and lateral translation make it possible to distinguish individuals with patellofemoral pain syndrome and clinical evidence of patellar malalignment from those with patellofemoral pain syndrome and no clinical evidence of malalignment and from individuals with no knee problems. METHODS: Three-dimensional patellofemoral joint kinematics in one knee of each of sixty volunteers (twenty in each group described above) were assessed with use of a new, validated magnetic resonance imaging-based method. Static low-resolution scans of the loaded knee were acquired at five different angles of knee flexion (ranging between -4 degrees and 60 degrees). High-resolution geometric models of the patella, femur, and tibia and associated coordinate axes were registered to the bone positions on the low-resolution scans to determine the patellar motion as a function of knee flexion angle. Hierarchical modeling was used to identify group differences in patterns of patellar spin, tilt, and lateral translation. RESULTS: No differences in the overall pattern of patellar motion were observed among groups (p>0.08 for all global maximum likelihood ratio tests). Features of patellar spin and tilt patterns varied greatly between subjects across all three groups, and no significant group differences were detected. At 19 degrees of knee flexion, the patellae in the group with patellofemoral pain and clinical evidence of malalignment were positioned an average of 2.25 mm more laterally than the patellae in the control group, and this difference was marginally significant (p=0.049). Other features of the pattern of lateral translation did not differ, and large overlaps in values were observed across all groups. CONCLUSIONS: It cannot be determined from our cross-sectional study whether the more lateral position of the patella in the group with clinical evidence of malalignment preceded or followed the onset of symptoms. It is clear from the data that an individual with patellofemoral pain syndrome cannot be distinguished from a control subject by examining patterns of spin, tilt, or lateral translation of the patella, even when clinical evidence of mechanical abnormality was observed.

Needle artifact localization in 3T MR images.

This work explores an image-based approach for localizing needles during MRI-guided interventions, for the purpose of tracking and navigation. Susceptibility artifacts for several needles of varying thickness were imaged, in phantoms, using a 3 tesla MRI system, under a variety of conditions. The relationship between the true needle positions and the locations of artifacts within the images, determined both by manual and automatic segmentation methods, have been quantified and are presented here.

The fog-3 gene and regulation of cell fate in the germ line of Caenorhabditis elegans.

In the nematode Caenorhabditis elegans, germ cells normally adopt one of three fates: mitosis, spermatogenesis or oogenesis. We have identified and characterized the gene fog-3, which is required for germ cells to differentiate as sperm rather than as oocytes. Analysis of double mutants suggests that fog-3 is absolutely required for spermatogenesis and acts at the end of the regulatory hierarchy controlling sex determination for the germ line. By contrast, mutations in fog-3 do not alter the sexual identity of other tissues. We also have characterized the null phenotype of fog-1, another gene required for spermatogenesis; we demonstrate that it too controls the sexual identity of germ cells but not of other tissues. Finally, we have studied the interaction of these two fog genes with gld-1, a gene required for germ cells to undergo oogenesis rather than mitosis. On the basis of these results, we propose that germ-cell fate might be controlled by a set of inhibitory interactions among genes that specify one of three fates: mitosis, spermatogenesis or oogenesis. Such a regulatory network would link the adoption of one germ-cell fate to the suppression of the other two.

Genes required for the engulfment of cell corpses during programmed cell death in Caenorhabditis elegans.

After programmed cell death, a cell corpse is engulfed and quickly degraded by a neighboring cell. For degradation to occur, engulfing cells must recognize, phagocytose and digest the corpses of dying cells. Previously, three genes were known to be involved in eliminating cell corpses in the nematode Caenorhabditis elegans: ced-1, ced-2 and nuc-1. We have identified five new genes that play a role in this process: ced-5, ced-6, ced-7, ced-8 and ced-10. Electron microscopic studies reveal that mutations in each of these genes prevent engulfment, indicating that these genes are needed either for the recognition of corpses by other cells or for the initiation of phagocytosis. Based upon our study of double mutants, these genes can be divided into two sets. Animals with mutations in only one of these sets of genes have relatively few unengulfed cell corpses. By contrast, animals with mutations in both sets of genes have many unengulfed corpses. These observations suggest that these two sets of genes are involved in distinct and partially redundant processes that act in the engulfment of cell corpses.

Specification of germ cell fates by FOG-3 has been conserved during nematode evolution.

Rapid changes in sexual traits are ubiquitous in evolution. To analyze this phenomenon, we are studying species of the genus Caenorhabditis. These animals use one of two different mating systems-male/hermaphroditic, like the model organism Caenorhabditis elegans, or male/female, like C. remanei. Since hermaphrodites are essentially females that produce sperm for self-fertilization, elucidating the control of cell fate in the germ line in each species could provide the key to understanding how these mating systems evolved. In C. elegans, FOG-3 is required to specify that germ cells become sperm. Thus, we cloned its homologs from both C. remanei and C. briggsae. Each species produces a single homolog of FOG-3, and RNA-mediated interference indicates that FOG-3 functions in each species to specify that germ cells develop as sperm rather than as oocytes. What factors account for the different mating systems? Northern analyses and RT-PCR data reveal that the expression of fog-3 is always correlated with spermatogenesis. Since the promoters for all three fog-3 genes contain binding sites for the transcription factor TRA-1A and are capable of driving expression of fog-3 in C. elegans hermaphrodites, we propose that alterations in the upstream sex-determination pathway, perhaps acting through TRA-1A, allow spermatogenesis in C. elegans and C. briggsae XX larvae but not in C. remanei.

In Caenorhabditis elegans, the RNA-binding domains of the cytoplasmic polyadenylation element binding protein FOG-1 are needed to regulate germ cell fates.

FOG-1 controls germ cell fates in the nematode Caenorhabditis elegans. Sequence analyses revealed that FOG-1 is a cytoplasmic polyadenylation element binding (CPEB) protein; similar proteins from other species have been shown to bind messenger RNAs and regulate their translation. Our analyses of fog-1 mutations indicate that each of the three RNA-binding domains of FOG-1 is essential for activity. In addition, biochemical tests show that FOG-1 is capable of binding RNA sequences in the 3'-untranslated region of its own message. Finally, genetic assays reveal that fog-1 functions zygotically, that the small fog-1 transcript has no detectable function, and that missense mutations in fog-1 cause a dominant negative phenotype. This last observation suggests that FOG-1 acts in a complex, or as a multimer, to regulate translation. On the basis of these data, we propose that FOG-1 binds RNA to regulate germ cell fates and that it does so by controlling the translation of its targets. One of these targets might be the fog-1 transcript itself.

An estimation/correction algorithm for detecting bone edges in CT images.

The normal direction of the bone contour in computed tomography (CT) images provides important anatomical information and can guide segmentation algorithms. Since various bones in CT images have different sizes, and the intensity values of bone pixels are generally nonuniform and noisy, estimation of the normal direction using a single scale is not reliable. We propose a multiscale approach to estimate the normal direction of bone edges. The reliability of the estimation is calculated from the estimated results and, after re-scaling, the reliability is used to further correct the normal direction. The optimal scale at each point is obtained while estimating the normal direction; this scale is then used in a simple edge detector. Our experimental results have shown that use of this estimated/corrected normal direction improves the segmentation quality by decreasing the number of unexpected edges and discontinuities (gaps) of real contours. The corrected normal direction could also be used in postprocessing to delete false edges. Our segmentation algorithm is automatic, and its performance is evaluated on CT images of the human pelvis, leg, and wrist.

Magnetic resonance imaging for in vivo assessment of three-dimensional patellar tracking.

We have developed a non-invasive measurement technique which can ultimately be used to quantify three-dimensional patellar kinematics of human subjects for a range of static positions of loaded flexion and assessed its accuracy. Knee models obtained by segmenting and reconstructing one high-resolution scan of the knee were registered to bone outlines obtained by segmenting fast, low-resolution scans of the knee in static loaded flexion. We compared patellar tracking measurements made using the new method to measurements made using Roentgen stereophotogrammetric analysis in three cadaver knee specimens loaded through a range of flexion in a test rig. The error in patellar spin and tilt measurements was less than 1.02 degrees and the error in lateral patellar shift was 0.88 mm. Sagittal plane scans provided more accurate final measurements of patellar spin and tilt, whereas axial plane scans provided more accurate measurements of lateral translation and patellar flexion. Halving the number of slices did not increase measurement error significantly, which suggests that scan times can be reduced without reducing accuracy significantly. The method is particularly useful for multiple measurements on the same subject because the high-resolution bone-models need only be created once; thus, the potential variability in coordinate axes assignment and model segmentation during subsequent measurements is removed.

Computer-assisted guidewire insertion for hip fracture fixation.

OBJECTIVE: : This study was designed to test in a laboratory setting a novel computer-assisted fluoroscopic technique and a conventional fluoroscopic technique for open reduction and internal fixation (ORIF) of hip fractures. Our hypothesis is that a novel computer-assisted fluoroscopic technique will achieve acceptable guidewire placement in one pass, with decreased fluoroscopic time and with accuracy and precision better than conventional technique. DESIGN: Prospective, randomized trials. SETTING: Laboratory. PARTICIPANTS: Thirty, Sawbone, femur phantoms. INTERVENTION: Dynamic hip screw guidewires were inserted into 15 femur phantoms under fluoroscopic guidance by using computer-assisted fluoroscopic ORIF technique, and 15 femurs were inserted by using a conventional fluoroscopic-assisted ORIF technique. MAIN OUTCOME MEASUREMENTS: Ideal guidewire placement was defined as the center of the femoral head, 5 mm from the apical bone edge on anteroposterior and lateral views. Accuracy was measured as distance to ideal placement, and the number of passes and fluoroscopic time were noted for each trial. RESULTS: The computer-assisted technique achieved an average guidewire placement that was as accurate as the conventional technique in fewer passes, 1.1 +/- 0.2 (mean +/- standard deviation) compared with 2.4 +/- 1.1 (P < 0.0001), respectively, and with fewer fluoroscopic images, 2 +/- 0 compared with 13.5 +/- 3 (P < 0.0002), respectively. Guidewire placement in both groups was within the tip-apex distance defined by Baumgaertner et al. CONCLUSIONS: The computer-assisted technique was significantly more accurate and precise than conventional technique. It also required fewer drill tracks through the femur and exposed the patient and the surgical team to significantly less ionizing radiation.

A point-selection algorithm based on spatial-stiffness analysis of rigid registration.

OBJECTIVE: We propose a model of shape-based registration that leads to a task-specific algorithm for preoperatively selecting a set of model registration points. MATERIALS AND METHODS: We performed five sets of computer simulations using registration points generated by our algorithm and two noise amplification index (NAI) algorithms on the basis of the research of Simon 20. We used several different bone surface models (distal radius, proximal femur and tibia) computed from CT images of patient volunteers. The number of registration points used varied between 6 and 30. RESULTS: Our algorithm was faster than the NAI-based algorithms by factors of approximately 4 and 200. It had equal or better performance in terms of target registration error (TRE) when compared with the other algorithms. Our simulations also showed that point selection can have a large effect on TRE behavior; in particular, poor point selection does not necessarily decrease TRE as more registration points are added. CONCLUSIONS: Our point-selection algorithm produces model registration points with similar or better TRE behavior than the NAI-based algorithms we tested, and it does so with significantly less computation time.

The influence of osteophyte depiction in CT for patient-specific guided hip resurfacing procedures.

PURPOSE: An accurate fit of a patient-specific instrument guide during an intervention is one of the critical factors affecting accuracy of the surgical procedure. In this study, we investigated how well osteophytes, which are abnormal bone growths that form along joints, are depicted in clinical preoperative CT scans and estimated the influence of such depiction errors on the intraoperative accuracy of the guide. METHODS: In 34 hip resurfacing patients, 227 osteophyte surface points on the anterior aspect of the femoral neck were collected intraoperatively, using an optoelectronic navigation system. These points were registered to a preoperative CT scan of the patient, and distances between collected points and segmented virtual bone surface, as well as Hounsfield units for these points, were determined. We simulated the registration error of a patient-specific guide, using a modified registration algorithm, to test placement on the anterior aspect of the femoral neck without removing any osteophytes. This error was then applied to the surgical plan of the femoral central-pin position and orientation for evaluation. RESULTS: The average distance between the collected points and the segmented surface was 2.6 mm. We estimated the average error for the entrance point of the central-pin to be 0.7 mm in the distal direction and 3.2 mm in the anterior direction. The average orientation error was 2.8° in anteversion. CONCLUSIONS: The depiction of osteophytes in clinical preoperative CT scans for proximal femurs can be unreliable and can possibly result in significant intraoperative instrument alignment errors during image-guided surgeries.

Dose dependency of dextromethorphan for cytochrome P450 2D6 (CYP2D6) phenotyping.

Most dextromethorphan CYP2D6 phenotyping studies use a 30-mg dose, but data that show superiority of any particular dose are lacking. We compared metabolic ratios from six different dextromethorphan phenotyping doses to ascertain whether linearity existed over a dosage range. Forty subjects were enrolled in the study. Each subject received 0.05 mg/kg, 0.15 mg/kg, 0.3 mg/kg, 30 mg, 0.8 mg/kg, and 1.2 mg/kg dextromethorphan in a randomized crossover fashion. Urinary dextromethorphan to dextrorphan molar ratios were used to measure CYP2D6 activity. Single blood samples were obtained for CYP2D6 genotyping, which revealed one poor metabolizer and 39 extensive metabolizers. A statistical difference was found for the molar ratio between the 0.8 mg/kg and the 1.2 mg/kg dose compared with the other four doses. None of the 39 genotypic extensive metabolizers were incorrectly phenotyped with any of these doses. These data support the use of moderate doses of dextromethorphan for phenotyping to avoid dose dependency.

Non-invasive assessment of swallowing and respiration in Parkinson's disease.

Oro-pharyngeal dysphagia is well recognised but often underestimated in people with Parkinson's disease. Asymptomatic patients may fail to receive timely advice or therapy, thus placing them at risk. The aim of this study was to determine whether subclinical abnormalities in swallowing and discrete changes in function such as those produced by prompting can be detected by non-invasive methods. We examined 12 people with idiopathic Parkinson's disease and 14 elderly comparison subjects. Five components of respiratory synchronisation and swallowing efficiency were monitored using the Exeter Dysphagia Assessment Technique. Ten feeding trials were administered under standard quiet conditions. The patients were then restudied using verbal prompts when the spoon was presented to the mouth. The duration of two oro-pharyngeal events and the frequency of respiratory variables were compared for unrelated and related samples. Results showed the oral and pharyngeal parts of the swallow to be significantly slower in those with Parkinson's disease. These patients required significantly more swallows to clear a 5-ml bolus, and fewer swallows were followed by expiration. When the patients were verbally prompted, there was a significant reduction in the duration of the oral part. This study demonstrates that non-invasive methods can be used to detect subclinical difficulties with swallowing amongst a group of asymptomatic patients with PD and that these methods are sensitive to small changes in function produced by a verbal cue.

Effortful touch with minimum movement: revisited.

The ecological static moment-torque model proposed by C. Carello, P. Fitzpatrick, I. Domaniewicz, T.C. Chan, and M.T. Turvey (1992) does not uniquely explain the perception of rod length by static holding. Guided by a mechanical analysis of the gravitational forces and torques produced in the hand as it statically holds rods of different lengths and materials at different orientations, we offer 2 additional theoretical explanations, the force-torque and weight-percept models. Experiment 1 demonstrates that all 3 models predict perceived rod length with considerable success. Experiment 2 provides clear experimental support for the force-torque and weight-percept models over the static moment-torque model. Experiment 3 pits the former 2 models against each other. Current results favor the weight-percept model. Implications for theories of haptic weight perception and design of a new tactile sensor are also considered.

The feasibility of measuring total body carbon by counting neutron inelastic scatter gamma rays.

A technique is examined for measuring the mass of carbon of both ambulatory and non-ambulatory subjects. The method is based upon the detection of the 4.43 MeV gamma rays emitted from carbon nuclei when the body is irradiated with fast neutrons. The supine subject is irradiated laterally by a horizontal collimated beam of 14 MeV neutrons and the emitted gamma rays are counted by a shielded NaI(Tl) detector placed underneath the subject. The method has been calibrated for all sizes of subjects from 30 to 90 kg and there appears to be no significant interference from the other bulk elements of the body. Body carbon has been measured in six normal volunteers; body nitrogen was also determined by measuring the 13N induced in each subject in a second irradiation. Body fat was estimated from the measured carbon and nitrogen, and the values compared with those derived from skinfold thicknesses. The technique is proposed as a method of estimating long-term energy expenditure.