Tibiofemoral articular cartilage composition differs based on serum biochemical profiles following anterior cruciate ligament reconstruction.

OBJECTIVE: Biochemical joint changes contribute to posttraumatic osteoarthritis (PTOA) development following anterior cruciate ligament reconstruction (ACLR). The purpose of this longitudinal cohort study was to compare tibiofemoral cartilage composition between ACLR patients with different serum biochemical profiles. We hypothesized that profiles of increased inflammation (monocyte chemoattractant protein-1 [MCP-1]), type-II collagen turnover (type-II collagen breakdown [C2C]:synthesis [CPII]), matrix degradation (matrix metalloproteinase-3 [MMP-3] and cartilage oligomeric matrix protein [COMP]) preoperatively to 6-months post-ACLR would be associated with greater tibiofemoral cartilage T1ρ relaxation times 12-months post-ACLR. DESIGN: Serum was collected from 24 patients (46% female, 22.1 ± 4.2 years old, 24.0 ± 2.6 kg/m2 body mass index [BMI]) preoperatively (6.4 ± 3.6 days post injury) and 6-months post-ACLR. T1ρ Magnetic Resonance Imaging (MRI) was collected for medial and lateral tibiofemoral articular cartilage at 12-months post-ACLR. A k-means cluster analysis was used to identify profiles based on biomarker changes over time and T1ρ relaxation times were compared between cluster groups controlling for sex, age, BMI, concomitant injury (either meniscal or chondral pathology), and Marx Score. RESULTS: One cluster exhibited increases in MCP-1 and COMP while the other demonstrated decreases in MCP-1 and COMP preoperatively to 6-months post-ACLR. The cluster group with increases in MCP-1 and COMP demonstrated greater lateral tibial (adjusted mean difference = 3.88, 95% confidence intervals [1.97-5.78]) and femoral (adjusted mean difference = 12.71, 95% confidence intervals [0.41-23.81]) T1ρ relaxation times. CONCLUSION: Profiles of increased serum levels of inflammation and matrix degradation markers preoperatively to 6-months post-ACLR are associated with MRI changes consistent with lesser lateral tibiofemoral cartilage proteoglycan density 12-months post-ACLR.

Synovial fluid concentrations of matrix Metalloproteinase-3 and Interluekin-6 following anterior cruciate ligament injury associate with gait biomechanics 6 months following reconstruction.

OBJECTIVE: To compare gait biomechanics 6 months following anterior cruciate ligament (ACL) reconstruction (ACLR) between patients with the highest and lowest concentrations of synovial fluid (SF) interleukin-6 (IL-6) and matrix metalloproteinase-3 (MMP-3), as well as compared to uninjured controls. DESIGN: SF concentrations of IL-6 and MMP-3 were collected 7 ± 4 days post injury in 38 ACL injured patients (55% female, 21±4yrs, 25.3 ± 5.2BMI). ACL injured individuals were stratified into the lowest and highest quartiles based on IL-6 (IL-6Lowest and IL-6Highest) and MMP-3 (MMP-3Lowest and MMP-3Highest) concentrations. Gait biomechanics were collected on the injured limb 6 months post-ACLR and in 38 uninjured controls (50% female, 21±3yrs, 23.8 ± 2.8BMI). Functional analyses of variance were used to compare vertical ground reaction force (vGRF), knee flexion angle (KFA), and internal knee extension moment (KEM) waveforms throughout stance phase of gait to determine the proportions of stance differing between limbs and groups. RESULTS: Compared to uninjured controls, IL-6High and MMP-3High ACL subgroups demonstrated lesser vGRF (largest differences: IL-6, 7.88%BW; MMP-3, 11.05%BW) during early-stance and greater vGRF (largest differences: IL-6, 6.21%BW; MMP-3, 5.85%BW) in mid-stance, lesser KFA (largest differences: IL-6, 3.11°; MMP-3, 3.72°) and lesser KEM (largest differences: IL-6, 0.96%BW•m; MMP-3, 1.07%BW•m) in early-stance, as well as greater KFA in mid-stance (largest differences: IL-6, 1.5°; MMP-3, 2.95°). CONCLUSIONS: High SF concentrations of a proinflammatory cytokine and a degradative enzyme early post-ACL injury are associated with aberrant gait biomechanics in the injured limb at 6 months post-ACLR (i.e., lesser vGRF, KFA and KEM) linked to posttraumatic osteoarthritis development.

Osteolysis after rotator cuff repair with bioabsorbable anchors.

PURPOSE: The current study was designed to evaluate the rate of osteolysis and the clinical and functional outcomes in patients who underwent mini-open rotator cuff repairs using first generation bioabsorbable suture anchors. Our hypothesis was that patients with osteolysis noted on post-repair MRI would have an accompanying decrease in functional and clinical patient outcomes when compared with patients who did not have osteolysis evident on post-repair MRI. TYPE OF STUDY: Clinical retrospective study. METHODS: Between September 2000 and May 2004, 76 patients were repaired using first generation Bio-Corkscrew suture anchors (Arthrex, Naples, FL). 30 patients were available for complete follow-up evaluation. The mean follow-up time was 36 months (range 24-58). Patients were assessed with the Constant-Murley Score, radiographs and magnetic resonance imaging (MRI). Post-operative strength was measured using an Isokinetic Cybex-Dynamometer. 14 patients had osteolysis evident on MRI (Group A) while 16 patients did not have osteolysis on MRI (Group B). RESULTS: In both groups, a total of 70 bio-anchors were used. 22 anchors showed osteolytic changes on MRI (Group A). Concerning ROM, there was no statistical difference in both groups. The Constant-Score was statistically not different in both groups A (92.4) and B (83.7). On MRI-scans, there were repair failures in both groups (A, 2 reruptures; B, 3 reruptures). CONCLUSIONS: Although, we found a high rate of osteolysis after rotator cuff repair with bioabsorbable anchors, these results did not change the clinical outcomes after rotator cuff repair. Recurrent tears were not significantly different in both groups and are comparable to rerupture rates in prior studies. More studies are needed to verify the effect of osteolysis over the long term.

Chemical modification of epibatidine causes a switch from agonist to antagonist and modifies its selectivity for neuronal nicotinic acetylcholine receptors.

BACKGROUND: Studies of ligand gated channels strongly rely on the availability of compounds that can activate or inhibit with high selectivity one set or a subset of defined receptors. The alkaloid epibatidine (EPB), originally isolated from the skin of an Ecuadorian poison frog, is a very specific agonist for the neuronal nicotinic acetylcholine receptors (nAChRs). We used EPB derivatives to investigate the pharmacophore of nAChR subtypes. RESULTS: Optically pure enantiomers of EPB analogues were synthesised. Analogues were obtained altered in the aromatic part: the chlorine was eliminated and the relative position of the pyridyl nitrogen changed. Voltage clamp electrophysiology was performed with these compounds on neuronal nAChRs reconstituted in Xenopus oocytes. The EPB derivatives show different activities towards the various nAChR subtypes. CONCLUSIONS: Small changes in the molecular structure of EPB produce marked changes in its capacity to activate the nAChRs. Subtype specificity can be obtained by changing the position of or by eliminating the pyridyl nitrogen.

Neuronal nAChR stereoselectivity to non-natural epibatidine derivatives.

The frog toxin epibatidine is one of the most powerful ligands of the neuronal nicotinic receptors and derivatives show promising possibilities for labeling in positron emission tomography studies. In an attempt to reduce epibatidine toxicity, new methyl derivatives were synthesized, tested in positron emission tomography imaging and in electrophysiology. labeling as well as physiological experiments highlighted the differences in sensitivity of the neuronal nicotinic acetylcholine receptors between two methyl enantiomers and the reduction in sensitivity caused by introducing the methyl group. At present, epibatidine derivatives seem the most promising compounds for in vivo labeling of neuronal nicotinic acetylcholine receptors.

A new look at the neuronal nicotinic acetylcholine receptor pharmacophore.

Interest in the field of nicotinic receptors has been recently stimulated both by the discovery of the potential therapeutic effects of new agonists, and by the discovery of an association between nicotinic receptor mutations and human neurological diseases. Expression of human receptors in an exogenous system allows their study in isolation. Receptors reconstituted by pairwise injection of either alpha4 or alpha3 with beta2 or beta4 subunits displayed important differences between the resulting receptor subtypes. These results were further compared with those obtained with alpha3:alpha4 fusion proteins. The modifications of either the ligand-binding site in the N-terminal domain or in the ionic pore domain were found to affect the pharmacological properties of the receptors. Finally, the analysis of non-natural derivatives of epibatidine demonstrates how an agonist can be modified to be selective at one receptor subtype or to become an antagonist. These data are well explained on the basis of a three-state allosteric model.

Comparison of N-[(11)C]methyl-norchloroepibatidine and N-[(11)C]methyl-2-(2-pyridyl)-7-azabicyclo[2.2.1]heptane with N-[(11)C]methyl-epibatidine in small animal PET studies.

Structural variations of the nicotinic acetylcholine receptor radioligand N-[(11)C]methyl-epibatidine were made to form (11)C-labeled N-methyl-norchloroepibatidine (N-methyl-NorchloroEPB) and N-methyl-2-(2-pyridyl)-7-azabicyclo[2.2.1]heptane (N-methyl-2PABH). Radiosyntheses were performed by methylation with high radiochemical purities (>98%) and with specific activities between 140 and 500 GBq/micromol at the end of synthesis. The radiochemical yield (decay-corrected, related to [(11)C]CH(3)I) was between 5 and 10%. Positively and negatively radiolabeled enantiomers were prepared in high optical purity (>98%ee) by labeling of the appropriate optically active substrates, which were obtained via chiral high performance liquid chromatography. For in vivo studies radioligands were administered intravenously in rats. Brain uptake curves were acquired and combined with blocking experiments. Brain uptake of N-[(11)C]methyl-NorchloroEPB was similar to that of N-[(11)C]methyl-EPB whereas N-[(11)C]methyl-2PABH with the modified pyridine ring had a significantly lower uptake.

Synthesis and in Vivo studies of [C-11]N-methylepibatidine: comparison of the stereoisomers.

The carbon-11-labelled nicotinic acetylcholine receptor (nAChR) agonist N-methylepibatidine was evaluated in vitro and in vivo as a possible positron emission tomography (PET)-tracer for nicotinic receptors in the central nervous system (CNS). The racemic mixture and both enantiomers of N-methylepibatidine were compared. Biodistribution and metabolites for blood and brain of [C-11]N-methylepibatidine were determined in mice. Whole body rat PET data were acquired for both stereoisomers. The regional distribution of the N-methyl-(-)-epibatidine in the brain was determined by a PET scan in a pig. Characteristic differences were found for the in vivo behavior of the stereoisomers of [C-11]N-methylepibatidine.

Synthesis and in vivo studies of the stereoisomers of N-[11C]methyl-homoepibatidine.

The carbon-11 labeled enantiomers of nicotinic acetylcholine receptor (nAChR) ligand N-[11C]methyl-homoepibatidine have been synthesized to study the neuronal nicotinic acetylcholine receptors (nAChRs). In vivo evaluations were performed in mice and pig using positron emission tomography (PET). The radioligands displayed a strong enantioselectivity. The (-)-enantiomer showed high uptake in the brain while the (+)-enantiomer was rapidly washed out. In metabolite studies in mice >65% unchanged ligand was found in the blood after 60 minutes. No metabolites were found in the brain. After intravenous application of N-[11C]methyl-(-)-homoepibatidine in the pig specific accumulation in the thalamus was seen. Blocking experiments with cytisine showed specific binding consistent with labeling of the alpha4beta2-nAChR-subtype in the brain. Quantitative kinetic modeling of radiotracers in the pig brain was performed using the arterial input function. The brain uptake of the (-)-isomer was best fitted by a three-compartment model. High distribution volumes were found in the thalamus (DV(TOT) = 66.617, DV(S) = 59.910) versus a low uptake in the cerebellum (DV(TOT) = 8.605m, DV(S) = 1.898). The binding characteristics suggest N-[11C]methyl-(-)-homoepibatidine to be suited for PET imaging studies, but high toxicity prevents routine use in humans.

Metastatic disease of the femur. Surgical management.

Treatment of actual or impending pathologic fractures of the femur provides the senior author with some of the most rewarding surgical interventions of his practice. The patients' survival outlook is not changed, but their quality of life is enhanced significantly. Most health care providers usually provide the metastatic cancer patient only temporary symptomatic relief, at best, and often at the expense of continued pain, suffering, or sickness, such as is seen with chemotherapy-associated morbidity. Patients with metastatic bone disease are usually incredibly grateful for the restoration of function and diminution of their pain that results from the proper operation on metastatic bone disease. These patients typically are among the most appreciative patients and often express their gratitude when seen in follow-up in the clinic or office. Despite their metastatic disease state, their usual enthusiasm is uplifting to the surgeon and to the staff. To help a patient be pain-free and functional in the waning days of his or her life affords the patient, the physician, and the physician's staff with an emotionally rewarding experience and one that is well worth the time and effort required to care for these patients. By following the techniques outlined in this article, most patients with metastatic disease of the femur can be appropriately managed with excellent results.

Femoral recon nails for metastatic disease: indications, technique, and results.

The senior author has used 41 femoral recon nails of one design in 41 consecutive patients with 30 impending and 11 pathologic femur fractures. All nails were inserted with minimally invasive surgical technique. The hospital stay was shorter (average, 5.6 days) and discharge to home was more likely (77%) after stabilization of impending pathologic fractures compared with fixation of completed fractures (length of hospital stay averaged 7.8 days, with a 36% discharge-to-home rate), as patients with completed fractures required a higher level of postoperative care. Fixation prior to fracture occurrence results in predictably better early results than that of fixation after fracture occurrence, confirming the benefit of prophylactic fixation of impending pathologic fractures. To date, there have been no fixation failures and only one significant complication: a nonfatal pulmonary embolus. This technique provides a safe and effective method of stabilizing properly selected femoral lesions resulting from metastatic disease, especially impending pathologic fractures.

Stability of facial affective expressions in schizophrenia.

Thirty-two videorecorded interviews were conducted by two interviewers with eight patients diagnosed with schizophrenia. Each patient was interviewed four times: three weekly interviews by the first interviewer and one additional interview by the second interviewer. 64 selected sequences where the patients were speaking about psychotic experiences were scored for facial affective behaviour with Emotion Facial Action Coding System (EMFACS). In accordance with previous research, the results show that patients diagnosed with schizophrenia express negative facial affectivity. Facial affective behaviour seems not to be dependent on temporality, since within-subjects ANOVA revealed no substantial changes in the amount of affects displayed across the weekly interview occasions. Whereas previous findings found contempt to be the most frequent affect in patients, in the present material disgust was as common, but depended on the interviewer. The results suggest that facial affectivity in these patients is primarily dominated by the negative emotions of disgust and, to a lesser extent, contempt and implies that this seems to be a fairly stable feature.

The relationship between trochlear dysplasia and medial patellofemoral ligament rupture location after patellar dislocation: an MRI evaluation.

The medial patellofemoral ligament (MPFL) and the native trochlear geometry represent two of the most critical components of patellofemoral stability. We sought to define the relationship between trochlear dysplasia and MPFL rupture location in patients with documented patellar dislocations. We hypothesized that patients with lower grades of trochlear dysplasia would have patellar based MPFL ruptures, while patients with higher grade dysplasia would have femoral-sided ruptures. We reviewed post-injury MRIs of 59 patients with documented patella dislocation. Information gathered included: type of trochlear dysplasia in the axial plane MRI, location of MPFL rupture, patellar height ratio, tibial tuberosity to trochlear groove distance (TTTG), number of dislocations prior to MRI, and time between the latest patella dislocation and the MRI. Statistical calculations utilized the Chi-Square-Test. We classified 11 cases as a dysplasia type A, 35 as a type B, 11 as a type C, and 2 cases as a trochlear dysplasia type D. In 7 patients (12%) the MPFL rupture was patella based, in 18 patients (31%) intra-ligamentous, in 33 cases (56%) femoral sided and in one case no MPFL could be identified. In contrast to our original hypothesis, the type of trochlear dysplasia does not appear to be related to the rupture location of the MPFL after patellar dislocation. According to our results, it is not possible to presume the location of the MPFL rupture based on assessment of the trochlear morphology. Therefore, a MRI is mandatory for final indication of any surgery.

Donor-site morbidity after osteochondral autologous transplantation for lesions of the talus.

BACKGROUND: Autologous osteochondral transplantation is accepted as one of the major treatment options for cartilage defects of the talus. One disadvantage of this technique is the need to harvest a donor graft from a normal knee. The potentially detrimental effect of graft harvest on knee function remains unclear. METHODS: Two hundred patients who had transplantation of an autologous osteochondral graft obtained from an asymptomatic knee for the treatment of an osteochondral defect of the talus were evaluated. Of the 200 patients, 112 were followed for a minimum of two years (mean duration of follow-up, fifty-five months). The WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) and the Lysholm score were used to assess functional outcome. Variables that were examined included the number of grafts, total size of the harvested cylinders, patient age, body mass index, and overall satisfaction of the patient with the result of the procedure at the knee. A multiple linear regression analysis was utilized to determine the influence of each parameter on the WOMAC and Lysholm scores. In addition, the Lysholm scores for the entire patient group were reviewed to determine how long after the index surgery clinical improvement ceased. RESULTS: The mean postoperative WOMAC score (and standard deviation) for the 112 patients who had been followed for a minimum of two years was 5.5% +/- 0.1%, and the mean postoperative Lysholm score was 89 +/- 17 points. The number of grafts, the size of the transplanted cylinders, and patient age did not influence either the Lysholm or the WOMAC score. A higher body mass index and lower general satisfaction ratings did negatively influence the Lysholm and WOMAC scores. Gradual clinical improvement, as measured with the Lysholm score for all 200 study subjects, continued throughout the postoperative period. CONCLUSIONS: Donor-site morbidity of a knee from which a graft has been harvested can potentially lead to functional impairment. In our study, the functional outcome of the knee was not affected by the number of donor grafts, the size of the donor grafts, or the age of the patient. Surgeons performing osteochondral transplantations and harvesting autografts from the knee should be aware of the potentially negative effect of a higher body mass index on clinical outcomes after surgery.

Behavior of sutures used in anterior cruciate ligament reconstructive surgery.

This study was performed to determine the material properties of sutures commonly used in orthopedic surgery in order to allow selection of the most appropriate one for securing a hamstring or quadriceps tendon graft in anterior cruciate ligament (ACL) reconstruction. Three suture materials (number 5 Ticron, number 5 Ethibond, and 5 mm Mersilene tape) were tested. The ultimate tensile load (UTL) with and without a knot, modulus of elasticity, effect of conditioning on the behavior of the suture, and plastic deformation were determined for each suture. Prior conditioning significantly improved the plastic deformation characteristics of all three sutures. Mersilene possessed the highest UTL both with and without knots, and its plastic deformation was significantly lower than that of Ticron or Ethibond. We feel that these characteristics make it the best suture for use in securing hamstring or tendon grafts in ACL surgery. Because of the high UTL achieved by Mersilene tape in the knotted surgical loop construct (nearly 500 N), it may be possible to achieve fixation integrity approaching that of interference fixation with bone blocks.

Synthesis and electrophysiological studies of a novel epibatidine analogue.

The new epibatidine analogue exo-2-(2-pyridyl)-7-azabicyclo[2.2.1]heptane (2PABH) was synthesised. Separation of enantiomers was performed on chiral HPLC chromatography in polar-organic phase mode at 0 degree C. Enantiomeric purity was greater than 99.8%ee for the (-)- and 90.5%ee for the (+)-enantiomer respectively. Optical rotation was determined to be [alpha]23D = +/- 13 degrees. Electrophysiological studies of 2PABH were carried out on alpha 4 beta 2, alpha 3 beta 4 and alpha 7 nAChR subtypes cloned from rat and reconstituted in Xenopus oocytes. Both enantiomers could not significantly activate the heteromeric subtypes. The homomeric alpha 7 nAChR displays a high sensitivity only towards (-)-2PABH. The EC50 for (-)-2PABH and ACh were determined (32.5 +/- 9.5 microM, 137.3 +/- 16.5 microM). (-)-2PABH was shown to be a partial agonist (80% of ACh). Thus the efficacy of 2PABH differs markedly from that of epibatidine. The intramolecular N-N-distance and the spatial pyridine nitrogen orientation play a central role in nAChR recognition.