Prior Treatment with AICAR Causes the Selective Phosphorylation of mTOR Substrates in C2C12 Cells.

Metabolic stress in skeletal muscle cells causes sustained metabolic changes, but the mechanisms of the prolonged effects are not fully known. In this study, we tested C2C12 cells with the AMP-activated protein kinase (AMPK) stimulator AICAR and measured the changes in the metabolic pathways and signaling kinases. AICAR caused an acute increase in the phosphorylation of the AMPK target ULK1, the mTORC1 substrate S6K, and the mTORC2 target Akt. Intriguingly, prior exposure to AICAR only decreased glucose-6 phosphate dehydrogenase activity when it underwent three-hour recovery after exposure to AICAR in a bicarbonate buffer containing glucose (KHB) instead of Dulbecco's Minimum Essential Medium (DMEM). The phosphorylation of the mTORC1 target S6K was increased after recovery in DMEM but not KHB, although this appeared to be specific to S6K, as the phosphorylation of the mTORC1 target site on ULK1 was not altered when the cells recovered in DMEM. The phosphorylation of mTORC2 target sites was also heterogenous under these conditions, with Akt increasing at serine 473 while other targets (SGK1 and PKCα) were unaffected. The exposure of cells to rapamycin (an mTORC1 inhibitor) and PP242 (an inhibitor of both mTOR complexes) revealed the differential phosphorylation of mTORC2 substrates. Taken together, the data suggest that prior exposure to AICAR causes the selective phosphorylation of mTOR substrates, even after prolonged recovery in a nutrient-replete medium.

Two dimensionless parameters and a mechanical analogue for the HKB model of motor coordination.

The widely cited Haken-Kelso-Bunz (HKB) model of motor coordination is used in an enormous range of applications. In this paper, we show analytically that the weakly damped, weakly coupled HKB model of two oscillators depends on only two dimensionless parameters; the ratio of the linear damping coefficient and the linear coupling coefficient and the ratio of the combined nonlinear damping coefficients and the combined nonlinear coupling coefficients. We illustrate our results with a mechanical analogue. We use our analytic results to predict behaviours in arbitrary parameter regimes and show how this led us to explain and extend recent numerical continuation results of the full HKB model. The key finding is that the HKB model contains a significant amount of behaviour in biologically relevant parameter regimes not yet observed in experiments or numerical simulations. This observation has implications for the development of virtual partner interaction and the human dynamic clamp, and potentially for the HKB model itself.

Ankle instability: current concepts, diagnosis, and treatment.

Our approach to the problem of ankle sprains and instability is reviewed. After diagnostic evaluation (including stress roentgenography, arthrography, or tenography if necessary), most of our patients are treated either by taping if they have a grade 1 or 2 sprain or by casting if they have a grade 3 disruption. If the injury should progress to chronic instability despite this treatment regimen, which is an unusual occurrence, satisfactory reconstructive procedures are available. Indications for acute primary repair are limited.

Salter-Harris Type-IV injuries of the distal tibial epiphyseal growth plate, with emphasis on those involving the medial malleolus.

Salter-Harris Type-IV fractures of the epiphysis extend through the articular cartilage, epiphysis, physis, and metaphysis and have a high rate of complications secondary to premature partial closure of the physis. In this study we attempted to determine which Type-IV fractures of the distal end of the tibia result in premature partial closure, how the various treatment modalities affect the risk of premature physeal closure, and how the complication itself might be best managed. Thirty-two Type-IV fractures of the distal end of the tibia were seen at the Mayo Clinic during a five-year period. Eighteen injuries involved the medial malleolus, thirteen were so-called triplane fractures, and one was a fracture of the lateral part of the plafond. In the eighteen ankles with a fracture that involved the medial malleolus, extension of the fracture into the metaphysis could often be appreciated only on oblique roentgenograms. The patients' ages at the time of fracture ranged from one year and one month to fifteen years and six months old. In nine of the eighteen tibiae with a fracture of the medial malleolus premature partial closure of the distal physis developed, resulting in angular deformity or limb-length discrepancy sufficient to require operative treatment (epiphyseodesis, corrective osteotomy, or excision of a physeal bar). A physeal bar was best detected by tomograms made in two planes and by scanograms. Bar formation may be treated by excision of the bar, arrest of the whole physis, osteotomy, or combinations of these procedures. Of the thirteen patients with a triplane fracture and the one with a Type-IV fracture of the lateral part of the plafond, all fourteen were near maturity at the time of injury, and no growth-arrest problems developed.

Tibiotalocalcaneal arthrodesis for arthritis and deformity of the hind part of the foot.

We devised a method for tibiotalocalcaneal arthrodesis to treat deformities or degenerative arthritis, or both, that involve the tibiotalar and talocalcaneal joints. Satisfactory results were obtained in approximately 75 per cent of twenty-one patients; osseous union was radiographically evident in all but three patients. Secondary degenerative changes in the adjacent joints were not evident radiographically during a period of follow-up that ranged from 2.5 to seven years.

Isolated talocalcaneal arthrodesis. A technique using moldable bone graft.

Combined autogenous iliac-crest bone-grafting and fixation with a pin or screw was used to achieve a fusion of the talocalcaneal joint in forty-one adults (forty-five arthrodeses). At a mean length of follow-up of fifty-seven months (range, thirty to ninety-six months), thirty-seven (90 per cent) of the patients were satisfied with the result. Objectively, the results were excellent after thirty-nine arthrodeses (87 per cent), good or fair after five (11 per cent), and poor after one (2 per cent). There was one non-union and one superficial wound infection. At the time of follow-up, no secondary degenerative changes in the associated joints of the hind part of the foot were identified on roentgenograms. The surgical technique appears to be appropriate and effective in the treatment of arthritis of the talocalcaneal joint in adults.

Acquired adult flat foot secondary to posterior tibial-tendon pathology.

Nineteen patients with the clinical diagnosis of dysfunction of the posterior tibial tendon underwent surgical exploration. Four types of lesions were identified: avulsion of the tendon at the insertion (Group I), mid-substance rupture of the tendon (Group II), an in-continuity tear of the tendon (Group III), and no tendon tear, tenosynovitis only (Group IV). These conditions could not be separated preoperatively by clinical or radiographic means. The patients in Group I were treated by reinsertion of the tendon; in Group II, by flexor tendon transfer; and in Groups III and IV, by synovectomy. At follow-up, most patients in Group I reported no improvement, but the patients in Groups II, III, and IV showed both subjective and objective improvement. The signs and symptoms of dysfunction of the posterior tibial tendon are not specific for mid-substance ruptures of the tendon but also can occur with avulsions or synovitis, or perhaps from other, as yet undefined lesions.

Condylar total knee arthroplasty after failed proximal tibial osteotomy.

Data were collected retrospectively on thirty-five patients who had a failed osteotomy of the proximal part of the tibia for unicompartmental osteoarthrosis of the knee that was treated with a cruciate condylar, total condylar, kinematic condylar, or cemented porous-coated anatomical total knee prosthesis. The patients were evaluated clinically and roentgenographically before and after the arthroplasty. The minimum period of follow-up was twenty-nine months (mean, forty-four months). On the basis of the knee-rating scale of The Hospital for Special Surgery, 89 per cent of the patients had either an excellent or a good result after the arthroplasty. No result was a failure. One patient had loosening of the patellar component, but no other loosening was identified. The results of total knee arthroplasty after osteotomy of the proximal part of the tibia were found to be comparable with the results after arthroplasty in knees that had not had a prior osteotomy. The intraoperative and postoperative rates of complications were not higher, and no untoward technical difficulties were encountered at surgery. These data support the clinical impression that an osteotomy of the proximal part of the tibia does not "burn any bridges" insofar as a future successful arthroplasty is concerned.

Atlanto-occipital fusion for dislocation in children with neurologic preservation. A case report.

STUDY DESIGN: A retrospective clinical review of patients with atlanto-occipital dislocations. OBJECTIVES: To determine if fusion of the occiput to C1 can be accomplished without extension to the axis. SUMMARY OF BACKGROUND DATA: Patients with atlanto-occipital dislocations who have preservation of spinal cord function are quite rare. The standard approach to stabilization has been fusion of the occiput to the axis (C2). This may compromise rotation unnecessarily, however. The authors investigated the success of attempting to fuse only the occiput to C1 in children. METHODS: Two children with atlanto-occipital dislocation who had normal neurologic function underwent fusion from the occiput to the atlas after reduction. RESULTS: Both cases showed successful fusion with no unwanted extension to lower levels. Full head rotation was preserved. CONCLUSIONS: This technique restores stability without restricting rotation.

Stability of the loaded ankle. Relation between articular restraint and primary and secondary static restraints.

The stabilizing capacity of the ligaments and articular surface in the ankle was determined under defined physiologic loading conditions. The concept of primary and secondary constraints was adapted to the ankle. With physiologic loading, the articular surface accounted for 30% and 100% of stability in rotation and version, respectively. That the articular surface was the sole source of inversion and eversion stability under the prescribed physiologic loading conditions has not been previously reported. The demonstration that the articular surface resists inversion displacement in the loaded ankle supports the conclusion of previous studies that rotation, rather than inversion, may account for a type of clinically symptomatic ankle instability. Further, ankle instability may occur during loading and unloading but not once the ankle is fully loaded. The results of our study confirm the importance of the anterior talofibular and calcaneofibular ligaments and suggest an important role for the deltoid ligament.

Acute repair and delayed reconstruction for lateral ankle instability: twenty-year follow-up study.

OBJECTIVES: To determine long-term results of patients who underwent primary ligament repair and delayed reconstruction for lateral ligament instability. DESIGN: Retrospective. SETTING: Outpatient clinic. PATIENTS/PARTICIPANTS: Patients who had undergone acute repair or delayed reconstruction at this institution between 1958 and 1977, excluding patients who were deceased or who could not be located. INTERVENTION: Forty-eight patients (fifty-three ankles) underwent twenty-two primary ligament repairs and thirty-one delayed reconstruction operations. MAIN OUTCOME MEASUREMENTS: Clinical results graded with clinical scale and radiologic results based on stress radiographs and plain film radiographs. RESULTS: At an average of twenty years after operation (range 12 to 33 years), patients were satisfied with forty-nine ankles, satisfied with reservations with two ankles, and dissatisfied with two ankles. Clinical results after repair were excellent in twenty ankles, good in one, fair in none, and poor in one. After reconstruction, the results were excellent in twenty-one ankles, good in six, fair in one, and poor in three. In the primary repair group, the mean talar tilt with stress testing improved from 20.7 +/- 10.7 degrees before operation to 2.8 +/- 3.0 degrees after operation. In the reconstruction group, the mean talar tilt improved from 20.7 +/- 8.4 degrees before operation to 2.8 +/- 3.5 degrees after operation. CONCLUSIONS: Clinical and radiologic results were similar in the repair and reconstruction groups. The majority of severe (Grade III) ankle sprains may be treated nonoperatively, but if residual instability occurs, late reconstruction should achieve satisfactory results.

Ankle instability: in vitro kinematics in response to axial load.

This study was undertaken to elucidate the kinematics of hindfoot instability. An axial load was applied to the inverted hindfoot. Unlike prior studies, axial rotation was not constrained. Using computerized tomography, measurements were made on the axial views of external or internal rotation of the leg, talus, and calcaneus. On the coronal views, tilting of the talus at the ankle and subtalar joints was assessed. No tilting of the talus in the mortise occurred with isolated release of the anterior talofibular (ATF) or calcaneofibular (CF) ligament. In every specimen, talar tilt occurred only after both ligaments were released, averaging 20.6 degrees. External rotation of the leg occurred with inversion averaging 11.1 degrees in the intact specimen. The leg averaged a further external rotation of 4.9 degrees after ATF release and 12.8 degrees further than the intact inverted specimens when both ligaments (ATF-CF) had been released. In earlier reports on the subject, the articular surfaces were believed to be the main constraint against tilting of the talus. In those studies, either axial rotation was constrained while inversion was allowed, or vice versa. Based on the data reported here, the ATF and the CF work in tandem to prevent tilting of the talus, and the articular surfaces do not seem to prevent tilting of the talus in the mortise.

High tibial osteotomy.

The results of high tibial osteotomy performed in a 12-year period in 75 patients (88 knees) were followed for at least five years or until failure occurred. Of the 86 knees available for subjective follow-up evaluation, 64 were in men and 22 were in women. Roentgenographic data were available for 75 knees. The results were rated good (no or minimal pain, occasional analgesics required, slight limitation of activity), fair (regular analgesics required, noticeable decrease in activity), poor (moderate to severe pain, marked decrease in activity), or failed (arthroplasty required). On the basis of these definitions, 51% of the results were good, 9% were fair, 4% were poor, and 36% were failed. Results were satisfactory in 94% at two years, 87% at five years, and 69% at ten years. The absolute amount of angular correction did not correlate with the results. The change in axial alignment with time was unpredictable. Gender and age of patient were not factors in the outcome, although women seemed to require a longer period to become support-free. Better long-term results were obtained if the correction was to 10 degrees or more of anatomic valgus.

Total knee arthroplasty in Paget's disease of the knee.

Seven patients with Paget's disease about the knee underwent total knee arthroplasty; they accounted for 0.1% of the population who underwent knee arthroplasty at the author's institution. The results were satisfactory at up to 12 years of follow-up study. Two patients had radiographic evidence of loosening, but neither required revision.

The control of deviant sexual behaviour by drugs. I. Behavioural changes following oestrogens and anti-androgens.

PIP: Using attitudinal, behavorial, and physiological measures, the effects of cyproterone acetate and ethinyl estradiol on the sexual behavior of sexual offenders was assessed. The effects of the drugs did not differ significantly on any measure. Compared to no treatment, both drugs lowered sexual interest and sexual activity. Sexual attitudes were not changed. No important side effects were noted. These studies do not indicate what long-term side effects might be expected. Further research will be needed to determine these. Since estrogens carry the risk of serious and irreversible side effects, cyproterone acetate seems to be more desirable for controlling sexual behavior.^ieng

Three-dimensional kinematics of ankle instability following serial sectioning of lateral collateral ligaments.

Triaxial kinematics of ankle instability were studied in vitro by applying an inversion force to seven nonaxially loaded cadaveric ankle-foot specimens. In intact specimens, mean maximal adduction of the tibia with respect to the calcaneus was 38 degrees and mean maximal external rotation was 24 degrees; maximal displacement occurred near full plantar flexion. Increases after release of ligaments were as follows: calcaneofibular, maximal adduction 10%, external rotation 3% near 15 degrees of plantar flexion; anterior talofibular, adduction 30%, external rotation 8% at 30 degrees of plantar flexion; both, adduction 41%, external rotation 65% near 0 degree of flexion; all three lateral collateral, adduction 42%, external rotation 240% in slight dorsiflexion. Regardless of the status of the lateral collateral ligaments, the talus adducted and externally rotated 18 degrees +/- 1 degree with respect to the calcaneus. Hence, collateral ligament release had no effect on subtalar motion.

Ankle instability: comparison of primary repair and delayed reconstruction after long-term follow-up study.

Twenty-five consecutive primary ligament repairs and 40 delayed reconstructions for lateral collateral ankle ligament injuries were studied. Response to a questionnaire provided a 94% subjective evaluation at a mean of 9.5 years after surgery; 97% of patients were satisfied with the surgical result. Clinical examination, stress radiography, and biomechanical gait analysis studies were performed on 39 patients at four years or more after surgery (mean, 9.6 years). In 14% of those with ligament repair and 41% of those with reconstructive procedures, mean residual talar tilt with stress testing was 3.2 degrees and 5.2 degrees, respectively. Gait studies did not demonstrate a consistent abnormal gait pattern, even with side slope walking, and did not correlate with the talar tilt values. There was no significant measurable difference between the results of repair and reconstruction. Thus, most severe Grade III sprains can be managed nonoperatively, and if late residual instability occurs, a reconstructive procedure can be offered with confidence that the result will be equivalent subjectively and roughly comparable objectively to that of the immediate repair.

Comparison of non-collagenous type IV collagen subunits in human glomerular basement membrane, alveolar basement membrane, and placenta.

This study examines the similarities and differences in the noncollagenous domain (NC1) of type IV collagen from human glomerular basement membrane (hGBM), alveolar basement membrane (hABM), and placenta (hPBM). Following collagenase digestion, NC1 domain was isolated on Bio-Gel A-0.5m or by cation exchange chromatography on S-Sepharose. NC1 from each source was characterized by SDS PAGE, and two dimension NEPHGE/SDS PAGE. Immunoblotting and ELISA inhibition was performed using antibody probes specific for M28 , M28+, M26 and M24 monomer subunits of human NC1. It was observed that all NC1 subunits were present in hGBM and hABM derived material, however M28 and M28+ monomers were absent in hPBM NC1. These findings indicate that while alpha 1(IV) and alpha 2(IV) collagen chains are present in hGBM, hABM and hPBM, alpha 3(IV) and alpha 4(IV) collagen chains are only found in hGBM and hABM but are absent in hPBM. It can now be appreciated that heterogeneity of alpha (IV) chain composition exists in basement membranes from various organs.

Profiles of cognitive performance associated with reading disability in temporal lobe epilepsy.

92 patients with temporal lobe epilepsy (TLE) were classified into reading deficient (RD; N = 41) and non-reading deficient (no-RD; N = 51) groups. A cutoff of 80 was used to further classify patients as having low average or better (AVG: IQ > 79) or below average (LOW: 69 < IQ < 80) intellectual ability. Differences between RD-AVG and no-RD-AVG patients in profiles of performance on cognitive tests were specific to verbal and non-verbal memory and verbal abilities, but not visuoconstructional and executive abilities. RD-LOW patients exhibited globally reduced abilities. Profiles of performance on cognitive tests were sensitive to side of seizure onset in the no-RD AVG group, but not the RD-AVG or RD-LOW groups. These data suggest that a group of patients with TLE and reduced academic achievement exhibit cognitive deficits suggestive of a language learning disability, and that cognitive tests are less sensitive to side of seizure onset in this group.