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.

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.

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.

Evaluation of the accuracy and response time of STAT-mode continuous cardiac output.

OBJECTIVES: This study was conducted to compare continuous cardiac output (CCO) with bolus thermodilution cardiac output (BTD) at steady state, and to compare the response time of STAT CCO with that of trend CCO, mean arterial pressure, and mixed venous oxygen saturation [SvO2] during an acute hemodynamic change. DESIGN: Prospective study. SETTING: University hospital. PARTICIPANTS: Twenty-nine patients undergoing cardiac surgery or liver transplantation. INTERVENTIONS: STAT and trend CCO were compared with BTD cardiac output during steady state intraoperatively and postoperatively in the intensive care unit. Ten patients, who required epicardial pacing after cardiac surgery, were studied to compare the response time of STAT CCO with that of trend CCO, mean arterial pressure, and BvO2 after a 10% to 20% increase in pacing rate. MEASUREMENTS AND MAIN RESULTS: A total of 108 cardiac output data sets were analyzed at steady state. Steady state was defined as stable heart rate and mean arterial pressure (+/- 5%) and stable central venous pressure (+/- 2 mmHg) measured immediately before and after each data set. Cardiac output ranged from 2.3 to 8.5 L/min. The correlation between STAT CCO and BTD was r = 0.94, and for trend CCO and BTD was r = 0.94. The bies and precision for STAT CCO versus BTD were 0.06 L/min (Cl 95%: -0.08 to 0.18) and 0.61 L/min. The bias and precision for trend CCO versus BTD were 0.06 L/min (Cl 95%: -0.04 to 0.16) and 0.49 L/min. Eleven data sets were analyzed to study response time of STAT CCO, which was defined as the first time the percent change of the mean of each variable was significantly increased from baseline. Significant increases in mean arterial pressure and SvO2 were detected after 30 seconds (2.5%, p = 0.01) and 90 seconds (2.0%, p = 0.04), respectively. A significant increase in STAT CCO was reached at 270 seconds (4.4%, p = 0.005). Trend CCO tended to increase but did not reach statistical significance within 6 minutes. CONCLUSIONS: STAT and trend CCO are accurate and precise and show close agreement with BTD cardiac output at steady state. The faster algorithm of STAT CCO offers some advantage over trend CCO during an acute hemodynamic change. However, because of the averaging process for determining CCO, the response time of STAT CCO is slower than that of mean arterial pressure and SvO2.

Anesthesia type does not influence early graft patency or limb salvage rates of lower extremity arterial bypass.

PURPOSE: The effect of anesthesia type on 30-day graft patency and limb salvage rates was evaluated in patients who underwent femoral to distal artery bypass. METHODS: Of 423 patients randomly assigned to receive general, spinal, or epidural anesthetic, 76 did not meet protocol standards and 32 had inadequate anesthesia. A chart review of the remaining 315 patients was undertaken to obtain surgical information not recorded in the original study. All patients were monitored with radial and pulmonary artery catheters. After surgery, patients were in a monitored setting for 48 to 72 hours and had graft function assessments hourly during the first 24 hours and then every 8 hours until discharge. RESULTS: Fifty-one patients were lost to follow-up (15 general, 22 spinal, 14 epidural). Baseline clinical characteristics were similar for the three groups except prior carotid artery surgery, which was more common in the spinal group. Indications for surgery were also similar except for a higher incidence of nonhealing ulcer in the epidural group. There were no differences among groups for 30-day graft patency with or without reoperation, 30-day graft occlusion, death, amputation, or length of hospital stay. CONCLUSION: These results suggest that the type of anesthetic given for femoral to distal artery bypass does not significantly affect 30-day occlusion rate, limb salvage rate, or hospital length of stay.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.