Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients

We characterized metabolic and mitogenic signaling pathways in isolated skeletal muscle from well-matched type 2 diabetic and control subjects. Time course studies of the insulin receptor, insulin receptor substrate (IRS)-1/2, and phosphatidylinositol (PI) 3-kinase revealed that signal transduction through this pathway was engaged between 4 and 40 min. Insulin-stimulated (0.6-60 nmol/l) tyrosine phosphorylation of the insulin receptor beta-subunit, mitogen-activated protein (MAP) kinase phosphorylation, and glycogen synthase activity were not altered in type 2 diabetic subjects. In contrast, insulin-stimulated tyrosine phosphorylation of IRS-1 and anti-phosphotyrosine-associated PI 3-kinase activity were reduced 40-55% in type 2 diabetic subjects at high insulin concentrations (2.4 and 60 nmol/l, respectively). Impaired glucose transport activity was noted at all insulin concentrations (0.6-60 nmol/l). Aberrant protein expression cannot account for these insulin-signaling defects because expression of insulin receptor, IRS-1, IRS-2, MAP kinase, or glycogen synthase was similar between type 2 diabetic and control subjects. In skeletal muscle from type 2 diabetic subjects, IRS-1 phosphorylation, PI 3-kinase activity, and glucose transport activity were impaired, whereas insulin receptor tyrosine phosphorylation, MAP kinase phosphorylation, and glycogen synthase activity were normal. Impaired insulin signal transduction in skeletal muscle from type 2 diabetic patients may partly account for reduced insulin-stimulated glucose transport; however, additional defects are likely to play a role.     

Effect of ATP-potassium channel opener nicorandil on long-term cardiac preservation

BACKGROUND: ATP-sensitive potassium channels have been shown to be one of the important protective mechanisms for the ischemic myocardium. The purpose of this study was to evaluate the protective effect of nicorandil, an ATP-sensitive potassium channel opener, on myocardium during 6 hours hypothermic preservation. METHODS: Preserved rat hearts were randomly divided into 4 groups according to cardioplegia and preservation protocols as follows: (1) histidine-tryptophan-ketoglutarate solution (HTK) for both cardioplegic and immersing solutions (group A); (2) nicorandil-added HTK for cardioplegic solution and nicorandil-free HTK for immersing solution (group B); (3) nicorandil-free HTK for cardioplegic solution and nicorandil-added HTK for immersing solution (group C); and (4) nicorandil-added HTK for both cardioplegic and immersing solutions (group D). RESULTS: The recovery of postischemic cardiac function, including left ventricular developed pressure and end-diastolic pressure, was significantly improved in group B and group C as compared with the other groups (p<0.05). Postischemic intracellular calcium concentration was significantly lower in group B and group C than in group A (p<0.05). CONCLUSIONS: We concluded that nicorandil-induced hyperpolarizing arrest could reduce ischemia-derived myocyte injury and inhibit the influx of calcium into the myocytes in long-term cardiac preservation.     

Complete atrioventricular septal defect associated with tetralogy of Fallot. Favourable outcome of transatrial transpulmonary repair

BACKGROUND: Complete correction of atrioventricular septal defect (AVSD) associated with tetralogy of Fallot (TOF) has been reported to account for an increased surgical risk. Impaired right ventricular function after classic transventricular repair, residual outflow tract stenosis, and incompetence of the pulmonary or atrioventricular valves are considered to be essential factors affecting the results. METHODS: From 3/95 to 6/98 six consecutive patients with AVSD and TOF underwent repair (age 18 months to 7.3 years) using a combined transatrial-transpulmonary approach. RV outflow tract balloon dilatation preceded transatrial correction in 4 patients. Pulmonary annulotomy but not transanular patching was necessary in 4 cases. The septal defects were closed by two separate patches using a Dacron patch with short depth and anterior extension for the ventricular component. RESULTS: All patients survived and had stable sinus rhythm. Echocardiography demonstrated mild, but hemodynamically insignificant mitral regurgitation in two and tricuspid regurgitation in four patients. Right ventricle to pulmonary artery gradients ranged from 5 to 35 mmHg (mean 24.2 mmHg) without progression. During follow-up ranging from 4 months to 3.5 years (mean 16.8 months) no reoperation was necessary. CONCLUSIONS: The transatrial-transpulmonary approach for correction of AVSD with TOF contributes to improved results after repair of this rare combination of defects.     

Impact of hollow-fiber membrane surface area on oxygenator performance: Dideco D903 Avant versus a prototype with larger surface area

This study compares the gas transfer capacity, the blood trauma, and the blood path resistance of the hollow-fiber membrane oxygenator Dideco D 903 with a surface area of 1.7 m2 (oxygenator 1.7) versus a prototype built on the same principles but with a surface area of 2 m2 (oxygenator 2). Six calves (mean body weight: 68.2 +/- 3.2 kg) were connected to cardiopulmonary bypass (CPB) by jugular venous and carotid arterial cannulation, with a mean flow rate of 4 l/min for 6 h. They were randomly assigned to oxygenator 1.7 (N = 3) or 2 (N = 3). After 7 days, the animals were sacrificed. A standard battery of blood samples was taken before the bypass, throughout the bypass, and 24 h, 48 h, and 7 days after the bypass. The oxygenator 2 group showed significantly better total oxygen and carbon dioxide transfer values throughout the perfusion (p < .001 for both comparison). Hemolytic parameters (lactate dehydrogenase and free plasma hemoglobin) exhibited a slight but significant increase after 5 h of bypass in the oxygenator 1.7 group. The pressure drop through the oxygenator was low in both groups (range, 43-74 mmHg). With this type of hollow-fiber membrane oxygenator, an increased surface of gas exchange from 1.7 m2 to 2 m2 improves gas transfer, with a limited impact on blood trauma and no increase of blood path resistance.     

The extent of biopsy involvement as an independent predictor of extraprostatic extension and surgical margin status in low risk prostate cancer: implications for treatment selection

PURPOSE: We identify predictors of extraprostatic extension and positive surgical margins in patients with low risk prostate cancer (prostate specific antigen [PSA] 10 ng./ml. or less, biopsy Gleason score 7 or less and clinical stage T1c-2b). MATERIALS AND METHODS: From August 1997 to January 1999, 143 previously untreated patients underwent radical retropubic prostatectomy for clinically localized prostate cancer. A total of 62 patients were low risk, with PSA 10 ng./ml. or less, biopsy Gleason score 7 or less and clinical stage T1c-2b, and had sextant biopsy with separate pathological evaluation of each sextant cores. PSA, clinical stage, biopsy Gleason score, average percentage of cancer in the entire biopsy specimen, maximum percentage of cancer on the most involved core, number of cores involved and bilaterality were evaluated for association with extraprostatic extension, seminal vesicle involvement and positive surgical margins. RESULTS: Of the 62 patients 13 (21%) had extraprostatic extension, 6 (10%) seminal vesicle involvement and 20 (32%) positive surgical margins. Average percentage greater than 10% and maximum percentage greater than 25% were associated with extraprostatic extension (p = 0.01 and 0.004, respectively). Average percentage greater than 10%, maximum percentage greater than 25%, more than 2 cores involved and bilaterality were associated with positive surgical margins (p = 0.007, 0.01, 0.002 and 0.03, respectively). On multivariate analysis maximum percentage remained the only independent predictor of extraprostatic extension (p = 0.03), and the number of cores involved remained an independent predictor of positive surgical margins (p = 0.01). Biopsy Gleason score, PSA and clinical stage did not correlate with extraprostatic extension or positive surgical margins in this patient population. CONCLUSIONS: In low risk prostate cancer the extent of biopsy involvement significantly correlates with the risk of extraprostatic extension and positive surgical margins. Biopsy information should be considered when selecting and modifying treatment modalities.     

Quantitative description of the far-lateral transcondylar transtubercular approach to the foramen magnum and clivus

OBJECT: The purpose of this study was to evaluate the far-lateral transcondylar transtubercular approach (complete FLA) based on quantitative measurements of the exposure of the foramen magnum and petroclival area obtained after each successive step of this approach. METHODS: The complete FLA was reproduced in eight specially prepared cadaveric heads (a total of 15 sides). The approach was divided into six steps: 1) C-1 hemilaminectomy and suboccipital craniectomy with unroofing of the sigmoid sinus (basic FLA); 2) partial resection of the occipital condyle (up to the hypoglossal canal); 3) removal of the jugular tuberculum; 4) mastoidectomy (limited to the labyrinth and the fallopian canal) and retraction of the sigmoid sinus; 5) resection of the lateral mass of C-1 with mobilization of the vertebral artery; and 6) resection of the remaining portion of the occipital condyle. After each successive step, a standard set of measurements was obtained using a frameless stereotactic device. The measurements were used to estimate two parameters: the size of the exposed petroclival area and the size of a spatial cone directed toward the anterior rim of the foramen magnum, which depicts the amount of surgical freedom available for manipulation of instruments. The initial basic FLA provided exposure of only 21 +/- 6% of the petroclival area that was exposed with the full, six-step maximally aggressive (complete) FLA. Likewise, only 18 +/- 9% of the final surgical freedom was obtained after the basic FLA was performed. Each subsequent step of the approach increased both petroclival exposure and surgical freedom. The most dramatic increase in petroclival exposure was noted after removal of the jugular tuberculum (71 +/- 12% of final exposure), whereas the least improvement in exposure occurred after the final step, which consisted of total condyle resection. CONCLUSIONS: The complete FLA provides wide and sufficient exposure of the foramen magnum and lower to middle clivus. The complete FLA consists of several steps, each of which contributes to increasing petroclival exposure and surgical freedom. However, the FLA may be limited to the less aggressive steps, while still achieving significant exposure and surgical freedom. The choice of complete or basic FLA thus depends on the underlying pathological condition and the degree of exposure required for effective surgical treatment.     

Use of alternative medicine by patients undergoing cardiac surgery

OBJECTIVE: Complementary and alternative medicine may influence cardiac surgical care by inducing coagulopathies and interacting with perioperative medications. We evaluated the significance of complementary and alternative medicine use in an acutely ill cardiac surgical population and assessed the willingness of patients to reveal these activities to their physicians and surgeons. METHODS: A total of 376 consecutive patients undergoing preoperative or postoperative cardiothoracic surgical evaluations at an urban academic medical center were approached to complete a survey regarding use and attitudes toward complementary and alternative medicine. All surveys were administered and collected between March and May 1998. RESULTS: Completion rate was 70% (n = 263). Respondents were predominantly male (72%), white (76%), and well educated (59%). The overall rate of complementary and alternative medicine use was 75%, but excluding prayer and vitamins, which are often not considered complementary and alternative medicine therapies, the rate was 44%. There was no correlation between the use of complementary and alternative medicine and the parameters of gender, age, race, or education level. Only 17% responded that they had discussed complementary and alternative medicine with their physicians, and 48% responded that they did not want to discuss the topic at all. CONCLUSIONS: Complementary and alternative medicine is used as frequently in patients undergoing cardiac surgery, as in the general population. Physicians and surgeons should be aware that patients have no inherent predisposition toward or against using complementary and alternative medicine, but that they are unlikely to volunteer their experience with it. The unwillingness of patients to discuss complementary and alternative medicine with physicians has serious implications for their safety, especially in acute care situations.     

Recombinant human complement C5a receptor antagonist reduces infarct size after surgical revascularization

OBJECTIVES: This study tested the hypothesis that a recombinant human C5a antagonist, CGS 32359, attenuates neutrophil activation and reduces infarct size in a porcine model of surgical revascularization. METHODS: CGS 32359 (0.16-16 micromol/L) dose-dependently inhibited superoxide production by human C5a-activated porcine neutrophils (18 +/- 3.7 vs 1.6 +/- 0.5 nmol/5 min/5 x 10(6) neutrophils; P <.05) and reduced neutrophil adherence to coronary endothelium from 194 +/- 9 to 43 +/- 6 neutrophils/mm(2) (P <.05). The left anterior descending coronary artery was occluded for 50 minutes, after which saline solution (n = 8), mannitol-buffer vehicle (n = 9, 102 mg/kg bolus, 102 mg. kg(-1). h(-1)), or CGS 32359 (CGS, n = 7, 60 mg/kg bolus, 60 mg. kg(-1). h(-1)) was infused. After ischemia, 1-hour arrest was achieved by means of multidose hypothermic (4 degrees C) blood cardioplegia, followed by 2.5 hours of off-bypass reperfusion. The ligature on the left anterior descending artery was released before the second infusion of cardioplegic solution. RESULTS: Area at risk was similar in all groups (saline solution, 27% +/- 2%; mannitol-buffer vehicle, 26% +/- 2%; CGS, 26% +/- 2% left ventricular mass). Infarct size (area necrosis/area at risk) was significantly reduced by CGS (18% +/- 6%, P <.05) versus saline solution (52% +/- 3%) and mannitol-buffer vehicle (60% +/- 4%). Postischemic systolic shortening (sonomicrometry) in the area at risk was significantly improved with CGS (0.8% +/- 0.9%) compared with saline solution (-3.7% +/- 1.1%) and mannitol-buffer vehicle (-6.4% +/- 1.0%). Myeloperoxidase activity from accumulated neutrophils was less in the ischemic zone of CGS (0.014 +/- 0.002 U/100 mg tissue; P <.05) than mannitol-buffer vehicle (0.133 +/- 0.012 U/100 mg tissue). CONCLUSIONS: We conclude that the recombinant human C5a receptor antagonist CGS 32359 inhibits surgical ischemia-reperfusion injury after coronary occlusion.     

Polyimide cuff electrodes for peripheral nerve stimulation

This paper describes a new tripolar spiral cuff electrode, composed of a thin (10 microm) and flexible polyimide insulating carrier and three circumneural platinum electrodes, suitable for stimulation of peripheral nerves. The cuffs were implanted around the sciatic nerve of two groups of ten rats each, one in which the polyimide ribbon was attached to a plastic connector to characterize the in vivo stimulating properties of the electrode, and one without a connector for testing possible mechanical nerve damage by means of functional and histological methods. The polyimide cuff electrodes induced only a very mild foreign body reaction and did not change the nerve shape over a 2-6 month implantation period. There were no changes in the motor and sensory nerve conduction tests, nociceptive responses and walking track pattern over follow-up, and no morphological evidence of axonal loss or demyelination, except in one case with partial demyelination of some large fibers after 6 months. By delivering single electrical pulses through the cuff electrodes graded recruitment curves of alpha-motor nerve fibers were obtained. Recruitment of all motor units was achieved with a mean charge density lower than 4 microC/cm(2) for a pulse width of 50 micros at the time of implantation as well as 45 days thereafter. These data indicate that the polyimide cuff electrode is a stable stimulating device, with physical properties and dimensions that avoid nerve compression or activity-induced axonal damage.     

Sleep loss and daytime sleepiness in the general adult population of Japan

Presynaptic dopamine metabolism was studied in a group of patients with schizophrenia and in an age- and gender-matched normal control group using 6-[(18)F]fluoro-L-DOPA ((18)F-DOPA) and positron emission tomography (PET). Nineteen patients, nine drug-free, 10 on neuroleptics, and 13 normal control subjects underwent PET scans using (18)F-DOPA. The neuroleptic-treated patients were taking typical neuroleptics (N=4) or the atypical neuroleptic, clozapine (N=6). The ratio of specific/non-specific activity was calculated for eight cortical and subcortical regions of interest. Medication-free patients had a significant reduction in (18)F-DOPA uptake in the ventral striatum (P=0.04) and significantly increased uptake in the posterior cingulate (P=0.02) compared with normal control subjects. The 18F-DOPA PET technique proved to be useful and sensitive in detecting changes in dopamine metabolism in patients with schizophrenia in vivo. The results of this study provide evidence of an aberrant dopamine system in schizophrenia.