Acute and chronic effects of insulin on leptin production in humans: Studies in vivo and in vitro

This study was undertaken to investigate the changes in obesity (OB) gene expression and production of leptin in response to insulin in vitro and in vivo under euglycemic and hyperglycemic conditions in humans. Three protocols were used: 1) euglycemic clamp with insulin infusion rates at 40, 120, 300, and 1,200 mU / m / min carried out for up to 5 h performed in 16 normal lean individuals, 30 obese individuals, and 31 patients with NIDDM; 2) 64-to 72-h hyperglycemic (glucose 12.6 mmol/l) clamp performed on 5 lean individuals; 3) long-term (96-h) primary culture of isolated abdominal adipocytes in the presence and absence of 100 nmol/l insulin. Short-term hyperinsulinemia in the range of 80 to > 10,000 microU/ml had no effect on circulating levels of leptin. During the prolonged hyperglycemic clamp, a rise in leptin was observed during the last 24 h of the study (P < 0.001). In the presence of insulin in vitro, OB gene expression increased at 72 h (P < 0.01), followed by an increase in leptin released to the medium (P < 0.001). In summary, insulin does not stimulate leptin production acutely; however, a long-term effect of insulin on leptin production could be demonstrated both in vivo and in vitro. These data suggest that insulin regulates OB gene expression and leptin production indirectly, probably through its trophic effect on adipocytes.     

Complications associated with pectoral cardioverter-defibrillator implantation: comparison of subcutaneous and submuscular approaches. Worldwide Jewel Investigators

OBJECTIVES: The aim of this study was to compare complications in a large cohort of patients undergoing pectoral cardioverter-defibrillator implantation with a subcutaneous or submuscular approach. BACKGROUND: Pectoral placement of implantable cardioverter-defibrillator (ICD) pulse generators is now routine because of downsizing of these devices. subcutaneous implantation has been advocated by some because it is a simple surgical procedure comparable to pacemaker insertion. Others have favored submuscular insertion to avoid wound complications. These surgical approaches have not been compared previously. METHODS: The subjects for this study were 1,000 consecutive patients receiving a Medtronic Jewel ICD at 93 centers worldwide. Cumulative follow-up for all patients was 633.7 patient-years, with 64.9% of patients followed up for > or = 6 months. The complications evaluated were erosion, pocket hematoma, seroma, wound infection, dehiscence, device migration, lead fracture and dislodgment. RESULTS: Subcutaneous implantation was performed in 604 patients and submuscular implantation in the remaining 396. The median procedural times were shorter for subcutaneous implantation (p = 0.014). In addition, the cumulative percentage of patients free from erosion was greater for subcutaneous implantations (p = 0.03, 100% vs. 99.1% at 6 months). However, lead dislodgment was more common with subcutaneous implantations (p = 0.019, 2.3% vs. 0.5% at 6 months) and occurred primarily during the first month postoperatively. Overall, there were no significant differences in cumulative freedom from complications between groups (4.1% vs. 2.5%, p = 0.1836). CONCLUSIONS: Subcutaneous pectoral implantation of this ICD can be performed safely and has a low complication rate. This approach requires a simple surgical procedure and, compared with the submuscular approach, is associated with shorter procedure times and comparable overall complication rates. However, early follow-up is important in view of the increased lead dislodgment rate.     

Role of the thrombin receptor's cytoplasmic tail in intracellular trafficking. Distinct determinants for agonist-triggered versus tonic internalization and intracellular localization

The G protein-coupled thrombin receptor is activated by an irreversible proteolytic mechanism and, perhaps as a result, exhibits an unusual trafficking pattern in the cell. Naive receptors tonically cycle between the cell surface and a protected intracellular pool, whereas receptors cleaved and activated at the cell surface internalize and move to lysosomes. Toward understanding how these trafficking events are regulated, we examined a series of receptor mutants. A receptor with alanine substitutions at all potential phosphorylation sites in the cytoplasmic tail failed to display agonist-triggered internalization but, like wild type receptor, displayed robust signaling, tonic cycling, and localization to both the cell surface and an intracellular pool. A truncation mutant that lacked most of the cytoplasmic tail also signaled robustly, lacked phosphorylation, and was defective in agonist-triggered internalization. However, in contrast to the specific phosphorylation site mutant, the truncation mutant did not display tonic cycling and localized exclusively to the cell surface. An analysis of a series of truncation mutants localized residues important for receptor trafficking to a 10-amino acid stretch in its cytoplasmic tail. These data suggest that phosphorylation may trigger internalization of activated thrombin receptors but that a second phosphorylation-independent signal mediates tonic internalization of naive receptors. They further suggest that maintenance of the intracellular pool of naive thrombin receptors requires tonic receptor internalization.     

Load to failure of common meniscal repair techniques: effects of suture technique and suture material

Success of meniscal repair with early or immediate motion depends on the ability of the suture fixation to withstand the loads applied. Vertical and horizontal mattress suture techniques were tested using 2-0 Ethibond, and 0-PDS and 1-PDS sutures (Ethicon, Somerville, NJ). Mulberry knot technique was tested with 0-PDS and 1-PDS sutures. Twenty menisci (60 sutures) were tested for each suture material. Sutures were placed 3 to 4 mm from the peripheral edge of the meniscus with double barreled cannulas for vertical and horizontal mattress techniques or a spinal needle for the mulberry knot technique, reproducing clinical techniques of meniscal repair. Mechanical testing of suture fixation was performed to failure at a rate of 10 mm/min on a MTS material testing system (MTS Systems Corp, Minneapolis, MN). Suture pullouts were reported as the load displacement to failure from the inner fragment only, because clinical failure would ensue should a suture pull through the inner fragment of a tear. Vertical mattress technique with 1-PDS suture had significantly greater load to failure than any other combination (P < .05). Analysis of variance showed that the vertical mattress technique had statistically superior pullout strength (P < .0001) compared with the horizontal mattress and mulberry knot techniques, which were statistically similar. There were significant differences (P < .0001) between suture types, with 1-PDS proving best compared with 0-PDS, which was stronger than 2-0 Ethibond. Selection of suture material had the greatest impact on vertical mattress load to failure and was not important to the strength of the other techniques.     

4-Aminoquinoline resistance of Plasmodium falciparum: insights from the study of amodiaquine uptake

The relationship between antimalarial activity and drug accumulation of chloroquine and amodiaquine was evaluated with four chloroquine-resistant and two chloroquine-susceptible isolates of Plasmodium falciparum. Susceptibility of the strains to amodiaquine was correlated with susceptibility to chloroquine (r2 = 0.96). Similarly, accumulation of amodiaquine was correlated with accumulation of chloroquine (r2 = 0.94). Accumulation of both chloroquine and amodiaquine was significantly reduced in chloroquine-resistant isolates (p < 0.005). For the panel of isolates, the accumulation ratio of both drugs was inversely proportional to drug susceptibility (r2 = 0.963 and 0.994 for amodiaquine and chloroquine, respectively). Time course studies highlighted a reduced initial rate of amodiaquine accumulation in chloroquine-resistant isolates compared with chloroquine-susceptible isolates, with no evidence of an enhanced drug efflux rate. Daunomycin, a modulator of parasite chloroquine transport, significantly increased steady state accumulation of both drugs in chloroquine-resistant isolates and, to a lesser extent, in chloroquine-susceptible isolates. Furthermore, daunomycin increased the initial rate of accumulation of amodiaquine in both chloroquine-resistant and chloroquine-susceptible isolates. Resistance to 4-aminoquinoline drugs is associated with reduced drug permeability rather than enhanced cellular exit of preaccumulated drug, and daunomycin seems to increase the permeability of parasites to aminoquinolines. A new model of 4-aminoquinoline resistance is proposed to take account of these and earlier observations.     

Molecular mimicry as a therapeutic approach for an autoimmune disease: oral treatment of uveitis-patients with an MHC-peptide crossreactive with autoantigen--first results

In the rat model of experimental autoimmune uveitis (EAU) we have demonstrated that a peptide from the sequence of human disease-associated MHC-class I antigens can induce uveitis upon immunization. Moreover, oral administration of this MHC-peptide tolerized Lewis rats to the disease induced with two different retinal autoantigens, retinal S-antigen (S-Ag) and IRBP. In uveitis patients T cells responding to S-Ag peptide also respond to the MHC-peptide, which shows crossreactivity with the major epitope from S-Ag due to some shared discontinuous amino acid homologies. The 14-mer peptide B27PD is derived from the sequence of all HLA-B antigens that are statistically associated with uveitis (including HLA-B27). Patients with long-lasting endogenous uveitis, suffering from side effects of conventional immuno-suppressive therapy or being therapy-refractive, were orally tolerized with peptide B27PD in this first open therapeutic trial. Patients received peptide three times a week over a 12 weeks period, while only low dose steroids were allowed as concomitant medication. The aims were (1) to investigate whether immunosuppressive therapy could be discontinued and steroids reduced while relapses of ocular inflammation reside and (2) to search for side effects. The Helsinki Declaration was strictly observed and the study design approved by the local ethical committee. The first patients orally tolerized with the HLA-peptide (two had stopped azathioprine immediately prior to onset of oral peptide treatment) could discontinue their steroids because of reduced intraocular inflammation. No side effects of therapy were observed. Oral tolerance induction with a peptide derived from the patients' own HLA-antigens and crossreactive with the organ-specific autoantigen seems to be a potent therapeutic approach.     

Patterns of recovery among Norwegian heart surgery patients

Utilizing a prospective longitudinal design, the recovery pattern of 91 heart patients was followed for the first 8 weeks following coronary artery by-pass graft surgery. The patients' perceived and actual performance of walking, their resumption of roles, and social support and family functioning were measured pre-operatively and at 4 and 8 weeks postoperatively. Findings indicate that recovery is swift in terms of health and physical functioning, somewhat more time-consuming in terms of role functioning, and delayed with regard to work-related role activities. Contrary to American findings, the heart surgery recovery process did not significantly affect family functioning in this Norwegian sample. Social support was experienced as high throughout the recovery period, with spouses and children being the main providers.     

Isolated traumatic dislocation of the hip. Long-term results in 50 patients

From 1974 to 1989, we treated 50 patients with a simple dislocation of the hip: 38 were posterior dislocations and 12 were anterior. All dislocations primarily treated at our hospital were reduced by closed methods within three hours (mean 85 minutes (10 to 180)) and 43 were reviewed after an average follow-up of 8 years (2 to 17). It is widely held that isolated hip dislocation reduced within six hours gives an excellent outcome, but we found a significant number of complications. There were radiological signs of partial avascular necrosis in two, mild osteoarthritis in seven, and moderate degeneration in two. Heterotopic ossification was seen in four patients, but 29 of 33 MRI examinations were normal. Objective evaluation according to the Thompson and Epstein (1951) criteria showed fair and poor results in 3 of 12 anterior dislocations, but in 16 of 30 posterior dislocations. In six of the seven patients with no other severe injury, the hip had an excellent or good result; in only three of the eight patients with severe multiple injuries was this the case. The important factors in the long-term prognosis appear to be the direction of the dislocation and the overall severity of injuries.