Sustained endotoxemia leads to marked down-regulation of early steps in the insulin-signaling cascade

OBJECTIVES: To determine the effects of sustained, 3-day endotoxin infusion on early steps of the insulin-signaling pathway in rat liver and skeletal muscle in vivo; to examine insulin signaling in well-established acute endotoxin models of insulin resistance. DESIGN: Prospective, controlled animal study. SETTING: University research laboratory. SUBJECTS: Male Sprague-Dawley rats: 24 in the 3-day endotoxin study, 22 in each acute endotoxin study. INTERVENTIONS: In prolonged endotoxemia studies, endotoxin (1 mg.kg-1.24 hrs-1) was administered via jugular venous catheter for 74 hrs. Insulin was then injected, and liver and skeletal muscle were removed after 5 mins. In acute endotoxemia studies, an endotoxin bolus (1 mg/kg) was administered, and insulin-signaling responses were studied after 4 hrs. MEASUREMENTS AND MAIN RESULTS: In liver of rats with sustained endotoxemia, there were significant decreases in insulin-stimulated tyrosine phosphorylation of insulin receptors (74%), insulin receptor substrate (IRS)-1 (74%), and IRS2 (53%); binding of the p85 subunit of phosphatidylinositide 3-kinase to IRS1 (80%); and IRS1-precipitable phosphatidylinositide 3-kinase activity (>90%). These findings were associated with significant reductions in abundance of insulin receptors (37%), IRS1 (60%), and IRS2 (23%). Signaling in skeletal muscle was similarly affected, with reduced IRS1 phosphorylation (49%), IRS1 abundance (50%), and binding of p85 to IRS1 (57%). Insulin signaling 4 hrs after endotoxin administration was not different from controls. CONCLUSIONS: Prolonged endotoxemia is associated with marked deficits in early steps of the insulin-signaling pathway, which are at least partly explained by reduced abundance of the insulin receptor and IRS proteins. Signaling defects were not evident 4 hrs after endotoxin administration under conditions of adequate nutrition, indicating that insulin resistance develops gradually, may require concomitant malnutrition, and is not reversed by the development of endotoxin tolerance.     

Reconstruction of forearm deformities in multiple cartilaginous exostoses

The management of complex forearm deformities in patients with multiple cartilaginous exostoses is controversial. The objective of this study is to look into the outcome of treatment with the combined use of ulna lengthening, radial osteotomy, and excision of exostosis in our six patients, who all had Masada type 1 deformity of the forearm. Clinical assessment was performed using the pre- and postoperative range of motion of the wrist, forearm and elbow. The chief symptom each patient had was noted as well as the demographic data of all patients. Radiological assessment was performed by checking the degree of negative ulna variance, the radial articular angle, and the degree of carpal slip. The degree of satisfaction of the patients and their parents were noted. Good clinical and radiological results were obtained at a mean follow-up of 2.5 years. All patients and parents were satisfied and there was no recurrence of deformity in the latest follow-up. The authors believe in early and aggressive treatment of Masada type 1 deformity of the wrist and forearm for multiple cartilaginous exostoses with a combination of excision of exostosis, ulna lengthening and radial osteotomy.     

Preoperative FLAC/Granulocyte-Colony-Stimulating Factor Chemotherapy for Stage II Breast Cancer: A Prospective Randomized Trial

Background: Preoperative chemotherapy for stage II breast cancer may reduce locoregional tumors and provides initial treatment for systemic micrometastases. We conducted a prospective, randomized trial to evaluate the ability of intensive preoperative chemotherapy to enhance the outcome of this approach.Methods: Patients with clinical stage II breast cancer (T2N0, T1N1, and T2N1) were prospectively randomized to receive either preoperative or postoperative chemotherapy with five 21-day cycles of fluorouracil, leucovorin calcium, doxorubicin, and cyclophosphamide (FLAC)/granulocyte-colony-stimulating factor. Local therapy consisted of modified radical mastectomy or segmentectomy/axillary dissection/breast radiotherapy, according to patient preference.Results: Fifty-three women were randomized (26 preoperative chemotherapy and 27 postoperative chemotherapy). The objective clinical response rate of the primary tumor to preoperative chemotherapy was 80%, and the pathologic complete response rate was 20%. Preoperative chemotherapy reduced the overall incidence and number of axillary lymph node metastases. There was no difference in the use of breast-conserving local therapy between the two treatment arms. There were 20 local/regional or distant recurrences (9 preoperative and 11 postoperative). There was no difference in the overall or disease-free survival between the preoperative and postoperative chemotherapy arms.Conclusions: Preoperative FLAC/granulocyte-colony-stimulating factor chemotherapy was effective against local/regional tumors in stage II breast cancer but was otherwise comparable to postoperative chemotherapy.     

Rhodococcus equi peritonitis in continuous ambulatory peritoneal dialysis

The human Rhodococcus equi (R. equi) infection is now emerging, although extrapulmonary manifestation and isolation from patients without human immunodeficiency virus (HIV) infection remains unusual. Considerable effort is required to correctly identify and diagnose this facultative pathogen in patients with peritonitis in end-stage renal failure (ESRF) on continuous ambulatory peritoneal dialysis (CAPD). In the six cases of R. equi CAPD peritonitis reported in this series, diagnoses were made, on average, after 15 days and prolonged antibiotic therapy with morbidity in two patients. A diagnosis of R. equi should be considered in patients with suspected diphtheroid or Nocardia CAPD peritonitis, even with no history of animal contact. This study is the largest series on R. equi CAPD peritonitis and highlights the impact of this disease.     

Improved health-related quality of life and left ventricular hypertrophy among dialysis patients treated with parathyroidectomy

BACKGROUND: We prospectively studied changes in the perception of health-related quality of life, pruritus, and degree of left ventricular hypertrophy in end-stage renal disease patients with tertiary hyperparathyroid disorder, before and 6 months after total parathyroidectomy treatment. METHODS: A series of 12 consecutive patients were enrolled. Throughout the follow-up period, all subjects completed the Kidney Disease Quality of Life Short Form-36 (KDQOL SF-36) questionnaire at inclusion and after 6 months. Serial clinical and physiological parameters including uremic pruritus, blood pressure control and left ventricular hypertrophy measured by echocardiography were recorded. RESULTS: Mean scores of the KDQOL SF-36 questionnaires were substantially higher 6 months after parathyroidectomy, with reference to physical functioning, bodily pain, role-physical, role-emotional, symptom list and burden of kidney disease. Parathyroidectomy resulted in a 22% reduction in left ventricular mass index, with significant improvement from the baseline value of 246 +/- 131 to 192 +/- 131 g/m2 (p = 0.03). CONCLUSION: Our findings highlight the potential importance of parathyroidectomy in improving health-related quality of life and left ventricular hypertrophy among dialysis patients with tertiary hyperparathyroidism.     

Kinematic Analysis of Javelin Throw Performed by Wheelchair Athletes of Different Functional Classes

The purpose of this study was to identify those kinematic characteristics that are most closely related to the functional classification of a wheelchair athlete and measured distance of a javelin throw. Two S-VHS camcorders (60 field·s^-1) were used to record the performance of 15 males of different classes. Each subject performed 6-10 throws and the best two legal throws from each subject were selected for analysis. Three-dimensional kinematics of the javelin and upper body segments at the instant of release and during the throw (delivery) were determined. The selection of kinematic parameters that were analyzed in this study was based on a javelin throw model showing the factors that determine the measured distance of a throw. The average of two throws for each subject was used to compute Spearman rank correlation coefficients between selected parameters and measured distance, and between selected parameters and the functional classification. The speeds and angles of the javelin at release, ranged from 9.1 to 14.7 m·s^-1 and 29.6 to 35.8°, respectively, were smaller than those exhibited by elite male able-bodied throwers. As expected, the speed of the javelin at release was significantly correlated to both the classification (p<0.01) and measured distance (p<0.001). Of the segmental kinematic parameters, significant correlations were found between the trunk inclination at release and classification and between the angular speed at release and measured distance (p<0.01 for both). The angular speed of the shoulder girdle at release and the average angular speeds of the shoulder girdle during the delivery were significantly correlated to both the classification and measured distance (p<0.05). The results indicate that shoulder girdle movement during the delivery is an important determinant of classification and measured distance.Key words: Biomechanics, disability, athletics, field events     

Surgical management of endoscopic retrograde cholangiopancreatography-related perforations

Background: A retrospective review was carried out of consecutive cases of endoscopic retrograde cholangiopancreatography (ERCP)‐related perforation to identify risk factors and technique affecting surgical outcome. Methods: Eighteen patients (0.45%) out of 4030 ERCP performed were operated on for ERCP‐related perforation at Singapore General Hospital. Results: The group's median age was 72.5 years and 14 patients had ductal stone disease. Five perforations were discovered at ERCP while 10 required computed tomography for diagnosis. Eight patients were operated on within 24 h whereas 10 patients had surgery after 24 h. Five of six with type I (lateral duodenal) perforations had early surgery versus one of seven with type II (peri‐Vaterian; P = 0.03). There were four type III (bile duct) perforations and one type IV (retroperitoneal air). Five of six patients with type I perforation had simple repair compared with five of seven type II requiring the complex duodenal diversion procedure (P = 0.10). Three patients (16.7%) succumbed after surgery due to sepsis and myocardial infarction. Advanced age>70 years resulted in higher mortality of 30% versus none in patients <70 years (P = 0.22). Conclusions: Early diagnosis is important but difficult especially for the type II perforations. Duodenal diversion is used more frequently in patients with type II perforations and those operated on late. Advanced age contributes to poorer outcome in surgical treatment of ERCP perforations.