Leptin stimulates the release of pro-inflammatory cytokines in hypothalamic astrocyte cultures from adult and aged rats

Metabolic Brain Disease - Leptin is an adipose tissue-derived hormone that acts on the hypothalamus in order to maintain energy homeostasis. However, leptin can also induce an inflammatory...     

Objectively measured daily-life physical activity of moderate-to-severe Brazilian asthmatic women in comparison to healthy controls: A cross-sectional study

Considering the complex relationship between asthma symptoms and exercise, asthmatics are usually believed to be less active in daily life than healthy subjects. However, few studies have objectively assessed daily-life physical activity (DLPA) of asthmatic adults. Objective: To objectively assess DLPA of a sample of Brazilian asthmatic women in comparison to healthy controls, and to investigate the associations between DLPA and asthma control, health-related quality of life, anxiety and depression levels, and the Six-minute walk test (6MWT) in this population. Methods: Sixty-six women were included, 36 in the asthma group (AG) and 30 in the control group (CG). The AG was composed by clinically stable moderate-to-severe asthmatics. The CG was composed by apparently healthy volunteers. All subjects underwent DLPA assessment (considered as the average of steps taken during six consecutive days measured by a pedometer) and performed the 6MWT. Additionally, participants in the AG were assessed using the Asthma Control Questionnaire, the Asthma Quality of Life Questionnaire (AQLQ), and the Hospital Anxiety and Depression Scale. Results: There was no difference between the AG and the CG regarding DLPA (7490.3 ± 3330.2 vs 6876.4 ± 3242.1 steps respectively, p = 0.45), even after adjustment for covariates. DLPA was significantly correlated to the activity limitation domain of the AQLQ among asthmatics (r = 0.43, p < 0.01). Conclusion: Despite the association between self-perceived activity limitation and DLPA among asthmatics, there were no differences regarding DLPA between a sample of moderate-to-severe Brazilian asthmatic women and apparently healthy controls.     

Development and validation of the Workplace Interruptions Measure

In 3 studies, we developed and tested the first comprehensive, self‐report measure of workplace interruptions. The Workplace Interruptions Measure (WIM) is based on a typology of interruptions that included intrusions, distractions, discrepancy detections, and breaks. The four‐factor structure was reduced to a 12‐item measure in Study 1 (N = 317) and confirmed in a diverse sample of employees in Study 2 (N = 160). Study 3 (N = 323) further examined the psychometric properties of the WIM in a sample of university faculty and staff. Studies 2 and 3 demonstrated that both effort‐enhancing interruptions (intrusions, distractions, and discrepancy detections) and recovery‐enhancing interruptions (breaks) were associated with stressors and strains. Distractions, discrepancy detections, and breaks uniquely predicted strain outcomes beyond other workplace stressors (i.e., quantitative workload, interpersonal conflict, and role conflict). We discuss implications of the WIM for the theory and practice of interruptions research.     

Tumor-specific targeting of pancreatic cancer with Shiga toxin B-subunit

Pancreatic carcinoma is one of the most aggressive tumor entities, and standard chemotherapy provides only modest benefit. Therefore, specific targeting of pancreatic cancer for early diagnosis and therapeutic intervention is of great interest. We have previously shown that the cellular receptor for Shiga toxin B (STxB), the glycosphingolipid globotriaosylceramide (Gb(3) or CD77) is strongly increased in colorectal adenocarcinoma and their metastases. Here, we report an upregulation of Gb(3) in pancreatic adenocarcinoma (21 of 27 cases) as compared with matched normal tissue (n = 27). The mean expression was highly significantly increased from 30 ± 16 ng Gb(3)/mg tissue in normal pancreas to 61 ± 41 ng Gb(3)/mg tissue (mean ± SD, P = 0.0006), as evidenced by thin layer chromatography. Upregulation of Gb(3) levels did not depend on tumor stage or grading and showed no correlation with clinical outcome. Tumor cells and endothelial cells were identified as the source of increased Gb(3) expression by immunocytochemistry. Pancreatic cancer cell lines showed rapid intracellular uptake of STxB to the Golgi apparatus, following the retrograde pathway. The therapeutic application of STxB was tested by specific delivery of covalently coupled SN38, an active metabolite of the topoisomerase I inhibitor irinotecan. The cytotoxic effect of the STxB-SN38 compound in pancreatic cancer cell lines was increased more than 100-fold compared with irinotecan. Moreover, this effect was effectively blocked by competing incubation with nonlabeled STxB, showing the specificity of the targeting. Thus, STxB constitutes a promising new tool for specific targeting of pancreatic cancer.     

Identification of Patients with High-Risk Stage II Colon Cancer for Adjuvant Therapy

Purpose Adjuvant therapy for Stage II colon cancer remains controversial but may be considered for patients with high-risk features. The purpose of this study was to assess the prognostic significance of commonly reported clinicopathologic features of Stage II colon cancer to identify high-risk patients. Methods We analyzed a prospectively maintained database of patients with colon cancer who underwent surgical treatment from 1990 to 2001 at a single specialty center. We identified 448 patients with Stage II colon cancer who had been treated by curative resection alone, without postoperative chemotherapy. Results With median follow-up of 53 months, 5-year disease-specific survival for this cohort was 91 percent. Univariate and multivariate analyses identified three independent features that significantly affected disease-specific survival: tumor Stage T4 (hazard ratio (HR), 2.7; 95 percent confidence interval (CI), 1.1–6.2; P = 0.02), preoperative carcinoembryonic antigen >5 ng/ml (HR, 2.1; 95 percent CI, 1.1–4.1; P = 0.02), and presence of lymphovascular or perineural invasion (HR, 2.1; 95 percent CI, 1–4.4; P = 0.04). Five-year disease-specific survival for patients without any of the above poor prognostic features was 95 percent; five-year disease-specific survival for patients with one of these poor prognostic features was 85 percent; and five-year disease-specific survival for patients with ≥2 poor prognostic features was 57 percent. Conclusions Patients with Stage II colon cancer generally have an excellent prognosis. However, the presence of multiple adverse prognostic factors identifies a high-risk subgroup. Use of commonly reported clinicopathologic features accurately stratifies Stage II colon cancer by disease-specific survival. Those identified as high-risk patients can be considered for adjuvant chemotherapy and/or enrollment in investigational trials. Read at the meeting of The American Society of Colon and Rectal Surgeons, St. Louis, Missouri, June 2 to 6, 2007. Reprints are not avaliable.     

Divergent proarrhythmic potential of macrolide antibiotics despite similar QT prolongation: fast phase 3 repolarization prevents early afterdepolarizations and torsade de pointes

Macrolide antibiotics are known to have a different proarrhythmic potential in the presence of comparable QT prolongation in the surface ECG. Because the extent of QT prolongation has been used as a surrogate marker for cardiotoxicity, we aimed to study the different electrophysiological effects of the macrolide antibiotics erythromycin, clarithromycin, and azithromycin in a previously developed experimental model of proarrhythmia. In 37 Langendorff-perfused rabbit hearts, erythromycin (150-300 microM, n = 13) clarithromycin (150-300 microM, n = 13), and azithromycin (150-300 microM, n = 11) led to similar increases in QT interval and monophasic action potential (MAP) duration. In bradycardic (atrioventricular-blocked) hearts, eight simultaneously recorded epi- and endocardial MAPs demonstrated increased dispersion of repolarization in the presence of all three antibiotics. Erythromycin and clarithromycin led to early afterdepolarizations (EADs) and torsade de pointes (TdP) after lowering of potassium concentration. In the presence of azithromycin, no EAD or TdP occurred. Erythromycin and clarithromycin changed the MAP configuration to a triangular pattern, whereas azithromycin caused a rectangular pattern of MAP prolongation. In 13 additional hearts, 150 microM azithromycin was administered after previous treatment with 300 microM erythromycin and suppressed TdP provoked by erythromycin. In conclusion, macrolide antibiotics lead to similar prolongation of repolarization but show a different proarrhythmic potential (erythromycin > clarithromycin > azithromycin). In the presence of azithromycin, neither EAD nor TdP occur. This effect may be related to a rectangular pattern of action potential prolongation, whereas erythromycin and clarithromycin cause triangular action potential prolongation and induce TdP.