New Indole Tubulin Assembly Inhibitors Cause Stable Arrest of Mitotic Progression, Enhanced Stimulation of Natural Killer Cell Cytotoxic Activity, and Repression of Hedgehog-Dependent Cancer

We designed 39 new 2-phenylindole derivatives as potential anticancer agents bearing the 3,4,5-trimethoxyphenyl moiety with a sulfur, ketone, or methylene bridging group at position 3 of the indole and with halogen or methoxy substituent(s) at positions 4-7. Compounds 33 and 44 strongly inhibited the growth of the P-glycoprotein-overexpressing multi-drug-resistant cell lines NCI/ADR-RES and Messa/Dx5. At 10 nM, 33 and 44 stimulated the cytotoxic activity of NK cells. At 20-50 nM, 33 and 44 arrested >80% of HeLa cells in the G2/M phase of the cell cycle, with stable arrest of mitotic progression. Cell cycle arrest was followed by cell death. Indoles 33, 44, and 81 showed strong inhibition of the SAG-induced Hedgehog signaling activation in NIH3T3 Shh-Light II cells with IC50 values of 19, 72, and 38 nM, respectively. Compounds of this class potently inhibited tubulin polymerization and cancer cell growth, including stimulation of natural killer cell cytotoxic activity and repression of Hedgehog-dependent cancer

Associations between depressive symptoms and disease progression in older patients with chronic kidney disease: results of the EQUAL study

Background Depressive symptoms are associated with adverse clinical outcomes in patients with end-stage kidney disease; however, few small studies have examined this association in patients with earlier phases of chronic kidney disease (CKD). We studied associations between baseline depressive symptoms and clinical outcomes in older patients with advanced CKD and examined whether these associations differed depending on sex. Methods CKD patients (>= 65 years; estimated glomerular filtration rate <= 20 mL/min/1.73 m(2)) were included from a European multicentre prospective cohort between 2012 and 2019. Depressive symptoms were measured by the five-item Mental Health Inventory (cut-off <= 70; 0-100 scale). Cox proportional hazard analysis was used to study associations between depressive symptoms and time to dialysis initiation, all-cause mortality and these outcomes combined. A joint model was used to study the association between depressive symptoms and kidney function over time. Analyses were adjusted for potential baseline confounders. Results Overall kidney function decline in 1326 patients was -0.12 mL/min/1.73 m(2)/month. A total of 515 patients showed depressive symptoms. No significant association was found between depressive symptoms and kidney function over time (P = 0.08). Unlike women, men with depressive symptoms had an increased mortality rate compared with those without symptoms [adjusted hazard ratio 1.41 (95% confidence interval 1.03-1.93)]. Depressive symptoms were not significantly associated with a higher hazard of dialysis initiation, or with the combined outcome (i.e. dialysis initiation and all-cause mortality). Conclusions There was no significant association between depressive symptoms at baseline and decline in kidney function over time in older patients with advanced CKD. Depressive symptoms at baseline were associated with a higher mortality rate in men

Agglomerazione di capitale umano e investimenti in formazione : il ruolo dell’istruzione degli imprenditori

Sulla base di un ampio dataset rappresentativo delle imprese anche di minore dimensione in Italia, il lavoro considera se il profilo individuale dell'imprenditore e l'agglomerazione di imprenditori con alto livello di istruzione hanno effetti sulle scelte di formazione dei lavoratori. L'analisi econometrica risolve i problemi potenziali di endogeneità

Agglomerazione di capitale umano e investimenti in formazione: il ruolo dell’istruzione degli imprenditori, Cap . 8, (with A.Ricci, E. Ghignoni, G. Croce), Mercato del Lavoro Capitale Umano e Imprese: Volumi ISFOL 2014, a cura di A. Ricci,

Negli ultimi anni le politiche del lavoro dirette ad accrescere la flessibilità contrattuale e deregolamentare le norme a tutela dell’impiego non hanno migliorato significativamente l’efficienza e la competitività delle imprese, né le prospettive occupazionali e salariali dei lavoratori. Il volume sviluppa questi argomenti sulla base di dati macroeconomici e microeconomici sulle imprese e sui lavoratori, proponendo analisi comparative a livello europeo e specifiche dell’esperienza italiana

Association between fibrinogen plasma levels and platelet counts in an outpatient population and in patients with coronary heart disease

Although numerous studies concern fibrinogen (FBG) associations, the relationship between platelet (PLT) count and FBG plasma levels has yet to be completely investigated. The present study concerns the association between FBG plasma levels and PLT count in 5891 patients (2831 men and 3060 women) attending our outpatients' laboratory. Of these, a subgroup of 4116 patients (1899 men and 2217 women) with normal values of the parameters investigated was selected. A group of 170 patients with coronary heart disease was also included. The parameters studied were FBG, PLT count, leukocyte count and age. Our results showed that, in the outpatient population, FBG was significantly correlated with the PLT count (P < 0.000001) and, as previously reported, with the leukocyte count and age. In the patients with coronary heart disease, there was a significant correlation between FBG and PLT count (P < 0.000001), to be considered very significant considering the limited number of patients, whereas no correlation with age or leukocyte count was found. The role of interleukin-6, both in FBG and PLT production, is well known and may explain the correlation between these two parameters. The association of FBG and PLT count has yet to be fully investigated in epidemiological studies, even though they play an important role as two of the major contributors to the pathogenesis and evolution of cardiovascular diseases. Blood Coagul Fibrinolysis 21:216-220 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins

Ivabradine: potential clinical applications in critically ill patients

It has been extensively demonstrated that an elevated heart rate is a modifiable, independent risk factor for cardiovascular events. A high heart rate increases myocardial oxygen consumption and reduces diastolic perfusion time. It can also increase ventricular diastolic pressures and induce ventricular arrhythmias. Critical care patients are prone to develop a stress induced cardiac impairment and consequently an increase in sympathetic tone. This in turn increases heart rate. In this setting, however, heart rate lowering might be difficult because the effects of inotropic drugs could be hindered by heart rate reducing drugs like beta-blockers. Ivabradine is a new selective antagonist of funny channels. It lowers heart rate, reducing the diastolic depolarization slope. Moreover, ivabradine is not active on sympathetic pathways, thus avoiding any interference with inotropic amines. We reviewed the literature available regarding heart rate control in critical care patients, focusing our interest on the use of ivabradine to assess the potential benefits of the drug in this particular setting