Damaged microtubules can inactivate BCL-2 by means of the mTOR kinase

Rapamycin, a specific inhibitor of the serine/threonine mTOR kinase, markedly inhibited both cell growth and apoptosis in human B-cell lines. Besides arresting cells in G(1) by increasing p27(kip1), rapamycin tripled the cellular level of the BCL-2 protein. The activity was dose-dependent and specific for the p27(kip1) and BCL-2 proteins. Rapamycin did not affect bcl-2 mRNA although it increased cellular BCL-2 concentration by inhibiting phosphorylation, a mechanism initiating the decay process. To add new insight, we combined rapamycin treatment with treatment by taxol, which, by damaging microtubules, can phosphorylate BCL-2 and activate apoptosis. It was found that the mTOR kinase was activated in cells treated with taxol or with nocodazole although it was inhibited in cells pre-treated with rapamycin. BCL-2 phosphorylation, apoptosis and hyperdiploidy were also inhibited by rapamycin. In contrast, taxol-induced microtubule stabilization or metaphase synchronization were not inhibited by rapamycin. Taken together, these findings indicate that mTOR belongs to the enzymatic cascade that, starting from damaged microtubules, phosphorylates BCL-2. By regulating apoptosis, in addition to the control of a multitude of growth-related pathways, mTOR plays a nodal role in signaling G(1) and G(2)-M events

High Levels of Circulating Type II Collagen Degradation Marker (CTx-II) Are Associated with Specific VDR Polymorphisms in Patients with Adult Vertebral Osteochondrosis

Both vitamin D and collagen have roles in osteocartilaginous homeostasis. We evaluated the association between the circulating 25-hydroxyvitamin D (25(OH)D) type I and II collagen degradation products (CTx-I, and CTx-II), and four vitamin D receptor gene (VDR) polymorphisms, in Italian males affected by low back pain (LBP) due to herniation/discopathy and/or vertebral osteochondrosis. FokI, BsmI, ApaI, and TaqI VDR-polymorphisms were detected through PCR-restriction fragment length polymorphism (RFLP), and circulating 25(OH)D, CTx-I and CTx-II were measured by immunoassays in 79 patients (of which 26 had osteochondrosis) and 79 age-, sex- and body mass index (BMI)-matched healthy controls. Among all 158 subjects, carriers of FF and Ff genotypes showed lower 25(OH)D than ff, which suggested a higher depletion of vitamin D in F allele carriers. Higher CTx-I concentrations were observed in TT versus Tt among controls, and Tt versus tt among LBP cases, which suggested a higher bone-cartilaginous catabolism in subjects bearing the T allele. Higher CTx-II concentrations were observed in patients with osteochondrosis bearing FF, bb, TT, or Aa genotypes in comparison with hernia/discopathy patients and healthy controls. Vertebral osteochondrosis shows peculiar genotypic and biochemical features related to vitamin D and the osteocartilaginous metabolism. Vitamin D has roles in the pathophysiology of osteochondrosis

Comparative evaluation of seven resistance interpretation algorithms and their derived genotypic inhibitory quotients for the prediction of 48 week virological response to darunavir-based salvage regimens

Background: the darunavir genotypic inhibitory quotient (gIQ) has been suggested as one of the predictors of virological response to darunavir-containing salvage regimens. Nevertheless, which resistance algorithm should be used to optimize the calculation of gIQ is still debated. The aim of our study was to compare seven different free-access resistance algorithms and their derived gIQs as predictors of 48 week virological response to darunavir-based salvage therapy in the clinical setting. Methods: patients placed on two nucleoside reverse transcriptase inhibitors\u200a+\u200a600/100 mg of darunavir/ritonavir twice daily \u200a\ub1\u200a enfuvirtide were prospectively evaluated. Virological response was assessed at 48 weeks. Darunavir resistance interpretation was performed according to seven different algorithms, of which two were weighted algorithms. Analysis of other factors potentially associated with virological response at 48 weeks was performed. Results: fifty-six treatment-experienced patients were included. Overall, 35 patients (62.5%) had a virological response at 48 weeks. Receiver operator characteristic curve analysis showed that De Meyer's weighted score (WS) and its derived gIQ (gIQ WS) were the most accurate parameters defining virological response, and related cut-offs showed the best sensitivity/specificity pattern. In univariate logistic regression analysis, baseline log viral load (P = 0.028), optimized background score 65 2 (P = 0.048), WS >5 (P = 0.001) and WS gIQ 65 600 (P\u200a<\u200a0.0001) were independently associated with virological response. In multivariate analysis, only baseline log viral load (P = 0.008) and WS gIQ 65 600 (P < 0.0001) remained in the model. Conclusions: in our study, although different resistance interpretation algorithms and derived gIQs were associated with virological response, gIQ WS was the most accurate predictive model for achieving a successful virological response

Progettare il cambiamento : la riabilitazione psichiatrica tra obiettivi generali, bisogni del paziente ed \u201cesigenze di protocollo\u201d

Diversi autori che da anni si occupano di riabilitazione psichiatrica evidenziano l\u2019importanza di progettare programmi riabilitativi personalizzati nella cui definizione il paziente \ue8 parte attiva, partecipe e presente alla propria cura (Liberman 1997, Farkas 2002, Ba 2003). Questo presuppone che il paziente sia \u201cpensato\u201d dall\u2019\ue9quipe come \u201csoggetto portatore di significati\u201d con cui entrare in relazione e cui offrire una serie di tecniche atte ad attivare processi di cambiamento. L\u2019agire riabilitativo si pone come obiettivo primario lo sviluppo delle potenzialit\ue0 e delle risorse del paziente al fine di permettergli un livello di funzionamento relazionale e sociale sufficientemente autonomo. Per raggiungere questo obiettivo la riabilitazione utilizza varie tecniche e strumenti la cui scelta dipende dalla istituzione e dalla ideologia teorica che ne ispira l\u2019operativit\ue0. Comune, pur nella diversit\ue0 di orientamento ideologico, \ue8 convinzione condivisa che basilare per la riuscita di ogni programma riabilitativo sia l\u2019ascolto del paziente, la definizione del contratto e la condivisione del percorso di cura. Riconoscere il paziente come portatore di risorse, oltre che di difficolt\ue0, come persona nella sua globalit\ue0, da sostenere e non da plasmare, \ue8 un\u2019operazione dotata di eticit\ue0 intrinseca (Carta I 1997). Oltre alla scelta di tecniche validate ed efficaci \ue8 importante che ogni progetto preveda una attenta valutazione del paziente e delle sue aspettative, delle sue potenzialit\ue0 sia all\u2019inizio del percorso riabilitativo che durante il programma stesso, questo per aiutare l\u2019\ue9quipe curante ad evitare il rischio sempre presente dell\u2019 \u201donnipotenza risanatrice\u201d - che tende a rispondere alle proprie aspettative piuttosto che a quelle del paziente - oppure al contrario dell\u2019\u201doblio\u201d nel caso di pazienti i cui tempi di cambiamento appaiono molti lunghi. In questa relazione si analizza l\u2019esperienza riabilitativa maturata dal 1978 ad oggi presso l\u2019Unit\ue0 di Riabilitazione del DSM dell\u2019Ospedale Maggiore Policlinico di Milano, focalizzando l\u2019attenzione sugli elementi del processo riabilitativo che permettono di attivare un processo di cambiamento pur nella complessit\ue0 della pratica quotidiana, fatta di richieste del paziente, di aspettative della famiglia e degli operatori, di protocolli per l\u2019accreditamento e definizioni di processo, di bisogni dei pazienti e di protocolli di ricerca

Le manifestazioni epatobiliari nella colite ulcerosa

La colangite sclerosante primitiva (Primary Sclerosing Cholangitis, PSC) rappresenta la manifestazione epatobiliare di maggiore rilevanza associata alla rettocolite ulcerosa (RCU), in termini di frequenza e severit\ue0 clinica. I pazienti con PSC ed RCU presentano un aumentato rischio di sviluppo di neoplasie epatiche ed extraepatiche, in particolare di colangiocarcinoma e neoplasia colorettale. Dati recenti indicano che, nella PSC, la terapia con acido ursodesossicolico ad alte dosi si \ue8 dimostrata in grado di indurre un miglioramento radiologico e della fibrosi epatica (staging bioptico); l\u2019impatto sulla sopravvivenza rimane da valutare. Il trapianto di fegato costituisce ad oggi l\u2019unica terapia curativa per i pazienti affetti da PSC in stadio avanzato e consente di ottenere un tasso di sopravvivenza a 5 anni dell\u201985% circa; il timing pi\uf9 appropriato resta tuttavia da definire. Steatosi epatica, epatite cronica, cirrosi, amiloidosi, ascessi epatici, trombosi portale e sindrome di Budd-Chiari rappresentano altre manifestazioni epatobiliari associate alla RCU

Bone grafting: historical and conceptual review, starting with an old manuscript by Vittorio Putti.

Vittorio Putti has been recognized as one of the founders of orthopedic science. He wrote a number of original papers on different topics from his vast experience of orthopedics. In a paper on bone grafting dated 1912, Putti demonstrated his modern way of thinking by his ability to study past experiences critically and by his willingness to compare his own experiences with those of other orthopedic surgeons. Putti's paper proposes principles that still apply today, and which can be considered as the basis of the modern science of grafting. The results of his work can be summarized as follows: a) The uniformity of bone graft integration processes, and a marked reduction in integration capacity in heteroplastic grafts. b) The osteogenetic incapability of the graft as opposed to the osteogenetic capability of the periosteum. c) Marked reduction in the biological capability of bone that has been treated with preservatives, boiled, or macerated. d) The importance of the quality of the tissues in which the bone graft is inserted, including the mechanical characteristics of the graft and its fixation. e) The importance of asepsis. f) The importance of functional exercise. These important experiences were achieved without Putti having any knowledge of immunology, vascular surgery, tissue preservation or non decalcified histology techniques