Thymic volume predicts long-term immune reconstitution in HIV-infected children treated with highly active antiretroviral therapy

Highly active antiretroviral therapy (HAART) suppresses viral replication and augments CD4 T cell counts. HAART-associated immune restoration is often difficult to predict. We verified whether increases in CD4 cells, and particularly in cells of the naive phenotype, would be associated in HAART-treated children with thymic volume. Long-term immune reconstitution is significantly better in children with bigger thymuses at the initiation of HAART. Thymic volume has a strong predictive value for the immunological effect of HAART

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

Efficacy and tolerability of multiple drug therapy in HIV-infected children

Objectives To characterize the efficacy and tolerability of multiple drug therapy (MDT) among heavily pre-treated HIV-infected children. Methods An observational study of seven children treated with 4\u20137 antiretroviral agents. MDT regimens were chosen with regard to past antiretroviral exposure and genotypic resistance data. Five children received MDT once, one child twice and one child four times. All patients had AIDS and severe CD4+ depletion and failed >2 PI-based HAART regimens. Results Virologic response, defined as a 65log10 decrease in plasma HIV-1 RNA at week 24, was achieved in 7/11 MDT. Successful MDT kept a sustained viral suppression (<50 copies/ml) at longest follow-up (72\u201396 weeks). Successful MDT obtained a great immune recovery: the median rise in absolute and percentage of CD4+ cells was 261 and 4 at week 24 and it reached 480 and 16 at 72\u201396 weeks. Adverse events were common but generally manageable. Mild/moderate gastrointestinal complaints and laboratory abnormalities were detected in 5/11 and 8/11 MDT. Grade 2 severity pancreatitis occurred in one case with chronic active hepatitis C. Pancreatitis resolved within 30 days of MDT interruption. Conclusions MDT may be a therapeutic option in children who failed to respond to most standard HAART regimens

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

A Labeled Natural Deduction System for a Fragment of CTL 17

We give a sound and complete labeled natural deduction system for an interesting fragment of CTL 17, namely the until-free version of BCTL 17. The logic BCTL 17 is obtained by referring to a more general semantics than that of CTL 17, where we only require that the set of paths in a model is closed under taking suffixes (i.e. is suffix-closed) and is closed under putting together a finite prefix of one path with the suffix of any other path beginning at the same state where the prefix ends (i.e. is fusion-closed). In other words, this logic does not enjoy the so-called limit-closure property of the standard CTL 17 validity semantics