Efalizumab-induced severe thrombocytopenia can be resolved

Efalizumab is a monoclonal a humanized recombinant IgG1 monoclonal antibody which targets the CD11a, the alpha-subunit of LFA-1 (lymphocyte function-associated antigen-1). It acts by blocking the T-lymphocyte pathogenetic mechanisms of psoriasis. Thrombocytopenia is an adverse event that occurs during therapy. Thrombocytopenia can be mild and can occur quite early during treatment, together with leukocytosis. Both adverse events tend to normalize with ongoing therapy, or, in cases worsening, with therapy suspension. There have been multiple reports of thrombocytopenia associated with efalizumab therapy for the treatment of psoriasis. The general recommendation is to check platelet counts monthly for the first 3 months of efalizumab therapy, then every 3 months for the duration of therapy. According to our experience on a wide range of patients, it is useful to check platelets every month for the first 6 months of therapy. We report a case of efalizumab-associated thrombocytopenia that occurred after 16 weeks of therapy together with clinical worsening of skin lesions. The peculiarity of our case is the absence of signs and symptoms linked to thrombocytopenia and the quick return to normal platelet count without corticosteroid therapy

Qualità microbiologica delle acque per emodialisi: quali i fattori di rischio? [Microbiological quality of hemodialysis water: what are the risk factors?]

Introduzione Un paziente in dialisi entra in contatto settimanalmente con un’ingente quantità d’acqua tramite il bagno di dialisi, in media 350 litri. È pertanto essenziale che questa soluzione abbia un’elevata qualità e purezza. Scopo del nostro studio è stato monitorare nel tempo la qualità microbiologica delle acque dell’emodialisi, al fine di individuare eventuali fattori che possano influenzarla. Metodi Abbiamo effettuato da Gennaio 2015 a Ottobre 2017 uno studio cross-sectional raccogliendo le acque delle apparecchiature dialitiche presso l’AOU Careggi. I campioni raccolti in maniera asettica e da tecnici specializzati, sono stati trasportati sotto ghiaccio a 4°C al Laboratorio di Rischio Biologico dell’Azienda USL Toscana Centro per le analisi di laboratorio. Risultati Sono stati raccolti 126 campioni di acqua. Coliformi, E. coli, Staphylococcus aureus, enterococchi sono risultati negativi in tutti i campioni. Pseudomonas aeruginosa è risultata positiva in un solo campione. Sia per le CFU a 37°C che a 22°C la tipologia di macchinario rappresenta l’unico fattore di rischio statisticamente significativo (OR 15.21 e OR 10.25 rispettivamente): i macchinari SDS hanno un rischio decisamente più alto di risultare positivi per le CFU a 37°C e 22°C. Conclusioni È necessario monitorare costantemente il sistema di trattamento delle acque di dialisi e questo ancor più nel caso di dispositivi con sistema SDS che, a causa del loro utilizzo discontinuo, possono essere soggetti più frequentemente, come dimostrato nel nostro studio, a maggiore contaminazione. PAROLE CHIAVE: sorveglianza, emodialisi, infezioniBACKGROUND: A dialyzed patient weekly gets in touch with a large amount of water (on average 350 liters) through the dialysis bath. It is therefore essential that this solution would have a high quality and purity. The aim of our study was to monitor the microbiological quality of the hemodialysis water in order to identify possible factors that could affect it. METHODS: We conducted a cross-sectional study from January 2015 to October 2017 collecting the dialysis water in AOU Careggi. Samples were aseptically collected by specialized technicians and then transported under ice at 4° C to the Laboratory of Biological Hazards of USL Toscana Centro for laboratory analyses. RESULTS: 126 water samples were collected. Coliforms, E. coli, Staphylococcus aureus, enterococci were not detected. Pseudomonas aeruginosa was found in only one sample. Both for CFU at 37° C and at 22° C, the type of device represented the only statistically significant risk factor (OR 15.21 and OR 10.25 respectively): SDS devices had a significantly higher risk of being positive for CFU at 37° C and 22° C. CONCLUSIONS: As our study demonstrated, the system producing dialysis water must be constantly monitored, especially in cases of SDS devices which may be subjected more frequently to a higher contamination, due to their discontinuous use. Copyright by Società Italiana di Nefrologia SIN, Rome, Italy

Liver haploinsufficiency of RuvBL1 causes hepatic insulin resistance and enhances hepatocellular carcinoma progression

RuvBL1 is an AAA+ ATPase whose expression in hepatocellular carcinoma (HCC) correlates with a poor prognosis. In vitro models suggest that targeting RuvBL1 could be an effective strategy against HCC. However, the role of RuvBL1 in the onset and progression of HCC remains unknown. To address this question, we developed a RuvBL1hep+/− mouse model and evaluated the outcome of DEN‐induced liver carcinogenesis up to 12 months of progression. We found that RuvBL1 haploinsufficiency initially delayed the onset of liver cancer, due to a reduced hepatocyte turnover in RuvBL1hep+/− mice. However, RuvBL1hep+/−mice eventually developed HCC nodules that, with aging, grew larger than in the control mice. Moreover, RuvBL1hep+/− mice developed hepatic insulin resistance and impaired glucose homeostasis. We could determine that RuvBL1 regulates insulin signaling through the Akt/mTOR pathway in liver physiology in vivo as well as in normal hepatocytic and HCC cells in vitro. Whole transcriptome analysis of mice livers confirmed the major role of RuvBL1 in the regulation of hepatic glucose metabolism. Finally, RuvBL1 expression was found significantly correlated to glucose metabolism and mTOR signaling by bioinformatic analysis of human HCC sample from the publicly available TGCA database. These data uncover a role of RuvBL1 at the intersection of liver metabolism, hepatocyte proliferation and HCC development, providing a molecular rationale for its overexpression in liver cancer

hERG1 channels modulate integrin signaling to trigger angiogenesis and tumor progression in colon cancer

Angiogenesis is a potential target for cancer therapy. We identified a novel signaling pathway that sustains angiogenesis and progression in colorectal cancer (CRC). This pathway is triggered by b1 integrin-mediated adhesion and leads to VEGF-A secretion. The effect is modulated by the human ether-a`-go-go related gene 1 (hERG1) K1 channel. hERG1 recruits and activates PI3K and Akt. This in turn increases the Hypoxia Inducible Factor (HIF)-dependent transcription of VEGF-A and other tumour progression genes. This signaling pathway has novel features in that the integrin- and hERG1-dependent activation of HIF (i) is triggered in normoxia, especially after CRC cells have experienced a hypoxic stage, (ii) involves NF-kB and (iii) is counteracted by an active p53. Blocking hERG1 switches this pathway off also in vivo, by inhibiting cell growth, angiogenesis and metastatic spread. This suggests that non-cardiotoxic anti-hERG1 drugs might be a fruitful therapeutic strategy to prevent the failure of anti-VEGF therapy