Clicks and Mortar: Taxing Multinational Business Profits in the Digital Age

This Article argues that governments should abandon the treaty concept of permanent establishment and adopt international tax reforms that restore the primacy of market country taxation of multi-national business profits promoted by domestic tax laws. Part I explores several emerging e-commerce issues that demonstrate the tension of introducing traditional tax norms to a digital environment. Part II reviews historical and recent developments in the international taxation of business profits and looks at the underlying trends and sentiments for reform of the existing system of global taxation of business income. Part III canvasses several prominent international tax reform alternatives proposed by governments, multilateral organizations and tax commentators around the world. Finally, Part IV proposes the adoption of tax rules and norms that allow each nation unfettered jurisdiction over business income, including e-commerce profits, derived from transactions completed within that country\u27s borders

effects of a new human recombinant mnsod in the treatment of photoaging and actinic keratosis

Physiological processes, as aerobic metabolism and inflammatory response, generate reactive oxygen species (ROS) that may induce cellular injury when their amount is increased and antioxidant defense mechanisms are overwhelmed. Also, ROS are generated following UV skin irradiation able to deplete the natural antioxidant defenses in the skin. The increase in exposure to UV may lead to photoaging and precancerous skin lesions (actinic keratosis). New antioxidant strategies in the prevention and therapy of skin lesions are urgently needed. In this study, we evaluated the antioxidant efficacy of a recombinant form of human manganese superoxide dismutase able to inhibit reactive oxygen species production in some patients affected by severe photoaging and actinic keratosis

Serum Albumin Is Inversely Associated With Portal Vein Thrombosis in Cirrhosis

We analyzed whether serum albumin is independently associated with portal vein thrombosis (PVT) in liver cirrhosis (LC) and if a biologic plausibility exists. This study was divided into three parts. In part 1 (retrospective analysis), 753 consecutive patients with LC with ultrasound-detected PVT were retrospectively analyzed. In part 2, 112 patients with LC and 56 matched controls were entered in the cross-sectional study. In part 3, 5 patients with cirrhosis were entered in the in vivo study and 4 healthy subjects (HSs) were entered in the in vitro study to explore if albumin may affect platelet activation by modulating oxidative stress. In the 753 patients with LC, the prevalence of PVT was 16.7%; logistic analysis showed that only age (odds ratio [OR], 1.024; P = 0.012) and serum albumin (OR, -0.422; P = 0.0001) significantly predicted patients with PVT. Analyzing the 112 patients with LC and controls, soluble clusters of differentiation (CD)40-ligand (P = 0.0238), soluble Nox2-derived peptide (sNox2-dp; P < 0.0001), and urinary excretion of isoprostanes (P = 0.0078) were higher in patients with LC. In LC, albumin was correlated with sCD4OL (Spearman's rank correlation coefficient [r(s)], -0.33; P < 0.001), sNox2-dp (r(s), -0.57; P < 0.0001), and urinary excretion of isoprostanes (r(s), -0.48; P < 0.0001) levels. The in vivo study showed a progressive decrease in platelet aggregation, sNox2-dp, and urinary 8-iso prostaglandin F2 alpha-III formation 2 hours and 3 days after albumin infusion. Finally, platelet aggregation, sNox2-dp, and isoprostane formation significantly decreased in platelets from HSs incubated with scalar concentrations of albumin. Conclusion: Low serum albumin in LC is associated with PVT, suggesting that albumin could be a modulator of the hemostatic system through interference with mechanisms regulating platelet activation

Effects of a New Human Recombinant MnSOD in the Treatment of Photoaging and Actinic Keratosis.

Physiological processes, as aerobic metabolism and inflammatory response, generate reactive oxygen species (ROS) that may induce cellular injury when their amount is increased and antioxidant defense mechanisms are overwhelmed. Also, ROS are generated following UV skin irradiation able to deplete the natural antioxidant defenses in the skin. The increase in exposure to UV may lead to photoaging and precancerous skin lesions (actinic keratosis). New antioxidant strategies in the prevention and therapy of skin lesions are urgently needed. In this study, we evaluated the antioxidant efficacy of a recombinant form of human manganese superoxide dismutase able to inhibit reactive oxygen species pro- duction in some patients affected by severe photoaging and actinic keratosi

Effetti della rMnSOD nella terapia delle discheratosi attiniche

Gli UV sono in grado di indurre modificazioni sia quantitative che qualitative delle cellule immunocompetenti e possono alterare l’immuno-sorveglianza verso i tumori cutanei. L’irradiazione ultravioletta stimola i cheratinociti a secernere citochine e fattori di crescita che intervengono sulle cellule deputate alla risposta immunitaria (Santoianni, 2003 ). Dati sperimentali, epidemiologici e clinici negli ultimi anni hanno messo in evidenza l’importanza dell’ultravioletto lungo nella genesi di cheratosi attiniche (Nino 2006). Organismi esposti a radiazioni ionizzanti sono principalmente danneggiati dai radicali liberi, generati dalla radiolisi dell'acqua contenuta nelle cellule. Inoltre è stata dimostrata una significativa riduzione del danno tissutale da irradiazione utilizzando trattamenti con una manganese superossido dismutasi. Le superossido dismutasi (SOD) sono enzimi che hanno un ruolo chiave nella prevenzione di tutte le patologie determinate dal danno ossidativo (Borrelli et al., 2009). Le SOD sono implicate nella difesa antiossidante di quasi tutte le cellule, poiché catalizzano la dismutazione del radicale superossido a perossido d’idrogeno che, successivamente, è convertito in ossigeno e acqua dall’enzima catalasi. Questi enzimi hanno la capacità di prevenire il danno provocato dagli alti livelli di ROS prodotti, in particolare da radiazioni ionizzanti (Epperly et al., 2003). Nelle cellule sono presenti tre isoforme: la SOD 1 è localizzata nel citosol, la SOD 2 nella matrice mitocondriale, mentre la SOD 3 è secreta nello spazio extracellulare (Oberley, 2005). L’isoforma SOD 2, conosciuta anche come manganese superossido dismutasi (MnSOD), ricopre un ruolo di notevole importanza nella conversione del radicale superossido (O2.-) nei mitocondri e, dunque, rappresenta la prima linea di difesa contro questo radicale (Wang et al., 2001). Recentemente nel laboratorio di ricerca del dott. Aldo Mancini (Istituto Nazionale Tumori G.Pascale) è stata isolata un’isoforma di SOD da cellule di liposarcoma umano in coltura (LSA-Type MnSOD) che ha mostrato sia in vivo che in vitro una azione citotossica specifica e selettiva solo per le cellule esprimenti il recettore per gli estrogeni. Pur avendo la stessa attività enzimatica comune a tutte le SOD, la LSA-Type MnSOD si differenzia dalla sua corrispondente nativa per la presenza del peptide leader (da 24 amminoacidi), evidentemente non clivato, che le conferisce la peculiare capacità di penetrare in tutte le cellule. Tale proteina è stata riprodotta in forma ricombinante, rMnSOD, a partire da uno specifico clone di cDNA derivato da cellule di liposarcoma umano (Mancini et al., 2006). La rMnSOD è risultata, in vitro, essere radioprotettiva per le cellule normali e radiosensibilizzante per quelle tumorali. Inoltre, animali sani, esposti a dosi letali di radiazioni ionizzanti in presenza della rMnSOD (1,4 µM), mediante iniezioni s.c. sono sopravvissuti al danno radiante rimanendo vivi 30 giorni dopo l'irradiazione, tempo in cui è stato interrotta il controllo della loro sopravvivenza. Al contrario, animali irradiati con le stessse dosi letali, in assenza della rMnSOD, morivano dopo 7-8 giorni dall’irradiazione (Borrelli et al.2009). La notevole capacità enzimatica della rMnSOD, in formulazione topica, di neutralizzare i radicali liberi che incontra e che si accumulano nei tessuti danneggiati da qualsivoglia noxa patogena, è stata dimostrata, inoltre, con il suo utilizzo nella cura di una necrosi profonda ed estesa a testa, collo, e natatoie di un esemplare di tartaruga marina Caretta caretta. Il trattamento topico di tali esemplari con rMnSOD ha consentito una piena restitutio ad integrum anche nei siti delle necrosi che avevano provocato esposizione dell'osso (Occhiello A. et al 2009). Sulla base dei risultati precedentemente ottenuti è stato allestito uno studio su pazienti afferenti alla Dermatologia dell'Ospedale Ascalesi di Napoli, i quali si sono spontaneamente dichiarati disponibili al trattamento con la formulazione cosmetica contenente la rMnSOD, Sono stati arruolati per lo studio 30 pazienti di entrambi i sessi di eta’ compresa tra i 35 e i 70 anni con fotodanno medio severo con presenza di discheratosi attiniche. I pazienti hanno praticato terapia topica con una formulazione O/A a base di rMnSOD, mattina e sera per due mesi. Ogni settimana è stato effettuato un controllo e sono state fotografate le lesioni per monitorare l'effetto della terapia. Già nella prima settimana è stato osservata una diminuzione dello stato infiammatorio in tutti i pazienti trattati. A due mesi di trattamento è stato osservato miglioramento consistente del fotodanno, migliorata la compattezza e la luminosità della cute con riduzione della elastosi solare e scomparsa o regressione parziale delle discheratosi. La formulazione topica della rMnSOD merita di essere considerata come un promettente farmaco con potente azione antiinfiammatoria utilizzabile in dermatologia. • Borrelli A, Schiattarella A, Mancini R, Morrica B, Cerciello V, Mormile M, d'Alesio V, Bottalico L, Morelli F, D'Armiento M, D'Armiento FP, Mancini A. Free Radical Biology and Medicine. 2009 Jan 1;46(1):110-6. Epub 2008 . • Epperly M.W., Gretton J. E., Sikora C.A., Jefferson M., Bernarding M., Nie S. and Greenberger J.S. (2003). Radiation Research. 160 (5): 568-578. • Mancini A., Borrelli A., Schiattarella A., Fasano S., Occhiello A., Pica A., Sher P., Tommasino M., Nüesch J. P. F. and Rommelaere J. (2006). International Journal of Cancer. 119 (4): 932-943. • Oberley L.W. Biomedicine & Pharmacotherapy. 59 (4): 143-148. • Occhiello A., Bentivegna F., Borrelli A., Schiattarella A., Mancini A., Pica A. Comparative clinical Pathology. DOI 10.1007/s00580-009-0816-9 • Wang L.I., Miller D.P., Sai Y., Liu G., Su L., Wain J.C., Lynch T.J. and Christiani D.C. (2001). Journal of the National Cancer Institute. 93 (23): 1818-1821. • Santoianni P., Nino M. Giornale italiano di dermatologia e venereologia. 2003. 138(6):455-64 • Nino M., Santoianni P. . Giornale italiano di dermatologia e venereologia 2006. 141(5):471-

Erratum to: Portal vein thrombosis relevance on liver cirrhosis: Italian Venous Thrombotic Events Registry (Intern Emerg Med, 10.1007/s11739-016-1416-8)

In the original publication, the second author name was incorrectly published as Roberto Gino Corazza. The correct name should read as \u201cGino Roberto Corazza\u201d. Also, the PRO-LIVER Study Collaborator, Dr. Gabriella Carnevale Maff\ue8 has not been included in the Appendix by mistake. The name of Dr. Carnevale Maffe` should read in the Appendix as follows: Bergamaschi Gaetano, Carnevale Maff\ue8 Gabriella, Masotti Michela, Costanzo Filippo (I\ub0 Clinica Medica, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Italy)

Incidence and Recurrence of Portal Vein Thrombosis in Cirrhotic Patients

Cirrhosis has been long considered a risk factor for bleeding due to the co-existence of the so-called \u2018coagulopathy\u2019. More recently, however, compelling evidences have been provided on the occurrence of thrombotic events in the portal and systemic circulation.3\u20135 Portal vein thrombosis (PVT) is predominantly observed in patients with moderate to severe liver failure with a variable prevalence ranging from 0.6 to 25%. Only fewstudies have provided a longitudinal assessment of the PVT incidence and its sequelae, including recurrence and survival.9\u201314 Due to the variability of PVT incidence and the paucity of data regarding recurrence and survival,15\u201320 we prospectively analysed the incidence and the recurrence of PVT in the population of Portal vein thrombosis Relevance On Liver cirrhosis: ItalianVenous thromboticEventsRegistry (PROLIVER), a multi-centre study,8 which involved 43 enrolling centres in Italy (ClinicalTrials.gov Identifier: NCT01470547)

Platelet Count Does Not Predict Bleeding in Cirrhotic Patients: Results from the PRO-LIVER Study.

OBJECTIVES: Thrombocytopenia is a hallmark for patients with cirrhosis and it is perceived as a risk factor for bleeding events. However, the relationship between platelet count and bleeding is still unclear. METHODS: We investigated the relationship between platelet count and major or clinical relevant nonmajor bleedings during a follow-up of ∼4 years. RESULTS: A total of 280 cirrhotic patients with different degrees of liver disease (67% males; age 64±37 years; 47% Child-Pugh B and C) were followed up for a median of 1,129 (interquartile range: 800-1,498) days yielding 953.12 patient-year of observation. The annual rate of any significant bleeding was 5.45%/year (3.57%/year and 1.89%/year for major and minor bleeding, respectively). Fifty-two (18.6%) patients experienced a major (n=34) or minor (n=18) bleeding event, predominantly from gastrointestinal origin. Platelet counts progressively decreased with the worsening of liver disease and were similar in patients with or without major or minor bleeding: a platelet count ≤50 × 103/μl was detected in 3 (6%) patients with and in 20 (9%) patients without any bleeding event. Conversely, prothrombin time-international normalized ratio was slightly higher in patients with overall or major bleeding. On Cox proportional hazard analysis, only a previous gastrointestinal bleeding (hazard ratio (HR): 1.96; 95% confidence interval: 1.11-3.47; P=0.020) and encephalopathy (HR: 2.05; 95% confidence interval: 1.16-3.62; P=0.013) independently predicted overall bleeding events. CONCLUSIONS: Platelet count does not predict unprovoked major or minor bleeding in cirrhotic patients

Platelet count does not predict bleeding in cirrhotic patients: Results from the PRO-LIVER Study

OBJECTIVES: Thrombocytopenia is a hallmark for patients with cirrhosis and it is perceived as a risk factor for bleeding events. However, the relationship between platelet count and bleeding is still unclear. METHODS: We investigated the relationship between platelet count and major or clinical relevant nonmajor bleedings during a follow-up of \ue2\u88\ubc4 years. RESULTS: A total of 280 cirrhotic patients with different degrees of liver disease (67% males; age 64\uc2\ub137 years; 47% Child\ue2\u80\u93Pugh B and C) were followed up for a median of 1,129 (interquartile range: 800\ue2\u80\u931,498) days yielding 953.12 patient-year of observation. The annual rate of any significant bleeding was 5.45%/year (3.57%/year and 1.89%/year for major and minor bleeding, respectively). Fifty-two (18.6%) patients experienced a major (n=34) or minor (n=18) bleeding event, predominantly from gastrointestinal origin. Platelet counts progressively decreased with the worsening of liver disease and were similar in patients with or without major or minor bleeding: a platelet count \ue2\u89\ua450\uc3\u97103/\uce\ubcl was detected in 3 (6%) patients with and in 20 (9%) patients without any bleeding event. Conversely, prothrombin time-international normalized ratio was slightly higher in patients with overall or major bleeding. On Cox proportional hazard analysis, only a previous gastrointestinal bleeding (hazard ratio (HR): 1.96; 95% confidence interval: 1.11\ue2\u80\u933.47; P=0.020) and encephalopathy (HR: 2.05; 95% confidence interval: 1.16\ue2\u80\u933.62; P=0.013) independently predicted overall bleeding events. CONCLUSIONS: Platelet count does not predict unprovoked major or minor bleeding in cirrhotic patients