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1. Risk factors and action thresholds for the novel coronavirus pandemic. Insights from the Italian Society of Nephrology COVID-19 Survey

Author

Nordio, M., Reboldi, G., Di Napoli, A., Quintaliani, G., Alberici, F., Postorino, M., Aucella, F., Messa, P., Brunori, G., Bosco, M., Malberti, F., Mandreoli, M., Mazzaferro, S., Movilli, E., Ravera, M., Salomone, M., Santoro, D., Postorinolimido, M. A., Bonomini, M., Stingone, A., Maccarone, M., Di Loreto, E., Stacchiotti, L., Malandra, R., Chiarella, S., D'Agostino, F., Fuiano, G., Nicodemo, L., Bonofiglio, R., Greco, S., Mallamaci, F., Barreca, E., Caserta, C., Bruzzese, V., Galati, D., Tramontana, D., Viscione, M., Chiuchiolo, L., Tuccillo, S., Sepe, M., Vitale, F., Ciriana, E., Martignetti, V., Caserta, D., Stizzo, A., Romano, A., Iulianiello, G., Cascone, E., Minicone, P., Chiricone, D., Delgado, G., Barbato, A., Celentano, S., Molfino, I., Coppola, S., Raiola, I., Abategiovanni, M., Borrelli, S., Margherita, C., Bruno, F., Ida, M., Aliperti, E., Potito, D., Cuomo, G., De Luca, M., Merola, M., Botta, C., Garofalo, G., Alinei, P., Paglionico, C., Roano, M., Vitale, S., Ierardi, R., Fimiani, V., Conte, G., Di Natale, G., Romano, M., Di Marino, V., Scafarto, A., Meccariello, S., Pecoraro, C., Di Stazio, E., Di Meglio, E., Cuomo, A., Maresca, B., Rotaia, E., Capasso, G., Auricchio, M., Pluvio, C., Maddalena, L., De Maio, A., Palladino, G., Buono, F., Gigliotti, G., Mancini, E., La Manna, G., Storari, A., Mosconi, G., Cappelli, G., Scarpioni, R., Gregorini, M., Rigotti, A., Mancini, W., Bianco, F., Boscutti, G., Amici, G., Tosto, M., Fini, R., Pace, G., Cioffi, A., Boccia, E., Di Lullo, L., Di Zazzo, G., Simonelli, R., Bondatti, F., Miglio, L., Rifici, N., Treglia, A., Muci, M., Baldinelli, G., Rizzi, E., Lonzi, M., De Cicco, C., Forte, F., De Paolis, P., Grandaliano, Giuseppe, Cuzziol, C., Torre, V. M., Sfregola, P., Rossi, V., Fabio, G., Flammini, A., Filippini, A., Onorato, L., Vendola, F., Di Daniela, N., Alfarone, C., Scabbia, L., Ferrazzano, M., Grotta, B. D., Gamberini, M., Fazzari, L., Mene, P., Morgia, A., Catucci, A., Palumbo, R., Puliti, M., Marinelli, R., Polito, P., Marrocco, F., Morabito, S., Rocca, R., Nazzaro, L., Lavini, R., Iamundo, V., Chiappini, M., Casarci, M., Morosetti, M., Hassan, S., Firmi, G., Galliani, M., Serraiocco, M., Feriozzi, S., Valentini, W., Sacco, P., Garibotto, G., Cappelli, V., Saffioti, C., Repetto, M., Rolla, D., Lorenz, M., Pedrini, L., Polonioli, D., Galli, E., Ruggenenti, P., Scolari, F., Bove, S., Costantino, E., Bracchi, M., Mangano, S., Depetri, G., La Milia, V., Farina, M., Zecchini, S., Savino, R., Melandri, M., Guastoni, C., Paparella, M., Gallieni, M., Minetti, E., Bisegna, S., Righetti, M., Badalamenti, S., Alberghini, E., Bertoli, S., Fabbrini, P., Albrizio, P., Rampino, T., Colturi, C., Rombola, G., Lucatello, A., Guerrini, E., Ranghino, A., Lenci, F., Fanciulli, E., Santarelli, S., Damiani, C., Garofalo, D., Sopranzi, F., Santoferrara, A., Di Luca, M., Galiotta, P., Brigante, M., Manganaro, M., Maffei, S., Berto, I., Besso, L., Viglino, G., Cusinato, S., Chiarinottichiappero, D. F., Tognarelli, G., Gianoglio, B., Forneris, G., Biancone, L., Savoldi, S., Vitale, C., Boero, R., Filiberti, O., Borzumati, M., Gesualdo, L., Lomonte, C., Gernone, G., Pallotta, G., Di Paolo, S., Vernaglione, L., Specchio, A., Stallone, G., Dell'Aquila, R., Sandri, G., Russo, F., Napoli, M., Marangi, A., Morrone, L., Di Stratis, C., Fresu, A., Cicu, F., Murtas, S., Manca, O., Pani, A., Pilloni, M., Pistis, R., Cadoni, M., Contu, B., Logias, F., Ivaldi, R., Fancello, S., Cossu, M., Lepori, G., Vittoria, S., Battiati, E., Arnone, M., Rome, M., Barbera, A., Granata, A., Collura, G., Dico, C. L., Pugliese, G., Di Natale, E., Rizzari, G., Cottone, L., Longo, N., Battaglia, G., Marcantoni, C., Giannetto, G., Tumino, G., Randazzo, F., Bellissimo, L., Faro, F. L., Grippaldi, F., Urso, S., Quattrone, G., Todaro, I., Vincenzo, D., Murgo, A., Masuzzo, M., Pisacane, A., Monardo, P., Pontorierro, M., Quari, C., Bauro, A., Chimenz, R. R., Alfio, D., Girasole, F., Cascio, A. L., Caviglia, A., Tornese, F., Sirna, F., Altieri, C., Cusumano, R., Saveriano, V., La Corte, A., Locascio, G., Rotolo, U., Musso, S., Risuglia, L., Blanco, G., Minardo, G., Castellino, S., Zappulla, Z., Randone, S., Di Francesca, M., Cassetti, C. C., Oddo, G., Buscaino, G., Mucaria, F., Barraco, V. I., Di Martino, A., Rallo, D., Dani, L., Campolo, G., Manescalchi, F., Biagini, M., Agate, M., Panichi, V., Casani, A., Traversari, L., Garosi, G., Tabbi, M., Selvi, A., Cencioni, L., Fagugli, R., Timio, F., Leveque, A., Manes, M., Mennella, G., Calo, L., Fiorini, F., Abaterusso, C., Calzavara, P., Meneghel, G., Bonesso, C., Gambaro, G., Gammaro, L., Rugiu, C., Ronco, C., Nordio M., Reboldi G., Di Napoli A., Quintaliani G., Alberici F., Postorino M., Aucella F., Messa P., Brunori G., Bosco M., Malberti F., Mandreoli M., Mazzaferro S., Movilli E., Ravera M., Salomone M., Santoro D., PostorinoLimido M.A., Bonomini M., Stingone A., Maccarone M., Di Loreto E., Stacchiotti L., Malandra R., Chiarella S., D'Agostino F., Fuiano G., Nicodemo L., Bonofiglio R., Greco S., Mallamaci F., Barreca E., Caserta C., Bruzzese V., Galati D., Tramontana D., Viscione M., Chiuchiolo L., Tuccillo S., Sepe M., Vitale F., Ciriana E., Martignetti V., Caserta D., Stizzo A., Romano A., Iulianiello G., Cascone E., Minicone P., Chiricone D., Delgado G., Barbato A., Celentano S., Molfino I., Coppola S., Raiola I., Abategiovanni M., Borrelli S., Margherita C., Bruno F., Ida M., Aliperti E., Potito D., Cuomo G., De Luca M., Merola M., Botta C., Garofalo G., Alinei P., Paglionico C., Roano M., Vitale S., Ierardi R., Fimiani V., Conte G., Di Natale G., Romano M., Di Marino V., Scafarto A., Meccariello S., Pecoraro C., Di Stazio E., Di Meglio E., Cuomo A., Maresca B., Rotaia E., Capasso G., Auricchio M., Pluvio C., Maddalena L., De Maio A., Palladino G., Buono F., Gigliotti G., Mancini E., La Manna G., Storari A., Mosconi G., Cappelli G., Scarpioni R., Gregorini M., Rigotti A., Mancini W., Bianco F., Boscutti G., Amici G., Tosto M., Fini R., Pace G., Cioffi A., Boccia E., Di Lullo L., Di Zazzo G., Simonelli R., Bondatti F., Miglio L., Rifici N., Treglia A., Muci M., Baldinelli G., Rizzi E., Lonzi M., De Cicco C., Forte F., De Paolis P., Grandaliano G., Cuzziol C., Torre V.M., Sfregola P., Rossi V., Fabio G., Flammini A., Filippini A., Onorato L., Vendola F., Di Daniela N., Alfarone C., Scabbia L., Ferrazzano M., Grotta B.D., Gamberini M., Fazzari L., Mene P., Morgia A., Catucci A., Palumbo R., Puliti M., Marinelli R., Polito P., Marrocco F., Morabito S., Rocca R., Nazzaro L., Lavini R., Iamundo V., Chiappini M., Casarci M., Morosetti M., Hassan S., Firmi G., Galliani M., Serraiocco M., Feriozzi S., Valentini W., Sacco P., Garibotto G., Cappelli V., Saffioti C., Repetto M., Rolla D., Lorenz M., Pedrini L., Polonioli D., Galli E., Ruggenenti P., Scolari F., Bove S., Costantino E., Bracchi M., Mangano S., Depetri G., La Milia V., Farina M., Zecchini S., Savino R., Melandri M., Guastoni C., Paparella M., Gallieni M., Minetti E., Bisegna S., Righetti M., Badalamenti S., Alberghini E., Bertoli S., Fabbrini P., Albrizio P., Rampino T., Colturi C., Rombola G., Lucatello A., Guerrini E., Ranghino A., Lenci F., Fanciulli E., Santarelli S., Damiani C., Garofalo D., Sopranzi F., Santoferrara A., Di Luca M., Galiotta P., Brigante M., Manganaro M., Maffei S., Berto I., Besso L., Viglino G., Cusinato S., ChiarinottiChiappero D.F., Tognarelli G., Gianoglio B., Forneris G., Biancone L., Savoldi S., Vitale C., Boero R., Filiberti O., Borzumati M., Gesualdo L., Lomonte C., Gernone G., Pallotta G., Di Paolo S., Vernaglione L., Specchio A., Stallone G., Dell'Aquila R., Sandri G., Russo F., Napoli M., Marangi A., Morrone L., Di Stratis C., Fresu A., Cicu F., Murtas S., Manca O., Pani A., Pilloni M., Pistis R., Cadoni M., Contu B., Logias F., Ivaldi R., Fancello S., Cossu M., Lepori G., Vittoria S., Battiati E., Arnone M., Rome M., Barbera A., Granata A., Collura G., Dico C.L., Pugliese G., Di Natale E., Rizzari G., Cottone L., Longo N., Battaglia G., Marcantoni C., Giannetto G., Tumino G., Randazzo F., Bellissimo L., Faro F.L., Grippaldi F., Urso S., Quattrone G., Todaro I., Vincenzo D., Murgo A., Masuzzo M., Pisacane A., Monardo P., Pontorierro M., Quari C., Bauro A., Chimenz R.R., Alfio D., Girasole F., Cascio A.L., Caviglia A., Tornese F., Sirna F., Altieri C., Cusumano R., Saveriano V., La Corte A., Locascio G., Rotolo U., Musso S., Risuglia L., Blanco G., Minardo G., Castellino S., Zappulla Z., Randone S., Di Francesca M., Cassetti C.C., Oddo G., Buscaino G., Mucaria F., Barraco V.I., Di Martino A., Rallo D., Dani L., Campolo G., Manescalchi F., Biagini M., Agate M., Panichi V., Casani A., Traversari L., Garosi G., Tabbi M., Selvi A., Cencioni L., Fagugli R., Timio F., Leveque A., Manes M., Mennella G., Calo L., Fiorini F., Abaterusso C., Calzavara P., Meneghel G., Bonesso C., Gambaro G., Gammaro L., Rugiu C., and Ronco C.

Subjects
Male, Contextual analysis, medicine.medical_treatment, Population, 030232 urology & nephrology, Recursive partitioning, 030204 cardiovascular system & hematology, Rate ratio, Risk Assessment, 03 medical and health sciences, 0302 clinical medicine, Classification tree, COVID-19, Renal replacement therapy, Risk Factors, Medical, Surveys and Questionnaires, Health care, medicine, Settore MED/14 - NEFROLOGIA, Humans, education, Pandemics, Societies, Medical, Female, Italy, Nephrology, education.field_of_study, business.industry, Multilevel model, Decision rule, Confidence interval, Original Article, Hemodialysis, business, Contextual analysi, Societies, Demography
Abstract

Background and aim: Over 80% (365/454) of the nation’s centers participated in the Italian Society of Nephrology COVID-19 Survey. Out of 60,441 surveyed patients, 1368 were infected as of April 23rd, 2020. However, center-specific proportions showed substantial heterogeneity. We therefore undertook new analyses to identify explanatory factors, contextual effects, and decision rules for infection containment. Methods: We investigated fixed factors and contextual effects by multilevel modeling. Classification and Regression Tree (CART) analysis was used to develop decision rules. Results: Increased positivity among hemodialysis patients was predicted by center location [incidence rate ratio (IRR) 1.34, 95% confidence interval (CI) 1.20–1.51], positive healthcare workers (IRR 1.09, 95% CI 1.02–1.17), test-all policy (IRR 5.94, 95% CI 3.36–10.45), and infected proportion in the general population (IRR 1.002, 95% CI 1.001–1.003) (all p < 0.01). Conversely, lockdown duration exerted a protective effect (IRR 0.95, 95% CI 0.94–0.98) (p < 0.01). The province-contextual effects accounted for 10% of the total variability. Predictive factors for peritoneal dialysis and transplant cases were center location and infected proportion in the general population. Using recursive partitioning, we identified decision thresholds at general population incidence ≥ 229 per 100,000 and at ≥ 3 positive healthcare workers. Conclusions: Beyond fixed risk factors, shared with the general population, the increased and heterogeneous proportion of positive patients is related to the center’s testing policy, the number of positive patients and healthcare workers, and to contextual effects at the province level. Nephrology centers may adopt simple decision rules to strengthen containment measures timely.

Published
2021

3. Clinical policies on the management of chronic kidney disease patients in Italy

Author

SIR SIN STUDY INVESTIGATORS ACCIARRI P, MENEGATO MA, ANCARANI E, ANDREUCCI V, ANTONELLI A, AURICCHIO MR, BALDUCCI A, BASSI A, BATTAGLIA G, BELLINGHERI G, BELTRAME A, BIAGINI M, BONFANTE L, BONOFIGLIO R, BONOMINI M, BORGHI M, BRIGANTE M, BUCCIANTI G, BUONGIORNO E, CABIBBE M, CANCARINI G, CAPISTRANO M, CAPPELLI G, CAPUANO M, CASCONE C, CATIZONE L, CATUCCI AE, CAVATORTA F, CHIARINOTTI D, CICCHETTI T, CONCAS G, CONCETTI M, CONTE F, CONTI M, CORATELLI P, CORTI MM, COSTANZO R, DAL CANTON A, D'APICE L, DAVID S, DE CRISTOFARO V, DEFERRARI G, DELLA GROTTA F, DE NICOLA, Luca, DE SANTO NG, DE SIMONE W, DI DANIELE N, DI GIULIO S, DI LANDRO D, DI LUZIO V, DI MAGGIO A, FAGUGLI R, FARINA M, FERIANI M, GALLIENI M, GAMBARO G, GIORDANO R, GRECO S, GRILLO C, HUBER W, LIUZZO G, LOCATELLI F, LOMBARDI L, LOPEZ T, MALBERTI F, MANCINI W, MANENTI F, MANISCO G, MARROCCO A, MATOCCI G, MERICO G, MESSA P, MINUTOLO, Roberto, MONARDO P, MORICONI L, MURRONE P, NARDO A, NASO A, NOBILE R, PANARELLO G, PAONE A, PARRAVANO M, PEDRINI L, PIAZZA V, PISTIS R, PROCIDA M, QUARELLO F, RAPISARDA F, RICCIARDI B, RINDI P, RONCO C, ROTOLO U, RUSSO G, SARANITI A, SASDELLI M, SAVICA V, SCANZIANI R, SIDOTI A, SPOTTI D, STALTERI A, STEFONI S, STELLA A, STRIPPOLI P, TEATINI U, TEODORO C, TOZZO C, TRIOLO G, ZOCCALI C., Locatelli F, Zoccali C, Acciarri P, Menegato MA, Ancarani E, Andreucci V, Antonelli A, Auricchio MR, Balducci A, Bassi A, Battaglia G, Bellingheri G, Beltrame A, Biagini M, Bonfante L, Bonofiglio R, Bonomini M, Borghi M, Brigante M, Buccianti G, Buongiorno E, Cabibbe M, Cancarini G, Capistrano M, Cappelli G, Capuano M, Cascone C, Catizone L, Catucci AE, Cavatorta F, Chiarinotti D, Cicchetti T, Concas G, Concetti M, Conte F, Conti M, Coratelli P, Corti MM, Costanzo R, Dal Canton A, D'Apice L, David S, De Cristofaro V, Deferrari G, Della Grotta F, De Nicola L, De Santo NG, De Simone W, Di Daniele N, Di Giulio S, Di Landro D, Di Luzio V, Di Maggio A, Fagugli R, Farina M, Feriani M, Gallieni M, Gambaro G, Giordano R, Greco S, Grillo C, Huber W, Liuzzo G, Lombardi L, Lopez T, Malberti F, Mancini W, Manenti F, Manisco G, Marrocco A, Matocci G, Merico G, Messa P, Minutolo R, Monardo P, Moriconi L, Murrone P, Nardo A, Naso A, Nobile R, Panarello G, Paone A, Parravano M, Pedrini L, Piazza V, Pistis R, Procida M, Quarello F, Rapisarda F, Ricciardi B, Rindi P, Ronco C, Rotolo U, Russo G, Saraniti A, Sasdelli M, Savica V, Scanziani R, Sidoti A, Spotti D, Stalteri A, Stefoni S, Stella A, Strippoli P, Teatini U, Teodoro C, Tozzo C, Triolo G., SIR SIN STUDY INVESTIGATORS ACCIARRI, P, Menegato, Ma, Ancarani, E, Andreucci, V, Antonelli, A, Auricchio, Mr, Balducci, A, Bassi, A, Battaglia, G, Bellingheri, G, Beltrame, A, Biagini, M, Bonfante, L, Bonofiglio, R, Bonomini, M, Borghi, M, Brigante, M, Buccianti, G, Buongiorno, E, Cabibbe, M, Cancarini, G, Capistrano, M, Cappelli, G, Capuano, M, Cascone, C, Catizone, L, Catucci, Ae, Cavatorta, F, Chiarinotti, D, Cicchetti, T, Concas, G, Concetti, M, Conte, F, Conti, M, Coratelli, P, Corti, Mm, Costanzo, R, DAL CANTON, A, D'Apice, L, David, S, DE CRISTOFARO, V, Deferrari, G, DELLA GROTTA, F, DE NICOLA, Luca, DE SANTO, Ng, DE SIMONE, W, DI DANIELE, N, DI GIULIO, S, DI LANDRO, D, DI LUZIO, V, DI MAGGIO, A, Fagugli, R, Farina, M, Feriani, M, Gallieni, M, Gambaro, G, Giordano, R, Greco, S, Grillo, C, Huber, W, Liuzzo, G, Locatelli, F, Lombardi, L, Lopez, T, Malberti, F, Mancini, W, Manenti, F, Manisco, G, Marrocco, A, Matocci, G, Merico, G, Messa, P, Minutolo, Roberto, Monardo, P, Moriconi, L, Murrone, P, Nardo, A, Naso, A, Nobile, R, Panarello, G, Paone, A, Parravano, M, Pedrini, L, Piazza, V, Pistis, R, Procida, M, Quarello, F, Rapisarda, F, Ricciardi, B, Rindi, P, Ronco, C, Rotolo, U, Russo, G, Saraniti, A, Sasdelli, M, Savica, V, Scanziani, R, Sidoti, A, Spotti, D, Stalteri, A, Stefoni, S, Stella, A, Strippoli, P, Teatini, U, Teodoro, C, Tozzo, C, Triolo, G, and Zoccali, C.

Subjects
Nephrology, medicine.medical_specialty, Referral, Anemia, medicine.medical_treatment, Context (language use), Metabolic Diseases, Internal medicine, Surveys and Questionnaires, Italian Society of Nephrology, chronic kidney disease, questionnaire, medicine, Humans, Intensive care medicine, Dialysis, Settore MED/14 - Nefrologia, Transplantation, business.industry, Guideline, medicine.disease, Italy, Chronic Disease, Kidney Diseases, Hemodialysis, Guideline Adherence, business, Kidney disease
Abstract

BACKGROUND: Recent studies have indicated that the implementation of international guidelines for the management of renal patients is suboptimal in Italy. The Italian Society of Nephrology (SIN) decided to undertake a multicentre study to obtain a clear picture of clinical policies on chronic kidney disease (CKD) in Italy. METHODS: A 76-item structured questionnaire, designed to evaluate the organization of clinical care, was administered to the director of each participating centre, within the context of a large observational trial in 100 Italian nephrology centres, collecting information on newly diagnosed CKD patients (K/DOQI stage 3-5) on conservative treatment. This paper reports the questionnaire results related to management of anaemia and bone metabolism disorders; assessment of renal function; creation of a vascular access for dialysis and referral of patients to a nephrologist. RESULTS: Clinical policies at the centre level deviated from guideline recommendations in 70% (timing of vascular access creation) to 25% (assessment of iron deficiency) of centres. Assessment of renal function differed from the recommended approach in 30% of centres; clinical policies related to anaemia and bone disease did not coincide with guideline standards in 50 and 40% of centres, respectively. Directors of renal unit estimates indicate that the creation of a vascular access occurs very late in 38% of patients and that referral to a nephrologist is late in approximately 40% of cases. CONCLUSION: This survey in Italy highlights important deviations of clinical policies at the centre level from guideline recommendations.

Published
2008

4. Prognostic role of LDL cholesterol in non-dialysis chronic kidney disease: Multicenter prospective study in Italy

Author

De Nicola, Luca, Provenzano, Michele, Chiodini, Paolo, D'Arrigo, Graziella, Tripepi, Giovanni, Del Vecchio, Lucia, Conte, Giuseppe, Locatelli, Francesco, Zoccali, Carmine, Minutolo, RobertoAcciarri P, Adorati, M, Ancarani, E, Andreucci, V, Antonelli, A, Auricchio, Mr, Balducci, A, Bassi, A, Battaglia, G, Bellingheri, G, Beltrame, A, Biagini, M, Bonfante, L, Bonofiglio, R, Bonomini, M, Borghi, M, Brigante, M, Buccianti, G, Buongiorno, E, Cabibbe, M, Cancarini, Giovanni, Capistrano, M, Cappelli, G, Capuano, M, Cascone, C, Catizone, L, Catucci, Ae, Cavatorta, F, Chiarinotti, D, Cicchetti, T, Concas, G, Concetti, M, Conte, F, Conte, G, Conti, M, Coratelli, P, Corti, Mm, Costanzo, R, Dal Canton, A, D'Apice, L, David, S, De Cristofaro, V, Deferrari, G, Della Grotta, F, De Santo NG, De Simone, W, Di Daniele, N, Di Giulio, S, Di Landro, D, Di Luzio, V, Di Maggio, A, Fagugli, R, Farina, M, Feriani, M, Gallieni, M, Gambaro, G, Giordano, R, Greco, S, Grillo, C, Huber, W, Liuzzo, G, Locatelli, F, Lombardi, L, Lopez, T, Malberti, F, Mancini, W, Manenti, F, Manisco, G, Marrocco, A, Matocci, G, Merico, G, Messa, P, Minutolo, R, Monardo, P, Moriconi, L, Murrone, P, Nardo, A, Naso, A, Nobile, R, Panarello, G, Paone, A, Parravano, M, Pedrini, L, Piazza, V, Pistis, R, Procida, M, Quarello, F, Rapisarda, F, Ricciardi, B, Rindi, P, Ronco, C, Rotolo, U, Russo, G, Santoro, D, Saraniti, A, Sasdelli, M, Savica, V, Scanziani, R, Sidoti, A, Spotti, D, Stalteri, A, Stefoni, S, Stella, A, Strippoli, P, Teatini, U, Teodoro, C, Tozzo, C, Triolo, G, Zoccali, C., De Nicola, L, Provenzano, M, Chiodini, P, D'Arrigo, G, Tripepi, G, Del Vecchio, L, Conte, G, Locatelli, F, Zoccali, C, and Minutolo, R

Subjects
Male, Nephrology, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Medicine (miscellaneous), Kidney Function Tests, Severity of Illness Index, chemistry.chemical_compound, Endocrinology, Risk Factors, Chronic kidney disease, 80 and over, Prospective Studies, Renal Insufficiency, Chronic, Prospective cohort study, Cardiovascular risk, Cholesterol, ESRD, LDL, Renal clinic, Nutrition and Dietetics, Cardiology and Cardiovascular Medicine, Aged, 80 and over, Medicine (all), Middle Aged, Prognosis, Diabetes and Metabolism, Italy, Cardiovascular Diseases, Female, Glomerular Filtration Rate, medicine.medical_specialty, Renal function, Median follow-up, Internal medicine, Diabetes mellitus, medicine, Humans, Renal replacement therapy, Renal Insufficiency, Chronic, Aged, business.industry, Cholesterol, LDL, medicine.disease, chemistry, business, Kidney disease
Abstract

Background and aims The prognostic role of LDL in non-dialysis chronic kidney disease (CKD) is still undefined. We addressed this question in a multicenter prospective study including patients referred to nephrologist for management. Methods and results 1306 patients with CKD stage III–V were studied at basal visit in 79 Italian nephrology clinics in 2004–2006, and then followed for survival analyses. Study endpoints were incident cardiovascular -CV events (fatal and major non-fatal) and renal events (start of renal replacement therapy or eGFR halving). Mean age was 67.6 ± 11.8 years, male 65%, diabetes 25%, CV disease 27%, and eGFR 35.8 ± 12.5 mL/min/1.73 m 2 . LDL was 119 ± 40 mg/dL, with high levels in 50.1% and 82.8% defined on the basis of the individual CV risk profile estimated according to ATPIII 2001 and ESC 2012 guidelines (LDL 100 to 160, and >70 or >100 mg/dL, respectively). Over a median follow up of 2.87 years, 178 CV and 181 renal events occurred. At multivariable Cox analyses, CV risk linearly increased with higher LDL (hazard ratio-HR per 40 mg/dL higher LDL: 1.20, 95% confidence intervals-CI 1.03–1.39); risk doubled when considering high LDL defined according to ESC 2012 (HR 2.37, 95%CI 1.39–4.03) while this association was not significant when considering the higher threshold levels of ATPIII 2001 (HR 1.10, 95%CI 0.82–1.49). No association emerged between LDL and renal risk. Conclusion In non-dialysis CKD patients, CV risk increases linearly with higher LDL and is more than doubled when considering the lower threshold values currently indicated for defining optimal LDL level.

Published
2015

5. Studio degli indicatori di risultato multipli nella popolazione affetta da irc in terapia conservativa (SIR-SIN). Risultati del questionario KDQOL-SF (Kidney Disease Quality of Life Short Form) sulla qualità della vita

Author

Locatelli F, Zoccali C, Catucci AE, Minutolo R, De Nicola L, Grillo C, Beltrame A, Fagugli R, Catizone L, Mancini W, Di Luzio V, Brigante M, Battaglia G, Adorati Menegato M, Bonfante L, Parravano M, Ronco C, Farina M, Spotti D, De Santo NG, Moriconi L, Bellinghieri G, Ricciardi B, Costanzo R, Conti M, Piazza V, Dal Canton A, Corti MM, Della Grotta F, Bonofiglio R, Paone A, Chiarinotti D, Messa PG, Teodoro C, Pedrini L, Feriani M, Greco S, Merico G, Gallieni M., STEFONI, SERGIO, Locatelli F, Zoccali C, Catucci AE, Minutolo R, De Nicola L, Grillo C, Beltrame A, Fagugli R, Catizone L, Mancini W, Di Luzio V, Brigante M, Battaglia G, Adorati Menegato M, Bonfante L, Stefoni S, Parravano M, Ronco C, Farina M, Spotti D, De Santo NG, Moriconi L, Bellinghieri G, Ricciardi B, Costanzo R, Conti M, Piazza V, Dal Canton A, Corti MM, Della Grotta F, Bonofiglio R, Paone A, Chiarinotti D, Messa PG, Teodoro C, Pedrini L, Feriani M, Greco S, Merico G, and Gallieni M

Published
2007

6. Diagnosi e trattamento dell'anemia nell'IRC in terapia conservativa. Dati preliminari dello studio SIN-SIR (Studio italiano Indicatori di Risultato multipli - Epidemiologia dell'IRC in Italia) della Società Italiana di Nefrologia

Author

Locatelli F, Zoccali C, Catucci AE, Savica V, Liuzzo G, Nardo A, Minutolo R, De Nicola L, Ricciardi B, Mancini W, Balducci A, Costanzo R, Di Luca M, Ariano R, Di Luzio V, Brigante M, Battaglia G, Di Landro D, Adorati Menegato M, Altieri P, Lodeserto C, D'Angelo A, Imbasciati E, Spotti D, Rapisarda F, Piazza V, Ronco C, De Santo NG, Stella A, Moriconi L, Dal Canton A, Auricchio MR, Corti MM, Della Grotta F, Grillo C, Cabibbe M, Bonofiglio R, Capistrano M, Paone A, Buongiorno E, Feliciani AL, Chiarinotti D, Gallieni M, Brambilla N, Piacentini A, Merico G, Del Santo A, Bottalico D., STEFONI, SERGIO, Locatelli F, Zoccali C, Catucci AE, Savica V, Liuzzo G, Nardo A, Minutolo R, De Nicola L, Ricciardi B, Mancini W, Balducci A, Costanzo R, Di Luca M, Ariano R, Di Luzio V, Brigante M, Battaglia G, Di Landro D, Adorati Menegato M, Altieri P, Lodeserto C, D'Angelo A, Imbasciati E, Spotti D, Rapisarda F, Piazza V, Ronco C, De Santo NG, Stella A, Moriconi L, Dal Canton A, Stefoni S, Auricchio MR, Corti MM, Della Grotta F, Grillo C, Cabibbe M, Bonofiglio R, Capistrano M, Paone A, Buongiorno E, Feliciani AL, Chiarinotti D, Gallieni M, Brambilla N, Piacentini A, Merico G, Del Santo A, and Bottalico D.

Subjects
ANEMIA, TERAPIA CONSERVATIVA, INSUFFICIENZA RENALE CRONICA
Published
2006

7. Studio SIR-SIN (Studio italiano Indicatori di Risultato multipli - Epidemiologia dell'IRC in Italia) della Societa Italiana di Nefrologia nella popolazione affetta da IRC in terapia conservativa. Dati preliminari

Author

Locatelli F, Zoccali C, Catucci AE, Savica V, Liuzzo G, Nardo A, Minutolo R, De Nicola L, Ricciardi B, Mancini W, Balducci A, Costanzo R, Di Luca M, Ariano R, Di Luzio V, Brigante M, Battaglia G, Di Landro D, Adorati Menegato M, Altieri P, Lodeserto C, D'Angelo A, Imbasciati E, Spotti D, Rapisarda F, Piazza V, Ronco C, De Santo NG, Stella A, Moriconi L, Dal Canton A, Auricchio MR, Corti MM, Della Grotta F, Grillo C, Cabibbe M, Bonofiglio R, Capistrano M, Paone A, Buongiorno E, Feliciani AL, Chiarinotti D, Gallieni M, Brambilla N, Piacentini A, Merico G, Del Santo A, Bottalico D., STEFONI, SERGIO, Locatelli F, Zoccali C, Catucci AE, Savica V, Liuzzo G, Nardo A, Minutolo R, De Nicola L, Ricciardi B, Mancini W, Balducci A, Costanzo R, Di Luca M, Ariano R, Di Luzio V, Brigante M, Battaglia G, Di Landro D, Adorati Menegato M, Altieri P, Lodeserto C, D'Angelo A, Imbasciati E, Spotti D, Rapisarda F, Piazza V, Ronco C, De Santo NG, Stella A, Moriconi L, Dal Canton A, Stefoni S, Auricchio MR, Corti MM, Della Grotta F, Grillo C, Cabibbe M, Bonofiglio R, Capistrano M, Paone A, Buongiorno E, Feliciani AL, Chiarinotti D, Gallieni M, Brambilla N, Piacentini A, Merico G, Del Santo A, and Bottalico D.

Subjects
INSUFFICIENZA RENAEL CRONICA, TERAPIA CONSERVATIVA
Published
2006

8. Timing di creazione dell'accesso vascolare per emodialisi. Dati preliminari dello studio SIN-SIR (Studio italiano Indicatori di Risultato multipli - Epidemiologia dell'IRC in Italia) della Società Italiana di Nefrologia nella popolazione affetta da IRC in terapia conservativa

Author

Locatelli F, Zoccali C, Catucci AE, Savica V, Liuzzo G, Nardo A, Minutolo R, De Nicola L, Ricciardi B, Mancini W, Balducci A, Costanzo R, Di Luca M, Ariano R, Di Luzio V, Brigante M, Battaglia G, Di Landro D, Adorati Menegato M, Altieri P, Lodeserto C, D'Angelo A, Imbasciati E, Spotti D, Rapisarda F, Piazza V, Ronco C, De Santo NG, Stella A, Moriconi L, Dal Canton A, Auricchio MR, Corti MM, Della Grotta F, Grillo C, Cabibbe M, Bonofiglio R, Capistrano M, Paone A, Buongiorno E, Feliciani AL, Chiarinotti D, Gallieni M, Brambilla N, Piacentini A, Merico G, Del Santo A, Bottalico D., STEFONI, SERGIO, Locatelli F, Zoccali C, Catucci AE, Savica V, Liuzzo G, Nardo A, Minutolo R, De Nicola L, Ricciardi B, Mancini W, Balducci A, Costanzo R, Di Luca M, Ariano R, Di Luzio V, Brigante M, Battaglia G, Di Landro D, Adorati Menegato M, Altieri P, Lodeserto C, D'Angelo A, Imbasciati E, Spotti D, Rapisarda F, Piazza V, Ronco C, De Santo NG, Stella A, Moriconi L, Dal Canton A, Stefoni S, Auricchio MR, Corti MM, Della Grotta F, Grillo C, Cabibbe M, Bonofiglio R, Capistrano M, Paone A, Buongiorno E, Feliciani AL, Chiarinotti D, Gallieni M, Brambilla N, Piacentini A, Merico G, Del Santo A, and Bottalico D.

Subjects
ACCESSO VASCOLARE, EMODIALISI, TERAPIA CONSERVATIVA, INSUFFICIENZA RENALE CRONICA
Published
2006

9. Chronic kidney disease (CKD) in Italy: A multicenter study. Results of a questionnaire on the clinical management of CKD stage 3-5 patients

Author

Locatelli, F., Zoccali, C., Catucci, Ae, Savica, V., Liuzzo, G., Nardo, A., Minutolo, R., Nicola, L., Ricciardi, B., Mancini, W., Balducci, A., Costanzo, R., Di Luca, M., Ariano, R., Di Luzio, V., Brigante, M., Battaglia, G., Menegato, Ma, Di Landro, D., Altieri, P., Auricchio, Mr, Lodeserto, C., Stefoni, S., D Angelo, A., Imbasciati, E., Spotti, D., Cristofaro, V., Rapisarda, F., Piazza, V., Claudio Ronco, De Santo NG, Stella, A., Dani, L., Dal Canton, A., Corti, Mm, Teodoro, C., Della Grotta, F., Grillo, C., Catizone, L., Cabibbe, M., Bonofiglio, R., Capistrano, M., Paone, A., Buongiorno, E., Feliciani, Al, Chiarinotti, D., Rotolo, U., Feriani, M., Garibotto, G., Gallieni, M., Merico, G., Del Santo, A., Bottalico, D., Locatelli F, Zoccali C, Catucci AE, Savica V, Liuzzo G, Nardo A, Minutolo R, De Nicola L, Ricciardi B, Mancini W, Balducci A, Costanzo R, Di Luca M, Ariano R, Di Luzio V, Brigante M, Battaglia G, Adorati Menegato M, Di Landro D, Altieri P, Auricchio MR, Lodeserto C, Stefoni S, D'Angelo A, Imbasciati E, Spotti D, De Cristofaro V, Rapisarda F, Piazza V, Ronco C, De Santo NG, Stella A, Dani L, Dal Canton A, Corti MM, Teodoro C, Della Grotta F, Grillo C, Catizone L, Cabibbe M, Bonofiglio R, Capistrano M, Paone A, Buongiorno E, Feliciani AL, Chiarinotti D, Rotolo U, Feriani M, Garibotto G, Gallieni M, Merico G, Del Santo A, and Bottalico D

Published
2006

10. Modalità di stima del filtrato glomerulare (FG) e inizio della dialisi. Dati preliminari dello studio SIR-SIN (Studio italiano Indicatori di Risultato multipli - Epidemiologia dell'IRC in Italia) della Societa Italiana di Nefrologia nella popolazione affetta da IRC in terapia conservativa

Author

Locatelli F, Zoccali C, Catucci AE, Savica V, Liuzzo G, Nardo A, Minutolo R, De Nicola L, Ricciardi B, Mancini W, Balducci A, Costanzo R, Di Luca M, Ariano R, Di Luzio V, Brigante M, Battaglia G, Di Landro D, Adorati Menegato M, Altieri P, Lodeserto C, D'Angelo A, Imbasciati E, Spotti D, Rapisarda F, Piazza V, Ronco C, De Santo NG, Stella A, Moriconi L, Dal Canton A, Auricchio MR, Corti MM, Della Grotta F, Grillo C, Cabibbe M, Bonofiglio R, Capistrano M, Paone A, Buongiorno E, Feliciani AL, Chiarinotti D, Gallieni M, Brambilla N, Piacentini A, Merico G, Del Santo A, Bottalico D., STEFONI, SERGIO, Locatelli F, Zoccali C, Catucci AE, Savica V, Liuzzo G, Nardo A, Minutolo R, De Nicola L, Ricciardi B, Mancini W, Balducci A, Costanzo R, Di Luca M, Ariano R, Di Luzio V, Brigante M, Battaglia G, Di Landro D, Adorati Menegato M, Altieri P, Lodeserto C, D'Angelo A, Imbasciati E, Spotti D, Rapisarda F, Piazza V, Ronco C, De Santo NG, Stella A, Moriconi L, Dal Canton A, Stefoni S, Auricchio MR, Corti MM, Della Grotta F, Grillo C, Cabibbe M, Bonofiglio R, Capistrano M, Paone A, Buongiorno E, Feliciani AL, Chiarinotti D, Gallieni M, Brambilla N, Piacentini A, Merico G, Del Santo A, and Bottalico D

Subjects
FILTRATO GLOMERULARE, DIALISI, INSUFFICIENZA RENALE CRONICA
Published
2006

11. Renal diseases & hypercalcemia

Author

Mancini, W, Lumachi, Franco, and Basso, Smm

Subjects
Parathyroidectomy, renal failure, calcium, hormone therapy, Hyperparathyroidism, PTHrP, Hyperparathyroidism, Parathyroid disease, Parathyroidectomy, PTH, Hypercalcemia, calcium, Parathyroid scintigraphy, MIBI, CT, menopause, parathyroid glands, ALP, osteocalcin, hormone therapy, BMD, bone mineral density, bone densitometry, itamin D, PTHrP, renal transplant, renal failure, FGF, menopause, osteocalcin, Parathyroid scintigraphy, bone densitometry, BMD, renal transplant, Hypercalcemia, Parathyroid disease, parathyroid glands, ALP, FGF, MIBI, bone mineral density, PTH, CT, itamin D
Published
2010

12. Clinical policies on the management of chronic kidney disease patients in Italy

Author

Locatelli, F, Zoccali, C, SIR SIN STUDY INVESTIGATORS, COLLABORATORS ACCIARRI, P, Menegato, Ma, Ancarani, E, Andreucci, V, Antonelli, A, Auricchio, Mr, Balducci, A, Bassi, A, Battaglia, G, Bellingheri, G, Beltrame, A, Biagini, M, Bonfante, L, Bonofiglio, R, Bonomini, M, Borghi, M, Brigante, M, Buccianti, G, Buongiorno, E, Cabibbe, M, Cancarini, Giovanni, Capistrano, M, Cappelli, G, Capuano, M, Cascone, C, Catizone, L, Catucci, Ae, Cavatorta, F, Chiarinotti, D, Cicchetti, T, Concas, G, Concetti, M, Conte, F, Conti, M, Coratelli, P, Corti, Mm, Costanzo, R, Dal, Canton, A, D'Apice, L, David, S, DE CRISTOFARO, V, Deferrari, G, DELLA GROTTA, F, Nicola, L, DE SANTO NG, DE SIMONE, W, DI DANIELE, N, DI GIULIO, S, DI LANDRO, D, Luzio, V, DI MAGGIO, A, Fagugli, R, Farina, M, Feriani, M, Gallieni, M, Gambaro, G, Giordano, R, Greco, S, Grillo, C, Huber, W, Liuzzo, G, Lombardi, L, Lopez, T, Malberti, F, Mancini, W, Manenti, F, Manisco, G, Marrocco, A, Matocci, G, Merico, G, Messa, P, Minutolo, R, Monardo, P, Moriconi, L, Murrone, P, Nardo, A, Naso, A, Nobile, R, Panarello, G, Paone, A, Parravano, M, Pedrini, L, Piazza, V, Pistis, R, Procida, M, Quarello, F, Rapisarda, F, Ricciardi, B, Rindi, P, Ronco, C, Rotolo, U, Russo, G, Saraniti, A, Sasdelli, M, Savica, V, Scanziani, R, Sidoti, A, Spotti, D, Stalteri, A, Stefoni, S, Stella, A, Strippoli, P, Teatini, U, Teodoro, C, Tozzo, C, Triolo, G, and Zoccali, C.

Subjects
Chrinic kidney disease, anemia
Published
2008

13. TIMING DI CREAZIONE DELL’ACCESSO VASCOLARE PER EMODIALISI. DATI PRELIMINARI DELLO STUDIO SIR-SIN (STUDIO ITALIANO INDICATORI DI RISULTATI MULTIPLI-EPIDEMIOLOGIA DELL’IRC IN ITALIA) DELLA SOCIETA’ ITALIANA DI NEFROLOGIA NELLA POPOLAZIONE AFFETTA DA IRC IN TERAPIA CONSERVATIVA

Author

Locatelli, F, Zoccali, C, Catucci, Ae, Savica, V, Liuzzo, G, Nardo, A, Minutolo, R, DE NICOLA, L, Ricciardi, B, Mancini, W, Balducci, A, Costanzo, R, DI LUCA, M, Ariano, R, DI LUZIO, V, Brigante, M, Battaglia, G, DI LANDRO, D, ADORATI MENEGATO, M, Altieri, P, Lodeserto, C, Dangelo, A, Imbasciati, E, Spotti, D, Rapisarda, Francesco, Piazza, V, Ronco, C, DE SANTO NG, Stella, A, Moriconi, L, DAL CANTON, A, Stefoni, S, Auricchio, Mr, Corti, Mm, DELLA GROTTA, F, Grillo, C, Cabibbe, M, Bonofiglio, R, Capistrano, M, Paone, A, Buongiorno, E, Feliciani, Al, Chiarinotti, D, Gallieni, M, Brambilla, N, Piacentini, A, Merico, G, DEL SANTO, A, and Bottalico, D.

Published
2006

14. MODALITA’ DI STIMA DEL FILTRATO GLOMERULARE(FG) E INIZIO DELLA DIALISI. DATI PRELIMINARI DELLO STUDIO SIR-SIN (STUDIO ITALIANO INDICATORI DI RISULTATI MULTIPLI-EPIDEMIOLOGIA DELL’IRC IN ITALIA) DELLA SOCIETA’ ITALIANA DI NEFROLOGIA NELLA POPOLAZIONE AFFETTA DA IRC IN TERAPIA CONSERVATIVA

Author

Locatelli, F, Zoccali, C, Catucci, Ae, Savica, V, Liuzzo, G, Nardo, A, Minutolo, R, DE NICOLA, L, Ricciardi, B, Mancini, W, Balducci, A, Costanzo, R, DI LUCA, M, Ariano, R, DI LUZIO, V, Brigante, M, Battaglia, G, DI LANDRO, D, ADORATI MENEGATO, M, Altieri, P, Lodeserto, C, Dangelo, A, Imbasciati, E, Spotti, D, Rapisarda, Francesco, Piazza, V, Ronco, C, DE SANTO NG, Stella, A, Moriconi, L, DAL CANTON, A, Stefoni, S, Auricchio, Mr, Corti, Mm, DELLA GROTTA, F, Grillo, C, Cabibbe, M, Bonofiglio, R, Capistrano, M, Paone, A, Buongiorno, E, Feliciani, Al, Chiarinotti, D, Gallieni, M, Brambilla, N, Piacentini, A, Merico, G, DEL SANTO, A, and Bottalico, D.

Published
2006

15. CHRONIC KIDNEY DISEASE IN ITALY: A MULTICENTER STUDY. RESULTS OF A QUESTIONNAIRE ON THE CLINICAL MANAGEMENT OF CKD STAGE 3-5 PATIENTS

Author

Locatelli, F, Zoccali, C, Catucci, Ae, Savica, V, Liuzzo, G, Nardo, A, Minutolo, R, DE NICOLA, L, Ricciardi, B, Mancini, W, Balducci, A, Costanzo, R, DI LUCA, M, Ariano, R, DI LUZIO, V, Brigante, M, Battaglia, G, ADORATI MENEGATO, M, DI LANDRO, D, Altieri, P, Auricchio, M. R., Lodeserto, C, Stefoni, S, Dangelo, A, Imbasciati, E, Spotti, D, DE CRISTOFORO, V, Rapisarda, Francesco, Piazza, V, Ronco, C, DE SANTO NG, Stella, A, Dani, L, DAL CANTON, A, Corti, M. M., Teodoro, C, DELLA GROTTA, F, Grillo, C, Catizone, L, Cabibbe, M, Bonofiglio, R, Capistrano, M, Paone, A, Buongiorno, E, Feliciani, A. L., Chiarinotti, D, Rotolo, U, Feriani, M, Garibotto, G, Gallieni, M, Merico, G, and DEL SANTO, A. AND BOTTALICO D.

Published
2006

16. ChemInform Abstract: Synthesis and Anticancer and Antiviral Activities of Various 2′- and 3′ -Methylidene-Substituted Nucleoside Analogues and Crystal Structure of 2′-Deoxy-2′-methylidenecytidine Hydrochloride.

Author

LIN, T.-S., primary, LUO, M.-Z., additional, LIU, M.-C., additional, CLARKE-KATZENBURG, R. H., additional, CHENG, Y.-C., additional, PRUSOFF, W. H., additional, MANCINI, W. R., additional, BIRNBAUM, G. I., additional, GABE, E. J., additional, and GIZIEWICZ, J., additional

Published
2010
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21. The role of deoxycytidine-metabolizing enzymes in the cytotoxicity induced by 3'-amino-2',3'-dideoxycytidine and cytosine arabinoside.

Author

Mancini, William and Mancini, W R

Subjects
ANIMAL experimentation, ANTINEOPLASTIC agents, CELL division, CELLS, COMPARATIVE studies, HYDROLASES, LEUKEMIA, RESEARCH methodology, MEDICAL cooperation, MICE, RESEARCH, CYTOMETRY, EVALUATION research, CYTARABINE, ZALCITABINE (Drug), DEOXYCYTIDINE, CANCER cell culture
Abstract

The cellular metabolism of 3'-amino-2',3'-dideoxycytidine (3'-NH2-dCyd), a cytotoxic agent previously reported to be a poor substrate for purified Cyd/dCyd deaminase (dCydD), was compared with that of cytosine arabinoside (ara-C) in cells that displayed dCydD activity (HeLa) and in cells that did not (L1210). Growth inhibition induced by 3'-NH2-dCyd was dependent on the levels of anabolic enzymes, particularly dCyd kinase (dCydK), whereas cytotoxicity induced by ara-C was dependent on the expression of both anabolic and catabolic enzyme activities. Competition kinetics using purified enzyme revealed that the binding affinity of ara-C to dCydK was 5-fold that of the amino analog. However, this binding advantage is apparently offset in cells that contain high levels of dCydD, since the Ki values for this enzyme were 0.2 and 23 mM for ara-C and 3'-NH2-dCyd, respectively. This was reflected in the decrease in analog sensitivity observed between the two cell lines, whereby the concentrations of ara-C and 3'-NH2-dCyd required to inhibit growth by 50% were 200 and 7 times higher, respectively, in the dCydD-containing HeLa cells as compared with the dCydD-deficient L1210 cells. The metabolic stability and cytotoxicity of 3'-NH2-dCyd was independent of cell number. An unexpected finding was the extent to which the effectiveness of ara-C could be mitigated by the number of dCydD-containing cells. A completely cytotoxic concentration of ara-C was rendered nontoxic by a 10-fold increase in cell number. This observation was supported by an increase in I-beta-D-arabinofuranosyluracil (ara-U) formation, a decrease in ara-C 5'-triphosphate (ara-CTP) accumulation, and a rise in cell viability with increasing cell number. These findings indicate that unlike ara-C, the effectiveness of 3'-NH2-dCyd is independent of the level of deaminase, which suggests its possible utility in situations in which high levels of deaminase are manifest. [ABSTRACT FROM AUTHOR]

Published
1992
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22. Sensitization of 1,3-bis(2-chloroethyl)-1-nitrosourea and cisplatin cytotoxicity by 5-bromo-2'-deoxyuridine in human glioma.

Author

R, Mancini W, R, Glaze E, L, Stetson P, and S, Greenberg H

Abstract

5-Bromo-2'-deoxyuridine (BrdUrd) was found to increase the cytotoxicity induced by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and cisplatin in human glioma cells. At a fixed concentration of BrdUrd and BCNU, the greatest cell loss was observed in exponentially growing cells. As cells approached plateau growth, cytotoxicity was reduced as indicated by greater cell viability. Under varying growth conditions the percentage of thymine replacement by bromouracil in DNA, as determined by gas chromatography/mass spectrometry analysis, declined as cultures approached maximum density. These data indicate BrdUrd must be incorporated into DNA for the enhanced effect to be observed. In exponentially growing cells, sensitization was dependent upon both the concentration of BrdUrd and alkylating agent. Using regression analysis (at 95% CL), a relationship between the level of bromouracil in DNA and the extent of enhanced cytotoxicity was observed at two concentrations of BCNU (r2 = 0.99, 0.96). Although it is known that bifunctional alkylating agents exert cytotoxicity by forming cross-links between cDNA strands, increased cross-link formation was not observed in BrdUrd substituted DNA as determined by alkaline elution. The data suggest that DNA damage induced by halogenated pyrimidines may not involve interstrand cross-links and that these agents may be useful in the treatment of glioma in combination with alkylating agents.

Published
1999

24. The relationship between incorporation of E-5-(2-Bromovinyl)-2'-deoxyuridine into herpes simplex virus type 1 DNA with virus infectivity and DNA integrity.

Author

Mancini, W R, De Clercq, E, and Prusoff, W H

Abstract

E-5-(2-Bromovinyl)-2'-deoxyuridine (BrvdUrd) produced a dose-dependent shift in the density of herpes simplex virus type 1 (HSV-1) DNA at concentrations which yielded potent inhibition of virus replication in cultured Vero cells. Although the density of cellular DNA was not altered by these concentrations of BrvdUrd, incorporation of this analogue into cellular DNA of HSV-1-infected cells has been previously observed in this laboratory. The degree of inhibition correlated with the amount of BrvdUrd substituted for thymidine in HSV-1 DNA. BrvdUrd-substituted DNA was more labile as determined by a dose-dependent increase in single strand breaks when examined by centrifugation in alkaline sucrose gradients. Thus, the potent antiviral action of BrvdUrd observed in cell culture correlates not only with its incorporation into HSV-1 DNA but also with an altered stability of this DNA.

Published
1983
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33. Albumin permeability in isolated glomeruli in incipient experimental diabetes mellitus

Author

Bruno Fabris, Riccardo Candido, Mary Artero, L. Armini, Faccini L, Michele Carraro, Mario Calci, W. Mancini, Cristina Zennaro, Renzo Carretta, Carraro, Michele, Mancini, W, Artero, M, Zennaro, Cristina, Faccini, L, Candido, R, Armini, L, Calci, M, Carretta, Renzo, and Fabris, Bruno

Subjects
Blood Glucose, Male, medicine.medical_specialty, Increased glomerular filtration rate, Endocrinology, Diabetes and Metabolism, Kidney Glomerulus, Renal function, Diabetic nephropathy, albumin permeability, streptozotocin, blood glucose, proteinuria, Blood Pressure, In Vitro Techniques, urologic and male genital diseases, Rats, Inbred WKY, Permeability, Nephropathy, Diabetes Mellitus, Experimental, Reference Values, Internal medicine, Internal Medicine, Medicine, Animals, Insulin, Rats, Wistar, Proteinuria, urogenital system, business.industry, Albumin, Serum Albumin, Bovine, Glomerular Hypertrophy, medicine.disease, female genital diseases and pregnancy complications, Iopamidol, Rats, Endocrinology, Hyperglycemia, Microalbuminuria, medicine.symptom, business, Glomerular Filtration Rate
Abstract

Aims/hypothesis. The pre-clinical phase of diabetic nephropathy is characterised by increased glomerular filtration rate and episodes of microalbuminuria. The cause of the microalbuminuria has been variably ascribed to alterations of the size or charge selective barriers of the glomerulus or both or as a consequence of the haemodynamic changes. Our aim was to investigate very early albumin permeability alterations in isolated glomeruli which were not subject to perfusion pressure. Methods. Isolated glomeruli were studied from 120 male Wistar rats, divided into three groups: streptozotocin-treated, streptozotocin-treated with insulin pellet implants, and controls. From each group ten animals were killed at 7, 14, 28, and 56 days after induction. Study variables included blood pressure, proteinuria, iopamidol clearance, albumin permeability and glomerular area. Subsequently, albumin permeability, proteinuria, and iopamidol clearance were determined in an additional group of 40 diabetic animals studied at 24, 72, 96, and 120 h after induction. Results. Albumin permeability increased steadily from induction in streptozotocin-treated animals, reaching a plateau at approximately 120 h. Glomerular filtration rate was shown to increase significantly at approximately 7 days and proteinuria correlated with it. Glomerular hypertrophy was observed both in streptozotocin-treated animals and in streptozotocin-treated rats with insulin pellet implants. Strict blood glucose control delayed the appearance of the permeability defect in isolated glomeruli and inhibited the increase in glomerular filtration in intact animals. It did not prevent glomerular hypertrophy. Conclusion/interpretation. An albumin permeability defect exists early in isolated non-perfused glomeruli from streptozotocin-treated rats and seems to be independent of glomerular filtration rate alterations. [Diabetologia (2000) 43: 235‐241]

34. The Management of Recurrent Urinary Tract Infection: Non-Antibiotic Bundle Treatment.

Author

Venturini S, Reffo I, Avolio M, Basaglia G, Del Fabro G, Callegari A, Tonizzo M, Sabena A, Rondinella S, Mancini W, Conte C, and Crapis M

Subjects
Humans, Female, Middle Aged, Adult, Recurrence, Vaccinium macrocarpon chemistry, Aged, Urinary Tract Infections drug therapy, Urinary Tract Infections microbiology, Anti-Bacterial Agents therapeutic use, Anti-Bacterial Agents administration & dosage, Quality of Life, Mannose, Probiotics administration & dosage, Probiotics therapeutic use
Abstract

Recurrent urinary tract infections (rUTIs) are a common condition with high morbidity and negatively impact the quality of life. They account for approximately 25% of all antibiotic prescriptions and are a public health concern in an era of increasing multidrug-resistant organisms (MDROs). Several non-antibiotic treatment strategies have been tried to curb antimicrobial use, and many are effective to some degree, but no experience testing multimodal interventions. We created a "care bundle" consisting of behavioral interventions, vaginal and oral probiotics, D-mannose, and cranberry to be followed for six months. We enrolled women with rUTIs over three years. Changes in urinary tract infections, antibiotic use, chronic symptoms, and quality of life were compared in the six months before and after participation in the study. Forty-seven women were enrolled in the study, six of whom were excluded from the final analysis. We observed a 76% reduction in urinary tract infections (p < 0.001) and a reduction in total antibiotic exposure of more than 90% (p < 0.001); all chronic symptoms showed a trend toward reduction. Adherence to the bundle was high (87.2%). Overall, 80.5% of women experienced an improvement in their quality of life. In our experience, a bundle protocol is effective in reducing recurrences and antimicrobial use in a cohort of women with rUTIs and results in a subjective improvement in chronic symptoms and quality of life. Further research with larger sample size is needed to confirm these findings., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Published
2024
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35. Development and Validation of the Acute PNeumonia Early Assessment Score for Safely Discharging Low-Risk SARS-CoV-2-Infected Patients from the Emergency Department.

Author

Venturini S, Pontoni E, Carnelos R, Arcidiacono D, Da Ros S, De Santi L, Orso D, Cugini F, Fossati S, Callegari A, Mancini W, Tonizzo M, Grembiale A, Crapis M, and Colussi G

Abstract

A continuous demand for assistance and an overcrowded emergency department (ED) require early and safe discharge of low-risk severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients. We developed ( n = 128) and validated ( n = 330) the acute PNeumonia early assessment (aPNea) score in a tertiary hospital and preliminarily tested the score on an external secondary hospital ( n = 97). The score's performance was compared to that of the National Early Warning Score 2 (NEWS2). The composite outcome of either death or oral intubation within 30 days from admission occurred in 101 and 28 patients in the two hospitals, respectively. The area under the receiver operating characteristic (AUROC) curve of the aPNea model was 0.86 (95% confidence interval (CI), 0.78-0.93) and 0.79 (95% CI, 0.73-0.89) for the development and validation cohorts, respectively. The aPNea score discriminated low-risk patients better than NEWS2 at a 10% outcome probability, corresponding to five cut-off points and one cut-off point, respectively. aPNea's cut-off reduced the number of unnecessary hospitalizations without missing outcomes by 27% (95% CI, 9-41) in the validation cohort. NEWS2 was not significant. In the external cohort, aPNea's cut-off had 93% sensitivity (95% CI, 83-102) and a 94% negative predictive value (95% CI, 87-102). In conclusion, the aPNea score appears to be appropriate for discharging low-risk SARS-CoV-2-infected patients from the ED.

Published
2022
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36. Sensitization of 1,3-bis(2-chloroethyl)-1-nitrosourea and cisplatin cytotoxicity by 5-bromo-2'-deoxyuridine in human glioma.

Author

Mancini WR, Glaze ER, Stetson PL, and Greenberg HS

Subjects
Bromodeoxyuridine pharmacokinetics, DNA, Neoplasm biosynthesis, Drug Synergism, Glioma, Humans, Kinetics, Tumor Cells, Cultured, Bromodeoxyuridine toxicity, Carmustine toxicity, Cell Survival drug effects, DNA Damage
Abstract

5-Bromo-2'-deoxyuridine (BrdUrd) was found to increase the cytotoxicity induced by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and cisplatin in human glioma cells. At a fixed concentration of BrdUrd and BCNU, the greatest cell loss was observed in exponentially growing cells. As cells approached plateau growth, cytotoxicity was reduced as indicated by greater cell viability. Under varying growth conditions the percentage of thymine replacement by bromouracil in DNA, as determined by gas chromatography/mass spectrometry analysis, declined as cultures approached maximum density. These data indicate BrdUrd must be incorporated into DNA for the enhanced effect to be observed. In exponentially growing cells, sensitization was dependent upon both the concentration of BrdUrd and alkylating agent. Using regression analysis (at 95% CL), a relationship between the level of bromouracil in DNA and the extent of enhanced cytotoxicity was observed at two concentrations of BCNU (r2 = 0.99, 0.96). Although it is known that bifunctional alkylating agents exert cytotoxicity by forming cross-links between cDNA strands, increased cross-link formation was not observed in BrdUrd substituted DNA as determined by alkaline elution. The data suggest that DNA damage induced by halogenated pyrimidines may not involve interstrand cross-links and that these agents may be useful in the treatment of glioma in combination with alkylating agents.

Published
1999

37. Bromodeoxyuridine-mediated radiosensitization in human glioma: the effect of concentration, duration, and fluoropyrimidine modulation.

Author

McLaughlin PW, Lawrence TS, Seabury H, Nguyen N, Stetson PL, Greenberg HS, and Mancini WR

Subjects
Animals, Floxuridine therapeutic use, Glioma drug therapy, Humans, In Vitro Techniques, Mice, Mice, Nude, Neoplasm Transplantation, Neoplasms, Experimental, Transplantation, Heterologous, Tumor Cells, Cultured drug effects, Tumor Cells, Cultured radiation effects, Bromodeoxyuridine administration & dosage, Glioma radiotherapy, Radiation-Sensitizing Agents administration & dosage
Abstract

Purpose: To define the relative influence of duration of exposure, concentration, and modulation by fluorodeoxyuridines (FdUrd) on the incorporation of 5-bromo-2-deoxyuridine (BrdUrd) into DNA of a human malignant glioma line (D-54) in vitro and in vivo., In Vitro Studies: an established human malignant glioma line (D-54) was exposed to a clinically achievable concentration of BrdUrd to model intravenous (1 microM BrdUrd) and intraarterial (4 microM BrdUrd) conditions. The influence of modulation was assessed using 1 nM FdUrd. Incorporation of BrdUrd, radiosensitization, and cytotoxicity were determined after 24, 72, and 120 h drug exposures. In Vivo studies: nude mice bearing D-54 xenografts were infused with BrdUrd at 100 mg/kg/day for 7 and 14 days or BrdUrd at 400 mg/kg/day for 5 days. The influence of modulation was assessed by combining 100 mg/kg/day of BrdUrd with 0.1, 0.3, and 1 mg/kg/day FdUrd for 7 days. Incorporation of BrdUrd into the DNA of tumor, gut, and marrow were determined., Results: In Vitro: thymidine replacement and radiosensitization were a function of concentration, and incorporation began to plateau after 2 to 3 population doublings. Modulation with 1 nM FdUrd significantly increased incorporation. Radiosensitization was a linear function of thymidine replacement under all conditions tested. In Vivo: infusion with 400 mg/kg/day for 5 days resulted in greater tumor incorporation (10.3 +/- 0.4% thymidine replaced) than treatment with 100 mg/kg/day for 14 days (6.0 +/- 0.6% of thymidine replaced). Infusion of FdUrd with BrdUrd increased normal tissue incorporation of BrdUrd, but failed to increase BrdUrd incorporation in tumor cells., Conclusion: These results suggest that relatively short, high dose rate infusions may be preferable to long, low dose rate infusions. The potential benefit of FdUrd modulation demonstrated in vitro may be difficult to realize using continuous systemic infusions.

Published
1994
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38. Halogenated pyrimidine sensitization of low dose rate irradiation in human malignant glioma.

Author

McLaughlin PW, Mancini WR, Stetson PL, Greenberg HS, Nguyen N, Seabury H, Heidorn DB, and Lawrence TS

Subjects
Dose-Response Relationship, Radiation, Humans, In Vitro Techniques, Radiotherapy Dosage, Survival Rate, Tumor Cells, Cultured drug effects, Tumor Cells, Cultured radiation effects, Bromodeoxyuridine therapeutic use, Glioma radiotherapy, Radiation-Sensitizing Agents therapeutic use
Abstract

Purpose: To determine the potential advantage of combining halogenated pyrimidine radiosensitization and continuous low dose rate irradiation in human malignant glioma., Methods and Materials: An established glioma line (U-251) was incubated with 5-bromo-2-doxyuridine (BrdUrd) at clinically achievable concentrations at three dose rates of interest--100 cGy/min (typical of external beam therapy), 43 cGy/hr (typical of temporary afterloaded implants), and 12 cGy/hr (typical of permanent implants)., Results: After exposure to 1 microM BrdUrd, the greatest enhancement ratio was seen at the 12 cGy/hr dose rate, implying a BrdUrd induced inverse dose rate effect independent of a G2M block. Under these conditions, the mean inactivation dose after 1 microM BrdUrd exposure was equivalent for 100 cGy/min and 12 cGy/hr., Conclusion: These results support the use of halopyrimidines as sensitizers of temporary afterloaded and permanent implants.

Published
1993
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39. Localization of the peripheral-type benzodiazepine binding site to mitochondria of human glioma cells.

Author

Olson JM, McNeel W, Young AB, and Mancini WR

Subjects
Alkaline Phosphatase analysis, Alkaline Phosphatase metabolism, Animals, Cell Line, DNA, Neoplasm analysis, Humans, Isoquinolines metabolism, Monoamine Oxidase analysis, Monoamine Oxidase metabolism, Rats, Receptors, GABA-A analysis, Succinate Dehydrogenase analysis, Succinate Dehydrogenase metabolism, Tritium, Glioma metabolism, Mitochondria metabolism, Receptors, GABA-A metabolism
Abstract

Subcellular fractionation was performed on human U251 glioblastoma cultures. In all subcellular fractions, the binding of the peripheral benzodiazepine ligand, [3H]PK 11195, correlated with the specific activity of monoamine oxidase (r = 0.95, p less than 0.001) and succinate dehydrogenase (r = 0.93, p less than 0.001), two mitochondrial enzymes. The specific activity of plasma membrane and nuclear markers correlated poorly with the presence of PK 11195 binding sites. These data support the mitochondrion as the primary location of peripheral-type benzodiazepine binding sites (PBBS) in human glioma cells. Mitochondria-rich preparations were then assayed for [3H]Ro5-4964 binding. Six nM [3H]Ro5-4964 failed to specifically bind to human U251 mitochondria, but bound vigorously to mitochondria from rat C6 glioma. These data indicate that the low affinity of Ro5-4864 for PBBS in human glioma cells compared to those in rat is due to interspecies receptor variation rather than impaired drug transport into human cells.

Published
1992
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40. Decrease in TTP pools mediated by 5-bromo-2'-deoxyuridine exposure in a human glioblastoma cell line.

Author

Shewach DS, Ellero J, Mancini WR, and Ensminger WD

Subjects
Antineoplastic Agents pharmacology, Bromodeoxyuridine pharmacology, Culture Media analysis, Deoxyuracil Nucleotides metabolism, Glioma metabolism, Humans, Tumor Cells, Cultured drug effects, Tumor Cells, Cultured metabolism, Bromodeoxyuridine metabolism, DNA, Neoplasm metabolism, Thymine Nucleotides metabolism
Abstract

The antitumor and radiosensitizing properties of 5-bromo-2'-deoxyuridine (BUdR) appear to be due, in part, to its incorporation into cellular DNA. To optimize conditions for incorporation of 5-bromo-2'-deoxyuridine-5'-monophosphate (BrdUMP) into DNA, we investigated the metabolism of BUdR to its DNA precursor form, the 5'-triphosphate BrdUTP, in the U251 human glioblastoma cell line. The results demonstrated that BrdUTP accumulated rapidly in this cell line, achieving steady-state values within 2 hr of drug addition. The level of BrdUTP accumulation was proportional to the amount of exogenous BUdR up to a concentration of 100 microM, without apparent saturation. Exposure of glioblastoma cells to BUdR was associated with substantial selective decreases in both the cellular dCTP and TTP pools, the extent of which was dependent on the exogenous BUdR concentration. In the absence of exogenous BUdR, BrdUTP was eliminated rapidly from cells with an initial half-life of approximately 15 min. As the cellular BrdUTP level declined, the dCTP and TTP levels increased to control values. Incorporation of BrdUMP into DNA appeared linear with time as long as the cellular BrdUTP level remained constant. This incorporation was not enhanced by the addition of 5-fluoro-2'-deoxyuridine (FUdR), a potent inhibitor of thymidylate synthetase, which at a concentration of 10 nM had no effect on TTP pools in this cell line. Thus, the decrease in cellular TTP pools mediated by BrdUTP allows the halogenated pyrimidine to enhance its own incorporation into DNA.

Published
1992
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41. Synthesis and anticancer and antiviral activities of various 2'- and 3'-methylidene-substituted nucleoside analogues and crystal structure of 2'-deoxy-2'-methylidenecytidine hydrochloride.

Author

Lin TS, Luo MZ, Liu MC, Clarke-Katzenburg RH, Cheng YC, Prusoff WH, Mancini WR, Birnbaum GI, Gabe EJ, and Giziewicz J

Subjects
Animals, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Antiviral Agents pharmacology, Antiviral Agents therapeutic use, Chemical Phenomena, Chemistry, Crystallization, Cytarabine adverse effects, Cytarabine therapeutic use, Deoxycytidine chemical synthesis, Deoxycytidine pharmacology, Deoxycytidine therapeutic use, Female, Humans, Leukemia L1210 drug therapy, Leukemia P388 drug therapy, Leukemia, Lymphoid drug therapy, Mice, Molecular Structure, Nucleosides pharmacology, Nucleosides therapeutic use, Sarcoma 180 drug therapy, Simplexvirus drug effects, Tumor Cells, Cultured, X-Ray Diffraction, Antineoplastic Agents chemical synthesis, Antiviral Agents chemical synthesis, Deoxycytidine analogs & derivatives, Nucleosides chemical synthesis
Abstract

Various 2'- and 3'-methylidene-substituted nucleoside analogues have been synthesized and evaluated as potential anticancer and/or antiviral agents. Among these compounds, 2'-deoxy-2'-methylidene-5-fluorocytidine (22) and 2'-deoxy-2'-methylidenecytidine (23) not only demonstrated potent anticancer activity in culture against murine L1210 and P388 leukemias, Sarcoma 180, and human CCRF-CEM lymphoblastic leukemia, producing ED50 values of 1.2 and 0.3 microM, 0.6 and 0.4 microM, 1.5 and 1.5 microM, and 0.05 and 0.03 microM, respectively, but also were active in mice against murine L1210 leukemia. Of all the tested drug dosage levels (25, 50, and 75 mg/kg, respectively) compound 23 had no toxic deaths and compound 22 yielded only one toxic death at the highest dosage level. On the contrary, in the same study, 1-beta-D-arabinofuranosylcytosine (ara-C) resulted in 2/5, 5/5, and 5/5 toxic deaths, respectively. Both compounds 22 and 23 have shown better anticancer activity than ara-C, yielding higher T/C x 100 values and some long-term survivors (greater than 60 days). In addition, compounds 22 and 23 were found to have, respectively, approximately 130 and 40 times lower binding affinity for cytidine/deoxycytidine deaminase derived from human KB cells compared to ara-C, suggesting that the two 2'-methylidene-substituted analogues may be more resistant to deamination. Cytoplasmic deoxycytidine kinase (dCK) was required for compounds 22 and 23 action. Furthermore, compounds 14, 22, 23, and 24 also have antiherpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) activity in cell culture. In addition, the crystal structure of 2'-deoxy-2'-methylidenecytidine hydrochloride (23-HCl) was determined by X-ray crystallography.

Published
1991
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42. Effect of verapamil on the uptake and efflux of etoposide (VP16) in both sensitive and resistant cancer cells.

Author

Feng MR, Liebert M, Wedemeyer G, Grossman HB, Mancini WR, Williams M, and Wagner JG

Subjects
Animals, Carcinoma, Transitional Cell pathology, Culture Media, Drug Resistance, Glucose pharmacology, Humans, Kinetics, Mice, Tumor Cells, Cultured, Urinary Bladder Neoplasms pathology, Carcinoma, Transitional Cell metabolism, Etoposide pharmacokinetics, Leukemia L1210 metabolism, Urinary Bladder Neoplasms metabolism, Verapamil pharmacology
Abstract

The effect of calcium antagonist verapamil on the uptake and efflux of Etoposide (VP16), a semi-synthetic derivative of podophylotoxin and a broad spectrum antineoplastic agent, has been investigated and compared in sensitive (UM-UC-2) and resistant (UM-UC-9) human bladder cancer cells, and L1210 leukemia cells, by using both radioisotope (3[H]-VP16) liquid scintillation and high performance liquid chromatography assay with electrochemical detection. The uptake of VP16 was rapid in all three cell lines, showing an initial rapid linear phase followed by a second slower phase, but at steady state the ratios of intracellular to extracellular VP16 concentrations were only 0.004-0.006. No significant difference in drug uptake was observed in sensitive UM-UC-2 and resistant UM-UC-9 cells at all concentrations studied. Verapamil at a concentration of 10 microM enhanced the intracellular VP-16 levels in all sensitive and resistant cell lines. The increments were 21.5% for UM-UC-2, 11.8% for UM-UC-9, and 31.0% for L1210 cells after 30 minutes incubation with 1 microM VP16. A slower efflux of VP16 was observed in verapamil treated cells in all three cell lines. There was a small increase in the nonexchangeable components in verapamil treated cells, although only 5-10% of VP16 was retained. No peak other than that of VP16 was detected in the HPLC chromatogram of extracts from both cell pellet and influx or efflux medium.

Published
1991
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43. Variability of 5-bromo-2'-deoxyuridine incorporation into DNA of human glioma cell lines and modulation with fluoropyrimidines.

Author

Mancini WR, Stetson PL, Lawrence TS, Wagner JG, Greenberg HS, and Ensminger WD

Subjects
Humans, Tumor Cells, Cultured drug effects, Tumor Cells, Cultured metabolism, Bromodeoxyuridine metabolism, DNA, Neoplasm metabolism, Floxuridine pharmacology, Fluorouracil pharmacology, Glioma metabolism
Abstract

Human glioma-derived cell lines were found to vary in their ability to incorporate the radiosensitizer 5-bromo-2'-deoxyuridine (BrdUrd) into DNA after one cell doubling. The U-251 cell line was the best incorporator of BrdUrd, whereas U-118 and D-54 demonstrated poor incorporation with respective C50 (BrdUrd concentration required for 50% of the maximum amount of BrdUrd incorporation into DNA) values of 2.8- and 6-fold greater than that of U-251 (P less than 0.001). Modulation of radiosensitizer uptake into DNA could be achieved using the thymidylate synthase inhibitors 5-fluorouracil or 5-fluoro-2'-deoxyuridine (FdUrd). Incorporation into U-251 cells increased only slightly in the presence of the fluoropyrimidines. The BrdUrd concentration required for 50% of the maximum amount of BrdUrd incorporation into DNA changed (P less than 0.001) from 1.8 +/- 0.11 microM (SD) in the absence of a modulator to 1.1 +/- 0.09 or 1.1 +/- 0.16 microM in the presence of 10 microM 5-fluorouracil or 5 nM FdUrd, respectively. The D-54 cell line, which was the worst incorporator of BrdUrd, was found to have an extensive amount of BrdUrd into DNA following biomodulation. The C50 in the absence of modulation was 7.3 +/- 1.3 microM, which was reduced (P less than 0.001) to 0.62 +/- 0.04 and 0.32 +/- 0.13 microM, respectively, in the presence of 10 microM 5-fluorouracil and 5 nM FdUrd. This represents a 12- to 22-fold reduction in the concentration of radiosensitizer required to achieve the same level of BrdUrd incorporation into DNA. Furthermore, this enhancement of BrdUrd DNA incorporation seen in the presence of the fluoropyrimidines is observed at clinically achievable concentrations. The degree of radiosensitization was solely dependent upon the amount of BrdUrd incorporated into DNA. D-54 cells grown in the presence of 0.18 microM BrdUrd plus 5 nM FdUrd or 2.8 microM BrdUrd alone yielded a similar level of BrdUrd incorporation into DNA and radiosensitization, though a 15-fold lower BrdUrd concentration was used in the presence of FdUrd. The combined use of a radiosensitizer with a fluoropyrimidine may overcome poor incorporation of BrdUrd into DNA that may exist among resistant subpopulations of cells within malignant glioma.

Published
1991

44. Production of herpes simplex virus type 1 thymidine kinase in the presence of thymidine analogues.

Author

Zucker ML, Mancini WR, Otto MJ, Lee JJ, and Prusoff WH

Subjects
Animals, Cell Line, Chlorocebus aethiops, Cricetinae, Humans, Simplexvirus metabolism, Thymidine metabolism, Thymidine Kinase isolation & purification, Dideoxynucleosides, Idoxuridine analogs & derivatives, Idoxuridine metabolism, Simplexvirus enzymology, Thymidine analogs & derivatives, Thymidine Kinase biosynthesis
Abstract

Treatment of herpes simplex virus type 1 (HSV-1) infected Vero, BHK, BHKtk- and LMtk- cells with 5-iodo-5'-amino-2',5'-dideoxyuridine (AIdUrd) caused increased synthesis of ICP36 and an increase in HSV-1 thymidine kinase (tk) activity at late times of infection. The overproduced ICP36 was identified as the HSV-1 encoded tk protein by immunoprecipitation. Whereas the thymidine analogue 5'-amino-5'-deoxythymidine (AdThd) caused an increase in HSV-1 tk synthesis and activity in wild type Vero and BHK cells, 5-iodo-2'-deoxyuridine (IdUrd) caused a similar increase only in tk- cells (LMtk-, BHKtk-). In vivo and in vitro stabilization studies using a [35S]methionine pulse-chase experiment or heat inactivation studies with purified HSV-1 tk revealed that stabilization of tk by the analogues could not account for the extent of the observed increase. Since overproduction of tk is observed only at late times of infection, it is suggested that the presence of these thymidine analogues in either the viral DNA or the cellular nucleotide pools is responsible for the observed differential effects.

Published
1986
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45. Specific inhibition of DNA biosynthesis induced by 3'-amino-2',3'-dideoxycytidine.

Author

Mancini WR, Williams MS, and Lin TS

Subjects
Animals, DNA Polymerase II metabolism, DNA Replication drug effects, DNA, Neoplasm drug effects, Dideoxynucleosides chemical synthesis, Dideoxynucleosides therapeutic use, Flow Cytometry, Kinetics, Leukemia L1210 drug therapy, Leukemia L1210 enzymology, Mice, Tumor Cells, Cultured cytology, Tumor Cells, Cultured drug effects, Tumor Cells, Cultured metabolism, Antineoplastic Agents pharmacology, Carcinoma, Ehrlich Tumor metabolism, DNA, Neoplasm biosynthesis, Dideoxynucleosides pharmacology, Zalcitabine analogs & derivatives
Abstract

3'-Amino-2',3'-dideoxycytidine (3'-NH2-dCyd) produced an S-phase-specific block in exponentially growing L1210 leukemia cells. The monophosphate and triphosphate forms of the drug were detected within a few hours of 3'-NH2-dCyd treatment of intact cells. No significant change in the deoxynucleoside triphosphate levels was observed during the early stages of treatment. However, by 24 h a 2-fold increase in the amount of the deoxynucleoside triphosphates was seen. The triphosphate form of the drug competitively inhibited dCTP incorporation into calf thymus DNA using highly purified DNA polymerase alpha. The Ki was determined to be 9.6 microM with respect to dCTP. Incorporation of the analogue into DNA was not detected. On the other hand, sucrose gradient analysis suggested that incorporation of the analogue into actively synthesized DNA may account for the biological activity of this compound. Treatment with 3'-NH2-dCyd induced single-strand breaks in actively synthesized DNA, but no double-strand breaks were observed in the presence of the analogue. The data indicate that 3'-amino-2',3'-dideoxycytidine specifically interferes with DNA replication at the level of DNA polymerase by inhibiting chain elongation.

Published
1988
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46. Isoquinoline and peripheral-type benzodiazepine binding in gliomas: implications for diagnostic imaging.

Author

Olson JM, Junck L, Young AB, Penney JB, and Mancini WR

Subjects
Benzodiazepinones metabolism, Brain Neoplasms diagnostic imaging, Brain Neoplasms metabolism, Cells, Cultured, Flunitrazepam metabolism, Glioma metabolism, Humans, Kinetics, Tomography, Emission-Computed, Benzodiazepines metabolism, Glioma diagnostic imaging, Isoquinolines metabolism
Abstract

Binding of the isoquinoline PK 11195 and of the benzodiazepines Ro5-4864 and flunitrazepam was compared in glioma cells and tissues. In human and rat glioma cell cultures [3H]PK 11195 bound with higher affinity (Kd = 14.01 and 15.76 nM, respectively) than either Ro5-4864 (Ki = 1200 and 84.9 nM, respectively) or flunitrazepam (Ki greater than 10,000 and = 848 nM, respectively). Autoradiograms of postmortem human brain sections containing glioma revealed that [3H]PK 11195 bound specifically to intact tumor cells and not to cells of normal cerebral cortex or necrotic areas of the tumor. Total [3H]Ro5-4864 or [3H]flunitrazepam binding to these sections was indistinguishable from nonspecific binding, and regions of tumor and normal brain could not be delineated. These results support the use of radiolabeled PK 11195 for clinical trials of imaging human gliomas by positron emission tomography.

Published
1988

47. Synthesis and biological activity of various 3'-azido and 3'-amino analogues of 5-substituted pyrimidine deoxyribonucleosides.

Author

Lin TS, Gao YS, and Mancini WR

Subjects
Animals, Deoxycytidine chemical synthesis, Deoxycytidine therapeutic use, Deoxycytidine Kinase antagonists & inhibitors, Deoxyuridine chemical synthesis, Deoxyuridine therapeutic use, Leukemia L1210 drug therapy, Mice, Sarcoma 180 drug therapy, Thymidine Kinase antagonists & inhibitors, Antineoplastic Agents chemical synthesis, Deoxycytidine analogs & derivatives, Deoxyuridine analogs & derivatives
Abstract

Various new 5-substituted 3'-azido- and 3'-amino derivatives of 2'-deoxyuridine and 2'-deoxycytidine have been synthesized and biologically evaluated. Among these compounds, 3'-amino-2',3'-dideoxy-5-fluorouridine (3), 3'-amino-2',3'-dideoxycytidine (7a), and 3'-amino-2',3'-dideoxy-5-fluorocytidine (7c) were found to be the most active against murine L1210 and sarcoma 180 neoplastic cells in vitro, with an ED50 of 15 and 1 microM, 0.7 and 4 microM, and 10 and 1 microM, respectively. The 3'-azido derivatives, 2 and 6c, were less active in comparison with their 3'-amino counterparts. In addition, the 5-fluoro-3'-amino nucleosides, 3 and 7c, were tested against L1210 leukemia bearing CDF1 mice. Our preliminary findings indicate that compound 7c (6 X 200 mg/kg) was as active as the positive control, 5-fluorouracil (6 X 20 mg/kg), yielding a T/C X 100 of 146 and 129, respectively. However, 3 was found to be inactive in this experiment.

Published
1983
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48. Synthesis and antineoplastic activity of 3'-azido and 3'-amino analogues of pyrimidine deoxyribonucleoside.

Author

Lin TS and Mancini WR

Subjects
Animals, Body Weight drug effects, DNA Replication drug effects, Leukemia L1210 metabolism, Mice, Pyrimidine Nucleosides pharmacology, Antineoplastic Agents pharmacology, Pyrimidine Nucleosides chemical synthesis
Abstract

Several new 3'-azido and 3'-amino nucleosides (8, 9, 12, and 13) have been synthesized and their biological activities evaluated. Among them, 3'-amino-2',3'-dideoxycytidine (13) was found to exhibit potent cytotoxic activity against both L1210 and S-180 cells in vitro with an ID50 of 0.7 and 4.0 microM, respectively. Furthermore, 13 has also shown antitumor activity against L1210 tumor bearing mice with a T/C X 100 value of 283.

Published
1983
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49. Presence of peripheral-type benzodiazepine binding sites on human erythrocyte membranes.

Author

Olson JM, Ciliax BJ, Mancini WR, and Young AB

Subjects
Benzodiazepinones blood, Clonazepam blood, Convulsants blood, Erythrocyte Membrane enzymology, Flunitrazepam blood, Humans, In Vitro Techniques, Isoquinolines blood, Kinetics, Monoamine Oxidase blood, Erythrocyte Membrane metabolism, Receptors, GABA-A metabolism
Abstract

A nanomolar affinity peripheral-type benzodiazepine binding site is described in human erythrocyte membranes. [3H]PK 11195 is displaced from this binding site by unlabeled drugs with the rank order PK 11195 greater than Ro 5-4864 greater than flunitrazepam much greater than clonazepam. Neither GABA nor a non-hydrolyzable analog of GTP have an effect on binding parameters. These data provide evidence that a peripheral-type benzodiazepine binding site, pharmacologically similar to the intracellular binding site described in other tissues, is present in the plasma membrane of human erythrocytes.

Published
1988
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50. Basic biochemical and pharmacological aspects of antiviral agents.

Author

Prusoff WH, Zucker M, Mancini WR, Otto MJ, Lin TS, and Lee JJ

Subjects
Acyclovir adverse effects, Acyclovir therapeutic use, Amantadine therapeutic use, Antiviral Agents therapeutic use, Bone Marrow Transplantation, Chemical Phenomena, Chemistry, Clinical Trials as Topic, DNA, Viral biosynthesis, Herpesviridae drug effects, Herpesviridae Infections drug therapy, Humans, Idoxuridine therapeutic use, Influenza A virus drug effects, Influenza A virus enzymology, Influenza A virus physiology, Influenza, Human drug therapy, Keratitis, Dendritic drug therapy, RNA, Viral biosynthesis, S-Adenosylhomocysteine metabolism, Thymidine Kinase metabolism, Trifluridine pharmacology, Trifluridine therapeutic use, Vidarabine therapeutic use, Viral Proteins biosynthesis, Acyclovir pharmacology, Amantadine pharmacology, Antiviral Agents pharmacology, Idoxuridine pharmacology, Vidarabine pharmacology, Virus Diseases drug therapy
Published
1985
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