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1.  The association of coffee intake with liver cancer incidence and chronic liver disease mortality in male smokers 
British Journal of Cancer  2013;109(5):1344-1351.
Coffee intake is associated with reduced risk of liver cancer and chronic liver disease as reported in previous studies, including prospective ones conducted in Asian populations where hepatitis B viruses (HBVs) and hepatitis C viruses (HCVs) are the dominant risk factors. Yet, prospective studies in Western populations with lower HBV and HCV prevalence are sparse. Also, although preparation methods affect coffee constituents, it is unknown whether different methods affect disease associations.
We evaluated the association of coffee intake with incident liver cancer and chronic liver disease mortality in 27 037 Finnish male smokers, aged 50–69, in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, who recorded their coffee consumption and were followed up to 24 years for incident liver cancer or chronic liver disease mortality. Multivariate relative risks (RRs) and 95% confidence intervals (CIs) were estimated by Cox proportional hazard models.
Coffee intake was inversely associated with incident liver cancer (RR per cup per day=0.82, 95% CI: 0.73–0.93; P-trend across categories=0.0007) and mortality from chronic liver disease (RR=0.55, 95% CI: 0.48–0.63; P-trend<0.0001). Inverse associations persisted in those without diabetes, HBV- and HCV-negative cases, and in analyses stratified by age, body mass index, alcohol and smoking dose. We observed similar associations for those drinking boiled or filtered coffee.
These findings suggest that drinking coffee may have benefits for the liver, irrespective of whether coffee was boiled or filtered.
PMCID: PMC3778279  PMID: 23880821
liver cancer; chronic liver disease; coffee preparation; filtered coffee; boiled coffee; prospective cohort
2.  Pigmentation-related phenotypes and risk of prostate cancer 
British Journal of Cancer  2013;109(3):747-750.
Solar ultraviolet radiation exposure has been inversely related to prostate cancer incidence and mortality, possibly mediated through vitamin D status. Pigmentation-related traits influence endogenous vitamin D synthesis and may alter risk of prostate cancer.
We examined prostate cancer in relation to hair and eye colour, and skin phototype in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort. Incident cancer was diagnosed in 1982 out of 20 863 men. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from Cox proportional hazards models.
Prostate cancer risk did not differ by eye colour or skin phototype. Men with naturally red hair were significantly less likely to develop prostate cancer (HR=0.46, 95% CI 0.24–0.89) than men with light brown hair (reference).
The red hair phenotype, which results from polymorphisms in the melanocortin-1-receptor (MC1R) gene, is associated with lower risk of prostate cancer. This pigmentation-related trait may influence prostate cancer development either directly, through genetic effects or regulatory mechanisms related to MC1R, another nearby gene, or other pigmentation genes, or indirectly, through associations with other exposures such as sunlight or vitamin D status.
PMCID: PMC3738118  PMID: 23860522
prostate cancer; MC1R; vitamin D; hair colour; red hair; pigmentation traits
3.  Influence of vitamin D binding protein on the association between circulating vitamin D and risk of bladder cancer 
British Journal of Cancer  2012;107(9):1589-1594.
There is little research investigating the role of vitamin D binding protein (DBP) in the association between 25-hydroxyvitamin D (25(OH)D) and disease risk.
Within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, 250 bladder cancer cases were randomly sampled and matched 1:1 to controls on age and date of blood collection. Odds ratios (OR) and 95% confidence intervals (CI) of bladder cancer were estimated by quartiles of DBP (measured by ELISA), 25(OH)D and the molar ratio of 25(OH)D:DBP, a proxy for free circulating 25(OH)D. Analyses were also conducted stratifying 25(OH)D by DBP (median split) and vice versa.
We found no direct association between circulating DBP levels and bladder cancer risk (P-trend=0.83). The inverse association between 25(OH)D and bladder cancer risk was unchanged after adjustment for DBP (Q4 vs Q1 OR=0.61, 95% CI=0.36–1.05; P-trend=0.04), and was stronger among men with lower DBP (low DBP: 25(OH)D Q4 vs Q1 OR=0.47, 95% CI=0.23–1.00; high DBP: 25(OH)D Q4 vs Q1 OR=0.83, 95% CI=0.40–1.75; P for interaction=0.11).
Our findings provide additional support for an aetiologic role for vitamin D in bladder cancer and suggest that free, rather than total, circulating vitamin D may be a more relevant exposure when examining bladder and, perhaps, other cancers.
PMCID: PMC3493763  PMID: 22990651
urinary bladder neoplasms; 25-hydroxyvitamin D; vitamin D binding protein; case–control study
4.  Baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF) 
McMurray, John J.V. | Anand, Inder S. | Diaz, Rafael | Maggioni, Aldo P. | O'Connor, Christopher | Pfeffer, Marc A. | Solomon, Scott D. | Tendera, Michal | van Veldhuisen, Dirk J. | Albizem, Moetaz | Cheng, Sunfa | Scarlata, Debra | Swedberg, Karl | Young, James B. | Amuchastegui, M. | Belziti, C. | Bluguermann, J. | Caccavo, M. | Cartasegna, L. | Colque, R. | Cuneo, C. | Fernandez, A. | Gabito, A. | Goicochea, R. | Gonzalez, M. | Gorosito, V. | Grinfeld, L. | Hominal, M. | Kevorkian, R. | Litvak Bruno, M. | Llanos, J. | Mackinnon, I. | Manuale, O. | Marzetti, E. | Nul, D. | Perna, E. | Riccitelli, M. | Sanchez, A. | Santos, D. | Schygiel, P. | Toblli, J. | Vogel, D. | Aggarwal, A. | Amerena, J. | De Looze, F. | Fletcher, P. | Hare, D. | Ireland, M. | Krum, H. | Lattimore, J. | Marwick, T. | Sindone, A. | Thompson, P. | Waites, J. | Altenberger, J. | Ebner, C. | Lenz, K. | Pacher, R. | Poelzl, G. | Charlier, F. | de Ceuninck, M. | De Keulenaer, G. | Dendale, P. | Maréchal, P. | Mullens, W. | Thoeng, J. | Vanderheyden, M. | Vanhaecke, J. | Weytjens, C. | Wollaert, B. | Albuquerque, D. | Almeida, D. | Aspe y Rosas, J. | Bocchi, E. | Bordignon, S. | Clausell, N. | Kaiser, S. | Leaes, P. | Martins Alves, S. | Montera, M. | Moura, L. | Pereira de Castro, R. | Rassi, S. | Reis, A. | Saraiva, J. | Simões, M. | Souza Neto, J. | Teixeira, M. | Benov, H. | Chompalova, B. | Donova, T. | Georgiev, P. | Gotchev, D. | Goudev, A. | Grigorov, M. | Guenova, D. | Hergeldjieva, V. | Ivanov, D. | Kostova, E. | Manolova, A. | Marchev, S. | Nikolov, F. | Popov, A. | Raev, D. | Tzekova, M. | Czarnecki, W. | Giannetti, N. | Haddad, H. | Heath, J. | Huynh, T. | Lepage, S. | Liu, P. | Lonn, E. | Ma, P. | Manyari, D. | Moe, G. | Parker, J. | Pesant, Y. | Rajda, M. | Ricci, J. | Roth, S. | Sestier, F. | Sluzar, V. | Sussex, B. | Vizel, S. | Antezana, G. | Bugueno, C. | Castro, P. | Conejeros, C. | Manriquez, L. | Martinez, D. | Potthoff, S. | Stockins, B. | Vukasovic, J. | Gregor, P. | Herold, M. | Jerabek, O. | Jirmar, R. | Kuchar, R. | Linhart, A. | Podzemska, B. | Soucek, M. | Spac, J. | Spacek, R. | Vodnansky, P. | Bronnum-Schou, J. | Clemmensen, K. | Egstrup, K. | Jensen, G. | Kjoller-Hansen, L. | Kober, L. | Markenvard, J. | Rokkedal, J. | Skagen, K. | Torp-Pedersen, C. | Tuxen, C. | Videbak, L. | Laks, T. | Vahula, V. | Harjola, V. | Kettunen, R. | Kotila, M. | Bauer, F. | Cohen Solal, A. | Coisne, D. | Davy, J. | De Groote, P. | Dos Santos, P. | Funck, F. | Galinier, M. | Gibelin, P. | Isnard, R. | Neuder, Y. | Roul, G. | Sabatier, R. | Trochu, J. | Anker, S. | Denny, S. | Dreykluft, T. | Flesch, M. | Genth-Zotz, S. | Hambrecht, R. | Hein, J. | Jeserich, M. | John, M. | Kreider-Stempfle, H. | Laufs, U. | Muellerleile, K. | Natour, M. | Sandri, M. | Schäufele, T. | von Hodenberg, E. | Weyland, K. | Winkelmann, B. | Tse, H. | Yan, B. | Barsi, B. | Csikasz, J. | Dezsi, C. | Edes, I. | Forster, T. | Karpati, P. | Kerekes, C. | Kis, E. | Kosa, I. | Lupkovics, 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L. | Senni, M. | Tavazzi, L. | Erglis, A. | Jasinkevica, I. | Kakurina, N. | Veze, I. | Volans, E. | Bagdonas, A. | Berukstis, E. | Celutkiene, J. | Dambrauskaite, A. | Jarasuniene, D. | Luksiene, D. | Rudys, A. | Sakalyte, G. | Sliaziene, S. | Aguilar-Romero, R. | Cardona-Muñoz, E. | Castro-Jimenez, J. | Chavez-Herrera, J. | Chuquiure Valenzuela, E. | De la Pena, G. | Herrera, E. | Leiva-Pons, J. | Lopez Alvarado, A. | Mendez Machado, G. | Ramos-Lopez, G. | Basart, D. | Buijs, E. | Cornel, J. | de Leeuw, M. | Dijkgraaf, R. | Dunselman, P. | Freericks, M. | Hamraoui, K. | Lenderlink, T. | Linssen, G. | Lodewick, P. | Lodewijks, C. | Lok, D. | Nierop, P. | Ronner, E. | Somsen, A. | van Dantzig, J. | van der Burgh, P. | van Kempen, L. | van Vlies, B. | Voors, A. | Wardeh, A. | Willems, F. | Dickstein, K. | Gundersen, T. | Hole, T. | Thalamus, J. | Westheim, A. | Dabrowski, M. | Gorski, J. | Korewicki, J. | Kuc, K. | Miekus, P. | Musial, W. | Niegowska, J. | Piotrowski, W. | Podolec, P. | Polonski, L. | Ponikowski, P. | Rynkiewicz, A. | Szelemej, R. | Trusz-Gluza, M. | Ujda, M. | Wojciechowski, D | Wysokinski, A. | Camacho, A. | Fonseca, C. | Monteiro, P. | Apetrei, E. | Bruckner, I. | Carasca, E. | Coman, I. | Datcu, M. | Dragulescu, S. | Ionescu, P. | Iordachescu-Petica, D. | Manitiu, I. | Popa, V. | Pop-Moldovan, A. | Radoi, M. | Stamate, S. | Tomescu, M. | Vita, I. | Aroutiounov, G. | Ballyuzek, M. | Bart, B. | Churina, S. | Glezer, M. | Goloshchekin, B. | Ivleva, A. | Kobalava, Z. | Kostenko, V. | Lopatin, Y. | Martynov, A. | Orlov, V. | Semernin, E. | Shogenov, Z. | Sidorenko, B. | Skvortsov, A. | Storzhakov, G. | Sulimov, V. | Talibov, O. | Tereshenko, S. | Tsyrline, V. | Zadionchenko, V. | Zateyshchikov, D. | Dzupina, A. | Hranai, M. | Kmec, J. | Micko, K. | Murin, J. | Pella, D. | Sojka, G. | Spisak, V. | Vahala, P. | Vinanska, D. | Badat, A. | Bayat, J. | Dawood, S. | Delport, E. | Ellis, G. | Garda, R. | Klug, E. | Mabin, T. | Naidoo, D. | Pretorius, M. | Ranjith, N. | Van Zyl, L. | Weich, H. | Anguita, M. | Berrazueta, J. | Bruguera i Cortada, J. | de Teresa, E. | Gómez Sánchez, M. | González Juanatey, J. | Gonzalez-Maqueda, I. | Jordana, R. | Lupon, J. | Manzano, L. | Pascual Figal, D. | Pulpón, L. | Recio, J. | Ridocci Soriano, F. | Rodríguez Lambert, J. | Roig Minguell, E. | Roig Minguell, E. | Romero, J. | Valdovinos, P. | Klintberg, L. | Kronvall, T. | Lycksell, M. | Morner, S. | Rydberg, E. | Swedberg, K. | Timberg, I. | Wikstrom, G. | Moccetti, T.4 | Ashok, J. | Banerjee, P. | Carr-White, G. | Cleland, J. | Connolly, E. | Francis, M. | Greenbaum, R. | Kadr, H. | Lindsay, S. | McMurray, J. | Megarry, S. | Memon, A. | Murdoch, D. | Senior, R. | Squire, I. | Tan, L. | Witte, K. | Adams, K. | Adamson, P. | Adler, A. | Altschul, L. | Altschuller, A. | Amirani, H. | Anand, I. | Andreou, C. | Ansari, M. | Antonishen, M. | Banchs, H. | Banerjee, S. | Banish, D. | Bank, A. | Barbagelata, A. | Barnard, D. | Bellinger, R. | Benn, A. | Berk, M. | Berry, B. | Bethala, V. | Bilazarian, S. | Bisognano, J. | Bleyer, F. | Blum, M. | Boehmer, J. | Bouchard, A. | Boyle, A. | Bozkurt, B. | Brown, C. | Burlew, B. | Burnham, K. | Butler, J. | Call, J. | Cambier, P. | Cappola, T. | Carlson, R. | Chandler, B. | Chandra, R. | Chandraratna, P. | Chernick, R. | Colan, D. | Colfer, H. | Colucci, W. | Connelly, T. | Costantini, O. | Dadkhah, S. | Dauber, I. | Davis, J. | Davis, S. | Denning, S. | Drazner, M. | Dunlap, S. | Egbujiobi, L. | Elkayam, U. | Elliott, J. | El-Shahawy, M. | Essandoh, L. | Ewald, G. | Fang, J. | Farhoud, H. | Felker, G. | Fernandez, J. | Festin, R. | Fishbein, G. | Florea, V. | Flores, E. | Floro, J. | Gabris, M. | Garg, M. | Gatewood, R. | Geller, M. | Ghali, J. | Ghumman, W. | Gibbs, G. | Gillespie, E. | Gilmore, R. | Gogia, H. | Goldberg, L. | Gradus-Pizlo, I. | Grainger, T. | Gudmundsson, G. | Gunawardena, D. | Gupta, D. | Hack, T. | Hall, S. | Hamroff, G. | Hankins, S. | Hanna, M. | Hargrove, J. | Haught, W. | Hauptman, P. | Hazelrigg, M. | Herzog, C. | Heywood, J. | Hill, T. | Hilton, T. | Hirsch, H. | Hunter, J. | Ibrahim, H. | Imburgia, M. | Iteld, B. | Jackson, B. | Jaffrani, N. | Jain, D. | Jain, A. | James, M. | Jimenez, J. | Johnson, E. | Kale, P. | Kaneshige, A. | Kapadia, S. | Karia, D. | Karlsberg, R. | Katholi, R. | Kerut, E. | Khoury, W. | Kipperman, R. | Klapholz, M. | Kosinski, E. | Kozinn, M. | Kraus, D. | Krueger, S. | Krum, H. | Kumar, S. | Lader, E. | Lee, C. | Levy, W. | Lewis, E. | Light-McGroary, K. | Loh, I. | Lombardi, W. | Machado, C. | Maislos, F. | Mancini, D. | Markus, T. | Mather, P. | McCants, K. | McGrew, F. | McLaurin, B. | McMillan, E. | McNamara, D. | Meyer, T. | Meymandi, S. | Miller, A. | Minami, E. | Modi, M. | Mody, F. | Mohanty, P. | Moscoso, R. | Moskowitz, R. | Moustafa, M. | Mullen, M. | Naz, T. | Noonan, T. | O'Brien, T. | Oellerich, W. | Oren, R. | Pamboukian, S. | Pereira, N. | Pitt, W. | Porter, C. | Prabhu, S. | Promisloff, 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European Journal of Heart Failure  2013;15(3):334-341.
This report describes the baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF) which is testing the hypothesis that anaemia correction with darbepoetin alfa will reduce the composite endpoint of death from any cause or hospital admission for worsening heart failure, and improve other outcomes.
Methods and results
Key demographic, clinical, and laboratory findings, along with baseline treatment, are reported and compared with those of patients in other recent clinical trials in heart failure. Compared with other recent trials, RED-HF enrolled more elderly [mean age 70 (SD 11.4) years], female (41%), and black (9%) patients. RED-HF patients more often had diabetes (46%) and renal impairment (72% had an estimated glomerular filtration rate <60 mL/min/1.73 m2). Patients in RED-HF had heart failure of longer duration [5.3 (5.4) years], worse NYHA class (35% II, 63% III, and 2% IV), and more signs of congestion. Mean EF was 30% (6.8%). RED-HF patients were well treated at randomization, and pharmacological therapy at baseline was broadly similar to that of other recent trials, taking account of study-specific inclusion/exclusion criteria. Median (interquartile range) haemoglobin at baseline was 112 (106–117) g/L.
The anaemic patients enrolled in RED-HF were older, moderately to markedly symptomatic, and had extensive co-morbidity.
PMCID: PMC3576902  PMID: 23329651
Heart failure; Anaemia
6.  Neurocognitive contributions to verbal fluency deficits in frontotemporal lobar degeneration 
Neurology  2009;73(7):535-542.
To test the hypothesis that different neurocognitive networks underlie verbal fluency deficits in frontotemporal lobar degeneration (FTLD).
Letter (“FAS”) and semantic (“animal”) fluency tests were administered to patients with a behavioral/dysexecutive disorder (bvFTLD; n = 71), semantic dementia (SemD; n = 21), and progressive nonfluent aphasia (PNFA; n = 26). Tests measuring working memory, naming/lexical retrieval, and semantic knowledge were also obtained. MRI voxel-based morphometry (VBM) studies were obtained on a subset of these patients (bvFTLD, n = 51; PNFA, n = 11; SemD, n = 10).
Patients with SemD were disproportionately impaired on the semantic fluency measure. Reduced output on this test was correlated with impaired performance on naming/lexical retrieval tests. VBM analyses related reduced letter and semantic fluency to anterior and inferior left temporal lobe atrophy. Patients with bvFTLD were equally impaired on both fluency tests. Poor performance on both fluency tests was correlated with low scores on working memory and naming/lexical retrieval measures. In this group, MRI-VBM analyses related letter fluency to bilateral frontal atrophy and semantic fluency to left frontal/temporal atrophy. Patients with PNFA were also equally impaired on fluency tests. Reduced semantic fluency output was correlated with reduced performance on naming/lexical retrieval tests. MRI-VBM analyses related semantic fluency to the right frontal lobe and letter fluency to left temporal atrophy.
Distinct neurocognitive networks underlie impaired performance on letter and semantic fluency tests in frontotemporal lobar degeneration subgroups.
= Alzheimer disease;
= analysis of variance;
= behavioral/dysexecutive subgroup;
= frontotemporal lobar degeneration;
= Mini-Mental State Examination;
= Montreal Neurological Institute;
= magnetic resonance;
= progressive nonfluent aphasia;
= semantic dementia;
= echo time;
= repetition time;
= voxel-based morphometry.
PMCID: PMC2730797  PMID: 19687454
7.  How a real time clinical data retrieval system might be applied to a tobacco cessation program 
Tobacco Control  2000;9(Suppl 1):i46-.
PMCID: PMC1766268  PMID: 10688932
8.  In vitro testing of a new transpedicular stabilization technique 
European Spine Journal  1997;6(4):249-255.
The rigidity of a pedicle screw implant is a critical biomechanical variable in lumbar spinal fusions. Sufficient rigidity is required for integration of bone grafts and to promote healing. Osteopenia, stress shielding, and compensatory hypermobility have been described as consequences of excessive rigidity. Little is known about the biomechanical characteristics of “semirigid” compared to “rigid” implants. A new implant, whose rigidity can be varied by selection of different implant components, was tested in vitro under well-defined loading conditions. The three-dimensional load-displacement behavior of all lumbar vertebrae involved in or adjacent to the two-level fusion was evaluated for two fusion modifications: bilateral rigid and bilateral semirigid. Cyclic fatigue loading was subsequently carried out under realistic conditions and motion testing repeated. The rigid device reduced the motion of the L3–4 transfixed segment in the primary movement planes by 87.3% with respect to the intact spine value in flexion/extension (FE), 86.3% in lateral bending (LB), and 76.8% in axial rotation (AR). The semirigid device achieved a reduction in motion of 79.6% (FE), 82.7% (LB), and 51.7% (AR). The semirigid implant was particularly easy to insert, because no bending of rods or plates was necessary. The implants showed no loosening or breakage after the fatigue testing. The results are compared to other available systems and the underlying biomechanics discussed.
PMCID: PMC3454640  PMID: 9294749
Spine; Spinal fusion; Biomechanics; Pedicle screw; Stress shielding
9.  Comparison of rectal and perirectal swabs for detection of colonization with vancomycin-resistant enterococci. 
Journal of Clinical Microbiology  1996;34(1):210-212.
Patients whose gastrointestinal tracts are colonized with vancomycin-resistant enterococci (VRE) may serve as a reservoir for nosocomial transmission. We compared the sensitivities and concordance of several methods used to detect VRE colonization. Eighty-two paired rectal and perirectal swabs were obtained from 13 patients over a 9-day period. The sensitivity of both rectal and perirectal swabs was 79%. There was 100% concordance of culture results between simultaneously obtained rectal and perirectal swabs, and the quantities of growth were similar by these two methods of detection. Our data suggest that rectal and perirectal swabs are equally sensitive for the detection of VRE colonization.
PMCID: PMC228765  PMID: 8748308
11.  Posterolateral approach for anterior resection and posterior stabilization of the upper cervical spine: a case report. 
The Iowa Orthopaedic Journal  1996;16:157-160.
Surgical approaches to atlanto-axial lesions are generally accomplished by either anterior (transoral) or posterior approaches as dictated by the location of the lesion. In certain patients, these approaches are combined, either in a single or staged procedure. Mechanical stabilization is much more readily accomplished posteriorly, as this allows easy incorporation of the occiput. While the transoral approach allows excellent exposure of the bodies of C1 and C2, it entails substantial surgical trauma. We describe the case of a woman with destruction of the anterior portions of the C1 and C2 vertebrae by metastatic breast cancer addressed by simultaneous anterior tumor debulking and posterior instrumentation through a posterolateral approach to the upper cervical spine.
PMCID: PMC2378123  PMID: 9129289
12.  Generation of a drug resistance profile by quantitation of mdr-1/P-glycoprotein in the cell lines of the National Cancer Institute Anticancer Drug Screen. 
Journal of Clinical Investigation  1995;95(5):2205-2214.
Identifying new chemotherapeutic agents and characterizing mechanisms of resistance may improve cancer treatment. The Anticancer Drug Screen of the National Cancer Institute uses 60 cell lines to identify new agents. Expression of mdr-1/P-glycoprotein was measured by quantitative PCR. Expression was detected in 39 cell lines; the highest levels were in renal and colon carcinomas. Expression was also detected in all melanomas and central nervous system tumors, but in only one ovarian carcinoma and one leukemia cell line. Using a modified version of the COMPARE program, a high correlation was found between expression of mdr-1 and cellular resistance to a large number of compounds. Evidence that these compounds are P-glycoprotein substrates includes: (a) enhancement of cytotoxicity by verapamil; (b) demonstration of cross-resistance in a multidrug-resistant cell line, (c) ability to antagonize P-glycoprotein, increasing vinblastine accumulation by decreasing efflux; and (d) inhibition of photoaffinity labeling by azidopine. Identification of many heretofore unrecognized compounds as substrates indicates that P-glycoprotein has a broader substrate specificity than previously recognized. This study confirms the validity of this novel approach and provides the basis for similar studies examining a diverse group of gene products, including other resistance mechanisms, putative drug targets, and genes involved in the cell cycle and apoptosis.
PMCID: PMC295832  PMID: 7738186
13.  Effect of dipyridamole on zidovudine pharmacokinetics and short-term tolerance in asymptomatic human immunodeficiency virus-infected subjects. 
Zidovudine delays the progression of infection and prolongs the survival of human immunodeficiency virus (HIV)-infected patients, but these benefits are limited by dose-related toxicity and the cost of the drug. Dipyridamole, in micromolar concentrations, acts synergistically with zidovudine, reducing the anti-HIV 95% inhibitory concentration of zidovudine 5- to 10-fold in vitro. We sought to establish a well-tolerated dose of dipyridamole for use in combination with zidovudine and to detect clinically significant pharmacokinetic interactions. Both objectives are essential for planning studies of the efficacy of the zidovudine-dipyridamole combination. Eleven asymptomatic HIV-infected subjects (median CD4+ cell count, 311 cells per mm3), 10 of whom had been on zidovudine at 500 mg/day for at least 6 months, were admitted to the study. Zidovudine pharmacokinetics were measured on day 1. Dipyridamole was then begun at 600 mg/day (subjects 1 to 3) or 450 mg/day (subjects 4 to 11), and zidovudine and dipyridamole pharmacokinetics were measured on day 5. All subjects given 600 mg of dipyridamole per day developed headache or nausea, or both. Six of eight subjects given dipyridamole at 450 mg/day developed headache or mild nausea that resolved after a median of 2 days. The area under the zidovudine concentration-time curve was not significantly different on day 1 in comparison with that on day 5 (P = 0.11). Symptoms were significantly correlated with the maximum zidovudine concentrations, which were achieved when dipyridamole was dosed concomitantly (p = 0.03). Total (free and protein-bound) dipyridamole trough concentrations were near those demonstrating synergy with zidovudine against HIV in vitro. Dipyridamole was highly protein bound, with a median free/total dipyridamole ratio of 0.7%; the percent free/total dipyridamole ratio was inversely correlated with alpha 1 acid glycoprotein concentrations (r2 =0.66). Results of the study indicate that adjustment of the zidovudine dose was not required to achieve equivalent zidovudine concentrations when zidovudine was administered in combination with dipyridamole at the doses studied. In the short study described here, the zidovudine-dipyridamole combinations was well tolerated in asymptomatic HIV-infected subjects after the occurrence of mild transient symptoms.
PMCID: PMC188146  PMID: 8067734
14.  A novel mammalian protein, p55CDC, present in dividing cells is associated with protein kinase activity and has homology to the Saccharomyces cerevisiae cell division cycle proteins Cdc20 and Cdc4. 
Molecular and Cellular Biology  1994;14(5):3350-3363.
A novel protein, p55CDC, has been identified in cycling mammalian cells. This transcript is readily detectable in all exponentially growing cell lines but disappears when cells are chemically induced to fall out of the cell cycle and differentiate. The p55CDC protein appears to be essential for cell division, since transfection of antisense p55CDC cDNA into CHO cells resulted in isolation of only those cells which exhibited a compensatory increase in p55CDC transcripts in the sense orientation. Immunoprecipitation of p55CDC yielded protein complexes with kinase activity which fluctuated during the cell cycle. Since p55CDC does not have the conserved protein kinase domains, this activity must be due to one or more of the associated proteins in the immune complex. The highest levels of protein kinase activity were seen with alpha-casein and myelin basic protein as substrates and demonstrated a pattern of activity distinct from that described for the known cyclin-dependent cell division kinases. The p55CDC protein was also phosphorylated in dividing cells. The amino acid sequence of p55CDC contains seven repeats homologous to the beta subunit of G proteins, and the highest degree of homology in these repeats was found with the Saccharomyces cerevisiae Cdc20 and Cdc4 proteins, which have been proposed to be involved in the formation of a functional bipolar mitotic spindle in yeast cells. The G beta repeat has been postulated to mediate protein-protein interactions and, in p55CDC, may modulate its association with a unique cell cycle protein kinase. These findings suggest that p55CDC is a component of the mammalian cell cycle mechanism.
PMCID: PMC358701  PMID: 7513050
15.  In vitro inhibition of human immunodeficiency virus (HIV) type 1 replication by C2 symmetry-based HIV protease inhibitors as single agents or in combinations. 
C2 symmetry-based human immunodeficiency virus (HIV) protease inhibitors were examined in vitro as single agents or in combination with 3'-azido-2',3'-dideoxythymidine (AZT) or 2',3'-dideoxyinosine for activity against HIV type 1 (HIV-1). Ten C2 symmetry-based or pseudo-C2 symmetry-based HIV protease inhibitors were active against a laboratory strain (HIV-1IIIB) in the HIV-1 cytopathic effect inhibition assay. Three inhibitors, A75925, A76928, and A77003, selected to represent a range of aqueous solubility and antiviral activity, were active against four different HIV-1 strains tested. These three inhibitors exhibited a significant inhibition of the cytopathic effect of HIV-1 against the CD4+ ATH8 cell line, with 90% inhibitory concentrations ranging from 0.1 to 4 microM. Cellular toxicity was negligible at up to 20 microM. Furthermore, they completely inhibited the replication of monocytotropic strain HIV-1Ba-L in purified monocytes and macrophages at 0.75 to 2 microM. Potent inhibitory activity against a primary HIV-1 isolate and an AZT-resistant HIV-1 variant was also observed for all three inhibitors in phytohemagglutinin-activated peripheral blood mononuclear cells. When these three HIV protease inhibitors and AZT or 2',3'-dideoxyinosine were used in combinations against a primary HIV isolate in phytohemagglutinin-activated peripheral blood mononuclear cells and the results were analyzed with the COMBO program package, their antiviral activities were identified to be synergistic in some cases and additive in others. The present data warrant further investigations of these compounds as potential antiviral agents for the therapy of HIV infections.
PMCID: PMC188763  PMID: 1510415
16.  Resection of intraocular squamous cell carcinoma. 
A patient with recurrent squamous cell carcinoma of the conjunctiva was referred with 20/20 vision in an eye with obvious intraocular extension. A modified iridocyclochoroidectomy was performed and the tumour was removed. Three and a half years later the patient's vision is 20/30 and there is no recurrence. This is the first case in which an eye has been successfully salvaged with documented intraocular squamous cell carcinoma of the conjunctiva.
PMCID: PMC504179  PMID: 1739709
17.  Differential inhibition of 2'-deoxycytidine salvage as a possible mechanism for potentiation of the anti-human immunodeficiency virus activity of 2',3'-dideoxycytidine by dipyridamole. 
Dipyridamole, a commonly used coronary vasodilator and antithrombotic drug, was recently shown to potentiate the activity of 3'-azido-3'-deoxythymidine and 2',3'-dideoxycytidine against the human immunodeficiency virus type 1 (HIV-1) in human monocyte-macrophages in vitro. We report in the present paper that in uninfected monocyte-macrophages dipyridamole significantly inhibits cellular salvage of [3H]deoxycytidine, whereas it does not affect the salvage of [3H]dideoxycytidine. Similar differential inhibition by dipyridamole of the salvage of thymidine, as opposed to 3'-azido-3'-deoxythymidine, was reported previously (G. V. Betageri, J. Szebeni, K. Hung, S. S. Patel, L. M. Wahl, M. Corcoran, and J. N. Weinstein, Biochem. Pharmacol. 40:867-870, 1990). Taken together, these observations suggest that inhibition of the salvage of competing physiological nucleosides may explain or contribute to the potentiating effect of dipyridamole on these antiviral dideoxynucleoside drugs.
PMCID: PMC284325  PMID: 1656858
18.  Effects of thymidine and uridine on the phosphorylation of 3'-azido-3'-deoxythymidine (zidovudine) in human mononuclear cells. 
The effects of thymidine and uridine on the phosphorylation of 3'-azido-3'-deoxythymidine (AZT) were studied in various human mononuclear cell preparations. Thymidine suppressed [3H]AZT phosphorylation in the same concentration range (20 to 100 microM) in which it antagonizes the anti-human immunodeficiency virus activity of AZT. Uridine, in turn, had no influence on AZT phosphorylation, just as it has no effect on the anti-human immunodeficiency virus activity of AZT. These findings are consistent with a close relationship between the inhibition of AZT phosphorylation and the influence of physiological nucleosides on the antiviral activity of AZT.
PMCID: PMC244969  PMID: 2014977
20.  Lumbar Disc Herniation—A Ten-Year Follow-up 
This is a 10 year follow-up longitudinal case study of two treatment groups. Group I (85 patients) was treated with chymopapain and Group II (71 patients) was treated with open discectomy.
The study questionnaire contained six well accepted pain measures. Validity studies demonstrated these measures to be adequate reflections of the patient's condition and that all six measures were significantly related (Pearson's r, p<.003). The chymopapain and discectomy groups were not distinguishable on the basis of these pain outcome measures. An additional test of the relationship between pain outcomes and body mass (Kg/M2) demonstrated that discectomy patients who reported greater pain had significantly greater body mass, (p<.004).
Recurrence rates did not differ significantly, but there was a trend for discectomy patients to report higher recurrence rates at both the 1- and 10-year periods. Superiority of one treatment over the other could not be unequivocally demonstrated.
Regardless of treatment modality, patients who returned to work between 6 and 12 weeks after treatment, but prior to complete recovery reported significantly greater pain at 10-year follow-up (p<.04). Patients who returned to work within 6 weeks of treatment but prior to recovery demonstrated a similar trend. However, for patients who had not recovered within 12 weeks of treatment, no differences were seen in long-term results, regardless of whether or not they had returned to work. Treatment satisfaction was similar but chymopapain patients were much more likely than discectomy patients to recommend the treatment to a friend (p<.01).
PMCID: PMC2328853

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