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Abstract In 2005 Manchester United was taken over by US businessman Malcolm Glazer, in part because of the club's brand name prominence in the global sport of soccer. This paper [...]

Abstract Background: Although elevated levels of C-reactive protein (CRP), interleukin (IL)-6, serum amyloid A protein (SAA) and total homocysteine (tHcy) have been associated with the increased likelihood of cardiovascular events, [...]

This paper studies global strategic marketing planning in the advent of worldwide competition and the growing rapidity of change in the international marketplace.

Latin America has emerged from the economic doldrums of the 1970s and 1980s to become a commercial power in its own right in the 1990s. The seeds for change were [...]

Global strategic marketing planning has emerged as a key process in managing today's worldwide marketplace. This survey of 90 large American global corporations reveals that most are bottom-up planners. US firms appear to have distinct cost and numbers orientations. Industry and competitive analyses are used in many companies, although managers appear to lack suitable frameworks for SWOT analyses. Economic climate changes tend to be most disruptive to global planning efforts. When faced with non-achievement of goals, most firms reformulate both objectives and strategies.

An examination of perceptions of television advertising restrictions across developed-developing markets, high-medium-low cultural context countries and individual markets showed that legal constraints oin TV advertising were relatively constant in developed-developing, high-medium-low cultural context countries while social constraints were more remarkable in developing nations. Developed countries, on the other hand, exhibited more liberal advertising policies. A surprising result was that high and low cultural context countries revealed similar trends in legal and social constraints, while a more liberated perspective was gleaned in medium context countries.

Controlling the foreign-based sales force is an increasingly important part of multinational sales management. U.S. firms favor tight, numerically based methods of evaluating sellers whereas non-U.S. tendencies are toward qualitative measures. This 14 multinational, 135 subsidiary study of salesperson evaluation methods in affiliates of U.S.-based firms shows that most U.S. companies 'do as the Romans do' in foreign markets and de-emphasize quantitative ratios in favor of softer qualitative measures. (Reprinted by permission of the publisher.)

The availability of advertising skills in the global market according to the perceptions of advertising executives was analyzed in terms of geographic region, market development level, country and market entry method. A sample population consisting of advertising managers from foreign affiliates of US-based advertising firms was asked to answer questionnaires that required information on agency practices and overseas market conditions. The 344 completed questionnaires were then analyzed. Results of the survey indicated a gradual shrinking of the supply of skilled workers. Advertising agencies in developing countries were more likely to experience market skill shortages than those in developed countries. Among developed nations, small countries, such as Austria, Switzerland and Greece, suffered the most from the scarcity of skilled workers.

Some companies can use the same advertising message throughout the world, while others must adapt their advertisements to particular areas. Multinational companies' (MNC) standardization and adaptation of advertisements were investigated by surveying 15 MNCs and studying 175 promotional messages. The results indicated that 40% of the MNCs had sales platform standardization, while 37% had standardization of creative contexts. Some 81.1% of the messages exhibited either consistent standardization or adaptation of both platforms and creative contexts. The probability of maintaining both creative contexts and sales platforms was 29.1%.

International Communication: An Executive Primer Euphoria frequently turns to paranoia when domestic executives face their first overseas assignment. Disturbing memories come pressing to the fore: * A college anthropology professor [...]

Little empirical research has been reported on multinational sales force management, and none on organizational aspects. Reported here are results from a 14 MNC-135 subsidiary survey of overseas sales management practices. They show that MNCs use independent sales organizations to augment company personnel in affluent markets, in physically-large countries, and where markets are geographically-dispersed or culturally fragmented. In addition, about one sales force in five covers more than one national market. Industry factors are important in the structuring of sales forces, suggesting that industry practices are carried into overseas markets. (Reprinted by permission of the publisher.)

The various aspects of the Japanese business system are not well-understood by foreigners, and as a result, few comprehend how the system as a whole works to support Japanese economic interests. An analysis indicates that Japan protects its markets to preserve an economic system which makes business responsible for retirement and social security and to maintain full employment. In Japan, economic forces and marketing forces come together to support Japan's business system. Industrialized countries which would like Japan to open its business system can suggest a number of changes including asking Japan to increase social security, unemployment, and retirement benefits so that consumers would not need to save as much; encouraging Japan to open its financial sector to international competition; and requesting that Japan establish a national policy to rationalize its distribution channels.

How do multinational corporations market consumer products from developed countries in less developed countries? What changes do MNCs typically introduce in the products they transfer? Why are such changes made? How do MNCs manage the process of adapting consumer products to LDC markets? To find the answers to these and other questions about multinational marketing, the authors recently conducted a survey of 61 subsidiaries of consumer goods manufacturers with operations in 22 LDCs. Their findings show that most consumer products that MNCs sell in developing countries originate in the companies' home markets. The temptation for many MNCs is to standardize their products across all markets. The authors find, however, that a ‘more appropriate’ marketing strategy is to tailor consumer products to local customs and market conditions. INSET: The survey. [ABSTRACT FROM AUTHOR]

Hyperlipidemia is a frequent and persistent complication in solid organ transplant recipients, leading to the high occurrence of cardiovascular disease in this patient population. Lipid abnormalities including increased total cholesterol, triglycerides (TG), and low-density lipoprotein-cholesterol have been reported frequently in transplantation patients and a variety of immunosuppressive therapies seem to be one of the main factors that influence posttransplant lipidemic profiles. For many years, tacrolimus (TAC) has been used as an immunosuppressive drug in transplantation. The aim of our investigation was to determine the effect of TAC administration on the plasma lipid profile and some key regulatory proteins of plasma lipid metabolism including cholesterol ester transfer protein, hepatic lipase and lipoprotein lipase (LPL) within renal transplant patients.

The effect of atorvastatin on adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1) expression and cholesterol efflux remains controversial. In an effort to clarify this issue, ABCA1 expression and apolipoprotein AI (apoAI)-mediated cholesterol efflux after atorvastatin treatment were investigated in THP-1 macrophages. Atorvastatin from 2 μM to 40 μM dose-dependently inhibited ABCA1 expression in human monocyte-derived macrophages and phorbol 12-myristate 13-acetate (PMA)-stimulated THP-1 monocytes. ApoAI-mediated cholesterol efflux was reduced in PMA-stimulated THP-1 cells treated with atorvastatin, this effect was abolished with acetylated low-density lipoprotein (LDL) pretreatment. Atorvastatin treatment also dose-dependently reduced liver X receptor α (LXRα) expression and Rho activation. Rho activation by farnysylpyophosphate (FPP) and lysophosphatidic acid (LPA) did not salvage, but further depressed, the cholesterol efflux and ABCA1 expression in the presence of atorvastatin. Without atorvastatin, Rho activation by mevalonate, FPP, and LPA diminished apoAI-mediated cholesterol efflux, and Rho activation by GTPγS also decreased ABCA1 messenger ribonucleic acid (mRNA) by 16%. Furthermore, Rho inhibition by C3 exoenzyme increased ABCA1 mRNA by 48% despite a 17% decrease in apoAI-mediated cholesterol efflux. LXRα agonists (T01901317 and 22(R)-hydroxycholesterol) prevented any reductions in cholesterol efflux or ABCA1 expression associated with atorvastatin treatment. Furthermore, Western blot analysis demonstrated the reciprocal inhibition of Rho and LXRα. In conclusion, atorvastatin decreases ABCA1 expression in noncholesterol-loaded macrophages in an LXRα- but not Rho-dependent pathway; this effect can be compromised after acetylated LDL cholesterol loading.

Macrophage-derived lipases are associated with atherosclerosis in human and animal studies. Despite numerous non-lipid-lowering effects of statins, their effect on macrophage LPL and endothelial lipase (EL) expression has not been investigated. In the present study, atorvastatin and simvastatin dose-dependently decreased LPL and EL expression as well as Rho, liver X receptor α (LXRα), and nuclear factor κB (NF-κB) activation in THP-1 macrophages. Atorvastatin-reduced LPL and EL expression was only partially recovered by mevalonate cotreatment, indicating that mechanisms independent of reductase inhibition may be present. By contrast, Rho activation by lysophosphatidyl acid further decreased LPL and EL expression in the presence or absence of atorvastatin. Another Rho activator, farnysyl pyrophosphate, decreased EL expression only in the absence of atorvastatin. LXRα activation by T0901317 and 22(R)-hydroxycholesterol not only rescued but also significantly increased LPL expression in the presence and absence of atorvastatin, respectively, whereas LXRα inhibition by 22(S)-hydroxycholesterol decreased LPL expression. By contrast, EL expression was suppressed by LXRα activation in the presence or absence of atorvastatin. NF-κB inhibition by SN50 was associated with an ∼30% reduction of EL expression. Furthermore, atorvastatin treatment significantly attenuated the lipid accumulation in macrophages treated with oxidized LDL. We conclude that atorvastatin reduces LPL and EL expression by reducing the activation of LXRα and NF-κB, respectively.

LPL and endothelial lipase (EL) are associated with macrophages in human atherosclerotic lesions, and overexpression of LPL in mouse macrophages is associated with a greater extent of atherosclerosis. To investigate potential mechanisms by which macrophage-derived lipase expression may mediate proatherogenic effects, we used lentivirus-mediated RNA interference to suppress the expression of either LPL or EL within THP-1 macrophages. After suppression of either LPL or EL, significant decreases in the concentration of interleukin-1{szligbeta}, interleukin-6, monocyte chemoattractant protein-1, and tumor necrosis factor-α were observed. Incubation of THP-1 macrophages with either mildly or extensively oxidized LDL consistently decreased cytokine expression, which was additive to that contributed by lipase suppression. Decreased lipase expression was also associated with an altered lipid composition, with reduced percentages of cholesterol (unesterified and esterified), triglycerides, and lysophosphatidylcholine. Microarray data indicated a decreased expression of proinflammatory genes, growth factors, and antiapoptotic genes. By contrast, there was an increased expression of lipoprotein receptors (scavenger receptor 1, low density lipoprotein receptor, scavenger receptor class B type I, and CD36). Thus, we conclude that the suppression of either LPL or EL decreases proinflammatory cytokine expression and influences the lipid composition of THP-1 macrophages. These results provide further insight into the specific metabolic and potential pathological roles of LPL and EL in human macrophages.

CHRISTON I. ARCHER, JOHN R. FERRIS, HOLGER H. HERWIG, and TIMOTHY H. E. TRAVERS. World History of Warfare. Lincoln: University of Nebraska Press, 2002. Pp. xii, 626. $29.95 (US). Reviewed by John A. LynnANGELOS CHANIOTIS and PIERRE DUCREY, eds. Army and Power in the Ancient World. Stuttgart: Franz Steiner Verlag, 2002. Pp. viii, 204. €44.00, paper. Reviewed by Arthur M. EcksteinMARTIN CARVER, ed. The Cross Goes North: Processes of Conversion in Northern Europe, AD 300-1300. York: York Medieval Press, University of York; Rochester, NY: Boydell Press, 2003. Pp. xiv, 588. $130.00 (US). Reviewed by John HoweDANIEL CANER. Wandering, Begging Monks: Spiritual Authority and the Promotion of Monasticism in Late Antiquity. Berkeley and Los Angeles: University of California Press, 2002. Pp. xiv, 325. $65.00 (US). Reviewed by John J. ContreniHUGH KENNEDY. The Armies of the Caliphs: Military and Society in the Early Islamic State. London and New York: Routledge, 2001. 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Reviewed by James J. SheehanROBERT L. SCHEINA. Latin America's Wars: I: The Age of the Caudillo, 1791–1899. Washington, DC: Brassey's, 2003. Pp. xxviii, 569. $29.95 (US), paper; CHRIS LEUCHARS. To the Bitter End: Paraguay and the War of the Triple Alliance. Westport: Greenwood Press, 2002. Pp. vi, 254. $68.95 (US). Reviewed by Timothy E. AnnaJOHN GASCOIGNE, with the assistance of PATRICIA CURTHOYS. The Enlightenment and the Origins of European Australia. New York: Cambridge University Press, 2002. Pp. xiii, 233. $65.00 (US). Reviewed by Marian QuartlyROBERT J. ANTONY and JANE KATE LEONARD, eds. Dragons, Tigers, and Dogs: Qing Crisis Management and the Boundaries of State Power in Late Imperial China. Ithaca, NY: Cornell University East Asia Program, 2002. Pp. xiii, 333. $19.00 (US), paper. Reviewed by John W. DardessJOEL MOKYR. The Gifts of Athena: Historical Origins of the Knowledge Economy. Princeton and Oxford: Princeton University Press, 2002. Pp. xiii, 359. $35.00 (US). Reviewed by David LindenfeldDANIEL H. BAYS and GRANT WACKER, eds. The Foreign Missionary Enterprise at Home: Explorations in North American Cultural History. Tuscaloosa and London: University of Alabama Press, 2003. Pp. x, 332. $60.00 (US). Reviewed by A. Hamish IonMIMI COLLIGAN. Canvas Documentaries: Panoramic Entertainments in Nineteenth-Century Australia and New Zealand. Melbourne: Melbourne University Press, 2002; dist. Chicago: Paul & Company. Pp. xvi, 250. $32.95 (US). Reviewed by Philippa Mein SmithMICHAEL STURMA. South Sea Maidens: Western Fantasy and Sexual Politics in the South Pacific. Westport: Greenwood Press, 2002. Pp. x, 193. $63.95 (US) Reviewed by Vicki LukerSUDIPTA SEN. Distant Sovereignty: National Imperialism and the Origins of British India. New York and London: Routledge, 2002. Pp. xxxi, 216. $22.95 (US), paper. Reviewed by M. J. MarshallCHARLES ESDAILE. The Peninsular War: A New History. London: Allen Lane, The Penguin Press, 2002. Pp. xv, 587. $49.99 (CDN). Reviewed by Philip G. DwyerMARKUS MOSSLANG, SABINE FREITAG, and PETER WENDE, eds. British Envoys to Germany, 1816–1866: II: 1830–1847. New York: Cambridge University Press for the Royal Historical Society in Association with the German Historical Institute, London, 2002. Pp. xxiii, 600. $70.00 (US). Reviewed by John ClarkeSEYMOUR DRESCHER. The Mighty Experiment: Free Labor versus Slavery in British Emancipation. New York: Oxford University Press, 2002. Pp. 307. $50.00 (US). Reviewed by Ralph A. AustenPATRICK KARL O'BRIEN and ARMAND CLESSE, eds. Two Hegemonies: Britain 1846–1914 and the United States 1941–2001. Aldershot and Burlington: Ashgate, 2002. Pp. xiii, 369. $84.95 (US). Reviewed by William R. ThompsonHOLLIS CLAYSON. Paris in Despair: Art and Everyday Life under Siege (1870–71). Chicago and London: University of Chicago Press, 2002. Pp. xxxi, 485. $55.00 (US). Reviewed by Gay L. GullicksonJEFFREY W. CODY. Exporting American Architecture, 1870–2000. London and New York: Routledge, 2003. Pp. xviii, 205. $39-95 (US), paper. Reviewed by Annabel Jane WhartonMICHAEL SCHMID. Der ≫Eiserne Kanzler≪ und die Generäle: Deutsche Rüstungs-politik in der Ära Bismarck (1871–1890). Paderborn: Verlag Ferdinand Schöningh, 2003. Pp. xii, 751. €65.00. Reviewed by Ulrich TrumpenerJULIE A. CHARLIP. Cultivating Coffee: The Farmers ofCarazo, Nicaragua, 1880–1930. Athens: Ohio University Center for International Studies, 2003. Pp. xiv, 288. $28.00 (US), paper. Reviewed by James ThompsonROBERT O. COLLINS. The Nile. New Haven and London: Yale University Press, 2002. Pp. x, 260. $39.95 (US); HEATHER J. SHARKEY. Living with Colo-nialism: Nationalism and Culture in the Anglo-Egyptian Sudan. Berkeley and Los Angeles: University of California Press, 2003. Pp. xiii, 232. $24.95 (US), paper. Reviewed by M. W. DalyCRAIG WILCOX. Australia's Boer War: The War in South Africa, 1899–1902. New York: Oxford University Press, 2002. Pp. xviii, 541. $75.00 (CDN). Reviewed by Keith SurridgeMARGARET MACMILLAN and FRANCINE MCKENZIE, eds. Parties Long Estranged: Canada and Australia in the Twentieth Century. Vancouver: University of British Columbia Press, 2003. Pp. vi, 288. $85.00 (CDN), cloth; $29.95 (CDN), paper. Reviewed by Coral BellMARK BLYTH. Great Transformations: Economic Ideas and Institutional Change in the Twentieth Century. New York: Cambridge University Press, 2002. Pp. xii, 284. $60.00 (US), cloth; $22.00 (US), paper. Reviewed by James K. GalbraithDANIEL JOSEPH WALTHER. Creating Germans Abroad: Cultural Policies and National Identity in Namibia. Athens: Ohio University Press, 2002. Pp. xiv, 268. $26.95 (US), paper. Reviewed by Jan-Bart GewaldSTEVEN G. MARKS. How Russia Shaped the Modern World: From Art to Anti-Semitism, Ballet to Bolshevism. Princeton and Oxford: Princeton University Press, 2003. Pp. xii, 393. $29.95 (US). Reviewed by William G. RosenbergRICHARD F. HAMILTON and HOLGER H. HERWIG, eds. The Origins of World War I. New York: Cambridge University Press, 2003. Pp. xiii, 537. $60.00 (US). Reviewed by Dominic LievenCHARLES DE GAULLE. The Enemy's House Divided, trans, and annotated, and with an intro., by Robert Eden. Chapel Hill and London: University of North Carolina Press, 2002; dist. Toronto: Scholarly Book Services. Pp. 1, 177. $53.75 (CDN). Reviewed by John S. HillSTÉPHANE AUDOIN-ROUZEAU and ANNETTE BECKER. 1914–1918: Understanding the Great War, trans. Catherine Temerson. London: Profile Books, 2002. Pp. v, 280. £15.00. Reviewed by Brian BondPAUL NUGENT. Smugglers, Secessionists, and Loyal Citizens on the Ghana-Togo Frontier: The Lie of the Borderlands since 1914. Athens: Ohio University Press, 2002. Pp. xiv, 302. –24.95 (US), paper. Reviewed by Dimitri Van Den BersselaarROGER CHICKERING and STIG FÖRSTER, eds. The Shadows of Total War: Europe, East Asia, and the United States, 1919–1939. Washington: German Historical Institute, and New York: Cambridge University Press, 2003. Pp. x, 364. –60.00 (US). Reviewed by Ian F. W. BeckettGAYNOR JOHNSON. The Berlin Embassy of Lord D'Abernon, 1920–1926. Basing-stoke and New York: Palgrave, 2002. Pp. xi, 221. –65.00 (US). Reviewed by Andrew J. CrozierIGNÁC ROMSICS. The Dismantling of Historic Hungary: The Peace Treaty of Trianon, 1920, trans. Mario D. Fenyo. Boulder: East European Monographs; Wayne, NJ: Center for Hungarian Studies and Publications, 2002; dist. New York: Columbia University Press. Pp. v, 201. $40.00 (US). Reviewed by Thomas SakmysterALAN DAWLEY. Changing the World: American Progressives in War and Revolution. Princeton and Oxford: Princeton University Press, 2003. Pp. x, 409. $29.95 (US). Reviewed by David S. FoglesongPRASENJIT DUARA. Sovereignty and Authenticity: Manchukuo and the East Asian Modern. Lanham: Rowman & Littlefield, 2003. Pp. xiii, 306. $49.95 (US). Reviewed by John J. StephanSANDRA WILSON. The Manchurian Crisis and Japanese Society, 1931–33. London and New York: Routledge, 2002. Pp. 252. $95.00 (US). Reviewed by Antony BestIAN NISH. Japanese Foreign Policy in the Interwar Period. Westport: Praeger, 2002. Pp. x, 212. $65.95 (US). Reviewed by Frederick DickinsonRAINER F. SCHMIDT. Die Aussenpolitik des Dritten Reiches, 1933–1939. Stuttgart: Klett-Cotta, 2002. Pp. 448. €25.00. Reviewed by Erich J. HahnHENRY G. GOLE. The Road to Rainbow: Army Planning for Global War, 1934–1940. Annapolis: Naval Institute Press, 2003. Pp. xxi, 224. $34.95 (US). Reviewed by Mark A. StolerHELEN GRAHAM. The Spanish Republic at War, 1936–1939. New York: Cambridge University Press, 2002. Pp. xiv, 472. $70.00 (US), cloth; $26.00 (US), paper. Reviewed by Willard C. Frank, Jr.FLORENTINO RODAO. Franco y el imperio japonés: Imágenes y propaganda en tiempos de guerra. Barcelona: Plaza and Janés, 2002. Pp. 668. €18.00 Reviewed by Raanan ReinALEXANDER B. ROSSINO. Hitler Strikes Poland: Blitzkrieg, Ideology, and Atro-city. Lawrence: University Press of Kansas, 2003. Pp. xv, 343. $34.95 (US). Reviewed by John J. KulczyckiRICHARD F. HILL. Hitler Attacks Pearl Harbor: Why the United States Declared War on Germany. Boulder and London: Lynne Rienner, 2003. Pp. vii, 227. $49.95 (US). Reviewed by Robert Freeman SmithPETER SCHRIJVERS. The GI War against Japan: American Soldiers in Asia and the Pacific during World War II.New York: New York University Press, 2002. Pp. xiii, 320. $45.00 (US). Reviewed by Marc GallicchioJON LATIMER. Alamein. Cambridge, MA: Harvard University Press, 2002. Pp. xiii, 400. $27.95 (US); MARK JOHNSTON and PETER STANLEY. Alamein: The Australian Story. New York: Oxford University Press, 2002. Pp. xii, 314. $60.00 (CDN). Reviewed by Saul KellyCHARLIE WHITHAM. Bitter Rehearsal: British and American Planning for a Post-war West Indies. Westport: Praeger, 2002. Pp. xxxvi, 224. –69.95 (US). Reviewed by J. Simon RofeJONATHAN E. LEWIS. Spy Capitalism: Itek and the CIA. New Haven and London: Yale University Press, 2002. Pp. vi, 329. $29.95 (US). Reviewed by Alan WarburtonWILLIAM GLENN GRAY. Germany's Cold War: The Global Campaign to Isolate East Germany, 1949–1969. Chapel Hill and London: University of North Carolina Press, 2003. Pp. xii, 351. $49.95 (US). Reviewed by Wilfried LothGREG DONAGHY. Tolerant Allies: Canada and the United States, 1963–1968. Montreal and Kingston: McGill-Queen's University Press, 2002. Pp. x, 235. $75.00 (CDN). Reviewed by Edelgard MahantROBERT J. TOPMILLER. The Lotus Unleashed: The Buddhist Peace Movement in South Vietnam, 1964–1966. Lexington: University Press of Kentucky, 2002. Pp. xii, 214. $35.00 (US). Reviewed by Edwin E. MoïseROBERT HOPKINS MILLER. Vietnam and Beyond: A Diplomat's Cold War Education. Lubbock: Texas Tech University Press, 2002. Pp. xix, 247. $36.50 (US). Reviewed by Lloyd C. GardnerPIERRE ASSELIN. A Bitter Peace: Washington, Hanoi, and the Making of the Paris Agreement. Chapel Hill and London: University of North Carolina Press, 2002; dist. Toronto: Scholarly Book Services. Pp. xx, 272. $32.95 (CDN), paper. Reviewed by Jussi M. HanhimäkiM. S. KOHLI and KENNETH CONBOY. Spies in the Himalayas: Secret Missions and Perilous Climbs. Lawrence: University Press of Kansas, 2002. Pp. xi, 226. $29.95 (US). Reviewed by Robert J. McMahonJOHN PRADOS. Lost Crusader: The Secret Wars of CIA Director William Colby. New York: Oxford University Press, 2003. Pp. xvii, 380. $35.00 (US). Reviewed by Timothy N. CastlePETER H. KOEHN and XIAO-HUANG YIN, eds. The Expanding Roles of Chinese Americans in US-China Relations: Transnational Networks and Trans-Pacific Interactions. Armonk: M. E. Sharpe, 2002. Pp. xl, 311. $66.95 (US), cloth; $25.95 (US), paper. Reviewed by Gordon H. ChangJEFFREY S. LANTIS. Strategic Dilemmas and the Evolution of German Foreign Policy since Unification. Westport: Praeger, 2002. Pp. xiii, 230. $64.95 (US). Reviewed by Stephen F. SzaboFREDERICK H. FLEITZ, JR. Peacekeeping Fiascos of the 1990s: Causes, Solutions, and US Interests. Westport: Praeger, 2002. 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Human hepatic lipase (hHL) mainly exists cell surface bound, whereas mouse HL (mHL) circulates in the blood stream. Studies have suggested that the carboxyl terminus of HL mediates cell surface binding. We prepared recombinant hHL, mHL, and chimeric proteins (hHLmt and mHLht) in which the carboxyl terminal 70 amino acids of hHL were exchanged with the corresponding sequence from mHL. The hHL, mHL, and hHLmt proteins were catalytically active using triolein and tributyrin as substrates. In transfected cells, the majority of hHLs bound to the cell surface, with only 4% of total extracellular hHL released into heparin-free media, whereas under the same conditions, 61% of total extracellular mHLs were released. Like mHL, hHLmt showed decreased cell surface binding, with 68% of total extracellular hHLmt released. To determine the precise amino acid residues involved in cell surface binding, we prepared a truncated hHL mutant (hHL471) by deleting the carboxyl terminal five residues (KRKIR). The hHL471 also retained hydrolytic activity with triolein and tributyrin, and showed decreased cell surface binding, with 40% of total extracellular protein released into the heparin-free media.These data suggest that the determinants of cell surface binding exist within the carboxyl terminal 70 amino acids of hHL, of which the last five residues play an important role.

Lecithin:cholesterol acyltransferase (LCAT) catalyzes the esterification of plasma lipoprotein cholesterol in mammals as part of the reverse cholesterol transport pathway. Studies of the natural mutations of LCAT revealed a region that is highly sensitive to mutations (residues 121–136) and it is highly conserved in six animal species. The purpose of these studies was to investigate the reactivity of wild type and several mutated forms of LCAT, with a series polyclonal antibodies to further characterize this specific domain (residues 121–136). Two polyclonal antibodies directed against the whole enzyme, one against human plasma LCAT and the other against purified recombinant LCAT, and one site specific polyclonal antibody, directed against the 121–136 region of LCAT, were employed. All three antibodies reacted with a recombinant form of purified LCAT; however, only the polyclonal antibodies directed against the whole enzyme were able to recognize the LCAT when it was adsorbed to a hydrophobic surface in a solid phase immunoassay, or when bound to HDL in a sink immunoassay. These findings indicate that the epitope(s) of the 121–136 region are not accessible to antibodies under these conditions. Three mutant forms of LCAT, representing alterations in the 121–136 region, were also examined for their immunoreactivity with the same panel of antibodies and compared to the wild-type enzyme. These studies demonstrate that in its native configuration the 121–136 region of LCAT is likely to reside on a surface of LCAT. Furthermore, mutations within this region appear to markedly impact the exposure of epitopes at additional sites. These findings suggest that the 121–136 region could play an important role in enzyme interaction with its hydrophobic lipoprotein substrates as mutations within this region appear to alter enzyme conformation, catalytic activity, and the specificity of LCAT.

MX2 is a novel morpholino anthracycline reported to have lower systemic toxicity than other anthracyclines. It has similar antitumour activity to adriamycin and is cytotoxic towards multi-drug resistant cells and anthracycline sensitive sublines of human and murine tumour cells. In this study MX2 showed a marked cytocidal effect compared to M2, the most cytotoxically active metabolite, and the nitrosourea, BCNU, when 30 ng/ml of each drug was added to separate flasks of C6 glioma cells grown in monolayer. The colony formation of C6 glioma cells was markedly inhibited by MX2 in a dose dependent manner. The LD₅₀values for MX2, M2 and BCNU were 10.5 ng/ml, 15.8 ng/ml and 465 ng/ml respectively. MX2 is likely to be bound to the main plasma protein, albumin, and can also interact with the plasma lipoproteins, particularly high density lipoprotein. The results in this study strongly support the further investigation of MX2 as a potential chemotherapeutic agent against brain tumours. Copyright 2000 Harcourt Publishers Ltd

A fluorescent pH indicator in conjunction with confocal microscopy, was used to map intracellular pH in a variety of cells and tissues with high spatial resolution. The new pH-sensitive fluorescent probe SNARF-1 was excited with the 488 nm band of the argon ion laser of a Bio-Rad MRC-500 confocal microscope. Ratio images were created with pixel-by-pixel division, with the intensity of these images representing a function of pH, that is independent of dye concentration, photobleaching or path length. Cell cultures of rat aortic smooth muscle were loaded with 20 μм SNARF-1/AM for 20 min at 37°C. Intracellular pH levels were calibrated in situby treatment of each cell with nigericin (20 μм) in solutions of known pH. The cytosolic pH of the majority of cells was uniform, however, pH gradients were evident between the cytosol and nuclear regions, indicating the ability of this technique to map intracellular and intraorganelle pH. Rat C6 glioblastoma spheroids were cultured then loaded with SNARF-1/AM at 10°C for 90 min. The pH values were calibrated in vitro, using SNARF-1 acid in buffered solutions of known pH. Ratio images of the bisected spheroids showed a marked gradient in pH from the outer cells compared with central necrotic cells. The degree of involvement of acidification in muscle fatigue was investigated by simultaneously determining force generation and intracellular pH in individual fibres of an intact rat muscle. The investigation was performed during a stimulation protocol which induced significant fatigue in the force response of the muscle. The fatigue protocol induced little change in cytosolic pH in the fibres. We show that the use of SNARF-1, in conjunction with confocal microscopy is a powerful technique for accurately mapping pH within single cells, multicellular tissues and intact organs, as well as for accurately recording dynamic changes in pH.

Abstract: The purpose of the present study was to investigate the pharmacokinetics and pharmacodynamics of the new morpholino anthracycline drug MX2. A total of 27 patients with advanced cancer participated in a dose-escalation study in the first cycle of treatment with drug given i.v. at doses of 10–50 mg/m2 (total dose 16.8–107.5 mg). The mean total systemic plasma clearance (CL) of MX2 was 2.98 ± 1.68 l/min, the mean volume of distribution at steady state was 1460 ± 749 l and mean elimination half-life was 10.8 ± 5.1 h. The area under the plasma concentration-time curve (AUC) of MX2 was linearly related to the dose per kilogram and the dose per body surface area (r 2 = 0.43, P < 0.01 and r 2 = 0.44, P < 0.01, respectively). CL did not correlate with total body weight, lean body mass or body surface area. The mean elimination half-lives of the metabolites M1, M2, M3 and M4 were 11.8 ± 5.0, 21.9 ± 11.8, 19.0 ± 11.3 and 12.3 ± 6.3 h, respectively. The fractional E max model produced a much better fit to the relative nadir neutrophil count versus dose data (r 2 = 0.42) than to the relative nadir neutrophil count versus AUC or peak concentration (C max) data (r 2 = 0.15 and 0.09, respectively). There seemed to be a threshold dose of about 65 mg of MX2 at or above which a large proportion of patients had a nadir neutrophil count of less than 0.5 × 109/l. This study shows that the pharmacokinetics of MX2 are similar to those of other anthracyclines. With other anthracyclines the degree of myelosuppression seems to depend more on the AUC and C max than on the delivered dose; however, with MX2 the degree of myelosuppression depends more on the dose given than on drug exposure expressed as the AUC or C max.

Carcinoma of the pancreas is the fifth leading cause of cancer death, with the majority of patients presenting with unresectable disease. Research into new adjuvant therapies is hampered by the lack of suitable in vivo and in vitro models. We have examined the potential of seven pancreatic carcinoma cell lines to grow as multicellular tumor spheroids (MTS). Three of seven (43) cell lines were scored positive for MTS formation, and the growth characteristics for spheroid models of the cell lines PANC1 and MIAPaCa2 are presented. Implantation of PANC1 MTS into the pancreas of athymic nude mice produces tumors with reproducible growth characteristics and histology.

Abstract: Purpose: To investigate the effect of granulocyte colony-stimulating factor (G-CSF) on the pharmacokinetics and pharmacodynamics of the new morpholino anthracycline drug MX2. Methods: A total of 25 patients with advanced malignant disease participated in a dose-escalation study in the first cycle of treatment given i.v. at doses of 50–80 mg/m2 (74–152 mg) with concomitant filgrastim (G-CSF, 5 μg/kg) given daily beginning at 24 h after the dose of MX2. Results: The mean fast distribution half-life (1.5  1.0 min) and the mean plasma clearance (2.18  0.95 l/min) were significantly lower than the respective mean values found in a previous study in which 27 patients had received MX2 (16.8–107.5 mg) alone (3.3  2.2 min and 2.98  1.68 l/min, respectively; P < 0.05). There was no correlation between plasma clearance and the delivered dose for the combined MX2-alone and MX2-filgrastim groups, indicating that the lower clearance observed in the G-CSF group was probably not due to the higher dose. Elimination half-lives of the metabolites M1 and M4 were significantly greater in the filgrastim group (19.8  14.7 and 11.8  5.0 h for M1 and 14.8  4.1 and 12.3  6.3 h for M2, respectively). Unlike the MX2-alone group, there was no relationship in the MX2- filgrastim group between the relative nadir neutrophil count and the dose or between the duration of grade IV neutropenia and the dose of MX2. Conclusions: This study shows that filgrastim decreased the plasma clearance of MX2 by approximately 25%, possibly by inhibition of metabolism.

To specify and localize carboxyl-terminal domain functions of human hepatic lipase (HL) and human lipoprotein lipase (LPL), two subdomain chimeras were created in which portions of the carboxyl-terminal domain were exchanged between the two lipases. The first chimera (HL-LPLC1) was composed of residues 1–344 of human HL, residues 331–388 of human LPL, and residues 415–476 of human HL. The second chimera (HL-LPLC2) consisted of just two segments, residues 1–414 of human HL and residues 389–448 of human LPL. These chimeric constructs effectively divided the HL C-terminal domain into halves, with corresponding LPL sequences either in the first or second portion of that domain. Both chimeras were lipolytically active and hydrolyzed triolein emulsions to a similar extent compared with native HL and LPL. Heparin-Sepharose chromatography demonstrated that HL-LPLC1 and HL-LPLC2 eluted at 0.80 and 1.3 mNaCl, respectively, elution positions that corresponded to native HL and LPL. Hence, substitution of LPL sequences into the HL carboxyl-terminal domain resulted in the production of functional lipases, but with distinct heparin binding properties. In addition, HL-LPLC2 trioleinase activity was responsive to apoC-II activation, although the -fold stimulation was less than that observed with native LPL. Moreover, an apoC-II fragment (residues 44–79) was specifically cross-linked to LPL and HL-LPLC2, but not to HL or HL-LPLC1. Finally, both chimeras hydrolyzed phospholipid with a specific activity similar to that of HL, which was unaffected by the presence of apoC-II. These findings indicated that in addition to a region found within the amino-terminal domain of LPL, apoC-II also interacted with the last half of the carboxyl-terminal domain (residues 389–448) to achieve maximal lipolytic activation. In addition, the relative heparin affinity of HL and LPL was determined by the final 60 carboxyl-terminal residues of each enzyme.

Human erythrocytes possess a lattice work of extrinsic proteins on the inner face of the membrane (‘cytoskeleton’) that maintains the shape and deformability of the cell. The major proteins of the cytoskeleton are spectrin and actin, which are attached to the membrane by protein bands 2.1 (‘ankyrin’) and 4.1. The interactions of spectrin/actin with erythrocyte membranes from normal subjects and from patients with hereditary spherocytosis (HS) have been studied by using an air-driven ultracentrifuge, which can rapidly separate membranes from soluble proteins (150000g for 30s). The total amount of spectrin/actin in HS and normal ghosts is similar. However, the rate of dissociation of spectrin and actin from HS erythrocyte membranes at low ionic strength is significantly lower than that observed for normal membranes. Spectrin and actin isolated from either HS or normal membranes re-associated in a similar manner to spectrin/actin-depleted vesicles prepared from normal cells. Scatchard analysis showed an average binding capacity of 278μg/mg of membrane protein. However, spectrin/actin-depleted vesicles prepared from HS cells bound significantly less spectrin/actin prepared from either the normal or abnormal cells (average binding capacity 158μg/mg of membrane protein). The defect was defined further by studying the cytoskeleton obtained by Triton X-100 extraction of membranes. Under conditions of low ionic strength cytoskeletons prepared from HS membranes dissociated more slowly than those prepared from normal membranes, and only 80% of the protein from HS cytoskeletons could be solubilized after 180min compared with 100% for normal cytoskeletons. The difference between HS and normal membranes, which persists in isolated cytoskeletons, suggests that alterations in either the primary structure or the degree of phosphorylation of protein bands 2.1 or 4.1 may be central to the molecular basis of hereditary spherocytosis.

Background:Chronic graft-versus-host disease (cGVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HCT). Treatment relies upon corticosteroids and immunosuppressive agents with limited efficacy and considerable side-effects. Evolving research points to the complex involvement of immune T, B, and myeloid cells in the pathogenesis of cGVHD. Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (BTK) and interleukin-2-inducible T-cell kinase (ITK) which inhibits the activation of B-cells, specific T-cell subsets, and certain myeloid cells that are implicated in cGVHD. Substantial clinical benefit was demonstrated in an open-label phase 1b/2 study of ibrutinib in patients with cGVHD that had failed frontline therapy (Miklos et al ASH 2016). Based upon this data, ibrutinib is indicated by the US FDA for the treatment of adult patients with cGVHD after failure of one or more lines of systemic therapy.