Cerebral malaria is a severe complication of Plasmodium falciparum infection associated with high mortality even when highly effective antiparasitic therapy is used. Adjunctive therapies that modify the pathophysiological processes caused by malaria are a possible way to improve outcome. This review focuses on the utility of PPARγ agonists as an adjunctive therapy for the treatment of cerebral malaria. The current knowledge of PPARγ agonist use in malaria is summarized. Findings from experimental CNS injury and disease models that demonstrate the potential for PPARγ agonists as an adjunctive therapy for cerebral malaria are also discussed. 1. Introduction Few diseases have the global health and economic impact of malaria [1]. In 2009, an estimated 225 million people were infected with malaria and close to a million people succumbed to their infection [2]. Malaria is caused by apicomplexan parasites belonging to the genus Plasmodium. Five species infect humans, Plasmodium falciparum, P. vivax, P. ovale, P. malariae, and most recently, P. knowlesi [3]. The majority of morbidity and mortality is caused by P. falciparum infection, with the highest burden born by children and pregnant women. In the absence of prompt and effective treatment, P. falciparum infection can progress quickly, rapidly becoming severe and fatal. The rise in drug-resistant parasites complicates the administration of effective treatment. Severe malaria has multiple manifestations that can occur singly or in combination. They include hyperparasitemia, high fever, haemoglobinuria, acute renal failure, acute pulmonary edema, metabolic acidosis and respiratory distress, hypoglycemia, anemia, and cerebral malaria, which is characterized by coma and convulsions. Cerebral malaria has the highest mortality rate of all the severe complications and is associated with long-term cognitive and neurological deficits in surviving children [4–6]. Intravenous artesunate is now the standard of care for severe malaria in both adults and children following the landmark SEAQUAMAT and AQUAMAT trials that demonstrated the superiority of artesunate over quinine in adults and in children [7, 8]. However, even with the improved efficacy of artesunate, fatality rates remained high, 15% in adults and 10.9% in children. Adjunctive therapies, defined as therapies administered in combination with antiparasitic drugs that modify pathophysiological processes caused by malaria, have been pursued as a way to improve the outcome of severe malaria. Adjunctive therapies may also help extend the efficacy of antiparasitic
References
[1]
R. W. Snow, C. A. Guerra, A. M. Noor, H. Y. Myint, and S. I. Hay, “The global distribution of clinical episodes of Plasmodium falciparum malaria,” Nature, vol. 434, no. 7030, pp. 214–217, 2005.
[2]
WHO, World Malaria Report, 2010.
[3]
B. Singh, L. K. Sung, A. Matusop et al., “A large focus of naturally acquired Plasmodium knowlesi infections in human beings,” The Lancet, vol. 363, no. 9414, pp. 1017–1024, 2004.
[4]
C. C. John, P. Bangirana, J. Byarugaba et al., “Cerebral malaria in children is associated with long-term cognitive impairment,” Pediatrics, vol. 122, no. 1, pp. e92–e99, 2008.
[5]
M. J. Boivin, “Effects of early cerebral malaria on cognitive ability in Senegalese children,” Journal of Developmental and Behavioral Pediatrics, vol. 23, no. 5, pp. 353–364, 2002.
[6]
M. J. Boivin, P. Bangirana, J. Byarugaba et al., “Cognitive impairment after cerebral malaria in children: a prospective study,” Pediatrics, vol. 119, no. 2, pp. e360–e366, 2007.
[7]
A. Dondorp, F. Nosten, K. Stepniewska, N. Day, and N. White, “Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial,” The Lancet, vol. 366, no. 9487, pp. 717–725, 2005.
[8]
A. M. Dondorp, C. I. Fanello, I. C. Hendriksen et al., “Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial,” The Lancet, vol. 376, no. 9753, pp. 1647–1657, 2010.
[9]
A. M. Dondorp, F. Nosten, P. Yi et al., “Artemisinin resistance in Plasmodium falciparum malaria,” The New England Journal of Medicine, vol. 361, no. 5, pp. 455–467, 2009.
[10]
N. J. White, “Artemisinin resistance—the clock is ticking,” The Lancet, vol. 376, no. 9758, pp. 2051–2052, 2010.
[11]
C. C. John, E. Kutamba, K. Mugarura, and R. O. Opoka, “Adjunctive therapy for cerebral malaria and other severe forms of Plasmodium falciparum malaria,” Expert Review of Anti-Infective Therapy, vol. 8, no. 9, pp. 997–1008, 2010.
[12]
T. E. Taylor, W. J. Fu, R. A. Carr et al., “Differentiating the pathologies of cerebral malaria by postmortem parasite counts,” Nature Medicine, vol. 10, no. 2, pp. 143–145, 2004.
[13]
A. R. Berendt, D. L. Simmons, J. Tansey, C. I. Newbold, and K. Marsh, “Intercellular adhesion molecule-1 is an endothelial cell adhesion receptor for Plasmodium falciparum,” Nature, vol. 341, no. 6237, pp. 57–59, 1989.
[14]
K. Silamut, N. H. Phu, C. Whitty et al., “A quantitative analysis of the microvascular sequestration of malaria parasites in the human brain,” American Journal of Pathology, vol. 155, no. 2, pp. 395–410, 1999.
[15]
G. D. H. Turner, H. Morrison, M. Jones et al., “An immunohistochemical study of the pathology of fatal malaria: evidence for widespread endothelial activation and a potential role for intercellular adhesion molecule-1 in cerebral sequestration,” American Journal of Pathology, vol. 145, no. 5, pp. 1057–1069, 1994.
[16]
A. Craig, D. Fernandez-Reyes, M. Mesri et al., “A functional analysis of a natural variant of intercellular adhesion molecule-1 (ICAM-1(Kilifi)),” Human Molecular Genetics, vol. 9, no. 4, pp. 525–530, 2000.
[17]
D. Fernandez-Reyes, A. G. Craig, S. A. Kyes et al., “A high frequency African coding polymorphism in the N-terminal domain of ICAM-1 predisposing to cerebral malaria in Kenya,” Human Molecular Genetics, vol. 6, no. 8, pp. 1357–1360, 1997.
[18]
J. W. Barnwell, A. S. Asch, R. L. Nachman, M. Yamaya, M. Aikawa, and P. Ingravallo, “A human 88-kD membrane glycoprotein (CD36) functions in vitro as a receptor for a cytoadherence ligand on Plasmodium falciparum-infected erythrocytes,” Journal of Clinical Investigation, vol. 84, no. 3, pp. 765–772, 1989.
[19]
C. F. Ockenhouse, N. N. Tandon, C. Magowan, G. A. Jamieson, and J. D. Chulay, “Identification of a platelet membrane glycoprotein as a falciparum malaria sequestration receptor,” Science, vol. 243, no. 4897, pp. 1469–1471, 1989.
[20]
P. Oquendo, E. Hundt, J. Lawler, and B. Seed, “CD36 directly mediates cytoadherence of Plasmodium falciparum parasitized erythrocytes,” Cell, vol. 58, no. 1, pp. 95–101, 1989.
[21]
C. Newbold, A. Craig, S. Kyes, A. Rowe, D. Fernandez-Reyes, and T. Fagan, “Cytoadherence, pathogenesis and the infected red cell surface in Plasmodium falciparum,” International Journal for Parasitology, vol. 29, no. 6, pp. 927–937, 1999.
[22]
L. Schofield and G. E. Grau, “Immunological processes in malaria pathogenesis,” Nature Reviews Immunology, vol. 5, no. 9, pp. 722–735, 2005.
[23]
G. E. Grau, T. E. Taylor, M. E. Molyneux et al., “Tumor necrosis factor and disease severity in children with falciparum malaria,” The New England Journal of Medicine, vol. 320, no. 24, pp. 1586–1591, 1989.
[24]
D. Kwiatkowski, A. V. S. Hill, I. Sambou et al., “TNF concentration in fatal cerebral, non-fatal cerebral, and uncomplicated Plasmodium falciparum malaria,” The Lancet, vol. 336, no. 8725, pp. 1201–1204, 1990.
[25]
B. D. Akanmori, J. A. L. Kurtzhals, B. Q. Goka et al., “Distinct patterns of cytokine regulation in discrete clinical forms of Plasmodium falciparum malaria,” European Cytokine Network, vol. 11, no. 1, pp. 113–118, 2000.
[26]
H. Brown, G. Turner, S. Rogerson et al., “Cytokine expression in the brain in human cerebral malaria,” Journal of Infectious Diseases, vol. 180, no. 5, pp. 1742–1746, 1999.
[27]
W. McGuire, A. V. S. Hill, C. E. M. Allsopp, B. M. Greenwood, and D. Kwjatkowski, “Variation in the TNF-α promoter region associated with susceptibility to cerebral malaria,” Nature, vol. 371, no. 6497, pp. 508–511, 1994.
[28]
J. C. Knight, I. Udalova, A. V. S. Hill et al., “A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria,” Nature Genetics, vol. 22, no. 2, pp. 145–150, 1999.
[29]
C. C. John, A. Panoskaltsis-Mortari, R. O. Opoka et al., “Cerebrospinal fluid cytokine levels and cognitive impairment in cerebral malaria,” American Journal of Tropical Medicine and Hygiene, vol. 78, no. 2, pp. 198–205, 2008.
[30]
C. C. John, R. Opika-Opoka, J. Byarugaba, R. Idro, and M. J. Boivin, “Low levels of RANTES are associated with mortality in children with cerebral malaria,” Journal of Infectious Diseases, vol. 194, no. 6, pp. 837–845, 2006.
[31]
C. C. John, G. S. Park, N. Sam-Agudu, R. O. Opoka, and M. J. Boivin, “Elevated serum levels of IL-1ra in children with Plasmodium falciparum malaria are associated with increased severity of disease,” Cytokine, vol. 41, no. 3, pp. 204–208, 2008.
[32]
V. Jain, H. B. Armah, J. E. Tongren et al., “Plasma IP-10, apoptotic and angiogenic factors associated with fatal cerebral malaria in India,” Malaria Journal, vol. 7, article 83, 2008.
[33]
K. E. Lyke, R. Burges, Y. Cissoko et al., “Serum levels of the proinflammatory cytokines interleukin-1 beta (IL-1β), IL-6, IL-8, IL-10, tumor necrosis factor alpha, and IL-12(p70) in Malian children with severe Plasmodium falciparum malaria and matched uncomplicated malaria or healthy controls,” Infection and Immunity, vol. 72, no. 10, pp. 5630–5637, 2004.
[34]
G. A. Awandare, B. Goka, P. Boeuf et al., “Increased levels of inflammatory mediators in children with severe Plasmodium falciparum malaria with respiratory distress,” Journal of Infectious Diseases, vol. 194, no. 10, pp. 1438–1446, 2006.
[35]
D. Faille, F. El-Assaad, M. C. Alessi, T. Fusai, V. Combes, and G. E. R. Grau, “Platelet-endothelial cell interactions in cerebral malaria: the end of a cordial understanding,” Thrombosis and Haemostasis, vol. 102, no. 6, pp. 1093–1102, 2009.
[36]
H. Brown, T. T. Hien, N. Day et al., “Evidence of blood-brain barrier dysfunction in human cerebral malaria,” Neuropathology and Applied Neurobiology, vol. 25, no. 4, pp. 331–340, 1999.
[37]
A. L. Conroy, H. Phiri, M. Hawkes et al., “Endothelium-based biomarkers are associated with cerebral malaria in Malawian children: a retrospective case-control study,” PLoS ONE, vol. 5, no. 12, Article ID e15291, 2010.
[38]
T. W. Yeo, D. A. Lampah, R. Gitawat et al., “Angiopoietin-2 is associated with decreased endothelial nitric oxide and poor clinical outcome in severe falciparum malaria,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 44, pp. 17097–17102, 2008.
[39]
F. E. Lovegrove, N. Tangpukdee, R. O. Opoka et al., “Serum angiopoietin-1 and -2 levels discriminate cerebral malaria from uncomplicated malaria and predict clinical outcome in African children,” PLoS ONE, vol. 4, no. 3, Article ID e4912, 2009.
[40]
T. W. Yeo, D. A. Lampah, E. Tjitra et al., “Relationship of cell-free hemoglobin to impaired endothelial nitric oxide bioavailability and perfusion in severe falciparum malaria,” Journal of Infectious Diseases, vol. 200, no. 10, pp. 1522–1529, 2009.
[41]
T. W. Yeo, D. A. Lampah, R. Gitawati et al., “Impaired nitric oxide bioavailability and L-arginine-reversible endothelial dysfunction in adults with falciparum malaria,” Journal of Experimental Medicine, vol. 204, no. 11, pp. 2693–2704, 2007.
[42]
G. Turner, “Cerebral malaria,” Brain Pathology, vol. 7, no. 1, pp. 569–582, 1997.
[43]
V. A. White, S. Lewallen, N. Beare, K. Kayira, R. A. Carr, and T. E. Taylor, “Correlation of retinal haemorrhages with brain haemorrhages in children dying of cerebral malaria in Malawi,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 95, no. 6, pp. 618–621, 2001.
[44]
H. Brown, S. Rogerson, T. Taylor et al., “Blood-brain barrier function in cerebral malaria in Malawian children,” American Journal of Tropical Medicine and Hygiene, vol. 64, no. 3-4, pp. 207–213, 2001.
[45]
I. M. Medana, N. P. Day, T. T. Hien et al., “Axonal injury in cerebral malaria,” American Journal of Pathology, vol. 160, no. 2, pp. 655–666, 2002.
[46]
I. M. Medana and M. M. Esiri, “Axonal damage: a key predictor of outcome in human CNS diseases,” Brain, vol. 126, no. 3, pp. 515–530, 2003.
[47]
R. Idro, N. E. Jenkins, and C. R. J. Newton, “Pathogenesis, clinical features, and neurological outcome of cerebral malaria,” The Lancet Neurology, vol. 4, no. 12, pp. 827–840, 2005.
[48]
N. H. Hunt, J. Golenser, T. Chan-Ling et al., “Immunopathogenesis of cerebral malaria,” International Journal for Parasitology, vol. 36, no. 5, pp. 569–582, 2006.
[49]
I. A. Clark, L. M. Alleva, and B. Vissel, “The roles of TNF in brain dysfunction and disease,” Pharmacology & Therapeutics, vol. 128, no. 3, pp. 519–548, 2010.
[50]
N. A. V. Beare, S. P. Harding, T. E. Taylor, S. Lewallen, and M. E. Molyneux, “Perfusion abnormalities in children with cerebral malaria and malarial retinopathy,” Journal of Infectious Diseases, vol. 199, no. 2, pp. 263–271, 2009.
[51]
V. A. White, S. Lewallen, N. A. V. Beare, M. E. Molyneux, and T. E. Taylor, “Retinal pathology of pediatric cerebral malaria in Malawi,” PLoS ONE, vol. 4, no. 1, Article ID e4317, 2009.
[52]
S. E.R. Bopp, V. Ramachandran, K. Henson et al., “Genome wide analysis of inbred mouse lines identifies a locus containing ppar-γ as contributing to enhanced malaria survival,” PLoS ONE, vol. 5, no. 5, Article ID e10903, 2010.
[53]
J. Berger and D. E. Moller, “The mechanisms of action of PPARs,” Annual Review of Medicine, vol. 53, pp. 409–435, 2002.
[54]
G. Pascual, A. L. Fong, S. Ogawa et al., “A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-γ,” Nature, vol. 437, no. 7059, pp. 759–763, 2005.
[55]
S. Giannini, M. Serio, and A. Galli, “Pleiotropic effects of thiazolidinediones: taking a look beyond antidiabetic activity,” Journal of Endocrinological Investigation, vol. 27, no. 10, pp. 982–991, 2004.
[56]
M. Lehrke and M. A. Lazar, “The many faces of PPARγ,” Cell, vol. 123, no. 6, pp. 993–999, 2005.
[57]
A. Szanto and L. Nagy, “The many faces of PPARγ: anti-inflammatory by any means?” Immunobiology, vol. 213, no. 9-10, pp. 789–803, 2008.
[58]
H. Ghanim, S. Dhindsa, A. Aljada, A. Chaudhuri, P. Viswanathan, and P. Dandona, “Low-dose rosiglitazone exerts an antiinflammatory effect with an increase in adiponectin independently of free fatty acid fall and insulin sensitization in obese type 2 diabetics,” Journal of Clinical Endocrinology and Metabolism, vol. 91, no. 9, pp. 3553–3558, 2006.
[59]
D. G. Alleva, E. B. Johnson, F. M. Lio, S. A. Boehme, P. J. Conlon, and P. D. Crowe, “Regulation of murine macrophage proinflammatory and anti-inflammatory cytokines by ligands for peroxisome proliferator-activated receptor-γ: counter-regulatory activity by IFN-γ,” Journal of Leukocyte Biology, vol. 71, no. 4, pp. 677–685, 2002.
[60]
S. W. Chung, B. Y. Kang, S. H. Kim, et al., “Oxidized low density lipoprotein inhibits interleukin-12 production in lipopolysaccharide-activated mouse macrophages via direct interactions between peroxisome proliferator-activated receptor-γ and nuclear factor-κB,” The Journal of Biological Chemistry, vol. 275, no. 42, pp. 32681–32687, 2000.
[61]
C. Jiang, A. T. Ting, and B. Seed, “PPAR-γ agonists inhibit production of monocyte inflammatory cytokines,” Nature, vol. 391, no. 6662, pp. 82–86, 1998.
[62]
M. Li, G. Pascual, and C. K. Glass, “Peroxisome proliferator-activated receptor γ-dependent repression of the inducible nitric oxide synthase gene,” Molecular and Cellular Biology, vol. 20, no. 13, pp. 4699–4707, 2000.
[63]
M. Ricote, A. C. Li, T. M. Willson, C. J. Kelly, and C. K. Glass, “The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation,” Nature, vol. 391, no. 6662, pp. 79–82, 1998.
[64]
M. Ricote, J. T. Huang, J. S. Welch, and C. K. Glass, “The peroxisome proliferator-activated receptorγ (PPARγ) as a regulator of monocyte/macrophage function,” Journal of Leukocyte Biology, vol. 66, no. 5, pp. 733–739, 1999.
[65]
D. S. Straus, G. Pascual, M. Li et al., “15-Deoxy-Δ-prostaglandin J2 inhibits multiple steps in the NF-κB signaling pathway,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 9, pp. 4844–4849, 2000.
[66]
J. S. Welch, M. Ricote, T. E. Akiyama, F. J. Gonzalez, and C. K. Glass, “PPARγ and PPARδ negatively regulate specific subsets of lipopolysaccharide and IFN-γ target genes in macrophages,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 11, pp. 6712–6717, 2003.
[67]
C. Faveeuw, S. Fougeray, V. Angeli et al., “Peroxisome proliferator-activated receptor γ activators inhibit interleukin-12 production in murine dendritic cells,” FEBS Letters, vol. 486, no. 3, pp. 261–266, 2000.
[68]
P. Gosset, A. S. Charbonnier, P. Delerive et al., “Peroxisome proliferator-activated receptor γ activators affect the maturation of human monocyte-derived dendritic cells,” European Journal of Immunology, vol. 31, no. 10, pp. 2857–2865, 2001.
[69]
P. Wang, P. O. Anderson, S. Chen, K. M. Paulsson, H. O. Sj？gren, and S. Li, “Inhibition of the transcription factors AP-1 and NF-κB in CD4 T cells by peroxisome proliferator-activated receptor γ ligands,” International Immunopharmacology, vol. 1, no. 4, pp. 803–812, 2001.
[70]
R. B. Clark, D. Bishop-Bailey, T. Estrada-Hernandez, T. Hla, L. Puddington, and S. J. Padula, “The nuclear receptor PPARγ and immunoregulation: PPARγ mediates inhibition of helper T cell responses,” Journal of Immunology, vol. 164, no. 3, pp. 1364–1371, 2000.
[71]
R. Cunard, M. Ricote, D. DiCampli et al., “Regulation of cytokine expression by ligands of peroxisome proliferator activated receptors,” Journal of Immunology, vol. 168, no. 6, pp. 2795–2802, 2002.
[72]
N. Marx, F. Mach, A. Sauty et al., “Peroxisome proliferator-activated receptor-γ activators inhibit IFN-γ- induced expression of the T cell-active CXC chemokines IP-10, Mig, and I-TAC in human endothelial cells,” Journal of Immunology, vol. 164, no. 12, pp. 6503–6508, 2000.
[73]
V. Pasceri, H. D. Wu, J. T. Willerson, and E. T. H. Yeh, “Modulation of vascular inflammation in vitro and in vivo by peroxisome proliferator-activated receptor-γ activators,” Circulation, vol. 101, no. 3, pp. 235–238, 2000.
[74]
P. D. Storer, J. Xu, J. Chavis, and P. D. Drew, “Peroxisome proliferator-activated receptor-gamma agonists inhibit the activation of microglia and astrocytes: implications for multiple sclerosis,” Journal of Neuroimmunology, vol. 161, no. 1-2, pp. 113–122, 2005.
[75]
J. D. Ji, H. J. Kim, Y. H. Rho et al., “Inhibition of IL-10-induced STAT3 activation by 15-deoxy-Δ12,14-prostaglandin J,” Rheumatology, vol. 44, no. 8, pp. 983–988, 2005.
[76]
E. J. Park, S. Y. Park, E. H. Joe, and I. Jou, “15d-PGJ and rosiglitazone suppress Janus kinase-STAT inflammatory signaling through induction of suppressor of cytokine signaling 1 (SOCS1) and SOCS3 in glia,” The Journal of Biological Chemistry, vol. 278, no. 17, pp. 14747–14752, 2003.
[77]
P. D. Drew, J. Xu, and M. K. Racke, “PPAR-γ: therapeutic potential for multiple sclerosis,” PPAR Research, vol. 2008, Article ID 627463, 2008.
[78]
R. Vemuganti, “Therapeutic potential of PPARγ activation in stroke,” PPAR Research, vol. 2008, Article ID 461981, 2008.
[79]
J. J. Bright, S. Kanakasabai, W. Chearwae, and S. Chakraborty, “PPAR regulation of inflammatory signaling in CNS diseases,” PPAR Research, vol. 2008, Article ID 658520, 2008.
[80]
R. Kapadia, J. H. Yi, and R. Vemuganti, “Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists,” Frontiers in Bioscience, vol. 13, no. 5, pp. 1813–1826, 2008.
[81]
C. A. Homewood, G. A. Moore, D. C. Warhurst, and E. M. Atkinson, “Purification and some properties of malarial pigment,” Annals of Tropical Medicine and Parasitology, vol. 69, no. 3, pp. 283–287, 1975.
[82]
E. Schwarzer, H. Kühn, E. Valente, and P. Arese, “Malaria-parasitized erythrocytes and hemozoin nonenzymatically generate large amounts of hydroxy fatty acids that inhibit monocyte functions,” Blood, vol. 101, no. 2, pp. 722–728, 2003.
[83]
S. Pizzimenti, S. Laurora, F. Briatore, C. Ferretti, M. U. Dianzani, and G. Barrera, “Synergistic effect of 4-hydroxynonenal and PPAR ligands in controlling human leukemic cell growth and differentiation,” Free Radical Biology and Medicine, vol. 32, no. 3, pp. 233–245, 2002.
[84]
E. Schwarzer, M. Alessio, D. Ulliers, and P. Arese, “Phagocytosis of the malarial pigment, hemozoin, impairs expression of major histocompatibility complex class II antigen, CD54, and CD11c in human monocytes,” Infection and Immunity, vol. 66, no. 4, pp. 1601–1606, 1998.
[85]
D. Taramelli, “The heme moiety of malaria pigment (β-Hematin) mediates the inhibition of nitric oxide and tumor necrosis factor-α production by lipopolysaccharide-stimulated macrophages,” Experimental Parasitology, vol. 81, no. 4, pp. 501–511, 1995.
[86]
P. Deshpande and P. Shastry, “Modulation of cytokine profiles by malaria pigment—Hemozoin: role of IL-10 in suppression of proliferative responses of mitogen stimulated human PBMC,” Cytokine, vol. 28, no. 6, pp. 205–213, 2004.
[87]
O. Skorokhod, E. Schwarzer, T. Grune, and P. Arese, “Role of 4-hydroxynonenal in the hemozoin-mediated inhibition of differentiation of human monocytes to dendritic cells induced by GM-CSF/IL-4,” BioFactors, vol. 24, no. 1–4, pp. 283–289, 2005.
[88]
O. R. Millington, C. Di Lorenzo, R. S. Phillips, P. Garside, and J. M. Brewer, “Suppression of adaptive immunity to heterologous antigens during Plasmodium infection through hemozoin-induced failure of dendritic cell function,” Journal of Biology, vol. 5, article 5, 2006.
[89]
T. Scorza, S. Magez, L. Brys, and P. De Baetselier, “Hemozoin is a key factor in the induction of malaria-associated immunosuppression,” Parasite Immunology, vol. 21, no. 11, pp. 545–554, 1999.
[90]
O. A. Skorokhod, M. Alessio, B. Mordmüller, P. Arese, and E. Schwarzer, “Hemozoin (malarial pigment) inhibits differentiation and maturation of human monocyte-derived dendritic cells: a peroxisome proliferator-activated receptor-γ-mediated effect,” Journal of Immunology, vol. 173, no. 6, pp. 4066–4074, 2004.
[91]
I. D. McGilvray, L. Serghides, A. Kapus, O. D. Rotstein, and K. C. Kain, “Nonopsonic monocyte/macrophage phagocytosis of Plasmodium falciparum-parasitized erythrocytes: a role for CD36 in malarial clearance,” Blood, vol. 96, no. 9, pp. 3231–3240, 2000.
[92]
S. N. Patel, L. Serghides, T. G. Smith et al., “CD36 Mediates the Phagocytosis of Plasmodium falciparum-Infected Erythrocytes by Rodent Macrophages,” Journal of Infectious Diseases, vol. 189, no. 2, pp. 204–213, 2004.
[93]
Z. Su, A. Fortin, P. Gros, and M. M. Stevenson, “Opsonin-independent phagocytosis: an effector mechanism against acute blood-stage Plasmodium chabaudi AS infection,” Journal of Infectious Diseases, vol. 186, no. 9, pp. 1321–1329, 2002.
[94]
L. Serghides, T. G. Smith, S. N. Patel, and K. C. Kain, “CD36 and malaria: friends or foes?” Trends in Parasitology, vol. 19, no. 10, pp. 461–469, 2003.
[95]
K. Ayi, S. N. Patel, L. Serghides, T. G. Smith, and K. C. Kain, “Nonopsonic phagocytosis of erythrocytes infected with ring-stage Plasmodium falciparum,” Infection and Immunity, vol. 73, no. 4, pp. 2559–2563, 2005.
[96]
T. G. Smith, L. Serghides, S. N. Patel, M. Febbraio, R. L. Silverstein, and K. C. Kain, “CD36-mediated nonopsonic phagocytosis of erythrocytes infected with stage I and IIA gametocytes of Plasmodium falciparum,” Infection and Immunity, vol. 71, no. 1, pp. 393–400, 2003.
[97]
S. N. Patel, Z. Lu, K. Ayi, L. Serghides, D. C. Gowda, and K. C. Kain, “Disruption of CD36 impairs cytokine response to Plasmodium falciparum glycosylphosphatidylinositol and confers susceptibility to severe and fatal malaria in vivo,” Journal of Immunology, vol. 178, no. 6, pp. 3954–3961, 2007.
[98]
L. Serghides and K. C. Kain, “Peroxisome proliferator-activated receptor γ-retinoid X receptor agonists increase CD36-dependent phagocytosis of Plasmodium falciparum-parasitized erythrocytes and decrease malaria-induced TNF-α secretion by monocytes/macrophages,” Journal of Immunology, vol. 166, no. 11, pp. 6742–6748, 2001.
[99]
L. K. Erdman, G. Cosio, A. J. Helmers, D. C. Gowda, S. Grinstein, and K. C. Kain, “CD36 and TLR interactions in inflammation and phagocytosis: implications for malaria,” Journal of Immunology, vol. 183, no. 10, pp. 6452–6459, 2009.
[100]
V. A. Fadok, M. L. Warner, D. L. Bratton, and P. M. Henson, “CD36 is required for phagocytosis of apoptotic cells by human macrophages that use either a phosphatidylserine receptor or the vitronectin receptor (α(V)β3),” Journal of Immunology, vol. 161, no. 11, pp. 6250–6257, 1998.
[101]
N. Platt, R. P. da Silva, and S. Gordon, “Recognizing death: the phagocytosis of apoptotic cells,” Trends in Cell Biology, vol. 8, no. 9, pp. 365–372, 1998.
[102]
L. Serghides, S. N. Patel, K. Ayi et al., “Rosiglitazone modulates the innate immune response to Plasmodium falciparum infection and improves outcome in experimental cerebral malaria,” Journal of Infectious Diseases, vol. 199, no. 10, pp. 1536–1545, 2009.
[103]
S. Gordon and F. O. Martinez, “Alternative activation of macrophages: mechanism and functions,” Immunity, vol. 32, no. 5, pp. 593–604, 2010.
[104]
K. Ayi, F. Turrini, A. Piga, and P. Arese, “Enhanced phagocytosis of ring-parasitized mutant erythrocytes: a common mechanism that may explain protection against falciparum malaria in sickle trait and beta-thalassemia trait,” Blood, vol. 104, no. 10, pp. 3364–3371, 2004.
[105]
T. N. Williams, “Human red blood cell polymorphisms and malaria,” Current Opinion in Microbiology, vol. 9, no. 4, pp. 388–394, 2006.
[106]
K. Ayi, G. Min-Oo, L. Serghides et al., “Pyruvate kinase deficiency and malaria,” The New England Journal of Medicine, vol. 358, no. 17, pp. 1805–1810, 2008.
[107]
L. Schofield and F. Hackett, “Signal transduction in host cells by a glycosylphosphatidylinositol toxin of malaria parasites,” Journal of Experimental Medicine, vol. 177, no. 1, pp. 145–153, 1993.
[108]
G. Krishnegowda, A. M. Hajjar, J. Zhu et al., “Induction of proinflammatory responses in macrophages by the glycosylphosphatidylinositols of Plasmodium falciparum: cell signaling receptors, glycosylphosphatidylinositol (GPI) structural requirement, and regulation of GPI activity,” The Journal of Biological Chemistry, vol. 280, no. 9, pp. 8606–8616, 2005.
[109]
G. Cantini, A. Lombardi, E. Borgogni et al., “Peroxisome-proliferator-activated receptor gamma (PPARγ) is required for modulating endothelial inflammatory response through a nongenomic mechanism,” European Journal of Cell Biology, vol. 89, no. 9, pp. 645–653, 2010.
[110]
M. M. Stevenson and E. M. Riley, “Innate immunity to malaria,” Nature Reviews Immunology, vol. 4, no. 3, pp. 169–180, 2004.
[111]
A. K. Boggild, S. Krudsood, S. N. Patel et al., “Use of peroxisome proliferator-activated receptor γ agonists as adjunctive treatment for Plasmodium falciparum malaria: a randomized, double-blind, placebo-controlled trial,” Clinical Infectious Diseases, vol. 49, no. 6, pp. 841–849, 2009.
[112]
A. H. Shankar, B. Genton, R. D. Semba et al., “Effect of vitamin A supplementation on morbidity due to Plasmodium falciparum in young children in Papua New Guinea: a randomised trial,” The Lancet, vol. 354, no. 9174, pp. 203–209, 1999.
[113]
L. Serghides and K. C. Kain, “Mechanism of protection induced by vitamin A in falciparum malaria,” The Lancet, vol. 359, no. 9315, pp. 1404–1406, 2002.
[114]
N. C. Inestrosa, J. A. Godoy, R. A. Quintanilla, C. S. Koenig, and M. Bronfman, “Peroxisome proliferator-activated receptor γ is expressed in hippocampal neurons and its activation prevents β-amyloid neurodegeneration: role of Wnt signaling,” Experimental Cell Research, vol. 304, no. 1, pp. 91–104, 2005.
[115]
S. H. Ramirez, D. Heilman, B. Morsey, R. Potula, J. Haorah, and Y. Persidsky, “Activation of peroxisome proliferator-activated receptor γ (PPARγ) suppresses rho GTPases in human brain microvascular endothelial cells and inhibits adhesion and transendothelial migration of HIV-1 infected monocytes,” Journal of Immunology, vol. 180, no. 3, pp. 1854–1865, 2008.
[116]
S. Moreno, S. Farioli-vecchioli, and M. P. Cerù, “Immunolocalization of peroxisome proliferator-activated receptors and retinoid X receptors in the adult rat CNS,” Neuroscience, vol. 123, no. 1, pp. 131–145, 2004.
[117]
W. H.-H. Sheu, H. C. Chuang, S. M. Cheng, M. R. Lee, C. C. Chou, and F. C. Cheng, “Microdialysis combined blood sampling technique for the determination of rosiglitazone and glucose in brain and blood of gerbils subjected to cerebral ischemia,” Journal of Pharmaceutical and Biomedical Analysis, vol. 54, no. 4, pp. 759–764, 2011.
[118]
A. Szklarczyk, M. Stins, E. A. Milward et al., “Glial activation and matrix metalloproteinase release in cerebral malaria,” Journal of Neurovirology, vol. 13, no. 1, pp. 2–10, 2007.
[119]
C. K. Combs, D. E. Johnson, J. C. Karlo, S. B. Cannady, and G. E. Landreth, “Inflammatory mechanisms in Alzheimer's disease: inhibition of β- amyloid-stimulated proinflammatory responses and neurotoxicity by PPARγ agonists,” Journal of Neuroscience, vol. 20, no. 2, pp. 558–567, 2000.
[120]
A. Lombardi, G. Cantini, E. Piscitelli et al., “A new mechanism involving ERK contributes to rosiglitazone inhibition of tumor necrosis factor-α and interferon-γ inflammatory effects in human endothelial cells,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 28, no. 4, pp. 718–724, 2008.
[121]
S. Z. Duan, M. G. Usher, and R. M. Mortensen, “Peroxisome proliferator-activated receptor-γ-mediated effects in the vasculature,” Circulation Research, vol. 102, no. 3, pp. 283–294, 2008.
[122]
M. Joner, A. Farb, QI. Cheng et al., “Pioglitazone inhibits in-stent restenosis in atherosclerotic rabbits by targeting transforming growth factor-β and MCP-1,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 27, no. 1, pp. 182–189, 2007.
[123]
N. Marx, G. Sukhova, C. Murphy, P. Libby, and J. Plutzky, “Macrophages in human atheroma contain PPARγ: differentiation-dependent peroxisomal proliferator-activated receptor γ (PPARγ) expression and reduction of MMP-9 activity through PPARγ activation in mononuclear phagocytes in vitro,” American Journal of Pathology, vol. 153, no. 1, pp. 17–23, 1998.
[124]
C. X. Wang, X. Ding, R. Noor, C. Pegg, C. He, and A. Shuaib, “Rosiglitazone alone or in combination with tissue plasminogen activator improves ischemic brain injury in an embolic model in rats,” Journal of Cerebral Blood Flow and Metabolism, vol. 29, no. 10, pp. 1683–1694, 2009.
[125]
A. Ferreira, J. Balla, V. Jeney, G. Balla, and M. P. Soares, “A central role for free heme in the pathogenesis of severe malaria: the missing link?” Journal of Molecular Medicine, vol. 86, no. 10, pp. 1097–1111, 2008.
[126]
R. Medzhitov, “Damage control in host-pathogen interactions,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 37, pp. 15525–15526, 2009.
[127]
M. C. Delmas-Beauvieux, E. Peuchant, M. F. Dumon, M. C. Receveur, M. Le Bras, and M. Clerc, “Relationship between red blood cell antioxidant enzymatic system status and lipoperoxidation during the acute phase of malaria,” Clinical Biochemistry, vol. 28, no. 2, pp. 163–169, 1995.
[128]
Z. Bagi, A. Koller, and G. Kaley, “PPARγ activation, by reducing oxidative stress, increases NO bioavailability in coronary arterioles of mice with Type 2 diabetes,” American Journal of Physiology, vol. 286, no. 2, pp. H742–H748, 2004.
[129]
I. Inoue, S. -I. Goto, T. Matsunaga et al., “The ligands/activators for peroxisome proliferator-activated receptor α (PPARα) and PPARγ increase Cu2+,Zn2+-superoxide dismutase and decrease p22phox message expressions in primary endothelial cells,” Metabolism, vol. 50, no. 1, pp. 3–11, 2001.
[130]
J. Hwang, D. J. Kleinhenz, B. Lassègue, K. K. Griendling, S. Dikalov, and C. M. Hart, “Peroxisome proliferator-activated receptor-γ ligands regulate endothelial membrane superoxide production,” American Journal of Physiology, vol. 288, no. 4, pp. C899–C905, 2005.
[131]
X. Zhao, R. Strong, J. Zhang et al., “Neuronal PPARγ deficiency increases susceptibility to brain damage after cerebral ischemia,” Journal of Neuroscience, vol. 29, no. 19, pp. 6186–6195, 2009.
[132]
X. Zhao, G. Sun, J. Zhang et al., “Hematoma resolution as a target for intracerebral hemorrhage treatment: role for peroxisome proliferator-activated receptor γ in microglia/macrophages,” Annals of Neurology, vol. 61, no. 4, pp. 352–362, 2007.
[133]
J. Hwang, D. J. Kleinhenz, H. L. Rupnow et al., “The PPARγ ligand, rosiglitazone, reduces vascular oxidative stress and NADPH oxidase expression in diabetic mice,” Vascular Pharmacology, vol. 46, no. 6, pp. 456–462, 2007.
[134]
C. De Ciuceis, F. Amiri, M. Iglarz, J. S. Cohn, R. M. Touyz, and E. L. Schiffrin, “Synergistic vascular protective effects of combined low doses of PPARα and PPARγ activators in angiotensin II-induced hypertension in rats,” British Journal of Pharmacology, vol. 151, no. 1, pp. 45–53, 2007.
[135]
G. Kr？nke, A. Kadl, E. Ikonomu et al., “Expression of heme oxygenase-1 in human vascular cells is regulated by peroxisome proliferator-activated receptors,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 27, no. 6, pp. 1276–1282, 2007.
[136]
L. E. Otterbein, F. H. Bach, J. Alam et al., “Carbon monoxide has anti-inflammatory effects involving the mitogen- activated protein kinase pathway,” Nature Medicine, vol. 6, no. 4, pp. 422–428, 2000.
[137]
J. Chen-Roetling, L. Benvenisti-Zarom, and R. F. Regan, “Cultured astrocytes from heme oxygenase-1 knockout mice are more vulnerable to heme-mediated oxidative injury,” Journal of Neuroscience Research, vol. 82, no. 6, pp. 802–810, 2005.
[138]
A. Pamplona, A. Ferreira, J. Balla et al., “Heme oxygenase-1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria,” Nature Medicine, vol. 13, no. 6, pp. 703–710, 2007.
[139]
J. S. Beckman and W. H. Koppenol, “Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and the ugly,” American Journal of Physiology, vol. 271, no. 5, pp. C1424–C1437, 1996.
[140]
N. M. Anstey, J. B. Weinberg, M. Y. Hassanali et al., “Nitric oxide in Tanzanian children with malaria: inverse relationship between malaria severity and nitric oxide production/nitric oxide synthase type 2 expression,” Journal of Experimental Medicine, vol. 184, no. 2, pp. 557–567, 1996.
[141]
I. Gramaglia, P. Sobolewski, D. Meays et al., “Low nitric oxide bioavailability contributes to the genesis of experimental cerebral malaria,” Nature Medicine, vol. 12, no. 12, pp. 1417–1422, 2006.
[142]
T. W. Yeo, D. A. Lampah, R. Gitawati et al., “Recovery of endothelial function in severe falciparum malaria: relationship with improvement in plasma L-arginine and blood lactate concentrations,” Journal of Infectious Diseases, vol. 198, no. 4, pp. 602–608, 2008.
[143]
D. Garcia-Santos and J. A. B. Chies, “HO-1 polymorphism as a genetic determinant behind the malaria resistance afforded by haemolytic disorders,” Medical Hypotheses, vol. 74, no. 5, pp. 807–813, 2010.
[144]
T. Matsumoto, E. Noguchi, T. Kobayashi, and K. Kamata, “Mechanisms underlying the chronic pioglitazone treatment-induced improvement in the impaired endothelium-dependent relaxation seen in aortas from diabetic rats,” Free Radical Biology and Medicine, vol. 42, no. 7, pp. 993–1007, 2007.
[145]
C. Romera, O. Hurtado, J. Mallolas et al., “Ischemic preconditioning reveals that GLT1/EAAT2 glutamate transporter is a novel PPARγ target gene involved in neuroprotection,” Journal of Cerebral Blood Flow and Metabolism, vol. 27, no. 7, pp. 1327–1338, 2007.
[146]
Y. Wang and Z. H. Qin, “Molecular and cellular mechanisms of excitoxic neuronal death,” Apoptosis, vol. 15, no. 11, pp. 1382–1402, 010.
[147]
A. S. Miranda, L. B. Vieira, N. Lacerda-Queiroz et al., “Increased levels of glutamate in the central nervous system are associated with behavioral symptoms in experimental malaria,” Brazilian Journal of Medical and Biological Research, vol. 43, no. 12, pp. 1173–1177, 2010.
[148]
L. A. Sanni, C. Rae, A. Maitland, R. Stocker, and N. H. Hunt, “Is ischemia involved in the pathogenesis of murine cerebral malaria?” American Journal of Pathology, vol. 159, no. 3, pp. 1105–1112, 2001.
[149]
X. Zhao, Z. Ou, J. C. Grotta, N. Waxham, and J. Aronowski, “Peroxisome-proliferator-activated receptor-gamma (PPARγ) activation protects neurons from NMDA excitotoxicity,” Brain Research, vol. 1073-1074, no. 1, pp. 460–469, 2006.
[150]
S. Uryu, J. Harada, M. Hisamoto, and T. Oda, “Troglitazone inhibits both post-glutamate neurotoxicity and low-potassium-induced apoptosis in cerebellar granule neurons,” Brain Research, vol. 924, no. 2, pp. 229–236, 2002.
[151]
B. García-Bueno, J. R. Caso, B. G. Pérez-Nievas, P. Lorenzo, and J. C. Leza, “Effects of peroxisome proliferator-activated receptor gamma agonists on brain glucose and glutamate transporters after stress in rats,” Neuropsychopharmacology, vol. 32, no. 6, pp. 1251–1260, 2007.
[152]
R. K. Kaundal and S. S. Sharma, “Peroxisome proliferator-activated receptor gamma agonists as neuroprotective agents,” Drug News Perspect, vol. 23, no. 4, pp. 241–256, 2010.
[153]
S. Sundararajan and G. E. Landreth, “Antiinflammatory properties of PPARγ agonists following ischemia,” Drug News and Perspectives, vol. 17, no. 4, pp. 229–236, 2004.
[154]
S. Sundararajan, J. L. Gamboa, N. A. Victor, E. W. Wanderi, W. D. Lust, and G. E. Landreth, “Peroxisome proliferator-activated receptor-γ ligands reduce inflammation and infarction size in transient focal ischemia,” Neuroscience, vol. 130, no. 3, pp. 685–696, 2005.
[155]
Y. Zhao, A. Patzer, P. Gohlke, T. Herdegen, and J. Culman, “The intracerebral application of the PPARγ-ligand pioglitazone confers neuroprotection against focal ischaemia in the rat brain,” European Journal of Neuroscience, vol. 22, no. 1, pp. 278–282, 2005.
[156]
Y. Zhao, A. Patzer, T. Herdegen, P. Gohlke, and J. Culman, “Activation of cerebral peroxisome proliferator-activated receptors gamma promotes neuroprotection by attenuation of neuronal cyclooxygenase-2 overexpression after focal cerebral ischemia in rats,” FASEB Journal, vol. 20, no. 8, pp. 1162–1175, 2006.
[157]
Y. Luo, W. Yin, A. P. Signore et al., “Neuroprotection against focal ischemic brain injury by the peroxisome proliferator-activated receptor-γ agonist rosiglitazone,” Journal of Neurochemistry, vol. 97, no. 2, pp. 435–448, 2006.
[158]
K. Tureyen, R. Kapadia, K. K. Bowen et al., “Peroxisome proliferator-activated receptor-γ agonists induce neuroprotection following transient focal ischemia in normotensive, normoglycemic as well as hypertensive and type-2 diabetic rodents,” Journal of Neurochemistry, vol. 101, no. 1, pp. 41–56, 2007.
[159]
Y. Kasahara, A. Taguchi, H. Uno et al., “Telmisartan suppresses cerebral injury in a murine model of transient focal ischemia,” Brain Research, vol. 1340, pp. 70–80, 2010.
[160]
T. Haraguchi, K. Iwasaki, K. Takasaki et al., “Telmisartan, a partial agonist of peroxisome proliferator-activated receptor γ, improves impairment of spatial memory and hippocampal apoptosis in rats treated with repeated cerebral ischemia,” Brain Research, vol. 1353, pp. 125–132, 2010.
[161]
A. Hyong, V. Jadhav, S. Lee et al., “Rosiglitazone, a PPAR gamma agonist, attenuates inflammation after surgical brain injury in rodents,” Brain Research, vol. 1215, pp. 218–224, 2008.
[162]
M. Allahtavakoli, A. Shabanzadeh, A. Roohbakhsh, and A. Pourshanazari, “Combination therapy of rosiglitazone, a peroxisome proliferator-activated receptor-γ ligand, and NMDA receptor antagonist (MK-801) on experimental embolic stroke in rats,” Basic and Clinical Pharmacology and Toxicology, vol. 101, no. 5, pp. 309–314, 2007.
[163]
N. Schintu, L. Frau, M. Ibba et al., “PPAR-gamma-mediated neuroprotection in a chronic mouse model of Parkinson's disease,” European Journal of Neuroscience, vol. 29, no. 5, pp. 954–963, 2009.
[164]
L. P. Quinn, B. Crook, M. E. Hows et al., “The PPARγ agonist pioglitazone is effective in the MPTP mouse model of Parkinson's disease through inhibition of monoamine oxidase B,” British Journal of Pharmacology, vol. 154, no. 1, pp. 226–233, 2008.
[165]
M. Kiaei, K. Kipiani, J. Chen, N. Y. Calingasan, and M. F. Beal, “Peroxisome proliferator-activated receptor-gamma agonist extends survival in transgenic mouse model of amyotrophic lateral sclerosis,” Experimental Neurology, vol. 191, no. 2, pp. 331–336, 2005.
[166]
L. Escribano, A. M. Simón, A. Pérez-Mediavilla, P. Salazar-Colocho, J. D. Río, and D. Frechilla, “Rosiglitazone reverses memory decline and hippocampal glucocorticoid receptor down-regulation in an Alzheimer's disease mouse model,” Biochemical and Biophysical Research Communications, vol. 379, no. 2, pp. 406–410, 2009.
[167]
G. S. Watson, B. A. Cholerton, M. A. Reger et al., “Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study,” American Journal of Geriatric Psychiatry, vol. 13, no. 11, pp. 950–958, 2005.
[168]
M. E. Risner, A. M. Saunders, J. F. B. Altman et al., “Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease,” Pharmacogenomics Journal, vol. 6, no. 4, pp. 246–254, 2006.
[169]
C. C. Kaiser, D. K. Shukla, G. T. Stebbins et al., “A pilot test of pioglitazone as an add-on in patients with relapsing remitting multiple sclerosis,” Journal of Neuroimmunology, vol. 211, no. 1-2, pp. 124–130, 2009.
[170]
J. A. Dormandy, B. Charbonnel, D. J. Eckland et al., “Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial in macroVascular Events): a randomised controlled trial,” The Lancet, vol. 366, no. 9493, pp. 1279–1289, 2005.
[171]
W. H. W. Tang, “Do thiazolidinediones cause heart failure? A critical review,” Cleveland Clinic Journal of Medicine, vol. 73, no. 4, pp. 390–397, 2006.
[172]
G. A. Diamond, L. Bax, and S. Kaul, “Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death,” Annals of Internal Medicine, vol. 147, no. 8, pp. 578–581, 2007.
