P J Pussinen

Summary

Affiliation: University of Helsinki
Country: Finland

Publications

  1. doi request reprint The balance of serum matrix metalloproteinase-8 and its tissue inhibitor in acute coronary syndrome and its recurrence
    Pirkko J Pussinen
    Institute of Dentistry, University of Helsinki, P O Box 63, FI 00014 Helsinki, Finland
    Int J Cardiol 167:362-8. 2013
  2. ncbi request reprint Periodontal infections and atherosclerosis: mere associations?
    Pirkko J Pussinen
    Institute of Dentistry, University of Helsinki, and Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Helsinki, Finland
    Curr Opin Lipidol 15:583-8. 2004
  3. ncbi request reprint Severe periodontitis enhances macrophage activation via increased serum lipopolysaccharide
    Pirkko J Pussinen
    Institute of Dentistry, University of Helsinki, PO Box 63 Haartmaninkatu 8, FIN 00014, Helsinki University, Finland
    Arterioscler Thromb Vasc Biol 24:2174-80. 2004
  4. ncbi request reprint Serum antibody levels to Actinobacillus actinomycetemcomitans predict the risk for coronary heart disease
    Pirkko J Pussinen
    Institute of Dentistry, University of Helsinki, and Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, P O Box 63, FI 00014 Helsinki, Finland
    Arterioscler Thromb Vasc Biol 25:833-8. 2005
  5. ncbi request reprint Periodontitis decreases the antiatherogenic potency of high density lipoprotein
    Pirkko J Pussinen
    Institute of Dentistry, University of Helsinki, Finland
    J Lipid Res 45:139-47. 2004
  6. ncbi request reprint Serum microbial- and host-derived markers of periodontal diseases: a review
    Pirkko J Pussinen
    Institute of Dentistry, University of Helsinki, Finland
    Curr Med Chem 14:2402-12. 2007
  7. ncbi request reprint Endotoxemia, immune response to periodontal pathogens, and systemic inflammation associate with incident cardiovascular disease events
    Pirkko J Pussinen
    Institute of Dentistry, University of Helsinki, Haartmaninkatu 8, PO Box 63, FI 00014 Helsinki, Finland
    Arterioscler Thromb Vasc Biol 27:1433-9. 2007
  8. pmc Endotoxemia is associated with an increased risk of incident diabetes
    Pirkko J Pussinen
    Institute of Dentistry, University of Helsinki, Helsinki, Finland
    Diabetes Care 34:392-7. 2011
  9. ncbi request reprint Systemic exposure to Porphyromonas gingivalis predicts incident stroke
    Pirkko J Pussinen
    Institute of Dentistry, University of Helsinki, PO Box 63, FI 00014 Helsinki, Finland
    Atherosclerosis 193:222-8. 2007
  10. ncbi request reprint Antibodies to periodontal pathogens and stroke risk
    Pirkko J Pussinen
    Institute of Dentistry, University of Helsinki, P O Box 63 Haartmaninkatu 8, FIN 00014 Helsinki, Finland
    Stroke 35:2020-3. 2004

Detail Information

Publications47

  1. doi request reprint The balance of serum matrix metalloproteinase-8 and its tissue inhibitor in acute coronary syndrome and its recurrence
    Pirkko J Pussinen
    Institute of Dentistry, University of Helsinki, P O Box 63, FI 00014 Helsinki, Finland
    Int J Cardiol 167:362-8. 2013
    ..We analysed the diagnostic value of serum MMP-8 and tissue inhibitor of metalloproteinase-1 (TIMP-1) concentrations in acute coronary syndrome (ACS) and their prognostic value in ACS recurrence...
  2. ncbi request reprint Periodontal infections and atherosclerosis: mere associations?
    Pirkko J Pussinen
    Institute of Dentistry, University of Helsinki, and Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Helsinki, Finland
    Curr Opin Lipidol 15:583-8. 2004
    ..In this review we discuss the recent findings on the systemic effects of periodontitis, which may contribute to the pathogenesis of atherosclerosis, with a special emphasis on lipoproteins...
  3. ncbi request reprint Severe periodontitis enhances macrophage activation via increased serum lipopolysaccharide
    Pirkko J Pussinen
    Institute of Dentistry, University of Helsinki, PO Box 63 Haartmaninkatu 8, FIN 00014, Helsinki University, Finland
    Arterioscler Thromb Vasc Biol 24:2174-80. 2004
    ..We investigated whether periodontal treatment affects proatherogenic properties of low-density lipoprotein (LDL) and, thus, macrophage activation...
  4. ncbi request reprint Serum antibody levels to Actinobacillus actinomycetemcomitans predict the risk for coronary heart disease
    Pirkko J Pussinen
    Institute of Dentistry, University of Helsinki, and Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, P O Box 63, FI 00014 Helsinki, Finland
    Arterioscler Thromb Vasc Biol 25:833-8. 2005
    ..The association between serum antibody levels to major periodontal pathogens and coronary heart disease (CHD) was analyzed in a prospective population-based study...
  5. ncbi request reprint Periodontitis decreases the antiatherogenic potency of high density lipoprotein
    Pirkko J Pussinen
    Institute of Dentistry, University of Helsinki, Finland
    J Lipid Res 45:139-47. 2004
    ....
  6. ncbi request reprint Serum microbial- and host-derived markers of periodontal diseases: a review
    Pirkko J Pussinen
    Institute of Dentistry, University of Helsinki, Finland
    Curr Med Chem 14:2402-12. 2007
    ..Based on literature review, we encourage research and development of serum screening methods for periodontitis that could be used by general physicians...
  7. ncbi request reprint Endotoxemia, immune response to periodontal pathogens, and systemic inflammation associate with incident cardiovascular disease events
    Pirkko J Pussinen
    Institute of Dentistry, University of Helsinki, Haartmaninkatu 8, PO Box 63, FI 00014 Helsinki, Finland
    Arterioscler Thromb Vasc Biol 27:1433-9. 2007
    ..We investigated in a prospective study the associations of serum endotoxin, antibodies to periodontal pathogens, and inflammation markers with the risk of incident CVD...
  8. pmc Endotoxemia is associated with an increased risk of incident diabetes
    Pirkko J Pussinen
    Institute of Dentistry, University of Helsinki, Helsinki, Finland
    Diabetes Care 34:392-7. 2011
    ..Diabetes is accompanied with a chronic low-grade inflammation, which may in part be mediated by endotoxins derived from Gram-negative bacteria...
  9. ncbi request reprint Systemic exposure to Porphyromonas gingivalis predicts incident stroke
    Pirkko J Pussinen
    Institute of Dentistry, University of Helsinki, PO Box 63, FI 00014 Helsinki, Finland
    Atherosclerosis 193:222-8. 2007
    ..31 (1.31-8.40, p=0.012) for stroke. No association between antibody levels to Actinobacillus actinomycetemcomitans and stroke was found. The results suggest that the systemic exposure to P. gingivalis may predispose to incident stroke...
  10. ncbi request reprint Antibodies to periodontal pathogens and stroke risk
    Pirkko J Pussinen
    Institute of Dentistry, University of Helsinki, P O Box 63 Haartmaninkatu 8, FIN 00014 Helsinki, Finland
    Stroke 35:2020-3. 2004
    ..Therefore, the aim of the study was to investigate whether elevated levels of serum antibodies to major periodontal pathogens predict stroke in a case-control study...
  11. doi request reprint Periodontal pathogen carriage, rather than periodontitis, determines the serum antibody levels
    Pirkko J Pussinen
    Department of Oral and Maxillofacial Diseases, Institute of Dentistry, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
    J Clin Periodontol 38:405-11. 2011
    ..We investigated in a nationally representative sample, how periodontitis modifies the association between the carriage of periodontal pathogens and serology...
  12. pmc Periodontitis is associated with a low concentration of vitamin C in plasma
    Pirkko J Pussinen
    Institute of Dentistry, University of Helsinki, and Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital Helsinki, Finland
    Clin Diagn Lab Immunol 10:897-902. 2003
    ..In conclusion, P. gingivalis infection is associated with low concentrations of vitamin C in plasma, which may increase colonization of P. gingivalis or disturb the healing of the infected periodontium...
  13. ncbi request reprint Antibodies to periodontal pathogens are associated with coronary heart disease
    Pirkko J Pussinen
    Institute of Dentistry, University of Helsinki and Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Helsinki, Finland
    Arterioscler Thromb Vasc Biol 23:1250-4. 2003
    ....
  14. ncbi request reprint Plasma phospholipid transfer protein-mediated reactions are impaired by hypochlorite-modification of high density lipoprotein
    Pirkko J Pussinen
    Institute of Dentistry, University of Helsinki, P O Box 63, FIN 00014, Helsinki, Finland
    Int J Biochem Cell Biol 35:192-202. 2003
    ..Based on these findings, we conclude that the substrate properties of HOCl-modified HDL3 and TG-HDL3 in PLTP-mediated processes are impaired, which indicates that the anti-atherogenic properties of HDL are impaired...
  15. pmc Multiserotype enzyme-linked immunosorbent assay as a diagnostic aid for periodontitis in large-scale studies
    P J Pussinen
    Institute of Dentistry, University of Helsinki, Helsinki, Finland
    J Clin Microbiol 40:512-8. 2002
    ..51 +/- 4.23 mm(2). The serotype mixture ELISA is suitable for measuring antibodies against periodontal pathogens in large epidemiological studies in order to evaluate the role of periodontitis as a risk factor for other diseases...
  16. ncbi request reprint The role of plasma phospholipid transfer protein (PLTP) in HDL remodeling in acute-phase patients
    P J Pussinen
    National Public Health Institute, Department of Molecular Medicine, Biomedicum Helsinki, Helsinki, Finland
    Biochim Biophys Acta 1533:153-63. 2001
    ..We suggest that the decrease of HDL during the acute phase is caused by reduced LCAT and increased PLTP activities both increasing the plasma levels of lipid-poor apoA-I particles...
  17. ncbi request reprint Acute-phase HDL in phospholipid transfer protein (PLTP)-mediated HDL conversion
    P J Pussinen
    National Public Health Institute, Department of Biochemistry, Mannerheimintie 166, FIN 00300, Helsinki, Finland
    Atherosclerosis 155:297-305. 2001
    ..However, PLTP-mediated in vitro degradation of apo A-I in AP-HDL was more effective than that of native HDL, which may be associated with a faster catabolism of inflammatory HDL...
  18. doi request reprint Periodontopathogen- and host-derived immune response in acute coronary syndrome
    H Alfakry
    Institute of Dentistry, University of Helsinki, Helsinki, Finland
    Scand J Immunol 74:383-9. 2011
    ..Despite the observed cross-reactivity in the systemic IgG-class antibody response to HSP60 and A. actinomycetemcomitans, the pathogen carriage in saliva or the periodontal status did not affect the HSP60 antibody levels in ACS patients...
  19. doi request reprint Lymphotoxin alpha LTA+496C allele is a risk factor for periodontitis in patients with coronary artery disease
    A Palikhe
    Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
    Tissue Antigens 71:530-7. 2008
    ..56; 95% CI = 1.05-2.30; P = 0.026) remained as significant risk factors for periodontitis. In conclusion, the major finding of this study is that the LTA+496C allele is associated with periodontitis in patients with CAD...
  20. ncbi request reprint Binding of phospholipid transfer protein (PLTP) to apolipoproteins A-I and A-II: location of a PLTP binding domain in the amino terminal region of apoA-I
    P J Pussinen
    National Public Health Institute, Department of Biochemistry, Helsinki, Finland
    J Lipid Res 39:152-61. 1998
    ..These results show that PLTP binds to both apoA-I and apoA-II, and that the PLTP binding domain of apoA-I resides in the amino terminal region...
  21. doi request reprint Pro-atherogenic lung and oral pathogens induce an inflammatory response in human and mouse mast cells
    Anna Oksaharju
    Wihuri Research Institute, Kalliolinantie, Helsinki, Finland
    J Cell Mol Med 13:103-13. 2009
    ..Pro-atherogenic Cpn and Aa induce a pro-inflammatory response in cultured human connective tissue-type mast cells and activation of mouse aortic mast cells in vivo...
  22. ncbi request reprint Serum antibody response to periodontal pathogens and herpes simplex virus in relation to classic risk factors of cardiovascular disease
    Tiina Vilkuna-Rautiainen
    Institute of Dentistry, University of Helsinki, Finland
    Int J Epidemiol 35:1486-94. 2006
    ..We studied joint immune response against two major periodontal pathogens and herpes simplex virus (HSV) in relation to established risk factors of CVD...
  23. doi request reprint Chlamydial LPS and high-sensitivity CRP levels in serum are associated with an elevated body mass index in patients with cardiovascular disease
    Taina Lajunen
    Respiratory Infection Unit, National Public Health Institute, Oulu, Finland
    Innate Immun 14:375-82. 2008
    ..Our aim was to study if serum chlamydial lipopolysaccharide (cLPS), C. pneumoniae antibodies and high-sensitivity C-reactive protein (hsCRP) levels are associated with BMI...
  24. ncbi request reprint High serum antibody levels to Porphyromonas gingivalis predict myocardial infarction
    Pirkko J Pussinen
    Institute of Dentistry, University of Helsinki bDepartment of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Finland
    Eur J Cardiovasc Prev Rehabil 11:408-11. 2004
    ..However, seroepidemiologic evidence based on prospective data on this association is totally lacking...
  25. ncbi request reprint Clarithromycin reduces recurrent cardiovascular events in subjects without periodontitis
    Susanna Paju
    Institute of Dentistry, University of Helsinki, and Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Helsinki, Finland
    Atherosclerosis 188:412-9. 2006
    ..Long-term clarithromycin therapy seems to be beneficial in prevention of recurrent cardiovascular events in non-periodontitis but not in periodontitis patients...
  26. ncbi request reprint Pro-atherogenic properties of lipopolysaccharide from the periodontal pathogen Actinobacillus actinomycetemcomitans
    Laura Lakio
    Institute of Dentistry, University of Helsinki, and Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Helsinki, Finland
    J Endotoxin Res 12:57-64. 2006
    ..The results suggest that the pro-atherogenic potential of A. actinomycetemcomitans LPS may depend on the infecting strain and correlate with the periodontopathogenic potential of the pathogen...
  27. ncbi request reprint Dental infections and cardiovascular diseases: a review
    Kimmo J Mattila
    Helsinki University Central Hospital, Division of Infectious Diseases, Helsinki, Finland
    J Periodontol 76:2085-8. 2005
    ..This may be due to genetic reasons and may also apply to other chronic low-grade infections...
  28. pmc Population-based study of salivary carriage of periodontal pathogens in adults
    Eija Kononen
    Anaerobe Reference Laboratory, Department of Bacterial and Inflammatory Diseases, National Public Health Institute KTL, Mannerheimintie 166, FI 00300 Helsinki, Finland
    J Clin Microbiol 45:2446-51. 2007
    ..000), T. denticola (P = 0.000), and A. actinomycetemcomitans (P = 0.004). The data suggest that distinct species have a different carriage profile, depending on variables such as age, educational level, and periodontal status...
  29. doi request reprint Detection and quantification of five major periodontal pathogens by single copy gene-based real-time PCR
    Kati Hyvärinen
    Institute of Dentistry, University of Helsinki, and Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Helsinki, Finland
    Innate Immun 15:195-204. 2009
    ..821 (95% CI, 0.758-0.885, P50.001). Our prominently sensitive and specific assay may have major importance in the diagnosis, prevention, and treatment of periodontitis...
  30. doi request reprint Salivary interleukin-1beta concentration and the presence of multiple pathogens in periodontitis
    Ulvi Kahraman Gursoy
    Department of Oral and Maxillofacial Surgery, Institute of Dentistry, Helsinki University Central Hospital, University of Helsinki, PO Box 63, 00014 Helsinki, Finland
    J Clin Periodontol 36:922-7. 2009
    ..This study aimed to find salivary enzymes and/or cytokines that would reflect periodontitis, alone or in combination with salivary microbial markers...
  31. pmc Chlamydial and periodontal pathogens induce hepatic inflammation and fatty acid imbalance in apolipoprotein E-deficient mice
    Kati Hyvärinen
    Institute of Dentistry, University of Helsinki, Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Finland
    Infect Immun 77:3442-9. 2009
    ..Our results indicate that proatherogenic pathogens infect the liver, causing proinflammatory alterations and lipid disturbances. This infection may maintain chronic systemic inflammation attributable to atherogenesis...
  32. doi request reprint Salivary MMP-8, TIMP-1, and ICTP as markers of advanced periodontitis
    Ulvi Kahraman Gursoy
    Institute of Dentistry, University of Helsinki, Helsinki, Finland
    J Clin Periodontol 37:487-93. 2010
    ..In addition, we compared two MMP-8 detection methods, a time-resolved immunofluorometric assay (IFMA) and an enzyme-linked immunoassay (ELISA), to differentiate periodontitis subjects from controls...
  33. pmc Local and systemic responses in matrix metalloproteinase 8-deficient mice during Porphyromonas gingivalis-induced periodontitis
    Heidi Kuula
    Biomedicum Helsinki, Institute of Dentistry, P O Box 63 Haartmaninkatu 8, 00014 University of Helsinki, Helsinki, Finland
    Infect Immun 77:850-9. 2009
    ..Bacterium-induced periodontitis, especially in MMP8(-/-) mice, is associated with systemic inflammatory and lipoprotein changes that are likely involved in early atherosclerosis...
  34. pmc Detection of multiple pathogenic species in saliva is associated with periodontal infection in adults
    Susanna Paju
    Institute of Dentistry, PL 41, FI 00014 University of Helsinki, Helsinki, Finland
    J Clin Microbiol 47:235-8. 2009
    ..In 1,198 subjects, the detection of multiple species, rather than the presence of a certain pathogen, in saliva was associated with periodontitis as determined by the number of teeth with deepened periodontal pockets...
  35. pmc Actinobacillus actinomycetemcomitans serotype d-specific antigen contains the O antigen of lipopolysaccharide
    Laura Lakio
    Institute of Dentistry, University of Helsinki, and Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Finland
    Infect Immun 71:5005-11. 2003
    ..actinomycetemcomitans serotype d. In conclusion, our results show that the A. actinomycetemcomitans serotype d-specific antigen contains the O-antigenic structure of LPS...
  36. ncbi request reprint Is periodontal infection behind the failure of antibiotics to prevent coronary events?
    Susanna Paju
    Institute of Dentistry, University of Helsinki and Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, PO Box 63, 00014 Helsinki, Finland
    Atherosclerosis 193:193-5. 2007
    ..We discuss the systemic effects of periodontal infection and consider studies to test our hypothesis, which offers a novel viewpoint for discussion of antibiotics in coronary-disease prevention...
  37. pmc Antigenically diverse reference strains and autologous strains of Actinobacillus actinomycetemcomitans are equally efficient antigens in enzyme-linked immunosorbent assay analysis
    Tiina Vilkuna-Rautiainen
    Institute of Dentistry, University of Helsinki, Helsinki, Finland
    J Clin Microbiol 40:4640-5. 2002
    ..Elevated serum IgG levels against A. actinomycetemcomitans can be detected equally well using either the autologous strains or a variety of antigenically diverse reference strains as antigens...
  38. ncbi request reprint Aggregatibacter actinomycetemcomitans induces MMP-9 expression and proatherogenic lipoprotein profile in apoE-deficient mice
    Anita M Tuomainen
    Institute of Dentistry, University of Helsinki, Helsinki, Finland
    Microb Pathog 44:111-7. 2008
    ..The results indicate that A. actinomycetemcomitans contributes to disturbed lipoprotein profiles, inflammatory reaction, and matrix remodelling which are known to promote the development of atherosclerosis...
  39. ncbi request reprint Serum matrix metalloproteinase-8 concentrations are associated with cardiovascular outcome in men
    Anita M Tuomainen
    Institute of Dentistry, University of Helsinki, Haartmaninkatu 8, P O Box 63, FI 00014 Helsinki, Finland
    Arterioscler Thromb Vasc Biol 27:2722-8. 2007
    ..Results on the association of serum MMP-8 concentrations and cardiovascular diseases (CVD) are, however, scarce and contradictory...
  40. doi request reprint Lipopolysaccharide associates with pro-atherogenic lipoproteins in periodontitis patients
    K A Elisa Kallio
    Institute of Dentistry, University of Helsinki, and Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Helsinki, Finland
    Innate Immun 14:247-53. 2008
    ..Shift of LPS toward lipoproteins with lower densities may result in less effective endotoxin scavenging. Our aim was to determine plasma LPS activity and lipoprotein-distribution before and after treatment in periodontitis patients...
  41. doi request reprint Collagenase-2 (MMP-8) as a point-of-care biomarker in periodontitis and cardiovascular diseases. Therapeutic response to non-antimicrobial properties of tetracyclines
    Timo Sorsa
    Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Institute of Dentistry, University of Helsinki, Helsinki, Finland
    Pharmacol Res 63:108-13. 2011
    ..Research in periodontology and cardiology has identified a need for the development of innovative point-of-care diagnostic tests for MMP-8. We summarize and review the recent studies on these topics...
  42. doi request reprint Acute myocardial infarction elevates serine protease activity in saliva of patients with periodontitis
    P Mäntylä
    Institute of Dentistry, University of Helsinki, Helsinki, Finland
    J Periodontal Res 47:345-53. 2012
    ..Therefore, we compared the activities of elastase and cathepsin G in saliva from patients with AMI and from systemically healthy subjects (non-AMI) with similar periodontal conditions...
  43. ncbi request reprint Molecular cloning and functional expression of cDNA encoding the pig plasma phospholipid transfer protein
    P J Pussinen
    Department of Biochemistry, National Public Health Institute, Helsinki, Finland
    J Lipid Res 38:1473-81. 1997
    ..This study forms the basis for future work on the structure-function relationships in pig PLTP...
  44. doi request reprint Elevated MMP-8 and decreased myeloperoxidase concentrations associate significantly with the risk for peripheral atherosclerosis disease and abdominal aortic aneurysm
    P Pradhan-Palikhe
    Institute of Dentistry, University of Helsinki, Helsinki, Finland
    Scand J Immunol 72:150-7. 2010
    ..001) and MPO (P = 0.008) concentrations. Combination of high MMP-8 and low MPO level in serum eventually reflecting selectively modified neutrophil degranulation may indicate increased risk for arterial disease...
  45. ncbi request reprint Infectious burden as a determinant of atopy-- a comparison between adults in Finnish and Russian Karelia
    Leena C von Hertzen
    Skin and Allergy Hospital, Helsinki University Central Hospital, Helsinki, Finland
    Int Arch Allergy Immunol 140:89-95. 2006
    ..We investigated the association between markers of infections and occurrence of atopy among adults in eastern Finland and western Russia, two adjacent areas with profound differences in living conditions and lifestyles...
  46. doi request reprint Chlamydial lipopolysaccharide (cLPS) is present in atherosclerotic and aneurysmal arterial wall--cLPS levels depend on disease manifestation
    Pirkka Vikatmaa
    Department of Vascular Surgery, Helsinki University Central Hospital, Helsinki, Finland
    Cardiovasc Pathol 19:48-54. 2010
    ..Chlamydial lipopolysaccharide (cLPS) detection is a method used conventionally in routine chlamydial diagnosis of gynecological or ophthalmic samples...
  47. pmc Serum lipopolysaccharide activity is associated with the progression of kidney disease in finnish patients with type 1 diabetes
    Mariann Nymark
    Folkhalsan Institute of Genetics, Folkhalsan Research Center, Biomedicum Helsinki, Finland
    Diabetes Care 32:1689-93. 2009
    ..The aim of the study was to investigate whether serum lipopolysaccharide (LPS) activities are associated with the progression of kidney disease in patients with type 1 diabetes...