The Surgeon General Lies That Smoking Causes Heart Disease

The Real Scientific Definition of Causality

"How can we test hypotheses on the etiologic relation of particular viruses to particular tumors? There is no simple answer to this, but perhaps an important part of the answer is a negative statement: we do not test such hypotheses by being bound to Koch's postulates. Scientific proof of an hypothesis consists of elimination of all conceivable and reasonable alternative explanations, not in filling in the blanks in a prescribed set of rules. Koch's postulates are a precise formulation of experimental requirements for eliminating alternative hypotheses in the testing of one particular pathogenetic model, that is, that an infectious agent produces disease reaction during its period of active multiplication. When pathogenesis involves delayed onset of symptomatology, Koch's model just does not apply. Instead, we must formulate or predict the host-parasite relationship we think may obtain, examine this model for what inferences can be made, and then devise means of testing for the expected outcome of those inferences which are unique for that model." (A Survey of the Tumor Virus Problem from an Epidemiologic Standpoint. Wallace P. Rowe, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, USPHS, Bethesda, Md. Cancer Research 1965 Sep;25(8):1277-1282, pdf page 5.) The same delayed onset of symptomatology applies in the case of heart disease, so the same criteria of causality are appropriate.

Rowe / Cancer Research 1965 full article (pdf, 7pp)

The Surgeon General's blame of smoking is based on a fraudulent fill-in-the-blanks definition of causality. There is no mention in the chapter of any viral or bacterial pathogen which has been implicated as a cause of heart disease. The Surgeon General report not only does NOT eliminate other possible explanations, it steadfastly ignores them, along with any evidence of any kind which contradicts the predrawn conclusions. These are the methods employed by "creation science" and kangaroo courts, and every Surgeon General report from the very beginning has been a deliberate fraud against the public. It is furthermore a brazen attempt to impose a compulsory state religion of charlatanism on the American people!

The Surgeon General Lies That Smoking Causes Endothelial Injury

"2. Cigarette smoking leads to endothelial injury and dysfunction in both coronary and peripheral arteries. There is consistent evidence that oxidizing chemicals and nicotine are responsible for endothelial dysfunction." (Conclusions. Chapter 6: Cardiovascular Diseases. A Report of the Surgeon General: How Tobacco Smoke Causes Disease, pdf p. 58.) Based on claims that "Smokers have reduced numbers of circulating endothelial progenitor cells and impaired endothelium-dependent vasodilation. (Vasa et al. 2001, Hill et al. 2003). In addition, smoking cessation was associated with a rebound in the number of circulating endothelial progenitor cells and improvement in endothelium-dependent vasodilation (Moreno et al. 1998; Kondo et al. 2004)," p. 371 [pdf p. 21].

http://www.surgeongeneral.gov/library/tobaccosmoke/report/chapter6.pdf

But endothelial damage is reflected by high numbers of circulating mature apoptotic endothelial cells (mature cells which killed themselves), not by low numbers of circulating progenitor cells (immature ones), which replace them. And, the number of circulating progenitor cells is higher while endothelial damage is occurring, not after it has ended. (Interferon beta modulates endothelial damage in patients with cardiac persistence of human parvovirus b19 infection. C Schmidt-Lucke, F Spillmann, T Bock, U Kühl, S Van Linthout, HP Schultheiss, C Tschöpe. J Infect Dis. 2010 Mar 15;201(6):936-945.)

http://jid.oxfordjournals.org/content/201/6/936.long

"Endothelial generation of adhesion molecules increases in smokers, as evidenced by higher plasma levels of soluble adhesion molecules (Blann et al. 1997, 1998). These molecules include soluble forms of the vascular cell adhesion molecule (sVCAM) and the intercellular adhesion molecule (sICAM)." [SGR Ch. 6, pdf p. 21]

CMV Increases Expression of Adhesion Molecule Genes

Alterations in the expression of ELAM-1, ICAM-1 and VCAM-1 after in vitro infection of endothelial cells with a clinical isolate of human cytomegalovirus. S Shahgasempour, SB Woodroffe, HM Garnett. Microbiol Immunol 1997;41(2):121-129. "Human cytomegalovirus (HCMV) infection of endothelial cells resulted in increased adhesion of the cells to peripheral blood leukocytes. It was demonstrated by flow cytometry that increased adhesiveness parallels the increased expression of cell surface adhesion molecules (ELAM-1, ICAM-1, VCAM-1). "

http://www.ncbi.nlm.nih.gov/pubmed/9087954

Intercellular adhesion molecule-1 expression in endothelial cells is activated by cytomegalovirus immediate early proteins. LJ Burns, JC Pooley, DJ Walsh, GM Vercellotti, ML Weber, A Kovacs. Transplantation 1999 Jan 15;67(1):137-144. "Infection of HUVECs with HCMV resulted in a rapid rise in ICAM-1 mRNA levels, suggesting that the viral IE proteins were involved in gene activation. The HCMV IE1 and IE2 proteins synergistically activated both transfected and endogenous ICAM-1 gene expression."

http://www.ncbi.nlm.nih.gov/pubmed/9921810

Cytomegalovirus infection of vascular cells induces expression of pro-inflammatory adhesion molecules by paracrine action of secreted interleukin-1beta. TJ Dengler, MJ Raftery, M Werle, R Zimmermann, G Schönrich. Transplantation 2000 Mar 27;69(6):1160-1168. "On HUVEC, surface expression of vascular cell adhesion molecule-1 and E-selectin was induced de novo on HCMV infection and intercellular adhesion molecule-1 expression was increased by >200%. On hvSMC, intercellular adhesion molecule-1 surface expression induced de novo, although vascular cell adhesion molecule-1 and E-selectin were not changed... Expression of surface molecules could be enhanced in noninfected HUVEC and hvSMC by incubation with virus-free conditioned supernatant from HCMV-infected cells or by coincubation in transwells with infected cells. The responsible agent could be identified as IL- interleukin- (IL) 1beta by detection of de novo secretion of IL-1beta by HCMV-infected cells and by prevention of adhesion molecule up-regulation after addition of an IL-1-converting enzyme inhibitor or IL-1 receptor antagonist."

http://www.ncbi.nlm.nih.gov/pubmed/10762222

Effect of cytomegalovirus immediate early gene products on endothelial cell gene activity. E Guetta, EM Scarpati, PE DiCorleto. Cardiovasc Res 2001 Jun;50(3):538-546. "CMV immediate early gene expression resulted in an increase in monocyte adhesion to ECs and in the relative promoter activities of cellular growth factor and adhesion molecule genes. In addition, the viral major immediate early promoter was regulated in EC by thrombin and the immediate early gene products."

http://cardiovascres.oxfordjournals.org/content/50/3/538.long

Human cytomegalovirus (HCMV) infection of endothelial cells promotes naive monocyte extravasation and transfer of productive virus to enhance hematogenous dissemination of HCMV. GL Bentz, M Jarquin-Pardo, G Chan, MS Smith, C Sinzger, AD Yurochko. J Virol 2006 Dec;80(23):11539-11555. "We show here that HCMV infection of endothelial cells increased the recruitment and transendothelial migration of monocytes. Infection of endothelial cells promoted the increased surface expression of cell adhesion molecules (intercellular cell adhesion molecule 1, vascular cell adhesion molecule 1, E-selectin, and platelet endothelial cell adhesion molecule 1), which were necessary for the recruitment of naïve monocytes to the apical surface of the endothelium and for the migration of these monocytes through the endothelial cell layer. As a mechanism to account for the increased monocyte migration, we showed that HCMV infection of endothelial cells increased the permeability of the endothelium. The cellular changes contributing to the increased permeability and increased naïve monocyte transendothelial migration include the disruption of actin stress fiber formation and the decreased expression of lateral junction proteins (occludin and vascular endothelial cadherin). Finally, we showed that the migrating monocytes were productively infected with the virus, documenting that the virus was transferred to the migrating monocyte during passage through the lateral junctions."

http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/16987970/

High T-cell response to human cytomegalovirus induces chemokine-mediated endothelial cell damage. CA Bolovan-Fritts, RN Trout, SA Spector. Blood 2007 Sep 15;110(6):1857-63. "[D]onors with high frequencies of antigen-specific T cells to CMV (high responders) induce higher levels of activation-associated chemokines such as fractalkine, RANTES (regulated on activation, normal T cell expressed and secreted), and macrophage inflammatory protein-1beta, together with cell-adhesion markers in endothelial cells compared with donors with low levels of CMV-specific T cells (low responders). High-responder cultures had higher levels of leukocyte recruitment and adherence to the endothelial monolayers associated with progressive damage and loss of the endothelial cells. These processes that led to endothelial destruction only required viral antigen and did not require infectious virus."

http://www.ncbi.nlm.nih.gov/pubmed/17519388

The Surgeon General Lies

Furthermore, study findings indicate that smoking impairs capacity to lyse the thrombus that is formed. Plasma levels of tissue plasminogen activator (tPA), a thrombolytic protein produced by the endothelium, are reduced in smokers (Newby et al. 2001). In contrast, smoking increases levels of plasminogen activator inhibitor-1 (PAI-1) (Simpson et al. 1997)." [SGR Ch. 6, pdf p. 21].

Chlamydia pneumoniae and CMV Induce PAI-1

Human cytomegalovirus infection induces mRNA expression and secretion of plasminogen inhibitor type-1 in endothelial cells. SB Woodroffe, S Kuan. J Med Virol 1998 Aug;55(4):268-271. "HCMV induced the expression of PAI-1-mRNA at 2-5 days postinfection (maximum expression was at 3 days postinfection which was 40% higher than control). HCMV also induced secretion of PAI-1 at 2-5 days postinfection."

http://www.ncbi.nlm.nih.gov/pubmed/9661834

Chlamydia pneumoniae infection of vascular smooth muscle and endothelial cells activates NF-kappaB and induces tissue factor and PAI-1 expression: a potential link to accelerated arteriosclerosis. R Dechend, M Maass, J Gieffers, R Dietz, C Scheidereit, A Leutz, DC Gulba. Circulation 1999 Sep 28;100(13):1369-1373. "Human vascular endothelial and smooth muscle cells were infected with a strain of C. pneumoniae isolated from an arteriosclerotic coronary artery. Tissue factor, PAI-1, and interleukin-6 expression was increased in infected cells."

http://circ.ahajournals.org/cgi/content/full/100/13/1369

Intracellular infections enhance interleukin-6 and plasminogen activator inhibitor 1 production by cocultivated human adipocytes and THP-1 monocytes. JJ Bouwman, RJ Diepersloot, FL Visseren. Clin Vaccine Immunol 2009 Aug;16(8):1222-1227. "IL-6 production by CMV-infected adipocytes was increased relative to that of uninfected adipocytes (P < 0.01). IL-6 production by CMV-infected cocultures was 16- to 37-fold higher than that of uninfected adipocytes (P < 0.001). IL-6 production in influenza A virus-infected cocultures was increased 12- to 20-fold (P < 0.05). Only CMV infection increased levels of PAI-1 in cocultures (fourfold; P < 0.05). Soluble factors produced by THP-1 macrophages rather than by adipocytes were responsible for the increased production of IL-6 in cocultures. Infection of cocultivated human adipocytes and THP-1 monocytes with CMV or influenza A virus led to increased production of IL-6 and PAI-1."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2725538/

The Surgeon General Lies

"Smoking also impairs the ability of the endothelium to resist thrombosis. Compared with nonsmokers, smokers have higher levels of von Willebrand factor protein (MacCallum 2005) and tissue factor (Matetzky et al. 2000; Sambola et al. 2003), which may be generated by the endothelium." [SGR Ch. 6, pdf p. 21]

CMV and HSV Enhance Thrombosis

Enhanced thrombin generation and platelet binding on herpes simplex virus-infected endothelium. MR Visser, PB Tracy, GM Vercellotti, JL Goodman, JG White, HS Jacob. Proc Natl Acad Sci USA 1988 Nov;85(21):8227-8230. "In this report we show that very early infection of human endothelial cells with HSV-1 appears to alter surface conformation as detected by merocyanine 540 staining. Concomitantly, the efficiency of prothrombinase complex assembly increases, resulting in a 2- to 3-fold accelerated rate of thrombin generation on the cell surface. Increased thrombin generation is probably doubly procoagulant, since we also demonstrate that thrombin-induced platelet accumulation on HSV-infected endothelium (50.7 +/- 9.3%) is increased compared to uninfected endothelium (9.5 +/- 2.1%; P less than 0.002). Associated with HSV infection, prostacyclin secretion in response to thrombin is diminished by a factor of 20, probably explaining the enhanced platelet attachment."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC282402/

von Willebrand factor mediates platelet adhesion to virally infected endothelial cells. OR Etingin, RL Silverstein, DP Hajjar. Proc Natl Acad Sci USA 1993 Jun 1;90(11):5153-5156. "HSV-infected HUVECs secreted 5-fold more vWF than uninfected cells (Fig. 1). Ad2-infected cells (a DNA virus control) secreted vWF at similar levels as control cells... HSV infection induced a 4-fold increase in platelet adhesion as compared with uninfected cells or cells infected with the non-gC expressing HSV mutant NS-1."

http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/8389471/

Acute rejection before cytomegalovirus infection enhances von Willebrand factor and soluble VCAM-1 in blood. AM Kas-Deelen, MC Harmsen, EF De Maar, WW Oost-Kort, JW Tervaert, J Van Der Meer, WJ Van Son, TH The. Kidney Int 2000 Dec;58(6):2533-2542. "Plasma levels of VWF and sVCAM-1 increased twofold during severe HCMV infection. Moreover, the plasma levels of VWF correlated with detectable cytomegalic and noninfected ECs in blood. The kinetics of changes in VWF and ECs (CEC and EC) demonstrated the relationship with HCMV-induced vascular damage."

http://www.ncbi.nlm.nih.gov/pubmed/11115088

Procoagulant and inflammatory response of virus-infected monocytes. JJ Bouwman, FL Visseren, MC Bosch, KP Bouter, RJ Diepersloot. Eur J Clin Invest 2002 Oct;32(10):759-766. "Monocytes play a prominent role in inflammation, coagulation and atherosclerosis by their ability to produce tissue factor (TF) and cytokines... Chlamydia pneumoniae- and CMV-infected monocytes decreased the clotting time by 60%, and influenza-infected monocytes by 19%, as compared to uninfected monocytes. Procoagulant activity was absent when Factor VII-deficient plasma or anti-TF antibodies were used. Monocytes produced both IL-6 and IL-8 after infection with CMV (317 pg mL-1 and 250 pg mL-1) or Cp (733 pg mL-1 and 268 pg mL-1). Similar results were obtained for influenza virus-infected monocytes, but the levels of both cytokines were 3-5-fold higher (1797 pg mL-1 and 725 pg mL-1)."

http://www.ncbi.nlm.nih.gov/pubmed/12406025

Human cytomegalovirus infection of endothelial cells triggers platelet adhesion and aggregation. A Rahbar, C Söderberg-Nauclér. J Virol. 2005 Feb;79(4):2211-2220. "At 7 days after infection, platelet adherence and aggregation were greater in infected than in uninfected cultures (2,000 platelets/100 cells and 225 +/- 15 [mean +/- standard error of the mean] aggregates/five microscopic fields versus 100 platelets/100 cells and no aggregates). von Willebrand factor (vWF), ICAM-1, and VCAM-1 but not collagen IV, E-selectin, P-selectin, CD13, and CD31 were expressed at higher levels on infected cells than on uninfected cells... The increased thrombogenicity was dependent on active virus replication and could be inhibited by foscarnet and ganciclovir; these results suggest that a late viral gene may be mediating this phenomenon, which may contribute to vascular catastrophes in patients with atherosclerotic disease." Platelets incubated with supernatants from HCMV-infected cells collected at 5 and 7 days released high levels of P-selectin and serotonin.

http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=15681423

The Surgeon General Lies

"Joannides and colleagues (1995) extended this finding by showing that flow-mediated vasodilation of the brachial artery could be abolished by pharmacologic antagonism of ENOS. Subsequently, numerous studies used this approach to document impairment of flow-mediated, endothelium-dependent vasodilation in smokers and in persons exposed to secondhand smoke (Celermajer et al. 1993, 1996; Barua et al. 2001)." SGR Ch. 6, p 372 [pdf p. 22].

But flow-mediated vasodilation, which they inhibited, is the primary mechanism for release of nitric oxide: "Physiologically, the most important stimulus for the continuous formation of NO is the viscous drag (shear stress) generated by the streaming blood on the endothelial layer... Here we demonstrate that the serine/threonine protein kinase Akt/PKB mediates the activation of eNOS, leading to increased NO production. Inhibition of the phosphatidylinositol-3-OH kinase/Akt pathway or mutation of the Akt site on eNOS protein (at serine 1177) attenuates the serine phosphorylation and prevents the activation of eNOS. Mimicking the phosphorylation of Ser 1177 directly enhances enzyme activity and alters the sensitivity of the enzyme to Ca2+, rendering its activity maximal at sub-physiological concentrations of Ca2+. Thus, phosphorylation of eNOS by Akt represents a novel Ca2+-independent regulatory mechanism for activation of eNOS." (Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. S Dimmeler, I Fleming, B Fisslthaler, C Hermann, R Busse, AM Zeiher. Nature 1999 Jun 10;399(6736):601-605.)

http://www.ncbi.nlm.nih.gov/pubmed/10376603

"Researchers also observed that tobacco use impaired endothelium-dependent vasodilation in the coronary microcirculation. Intracoronary infusion of acetylcholine induced vasodilation that was partly attributable to release of NO, and this response was blunted in persons who smoked (Kugiyama et al. 1996)." SGR Ch. 6, p 372 [pdf p. 22].

CMV Impairs eNOS Activation

Human cytomegalovirus inhibits Akt-mediated eNOS activation through upregulating PTEN (phosphatase and tensin homolog deleted on chromosome 10). YH Shen, L Zhang, B Utama, J Wang, Y Gan, X Wang, J Wang, L Chen, GM Vercellotti, JS Coselli, JL Mehta, XL Wang. Cardiovasc Res 2006 Feb 1;69(2):502-511. "We found that HCMV inhibited eNOS phosphorylation/activation in HAECs. The signaling upstream of eNOS involving Akt and PDK1 were also suppressed by the HCMV infection. Moreover, HCMV infection increased the expression of PTEN (phosphatase and tensin homolog deleted on chromosome 10). Silencing PTEN expression with specific siRNA reversed the inhibitory effects on eNOS activation in HCMV-infected cells indicating the involvement of PTEN in mediating HCMV's inhibitory effects. Next we observed that the activation of p38 MAPK stress signaling pathway mediates HCMV's effects on PTEN up-regulation and eNOS inactivation."

http://cardiovascres.oxfordjournals.org/content/69/2/502.long

The Surgeon General Lies

"Exposure of cultured endothelial cells derived from human coronary arteries or umbilical veins to sera from smokers reduced expression and activity of ENOS (Barua et al. 2001, 2003). The researchers attributed this effect partly to the oxygen-derived free radicals in tobacco smoke. In addition, the half-life of NO was markedly shortened by oxidative stress (Rubanyi and Vanhoutte 1986)." SGR Ch. 6, p 372 [pdf p. 22].

CMV Impairs Vascular Function

Cytomegalovirus infection impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine in transplant arteriosclerosis. M Weis, TN Kledal, KY Lin, SN Panchal, SZ Gao, HA Valantine, ES Mocarski, JP Cooke. Circulation 2004 Feb 3;109(4):500-505. "Heart transplant recipients manifested elevated plasma ADMA levels compared with healthy control subjects. Transplant patients with CMV DNA-positive leukocytes had higher plasma ADMA concentrations and more extensive transplant arteriopathy (TA). Human microvascular endothelial cells infected with the CMV isolates elaborated more ADMA. The increase in ADMA was temporally associated with a reduction in the activity of dimethylarginine dimethylaminohydrolase (DDAH, the enzyme that metabolizes ADMA). Infected cultures showed high levels of oxidative stress with enhanced endothelial production of superoxide anion."

http://circ.ahajournals.org/cgi/content/full/109/4/500

The Surgeon General Lies

"Researchers observed the effect of nicotine in promoting pathologic angiogenesis in numerous murine models of tobacco-related diseases, including lung cancer, atherosclerosis, and retinopathy (Heeschen et al. 2001, 2002; Natori et al. 2003; Shin et al. 2004; Suñer et al. 2004)." SGR Ch. 6, p. 373 [pdf p. 23].

CMV Causes Pathologic Angiogenesis

Upregulation of functionally active vascular endothelial growth factor by human cytomegalovirus. B Reinhardt, P Schaarschmidt, A Bossert, A Lüske, G Finkenzeller, T Mertens, D Michel. J Gen Virol 2005 Jan;86(Pt 1):23-30. "It was shown that HCMV infection leads to upregulation of vascular endothelial growth factor (VEGF) expression in human foreskin fibroblasts and coronary artery smooth muscle cells (SMC). Activation of VEGF transcription by HCMV infection was confirmed by transient-expression experiments, which revealed that a short promoter fragment, pLuc135 (-85 to +50), is sufficient for activation... Incubation of endothelial cells with supernatants from HCMV-infected SMC cultures induced upregulation of VEGF receptor-2 expression on endothelial cells, as well as a significant upregulation of DNA synthesis, implicating cell proliferation. The mean incline of DNA synthesis at 48 and 72 h post-infection was 148 and 197 %, respectively."

http://vir.sgmjournals.org/cgi/content/full/86/1/23

Human cytomegalovirus secretome contains factors that induce angiogenesis and wound healing. J Dumortier, DN Streblow, AV Moses, JM Jacobs, CN Kreklywich, D Camp, RD Smith, SL Orloff, JA Nelson. J Virol 2008 Jul;82(13):6524-6535. "We analyzed virus-free supernatants from HCMV-infected cells (HCMV secretomes) for growth factors, by mass spectrometry and immunoassays, and found that the HCMV secretome contains over 1,000 cellular proteins, many of which are involved in AG/WH. Importantly, functional assays demonstrated that CMV but not herpes simplex virus secretomes not only induce AG/WH but also promote neovessel stabilization and endothelial cell survival for 2 weeks. These findings suggest that CMV acceleration of TVS [transplant vascular sclerosis] occurs through virus-induced growth factors and cytokines in the CMV secretome."

http://jvi.asm.org/cgi/content/full/82/13/6524?view=long&pmid=18448536

Human CMV infection of endothelial cells induces an angiogenic response through viral binding to EGF receptor and beta1 and beta3 integrins. GL Bentz, AD Yurochko. Proc Natl Acad Sci USA 2008 Apr 8;105(14):5531-5536. "We now document that HCMV infection results in increased EC proliferation, motility, and capillary tube formation. The observed HCMV-induced angiogenic response depended on viral binding to and signaling through the beta(1) and beta(3) integrins and the epidermal growth factor receptor, via their ability to activate the phosphatidylinositol 3-kinase and the mitogen-activated protein kinase signaling pathways."

http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18375753/

The human cytomegalovirus-encoded chemokine receptor US28 promotes angiogenesis and tumor formation via cyclooxygenase-2. D Maussang, E Langemeijer, CP Fitzsimons, M Stigter-van Walsum, R Dijkman, MK Borg, E Slinger, A Schreiber, D Michel, CP Tensen, GA van Dongen, R Leurs, MJ Smit. Cancer Res 2009 Apr 1;69(7):2861-2869. "Previously, we have shown that US28 expression induces an oncogenic phenotype both in vitro and in vivo. Microarray analysis revealed differential expression of genes involved in oncogenic signaling in US28-expressing NIH-3T3 cells. In particular, the expression of cyclooxygenase-2 (COX-2), a key mediator of inflammatory diseases and major determinant in several forms of cancer, was highly up-regulated. US28 induced increases in COX-2 expression via activation of nuclear factor-kappaB, driving the production of vascular endothelial growth factor. Also, in HCMV-infected cells, US28 contributed to the viral induction of COX-2."

http://cancerres.aacrjournals.org/content/69/7/2861.long

IL-6 in human cytomegalovirus secretome promotes angiogenesis and survival of endothelial cells through the stimulation of survivin. S Botto, DN Streblow, V Defilippis, L White, CN Kreklywich, PP Smith, P Caposio. Blood 2011 Jan 6;117(1):352-361. "Several cytokines were significantly induced in the HCMV secretomes including IL-6, GM-CSF, and IL-8/CXCL8. Using in vitro angiogenesis assays, neutralization of IL-6 significantly reduced neovessel formation. Addition of the HCMV secretome to preformed vessels extended neovessel survival but this effect was blocked by neutralization of IL-6. In these cells IL-6 prevented apoptosis by blocking caspase 3 and 7 activation through the induction of survivin. Neutralization of IL-6 receptor on EC abolished the ability of HCMV secretome to increase survivin expression and activated effector caspases. Moreover, survivin shRNA expression induced rapid regression of tubule capillary networks in EC stimulated with HCMV secretome and activated effector caspases. These observations may explain how CMV accelerates vascular disease despite limited infection in tissues." It was not suppressed by gancyclovir.

http://www.ncbi.nlm.nih.gov/pubmed/20930069
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3037756/

The Surgeon General Lies

"In clinically relevant levels,... nicotine promoted survival, proliferation, and migration of endothelial cells (Heeschen et al. 2001, 2002). Nicotine also induced elaboration and release of angiogenic factors, including NO, prostacyclin, vascular endothelial growth factor, and fibroblast growth factor (Carty et al. 1996; Heeschen et al. 2001a; Lane et al. 2005). These effects of nicotine were mediated by nAChRs on the endothelium (Heeschen et al. 2002)." SGR Ch. 6, p. 373 [pdf p. 23].

CMV and HSV Induce VEGF and FGF

Induction of an endothelial cell growth factor by human cytomegalovirus infection of fibroblasts. J Alcami, T Barzu, S Michelson. J Gen Virol 1991 Nov;72 ( Pt 11):2765-2770. "Human cytomegalovirus (HCMV) induction of growth factors in fibroblasts was investigated after establishing serum-free culture conditions conducive to viral replication. HCMV infection induced a type II heparin-binding growth factor which stimulated human endothelial cell proliferation."

http://vir.sgmjournals.org/cgi/reprint/72/11/2765

Herpes virus infection of endothelium: new insights into atherosclerosis. HS Jacob, M Visser, NS Key, JL Goodman, CF Moldow, GM Vercellotti. Trans Am Clin Climatol Assoc 1992;103:95-104. Review. "First, granulocytes are attracted to, and avidly bind, endothelium infected for very brief periods. This interaction is associated with denudation of intact cells as well as actual cytolysis through release of PMN proteases and toxic oxygen species. Second, several potentially additive abnormalities of HSV-infected endothelium would seem to foster coagulation. These include: a) its loss of surface heparans and thrombomodulin; b) its inability to synthesize prostacyclin with associated incapacity to deter platelet adhesion; c) its disordered membrane lipid conformation which is likely associated with excessive surface thrombin generation; and d) its unique ability to generate and release tissue factor. We speculate that mechanical abrasion may reactivate latent herpes (HSV or CMV) infection in endothelial cells particularly those exposed to high shear forces--for instance, at vessel bifurcations."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376689/

Strain specific effects of cytomegalovirus on endothelial cells: implications for investigating the relationship between CMV and cardiac allograft vasculopathy. R Srivastava, M Curtis, S Hendrickson, WH Burns, JD Hosenpud. Transplantation 1999 Nov 27;68(10):1568-1573. "Two growth factors, platelet-derived growth factor-A and basic fibroblast growth factor were augmented by one of the two clinical strains of CMV (Clin 2) (P=0.0091 and P=0.0018, respectively). Transforming growth factor -alpha and insulin-like growth factor expression were significantly reduced by both clinical strains and AD-169. Two other growth factors, heparin-binding epidermal growth factor and transforming growth factor-beta were not altered by infection with any strain. No strain altered MHC class II expression. MHC class I expression was increased with one of the two clinical strains (Clin 1, P=0.0006) and decreased by AD-169 (P=0.0016). Clin 2 and Towne had no effect on MHC class I expression."

http://www.ncbi.nlm.nih.gov/pubmed/10589956

DNA containing CpG motifs induces angiogenesis. M Zheng, DM Klinman, M Gierynska, BT Rouse. Proc Natl Acad Sci USA 2002 Jun 25;99(13):8944-8949. "By using a murine corneal micropocket assay, we found that HSV DNA (which contains a significant excess of potentially bioactive 'CpG' motifs when compared with mammalian DNA) induces angiogenesis. Moreover, synthetic oligodeoxynucleotides containing CpG motifs attract inflammatory cells and stimulate the release of vascular endothelial growth factor (VEGF), which in turn triggers new blood vessel formation." "This pattern of CpG expression is reminiscent of bacterial DNA, which has well established proinflammatory effects."

http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/12060721/

Active cytomegalovirus infection in aortic smooth muscle cells from patients with abdominal aortic aneurysm. S Gredmark-Russ, M Dzabic, A Rahbar, A Wanhainen, M Björck, E Larsson, JB Michel, C Söderberg-Nauclér. J Mol Med 2009 Apr;87(4):347-356. "CMV immediate-early and late antigens were expressed in SMCs in the lesions and were associated with 5-lipoxygenase (5-LO) expression. CMV-positive intimal SMCs migrated 6.6 +/- 1.5 times more efficiently than CMV-negative medial SMCs (p < 0.05). In vitro CMV infection of medial SMCs resulted in a 3.2 +/- 1.2 times increase in migration (p < 0.05). The intimal migration was significantly inhibited by antibodies against basic fibroblast growth factor (bFGF; p < 0.05) in a dose-dependent fashion."

http://www.ncbi.nlm.nih.gov/pubmed/19083194

The Surgeon General Lies

"Inhibition of ACE [angiotensin converting enzyme] normalized impaired bradykinin mediated, endothelium-dependent venodilation in smokers (Chalon et al. 1999). Furthermore, coronary vasomotor responses to acetylcholine in patients with CHD improved in response to the ACE inhibitor quinapril to a much greater extent in smokers than in nonsmokers (Schlaifer et al. 1999). ACE inhibitors have an antioxidant activity, which could contribute to the clinical benefit in smokers." SGR Ch. 6, p. 373 [pdf p. 24].

CMV reduces response to bradykinin

Predisposition to atherosclerosis by infections: role of endothelial dysfunction. A Prasad, J Zhu, JP Halcox, MA Waclawiw, SE Epstein, AA Quyyumi. Circulation 2002 Jul 9;106(2):184-190. "Immunoglobulin-G antibody titers to cytomegalovirus, Chlamydia pneumoniae, Helicobacter pylori, hepatitis A virus, and herpes simplex virus-1 were measured. Pathogen burden was defined as the number of positive antibodies. Although positive serology to individual pathogens tended to be associated with increased incidence of coronary arteriosclerosis (CAD), the pathogen burden correlated with the presence of CAD, even after adjustment for risk factors (OR 1.3; 95% CI, 1.05 to 1.6, P=0.018). Moreover, the severity of CAD was independently associated with the pathogen burden (P=0.001). Pathogen burden was an independent predictor of endothelial dysfunction, determined as the percent change in coronary vascular resistance in response to ACH [acetylcholine] (P=0.009) but not the responses to sodium nitroprusside or adenosine. Pathogen burden was also an independent determinant of endothelial function in the subgroup with angiographically normal coronary arteries."

http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=12105156

Human cytomegalovirus seropositivity is associated with impaired vascular function. C Grahame-Clarke, NN Chan, D Andrew, GL Ridgway, DJ Betteridge, V Emery, HM Colhoun, P Vallance. Circulation 2003 Aug 12;108(6):678-83. "Individuals who were seropositive for CMV had reduced responses to bradykinin (P=0.005) and glyceryl trinitrate (P=0.006). The reduced response to bradykinin remained significant (P=0.045) after adjusting for the response to glyceryl trinitrate and was independent of conventional risk factors. Positive serology for the other organisms did not have an independent effect on reactivity. There was a weaker association between CMV and coronary artery calcification (P=0.09). Positive serology for each of the other pathogens did not affect reactivity, but there was a relation between total pathogen burden and impaired vascular reactivity. No significant differences were found between diabetics and nondiabetics."

http://circ.ahajournals.org/cgi/content/full/108/6/678

The Surgeon General Lies

"Studies have reported that sudden cardiac death is 2.5 times higher in smokers than in nonsmokers (Kannel et al. 1984; Goldenberg et al. 2003). Research findings broadly implicated activation of platelets and subsequent focal ischemia in sudden cardiac death among smokers. The turnover of platelets is accelerated in cigarette smokers (Fuster et al. 1981). Researchers related the number of newly formed reticulated platelets, rather than absolute platelet count, to incidence of thrombotic events (Rinder et al. 1998)." SGR Ch. 6, p. 373 [pdf p. 25].

Enteroviruses and Other Infections Cause Sudden Cardiac Death

Analysis of sudden unexpected death in southern Ontario, with emphasis on myocarditis. P Wentworth, LA Jentz, AE Croal. Can Med Assoc J 1979 Mar 17;120(6):676-680, 706. Review of 2427 autopsies performed between Jan. 1, 1969 and Aug. 15, 1978. "Of the 1299 cases of sudden unexpected death investigated by a coroner almost 28% were due to unnatural causes--violence or poisoning. The main cause of natural sudden death was coronary artery disease, which accounted for 43.3% of all the sudden unexpected deaths. In 20 cases the cause of death was thought to be viral myocarditis, and in 9 of the 20 there was serologic evidence of at least previous coxsackievirus disease. Two of the nine cases were of special interest because of the finding of giant-cell myocarditis in one and aortic valve disease in the other. Eleven of the 20 persons were aged 13 to 46 years. These findings support the view that the most serious manifestation of enterovirus infection today is cardiac damage by coxsackieviruses."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1819176/

Viral myocarditis and coagulopathy: increased tissue factor expression and plasma thrombogenicity. S Antoniak, U Boltzen, A Riad, A Kallwellis-Opara, M Rohde, A Dörner, C Tschöpe, M Noutsias, M Pauschinger, HP Schultheiss, U Rauch. J Mol Cell Cardiol 2008 Jul;45(1):118-126. "We investigated the effects of viral infection on Tissue Factor (TF) expression and activity in mice within the myocardium to understand increased thrombosis during myocarditis. Mice were infected with coxsackie virus B3 (CVB3)... Furthermore, we analyzed myocardial tissues from patients with suspected inflammatory cardiomyopathy. TF protein expression was maximally 5-fold elevated 8 days p.i. in mice and remained increased on day 28 p.i. (P<0.001 vs. non-infected controls). Alterations in TF expression were associated with fibrin deposits within the myocardium. The TF pathway inhibitor protein expression in the myocardium was not altered during myocarditis. Active cellular TF co-localized with CD3 positive cells and VCAM-1 positive endothelial cells in the myocardium. The TF expression was positively correlated with the amount of infiltrating CD3 and Mac3 positive cells (Spearman-Rho rho=0.749 P<0.0001 for CD3(+) and rho=0.775 P<0.0001 for Mac3(+); N=35). Increased myocardial TF expression was associated with a 2-fold elevated plasma activity (P<0.05 vs. non-infected controls). In the human hearts, the TF expression correlated positively with an endothelial cell activation marker (rho=0.523 P<0.0001 for CD62E; N=54). Viral myocarditis is a hypercoagulative state which is associated with increased myocardial TF expression and activity. Upregulation of TF contributes to a systemic activation of the coagulation cascade."

http://www.ncbi.nlm.nih.gov/pubmed/18495150

Histologic and in situ viral findings in the myocardium in cases of sudden, unexpected death. AM Cioc, GJ Nuovo. Mod Pathol 2002 Sep;15(9):914-922. Thirteen individuals aged 2 to 67 years, by PCR. "Coxsackie virus B (5 cases), rotavirus (4 cases), HIV-1 (2 cases), influenza A (1 case), and influenza B (1 case). Immunohistochemical detection of viral proteins was found in the five Coxsackie virus cases and four rotavirus cases. The mononuclear inflammatory infiltrate was diffuse and marked only in the cases of influenza A and HIV-1, as well as one of the Coxsackie virus and rotavirus cases, respectively. Immunohistochemical analysis showed that the most common cell type in the inflammatory infiltrates was CD68-positive macrophages. Direct myocyte infection was most prominent in the cases of Coxsackie virus infection. In summary, in situ viral detection was documented in each case of idiopathic myocarditis associated with sudden, unexpected death; in 6/13 cases, the myocarditis was focal and minimal. Although Coxsackie virus was, as expected, the most common virus noted, other viruses including rotavirus and HIV-1 were also observed, highlighting the need for comprehensive viral and histologic analyses in such cases." Many other viruses are associated with viral myocarditis, including Coxsackie A, influenza A, cytomegalovirus, and adenovirus.

http://www.nature.com/modpathol/journal/v15/n9/full/3880629a.html

Influenza and its relationship to circulatory disorders. DM Fleming, KW Cross, RS Pannell. Epidemiol Infect 2005 Apr;133(2):255-262. Epidemiol Infect 2005 Apr;133(2):255-262. Data from the Royal College of General Practitioners, England, in winter 1994/1995 to 1999/2000. "The large cross-correlation coefficients of deaths (circulatory and respiratory) with GP respiratory episodes at weekly lags of 0, -1 and 1 were evidence that the deaths and episode distributions were contemporaneous... Increased circulatory deaths contemporary with new incident cases of respiratory episodes but with no concomitant increase in admissions suggests rapid death during the acute phase of illness." Fig. 2 shows that during flu peaks, circulatory deaths exceeded GP visits, and were also followed by a deficit of circulatory admissions. "Many of the deaths must, therefore, be occurring in the community suggesting rapid progress of the illness or sudden death. This would be consistent with the many reports of ECG abnormalities associated with influenza. Sudden death from dysrhythmia is rarely diagnosed and is not evident on autopsy findings."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2870244/pdf/15816150.pdf

The Surgeon General Lies

"Urinary excretion of thromboxane metabolites (TxMs), such as 2,3-dinor thromboxane B2 (TxB2) and 11-dehydro TxB2, which are markers of platelet activation in vivo, increases in smokers in a dose-dependent manner (Murray et al. 1985)." SGR Ch. 6, p. 373 [pdf p. 25].

Helicobacter pylori Infection Causes Persistent Platelet Activation

Helicobacter pylori infection causes persistent platelet activation in vivo through enhanced lipid peroxidation. G Davì, M Neri, A Falco, D Festi, T Taraborelli, G Ciabattoni, S Basili, F Cuccurullo, C Patrono. Arterioscler Thromb Vasc Biol 2005 Jan;25(1):246-251. "Urinary 8-iso-PGF2alpha and 11-dehydro-TXB2 excretion was significantly higher in the H pylori-positive individuals than in controls. A significant direct correlation was found between the degree of positivity to the 13C-urea breath test and urinary 8-iso-PGF2alpha excretion. The latter was linearly correlated with urinary 11-dehydro-TXB2. Successful eradication of H pylori infection led to a significant reduction in both 8-iso-PGF(2alpha) and 11-dehydro-TXB2." All subjects were never-smokers.

http://atvb.ahajournals.org/cgi/pmidlookup?view=long&pmid=15472127

The Surgeon General Lies

"Abstinence from smoking was also associated with decreased agonist-induced platelet aggregation ex vivo. Furthermore, levels of intraplatelet nitrotyrosine and urinary 8-hydroxy-2’-deoxyguanosine which are markers of oxidative stress, were also depressed after smoking cessation. One study showed that supplementation with vitamin C restored NO levels and platelet aggregation in current smokers to levels observed in nonsmokers (Takajo et al. 2001)." SGR Ch. 6, p. 373 [pdf p. 26].

Helicobacter pylori Infection Causes Oxidative Stress

Possibility of chemoprevention by the eradication of Helicobacter pylori: oxidative DNA damage and apoptosis in H. pylori infection. KB Hahm, KJ Lee, SY Choi, JH Kim, SW Cho, H Yim, SJ Park, MH Chung. Am J Gastroenterol 1997 Oct;92(10):1853-1857. In human gastric mucosa biopsies, "The 8-OH-dG contents of healthy normal controls with negative H. pylori were 4.31 +/- 2.33 (8-OH-dG/10(5) dG), whereas those of patients with positive H. pylori were 10.40 +/- 7.25. The difference between these two values was statistically significant (p < 0.01). The 8-OH-dG contents were significantly decreased after the eradication of H. pylori (12.22 +/- 2.09 vs. 2.42 +/- 1.22, p < 0.001). After the eradication of H. pylori, both the apoptotic index and the iNOS scores were significantly decreased, compared with those before eradication (3.72 +/- 1.74 vs. 1.17 +/- 1.06 for apoptosis and 10.34 +/- 6.79 vs. 1.43 +/- 1.14 for iNOS, p < 0.001). Statistically significant correlations were observed among apoptotic index, iNOS score, degree of inflammation, and density of H. pylori (p < 0.05)."

http://www.ncbi.nlm.nih.gov/pubmed/9382051

Role of Helicobacter pylori CagA+ infection in determining oxidative DNA damage in gastric mucosa. A Papa, S Danese, A Sgambato, R Ardito, G Zannoni, A Rinelli, FM Vecchio, N Gentiloni-Silveri, A Cittadini, G Gasbarrini, A Gasbarrini. Scand J Gastroenterol. 2002 Apr;37(4):409-413. "High expression of 8-OHdG was detected in 14/20 (70%) H. pylori-positive patients (13 CagA+ and 1 CagA-) and in 2/10 (20%) H. pylori-negative patients," in gastric mucosa.

http://www.ncbi.nlm.nih.gov/pubmed/11989831

Helicobacter pylori CagA status, mucosal oxidative damage and gastritis phenotype: a potential pathway to cancer? F Farinati, R Cardin, VM Russo, G Busatto, M Franco, M Rugge. Helicobacter 2003 Jun;8(3):227-234. 118 patients. "cagA-positive infection significantly correlated with a higher prevalence of atrophic-metaplastic lesions (p = 0.04). cagA-positive patients had higher 8-hydroxydeoxyguanosine levels than both cagA-negative and H. pylori-negative cases (p = 0.01). The 8-hydroxydeoxyguanosine levels were significantly higher in multifocal atrophic gastritis (p = 0.04). The odds ratio for cagA-positive patients having 8OHdG levels above a cut-off calculated on the basis of the ROC curves were 7.12, overall, reaching 11.25 when only patients younger than 50 were considered."

http://www.ncbi.nlm.nih.gov/pubmed/12752735

Chronic gastritis with expression of inducible nitric oxide synthase is associated with high expression of interleukin-6 and hypergastrinaemia. H Kai, M Ito, Y Kitadai, S Tanaka, K Haruma, K Chayama. Aliment Pharmacol Ther 2004 Jun 15;19(12):1309-1314. 103 patients with H. pylori infection. "Thirty-seven of 103 (35.6%) gastric mucosa specimens showed simultaneous expression of inducible nitric oxide synthase and nitrotyrosine. In these patients (inducible nitric oxide synthase-positive group), the serum level of gastrin was significantly higher than that of the inducible nitric oxide synthase-negative group (509.5 +/- 141.5 pg/mL vs. 210.0 +/- 227.2 pg/mL; P < 0.01), whereas there were no significant differences in serum levels of pepsinogen, anti-parietal cell antibody, and nitrate and nitrite or in scores of histological gastritis. Interleukin-6 levels were significantly higher in the inducible nitric oxide synthase-positive group than in the inducible nitric oxide synthase-negative group (25.9 +/- 7.0 pg/mg protein vs. 10.6 +/- 4.9 pg/mg protein; P < 0.05)." [Note that CMV induces IL-6 - cast]

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2036.2004.01965.x/pdf

Should increased levels of urinary 8-hydroxydeoxyguanosine in chronic gastritis imply intestinal metaplasia or gastric atrophy? F Albayrak, MH Uyanik, H Dursun, Y Albayrak, S Altas, A Uyanik, S Cerrah, Y Bayir. South Med J 2010 Aug;103(8):753-757. 77 outpatients with chronic gastritis. "The mean amount of 8-OHdG (microg/g creatinine) in 77 subjects was 18.07 +/- 13.49 x 10(-3) microg/g creatinine. The levels of urinary 8-OHdG in the H pylori-positive gastritis patients were also significantly higher than those in the H pylori-negative gastritis patients (P=0.003, respectively, 20.42 +/- 13.33 x 10(-3) microg/g creatinine, 13.16 +/- 12.71 x 10(-3) microg/g creatinine). The level of urinary 8-OHdG was markedly higher in patients with gastric atrophy and intestinal metaplasia than in those without (P=0.000, P=0.002, respectively). There were significant correlations between levels of urinary 8-OHdG and both the atrophy score (r=0.441, P=0.000) and the intestinal metaplasia score (r=0.436, P=0.000)."

http://www.ncbi.nlm.nih.gov/pubmed/20622725

The Surgeon General Lies

Oxidative Stress and Platelet Function. Cigarette smoke has been shown to be an abundant source of free radicals (Church and Pryor 1985). Levels of isoprostanes—quantitative indices of in vivo oxidative stress—are higher in smokers than in nonsmokers (Reilly et al. 1996; Chehne et al. 2001; Dietrich et al. 2002), and they decrease with smoking cessation (Reilly et al. 1996; Praticò et al. 1997). Studies demonstrated elevated production of isoprostanes and decreased levels of reduced glutathione in the platelets of smokers (Takajo et al. 2001). Intraplatelet levels of nitrotyrosine, which is a marker of modification of proteins induced by oxidative stress, decreased with smoking abstinence but increased rapidly when smoking was resumed, together with return of increased sensitivity to agonist-induced platelet aggregation ex vivo (Morita et al. 2005). In another study, products from activated platelets induced oxidative stress in vascular smooth muscle cells, which is associated with increased expression of tissue factor, a highly thrombogenic protein (Görlach et al. 2000). Other investigators showed that administration of antioxidants to persons with diabetes, just as to smokers, decreased production of isoprostane and urinary TxM (Davì et al. 1999) and decreased platelet aggregation ex vivo (Salonen et al. 1991). SGR Ch. 6, p. 373 [pdf p. 27].

Isoprostanes Are a Red Herring

Association between both lipid and protein oxidation and the risk of fatal or non-fatal coronary heart disease in a human population. M Woodward, KD Croft, TA Mori, H Headlam, XS Wang, C Suarna, MJ Raftery, SW MacMahon, R Stocker. Clin Sci (Lond) 2009 Jan;116(1):53-60. 227 cases, 420 controls. "The role of oxidative damage in the aetiology of coronary disease remains controversial, as clinical trials investigating the effect of antioxidants have not generally been positive... F2-Isoprostanes in cases (median, 1146 pmol/l) were not different from controls (1250 pmol/l); the odds ratio (95% confidence interval) for a 1 S.D. increase in F2-isoprostanes was 1.08 (0.91-1.29). Similarly, there was no independent association between the presence of oxidized apoA-I, detected in approx. 20% of the samples, and coronary risk. In conclusion, we found no evidence of associations between markers of lipid (F2-isoprostanes) and protein (oxidized apoA-I) oxidation and the risk of fatal or non-fatal coronary heart disease in a general population."

http://www.clinsci.org/cs/116/0053/cs1160053.htm

Chlamydia pneumoniae Causes Oxidative Stress and Activates Platelets

Chlamydia pneumoniae binds to platelets and triggers P-selectin expression and aggregation: a causal role in cardiovascular disease? H Kälvegren, M Majeed, T Bengtsson. Arterioscler Thromb Vasc Biol 2003 Sep 1;23(9):1677-1683. "We found that C pneumoniae, at a chlamydia:platelet ratio of 1:15, adheres to platelets and triggers P-selectin expression after 1 minute and causes an extensive aggregation and ATP secretion after 20 minutes of incubation. Inhibition of glycoprotein IIb/IIIa with Arg-Gly-Asp-Ser or abciximab markedly reduced C pneumoniae-induced platelet aggregation."

http://atvb.ahajournals.org/cgi/content/full/23/9/1677

Chlamydia pneumoniae induces nitric oxide synthase and lipoxygenase-dependent production of reactive oxygen species in platelets. Effects on oxidation of low density lipoproteins. H Kälvegren, H Bylin, P Leanderson, A Richter, M Grenegård, T Bengtsson. Thromb Haemost 2005 Aug;94(2):327-335. "We found that C. pneumoniae stimulated platelet production of ROS. Polymyxin B treatment of C. pneumoniae, but not elevated temperature, abolished the stimulatory effects on platelet ROS-production, which suggests that chlamydial lipopolysaccharide has an important role. Inhibition of nitric oxide synthase with nitro-L-arginine, lipoxygenase with 5,8,11-eicosatriynoic acid and protein kinase C with GF 109203X significantly lowered the production of radicals. In contrast, inhibition of NADPH-oxidase with di-phenyleneiodonium (DPI) did not affect the C. pneumoniae induced ROS-production. These findings suggest that the activities of nitric oxide synthase and lipoxygenase are the sources for ROS and that the generation is dependent of the activity of protein kinase C. The C. pneumoniae-induced ROS-production in platelets was associated with an extensive oxidation of LDL, which was significantly higher compared to the effect obtained by separate exposure of LDL to C. pneumoniae or platelets."

http://preview.tinyurl.com/64s3m4t

The Surgeon General Blames Smoking for Normal Immune Reaction to Infection

"Polymorphonuclear Leukocytes. In one study, persons who smoked had higher numbers of circulating polymorphonuclear leukocytes than did nonsmokers (Sela et al. 2002). In other research, neutrophils from smokers had higher levels of myeloperoxidase (Bridges et al. 1985) and increased expression of integrins CD11b, CD15, and CD63, which are markers of leukocyte activation (Gustafsson et al. 2000). Furthermore, when stimulated, these leukocytes released superoxide at a faster rate than did leukocytes from nonsmokers (Sela et al. 2002), which further increased local oxidative stress. Studies documented a greater variety of circulating cellular adhesion molecules, including ICAM-1, VCAM, P-selectin, and E-selectin, in smokers than in nonsmokers (Mazzone et al. 2001; Bermudez et al. 2002). An increase in these cellular adhesion molecules (monocytes) may facilitate recruitment of inflammatory cells to sites of vascular injury (Figure 6.7)." SGR Ch. 6, p. 373 [pdf p. 28].

Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. AW Sylwester, BL Mitchell, JB Edgar, C Taormina, C Pelte, F Ruchti, PR Sleath, KH Grabstein, NA Hosken, F Kern, J. A Nelson, and LJ Picker. J Exp Med 2005;202(5):673-685. "We further documented that total HCMV-specific T cell responses in seropositive subjects were enormous, comprising on average ∼10% of both the CD4+ and CD8+ memory compartments in blood, whereas cross-reactive recognition of HCMV proteins in seronegative individuals was limited to CD8+ T cells and was rare." "Although there are few comparative data for pan-proteome immunogenicity analysis of other human viral infections, previous reports assessing T cell responses to viral lysates, infected cells, or immunodominant epitopes strongly suggest that the frequencies of HCMV-specific T cells in healthy subjects considerably exceed those observed for other common viruses, including measles, mumps, influenza, adenovirus, poxvirus, and even other persistent Herpes family viruses (e.g., Herpes simplex, Herpes zoster) and are comparable with frequencies of HIV-specific T cells in active HIV infection." "[O]ur observation that ∼30% of adult subjects have HCMV-specific populations comprising >20% of their circulating CD4+ and/or CD8+ memory T cell repertoire suggests that HCMV-specific T cell responsiveness might be excessive in some individuals, perhaps with detrimental clinical effects."

http://jem.rupress.org/content/202/5/673.full

Induction of polymorphonuclear leukocyte response by human cytomegalovirus. PJ Skarman, A Rahbar, X Xie, C Söderberg-Nauclér. Microbes Infect 2006 May;8(6):1592-1601. "We found that HCMV infection without N-formyl-methionyl-leucyl-phenylalanine (fMLP) stimulation increased the surface expression of CD11b to the same extent as fMLP stimulation of mock infected cells... We also found that apoptosis was significantly inhibited in HCMV-infected neutrophils."

http://www.ncbi.nlm.nih.gov/pubmed/16702012

T lymphocytes in acute bacterial infection: increased prevalence of CD11b(+) cells in the peripheral blood and recruitment to the infected site. C Wagner, D Kotsougiani, M Pioch, B Prior, A Wentzensen, GM Hänsch. Immunology 2008 Dec;125(4):503-509. "T-cell activation, particularly of CD8(+) cells, is invariably associated with viral infections. We now provide evidence for the activation of T cells in patients with localized bacterial soft tissue infections. During acute disease we detected in the peripheral blood of these patients, small though conspicuous populations of CD4(+) CD28(+) CD11b(+) and CD8(+) CD28(+) CD11b(+) cells, indicative of an expansion of effector T cells. Moreover, we identified CD4(+) and CD8(+) cells at the infected site, in addition to highly activated polymorphonuclear neutrophils (PMN). In keeping with their role as first-line defence, PMN were preponderant, but T cells amounted to 20% of the infiltrated cells. The majority of the infiltrated T cells expressed CXCR6, a homing receptor for non-lymphoid tissue. The infiltrated T cells produced interferon-gamma (IFN-gamma), while the peripheral blood cells obtained at the same time did not. In conclusion, in response to localized bacterial infections, T cells are activated and recruited to the infected site. We propose that these T cells, e.g. by producing IFN-gamma, enhance the efficiency of the infiltrated phagocytic cells, particularly of the PMN, thereby supporting the local host defence."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2612546/

Myeloperoxidase as serum marker for detection of CMV infections and rejections in patients after liver or heart transplantation. S Zelzer, P Stiegler, M Kapitan, S Schaffellner, M Schweiger, M Stettin, T Stojakovic, M Truschnig-Wilders, KH Tscheliessnigg, G Khoschsorur. Transpl Immunol 2009 Jan;20(3):121-126. "Data from individual TX [transplant] patients, however, indicate that MPO levels rise distinctly earlier with infection (CMV) than with rejection, enabling earlier detection of the complication and initiation of suitable treatment."

http://www.ncbi.nlm.nih.gov/pubmed/18930821

Activation of T Lymphocytes in Response to Persistent Bacterial Infection: Induction of CD11b and of Toll-Like Receptors on T Cells. D Kotsougiani, M Pioch, B Prior, V Heppert, GM Hänsch, C Wagner. Int J Inflam 2010 Apr 22;2010:526740. "T cell activation is invariably associated with virus infections, but activation of T cells is also noted, for example, in patients with persistent bacterial infections with intracellular pathogens or localised bacterial biofilms. The latter is characterised by a destructive inflammatory process. Massive infiltration of leukocytes, predominantly of polymorphonuclear neutrophils (PMNs) and of T lymphocytes, is seen. While PMN influx into sites of bacterial infection is in line with their role as "first-line defence" a role of T cells in bacterial infection has not yet been delineated. We now found evidence for activation and expansion of peripheral blood T cells and an upregulation of Toll-like receptors 1, 2, and 4 on small portions of T cells. T cells recovered from the infected site were terminally differentiated and produced interferon gamma, a cytokine known to enhance functions of phagocytic cells, leading to the conclusion that infiltrated T cells support the local immuner defence."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2989653/

Human cytomegalovirus IE1 protein elicits a Type II interferon-like host cell response that depends on activated STAT1 but not interferon-γ. T Knoblach, B Grandel, J Seiler, M Nevels, C Paulus. PLoS Pathogens 2011;7(4):e1002016. 13 (34%) of 38 genes were down-regulated by a factor between 2.0 and 5.5 while 25 (66%) were up-regulated by a factor between 2.0 and 41.9. "According to [the Gene Omtology classification system], the most significantly enriched 'biological process' terms with respect to the 25 IE1-activated genes are: 'immune system process', 'immune response', 'inflammatory response', 'response to wounding', 'response to stimulus', 'defense response', 'chemotaxis', 'taxis', and 'regulation of cell proliferation'. In fact, virtually all IE1-induced genes with assigned functions have been implicated in adaptive or innate immune processes including inflammation. Moreover, 7 (28%) of the 25 genes encode known cytokines or other soluble mediators, namely the chemokine (C-X-C motif) ligands CXCL9, CXCL10 and CXCL11, the chemokine (C-C motif) ligand CCL11, endothelin 1 (encoded by EDN1), and the tumor necrosis factor (TNF) superfamily members 4 (TNFSF4, also known as OX40 ligand) and 18 (TNFSF18, also known as GITR ligand). This observation is also illustrated by the fact that, according to GO, the most significantly enriched 'molecular function' terms in the IE1-activated transcriptome are: 'cytokine receptor binding', 'cytokine activity', 'chemokine activity', 'chemokine receptor binding', and 'G-protein-coupled receptor binding'. Furthermore, the top 'cellular component' category is 'extracellular space'."

http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1002016

The Surgeon General Lies

"Monocytes from smokers demonstrated increased expression of the integrins CD11b and CD18, which augment adhesiveness of monocytes to endothelial cells, at least in vitro (Weber et al. 1996)." SGR Ch. 6, p. 373 [pdf p. 28].

Monocytes are a major site of persistence of human cytomegalovirus in peripheral blood mononuclear cells. J Taylor-Wiedeman, JG Sissons, LK Borysiewicz, JH Sinclair. J Gen Virol 1991 Sep;72 ( Pt 9):2059-2064. "In five of six seropositive subjects, HCMV was found predominantly in the non-T cell population. Further analysis suggested that the virus was present in adherent cells and CD14+ cells. In three of nine seronegative subjects we could demonstrate HCMV DNA, which we do not believe was due to contamination, reproducibly by PCR. In one of these seronegative subjects, HCMV DNA was present predominantly in the non-T cell fraction of PBM cells. No HCMV DNA was detectable in the remaining six seronegative subjects. We conclude that, within the PBM cells of normal asymptomatic seropositive and some seronegative subjects, HCMV is present predominantly in the monocyte fraction. In addition, the detection of HCMV sequences in seronegative subjects may indicate that infection with HCMV is more widespread than conventional seroepidemiology suggests."

http://vir.sgmjournals.org/cgi/pmidlookup?view=long&pmid=1654370

The effect of virus infection on the adherence of leukocytes or platelets to endothelial cells. AH Span, MC van Dam-Mieras, W Mullers, J Endert, AD Muller, CA Bruggeman. Eur J Clin Invest 1991 Jun;21(3):331-338. "In this study we show that early infection of endothelial cell monolayers with Herpes Simplex virus type 1 (HSV-1) or Cytomegalovirus (CMV) results in an increased monocyte (MC) and polymorphonuclear leukocyte (PMN) adherence, but not in an increased platelet adhesion. Further, is demonstrated that MC and PMN respond differently to virus infected endothelial cell monolayers: PMN adhesion to CMV infected cells is approximately 430% of the control adherence, while the MC adherence is increased to 160%. Also, a difference in virus acting is observed: the adherence of MC or PMN to HSV-1 infected endothelial cells is caused by a secreted adherence promoting factor, while the adherence of MC or PMN to CMV infected endothelial cells seems to be a cell-bound phenomenon."

http://www.ncbi.nlm.nih.gov/pubmed/1653707

Roles of phosphatidylinositol 3-kinase and NF-kappaB in human cytomegalovirus-mediated monocyte diapedesis and adhesion: strategy for viral persistence. MS Smith, ER Bivins-Smith, AM Tilley, GL Bentz, G Chan, J Minard, AD Yurochko. J Virol 2007 Jul;81(14):7683-7694. "HCMV infection of primary human monocytes promotes their transendothelial migration and differentiation into proinflammatory macrophages permissive for the replication of the original input virus... We found that the beta(1) integrins, the beta(2) integrins, intracellular adhesion molecule 1 (ICAM-1), and ICAM-3 were upregulated following HCMV infection and that they played a key role in the firm adhesion of infected monocytes to the endothelium."

http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=17507481

The Surgeon General Lies

"Study findings indicate that circulating levels of fibrinogen increase in smokers and decrease with smoking cessation (Thomas et al. 1995; Hunter et al. 2001; Tuut and Hense 2001). Also, research suggests that elevated fibrinogen values are an independent risk factor for CHD (Paramo et al. 2004) and deep-vein thrombosis (Vayá et al. 2002). For CVD, the predictive effect was reportedly similar and additive to traditional cardiovascular risk factors (Woodward et al. 1998). The effect of fibrinogen on CVD is partly attributable to smoking and seems to be mediated through alterations in rates of synthesis by the liver. Use of snuff is not associated with increased fibrinogen levels (Eliasson et al. 1995)." SGR Ch. 6, p. 373 [pdf p. 29].

C. pneumoniae and CMV Increase Fibrinogen Production

[Fibrinogen is synthesised in the liver by hepatocytes, and in bone marrow by megakaryocytes (which make platelets). Certain cytokines such as IL-3, IL-6, IL-11, LIF, erythropoietin, and thrombopoietin all stimulate the maturation of megakaryocytic progenitor cells.]

Acute-phase response of human hepatocytes after infection with Chlamydia pneumoniae and cytomegalovirus. MS Verkerk, FL Visseren, K Paul Bouter, RJ Diepersloot. Eur J Clin Invest 2003 Aug;33(8):720-725. "Fibrinogen production was increased significantly in a dose-dependent manner after infection with CMV (50 microL: P=0.022 and 100 microL: P<0.001) and C. pneumoniae (P=0.012). Cytomegalovirus infection resulted in an increase of IL-6 production compared with uninfected cells (P=0.048). Cytomegalovirus and C. pneumoniae infection did not result in a significantly increase of PAI-1 production by hepatocytes."

http://www.ncbi.nlm.nih.gov/pubmed/12864783

Detection of Chlamydia pneumoniae in liver transplant patients with chronic allograft rejection. G Lotz, S Simon, A Patonai, P Sótonyi, B Nemes, C Sergi, T Glasz, T Füle, B Nashan, Z Schaff. Transplantation 2004 May 27;77(10):1522-1528. "In all 10 rejected liver samples, Chlamydia pneumoniae was detected by PCR, whereas only one of the healthy control samples and one of the samples with acute rejection were found to be positive. Immunohistochemistry showed similar results. The positive signals of Chlamydia pneumoniae were localized mainly in the hepatocytes, sinusoidal and perisinusoidal cells, and the cells of portal tracts, whereas most of the altered hepatic arteries showed no or very weak positivity Conclusions: The results strongly suggest an association between the occurrence of Chlamydia pneumoniae and the presence of foam cell arteriopathy in transplanted livers."

http://www.ncbi.nlm.nih.gov/pubmed/15239615

Azithromycin inhibits interleukin-6 but not fibrinogen production in hepatocytes infected with cytomegalovirus and chlamydia pneumoniae. JJ Bouwman, FL Visseren, PK Bouter, RJ Diepersloot. J Lab Clin Med 2004 Jul;144(1):18-26. "C pneumoniae-infected hepatocytes produce IL-6 (2667 +/- 309 pg/mL vs 137 +/- 120 pg/mL in uninfected cells after 96 hours. Incubation with 0.016 microg/mL azithromycin decreased IL-6 levels to a mean of 1516 +/- 402 pg/mL, and incubation with 0.125 and 1 microg/mL azithromycin decreased IL-6 to 871 +/- 364 and 752 +/- 403 pg/mL, respectively. C pneumoniae-induced IL-6 production was time- and dose-dependent. The interaction of C pneumoniae with azithromycin treatment was significant, indicating an inhibitory effect of azithromycin on C pneumoniae-induced IL-6 production. CMV infection did not lead to IL-6 production by hepatocytes. C pneumoniae and CMV infection did not induce any changes in PAI-1 production. Fibrinogen production was increased by CMV infection after 72 hours (838 +/- 88 ng/mL; P <.01) and after 96 hours by infection with both C pneumoniae and CMV (765 +/- 100 and 846 +/- 123 ng/mL, respectively; P <.05)."

http://www.ncbi.nlm.nih.gov/pubmed/15252403

The Surgeon General Lies

"Nitration of tyrosine residues, a marker of NO-dependent damage, is increased in smokers (Petruzzelli et al. 1997). Presence of these residues depends strictly on availability of nitrogen dioxide radicals that are in turn derived from ONOO− (Kirsch et al. 2002). Tyrosine nitration modifies a variety of proteins, including fibrinogen (Petruzzelli et al. 1997; Pignatelli et al. 2001). Nitrogenated fibrinogen is more reactive and thrombogenic than is native fibrinogen (Gole et al. 2000), a fact that seems attributable to accelerated formation of clots without modification in plasmin-induced thrombolysis (Vadseth et al. 2004)... ONOO− is likely to derive from interaction of NO from cigarette smoke with superoxide radicals from pulmonary macrophages (Deliconstantinos et al. 1994). In studies of both animal models and human volunteers, even brief exposure to tobacco smoke induced prolonged production (>30 minutes) of ONOO−, apparently from pulmonary macrophages (Deliconstantinos et al. 1994)." SGR Ch. 6, p. 373 [pdf p. 29].

[The whole load of tripe in this section is of interest primarily to the charlatan cult of magic fruits and vegetables and free radicals, who obsessively jam their rubbish down the public's throats despite the utter worthlessness of their quack nostrums revealed in prospective studies.]

Role of reactive oxygen intermediates in cytomegalovirus gene expression and in the response of human smooth muscle cells to viral infection. E Speir, T Shibutani, ZX Yu, V Ferrans, SE Epstein. Circ Res 1996 Dec;79(6):1143-1152. "Using confocal microscopy to identify a redox-sensitive fluorescent marker, we found that CMV infection of SMCs generates intracellular reactive oxygen intermediates (ROIs). CMV also activated nuclear factor kappa B (NF kappa B), a cellular transcription factor, as demonstrated by increased NF kappa B binding to DNA (electrophoretic mobility shift assay). Antioxidants inhibited activation, suggesting a role of ROIs in CMV-induced NF kappa B activation. By using antioxidants to assess the role of ROIs in modulating virally mediated effects, we also found that CMV-induced ROIs (1) are critical to the transactivation of the viral major immediate promoter (MIEP) by its immediate-early protein IE72 (determined by cotransfection of an IE72 expression vector and a reporter gene downstream from the MIEP) and (2) are necessary for IE72 expression (determined by immunocytochemistry) and viral replication (determined by viral titer assay on indicator cells) following CMV infection of SMCs. Because ROIs, through activation of NF kappa B, can also induce expression of cellular genes involved in immune and inflammatory responses, the ROI response to CMV infection may also represent a parallel survival mechanism that has evolved in the host cell to protect against viral infection. We conclude that CMV induces intracellular ROI generation within minutes after infection of SMCs and then uses these ROIs to facilitate its own gene expression and replication."

http://circres.ahajournals.org/cgi/content/full/79/6/1143

Superoxide generation by monocytes following infection with human cytomegalovirus. S Suzuki, M Kameoka, T Nakaya, T Kimura, N Nishi, K Hirai, K Ikuta. Immunopharmacology 1997 Oct;37(2-3):185-190. "A significant level of superoxide (O2-) generation was observed in a U937-derived subclone following infection with human cytomegalovirus (HCMV). Although there were no detectable levels of viral mRNA and/or protein expression, HCMV DNA content transiently increased immediately before O2- generation. Similarly, O2- generation was also observed in peripheral blood monocytes derived from healthy donors."

http://www.ncbi.nlm.nih.gov/pubmed/9403337

[Superoxide generation and human cytomegalovirus infection]. S Suzuki, T Kimura, K Ikuta. Nippon Rinsho 1998 Jan;56(1):75-78. Review. "Healthy donor-derived peripheral blood monocytes/macrophages, which seem to be the major reservoir for HCMV in vivo, showed significantly higher generation of O2- after HCMV infection. The importance of O2- in cytomegalovirus pneumonitis was also supported in a mouse model system using mouse cytomegalovirus. In addition, the importance of HCMV-induced ROI was also shown in the restenosis and atherosclerosis of smooth muscle cells."

http://www.ncbi.nlm.nih.gov/pubmed/9465668

The Surgeon General Lies

"Thus, many of the effects from active smoking can be observed in persons involuntarily exposed to cigarette smoke. The magnitude of the effect of secondhand smoke is relatively large considering the low systemic exposure to tobacco smoke for nonsmokers compared with that for active smokers and supports the finding of high cardiovascular risk at low levels of exposure to smoke." SGR Ch. 6, p. 373 [pdf p. 29].

The real reason that "The magnitude of the effect of secondhand smoke is relatively large considering the low systemic exposure to tobacco smoke" is because these charlatams are deliberately falsely blaming the effects of infection on smoking and secondhand smoke.

See also:

CMV & other infections cause heart disease
Chlamydia pneumoniae causes heart disease
The Lie That Secondhand Smoke Causes Heart Disease
The Surgeon General Lies About Cancer

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cast 12-25-12