Periodontitis and Cardiovascular Diseases. Consensus Report.

Background: In Europe cardiovascular disease (CVD) is responsible for 3.9 million deaths (45% of deaths), being ischaemic heart disease, stroke, hypertension (leading to heart failure) the major cause of these CVD related deaths. Periodontitis is also a chronic non-communicable disease (NCD) with a high prevalence, being severe periodontitis, affecting 11.2% of the world's population, the sixth most common human disease. Material and Methods: There is now a significant body of evidence to support independent associations between severe periodontitis and several NCDs, in particular CVD. In 2012 a joint workshop was held between the European Federation of Periodontology (EFP) and the American Academy of Periodontology to review the literature relating periodontitis and systemic diseases, including CVD. In the last five years important new scientific information has emerged providing important emerging evidence to support these associations. Results and Conclusions: The present review reports the proceedings of the workshop jointly organised by the EFP and the World Heart Federation (WHF), which has updated the existing epidemiological evidence for significant associations between periodontitis and CVD, the mechanistic links and the impact of periodontal therapy on cardiovascular and surrogate outcomes. This review has also focused on the potential risk and complications of periodontal therapy in patients on anti thrombotic therapy and has made recommendations for dentists, physicians and for patients visiting both the dental and medical practices.

Acute stent thrombosis after a "stroll for fresh air". A case of the smoking gun.

We present a case of a patient who underwent a percutaneous coronary intervention and excused himself for some "fresh air". He subsequently developed acute stent thrombosis. We discuss the contribution of acute cigarette smoking to this serious complication after stent implantation.

Advances in the differentiation of constrictive pericarditis and restrictive cardiomyopathy.

The diagnosis of constrictive pericarditis should be considered in any patient with unexplained right heart failure. The differentiation between constrictive pericarditis and restrictive cardiomyopathy is based on a combination of clinical presentation, history and imaging, and on occasion, on the basis of invasive hemodynamic studies or biopsy. Pertinent anatomic and physiologic findings on cardiac imaging modalities including echocardiography, computed tomography and cardiac magnetic resonance imaging are reviewed, and in many cases the diagnosis can be determined on the basis of imaging. Hemodynamic studies may clarify the diagnosis, and biopsy may find treatable causes of disease.

Immunomodulation of experimental colitis: the role of NK1.1 liver lymphocytes and surrogate antigens--bystander effect.

The imbalance between Th1 pro-inflammatory and Th2 anti-inflammatory cytokine-producing cells plays a major role in the pathogenesis of inflammatory bowel disease (IBD). Induction of oral tolerance to colitis-extracted proteins was previously shown to down-regulate the anti-colon immune response, thereby alleviating experimental colitis. Immune bystander effect and liver-associated lymphocytes expressing the NK1.1 marker (NK1.1(+) LAL) have been suggested as being important in tolerance induction. The aims of the present study were to determine whether oral administration of inflammatory and non-inflammatory colon-extracted proteins of different species can induce peripheral immune tolerance and alleviate experimental colitis; and to examine the role of NK1.1(+) LAL in oral tolerance induction. Colitis was induced in C57/B6 mice by intracolonic instillation of trinitrobenzene sulphonic acid (TNBS). Mice received six oral doses of colonic proteins extracted from TNBS-colitis colonic wall, or normal colonic wall, from four different species. Standard clinical, macroscopic, and microscopic scores were used for colitis assessment. Serum interferon gamma (IFNgamma) and interleukin 10 (IL10) levels were measured by ELISA. To evaluate the role of NK1.1(+) LAL in maintaining the balance between immunogenic and tolerogenic subsets of cells, their cytotoxicity functions were tested in tolerized and non-tolerized-mice. The administration of mouse-derived colitis-extracted proteins, or of surrogate proteins extracted from normal mouse colon, or from rat or human inflammatory colons, was found to alleviate experimental colitis. Tolerized mice had less diarrhoea; showed a marked reduction of colonic ulceration, intestinal and peritoneal adhesions, wall thickness, and oedema; and demonstrated a significant improvement of all microscopic parameters for colitis. Induction of tolerance led to an increase in IL10 and a decrease in IFNgamma serum levels. NK1.1(+) LAL cytotoxicity function increased markedly in tolerized mice. In contrast, mice fed with proteins extracted from normal rat, rabbit, and human colon, or from rabbit inflammatory colon, developed severe colitis, with a marked increase in IFNgamma and a decrease in IL10 serum levels, and down-regulation of NK1.1(+) LAL function. This study has shown that oral tolerance can be induced in experimental colitis by means of the feeding of surrogate antigens; this alleviates experimental colitis. NK1.1(+) LAL cytotoxicity function is associated with peripheral tolerance induction and may help to maintain the Th1/Th2 immune balance.

The evaluation of pleural effusions in patients with heart failure.

PURPOSE: To determine the causes of pleural effusions in patients with heart failure, and the association of the characteristics of these statistics with the use of diuretics. SUBJECTS AND METHODS: Eighty-one patients with a definite diagnosis of heart failure who underwent thoracentesis were evaluated. Fluids were classified as transudates or exudates using Light's criteria. RESULTS: Forty-one effusions (in 34 patients) were transudates, and 54 (in 47 patients) were exudates. A specific cause was found for 32 of the exudates (27 patients); except for heart failure, no obvious cause was found for the remaining 22 fluids (20 patients). Exudates with a specific cause for an exudate were more likely to have at least two of Light's criteria (18 of 27 [67%]) than did exudates without a known cause (2 of 21 [10%]). Intravenous diuretic therapy in the 24 hours before thoracentesis was significantly more common among patients with exudates without a specific cause. CONCLUSIONS: Patients with heart failure may have exudative pleural effusions without an obvious cause except heart failure.

Amelioration of immune-mediated experimental colitis: tolerance induction in the presence of preexisting immunity and surrogate antigen bystander effect.

Oral tolerance is a recognized procedure for induction of antigen-specific peripheral immune hyporesponsiveness. Recently, it has been shown that oral tolerance can be used to prevent experimental colitis. The aim of this study was to test whether induction of oral tolerance toward proteins extracted from inflammatory and noninflammatory colons can alleviate preexisting experimental colitis. Colitis was induced in BALB/c mice by intracolonic instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS). Mice received five oral doses of colonic proteins extracted from TNBS-induced colitis or normal colons, before, or 7 days after colitis was induced. Standard clinical, macroscopic, and microscopic scores were used for colitis assessment. Serum interferon gamma (IFNgamma) and interleukin (IL)4 levels were measured by enzyme-linked immunosorbent assay. Feeding of colitis- or normal colon-extracted proteins before, or following colitis induction, ameliorated colonic inflammation as shown by decreased diarrhea, increased body weight, reduction of colonic ulcerations, intestinal and peritoneal adhesions, wall thickness, and edema. Histological parameters for colitis were markedly improved in tolerized animals, and there was a significant reduction in inflammatory response and mucosal ulcerations. Tolerized mice developed an increase in IL4 and a decrease in IFNgamma serum levels. The results show that induction of oral tolerance to colitis- or normal colon-extracted proteins down-regulated preexisting anticolon immune response, thereby ameliorating experimental colitis. Tolerance induction was mediated via a shift from a proinflammatory T helper (Th)1 to an anti-inflammatory Th2 immune response.

Downregulation of a tumor promotion immune response via induction of oral tolerance towards tumor-associated-antigens: can we 'eat the tumor'?

The mechanism by which hepatocellular carcinoma (HCC) develops and the role of the hepatitis B virus (HBV) in inducing tumors, are not yet well understood. Patients persistently infected with HBV tend to have a defective immune response against the virus, which fails to clear the virus and also induces liver injury. This defective response may also have an inducible effect on the virus and on cells that express HBV antigens, as well as play a role in the growth of neoplasm. It is possible that one of the mechanisms of tumor growth is related to a deviant immune response towards viral or tumor associated antigens. We describe two responses against the tumor. A 'good' response that would suppress the tumor and a 'bad' response that would promote it and theorize that the net balance between 'bad' and 'good' responses of the immune system towards a cancerous cell and/or antigen will predict whether a tumor grows or is suppressed. Oral tolerance involves the induction of immunological hyporesponsiveness towards specific antigens. It was shown that oral tolerance induces antigen-specific immune suppression towards tumor-associated-antigens by feeding of HBV or other tumor proteins. We hypothesize that induction of immune tolerance towards tumor-associated antigens will suppress the immune response towards these antigens, thus reducing the 'bad' response. The proposed new treatment strategy would redirect the focus from augmenting anti-tumor immune responses to inducing host tolerance towards the tumor.

Co-occurrence of hepatocellular carcinoma and lymphoma in patients with hepatitis C virus cirrhosis.

The association of hepatitis C virus (HCV) with neoplasia is not completely understood. Hepatitis C virus is hepatolymphotrophic. It is considered an inducing factor of hepatocellular carcinoma (HCC) and is associated with various types of lymphomas. We describe a patient with HCV cirrhosis who developed gastric lymphoma and HCC, and we review the current data and theories about the oncogenesis of HCV.

Intravascular stent implantation of the celiac artery in the treatment of chronic mesenteric ischemia.

We report a case of chronic mesenteric ischemia that caused abdominal angina and weight loss in an 80-year-old woman. A mesenteric angiogram revealed total occlusion of the superior mesenteric artery and 90% stenosis of the celiac and inferior mesenteric arteries. Balloon angioplasty of the celiac artery failed because of elastic recoil. A 15-mm Palmaz-Schatz stent was dilated to 6 mm in the proximal celiac artery with an excellent angiographic result and complete resolution of symptoms. A clinical, 1-year follow-up demonstrated success with no recurrence of pain. This case report illustrates the value of balloon dilatation and stent implantation in a patient with atherosclerotic narrowing of multiple abdominal visceral arteries.

Glucose-6-phosphate dehydrogenase deficiency is associated with increased initial clinical severity of acute viral hepatitis A.

BACKGROUND AND AIM: In glucose-6-phosphate dehydrogenase (G6PD) deficiency, the enzyme is deficient in liver cells as well as in erythrocytes. It has been suggested that this may be associated with a more severe clinical presentation of acute viral hepatitis A. The aim of this study is to determine the severity of liver disease in patients with viral hepatitis and G6PD deficiency. METHODS: Eighteen patients with diagnosed G6PD deficiency and acute hepatitis A were compared with 18 matched control patients with hepatitis A in a university hospital for liver disease severity and clinical outcome. RESULTS: Two of 18 patients with G6PD deficiency had neurological deterioration. Patients with G6PD deficiency had a mean peak prothrombin time (PT) that was significantly prolonged as compared with the control group (15.5 +/- 3.7 vs 12.9 +/- 2.0 s, respectively, P < 0.02), and a significantly higher proportion had an abnormal PT (PT > 13.3 s): 61 versus 11% (P < 0.0001). Hemolysis occurred in 44% of the G6PD deficiency patients. Total and direct bilirubin were significantly higher in all patients with G6PD deficiency, including patients without hemolysis. There was no significant difference in liver enzyme levels between the two groups. Patients with G6PD deficiency had a longer average hospital stay (9.5 +/- 4.8 vs 3.4 +/- 0.8 days, respectively, P < 0.001). There was no difference in the final clinical outcome between the two groups, and recovery of liver function was seen in all patients. CONCLUSIONS: Glucose-6-phosphate dehydrogenase deficiency in patients with hepatitis A causes a more severe initial clinical presentation, but does not alter the final clinical outcome.

Mefloquine-induced acute hepatitis.

Mefloquine is an effective drug for prophylaxis and treatment of malaria caused by Plasmodium falciparum. It is generally well tolerated with few side effects. Minimal elevation of liver function tests has been reported after exposure to mefloquine, especially in susceptible individuals with prior abnormal liver function tests. Our patient, who had had elevated liver function tests attributed to heart failure, experienced an acute elevation of liver transaminases 6 weeks after exposure to mefloquine 250 mg/week. Cessation of the drug caused test results to return to normal. Mefloquine should be prescribed cautiously in patients with liver disease.

Induction of oral tolerance towards hepatitis B envelope antigens in a murine model.

BACKGROUND: Hepatitis B virus (HBV) is a non-cytopathic virus, and the hepatocellular injury that occurs as a consequence of HBV infection is mediated by the host antiviral immune response. Subjects with natural tolerance to HBV have minimal or no liver injury despite chronic viremia. We have shown that immune tolerance towards viruses can be induced by oral administration of viral proteins. AIMS: To test whether oral induction of tolerance can be induced towards HBV antigens, and whether oral tolerance induction downregulates preexisting anti-HBV immune response. METHODS: Oral tolerance was induced via feeding of five low oral doses of HBV proteins (HBsAg+preS1+preS2, BioHepB). This was followed by two inoculations with the BioHepB vaccine. Humoral immune tolerance was evaluated by measuring serum levels of anti-HBs antibody titers at monthly intervals. To determine if oral tolerance induction downregulates pre-existing anti-HBs immunity, mice were inoculated twice with the BioHepB vaccine, followed by feeding of BioHepB-HBV proteins. RESULTS: Feeding of HBV proteins markedly inhibited production of anti-HBs antibodies in naive mice. Anti-HBs titers were 45 versus 135 mIU/ml, in tolerized versus non-tolerized controls (P<0.005). Moreover, oral tolerance induction effectively down-regulated pre-existing immunity and reduced the anti-HBs titers in previously immunized mice to 112 versus 223 mIU/ml, in tolerized compared with non-tolerized controls (P<0.01). CONCLUSIONS: Induction of oral tolerance towards HBV proteins downregulates the antiviral humoral immune response in naive mice, and in the presence of preexisting anti-HBV immunity. This approach should be further investigated as a method for alleviation of antiviral-mediated liver injury in chronic HBV hepatitis.

Anti-dsDNA antibodies in sarcoidosis.

BACKGROUND: Sarcoidosis is a chronic multisystem disorder characterized by an exaggerated cellular immune response to antigens with the production of various antibodies including rheumatoid factor and antinuclear antibodies (ANA). The prevalence and significance of antibodies to double-stranded DNA (anti-dsDNA) in sarcoid patients is unknown. The occurrence of anti-dsDNA antibodies is known to be a specific marker of systemic lupus erythematosus (SLE). Sarcoidosis can occur with SLE. It is unclear if anti-dsDNA antibodies in patients with sarcoidosis signify the eventual development of SLE. OBJECTIVES: To determine the prevalence of anti-dsDNA antibodies in patients with sarcoidosis in a university hospital and their significance in predicting the diagnosis of associated SLE. METHODS: In a retrospective study, 34 patient files with diagnosed sarcoidosis in a university hospital during a period of 15 years were reviewed for serological markers, including ANA, anti-dsDNA, and immunoglobulin and C3 levels. The occurrence of SLE in these patients also was evaluated. RESULTS: ANA were positive in 10 of 34 of the patients screened. Two patients with sarcoidosis had antibodies to dsDNA. C3 levels in these 34 patients were an average of 87.7 +/- 25.3 mg/100 mL, which is within the normal range. IgG immunoglobulin levels were an average of 2,206 +/- 999 mg/100 mL, which was above normal limits. The 2 patients who were positive for anti-dsDNA had normal C3 levels and SLE did not develop during a follow-up period of 10 to 15 years. CONCLUSIONS: Anti-dsDNA antibodies may occur in patients with sarcoidosis, but their presence does not predict the subsequent development of SLE.

Induction of oral tolerance in splenocyte recipients toward pretransplant antigens ameliorates chronic graft versus host disease in a murine model.

Chronic graft versus host disease (cGVHD) is a major complication that can develop after bone marrow transplantation. It involves an immune-mediated attack by transplanted donor lymphocytes, and often results in inflammatory damage of host target organs. Immune hyporesponsiveness induced by oral antigen administration has been recently shown to prevent the development of cGVHD in a murine model. The aim of this study was to evaluate whether tolerance induction in bone marrow transplant (BMT) recipients after transplantation, toward their pretransplant antigens, can alleviate preexisting cGVHD in a mouse model. cGVHD was generated by infusing 2.5 x 10(7) splenocytes from B10.D2 donor mice, to sublethally irradiated (6 Gy) BALB/c recipient mice, which differ by minor histocompatibility antigens. Transplantation resulted in cGVHD, with characteristic scleroderma-like cutaneous fibrosis, increased skin collagen content, decreased body weight, and hepatic and small bowel inflammation. Oral tolerance was induced by feeding recipient BALB/c mice with proteins extracted from BALB/c splenocytes for 11 days after B10.D2 splenocyte transplantation. Tolerance induction was evidenced by a significant reduction in mixed lymphocyte response of effector splenocytes from tolerant BALB/c mice transplanted with B10.D2 splenocytes against BALB/c target splenocytes. Oral tolerance decreased skin collagen deposits. Reduction of collagen alpha1(I) gene expression and skin collagen were shown by in situ hybridization and histochemistry, respectively. Liver and bowel biopsy specimens revealed less inflammation. Serum IL-10 levels were higher in tolerant mice than in controls, whereas IFNgamma was significantly reduced. Oral tolerance of BMT recipients toward their pretransplant antigens after splenocyte transplantation down-regulated the immune attack by transplanted cells, thus ameliorating cGVHD.

Liver-associated lymphocytes expressing NK1.1 are essential for oral immune tolerance induction in a murine model.

Oral tolerance is the induction of immunological hyporesponsiveness towards orally administered antigens. Tolerance initiation involves induction of anti-inflammatory (Th2) lymphocytes, with downregulation of pro-inflammatory (Th1) lymphocytes. The liver was previously shown to play a critical role in oral tolerance induction. The aim of the present study was to test whether liver-associated-lymphocytes expressing the NK1.1 marker (NK1.1+ LAL) are substantial for induction of oral tolerance in an experimental colitis model. Colitis was induced in C57 mice by intracolonic instillation of trinitrobenzensulfonic acid (TNBS). Mice received five oral doses of colonic proteins extracted from TNBS-colitis colonic wall. Anti-NK1.1 monoclonal antibodies were injected before tolerance induction. Colitis was assessed by standard clinical, macroscopic, and microscopic scores. Serum IFN-gamma, TGF-beta1, and IL4 levels were measured by enzyme-linked immunosorbent assay. To evaluate the role of NK1.1+ LAL in keeping the balance between immunogenic and tolerogenic subsets of cells, we tested whether peripheral lymphocytes harvested from tolerized and NK1.1-depleted nontolerized mice can adoptively transfer the tolerance into naive irradiated rats. Depletion of NK1.1+ LAL prevented immune tolerance induction in the experimental colitis model. NK1.1+ LAL-depleted nontolerized mice, disclosed severe clinical, macroscopic, and microscopic parameters of colitis. These mice had significantly lower TGF-beta1, IL4, and higher IFN-gamma serum levels, and their lymphocytes failed to transfer the tolerance into naive animals. In contrast, the feeding of colitis-extracted proteins, without NK1.1+ LAL depletion, markedly alleviated the disease. Tolerized mice had higher IL4 and TGF-beta1 and lower IFN-gamma serum levels, and adoptive transfer of their suppressor splenocytes markedly alleviated colitis in naive recipients. NK1.1+ LAL plays a critical role in oral tolerance induction. Depletion of this subset of LAL prevents a shift from Th1 to a Th2 type of immune response, hindering the ability to induce immune tolerance.