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  • 1.
    Aberg, Carola Höglund
    et al.
    Umeå University, Faculty of Medicine, Odontology. Umeå University, Faculty of Medicine, Odontology, Periodontology.
    Sjödin, Bengt
    Lakio, Laura
    Pussinen, Pirkko J
    Johansson, Anders
    Umeå University, Faculty of Medicine, Odontology. Umeå University, Faculty of Medicine, Odontology, Periodontology.
    Claesson, Rolf
    Umeå University, Faculty of Medicine, Odontology. Umeå University, Faculty of Medicine, Odontology, Oral Microbiology.
    Presence of Aggregatibacter actinomycetemcomitans in young individuals: a 16-year clinical and microbiological follow-up study.2009In: Journal of clinical periodontology, ISSN 1600-051X, Vol. 36, no 10, p. 815-22Article in journal (Refereed)
    Abstract [en]

    AIM: To look for clinical signs of periodontal disease in young adults who exhibited radiographic bone loss and detectable numbers of Aggregatibacter actinomycetemcomitans in their primary dentition. MATERIAL AND METHODS: Periodontal status and radiographic bone loss were examined in each of the subjects 16 years after the baseline observations. Techniques for anaerobic and selective culture, and checkerboard, were used to detect periodontitis-associated bacterial species. The isolated A. actinomycetemcomitans strains were characterized by polymerase chain reaction. RESULTS: Signs of localized attachment loss were found in three out of the 13 examined subjects. A. actinomycetemcomitans was recovered from six of these subjects and two of these samples were from sites with deepened probing depths and attachment loss. Among the isolated A. actinomycetemcomitans strains, serotypes a-c and e, but not d or f, were found. None of the isolated strains belonged to the highly leucotoxic JP2 clone, and one strain lacked genes for the cytolethal distending toxin. CONCLUSIONS: This study indicates that the presence of A. actinomycetemcomitans and early bone loss in the primary dentition does not necessarily predispose the individual to periodontal attachment loss in the permanent dentition.

  • 2. Aleksandrova, Krasimira
    et al.
    Boeing, Heiner
    Nöthlings, Ute
    Jenab, Mazda
    Fedirko, Veronika
    Kaaks, Rudolf
    Lukanova-McGregor, Annekatrin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Boffetta, Paolo
    Trepo, Elisabeth
    Westhpal, Sabine
    Duarte-Salles, Talita
    Stepien, Magdalena
    Overvad, Kim
    Tjønneland, Anne
    Halkjær, Jytte
    Boutron-Ruault, Marie-Christine
    Dossus, Laure
    Racine, Antoine
    Lagiou, Pagona
    Bamia, Christina
    Benetou, Vassiliki
    Agnoli, Claudia
    Palli, Domenico
    Panico, Salvatore
    Tumino, Rosario
    Vineis, Paolo
    Bueno-de-Mesquita, Bas
    Peeters, Petra H
    Gram, Inger Torhild
    Lund, Eiliv
    Weiderpass, Elisabete
    Quirós, J Ramón
    Agudo, Antonio
    Sánchez, María-José
    Gavrila, Diana
    Barricarte, Aurelio
    Dorronsoro, Miren
    Ohlsson, Bodil
    Lindkvist, Björn
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Khaw, Kay-Tee
    Wareham, Nicholas
    Travis, Ruth C
    Riboli, Elio
    Pischon, Tobias
    Inflammatory and metabolic biomarkers and risk of liver and bilary tract cancer2014In: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 60, no 3, p. 858-871Article in journal (Refereed)
    Abstract [en]

    Obesity and associated metabolic disorders have been implicated in liver carcinogenesis; however there is little data on the role of obesity-related biomarkers on liver cancer risk. We studied prospectively the association of inflammatory and metabolic biomarkers with risks of hepatocellular carcinoma (HCC), intra-hepatic bile duct (IBD) and gallbladder and bilary tract cancers outside of the liver (GBTC) in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC). Over an average of 7.7 years, 296 participants developed HCC (n=125), GBTC (n=137) or IBD (n=34). Using risk set sampling, controls were selected in a 2:1 ratio and matched for recruitment center, age, sex, fasting status, time of blood collection. Baseline serum concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), C-peptide, total, high-molecular-weight (HMW) adiponectin, leptin, fetuin-a, and glutamatdehydrogenase (GLDH) were measured and incidence rate ratios (IRRs) and 95% confidence intervals (CI-s) estimated using conditional logistic regression. After adjustment for lifestyle factors, diabetes, hepatitis infection and adiposity measures, higher concentrations of CRP, IL-6, C-peptide and non-HMW adiponectin were associated with higher risk of HCC (IRR per doubling of concentrations = 1.22; 95%CI = 1.02-1.46, P=0.03; 1.90; 95%CI = 1.30-2.77, P=0.001; 2.25; 95%CI = 1.43-3.54, P=0.0005 and 2.09; 95%CI = 1.19-3.67, P=0.01, respectively). CRP was associated also with risk of GBTC (IRR = 1.22; 95%CI = 1.05-1.42, P=0.01). GLDH was associated with risks of HCC (IRR = 1.62; 95%CI = 1.25-2.11, P=0.0003) and IBD (IRR = 10.5; 95%CI = 2.20-50.90, P=0.003). The continuous net reclassification index was 0.63 for CRP, IL-6, C-peptide and non-HMW adiponectin, and 0.46 for GLDH indicating good predictive ability of these biomarkers. Conclusion: Elevated levels of biomarkers of inflammation and hyperinsulinemia are associated with a higher risk of HCC, independent of obesity and established liver cancer risk factors.

  • 3. Al-Otaibi, M
    et al.
    Al-Harthy, M
    Gustafsson, A
    Johansson, Anders
    Umeå University, Faculty of Medicine, Odontology, Periodontology.
    Claesson, Rolf
    Umeå University, Faculty of Medicine, Odontology, Oral Microbiology.
    Angmar-Månsson, B
    Subgingival plaque microbiota in Saudi Arabians after use of miswak chewing stick and toothbrush2004In: Journal of Clinical Periodontology, ISSN 0303-6979, E-ISSN 1600-051X, Vol. 31, no 12, p. 1048-53Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The chewing stick, the miswak, is used in many developing countries as the traditional means for oral hygiene. It is prepared from the roots, twigs and stem of Salvadora persica or other alternative local plants. OBJECTIVES: To compare the effects of the chewing stick miswak (from S. persica) and toothbrush on subgingival plaque microflora among Saudi Arabian individuals. Further, to investigate whether components extracted from S. persica may interfere with the subgingival plaque micro-organisms. MATERIAL AND METHODS: Fifteen healthy Saudi Arabian male volunteers aged 21-36 years were included in a single-blind, randomized cross-over study. The participants were taught how to use each device properly. Plaque sampling for DNA test was performed at the baseline, 1 week after professional tooth cleaning, and after 3 weeks of either miswak or toothbrush use. Identification and quantification of microbial species were performed by the checkerboard method, using whole genomic, digoxigenin-labelled DNA probes. Inhibition zones around miswak were examined on agar plates with Actinobacillus actinomycetemcomitans and the leukotoxicity of this bacterium was analyzed in a bioassay with macrophages+/-extracts of miswak. RESULTS: Miswak and toothbrushing had a similar influence on the levels of the subgingival microbiota. However, A. actinomycetemcomitans was significantly more reduced by miswak (p<0.05) than by toothbrushing. These results were supported by our in vitro results which, indicated that extracts from S. persica might interfere with the growth and leukotoxicity of A. actinomycetemcomitans. CONCLUSIONS: In contrast to toothbrush use, miswak use significantly reduced the amount of A. actinomycetemcomitans in the subgingival plaque.

  • 4.
    Behnam Motlagh, Parviz
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Tyler, Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Brännstrom, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Co-expression of Globotriasosylceramide (Gb3) With MDR1 in Cisplatin-resistant Pleural Mesothelioma and Non-small Cell Lung Cancer Cell May Lead to a New Tumour Resistance Treatment Approach2011Conference paper (Refereed)
  • 5.
    Behnam-Mothlag, Parviz
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Tyler, Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Karlsson, Terese
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Cisplatin Resistance in Malignant Pleural Mesothelioma2012In: Mesotheliomas: Synonyms and Definition, Epidemiology, Etiology, Pathogenesis, Cyto-Histopathological Features, Clinic, Diagnosis, Treatment, Prognosis / [ed] Alexander Zubritsky, Zagreb: InTech, 2012, Vol. 11, p. 169-186Chapter in book (Refereed)
  • 6.
    Behnam-Motlagh, Parviz
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Tyler, Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Verotoxin-1 Treatment or Manipulation of its Receptor Globotriaosylceramide (Gb3) for Reversal of Multidrug Resistance to Cancer Chemotherapy2010In: Toxins, ISSN 2072-6651, Vol. 2, no 10, p. 2467-2477Article, review/survey (Refereed)
    Abstract [en]

    A major problem with anti-cancer drug treatment is the development of acquired multidrug resistance (MDR) of the tumor cells. Verotoxin-1 (VT-1) exerts its cytotoxicity by targeting the globotriaosylceramide membrane receptor (Gb3), a glycolipid associated with multidrug resistance. Gb3 is overexpressed in many human tumors and tumor cell lines with inherent or acquired MDR. Gb3 is co-expressed and interplays with the membrane efflux transporter P-gp encoded by the MDR1 gene. P-gp could act as a lipid flippase and stimulate Gb3 induction when tumor cells are exposed to cancer chemotherapy. Recent work has shown that apoptosis and inherent or acquired multidrug resistance in Gb3-expressing tumors could be affected by VT-1 holotoxin, a sub-toxic concentration of the holotoxin concomitant with chemotherapy or its Gb3-binding B-subunit coupled to cytotoxic or immunomodulatory drug, as well as chemical manipulation of Gb3 expression. The interplay between Gb3 and P-gp thus gives a possible physiological approach to augment the chemotherapeutic effect in multidrug resistant tumors.

  • 7. Belibasakis, George
    et al.
    Brage, Monica
    Umeå University, Faculty of Medicine, Odontology, Periodontology. Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Lagergård, Teresa
    Johansson, Anders
    Umeå University, Faculty of Medicine, Odontology.
    Cytolethal distending toxin upregulates RANKL expression in Jurkat T-cells: Cdt upregulates RANKL2008In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 116, no 6, p. 499-506Article in journal (Refereed)
    Abstract [en]

    Cytolethal distending toxin, a bacterial exotoxin produced by a number of Gram-negative species, causes growth arrest and morphological alterations in host cells. Among these species are Haemophilus ducreyi, the etiological agent of chancroid, and the periodontal pathogen Aggregatibacter actinomycetemcomitans, highly implicated in localized aggressive periodontitis. CDT induces receptor activator of NF-kappaB ligand (RANKL) expression in periodontal fibroblasts, the key bone-resorbing cytokine. T-cells are actively involved in localized inflammation-induced bone destruction, including periodontitis. The aim of this study was to investigate the effects of purified CDT on the expression of RANKL and its decoy receptor osteoprotegerin (OPG), in the Jurkat T-cell line. Quantitative real-time PCR indicated that 100 pg/ml of purified H. ducreyi CDT upregulated RANKL mRNA expression by 2.2-fold, after 24 h of exposure. This increase was corroborated by a 2.0-fold increase in RANKL protein release, as determined by ELISA. OPG was not detected in this experimental system. In conclusion, CDT enhances RANKL expression in T-cells, denoting that these cells are a potential target for the toxin and strengthening the potential link between this virulence factor and mechanisms associated with localized bone resorption.

  • 8. Belibasakis, Georgios N
    et al.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Aggregatibacter actinomycetemcomitans targets NLRP3 and NLRP6 inflammasome expression in human mononuclear leukocytes2012In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 59, no 1, p. 124-130Article in journal (Refereed)
    Abstract [en]

    Periodontitis is an inflammatory condition that destroys the tooth-supporting tissues, as a result of local bacterial infection. Aggregatibacter actinomycetemcomitans is a Gram-negative facultative anaerobic species, highly associated with aggressive periodontitis. Periodontal inflammation is dominated by cytokines of the Interleukin (IL)-1 family. Prior to their secretion by mononuclear cells, IL-1 cytokines are processed by intracellular protein complexes, known as "inflammasomes", which can sense the bacterial challenge. The aim of this study was to investigate which inflammasomes are regulated in mononuclear cells in response to A. actinomycetemcomitans. The D7SS strain and its derivative leukotoxin and cytolethal distending toxin knock-out mutant strains were used to infect human mononuclear cells at a 1:10 cell: bacteria ratio, for 3h. The expression of various inflammasome components in the cells was investigated by TaqMan quantitative real-time polymerase chain reaction (qPCR). The expressions of NOD-like receptor protein (NLRP)1, NLRP2 and Absent In Melanoma (AIM)2 inflammasome sensors, as well as their effector Caspase-1 were not affected. However, NLRP3 was up-regulated, while NLRP6 was down-regulated. This effect was not dependent on the leukotoxin or the cytolethal distending toxin, as demonstrated by the use of specific gene knock-out mutant strains. IL-1β and IL-18 expressions were also up-regulated by the bacterial challenge. In conclusion, A. actinomycetemcomitans enhances NLRP3 and reduces NLRP6 inflammasome expression, irrespective of its major virulence factors, confirming the high pathogenic profile of this species, and providing further insights to the mechanisms of periodontal inflammation.

  • 9.
    Belibasakis, Georgios N
    et al.
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology. Umeå University, Faculty of Medicine, Odontology, Oral Microbiology.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Odontology, Periodontology.
    Wang, Y
    Chen, C
    Kalfas, S
    Lerner, Ulf
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    The cytolethal distending toxin induces receptor activator of NF-κB ligand expression in human gingival fibroblasts and periodontal ligament cells2005In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 73, no 1, p. 342-351Article in journal (Refereed)
    Abstract [en]

    Actinobacillus actinomycetemcomitans is associated with localized aggressive periodontitis, a disease characterized by rapid loss of the alveolar bone surrounding the teeth. Receptor activator of NF-kappaB Ligand (RANKL) and osteoprotegerin (OPG) are two molecules that regulate osteoclast formation and bone resorption. RANKL induces osteoclast differentiation and activation, whereas OPG blocks this process by acting as a decoy receptor for RANKL. The purpose of this study was to investigate the effect of A. actinomycetemcomitans on the expression of RANKL and OPG in human gingival fibroblasts and periodontal ligament cells. RANKL mRNA expression was induced in both cell types challenged by A. actinomycetemcomitans extract, whereas OPG mRNA expression remained unaffected. Cell surface RANKL protein was also induced by A. actinomycetemcomitans, whereas there was no change in OPG protein secretion. A cytolethal distending toxin (Cdt) gene-knockout strain of A. actinomycetemcomitans did not induce RANKL expression, in contrast to its wild-type strain. Purified Cdt from Haemophilus ducreyi alone, or in combination with extract from the A. actinomycetemcomitans cdt mutant strain, induced RANKL expression. Pretreatment of A. actinomycetemcomitans wild-type extract with Cdt antiserum abolished RANKL expression. In conclusion, A. actinomycetemcomitans induces RANKL expression in periodontal connective tissue cells. Cdt is crucial for this induction and may therefore be involved in the pathological bone resorption during the process of localized aggressive periodontitis.

  • 10.
    Belibasakis, Georgios N
    et al.
    Umeå University, Faculty of Medicine, Odontology, Oral Microbiology. Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Odontology, Periodontology.
    Wang, Y
    Chen, C
    Lagergård, T
    Kalfas, S
    Lerner, Ulf
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Cytokine responses of human gingival fibroblasts to Actinobacillus actinomycetemcomitans cytolethal distending toxin2005In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 30, no 2, p. 56-63Article in journal (Refereed)
    Abstract [en]

    Actinobacillus actinomycetemcomitans is implicated in the pathogenesis of localized aggressive periodontitis, and has the capacity to express a cytolethal distending toxin (Cdt). Gingival fibroblasts (GF) are resident cells of the periodontium, which can express several osteolytic cytokines. The aims of this study were a) to investigate the role of Cdt in A. actinomycetemcomitans-induced expression of osteolytic cytokines and their cognate receptors in GF and b) to determine if the previously demonstrated induction of receptor activator of NFkappaB ligand (RANKL) by A. actinomycetemcomitans is mediated by these pro-inflammatory cytokines or by prostaglandin E(2) (PGE(2)). A. actinomycetemcomitans clearly induced interleukin (IL)-6, IL-1beta, and to a minimal extent, tumor necrosis factor (TNF)-alpha mRNA expression. At the protein level, IL-6 but not IL-1beta or TNF-alpha expression was stimulated. The mRNA expression of the different receptor subtypes recognizing IL-6, IL-1beta and TNF-alpha was not affected. A cdt-knockout strain of A. actinomycetemcomitans had similar effects on cytokine and cytokine receptor mRNA expression, compared to its parental wild-type strain. Purified Cdt stimulated IL-6, but not IL-1beta or TNF-alpha protein biosynthesis. Antibodies neutralizing IL-6, IL-1 or TNF-alpha, and the PGE(2) synthesis inhibitor indomethacin, did not affect A. actinomycetemcomitans-induced RANKL expression. In conclusion, a) A. actinomycetemcomitans induces IL-6 production in GF by a mechanism largely independent of its Cdt and b) A. actinomycetemcomitans-induced RANKL expression in GF occurs independently of IL-1, IL-6, TNF-alpha, or PGE(2).

  • 11.
    Belibasakis, Georgios N
    et al.
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology. Umeå University, Faculty of Medicine, Odontology, Oral Microbiology.
    Mattsson, Anna
    Umeå University, Faculty of Medicine, Odontology, Periodontology.
    Wang, Ying
    Chen, Casey
    Johansson, Anders
    Umeå University, Faculty of Medicine, Odontology, Periodontology.
    Cell cycle arrest of human gingival fibroblasts and periodontal ligament cells by Actinobacillus actinomycetemcomitans: involvement of the cytolethal distending toxin2004In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 112, no 10, p. 674-685Article in journal (Refereed)
    Abstract [en]

    The cytolethal distending toxin (Cdt) is produced by several Gram-negative bacterial species and causes growth arrest and morphological alterations in mammalian cells. Actinobacillus actinomycetemcomitans, which is involved in the pathogenesis of localized aggressive periodontitis, also produces a Cdt that affects periodontal connective tissue cells. The aim of this study was to investigate in which phase of the cell cycle these cells are arrested and enlarged when challenged with A. actinomycetemcomitans, and to evaluate the involvement of its Cdt. Human gingival fibroblasts and periodontal ligament cells were challenged with A. actinomycetemcomitans extract, or with purified Cdt, and cell cycle analysis was performed by propidium iodide staining and flow cytometry. Cells exposed to an A. actinomycetemcomitans wild-type strain, or to purified Cdt, were arrested in both G1 and G2/M phases, and appeared enlarged compared to the corresponding controls. The cellular enlargement occurred in both G1 and G2/M arrested cells. In contrast, cells exposed to an A. actinomycetemcomitans cdt-knockout mutant strain showed cell cycle phase distribution and size similar to the controls. In conclusion, A. actinomycetemcomitans causes a combined G1 and G2/M growth arrest and enlargement in periodontal connective tissue cells, which is attributed to its Cdt.

  • 12. Belibasakis, GN
    et al.
    Bostanci, N
    Hashim, A
    Johansson, Anders
    Umeå University, Faculty of Medicine, Odontology, Periodontology.
    Aduse-Opoku, J
    Curtis, MA
    Hughes, FJ
    Regulation of RANKL and OPG gene expression in human gingival fibroblasts and periodontal ligament cells by Porphyromonas gingivalis: a putative role of the Arg-gingipains2007In: Microbial Pathogenesis, ISSN 0882-4010, E-ISSN 1096-1208, Vol. 43, no 1, p. 46-53Article in journal (Refereed)
    Abstract [en]

    Porphyromonas gingivalis is highly implicated in the pathogenesis of periodontitis, which is characterized by the destruction of periodontal connective tissues and the supporting alveolar bone. Receptor Activator of NF-kappaB Ligand (RANKL) stimulates bone resorption, whereas osteoprotegerin (OPG) blocks its action, and this bi-molecular system is implicated in periodontitis. The aim of this work was (a) to investigate the regulation of RANKL and OPG gene expression in human periodontal ligament (PDL) cells and gingival fibroblasts (GF), in response to P. gingivalis culture supernatants, by quantitative real-time PCR and (b) to attempt to identify putative virulence factors involved in this process. The results indicated that P. gingivalis induced RANKL and reduced OPG mRNA expression by the studied cells, resulting in an increased RANKL/OPG expression ratio. Heat-inactivation of P. gingivalis resulted in significant reduction of RANKL mRNA expression. A Lys-gingipain mutant strain did not affect, whereas an Arg-gingipain mutant strain further enhanced RANKL mRNA expression, compared to their parental wild-type strain. In conclusion, P. gingivalis up-regulates the RANKL/OPG expression ratio in GF and PDL cells, denoting an enhanced osteoclastogenic potential by the cells. The component mainly responsible for RANKL induction appears to be proteinaceous, and it may be regulated by the Arg-gingipains.

  • 13.
    Boles, Usama
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology. Cardiology Department, Letterkenny University Hospital, Letterkenny, Co. Donegal, Ireland.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Wiklund, Urban
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Sharif, Zain
    David, Santhosh
    McGrory, Siobhan
    Henein, Michael Y.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology. Molecular & Clinical Sciences Research Institute, St. George University, London, UK.
    Cytokine Disturbances in Coronary Artery Ectasia Do Not Support Atherosclerosis Pathogenesis2018In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 19, no 1, article id 260Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Coronary artery ectasia (CAE) is a rare disorder commonly associated with additional features of atherosclerosis. In the present study, we aimed to examine the systemic immune-inflammatory response that might associate CAE.

    METHODS: Plasma samples were obtained from 16 patients with coronary artery ectasia (mean age 64.9 ± 7.3 years, 6 female), 69 patients with coronary artery disease (CAD) and angiographic evidence for atherosclerosis (age 64.5 ± 8.7 years, 41 female), and 140 controls (mean age 58.6 ± 4.1 years, 40 female) with normal coronary arteries. Samples were analyzed at Umeå University Biochemistry Laboratory, Sweden, using the V-PLEX Pro-Inflammatory Panel 1 (human) Kit. Statistically significant differences (p < 0.05) between patient groups and controls were determined using Mann-Whitney U-tests.

    RESULTS: The CAE patients had significantly higher plasma levels of INF-γ, TNF-α, IL-1β, and IL-8 (p = 0.007, 0.01, 0.001, and 0.002, respectively), and lower levels of IL-2 and IL-4 (p < 0.001 for both) compared to CAD patients and controls. The plasma levels of IL-10, IL-12p, and IL-13 were not different between the three groups. None of these markers could differentiate between patients with pure (n = 6) and mixed with minimal atherosclerosis (n = 10) CAE.

    CONCLUSIONS: These results indicate an enhanced systemic pro-inflammatory response in CAE. The profile of this response indicates activation of macrophages through a pathway and trigger different from those of atherosclerosis immune inflammatory response.

  • 14. Bougas, Kostas
    et al.
    Ransjö, Maria
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Effects of Porphyromonas gingivalis surface-associated material on osteoclast formation2013In: Odontology: official journal of The Society of the Nippon Dental University, ISSN 1618-1247, E-ISSN 1618-1255, Vol. 101, no 2, p. 141-149Article in journal (Refereed)
    Abstract [en]

    Porphyromonas gingivalis strongly correlates with periodontitis, but the underlying mechanisms causing dentoalveolar bone resorption are not fully understood. As contradictory effects of P. gingivalis on osteoclastogenesis have been reported, this study investigates the effect of P. gingivalis extract on osteoclast formation. Osteoclast formation in mouse bone marrow (MBM) cell cultures and RAW 264.7 cells was stimulated by nuclear factor-κB ligand (RANKL) or parathyroid hormone (PTH). Cells were cultured with and without P. gingivalis surface-associated material and phenotypic characteristics were examined using microscopy, flow cytometry, and RT-PCR. P. gingivalis significantly decreased osteoclast formation and the expression of osteoclast phenotypic markers in PTH-stimulated MBM cultures. Additionally, P. gingivalis inhibited expression of osteoclast differentiation factors and stimulated expression of the mouse macrophage marker F4/80. The presence of P. gingivalis in RANKL-stimulated MBM cultures and RAW 264.7 cells inhibited osteoclastogenesis. Interestingly, a transient exposure with P. gingivalis before PTH stimulation increased osteoclastogenesis in MBM cultures. Flow cytometric analyses of cells transiently exposed to P. gingivalis demonstrated an increased proportion of potential osteoclast precursor cells. We conclude that a transient exposure of MBM cultures to P. gingivalis increases the number of osteoclast precursors and osteoclast formation, whereas a prolonged exposure completely abolishes osteoclastogenesis.

  • 15.
    Brage, Monica
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Holmlund, A
    Umeå University, Faculty of Medicine, Department of Odontology.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Humoral immune response to Aggregatibacter actinomycetemcomitans leukotoxin2011In: Journal of Periodontal Research, ISSN 0022-3484, E-ISSN 1600-0765, Vol. 46, no 2, p. 170-175Article in journal (Refereed)
    Abstract [en]

    Background and Objective: Periodontal disease is an inflammatory condition caused by bacterial infections that result in loss of the tooth supporting tissue. The periodontal pathogens produce virulence factors with capacity to affect the host immune response. Aggregatibacter actinomycetemcomitans is a periodontal pathogen that produces a leukotoxin that specifically affects human leukocytes. The aims of the present study were to examine the presence and function of systemic antibodies to the leukotoxin. Material and Methods:  One hundred and ninety-seven middle-aged (57 ± 5 years) Swedes with well-documented periodontal status and medical factors related to cardiovascular diseases were studied. These data have been published previously. The serum samples were examined for the presence of leukotoxin antibodies by western blot and the capacity to neutralize leukotoxicity in an activity assay with leukotoxin and cultured leukemic cells. Results:  The results showed a high prevalence (57%) of antibodies against A. actinomycetemcomitans leukotoxin in the analyzed population. These antibodies were correlated with leukotoxin neutralizing capacity as well as with the ELISA titers of A. actinomycetemcomitans-specific IgA and IgG. In addition, high levels of leukotoxin antibodies were correlated with increasing age, but not with periodontal disease parameters or cardiovascular risk factors. Conclusion:  Systemic antibodies against A. actionmycetemcomitans leukotoxin were common in this adult Swedish population. These antibodies might contribute to limit the systemic effects of the infection.

  • 16.
    Brundin, Malin
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Figdor, David
    Department of Microbiology, Monash University, Melbourne, Australia.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Sjögren, Ulf
    Umeå University, Faculty of Medicine, Department of Odontology.
    Preservation of bacterial dna by human dentin2014In: Journal of Endodontics, ISSN 0099-2399, E-ISSN 1878-3554, Vol. 40, no 2, p. 241-245Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: The capacity of dentin and collagen to bind DNA and protect against spontaneous and nuclease-induced degradation was evaluated individually and by the incubation of DNA with nuclease-producing bacteria in a mixed culture.

    METHODS: Extracted Fusobacterium nucleatum DNA was incubated with dentin shavings or collagen for 90 minutes. The DNA-bound substrates were incubated in different media (water, sera, and DNase I) for up to 3 months. Amplifiable DNA was released from dentin using EDTA,or from collagen using proteinase K, and evaluated by polymerase chain reaction (PCR). The stability of dentin-bound DNA was also assessed in a mixed culture (Parvimonas micra and Pseudoramibacter alactolyticus) containing a DNase-producing species, Prevotella intermedia. Samples were analyzed for amplifiable DNA.

    RESULTS: In water, dentin-bound DNA was recoverable by PCR at 3 months compared with no detectable DNA after 4 weeks in controls (no dentin). DNA bound to collagen was detectable by PCR after 3 months of incubation in water. In 10% human sera, amplifiable DNA was detectable at 3 months when dentin bound and in controls (no dentin). In mixed bacterial culture, dentin-bound DNA was recoverable throughout the experimental period (3 months), compared with no recoverable F. nucleatum DNA within 24 hours in controls (no dentin).

    CONCLUSIONS: There is a strong binding affinity between DNA and dentin, and between DNA and serum proteins or collagen. These substrates preserve DNA against natural decomposition and protect DNA from nuclease activity, factors that may confound molecular analysis of the endodontic microbiota yet favor paleomicrobiological studies of ancient DNA.

  • 17. Buhlin, Kare
    et al.
    Holmer, Jacob
    Gustafsson, Anders
    Hörkkö, Sohvi
    Pockley, Alan Graham
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Paju, Susanna
    Klinge, Björn
    Pussinen, Pirkko
    Association of periodontitis with persistent, pro-atherogenic antibody responses2015In: Journal of Clinical Periodontology, ISSN 0303-6979, E-ISSN 1600-051X, Vol. 42, no 11, p. 1006-1014Article in journal (Refereed)
    Abstract [en]

    AIM: To study antibody responses associated with molecular mimicry in periodontitis.

    MATERIAL AND METHODS: Fifty-four periodontitis cases (mean age 54.0 years) and 44 controls (53.6 years) were examined, after which cases received periodontal treatment. Established immunoassays were used to analyse levels of antibodies against two pathogens, Aggregatibacter actinomycetemcomitans (Aa) and Porphyromonas gingivalis (Pg), heat shock proteins (Hsp), Hsp60, Hsp65, and Hsp70, and epitopes of oxidized low density lipoprotein (oxLDL) (CuOx-LDL and MDA-LDL) in plasma samples that were collected at baseline, after 3 (n=48) and 6 (n=30) months.

    RESULTS: When age, sex, smoking habit, and the number of teeth were considered in multivariate logistic regressions, Aa and Pg IgG, Hsp65-IgA, CuOx-LDL-IgG and -IgM and MDA-LDL-IgG antibody levels were associated with periodontitis, whereas Hsp60-IgG2 antibody levels were inversely associated. The Aa antibody levels significantly correlated with the levels of IgA antibodies to Hsp65 and Hsp70, and both OxLDL IgA-antibody levels. The levels of antibodies to Pg correlated with IgG antibodies to Hsp60, Hsp70 and both oxLDL antibody epitopes. None of the antibody levels changed significantly after treatment.

    CONCLUSIONS: Periodontitis is associated with persistently high levels of circulating antibodies that are reactive with pathogen- and host-derived antigens.

  • 18.
    Bylund, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Saarinen, Niina
    Zhang, Jie-Xian
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology, Periodontology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Adlercreutz, Herman
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Mäkelä, Sari
    Anticancer effects of a plant lignan 7-hydroxymatairesinol on a prostate cancer model in vivo.2005In: Experimental biology and medicine (Maywood, N.J.: Print), ISSN 1535-3702, E-ISSN 1535-3699, Vol. 230, no 3, p. 217-223Article in journal (Refereed)
    Abstract [en]

    Clinical intervention studies and experimental studies with lignan-rich diets suggest that lignans may have inhibitory effects on prostate cancer, but no clinical or experimental studies with purified lignans have been published. The purpose of this study was to investigate the effect of a plant lignan 7-hydroxymatairesinol (HMR) on LNCaP human prostate cancer xenografts in athymic mice. Athymic nude male mice were injected subcutaneously with LNCaP cells. Starting 3 days after tumor cell injections, a control diet or a control diet supplemented with 0.15% or 0.30% of HMR was administered to mice and the tumor take rate and growth was observed for 9 weeks. HMR diet inhibited the growth of LNCaP tumors. Mice treated with HMR had smaller tumor volume, lower tumor take rate, increased proportion of nongrowing tumors, and higher tumor cell apoptotic index compared with controls. Furthermore, the cell proliferation index was reduced in mice receiving the 0.30% HMR diet compared with mice receiving the control diet. Our results suggest that dietary HMR started at the early phase of the tumor development inhibits the growth of the LNCaP human prostate cancer xenografts in athymic male mice.

  • 19. Carlsson, G
    et al.
    Wahlin, Ylva-Britt
    Umeå University, Faculty of Medicine, Odontology, Oral and Maxillofacial Radiology.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Odontology, Periodontology.
    Olsson, A
    Eriksson, T
    Claesson, Rolf
    Umeå University, Faculty of Medicine, Odontology.
    Hänström, Lennart
    Umeå University, Faculty of Medicine, Odontology.
    Henter, JI
    Periodontal disease in patients from the original Kostmann family with severe congenital neutropenia2006In: Journal of Periodontology, ISSN 0022-3492, E-ISSN 1943-3670, Vol. 77, no 4, p. 744-751Article in journal (Refereed)
    Abstract [en]

    Patients with Kostmann syndrome (severe congenital neutropenia [SCN]) typically normalize their absolute neutrophil count (ANC) upon granulocyte colony-stimulating factor (G-CSF) therapy. However, although they no longer experience life-threatening bacterial infections, they frequently still have recurrent gingivitis and even severe periodontitis, often starting in early childhood. METHODS: We studied the periodontal disease in the four surviving patients belonging to the family originally described by Kostmann. Their odontological records, x-rays, color photos, bacterial cultures, serum antibodies to oral bacteria, and histopathological examinations were reviewed. The data were also correlated to previous investigations on their antibacterial peptides and molecular biology. RESULTS: Three patients had periodontal disease, despite normal ANC and professional dental care, and had neutrophils deficient in antibacterial peptides. One of these patients also had a heterozygous mutation in the neutrophil elastase gene, had severe periodontal disease and overgrowth of the periodontal pathogen Actinobacillus actinomycetemcomitans in the dental flora, and 15 permanent teeth had been extracted by the age of 27. One bone marrow-transplanted patient had no periodontal disease. CONCLUSIONS: Normalized ANC levels are not sufficient to maintain normal oral health in SCN patients, and because neutrophils are important for first-line defense and innate immunity, the deficiency of the antibacterial peptide LL-37 probably explains their chronic periodontal disease. Professional dental care is still important for SCN patients, despite treatment with G-CSF and normal ANC levels. Whether antibacterial peptides play a role in the pathogenesis of periodontitis in other patients remains to be elucidated.

  • 20. Chatziioannou, Aristotelis
    et al.
    Georgiadis, Panagiotis
    Hebels, Dennie G
    Liampa, Irene
    Valavanis, Ioannis
    Bergdahl, Ingvar A
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Palli, Domenico
    Chadeau-Hyam, Marc
    Siskos, Alexandros P
    Keun, Hector
    Botsivali, Maria
    de Kok, Theo M C M
    Pérez, Almudena Espín
    Kleinjans, Jos C S
    Vineis, Paolo
    Kyrtopoulos, Soterios A
    Blood-based omic profiling supports female susceptibility to tobacco smoke-induced cardiovascular diseases2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 42870Article in journal (Refereed)
    Abstract [en]

    We recently reported that differential gene expression and DNA methylation profiles in blood leukocytes of apparently healthy smokers predicts with remarkable efficiency diseases and conditions known to be causally associated with smoking, suggesting that blood-based omic profiling of human populations may be useful for linking environmental exposures to potential health effects. Here we report on the sex-specific effects of tobacco smoking on transcriptomic and epigenetic features derived from genome-wide profiling in white blood cells, identifying 26 expression probes and 92 CpG sites, almost all of which are affected only in female smokers. Strikingly, these features relate to numerous genes with a key role in the pathogenesis of cardiovascular disease, especially thrombin signaling, including the thrombin receptors on platelets F2R (coagulation factor II (thrombin) receptor; PAR1) and GP5 (glycoprotein 5), as well as HMOX1 (haem oxygenase 1) and BCL2L1 (BCL2-like 1) which are involved in protection against oxidative stress and apoptosis, respectively. These results are in concordance with epidemiological evidence of higher female susceptibility to tobacco-induced cardiovascular disease and underline the potential of blood-based omic profiling in hazard and risk assessment.

  • 21.
    Claesson, Rolf
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Gudmundson, Jan
    Östersund, Sweden.
    Höglund-Åberg, Carola
    Umeå University, Faculty of Medicine, Department of Odontology.
    Haubek, Dorte
    Aarhus, Denmark.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Detection of a 640-bp deletion in the Aggregatibacter actinomycetemcomitans leukotoxin promoter region in isolates from an adolescent of Ethiopian origin2015In: Journal of Oral Microbiology, ISSN 2000-2297, E-ISSN 2000-2297, Vol. 7, article id 26974Article in journal (Refereed)
    Abstract [en]

    The expression of the leukotoxin of Aggregatibacter actinomycetemcomitans is regulated by the leukotoxin promoter. A 530-bp deletion or an 886-bp insertion sequence (IS) element in this region has earlier been described in highly leukotoxic isolates. Here, we report on highly leukotoxic isolate with a 640-bp deletion, which was detected in an adolescent of Ethiopian origin.

  • 22.
    Claesson, Rolf
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Höglund-Åberg, Carola
    Umeå University, Faculty of Medicine, Department of Odontology.
    Haubek, Dorte
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Age-related prevalence and characteristics of Aggregatibacter actinomycetemcomitans in periodontitis patients living in Sweden2017In: Journal of Oral Microbiology, ISSN 2000-2297, E-ISSN 2000-2297, Vol. 9, article id 1334504Article in journal (Refereed)
    Abstract [en]

    Background: The presence of Aggregatibacter actinomycetemcomitans in patients with periodontitis has been extensively studied for decades. Objective: To study the prevalence of A. actinomycetemcomitans in younger and older periodontitis patients and to genetically characterize isolates of this bacterium. Design: Data from microbiological analyses of 3459 subgingival plaque samples collected from 1445 patients, 337 'younger' patients (<= 35 yrs) and 1108 'older' patients (>35 yrs) during 15 years (2000-2014), has been summerized. Isolates of A. actinomycetemcomitans were serotyped, leukotoxin promoter typed (JP2 and non JP2) and arbitrarily primed PCR (APPCR) genotyped. The origin of the JP2 genotype detected in the study population was determined. Results: The prevalence of A. actinomycetemcomitans was higher among younger than older patients and samples from the younger patients contained higher proportions of the bacterium. Serotype b was more prevalent among younger patients and the majorty of these isolates was from the same AP-PCR genotype. The JP2 genotype was detected in 1.2% of the patients, and the majority of these carriers were of non-African origin. Conslusions: For presence and charcteristics of A. actinomycetemcomitans in clinical samples the age of the carriers were a discriminating factor. Additional, apparently non- African carriers of the JP2 genotype of A. actinomycetemcomitans were identified.

  • 23.
    Claesson, Rolf
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Kanasi, Eleni
    Umeå University, Faculty of Medicine, Department of Odontology.
    Anders, Johansson
    Umeå University, Faculty of Medicine, Department of Odontology.
    Sotirios, Kalfas
    School of Dentistry, Aristotle University of Thessaloniki, Thessaloniki, Greece.
    A new cleavage site for elastase within the complement component 32010In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 118, no 10, p. 765-768Article in journal (Refereed)
    Abstract [en]

    The lysosomal enzyme elastase was earlier shown to cleave the complement molecule C3. During somepreliminary experiments on the interactions of certain pathogenic bacteria with the innate defencemechanisms, we observed C3 cleavage, in the presence of elastase, to fragments not previouslydescribed. To elucidate this proteolytic reaction, the present study was conducted. Degradation of C3in mixtures with elastase or cathepsin G was detected by an immunoblot procedure using anti-C3c andanti-C3d antibodies after separating the proteins by SDS-PAGE. Certain C3 fragments were analysedfor amino acid sequence. The results revealed the existence of a cleavage site for elastase at the positionalanine1350 ⁄ lysine1351 of the C3 molecule, which has not been previously described. The fragmentresulted from this cleavage has a size of about 39 kDa and it contains a part or the whole of C3d. Thiscleavage was distinct from the one previously described at position 987 ⁄ 988, which gives a 34 kDaC3d-containing fragment.

  • 24.
    Claesson, Rolf
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Lagervall, Maria
    Department of Periodontology at Skanstull, Stockholm County Council, Stockholm, Sweden.
    Höglund-Åberg, Carola
    Umeå University, Faculty of Medicine, Department of Odontology.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Haubek, Dorte
    Department of Pediatric Dentistry, School of Dentistry, Aarhus, Denmark.
    Detection of the highly leucotoxic JP2 clone of Aggregatibacter actinomycetemcomitans in members of a Caucasian family living in Sweden2011In: Journal of Clinical Periodontology, ISSN 0303-6979, E-ISSN 1600-051X, Vol. 38, no 2, p. 115-121Article in journal (Refereed)
    Abstract [en]

    Background: Carriers of the JP2 clone of Aggregatibacter actinomycetemcomitans exhibit an enhanced risk for developing aggressive periodontitis compared with individuals carrying non-JP2 clones. While the JP2 clone is almost exclusively detected among adolescents of African descent, reports on Caucasians colonized with the JP2 clone are remarkably few.

    Objective: The aim of this paper is to report on the history of periodontal disease and microbiological findings in a Caucasian family.

    Material and Methods: A. actinomycetemcomitans and other periodontitis-associated bacterial species in subgingival plaque samples were quantified by conventional culture technique. Leucotoxin promoter typing, serotyping and further characterizations of A. actinomycetemcomitans isolates were performed by PCR. DNA sequencing of the pseudogene, hbpA was performed to determine the origin of the detected JP2 clones. Further, genetically ancestry testing of family members was carried out.

    Results: The JP2 clone was detected in samples from two of the family members, a 33-year-old daughter and her 62-year-old mother. Relationship of their JP2 clones with JP2 clone strains from the Mediterranean area of Africa was indicated. Genotyping confirmed the Caucasian origin of all family members.

    Conclusions: Caucasian JP2 carriers exist and older subjects can carry the JP2 clone of A. actinomycetemcomitans.

  • 25.
    Dahlén, Gunnar
    et al.
    Göteborgs Universitet.
    Claesson, Rolf
    Umeå University, Faculty of Medicine, Department of Odontology.
    Höglund Åberg, Carola
    Umeå University, Faculty of Medicine, Department of Odontology, School of Dentistry.
    Haubek, Dorte
    Aarhus University Denmark.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology, School of Dentistry.
    Kwamin, Francis
    Ghana University, Ghana.
    Subgingival bacteria in Ghanaian adolescents with or without progression of attachment loss2014In: Journal of Oral Microbiology, ISSN 2000-2297, E-ISSN 2000-2297, Vol. 6, article id 23977Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: This study describes subgingival bacterial profiles associated with clinical periodontal status in Ghanaian adolescents with or without progression of attachment loss.

    MATERIALS AND METHODS: Among 500 adolescents included in a cohort study, 397 returned 2 years later for a periodontal re-examination, including full-mouth CAL measurements. At follow-up, a subgroup of 98 adolescents was also subjected to bacterial sampling with paper points at four periodontal sites (mesial aspect of 11, 26, 31, and 46) and analyzed with the checkerboard DNA-DNA hybridization technique against DNA-probes from nine periodontitis-associated bacterial species.

    RESULTS: The 98 Ghanaian adolescents examined in the present study were similar to the entire group examined at the 2-year follow-up with respect to age, gender, and CAL ≥3 mm. A high detection frequency of Fusobacterium nucleatum and Prevotella intermedia (>99%) using checkerboard analysis was found, while for Aggregatibacter actinomycetemcomitans the detection frequency was <50%. A strong correlation was found at the individual level between the presence of P. intermedia and the total CAL change, and P. intermedia and Porphyromonas gingivalis were strongly correlated with a change in CAL and probing pocket depth (PPD) at the sampled sites. In a linear regression model, a significant discriminating factor for the total CAL change in the dentition during the 2-year follow-up period was obtained for P. intermedia and public school.

    CONCLUSION: This study indicates that subgingival bacterial species other than A. actinomycetemcomitans, for example, P. intermedia, have a significant association with periodontal breakdown (change in CAL) in Ghanaian adolescents with progression of periodontal attachment loss.

  • 26. Engström, Marianne
    et al.
    Eriksson, Kaja
    Lee, Linkiat
    Hermansson, Monika
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Nicholas, Anthony P.
    Gerasimcik, Natalija
    Lundberg, Karin
    Klareskog, Lars
    Catrina, Anca Irinel
    Yucel-Lindberg, Tülay
    Increased citrullination and expression of peptidylarginine deiminases independently of P. gingivalis and A. actinomycetemcomitans in gingival tissue of patients with periodontitis2018In: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 16, article id 214Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A relationship between rheumatoid arthritis (RA) and periodontitis has been suggested from findings that individuals with RA are prone to have advanced periodontitis and vice versa. In search of possible common pathogenetic features of these two diseases, we investigated the presence of citrullinated proteins and expression of endogenous peptidylarginine deiminases (PAD2 and PAD4), in periodontal tissue of individuals with periodontitis and healthy controls, in relation to the periodontal pathogens Porphyromonas gingivalis (P. gingivalis) and Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans), producing leukotoxin as virulence factor. These two oral bacteria have been suggested to be linked to anti-citrullinated protein antibodies in patients with RA.

    METHODS: Gingival tissue biopsies were obtained from 15 patients with periodontitis and 15 individuals without periodontal disease. Presence of CD3-positive lymphocytes, citrullinated proteins, PAD2, PAD4, P. gingivalis as well as A. actinomycetemcomitans and Mannheimia haemolytica produced leukotoxins were analysed by immunohistochemistry, followed by triple-blind semi-quantitative analysis. Mann-Whitney and Fisher's exact tests were used to analyse differences between groups. PADI2 and PADI4 mRNA levels were assessed by RT-qPCR and analysed using Wilcoxon signed rank test.

    RESULTS: Increased staining of citrullinated proteins was observed in gingival connective tissue from subjects with periodontitis (80%, 12/15) compared to healthy gingival tissue (27%, 4/15), whereas no differences were observed in gingival epithelium. There was also an increased staining of the citrullinating enzymes PAD2 and PAD4 in gingival connective tissue of patients with periodontitis whereas similar levels of PAD2 and PAD4 were observed in the gingival epithelium of the two groups. Similarly, the mRNA levels of PADI2 and PADI4 were also increased in the gingival tissue of patients with periodontitis compared to healthy controls. Furthermore, presence of P. gingivalis and leukotoxins was comparable in both epithelium and connective tissue, from the different investigated individuals with and without periodontitis, and there were no correlations between the presence of periodontal pathogens and the expression of citrullinated proteins or PAD enzymes.

    CONCLUSION: Chronic gingival inflammation is associated with increased local citrullination and PAD2 and PAD4 expression in periodontitis. The increased citrullination and PAD2 and PAD4 expression in periodontitis were, however, independent of the presence of periodontal pathogen P. gingivalis and A. actinomycetemcomitans leukotoxin.

  • 27. Fanidi, Anouar
    et al.
    Muller, David C
    Midttun, Øivind
    Ueland, Per Magne
    Vollset, Stein Emil
    Relton, Caroline
    Vineis, Paolo
    Weiderpass, Elisabete
    Skeie, Guri
    Brustad, Magritt
    Palli, Domenico
    Tumino, Rosario
    Grioni, Sara
    Sacerdote, Carlotta
    Bueno-de-Mesquita, H B As
    Peeters, Petra H
    Boutron-Ruault, Marie-Christine
    Kvaskoff, Marina
    Cadeau, Claire
    Huerta, José María
    Sánchez, Maria-José
    Agudo, Antonio
    Lasheras, Cristina
    Quirós, J Ramón
    Chamosa, Saioa
    Riboli, Elio
    Travis, Ruth C
    Ward, Heather
    Murphy, Neil
    Khaw, Kay-Tee
    Trichopoulou, Antonia
    Lagiou, Pagona
    Papatesta, Eleni-Maria
    Boeing, Heiner
    Kuehn, Tilman
    Katzke, Verena
    Steffen, Annika
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Brennan, Paul
    Johansson, Mattias
    Circulating vitamin D in relation to cancer incidence and survival of the head and neck and oesophagus in the EPIC cohort2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 36017Article in journal (Refereed)
    Abstract [en]

    Experimental and epidemiological data suggest that vitamin D play a role in pathogenesis and progression of cancer, but prospective data on head and neck cancer (HNC) and oesophagus cancer are limited. The European Prospective Investigation into Cancer and Nutrition (EPIC) study recruited 385,747 participants with blood samples between 1992 and 2000. This analysis includes 497 case-control pairs of the head and neck and oesophagus, as well as 443 additional controls. Circulating 25(OH)D3 were measured in pre-diagnostic samples and evaluated in relation to HNC and oesophagus cancer risk and post-diagnosis all-cause mortality. After controlling for risk factors, a doubling of 25(OH)D3 was associated with 30% lower odds of HNC (OR 0.70, 95% confidence interval [95% CI] 0.56-0.88, Ptrend = 0.001). Subsequent analyses by anatomical sub-site indicated clear inverse associations with risk of larynx and hypopharynx cancer combined (OR 0.55, 95CI% 0.39-0.78) and oral cavity cancer (OR 0.60, 95CI% 0.42-0.87). Low 25(OH)D3 concentrations were also associated with higher risk of death from any cause among HNC cases. No clear association was seen with risk or survival for oesophageal cancer. Study participants with elevated circulating concentrations of 25(OH)D3 had decreased risk of HNC, as well as improved survival following diagnosis.

  • 28. Georgiadis, Panagiotis
    et al.
    Hebels, Dennie G
    Valavanis, Ioannis
    Liampa, Irene
    Bergdahl, Ingvar A
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Palli, Domenico
    Chadeau-Hyam, Marc
    Chatziioannou, Aristotelis
    Jennen, Danyel G J
    Krauskopf, Julian
    Jetten, Marlon J
    Kleinjans, Jos C S
    Vineis, Paolo
    Kyrtopoulos, Soterios A
    Omics for prediction of environmental health effects: Blood leukocyte-based cross-omic profiling reliably predicts diseases associated with tobacco smoking.2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 20544Article in journal (Refereed)
    Abstract [en]

    The utility of blood-based omic profiles for linking environmental exposures to their potential health effects was evaluated in 649 individuals, drawn from the general population, in relation to tobacco smoking, an exposure with well-characterised health effects. Using disease connectivity analysis, we found that the combination of smoking-modified, genome-wide gene (including miRNA) expression and DNA methylation profiles predicts with remarkable reliability most diseases and conditions independently known to be causally associated with smoking (indicative estimates of sensitivity and positive predictive value 94% and 84%, respectively). Bioinformatics analysis reveals the importance of a small number of smoking-modified, master-regulatory genes and suggest a central role for altered ubiquitination. The smoking-induced gene expression profiles overlap significantly with profiles present in blood cells of patients with lung cancer or coronary heart disease, diseases strongly associated with tobacco smoking. These results provide proof-of-principle support to the suggestion that omic profiling in peripheral blood has the potential of identifying early, disease-related perturbations caused by toxic exposures and may be a useful tool in hazard and risk assessment.

  • 29.
    Gonzales, Jose Roberto
    et al.
    Department of Periodontology, Justus-Liebig University of Giessen.
    Groeger, Sabine
    Department of Periodontology, Justus-Liebig University of Giessen.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Meyle, Jörg
    Department of Periodontology, Justus-Liebig University of Giessen.
    T helper cells from aggressive periodontitis patients produce higher levels of interleukin-1 beta and interleukin-6 in interaction with Porphyromonas gingivalis2014In: Clinical Oral Investigations, ISSN 1432-6981, E-ISSN 1436-3771, Vol. 18, no 7, p. 1835-1843Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: In this study, we analyzed the production of Interleukin-1 beta (IL-1β) and IL-6 by activated CD4+ cells obtained from aggressive periodontitis (AgP) patients in comparison with healthy subjects (HC).

    MATERIALS AND METHODS: CD4+ cells were automatically separated from lymphocytes obtained from peripheral blood of patients with AgP and healthy controls. Cells were activated for 4, 8, and 24 h with three different stimuli: anti-CD3/anti-CD28, phytohemagglutinin (PHA), and Porphyromonas gingivalis (P. gingivalis) outer membrane protein (OMP). Protein levels were measured in supernatants of activated CD4+ cells by a bead-based immunoassay (CBA). In addition, serum antibodies against P. gingivalis were determined. Data were analyzed using U test (p < 0.05).

    RESULTS: T helper cells of AgP patients activated with P. gingivalis OMP produced higher levels of IL-1β and IL-6 in comparison with healthy controls (p < 0.05). Neither the activation with anti-CD3/anti-CD28 nor the activation with PHA showed significantly different production of IL-1β and IL-6 by the cells 25 % of patients and 17 % of controls presented with high serum reactivity to P. gingivalis.

    CONCLUSION: In view of these results, it is possible to conclude that P. gingivalis contributes to the pathogenesis of AgP by inducing high levels of pro-inflammatory cytokines such as IL-1β and IL-6 by peripheral CD4+ T helper cells.

    CLINICAL RELEVANCE: In accordance with the clinical parameters and the immunological data, we suggest that full-mouth disinfection with adjunctive systemic antibiotics might be the anti-infectious non-surgical periodontal treatment of choice in this type of patients. Microbiological analyses at the beginning and at the end of the periodontal treatment are recommended. However, it is necessary to verify these data in longitudinal clinical studies.

  • 30.
    Hallmans, Göran
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Agren, A
    Johansson, G
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology, Periodontology.
    Stegmayr, Birgitta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Jansson, JH
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lindahl, B
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Nilsson, M
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology, Cariology.
    Weinehall, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Cardiovascular disease and diabetes in the Northern Sweden Health and Disease Study Cohort: evaluation of risk factors and their interactions.2003In: Scandinavian Journal of Public Health. Supplement Links, ISSN 1403-4956, Vol. 61, p. 18-24Article in journal (Refereed)
    Abstract [en]

    The purpose of this paper is, first, to describe the organization, sampling procedures, availability of samples/database, ethical considerations, and quality control program of the Northern Sweden Health and Disease Study Cohort. Secondly, some examples are given of studies on cardiovascular disease and diabetes with a focus on the biomarker programme. The cohort has been positioned as a national and international resource for scientific research.

  • 31.
    Hallmans, Göran
    et al.
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Nutritional Research.
    Zhang, Jie-Xian
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Nutritional Research.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Stattin, P
    Johansson, Anders
    Umeå University, Faculty of Medicine, Odontology, Periodontology.
    Johansson, I
    Hultén, K
    Winkvist, A
    Aman, P
    Lenner, P
    Adlercreutz, H
    Rye, lignans and human health2003In: Proceedings of the Nutrition Society, ISSN 0029-6651, E-ISSN 1475-2719, Vol. 62, no 1, p. 193-9Article in journal (Refereed)
    Abstract [en]

    Rye bran contains a high content not only of dietary fibre, but also of plant lignans and other bioactive compounds in the so-called dietary fibre complex. Blood concentrations of lignans such as enterolactone have been used as biomarkers of intake of lignan-rich plant food. At present,evidence from studies in human subjects does not warrant the conclusion that rye, whole grains orphyto-oestrogens protect against cancer. Some studies, however, have pointed in that direction,especially in relation to cancers of the upper digestive tract. A number of prospective epidemiological studies have clearly shown a protective effect of wholegrain cereals against myocardial infarctions. A corresponding protective effect against diabetes and ischaemic stroke(brain infarct) has also been demonstrated. It seems reasonable to assume that these protective effects are associated with one or more factors in the dietary fibre complex.

  • 32.
    Haubek, Dorte
    et al.
    Århus universitet.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Pathogenicity of the highly leukotoxic JP2 clone of Aggregatibacter actinomycetemcomitans and its geographic dissemination and role in aggressive periodontitis2014In: Journal of Oral Microbiology, ISSN 2000-2297, E-ISSN 2000-2297, Vol. 6, article id 23980Article in journal (Refereed)
    Abstract [en]

    For decades, Aggregatibacter actinomycetemcomitans has been associated with aggressive forms of periodontitis in adolescents. In the middle of the 1990s, a specific JP2 clone of A. actinomycetemcomitans, belonging to the cluster of serotype b strains of A. actinomycetemcomitans and having a number of other characteristics, was found to be strongly associated with aggressive forms of periodontitis, particularly in North Africa. Although several longitudinal studies still point to the bacterial species, A. actinomycetemcomitans as a risk factor of aggressive periodontitis, it is now also widely accepted that the highly leukotoxic JP2 clone of A. actinomycetemcomitans is implicated in rapidly progressing forms of aggressive periodontitis. The JP2 clone strains are highly prevalent in human populations living in Northern and Western parts of Africa. These strains are also prevalent in geographically widespread populations that have originated from the Northwest Africa. Only sporadic signs of a dissemination of the JP2 clone strains to non-African populations have been found despite Africans living geographically widespread for hundreds of years. It remains an unanswered question if a particular host tropism exists as a possible explanation for the frequent colonization of the Northwest African population with the JP2 clone. Two exotoxins of A. actinomycetemcomitans are known, leukotoxin (LtxA) and cytolethal distending toxin (Cdt). LtxA is able to kill human immune cells, and Cdt can block cell cycle progression in eukaryotic cells and thus induce cell cycle arrest. Whereas the leukotoxin production is enhanced in JP2 clone strains thus increasing the virulence potential of A. actinomycetemcomitans, it has not been possible so far to demonstrate such a role for Cdt. Lines of evidence have led to the understanding of the highly leukotoxic JP2 clone of A. actinomycetemcomitans as an aetiological factor of aggressive periodontitis. Patients, who are colonized with the JP2 clone, are likely to share this clone with several family members because the clone is transmitted through close contacts. This is a challenge to the clinicians. The patients need intense monitoring of their periodontal status as the risk for developing severely progressing periodontal lesions are relatively high. Furthermore, timely periodontal treatment, in some cases including periodontal surgery supplemented by the use of antibiotics, is warranted. Preferably, periodontal attachment loss should be prevented by early detection of the JP2 clone of A. actinomycetemcomitans by microbial diagnostic testing and/or by preventive means.

  • 33. Hirschfeld, Josefine
    et al.
    Roberts, Helen M
    Chapple, Iain L C
    Parčina, Marijo
    Jepsen, Søren
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Claesson, Rolf
    Umeå University, Faculty of Medicine, Department of Odontology.
    Effects of Aggregatibacter actinomycetemcomitans leukotoxin on neutrophil migration and extracellular trap formation.2016In: Journal of Oral Microbiology, ISSN 2000-2297, E-ISSN 2000-2297, Vol. 8, article id 33070Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Aggressive periodontitis is associated with the presence of Aggregatibacter actinomycetemcomitans, a leukotoxin (Ltx)-producing periodontal pathogen. Ltx has the ability to lyse white blood cells including neutrophils.

    OBJECTIVES: This study was aimed at investigating the interactions between neutrophils and Ltx with regard to the chemotactic properties of Ltx and the release of neutrophil extracellular traps (NETs).

    METHODS: Neutrophils from healthy blood donors were isolated and incubated for 30 min and 3 h with increasing concentrations of Ltx (1, 10, and 100 ng/mL) as well as with A. actinomycetemcomitans strains (NCTC 9710 and HK 1651) producing different levels of Ltx. Formation of NETs and cell lysis were assessed by microscopy, fluorescence-based assays, and measurement of released lactate dehydrogenase. Neutrophil migration in response to different Ltx gradients was monitored by real-time video microscopy, and image analysis was performed using ImageJ software.

    RESULTS: Although Ltx (10 and 100 ng/mL) and the leukotoxic A. actinomycetemcomitans strain HK 1651 lysed some neutrophils, other cells were still capable of performing NETosis in a concentration-dependent manner. Low doses of Ltx and the weakly leukotoxic strain NCTC 9710 did not lead to neutrophil lysis, but did induce some NETosis. Furthermore, all three concentrations of Ltx enhanced random neutrophil movement; however, low directional accuracy was observed compared with the positive control (fMLP).

    CONCLUSIONS: The results indicate that Ltx acts both as a neutrophil activator and also causes cell death. In addition, Ltx directly induces NETosis in neutrophils prior to cell lysis. In future studies, the underlying pathways involved in Ltx-meditated neutrophil activation and NETosis need to be investigated further.

  • 34.
    Höglund Åberg, Carola
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Antonoglou, Georgios
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Haubek, Dorte
    Section for Pediatric Dentistry, Department of Dentistry, Health, Århus University, Århus, Denmark.
    Kwamin, Francis
    Dental School University of Ghana, Accra, Ghana.
    Claesson, Rolf
    Umeå University, Faculty of Medicine, Department of Odontology.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Cytolethal distending toxin in isolates of Aggregatibacter actinomycetemcomitans from Ghanaian adolescents and association with serotype and disease progression 2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 6, p. e65781-Article in journal (Refereed)
    Abstract [en]

    Background and Objectives: The cytolethal distending toxin (Cdt) is a highly conserved exotoxin that are produced by a number of Gram negative bacteria, including Aggregatibacter actinomycetemcomitans, and affects mammalian cells by inhibiting cell division and causing apoptosis. A complete cdt-operon is present in the majority of A. actinomycetemcomitans, but the proportion of isolates that lack cdt-encoding genes (A, B and C) varies according to the population studied. The objectives of this study were to examine serotype, Cdt-genotype, and Cdt-activity in isolates of A. actinomycetemcomitans collected from an adolescent West African population and to examine the association between the carrier status of A. actinomycetemcomitans and the progression of attachment loss (AL).

    Material and Methods: A total of 249 A. actinomycetemcomitans isolates from 200 Ghanaian adolescents were examined for serotype and cdt-genotype by PCR. The activity of the Cdt-toxin was examined by DNA-staining of exposed cultured cells and documented with flow cytometry. The periodontal status of the participants was examined at baseline and at a two-year follow-up.

    Results: Presence of all three cdt-encoding genes was detected in 79% of the examined A. actinomycetemcomitans isolates. All these isolates showed a substantial Cdt-activity. The two different cdt-genotypes (with and without presence of all three cdt-encoding genes) showed a serotype-dependent distribution pattern. Presence of A. actinomycetemcomitans was significantly associated with progression of AL (OR = 5.126; 95% CI = [2.994 - 8.779], p < 0.001).

    Conclusion: A. actinomycetemcomitans isolated from the Ghanaian adolescents showed a distribution of serotype and cdt-genotype in line with results based on other previously studied populations. Presence of A. actinomycetemcomitans was significantly associated with disease progression, in particular the b serotype, whereas the association with disease progression was not particularly related to cdt-genotype, and Cdt-activity.

  • 35.
    Höglund Åberg, Carola
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Haubek, Dorte
    Århus University.
    Kwamin, Francis
    Ghana University.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Claesson, Rolf
    Umeå University, Faculty of Medicine, Department of Odontology.
    Leukotoxic activity of Aggregatibacter actinomycetemcomitans and periodontal attachment loss2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 8, p. e104095-Article in journal (Refereed)
    Abstract [en]

    Aggregatibacter actinomycetemcomitans is a Gram-negative periodontitis-associated bacterium that expresses a toxin that selectively affects leukocytes. This leukotoxin is encoded by an operon belonging to the core genome of this bacterial species. Variations in the expression of the leukotoxin have been reported, and a well-characterized specific clonal type (JP2) of this bacterium with enhanced leukotoxin expression has been isolated. In particular, the presence of the JP2 genotype significantly increases the risk for the progression of periodontal attachment loss (AL). Based on these findings we hypothesized that variations in the leukotoxicity are linked to disease progression in infected individuals. In the present study, the leukotoxicity of 239 clinical isolates of A. actinomycetemcomitans was analysed with different bioassays, and the genetic peculiarities of the isolates were related to their leukotoxicity based on examination with molecular techniques. The periodontal status of the individuals sampled for the presence of A. actinomycetemcomitans was examined longitudinally, and the importance of the observed variations in leukotoxicity was evaluated in relation to disease progression. Our data show that high leukotoxicity correlates with an enhanced risk for the progression of AL. The JP2 genotype isolates were all highly leukotoxic, while the isolates with an intact leukotoxin promoter (non-JP2 genotypes) showed substantial variation in leukotoxicity. Genetic characterization of the non-JP2 genotype isolates indicated the presence of highly leukotoxic genotypes of serotype b with similarities to the JP2 genotype. Based on these results, we conclude that A. actinomycetemcomitans harbours other highly virulent genotypes besides the previously described JP2 genotype. In addition, the results from the present study further highlight the importance of the leukotoxin as a key virulence factor in aggressive forms of periodontitis.

  • 36.
    Höglund Åberg, Carola
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Kelk, Peyman
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Aggregatibacter actinomycetemcomitans: virulence of its leukotoxin and association with aggressive periodontitis2015In: Virulence, ISSN 2150-5608, Vol. 6, no 3, p. 188-195Article, review/survey (Refereed)
    Abstract [en]

    Periodontitis is an infection-induced inflammatory disease that causes loss of the tooth supporting tissues. Much focus has been put on comparison of the microbial biofilm in the healthy periodontium with the diseased one. The information arising from such studies is limited due to difficulties to compare the microbial composition in these two completely different ecological niches. A few longitudinal studies have contributed with information that makes it possible to predict which individuals who might have an increased risk of developing aggressive forms of periodontitis, and the predictors are either microbial or/and host-derived factors. The most conspicuous condition that is associated with disease risk is the presence of Aggregatibacter actinomycetemcomitans at the individual level. This Gram-negative bacterium has a great genetic variation with a number of virulence factors. In this review we focus in particular on the leukotoxin that, based on resent knowledge, might be one of the most important virulence factors of A. actinomycetemcomitans.

  • 37.
    Höglund Åberg, Carola
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Kwamin, Francis
    Ghana University.
    Claesson, Rolf
    Umeå University, Faculty of Medicine, Department of Odontology.
    Dahlén, Gunnar
    Göteborgs Universitet.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Haubek, Dorte
    Århus Universitet, Danmark.
    Progression of attachment loss is strongly associated with presence of the JP2 genotype of Aggregatibacter actinomycetemcomitans: a prospective cohort study of a young adolescent population2014In: Journal of Clinical Periodontology, ISSN 0303-6979, E-ISSN 1600-051X, Vol. 41, no 3, p. 232-241Article in journal (Refereed)
    Abstract [en]

    AIM: To assess the progression of attachment loss (AL) during a two-year period according to the presence of JP2 and non-JP2 genotypes of A. actinomycetemcomitans in a Ghanaian adolescent population.

    METHODS: A total of 500 adolescents (mean age 13.2 years, SD± 1.5) were enrolled in the study. After two years, 397 (79.4%) returned for a periodontal re-examination, including the measurement of AL. The carrier status of the JP2 and non-JP2 genotypes of A. actinomycetemcomitans was evaluated in a baseline examination two years earlier.

    RESULTS: Individuals who carried the JP2 genotype of A. actinomycetemcomitans had a significantly increased risk (relative risk (RR) = 7.3) of developing AL ≥ 3 mm. The mean AL at the follow-up and the mean two-year progression of AL was significantly higher in the JP2 genotype-positive group (n=38) compared with the group positive for the non-JP2 genotypes of A. actinomycetemcomitans (n=169), and the group of A. actinomycetemcomitans-negative individuals (n=190). The JP2 genotype was strongly associated with the progression of AL ≥ 3 mm (OR= 14.3). The non-JP2 genotypes of A. actinomycetemcomitans were also, however less pronounced, associated with the progression of AL ≥ 3 mm (OR=3.4).

    CONCLUSION: The JP2 genotype of A. actinomycetemcomitans is strongly associated with the progression of AL.

  • 38.
    Höglund Åberg, Carola
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Kwamin, Francis
    Univ Ghana, Sch Dent, Accra, Ghana.
    Claesson, Rolf
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Microbiology.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology. Umeå University, Faculty of Medicine, Department of Odontology, Oral Microbiology.
    Haubek, Dorte
    Århus Univ, Dept Dent, Århus, Denmark.
    Presence of JP2 and Non-JP2 genotypes of aggregatibacter actinomycetemcomitans and periodontal attachment loss in adolescents in Ghana2012In: Journal of Periodontology, ISSN 0022-3492, E-ISSN 1943-3670, Vol. 83, no 12, p. 1520-1528Article in journal (Refereed)
    Abstract [en]

    Background: Limited data are reported concerning the presence of A. actinomycetemcomitans and attachment loss (AL) in sub-Saharan countries. The authors investigate the carrier frequency of JP2 and non-JP2 genotypes of A. actinomycetemcomitans and the presence of AL in Ghanaian adolescents and evaluate socioeconomic conditions and oral hygiene practices. Methods: Five hundred individuals (mean +/- SD age: 13.2 +/- 1.5 years) in public and private schools were interviewed about demographic characteristics and oral hygiene practices and were given a full-mouth periodontal examination. Subgingival plaque samples were obtained from periodontal sites around permanent first molars and incisors. The carrier status of A. actinomycetemcomitans at the individual level was determined based on results obtained by cultivation and polymerase chain reaction. Results: The findings of this study show a relatively high carrier rate of JP2 and non-JP2 genotypes of Aggregatibacter actinomycetemcomitans in the Ghanaian adolescent population and the presence of this bacterium is associated with the occurrence of AL. The overall carrier rate of A. actinomycetemcomitans was 54.4%, and the highly leukotoxic JP2 genotype was detected in 8.8% of the study population. A total of 107 (21.4%) individuals had >= 1 tooth with AL >= 3 mm. The majority of the individuals carrying A. actinomycetemcomitans (80.1%) (P<0.001) and of the periodontally diseased individuals (91.6%) (P<0.001) were found in public schools. Conclusions: A. actinomycetemcomitans and AL were frequently found in Ghanaian adolescents. The school type was the strongest predictor of both presence of A. actinomycetemcomitans and AL.

  • 39.
    Janson, Veronica
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Resistance to caspase-8 and -9 fragments in a malignant pleural mesothelioma cell line with acquired cisplatin-resistance.2010In: Cell death & disease, ISSN 2041-4889, Vol. 1, no 9, p. e78-Article in journal (Refereed)
    Abstract [en]

    Apoptotic cysteine-aspartate proteases (caspases) are essential for the progression and execution of apoptosis, and detection of caspase fragmentation or activity is often used as markers of apoptosis. Cisplatin (cis-diamminedichloroplatinum (II)) is a chemotherapeutic drug that is clinically used for the treatment of solid tumours. We compared a cisplatin-resistant pleural malignant mesothelioma cell line (P31res1.2) with its parental cell line (P31) regarding the consequences of in vitro acquired cisplatin-resistance on basal and cisplatin-induced (equitoxic and equiapoptotic cisplatin concentrations) caspase-3, -8 and -9 fragmentation and proteolytic activity. Acquisition of cisplatin-resistance resulted in basal fragmentation of caspase-8 and -9 without a concomitant increase in proteolytic activity, and there was an increased basal caspase-3/7 activity. Similarly, cisplatin-resistant non-small-cell lung cancer cells, H1299res, had increased caspase-3 and -9 content compared with the parental H1299 cells. In P31 cells, cisplatin exposure resulted in caspase-9-mediated caspase-3/7 activation, but in P31res1.2 cells the cisplatin-induced caspase-3/7 activation occurred before caspase-8 or -9 activation. We therefore concluded that in vitro acquisition of cisplatin-resistance rendered P31res1.2 cells resistant to caspase-8 and caspase-9 fragments and that cisplatin-induced, initiator-caspase independent caspase-3/7 activation was necessary to overcome this resistance. Finally, the results demonstrated that detection of cleaved caspase fragments alone might be insufficient as a marker of caspase activity and ensuing apoptosis induction.

  • 40. Jenab, M
    et al.
    Riboli, E
    Ferrari, P
    Friesen, M
    Sabate, J
    Norat, T
    Slimani, N
    Tjonneland, A
    Olsen, A
    Overvad, K
    Boutron-Ruault, MC
    Clavel-Chapelon, F
    Boeing, H
    Schulz, M
    Linseisen, J
    Nagel, G
    Trichopoulou, A
    Naska, A
    Oikonomou, E
    Berrino, F
    Panico, S
    Palli, D
    Sacerdote, C
    Tumino, R
    Peeters, PH
    Numans, ME
    Bueno-de Mesquita, HB
    Buchner, FL
    Lund, E
    Pera, G
    Chirlaque, MD
    Sanchez, MJ
    Arriola, L
    Barricarte, A
    Quiros, JR
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Odontology, Cariology.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Odontology, Periodontology.
    Berglund, G
    Bingham, S
    Khaw, KT
    Allen, N
    Key, T
    Carneiro, F
    Save, V
    Del Giudice, G
    Plebani, M
    Kaaks, R
    Gonzalez, CA
    Plasma and dietary carotenoid, retinol and tocopherol levels and the risk of gastric adenocarcinomas in the European prospective investigation into cancer and nutrition2006In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 95, no 3, p. 406-415Article in journal (Refereed)
    Abstract [en]

    Despite declining incidence rates, gastric cancer (GC) is a major cause of death worldwide. Its aetiology may involve dietary antioxidant micronutrients such as carotenoids and tocopherols. The objective of this study was to determine the association of plasma levels of seven common carotenoids, their total plasma concentration, retinol and - and -tocopherol, with the risk of gastric adenocarcinoma in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC), a large cohort involving 10 countries. A secondary objective was to determine the association of total sum of carotenoids, retinol and -tocopherol on GCs by anatomical subsite (cardia/noncardia) and histological subtype (diffuse/intestinal). Analytes were measured by high-performance liquid chromatography in prediagnostic plasma from 244 GC cases and 645 controls matched by age, gender, study centre and date of blood donation. Conditional logistic regression models adjusted by body mass index, total energy intake, smoking and Helicobacter pylori infection status were used to estimate relative cancer risks. After an average 3.2 years of follow-up, a negative association with GC risk was observed in the highest vs the lowest quartiles of plasma -cryptoxanthin (odds ratio (OR)=0.53, 95% confidence intervals (CI)=0.30-0.94, Ptrend=0.006), zeaxanthin (OR=0.39, 95% CI=0.22-0.69, Ptrend=0.005), retinol (OR=0.55, 95% CI=0.33-0.93, Ptrend=0.005) and lipid-unadjusted -tocopherol (OR=0.59, 95% CI=0.37-0.94, Ptrend=0.022). For all analytes, no heterogeneity of risk estimates or significant associations were observed by anatomical subsite. In the diffuse histological subtype, an inverse association was observed with the highest vs lowest quartile of lipid-unadjusted -tocopherol (OR=0.26, 95% CI=0.11-0.65, Ptrend=0.003). These results show that higher plasma concentrations of some carotenoids, retinol and -tocopherol are associated with reduced risk of GC.

  • 41.
    Jensen, Anne B.
    et al.
    Aarhus University, Denmark.
    Haubek, Dorte
    Aarhus University, Denmark.
    Claesson, Rolf
    Umeå University, Faculty of Medicine, Department of Odontology.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Nørskov-Lauritsen, Niels
    Aarhus University, Denmark.
    Comprehensive antimicrobial susceptibility testing of a large collection of clinical strains of Aggregatibacter actinomycetemcomitans does not identify resistance to amoxicillin2019In: Journal of Clinical Periodontology, ISSN 0303-6979, E-ISSN 1600-051X, Vol. 46, no 8, p. 846-854Article in journal (Refereed)
    Abstract [en]

    AIM: The present study aims to determine the susceptibility of Aggregatibacter actinomycetemcomitans to amoxicillin by investigating a large collection of oral strains of diverse geographical origin.

    METHODS: Two hundred and fifty-seven A. actinomycetemcomitans strains were serotyped using a multiplex polymerase chain reaction, and minimal inhibitory concentration (MIC) values of amoxicillin were determined using the agar dilution method (range 0.25 to 8.0 mg/L). The plates were spot-wise inoculated with approximately 104 colony-forming units, incubated in 5% CO2 at 37 C°, and visually inspected after 24 and 48 hours. A MIC ≤ 2.00 mg/L was categorised as susceptible using EUCAST interpretative criteria for Haemophilus species.

    RESULTS: Amoxicillin MIC-values varied from 0.25 mg/L to 2.00 mg/L, and all tested strains, including strains previously reported as resistant, were susceptible to amoxicillin. The MIC50 was 1.00 mg/L and the MIC90 was 2.00 mg/L.

    CONCLUSION: Meticulous investigation of strains including isolates previously reported as resistant could not confirm the emergence of resistance to β-lactams in A. actinomycetemcomitans. Based on the present in vitro results, amoxicillin can be considered a key oral antimicrobial agent for treatment of A. actinomycetemcomitans. This article is protected by copyright. All rights reserved.

  • 42.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Aggregatibacter actinomycetemcomitans Leukotoxin: a Powerful Tool with Capacity to Cause Imbalance in the Host Inflammatory Response2011In: Toxins, ISSN 2072-6651, Vol. 2, no 3, p. 242-259Article in journal (Refereed)
    Abstract [en]

    Aggregatibacter actinomycetemcomitans has been described as a member of the indigenous oral microbiota of humans, and is involved in the pathology of periodontitis and various non-oral infections. This bacterium selectively kills human leukocytes through expression of leukotoxin, a large pore-forming protein that belongs to the Repeat in Toxin (RTX) family. The specificity of the toxin is related to its prerequisite for a specific target cell receptor, LFA-1, which is solely expressed on leukocytes. The leukotoxin causes death of different leukocyte populations in a variety of ways. It activates a rapid release of lysosomal enzymes and MMPs from neutrophils and causes apoptosis in lymphocytes. In the monocytes/macrophages, the toxin activates caspase-1, a cysteine proteinase, which causes a proinflammatory response by the activation and secretion of IL-1β and IL-18. A specific clone (JP2) of A. actinomycetemcomitans with enhanced leukotoxin expression significantly correlates to disease onset in infected individuals. Taken together, the mechanisms by which this toxin kills leukocytes are closely related to the pathogenic mechanisms of inflammatory disorders, such as periodontitis. Therapeutic strategies targeting the cellular and molecular inflammatory host response in periodontal diseases might be a future treatment alternative

  • 43.
    Johansson, Anders
    et al.
    Umeå University, Faculty of Medicine, Odontology, Periodontology.
    Buhlin, K
    Koski, R
    Gustafsson, A
    The immunoreactivity of systemic antibodies to Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis in adult periodontitis2005In: European Journal of Oral Sciences, ISSN 0909-8836, E-ISSN 1600-0722, Vol. 113, no 3, p. 197-202Article in journal (Refereed)
    Abstract [en]

    Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis secrete several potent virulence factors and are known to be two of the major periodontal pathogens. In the present case-control study, the systemic immunoreactivity to A. actinomycetemcomitans exotoxins, cytolethal distending toxin (Cdt) and leukotoxin was analyzed in adult subjects with periodontitis and in periodontally healthy controls. Furthermore, systemic immunoreactivity to P. gingivalis was analyzed in these subjects. Reactivity to the A. actinomycetemcomitans toxins was determined in bioassays that quantified neutralizing antibodies, and P. gingivalis antibodies were detected by enzyme-linked immunosorbent assay (ELISA). The results showed a significantly enhanced immunoreactivity to P. gingivalis in the subjects with periodontitis, while the reactivity to A. actinomycetemcomitans leukotoxin showed no significant difference between patients and controls. However, combined immunoreactivity to leukotoxin and Cdt was more prevalent in the subjects with periodontitis than in the controls. In addition, immunoreactivity to leukotoxin correlated to periodontitis in men but not in women. In conclusion, data from the present study indicate that immunoreactivity to P. gingivalis is frequent in adult periodontitis, while the role of A. actinomycetemcomitans seems to be more complex and depends on gender of the infected subject as well as the virulence of the bacteria. (c) Eur J Oral Sci, 2005

  • 44.
    Johansson, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Buhlin, Kåre
    Sorsa, Timo
    Pussinen, Pirkko J
    Systemic Aggregatibacter Actinomycetemccomitans Leukotoxin-Neutralizing Antibodies in Periodontitis2017In: Journal of Periodontology, ISSN 0022-3492, E-ISSN 1943-3670, Vol. 88, no 1, p. 122-129Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The leukotoxin expressed by Aggregatibacter actinomycetemcomitans is a powerful exotoxin, which can cause imbalance in the host response. Immunoreactivity to the leukotoxin is a marker for the presence of leukotoxic A. actinomycetemcomitan, a presence that may modify the disease pattern of the colonized individuals. The aim of the present study was to examine the presence of systemic immunoreactivity to A. actionmycetemcomitans leukotoxin in relation to clinical and inflammatory findings in individuals with or without periodontitis (n = 88).

    METHODS: The periodontal status was examined in a population of cases (n = 49) and controls (n = 39), and the cases received periodontal treatment. Systemic biomarkers associated with inflammation and infections, as well as the clinical parameters, were analyzed at baseline, three months after treatment and six months after.

    RESULTS: The presence of immunoreactivity against leukotoxin was associated with impaired remission of the disease after periodontal treatment. This immunoreactivity was also significantly associated with increased systemic levels of A. actinomycetemcomtans-specific immunoglobulins and increasing age.

    CONCLUSION: The presence and levels of systemic immunoreactivity against A. actinomycetemcomitans leukotoxin are associated with a decreased remission after otherwise successful periodontal treatment.

  • 45.
    Johansson, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Claesson, Rolf
    Umeå University, Faculty of Medicine, Department of Odontology.
    Hänström, Lennart
    Umeå University, Faculty of Medicine, Department of Odontology.
    Kalfas, S
    Umeå University, Faculty of Medicine, Department of Odontology.
    Serum-mediated release of leukotoxin from the cell surface of the periodontal pathogen Actinobacillus actinomycetemcomitans.2003In: European Journal of Oral Sciences, ISSN 0909-8836, E-ISSN 1600-0722, Vol. 111, no 3, p. 209-215Article in journal (Refereed)
    Abstract [en]

    The leukotoxin of the periodontopathogen Actinobacillus actinomycetemcomitans is an important virulence factor that lyses human neutrophils and monocytes and thus, it may enable the bacterium to evade the local host defense. The toxin also induces degranulation of neutrophils and cytokine release in monocytes. To trigger these biological activities, leukotoxin has to be released from the bacterium and diffuse into the periodontal tissues. To date, the conditions found to cause toxin release have been artificial and have included high ion concentration and alkaline conditions. To study the release of the toxin under conditions mimicking the natural environment of the periodontium the ability of human serum to enable leukotoxin release from the bacterial surface was examined. Suspensions of leukotoxic A. actinomycetemcomitans strains were incubated with various concentrations of human serum or serum albumin. The suspensions were centrifuged and the leukotoxin in the supernatants or the cell pellets was detected by gel electrophoresis and immunoblotting. Serum was found to cause the rapid release of leukotoxin from the bacteria in a concentration-dependent manner. Pure albumin exhibited a similar effect. The leukotoxin released was active against human neutrophils. Only a minor proportion of it was associated with membranous vesicles produced by the bacteria. The results indicate that serum, a fluid closely related to the exudate in inflamed periodontal pockets, releases leukotoxin from the cell surface of A. actinomycetemcomitans. The process may enable the diffusion of the toxin from the bacterial biofilm into the surrounding tissues, where it can exert its biological effect.

  • 46.
    Johansson, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Claesson, Rolf
    Umeå University, Faculty of Medicine, Department of Odontology.
    Höglund Åberg, Carola
    Umeå University, Faculty of Medicine, Department of Odontology.
    Haubek, D.
    Oscarsson, Jan
    Umeå University, Faculty of Medicine, Department of Odontology.
    The cagE gene sequence as a diagnostic marker to identify JP2 and non-JP2 highly leukotoxic Aggregatibacter actinomycetemcomitans serotype b strains.2017In: Journal of Periodontal Research, ISSN 0022-3484, E-ISSN 1600-0765, Vol. 52, no 5, p. 903-912Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND OBJECTIVE:Aggregatibacter actinomycetemcomitans is involved in oral and systemic infections, and is associated with, eg aggressive forms of periodontitis and with endocarditis. The cagE gene encodes a ≈39 kDa putative exotoxin expressed by A. actinomycetemcomitans. The level of conservation of cagE, and its possible significance in periodontal disease, has not yet been thoroughly investigated. In the present study, the role of the cagE gene as a diagnostic marker has been investigated.

    MATERIAL AND METHODS:We have used conventional polymerase chain reaction (PCR), quantitative PCR and whole genome sequencing data to determine the prevalence of cagE in A. actinomycetemcomitans based on analysis of: (i) 249 isolates, collected and cultivated in a Ghanaian longitudinal cohort study; (ii) a serotype b collection of 19 strains; and (iii) the 36 A. actinomycetemcomitans genomes available in the NCBI database.

    RESULTS:Whereas cagE was absent in the other serotypes, our data support that this gene sequence is linked to a virulent and highly leukotoxic group of serotype b strains, including both JP2 and non-JP2 genotypes of A. actinomycetemcomitans.

    CONCLUSION:We propose that cagE has the potential to be used as a PCR-based gene marker for the identification of a virulent and highly leukotoxic group of serotype b strains, including both JP2 and non-JP2 genotypes. This finding might be of importance in the risk assessment of the development of periodontal attachment loss in young individuals and hence suggested to be a relevant discovery in future development of new diagnostic tools and/or treatment strategies.

  • 47.
    Johansson, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Claesson, Rolf
    Umeå University, Faculty of Medicine, Department of Odontology.
    Höglund-Åberg, Carola
    Umeå University, Faculty of Medicine, Department of Odontology.
    Haubek, Dorte
    Lindholm, Mark
    Umeå University, Faculty of Medicine, Department of Odontology.
    Jasim, Sarah
    Umeå University, Faculty of Medicine, Department of Odontology.
    Oscarsson, Jan
    Umeå University, Faculty of Medicine, Department of Odontology.
    Genetic Profiling of Aggregatibacter actinomycetemcomitans Serotype B Isolated from Periodontitis Patients Living in Sweden2019In: Pathogens, ISSN 2076-0817, Vol. 8, no 3, p. 1-13, article id 153Article in journal (Refereed)
    Abstract [en]

    The bacterium Aggregatibacter actinomycetemcomitans is associated with aggressive forms of periodontitis and with systemic diseases, such as endocarditis. By assessing a Ghanaian longitudinal adolescent cohort, we earlier recognized the cagE gene as a possible diagnostic marker for a subgroup of JP2 and non-JP2 genotype serotype b A. actinomycetemcomitans strains, associated with high leukotoxicity as determined in a semi-quantitative cell assay. This group of A. actinomycetemcomitans is associated with the progression of attachment loss. In the present work, we used conventional polymerase chain reaction (PCR) and quantitative PCR to perform the cagE genotyping of our collection of 116 selected serotype b A. actinomycetemcomitans strains, collected over a period of 15 years from periodontitis patients living in Sweden. The A. actinomycetemcomitans strains carrying cagE (referred to as cagE+; n = 49) were compared to the cagE-negative strains (n = 67), present at larger proportions in the subgingival plaque samples, and were also much more prevalent in the young (≤35 years) compared to in the old (>35 years) group of patients. Our present results underline the potential use of cagE genotyping in the risk assessment of the development of periodontal attachment loss in Swedish adolescents.

  • 48.
    Johansson, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Dahlén, Gunnar
    Odontologi, Göteborgs Universitet.
    Bacterial virulence factors that contributes to periodontal disease2017In: Pathogenesis of periodontal disease: biological concepts for clinicians / [ed] Nagihan Bostanci, Georgios N. Belibasakis, Cham: Springer Berlin/Heidelberg, 2017, p. 31-49Chapter in book (Refereed)
    Abstract [en]

    In this chapter, the role of different microbial virulence factors in relation to the pathogenesis of periodontal diseases is addressed. These factors are molecules produced by pathogens and contribute to their pathogenicity by promoting colonization and affecting host response. The importance of different virulence factors in the life of the oral biofilm and the interplay with the host’s response is exemplified here by two of the major, and most well studied, periodontal pathogens, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans. Both of these microbes have great genetic intraspecies diversity and express a number of different virulence factors, which have the capacity to cause imbalance in the host’s response. A. actinomycetemcomitans is the major pathogen in aggressive forms of periodontitis (Fig. 4.1) that affect young individuals, while P. gingivalis is frequently detected in periodontal pockets of individuals with the chronic forms of the disease (Fig. 4.2). However, the role of these two bacteria in periodontal breakdown is still not entirely clear.

  • 49.
    Johansson, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Eriksson, Marie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Åhren, Ann-Marie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Boman, Kurt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology, Cariology.
    Prevalence of systemic immunoreactivity to Aggregatibacter actinomycetemcomitans leukotoxin in relation to the incidence of myocardial infarction2011In: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 11, no 1, p. 55-Article in journal (Refereed)
    Abstract [en]

    Background: Chronic infections and associated inflammatory markers are suggested risk factors for cardiovascular disease (CVD). The proinflammatory cytokine, interleukin (IL)-1, is suggested to play a role in the regulation of local inflammatory responses in both CVD and periodontitis. The leukotoxin from the periodontal pathogen Aggregatibacter actinomycetemcomitans has recently been shown to cause abundant secretion of IL-1 from macrophages. The aim of the present study was to compare the prevalence of systemic immunoreactivity to A. actinomycetemcomitans leukotoxin in myocardial infarction (MI) cases (n=532) and matched controls (n=1000) in a population-based case and referents study in northern Sweden.

    Methods: Capacity to neutralize A. actinomycetemcomitans leukotoxin was analyzed in a bioassay with leukocytes, purified leukotoxin, and plasma. Plasma samples that inhibited lactate-dehydrogenase release from leukotoxin-lysed cells by 50 % were classified as positive.

    Results: Neutralizing capacity against A. actinomycetemcomitans leukotoxin was detected in 53.3% of the plasma samples. The ability to neutralize leukotoxin correlated to increasing age in men (n=1082) but not in women (n=450). There was no correlation between presence of systemic leukotoxin neutralization capacity and the incidence of MI, except for women (n=146). Women with a low neutralizing capacity had a significantly higher incidence of MI than those who had a high neutralizing capacity.

    Conclusions: Systemic immunoreactivity against A. actinomycetemcomitans leukotoxin was found at a high prevalence in the analyzed population of adults from northern Sweden. The results from the present study do not support the hypothesis that systemic leukotoxin-neutralizing capacity can decrease the risk for MI.

  • 50.
    Johansson, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Eriksson, Marie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Åhrén, Ann-Marie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Stegmayr, Birgitta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Systemic antibodies to the leukotoxin of the oral pathogen Actinobacillus actinomycetemcomitans correlate negatively with stroke in women2005In: Cerebrovascular Diseases, ISSN 1015-9770, E-ISSN 1421-9786, Vol. 20, no 4, p. 226-232Article in journal (Refereed)
    Abstract [en]

    Background: Chronic infections and associated inflammatory markers are suggested risk factors for cardiovascular diseases (CVD) and stroke. The proinflammatory cytokine interleukin (IL)-1β is suggested to play a role in the regulation of local inflammatory responses in both CVD and periodontitis. The leukotoxin from the periodontal pathogen Actinobacillus actinomycetemcomitans has recently been shown to cause abundant secretion of IL-1β  from macrophages. The aim of the present study was to compare the prevalence of systemic antibodies to A. actinomycetemcomitansleukotoxin in stroke cases (n = 273) and matched controls (n = 546) in an incident case-control study nested within the Northern Sweden MONICA and Västerbotten Intervention cohorts.

    Methods: Antibodies to A. actinomycetemcomitans leukotoxin were analyzed in a bioassay with HL-60 cells (leukocytes), purified A. actinomycetemcomitans leukotoxin, and plasma. Plasma samples which inhibited lactate dehydrogenase release from leukotoxin-lysed cells by ≥50% were classified as antibody positive.

    Results: Antibodies to A. actinomycetemcomitans leukotoxin were detected in 18.8% of the women and 15.2% of the men. Women with those antibodies had a significantly decreased risk for stroke (OR = 0.28, 95% CI: 0.13–0.59), but not men (OR = 0.88, 95% CI: 0.52–1.51).

    Conclusion: The immunoreactivity to A. actinomycetemcomitans leukotoxin correlates negatively with a future stroke in woman, but not in men. Further studies are needed to explain the underlying mechanisms, as well as the biological relevance of this finding.

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