Associations between cigarette smoking and mitochondrial DNA abnormalities in buccal cells

DNA alterations in mitochondria are believed to play a role in carcinogenesis and are found in smoking-related cancers. We sought to replicate earlier findings for the association of smoking with increased mitochondrial DNA (mtDNA) content in buccal cells and further hypothesized that there would be an increased number of somatic mtDNA mutations in smokers. Buccal cells and blood lymphocytes were studied from 42 healthy smokers and 30 non-smokers. Temporal temperature gradient electrophoresis screening and sequencing was used to identify mtDNA mutations. The relative mtDNA content was determined by real-time polymerase chain reaction. Assuming that mtDNA in lymphocytes represents the inherited sequence, it was found that 31% of smokers harbored at least one somatic mtDNA mutation in buccal cells with a total of 39 point mutations and 8 short deletions/insertions. In contrast, only 23% of non-smokers possessed mutations with a total of 10 point mutations and no insertions/deletions detected. mtDNA somatic mutation density was higher in smokers (0.68/10 000 bp per person) than in non-smokers (0.2/10 000 bp per person). There was a statistically significant difference in the pattern of homoplasmy and heteroplasmy mutation changes between smokers and non-smokers. Whereas non-smokers had the most mutations in D-loop region (70%), smokers had mutations in both messenger RNA encoding gene (36%) and D-loop region (49%). The mean ratio of buccal cells to lymphocytes of mtDNA content in smokers was increased (2.81) when compared with non-smokers (0.46). These results indicate that cigarette smoke exposure affects mtDNA in buccal cells of smokers. Additional studies are needed to determine if mitochondrial mutation assays provide new or complementary information for estimating cigarette smoke exposure at the cellular level or as a cancer risk biomarker

The Cross-Talk between Spirochetal Lipoproteins and Immunity

Spirochetal diseases such as syphilis, Lyme disease and leptospirosis are major threats to public health. However the immunopathogenesis of these diseases has not been fully elucidated. Spirochetes interact with the host through various structural components such as lipopolysaccharides (LPS), surface lipoproteins and glycolipids. Although spirochetal antigens such as LPS and glycolipids may contribute to the inflammatory response during spirochetal infections, spirochetes such as Treponema pallidum and Borrelia burgdorferi lack LPS. Lipoproteins are most abundant proteins that are expressed in all spirochetes and often determine how spirochetes interact with their environment. Lipoproteins are proinflammatory, may regulate responses from both innate and adaptive immunity and enable the spirochetes to adhere to the host or the tick midgut or to evade the immune system. However, most of the spirochetal lipoproteins have unknown function. Herein, the immunomodulatory effects of spirochetal lipoproteins are reviewed and are grouped into two main categories: effects related to immune evasion and effects related to immune activation. Understanding lipoprotein-induced immunomodulation will aid in elucidating innate immunopathogenesis processes and subsequent adaptive mechanisms potentially relevant to spirochetal disease vaccine development and to inflammatory events associated with spirochetal diseases

CD14 Signaling Restrains Chronic Inflammation through Induction of p38-MAPK/SOCS-Dependent Tolerance

Current thinking emphasizes the primacy of CD14 in facilitating recognition of microbes by certain TLRs to initiate pro-inflammatory signaling events and the importance of p38-MAPK in augmenting such responses. Herein, this paradigm is challenged by demonstrating that recognition of live Borrelia burgdorferi not only triggers an inflammatory response in the absence of CD14, but one that is, in part, a consequence of altered PI3K/AKT/p38-MAPK signaling and impaired negative regulation of TLR2. CD14 deficiency results in increased localization of PI3K to lipid rafts, hyperphosphorylation of AKT, and reduced activation of p38. Such aberrant signaling leads to decreased negative regulation by SOCS1, SOCS3, and CIS, thereby compromising the induction of tolerance in macrophages and engendering more severe and persistent inflammatory responses to B. burgdorferi. Importantly, these altered signaling events and the higher cytokine production observed can be mimicked through shRNA and pharmacological inhibition of p38 activity in CD14-expressing macrophages. Perturbation of this CD14/p38-MAPK-dependent immune regulation may underlie development of infectious chronic inflammatory syndromes

Immunmodulation und neue Therapiestrategien in der Lyme borreliose

If infection with Borrelia burgdorferi is not treated adequately with antibiotics in an early stage, it may lead to Lyme borreliosis (LB), a chronic multisystemic disorder which is difficult to cure. In some cases the pathogen survives in spite of antibiotic treatments. It is challenging to understand why Borrelia are often not eradicated, although being recognized by the host s immune defense and occasionally inducing a strong inflammatory reaction. Thus, it remains an area of debate how this pathogen persists in human tissues. This question was addressed in the present thesis, examining possible immune evasion mechanisms of Borrelia. We propose that Borrelia modulate the host s immune system in order to evade clearance in the immunologically competent host. Tolerance could represent the mechanism inhibiting host response thereby enabling survival and persistence of the pathogen. Promising results were obtained testing a novel treatment strategy for late stage LB, a combination of Filgrastim as an immunosupportive therapy with antibiotics. The respective clinical trial based on these findings was recently started

Selbstermuntrungen zur Verehrung Gottes

von J. S. Diterich, Oberkonstistorialrath [et]c.Zum besten der Grottkauischen SchulanstaltVorlageform des Erscheinungsvermerks: Grottkau 1790. Im Verlag der Schulbuchhandlung

Unterweisung zur Glückseligkeit nach der Lehre Jesu

Layoutgetreues Digitalisat der Ausg.: Berlin : Nicolai, 1782. - Neue vermehrte Aufl. - Standort: Universität Marburg, Bibliothek Evangelische Theologie [381] (Gesangbuchsammlung) Signatur: PTh Dp Schu 1782 sekr. - Bemerkungen: In Fraktur. - Digitalisiert 201

Andachten die auch dem Gesangbuch zum gottesdienstlichen Gebrauch in den Königlich Preussischen Landen beygefügt werden können

Layoutgetreues Digitalisat der Ausg.: Berlin : Mylius, 1781 Standort: Universität Marburg, Bibliothek Evangelische Theologie [381] (Gesangbuchsammlung) Signatur: PTh Dp Pr II 1781 sekr. Bemerkungen: In Fraktur. - [Verfasser: Johann Samuel Diterich; Johann Joachim Spalding; Wilhelm Abraham Teller] Digitalisiert 201