61 research outputs found

    Feline sino-nasal and sino-orbital aspergillosis

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    Feline sino-nasal and sino-orbital aspergillosis. This thesis characterizes upper respiratory tract aspergillosis (URTA) in domestic cats, an emerging mycosis caused by fungi from Genus Aspergillus. Affected cats were 1.5 to13 years old (median 5 y). Brachycephalic purebred cats were over-represented. Sino-orbital aspergillosis (SOA) was more common than sino-nasal aspergillosis (SNA). Fungal pathogens were cultured readily. Aspergillus fumigatus was the most common cause of SNA. In all cases of SOA, the fungal pathogen was an uncharacterised species within the Aspergillus viridinutans complex in Aspergillus section Fumigati. This pathogen, also isolated from a dog and a human with aspergillosis, was subsequently identified as a novel species, A. felis (neosartorya-morph), using a polyphasic taxonomic approach including comparative sequence analysis of the ITS, partial β-tubulin and calmodulin genes. A. felis is heterothallic with a functioning reproductive cycle, as confirmed by mating-type analysis, teleomorph induction and ascospore germination. It can be distinguished from A. viridinutans by growth at 45 °C and from A. fumigatus by lack of growth at 50 °C. Computed tomography was used to investigate pathogenesis of URTA. Findings support that the nasal cavity is the portal of entry for fungal spores in feline URTA and that extension to involve the orbit is via direct naso-orbital communication from bone lysis. Sera from cats with URTA, and two control groups were tested to detect Aspergillus-specific antibodies using an agar-gel double immunodiffusion (AGID) assay and an indirect IgG ELISA. The sensitivity (SE) of the AGID was 43% and specificity (SP) was 100%. At a cut-off value of 6 ELISA Units/mL the SE of the IgG ELISA was 95.2% and SP was 92 - 92.9%. Aspergillus-specific antibodies against A. fumigatus and four cryptic species (A. felis, A. thermomutatus, A. lentulus, A. udagawae) were detected. Detection of Aspergillus-specific antibodies by IgG ELISA has high SE and SP for diagnosis of feline URTA

    HOST-PATHOGEN INTERACTIONS IN PNEUMOCYSTIS INFECTION

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    Pneumocystis remains the most common opportunistic infection in patients with HIV/AIDS and can cause a life-threatening fulminant pneumonia. Pneumocystis pneumonia is re-emerging in the HIV-negative population, as immunosuppressive medications have greater use clinically. As the at-risk population increases, understanding the underlying host responses that can lead to protection against Pneumocystis becomes imperative. To that end, we characterized the early CD4+ T-cell dependent eosinophilic response to Pneumocystis murina. Importantly, we demonstrated that eosinophils have potent anti-Pneumocystis activity both in vitro and in vivo. However, eosinophils in the lung can also lead to pathology as seen in allergic airway inflammation in asthma. We therefore compared Pneumocystis to the common airway allergen, house dust mite, and demonstrated that the immune response to both pathogens was highly similar. Pneumocystis antigen exposure resulted in increased airway hyperresponsiveness and mucus production in a Th2-dependent and eosinophil-independent manner. From a translational standpoint, a subset of patients with severe asthma had increased anti-Pneumocystis IgG and IgE antibodies. Patients with high anti-Pneumocystis IgG levels had worsened cough and lung function as measured by spirometry, suggesting that Pneumocystis exposure may be correlated with worsened disease. As Pneumocystis infection induces such a potent adaptive immune response, we next examined local immunity to Pneumocystis. Inducible bronchus associated lymphoid tissue (iBALT) has been characterized in several models of lung infection and contributes to protection. Pneumocystis infection and exposure in a co-housing model resulted in the formation of iBALT structures in a CXCL13-dependent manner. Importantly, CXCL13 regulation appeared to be dependent on both Th2 and Th17 CD4+ T-cells in vivo and in pulmonary fibroblasts in vitro. The host response to Pneumocystis is limited in patients with global immunosuppression and the identification of novel drug and vaccine targets is lacking. Towards that end, we annotated the Pneumocystis genome and as proof-of-principle, demonstrated that the kinome (specifically VPS34) was druggable in vitro. Additionally, we utilized various –omics techniques to identify Meu10 and GSC-1 as novel vaccine targets capable of providing partial protection against Pneumocystis. Together, these studies identified novel protective and pathologic immune responses to Pneumocystis and enabled a top-down approach of anti-Pneumocystis therapeutic development

    Small molecules, big consequences:novel therapeutic approaches for treating chronic inflammatory diseases

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    Obesity has become a global epidemic due to increase in sedentary lifestyle and calorie intake. In addition to increased BMI, obese patients display a persistent, low-grade inflammatory response known as "metabolic inflammation." This metabolic inflammation is linked to several diseases, including heart diseases, non-alcoholic fatty liver disease (NAFLD), type 2 diabetes as well as inflammatory bowel disease (IBD). The focus of this thesis is to understand the mechanism underlying these metabolic inflammatory processes with a goal to identify novel and safe therapeutic approaches. One of the main mechanisms responsible for this metabolic inflammatory response is the disturbed cholesterol metabolism in macrophages, which are immune cells that kill and clear pathogens. This thesis tested small-molecule compounds that help improve cholesterol metabolism in macrophages and thereby reduce inflammation using several mice models. In addition, this thesis also discussed the importance of non-pharmacological stress-reduction strategies in reducing inflammation and improving quality of life in these patients

    3Ts in Gastrointestinal Microbiome Era: Technology, Translational Research and Transplant

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    We have entered a new era where some concepts of the complex community of microorganisms (microbiota comprising bacteria, fungi, viruses, bacteriophages and helminths) are being re-discovered and re-visited. Microbiota and human interaction is not new; they have shared a long history of co-existence. Nevertheless, the opportunities to understand the role of these microorganisms in human diseases and to design a potential treatment were limited. At present, thanks to development of innovative and cutting-edge molecular biological and microbiological technologies as well as clinical informatics and bioinformatics skills, microbiome application is moving into clinics. Approaches to therapy based on prebiotics, probiotics and lately on fecal microbiota transplantation has revolutionized medicine. Microbiota outnumbers our genes and is now regarded as another organ of the body. The gastrointestinal tract and gut microbiota display a well-documented symbiotic relationship. Disruption of intestinal microbiota homeostasis—called dysbiosis—has been associated with several diseases. Whether dysbiosis is a cause or consequence of disease initiation and progression still needs to be investigated in more depth. The aim of this book is to highlight recent advances in the field of microbiome research, which are now shaping medicine, and current approaches to microbiome-oriented therapy for gastrointestinal diseases. Dr. Rinaldo Pellicano Dr. Sharmila Fagoonee Guest Editor

    Transient elastography for assessing and monitoring of liver steatosis and fibrosis

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    Summary Transient elastography (TE) is a novel method to assess and monitor non-alcoholic fatty liver disease (NAFLD) non-invasively by simultaneously quantifying steatosis using the controlled attenuation parameter (CAP) and liver stiffness using the liver stiffness measurement (LSM). We carried out four studies using TE as the central method to explore its value for research and clinical practice. We found a positive correlation between CAP and ultrasonography in the detection of steatosis in a cohort of 174 patients with chronic liver diseases. Furthermore, patatin-like phospholipase domain containing 3 (PNPLA3) p.148M, a known genetic risk factor for NAFLD, was associated with CAP, but not with LSM. No association was observed for CAP and LSM and transmembrane 6 superfamily member 2 (TM6SF2) p.167K, which is another known genetic risk factor for NAFLD. However, for both variants an association with serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities was demonstrated. Overall, carriers of the PNPLA3 risk allele [M] had an increased risk for the development of hepatic phenotypes in general and more specifically an increased odds of 2.4 for steatosis. This is the first time steatosis assessed by CAP was used in a genetic study. To investigate the short-term modulation of liver fat, we carried out the first intervention study using TE. In 60 patients with hepatic steatosis, fourteen days of a hypocaloric high-fiber, high-protein diet resulted in significant reductions in liver fat by 14% and in body weight by 4.8%. There is evidence that PNPLA3 modulated this dietary-related response. Furthermore, liver stiffness, body composition, serum liver enzymes and metabolic markers improved significantly. The UKS-study availed of CAP and LSM during occupational health check-ups and suggests that the prevalence of NAFLD is underdiagnosed in 104 hospital employees. The study also observed that TE is superior to serum parameters for diagnosing hepatic steatosis and fibrosis. By use of body impedance analysis (BIA) and a tape measure, we were able to demonstrate that body fat mass and waist circumference are the strongest predictors for steatosis. This is the first study that availed of CAP and LSM during occupational health check-ups. The recommendations for the use of TE to assess fibrosis are weaker in the German guideline as opposed to the European guideline on NAFLD. Neither of the guidelines however, provides a statement on assessing steatosis using CAP. Consequently, we analyzed almost 6,700 TE measurements obtained over a period of 3.5 years in patients and the general population. The results reflect the feasibility of TE and subsequently, we introduced the term “EGK des Hepatologen”, translating to “ECG of the hepatologist”.Zusammenfassung Die transiente Elastographie (TE) ist eine neuartige Methode zur nichtinvasiven Beurteilung und Überwachung der nichtalkoholischen Fettlebererkrankung (NAFLD), bei der gleichzeitig die Leberverfettung mittels Controlled Attenuation Parameter (CAP) und die Lebersteifigkeit mittels Lebersteifigkeitsmessung (LSM) quantifiziert wird. Die Bedeutung der Methode für Forschung und klinische Praxis wurde in vier Studien untersucht. Bei 174 Patienten mit chronischen Lebererkrankungen konnte bei der Detektion der Steatose eine positive Korrelation zwischen CAP und der Messung mittels Ultraschall gezeigt werden. Für Patatin-ähnliche Phospholipase-Domäne 3 (PNPLA3) p.148M, ein bekannter genetischer Risikofaktor für NAFLD, konnte ein Zusammenhang mit CAP, nicht aber mit LSM, gezeigt werden. Für Transmembran-6-Superfamilienmitglied 2 (TM6SF2) p.167K, einem weiteren NAFLD-Risikofaktor, konnten weder für CAP, noch für LSM ein Zusammenhang nachgewiesen werden. Eine Assoziation mit Serum-Alanin-Aminotransferase (ALT) und Aspartat-Aminotransferase (AST) Aktivitäten wurde hingegen für beide genetische Varianten gezeigt. Träger des Risikoallels [M] hatten ein erhöhtes Risiko für die Entwicklung eines hepatischen Phänotyps und eine erhöhte Wahrscheinlichkeit für die Entwicklung einer Steatose um das 2,4-Fache. In dieser Studie wurde die CAP zum ersten Mal zur Detektion der Steatose in einer genetischen Studie eingesetzt. Die kurzfristige Modulation von Leberfett wurde in der ersten Interventionsstudie mit TE durchgeführt. Bei 60 Patienten mit Steatose führten vierzehn Tage einer hypokalorischen, ballaststoffreichen und proteinreichen Diät zu einer signifikanten Reduktion des Leberfetts um 14% und des Körpergewichts um 4,8%. Es gibt Hinweise darauf, dass PNPLA3 die ernährungsbedingte Reduktion beeinflusst. Weiterhin verbesserten sich Lebersteifigkeit, Körperzusammen-setzung, Serumleberenzyme und metabolische Marker signifikant. Die UKS-Studie konnte mithilfe von CAP und LSM im Rahmen der betrieblichen Gesundheitsförderung zeigen, dass die Prävalenz von NAFLD bei 104 Krankenhausangestellten unterdiagnostiziert ist und dass TE den Serumparametern zur Diagnose von Steatose und Fibrose überlegen ist. Dabei wurde weiterhin gezeigt, dass gemessen mittels Körperimpedanzanalyse (BIA) und einem einfachen Maßband, Körperfettmasse und Taillenumfang die stärksten Prädiktoren für die Steatose sind. Dies ist die erste Studie, bei der bei arbeitsmedizinischen Vorsorgeuntersuchungen auf CAP und LSM angewendet wurde. Die Empfehlungen zur Verwendung von TE zur Beurteilung der Fibrose sind in der deutschen Leitlinie gegenüber der europäischen Leitlinie zu NAFLD schwächer ausgeprägt.Keine der Leitlinien macht eine Aussage zur Beurteilung der Leberverfettung mittels CAP. Eine Auswertung von fast 6.700 TE-Messungen bei Patienten und der Allgemeinbevölkerung über einen Zeitraum von 3,5 Jahren macht die Durchführbarkeit der transienten Elastographie deutlich und lässt sich durch den dafür eingeführten Begriff "EGK des Hepatologen" trefflich beschreiben
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