Realiza la evaluación fitoquímica y la actividad anti-Helicobacter pylori del aceite esencial de Minthostachys mollis “muña” en pacientes del Hospital Militar Central diagnosticados con gastritis. Las hojas de M. mollis se recolectaron en Tranca (3300 m.s.n.m.), distrito de Vinchos, provincia de Huamanga, Región Ayacucho. Se extrajo el aceite esencial (AE) por arrastre con vapor de agua, resultando con un rendimiento de 2,00 %v/p, densidad 0,9041 g/mL, índice de refracción 1,56689 a 20 ºC. La composición química fue determinada por el método cromatografía de gases acoplada a espectrometría de masas, resultando: D-mentona (39,75 %), pulegona (22,45 %), (2S-trans)-5-metil-2-(1-metiletil) - (ciclohexanona (10,24 %), β-linalol (3,33 %) y neomentol (2,13 %). Por el método de Artemia salina se evaluó la bioactividad y citotoxicidad, mostrando una CL50=15,24 mg/Kg. La dosis letal media oral aguda (DL50) = 2,21 mL/kg, en ratas albinas de acuerdo al método de dosis límite, catalogada de baja toxicidad. A los tres grupos en estudio se administró vía oral por diez días cápsulas de gelatina aceite esencial de M. mollis, 300 mg, 700 mg y 1000 mg + omeprazol 40 mg respectivamente usándose como vehículo el aceite de Plukenetia volubilis “sacha inchi”; al grupo de control positivo se suministró por vía oral en dosis diaria cápsulas de amoxicilina 1500 mg + claritromicina 1000 mg + omeprazol 40 mg, durante diez días. Al grupo control negativo se administró por vía oral en dosis diaria aceite de P. volubilis en cápsulas en iguales condiciones. Después de 30 días de tratamientos se realizó una endoscopia alta para el control a todos los grupos en estudio; con el tratamiento clásico antibióticos + omeprazol se observó la erradicación de la mencionada bacteria y con el tratamiento de AE + omeprazol no se observó la erradicación. Se concluye que el aceite esencial de Minthostachys mollis “muña” bajo las condiciones de este ensayo no presenta actividad anti-Helicobacter pylori. / Tesis

Introduction: Hypertension is an important public health challenge worldwide, being the leading cause of cardiovascular disease, morbidity and mortality. It is particularly prevalent in people in sub-Saharan Africa, especially in urban areas. There is an urgent need to develop strategies to prevent, detect, treat, and control hypertension effectively in the African region. Helicobacter pylori, a gram-negative bacterium responsible for many gastric disorders worldwide, has been associated with hypertension in some previous studies; where blood pressure of patients with Helicobacter pylori infection did not subside after hypertensive treatment, when compared to patients without Helicobacter pylori infections. This effect was suggested to be due to Helicobacter pylori produced and modified cardiotonic steroids that are found in elevated concentrations in hypertensive patients. Cardiotonic steroids are positive inotropic agents which are known to increase blood pressure. A sensitive analytical method is needed to detect and quantify the low concentrations of cardiotonic steroids in biological samples. Materials and Methods: An extraction method was optimised using reversed phase Solid Phase Extraction. A targeted liquid chromatography tandem mass spectrometry method using an Agilent binary series 1100/1200 LC system with a Kinetex C18 RP column (100 x 2.1 mm, 2.6 µm) coupled to a Sciex 4000QTRAP tandem mass spectrometer was developed and validated for the detection and quantitation of 9 different cardiotonic steroids in both solvent and whole blood. The method was validated according to the International Conference on Harmonization guidelines with regards to precision, accuracy, sensitivity, selectivity, linearity, range, limit of detection, limit of quantification, reproducibility, recovery, carry-over and stability. Media from Helicobacter pylori cultures and faecal samples from human and different normo- and hypertensive rat strains were analysed. Data analysis was performed with Analyst® Software (version 1.5.2) and multiple t-test and Kruskal Wallis test using GraphPad Prism 8 software. Results and Discussion: The calibration curves of tested cardiotonic steroids were linear over a concentration range of 0.1-40 ng/mL with coefficients of determination greater than 0.990 except for telocinobufagin. The analytical method was selective with an estimated limit of detection and limit of quantification between 0.02-0.5 ng/mL and 0.1-2 ng/mL respectively. All tested cardiotonic steroids showed good recovery of over 70%. Accuracy and precision were found to be within acceptable limits of 15% and 20% at lowest limit of quantification for almost all the analytes and their stability in blood and solvent at room temperature, 4°C, -20°C and -80°C was tested for a month. Cardiotonic steroids were detected in Helicobacter pylori cultures and faecal samples with the exception of ouabain and proscillaridin A which were not detected at all. Although Helicobacter pylori were shown to produce cardiotonic steroids in vitro, no evidence of the effect of Helicobacter pylori on cardiotonic steroids production was detected in different normo- and hypertensive rat groups. Conclusion: The quantitative analytical method was successfully validated, over expected in vivo concentration ranges for 8 different cardiotonic steroids. The extraction and analytical methods were both successfully applied to Helicobacter pylori cultures and faecal rat samples where cardiotonic steroids were detected. / Dissertation (MSc)--University of Pretoria 2020. / National Research Foundation Student bursary / Pharmacology / MSc (Pharmacology) / Unrestricted

Hintergrund: Der EGILS (European Gastro-Intestinal Lymphoma Study) Consensus Report von 2011 enthält als zentralen Therapiebaustein die H.p.-Eradikationsbehandlung mit nachfolgendem „Watch-and-Wait“ bzw. die Nachsorge nach Vollremission. Voraussetzung für eine strukturierte Nachsorge ist eine gute Patientencompliance. Eine Studie über Dauer und praktische Umsetzbarkeit der Nachsorge, insbesondere nach Vollremission, gibt es bisher nicht. Ziel: Ziel dieser retrospektiven Arbeit war es zu überprüfen, ob die von der EGILS empfohlenen Nachsorgeintervalle von den Patienten nach einer alleinigen H.p.-Eradikation eingehalten werden. Ferner sollte auf dieser Grundlage und unter Berücksichtigung des Therapieerfolgs eine Empfehlung für optimale Nachsorgeintervalle nach klinischer Vollremission erarbeitet werden. Methode: 106 Patienten (50 weiblich; 56 männlich); Alter 59 (33 – 85) Jahre mit beliebigem H.p.Status, histologisch gesichertem gastralem MALT-Lymphom und alleiniger H.p.-Eradikationsbehandlung wurden eingeschlossen. Grundlage zur Beurteilung war, bis zur Vollremission, das Nachsorgeschema gemäß EGILS (alle 4-6 Monate); danach erfolgte die Nachsorge alle 6 bis 12 Monate. Die Compliance wurde bei jedem Patienten als das Verhältnis aus erfüllter Nachsorgepflicht zu individueller Gesamtdauer der Nachsorge berechnet und über alle Patienten gemittelt. Ergebnisse: Die meisten Patienten erreichen nach alleiniger H.p.-Eradikation unabhängig vom H.p.-Status eine Vollremission (ca. 71%). Die Nachsorgen wurden über den gesamten Beobachtungszeitraum zu ca. 55% eingehalten. Patienten mit Interesse an einer Nachsorge nehmen diese über Jahre hinweg sehr zuverlässig war. In dieser Patientengruppe liegt die Compliance bei ca. 95%. Schlussfolgerung: Die exzellente Prognose gastraler MALT-Lymphome, unabhängig vom H.p.-Status, und die hohe Bereitschaft der Patienten für Nachsorgeuntersuchungen auch nach Vollremission erhöht die Attraktivität einer „Watch-and-Wait“-Strategie. Nach klinischer Vollremission sind jährliche endoskopische Nachsorgeuntersuchungen praktisch umsetzbar. / Background: The European gastrointestinal lymphoma study (EGILS) consensus report from 2011 included as a central therapy basis the H pylori eradication treatment with subsequent “watch and wait” as well as follow-up care after full remission. The main requirement for a structured follow up care is good patient compliance. A study about the duration and the practical feasibility of follow up care, especially after full remission has not been carried out to date. Aims: The aim of this retrospective work was to review whether patients were complying with the EGILS recommended follow-up intervals after a single H pylori eradication treatment. Furthermore, on this basis and in consideration of treatment success, a recommendation for the optimal follow-up interval after a full clinical remission should be developed. Methods: 106 patients (50 females, 56 males) with an average age of 59 years (33-85) with a variable H pylori status, histologically confirmed gastric MALT-lymphoma and a single H pylori eradication treatment, were included. The basis of assessment was, up to full remission, the follow-up scheme in accordance with EGILS (4-6 months) thereafter follow up in 6-12 months. The compliance for every patient was calculated as the ratio of fulfilled follow-up care obligations to individual duration of follow-up care and averaged out over all Patients. Results: The majority of patients reached a full remission after a single H pylori eradication independent of H pylori status (ca. 71%). Ca 55% of the follow-up care was adhered to the whole observation period. Patients with an interest continued to take part reliably in follow-up care for many years. The compliance in this patient group was ca 95%. Conclusion: The excellent prognosis of gastric MALT-lymphoma, independent of H pylori status and the willingness of the patients to have aftercare-check-ups even after a full remission, increases the attraction of a “watch and wait” strategy. After a full clinical remission, yearly endoscopic check-ups can be easily implemented.

This work explores the effects of body shape and configuration of flagella on motility of Helicobacter pylori, a helical-shaped bacterium that inhabits the viscoelastic gastric mucosa and causes gastritis, ulcers and gastric cancer. Although it is well known that different shapes produce different hydrodynamic drag thus altering the speed and that helical shapes generate additional thrust this has not been quantitatively established for flagellated bacteria. Using fast time-resolution and high-magnification two-dimensional phase-contrast microscopy to simultaneously image and track individual H. pylori and its rod-shaped isogenic mutant in broth and mucin solutions, the shape as well as rotational and translational speed was determined. In collaboration with Professor Henry Fu and Mehdi Jabbarzadeh the experimental data was used to validate the method of regularized Stokeslets by directly comparing the observed speeds to numerical calculations. The results show that due to relatively slow body rotation rates, the helical shape makes at most a 15% contribution to speeds. In order to explore the effects of arrangement of flagella on motility three different Helicobacter spp. were examined: H. suis (bipolar, multiple flagella), H. cetorum (bipolar, single flagellum) and H. pylori (unipolar, multiple flagella) swimming in broth and mucin. Results show that regardless of media, the flagella bundles of bipolar bacteria can assume one of two configurations interchangeably: extended away from the body or wrapped around it. H. suis predominantly swims with the lagging flagella extended behind the body and the leading flagella wrapped around it, but cases where both bundles are extended or both are wrapped have also been observed. In addition the effects of varying pH on motility of H. suis in broth and mucin were investigated. In broth the rotational speed is not significantly affected by varying pH and the peak of the speed distribution shifts to lower values as the pH decreases. However in mucin the rotational speed decreases by a factor of 20 from pH5 to 4 and the motion is completely hindered below pH4. This indicates that H. suis is unable to move below pH4, in agreement with previous findings on H. pylori, due to gelation of mucin below pH4.

This dissertation is author version of following the journal article. Takahiro Shimizu, Hiroyuki Marusawa, Yuko Matsumoto, Tadashi Inuzuka, Atsuyuki Ikeda, Yosuke Fujii, Sachiko Minamiguchi, Shin’ichi Miyamoto, Tadayuki Kou, Yoshiharu Sakai, Jean E. Crabtree, Tsutomu Chiba, Accumulation of Somatic Mutations in TP53 in Gastric Epithelium With Helicobacter pylori Infection, Gastroenterology, Volume 147, Issue 2, August 2014, Pages 407-417.e3, ISSN 0016-5085, http://dx.doi.org/10.1053/j.gastro.2014.04.036. / 京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18543号 / 医博第3936号 / 新制||医||1006(附属図書館) / 31443 / 京都大学大学院医学研究科医学専攻 / (主査)教授 羽賀 博典, 教授 小川 誠司, 教授 武藤 学 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21299号 / 医博第4388号 / 新制||医||1030(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 妹尾 浩, 教授 中川 一路, 教授 川上 浩司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24138号 / 医博第4878号 / 新制||医||1060(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 村川 泰裕, 教授 波多野 悦朗, 教授 武藤 学 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

infection is a leading cause of gastric cancer, which is the second-most common cancer-related death in the world. The chronic inflammatory environment in the gastric mucosal epithelia during infection stimulates intracellular signaling pathways, namely inflammatory signals, which may lead to the promotion and progression of cancer cells. We herein report two important signal transduction pathways, the LPS-TLR4 and CagA-MET pathways. Upon stimulation, lipopolysaccharide (LPS) binds to toll-like receptor 4 (TLR4) mainly on macrophages and gastric epithelial cells. This induces an inflammatory response in the gastric epithelia to upregulate transcription factors, such as NF-κB, AP-1, and IRFs, all of which contribute to the initiation and progression of gastric cancer cells. Compared with other bacterial LPSs, LPS has a unique function of inhibiting the mononuclear cell (MNC)-based production of IL-12 and IFN-γ. While this mechanism reduces the degree of inflammatory reaction of immune cells, it also promotes the survival of gastric cancer cells. The HGF/SF-MET signaling plays a major role in promoting cellular proliferation, motility, migration, survival, and angiogenesis, all of which are essential factors for cancer progression. infection may facilitate MET downstream signaling in gastric cancer cells through its CagA protein via phosphorylation-dependent and/or phosphorylation-independent pathways. Other signaling pathways involved in infection include EGFR, FAK, and Wnt/β-Catenin. These pathways function in the inflammatory process of gastric epithelial mucosa, as well as the progression of gastric cancer cells. Thus, infection-mediated chronic inflammation plays an important role in the development and progression of gastric cancer.

Helicobacter pylori (H. pylori) is a Gram-negative bacterium that infects and resides in the gastric mucosa of humans. Without treatment, H. pylori infection may cause chronic inflammation of the gastric mucosa. This inflammation creates progressive damage to the lining of the stomach and can lead to multiple diseases located in the upper gastrointestinal region. Worldwide prevalence of H. pylori infection is estimated to be close to 50%. H. pylori has been identified as the primary cause of peptic ulcer disease, gastric cancer, and mucosa-associated lymphoid tissue lymphoma. The purpose of this study was to identify the prevalence and risk factors associated with H. pylori infection among students, faculty, and staff at the University of Central Florida. A cross-sectional design with a convenience sample was implemented to acquire a study population of 60 participants. The sample was analyzed through the use of a twenty question survey and a rapid blood antibody test kit. The infection rate of the sample was 1.75%. Statistically significant results were found for the relationship between age and upper gastrointestinal symptoms. Trends were also noticed between alcohol consumption, stress levels, and upper gastrointestinal symptoms.

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