Visceral hypersensitivity is the heightened response to sensory stimuli. Visceral sensations are transmitted through primary afferent neurons in the dorsal root ganglion (DRG) and the sensitization of the neural pathway leads to modification in spinal ascending and descending neurons. The aim of this investigation is to determine the effects of brain-derived neurotrophic factor (BDNF) and its signaling pathway on sensory neuronal activation during colitis. In order to evaluate this, levels of calcitonin-gene related peptide (CGRP), a neuropeptide marker for nociceptive transmission, and phosphorylated cAMP-response element binding protein (pCREB), a molecular switch in neuronal plasticity, were studied in response to BDNF in vivo and in vitro. Colitis caused an increase in the levels of CGRP and pCREB in thoracolumbar DRG, which was attenuated by BDNF neutralizing antibody and PLC inhibitor, U73122, but not PI3K inhibitor, LY294002. BDNF-induced CGRP expression and CREB activation in DRG culture was also blocked by PLC inhibitor, U73122, but not PI3K inhibitor, LY294002, or MEK kinase inhibitor, PD98059. These results suggest a unique signaling pathway, i.e. the PLC-γ pathway, is mediating BDNF action on sensory neuronal activation during colitis.

Thesis (doctoral)--Universität Leipzig, 1903. / Includes bibliographical references.

Human populations are at risk of exposure to constitutive androstane receptor (CAR) activators present in a range of substances, including pharmaceuticals, plasticizers and crop protection agents. What exposure to CAR activators means for human health is uncertain. Activation of CAR in rodents is associated with liver hyperplasia, increased proliferation and eventual hepatocarcinoma; however the effect in human hepatic cells is unclear. There are two methods by which a compound can achieve activation of CAR; directly or indirectly via cellular signalling pathways. Phenobarbital is a prototypical activator of CAR and does so in an indirect manner via suppression of epidermal growth factor receptor (EGFR) signalling. Direct activation of CAR in rodents also causes hepatocellular carcinoma but the human outcome is less clear. We have carried out microarray and miRNA analysis of CITCO (a potent and selective hCAR ligand) treated primary human hepatocytes. To mitigate the well documented effect of primary hepatocyte dedifferentiation primary hepatocytes were cultured in dynamic three dimensional culture in vitro. Gene expression changes indicate that direct activation of hCAR causes the promotion of a pro-proliferative and anti-apoptotic phenotype. The miRNA expression profile is crucially different to rodent data that is currently published. Despite the pro-proliferative phenotype shown there is no evidence that primary human hepatocytes proliferate in response to direct activation of CAR by CITCO. This leaves the possibility that a proliferative response may be observed in vivo or that the changes in gene expression are solely a human physiological adaptation to direct hCAR activation by CITCO and no proliferation would occur. The effect on human health and liver toxicity is unclear but this body of work has provided data that may be used to further understand the mechanistic effects of direct hCAR activation in human hepatocytes. A more complete understanding of this will help to inform the toxic potential of direct hCAR activation in vivo.

Thesis (doctoral)--Rijksuniversiteit te Groningen.

The objective of this thesis was to delineate aspects of the control mechanisms of mammalian pepsinogen secretion. In order to accomplish this goal, a comprehensive study was undertaken which would establish an historical perspective of the subject, validate appropriate methodology and then seek to answer specific questions regarding the physiology and pathophysiology of pepsinogen secretion. More specifically, the objectives of this thesis were: 1. To review the historical background of the subject of pepsinogen in the context of the physiology of digestion with specific emphasis on the work and lives of the two major initial proponents of pepsinogen research (Schwann and Langley). 2. To provide a contemporary overview and evaluation of the current status of pepsinogen pathophysiology. 3. To modify and adapt experimental models necessary for the study of pepsinogen and acid secretion in mammalian gastric mucosa and cells. 4. To establish and validate a pepsinogen assay sensitive and reproducible enough for use in mammalian mucosa! and cellular secretory systems. 5. To delineate the fundamental (second messenger) control mechanisms (cyclic AMP and calcium calmodulin) of pepsinogen secretion in the isolated gastric gland model. 6. To define whether the process of pepsinogen secretion is independent of acid secretion in intact mucosa! preparations. 7. To identify different classes of pharmacological agents which would inhibit pepsinogen secretion and/or release. 8. To identify whether conditions present in critically ill patients liable to mucosal "stress ulceration" might influence the release of pepsinogen.

Common presenting symptoms of Lung cancer are cough, hemoptysis, chest pain, dyspnea, pleurisy. Dysphagia is a very uncommon presenting feature of Lung cancer. Incidence of Dysphagia in Lung cancer is unclear from Literature. Causes of Dysphagia in case of Lung cancer are Anatomically classified as Oropharyngeal and Esophageal. Causes of oropharyngeal dysphagia are oral candidiasis, oropharyngeal Metastasis of Lung cancer. Causes of esophageal dysphagia are Cervical or Mediastinal Lymphadenopathy, Motor dysfunction because of Brain stem Metastasis, Lambert eaton syndrome, Esophageal candidiasis, Radiation esophagitis. Here by we present an Unusual presentation of an aggressive disease, poorly differentiated SCLC presenting as Mid esophageal dysphagia secondary to extrinsic esophageal compression. 65 year old female with past medical history of Diabetes, Hypertension presented with complaints of worsening sub sternal chest pain radiating to back since last 2 days and progressive dysphagia. Pt underwent Left heart catheterization revealing non obstructive coronary artery disease. Modified Barium swallow showed stasis of contrast in mid esophagus, Endoscopy showed extrinsic compression of the proximal esophagus, normal mucosa. Computerized tomography of chest was done for further evaluation, revealing extensive left cervical, mediastinal, left hilar lymphadenopathy causing extrinsic compression of the esophagus and encasement of the left hilar structures. Further evaluation through Bronchoscopic biopsy of her left upper lobe mass reveals poorly differentiated small cell carcinoma. Staging was performed revealing limited stage disease. Started on concurrent chemotherapy with cisplatin, etoposide and radiation. As SCLC is highly responsive to chemotherapy and radiotherapy sensitive patient got symptomatic relief by the end of first cycle. SCLC is an aggressive lung cancer. As it is a micro metastatic disease in nature at presentation, it’s management is entirely different from Non SCLC. SCLC being an aggressive disease can cause dysphagia in 1-2% during the disease course. SCLC presenting as dysphagia is almost never reported in the literature. Our patient presented with severe dysphagia, described it as “a tennis ball sitting in her food pipe”. Fortunately she presented to the Emergency room with dysphagia and associated chest pain, we were able to make early diagnosis of SCLC, initiate treatment. Delay in the diagnosis lead to rapid progression of disease and poor prognosis. Through our case we wanted to convey that it is very important to obtain meticulous history, keeping broad differentials, which can help improve prognosis. Because not always the presenting features are from the organ of involvement it could be from the contiguous spread or compression.

Introduction A biloma is a loculated accumulation of bile outside of the biliary tree; it can either be intrahepatic or extrahepatic. They are usually caused by trauma, iatrogenic procedures like endoscopic retrograde cholangiopancreatography (ERCP), laparoscopic cholecystectomy, percutaneous procedures like transcatheter arterial chemoembolization, microwave ablation, or percutaneous biliary drainage. We are presenting a case of a 78-year-old male with an incidental diagnosis of large biloma noted on CT scan which was obtained for routine lung cancer screening. Case presentation A 78-year-old male with a past medical history of prostate cancer and diabetes was admitted to the hospital after a routine Low dose CT lung screening for lung cancer showed an incidental finding of a liver lesion suggestive of neoplasm. Abdominal examination was unremarkable. CT abdomen and pelvis showed a 9 cm cystic and solid liver lesion in segment 5 associated with gallbladder fossa. The gallbladder was large, and hydropic, with an irregular wall, consistent with intrahepatic rupture of the gallbladder. Blood cultures were negative with no organisms seen on the gram stain, and no growth on the anaerobic culture as well. CT was concerning for cholangiocarcinoma associated with the gallbladder or could be intrahepatic rupture of the gallbladder. Ultrasound-guided Biopsy of the lesion showed needle core fragments of liver parenchyma with granulation tissue with cholestatic pigment associated with foreign body giant cell reaction. Rare foci of necrosis were present. The adjacent hepatocytes showed reactive changes. The overall findings were consistent with intrahepatic biloma. A Cholecystostomy tube was placed to drain the biloma. Repeat CT showed persistent intrahepatic biloma with slightly reduced size. A pigtail catheter was placed to drain the biloma. Discussion Spontaneous bilomas are a rare entity caused by bile leaks that are encapsulated either inside or outside of the liver without cause. Most often, they are secondary to iatragenic or traumatic causes. The common manifestations of biloma are abdominal pain, jaundice, fever, and leukocytosis, none were found in our patient. Appropriate diagnostic imaging includes Ultrasound, HIDA, CT, or even MR imaging. Differential diagnoses include bilhemia, angioma, abscess, cystic lesions, lymphocele, seroma, or hematomas, which can be differentiated with fluid studies. Complications such as infection, perforation, and impingement on surrounding structures may arise. Radiological image-guided aspiration gives us a definitive diagnosis, fluid studies help rule out the infection. Smaller bilomas less than 4 cm may resolve. Treatment of choice may include minimally invasive techniques such as percutaneous drainage or endoscopic retrograde cholangiopancreatography with appropriate stent placement and surgical removal for those that are refractory to treatment.

by Ng Chung Ying Davy. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1994. / Includes bibliographical references (leaves 91-103). / ACKNOWLEDGMENT --- p.1 / ABSTRACT --- p.2 / Chapter CHAPTER 1 : --- INTRODUCTION --- p.3 / Chapter CHAPTER 2 : --- LITERATURE REVIEW --- p.5 / Chapter 2.1. --- The History of Laser --- p.5 / Chapter 2.1.1 --- Pre-Maser History (1917 - 1952) --- p.5 / Chapter 2.1.2. --- The Development of the Maser (1953 - 1959) --- p.6 / Chapter 2.1.3. --- The Development of the Laser (1960 - 1961) --- p.7 / Chapter 2.1.4. --- Expanding the Laser Concept (1962 - 1966) --- p.8 / Chapter 2.1.5. --- New Laser Development (1967 - at present) --- p.11 / Chapter 2.2. --- Basic Laser System --- p.11 / Chapter 2.2.1. --- The Active Laser Media --- p.12 / Chapter 2.2.2. --- The Source of Excitation Energy --- p.12 / Chapter 2.2.3. --- A Febry-Perot Interferometer --- p.13 / Chapter 2.3. --- Basic operational principles of laser --- p.13 / Chapter 2.4. --- Characteristics of Laser Radiation --- p.14 / Chapter 2.5. --- Laser Reactions in Living Tissue --- p.15 / Chapter 2.5.1. --- Laser Interactions with the Eye --- p.15 / Chapter 2.5.2. --- Laser Interaction with the Skin and its Appendages --- p.16 / Chapter 2.5.3. --- Laser Interaction with other tissues --- p.16 / Chapter 2.6. --- Thermal Effect of Laser Irradiation of Living Tissues --- p.20 / Chapter 2.7. --- Medical lasers and their applications --- p.21 / Chapter 2.7.1. --- Neodymium-doped yttrium-aluminium- garnet (Nd:YAG) laser --- p.21 / Chapter 2.7.2. --- Argon laser --- p.21 / Chapter 2.7.3. --- Carbon dioxide laser --- p.22 / Chapter 2.7.4. --- Tunable dye laser --- p.22 / Chapter 2.7.5. --- Gold Vapour Laser --- p.23 / Chapter 2.7.6. --- Copper Vapour Laser --- p.23 / Chapter 2.8. --- Port-wine stains --- p.24 / Chapter 2.8.1. --- Pathology of port-wine stains --- p.24 / Chapter 2.8.2. --- Treatment of port-wine stains by lasers --- p.24 / Chapter 2.9. --- Laser Therapy in the Gastrointestinal Tract --- p.28 / Chapter 2.10. --- Esophageal varices --- p.30 / Chapter 2.10.1. --- Etiology of oesophageal varices --- p.30 / Chapter 2.10.2. --- Pathology of oesophageal varices --- p.31 / Chapter 2.10.3. --- Diagnosis of esophageal varices --- p.31 / Chapter 2.10.4. --- Treatment of esophageal varices --- p.33 / Chapter CHAPTER 3 : --- ANIMAL EXPERIMENTS --- p.42 / Chapter 3.1. --- General Materials --- p.42 / Chapter 3.1.1. --- Equipment --- p.43 / Chapter 3.1.2. --- Drugs and chemical --- p.47 / Chapter 3.1.3. --- Laboratory Animals --- p.48 / Chapter 3.1.4. --- Surgical Instruments --- p.49 / Chapter 3.1.7. --- Disposable --- p.49 / Chapter 3.1.8. --- Sutures --- p.49 / Chapter 3.1.9. --- Histopathological Preparation --- p.50 / Chapter 3.2. --- Experiment 1 : Iatrogenic perforation of the rat's stomach by the continues application of the Copper Vapour Laser at different power level --- p.51 / Chapter 3.2.1. --- Introduction --- p.51 / Chapter 3.2.2. --- Methods --- p.52 / Chapter 3.2.3. --- Results --- p.55 / Chapter 3.2.4. --- Discussion --- p.60 / Chapter 3.3. --- Experiment 2 : Obliteration of the rats' mesenteric vein with the Copper Vapour Laser --- p.61 / Chapter 3.3.1. --- Introduction --- p.61 / Chapter 3.3.2. --- Method --- p.62 / Chapter 3.3.3. --- Results --- p.63 / Chapter 3.3.4. --- Discussion --- p.65 / Chapter CHAPTER 4 : --- CONCLUSION --- p.67 / REFERENCES --- p.91

<p>Abstract Redacted.</p> / Master of Science (MSc)

Helicobacter pylori (Hp) is a major cause of peptic ulcer disease (PUD) and gastric cancer, yet the infection remains asymptomatic in most people. One factor that influences the outcome of Hp infection is the host immune response. Expression of the immune-stimulating cytokine interleukin-17 (IL-17) is increased in the human Hp-infected gastric mucosa, but its cellular source and role in pathology are unclear. In this study dendritic cell cytokine responses to Hp stimulation were studied, and relative IL-12p70 and IL-23 concentrations compared, to assess the potential of Hp to promote differentiation of IL-17-secreting T-helper cells (Th17). The effect of Hp virulence factors on cytokine secretion was assessed and monocyte-derived DC (MoDCs) and CD1c+ myeloid DC (MyDC) responses compared. MoDCs produced high concentrations of IL-12p70 upon Hp stimulation. There was also an~ IL-23 MoDCs response, but this was >10-fold lower than the IL-12p70 response. Both IL-12p70 and IL-23 responses were significantly reduced when Hp isogenic mutants for the virulence factor dupA were used, although the effect on MoDC IL-12p70 and IL-23 secretion was less marked than previously reported for monocytes. MyDCs produced lower concentrations of IL-23 than MoDCs, and no detectable IL-12p70. It is known that Hp infection can have systemic effects, so next peripheral blood mononuclear cells (PBMCs) from 21 Hp+ and 13 uninfected patients were stimulated with Hp or control antigen and Th17 and Th1 cell frequencies analyzed by flow cytometry. A systemic Hp-specific Th17 response was identified with higher Th17 cell frequencies in the Hp+ patients compared to the uninfected controls (2.0-fold, p=0.027). A variable proportion of these cells also secreted IFNgamma (median 33%, n=21), but there was no significant correlation between Th17 and Th1 cell frequencies. Peripheral blood Th1 cells were also increased in Hp+ patients (2.1-fold, p=0.018). No significant difference was found between peripheral blood Th17 and Th1 frequencies in the Hp+ patients. The concentrations of Th17, Th1, Th2 and Treg cytokines in the gastric mucosa of Hp+ patients and uninfected controls were investigated using luminex and real-time PCR. High levels of Il-17 expression in the infected compared to uninfected gastric mucosa were confirmed at both the mRNA and protein level (mRNA: 42.6-fold, p<0.0001; protein 3.5-fold, p<0.0001). Il-17 concentrations correlated with the levels of Il-17F (p=0.80, p<0.0001) and the chemokines CCl20 (p=0.59, p<0.0001) and Il-8 (p=0.49, p=0.0004). Concentrations of the Th17-differentiating cytokines IL-1beta, IL-6, IL-21 and IL-23 were not increased in the Hp+ gastric biopsies, although IL-23 was present at high concentrations in all samples regardless of Hp infection status. IL-17 was present at higher concentrations than IFNgamma (3.9-fold, p<0.0001), IL-4 (3.0-fold, p<0.0001) and IL-10 (6.8-fold, p<0.0001) in Hp+ gastric biopsies. IFNG mRNA was also more highly expressed than IL17 mRNA (3.3-fold, p=0.016). To identify the cellular source of the IL-17 mononuclear cells were extracted from gastric biopsies, stimulated with PMA/ionomycin and analyzed by flow cytometry. Amongst biopsy CD3+ T cells from 10 Hp+ patients, IL-17 was produced mainly by CD4+ Th17 cells (68.5%), although CD8+/l-17+ (24.7%) and CD4-CD8- (18.2%) cells also made a significant contribution. High IL-17 concentrations were associated with increased inflammation (2.4-fold, p=0.024) and neutrophil infiltration (2.4-fold, p=0.031). RORC2 mRNA expression was weakly associated with PUD (p=0.046, 1.4-fold) but, surprisingly, no association was found between the IL-17 response and incidence of PUD or precancerous changes. In conclusion Hp can stimulate DCs to produce IL-23 in vitro, and high levels of this Th17-differentiating cytokine were found in gastric mucosal biopsies. Stimulation with dupA null Hp strains led to reduced IL-12p70 and IL-23 secretion, suggesting a possible mechanism of action for this recently discovered virulence factor. Culturing Hp with MoDCs and MyDCs yielded quite different results, and it remains unknown whether either model closely reflects gastric mucosal DC responses. Hp-specific Th17 responses were identified in the peripheral blood of patients with active Hp infection for the first time. Th17 cells were identified as the main cellular source of IL-17 in the Hp-infected gastric mucosa but there were also significant numbers of CDS+IL-17+ and CD4-CDS-IL-17+ T cells, which have not previously been described in this context. High mucosal concentrations of IL-17 and association of this cytokine with infiltration of immune cells indicate that it is an important component of the human immune response to Hp. However, no association between IL-17 and risk of disease was detected in this study, although RORC2 expression was weakly associated with PUD. The role of I L-17/Th 17 in Hp related disease warrants further investigation.