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Sepsis, septic shock and multiple organ dysfunction syndrome: selected cellular immune mechanisms and methodological aspects
Karvunidis, Thomas ; Matějovič, Martin (advisor) ; Firment, Jozef (referee) ; Průcha, Miroslav (referee)
SEPSIS, SEPTIC SHOCK AND MULTIPLE ORGAN DYSFUNCTION SYNDROME: SELECTED CELLULAR IMMUNE MECHANISMS AND METHODOLOGICAL ASPECTS MUDr. Thomas Karvunidis ABSTRACT Sepsis and septic shock with multiple organ dysfunction syndrome are frequent life-threatening conditions. Despite long-time scientific effort, their exact pathophysiology, causal treatment, and prevention remain obscure. The numbers of mediators and elements (e.g. leukocytes, thrombocytes, endothelium/microcirculation etc.) have been suggested as key mediators in the process of initiation and modulation of this dreadful disease. The aim of the thesis is to better describe and document the cellular mechanisms in the pathophysiology of sepsis, septic shock and multiple organ dysfunction syndrome using different analytic methods including microcirculation assessment, flowcytometry, and proteomics. The first original manuscript studied the role of neutrophils in the process of microcirculation impairment in septic shock patients, as a central pathophysiological mechanism of systemic inflammation. The real-time intravital videomicroscopy technique was used. This is the first clinical study reporting microvascular changes in septic shock patients with chemotherapy-induced cytopenia. The microcirculation injury was identical in cytopenic compared to...
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Replacement and Support of Vital Organs in Sepsis Pathophysiology and New Aspects of Treatments
Martínková, Vendula ; Matějovič, Martin (advisor) ; Chytra, Ivan (referee) ; Charvát, Jiří (referee)
Infectious diseases are the worldwide leading cause of morbidity and mortality. Sepsis is the major cause of death in infectious diseases. It is one of the most serious and also one of the most difficult treatable conditions of contemporary medicine. Sepsis is the main cause of death in intensive care units. Causal therapy of sepsis does not yet exist. With a far better understanding of patho/physiological mechanism of sepsis, it is possible to model new preclinical experiments to verify the efficiency and security of new therapeutic procedures. Large animal experiments in progressive sepsis, with the use of domestic porcine, play a vital role. Long-standing experience with this model and similarity to human facilitate the realization of more complex experiments with potential for the relevant translation of results into the subsequent clinical studies on human subjects. The objective of this doctoral dissertation was to assess on the clinically relevant model: 1) the efficiency and security of extracorporeal membrane oxygenation in the event of vasoplegic septic shock; and 2) the benefit of two innovative therapeutic approaches to treatment of sepsis: a) the intravenous administration of mesenchymal stem cells; and b) the activation of the neuro-inflammatory reflex through the vagus nerve stimulation.
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Sepsis and Sepsis-associated Acute Kidney Injury: Molecular Mechanism and Lovel Aspects of Treatment
Horák, Jan ; Matějovič, Martin (advisor) ; Šrámek, Vladimír (referee) ; Balík, Martin (referee)
Sepsis is the most common cause of death in the intensive care units worldwide. Despite the undeniable progress in pre- and clinical research, the effective causal therapeutic strategy still does not exist. Given to extremely complex and heterogenic host response to presence of infection, the paradigm "one disease, one drug" is obviously flawed and combination of multiple targets that involves early immunomodulation and cellular protection are needed. Cellular therapy using mesenchymal stem cells represents strategy that brought positive results in experiments with rodent septic models. Part of this thesis is dedicated to evaluation of safety and efficacy of stem cells intravenous administration to well-established large animal model of progressive peritoneal sepsis. Affecting of the neuroinflammatory reflex through the vagus nerve stimulation showed potential to attenuate sepsis in rodents. Rest of the text is dedicated to evaluation of vagus nerve stimulation effectivity in our model. KEYWORDS Sepsis, sepsis-associated acute kidney injury, mesenchymal stem cells, vagus nerve stimulation
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Inflammatory bowel diseases in pregnancy
Koželuhová, Jana ; Matějovič, Martin (advisor) ; Keil, Radan (referee) ; Hep, Aleš (referee)
Inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis, can affect mainly young people in their reproductive years. IBD therefore has a major impact on patient's family planning decisions. Management of IBD in pregnancy requires a challenging balance between optimal disease control and drug safety. An unanswered question is the impact of the course of childbirth in women with preexisting IBD regarding anal sphincter function and development of anal or fecal incontinence. To this date there aren't any clinically relevant guidelines for managing childbirth in women with IBD. From gastroenterologist's point of view, a clear indication for Caesarean section (CS) is active perianal disease or active IBD with rectal involvement, a relative indication for CS is ileal-pouch-anal anastomosis (IPAA) or ileal-rectal anastomosis in women after colectomy for refractory UC. Studies have shown a lack of knowledge among both patients and physicians regarding reproductive issues in IBD. The main aim of this thesis was first to assess risk of vaginal delivery in development of anal incontince, second to evaluate the safety of biologic therapy during pregnancy in women with inflammatory bowel disease. We present a study researching the morbidity of children born to mothers treated with biological...
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Analysis and identification of proteins in organ dysfunction using proteomic methods
Tůma, Zdeněk ; Matějovič, Martin (advisor) ; Lopot, František (referee) ; Hernychová, Lenka (referee)
Proteomics is the large-scale study of proteins, particularly their structures and functions. Proteomics has been utilized in medicine for investigation of disease mechanisms and biomarker discovery. Instrumental methods cover sample preparation, protein and peptide separation and mass spectrometry. At present, there is no proteomic method that can be used as universal for every sample. Analytical methods need to be adapted and optimized for certain samples. The aim of this work was to create methodic procedures and to interpret results of experimental and clinical research. The first part of the thesis includes experiments utilizing proteomics to study changes in the plasma proteome clinically relevant porcine model of sepsis-induced peritonitis. Proteomic analyzes were also starting methodological strategies in experiments aimed at kidney physiology and pathophysiology of acute kidney injury during sepsis. Renal biopsies were analyzed in order to study the time course of proteome changes caused by sepsis and surgery. The second part of the thesis contains experiments studying biocompatibility. A method for elution of proteins interacting with adsorbents used in extracorporeal liver support system and with hemodialyzer capillaries was prepared. Analysis of proteins adsorbed to polysulfone...
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Acute kidney injury in critically ill: experimental and clinical approaches
Valešová, Lenka ; Matějovič, Martin (advisor) ; Nalos, Marek (referee) ; Kieslichová, Eva (referee)
Acute kidney injury (AKI) complicates more than one third of intensive care unit admissions and is burdened by high morbidity and mortality of affected patients, with incidence steadily rising. Sepsis is the leading cause of AKI in critically ill. Despite growing insights into the pathogenesis of sepsis- induced AKI, we are so far not able to define successful AKI prevention and treatment. We aimed at assessing molecular mechanisms of sepsis- induced AKI using clinically relevant large animal model of sepsis and implementing new techniques of molecular biology- genomics and proteomics. Although acidosis is a common acid base disorder in critically ill, its role remains controversial. It is unknown whether acidosis is a marker of disease severity or is directly implicated in pathogenesis of acute organ dysfunction states. Its protective role is discussed with growing evidence of acidosis induced cellular energetics downregulation and reduced oxygen demand in stress conditions. We aimed to evaluate physiological effects of different types of acidosis on healthy organism on systemic and regional level, including a complex research of its effects on kidney to search for new AKI preventive and treatment modalities, which permissive acidosis could represent. Key words Acute kidney injury - sepsis -...
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Sepsis, septic shock and multiple organ dysfunction syndrome: selected cellular immune mechanisms and methodological aspects
Karvunidis, Thomas ; Matějovič, Martin (advisor) ; Firment, Jozef (referee) ; Průcha, Miroslav (referee)
SEPSIS, SEPTIC SHOCK AND MULTIPLE ORGAN DYSFUNCTION SYNDROME: SELECTED CELLULAR IMMUNE MECHANISMS AND METHODOLOGICAL ASPECTS MUDr. Thomas Karvunidis ABSTRACT Sepsis and septic shock with multiple organ dysfunction syndrome are frequent life-threatening conditions. Despite long-time scientific effort, their exact pathophysiology, causal treatment, and prevention remain obscure. The numbers of mediators and elements (e.g. leukocytes, thrombocytes, endothelium/microcirculation etc.) have been suggested as key mediators in the process of initiation and modulation of this dreadful disease. The aim of the thesis is to better describe and document the cellular mechanisms in the pathophysiology of sepsis, septic shock and multiple organ dysfunction syndrome using different analytic methods including microcirculation assessment, flowcytometry, and proteomics. The first original manuscript studied the role of neutrophils in the process of microcirculation impairment in septic shock patients, as a central pathophysiological mechanism of systemic inflammation. The real-time intravital videomicroscopy technique was used. This is the first clinical study reporting microvascular changes in septic shock patients with chemotherapy-induced cytopenia. The microcirculation injury was identical in cytopenic compared to...
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Gastrointestinal tract dysfunction in critical ill patients
Balihar, Karel ; Matějovič, Martin (advisor) ; Kula, Roman (referee) ; Martínek, Jan (referee)
Multiorgan dysfunction syndrom is the major driving pathophysiological mechanism of morbidity and mortality in critically ill patients. Gastrointestinal dysfunction usually develops as a result critical illness and it is believed to play a key role in the development and progression of multiple organ dysfunction. Moreover, any primary disorder of the gastrointestinal tract, if severe enough, can lead to a critical state and secondary multiorgan dyfunction. Despite intensive experimental and clinical research, reliable tools for monitoring and evaluation of the severity of gastrointestinal dysfunction remain unknown. In the same line, therapy of this complex pathology remains largely supportive. The aim of this thesis was first to explain the severity of the most common and most serious nosocomial infection of the digestive tract, second to elucidate the safety and effectiveness of the endoscopic dual enteral probe insertion in ventilated critically ill patients, and, third to evaluate new diagnostic tools of the gastrointestinal dysfunction. Finally, we present an ongoing project aimed at investigating esophageal dysfunction in mechanically ventilated critically ill patients.
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The role of cholesterol, its precursors and oxidative products in clinically serious conditions
Vyroubal, Pavel ; Zadák, Zdeněk (advisor) ; Matějovič, Martin (referee) ; Dítě, Petr (referee)
The role of cholesterol, its precursors and oxidative products in clinically serious conditions Objective: The aim of the study was to elucidate the role and importance of hypocholesterolemia in clinically serious conditions. It was a monocentric, prospective clinical study. Material and Methods: Two groups of patients were recruited into the study - one group consisted of patients with coronary heart disease (CHD), who underwent miniinvasive cardiosurgical operation without extracorporeal circulation (n=22) and the other group of patients, who sustained polytrauma (n=31). Fifty three patients were recruited into the study. We performed the determination of sterols (total cholesterol, HDL cholesterol, LDL cholesterol, triacylglycerols) and their precursors (β-sitosterol, campesterol, lathosterol, skvalen), interleukin IL-6, insulin, C-peptid and cortisol in the blood serum. The short version of ACTH stimulation test was performed. The oxidative burst of granulocytes was evaluated. The blood samples were taken on the day of admission, the first, the fourth and the eighth post-operative and post-traumatic day. Results: There was a significant early decline of total cholesterol (TC) and LDL cholesterol level followed by full recovery during observed period. There was a decline of cholesterol synthesis...
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Acute kidney injury in sepsis: phatophysiological and therapeutical aspects
Chvojka, Jiří ; Matějovič, Martin (advisor) ; Kasal, Eduard (referee) ; Maňák, Jan (referee) ; Balík, Martin (referee)
Sepsis and septic shock remain major cause of mortality in non-coronary intenisve care units. Prognosis of septic patiens worsens further in case of concomitant acute kidney injury. Pathophysiological pathways leading to renal dysfunction in sepsis remain unclear despite of enormous experimental and clinical research. Similarly, the role of extracorporeal blood purification techniques as an adjunctive treatment in sepsis is highly controversial. The aim of our study was to dynamically assess renal haemodynamic, microvascular and metabolic responses in a porcine clinically relevant model of septic shock. The same experimental model was used in experiments elucidating potential benefit effects of two distinct haemopurification methods on different biological responses to infectious insult.
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