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3. A commission of the Ministry of healthcare on selection of candidates for cochlear implantation was created.
4. A system of individual audiologic and surdo-pedagogical monitoring of implanted children is organized.
5. A set of documents and information materials on rehabilitation of implanted children is developed for parents for further activities in the family.
6. Work with parents and guardians of the patients is performed in order to establish social partnership and consolidate individual responsibility.
7. All-round consultation and methodical help is provided in the regions of the republic through the unified center ofcochlear implantation.
8. Cooperation with all world centers for cochlear implantation is established in order to apply and implement latest world achievements in the sphere of rehabilitation of children with hearing disorders.
The program of cochlear implantation in children with profound hearing loss and deafness and results obtained over a short
period (2 years) received high evaluation and are recognized in terms of their uniqueness and efficiency as «Uzbek model» by the specialists from leading clinics and centers of the world.
Thus, at the RSSRMC for Pediatrics, a program on cochlear implantation in children with profound hearing loss and deafness conforming to the world standards, herewith, beneficially different from the programs in other countries in terms of complex and stage-by-stage approach in rehabilitation, is developed and successfully implemented. The complexity of the program lies in the fact that it includes and monitors all stages of cochlear implantation and rehabilitation of children with profound hearing loss and deafness. All this determined high efficiency of hearing and speech rehabilitation in children with profound hearing loss and deafness, expressed reduction of the indicator of hearing disability in Uzbekistan, increase of the quality of life and integration of the children of the given cohort in the process of studying and society.
References:
1. Альтман Я. А., Таварткиладзе Г. А. Руководство по аудиологии. - М.: ДМК Пресс, - 2003. - 360 с.
2. Королева И. В. Введение в аудиологию и слухопротезирование. - СПб.: Каро, - 2012. - 400 с.
3. Понамарева Л. П., Ширина Н. С. Аудиологическое тестирование новорожденных детей. «Вопросы современной педиатрии» том 3, - № 3-2004. - С. 20-23.
DOI: http://dx.doi.org/10.20534/ESR-16-9.10-65-70
Aripov Utkur Rashidovich Tursumetov Abdusattar Abdumalikovich Rasul Sadykov, MD, PhD Tashkent Pediatric Medical Institute E-mail: [email protected]
Animal models of peritonitis
Abstract: Understanding the role of pathogens and endotoxin in peritonitis and its complications may improve accuracy of diagnosis and development of therapeutic options. The etiology of peritonitis is multifactorial and affects cardiovascular, immunological and endocrine systems of the human body. Animal models are the essential contributor in the evaluation of efficacy and safety of potential therapeutic agents. However, their physiological limitations often restrict their usefulness and cause barriers to translate study results into clinical practice. Careful differentiation of models can help study different aspects of the disease. Evidence-based information could potentially contribute to the interpretation of results of animal studies, which can be successfully used in clinical trials.
Keywords: peritonitis, spontaneous bacterial peritonitis (SBP), infections, sepsis, immune system, lipopolysaccharide (LPS), endotoxins, zymosan, inflammation, Toll-like receptor 4 (TLR4), Tumour Necrosis Factor alpha (TNF-a), Interleukin, Polymorphonuclear Leukocytes (PMNs), macrophages, cytokines, cecal ligation and puncture (CLP).
Introduction
Intra-abdominal infections remain a major challenge in clinical practice and represent a leading cause of morbidity and mortality. Intra-abdominal infections represent a wide variety of pathological conditions that involve lesions of all the intra-abdominal organs. The most common cause of peritoneal infections is contamination of the peritoneal cavity by the loss of integrity of endogenous gastrointestinal microflora, which results in secondary peritonitis. Primary peritonitis or spontaneous bacterial peritonitis is less common and generally happens in the occurrence of ascites without an evident source of infection.
Spontaneous bacterial peritonitis (SBP) is an infection of the peritoneal layer of the abdomen caused by bacteria that have no known cause. Spontaneous peritonitis is usually a complication of liver disease, such as cirrhosis. Advanced cirrhosis causes
a large extent of fluid build-up in the abdominal cavity (ascites) [40]. Ascites is predisposed to bacterial infection. SBP diagnosis is based on testing of the ascitic fluid obtained by paracentesis. Polymorphonuclear (PMN) cell count in the ascitic fluid is important for the diagnosis and management of spontaneous bacterial peritonitis (SBP). In more recent Prospective studies reported inpatient non-infection-related mortality rates have still been quite high at 20% to 40%.
The intestinal microflora and bacterial translocation (BT) are considered to be significant factors in the pathogenesis of SBP. The translocation of bacteria from the intestine to mesenteric lymph nodes occurs normally. When this physiological occurrence of BT increases in frequency or severity it leads on to bacteremia and following colonization of ascitic fluid. Additionally, invasive procedures can cause hospital-acquired SBP. Escherichia coli, Klebsiella
pneumonia, and streptococci are the widespread microorganisms being the most frequent isolated microorganisms. The most common pathogen organisms associated with secondary peritonitis were Enterococcus species, Candida species, and Staphylococcus epidermidis, followed by E. coli, Enterobacter species, B. fragilis, and Pseudomonas species [1].
A contamination may appear during peritoneal dialysis due to unclean surroundings, poor hygiene or contaminated equipment. Peritonitis also may be caused by the complication of gastrointestinal surgery, using the nourishing tubes or by a procedure of fluid withdrawal from the abdomen (paracentesis). A ruptured appendix, stomach ulcer or intestine perforation may trigger bacteria leakage to the peritoneum. Injury or trauma may also lead to peritonitis by spreading bacteria or chemicals from other organs of the body to allocate to the peritoneum.
The intestinal microflora and bacterial translocation (BT) are considered to be significant factors in the pathogenesis of SBP. The translocation of bacteria from the intestine to mesenteric lymph nodes occurs normally. When this physiological occurrence of BT increases in frequency or severity it leads on to bacteremia and following colonization of ascitic fluid. Additionally, invasive procedures can cause hospital-acquired SBP. Escherichia Coli, Klebsiella Pneumonia and Streptococci are the widespread microorganisms being the most frequent isolated microorganisms [33]. The most common pathogen organisms associated with secondary peritonitis were Enterococcus Species, Candida Species, and Staphylococcus Epidermidis, followed by E. Coli, Enterobacter Species, B. fragilis, and Pseudomonas Species [16; 34].
A contamination may appear during peritoneal dialysis due to unclean surroundings, poor hygiene or contaminated equipment. Peritonitis also may be caused by a complication of gastrointestinal surgery, using the nourishing tubes or by the procedure of fluid withdrawal from the abdomen (paracentesis). A ruptured appendix, stomach ulcer or intestine perforation may trigger bacteria leakage to the peritoneum. Injury or trauma may also lead to peritonitis by spreading bacteria or chemicals from other organs of the body to allocate to the peritoneum.
Animal models play a crucial role in creating clinical changes for studying pathogenesis and initial assessment of prospective therapeutic agents. Experimental animal models have high fundamental adaptability, differences within animal species and are also not entirely understood. The determined advantages of testing treatments in experimental animal studies have rarely been transformed into human clinical trials. This review summarizes the most common animal peritonitis animal models and explains animals study difference and limitations, which affect the process of turning experimental treatment into clinical trials.
Discussion
Several types of animal models ofperitonitis are currently used to study the cause of bacterial peritonitis and investigate the molecular changes in the body. The purpose of this review is to review common animal models of infected peritonitis, also determine additional aspects, which need to be further designed.
Animal models of peritonitis can be divided into three categories: exogenously administered toxins (lipopolysaccharide (LPS), endotoxins or zymosan); administration of an exogenous viable pathogen (bacteria); alteration of the animal's endogenous protective barrier (intestinal permeability and bacterial translocation) [21, 23]. All these models have advantages of using as potential experimental models to help study mechanisms as well as new treatments for peritonitis. Nonetheless, when reflecting the translation of ani-
mal models to the development of effective therapeutics approaches, there are many examples of limitations and inconsistencies.
While conducting pre-clinical studies it would be the optimal methodology when using the model that closely enough imitates the progression of human disease. Each model has its own tactic to study disease, however, it is still in the stage of development of the design animal model which perfectly minims the disease.
Bacterial endotoxin and zymosan
Gram-negative bacteria and their endotoxins may be a trigger factor in many serious diseases. Overwhelming innate immune responses to systemic inflammation contribute to the clinical manifestation of sepsis and septic shock. Systemic infections (septicemias) caused by invasive Gram-negative bacteria are the basis of endotoxin exposure. Endotoxin-induced acute peritonitis showed the kinetics of intraperitoneal LPS resorption and its steadfast translocation into the vascular compartment [3; 4].
Exposure to endotoxin induces a systemic inflammatory response that engages immune cells, blood vessels, and molecular mediator. Acute inflammation is the early response of the body to destructive inducements and is accomplished by the boosted extrapolation of leukocytes (particularly granulocytes) and plasma into the injured tissues. Clinical signs of inflammation are fever, increased heart and respiratory rates, and other systemic symptoms. Chronic inflammation causes change cell type at the place of inflammation, such as mononuclear cells (lymphocytes, monocytes, and macrophages).
Endotoxins are complex lipopolysaccharides (LPS), which consist of a hydrophobic domain as lipid A, of a non-repetitive oligosaccharide, and a distal polysaccharide termed O-antigen. Lipid A is a glucosamine-based phospholipid that builds up the outer monolayer of the outer membranes of most Gram-negative bacteria [47, 52].
Lipopolysaccharides typically consist of a hydrophobic domain known as lipid A (or endotoxin), a non-repeating "core" oligosaccharide, and a distal polysaccharide (or O-antigen). Lipid A (endotoxin), the hydrophobic anchor of lipopolysaccharide (LPS), is a glucosamine-based phospholipid that makes up the outer monolayer of the outer membranes of most Gram-negative bacteria. Lipopolysaccharide (LPS) is the ligand of Toll-like receptor 4 (TLR4), which plays a crucial role in the early native immune reaction to attacking pathogens by recognizing microorganism [1].
Latest studies propose that the administration of LPS produces and releases of several cytokines, such as tumour necrosis factor alpha (TNF-a), interleukin 1 (IL-1), IL-6, and gamma interferon [1; 52]. Attachment of LPS to TLR4 leads to the activation of NF-kB through the enrolment and activation of MyD88, IL-1R kinase (IRAK), TNFR associated factor 6 (TRAF-6), as well as NADPH oxidase [1; 27; 32]. NF-kB is crucial element in the transcription of genes, which is associated with innate immunity and inflammation reactions [2; 12; 14]. The massive production of inflammatory cytokines causes systemic inflammatory response syndrome (SIRS), which is the main cause of death in septic patients [42; 26; 27].
The animal model with LPS can stipulate important insights into mechanisms of the host response to pathogens. Inoculation of animals with pure or mixed bacterial flora has been a common tool for studying sepsis mechanisms. Nevertheless, high doses of bacteria frequently cause intoxication with endotoxins rather than mimic the infection [8; 12].
Zymosan is prepared from the cell wall of Saccharomyces cerevisiae and consists ofprotein-carbohydrate complexes. It is often used to induce experimental sterile inflammation, including proinflammatory cytokines, protein phosphorylation and inositol phosphate formation.
Peritoneal injection of zymosan A induces local and systemic inflammation with 58% mortality [35]. Recent studies showed that zymosan induces double-hit model with raised systemic proinflammatory and local peritoneal cytokine response (interleukin [IL]-1, tumor necrosis factor, IL-6) and moderately increased anti-inflammatory cytokines (IL-10, transforming growth factor) [7; 8; 32].
A lower dose of zymosan causes transient (temporary) inflammation characterized by neutrophil clearance followed by infiltration of resolution-phase macrophages, whereas a higher dose of zymosan induces more destructive and prolonged inflammation. It was shown, that a low dose of 0.1 mg Zymosan, triggers a mild and temporary inflammation leading to full recovery, and a higher dose of10 mg, which causes a more progressive and prolonged reaction leading to systemic inflammation. Experiments revealed, in acute zymosan-induced inflammation, polymorphonuclear leukocytes (PMNs) elevated in 8-24 hours and cleared thereafter. The level of macrophages had risen at 72 hours and remained in the peritoneum for up to 3 weeks after induction. Whereas, high-dose zymosan caused elevation of PMN and macrophages in 72 hours. Innate immune is illustrated by the early influx of polymorphonuclear leukocytes followed by monocyte-derived macrophages, with further returning injured tissues to normal physiological state.
Recent studies, presented correlation between plasma and peritoneal inflammatory mediators in patients with secondary peritonitis. Levels of IL-1, TNFa, IL-6, IL-10 and IFNy were detected at high concentrations in the peritoneal fluid of the patients with peritonitis [37]. The higher plasma cytokines is occurred in patients with bacteremia, where monocytes involvement can be affected. Only 16% of patients were positive for blood culture in the first 48 hours [41]. Results confirmed the fact that both pro- and anti-inflammatory mediators were involved concurrently in the peritoneum ofpatients with peritonitis [16].
Chemical Peritonitis- Brewer thioglycollate method
Macrophages are one of the first immune cells to respond to infection or injury of the host tissue. Macrophages initiate a proinflammatory reaction, apoptosis, and phagocytosis [44] Sterile inflammation is a tissue response to cellular damage in the absence of pathogens. Tissue-resident macrophages produce cytokines and chemokines that activate neutrophils and other macrophages. Monocytes and macrophages are the secondary line of inflammatory cells after neutrophils. Neutrophils have a short lifetime due to apoptosis [26; 48], whereas macrophages have longer lifetime and are an essential component in the clearance of neutrophils through phagocytosis. Apart from to leukocyte enrolment, another early immune response includes of secretion of the inflammatory mediators, such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-a, and anti-inflammatory mediators such as IL-10 [21; 22].
Thioglycollate (TG) stimulated peritonitis is a suitable model, which stimulate most clinical features of inflammation, inflammatory mediator production and leukocyte accumulation. Intraperitoneal injections of thioglycollate in mice induce rapid and abundant enrolment of neutrophils into peritoneum without stimulating degranulation [36; 6]. Neutrophils are afterward gradually cleared from the peritoneal cavity by apoptosis and are replaced by a population of monocytes, macrophages and leukocytes.
P. C. J. Leijh etc revealed, that increased number of peritoneal exudate macrophages was present at 4-day post injection. TG-elicited cells were double sized compare to resident macrophages. Whereas, the size and number of cells were back normal on 5-day post injection [22]. The high recruitment of granulocytes was observed at the 1-day post TG injection.
Acute TG induced peritonitis, is an optimal source for simulating cardiovascular M9 responses, M9 recruitment, M9 apoptosis [48], and cytokine production. Early stage of inflammatory diseases, with mimicking activation and involvement of inflammatory mediators are essential in understanding leukocytes recruitment to inflamed tissue. It has been suggested that the optimal period of therapeutic intervention with potential enhancement of clinical outcome is expected to be in the early stage of inflammation [28].
Cecal ligation and puncture.
Cecal ligation and puncture Cecal ligation and puncture (CLP) characterize a peritonitis model with clinical features ofpolymicrobi-al infection similar to peritonitis in humans [13]. Bacterial invasion of the peritoneal cavity due to intestinal leakage is the most common cause of septic peritonitis. In comparison to other animal models of polymicrobial septic peritonitis, CLP can be initiated in any mouse strain of different age and sex. It is a comparatively easy and low-cost surgical procedure. Septic peritonitis is caused by vast infiltration of neutrophils and macrophages into the peritoneum. The CLP model imitates the human diseases of ruptured appendicitis or perforated diverticulitis [14]. This model produces a bowel perforation with leakage of fecal contents into the peritoneum, which creates a mixed infection and causes an inflammatory reaction with tissue destruction, tissue necrosis, and systemic toxicity.
CLP model mimics the hemodynamic and metabolic phases of human sepsis. However, the load offecal material that leaks from the ligated caecum is problematic to control for different studies. Plasma IL-6 levels have been known as a potential marker of disease severity and mortality indicator. Elevation of IL-6 levels was associated with mortality, with no evidence of a correlation between early and late death.
Schietroma, M etc presented acute response, immunologic status, and bacterial translocation from laparoscopic surgery. The cecum contains a high concentration of gram-negative and grampositive bacteria. After planting the punctured cecum into the peritoneum, feces content translocate into the abdomen creating a severe peritonitis. Depending on conditions, CLP causes a local infection followed by a systemic bacteremia [43].
The pro-inflammatory period in early sepsis is associated with elevation cytokines and chemokines in the plasma, such as IL-6 and macrophage inflammatory protein 1-alpha (MIP-1a) [10]. Inflammatory mediators promote leukocyte transmigration to sites of inflammation. This model causes early death (in 48 hours), which can be explained by overstressed inflammatory reaction, hypovolemic shock, and ineffective tissue perfusion. CLP is considered a clinically applicable model of sepsis. It imitates most relevant clinical features of the disease and is associated with an early hyper-inflammatory following by hypo-inflammatory reactions. Innate immune effector cells such as macrophage produce anti-inflammatory cytokine, IL-10 and Th2 cytokine, IL-4 [30; 53]. Slow change from a pro-inflammatory to an anti-inflammatory state might affect the septic patient to develop nosocomial infections, which can lead to further organ compromise, organ failure, and death. Many researchers support the fact that sepsis causes immune suppression. This model appears to prolong survival of animals, which might be compromised with inadequately repossess of necrotic cecum and development of an abscess. Healthy mice are able to trigger an effective immune reaction in CLP model with an elevation of cytokine levels in 2-6 h and an initial peritoneal neutrophil invasion, causing a clearance of the systemic infection in 2-3 days.
Bacterial peritonitis (BP)
Acute bacterial peritonitis is the development of a bacterial infection in the peritoneal cavity causing peritonitis. 60% of the BP incidents are caused by enteric Gram-negative bacilli- Escherichia
coli and Klebsiella spp., which can be found in up to 60% of the cases [34; 9]. Contrary to innovations in surgery and antimicrobial therapy, the mortality rates of peritonitis vary from 30% to 50% [15,49]. A serious complication of peritonitis includes systemic inflammation and sepsis with a fatality rate more than 80%. Retrospectively analyzes ofpatients with severe intra-abdominal infection revealed, predominant bacteria isolated from pus flora were Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), Klebsiella pneumoniae (K. pneumoniae), Enterococcus faecalis and Pseudomonas aeruginosa (P. aeruginosa). [19; 24; 31]
Escherichia coli (E. coli) is one of the most common organisms that cause gram-negative peritonitis and is associated with a high probability of mortality and technique failure. Multiple bacteria can cause peritoneal infection, but Escherichia coli is the most commonly isolated in peritonitis (60%) [29]. Host, as well as bacterial factors, may be involved in the development of the bacterial peritonitis. Pathogen-associated molecule patterns with the involvement of lipopolysaccharide and lipid A, lipoteichoic acid and peptidoglycan may cause a systemic inflammatory response [46; 50].
LPS is a main immunogenic component ofE. coli can stimulate activation of inflammatory responses to these pathogens. LPS is recognized by Toll-like receptor 4, CD14 and MD-2 on host innate immune cells and can activate the transcription factor NFkB, which is an important key in controlling the immune response to infection by production ofpro-inflammatory cytokines that initiate the adaptive immune response [38, 39]. However, studies show that infecting peritoneal cavity with E. coli does not activate a cytokine host response [5, 45]. E. coli has pathogenic features to the host mostly through endotoxin, causing systemic septic reaction and, initially, the local response of the peritoneal cavity [18]. According to some authors, low plasma IFNy is associated with increased mor tality [30, 51] while others reported that prophylactic inhibition of IFNy improves survival [20; 53].
Postoperative patients have completely special host defense mechanisms in comparison to patients with peritonitis and posttrauma [11]. Mouse peritonitis models are important to imitate particular processes of disease but can't manipulate all spectrums of physiological variations that appear in humans. Clinical data confirmed that IL-1, TNFa, IL-6, IL-10, and IFNy appear at high concentrations in the peritoneal fluid of patients with peritonitis. Florence Riché etc conducted comparable laboratory analysis of peritoneal fluids of patients with peritonitis revealed higher plasma levels of all cytokines whereas peritoneal fluid showed no elevation of cytokines [25; 37].
Conclusions
Animal models have limitations to imitate the complexity of human disease, pathophysiology, and progression. The question "how effectively translate scientific findings into clinical practice" remains unanswered. Experimental discoveries are part of the basic research, where pre-clinical animal studies can be translated into human clinical trials. Animal models still remain as essential contributor in the evaluation of efficacy and safety of new therapeutic agents. However, their physiological limitations often restrict their usefulness. In spite of significant success achieved through pre-clinical studies, almost 85% of early clinical trials for new therapeutic drugs fail.
The failure of translation of animal studies to humans might be due to inaccurate methodology and differences of experimental models to precisely imitate the physiological features of human disease.
Animal models of peritonitis are not well established and cannot completely recreate the human disease. Lack of evidence, different organism, and not accurate modeling can cause inconsistencies in results. Careful differentiation of models can help study different aspects of the disease. Evidence-based information could potentially contribute to the interpretation of results of animal studies, which can eventually be used in clinical trials.
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DOI: http://dx.doi.org/10.20534/ESR-16-9.10-70-73
Asadullaev Ulugbek Maksudovich, Republican Scientific Center of Neurosurgery of Uzbekistan E-mail: [email protected] Kariev Gayrat Maratovich, Tashkent Medical Pediatric Institute Republican Scientific Center of Neurosurgery of Uzbekistan
E-mail: [email protected] Mamadaliev Dilshod Muhammadvalievich, Republican Scientific Center of Neurosurgery of Uzbekistan
E-mail: [email protected]
Staged surgery of deep midline tumors. Comparative analysis and literature review
Abstract: This article analyzes the results of clinical observation of255 patients with deep midline tumors accompanied by secondary obstructive hydrocephalus. Of them75 (29.41%) patients underwent endoscopic third ventriculostomy (ETV) as a first step, followed a week later by tumor resection as a second step of treatment. In 85 (33.33%) patients ETV and tumor resection was performed simultaneously, and 95 (37.25%) patients tumor resection with ventriculocisternostomy by Torkildsen's method was done. In ETV group condition of the patients is significantly improved after adequate correction of CSF circulation. All patients complained of headaches, symptoms of raised intracranial pressure or visual disturbances and vomiting or cerebellar ataxia. Complete tumor removal was achieved in 190 cases and partial removal or biopsy in the remaining 65. ETV was successful in 177 (87.50%) cases but failed in one. Two patients experienced intraoperative transitory bradycardia. Two postoperative complications occurred (one meningitis and one CSF leak). No death related to procedures occurred. Hospital stay ranged from 9 to 21 days (mean, 12.71 days). Follow up range was 4 months to 10 months. Keywords: posterior fossa tumors, third ventricular tumors, ETV, staged surgery.
The posterior cranial fossa considered not only the largest and deepest fossa, it is the fossa that containing most complex anatomical structures. All the vital pathways regulating consciousness, motor, sensory and balance functions. Only 2 of the 12 pairs of cranial nerves are located entirely outside of posterior cranial fossa, the 10 other pairs have a segment within posterior fossa [1].
The surgery of posterior cranial fossa tumors are still remaining one of the challenging cases of practical neurosurgery [1; 2; 5;
13]. The features of brain tumors associated with hydrocephalus, requires the solution of two important issues. Firstly, elimination of a progression of the hydrocephalic syndrome; secondly, resection of brain tumor itself [2-4]. Conventional methods of surgical correction of hydrocephalic syndrome are ventriculocisternostomy (VCS) by Torkildsen, ventriculoperitoneal shunting, ventriculoatriostomy have a number of contraindications and are traumatic in some point. Most these interventions often contribute to the development of
