Form Of Encephalitis Research Articles

H-101 The development of oncolytic herpes simplex viruses for the treatment of glioblastoma multiforme

In the pursuit of genes that influence the pathogenesis of herpes simplex virus (HSV), the γ134.5 gene was identified between the Roizman and Whitley laboratories. It is a diploid gene that maps in the inverted repeat of the UL segment of the genome. This gene controls neurovirulence, replicating in dividing cells but not post mitotic cells. Studies with an HSV deleted in both copies of γ134.5, demonstrated that direct intracerebral inoculation failed to result inmortality, even at doses of 106 viral particles. A virus in which the gene was re-engineered back into the genome resulted in neurovirulence equivalent to that of wild type virus. Further, it was recognized that this virus was capable of replicating in tumor cells, prompting studies in a variety of different tumor models. Among the most susceptible were cells obtained from patients with glioblastoma multiforme. This first-generation virus, G207, in addition to the deletion of both copies of the γ134.5 gene, also had a second site mutation in ribonucleotide reductase. This latter mutation was introduced to prevent the potential for reversion of G207 to wild type virus, ergo restoring its neurovirulence. In order to improve replication competence of G207, a second-generation virus, M032, was engineered that similarly had deletions in the γ134.5 gene but now expressed human-IL-12 which was capable of inducing an immune response in the brain as well also having anti-angiogenic properties. In order to test the hypothesis that G207 had a biological effect, studies of intratumoral administration in, first, SCID mice and, then, immune competent mice demonstrated prolonged survival and, in some cases, survival with no evidence of residual tumor. Further, the kinetics of viral replication in these tumors was established which proved enhanced replication with M032 as compared to G207. To determine if it was possible to further enhance viral replication, low grade radiation was introduced into the experimental murine studies. In so doing, viral replication was enhanced by approximately one log additionally. Biodistribution studies work performed in aotus monkeys proved safety with no evidence of toxicity. Importantly, attempts at reactivation of virus from sensory ganglia and the brain were unsuccessful. With these data, clinical grade production of virus was undertaken, according to GMP regulations. Three phase 1B studies have been completed in adults with recurrent glioblastoma multiforme utilizing the first generation virus, G207. The studies were dose-escalating and undertaken to prove safety and potential efficacy. With the third study, low-dose radiation was added to the clinical protocol. The following findings were noted. First, there was no evidence of toxicity upon direct occupation of G207 into the tumor bed. Second, no patients excreted G207 from a peripheral site. Third, of the patients entered in the clinical trial, 5 of 27 were long term survivors with no evidence of residual tumor >3 years after inoculation. For our adult studies, M032 was introduced into a similar population to again determine safety and the potential for efficacy in a dose-escalating fashion. These studies are ongoing. In parallel, studies in children with recurrent glioblastoma multiforme have been initiated with G207. Parenthetically, G207 replicates by a log greater in pediatric tumors as compared to those of adults. The results obtained to date again indicated no evidence of toxicity upon direct intratumoral inoculation in the brain and, more importantly, long-term survival several of these children both without evidence of relapse and an improved Karnosky performance score (5 of 7 patients). Serial imaging of these children demonstrates continued improvement 18 months after a single treatment. These data taken together for both viruses indicate safety of intracerebral inoculation of an engineered HSV. Specifically, in no patient was there evidence of herpes encephalitis or any other form of encephalitis. In addition, while the data are limited, preliminary findings suggest a beneficial survival effect for the children who participated in this trial. The results of the adult studies with M032 are ongoing. Serial outcome data, including radiological responses will be presented.

An Assay to Determine Mechanisms of Rapid Autoantibody-Induced Neurotransmitter Receptor Endocytosis and Vesicular Trafficking in Autoimmune Encephalitis.

N-Methyl-D-aspartate (NMDA) receptors (NMDARs) are among the most important excitatory neurotransmitter receptors in the human brain. Autoantibodies to the human NMDAR cause the most frequent form of autoimmune encephalitis involving autoantibody-mediated receptor cross-linking and subsequent internalization of the antibody-receptor complex. This has been deemed to represent the predominant antibody effector mechanism depleting the NMDAR from the synaptic and extra-synaptic neuronal cell membrane. To assess in detail the molecular mechanisms of autoantibody-induced NMDAR endocytosis, vesicular trafficking, and exocytosis we transiently co-expressed rat GluN1-1a-EGFP and GluN2B-ECFP alone or together with scaffolding postsynaptic density protein 95 (PSD-95), wild-type (WT), or dominant-negative (DN) mutant Ras-related in brain (RAB) proteins (RAB5WT, RAB5DN, RAB11WT, RAB11DN) in HEK 293T cells. The cells were incubated with a pH-rhodamine-labeled human recombinant monoclonal GluN1 IgG1 autoantibody (GluN1-aAbpH−rhod) genetically engineered from clonally expanded intrathecal plasma cells from a patient with anti-NMDAR encephalitis, and the pH-rhodamine fluorescence was tracked over time. We show that due to the acidic luminal pH, internalization of the NMDAR-autoantibody complex into endosomes and lysosomes increases the pH-rhodamine fluorescence. The increase in fluorescence allows for mechanistic assessment of endocytosis, vesicular trafficking in these vesicular compartments, and exocytosis of the NMDAR-autoantibody complex under steady state conditions. Using this method, we demonstrate a role for PSD-95 in stabilization of NMDARs in the cell membrane in the presence of GluN1-aAbpH−rhod, while RAB proteins did not exert a significant effect on vertical trafficking of the internalized NMDAR autoantibody complex in this heterologous expression system. This novel assay allows to unravel molecular mechanisms of autoantibody-induced receptor internalization and to study novel small-scale specific molecular-based therapies for autoimmune encephalitis syndromes.

Recognizing psychiatric presentations of anti-NMDA receptor encephalitis in children and adolescents: A synthesis of published reports.

The aim of this study was to improve early recognition of anti-N-methyl-d-aspartate receptor encephalitis (anti-NMDArE) in children and adolescents by identifying characteristic temporal patterns of clinical features in patients likely to be referred for psychiatric evaluation. In this form of autoimmune encephalitis, NMDAr hypofunction is caused by autoantibodies to receptor surface components. Clinical outcomes following prompt immunotherapy are usually good, but delayed treatment often results in a protracted course with significant residual disability or death. Anti-NMDArE frequently mimics psychiatric disorders, so most patients are referred initially to a psychiatrist and treated for days or weeks before being correctly diagnosed. A systematic search of PubMed and EMBASE electronic databases identified all published reports of antibody-confirmed anti-NMDArE associated with psychiatric symptoms in patients <19 years old. Redundant reports were eliminated manually. For each patient, the order in which each feature was first observed was ranked relative to others. Median temporal ranks were used to compare the sequencing of individual features and major symptom domains. One hundred and sixty seven cases (121 females) met the inclusion criteria. The most common features were dyskinesias (77.8%), seizures (72.5%), mutism or staring (40.7%), insomnia (39.5%), language dysfunction (36.5%), fever (31.1%), disorientation/confusion (28.7%), reduced arousal (28.1%), and memory disturbance (26.9%). The configuration and temporal sequencing of features were highly variable between individuals. Clinicians need to suspect this disorder: if new behavioral symptoms arise in the context of a recent viral prodrome; if they are accompanied by dyskinesias, seizures or insomnia; or if psychiatric symptoms are unusual (e.g., non-verbal auditory hallucinations).

New Genetic Marker of Human Predisposition to Severe Forms of Tick-Borne Encephalitis

The causative agent of tick-borne encephalitis (a neurotropic RNA virus from the Flavivirus genus) can cause both severe paralytic forms of the disease (meningoencephalitis, etc.) and milder nonparalytic forms (fever and meningitis). The organism response to viral infection (and, as a consequence, the nature and outcome of the disease) significantly depends on individual peculiarities of the human organism protective systems predetermined by genome structure. Human genetic predisposition to tick-borne encephalitis has been poorly studied. In the present work, the results of the search for new genes that predetermine the peculiarities and outcome of tick-borne encephalitis in humans are presented. The aim of the work was to verify the association between three previously detected (using the exome sequencing on a limited sample of tick-borne encephalitis patients with severe forms) SNPs: intronic rs3109675 (C/T) in the COL5A1 gene, intronic rs41554313 (A/G) in the POLRMT gene, and intergenic rs10006630 (C/A), and the predisposition to tick-borne encephalitis in a Russian population (using an extended sample of patients with different forms of tick-borne encephalitis). The association of the rs10006630 SNP located in chromosome 4 between the FABP2 and LINC01061 genes with a predisposition to tick-borne encephalitis was confirmed. This SNP can be considered as a new genetic marker of a human predisposition to severe forms of tick-borne encephalitis. The possible regulatory role of this SNP in the functioning of neighboring genes and a mechanism of its effect on the development of predisposition to severe forms of tick-borne encephalitis require further study.

Neurological complications associated with dengue virus infection

Dengue is an arboviral infection caused by the dengue virus. The neurological complications associated with this infection are reviewed. The neurotropic nature of dengue virus has been confirmed in epidemiological studies, case series and histopathological studies. The range of neurological complications is 5.6-14.6%, and they are more frequent in serotypes 1 and 3. Encephalopathy is the most common neurological syndrome (0.5-6%) and its prevalence is higher in children and adolescents. The detection of the viral antigen in brain tissue and the presence of pleocytosis or RNA in cerebrospinal fluid are evidence of the neurotropic nature of dengue virus, which manifests itself in the form of encephalitis. Neurological syndromes during convalescence (disseminated acute cerebellitis, opsoclonus-myoclonus syndrome, mononeuritis, poly-radiculoneuritis and plexitis) appear to be immunomediated. Myelitis can occur during acute dengue virus infection and through an immunomediated mechanism in the convalescence phase. Myalgias, myositis, rhabdomyolysis and hypokalemic paralysis are examples of muscular dysfunction associated with the dengue virus. The incidence of stroke is 0.26%, and may be ischaemic or haemorrhagic. Ophthalmological complications include maculopathy, retinal haemorrhage, optic neuropathy and vitritis. The spectrum of neurological complications from dengue virus is broad. There are no reliable data on its real incidence because most of the studies published to date are isolated series or cases.

Chapter 10: Diagnosis

• TBE appears with non-characteristic clinical symptoms, which cannot be distinguished from oth-er forms of viral encephalitis or other diseases. • Cerebrospinal fluid and neuro-imaging may give some evidence of TBE, but ultimately cannot confirm the diagnosis. • Thus, proving the diagnosis “TBE” necessarily requires confirmation of TBEV-infection by detec-tion of the virus or by demonstration of specific antibodies from serum and/or cerebrospinal fluid. • During the phase of clinic symptoms from the CNS, the TBEV can only rarely be detected in the cerebrospinal fluid of patients. • Most routinely used serological tests for diagnosing TBE (ELISA, HI, IFA) show cross reactions resulting from either Infection with other flaviviruses or with other flavivirus vaccines.

Anti-N-methyl-d-aspartate Receptor Encephalitis: A Case Series and Review of the Literature.

Anti-NMDAR (N-methyl-d-aspartate receptor) encephalitis is a potentially severe form of encephalitis associated with antibodies against NR1 and NR2 subunits of the NMDAR. Anti-NMDAR encephalitis is a treatable cause of encephalitis. An underlying tumor should be actively looked for as this is also considered to be a paraneoplastic syndrome. We report two children with anti-NMDAR encephalitis with a literature review of current evidence in diagnosing and managing this rare condition. Resection of the tumor, glucocorticoids, intravenous immunoglobulin, and plasma exchange often result in improvement, usually within four weeks. Outcome corresponds with the rapidity of commencing appropriate treatment.

An evolving redefinition of autoimmune encephalitis.

Autoimmune encephalitis encompasses a wide variety of protean pathologic processes associated with the presence of antibodies against neuronal intracellular proteins, synaptic receptors, ion channels and/or neuronal surface proteins. This type of encephalitis can also involve children with complex patterns of seizures and unexpected behavioural changes, which jeopardize their prompt recognition and treatment. Many epidemiological studies have shown that numerous immune-based forms of encephalitis can be encountered, almost surpassing the rate of postinfectious encephalitides. However, the overall exact prevalence of autoimmune encephalopathies remains underestimated, and the definition of diagnostic algorithms results muddled. The spectrum of neuropsychiatric manifestations in the pediatric population with autoimmune encephalitis is less clear than in adults, but the integration of clinical, immunological, electrophysiological and neuroradiological data is essential for a general approach to patients. In this review we report the most relevant data about both immunologic and clinical characteristics of the main autoimmune encephalitides recognized so far, with the aim of assisting clinicians in the differential diagnosis and favouring an early effective treatment. Correlations between phenotype and autoantibodies involved in the neurological damage of autoimmune encephalitis are largely unknown in the first years of life, because of the relatively small number of pediatric patients adequately studied. Future multicenter collaborative studies are needed to improve the diagnostic approach and tailor personalized therapies in the long-term.

Tuberculous Encephalopathy Mimicking Limbic Encephalitis and Large Intraparenchymal Mass: A Challenge In Diagnosis

Tuberculosis of central nervous system (CNS TB) being endemic in Malaysia, most commonly presents as tuberculoma or meningitis. Less commonly, this specific disease entity presents as cerebritis, miliary form, encephalitis and large intraparenchymal mass. At the cellular level, it was even postulated that the pathogenesis of the most common form of CNS TB is way different from the rarer form of encephalitis. Parenchymal involvement of CNS TB is primarily believed as a result of leptomeningeal/ ependymal extension or gross occlusion of basal arteries due to exudates and arteritis. However, the pathogenesis of TB encephalitis was postulated to result from type IV direct (allergic type) hypersensitivity which is similar to other demyelinating diseases at present. Here, we highlight an extremely rare imaging manifestation of CNS TB, which impersonates limbic encephalitis and large intraparenchymal mass imposing a diagnostic dilemma.

Abnormal level of consciousness predicts outcomes of patients with anti-NMDA encephalitis

Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is an acute form of encephalitis with an autoimmune etiology. We aimed to study clinical characteristics and treatment outcomes and assess the predictive factors associated with patient outcome. In this retrospective study, patients who presented with cardinal symptoms of anti-NMDA encephalitis and positive anti-NMDA receptor antibody results in their cerebrospinal fluid were included in the study. Thirty-one patients were identified. The median age of onset was 19 years (IQR 15.0–31.0). Females were predominant (61.8%). The main clinical symptoms were neuropsychiatric symptoms (87.1%) followed by abnormal movement (71%), seizures (51.1%), and autonomic instability (41.9%). Eleven patients (35.5%) exhibited decreased levels of consciousness. Abnormal MRI results were found in only 35.5% of the patients. CSF abnormalities usually involved mild pleocytosis. Only 67.7% of serum samples were positive against the anti-NMDAR antibody, whereas 100% of CSF samples were positive. Tumor-related information was only available for 20 patients. Only one case involved an ovarian teratoma. All patients received first-line therapy (intravenous pulse methylprednisolone and plasmapheresis). Three patients were treated with second-line therapy (IV cyclophosphamide). Twenty patients (64.5%) had favorable outcomes in our cohort (mRS 0–2) after a 1-year follow-up. An abnormal level of consciousness was a factor associated with a nonfavorable outcome (OR 15.65, 95% CI 2.30–106.29, p value <0.01).

О возможности применения триазавирина в комплексном лечении клещевого вирусного энцефалита у взрослых

Поиск новых эффективных методов лечения клещевого вирусного энцефалита связан с распространенностью заболевания, тяжелым поражением центральной нервной системы, приводящим к инвалидизации и гибели больных. Представлены промежуточные результаты открытого наблюдательного исследования, в котором апробирована тактика комплексной противовирусной терапии, включающей триазавирин (риамиловир) при клещевом вирусном энцефалите. Основным механизмом действия триазавирина является ингибирование синтеза вирусных РНК и репликации геномных фрагментов, тем самым препарат тормозит жизненный цикл вирусных белков и обеспечивает прямое противовирусное действие. После приема триазавирина в комплексной терапии у больных с лихорадочными формами клещевого энцефалита отмечено сокращение лихорадочного периода до (3,5 ± 1,0) дней, по сравнению с пациентами, не получавшими его (5,0 ± 1,5) дней (p &lt; 0,05); уменьшение продолжительности и выраженности головной боли (p &lt; 0,001). За время применения триазавирина у пациентов быстрее купировались гиперестезия и светобоязнь (в среднем на 50 %, p &lt; 0,001). Результаты проведённого исследования позволяют отнести триазавирин к препаратам первой линии при клещевом вирусном энцефалите, наряду с другими этиотропными средствами.

Rabies and Bornavirus encephalitis : Fatal emerging viral encephalitis-a potential problem for organ recipients

A severe, often fatal encephalitis needs to be extensively and carefully clarified, especially when it occurs in apatient weeks or months after an organ transplantation. If the donor was viremic at the time of the organ removal or living viruses were present in the organ tissue, many viruses can be transferred to the organ recipient. This has been repeatedly reported in recent years and decades. In this overview rabies is discussed as a particularly important form of viral encephalitis, which is transferred via organs and always has a fatal outcome, because patients carry ahigh risk of infection for all caregivers. Bornavirus has been known in veterinary medicine for many decades and in human medicine has been discussed as possibly being associated with psychiatric diseases. Very recently Bornavirus has been identified as the causative pathogen of fatal encephalitis in organ recipients. The aim of this article is to raise awareness for rabies and Bornavirus disease in intensive care medicine and neurology for organ donors and those taking care of organ recipients. Prevention by knowledge can be lifesaving.

Critical Care Management of Anti-N-Methyl-D-Aspartate Receptor Encephalitis.

Anti-N-methyl-D-aspartate receptor encephalitis is considered an immune-mediated form of encephalitis with paraneoplastic and nonparaneoplastic forms. Delay in recognition is common and patients typically present to the ICU without a diagnosis or with complications following a delayed diagnosis. The aim of this review is to provide a focused overview for the ICU clinician regarding presentation, diagnosis, and critical care management. PubMed database search with manual review of articles involving anti-N-methyl-D-aspartate receptor encephalitis. Anti-N-methyl-D-aspartate receptor encephalitis is increasingly encountered in the ICU. The cascade of events initiating anti-N-methyl-D-aspartate receptor antibody formation may involve an infectious trigger particularly in the setting of teratoma. Following a prodrome, most patients develop psychiatric symptoms followed by movement disorder. Classical, psychiatric, and catatonic phenotypes may be distinguished based on the presence and severity of symptoms. Early immunotherapy and low initial cerebrospinal fluid inflammation are independent predictors of positive outcomes in ICU patients. Concomitant organ failure, status epilepticus, and the identification of a tumor did not influence outcome in critically ill patients. Supportive care in the ICU includes management of various manifestations of dyskinesia, status epilepticus, autonomic disorders, and the need for general sedation. Common treatment strategies and limitations are discussed including the emerging role of bortezomib. Intensivists should be familiar with the presentation and management of anti-N-methyl-D-aspartate receptor encephalitis. Early diagnosis and immediate implementation of steroids, immunoglobulins, and/or plasmapheresis and immune therapy are associated with a good neurologic outcome although response may be delayed. The selection and timing of second-line immune therapy requires further study.

Haplotype analysis of the HFE gene among patients with different forms of tick-borne encephalitis

Haplotype analysis of the HFE gene among patients with different forms of tick-borne encephalitis

Effect of LGI1 antibody-positive IgG on hippocampal neuron survival: a preliminary study.

Anti-leucine-rich glioma inactivated 1 (anti-LGI1) encephalitis is one of the most frequently encountered forms of autoimmune encephalitis. Many patients with anti-LGI1 encephalitis develop permanent hippocampal neuron loss and chronic neuropsychiatric symptoms, suggesting that LGI antibodies (Ab) might have a neurotoxic action. To investigate this hypothesis, purified serum IgG of three patients with anti-LGI1 encephalitis and six healthy controls were incubated with cultured primary hippocampal neurons obtained from newborn mice. Nontreated cells were used as controls. The viability of IgG-treated neurons was evaluated by propidium iodide staining. Apoptotic mechanisms were assessed by JC-1 assay and mRNA expression level measurement of apoptosis-related genes using real-time PCR. The effect of IgG treatment on calcium influx was analyzed by fluo-4 calcium imaging. LGI1-Ab+ IgG increased the number of propidium iodide positive neurons, reduced mitochondrial membrane potentials, upregulated caspase-3 and Bax mRNA expression levels and downregulated Bcl-2 mRNA expression levels of neurons. LGI1-Ab+ IgG-treated neurons showed lower calcium staining than healthy controls IgG-treated and non-IgG-treated neurons. Our results indicate a neurotoxic role of LGI1-Ab. This neurotoxicity is likely mediated through induction of apoptosis and reduction of calcium currents.

Autoimmune Anti-NMDA Receptor Encephalitis

Encephalitis with antibodies to glutamate NMDA receptors (anti-NMDA receptor encephalitis, ANRE) is a relatively common form of autoimmune encephalitis. Clinical symptoms at onset are similar to the symptoms of exacerbation of schizophrenia, such that these patients are often hospitalized in psychiatric institutions. Considering the high lethality of this condition, and also its potential curability, detection of ANRE is an important clinical task. We present here the first laboratory confirmed case of ANRE in the Russian literature. Difficulties preventing the prompt resolution of the condition are presented, along with criteria for its diagnosis and a treatment algorithm.

Subacute Sclerosing Panencephalitis (SSPE): A Fatal Aftermath of Measles Infection

Subacute Sclerosing Panencephalitis (SSPE) is a progressive form of encephalitis without a cure. This case report pertains to a primigravida diagnosed with SSPE in her fifth month of pregnancy. She has been married for two years. During her sixth month of pregnancy, she developed signs of SSPE such as behavioral and personality changes, social detachment, reduced involvement in household work which progressed to mutism, altered sensorium, involuntary movement of right half of face and myoclonic jerks involving right upper and lower limbs, in spite of that, she delivered a baby boy who within a month died due to diarrhea. The patient had several episodes of seizures which subsided with antiepileptic and antiviral drugs initially but on March 3, 2018 she again had myoclonic episodes of seizures, from which she did not recover. EEG findings showed periodic episodes of high-amplitude delta-frequency activity associated with the involuntary movements, superimposed on relatively normal background activity and elevated levels of gamma globulin and measles antibody in serum and cerebrospinal fluid was suggestive of SSPE. During pregnancy, marked by physiological immunosuppression, there is a greater chance of SSPE outbreak which requires constant care, follow up and observing initial manifestations of SSPE to delay the course of disease with symptomatic medications or treatment when the inflammatory changes are, possibly, still reversible. The long-term outlook for people with subacute sclerosing panencephalitis (SSPE) is poor. Since the condition is always fatal, the only way to prevent SSPE is to get the measles vaccination

Acute Disseminated Encephalomyelitis Secondary to Herpes Virus Infection in a Child

The acute disseminated encephalomyelitis ADEM is a rare form of encephalitis. We report a case after herpes infection. The diagnosis was based on the existence of post-infectious and neurological signs and demyelinating reaching the white matter in the magnetic resonance imaging MRI. The outcome was favourable after treatment with high-dose steroids.

Microbiological diagnosis of infections caused by Listeria monocytogenes

Listeria monocytogenes are Gram-positive, relatively anaerobic bacteria, widely distributed in the natural environment (soil, water, sewage, plants and vegetables, food products), causing a disease called listeriosis in humans. Listeriosis is manifested most often in the form of bacteremia, meningitis and encephalitis, perinatal infections as well as gastroenteritis. Currently, it is perceived as a contemporary threat to human life and health. This review discusses the microbiology diagnosis of infections caused by Listeria monocytogenes in humans.

Listeriosis. Modern perception of epidemiological threat

Abstract The presence of Listeria rods, especially Listeria monocytogenes, in the environment and food products, contributes each year to death of both humans and animals. The ability of bacteria to lead a saprophytic and parasitic existence as well as insensitivity to many physicochemical factors greatly facilitates the spread and guarantees access to a wide range of vulnerable organisms. Although the factors predisposing to infection result in a relatively low incidence of disease, infections are characterized by high mortality and often the need of hospitalization. The disease most often manifests itself in the form of bacteremia, meningitis and encephalitis as well as perinatal infections. The way Listeria spreads in the body contributes to the identification of new types of the disease. Recent studies on the acquisition of pathogenicity traits, dose and development of antibiotic resistance as well as numerous reports on incidence of these bacteria and the epidemics they caused, have led to more efficient monitoring of the pathogen . The qualification of the disease has also changed and, currently, listeriosis is considered a contemporary threat to life and health. 1. Introduction. 2. Genus Listeria. Characteristics and traits responsible for pathogenicity. 3. Listeriosis. Transmission pathways. 4. The beginning and course of the infection. 5. Clinical forms of listeriosis. 5.1. Bacteremia. 5.2. Central nervous system infections. 5.3. Perinatal infections. 5.4. Gastroenteritis. 5.5. Spontaneous bacterial peritonitis (SBP). 5.6. Endocarditis. 5.7. Inflammation and liver abscess. 5.8. Skin and eye infections. 5.9. Musculoskeletal infection. 6. Monitoring. 7. Normalization. 8. Summary