Pathogenesis Of Complications Research Articles

Bacterial complications after liver transplantation. Promising directions for further research

This article is presented in form of a current literature review on bacterial complications of the early post-liver transplantation period and promising areas for studying the effect of bacterial flora in patients after liver transplantation. The paper describes the problem of the emergence, spread, and pathogenesis of various bacterial complications, as well as current concepts of various bacterial complication’s impact on the results of liver transplantation. The results of ventilatorassociated pneumonia in patients after liver transplantation are given. A theoretical analysis of bacterial complications from the standpoint of microbiota effects on the biliary tree was carried out. The review also highlights a relatively new conceptual approach in examining the results of scientific research using the "Machine Learning Method”. The so-called CDC “Big Four” was chosen as the main infectious nomenclature in this article. However, catheter-associated bacterial complications, which pathogenesis has been sufficiently studied to date, have been replaced by a relatively new group of complications – bacteriobilia. This review also contains a brief statistical data collected in the frames of the NCT04281797 study. Own cohort data consisted of 57 patients who underwent orthotopic liver transplantation from a post-mortem donor. Surgical site infection was the most common bacterial complication of the early postoperative period. The most common causative agent of bacterial infection was Klebsiella pneumonia and Enterococcus.

1482-P: Neutrophil Inflammasome Is Activated in Diabetes and Contributes to the Exacerbated NETosis

Activation of the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome has recently been implicated in driving the pathogenesis of diabetic complications. While diabetes is known to increase NETosis propensity, little is known whether neutrophil NLRP3 mediates NETosis in diabetes, and if organelles that govern metabolic homeostasis contribute to aberrant activation of NLRP3. In this study, we sought to examine if neutrophil NLRP3 is activated in diabetes, and if key metabolic organelles are involved in the activation of NLRP3, resulting in NETosis upregulation. We found that pre-treatment of blood neutrophils isolated from mice and humans with diabetes using MCC-950, a potent and specific NLRP3 inhibitor, normalized NET formation to levels similar to those of neutrophils isolated from healthy mice and humans. Similar to blood neutrophils, HL-60-derived neutrophils primed in high glucose also showed reduced NETosis when pre-treated with MCC-950. Notably, compared to their normoglycemic counterparts, neutrophils isolated from mice and humans with diabetes exhibited increased speck formation of the inflammasome adaptor protein, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) even at baseline, indicative of heightened NLRP3 activation in diabetes. In mouse neutrophils, confocal microscopy revealed that oxidized DNA release into the cytoplasm is a prerequisite for ASC speck formation, which co-localized with mitochondria. In addition, MCC-950 yielded no further reduction in NET formation when HL-60-derived neutrophils were pre-treated with tauroursodeoxycholic acid, an alleviator of endoplasmic reticulum (ER) stress. In summary, our findings suggest that mitochondria and ER stress may synergize in the activation of neutrophil NLRP3 that exacerbates NETosis in diabetes. Therapeutics that aim at intercepting the pathway may alleviate NET-mediated chronic inflammation in diabetes. Disclosure L.Wang: None. R.Dalan: None. S.Wong: None. Funding Nanyang Assistant Professorship; Singapore Ministry of Education Academic Research Fund Tier 1 (RG25/20); Nanyang President's Graduate Scholarship

Neurotoxic properties of the Zika virus envelope protein

Prenatal Zika virus (ZIKV) infection is a serious global concern as it can lead to brain injury and many serious birth defects, collectively known as congenital Zika syndrome. Brain injury likely results from viral mediated toxicity in neural progenitor cells. Additionally, postnatal ZIKV infections have been linked to neurological complications, yet the mechanisms driving these manifestations are not well understood. Existing data suggest that the ZIKV envelope protein can persist in the central nervous system for extended periods of time, but it is unknown if this protein can independently contribute to neuronal toxicity. Here we find that the ZIKV envelope protein is neurotoxic, leading to overexpression of poly adenosine diphosphate -ribose polymerase 1, which can induce parthanatos. Together, these data suggest that neuronal toxicity resulting from the envelope protein may contribute to the pathogenesis of post-natal ZIKV-related neurologic complications.

#4472 POLYMORPHISMS OF THE GENE FOR GALECTIN-3 IN PATIENTS IN THE TERMINAL PHASE OF RENAL INSUFFICIENCY

Abstract Background and Aims Chronic kidney disease (CKD) is a major health problem worldwide. The last stage of CKD is end-stage renal disease (ESRD), which is characterized by a progressive decrease in glomerular filtration rate (GFR). End-stage renal failure is often complicated by anemia, uremic cardiomyopathy, and renal osteodystrophy, which can be fatal. Therefore, it is necessary to identify the risk factors that can lead to ESRD or death. In addition to well-defined early markers such as diabetes, hypertension, and obesity, it is necessary to identify other markers that would help in the prediction of the disease. It has been shown that genetic factors also have an influence on renal function, pathogenesis, and disease progression, which is confirmed by the results of genome-wide association studies (GWASs). The results of GWASs show that glomerular filtration rate and renal function are affected by several gene loci. Galectin 3 (Gal-3) is the only representative chimera type of the galectin family, which forms a pentameric structure on the cell surface after binding to glycoproteins or glycolipids. The results of numerous studies have shown that Gal-3 plays a significant role in fibrosis, inflammation, and proliferation. Increased circulating levels of Gal-3 have been associated with various diseases, including cancer, immunological disorders, and cardiovascular disease. Method A total of 108 ESRD patients and 38 healthy controls were enrolled in the study. Genotyping of LGALS3 geners 4644, rs4652, and rs11125 polymorphisms was performed by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). Results By multivariate logistic regression analysis, we found that LGALS3 rs4644 CC and rs4652 AA genotypes were significantly associated with a higher risk for lower hemoglobin, higher level of parathyroid hormone, and also occurrence of diabetes mellitus and arterial hypertension. The CAA haplotype was significantly more common in patients with diabetes, low hemoglobin level, and normal PTH level. It has been observed as well that the ACT haplotype was more common in patients with low glomerular filtration, lowPTH, and normal hemoglobin level. Conclusion We found that the LGALS3 rs4644 and rs4652 gene polymorphism may be involved in the pathogenesis and appearance of complications in ESRD patients and thus could be considered a new genetic risk factor in this population.

Effects of Diabetes Mellitus-Related Dysglycemia on the Functions of Blood-Brain Barrier and the Risk of Dementia.

Diabetes mellitus is one of the most common metabolic diseases worldwide, and its long-term complications include neuropathy, referring both to the peripheral and to the central nervous system. Detrimental effects of dysglycemia, especially hyperglycemia, on the structure and function of the blood-brain barrier (BBB), seem to be a significant backgrounds of diabetic neuropathy pertaining to the central nervous system (CNS). Effects of hyperglycemia, including excessive glucose influx to insulin-independent cells, may induce oxidative stress and secondary innate immunity dependent inflammatory response, which can damage cells within the CNS, thus promoting neurodegeneration and dementia. Advanced glycation end products (AGE) may exert similar, pro-inflammatory effects through activating receptors for advanced glycation end products (RAGE), as well as some pattern-recognition receptors (PRR). Moreover, long-term hyperglycemia can promote brain insulin resistance, which may in turn promote Aβ aggregate accumulation and tau hyperphosphorylation. This review is focused on a detailed analysis of the effects mentioned above towards the CNS, with special regard to mechanisms taking part in the pathogenesis of central long-term complications of diabetes mellitus initiated by the loss of BBB integrity.

RADIAL ARTERY PHENOTYPING IN SYSTEMIC SCLEROSIS THROUGH ULTRA-HIGH FREQUENCY ULTRASOUND: A RADIOMIC APPROACH

Objective: Systemic sclerosis (SSc) is a disorder characterized by a massive vascular involvement. Imaging biomarkers of vascular involvement in SSc may have potential clinical implications for prediction of the pathogenesis of vascular complications. This study is aimed at identifying possible patterns of vascular wall disarray and remodeling in radial arteries of SSc patients, by means of ultrahigh frequency ultrasound (UHFUS). Design and method: 5 end-diastolic frames of the right radial arteries of 41 patients with SSc and 41 healthy controls were obtained by VevoMD (70 MHz probe, FUJIFILM, VisualSonics, Toronto, Canada). 74 radiomic features and 4 engineered parameters were extracted: inner and outer layer thickness, and presence of adjunctive acoustic interfaces (triple signal). A feature selection algorithm was applied to reduce the number of features. The selected features were used to train classification model, using Linear Support Vector Machine (SVM). Results: The SVM classification model showed good performance (sensitivity = 0.63, specificity = 0.88, accuracy = 0.75, AUC = 0.75) to discriminate SSc patients from controls using fifteen selected features. Inner layer (208±61 vs 179±47 μm, p = 0.04) and outer layer thickness (104±22 vs 120±36 μm, p = 0.03) were significantly higher in SSc than in controls, triple signal pattern more frequent in patients (p = 0.002). Conclusions: Wall ultrastructure of radial arteries of SSc patients is altered: inner and outer layer thickened, showing frequently a triple signal pattern. Radiomic approach allow to distinguish between radial images from SSc patients and controls with a 75% accuracy.

The influence of nanodispersed cerium oxide on the development of oxidative stress and the production of nitric oxide in patients with type 2 diabetes mellitus

Background. In the pathogenesis of complications of diabetes mellitus (DM), in addition to glucotoxicity, the development of oxidative stress plays a leading role. Antioxidants have been of great interest for physicians in recent years. Contemporary diabetology have been focused on the search and practical implementation of pathogenetic medications that can affect the main chains of DM and prevent its negative consequences. Purpose of the study is to determine the effect of nanodispersed cerium oxide (NCO) on the production of nitric oxide (NO), the activity of antioxidant enzymes and the intensity of lipid peroxidation in the blood of patients with type 2 diabetes mellitus. Materials and methods. Seventy-two patients aged 36 to 66 years, average age of 55.20±6.82 years, who received treatment at the Municipal Clinical Hospital 2 in Poltava from July to December 2022 have been involved in the study. They have been divided into 2 groups: controls (n=35), which included people without diabetes; experimental group (n=37), which consisted of patients diagnosed with type 2 DM. Results. The use of NCO in patients with type 2 DM significantly reduces the activity of inducible NO synthase in the blood by 34.70% and the activity of arginases by 52.17% compared to the levels before treatment. The use of nanodispersed cerium oxide in the treatment of type 2 DM increases the activity of superoxide dismutase in the blood by 102.74%, and the activity of catalase by 103.04% compared to same indicators in the experimental group before therapy. Notably, blood malondialdehyde was significantly lower (by 2.35 times) compared to the same indicator before treatment. Conclusions. The use of NCO in patients with type 2 diabetes mellitus leads to an increase in antioxidant protection and a decrease in the intensity of lipid peroxidation in blood. NCO reduces the production of nitric oxide from the inducible NO synthase and weakens the competition between NO synthases and arginases for the reaction substrate. The findings of the study justify the need to include antioxidants in the pathogenetic therapy of diabetes mellitus and its complications.

Profiling of Differentially Expressed MicroRNAs in Human Umbilical Vein Endothelial Cells Exposed to Hyperglycemia via RNA Sequencing.

Hyperglycemia is the hallmark of diabetes mellitus that results in oxidative stress, apoptosis, and diabetic vascular endothelial dysfunction. An increasing number of microRNAs (miRNAs) have been found to be involved in the pathogenesis of diabetic vascular complications. However, there is a limited number of studies that characterize the miRNA profile of endothelial cells exposed to hyperglycemia. Therefore, this study aims to analyze the miRNA profile of human umbilical-vein endothelial cells (HUVECs) exposed to hyperglycemia. HUVECs were divided into two groups: the control (treated with 5.5 mM glucose) and hyperglycemia (treated with 33.3 mM glucose) groups. RNA sequencing identified 17 differentially expressed miRNAs between the groups (p < 0.05). Of these, 4 miRNAs were upregulated, and 13 miRNAs were downregulated. Two of the most differentially expressed miRNAs (novel miR-1133 and miR-1225) were successfully validated with stem-loop qPCR. Collectively, the findings show that there is a differential expression pattern of miRNAs in HUVEC following exposure to hyperglycemia. These 17 differentially expressed miRNAs are involved in regulating cellular functions and pathways related to oxidative stress and apoptosis that may contribute to diabetic vascular endothelial dysfunction. The findings provide new clues on the role of miRNAs in the development of diabetic vascular endothelial dysfunction, which could be useful in future targeted therapy.

Влияние пилинга внутренней пограничной мембраны на сосудистую плотность капиллярных сплетений сетчатки

Relevance. Diabetic macular edema (DME) in combination with epimacular fibrosis (EMF) is an indication for vitreoretinal surgical treatment. The necessity of the retinal internal limiting membrane (ILM) peeling is debatable. The question of assessing the anatomy and function of the eyes in the early and late postoperative period is relevant, in particular, the study of the retinal capillary plexuses (RCP) characteristics such that its vascular density. The perpose of the study was to evaluate the presence and nature of the various ILM peeling methods effect on the RCP vascular density in patients with proliferative diabetic retinopathy and DME in combination with EMF in the early and late periods after treatment. Material and methods. A randomized case-control study was conducted on three comparable groups of patients. Surgical treatment was performed – vitrectomy with ILM peeling. The groups differed in the ILM peeling methods. In the early (1 month) and late (1 year) postoperative period, the RCP vascular density CAS was assessed, as well as the development of complications: DME, EMF recurrence, and retinal atrophy. Results. Statistically significant intra- and intergroup differences in the values of indicators of RCP vascular density during the entire period of observation were not revealed. It has been established that the initially higher vascular density in the superficial and deep RCP tends to remain at this level in the early and late postoperative period. Statistically significant relationships between RCP vascular density and the development of postoperative DME, recurrence of EMF or retinal atrophy have not been established. Conclusion. According to the results of our study, ILM peeling does not have a significant effect on the RCP vascular in the early and late postoperative period. The pathogenesis of postoperative complications and their relationship with the state of the RCP require further study. Keywords: vitreoretinal surgery, vitreomacular interface, retinal internal limiting membrane, dosed fovea-sparing ILM peeling, optical coherence tomography, optical coherence tomographyangiography, vascular density, automatic image analysis

Ретинальные изменения после коронавирусной инфекции

The SARS-CoV-2 coronavirus infection pandemic has caused 667 million cases. COVID-19 is a severe acute respiratory infection caused by the SARS-CoV-2 coronavirus. The virus primarily affects the respiratory system and runs the gamut from respiratory infection, to acute respiratory distress syndrome. Various ophthalmologic manifestations in both the anterior and posterior segment of the eye are increasingly reported in the literature. Purpose. Present clinical cases of retinal changes after coronavirus infection. Material and methods. We present two clinical observations of patients with ophthalmic manifestations in the posterior segment of the eyes that developed after a coronavirus infection. All patients underwent ophthalmological examination including visometry, anterior segment biomicroscopy, and ophthalmoscopy with non-contact Volk 78D lens, optical coherence tomography (OCT) of macular area and angioregim OCT (DRI OCT Triton plus, Japan). Treatment and recommendations were individualized according to ophthalmological indications. Results. Stabilization of retinal changes after coronavirus infection. There was an increase in maximum corrected visual acuity (MCOZ), reduction of macular edema. Conclusion. It is necessary to pay attention to complaints of the visual organ in patients with coronavirus infection in the early stages of the disease and in the nearest months after recovery. Our clinical observations show the need for further study of pathogenesis, clinic and treatment methods of ophthalmologic complications associated with coronavirus infection. Keywords: coronavirus disease, postthrombotic retinopathy, macular neovascular membrane

Classification of common variable immunodeficiency through immunological and clinical phenotyping in Moroccan patients.

Objective: Common variable immunodeficiency (CVID) is a complex inborn error of humoral immunity with complications of both infectious and non-infectious origins. Classifications of CVID patients provide a clearer understanding of the pathogenesis, prediction, and management of non-infectious complications. This study aims to classify Moroccan CVID patients based on the European classification (EUROclass). Materials and Methods: We recruited 20 CVID patients meeting standard diagnostic criteria (5-6). After collecting clinical and demographic data, we used flow cytometry to analyze B-cell subsets and group patients and assess the relation of each group with clinical manifestations. Results: 90% of the patients in our cohort study had a history of respiratory infections. The noninfectious manifestations included splenomegaly, autoimmunity, lymphadenopathy, and granulomatous diseases diagnosed in 50%, 45%, 40%, and 25% of patients, respectively. We observed significant co-occurrence of splenomegaly with autoimmunity and granulomatous diseases to a lesser extent. Patients had a significant reduction in total, switched memory, marginal zone-like, plasma blasts, and a substantial increase in the percentage of activated B cells, suggesting a defect in the late phases of B-cell differentiation. This condition was linked with an increased occurrence of splenomegaly and granulomatous affections. Besides, patients also had an expansion of CD21low B-cells, which was strongly associated with splenomegaly. Conclusion: The classification of the first Moroccan cohort of CVID patients showed agreement with previous results. It suggests the possibility of adopting this approach on a global scale for better diagnosis and follow-up of CVID patients.

РОЛЬ ИММУННОГО МЕХАНИЗМА В РАЗВИТИИ ДИСФУНКЦИИ ЭНДОТЕЛИЯ И АПОПТОЗА У БЕРЕМЕННЫХ ЖЕНЩИН С ТЯЖЕЛЫМИ ОСЛОЖНЕНИЯМИ

In order to identify the role of cellular and humoral immunity, nonspecific resistance, cytokine spec-trum in the development of endothelial dysfunction and apoptosis in the pathogenesis of obstetric complications, 40 women with severe pregnancy complications and critical conditions associated with thrombotic micro angiopathy and 30 patients with physiologically occurring pregnancy were exam-ined. The assessment of cellular elements of peripheral blood, indicators of cellular and humoral im-munity, the level of cytokines, a disintegrin and metalloprotease with thrombospondin-1-like domains, member 13 (ADAMTS – 13), Willebrand factor, apoptosis-inducing factor, CD95, progesterone and the number of endotheliocytes is given.&#x0D; The conducted study indicates the failure of the functional state of both innate and acquired immunity in women with complicated pregnancy. The leading role in the development of endothelial dysfunction and the mechanism of apoptosis in pregnant women with severe complications and criti-cal cases associated with thrombotic microangiopathy belongs to an insufficient reserve of nonspecific resistance, impaired cellular and humoral immunity with low background progesterone level and high cytokine activity

The activation value of the renin-angiotensin-aldosterone system in the pathogenesis of late complications of DM 2

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Abstract #1408228: Potential Association Among Enteroviruses, Acute Flaccid Myelitis and Type 1 Diabetes

Non-polio enteroviruses, like EV-D68, caused a nationwide outbreak of respiratory illness in the US in the fall of 2021. It has been shown that EV-D68 plays a role in causing acute flaccid myelitis (AFM). In addition, the association between enterovirus infections and type 1 diabetes (T1DM) has been widely studied and established. We report a case in which a 19-year-old male consulted for progressively ascending bilateral weakness in the lower extremities. Four weeks prior, he was diagnosed with T1DM and diabetic ketoacidosis (DKA). On exam, he had decreased sensation to light touch, vibration, and temperature below the knees, decreased motor strength 2/5 in bilateral lower extremities, and absence of patellar and Achille reflexes. Thyroid tests, Creatinine Kinase, Aldolase, and vitamin B12 were all normal. Spine MRI showed an enhancement along the L5 and sacral roots. CSF studies were significant for the positive oligoclonal band, the elevated protein level (87gm/dL), and no white blood cell count. CSF gram stain was negative for any organisms. EBV, HSV, and HIV testing were negative. A nonspecific respiratory panel only performed at the time of diagnosis with AFM was negative. The electromyogram did not show any type of acute inflammatory demyelinating polyneuropathy or evidence of myopathy. CT abdomen/pelvis demonstrated mild splenomegaly with small swollen lymph nodes of the periaortic and mesenteric area, which are commonly seen in viral infections. A Digital Subtraction Angiography study did not show any abnormality in spinal vessels. The patient received immunoglobulin and steroid, which was stopped early due to bradycardia and hyperglycemia. Neurology diagnosed the patient with AFM secondary to viral infection, in which the patient may have been infected prior to his diagnosis of DKA. The patient’s weakness resolved, and he was discharged with basal-bolus insulin and is to follow up with neurology and endocrinology outpatient. Enterovirus infection has been associated with T1DM and AFM. While the Respiratory PCR Panel was negative, it was only obtained several weeks after the onset of symptoms. Pathogenesis of extra-respiratory complications of enteroviruses may associate with viremia and systemic dissemination of the virus, which may not be detected by a respiratory PCR panel. Infection by an enterovirus remains the most likely etiology for both immune-mediated disorders, especially during a nationwide outbreak. We recommend providers consider enterovirus infection as a potential cause of AFM, and autoimmune diabetes in order to perform a throughout workup. In a patient with hyperglycemia and flaccid paralysis, T1DM should be suspected.

RNase2 is a possible trigger of acute-on-chronic inflammation leading to mRNA vaccine-associated cardiac complication

Post-mRNA vaccination-associated cardiac complication is a rare but life-threatening adverse event. Its risk has been well balanced by the benefit of vaccination-induced protection against severe COVID-19. As the rate of severe COVID-19 has consequently declined, future booster vaccination to sustain immunity, especially against infection with new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, may encounter benefit-risk ratios that are less favorable than at the start of the COVID-19 vaccination campaign. Understanding the pathogenesis of rare but severe vaccine-associated adverse events to minimize its risk is thus urgent. Here, we report a serendipitous finding of a case of cardiac complication following a third shot of COVID-19 mRNA vaccine. As this case was enrolled in a cohort study, pre-vaccination and pre-symptomatic blood samples were available for genomic and multiplex cytokine analyses. These analyses revealed the presence of subclinical chronic inflammation, with an elevated expression of RNASE2 at pre-booster baseline as a possible trigger of an acute-on-chronic inflammation that resulted in the cardiac complication. RNASE2 encodes for the ribonuclease RNase2, which cleaves RNA at the 3' side of uridine, which may thus remove the only Toll-like receptor (TLR)-avoidance safety feature of current mRNA vaccines. These pre-booster and pre-symptomatic gene and cytokine expression data provide unique insights into the possible pathogenesis of vaccine-associated cardiac complication and suggest the incorporation of additional nucleoside modification for an added safety margin. This work was funded by the NMRC Open Fund-Large Collaborative Grant on Integrated Innovations on Infectious Diseases (OFLCG19May-0034).

Hypoxia-Inducible Pathway Polymorphisms and Their Role in the Complications of Prematurity.

Excessive oxidative stress resulting from hyperoxia or hypoxia is a recognized risk factor for diseases of prematurity. However, the role of the hypoxia-related pathway in the development of these diseases has not been well studied. Therefore, this study aimed to investigate the association between four functional single nucleotide polymorphisms (SNPs) in the hypoxia-related pathway, and the development of complications of prematurity in relation to perinatal hypoxia. A total of 334 newborns born before or on the 32nd week of gestation were included in the study. The SNPs studied were HIF1A rs11549465 and rs11549467, VEGFA rs2010963, and rs833061. The findings suggest that the HIF1A rs11549465T allele is an independent protective factor against necrotizing enterocolitis (NEC), but may increase the risk of diffuse white matter injury (DWMI) in newborns exposed to hypoxia at birth and long-term oxygen supplementation. In addition, the rs11549467A allele was found to be an independent protective factor against respiratory distress syndrome (RDS). No significant associations with VEGFA SNPs were observed. These findings indicate the potential involvement of the hypoxia-inducible pathway in the pathogenesis of complications of prematurity. Studies with larger sample sizes are needed to confirm these results and explore their clinical implications.

Differences in immune response in patients with chronic opisthorchiasis invasion related to clinical manifestations of hepatobiliary system diseases

The aim of the study was to identify differences in the immune response in chronic opisthorchiasis with or without clinical manifestations of hepatobiliary system diseases. A comparison of laboratory parameters of immune system functioning (lymphocyte phenotypes detected by flow cytometry, concentrations of immunoglobulins and cytokines, indicators of nonspecific resistance) in patients with chronic opisthorchiasis (caused by Opisthorchis felineus) lacking clinical manifestations and with manifestations of cholecystitis, cholangitis, pancreatitis, gastritis, gastroduodenitis, confirmed by ultrasound and FGDS. It was found that the immunological parameters of the innate immune response were increased in all patients with chronic opisthorchiasis compared with the control group of apparently healthy subjects, which indicates activated macrophage-phagocytic arm in patients with opisthorchiasis invasion. The indicator of the stimulated NBT test is maximal in chronic opisthorchiasis without hepatobiliary system diseases, in case of comorbidity with such diseases it declines, but remains significantly higher than the values of the control group. This may be due to the exhaustion in the reserve capabilities of bactericidal neutrophil systems in patients with symptoms of damage to the hepatobiliary system due to prolonged inflammation. Indicators of the cellular arm in patients with chronic opisthorchiasis without clinical manifestations of hepatobiliary system diseases demonstrate a decrease in the absolute and relative level of cytotoxic T-lymphocytes. In the group with picture of hepatobiliary system disorders, an even deeper imbalance of indicators is revealed: the relative and absolute level of lymphocytes, the absolute count of T-lymphocytes are reduced, which may indicate about involvement of cellular immunity in the pathogenesis of complications of chronic opisthorchiasis. In all examined patients with chronic opisthorchiasis, the humoral immune response was also activated the total immunoglobulin E was significantly increased; at the same time, in patients with hepatobiliary system lesions, this parameter increases even more and a decrease in B-lymphocytes is detected. In all patients with chronic opisthorchiasis, there is also an increased level of proinflammatory cytokine IL-8, which rises even more in the group with hepatobiliary system diseases. The data obtained indicate the involvement of all arms of the immune response in a prominent inflammatory process when chronic opisthorchiasis is complicated by clinically overt hepatobiliary system diseases: the degree of deviation in the indicators of the innate and adaptive immune response from the norm and from those in uncomplicated opisthorchiasis increases.

Role of ADMA in the pathogenesis of microvascular complications in type 2 diabetes mellitus.

Diabetic microangiopathy is a typical and severe problem in diabetics, including diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, and diabetic cardiomyopathy. Patients with type 2 diabetes and diabetic microvascular complications have significantly elevated levels of Asymmetric dimethylarginine (ADMA), which is an endogenous inhibitor of nitric oxide synthase (NOS). ADMA facilitates the occurrence and progression of microvascular complications in type 2 diabetes through its effects on endothelial cell function, oxidative stress damage, inflammation, and fibrosis. This paper reviews the association between ADMA and microvascular complications of diabetes and elucidates the underlying mechanisms by which ADMA contributes to these complications. It provides a new idea and method for the prevention and treatment of microvascular complications in type 2 diabetes.

The role of viruses in human acute appendicitis: a systematic literature review.

There have been debates about the human appendix function, and while previous research suggested it might be a vestigial organ with no functional significance, recent studies have pointed out that it might have an important role in the immune system. Acute appendicitis (AA) is a common cause of emergency abdominal surgery in the world. Some epidemiologic investigations have found an association between appendicitis and viral infections. In this study, we have reviewed systematically articles to discover viral infections that cause appendicitis and find any possible correlations between the two. This systematic review was performed by searching among electronic databases including Web of Science, PubMed, Scopus, and EMBASE on viruses and appendicitis topics. Conducted search leads to 983 results in all databases after the duplicate removal and screening by title, abstract, and full-text based on inclusion criteria lead to 19 studies. There were several assays to detect the viruses, which are thought to be AA causative agents. RT-PCR and immunoassays were the mainstay methods to detect the probable cause. Investigations suggested that some viruses including measles virus (MV), influenza virus, dengue fever virus (DFV), human immunodeficiency virus (HIV), human herpesviruses, rotavirus, and adenovirus are associated with acute appendicitis. Despite the available reports, the specific mechanisms behind the relationship between acute appendicitis and viral infections are yet to be understood. Therefore, further investigations are necessary to find out the pathogenesis and pathophysiology of viral complications in appendicitis.

Understanding the Pathogenesis of Cardiac Complications in Patients with Propionic Acidemia and Exploring Therapeutic Alternatives for Those Who Are Not Eligible or Are Waiting for Liver Transplantation.

The guidelines for the management of patients affected by propionic acidemia (PA) recommend standard cardiac therapy in the presence of cardiac complications. A recent revision questioned the impact of high doses of coenzyme Q10 on cardiac function in patients with cardiomyopathy (CM). Liver transplantation is a therapeutic option for several patients since it may stabilize or reverse CM. Both the patients waiting for liver transplantation and, even more, the ones not eligible for transplant programs urgently need therapies to improve cardiac function. To this aim, the identification of the pathogenetic mechanisms represents a key point. Aims: This review summarizes: (1) the current knowledge of the pathogenetic mechanisms underlying cardiac complications in PA and (2) the available and potential pharmacological options for the prevention or the treatment of cardiac complications in PA. To select articles, we searched the electronic database PubMed using the Mesh terms "propionic acidemia" OR "propionate" AND "cardiomyopathy" OR "Long QT syndrome". We selected 77 studies, enlightening 12 potential disease-specific or non-disease-specific pathogenetic mechanisms, namely: impaired substrate delivery to TCA cycle and TCA dysfunction, secondary mitochondrial electron transport chain dysfunction and oxidative stress, coenzyme Q10 deficiency, metabolic reprogramming, carnitine deficiency, cardiac excitation-contraction coupling alteration, genetics, epigenetics, microRNAs, micronutrients deficiencies, renin-angiotensin-aldosterone system activation, and increased sympathetic activation. We provide a critical discussion of the related therapeutic options. Current literature supports the involvement of multiple cellular pathways in cardiac complications of PA, indicating the growing complexity of their pathophysiology. Elucidating the mechanisms responsible for such abnormalities is essential to identify therapeutic strategies going beyond the correction of the enzymatic defect rather than engaging the dysregulated mechanisms. Although these approaches are not expected to be resolutive, they may improve the quality of life and slow the disease progression. Available pharmacological options are limited and tested in small cohorts. Indeed, a multicenter approach is mandatory to strengthen the efficacy of therapeutic options.