Pathogenetic Process Research Articles

Endothelial-platelet interaction in sepsis

Introduction. Endothelial cells and platelets are actively involved in pathogenetic processes in sepsis — an unregulated reaction of the host organism in response to infection, leading, on the one hand, to the development of prothrombotic, and on the other hand, to hemorrhagic readiness.Aim — to summarize the current information on the mechanisms of intercellular interaction between endotheliocytes and platelets in sepsis.Main findings. The development of multiple organ failure, which increases the likelihood of an unfavorable outcome of sepsis, is partly due to endothelial dysfunction, as well as the involvement of platelets in the pathogenetic process. Under physiological conditions, an anatomically and functionally intact endothelium is important to prevent microvascular thrombosis. Although platelets are most associated with hemostasis, they perform many other functions, including participation in inflammatory processes through complement activation, interaction with leukocytes and monocytes, participation in host defense against infection, and regulation of vascular tone. There is also abundant evidence that suggests that the processes regulating hemostasis evolved as a component of the inflammatory response to infection. Many of these interaction points occur on the surface of endothelial cells, linking these two cell types, endotheliocytes and platelets, in initiating and regulating blood clotting and inflammation. Various mechanisms may contribute to direct and indirect platelet activation in sepsis, including pathogen-induced platelet activation, pathogen- and inflammation-induced endothelial and leukocyte activation, and complement-mediated platelet activation.

Therapeutic potential of kaempferol on Streptococcus pneumoniae infection

Co-infections with pathogens and secondary bacterial infections play significant roles during the pandemic coronavirus disease 2019 (COVID-19) pathogenetic process, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Notably, co-infections with Streptococcus pneumoniae (S. pneumoniae), as a major Gram-positive pathogen causing pneumonia or meningitis, severely threaten the diagnosis, therapy, and prognosis of COVID-19 worldwide. Accumulating evidences have emerged indicating that S. pneumoniae evolves multiple virulence factors, including pneumolysin (PLY) and sortase A (SrtA), which have been extensively explored as alternative anti-infection targets. In our study, natural flavonoid kaempferol was identified as a potential candidate drug for infection therapeutics via anti-virulence mechanisms. We found that kaempferol could interfere with the pore-forming activity of PLY by engaging with catalytic active sites and consequently inhibit PLY-mediated cytotoxicity. Additionally, exposed to kaempferol significantly reduced the SrtA peptidase activity by occupying the active sites of SrtA. Further, the biofilms formation and bacterial adhesion to the host cells could be significantly thwarted by kaempferol incubation. In vivo infection model by S. pneumoniae highlighted that kaempferol oral administration exhibited notable treatment benefits, as evidenced by decreased bacterial burden, suggesting that kaempferol has tremendous potential to attenuate S. pneumoniae pathogenicity. Scientifically, our study implies that kaempferol is a promising therapeutic option by targeting bacterial virulence factors.

The joint role of collagen turn-over biomarkers and late gadolinium enhancement to predict cardiovascular outcome in nonischemic dilated cardiomyopathy

Abstract Background Myocardial scarring is a primary pathogenetic process in nonischemic dilated cardiomyopathy (NIDCM) which is responsible for progressive cardiac remodeling and heart failure, severely impacting the survival of these patients. Although several collagens turn-over biomarkers have been associated with myocardial fibrosis, their clinical utility is still limited. Late gadolinium enhancement (LGE) determined by cardiac magnetic resonance imaging (CMR) has become a feasible method to detect myocardial replacement fibrosis. Purpose We sought to evaluate the association between collagen turn-over biomarkers and replacement myocardial scarring by CMR and, also, to test their ability to predict outcome in conjunction with LGE in patients with NIDCM. Method We conducted a prospective study on 194 patients (48.7±14.3 years of age; 74% male gender) with NIDCM. CMR was used to determine the presence and extent of LGE. Several collagen turn-over biomarkers were determined at the diagnosis, comprising galectin-3 (Gal3), procollagen type I carboxy-terminal pro-peptide (PICP) and N-terminal pro-peptide of procollagen type III (PIIINP). A composite outcome (all-cause mortality, ventricular tachyarrhythmias, heart failure hospitalization) was ascertained over a median of 26 months. Of all, 17% (n=33) of patients reached the outcome: all-cause mortality (n=6), malignant ventricular tachyarrhythmia (n=14) and HF hospitalization (n=13). Results Gal3, PICP and PIIINP were considerably increased in those with LGE+ (p<0.001), being also directly correlated with LGE mass (r2=0.42; r2=0.44; r2=0.31; all p<0.001). Receiver operating characteristic (ROC) analysis revealed significant ability to diagnose LGE, with area under the ROC: 0.816 for Gal3, 0.705 for PICP, and 0.757 for PIIINP (all p<0.0001). Kaplan-Meier analysis showed that at a threshold of >13.8 ng/dL for Gal3 and >97 ng/dL for PICP, they significantly predicted the outcome (HR=2.66, p<0.001; HR=1.93, p<0.002). Moreover, for a combined model of LGE+/Gal3+/PICP+, time-to-event analysis demonstrated the highest ability to predict composite outcome, as compared to any other models (p=0.004). Nevertheless, in multivariate analysis, after adjustment for covariates, only LGE+ and Gal3+ remained independent predictors for outcome (p=0.008; p=0.04). Conclusion In patients with NIDCM, serum collagen turn-over biomarkers such as Gal3, PICP and PIIINP are closely related to the presence and extent of LGE and can significantly predict cardiovascular outcome. The joint use of LGE with Gal3 and PICP significantly improved outcome prediction. Funding Acknowledgement Type of funding sources: None.

Parkinson's Disease: Risk Factor Modification and Prevention.

The global burden of Parkinson's disease (PD) has increased from 2.5 to 6.1 million since the 1990s. This is expected to rise as the world population ages and lives longer. With the current consensus on the existence of a prediagnostic phase of PD, which can be divided into a preclinical stage and a prodromal stage, we can better define the risk markers and prodromal markers of PD in the broader context of PD pathogenesis. Here, we review this pathogenetic process, and discuss the evidence behind various heritability factors, exposure to pesticides and farming, high dairy consumption, and traumatic brain injuries that have been known to raise PD risk. Physical activity, early active lifestyle, high serum uric acid, caffeine consumption, exposure to tobacco, nonsteroidal anti-inflammatory drugs, and calcium channel blockers, as well as the Mediterranean and the MIND diets are observed to lower PD risk. This knowledge, when combined with ways to identify at-risk populations and early prodromal PD patients, can help the clinician make practical recommendations. Most importantly, it helps us set the parameters for epidemiological studies and create the paradigms for clinical trials.

Tolosa-Hunt Syndrome and IgG4 Diseases in Neuro-Ophthalmology.

Tolosa-Hunt syndrome (THS) remains a challenging diagnosis for many neurologists. Often believed to be a rare presentation, the classical presentation is known to involve cranial nerves and tissues surrounding the cavernous sinus. Traditionally, a diagnosis of THS is considered when all secondary conditions have been ruled out. Yet, newer findings have elaborated a complex pathogenetic process with some overlap from the IgG4 spectrum of disorders, with which it shares many phenotypic similarities. In this narrative review, we present an updated picture of the condition focusing on the latest developments in the pathogenesis, diagnosis, and clinical management of these two conditions and use illustrative examples to highlight the salient features of this rare presentation.

CircKMT2E Protect Retina from Early Diabetic Retinopathy through SIRT1 Signaling Pathway via Sponging miR-204-5p.

Objective To explore the changes of circRNAs in the retina of diabetic patients without diabetic retinopathy (DR) to screen latent protective factor. Methods The sequencing data of the retina from three diabetic donors that possess no noticeable pathological feature of the retina at ultimate eye inspection and three healthy donative samples were involved in this study. Herein, we carried out bioinformatics analysis to disclose the expression pattern and characteristics of circRNAs on the basis of Gene Ontology as well as KEGG pathway analyses. Then, sequencing data were applied to infer the interaction between selected circRNAs and miR-204-5p. The potential miRNA response elements for the annotated circRNAs and their target gene were speculated using TargetScan as well as miRanda. Results RNA sequencing detected 28,978 alternative circRNAs. Thereinto, 1063 were expressed with significant difference. circKMT2E was upregulated more than two folds in alloxan-induced diabetic retinal tissues compared with normal retinal tissues, exhibiting an expression trend opposite to miR-204-5p. Bioinformatics analysis showed that circKMT2E have four seed sequences on hsa-miR-204-5p. Thus, circKMT2E was speculated to have function on the basis of sponging miR-204-5p in order to participate in the pathogenetic process of DR. Besides, miR-204-5p was speculated to be able to bind SIRT1, which can interact with its target proteins, and adjusts various cell functions including cellular inflammatory responses, proliferation, as well as apoptosis. Conclusion The upregulation of circKMT2E in the early stage of DR may be involved in its pathogenesis and may activate the SIRT1 signaling pathway to protect the retina by the sponge function to miR-204-5p.

Comprehensive Review on Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory, systemic, progressive, autoimmune disease in which the body’s immune system whose major role is to protect the health by attacking foreign bacteria and viruses are mistakenly, attacking the joints resulting in thickened synovium, pannus formation & destruction of bone, cartilage. Many complications can follow such as permanent joint damage requiring arthroplasty, rheumatoid vasculitis and elty’s syndrome requiring splenectomy if it remains unaddressed. Still now researchers are unable to know the exact cause of this disease. However, it is believed that age, gender, genetics and environmental exposure (cigarette smoking, air pollutants and occupational) play a role in development of RA. As there is no cure for RA, the treatment goals are to reduce the pain and stop/slow the further damage. The identification of novel autoantibodies has improved diagnostic accuracy, and newly developed classification criteria facilitate the recognition and study of the disease early in its course. New clinical assessment tools are able to better characterize disease activity states, which are correlated with progression of damage and disability and permit improved follow up. In addition, better understanding of the pathogenesis of RA through recognition of key cells and cytokines has led to the development of targeted disease-modifying antirheumatic drugs. Altogether, the improved understanding of the pathogenetic processes involved, rational use of established drugs and development of new drugs and reliable assessment tools have drastically altered the lives of individuals with RA over the past 2 decades. In this review, we discuss the epidemiology, pathophysiology, diagnosis and management of RA. Keywords: Rheumatoid arthritis, Pathogenesis, Disease modifying anti-arthritic drugs, Genetics, Environmental, Autoantibodies

Promising Roles of Circular RNAs as Biomarkers and Targets for Potential Diagnosis and Therapy of Tuberculosis.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) infection, remains one of the most threatening infectious diseases worldwide. A series of challenges still exist for TB prevention, diagnosis and treatment, which therefore require more attempts to clarify the pathological and immunological mechanisms in the development and progression of TB. Circular RNAs (circRNAs) are a large class of non-coding RNA, mostly expressed in eukaryotic cells, which are generated by the spliceosome through the back-splicing of linear RNAs. Accumulating studies have identified that circRNAs are widely involved in a variety of physiological and pathological processes, acting as the sponges or decoys for microRNAs and proteins, scaffold platforms for proteins, modulators for transcription and special templates for translation. Due to the stable and widely spread characteristics of circRNAs, they are expected to serve as promising prognostic/diagnostic biomarkers and therapeutic targets for diseases. In this review, we briefly describe the biogenesis, classification, detection technology and functions of circRNAs, and, in particular, outline the dynamic, and sometimes aberrant changes of circRNAs in TB. Moreover, we further summarize the recent progress of research linking circRNAs to TB-related pathogenetic processes, as well as the potential roles of circRNAs as diagnostic biomarkers and miRNAs sponges in the case of Mtb infection, which is expected to enhance our understanding of TB and provide some novel ideas about how to overcome the challenges associated TB in the future.

The Role of Polyamines in the Mechanisms of Cognitive Impairment

—As the population ages, age-related cognitive impairments are becoming an increasingly pressing problem. Currently, the role of polyamines (putrescine, spermidine, and spermine) in the pathogenesis of cognitive impairments of various origin is actively discussed. It was shown that the content of polyamines in the brain tissue decreases with age. Exogenous administration of polyamines makes it possible to avoid cognitive impairment and/or influence the pathogenetic processes associated with disease progression. There are 3 known ways that polyamines can enter the human body: food, synthesis by intestinal bacteria, and biosynthesis in the body. Currently, one of the most promising approaches to the prevention of cognitive impairment is the use of foods with a high content of polyamines, as well as the use of various probiotics that affect intestinal bacteria that synthesize polyamines. Since 2018, in a number of European countries projects have been launched aimed at evaluation of the impact of a diet high in polyamines on cognitive processes. The review, based on analysis of modern scientific literature and the authors' own data, presents material on the effect of polyamines on cognitive processes and the role of polyamines in the regulation of neurotransmitter processes, and discusses the role of polyamines in cognitive disorders in mental and neurological diseases.

Discovering common pathogenetic processes between COVID-19 and sepsis by bioinformatics and system biology approach.

Corona Virus Disease 2019 (COVID-19), an acute respiratory infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has spread rapidly worldwide, resulting in a pandemic with a high mortality rate. In clinical practice, we have noted that many critically ill or critically ill patients with COVID-19 present with typical sepsis-related clinical manifestations, including multiple organ dysfunction syndrome, coagulopathy, and septic shock. In addition, it has been demonstrated that severe COVID-19 has some pathological similarities with sepsis, such as cytokine storm, hypercoagulable state after blood balance is disrupted and neutrophil dysfunction. Considering the parallels between COVID-19 and non-SARS-CoV-2 induced sepsis (hereafter referred to as sepsis), the aim of this study was to analyze the underlying molecular mechanisms between these two diseases by bioinformatics and a systems biology approach, providing new insights into the pathogenesis of COVID-19 and the development of new treatments. Specifically, the gene expression profiles of COVID-19 and sepsis patients were obtained from the Gene Expression Omnibus (GEO) database and compared to extract common differentially expressed genes (DEGs). Subsequently, common DEGs were used to investigate the genetic links between COVID-19 and sepsis. Based on enrichment analysis of common DEGs, many pathways closely related to inflammatory response were observed, such as Cytokine-cytokine receptor interaction pathway and NF-kappa B signaling pathway. In addition, protein-protein interaction networks and gene regulatory networks of common DEGs were constructed, and the analysis results showed that ITGAM may be a potential key biomarker base on regulatory analysis. Furthermore, a disease diagnostic model and risk prediction nomogram for COVID-19 were constructed using machine learning methods. Finally, potential therapeutic agents, including progesterone and emetine, were screened through drug-protein interaction networks and molecular docking simulations. We hope to provide new strategies for future research and treatment related to COVID-19 by elucidating the pathogenesis and genetic mechanisms between COVID-19 and sepsis.

Autoimmune and immunoserological markers of COVID-19 pneumonia: Can they help in the assessment of disease severity.

BackgroundImmune dysregulation and associated inefficient anti-viral immunity during Coronavirus Disease 2019 (COVID-19) can cause tissue and organ damage which shares many similarities with pathogenetic processes in systemic autoimmune diseases. In this study, we investigate wide range autoimmune and immunoserological markers in hospitalized patients with COVID-19.MethodsStudy included 51 patients with confirmed Severe Acute Respiratory Syndrome Coronavirus 2 infection and hospitalized due to COVID-19 pneumonia. Wide spectrum autoantibodies associated with different autoimmune inflammatory rheumatic diseases were analyzed and correlated with clinical and laboratory features and pneumonia severity.ResultsAntinuclear antibodies (ANA) positivity was found in 19.6%, anti-cardiolipin IgG antibodies (aCL IgG) in 15.7%, and anti-cardiolipin IgM antibodies (aCL IgM) in 7.8% of patients. Positive atypical x anti-neutrophil cytoplasmic antibodies (xANCA) were detected in 10.0% (all negative for Proteinase 3 and Myeloperoxidase) and rheumatoid factor was found in 8.2% of patients. None of tested autoantibodies were associated with disease or pneumonia severity, except for aCL IgG being significantly associated with higher pneumonia severity index (p = 0.036). Patients with reduced total serum IgG were more likely to require non-invasive mechanical ventilation (NIMV) (p < 0.0001). Serum concentrations of IgG (p = 0.003) and IgA (p = 0.032) were significantly lower in this group of patients. Higher total serum IgA (p = 0.009) was associated with mortality, with no difference in serum IgG (p = 0.115) or IgM (p = 0.175). Lethal outcome was associated with lower complement C4 (p = 0.013), while there was no difference in complement C3 concentration (p = 0.135).ConclusionIncreased autoimmune responses are present in moderate and severe COVID-19. Severe pneumonia is associated with the presence of aCL IgG, suggesting their role in disease pathogenesis. Evaluation of serum immunoglobulins and complement concentration could help assess the risk of non-invasive mechanical ventilation NIMV and poor outcome.

Pro-inflammatory versus anti-inflammatory cytokines in psoriatic patients (case-control study).

Psoriasis (PsO) is a systemic autoimmune disease. Many pro-inflammatory and anti-inflammatory biomarkers have been associated with the pathogenetic process of psoriasis. IL-35 act as an anti-inflammatory cytokine through downregulation of TH-17 cell development and cytokine production. So, IL-35 might be utilized as potential future therapeutic agent for psoriasis. To investigate the association between inflammatory (IL-17, TNF-α, IFN-γ) and anti-inflammatory cytokines (IL-35, TGF-β) in psoriasis patients. A case-control study enrolled two groups: (Group I: 40 patients with psoriasis) and (Group II: 40 healthy age and sex-matched subjects). Full history was taken from all cases along with full dermatologic examination. The assessment of psoriasis severity was conducted by using PASI score. Assessment of inflammatory (IL-17, TNF-α, IFN-γ) and anti-inflammatory cytokines (IL-35, TGF-β) was performed by using ELISA technique. There was a statistically significant increase of mean level of TNF-α, IL-17, and IFN-γ among psoriasis cases in comparison with controls. The mean level of TGF-β and IL-35 was statistically significantly reduced among the psoriasis cases in comparison with controls. TNF-α, IL-17, and IFN-γ showed a significant strong positive association in between and statistically significant strong negative relationship with IL-35 and TGF-β. IL-35 has a significant role in the pathogenetic process of PsO, and it serves as a potential future therapeutic agent for psoriasis. The current results could be used as a clue for the utilization of inflammatory (IL-17, TNF-α, IFN-γ) versus anti-inflammatory cytokines (IL-35, TGF-β) in psoriasis patients as a diagnostic biomarker for severity of cases with psoriasis.

Biochemical markers of thrombotic complications in the acute period of ischemic stroke

To study the profile of biochemical markers of the hemostasis system, to clarify their role and relationships in the pathogenesis of the development of thrombotic complications (TC) of ischemic stroke (IS) and the associated assessment of the possibilities of their diagnostic application. The study group included 302 patients (164 men, 138 women) who were admitted to the hospital with a diagnosis of IS within 24 hours of the onset of the disease. The diagnosis was confirmed by computed tomography. The average age of patients was 69 (5088) years. Blood was taken from all patients on the 1st day of the disease to determine the profile of analytes presumably associated with the pathogenesis of TC. Levels of homocysteine, protein C inhibitor, thrombomodulin, plasminogen, tissue plasminogen activator, urokinase, plasminogen activator type 1 inhibitor, t-PA/PAI-1 complex, vitronectin, plasmin-2-antiplasmin complex, D-dimer, fibronectin were determined in blood serum by ELISA. TC in the acute period of IS (up to 21 days) were recorded in 32 (10.6%, 95% CI 7.3714.3) patients, of which pulmonary embolism was observed in 27 (8.94%, 95% CI 5.9812.4) patients, deep vein thrombosis in 5 (1.66%, 95% CI 0.473.47) patients. The results of the study of a panel of specific proteins involved in pathogenetic processes accompanying necrosis of brain tissue in IS demonstrated that of the entire list of markers of the hemostasis system activation selected for the study, the most significant are: the concentration of fibronectin in the prognosis of the absence of TC with a threshold value of more than 61 mkg/ml and OR 4.4 (95% CI 1.512.9, p=0.011), and the concentration of the t-PA/PAI-1 complex in the prognosis of the development of TC with a threshold value of more than 14 ng/ml and OR 11.3 (95% CI 1.18109.3, p=0.03). The significance of the t-PA/PAI-1 complex and fibronectin as markers of TC in IS may be due to a violation of the activation processes of the fibrinolytic link of hemostasis and the accumulation of non-deposited compounds that damage the vascular wall.

Autophagy and Apoptosis in Acute Brain Injuries: From Mechanism to Treatment.

Significance: Autophagy and apoptosis are two important cellular mechanisms behind brain injuries, which are severe clinical situations with increasing incidences worldwide. To search for more and better treatments for brain injuries, it is essential to deepen the understanding of autophagy, apoptosis, and their interactions in brain injuries. This article first analyzes how autophagy and apoptosis participate in the pathogenetic processes of brain injuries respectively and mutually, then summarizes some promising treatments targeting autophagy and apoptosis to show the potential clinical applications in personalized medicine and precision medicine in the future. Recent Advances: Most current studies suggest that apoptosis is detrimental to brain recovery. Several studies indicate that autophagy can cause unnecessary death of neurons after brain injuries, while others show that autophagy is beneficial for acute brain injuries (ABIs) by facilitating the removal of damaged proteins and organelles. Whether autophagy is beneficial or detrimental in ABIs depends on many factors, and the results from different research groups are diverse or even controversial, making this topic more appealing to be explored further. Critical Issues: Neuronal autophagy and apoptosis are two primary pathological processes in ABIs. How they interact with each other and how their regulations affect the outcome and prognosis of brain injuries remain uncertain, making these answers more critical. Future Directions: Insights into the interplay between autophagy and apoptosis and the accurate regulations of their balance in ABIs may promote personalized and precise treatments in the field of brain injuries. Antioxid. Redox Signal. 38, 234-257.

Potential roles of non-lymphocytic cells in the pathogenesis of IgG4-related disease.

Studies have confirmed the involvement of a variety of lymphocyte subsets, including type 2 helper T lymphocytes (Th2) and IgG4+ B lymphocytes, in the pathogenesis of IgG4-related disease (IgG4-RD). Those lymphocytes contribute to the major pathogenetic features of IgG4-RD. However, they are not the only cellular components in the immunoinflammatory environment of this mysterious disease entity. Recent studies have suggested that various non-lymphocytic components, including macrophages and fibroblasts, may also play an important role in the pathogenetic process of IgG4-RD in terms of contributing to the chronic and complex progress of the disease. Therefore, the potential role of non-lymphocyte in the pathogenesis of IgG4-RD is worth discussing.

Changes in Expression of the Connective Tissue Growth Factor in the Kidneys of Diabetic Rats During Aging

Background: Diabetic nephropathy (DN) is the most common cause of chronic renal failure in the world. There appears to be different pathogenetic, hemodynamic and metabolic processes leading to the pathologic mechanisms in DN. We studied the expression of connective tissue growth factor (CTGF) in the kidneys of diabetic rats over time.Methods: Male Sprague-Dawley rats were injected with 55mg/kg streptozotocin (STZ) (diabetes mellitus (DM) group) or with citrate buffer (control group). The rat kidneys were harvested 2 weeks, 2 months, 6 months and 12 months following the STZ challenge, and sectioned into three different kidney structures: glomeruli, proximal convoluted tubule (PCT) and distal convoluted tubule (DCT). Sections were immunohistochemically stained to monitor the expression of CTGF. Results:Significant differences in CTGF expression were observed 2 weeks and 2 months after the STZ challenge, with higher CTGF expression in diabetic rats. Two weeks post DM onset, high CTGF expression was demonstrated in the distal tubules of the diabetic rats. The expression of CTGF in the glomeruli of diabetic rats washighest 12 months after diabetes induction, with a complete absence of CTGF expression in the control groups throughout the study.Conclusions:The major change in expression of CTGF occurs within the first 2 months of DM, particularly in the DTC, implying an early onset of pathophysiological changes in diabetic kidneys, which would normally occur with aging. These findings help to contribute to our understanding of changes associated with DN and guide towards potentially appropriate treatment modalities.Key words: diabetes mellitus (DM), nephropathy, chronic renal failure, connective tissue growth factor (CTGF)

Using the syndrome approach to the diagnosis of autism in children

Autism spectrum disorders in children is a very urgent problem. Today, there is an increase in the number of children suffering from autism spectrum disorders around the world. The relevance of early diagnosis of autism spectrum disorders for timely treatment and correction is high. However, the diagnostic criteria for ASD require an assessment of certain psychomotor skills in a child, which mature much later than necessary for a timely diagnosis, so the diagnosis is made by 5-7 years. New clinical guidelines suggest that primary screening should be performed by a pediatrician. However, practice shows that in reality this does not happen. The reason for this is not only a contradiction in the diagnostic criteria, but also the current ICD-10 classification, which does not reflect the pathogenetic processes in the child's body. Despite this, new clinical guidelines recognize the role of genetic disorders and epigenetic factors in the development of autism spectrum disorders. In this regard, it is proposed to consider autism spectrum disorders as a syndrome that accompanies various genetic disorders, both chromosomal and monogenic anomalies. This approach enables early diagnosis of autism spectrum disorders, as well as the development of treatment and correction methods based on pathogenetic disorders. Currently, more than 100 genes associated with autism are known. In the above studies, it was noted that the polygenic nature of disorders in autism does not allow focusing on phenotypic features. Probably, this is the reason for the difficulties in diagnosing autism by external signs and the low efficiency of the currently known screening methods for diagnosing autism spectrum disorders. Therefore, autism spectrum disorders must be considered from the point of view of pathogenetic changes in the child's body, usually of a hereditary nature, which will allow us to offer effective methods of diagnosis, treatment and correction.

Histological diversity of anti-PD1-induced colitis.

Histological data on anti-PD1-associated colitis are limited, while the colitis subtypes are still not clearly defined and different terms are being used. The aim of the study was to explore the histopathology of anti-PD1-induced colitis. Colonic biopsies from 9 patients under anti-PD1 agents presenting diarrhea were examined. Histological evaluation revealed colitis of mild to moderate severity in almost all cases. Four distinct dominant histological patterns were identified with nearly the same incidence: Ulcerative colitis (UC)-like (n=2), GVHD-like (n=2), collagenous-like (n=3) and a mixed colitis pattern combining features of microscopic and UC-like colitis (n=2). The latter was additionally characterized by high crypt epithelium apoptosis and cryptitis with mixed inflammatory infiltrate. Thickening of the subepithelial band of collagen, detachment of the surface epithelium and increased apoptosis of the crypt epithelium were commonly encountered features, irrespective of colitis subtype. CD4/CD8 ratio was lower in the "combined" and higher in the GVHD-like subtype. Anti-PD1-induced colitis is expressed by different patterns of injury which share distinct histological hallmarks harboring diagnostic value, while a "combined" colitis subtype is being established. The histological alterations are indicative of mucosa barrier damage after antΙ-PD1 treatment and its participation in the pathogenetic process.

Normal and abnormal development of the aortic valve and ascending aortic wall: a comprehensive overview of the embryology and pathology of the bicuspid aortic valve.

A bicuspid aortic valve (BAV) is the most prevalent congenital cardiac anomaly, in which the valve has only two leaflets, instead of the normal three. Patients with a BAV have an increased risk of aneurysm formation and the development of an aortic dissection. Vascular smooth muscle cells in both the non- and dilated aortic wall are characterized by a maturation defect in all BAV patients, as compared to patients with a tricuspid aortic valve, which can contribute to inherent developmental susceptibility. Besides structural abnormalities of the vascular wall, a turbulent blood flow, caused by bicuspid valve geometry, could expedite the pathological process in the aortic wall, leading to aortopathy. Although the risk for aortopathy is significant, not all BAV patients experience (acute) aortic complications in their lifespan, highlighting the complexity of the pathogenetic process. Recent studies have focused on the embryonic development of semilunar valves and the ascending aortic wall. Their findings highlight that a defect in the embryogenesis could not only explain the development of a malformed aortic valve but also the increased risk for ascending aorta and arch pathology. This review presents an overview of the normal and abnormal development of the aortic valve and the aortic wall: a common defect in early embryogenesis causes the development of a BAV and associated aortopathy.

Ectopic Schistosomiasis Presenting as Ruptured Appendicitis with Periappendiceal Abscess Formation: An Alternative Pathogenetic Perspective

Schistosomiasis is still a public health burden in the Philippines. Chronic infection with Schistosoma japonicum, the only species endemic in the Philippines, clinically manifests itself in a wide variety of pathologies usually correlated with the anatomical site of adult worm activity and deposition of eggs. One of the documented ectopic sites for Schistosoma ova is the appendix. A rare sequela of this is acute appendicitis and an even rarer consequence is progression to appendiceal rupture leading to acute peritonitis. We present a case of a 27-year-old Filipino residing in Davao City but born in Agusan Province who initially complained of right lower quadrant abdominal pain but presented at the emergency room with generalized abdominal tenderness with signs of peritoneal irritation. Exploratory laparotomy with an infraumbilical incision revealed ruptured appendicitis with periappendiceal abscess formation and appendectomy was subsequently done. Schistosoma infection of the appendix was subsequently established by histopathological analysis. Furthermore, features observed suggest an atypical pathogenetic process contrary to the putative pathogenesis of most cases of acute appendicitis.