Immunohistochemical Analysis of IL-19 and IL-24 Expression in Inflammatory Bowel Disease (IBD) Patients: Results From a Single Center Retrospective Study.

Background IL-19 and IL-24 induce proinflammatory cytokine production through the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. The primary objective of this study was to investigate any changes in IL-19 and IL-24 expression between inflammatory bowel disease (IBD) patients and healthy controls, as well as before and after the initiation of biologics. The secondary objective was to investigate any relation between their expression and disease phenotype and activity.  Methods IL-19 and IL-24 expression was measured in intestinal tissue samples from 121 patients with moderate to severe IBD versus healthy controls using immunohistochemistry. Their expression was then measured 12 months after treatment on the patient group treated with biologics. The disease activity was measured before and after treatment using the Harvey Bradshaw Index (HBI) for Crohn's disease (CD) patients and the Mayo Score (MS) for ulcerative colitis (UC) patients. Data were analyzed using SPSS (IBM Inc., Armonk, New York).  Results IL-19 expression was raised in the IBD group versus healthy controls. In the CD group, the IL-19 expression was related with the disease activity score post-biologic treatment. IL-24 was also highly expressed in patients with active UC and CD and was increased post-treatment. Its expression in UC was statistically related with the MS. Conclusions IL-24 and IL-19 are key factors in IBD-related intestinal inflammation and this is one of the few human studies to suggest that. An immunosuppressive role of IL-24 was demonstrated in the UC group. A future use as biomarkers of disease activity and response to treatment might be feasible.

Grading Challenges and Prognostic Insights in Chromophobe Renal Cell Carcinoma: A Retrospective Study of 72 Patients.

Chromophobe RCC (ChRCC) carries the best prognosis among all RCC subtypes, yet it lacks a proper grading system. Various systems have been suggested in the past, causing much controversy, and Avulova et al. recently proposed a promising four-tier grading system that takes into consideration tumor necrosis. Dysregulation of the mammalian target of the rapamycin (mTOR) pathway plays a key role in ChRCC pathogenesis, highlighting its molecular complexity. The present retrospective study aimed to evaluate the prognostic factors associated with a more aggressive ChRCC phenotype. Materials and Methods: Seventy-two patients diagnosed with ChRCC between 2004 and 2017 were included in our study. Pathology reports and tissue blocks were reviewed, and immunohistochemistry (IHC) was performed in order to assess the expressions of CYLD (tumor-suppressor gene) and mTOR, among other markers. Univariate analysis was performed, and OS was assessed using the Kaplan-Meier method. Results: In our study, 74% of patients were male, with a mean age of 60 years, and the mean tumor size was 63 mm (±44). The majority (54%) were followed for more than 10 years at intervals ranging between 44 and 222 months. The risk of death was significantly higher for patients that were classified as Grade 4 in the Avulova system (HR: 5.83; 95% CI, 1.37-24.7; p: = 0.017). As far as the IHC is concerned, mTOR expression was associated with an HR of 8.57 (95% CI, 1.91-38.5; p = 0.005), and CYLD expression was associated with an HR of 17.3 (95% CI, 1.57-192; p = 0.02). Conclusions: In our study, the Avulova grading system seems to be positively correlated with OS in patients diagnosed with ChRCC. Furthermore, an elevated mTOR expression also shows a negative correlation with OS, whereas an elevated CYLD expression does not seem to exert a protective role. However, because only a small proportion (4.2%) of our patients died due to ChRCC, despite the long follow-up period, the results must be interpreted with caution. Further research is needed to validate our findings.

The Impact of Lifestyle on the Secondary Sex Ratio: A Review.

The secondary sex ratio (SSR), indicating the ratio of male to female live births, has garnered considerable attention within the realms of reproductive biology and public health. Numerous factors have been posited as potential trendsetters of the SSR. Given the extensive research on the impact of daily behaviors and habits on individuals' reproductive health, there is a plausible suggestion that lifestyle choices may also influence the SSR. By synthesizing the existing literature on the current research field, this comprehensive review indicates that an elevated SSR has been associated with an increased intake of fatty acids and monosaccharides, proper nutrition, higher educational levels, financial prosperity, and favorable housing conditions. On the other hand, a decreased SSR may be linked to undernutrition, socioeconomic disparities, and psychological distress, aligning with the Trivers-Willard hypothesis. Occupational factors, smoking habits, and cultural beliefs could also contribute to trends in the SSR. Our review underscores the significance of considering the aforementioned factors in studies examining the SSR and emphasizes the necessity for further research to unravel the mechanisms underpinning these connections. A more profound comprehension of SSR alterations due to lifestyle holds the potential to adequately develop public health interventions and healthcare strategies to enhance reproductive health and overall well-being.

Effects of hazardous chemicals on secondary sex ratio: A comprehensive review.

The secondary sex ratio (SSR), defined as the ratio of male to female offspring at birth, has garnered significant scientific interest due to its potential impact on population dynamics and evolution. In recent years, there has been a growing concern regarding the potential consequences of environmental chemicals on the SSR, given their widespread exposure and potential enduring ramifications on the reproductive system. While SSR serves as an indicator of health, ongoing research and scientific inquiry are being conducted to explore the potential relationship between chemicals and offspring ratio. Although some studies have suggested a possible correlation, others have yielded inconclusive results, indicating that the topic is intricate and still needs to be elucidated. The precise mechanism by which chemical agents exert their influence on the SSR remains ambiguous, with disruption of the endocrine system being a prominent justification. In light of the complex interplay between chemical exposure and SSR, the present review aims to comprehensively examine and synthesize existing scientific literature to gain a deeper understanding of how specific chemical exposures may impact SSR. Insights into chemical hazards that shift SSR patterns or trends could guide prevention strategies, including legislative bans of certain chemicals, to minimize environmental and public health risks.

Clinical and Genetic Correlation in Neurocristopathies: Bridging a Precision Medicine Gap.

Neurocristopathies (NCPs) encompass a spectrum of disorders arising from issues during the formation and migration of neural crest cells (NCCs). NCCs undergo epithelial-mesenchymal transition (EMT) and upon key developmental gene deregulation, fetuses and neonates are prone to exhibit diverse manifestations depending on the affected area. These conditions are generally rare and often have a genetic basis, with many following Mendelian inheritance patterns, thus making them perfect candidates for precision medicine. Examples include cranial NCPs, like Goldenhar syndrome and Axenfeld-Rieger syndrome; cardiac-vagal NCPs, such as DiGeorge syndrome; truncal NCPs, like congenital central hypoventilation syndrome and Waardenburg syndrome; and enteric NCPs, such as Hirschsprung disease. Additionally, NCCs' migratory and differentiating nature makes their derivatives prone to tumors, with various cancer types categorized based on their NCC origin. Representative examples include schwannomas and pheochromocytomas. This review summarizes current knowledge of diseases arising from defects in NCCs' specification and highlights the potential of precision medicine to remedy a clinical phenotype by targeting the genotype, particularly important given that those affected are primarily infants and young children.

The role of IL-19, IL-24, IL-21 and IL-33 in intestinal mucosa of inflammatory bowel disease: A narrative review.

Interleukins are potential therapeutic targets that can alter the prognosis and progression of inflammatory bowel disease (IBD). The roles of IL-6, IL-10, IL-17, and IL-23 have been extensively studied, setting the stage for the development of novel treatments for patients with IBD. Other cytokines have been less extensively studied. Members of the IL-20 family, mainly IL-19 and IL-24, are involved in the pathogenesis of IBD, but their exact role remains unclear. Similarly, IL-33, a newly identified cytokine, has been shown to control the Th1 effector response and the action of colonic Tregs in animal models of colitis and patients with IBD. IL-21 is involved in the Th1, Th2, and Th17 responses. Data support a promising future use of these interleukins as biomarkers of severe diseases and as potential therapeutic targets for novel monoclonal antibodies. This review aims to summarize the existing studies involving animal models of colitis and patients with IBD to clarify their role in the intestinal mucosa.

Periostin is overexpressed, correlated with fibrosis and differs among grades of cardiomyocyte hypertrophy in myectomy tissue of patients with hypertrophic cardiomyopathy.

Periostin, a secreted matricellular protein, has been implicated in cardiac extracellular matrix remodeling and fibrosis. Evidence suggest that periostin stimulates cardiomyocyte hypertrophy. The current study aims to investigate the extent of periostin expression in patients with advanced Hypertrophic Cardiomyopathy (HCM) and its correlation with fibrosis and hallmark histopathological features of the disease. Interventricular septal tissue from thirty-nine HCM patients who underwent myectomy and five controls who died from non-cardiac causes was obtained. Staining with Masson's Trichrome and immunohistochemistry were used to localize fibrosis and periostin respectively. The extent of fibrosis and the expression of periostin were defined as the stained percentage of total tissue area using digital pathology software. Periostin expression was higher in HCM patients compared to controls (p<0.0001), positively correlated with the extent of fibrosis (r = 0.82, p<0.001), positively correlated with maximal interventricular septal thickness (Rho = 0.33, p = 0.04) and negatively correlated with LVEF (r = -0.416, p = 0.009). Periostin was approximately co-localized with fibrosis. Mean periostin expression was lower in patients with mild grade cardiomyocyte hypertrophy compared to those with moderate grade (p = 0.049) and lower in patients with mild grade replacement fibrosis compared to moderate grade (p = 0.036). In conclusion, periostin is overexpressed in advanced HCM, correlated with fibrosis and possibly related to cardiomyocyte hypertrophy.

Detecting Apoptotic Human Lens Epithelial Cells With Transmission Electron Microscopy.

Introduction Cataract formation is a prevalent issue worldwide, and understanding the cellular processes involved is crucial to advancing treatment options. The scope of the study was to explore the presence of apoptotic cells in the lens epithelium of Greek patients with senile cataracts using transmission electron microscopy (TEM). Methods Twenty-one patients with senile cataracts were included in this cross-sectional study, and their anterior lens capsules were thoroughly examined. The presence of apoptosis was ultrastructurally investigated, and its association with age, gender, biomicroscopic type of cataract, the coexistence of exfoliation syndrome (XFS), diabetes mellitus, and glaucoma was statistically correlated. Results We detected apoptotic cells in nine of the 21 patients. Morphological features indicative of apoptosis in the nuclei included degradation, nuclear membrane irregularity, reduction of nuclear volume, condensation, and margination of chromatin. The cytoplasm either appeared denser or contained vacuoles. Budding with membrane blebbing and pinopode-like projections were frequently observed. Apoptotic cells appeared smaller, exhibiting loose connections with neighboring cells and the basement membrane (BM). Interestingly, apoptotic bodies were also detected. Conclusions None of the examined risk factors showed a connection to apoptosis, whereas neighboring lens epithelial cells (LECs) phagocytose apoptotic bodies, seemingly assumed the role of macrophages. Comparing apoptosis rates between populations with different sun exposure levels could help reveal the relationship between ultraviolet B radiation exposure, apoptosis, and cataract formation.

Investigation of Clinically Significant Molecular Aberrations in Patients with Prostate Cancer: Implications for Personalized Treatment, Prognosis and Genetic Testing.

The data on tumor molecular profiling of European patients with prostate cancer is limited. Our aim was to evaluate the prevalence and prognostic and predictive values of gene alterations in unselected patients with prostate cancer. The presence of gene alterations was assessed in patients with histologically confirmed prostate cancer using the ForeSENTIA® Prostate panel (Medicover Genetics), targeting 36 clinically relevant genes and microsatellite instability testing. The primary endpoint was the prevalence of gene alterations in homologous recombination repair (HRR) genes. Overall, 196 patients with prostate cancer were evaluated (median age 72.2 years, metastatic disease in 141 (71.9%) patients). Gene alterations were identified in 120 (61%) patients, while alteration in HRR genes were identified in 34 (17.3%) patients. The most commonly mutated HRR genes were ATM (17, 8.7%), BRCA2 (9, 4.6%) and BRCA1 (4, 2%). The presence of HRR gene alterations was not associated with advanced stage (p = 0.21), age at diagnosis (p = 0.28), Gleason score (p = 0.17) or overall survival (HR 0.72; 95% CI: 0.41-1.26; p = 0.251). We identified clinically relevant somatic gene alterations in European patients with prostate cancer. These molecular alterations have prognostic significance and therapeutic implications and/or may trigger genetic testing in selected patients. In the era of precision medicine, prospective research on the predictive role of these alterations for innovative treatments or their combinations is warranted.

Expression of IL-21 and IL-33 in Intestinal Mucosa of Inflammatory Bowel Disease: An Immunohistochemical Study.

Interleukins are considered to be potential therapeutic targets that can alter the prognosis and disease progression of IBD. IL-21 has proven to be involved in effector Th1, Th2 and Th17 responses. Similarly, IL-33, a newly identified cytokine, has been shown to control the Th1 effector response and the action of the colonic Tregs in animal models of colitis and patients with IBD. In this retrospective study, we have studied the expression of these interleukins, using immunohistochemistry, in 121 patients with moderate to severe IBD before and after treatment with biologics. The results were statistically processed using SPSSTM. Increased IL-21 expression was found in the UC and CD groups versus the controls. The IL-33 expression was found to be increased in the post-treatment UC and CD groups, suggesting a protective role of this interleukin against bowel inflammation. The IL-33 expression post-treatment was reversely correlated with the activity index score in CD patients, suggesting a better response to treatment in patients with higher IL-33 mucosa levels. This is the first immunohistochemical study of the expression of those interleukins in bowel mucosa before and after treatment with biologics. These data support a possibly promising future use of these interleukins as biomarkers of severe disease and response to treatment and as potential therapeutic targets for novel monoclonal antibodies.

Cardiomyopathies in children: An overview.

Paediatric cardiomyopathies form a heterogeneous group of disorders characterized by structural and electrical abnormalities of the heart muscle, commonly due to a gene variant of the myocardial cell structure. Mostly inherited as a dominant or occasionally recessive trait, they might be part of a syndromic disorder of underlying metabolic or neuromuscular defects or combine early developing extracardiac abnormalities (i.e., Naxos disease). The annual incidence of 1 per 100,000 children appears higher during the first two years of life. Dilated and hypertrophic cardiomyopathy phenotypes share an incidence of 60% and 25%, respectively. Arrhythmogenic right ventricular cardiomyopathy (ARVC), restrictive cardiomyopathy, and left ventricular noncompaction are less commonly diagnosed. Adverse events such as severe heart failure, heart transplantation, or death usually appear early after the initial presentation. In ARVC patients, high-intensity aerobic exercise has been associated with worse clinical outcomes and increased penetrance in at-risk genotype-positive relatives. Acute myocarditis in children has an incidence of 1.4-2.1 cases/per 100,000 children per year, with a 6-14% mortality rate during the acute phase. A genetic defect is considered responsible for the progression to dilated cardiomyopathy phenotype. Similarly, a dilated or arrhythmogenic cardiomyopathy phenotype might emerge with an episode of acute myocarditis in childhood or adolescence. This review provides an overview of childhood cardiomyopathies focusing on clinical presentation, outcome, and pathology.

Origin and Emergence of Microglia in the CNS-An Interesting (Hi)story of an Eccentric Cell.

Microglia belong to tissue-resident macrophages of the central nervous system (CNS), representing the primary innate immune cells. This cell type constitutes ~7% of non-neuronal cells in the mammalian brain and has a variety of biological roles integral to homeostasis and pathophysiology from the late embryonic to adult brain. Its unique identity that distinguishes its "glial" features from tissue-resident macrophages resides in the fact that once entering the CNS, it is perennially exposed to a unique environment following the formation of the blood-brain barrier. Additionally, tissue-resident macrophage progenies derive from various peripheral sites that exhibit hematopoietic potential, and this has resulted in interpretation issues surrounding their origin. Intensive research endeavors have intended to track microglial progenitors during development and disease. The current review provides a corpus of recent evidence in an attempt to disentangle the birthplace of microglia from the progenitor state and underlies the molecular elements that drive microgliogenesis. Furthermore, it caters towards tracking the lineage spatiotemporally during embryonic development and outlining microglial repopulation in the mature CNS. This collection of data can potentially shed light on the therapeutic potential of microglia for CNS perturbations across various levels of severity.

Addressing Spaceflight Biology through the Lens of a Histologist-Embryologist.

Embryogenesis and fetal development are highly delicate and error-prone processes in their core physiology, let alone if stress-associated factors and conditions are involved. Space radiation and altered gravity are factors that could radically affect fertility and pregnancy and compromise a physiological organogenesis. Unfortunately, there is a dearth of information examining the effects of cosmic exposures on reproductive and proliferating outcomes with regard to mammalian embryonic development. However, explicit attention has been given to investigations exploring discrete structures and neural networks such as the vestibular system, an entity that is viewed as the sixth sense and organically controls gravity beginning with the prenatal period. The role of the gut microbiome, a newly acknowledged field of research in the space community, is also being challenged to be added in forthcoming experimental protocols. This review discusses the data that have surfaced from simulations or actual space expeditions and addresses developmental adaptations at the histological level induced by an extraterrestrial milieu.

Valproic acid induced selective apoptosis of ocular fibrous tunic in mice fetuses.

BACKGROUND: Valproic acid (VPA), a prescribed drug commonly used for various neurological perturbations, has been implicated in teratogenic inflictions on developing fetuses during pregnancy. The purpose of this research was to delineate the gross morphological and histological effects of VPA in the developing eye tunics and lens. METHODS: A time-dependent administration of 500 mg/kg VPA to BALB/c groups of female mice was coordinated during organogenesis (gestational days 7, 8, and 9) and compared to controls that received normal saline. Seized fetuses were checked for macroscopic eye anomalies, histological malformations with Azan trichrome staining, and levels of apoptotic activity with the terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay. RESULTS: Histochemical analysis showed that VPA-treated groups exhibited collagen deficiency (2.5-50% decrease in aniline blue intensity) and a marked increase in TUNEL-positive cells (p < .05) in corneal stroma and sclera/choroid layers while less was detected in retina and lens, when compared to controls. CONCLUSIONS: Since the evaluation of the inner structures did not manifest major differences, we conclude that VPA teratogenic influence display eclectic toxicity, as seen by increased apoptosis to eye layers with high degree fibrous context, particularly the outer tunics.

Congenital Herpes Simplex Virus: A Histopathological View of the Placenta.

Congenital Herpes simplex virus (HSV) infection is considered a common pregnancy pathology that is not always easy to diagnose. This study aimed to present the spectrum of placental histopathological lesions in pregnancies complicated by HSV infection. MEDLINE and Google Scholar databases were searched using the keywords "HSV" and "placental histopathology" up to June 20, 2022. Study inclusion required presenting placental histopathological anomalies in pregnant women diagnosed with HSV infection antenatally, during labor, or postnatally. Herein, we briefly present placental pathogenesis conditions, which have been correlated with congenital HSV infection, providing clinicians with a short review describing herpetic placental pathology.

Developmental Cues and Molecular Drivers in Myelinogenesis: Revisiting Early Life to Re-Evaluate the Integrity of CNS Myelin.

The mammalian central nervous system (CNS) coordinates its communication through saltatory conduction, facilitated by myelin-forming oligodendrocytes (OLs). Despite the fact that neurogenesis from stem cell niches has caught the majority of attention in recent years, oligodendrogenesis and, more specifically, the molecular underpinnings behind OL-dependent myelinogenesis, remain largely unknown. In this comprehensive review, we determine the developmental cues and molecular drivers which regulate normal myelination both at the prenatal and postnatal periods. We have indexed the individual stages of myelinogenesis sequentially; from the initiation of oligodendrocyte precursor cells, including migration and proliferation, to first contact with the axon that enlists positive and negative regulators for myelination, until the ultimate maintenance of the axon ensheathment and myelin growth. Here, we highlight multiple developmental pathways that are key to successful myelin formation and define the molecular pathways that can potentially be targets for pharmacological interventions in a variety of neurological disorders that exhibit demyelination.

Renal Injuries after Cardiac Arrest: A Morphological Ultrastructural Study.

BACKGROUND: This study aims to investigate the probable lesions and injuries induced in the renal tissue after a cardiac arrest. The renal ischemia-reperfusion model in cardiac arrest describes the effects of ischemia in the kidneys, alongside a whole-body ischemia-reperfusion injury. This protocol excludes ischemic conditions caused by surgical vascular manipulation, venous injury or venous congestion. METHODS: For the experimental study, 24 swine were subjected to cardiac arrest. Seven minutes later, the cardiopulmonary resuscitation technique was performed for 5 min. Afterwards, advanced life support was provided. The resuscitated swine consisted one group and the non-resuscitated the other. Tissue samples were obtained from both groups for light and electron microscopy evaluation. RESULTS: Tissue lesions were observed in the tubules, parallel to destruction of the microvilli, reduction in the basal membrane invaginations, enlarged mitochondria, cellular vacuolization, cellular apoptosis and disorganization. In addition, fusion of the podocytes, destruction of the Bowman's capsule parietal epithelium and abnormal peripheral urinary space was observed. The damage appeared more extensive in the non-resuscitated swine group. CONCLUSIONS: Acute kidney injury is not the leading cause of death after cardiac arrest. However, evidence suggests that the kidney damage after a cardiac arrest should be highly considered in the prognosis of the patients' health outcome.

Factors Affecting the Nuclei in Newborn and Children.

It is known that children are more sensitive to the effects of medical treatments and environment than adults. Today there is limited information regarding the differences in genotoxic effects in children. The micronucleus assay is a method that is used to monitor genotoxicity, and it was validated several years before. Today there is international interest for exfoliated buccal cells. Most of the micronuclei studies in children have been performed with the analyses of lymphocytes. However, there is vast interest in using exfoliated cells from the oral cavity. The reason is that other type of cells are acquired non-invasively, this is an important issue in paediatric cohorts. Unfortunately a limitation of measuring micronuclei frequency is that it has been observed to be low in newborns and on the other hand there are a large number of patients and cell sample counts. It has been observed that radiation exposure and environmental pollutants increase the micronuclei frequency in newborn and children. Regarding the medical treatments, there is little data and several studies are needed to optimise the doses. There is the need to observe if there is a relationship between micronuclei in lymphocytes and exfoliated cells and to identify the baseline of the micronuclei levels. Moreover, we evaluate the changes in response to the toxic agents. Prospective cohorts studies will clarify the predictive value of micronuclei for cancer and chronic diseases for both children and adults. Novel molecular technologies will assist in the elucidation of different biological pathways and molecular mechanisms connected with the micronulcei levels in newborn and children.

Post-Cardiac Arrest Syndrome Is Not Associated With an Early Bacterial Translocation.

BACKGROUND: The aim of this study was to investigate bacterial translocation and its possible role in the development of post-resuscitation inflammatory response following Cardio-Pulmonary Resuscitation (CPR) after cardiac arrest. METHODS: Munich female swine were employed for a model of cardiac arrest via application of electrical current. After 7 min, CPR was initiated, and animals were either successfully return to spontaneous circulation (ROSC) within 40 min or not (no-ROSC). At the end of experimental period and prior to sacrifice, samples from the intestine, mesenteric lymph nodes (MLN), liver and portal vein blood were obtained. Evaluation of inflammation and gut permeability was performed; MLN, liver and portal vein samples were analyzed for 16 s rRNA detection and cytokine mRNA expression. RESULTS: A decreased expression of the tight junction protein Occludin, with higher levels of inflammation, greater epithelial disintegration, ulceration, loss of crypts and villi height were found in the intestines of the ROSC swine in comparison to no-ROSC. The macrophage surface antigen CD-14 staining was relatively more intense in the ROSC than in no-ROSC. Higher levels of TNF-α mRNA expression were present in the liver of the ROSC group. Finally, despite the inflammatory response and the gut mucosal alterations in ROSC group, no bacterial translocation was detected in liver, MLN and portal vein. CONCLUSIONS: We show that resuscitation from cardiac arrest induces inflammatory response and intestinal permeability in swine 4h after resuscitation, but not a bacterial translocation. Bacterial translocation is not an early phase phenomenon but probably part of the pathophysiologic sequelae.