Inflammaging: Expansion of Molecular Phenotype and Role in Age-Associated Female Infertility.

Cellular aging is considered as one of the main factors implicated in female infertility. We evaluated the expression of senescence-associated secretory phenotype (SASP) markers and additional molecular factors in an in vitro model of cellular aging. We induced genotoxic stress (UVB/UVA ray irradiation) in primary human endometrial cells obtained from female subjects of young reproductive age (<35 years of age). We assessed the expression levels of IL-6, IL-8, IL-1α, MMP3, SIRT-1, SIRT-6, TERF-1, and CALR at the mRNA level by RT-qPCR and at the protein level by immunofluorescence and confocal microscopy in primary human endometrial cells upon induction of genotoxic stress and compared them to untreated cells. Statistically significant differences were found for the expression of SIRT-1, SIRT-6, and TERF, which were found to be decreased upon induction of cell senescence through genotoxic stress, while IL-6, IL-8, IL-1α, MMP3, and p16 were found to be increased in senescent cells. We propose that these molecules, in addition to SAS-linked factors, could represent novel markers, and eventually potential therapeutic targets, for the aging-associated dysfunction of the female reproductive system.

COVID-19 in Children: Molecular Profile and Pathological Features.

Although the World Health Organization has declared the end of the COVID-19 pandemic, doctors continue to register new cases of the disease among both adults and children. Unfortunately, the course of COVID-19 in children can have a severe form, with death being a potential outcome. The absence of published works discussing the pathological morphology of COVID-19 in children prevents the objective analysis of the disease's pathogenesis, including among the adult population. In this vein, the objective of our study is to identify the morphological features of the lungs' involvement and evaluate virus-host interactions in the case of COVID-19 in patients at a pediatric medical practice. We present the results of the study of the lungs of three children who died due to COVID-19, highlighting the predominant involvement of their respiratory organs at different stages of the disease (5, 21, and 50 days). This article presents data obtained from histopathological and immunohistochemical investigations, taking into account the results of clinical and laboratory indicators and intravital and postmortem SARS-CoV-2 PCR investigations. The common finding of all of the examined COVID-19 cases is the involvement of the endothelium in microcirculation vessels, which are considered to be a primary target of various pathogenic influencing factors. We also discuss both the significance of apoptosis as a result of virus-host interactions and the most likely cause of endothelium cell destruction. The results of this study could be useful for the development of endothelium-protective therapy to prevent the progression of disseminated intravascular coagulation syndrome.

Melatonin as the Cornerstone of Neuroimmunoendocrinology.

Much attention has been recently drawn to studying melatonin - a hormone whose synthesis was first found in the epiphysis (pineal gland). This interest can be due to discovering the role of melatonin in numerous physiological processes. It was the discovery of melatonin synthesis in endocrine organs (pineal gland), neural structures (Purkinje cells in the cerebellum, retinal photoreceptors), and immunocompetent cells (T lymphocytes, NK cells, mast cells) that triggered the evolution of new approaches to the unifield signal regulation of homeostasis, which, at the turn of the 21st century, lead to the creation of a new integral biomedical discipline - neuroimmunoendocrinology. While numerous hormones have been verified over the last decade outside the "classical" locations of their formation, melatonin occupies an exclusive position with regard to the diversity of locations where it is synthesized and secreted. This review provides an overview and discussion of the major data regarding the role of melatonin in various physiological and pathological processes, which affords grounds for considering melatonin as the "cornerstone" on which neuroimmunoendocrinology has been built as an integral concept of homeostasis regulation.

Sudden infant death syndrome: Melatonin, serotonin, and CD34 factor as possible diagnostic markers and prophylactic targets.

Sudden infant death syndrome (SIDS) is one of the primary causes of death of infants in the first year of life. According to the WHO's data, the global infant mortality rate is 0.64-2 per 1,000 live-born children. Molecular and cellular aspects of SIDS development have not been identified so far. The purpose of this paper is to verify and analyze the expression of melatonin 1 and 2 receptors, serotonin (as a melatonin precursor), and CD34 molecules (as hematopoietic and endothelial markers of cardiovascular damage) in the medulla, heart, and aorta in infants who died from SIDS. An immunohistochemical method was used to investigate samples of medulla, heart, and aorta tissues of infants 3 to 9 months of age who died from SIDS. The control group included children who died from accidents. It has been shown that the expression of melatonin receptors as well as serotonin and CD34 angiogenesis markers in tissues of the medulla, heart, and aorta of infants who died from SIDS is statistically lower as compared with their expression in the same tissues in children who died from accidents. The obtained data help to clarify in detail the role of melatonin and such signaling molecules as serotonin and CD34 in SIDS pathogenesis, which can open new prospects for devising novel methods for predictive diagnosis of development and targeted prophylaxis of SIDS.

Melatonin, Its Beneficial Effects on Embryogenesis from Mitigating Oxidative Stress to Regulating Gene Expression.

Embryogenesis is a complex multi-stage process regulated by various signaling molecules including pineal and extrapineal melatonin (MT). Extrapineal MT is found in the placenta and ovaries, where it carries out local hormonal regulation. MT is necessary for normal development of oocytes, fertilization and subsequent development of human, animal and avian embryos. This review discusses the role of MT as a regulator of preimplantation development of the embryo and its implantation into endometrial tissue, followed by histo-, morpho- and organogenesis. MT possesses pronounced antioxidant properties and helps to protect the embryo from oxidative stress by regulating the expression of the NFE2L2, SOD1, and GPX1 genes. MT activates the expression of the ErbB1, ErbB4, GJA1, POU5F1, and Nanog genes which are necessary for embryo implantation and blastocyst growth. MT induces the expression of vascular endothelial growth factor (VEGF) and its type 1 receptor (VEGF-R1) in the ovaries, activating angiogenesis. Given the increased difficulties in successful fertilization and embryogenesis with age, it is of note that MT slows down ovarian aging by increasing the transcription of sirtuins. MT administration to patients suffering from infertility demonstrates an increase in the effectiveness of in vitro fertilization. Thus, MT may be viewed as a key factor in embryogenesis regulation, including having utility in the management of infertility.

Maternal Melatonin Deficiency Leads to Endocrine Pathologies in Children in Early Ontogenesis.

The review summarizes the results of experimental and clinical studies aimed at elucidating the causes and pathophysiological mechanisms of the development of endocrine pathology in children. The modern data on the role of epigenetic influences in the early ontogenesis of unfavorable factors that violate the patterns of the formation of regulatory mechanisms during periods of critical development of fetal organs and systems and contribute to the delayed development of pathological conditions are considered. The mechanisms of the participation of melatonin in the regulation of metabolic processes and the key role of maternal melatonin in the formation of the circadian system of regulation in the fetus and in the protection of the genetic program of its morphofunctional development during pregnancy complications are presented. Melatonin, by controlling DNA methylation and histone modification, prevents changes in gene expression that are directly related to the programming of endocrine pathology in offspring. Deficiency and absence of the circadian rhythm of maternal melatonin underlies violations of the genetic program for the development of hormonal and metabolic regulatory mechanisms of the functional systems of the child, which determines the programming and implementation of endocrine pathology in early ontogenesis, contributing to its development in later life. The significance of this factor in the pathophysiological mechanisms of endocrine disorders determines a new approach to risk assessment and timely prevention of offspring diseases even at the stage of family planning.

Inflammaging of Female Reproductive System: A Molecular Landscape.

Aging is a complex biological process, a major aspect of which is the accumulation of somatic changes throughout life. Cellular senescence is a condition in which cells undergo an irreversible cell cycle arrest in response to various cellular stresses. Once the cells begin to senesce, they become more resistant to any mutagens, including oncogenic factors. Inflammaging (inflammatory aging) is an age-related, chronic, and systemic inflammatory condition realized by cells with the Senescence-Associated Secretory Phenotype (SASP). These recently recognized senescent phenotypes associated with aging have been reported to promote better wound healing, embryonic development, as well as stimulation and extension of the tumor process. It is assumed that cellular senescence contributes to the age-related decline of reproductive function due to the association of senescent cells with aging and age-related diseases. Thus, SASPs have both positive and negative effects, depending on the biological context. SASP cell accumulation in tissues contributes to an age-related functional decline of the tissue and organ state. In this review, the term "cellular senescence" is used to refer to the processes of cells irreversible growth inhibition during their viable state, while the term "aging" is used to indicate the deterioration of tissues due to loss of function. Late reproductive age is associated with infertility and possible complications of the onset and maintenance of pregnancy. Senescent cells express pro-inflammatory cytokines, growth factors, and matrix metalloproteinases and some other molecules collectively called the Senescence-Associated Secretory Phenotype (SASP).

Morphological and Immunohistochemical Features of Placental Damage in Cases of Perinatal Death: Institutional Experience with Emphasis on Viral Etiology.

OBJECTIVE: Intrauterine hypoxia/asphyxia is not the cause, but a consequence of different pathological conditions that requires a more detailed study of the morphogenesis of perinatal death. METHODS: Structural changes in placentas of intrauterine fetal demise (IUFD) in different stages of intrauterine period and placentas in early neonatal death were reviewed and compared. Control group was composed of term placentas without evidence of perinatal asphyxia or other neonatal abnormalities. Immunohistochemical investigation was performed by antibodies to Herpes simplex virus (HSV), Cytomegalovirus (CMV), and tumor necrosis factor (TNF). Morphometric analysis was performed using the Pannoramic Midi II histoscanner of "3DHISTECH" company. RESULTS: The histologic examination of placentas revealed differences between IUFD and early neonatal death. Predominant localization of HSV and CMV antigens was noted in the walls of capillaries and in placental villous stroma in absolute majority of IUFD and early neonatal death cases; importantly, colocalization of TNF, HSV, and CMV antigens was also detected in cases of IUFD and early neonatal period. CONCLUSION: Damage of placental vessels due to the influence of pathogenic factors (virus antigens, TNF) can cause acute or chronic intrauterine fetus hypoxia which is a leading pathogenetic factor of perinatal death.

The new differential diagnostic test for the lichenoid drug eruption.

The differential diagnosis between lichenoid drug eruption (LDE) and lichen planus (LP) is difficult due to similar clinical and histological signs but important for treatment and prognosis. The purpose of this study was to propose the new diagnosis method for differentiate LDE from LP. During 2015-2018, 20 patients with confirmed LDE, 13 patients with LP and 134 controls were examined and treated at the Lenoblcenter. All enrolled patients were underwent the injection of 0.5 mL of the 2% lidocaine solution by insulin syringe into the papule with following histological examination. The formation of a blister (bulla) at the site of injection was considered a positive test result. Among LDE, 18 of 20 patients were found positive for developing blister (bulla) and two results were questionable. In 12 of 13 LP patents, bulla on the site of injection was not identified and the result of one patient was nonspecific. All control patients were negative for the proposed test. The histological sections showed that the bulla has corresponded to the separation of the epidermis from the dermis. Intracutaneous injection of 0.5 mL of lidocaine into the papule is an easy highly specific and sensitive method to differentiate LDE from LP.

The Role of Prenatal Melatonin in the Regulation of Childhood Obesity.

There is a growing awareness that pregnancy can set the foundations for an array of diverse medical conditions in the offspring, including obesity. A wide assortment of factors, including genetic, epigenetic, lifestyle, and diet can influence foetal outcomes. This article reviews the role of melatonin in the prenatal modulation of offspring obesity. A growing number of studies show that many prenatal risk factors for poor foetal metabolic outcomes, including gestational diabetes and night-shift work, are associated with a decrease in pineal gland-derived melatonin and associated alterations in the circadian rhythm. An important aspect of circadian melatonin's effects is mediated via the circadian gene, BMAL1, including in the regulation of mitochondrial metabolism and the mitochondrial melatoninergic pathway. Alterations in the regulation of mitochondrial metabolic shifts between glycolysis and oxidative phosphorylation in immune and glia cells seem crucial to a host of human medical conditions, including in the development of obesity and the association of obesity with the risk of other medical conditions. The gut microbiome is another important hub in the pathoetiology and pathophysiology of many medical conditions, with negative consequences mediated by a decrease in the short-chain fatty acid, butyrate. The effects of butyrate are partly mediated via an increase in the melatoninergic pathway, indicating interactions of the gut microbiome with melatonin. Some of the effects of melatonin seem mediated via the alpha 7 nicotinic receptor, whilst both melatonin and butyrate may regulate obesity through the opioidergic system. Oxytocin, a recently recognized inhibitor of obesity, may also be acting via the opioidergic system. The early developmental regulation of these processes and factors by melatonin are crucial to the development of obesity and many diverse comorbidities.

The role of histological presentation in erythroderma.

BACKGROUND: Erythroderma is a serious medical condition characterized by inflamed red skin involving over 90% of the body. It can be the common presentation of different diseases, therefore clinical diagnosis can be problematic. Controversial data are reported regarding the diagnostic value of histological examination in erythroderma subjects. METHODS: A retrospective study was performed, investigating histological skin specimens of patients with a clinical diagnosis of erythroderma admitted to the Department of Dermatology of State Pediatric Medical University, Saint Petersburg, from 2001 to 2014. Histopathology examination was performed in each case by a pathologist with a special interest in the skin disease who was blind to any clinical information as well as to final diagnosis. RESULTS: Blinded histopathology examination alone was able to give the correct diagnosis in 61% (n = 50/82) of cases when compared to final diagnosis. A diagnosis of psoriasis was made in 23.2% (n = 19/82) of subjects, spongiotic dermatitis/eczema in 20.7% (n = 17/82), mycosis fungoides in 8.5% (n = 7/82), and drug eruption in 8.5%; histological diagnosis was inconclusive or not matching the final diagnosis when available in the remaining 39.1% of cases (n = 32/82). CONCLUSION: Erythroderma remains a condition difficult to study and treat. We showed that a correct judgment about its cause can be based on objective histopathological criteria in up to 60% of cases. More studies are needed to try to find out further histological and/or immunohistochemical markers that could help the clinician with the erythroderma etiology diagnostic process.

Distinctive Features of the Human Marginal Zone and Cajal-Retzius Cells: Comparison of Morphological and Immunocytochemical Features at Midgestation.

Despite a long history of research of cortical marginal zone (MZ) organization and development, a number of issues remain unresolved. One particular issue is the problem of Cajal-Retzius cells (C-R) identification. It is currently based on morphology and Reelin expression. The aim of this research is to investigate MZ cytoarchitectonics and Reelin-producing cells morphotypes in the superior temporal, pre- and postcentral cortex at GW24-26. We used Reelin (Reln) as the marker for C-R cells and microtubule-associated protein 2 (MAP2) and neurofilament heavy chain protein (N200) as markers of neuronal maturation. The MZ of all of the investigated areas had the distinct cytoarchitectonic of alternating cell sparse (MZP, SR) and cell dense (SGL, DGL) layers. The distribution of the neuromarkers across the MZ also showed layer specificity. MAP2-positive cells were only found in the SGL. N200 and Reelin-positive neurons in the MZP. N200-positive processes were forming a plexus at the DGL level. All of the N200-positive neurons found were in the MZP and had distinctive morphological features of C-R cells. All of the N200-positive neurons in MZ were also positive for Reelin, whereas MAP2-positive cells lack Reelin. Thus, the joint use of two immunomarkers allowed us to discern the C-R cells based on their morphotype and neurochemistry and indicate that the Reelin-positive cells of MZ at 24-26 GW were morphologically C-R cells. In the current study, we identified three C-R cells morphotypes. Using a 3D reconstruction, we made sure that all of them belonged to the single morphotype of triangular C-R cells. This approach will allow future studies to separate C-R cells from other Reelin-producing neurons which appear at later corticogenesis stages. In addition, our findings support the assumption that a plexus could be formed not only with C-R cells processes but also possibly by other cell processes by the poorly researched DGL, which is only allocated as a part of the human MZ.

Morphological manifestations of the atypical mycobacteriosis caused by nontuberculous mycobacteria in the HIV infected patients.

Infection with atypical mycobacteria (MAC) is a well-known complication of AIDS that typically occurs only in people with advanced immunodeficiency. We studied tissues from 13 patients with HIV and atypical mycobacterial infection who died in St Petersburg Russia from 2009-2012. Three patterns of disease were identified that suggest effects of host resistance. The first pattern was in people paucibacillary disease. They had positive blood cultures and histologic changes consistent with mycobacterial infection, but no stainable acid fast bacilli (AFB). The second group had disseminated infection in many organs including the lungs with extensive necrosis with many AFB. Finally, the third group had massive infection of many organs, but not the lungs, and only minimal necrosis. These observations suggest significant heterogeneity in atypical mycobacterial infections.

Diffractive variable attenuator for femtosecond laser radiation control.

We present a diffractive phase variable attenuator for femtosecond laser radiation control. It allows the control of beam power up to 0.75.10(13) W/cm(2) without introducing serious distortions in spectra and beam shape while it operates in zero order diffraction. The attenuator can operate with wavelengths from DUV to IR.

Zone-boundary optimization for direct laser writing of continuous-relief diffractive optical elements.

Enhancing the diffraction efficiency of continuous-relief diffractive optical elements fabricated by direct laser writing is discussed. A new method of zone-boundary optimization is proposed to correct exposure data only in narrow areas along the boundaries of diffractive zones. The optimization decreases the loss of diffraction efficiency related to convolution of a desired phase profile with a writing-beam intensity distribution. A simplified stepped transition function that describes optimized exposure data near zone boundaries can be made universal for a wide range of zone periods. The approach permits a similar increase in the diffraction efficiency as an individual-pixel optimization but with fewer computation efforts. Computer simulations demonstrated that the zone-boundary optimization for a 6 microm period grating increases the efficiency by 7% and 14.5% for 0.6 microm and 1.65 microm writing-spot diameters, respectively. The diffraction efficiency of as much as 65%-90% for 4-10 microm zone periods was obtained experimentally with this method.