Pathology Course Research Articles

Teaching clinical hematology and leukocyte differentiation in veterinary medicine using virtual patients.

Due to contact restrictions imposed because of the COVID-19 pandemic, we created a novel digital course on the Moodle learning platform for winter term in 2020. In the clinical pathology course (CPC) with hematological content, third-year students were able to work independently on 10 extra digital cases of internal medicine involving eight different animal species as a compensation for the reduction in traditional microscopy exercises. Each case presented was initiated using an anamnesis, also the participants to generate a differential blood count based on digitized leukocytes, previously been photographed using a microscope camera. The cases were successive and increased in complexity, for example through the increase in the number of different cell types to be differentiated. The participants had the opportunity to evaluate the course through a final module to rate user-friendliness and acceptance. The total results of the participants in 2021 were analyzed descriptively, focusing on success rates, time spent on the tasks, and number of attempts. A total of 237 (= 96%) of 247 students completed all cases, each assessing 1033 photographed blood cells in sum. The mean processing time was 22.48 min for a differentiation and the students spent an average of 1.48 attempts on it. A voluntary feedback form was completed by 192 (= 78%) students, with more than 95% rating the course positively in 12 evaluation questions, and 29 of 33 comments (= 87.88%) providing positive statements in a comment box. Suggestions for improvement primarily included more explanations on erythrocyte morphologies, followed by adjusting the difficulty level and improving the presentational set-up. Slight improvements in results, time spent on processing the tasks, and the number of attempts indicated an achievement of routine and confidence during the course and were associated with an increase of competency. The positive feedback showed a high acceptance of the digital format and students evaluated the course as improving the quality of teaching when combined with practical exercises.

Time-course analysis of frontal gene expression profiles in the rat model of posttraumatic stress disorder and a comparison with the conditioned fear model

Posttraumatic stress disorder (PTSD) is a complex disorder that involves physiological, emotional, and cognitive dysregulation that may occur after exposure to a life-threatening event. In contrast with the condition of learned fear with resilience to extinction, abnormal fear with impaired fear extinction and exaggeration are considered crucial factors for the pathological development of PTSD. The prefrontal cortex (mPFC) is considered a critical region of top-down control in fear regulation, which involves the modulation of fear expression and extinction. The pathological course of PTSD is usually chronic and persistent; a number of studies have indicated temporal progression in gene expression and phenotypes may be involved in PTSD pathology. In the current study, we use a well-established modified single-prolonged stress (SPS&FS) rat model to feature PTSD-like phenotypes and compared it with a footshock fear conditioning model (FS model); we collected the frontal tissue after extreme stress exposure or fear conditioning and extracted RNA for transcriptome-level gene sequencing. We compared the genetic profiling of the mPFC at early (<2 h after solely FS or SPS&FS exposure) and late (7 days after solely FS or SPS&FS exposure) stages in these two models. First, we identified temporal differences in the expressional patterns between these two models and found pathways such as protein synthesis factor eukaryotic initiation factor 2 (EIF2), transcription factor NF-E2-related factor 2 (NRF2)-mediated oxidative stress response, and acute phase responding signaling enriched in the early stage in both models with significant p-values. Furthermore, in the late stage, the sirtuin signaling pathway was enriched in both models; other pathways such as STAT3, cAMP, lipid metabolism, Gα signaling, and increased fear were especially enriched in the late stage of the SPS&FS model. However, pathways such as VDR/RXR, GP6, and PPAR signaling were activated significantly in the FS model's late stage. Last, the network analysis revealed the temporal dynamics of psychological disorder, the endocrine system, and also genes related to increased fear in the two models. This study could help elucidate the genetic temporal alteration and stage-specific pathways in these two models, as well as a better understanding of the transcriptome-level differences between them.

Innovative Tactical Training "Ucheniya"

In the course of a joint tactical training, the participants formed and improved effective communication skills, a model for the correct transmission of information, digital skills for predicting the course and outcomes of pathology. An important task in the course of trainings is the development, implementation in practice of remote technology for medical forecasting and remote consulting for employees of medical organizations.

Effect of physical activity on long COVID fatigue: an unsolved enigma.

Covid-19 disease is well documented and often the most common symptoms include myalgia and muscle fatigue. Approximately 10% of those infected complain of persistent fatigue even many months after the end of the acute phase of the disease. This gives rise to a condition different from the previous one and commonly known as 'post-acute COVID-19 syndrome' or simply Long-COVID. Although the origin of muscle fatigue is multifactorial, the state of prolonged fatigue observed in the Long-COVID syndrome suggests the existence of a possible state of atrophy or rather acute sarcopenia. Under these conditions, the use of physical activity programs can effectively counteract the state of atrophy underlying the fatigue phenomena observed. If this is also the situation during the Long-COVID, the muscular symptom should be positively influenced by the administration of programmed physical activity cycles. In fact, in patients with Long-COVID, the few published papers seem to indicate that patients who are physically active and who make an effort to engage in physical activity even during the illness have decreased duration and intensity of the illness. However, analysis of the studies in the literature also suggests that a small percentage of people with Long-COVID do not appear to benefit from the application of physical activity programs, so further studies on homogeneous samples are needed to provide a firm answer to the question: can planned physical activity help patients during the pathological course of Long-COVID?

Neutrophil gelatinase-associated lipocalin: function, specificity, role in the diagnosis of renal dysfunction in hypertensive patients with concomitant type 2 diabetes and obesity

Background. Neutrophil gelatinase-associated lipocalin (NGAL) belongs to the superfamily of lipocalins whose main function is the binding and transportation of hydrophobic molecules, si­derophores, as the most important ligands of NGAL. The diagnostic significance of NGAL as a marker of renal dysfunction, as well as its prognostic value in terms of the further prognosis of the course of renal pathology has now been confirmed. The purpose of the study: to determine the role of NGAL in the development of renal dysfunction in hypertensive patients with comorbid type 2 diabetes (T2D) and obesity. Materials and methods. One hundred and eleven patients with hypertension (50 men, 61 women) aged 54.37 ± 1.18 years and 20 controls were examined. During the examination, they were divi­ded into 4 groups depending on the presence of comorbid pathology: hypertension — the first group (n = 22); hypertension combined with obesity — the second group (n = 30); hypertension combined with T2D — the third group (n = 31); hypertension, T2D and obesity — the fourth group (n = 28). In all patients, body weight and height were measured, body mass index was calculated, levels of glycated hemoglobin, lipid metabolism, systolic and diastolic blood pressure were measured. The content of NGAL in blood serum was evaluated by the enzyme-linked immunosorbent assay. Results. The level of NGAL in all patients included in the study was significantly higher compared to the control group (p &lt; 0.01). However, it was highest in comorbidity of hypertension, T2D and obesity, which, in turn, indicates a high risk of interstitial fibrosis in these patients. A significant correlation was found between the level of NGAL and the concentration of cardiotrophin (p &lt; 0.032), catestatin (p &lt; 0.001), β2-microglobulin (p &lt; 0.001), cystatin (p &lt; 0.021), atherogenic coefficient (p &lt; 0.011), NT-proBNP (p &lt; 0.014), vitamin D (p &lt; 0.004). The obtained data demonstrate the significant role of NGAL in the development of early cardiovascular and renal complications in our patients. Conclusions. A significant increase in the level of NGAL was found in patients with hypertension, hypertension with T2D, hypertension with obesity, hypertension with T2DM and obesity compared to healthy individuals (p &lt; 0.01). A significant correlation of the NGAL level with the serum concentration of cardiotrophin, catestatin, cystatin C, β2-microglobulin, atherogenic coefficient, NT-proBNP, and vitamin D in the exami­ned patients was proved.

Distribution of polymorphic variants of the TNF-α and TNFRSF1α genes in miners with dust lung pathology

Introduction. Long-term exposure to coal-rock dust on the body causes the development of systemic inflammation, one of the development mechanisms of which is an increase in the production of pro-inflammatory cytokines as follows: TNF-α, IL-1β, IL-2, IL-6. The development and course of occupational pathology were shown to depend on the individual characteristics of the body of those who works in hazardous conditions. In this regard, it is necessary to establish the significance of the polymorphism of the TNF-α and TNFRSF1α genes in the development of dust lung pathology in workers of the main occupations of the mines in the South of Kuzbass. &#x0D; The aim of the study was to investigate the prevalence of polymorphic variants of the TNF-α (rs1800629) and TNFRSF1α (rs4149584) genes in miners with dust lung pathology.&#x0D; Materials and methods. A survey of one hundred twenty seven miners working for a long time in the mines of the south of Kuzbass was carried out. Of these: &#x0D; 69 miners with prolonged exposure to high concentrations of coal-rock dust with a previously proven diagnosis of dust lung pathology, 58 miners without a proven diagnosis of dust lung pathology working in the same sanitary and hygienic conditions (control). The typing of the TNF-α (rs1800629) and TNFRSF1α (rs4149584) genes was carried out using the Real-Time method.&#x0D; Results. The GG rs1800629 TNF-α genotype were shown to be a potent molecular genetic marker of the risk of developing dust lung pathology, the chance of detecting it in the group of the miners with dust pathology is almost 4 times higher than in the control group. The carriage of the A allele and the heterozygous AG rs1800629 TNF-α genotype reduce the probability of developing dust lung pathology. It has been established that the GG rs4149584 TNFRSF1α genotype can be a molecular and genetic marker of the risk of developing dust lung pathology, the chance of detecting it in the group of the miners with dust pathology is 2.6 times higher than in the control group.&#x0D; Limitations. The study was limited by relatively small size of the groups under study.&#x0D; Conclusion. The carriage of homozygous GG genotypes of the rs1800629 and rs4149584 polymorphic loci of the TNF-α and TNFRSF1α genes, respectively, is associated with the risk of developing dust lung pathology in miners in the South of Kuzbass. The carriage of the A allele and the heterozygous AG rs1800629 TNF-α genotype reduce the probability of developing dust lung pathology.

Laparoscopic prophylactic total gastrectomy with limited lymphadenectomy for CDH1 gene carriers.

CDH1 gene mutations are the leading etiology of hereditary diffuse gastric cancer with cumulative lifetime risk ranging up to 83%. Prophylactic total gastrectomy (PTG) is, therefore, recommended for CDH1 carriers. A laparoscopic approach may reduce operative risk versus an open operation, thus leading more patients with CDH1 mutations to pursue PTG prior to cancer development. However, more experience and oncologic outcome data are needed for a laparoscopic approach and indicated lymphadenectomy. A retrospective descriptive cohort study of adult patients with CDH1 mutations who underwent laparoscopic PTG with D1 lymphadenectomy between 2012 and 2022 was conducted at a single institution. All patients had preoperative EGD screening, and those with visible tumor lesions on surveillance EGD were excluded and not considered prophylactic. Demographics, family history, pathology, and operative course were obtained. Outcomes included complications, readmission, and postoperative weight change. Among 23 patients, median age was 48years (IQR 37, 53) and 15 (65%) were female. Family history for gastric and/or lobular breast cancer was present in 22 (96%) patients. The median [IQR] time from positive genetic testing to PTG was 347days [140, 625]. Pathologic evaluation showed five (22%) patients with foci of gastric cancer on pre-operative EGD biopsies, 10 (44%) in resected stomach specimens. All lymph nodes were negative. To address early postoperative complications, EJ anastomotic technique changed from EEA to GIA over the course of the study and feeding jejunostomy was no longer placed during PTG with minimal change in postoperative weight loss. This is the largest series, spanning 10years at a single institution, dedicated solely to a laparoscopic approach for risk-reducing PTG. A laparoscopic approach with limited lymphadenectomy resulted in acceptable surgical and oncologic outcomes. Despite no visible cancer, over half of our patients had foci of early gastric cancer. Therefore, CDH1 carriers should consider laparoscopic PTG.

New Prognostic Indicators in CLL: Relation to Disease Burden

Abstract Background Identifying prognostic markers is important for the clinical and pathological course of chronic lymphocytic leukemia (CLL). Cluster of differentiation CD49d expression and percentage of smudge cells in CLL patients have recently been reported as newer prognostic factor. Aim of the Study To estimate CD49d expression as an independent prognostic marker in CLL patients and to investigate its relation to the known prognostic factors Methods Thirty adults with CLL were enrolled. Smudge cells percentage was calculated by microscopic evaluation of blood smears. Testing of cluster of differentiation CD49d expression was done by flowcytometry and detection of ataxia telangiectasia mutated (ATM) gene, protein 53(P53) gene deletions and trisomy 12 were performed using fluorescent in situ hybridization (FISH). Results CD49d expression was associated with lymphadenopathy, splenomegaly, advanced staging, high total leucocytic count, immunophenotyping scoring, CD38 positivity, short LDT, low smear cell percentage, and presence of p53 deletion. Low percentage of Smear cell (&amp;lt;30%) showed a significantly higher incidence of lymphadenopathy and organomegaly. Additionally, it was associated with a high total leucocytic count, low platelet count, high atypical lymphocytic count and typical IPT scoring, shorter LDT, positive CD38 expression and CD49d expression and ATM and P53 deletions. Conclusion CD49d expression and low smudge cell percent were consistently associated with poor prognostic indicators, suggesting that they could be considered as adverse predictors and they should be merged together to improve the power of the prognostic panels of CLL in the clinical setting.

Early retinal neurovascular findings in post-transplant diabetes mellitus patients without clinical signs of diabetic retinopathy

BackgroundPost-transplant diabetes mellitus (PTDM) is a specific subtype of diabetes with an uncertain impact on mortality and morbidity in post-transplant patients. Diabetic retinopathy is the most common microvascular complication of diabetes mellitus, but the long-term clinical progression in PTDM is unknown. New technologies are being used to assess pre-clinical signs of retinal changes, such as swept-source optical coherence tomography (OCT) and OCT-angiography. The aim of this study was to detect pre-clinical structural and vascular changes in the retina using swept-source-OCT and OCT-angiography in patients with PTDM.MethodsIn this retrospective cohort study, post-kidney transplant patients were divided into PTDM and non-PTDM (control) groups. Both eyes of eligible PTDM patients and controls were included in this study. Inner retinal layer thickness was measured with swept-source-OCT. Retinal capillary density and the foveal avascular zone were measured with OCT-angiography.ResultsIn the PTDM group, reduced thickness was found in the inferior ganglion cell layer plus inner plexiform layer (95% CI -8.76 to -0.68; p = 0.022) and the temporal inferior segment (95% CI -10.23 to -0.76; p = 0.024) of the inner retina, as well as in the retinal nerve fiber layer in the temporal (95% CI -34.78 to -9.28 p = 0.001) and temporal inferior segments (95% CI -33.26 to -5.03 p = 0.008). No significant differences were found in the vascular capillary plexus between groups at all depths, segments, or foveal avascular zone (p = 0.088).ConclusionsAccording to OCT-angiography, PTDM patients had reduced inner neurosensory retinal layers but no significant change in vascular density, which suggests that early neuroretinal degeneration might occur prior to vascular changes secondary to PTDM. Prospective studies could help elucidate the clinical course of retinal neuropathy and microvascular pathology in PTDM and provide a better understanding of PTDM complications.

Increased Medial Temporal Tau Positron Emission Tomography Uptake in the Absence of Amyloid-β Positivity

An increased tau positron emission tomography (PET) signal in the medial temporal lobe (MTL) has been observed in older individuals in the absence of amyloid-β (Aβ) pathology. Little is known about the longitudinal course of this condition, and its association with Alzheimer disease (AD) remains unclear. To study the pathologic and clinical course of older individuals with PET-evidenced MTL tau deposition (TMTL+) in the absence of Aβ pathology (A-), and the association of this condition with the AD continuum. A multicentric, observational, longitudinal cohort study was conducted using pooled data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain Study (HABS), and the AVID-A05 study, collected between July 2, 2015, and August 23, 2021. Participants in the ADNI, HABS, and AVID-A05 studies (N = 1093) with varying degrees of cognitive performance were deemed eligible if they had available tau PET, Aβ PET, and magnetic resonance imaging scans at baseline. Of these, 128 participants did not meet inclusion criteria based on Aβ PET and tau PET biomarker profiles (A+ TMTL-). Tau and Aβ PET, magnetic resonance imaging, cerebrospinal fluid biomarkers, and cognitive assessments. Cross-sectional and longitudinal measures for tau and Aβ PET, cortical atrophy, cognitive scores, and core AD cerebrospinal fluid biomarkers (Aβ42/40 and tau phosphorylated at threonine 181 p-tau181 available in a subset). Among the 965 individuals included in the study, 503 were women (52.1%) and the mean (SD) age was 73.9 (8.1) years. A total of 51% of A- individuals and 78% of A+ participants had increased tau PET signal in the entorhinal cortex (TMTL+) compared with healthy younger (aged <39 years) controls. Compared with A- TMTL-, A- TMTL+ participants showed statistically significant, albeit moderate, longitudinal (mean [SD], 1.83 [0.84] years) tau PET increases that were largely limited to the temporal lobe, whereas those with A+ TMTL+ showed faster and more cortically widespread tau PET increases. In contrast to participants with A+ TMTL+, those with A- TMTL+ did not show any noticeable Aβ accumulation over follow-up (mean [SD], 2.36 [0.76] years). Complementary cerebrospinal fluid analysis confirmed longitudinal p-tau181 increases in A- TMTL+ in the absence of increased Aβ accumulation. Participants with A- TMTL+ had accelerated MTL atrophy, whereas those with A+ TMTL+ showed accelerated atrophy in widespread temporoparietal brain regions. Increased MTL tau PET uptake in A- individuals was associated with cognitive decline, but at a significantly slower rate compared with A+ TMTL+. In this study, individuals with A- TMTL+ exhibited progressive tau accumulation and neurodegeneration, but these processes were comparably slow, remained largely restricted to the MTL, were associated with only subtle changes in global cognitive performance, and were not accompanied by detectable accumulation of Aβ biomarkers. These data suggest that individuals with A- TMTL+ are not on a pathologic trajectory toward AD.

Exploring the impact of a ‘Clients-as-Tutors Program on speech-language pathology students’ and graduates understanding of client-centred practice

Purpose This study explored the impact of an Australian regional university’s Clients-as-Tutors Program (CTP) on speech-language pathology students’ perception and understanding of client-centred practice. Method Two focus group interviews comprising three final-year students and four newly graduated speech-language pathologists who had completed the CTP. An inductive thematic analysis was undertaken to identify salient themes. Result Three themes were identified: (a) learning from theory, (b) learning from others, and (c) learning from yourself. These themes represented all participants’ experiences in the CTP, yet there were unique, individual journeys that each participant experienced. Conclusion Findings from this study have the capacity to affect change in how client-centred practice is taught at universities across speech-language pathology and other health courses, to disrupt the traditional power structure between client and clinician, and to provide an evidence base for the role of experiential learning in this area.

Identification of hub genes and key signaling pathways by weighted gene co-expression network analysis for human aortic stenosis and insufficiency.

Human aortic valve stenosis (AS) and insufficiency (AI) are common diseases in aging population. Identifying the molecular regulatory networks of AS and AI is expected to offer novel perspectives for AS and AI treatment. Highly correlated modules with the progression of AS and AI were identified by weighted genes co-expression network analysis (WGCNA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed by the clusterProfiler program package. Differentially expressed genes (DEGs) were identified by the DESeqDataSetFromMatrix function of the DESeq2 program package. The protein-protein interaction (PPI) network analyses were implemented using the STRING online tool and visualized with Cytoscape software. The DEGs in AS and AI groups were overlapped with the top 30 genes with highest connectivity to screen out ten hub genes. The ten hub genes were verified by analyzing the data in high throughput RNA-sequencing dataset and real-time PCR assay using AS and AI aortic valve samples. By WGCNA algorithm, 302 highly correlated genes with the degree of AS, degree of AI, and heart failure were identified from highly correlated modules. GO analyses showed that highly correlated genes had close relationship with collagen fibril organization, extracellular matrix organization and extracellular structure organization. KEGG analyses also manifested that protein digestion and absorption, and glutathione metabolism were probably involved in AS and AI pathological courses. Moreover, DEGs were picked out for 302 highly correlated genes in AS and AI groups relative to the normal control group. The PPI network analyses indicated the connectivity among these highly correlated genes. Finally, ten hub genes (CD74, COL1A1, TXNRD1, CCND1, COL5A1, SERPINH1, BCL6, ITGA10, FOS, and JUNB) in AS and AI were found out and verified. Our study may provide the underlying molecular targets for the mechanism research, diagnosis, and treatment of AS and AI in the future.

Cerebroprotective effect of sitagliptin and aminoguanidine combination in disorders of cerebral circulation

The aim of the study was to evaluate a cerebroprotective activity of the sitagliptin and aminoguanidine combination in rats with an acute and chronic cerebral circulation insufficiency, as well as with a traumatic brain injury.Materials and methods. The study was carried out on male Wistar rats in 3 stages using, respectively, a model of a chronic pathology: a chronic cerebral circulation insufficiency (CCCI), as well as 2 models of the acute brain injury (BI): an acute cerebral circulation insufficiency (ACCI), and a traumatic brain injury (TBI). А CCCI was modeled by a bilateral stenosis of the common carotid arteries (by 50%), a model of a hemorrhagic stroke caused by an intracerebral injection of the autologous blood was used as a stroke, a TBI was modeled by a mechanical damage to the brain tissue. To assess the pathology course severity, the following tests were used: Adhesion test, Open field, Morris water maze test, as well as Garcia and Combs&amp;D’Alecy scales. In the animals with an acute damage to the brain at the end of the experiment, the severity of edema of the affected hemisphere was also determined. The treatment was with sitagliptin (10 mg/kg), aminoguanidine (25 mg/kg), or a combination thereof. The obtained data were subjected to the statistical processing.Results. In the course of the study, it was found out that the administration of a sitagliptin and aminoguanidine combination, unlike each of the components, had a cerebroprotective effect in the animals with a chronic or acute damage to the brain, reducing the severity of psychoneurological (cognitive and sensory-motor) disorders, as well as the brain edema.Conclusion. Aminoguanidine, as an iNOS blocker, enhances the action of sitagliptin, preventing the brain edema development and reducing the neurological deficit severity (the severity of cognitive and sensory-motor impairments) in the animals with an acute and chronic cerebral circulation insufficiency.

Seeing Voices: A Dynamic, Interprofessional Approach to Teaching Performing Arts and Speech-Language Pathology Students About Vocal Anatomy and Physiology

Seeing Voices was an interprofessional, technology-enabled, large-scale, teaching and learning event developed to address the need to improve voice students' knowledge of laryngeal anatomy and physiology toward understanding and maintaining vocal health. Seeing Voices trialed a novel interprofessional educational approach, collected both quantitative and qualitative data about student experiences of laryngostroboscopic examination, and built a databank of laryngeal recordings for future student learning. Seeing Voices involved two 3-hour seminars in a large, university lecture space, run by an interprofessional team (speech-language pathologists, vocal coach, Ear Nose and Throat consultant) with quality equipment projecting laryngeal images to large screens with expert commentary in real time. Participants were 18 students who volunteered for laryngeal examination (9 per seminar) and student attendees (n=175) from performing arts courses (classical singing, contemporary, jazz, musical theater, acting) and a speech-language pathology course. A quantitative evaluation of knowledge gained was undertaken using a Qualtrics survey. Results from pre (n=175; performing arts=120; speech-language pathology (SLP)=55) and postevent (n=99; performing arts=56; SLP=43) questionnaires were received from the students who attended. Interviews were collected from 15 of the 18 student volunteers about their experiences of nasendoscopic evaluation and data were analyzed using qualitative description and qualitative content analysis. Quantitative results demonstrated a strong trend toward increased knowledge following attendance at the event across year cohorts for both student groups. Qualitative interviews highlighted the value in seeing multiple examples of normal laryngeal functioning across different vocal techniques in real time. For those undertaking nasendoscopic examination, simultaneously seeing and feeling laryngeal maneuvers used in training appeared to promote understanding of their own vocal mechanism and the purpose of different vocal techniques. Seeing Voices offers a novel way to improve interprofessional collaboration, and engagement with, and understanding of, laryngeal anatomy and vocal health by students in performing arts and speech-language pathology courses.

GSK-3β-dependent Nrf2 antioxidant response modulates ferroptosis of lens epithelial cells in age-related cataract.

Oxidative stress-induced lens epithelial cells (LECs) death plays a pivotal role in age-related cataract (ARC) with severe visual impairment, in which ferroptosis is gradually receiving numerous attention resulting from lipid peroxide accumulation and reactive oxygen species (ROS) overproduction. However, the essential pathogenic factors and the targeted medical strategies still remain skeptical and indistinct. In this work, by transmission electron microscopy (TEM) analysis, the major pathological courses in the LECs of ARC patients have been identified as ferroptosis, which was manifested with remarkable mitochondrial alterations, and similar results were found in aged mice (24-month-old). Furthermore, the primary pathological processes in the NaIO3-induced mice and HLE-B3 cell model have also been verified to be ferroptosis with an irreplaceable function of Nrf2, proved by the increased sensitivity to ferroptosis when Nrf2 was blocked in Nrf2-KO mice and si-Nrf2-treated HLE-B3 cells. Importantly, it has been found that an increased expression of GSK-3β was indicated in low-Nrf2-expressed tissues and cells. Subsequently, the contributions of abnormal GSK-3β expression to NaIO3-induced mice and HLE-B3 cell model were further evaluated, inhibition of GSK-3β utilizing SB216763 significantly alleviated LECs ferroptosis with less iron accumulation and ROS generation, as well as reversed expression alterations of ferroptosis markers, including GPX4, SLC7A11, SLC40A1, FTH1 and TfR1, in vitro and in vivo. Collectively, our findings conclude that targeting GSK-3β/Nrf2 balance might be a promising therapeutic strategy to mitigate LECs ferroptosis and thus probably delay the pathogenesis and development of ARC.

Putting the Brakes on Accelerated Cognitive Decline in Alzheimer's Disease withEpileptic Activity.

Epileptic activity is known to exacerbate Alzheimer's disease (AD) pathology and worsen disease course. However, few studies have assessed whether treating epileptic activity with antiseizure drugs (ASDs) can improve patient outcomes. The current study by Hautecloque-Raysz et al. shows that patients with prodromal AD and epilepsy (epAD) fare well with ASD treatment, achieving seizure control in a large majority of cases using low dosage ASDs in monotherapy. Compared to slowly progressing AD patients without epilepsy, treated epAD patients experienced a similarly slow cognitive decline. These results suggest that ASDs that suppress seizures can improve outcomes in AD patients with epileptic activity.

Сердечные тропонины: современное представление о клиническом и прогностическом значении в многопрофильном стационаре

The increase of patients with elevated cardiac troponins in blood without signs of acute coronary syndrome in recent years, associated, among other reasons with the pandemic of coronavirus infection, has made differential diagnosis difficult for physicians of multidisciplinary hospitals. Aim of the study: to investigate the clinical and prognostic significance of elevated cardiac troponins associated with non-coronarogenic causes, including in the COVID-19 pandemic conditions. Materials and methods: a search of 57 literature sources from eLIBRARY, PubMed, Web of Science, Scopus, Google Scholar, and freely available Yandex and Google databases was performed. The results of the literature review showed that the use of highly sensitive cardiac troponins is relevant for clinical evaluation of the course and differential diagnosis of heart diseases (coronary and non-coronary) and other internal organs pathology, but the accuracy of the troponin test, combined with its nonspecificity, requires a cautious approach to the interpretation of the results. Also isolated elevation of cardiac troponins does not indicate the mechanism of myocardial damage and is not an indication for patients transfer to intensive care units or vascular centers. Routine use of troponin tests makes it difficult to make true diagnosis for patients in a multidisciplinary hospital. Many studies have shown that elevated troponin levels not associated with acute coronary syndrome have a negative prognostic value, but when the coronary event is excluded, elevated troponin levels should not be ignored; it is necessary to look for the cause of such changes. The integration of cardiac troponins in predicting the risk of occurrence, progression, and complications of various diseases is a promising area for further research.

Dysregulation of Histone Deacetylases Inhibits Trophoblast Growth during Early Placental Development Partially through TFEB-Dependent Autophagy-Lysosomal Pathway.

Dysregulated biological behaviors of trophoblast cells can result in recurrent spontaneous abortion (RSA)-whose underlying etiology still remains insufficient. Autophagy, a conserved intracellular physiological process, is precisely monitored throughout whole pregnancy. Although the exact mechanism or role remains elusive, epigenetic modification has emerged as an important process. Herein, we found that a proportion of RSA patients exhibited higher levels of autophagy in villus tissues compared to controls, accompanied with impaired histone deacetylase (HDAC) expression. The purpose of this study is to explore the connection between HDACs and autophagy in the pathological course of RSA. Mechanistically, using human trophoblast cell models, treatment with HDAC inhibitor (HDACI)-trichostatin A (TSA) can induce autophagy by promoting nuclear translocation and transcriptional activity of the central autophagic regulator transcription factor EB (TFEB). Specifically, overactivated autophagy is involved in the TSA-driven growth inhibition of trophoblast, which can be partially reversed by the autophagy inhibitor chloroquine (CQ) or RNA interference of TFEB. In summary, our results reveal that abnormal acetylation and autophagy levels during early gestation may be associated with RSA and suggest the potential novel molecular target TFEB for RSA treatment.

Recombinant ADAMTS-13 Improves Survival of Mice Subjected to Endotoxemia.

When stimulated by proinflammatory mediators, endothelial cells release ultra-large von Willebrand factor (ULVWF) multimers that are hyperactive in activating and aggregating platelets. These ULVWF multimers can accumulate in the circulation and on the inflamed endothelium because they are insufficiently cleaved by the metalloprotease ADAMTS-13, which becomes moderately deficient under conditions of systemic inflammation. This moderate ADAMTS-13 deficiency may lead to thrombotic complications that contribute to ischemic tissue injury and organ failure that are associated with severe infections. To test this hypothesis, we investigated whether recombinant ADAMTS-13 improves the pathological course of endotoxemia in lipopolysaccharide (LPS)-treated mice. C57BL/J6 mice received a bolus infusion of either 5 µg/mouse of ADAMTS-13 or vehicle control 30 min after LPS challenge and were monitored for seven-day survival. During the monitoring period, platelet counts, VWF antigen, and ADAMTS-13 activity were measured. Thrombosis was also examined by the immunohistochemistry in the liver. We found that ADAMTS-13 reduced mortality from 66% to 34.9%. The improved survival was associated with a greater recovery from thrombocytopenia, higher plasma ADAMTS-13 activity, and less thrombotic vascular occlusion. These results suggest that systemic inflammation could result in deficient ULVWF proteolysis by ADAMTS-13 and that ADAMTS-13 improves the outcomes of endotoxemia-induced inflammation.

The relationship between cardiovascular pathology and impaired glucose metabolism with vitamin D deficiency (literature review and own data)

Background. Vitamin D plays a significant role in many processes in the human body, which diversifies the symptoms of its insufficiency, so it is not always possible to diagnose its deficiency in a timely manner. At the same time, according to a number of clinical studies, an inverse relationship has been proven between a reduced level of vitamin D and mortality from all causes and cardiovascular diseases, the course of diabetes mellitus (DM), hypertension, chronic kidney disease, atherosclerosis, coronary heart disease; and the mechanisms of the influence of vitamin D deficiency on various metabolic processes have been revealed. The development and progression of cardiovascular diseases and vascular complications of DM are currently the main causes of disability and mortality of patients. All this substantiates the need to control and monitor the vitamin D supply in patients with this comorbid pathology. Aim of the study is to investigate the presence and severity of vitamin D deficiency in patients with type 2 DM and the presence of concomitant cardiac pathology. Materials and methods. Main group included 31 patients (17 men and 14 women aged 51.51 ± 1.73 years, with duration of DM of 8.59 ± 1.70 years) who were treated in the endocrinology clinic from October 2022 to May 2023. The comparison group consisted of 27 patients with type 2 DM who stayed in this clinic in 2020–2021. Serum level of 25-hydroxycholecalciferol (25(OH)D) was studied using the enzyme-linked immunosorbent assay. The level of vitamin D less than 20–30 ng/ml was considered as its insufficiency, and the level below 20 ng/ml as deficiency. Statistical processing was carried out using Microsoft Excel and Statistica 6.0. Results. In the main group, cardiac pathology manifested itself by the presence of hypertension detected in all patients (stage I — 6 cases; stage II — 21 and stage IІI — 4); coronary heart disease and cardiosclerosis — in 7 patients; heart failure of the first or second degree — in all individuals. All patients in the main group were vitamin D deficient or insufficient: 15 had a deficiency (12.96 ± 1.06 ng/ml), and 16 had an insufficiency (23.68 ± 0.72 ng/ml). In contrast to the comparison group, patients from the main group had a significantly lower average level of vitamin D (18.49 ± 1.16 ng/ml vs 28.98 ± 1.02 ng/ml, p &lt; 0.001). Taking into account a decrease in the level of vitamin D supply of patients, including those with comorbid pathology examined in 2022–2023, which is obviously associated with a long stay in shelters and a stressful situation caused by the state of war, and its impact on the course of cardiovascular diseases and diabetes, it is necessary to pay more attention to the detection and timely appropriate correction of vitamin D deficiency. Conclusions. In patients with type 2 diabetes and comorbid cardiovascular pathology, there is a decrease in the level of vitamin D supply. During the war in Ukraine, there is a probable deepening of vitamin D deficiency. The negative impact of vitamin D deficiency on the course of diabetes and cardiovascular pathology justifies the need to monitor vitamin D supply in such patients.