(1) Background: Angiotensin II, a major culprit in cardiovascular disease, activates mediators that are also involved in pathological cardiac remodelling. We aimed at investigating the effects of two of them: aldosterone (Ald) and transforming growth factor-beta-1 (TGF-β1 ), on cardiac remodelling in an in vivo model. (2) Methods: Six-week-old male wild-type (WT) and TGF-β1 -overexpressing transgenic (TGF-β1 -TG) mice were infused with subhypertensive doses of Ald for 2 weeks, and/or treated orally with eplerenone from postnatal day 21. Heart’s ventricles were examined: by morphometry, immunoblotting to assess intracellular signalling pathways, RT qPCR to determine hypertrophy and fibrosis marker genes. (3) Results: TGF-β1 -TG mice spontaneously developed cardiac hypertrophy and interstitial fibrosis, exhibited higher baseline phosphorylation of p44/42 and p38 kinases, fibronectin and ANP mRNA expression. Ald induced a comparable increase in ventricular heart weight-to-body-weight ratio and cardiomyocyte diameter in both strains, but less pronounced increase in interstitial fibrosis in transgenic compared to WT mice (23.6% vs 80.9%, p<0.005). Ald increased phosphorylation of p44/42 and p38 in WT but not TGF-β1 -TG mice. While eplerenone-enriched chow partially prevented Ald-induced cardiac hypertrophy in both genotypes and interstitial fibrosis in WT controls, it completely protected from additional fibrosis in transgenic mice. (4) Conclusions: Ald appears to induce cardiac hypertrophy independently of TGF-β1 , while in case of fibrosis downstream signalling pathways of these two factors probably converge

Mitochondrial dysfunction plays a pivotal role in numerous complex diseases. Understanding the molecular mechanisms by which the “powerhouse of the cell” turns into the “factory of death” is an exciting yet challenging task that can unveil new therapeutic targets. The mitochondrial matrix protein CyPD is a peptidylprolyl cis-trans isomerase involved in the regulation of the permeability transition pore (mPTP). The mPTP is a multi-conductance channel in the inner mitochondrial membrane whose dysregulated opening can ultimately lead to cell death and whose involvement in pathology has been extensively documented over the past few decades. Moreover, several mPTP-independent CyPD interactions have been identified, indicating that CyPD could be involved in the fine regulation of several biochemical pathways. To further enrich the picture, CyPD undergoes several post-translational modifications that regulate both its activity and interaction to its clients. Here, we will dissect what is currently known about CyPD and critically review the most recent literature about its involvement in neurodegenerative disorders, focusing on Alzheimer’s Disease and Parkinson’s Disease, supporting the notion that CyPD could serve as a promising therapeutic target for the treatment of such conditions. Notably, significant efforts have been made to develop CyPD-specific inhibitors, which hold promise for the treatment of such complex disorders.

Insulin receptors are internalized by endothelial cells; however, the impact of hyperinsulinemia on this process is not known. Thus, the aim of this study is to determine the role of hyperinsulinemia on insulin receptor function and internalization, as well as the potential impact of protein tyrosine phosphatase 1B (PTP1B). To this end, hippocampal microvessels were isolated from male C57Bl/6J mice on either a control or high-fat diet and assessed for insulin receptor signaling. Cell surface insulin receptors in brain microvascular endothelial cells were labelled with biotin to assess the role hyperinsulinemia plays on receptor internalization in response to stimulation, with and without Claramine treatment, a potent PTP1B antagonist. Our results indicated that insulin receptor levels increased in tandem with insulin receptor dysfunction in the high-fat diet mouse hippocampal microvessels. Hyperinsulinemic cell-receptors demonstrate a shift in splice variation towards decreased IR-A/IR-B ratios and demonstrate a higher membrane-localized proportion. This corresponded with decreased autophosphorylation at sites critical for receptor internalization and signaling, however, Claramine restored signaling and receptor internalization in hyperinsulinemic cells. In conclusion, hyperinsulinemia negatively impacts brain microvascular endothelial cell insulin receptor function and internalization, likely through both alternative splicing and increased negative feedback from PTP1B.

In atherosclerosis patients, vascular endothelial dysfunction is commonly observed with damage of vascular endothelial glycocalyx, an extracellular matrix-bound to and encapsulating the endothelial cell lining the blood vessel wall. Unfavorable lifestyle; smoking and physical inactivity, also induces glycocalyx degradation. Moreover, the vascular endothelial glycocalyx is damaged by various unfavorable disease conditions like as dehydration, acute infectious disease, trauma, sepsis, ARDS, Kawasaki disease, preeclampsia, gestational diabetes mellitus, hypertension, diabetes, chronic kidney disease, atherosclerosis, stroke, dementia, microvascular angina, acute coronary syndrome, and heart failure. The vascular endothelial glycocalyx has been shown to be important not only as a physical cytoprotective barrier for vascular endothelial cells but also as a mechanism that regulates intracellular cell signaling. Therefore, vascular endothelial glycocalyx has great potential to explore new strategies for assessing the benefit conditions of our healthy vasculature.

Lower urinary tract dysfunction is clinically important because it may cause urinary tract infections, mainly due to accumulation of residual urine, and adversely affect renal function. In addition, it may cause urinary incontinence, strongly affecting the child’s quality of life. The function of the lower urinary tract is closely associated with function of the bowel because constipation is commonly present with bladder dysfunction. The interplay between the lower urinary tract and bowel function, coupled with common conditions such as detrusor overactivity and voiding dysfunction, requires a nuanced diagnostic approach. Detrusor overactivity, a benign but socially harmful condition, is the principal cause of daytime urinary incontinence in childhood. It needs to be differentiated from more serious conditions such as neurogenic bladder dysfunction or urethral obstruction. Voiding dysfunction, a habitual sphincter contraction during voiding, is common in children with detrusor overactivity, may be selflimiting but may also result in residual urine and urinary tract infections. It may resemble, in severe cases, the neurogenic bladder dysfunction, most often caused by spinal dysraphism which very often leads to recurrent urinary tract infections and high intravesical pressures, jeopardizing renal function. Voiding diary is crucial in the initial evaluation of lower urinary tract function in children.

Dysfunction and selective loss of retinal ganglion cells (RGCs) is a known cause of vision loss in glaucoma and other neuropathies where ocular hypertension (OHT) is the major risk factor. We investigated the impact of transient non-ischemic OHT spikes (spOHT) on RGC function and viability in vivo to identify cellular pathways linking low-grade repetitive mechanical stress to RGC pathology. We found that repetitive spOHT had an unexpectedly high impact on intraocular homeostasis and RGC viability, while exposure to steady OHT (stOHT) of similar intensity and duration failed to induce pathology. The repetitive spOHT induced a rapid activation of the inflammasome, marked by the upregulation of NLRP1, NLRP3, AIM2, caspases -1, -3/7, -8, gasdermin D (GsdmD) and the release of interleukin-1β (IL-1β) and other cytokines into the vitreous. Similar effects were also detected after 5 weeks of exposure to chronic OHT in an induced glaucoma model. The onset of these immune responses in both spOHT and glaucoma models preceded a 50% deficit in pattern electroretinograms (PERG) amplitude, and significant loss of RGCs at 7 days post-injury. Inactivation of inflammasome complexes in NLRP1-/- , Casp1-/- and GsdmD-/- knockout animals, significantly suppressed the spOHT induced inflammatory response and protected RGCs. Our results demonstrate that mechanical stress produced by acute repetitive spOHT or chronic OHT is mechanistically linked to inflammasome activation, which leads to RGC dysfunction and death.

Elevation of the intermediate amino acid metabolite Homocysteine (Hcy) causes Hyperhomocysteinemia (HHcy), a metabolic disorder frequently associated with mutations in the methionine-cysteine metabolic cycle as well as with nutritional deficiency and aging. Previous literature suggest that HHcy is a strong risk factor for cardiovascular diseases. Severe HHcy is well established to correlate with vascular pathologies primarily via endothelial cell death. Though moderate HHcy is more prevalent and associated with an increased risk of cardiovascular abnormalities in later part of life, its precise role in endothelial physiology is largely unknown. In this study, we report that moderate elevation of Hcy causes endothelial dysfunction through impairment of their migration and proliferation. We established that unlike severe elevation of Hcy, moderate HHcy is not associated with suppressed endothelial VEGF/VEGFR signaling and oxidative stress induction. We further showed that moderate HHcy induces a sub-lethal ER stress that causes defective endothelial migration through abnormal actin cytoskeletal remodeling. We also found that sub-lethal increase of Hcy causes endothelial proliferation defect by suppressing mitochondrial respiration and concomitantly increases glycolysis to compensate the consequential ATP loss and maintain overall energy homeostasis. Finally, analyzing an available microarray dataset, we confirmed that these hallmarks of moderate HHcy are conserved in adult endothelial cells as well. Thus, we identified adaptive UPR and metabolic rewiring as two key mechanistic signatures in moderate HHcy-associated endothelial dysfunction. As HHcy is clinically associated with enhanced vascular inflammation and hypercoagulability, identifying these mechanistic pathways may serve as future targets to regulate endothelial function and health.

Cerebral ischemia, which is a leading cause of disability and mortality worldwide, sets off a chain of molecular and cellular pathologies that are associated with some central nervous system (CNS) disorders, mainly including ischemic stroke, Alzheimer's disease (AD), Parkinson's disease (PD), epilepsy and other CNS diseases. In recent times, despite significant advancements in the treatment of the pathological processes underlying various neurological illnesses, effective therapeutic approaches specifically targeted at minimizing the damage of such diseases remain absent. Remarkably, ischemia causes severe damage to cells in Ischemia-associated CNS Diseases. Cerebral ischemia initiates oxygen and glucose deprivation, which subsequently promotes mitochondrial dysfunction, including MPTP opening, mitophagy dysfunction, and excessive mitochondrial fission, triggering various forms of cell death, such as autophagy, apoptosis, as well as ferroptosis. Ferroptosis, a novel type of regulated cell death (RCD), is characterized by iron-dependent accumulation of lethal reactive oxygen species and lipid peroxidation. Mitochondrial dysfunction and ferroptosis both play critical roles in the pathogenic progression of Ischemia-associated CNS Diseases. In recent years, growing evidence has indicated that mitochondrial dysfunction interplays with ferroptosis to aggravate cerebral ischemia injury. However, the potential connections between mitochondrial dysfunction and ferroptosis in Cerebral Ischemia have not yet been clarified. Thus, we analyze the underlying mechanism between mitochondrial dysfunction and ferroptosis in Ischemia-associated CNS Diseases. We also discovered that GSH depletion and GPX4 inactivation cause lipoxygenase activation and calcium influx following cerebral ischemia injury, resulting in MPTP opening and mitochondrial dysfunction. Additionally, dysfunction in mitochondrial electron transport and an imbalanced fusion-to-fission ratio can lead to the accumulation of reactive oxygen species and iron overload, which further contribute to the occurrence of ferroptosis. This creates a vicious cycle that continuously worsens cerebral ischemia injury. In this study, our focus is on exploring the interplay between mitochondrial dysfunction and ferroptosis, which may offer new insights into potential therapeutic approaches for the treatment of Ischemia-associated CNS Diseases.

We aimed to investigate the mechanism underlying social stress (SS)-induced erectile dysfunction (ED) and evaluate the effects of a single sub-anesthetic dose of ketamine on SS-related ED. Male FVB mice were exposed to retired male C57BL/6 mice for 60 minutes daily over a 4-week period. In the third week, SS mice received intraperitoneal injections of either saline (SSS group) or ketamine (SSK group). Erectile function was assessed by measuring intra-cavernosal pressure (ICP) during electrical stimulation at the major pelvic ganglia. Corpus cavernosum (CC) strips were utilized for wire myography to assess their reactivity. Both SSS and SSK mice exhibited significantly lower ICP in response to electrical stimulation than control. SS mice showed increased contractility of CC induced by phenylephrine. Acetylcholine-induced relaxation was significantly reduced in SSS and SSK mice. Sodium nitroprusside-induced relaxation was higher in SSS mice compared to control and SSK mice. Nicotine-induced neurogenic and nitric oxide (NO)-dependent relaxation was significantly impaired in both SSS and SSK mice. Immunohistochemically analysis revealed co-localization of tyrosine hydroxylase and neuronal nitric oxide synthase (nNOS)-immunoreactive fibers in the CC. These findings highlight the complex nature of SS-related ED and suggest the limited efficacy of ketamine as a therapeutic intervention in this condition.

The Golgi apparatus (GA) dysfunctions in Parkinson’s Disease (PD), neurodevelopmental disorders (NDDs), cancer, and organelle structural biology (OSB) can provide insights into therapeutic targets, gene therapy, and drug design. Primary defects and fragmentation within the GA are implicated in a wide range of neurodegenerative diseases. GA defects typically result in mislocation of proteins, accumulation of undegraded proteins, and impaired glycosylation of proteins. Inhibition of vesicular trafficking by α-synuclein (aSyn) may affect the dopamine-producing neurons and neuromodulators. GA regulates apoptosis during pathological mechanisms of neurological diseases and could provide new avenues in treatments through translation research. PD patients bearing the hereditary E46K disease mutation manifest the clinical picture of parkinsonism. How do we provide high resolution nanoimages of the GA during disease to capture dysfunction? Could we visualize the aSyn traffic jam between vesicles in the organelles ER and GA? OSB is emerging as a field as more technology advances and is more accessible. Structural studies of the GA will advance the field of neurological disease forward with an in depth understanding of dysfunction, fragmentation, and defects. Discoveries of the GA in PD, NDDs, and cancer would break new ground and provide translational medicine data of these diseases. Future research could be visualizing high angle annular dark field-STEM (HAADF-STEM) tomograms, cryogenic electron tomography (cryo-ET), multiplex correlative light and electron microscopy (cryo-CLEM), nanobody-assisted tissue immunostaining for volumetric EM (NATIVE) and using soft X-ray tomography (SXT) and computational reconstruction of the GA.

COPD is a chronic inflammatory disease characterized by progressive airflow obstruction. Tobacco smoking is the main cause of COPD (COPD-TS), but chronic exposure to biomass smoke (COPD-BS), mainly wood smoke, is the second risk factor; both are considered to cause different phenotypes of COPD. COPD-BS is more eosinophilic than COPD-TS. The objective of the present study was to evaluate the serum level of interleukins involved in eosinophil maturation, recruitment, and survival, and their association with small airway obstruction, measuring cytokines by multiplex test (Bio-Plex) and evaluating the central airway resistance with impulse oscillometry (IOS), comparatively in patients with COPD due to biomass and smoking. The results showed that IL-1ra, IL-2, IL-4, IL-8, IL-9, IL-13, IL-17, and eotaxin were increased in COPD-BS related to COPD-TS. Resistance parameters showed that R5, X5, AX (area reactance), and R5-R20 were significantly higher in COPD-BS than in the COPD-TS group (p < 0.05). R20 was not different between the groups. These data suggest that the cytokines involved in the effect of eosinophils on airway inflammation in COPD-BS were increased compared with COPD-TS, which appears to be related to a predominance of peripheral airway obstruction in patients with COPD-BS more than in COPD-TS

Aim: In individuals with COVID-19, the study assessed the relationship between cytokine expression and pulmonary dysfunction. These correlations may help to suggest strategies for prevention and therapies of coronavirus disease outbreak. Patients and methods: 50 healthy participants and 100 COVID-19 patients participated in this study. COVID-19 participants were subdivided into moderate and severe groups based on the severity of their symptoms. In both patients and controls, measurements of white blood cells (WBCs), lymphocytes, C-reactive protein (CRP), interleukin (IL)-1, IL-4, IL-6, IL-18, and IL-35 were estimated. All the patients performed chest CT and CO-RADS score was assessed. Results: All patients had increased WBCs count and CRP, IL-1, IL-4, IL-6, IL-18, and IL-35 levels than healthy controls. While WBCs, CRP, and cytokines like IL-1β and IL-6 showed significantly higher levels in the severe group as compared to moderate patients, IL-4, IL-35, and IL-18 showed comparable levels in both disease groups. Furthermore, CO-RADS score was positively connected with WBCs, CRP, and cytokine levels (IL-35, IL-18, IL-6, IL-4 and IL-1β) in both groups, and lymphocyte levels in all patient groups considerably decreased as compared to the controls. CO-RADS score, also demonstrated a positive correlation with lymphocytes in the moderate COVID-19 patients, whereas in the severe patients, it demonstrated a negative correlation with lymphocytes. Conclusion: Severe COVID-19 patients, compared to individuals with moderate illness and healthy controls, patients had lower lymphocyte counts and increased CRP with greater WBCs counts. In contrast to moderate COVID-19 patients, severe COVID-19 patients had higher levels of IL-1β and IL-6, but IL-4, IL-18, and IL-35 between both illness categories at close levels. CO-RADS 5 was the most frequent category in both moderate and severe cases. Patients with a typical CO-RADS involvement had a higher CRP and white blood cell count with a lower lymphocyte count than the others. Cytokine levels were considered a surrogate markers of severe lung affection in COVID 19 patients.

Background. The treatment of coronary stenosis relies on invasive high risk surgical assessment to generate the fractional flow reserve diagnostics index, a ratio of distal to proximal pressures in respect of coronary atherosclerotic plaque causing stenosis. Non-invasive methods are therefore a need of the times. This study proposes an extensible mathematical description of the coronary vasculature that permits rapid estimation of the coronary fractional flow reserve. Methods. By adapting an existing closed loop model of human coronary blood flow, the effects of large vessel stenosis and microvascular disease on fractional flow reserve were quantified. Several simula-tions generated flow and pressure information which was used to compute fractional flow re-serve under a spectrum of conditions including focal stenosis, diffuse stenosis, and microvascular disease. Sensitivity analysis stratified the influence of model parameters on the index. The model was simulated as coupled non-linear ordinary differential equations and numerically solved us-ing an implicit higher order method. Results. Large vessel stenosis affected fractional flow re-serve. The model predicts that the presence, rather than severity, of microvascular disease affect coronary flow deleteriously. Sensitivity analysis revealed that heart rate may not affect the index. Conclusions. The model provides a computationally inexpensive instrument for future in silico coronary blood flow investigations as well as clinical-imaging decision making. A combination of focal and diffuse stenosis appears to be essential in reducing the index. In addition to pressure measurements in the large epicardial vessels, diagnosis of microvascular disease is essential. The independence of the index with respect to heart rate suggests that computationally inexpensive steady state simulations may provide sufficient information to reliably compute the index.

The pleiotropic biochemical and antioxidant functions of Vitamin C (Vit C) have recently sparked interest in its application in intensive care. Vit C protects important organ systems such as the cardiovascular, neurologic and renal system during inflammation and oxidative stress. Vit C also influences the systems of coagulation and inflammation and its application might prevent the development of organ damage. The current evidence of Vit C’s effect on the pathophysiological reactions during various acute stress events, such as sepsis, shock, trauma, burn and ischemia-reperfusion injury imposes the question, if the application of Vit C might be especially beneficial for cardiac surgery patients, who are routinely exposed to ischemia/reperfusion and subsequent inflammation, systematically affecting different organ systems. This review covers current knowledge about the role of Vit C in cardiac surgery patients with focus on its influence on organ dysfunctions. The relationships between Vit C and clinical health outcomes are reviewed with special emphasis on its application in cardiac surgery. Additionally, this review pragmatically discusses evidence regarding the administration of Vitamin C in every day clinical practice, tackling the issues of safety, monitoring, dosage and most the appropriate application strategy.

Relationship between the results of penile duplex doppler ultrasound (PDDU) and response to vardenafil was investigated in patients diagnosed with erectile dysfunction (ED). Data of 148 patients with ED were analysed retrospectively. Patients who did not respond to therapy were classified as Group I (n = 32), those responded partially were classified as Group II (n = 40) and complete responders were classified as Group III (n = 76). Age, comorbid diseases, vascular and penile pathology were compared among the three groups. While diabetes mellitus (DM) and dyslipedimia positivity adversely affect the response to treatment, the presence of hypertension (HT), peyronie's disease and priapism increase the therapeutic response to the treatment (p < 0.05). Arterial insufficiency was present in 20(30.3%), 25(37,9%) and 21(31.8%) of the patients in Group I, Group II and Group III, respectively (p = 0.001). Venous insufficiency was observed in 3(14.3%) patients in Group I and in 8(85.7%) patients in Group III (p = 0.001). Arterial/venous insufficiency was seen in 9(30%), 14(46.7%) and 7(23.3%) of the patients in Group I, Group II and Group III, respectively (p = 0.001). Response rate to treatment was highest in normal patients according to PDDU, followed by patients with venous insuffiency. Besides, it was found that DM decreased the response to treatment, whereas response was increased in cases with HT, priapism and Peyronie’s disease.

Background and Objectives: Similar to diabetes, the presence of left ventricular (LV) diastolic function (DD) has been reported in various studies which were conducted with people with a diagnosis of impaired fasting blood glucose (FBG). The study aimed to examine the effects of fasting blood glucose (FBG) levels on left atrial strain (LAS) estimated by two-dimensional echocardiography speckle tracking analyses in patients without known diabetes. Material and Methods: The study included 148 participants (74 female and 74 male) without a history of diabetes mellitus or chronic disease. The patients were divided into two groups as follows: individuals with FBG <100 mg/dl and those with FBG between 100-125 mg/dl after at least 8 hours of overnight fasting and according to these FBG levels STE measures were compared. Results: There was a significant decrease in the LA reservoir (52.3±15 vs. 44.5±10.7; p=0.001) and conduit strain (36.9±11.7 vs. 28.4±9.7; p=0.001) in the impaired FBG group. When the STE findings of both ventricles were compared, no significant difference was observed between the groups in right and LV strain imaging. Conclusion: In the earliest stage of LVDD, changes in atrial functional parameters become particularly evident. Echocardiographic analyses of these parameters can help to diagnose and determine the degree of LVDD while the morphological parameters are still normal. The addition of LAS imaging to the routine TTE study in patients with impaired FBG but without a DM diagnosis may be helpful in demonstrating subclinical LVDD or identifying patients at risk for LVDD in this patient group.

Due to the complex and variable anatomy of the left atrial appendage, percutaneous left atrial appendage closure (LAAC) can be challenging. In this study, we investigated the impact of fusion imaging (FI) on the LAAC learning curve of 2 interventionalists. The first interventionalist (IC 1) was initially trained without FI and continued his training with FI. The second interventionalist (IC 2) performed all procedures with FI. We compared the first 36 procedures without FI of IC 1 (group 1) with his next 36 interventions with FI (group 2). Furthermore, group 1 was compared to 36 procedures of IC 2 who directly started his training with FI (group 3). Group 1 demonstrated that the learning curve without FI has a flat course with weak correlations for fluoroscopy time, contrast volume, and procedure time, but not for dose area product. Group 2 with FI showed improvement with a steep course and strong correlations for all 4 parameters. In group 3 we also saw a steep progression with strong correlations. Furthermore, the mean measurements of the procedural parameters in the groups with FI decreased significantly as indicator for procedural efficacy. We demonstrated that FI may improve the learning curve of experienced and non-experienced ICs.

Humans can recombine thousands of different facial expressions. This variability is due to the ability to voluntarily or involuntarily modulate emotional expressions, which, in turn, depends on the existence of two anatomically separate pathways. The Voluntary (VP) and Involuntary (IP) pathways mediate the production of posed and spontaneous facial expressions, respectively, and might also affect the left and right sides of the face differently. This is a neglected aspect in the emotion literature, where posed expressions instead of genuine expressions are often used as stimuli. Two experiments with different induction methods were specifically designed to inves-tigate the unfolding of spontaneous and posed facial expressions of happiness along the facial vertical axis (left, right) with a high-definition 3D optoelectronic system. The results showed that spontaneous expressions were distinguished from posed facial movements as revealed by relia-ble spatial and speed key kinematic patterns in both experiments. Moreover, VP activation pro-duced a lateralization effect: compared with the felt smile, the posed smile involved an initial acceleration of the left corner of the mouth, while an early deceleration of the right corner oc-curred in the second phase of the movement, after the velocity peak.

With reference to our 4G model of final unification, strong coupling constant and strong interaction charge of magnitude $e_s\cong 2.95e$, it is possible to understand the nuclear stability range with a simple power law of the form, $A_s\cong \left(Z+2.95\right)^{1.2\pm0.015}$

Introduction In sacubitril-valsartan (sacub/v), the effects of an angiotensin II receptor blocker (ARB) exerted by valsartan are strengthened by the addition of sacubitril, an inhibitor of neutral endopeptidases. PARADIGM - HF study proved this association to be superior to enalapril in reducing both all-cause death and cardiovascular mortality, as well as heart failure (HF) hospitalizations in patients with cardiac insufficiency and reduced left ventricular ejection fraction( HFREF) belonging to NYHA class II-IV. To test whether even in our experience sacub/v is associated with favorable outcomes concerning mortality and morbidity, an outpatient small population of HFREF patients was retrospectively studied, of whom one third was treated with sacub/v instead of conventional therapy with ACE -inhibitors or ARBs. Methods A retrospective cohort study was carried out to assess the effects of sacub/v in addition to beta-blocker and mineral receptor antagonist (MRA) in a group of HFREF patients in NYHA classes II-III compared with conventional therapy (comprising ACE inhibitor or ARB added to beta-blocker plus a MRA) administered in a second group of HFREF patients with comparable clinical features retrospectively enrolled as controls. In the two groups, the therapeutic regimen was established in accordance with the preferences of the treating physician. Additionally, in both groups, evidence-based drug therapy was supplemented by the adjunct of a loop diuretic, usually furosemide, at variable doses. The primary outcomes of interest were all-cause death and HF hospitalizations. Safety outcomes were symptomatic hypotension, angioedema, hyperkalemia and worsening renal function. Results Mortality at six months was 6.8% in patients under therapy with sacub/v versus 34% in those treated with conventional therapy (odds ratio[OR] = 0.14; 95% CI: 0.04-0.49). Moreover, HF hospitalizations in the observation period considered were 4.5% in sacub/v group versus 59% in the conventional therapy group (OR = 0.03; 95% CI: 0.01–0.14). Safety outcomes included in our study (angioedema, hyperkalemia, hypotension and worsening renal function) showed a comparable profile in the two groups, with evidence of good tolerability of sacub/v , except for the side - effect " hypotension" (PAS < 100 mm Hg) , found in 15.9% of patients under sacub/v versus 5.7% reported in controls (OR = 3.14; 95% CI: 0.94–10.55). Conclusions In our experience, sacub/v has yielded a strong protection against both all-cause death and HF hospitalizations at six months , in the absence of significant noxious side effects. Nevertheless, considering the retrospective character of the study and the relatively exiguous sample size, further post marketing observational studies would be desirable . In particular, studies aiming at exploring safety of the new pharmacologic principle, namely mainly focusing on hypotension and angioedema, are warranted, in order to validate further this very efficacious molecule for therapy of chronic HF, especially stable HFREF in NYHA classes II-III.

Especially in the last two decades, due to the developments in durable mechanical circulatory support (MCS) technology and applications, left ventricular assist (LVAD) implantation has become used in more fragile end-stage heart failure patients with higher risk. Despite advances in technology and patient care processes, right heart failure remains the leading cause of morbidity and mortality after durable LVAD implantation. It is difficult to make decisions about the type and duration of MCS during preoperative evaluation, and many clinical, hemodynamic, biochemical and echocardiographic criteria must be taken into account when evaluating the right ventricle. Complex quantitative scoring systems, including measurements of different risk factors for postimplant right ventricular failure, and composite variables, including the anatomical and functional status of the right ventricle, have been used to decide between left or biventricular assist device implantation. The successful use of artificial intelligence (AI) and machine learning (ML) in various applications in the medical field has paved the way for the idea of using it to better predict possible conditions such as right heart failure after LVAD implantation. This review aims to evaluate the current situation of risk prediction models using AI and ML technology, which have become popular in recent years, and possible future developments in predicting right heart failure after the application of durable MCS systems.

The impact of controlled breathing on cognitive and affective processing has been recognized since ancient times, giving rise to multiple practices aimed at achieving different psychophysical states, mostly related to mental clarity and focus, stress reduction and relaxation. Previous scientific research explored the effects of unilateral nostril breathing (UNB) over brain activity, emotional and cognitive functions. Most evidence concluded for a contralateral effect, but many other controversial results make it difficult to come to an unambiguous interpretation. In the present study, we invited a pilot sample of 20 participants to take part in an 8-days breathing training, assigned either to the right nostril (URNB) or the left nostril breathing condition (ULNB). Then, each day, we assessed participants’ well-being indices with mood and mind-wandering scales. Results revealed that, after the daily practice, both groups reported improved well-being perception. However, the effect was specifically related to the nostril involved. URNB produced more benefits in terms of stress reduction and relaxation, while ULNB significantly reduced mind-wandering occurrences, increasingly over time. Our results are only partially in agreement with previous evidence, indicating the need for a more complex interpretive model that considers multiple brain networks and integrates central and peripheral nervous systems.

Neurodegeneration with brain iron accumulation (NBIA) is a group of rare neurogenetic dis-orders frequently associated with iron accumulation in the basal nuclei of the brain. Among NBIA subtypes, β -propeller protein-associated neurodegeneration (BPAN) is associated with mutations in the autophagy gene WDR45. The aim of this study was to demonstrate autophagic defects and secondary pathological con-sequences in cellular models derived from two patient harboring WDR45 mutations. Both protein and mRNA expression levels of WDR45 were decreased in patient-derived fibro-blasts. In addition, the increase of LC3B upon treatments with autophagy inducers or inhibitors was lower in mutant cells compared to control cells, suggesting decreased autophagosome formation and impaired autophagic flux. Transmission electron microscopy (TEM) analysis showed mitochondrial vacuolization associated with accumulation of lipofuscin-like aggregates containing undegraded material. Autophagy dysregulation was also associated with iron ac-cumulation and lipid peroxidation. In addition, mutant fibroblasts showed altered mitochon-drial bioenergetics. Antioxidants such as pantothenate, vitamin E and α-lipoic prevented lipid peroxidation and iron accumulation. However, antioxidants were not able to correct the ex-pression levels of WDR45 neither the autophagy defect nor cell bioenergetics. Our study demonstrated that WDR45 mutations in BPAN cellular models impaired autophagy, iron metabolism and cell bioenergetics. Antioxidant partially improved cell physiopathology, however autophagy and cell bioenergetics remained affected.

Prevention of obstetric trauma from damage to the pelvic floor is not always possible and sacral nerve stimulation (SNS) may be necessary later in life. Sacral nerve stimulation has been a promising innovation in the management of moderate to severe faecal incontinence and following sphincter repair failure. Although the indication spectrum for SNS is expanding, the success of neuromodulation for constipation is limited. Adverse events of SNS requiring re-intervention are not common but a long-term successful outcome may depend on interventions for maintenance of the device.

Oxidative phosphorylation (OxPhos) is the basic function of mitochondria although the land-scape of mitochondrial functions is continuously growing to include more aspects of cellular homeostasis. Thanks to the application of -omics technologies to the study of the OxPhos system, novel features emerge from the cataloging of novel proteins as mitochondrial thus adding de-tails to the mitochondrial proteome and defining novel metabolic cellular interrelations, espe-cially in the human brain. We focussed on the diversity of bioenergetics demand and different aspects of mitochondrial structure, functions, and dysfunction in the brain. Definition as ‘mitoexome’, ‘mitoproteome’ and ‘mitointeractome’ have entered the field of ‘mitochondrial medicine’. In this context, we reviewed several genetic defects that hamper the last step of aerobic metabolism mostly involving the nervous tissue as one of the most prominent energy-dependent tissues and, as consequence, as a primary target of mitochondrial dysfunction. The dual genetic determination of the OxPhos complexes is one of the reasons for the complexity of the geno-type-phenotype correlation when facing human diseases associated with mitochondria defects; clinically, are characterized by extremely heterogeneous symptoms, ranging from organ-specific to multisystemic dysfunction with different clinical courses. Finally, we briefly discuss the fu-ture directions of the multi-omics study of human brain disorders.

Fasudil, a potent Rho kinase (ROCK) inhibitor, can ameliorate LPS-induced acute lung injury (ALI) in mice, but the mechanism remains obscure. In this study, a mice model of ALI was established by intra-tracheal instillation of LPS. Histological changes, cytokine levels, lung permeability, and endothelial apoptosis were determined to evaluate the effects of fasudil on lung injury. The cellular and molecular biological mechanisms were explored by culturing human pulmonary microvascular endothelial cells (PMECs). The results showed that fasudil reduced LPS-induced lung inflammation, pulmonary hyperpermeability, and endothelial apoptosis in mice. In cultured human PMECs, fasudil inhibited LPS-induced caspse-3 cleavage and cell apoptosis. It also decreased LPS-induced hyperpermeability of human PMECs monolayer by reversing the down-regulation of intercellular junctions. Moreover, fasudil inhibited LPS-induced overexpression of chemokines and intercellular adhesion molecule (ICAM)-1 in human PMECs, which in turn suppressed neutrophil chemotaxis and neutrophil-endothelial adhesion. Further molecular researches showed fasudil inhibited LPS-induced activation of ROCK, NF-κB, and p38 in human PMECs. Our findings demonstrated that fasudil alleviated LPS-induced ALI by protecting endothelial function via inhibiting endothelial apoptosis, maintaining endothelial barrier integrity, and reducing endothelial inflammation. These effects of fasudil could be attributed to the inhibition of ROCK and its downstream NF-κB and p38 signaling pathways.

It has been proposed that procedures which up-regulate mitochondrial biogenesis and autophagy by replacing damaged mitochondria with healthy ones, may prevent the development of several heart diseases. A member of serine and threonine kinases, AMPK, could play essential roles in the autophagy and/or mitophagy. AMPK is widely distributed in various cells, which might play diverse regulatory roles in different tissues and/or organs. In fact, changes in the kinase function of AMPK due to alteration of activity have been linked with diverse pathologies including cardiac disorders. AMPK can regulate mitochondrial biogenesis via PGC1α signaling and also improve oxidative mitochondrial metabolism through inhibition of mTOR pathway, which may also modulate the autophagy/mitophagy through ULK1 and/or TGF-β signaling. Therefore, the modulation of AMPK in autophagy/mitophagy pathway might be considered as a therapeutic tactic for several cardiac disorders. As kinases are amongst the most controllable proteins, in general, the design of small molecules targeting kinases might be an eye-catching avenue to modulate the cardiac function. Some analyses of the molecular biology underlying mitophagy suggests that nutraceuticals and/or drugs including specific AMPK modulator as well as physical exercise and/or dietary restriction that could modulate AMPK may be useful against several heart diseases. In particular, some nutraceutical regimens may have encouraging potential for controlling some of cardiac disorders.

Atrial fibrillation (AF) is a cardiac arrhythmia caused by electrophysiological anomalies in the atrial tissue, tissue degradation, structural abnormalities, and comorbidities. A direct relation exists between AF and altered mitochondrial activity resulting from membrane potential loss, contractile dysfunction, or decreased ATP levels. This review aimed to elucidate the role of mitochondrial oxidative mechanisms in AF pathophysiology, the impact of mitochondrial oxidative stress on AF initiation and perpetuation, and current therapies. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Reviews. PubMed, Excerpta Medica Database, and Scopus were explored until June 2023 using "MESH terms." Bibliographic references from relevant papers were also included. Oxidative stress is an imbalance that causes cellular damage from excessive oxidation, resulting in conditions such as AF. An imbalance in reactive oxygen species production and elimination can cause mitochondrial damage, cellular apoptosis, and cardiovascular diseases. Oxidative stress and inflammation are intrinsically linked, and inflammatory pathways are highly correlated with the occurrence of AF. AF is an intricate cardiac condition that requires innovative therapeutic approaches. The involvement of mitochondrial oxidative stress in the pathophysiology of AF introduces novel strategies for clinical treatment.

Defects in low-density lipoprotein receptor (LDLR) are associated with familial hypercholesterolemia (FH), manifested by atherosclerosis and cardiovascular disease. Defective LDLR in hepatocytes leads to increased blood cholesterol level that damage vascular cells, especially endothelial cells, through oxidative stress and inflammation. However, the distinctions between endothelial cells from individuals with normal and defective LDLR are not yet fully comprehended. In this study, we obtained and examined endothelial derivatives of induced pluripotent stem cells (iPSC) generated previously from conditionally healthy donors and compound heterozygous FH patients carrying pathogenic LDLR alleles. In normal iPSC-derived endothelial cells (iPSC-EC), we detected the LDLR protein predominantly in its mature form, while iPSC-EC from patients with FH display reduced level of mature LDLR and show abolished low-density lipoprotein uptake. RNA-seq of iPSC-EC with mutant LDLR revealed a unique transcriptome profile comprising downregulated genes related to monocarboxylic acid transport, exocytosis and cell adhesion, as well as upregulated signaling pathways of cell secretion and leukocyte activation. Overall, these findings suggest that LDLR defects increases susceptibility of endothelial cells to inflammation and oxidative stress. This, combined with elevated extrinsic cholesterol levels, may result in accelerated endothelial dysfunction, contributing to early progression of atherosclerosis and other cardiovascular pathologies related to FH.

Consumption of high amounts of ethanol is a risk factor for development of cardiovascular diseases such as arterial hypertension. The hypertensive state induced by ethanol is a complex multi-factorial event, and oxidative stress is a pathophysiological hallmark of vascular dysfunction associated with ethanol consumption. Increasing levels of reactive oxygen species (ROS) in the vasculature triggers important processes underlying vascular injury, including accumulation of intracellular Ca2+ ions, reduced bioavailability of nitric oxide (NO), activation of mitogen-activated protein kinases (MAPKs), endothelial dysfunction, and loss of the anticontractile effect of perivascular adipose tissue (PVAT). The enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase plays a central role in vascular ROS generation in response to ethanol. Activation of the renin-angiotensin-aldosterone system (RAAS) is an upstream mechanism which contributes to NADPH oxidase stimulation, overproduction of ROS and vascular dysfunction. This review discusses the mechanisms of vascular dysfunction induced by ethanol, detailing the contribution of ROS to these processes. Data examining the association between neuroendocrine changes and vascular oxidative stress induced by ethanol are also reviewed and discussed. These issues are of paramount interest to public health as ethanol contributes to blood pressure elevation in the general population, and it is linked to cardiovascular conditions and diseases.

Background: Takayasu Arteritis (TAK) increases vascular stiffness and arterial resistance. Hypertension and atherosclerosis lead to similar changes. We investigated possible differences in cardiovascular remodeling between these diseases and whether the differences are correlated with immune cell expression. Methods: Patients with active TAK arteritis were compared with age- and sex-matched hypertensive and atherosclerotic patients. In a subpopulation of TAK patients, Treg/Th17 cells were measured before (T0) and after 18 months (T18) of infliximab treatment. Echocardiogram, supraaortic Doppler ultrasound, and lymphocytogram were performed in all patients. Histological and immunohistochemical evaluation of the vessel wall was performed to compare the in vivo results. Results: TAK patients have increased aortic valve dysfunction and diastolic dysfunction. These data have been associated with uric acid levels. A significant increase in aortic stiffness was also noted and associated with peripheral T lymphocyte levels. CD3+CD4+ cell infiltrates were detected in the vessel wall samples of these patients. They had a lower mean percentage of Tregs at T0 than controls, but levels increased significantly at T18. Opposite results were found in Th17 cells. Finally, TAK patients were found to have an increased risk of atherosclerotic cardiovascular disease (ASCVD). Conclusion: Our data suggest that different pathogenic mechanisms of vessel damage, including atherosclerosis, underlie TAK patients compared with control subjects. The increased risk of ASCVD in TAK patients correlates directly with the degree of inflammatory cell infiltration in the vessel wall. Infliximab restores the normal frequency of Tregs/Th17 in TAK patients and allows a possible reduction of steroids and immunosuppressants.

The prevalence of nonalcoholic fatty liver disease (NAFLD) has been rapidly increasing worldwide. A choline-deficient L-amino acid-defined high fat diet (CDHFD) has been used to create a mouse model of nonalcoholic steatohepatitis (NASH). There are some reports about the effects on mice of being fed CDAHFD for a long time, 1 to 3 months. However, the effect of this diet over a short period has been unknown. Therefore, we examined the effect of one week of feeding CDAHFD on the mouse liver. Feeding this diet for only one week induced lipid droplet deposition in the liver with increasing activity of liver-derived enzymes in the plasma. On the other hand, it did not induce fibrosis and cirrhosis. Additionally, it was demonstrated that mitochondrial respiration is significantly impaired with severe oxidative stress in the liver by CDAHFD, associated with a decreasing mitochondrial DNA copy number and complexes-proteins. In the gene expression analysis of the liver, inflammatory and oxidative stress markers were significantly increased by CDAHFD. These results demonstrated that one week of feeding CDAHFD to mice induces steatohepatitis with mitochondrial dysfunction and severe oxidative stress, without fibrosis, which can partially mimic the early stage of the NASH in humans.

Maintenance of intestinal barrier integrity is crucial for preventing inflammatory bowel diseases (IBDs) onset and exacerbations. In this work we study the effect of a fixed combination of Lactobacillus reuteri and Lactobacillus acidophilus and herbal extracts in an in vitro inflammation experimental model. Caco-2 cell monolayer was exposed to INF-γ+TNF-α or to LPS; Trans Epithelial Electrical Resistance (TEER) and paracellular permeability were investigated. ZO-1 and occludin tight junctions (TJs) were also investigated by mean of immunofluorescence. The pre-treatment with the fixed combination of probiotics and herbal extracts prevented the inflammation-induced TEER decrease, paracellular permeability increase and TJs translocation. In summary the fixed combination of probiotics and herbal extracts investigated in this research was found to be an interesting candidate for targeting the re-establishment of intestinal barrier function in IBDs conditions.

We investigate if anyone is being left behind in accessing safely managed drinking water (SM) in achieving the 2030 agenda. We use 23 countries grouped globally as critically insecure water (CIWC). The results indicate none of the CIWC had over 50% of the population accessing SM, N. America and Europe had highest percentages while Sub Saharan Africa had the least. People left behind are found in rural areas, in countries vulnerable to climate change because of poor governance, low-income, and women’s low education. Institutional quality, equity and equality should be improved in using resources critical to leaving no one behind.

Transseptal puncture is an established technique for achieving left atrium access during cardiac procedures. It is associated with low overall complication rate and high success rates. Although being almost a century old technique, recent years brought a substantial development in the field, allowing for faster and safer left atrium catheterization. In this paper we discuss its history, complications, available techniques and current state of the art.

In Holter monitoring, the precise detection of standard heartbeats and Ventricular Premature Contractions (PVCs) is paramount for accurate cardiac rhythm assessment. This study introduces a novel application of the 1D U-Net neural network architecture aimed at enhancing PVC detection in Holter recordings. Training data comprised the Icentia11k, INCART DB, and our custom dataset. The model’s efficacy was subsequently validated against traditional Holter analysis methodologies across multiple databases, including AHA DB, MIT 11 DB, NST, and another custom dataset encompassing challenging real-world examples. The results underscored the 1D U-Net model’s prowess in QRS complex detection, achieving near-perfect balanced accuracy scores across all databases. PVC detection exhibited variability, with balanced accuracy scores ranging from 0.909 to 0.986. Despite some databases, like the AHA DB, showcasing lower sensitivity metrics, their robust balanced accuracy accentuates the model’s equitable performance in discerning both false positives and negatives. In conclusion, while the 1D U-Net architecture is a formidable tool for QRS detection, there’s a clear avenue for further refinement in its PVC detection capability, given the inherent complexities and noise challenges in real-world PVC occurrences.

Metabolic-dysfunction associated steatotic liver disease (MASLD) is a chronic liver disease that affects more than a quarter of the global population, and is increasing worldwide, due to the pandemic of obesity. Insulin resistance is closely associated with the development and progression of MASLD. Hepatic entry of increased fatty acids (FA) released from adipose tissue, increase in FA synthesis and reduced FA oxidation in the liver, and hepatic overproduction of triglyceride (TG)-rich lipoproteins may induce the development of MASLD. Since insulin resistance also induces atherosclerosis, the leading cause for death in MASLD patients is cardiovascular disease (CVD). Considering that the development of CVD determines the prognosis of MASLD patients, the ideal therapeutic interventions for MASLD should reduce body weight, improve coronary risk factors, in addition to an improvement in liver functiom. Lifestyle modification such as diet and exercise and surgical interventions such as bariatric surgery and intragastric balloons have shown to improve MASLD by reducing body weight. Sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have been shown to improve coronary risk factors and to suppress the occurrence of CVD. Both SGLT2i and GLP-1 have been reported to improve liver enzymes, hepatic steatosis and fibrosis. We recently reported that the selective peroxisome proliferator-activated receptor-alpha (PPARα) modulator, pemafibrate, improved liver function. PPARα agonists have multiple anti-atherogenic properties. Here, we consider the pathophysiology of MASLD and the mechanisms of action of such drugs, and consider whether such drugs and the combination therapy of such drugs could be the ideal treatments for MASLD.

Nemaline myopathy (NM) is one of the most common forms of congenital myopathy and it is identified by the presence of "nemaline bodies" (rods) in muscle fibers by histopathological exam-ination. The most common forms of NM are caused by mutations in the ACTA1 (Actin Alpha 1) and NEB (Nebulin) genes. Clinical features include hypotonia and muscle weakness. Unfortunate-ly, there is no curative treatment and the pathogenetic mechanisms remains unclear. In this man-uscript, we examined the pathophysiological alterations in NM using dermal fibroblasts derived from patients with mutations in ACTA1 and NEB genes. Patients’ fibroblasts were stained with rhodamine phalloidin to analyze the polymerization of actin filaments by fluorescence microsco-py. We found that patients' fibroblasts showed incorrect actin filament polymerization compared to control fibroblasts. Actin filament polymerization defects was associated with mitochondrial dysfunction. Furthermore, we identified two mitochondrial boosting compounds, linoleic acid (LA) and L-carnitine (LCAR), that improved the formation of actin filaments in mutant fibro-blasts and corrected mitochondrial bioenergetics. Our results indicate that cellular models can be useful to study the pathophysiological mechanisms involved in NM and to find new potential therapies. Furthermore, targeting mitochondrial dysfunction with LA and LCAR can revert the pathological alterations in NM cellular models.

Background. Mitochondrial dysfunction has been identified as a pathophysiological hallmark of disease onset and progression in patients with Parkinsonian disorders. Besides the overall emergence of gene therapies in treating these patients, this highly relevant molecular concept has not yet been defined as a target for gene therapeutic approaches. Methods. This narrative review will discuss the experimental evidence suggesting mitochondrial dysfunction as a viable treatment target in patients with monogenic and idiopathic Parkinson’s disease. In addition, we will focus on general treatment strategies and crucial challenges which need to be overcome. Results. Our current understanding of mitochondrial biology in parkinsonian disorders opens up the avenue for viable treatment strategies in Parkinsonian disorders. Insights can be obtained from primary mitochondrial diseases. However, substantial knowledge gaps and unique challenges of mitochondria-targeted gene therapies need to be addressed to provide innovative treatments in the future. Conclusions. Mitochondria-targeted gene therapies are a potential strategy to improve an important primary disease mechanism in Parkinsonian disorders. However, further studies are needed to address the unique design challenges for mitochondria-targeted gene therapies.

Mitochondrial dysfunctions remained a pivotal mechanism in manifold neurodegenerative diseases. Mitochondrial homeostasis within the cell is an essential aspect of cell biology. Mitochondria which is also known as the power-generating set of the cell, have a dominant role in several processes associated with the genomic integrity and cellular equilibrium maintenance. They are involved in maintaining optimal cells functioning and guidance from possible DNA damage which could lead to mutations and onset of diseases. Conversely, system perturbations which could be due to environmental factors or senescence induce changes in the physiological balance and result in the mitochondrial functions impairment. The focal point of this review focuses on mitochondrial dysfunction as a significant condition in the onset of neuronal disintegration. We explain the pathways associated with the dysfunction of the mitochondria which are common amongst the most recurring neurodegenerative diseases including Alzheimers and Parkinsons disease. Do mitochondrial dysfunctions represent an early event in causing a shift towards neuropathological processes?

Introduction and objectives: a close association between metabolic syndrome among subjects with erectile dysfunction has been addressed, since mechanisms underlying metabolic syndrome compromise the blood flow to the penis in numerous ways. This study aims to analyze the relationship between erectile dysfunction and metabolic syndrome in a group of Mexican patients, to study the influence of other morbidity factors on erectile dysfunction, and to define the specific metabolic syndrome components most associated with erectile dysfunction severity. Methods: a descriptive and cross-sectional study was completed in a group of 86 adult Mexican patients with previous diagnosis of erectile dysfunction. Participants were classified as with or without metabolic syndrome. Erectile dysfunction severity, alcohol or tobacco consumption, and depressive behavior were identified through validated questionnaires and compared between both groups, as well as anthropometric, biochemical, and clinical parameters. Results: anthropometric measures, laboratory values, clinical characteristics and the Beck Depression Inventory score were significantly different among both groups. Additionally, more patients affected by severe and moderate erectile dysfunction were identified in the group with metabolic syndrome. Among the metabolic syndrome components, HbA1c >5.7% and fasting glucose >110 mg/dl were significantly associated to the development of erectile dysfunction (p = 0.004 and 0.04, respectively). Conclusions: metabolic syndrome components aggravate erectile dysfunction, particularly the lack of glycemic control manifested by Hb1Ac >5.7% and/or fasting glucose >110 mg/dL. The inclusion of fasting glucose and HbA1c as a complementary biochemical screening among patients with erectile dysfunction should be assessed.

This study aimed to identify and differentiate the factors that may affect the incidence of temporomandibular joint (TMJ) dysfunction in children with type 1 diabetes. We analyzed the TMJ symptoms, clinical and laboratory parameters of type 1 diabetes in a cohort of 101 consecutive patients. The participants were evaluated regarding the presence of pain in the masticatory muscles, TMJ sounds, mouth opening, maximum mouth opening, lateral and protrusive excursions, and Fonseca scores. The overall cohort showed a mean Fonseca score of 20 ± 13.89, referred to mild TMJ dysfunction. Of patients, 34.65% presented at least one clinical symptom and were defined as having dysfunction. The most frequently recorded symptom was TMJ sounds, presented in 16.8% of children. In subjects with dysfunction compared to those without dysfunction, a significant difference was found at height standard deviation scores, Fonseca scores and maximum mouth opening (p&lt;0.001). HbA1c levels, diabetes duration, age and gender did not reveal any significant differences between the patients with and without dysfunction. Type 1 diabetes is often associated with limited mouth opening and mild TMJ dysfunction. This dysfunction may reflect a more chronic condition and possibly exceeds the prevalence of cheiroartropathy. This study could be a starting point towards enhancing our understanding of clinically evident TMJ involvement in type 1 diabetes.

Given the accelerating scientific, clinical and consumer interest in highly-prevalent functional gastrointestinal disorders, appropriate therapeutic strategies are needed to address the many aspects of digestive dysfunction. Accumulating evidence for the crucifer-derived bioactive molecule, sulforaphane in upstream cellular defence mechanisms highlights its potential as a therapeutic candidate in targeting functional gastrointestinal conditions together with systemic disorders. This article catalogues the evolution of and rationale for a hypothesis that utilises multifunctional sulforaphane as the initial step in restoring the ecology of the gut ecosystem; it does this primarily by targeting the functions of intestinal epithelial cells. A growing body of work has identified the colonocyte as the driver of dysbiosis, so that targeting gut epithelial function could provide an alternative to targeting the microbes themselves for remediation of microbial dysbiosis. The hypothesis discussed herein has evolved over several years and is supported by case studies showing the application of sulforaphane in gastrointestinal disorders, related food intolerance and several systemic conditions. To our knowledge, this is the first time the effects of sulforaphane have been reported in a clinical environment where several of its key properties within the gut ecosystem appear to be related to its nutrigenomic effects on gene expression.

Background Some patients with mild cognitive impairment (MCI) experience gait disturbances. However, there are few reports on the relationship between gait disturbance and cognitive function in patients with MCI. Therefore, we investigated the neural correlates of gait characteristics related to cognitive dysfunction. Methods Eighty patients diagnosed with MCI from three dementia centres in Gangwon-do, Korea were recruited for this study. We defined MCI as a Clinical Dementia Rating global score of 0.5 or higher, with a memory domain score of 0.5 or greater. The patients were classified as having either early or late MCI based on their Mini Mental Status Examination z-scores. Multiple logistic regression analysis was performed to examine the association between the gait characteristics and cognitive impairment. Analyses included variables such as age, sex, years of education, number of comorbidities, body mass index and height. Results Gait velocity, step count, step length, heel-to-heel base support, swing and stance phase duration, and support time were associated with cognitive function. A decrease in gray matter volume in the right pericalcarine area was associated with gait characteristics related to cognitive dysfunction. An increase in the curvature of gray matter in the right entorhinal, right lateral orbitofrontal, right cuneus, and right and left pars opercularis areas was also associated with gait characteristics related to cognitive dysfunction. Conclusion Since gait impairment is an important factor in determining activities of daily living in patients with mild cognitive impairment, the evaluation of gait and cognitive functions in patients with mild cognitive impairment is important.

A Mitochondrial dysfunction and oxidative stress are major contributors to the pathophysiology of neurodegenerative diseases, including Alzheimer’s disease (AD). However, the mechanisms driving mitochondrial dysfunction and oxidative stress are unclear. Familial AD (fAD) is an early onset form of AD caused primarily by mutations in the presenilin-encoding genes. Previously, using Caenorhabditis elegans as a model system to study presenilin function, we found that loss of C. elegans presenilin orthologue, SEL-12, results in elevated mitochondrial and cytosolic calcium levels. Here, we provide evidence that elevated neuronal mitochondrial generated reactive oxygen species (ROS) and subsequent neurodegeneration in sel-12 mutants are a consequence of the increase of mitochondrial calcium levels and not cytosolic calcium levels. We also identify mTORC1 signaling as a critical factor in sustaining high ROS in sel-12 mutants in part through its repression of the ROS scavenging system SKN-1/Nrf. Our study reveals that SEL-12/presenilin loss disrupts neuronal ROS homeostasis by increasing mitochondrial ROS generation and elevating mTORC1 signaling, which exacerbates this imbalance by suppressing SKN-1/Nrf antioxidant activity.

Cigarette smoke (CS) exposure results in lung damage and inflammation through mitochondrial dysfunction. Mitochondria quality control is sustained by Miro1 (Rhot1), a calcium-binding membrane-anchored GTPase by its interaction with PINK1/Parkin during mitophagy. However, the exact mechanism that operates this interaction of mitophagy machinery in Miro1 degradation and CS-induced mitochondrial dysfunction that results in lung inflammation remains unclear. We hypothesized that mitochondrial Miro1 plays an important role in regulating mitophagy machinery and resulting lung inflammation by CS in mouse lung. We showed a role of Miro1 in CS-induced mitochondrial dysfunction and quality control mechanisms. The Rhot1Fl/Fl (WT) and lung epithelial cell-specific Rhot1 KO were exposed to mainstream CS for 3 days (acute) and 4 months (chronic). The cellular infiltration, cytokines, and lung histopathology were studied for the inflammatory response in the lungs. Acute CS exposure showed a notable increase in the total inflammatory cells, macrophages, and neutrophils associated with inflammatory mediators and Miro1 associated mitochondrial quality control proteins Parkin and OPA1. Chronic exposure showed an increase infiltration of total inflammatory cells and neutrophils versus air controls. Histopathological changes, such as pulmonary macrophages and neutrophils were increased in CS exposed mice. The epithelial Miro1 ablation led to augmentation of inflammatory cell infiltration with alteration in the levels of pro-inflammatory cytokines and histopathological changes. Thus, CS induces disruption of mitochondrial quality control mechanisms, and Rhot1/Miro1 mediates the process of CS-induced mitochondrial dysfunction ensuing lung inflammatory responses.

Neurological disorders, such as amyotrophic lateral sclerosis, Parkinson’s disease, and Alzheimer’s disease, are commonly associated with persistent neuro-inflammation, and there is an urgent need to discover new therapeutic agents that may target the various pathways involved in neurodegeneration. In this study, we investigated the therapeutic potential of folecitin, a flavonoid isolated from Hypericum oblongifolium, against lipopolysaccharide (LPS)-induced oxidative stress associated with neurodegeneration, amyloidogenic Aβ production pathway, and memory dysfunction in mice. LPS was administered i.p. at 250 µg/kg/day for 3 weeks, followed by the administration of folecitin at a dose of 30 mg/kg/day for the last two weeks. A Western blot technique was used to assess the expression of different proteins involved in oxidative stress, neurodegeneration, and neuronal synapse. Results indicated that folecitin significantly reduced LPS-induced apoptotic neurodegeneration, including the expression of BAX, Caspase-3, and PARP-1 proteins, inhibited BACE1, and the amyloidogenic Aβ production pathway. Folecitin improved both pre- and post-neuronal synapse, as well as memory dysfunction. Furthermore, folecitin significantly activated endogenous antioxidant proteins such as Nrf-2 and HO-1 via stimulating the phosphorylation of Akt proteins. These findings suggest that folecitin may be a suitable lead to design new drugs for neurotoxin-triggered neurodegenerative disorders.

Cardiac dynamics are traditionally linked to a left ventricle, right ventricle and septum morphology, a topography that differs from the heart’s 5-century-old anatomic description of containing a helix and circumferential wrap architectural configuration. Torrent Guasp’s helical ventricular myocardial band (HVMB) defines this anatomy and its structure, explains why the heart’s 6 dynamic actions of narrowing, shortening, lengthening, widening, twisting and uncoiling happen. This database raises questions about deductions behind “accepted cardiac mechanics”, and its functional aspects will challenge and overturn them. These suppositions include the LV, RV, and septum description, timing of mitral valve opening, isovolumic relaxation period, reasons for torsion/twisting, untwisting, reasons for longitudinal and circumferential strain, echocardiographic sub segmentation, resynchronization, RV function dynamics, and diastolic dysfunction’s cause and unrecognized septum impairment. Torrent Guasp’s revolutionary contributions may alter future understanding of the diagnosis and treatment of cardiac disease.

Atrial fibrillation (AF) is a common cardiac arrhythmia associated with significant morbidity and mortality. The role of epicardial adipose tissue (EAT), particularly in the left atrium, has garnered attention in the pathophysiology of AF. This review aims to provide an overview of the association between the thickness of left atrial epicardial adipose tissue (LA-EAT) and the incidence of AF, while exploring the arrhythmogenic effects of LA-EAT and the impact of epicardial fat tissue changes with age and in pathological conditions. A comprehensive search of PubMed was conducted, and relevant studies were selected based on their inclusion criteria. The findings suggest that increased LA-EAT thickness is associated with an elevated risk of AF, potentially mediated through inflammatory and proarrhythmic effects. Age-related changes in epicardial fat tissue and alterations in pathological conditions, such as obesity, metabolic syndrome, and cardiovascular diseases, further contribute to the development and progression of AF. Further research is needed to deepen our understanding of these mechanisms and their clinical implications.

Objective: We aimed to clarify the differences in the association between re-admission for heart failure (HF) and left atrial (LA) overload indices by sex in heart failure and a preserved ejection fraction (HFpEF). Methods: We analysed 898 HFpEF patients hospitalized for acute decompensated HF. Blood tests and transthoracic echocardiography were performed before discharge. The primary endpoint was re-admission for HF during the first year. Results: The ratio of diastolic elastance to arterial elastance (p=0.014), a relative index of LA pressure overload, in men and LA volume index (LAVI, p=0.020) in women were significant for re-admission for HF during the first year in the multivariable Fine-Gray analysis. Stroke volume (SV)/LA volume (LAV), another index for LAV overload, was not a significant prognostic factor of re-admission for HF during this time. Conclusion: LA overload was an important prognostic factor for HF re-readmission during the first year after enrolment in patients with HFpEF, but the indices relating to LA overload differed by sex.

This single-blind and cross-sectional study evaluated the role of Rho-kinase (ROCK) as a biomarker of the cardiovascular remodelling process assessed by echocardiography in competitive long-distance runners (LDR) during the training period before a marathon race. Thirty-six healthy male LDR (37.0±5.3 years; 174.0±7.0 height; BMI: 23.8±2.8; VO2-peak: 56.5±7.3 mL·kg-1·min-1) were separated into two groups according to previous training level: high-training (HT, n=16) ≥100 km·week-1 and low-training (LT, n=20) ≥70 and &lt;100 km·week-1. Also, twenty-one healthy nonactive subjects were included as a control group (CTR). A transthoracic echocardiography was performed and ROCK activity levels in circulating leukocytes were measured at rest (48-hr without exercising) the week before the race. HT group showed higher left ventricular mass index (LVMi) and left atrial volume index (LAVi) than other groups (p&lt;0.05, for both), also higher levels of ROCK activity were found in LDR (HT=6.17±1.41 vs CTR=1.64±0.66 (p&lt;0.01); vs LT=2.74±0.84; (p&lt;0.05)). In LDR a direct correlation between ROCK activity levels and LVMi (r=0.83; p&lt;0.001), and LAVi (r=0.70; p&lt;0.001) were found. In conclusion, in male competitive long-distance runners, the load of exercise implicated in marathon training is associated with ROCK activity levels and the left cardiac remodelling process assessed by echocardiography.

Abstract: Female pelvic floor dysfunction (FPFD) is a series of conditions caused by the displacement or dysfunction of the patient's pelvic organs due to defects, injuries, and deterioration of the pelvic floor supportive structures, with stress urinary incontinence and pelvic organ prolapse being the most common. The mechanism of pelvic floor dysfunction is complex and not yet fully understood, and is often related to one or more functional abnormalities of muscles, connective tissues, fascia, nerves and blood vessels. Specialized clinicians are often unable to cover the comprehensive medical professional information of various specialties such as gynecology and obstetrics, urology, anus and intestines, imaging, etc., and the systematic and comprehensive diagnosis and treatment of the disease will be limited. The application of artificial intelligence concepts in the medical field not only improves the diagnostic efficiency of physicians, but also provides reference and basis for the development of comprehensive treatment programs. This article follows and draws on the diagnosis and treatment process of pelvic floor dysfunction recommended in various guidelines, incorporates physical therapy techniques into the conventional non-surgical treatment of pelvic floor dysfunction, provides guidance for the diagnosis and treatment of pelvic floor dysfunction, and briefly introduces the clinical application and value of pelvic floor intelligent diagnosis and treatment in pelvic floor dysfunction.

BACKGROUND: The number of waitlisted patients requiring mechanical circulatory support (MCS) as a bridge to heart transplantation is increasing. The data concerning the results of double-bridge strategy are limited. We sought to investigate the post-transplant outcomes across the different bridge strategies. METHODS: We retrospectively reviewed a heart transplantation database from Jan 2009 to Jan 2019. Intra-aortic balloon pump (IABP), extracorporeal membrane oxygenation (ECMO), and ventricular assist devices (VAD) were the MCS that we investigated. The pre- and post-transplant characteristics and variables of patients bridged with the different types of MCS were collected. The post-transplant survival was compared using Kaplan-Meier survival analysis. RESULTS: A total of 251 heart transplants were reviewed; 115 without MCS and 136 with MCS. The patients were divided to five groups: Group 1 (no MCS): n=115; Group 2 (IABP): n=15; Group 3 (ECMO): n=33; Group 4 (ECMO-VAD): double-bridge (n=59); Group 5 (VAD): n=29. Survival analysis demonstrated that the 3-year post-transplant survival rates were significantly different among the groups (Log-rank p < 0.001). There was no difference in survival between group 4(ECMO-VAD) and group 1(no MCS)1 (p = 0.136), or between group 4(ECMO-VAD) and group 5(VAD) (p = 0.994). Group 3(ECMO) had significantly inferior 3-year survival than group 4(ECMO-VAD) and group 5(VAD). CONCLUSION: Double bridge may not lead to worse mid-term results in patients who could receive a transplantation. Initial stabilization with ECMO for critical patients before implantation of VAD might be considered as a strategy for obtaining an optimal post-transplant outcome.

Artificial Intelligence are creating a paradigm shift in health care, being phenotyping patients through clustering techniques one of the areas of interest. Objective: To develop a predictive model to classify heart failure (HF) patients according to their left ventricular ejection fraction (LVEF), by using available data in Electronic Health Records (EHR). Subjects and methods: 2854 subjects more than 25 years old with diagnose of HF and LVEF measured by echocardiography were selected to develop an algorithm to predict patients with reduced EF using supervised analysis. Performance of the algorithm developed were tested in heart failure patients from Primary Care. To select the most influencing variables, LASSO algorithm setting was used and to tackle the issue of one class exceed the other one by a large proportion we used the Synthetic Minority Oversampling Technique (SMOTE). Finally, Random Forest (RF) and XGBoost models were constructed. Results: Full XGBoost model obtained the maximized accuracy, a high negative predictive value and the highest positive predictive value. Gender, age, unstable angina, atrial fibrillation and acute myocardial infarct are the variables that most influence FE value. Applied in the EHR data set with a total 25594 patients with an ICD-code of HF and no regular follow-up in Cardiology clinics, 6170 (21.1%) were identified as those pertaining to the reduced EF group. Conclusion: The algorithm obtained is able to rescue a number of HF patients with reduced ejection fraction that can be take benefit for a protocol with strong recommendation to succeed. Furthermore, the methodology can be used for studies with data extracted from the Electronic Health Records.

Hypoxia can induce pulmonary edema (PE) and inflammation. Furthermore, hypoxia depresses left ventricular (LV) inotropy despite sympathetic activation. Here, we investigated the role of nitrosative stress and cardiovascular dysfunction in hypoxic lung injury. Additionally, we studied effects of adrenergic blockade (AB) on hypoxia-induced pulmonary injury. Eighty-six female rats were exposed for 72 h to normoxia or normobaric hypoxia and received infusions with NaCl, prazosin, propranolol or prazosin-propranolol combination. We evaluated hemodynamic function and performed histological and immunohistochemical analyses of the lung. Hypoxia significantly depressed LV but not right ventricular (RV) inotropic and lusitropic functions. AB significantly decreased LV function both in normoxia and hypoxia. AB effects on RV were weaker. Hypoxic rats showed signs of moderate PE and inflammation. This was accompanied by elevated levels of tumor necrosis factor (TNF)  and nitrotyrosine, a marker of nitrosative stress in the lungs. In hypoxia, all types of AB significantly reduced both TNF and nitrotyrosine to normoxic levels. However, AB did not attenuate PE. Results suggest that hypoxia-induced sympathetic activation contributes to inflammation and nitrosative stress in the lungs but not to PE. We suggest that AB in hypoxia aggravates hypoxia-induced inotropic LV dysfunction and backlog into pulmonary circulation, thus promoting PE.

Background: Systemic lupus erythematosus (SLE) is characterized by inflammation and cardiovascular complications. Our study aimed to investigate subclinical and early indicators of systolic myocardial dysfunction in SLE patients using advanced echocardiographic methods and biomarkers. Methods: In this cross-sectional study, we enrolled 102 SLE patients without known cardiac impairment and 51 healthy controls. Demographics, disease characteristics, laboratory results, disease activity (SLEDAI) and organ damage (SDI) indices were recorded. Left ventricular global longitudinal strain (GLS) and myocardial work indices were assessed by utilizing speckle tracking echocardiography. In addition, high sensitivity C-reactive protein (hsCRP), high sensitivity troponin (hsTn) and N-terminal-pro B-type natriuretic peptide (NT-proBNP) levels were measured in blood samples. Results: In comparison to controls, SLE patients had significantly higher GLS (-19.94±2.71%vs-21.15±1.55%, p&lt;0.001) and global wasted work (GWW) (94±71mmHg%vs71±49 mmHg%, p=0.025). Notably, NT-proBNP and hsTn were threefold and twofold higher in SLE group compared to control group, respectively (p&lt;0.001). Within SLE cohort, patients with at least moderate disease activity (SLEDAI≥4) both biomarkers were significantly elevated than those with low disease activity (SLEDAI&lt;4). Conclusion: Advanced echocardiographic parameters combined with specific biomarkers have a promising role in detecting systolic dysfunction at an early phase in SLE patients, potentially enabling timely interventions to mitigate cardiovascular risk.

Objective: The purpose of this study was to investigate the effects of Crocin on brain neuroterophins, cognition, sensory and motor dysfunction and compare to fingolimod effects in experimental model of demyelination with Ethidium Bromide EB in female Wistar rats. Methods: Animals were assigned in to 8 groups; Sham, Sham operated (ShOp), EAE, crocin treated (Cr5,10,20 mg/kg), Vehicle, Fingolompd (Fing) and fingolimod + crocin (Cr+Fing). Demyelination was induced by single dose injection of 10 μl of EB 0.1% into the fourth ventricle of the brain. Crocin and fingolimod were applied for 21 days, daily, oral gavage. BDNF, NGF1, nerve conduction velocities, tail flake latency, balance and behavioral variables were sampled and analyzed by paired t-test and ANOVA test with repeated post hoc measurements. Results: The results showed that crocin improves all studied factors, but remarkable imrovments were observed in dosage of 10 mg/kg. Crocin (10mg/kg) and fingolimod (1mg/kg) significantly improved cognition variables in open field test, sensory and motor nerve conduction velocity, tail flick latency and clinical signs (p<005). In addition, applying of crocin co-administered with fingolimod led to significant increases in all assessed factors, greater than crocin or fingolimod intervention alone (α≤0.001). Conclusion: Based on the current findings, crocin can improve the level of brain neurotrophins, exploratory behavior and nerve conduction after demyelination as close as fingolimod results. So, crocins can be considered as a neuro supportive agent in the management of degenerative diseases maybe similar to fingolimod mechanism.

The ongoing growth of international occurrence of depression and its ability to co-occur with other serious medical disorders such as heart disease, cancer, diabetes, and Parkinson’s disease is a current public health problem. Inhibitor of DNA-Binding/Differentiation (ID) proteins are part of a group of transcriptional factors that have been seen to be involved in neurocognitive disorders and therefore, may have influence on depressive disorders. Previously, it has been established that environmental estrogenic endocrine disruptors (EEDs) such as polychlorinated biphenyls (PCBs) & bisphenol A (BPA) have played an important role in the impact of depressive disorders. Hence, based on many studies, we consider the impact of these environmental pollutants on the group of ID proteins. Improved understanding of how the interaction of ID proteins by EED exposure can influence depressive disorders will contribute essential evidence that can further benefit our public health community with innovative knowledge to prevent these types of mental illnesses.

Recent works identified ClpXP, mitochondrial caseinolytic protease, as the only target of imipridones - new class of antitumor agents. Our study of the mechanism of imipridone derivative TR-57 action in SUM159 human breast cancer cells demonstrated mitochondrial fragmentation, degradation of mitochondrial mtDNA and mitochondrial dysfunction, due to inhibition of Complex I and Complex II activity. Complete inhibition of oxidative phosphorylation accom-panied with 90, 94, 88 and 87% decrease in the content of Complex I, II, III and IV proteins, respectively. The content of the FOF1-ATPase subunits decreased sharply by approximately 35% after 24 hours and remained unchanged up to 72 hours of incubation with TR-57. At the same time, a disappearance of the ATPIF1, natural inhibitor of mitochondrial FOF1-ATPase observed after 24 h exposure to TR-57. ATPase inhibitor oligomycin had no effect on the mitochondrial membrane potential in intact SUM159, whereas it caused a 65% decrease in TR-57-treated cells. SUM159 cells incubated with TR57 up to 72 hours retained the level of proteins facilitating the ATP transfer across the mitochondrial membranes: VDAC1 expression was not affected, while expression of ANT-1/2 and APC2 increased by 20% and 40%, respectively. Thus, our results suggest that alt-hough TR-57 treatment lead to complete inhibition of respiratory chain activity of SUM159 cells, hydrolysis of cytoplasmic ATP by reversal activity of FOF1-ATPase supports mitochondrial polarization.

Long COVID-19 syndrom appears after Severe Acute Respiratory Syndrome-Corona Virus (SARS-CoV-2) infection with acute damages to microcapillaries, microthombi and endotheliitis. However, the mech-anisms involved in these processes remain to be identified. All blood vessels are lined with a monolayer of endothelial cells called vascular endothelium of which one of the major properties is to prevent coagulation. VE cadherin is a component of endothelial cell junctions responsible for maintenance of the integrity of the vessels through homophilic interaction of its Ca++- dependent adhesive extracellular domain. We first provide evidence that VE-cadherin is a target in vitro for ACE2 cleavage because its extracellular domain (hrVE-ED) contains two amino acid sequences for ACE2 substrate recognition at the po-sitions 256P-F257 and 321PMKP-325L. Indeed, incubation of hrVE-ED with the active ecto-peptidase hrACE2 for 16 hrs in the presence of 10M ZnCl2 showed a dose-dependent (from 0.2 ng/ul to 2 ng/ul) decrease of the VE-cadherin immunoreactive band. In vivo, in the blood from patients having severe COVID-19, a circulating form of ACE2 was detected with an apparent molecular mass of 70 kDa while it was barely detectable in patients with mild infection. Of importance, in the patients with severe COVID-19 disease, the presence of three soluble fragments of VE-cadherin (70, 62, 54 kDa) were detected using the antiEC1 antibody while only the 54 kDa fragment was present in patients with mild disease. Altogether, these data clearly support a role for ACE2 on VE-cadherin cleavage leading to potential biomarkers in SARS-CoV2 infection related with the vascular disease in “Long COVID-19”.

Manipulating autophagy is a promising strategy for treating cancer as several autophagy inhibitors shown to induce autophagic cell death. One of these, autophagonizer (APZ), induces apoptosis-independent cell death by binding an unknown target via an unknown mechanism. To identify APZ targets we used a label-free drug affinity responsive target stability (DARTS) approach with a liquid chromatography/tandem mass spectrometry (LC-MS/MS) readout. Of 35 protein interactors, we identified Hsp70 as a key target protein of unmodified APZ in autophagy. Either APZ treatment or Hsp70 inhibition attenuates integrity of lysosomes, which leads to autophagic cell death exhibiting an excellent synergism with a clinical drug, temozolomide, in vitro, in vivo, and orthotropic glioma xenograft model. These findings demonstrate the potential of APZ to induce autophagic cell death and its development to combinational chemotherapeutic agent for glioma treatment. Collectively, our study demonstrated that APZ, a new autophagy inhibitor, can be used as a potent antitumor drug candidate to get over unassailable glioma and revealed a novel function of Hsp70 in lysosomal integrity regulation of autophagy.

We present the full case pictorial assay including preoperative imaging as well as the surgical correction of the uterine anomaly and associated complication of a very rare case of occult unicornuate right uterus with rudimentary non-communicating functioning left horn and its natural evolution following an initially incomplete surgical treatment.

Right-sided ligamentum teres (RSLT) is a rare anatomic variant in which the fetal umbilical vein connects to the right portal vein. Patients with RSLT frequently have hepatic vasculature and bile duct anomalies, which increase the risk of complications with hepatectomy. Most patients with RSLT undergo open hepatectomy. We describe a patient with RSLT and hepatocellular carcinoma who underwent laparoscopic hepatectomy. The patient was a 69-year-old man with hepatocellular carcinoma located in the left liver based on computed tomography (CT) and magnetic resonance imaging. Imaging also demonstrated RSLT. Three-dimensional CT analysis revealed independent right lateral type anomalies of the portal vein and bile duct. Laparoscopic extended left lateral sectionectomy was performed after careful surgical planning. Ultrasonography was used frequently during surgery to avoid damaging the right hepatic vasculature. The left lateral and partial left median sections were removed as planned. The patient’s postoperative recovery was uneventful. Avoiding injury to the right hepatic vasculature is essential when performing left lobectomy, including left lateral sectionectomy, in patients with RSLT. Laparoscopic hepatectomy can be performed safely in patients with RSLT, provided that careful surgical planning is conducted using preoperative three-dimensional CT analysis and intraoperative ultrasonography is used.

Otolith morphology analysis is one of the main tools used for fish or fish stock identification. Moreover, otolith shape can also be used in fish dietary studies (stomach content) for the identi-fication of prey fishes and their size according to the relationship between fish and otolith sizes. In the present study, the relationship between fish length and otolith morphological dimensions was investigated for the sabre squirrelfish, Sargocentron spiniferum (Forsskål, 1775) (family: Hol-ocentridae). Samples of 185 fish were collected from the coast of the Red Sea, Egypt. To analyze the relationship between fish and otolith, otolith morphometric measurements (length, width, area, perimeter, weight, sulcus, and ostium) and shape factors (aspect ratio, compactness, form factor, rectangularity, roundness, ellipticity, squareness) describing outline shape were extracted using image analysis. Generalized linear models were applied for the relationship between body length and each otolith morphology feature. From the relationships between the total length of fish and fourteen morphology features, only otolith length, caudal length, and squareness were significantly correlated with fish size. Our results provide more information for the relationship between fish length and otolith morphometric features.

HIV-associated cognitive dysfunction during combination antiretroviral therapy (cART) involves mitochondrial dysfunction, but the impact of contemporary cART on chronic metabolic changes in the brain and in latent HIV infection is unclear. We interrogated mitochondrial function in a human microglia (hμglia) cell line harboring inducible HIV provirus, and in SH-SY5Y cells, after exposure to individual antiretroviral drugs or cART, using the MitoStress assay. cART-induced changes in protein expression, reactive oxygen species (ROS) production, mitochondrial DNA copy number, and cellular iron were also explored. Finally, we evaluated the ability of ROS scavengers or plasmid-mediated overexpression of the antioxidant iron-binding protein, Fth1, to reverse mitochondrial defects. Contemporary antiretroviral drugs, particularly bictegravir, depressed multiple facets of mitochondrial function by 20-30%, with most pronounced effects in latently infected-HIV+ hμglia and SH-SY5Y cells. Latently HIV-infected hμglia exhibited upregulated glycolysis. Increases in total and/or mitochondrial ROS, mitochondrial DNA copy number, and cellular iron accompanied mitochondrial defects in hμglia and SH-SY5Y cells. In SH-SY5Y cells, cART reduced mitochondrial iron-sulfur-cluster-containing supercomplex and subunit expression and increased Nox2 expression. Fth1 overexpression or pre-treatment with N-acetylcysteine prevented cART-induced mitochondrial dysfunction. Contemporary cART impairs mitochondrial bioenergetics in hμglia and SH-SY5Y cells, partly through cellular iron accumulation; some effects differ by HIV latency.

While investigating the outcomes of balloon dilatation procedures in patients with congenital obstructive lesions of the heart, several parallel observations have been made. The purpose of this review is to present these observations/phenomena/innovations related to balloon dilatation of pulmonary stenosis (PS), aortic stenosis (AS), and aortic coarctation (AC). In subjects who had balloon pulmonary valvuloplasty (BPV), development of infundibular obstruction, electrocardiographic (ECG) changes, changes in right ventricular filling, role of balloon/annulus ratios on the results of BPV, and double balloon vs. single balloon BPV will be reviewed. In patients who had balloon aortic valvuloplasty (BAV), causes of aortic insufficiency and trans-umbilical venous approach for BAV will be tackled. In children who had balloon angioplasty (BA) of AC, aortic remodeling and biophysical response after BA of AC will be discussed.

Introduction: Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common condition associated with high morbidity and mortality. Although patients with heart failure (HF) are known to have an increased risk of PE, there is limited evidence regarding its specific impact on patients with acute PE, both in presentation and outcomes, and its relationship with left ventricular ejection fraction (LVEF). Material and Methods: A prospective observational study was conducted at two tertiary hospitals, including patients with symptomatic acute PE between January 2012 and December 2022. The primary objective of the study was the development of a composite outcome (mortality, major bleeding, and recurrence) within the first 30 days. The secondary objective was the development of early complications in patients with HF and reduced LVEF. Results: Out of 1991 patients included with symptomatic acute PE, 7.13% had a history of HF. Patients with HF were older and had more comorbidities. The HF group showed higher mortality (11.27% vs. 4.33%, p<0.001) and major bleeding (9.86% vs. 4.54%, p=0.005). In multivariate analysis, HF was an independent risk factor for the development of the composite outcome (HR 1.93; 95% CI: 1.35-2.76). Reduced LVEF was independently associated with a higher risk of bleeding (HR 3.44; 95% CI: 1.34-8.81). Conclusion: In patients with symptomatic acute pulmonary embolism, heart failure is independently associated with a higher risk of early complications. Additionally, heart failure with reduced LVEF is an independent risk factor for major bleeding.

A retrospective study was conducted on pathologically diagnosed arrhythmogenic cardiomyopathy (ACM) from consecutive cases over the past 34 years (n = 1,109). The cardiac conduction system (CCS) was removed in two blocks, containing the following structures: Sino-atrial node (SAN), atrio-ventricular junction (AVJ) including the atrio-ventricular node (AVN), the His bundle (HB), the bifurcation (BIF), the left bundle branch (LBB) and the right bundle branch (RBB). The ACM cases (2.07% of the total cases) consisted of 20 (86.96%) sudden unexpected cardiac death (SUCD) and 3 (13.04%) native explanted hearts; 16 (69.56%) were males and 7 (30.44%) were females, ranging in age from 5 to 65 (mean age ± SD, 36.13 ± 16.06) years. The following anomalies of the CCS, displayed as percentages of ACM SUCD cases, have been detected: Hypoplasia of SAN (80%) and/or AVJ (86.67%) due to fatty-fibrous involvement, AVJ dispersion and/or septation (46.67%), central fibrous body (CFB) hypoplasia (33.33%), fibromuscular dysplasia of SAN (20%) and/or AVN (26.67%) arteries, hemorrhage and infarct-like lesions of CCS (13.33%), islands of conduction tissue in CFB (13.33%), Mahaim fibers (13.33%), LBB block by fibrosis (13.33%), AVN tongue (13.33%), HB duplicity (6.67%%), CFB cartilaginous meta-hyperplasia (6.67%), and right sided HB (6.67%). Arrhythmias are the hallmark of ACM, not only from the fatty-fibrous disruption of the ventricular myocardium that accounts for reentrant ventricular tachycardia, but also from the fatty-fibrous involvement of CCS itself. The careful examination of the cardiac conduction system on serial sections was crucial in documenting the fatty-fibrous infiltration of CCS in ACM.

Our hypothesis that controlled ozone applications interfere into the redox balance of the biological organism (first published in 1998 with a preclinical trial on protecting the liver from CCl4 intoxication), has been verified over the last 2 decades in reactive oxygen species (ROS)-induced mitochondrial pathologies, such as rheumatoid arthritis, osteoarthritis, aging processes, diabetes-2 and in prevention of intoxications. Low-dose ozone acts as a redox bioregulator: The restoration of the disturbed redox balance is comprehensible in a number of preclinical and clinical studies by a remarkable increase of the antioxidant repair markers, here mainly shown as glutathione increase and a reduction in oxidative stress markers, mainly malondialdehyde. The mechanism of action is shown, relevant data are displayed, evaluated and comprehensively discussed: The repair side of the equilibrium increases by 21% up to 140% compared to the non-ozone treated groups and depending on the indication; the stress markers are simultaneously reduced, the redox system regains its balance.

Abstract: Objectives: To establish the expression profile of N6-methyladenosine(m6A) modifications in the hippocampus of mice with diabetic cognitive impairment (DCI) and elucidate the potential regulatory mechanism. Methods: A DCI model was established by feeding a high-fat diet to C57BL/6J mice. m6A and RNA sequencing was conducted to profile the m6A-tagged transcripts in the hippocampus. Results: Methylated RNA immunoprecipitation with next-generation sequencing and RNA sequencing analyses yielded differentially m6A-modified and expressed genes in the hippocampus of DCI mice, which were enriched in pathways involving synaptic transmission and axonal guidance. Mechanistic analyses revealed a remarkable change in m6A modification levels through alteration of the mRNA expression of m6A methyltransferases (METTL3 and METTL14) and demethylase (FTO) in the hippocampus of DCI mice. Conclusions: We identified a co-mediated specific RNA regulatory strategy that broadens the epigenetic regulatory mechanism of RNA-induced neurodegenerative disorders associated with metabolic and endocrine diseases.

Eustachian Tube Dysfunction is considered a common condition among ENT patients and requires careful history, clinical examination and appropriate investigations to obtain a diagnosis. The ETDQ-7 questionnaire is a useful tool to subjectively score severity of symptoms that are related to this pathology (Appendix A). This study aimed to adapt and validate the ETDQ-7 questionnaire in Greece to ensure correct and efficient use in the outpatient setting (Appendix B). The ETDQ-7 was translated into the Greek language following appropriate methodology. Data for the main study were collected from a sample of 75 Greek patients diagnosed with ETD as well as 25 patients that did not have ETD and who served as a control group. The participants completed the adapted ETDQ-7 questionnaire and underwent a clinical examination that was statistically correlated with their ETDQ-7 answers. Face and content validity were confirmed and the questionnaire was found easy to administer and to be completed by our patients. Test-retest reliability revealed similar internal consistency for the questions and good correlation between individual items and total score. Discriminative validity confirmed statistically significant difference between the two patient groups to ensure that the Greek version of ETDQ-7 is useful to confirm the diagnosis. The Greek version of the ETDQ-7 is safe and efficient to use among a variety of investigation methods for the diagnosis of ETD in the Greek speaking population.

The purpose of this study was to examine the impact of fructose consumption during the peri-pubertal period on the later onset of metabolic syndrome in rats. Additionally, the study sought to explore the potential of moderate-intensity physical training as a non-pharmacological approach to mitigate the fructose effects. Male rats, 30 days old, received 10% fructose, and were submitted to concomitant moderate-intensity training until 60 days old. They were divided into 4 groups: sedentary control (SC), sedentary fructose (SF), trained control (TC), and trained fructose (TF). Fructose consumption mainly affected adult animals, resulting in glucose intolerance, increased periepididymal fat, and increased total cholesterol, triglycerides, and insulin levels. Furthermore, these rats exhibited reduced sympathetic nerve activity. The moderate running led to a decrease in periepididymal and retroperitoneal adipose tissue, as well as a reduction in total cholesterol and improved glucose tolerance. Peri-pubertal rats that received combination treatments exhibited lower levels of glucose and insulin during an intraperitoneal glucose tolerance test. The results indicate that 10% fructose supplementation during peripuberty predisposes to metabolic syndrome in adulthood. However, simultaneous moderate-intensity exercise training attenuates these effects and induces positive changes in glycemic homeostasis, lipid metabolism, and autonomic nervous system activity.

The neurovascular niche is crucial for constant blood supply and blood-brain barrier (BBB) function and is altered in a number of different neurological conditions, making this an intensely active field of research. Brain vasculature is unique for its tight association of endothelial cells with astrocytic endfeet processes. Separation of the vascular compartment by centrifugation-based methods confirmed enrichment of astrocytic endfeet processes, making it possible to study the entire vascular niche with such methods. Several centrifugation-based separation protocols are found in the literature; however, with some constraints which limit their applicability and the scope of the studies. Here, we describe and validate a protocol for physically separating the neurovascular niche from the parenchyma, which is optimized for smaller tissue quantities. Using endothelial, neuronal and astrocyte markers, we show that quantitative Western blot-based target detection can be performed of both the vascular and parenchymal fractions using as little as a single mouse brain hemisphere. Validation of our protocol in rodent stroke models by detecting changes in serum albumin signals and astrocyte activation, i.e. increased glial fibrillary acidic protein expression, between the ipsilateral and the lesion-free contralateral hemisphere demonstrates this protocol as a new way of detecting BBB breakdown and astrogliosis, respectively.

Heart failure with reduced ejection fraction (HFrEF) is considered a major healthcare problem with frequent decompensations, high hospitalization and mortality rates. In severe heart failure (HF), the symptoms are refractory to medical treatment and require advanced therapeutic strategies. Early recognition of HF sub- and decompensation is the cornerstone of the timely treatment intensification and, therefore, improvement of the prognosis. Echocardiography is the gold standard for the assessment of systolic and diastolic functions. It allows to obtain accurate and non-invasive measurements of the ventricular function in HF. In severely compromised HF patients, advanced cardiovascular ultrasound modalities may provide a better assessment of intracardiac hemodynamic changes and subclinical congestion. Particularly, cardiovascular and lung ultrasound allow to make a more accurate diagnosis of subclinical congestion in HFrEF. The aim of this review is to summarize the advantages and limitations of currently available ultrasound modalities in the ambulatory monitoring of patients with HFrEF.

Background: Evaluation of left ventricular(LV) functions in patients with idiopathic premature ventricular contraction(PVC) with preserved LV Ejection Fraction(LVEF), especially in the subclinical stage, may be of great importance in terms of directing early treatment. Methods: A total of 122 patients, retrospectively recruited, were divided into three groups according to PVC burden: Group 1; 5%PVC<10%, Group 2; 10%PVC<15%, and Group 3; 15% PVC. Transthoracic echocardiography(TTE) was performed to evaluate LV parameters. Results: LV-GLS was found to be significantly lower in groups 2 and 3 with high PVC burden (18.89 ± 1.4, 17.55 ± 2.1, 16.26 ± 1.3; p<0.001 respectively). Correlation analysis revealed a positive and significant correlation between PVC burden with deterioration in LV-GLS (r:0.536; p<0.001). In addition, PVC burden was found to be an independent predictor of LV-GLS deterioration in multiple linear regression analysis(:0.525, p<0.001). The ROC curve analysis demonstrated that a PVC burden cut-off value of 8.4% was associated with a LV-GLS deterioration greater than -18, with a specificity of 75.4% and a sensitivity of 75.4% (AUC: 0.81 [0.73-0.88] 95% CI; p<0.001). Conclusions: PVC burden was an independent predictor of deterioration in LV-GLS. In the presence of subclinical LV injury associated with PVC burden, early catheter ablation strategies may be therapeutically beneficial.

Introduction: Left atrial hypertension is one of the pathophysiologies of heart failure with preserved ejection fraction. We hypothesized that left atrial pressure response (LAPR) to incremental pacing is higher in patients with atrial fibrillation (AF) and can predict left ventricular diastolic dysfunction. Methods: Patients requiring left atrial access as a part of a therapeutic procedure for AF (n=204, AF group) or supraventricular tachycardia (n=34, control group) were analyzed (male n=183, 54±12 years old). LAPR was measured during incremental pacing. Results: Baseline left atrial pressure and LAPR at all pacing rates were not different between the AF and control groups. They were higher in patients with a high E/e’ (≥ 8) than in those with a low E/e’ (&lt; 8). LAPR at a pacing interval of 400ms and E/e' were positively correlated (r=0.373, p&lt;0.001). Body mass index and a high E/e' were independent predictors of pacing-induced left atrial hypertension. Conclusions: The LAPR to incremental pacing was constant regardless of AF. The non-invasive echocardiographic marker E/e' reflected pacing-induced left atrial hypertension.

The aim of the current study was to determine the effectiveness of two surgical techniques regarding the cow respiratory rates, heart rates, and rumination time using two sensors: an experimental device that was created by the Institute of Biomedical Engineering of Kaunas University of Technology (Lithuania) and the “SCR” (SCR Engineers Ltd., Netanya, Israel) system. The cows were divided into two groups: PA1—cows treated by percutaneous abomasopexy (n = 10), and RSO2—cows treated by right side omentopexy (n = 8). For the control group (KH), according to the principle of analogues (number of lactations, breed, and days in milk), we selected clinically healthy cows (n = 9). After the surgical treatment for the abomasal displacement, the experimental device was applied for the recording of the heart and breathing rates; 12 hour tracking of the rumination time (RT) was implemented using the system ''SCR''; and the body temperature was measured. After 12 hours, the blood was taken for biochemical and morphological tests. The experimental device recorded 12 hours of the respiratory rate (RR) and heart beat rate (HBR) information. We determined the concentrations of the blood serum beta-hydroxybutyrate (BHB), calcium (Ca), phosphorus (Phos), magnesium (Mg), and iron (Fe), as well as the activities of aspartarte aminotransferase (AST) and gamma-glutamyl transferase (GGT). According to searches for relationships between the traditional blood biochemical and morphological parameters, and the parameters measured by the experimental device, the more efficient abomasal displacement surgical method was the right side omentopexy. With the sensors, we found, after right side omentopexy, a 5.19 beats/min lower (1.10-times) average value of the respiratory rate, 1.13-times higher level of the heart rate, a 0.15 oC higher temperature, and a 3.29-times lower rumination time compared to the clinical healthy cows. Further research with larger numbers of animals and longer experimental periods are needed prior to practical applications.

Tightly regulated and robust mitochondrial activities are critical for normal hearing. Previously, we demonstrated that Fus1 KO mice with mitochondrial dysfunction exhibit premature hearing loss. Molecular analysis of the cochlea revealed hyperactivation of the mTOR pathway, oxidative stress, altered mitochondrial morphology and quantity, suggesting compromised energy sensing and production. Here, we investigated whether pharmacological modulation of metabolic pathways using rapamycin (RAPA) or 2-deoxy-D-glucose (2-DG) supplementation can protect against hearing loss in female Fus1 KO mice. Additionally, we aimed to identify mitochondria- and Fus1-dependent molecular pathways and processes critical for hearing. We found that inhibiting mTOR or activating alternative mitochondrial energetic pathways to glycolysis protected hearing in the mice. Comparative gene expression analysis revealed dysregulation of critical biological processes in the KO cochlea, including mitochondrial metabolism, neural and immune responses, and cochlear hypothalamic–pituitary–adrenal axis signaling system. RAPA and 2-DG mostly normalized these processes, although some genes showed a drug-specific response or no response at all. Interestingly, both drugs resulted in a pronounced upregulation of critical hearing-related genes not altered in the non-treated KO cochlea, including cytoskeletal and motor proteins, and Ca2+-linked transporters and voltage-gated channels. These findings suggest that pharmacological modulation of mitochondrial metabolism and bioenergetics may restore and activate processes critical for hearing, thereby protecting against hearing loss

Binge drinking is associated with increased mortality and morbidity. Burkholderia pseudomallei, the causative agent of pneumonic melioidosis can occur in healthy humans; however, binge alcohol intoxication is a major risk factor. Previous findings indicate that a single binge alcohol episode increases Burkholderia spp. infection by reducing alveolar macrophage function. The aim of this study was to test the ability of the phytonutrient sulforaphane (SFN) to rescue the phagocytic function of alveolar macrophages when infected with Burkholderia spp. in vitro. B. thailandensis E264 was used as a useful BSL-1 model to determine the effects of SFN pre-treatment. The primary outcome was macrophage phagocytic killing, while the secondary outcome was the nuclear factor (erythroid-derived 2)-like (Nrf2) signaling response measured by western blot analysis. Results indicate that alveolar macrophages pre-treated with SFN (5 M) and challenged with 0.2% (v/v) alcohol for 3 or 8 h prior to live B. thailandensis infection improved intracellular killing of B. thailandensis ~2-fold compared to MH-S cells treated with alcohol alone. These data demonstrate that SFN may be an effective pre-treatment option to prevent alcohol mediated immune dysfunction and restore macrophage phagocytic killing of Burkholderia spp. and other similar opportunistic pathogens.

Abstract: SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) infection is associated, alongside with lung infection and respiratory disease, to cardiovascular dysfunction that occurs at any stage of the disease. This includes ischemic heart disease, arrhythmias, and cardiomyopathies. The common pathophysiological link between SARS-CoV-2 infection and the cardiovascular events is represented by coagulation abnormalities and disruption of factors released by endothelial cells which contribute in maintaining the blood vessels into an anti-thrombotic state. Thus, early alteration of the functionality of endothelial cells, which may be found soon after SARS-CoV-2 infection, seems to represent the major target of SARS CoV-2 disease state and accounts for the systemic vascular dysfunction that leads to detrimental effect in terms of hospitalization and death accompanying the disease. In particular, the molecular interaction of SARS-CoV-2 with ACE2 receptor located in endothelial cell surface, either at the pulmonary and systemic level, leads to early impairment of endothelial function which, in turn, is followed by vascular inflammation and thrombosis of peripheral blood vessels. This highlights systemic hypoxia and further aggravates the vicious circle that compromises the development of the disease leading to irreversible tissue damage and death of patients with SARS CoV-2 infection. The review aims to assess some recent advances to define the crucial role of endothelial dysfunction in the pathogenesis of vascular complications accompanying SARS-CoV-2 infection. In particular, the molecular mechanisms associated to the interaction of SARS CoV-2 with ACE2 receptor located on the endothelial cells are highlighted to support its role in compromising endothelial cell functionality. Finally, the consequences of endothelial dysfunction in enhancing pro-inflammatory and pro-thrombotic effects of SARS-CoV-2 infection are assessed in order to identify early therapeutic interventions able to reduce the impact of the disease in high-risk patients.

Covid-19 pandemic has captivated scientists to investigate if this new disease can affect the central nervous system (CNS). The most challenging symptoms of Covid-19 are related to respiratory distress, and most patients admitted in intensive care units cannot breathe by their own. Therefore, a crucial question is if respiratory distress can be partially explained by the CNS affection. SARS-Cov-2 is a beta-coronavirus that shares high similarities with SARS-CoV. The infection of SARS‐CoV has been reported in the brains from both patients and experimental animals, where the brainstem was heavily infected. Those coronaviruses have been able to invade the brainstem via a synapse‐connected route to the medullary respiratory center, where the infected regions included the nucleus of the solitary tract and nucleus ambiguous. The vagal afferent nerves from receptors in the lung communicate with the medulla and pons respiratory control centers to coordinate inspiration and expiration. This suggests that neuroinvasion of SARS‐CoV‐2 might play a role in the acute respiratory failure of Covid-19. Therefore, acute respiratory distress in Covid-19 can be partially explained by brainstem dysfunction, suggesting the needs of more specific and aggressive treatments with the direct participation of neurologists and neurointensivists.

Evidence has been accumulated demonstrating that heavy metals may accumulate in various organs leading to tissue damage and toxic effects in mammals. In particular, the Central Nervous System (CNS) seems to be particularly vulnerable to cumulative concentrations of heavy metals, though the pathophysiological mechanisms is still to be clarified. In particular the potential role of oligodendrocyte dysfunction and myelin production after exposure to subtoxic concentration of heavy metals is to be better assessed. Here we investigated on the effect of sub-toxic concentration of several essential (Cu^{2 +}, Cr³⁺, Ni²⁺, Co²⁺) and non-essential (Pb²⁺, Cd²⁺, Al³⁺) heavy metals on MO3.13 and SHSY5Y human oligodendrocyte and neuronal cell lines (grown individually or in co-culture). In particular, exposure of both cell lines to heavy metals produced a reduced cell viability of co-cultured cell lines compared to cells grown separately. This effect was more pronounced in neurons which were more sensitive to metals than oligodendrocytes when the cells were grown in co-culture. On the other hand, a significant reduction of lipid component in cells occurred after their exposure to heavy metals, an effect accompanied by substantial reduction of the main protein that makes up myelin (MBP) in co-cultured cells. Finally, the effect of heavy metals in oligodendrocytes were associated to imbalanced intracellular calcium ion concentration as measured through the fluorescent Rhod-2 probe, thus confirming that heavy metals, even used at subtoxic concentrations, lead to dysfunctional oligodendrocytes. In conclusion, our data show, for the first time, that sub-toxic concentrations of several heavy metals lead to dysfunctional oligodendrocytes, an effect highlighted when these cells are co-cultured with neurons. The pathophysiological mechanism(s) underlying this effect is to be better clarified. However, imbalanced intracellular calcium ion regulation, altered lipid formation and, finally, imbalanced myelin formation seem to play a major role in early stages of heavy metal-related oligodendrocyte dysfunction.

Background and Objectives: Proper use of oral anticoagulants is crucial in the management of non-valvular atrial fibrillation (AF) patients. Left atrial appendage closure (LAAC) may be considered for stroke prevention in patients with AF and contraindications for long-term anticoagulant treatment. We aimed to assess the anticoagulation status and LAAC indications in patients with AF from HECMOS (Hellenic Cardiorenal Morbidity Snapshot) survey. Materials and Methods: HECMOS was a nationwide snapshot survey of cardiorenal morbidity in hospitalized cardiology patients. HECMOS used an electronic platform to collect demographic and clinically relevant information from all patients hospitalized on March 3, 2022, in 55 different cardiology departments. In this substudy, we included patients with known AF without mechanical prosthetic valves and moderate to severe mitral valve stenosis. Patients with prior stroke, previous major bleeding, poor adherence to anticoagulants, and end-stage renal disease were considered candidates for LAAC. Results: Two hundred fifty-six patients (mean age 76.6±11.7, 148 males) were included in our analysis. Most of them (n=159; 62%) suffered from persistent AF. Mean CHA2DS2-VASc score was 4.28±1.7, while mean HAS-BLED score was 1.47±0.9. Three out of 3 patients with a CHA2DS2-VASc 0 or 1 (female) received improperly anticoagulants. Sixteen out of 18 patients with a CHA2DS2-VASc 1 or 2 (female) received anticoagulants. Thirty-three out of 235 patients with a CHA2DS2-VASc &gt; 1 or 2 (for female) did not receive improperly anticoagulants. Among 221 under anticoagulant therapy, 191 (86.4%) received non-vitamin K antagonist oral anticoagulants (NOACs) and 30 (13.6%) received vitamin K antagonists. Relative indications for LAAC were present in 64 patients with NVAF (60 had only one risk factor and 2 had two concurrent risk factors). In detail, 36 had a prior stroke, 17 patients had a history of major bleeding, 15 patients reported poor or no adherence to the anticoagulant therapy and 5 had eGFR&lt; 15 ml/min/1.73m2. Moreover, 33 had a HAS-BLED score ≥3. No LAAC treatment was recorded. Conclusions: Anticoagulation status was nearly optimal in a high thromboembolic risk population of cardiology patients, mainly treated with NOACs. One out of four AF patients should be screened for LAAC.

The growing increase in infections caused by C. tropicalis, associated with its drug resistance and consequent high mortality, especially in immunosuppressed people, today generates a serious global public health problem. In the search for new potential drug candidates that can be used as treatments or adjuvants in the control of infections by these pathogenic yeasts, the objective of this research was to evaluate the action of isoespintanol (ISO) against the formation of biofilms fungal, the mitochondrial membrane potential (∆Ψm) and its effect on the integrity of the cell wall. We report the ability of ISO to inhibit the formation of biofilms by up to 89.35%, in all cases higher than the values expressed by amphotericin B (AFB). Flow cytometric experiments using rhodamine 123 (Rh123) showed the ability of ISO to cause mitochondrial dysfunction in these cells. Likewise, experiments using calcofluor white (CFW) and analyzed by flow cytometry, showed the ability of ISO to affect the integrity of the cell wall by stimulating chitin synthesis; these changes in the integrity of the wall were also observed through transmission electron microscopy (TEM). These mechanisms are involved in the antifungal action of this monoterpene.

The brain of Drosophila melanogaster is comprised of some 100,00 neurons, 127 and 80 of which are dopaminergic and serotonergic, respectively. Their activity regulates behavioral functions equivalent to those in mammals, e.g. motor activity, reward and aversion, memory formation, feeding, sexual appetite etc. Mammalian dopaminergic and serotonergic neurons are known to be heterogeneous. They differ in their projections and in their gene expression profile. A sophisticated genetic tool box is available, which allows for targeting virtually any gene with amazing precision in Drosophila melanogaster. Similarly, Drosophila genes can be replaced by their human orthologs including disease-associated alleles. Finally, genetic manipulation can be restricted to single fly neurons. This has allowed for addressing the role of individual neurons in circuits, which determine attraction and aversion, sleep and arousal, odor preference etc. Flies harboring mutated human orthologs provide models, which can be interrogated to understand the effect of the mutant protein on cell fate and neuronal connectivity. These models are also useful for proof-of-concept studies to examine the corrective action of therapeutic strategies. Finally, experiments in Drosophila can be readily scaled up to an extent, which allows for drug screening with reasonably high throughput.

Mitochondria are classically termed as powerhouse of a mammalian cell. Most of the cellular chemical energy in the form of adenosine tri phosphate (ATP) is generated by mitochondria and dysregulation of mitochondrial functions thus can be potentially fatal of cellular homeostasis and health. Acute respiratory distress has been earlier linked to mitochondrial dysfunction. SARS-CoV-2 infection severity leads to acute respiratory distress syndrome (ARDS) and can be fatal. We tried to investigate possible connection between SARS-CoV-2, ARDS and mitochondria. Here, we report identification of SARS-CoV-2 non-structural proteins (particularly Nsp12 and 13) that have recognition sequence with respect to mitochondrial entry. We also report that these proteins can potentially shuttle between cytoplasm and mitochondria based on the localization signals and help in downstream maintenance of the virus. Their properties to use ATP for enzymatic activities may cause ATP scavenging allowing viral RNA functions in lieu of host cell health.

1) Background: We analyzed, by PET-SCAN, how growth hormone (GH) could act on the brain of an older woman, not GH-deficient, which was beginning to show some cognitive deficiencies and presented an ApoE genotype 4/3; 2) Methods: After performing a first psychometric study (TAVEC verbal learning test), the metabolic activity of brain structures related to knowledge, memory, and behavior was analyzed using 18-F Fluorodeoxyglucose PET-SCAN. The patient was then treated with GH (0.4 mg/day) for three weeks and on the last day under this treatment, a new PET-SCAN was performed. One month after beginning treatment with GH, a new TAVEC test was performed; 3) Results: GH administration normalized the cognitive deficits observed in the first psychometric test and increased significantly (P < 0.025) the metabolic activity in practically all brain cortical areas, specifically in the left hippocampus and left amygdala, although not in the left parahippocampus; and 4) Conclusions: This is the first study in which the positive effects of GH on cerebral metabolism have been visualized in a human patient. Our data confirm the positive effects of this hormone on cognition, memory and behavior in patients affected by mild cognitive impairments.

We document for the first time epsilon waves on the electrocardiogram of a patient with Dravet syndrome (DS) who does not exhibit structural cardiac pathology. DS, a severe form of pediatric epilepsy, involves mutations in the SCN1A gene, which disrupt sodium ion flow and increase the risk of sudden unexpected death in epilepsy. The epsilon waves, typically associated with arrhythmogenic right ventricular dysplasia, may also suggest a link between neuronal and cardiac dysfunctions. In our case, the epsilon waves appear to originate from abnormalities in sodium channels rather than structural changes in the myocardium. This finding underscores the importance of assessing both neurological and cardiac manifestations in patients with severe epilepsy, opening new avenues for the research and treatment of these interactions in DS.

Background Few data exist on comparative long-term outcomes of severe aortic stenosis (AS) patients with different flow-gradient patterns undergoing transcatheter aortic valve implantation (TAVI). This study sought to evaluate the impact of pre-TAVI flow-gradient pattern on long-term clinical outcomes after TAVI and assess changes in left ventricular ejection fraction (LVEF) of different subtypes of AS patients following TAVI. Methods Consecutive patients with severe AS undergoing TAVI in our institution were screened and prospectively enrolled. Patients were divided in four subgroups according to pre-TAVI flow/gradient pattern: (i) low flow - low gradient (LF-LG): stroke volume indexed (SVi) ≤ 35ml/m2 and mean gradient (MG) < 40mmHg), (ii) normal flow - low gradient (NF-LG): SVi > 35ml/m2 and MG < 40mmHg, (iii) low flow - high gradient (LF-HG) : SVi ≤ 35ml/m2 and MG ≥ 40mmHg and (iv) normal flow - high gradient (NF-HG): SVi > 35 ml/m2 and MG ≥ 40mmHg. Transthoracic echocardiography was repeated at 1-year follow-up. Clinical follow-up was obtained at 12 months, and yearly thereafter until 5-year follow up was complete for all patients. Results A total of 272 patients with complete echocardiographic and clinical follow-up were included in our analysis. Their mean age was 80±7 years and the majority of patients (N=138, 50.2%) were women. 62 patients (22.8% of the study population) were distributed in LF-LG group, 98 patients (36%) were LF-HG patients, 95 patients (34.9%) were NF-HG, while 17 patients (6.3%) were NF-LG. There was a greater prevalence of comorbidities among LF-LG AS patients. One-year all-cause mortality differed significantly between the four subgroups of AS patients (log rank p: 0.022) and was more prevalent among LF-LG patients (25.8%) compared to LF-HG (11.3%), NF-HG (6.3%) and NF-LG patients (18.8%). At 5-year follow-up, global mortality remained persistently higher among LF-LG patients (64.5%) compared to LF-HG (47.9%), NF-HG (42.9%) and NF-LG patients (58.8%) (log rank p: 0.029). At multivariable Cox hazard regression analysis, baseline SVi (HR: 0.951, 95% C.I.; 0.918 – 0.984), the presence of at least moderate tricuspid regurgitation at baseline (HR: 3.091, 95% C.I: 1.645 - 5.809) and at least moderate paravalvular leak (PVL) post-TAVI (HR: 1.456 , 95% C.I.: 1.106 - 1.792 ) were significant independent predictors of late global mortality. LF-LG patients and LF-HG patients exhibited a significant increase in LVEF at 1-year follow-up. A lower LVEF (p<0.001) and a lower Svi (p<0.001) at baseline were associated with LVEF improvement at 1 year. Conclusions Patients with LF-LG AS have acceptable 1-year outcomes with significant improvement in LVEF at 1-year follow-up, but exhibit an exceedingly high 5-year mortality following TAVI. The presence of low transvalvular flow and at least moderate tricuspid regurgitation at baseline and significant paravalvular leak post-TAVI were associated with poorer long-term outcomes in the entire cohort of AS patients. The presence of a low LVEF or a low SVi predicts LVEF improvement at 1-year.

Cardiogenic shock (CS) is part of a clinical syndrome consisting of acute left ventricular failure causing severe hypotension leading to inadequate organ and tissue perfusion. The most com-monly used devices to support patients affected by CS are Intra-Aortic Balloon Pump (IABP), Impella 2.5 pump and Extracorporeal Membrane Oxygenation. The aim of this study is the com-parison between Impella and IABP using CARDIOSIM© software simulator of the cardiovascular system. The results of the simulations included baseline conditions from a virtual patient in CS followed by IABP assistance in synchronized mode with different driving and vacuum pressures. Subsequently, the same baseline conditions were supported by the Impella 2.5 with different ro-tational speeds. The percentage variation with respect to baseline conditions was calculated for hemodynamic and energetic variables during IABP and Impella assistance. Impella pump driven with a rotational speed of 50000 rpm increased the total flow by 4.36% with a reduction in left ventricular end diastolic volume (LVEDV) by ≅15% to ≅30%. A reduction in left ventricular end systolic volume (LVESV) by ≅10% to ≅18% (≅12% to ≅33%) was observed with IABP (Impella) as-sistance. Taking into account the limitations of a simulation setting, this study highlights that assistance with the Impella device leads to higher reduction in LVESV, LVEDV, left ventricular external work and left atrial pressure-volume loop area compared to IABP support.

A chronic activated pro-inflammatory cytokine network (“inflamm-aging”) may amplify the neurodegenerative effects of a fall induced brain trauma in geriatric subjects. Our research aimed to evaluate how a trained machine learning algorithm may predict recent antecedent falls based only on specific serologic cytokines network analysis and how the consequences of these falls can be substantiated on standard head MRIs. All 279 subjects included in our study were selected from the ADNI1 dataset and all had a mild cognitive impairment diagnostic at the ADNI1 study baseline. A “train group” was built and included 14 subjects with a history of a recent, simple, standing-level fall. These were carefully matched with 14 similar subjects without any antecedent trauma. The “test group” included 251 subjects, all without any history of recent fall. The machine learning algorithm (classic C4.5 decision tree) was trained to detect a pattern of variation in 23 clinically relevant cytokines in relation with an antecedent fall. Changes in five cytokines (matrix metalloproteinase-7, eotaxin-1, interleukin-3, interleukin-8 and matrix metalloproteinase-9) were used for fall prediction in the “test” group. Once trained, the algorithm predicted a recent fall in 119 cases from the test group. The mean brain ventricular volume that was significantly different between fall/non-fall subgroups (41645.5±10337.2 vs 27127.3±6749.4 mm3, p=0.005) remained significant in the test group, after prediction between (41544.24±17343.4 vs 34553.5±10543.2 mm3, p=0.042). The hippocampus mean volume was also significantly different between in the test group (6297.3±1080.1 vs 6745.9±1123.7, p=0.0015). A significant brain ventricular difference was observed in the “65<y.o.” subgroup (p=0.04). If confirmed by larger prospective studies, our findings may increase the precision of the neuro-cognitive assessments in geriatric subjects.

Lower urinary tract dysfunction, such as incontinence or urinary retention, is one of the leading consequences of neurological diseases. This significantly impacts the quality of life for those affected, with implications extending not only to humans but also to clinical veterinary care. Having motor and sensory fibers, the pudendal nerve is an optimal candidate for neuromodulation therapies using bidirectional intraneural prostheses, paving the way towards the restoration of a more physiological urination cycle: bladder state can be detected from recorded neural signals, then an electrical current can be injected to the nerve based on the bladder real-time need. To develop such prostheses and investigate this novel approach, animal studies are still required since the morphology of the target nerve is fundamental to optimize the prosthesis design. This study aims to describe the porcine pudendal nerve as a model for neuromodulation studies aiming at restoring lower urinary tract dysfunction. Five male farm pigs were involved in the study. First, a surgical procedure to access the porcine pudendal nerve without muscle resection was developed. Then, an intraneural interface was implanted to confirm the presence of fibers innervating the external urethral sphincter by measuring its electromyographic activity. Finally, the morpho-physiology of the porcine pudendal nerve at the level of surgical exposure was described by using histological and immunohistochemical characterization. This analysis confirmed the nerve fasciculate nature and the presence of mixed fibers with a spatial and functional organization. These achievements pave the way for further pudendal neuromodulation studies by using a clinically relevant animal model with the potential for translating the findings into clinical applications.

Erectile dysfunction (ED) is a common and feared complication of radical prostatectomy (RP) for prostate cancer. Recently, tissue engineering is being attempted for post-prostatectomy ED, with controlled interactions between cells, growth factors, and extracellular matrix (ECM) being important for nerve regeneration's structural integrity. In this study, we evaluated the effects of biomechanical ECM patch on human bone marrow-derived mesenchymal stem cells (hBMSCs) morphology and behavior in bilateral cavernous nerve injury (BCNI) rat model. The ECM patch, made of decellularized human fibroblast-derived ECM (hFDM) and a biocompatible polyvinyl alcohol (PVA) hydrogel, was tested with human bone marrow-derived mesenchymal stem cells (hBMSCs) on a bilateral cavernous nerve injury (BCNI) rat model. In vitro analysis showed that the hFDM/PVA + hBMSCs patches significantly increased neural development markers. In vivo experiments demonstrated that the rats treated with the hFDM/PVA patch had higher ICP/MAP ratio, a higher ratio of smooth muscle to collagen, increased content of nNOS, higher levels of eNOS protein expression, and a higher cGMP level compared to the BCNI group. These results indicate that the hFDM/PVA patch is effective in promoting angiogenesis, smooth muscle regeneration, and nitrergic nerve regeneration, which could contribute to improved erectile function in post-prostatectomy ED.

Trueperella pyogenes is a common opportunistic pathogen which is one of the main causes of postpartum endometritis in dairy cows. As a substitute for antibiotics, the probiotic Lactobacillus rhamnosus GR-1 has been used in a wide range of clinical treatments. Our experiments were designed to establish a model of anti-damage which LGR-1 was used to protect bovine endometrial epithelial cells (BEECs) from inflammatory damage and cell destruction caused by T. pyogenes. Increased expression of NLRP3 inflammasomes and cytokines was observed following T. pyogenes challenge, but this increase was relieved by LGR-1 pretreatment. Immunofluorescence and Western blot analyses revealed that T. pyogenes infection also results in the damage of tight junction proteins in BEECs. The expression levels of Claudin-1, Occludin, and ZO-1 were decreased in cells only infected with T. pyogenes but not in cells pretreated with LGR-1. Moreover, the detection of the anti-apoptotic protein Bcl-2 and apoptotic proteins BAX, cytochrome c, as well as the activating effector caspase-3 revealed that T. pyogenes induced apoptosis of BEECs, which was also confirmed by DAPI staining to observe the morphological changes of the nuclei of cell apoptosis and by TUNEL staining to locate the cells undergoing apoptosis. Our data indicate that LGR-1 ameliorates the T. pyogenes–induced barrier dysfunction of BEECs and pre-application of LGR-1 could be an effective strategy for controlling T. pyogenes infection.

Ecklonia cava (E.cava) can alleviate vascular dysfunction in diseases associated with poor circulation. E. cava contains various polyphenols with different functions, but few studies have compared the effects of these polyphenols. Here, we comparatively investigated four major compounds present in an ethanoic extract of E. cava. These four major compounds were isolated and their effects were examined on monocyte-associated vascular inflammation and dysfunctions. Pyrogallol-phloroglucinol-6,6-bieckol (PPB) significantly inhibited monocyte migration in vitro by reducing levels of inflammatory macrophage differentiation and of its related molecular factors. In addition, PPB protected against monocyte-associated endothelial cell death by increasing the phosphorylations of PI3K-AKT and AMPK, decreasing caspase levels, and reducing monocyte-associated vascular smooth muscle cell proliferation and migration by decreasing the phosphorylations of ERK and AKT. The results of this study show that four compounds were effective for reduction of monocyte-associated vascular inflammation and dysfunctions, but PPB might be more useful for the treatment of vascular dysfunction in diseases associated with poor circulation.

At present Coronavirus disease-2019 (COVID-19) is one of the leading contributing factor to mortality and the impact of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection on the sinonasal tract has become more prominent, particularly with the rising awareness of olfactory dysfunction (OD). We extracted data from published papers available in electronic databases (Wiley online library, PubMed, and Nature). We used the following search terms alone or with combinations - Olfactory dysfunction, SARS-CoV-2, mechanism and treatments. We found worldwide up to 98% of patients confirmed OD due to COVID-19. Current studies have implied that regardless of the high self-reported recovery rate, 25–40% of patients after 1 or 2 months and approximately 15%–28% of patients at six months struggle to fully restore their sense of smell. Moreover, female sex, younger and older age, active smoking, and chronic lung disease are reported as the associated risk factors of OD. Although the pathophysiological mechanism of action(s) of the OD is yet to be explored in depth, central nervous system (CNS) entrance, olfactory bulb (OB) and sustentacular cell damage, neural routes inflammation, non-neuronal cells damage, decreased OB volume and deregulation of olfactory receptor genes are among the commonly reported mechanisms for the development of OD.

Cardiovascular diseases (CVDs) and type 2 diabetes mellitus (T2DM) are two of the four major chronic non-communicable diseases (NCDs), representing the leading cause of death worldwide. Several studies demonstrate that endothelial dysfunction (ED) plays a central role in the pathogenesis of these chronic diseases. Although it is well known that systemic chronic inflammation and oxidative stress are primarily involved in the development of ED, recent studies have shown that perivascular adipose tissue (PVAT) is implicated in its pathogenesis, also contributing to the progression of atherosclerosis and to insulin resistance (IR). In this review we describe the relationship between PVAT and ED, and we also analyse the role of PVAT in the pathogenesis of CVDs and T2DM, further assessing its potential therapeutic target with the aim of restoring normal ED and reducing global cardiovascular risk.

(1) Background: To identify the association between the presence or absence of raphe and aortic valve dysfunction as well as the presence of aortopathy in patients with bicuspid aortic valve (BAV); (2) Methods: This retrospective study enrolled 312 participants (mean [SD] age, 52.7 [14.3] years; 227 men [72.8%]) with BAV. The BAVs were divided into those with presence (raphe+) or absence (raphe-) of raphe. Valvular function was classified as normal, aortic regurgitation (AR), or aortic stenosis (AS) using TTE. The pattern of BAV aortopathy was determined by the presence of dilatation at the sinus of Valsalva and the middle ascending aorta using CCT.; (3) Results: BAVs with raphe+ had a higher prevalence of AR (148 [79.5%] vs. 48 [37.8%], P < .001) but a lower prevalence of AS (90 [48.6%] vs. 99 [78.0%], P < .001) compared with those with raphe-. The types of BAV aortopathy were significantly different (P = 0.021) according to those with BAV-raphe+ and BAV-raphe-.; (4) Conclusions: The presence of a raphe was significantly associated with a higher prevalence of AR but a lower prevalence of AS and combined dilatation of the aortic root and middle ascending aorta. The presence of raphe was an independent determinant of AR.

An ongoing EU Horizon 2020 Project called BionicVEST is investigating the effect of constant electrical stimulation (ES) of the inferior vestibular nerve in patients with bilateral vestibular dysfunction (BVD)[1]. The evidence is that constant ES results in improved postural stability and gait performance and so the question of central importance is how could constant ES of mainly saccular afferents in these BVD patients cause this improved performance? We suggest that the constant ES is substituting for the absent saccular neural input to the vestibular nuclei and the cerebellum in these BVD patients and indirectly via these structures to other structures which have been of great recent interest in motor control. One target area, the anterior midline cerebellum (the uvula) has recently been targeted as a location for deep brain stimulation in human patients to improve postural stability and gait. There are projections from midline cerebellum to basal ganglia including the striatum, structures involved in the initiation of gait. It may be that the effect of this activation of peripheral saccular afferent neurons is analogous to the effect of deep brain stimulation (DBS) by electrodes in basal ganglia acting to help alleviate the symptoms of patients with Parkinson's disease.

Cardiomyopathy is the leading cause of morbidity and mortality among all complications of type 2 diabetes (T2D) and obese patients. Diabetic cardiomyopathy (DC) is characterized by changes in cardiac morphology with declines in both systolic and diastolic functions. No rodent models fully captured phenotypes of DC. The ZDSD rat, a new generation of T2D rat model with intact leptin signaling features with slow onset of diabetes and obesity, which closely mimics the development of the disease in patients. Age-matched male ZDSD and SD rats were monitored for blood pressure, glucose and cardiac function using echocardiography. Animals were also challenged with 1 mg/kg dobutamine for the assessment of cardiac reserve. ZDSD rats developed hypertension from age of 18 weeks with blood pressure significantly higher than controls. At resting state, ZDSD rats showed biphasic changes in left ventricular posterior wall thickness and cavity volume. Concomitantly, both ejection fraction (EF) and transmitral E/A ratio of LV declined at 34 weeks old. Upon treatment with dobutamine, ZDSD lost cardiac contractility. Therefore, ZDSD rats may serve as a suitable preclinical model to study potential therapeutic approaches to treat cardiomyopathy with presence of metabolic syndromes.