COVID-19 and Mental Health: A "Pandemic Within a Pandemic".

The COVID-19 pandemic has brought significant changes in daily life for humanity and has had a profound impact on mental health. As widely acknowledged, the pandemic has led to notable increases in rates of anxiety, depression, distress, and other mental health-related issues, affecting both infected patients and non-infected individuals. COVID-19 patients and survivors face heightened risks for various neurological and psychiatric disorders and complications. Vulnerable populations, including those with pre-existing mental health conditions and individuals living in poverty or frailty, may encounter additional challenges. Tragically, suicide rates have also risen, particularly among young people, due to factors such as unemployment, financial crises, domestic violence, substance abuse, and social isolation. Efforts are underway to address these mental health issues, with healthcare professionals urged to regularly screen both COVID-19 and post-COVID-19 patients and survivors for psychological distress, ensuring rapid and appropriate interventions. Ongoing periodic follow-up and multidimensional, interdisciplinary approaches are essential for individuals experiencing long-term psychiatric sequelae. Preventive strategies must be developed to mitigate mental health problems during both the acute and recovery phases of COVID-19 infection. Vaccination efforts continue to prioritize vulnerable populations, including those with mental health conditions, to prevent future complications. Given the profound implications of mental health problems, including shorter life expectancy, diminished quality of life, heightened distress among caregivers, and substantial economic burden, it is imperative that political and health authorities prioritize the mental well-being of all individuals affected by COVID-19, including infected individuals, non-infected individuals, survivors, and caregivers.

A Tiny Viral Protein, SARS-CoV-2-ORF7b: Functional Molecular Mechanisms.

This study presents the interaction with the human host metabolism of SARS-CoV-2 ORF7b protein (43 aa), using a protein-protein interaction network analysis. After pruning, we selected from BioGRID the 51 most significant proteins among 2753 proven interactions and 1708 interactors specific to ORF7b. We used these proteins as functional seeds, and we obtained a significant network of 551 nodes via STRING. We performed topological analysis and calculated topological distributions by Cytoscape. By following a hub-and-spoke network architectural model, we were able to identify seven proteins that ranked high as hubs and an additional seven as bottlenecks. Through this interaction model, we identified significant GO-processes (5057 terms in 15 categories) induced in human metabolism by ORF7b. We discovered high statistical significance processes of dysregulated molecular cell mechanisms caused by acting ORF7b. We detected disease-related human proteins and their involvement in metabolic roles, how they relate in a distorted way to signaling and/or functional systems, in particular intra- and inter-cellular signaling systems, and the molecular mechanisms that supervise programmed cell death, with mechanisms similar to that of cancer metastasis diffusion. A cluster analysis showed 10 compact and significant functional clusters, where two of them overlap in a Giant Connected Component core of 206 total nodes. These two clusters contain most of the high-rank nodes. ORF7b acts through these two clusters, inducing most of the metabolic dysregulation. We conducted a co-regulation and transcriptional analysis by hub and bottleneck proteins. This analysis allowed us to define the transcription factors and miRNAs that control the high-ranking proteins and the dysregulated processes within the limits of the poor knowledge that these sectors still impose.

An Update on Myocarditis in Forensic Pathology.

In forensic medicine, myocarditis is a complicated topic in the context of sudden death and medical malpractice. A good knowledge of the etiopathology, histopathology, and available literature are both indispensable and essential for the correct management and evaluation of the causal link. Some agents, which are rarely lethal for humans, are not necessarily related to death from myocarditis, even if an infection in other organs such as the gastrointestinal tract is documented. The diagnosis of the causes of death is often difficult and confusing. In some cases, the hypothetical diagnosis of myocarditis as the cause of death is formulated by deduction, causing error and misleading the correct temporal evaluation of pathological events. We reviewed the literature realizing that histomorphological data are scarce and often poorly documented. Only after COVID-19 have the histomorphological aspects of myocarditis been better documented. This is due to poor autopsy practice and poor accuracy in identifying the specific histotype of myocarditis with identification of the responsible agent. We believe that four points are essential for a better understanding and complete diagnosis of the disease: (1) clinical classification of myocarditis; (2) etiological classification of myocarditis; (3) pathophysiology of viral and bacterial infections with host response; and (4) histopathological diagnosis with precise identification of the histotype and pathogen. In the review we provide histological images from authoritative scientific references with the aim of providing useful information and food for thought to readers.

Hypoplastic Left Heart Syndrome: About a Postnatal Death.

BACKGROUND: Hypoplastic left heart syndrome (HLHS) is a congenital heart disease that is associated with high mortality rates in the early neonatal period and during surgical treatments. This is mainly due to missed prenatal diagnosis, delayed diagnostic suspicion, and consequent unsuccessful therapeutic intervention. CASE REPORT: twenty-six hours after birth, a female newborn died of severe respiratory failure. No cardiac abnormalities and no genetic diseases had been evidenced or documented during intrauterine life. The case became of medico-legal concern for the assessment of alleged medical malpractice. Therefore, a forensic autopsy was performed. RESULTS: the macroscopic study of the heart revealed the hypoplasia of the left cardiac cavities with the left ventricle (LV) reduced to a slot and a right ventricular cavity that simulated the presence of a single and unique ventricular chamber. The predominance of the left heart was evident. CONCLUSIONS: HLHS is a rare condition that is incompatible with life, with very high mortality from cardiorespiratory insufficiency that occurs soon after birth. The prompt diagnosis of HLHS during pregnancy is crucial in managing the disease with surgery.

Pathophysiology of Early Brain Injury and Its Association with Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage: A Review of Current Literature.

Background: Delayed cerebral ischemia (DCI) is a common and serious complication of aneurysmal subarachnoid hemorrhage (aSAH). Though many clinical trials have looked at therapies for DCI and vasospasm in aSAH, along with reducing rebleeding risks, none have led to improving outcomes in this patient population. We present an up-to-date review of the pathophysiology of DCI and its association with early brain injury (EBI). Recent Findings: Recent studies have demonstrated that EBI, as opposed to delayed brain injury, is the main contributor to downstream pathophysiological mechanisms that play a role in the development of DCI. New predictive models, including advanced monitoring and neuroimaging techniques, can help detect EBI and improve the clinical management of aSAH patients. Summary: EBI, the severity of subarachnoid hemorrhage, and physiological/imaging markers can serve as indicators for potential early therapeutics in aSAH. The microcellular milieu and hemodynamic pathomechanisms should remain a focus of researchers and clinicians. With the advancement in understanding the pathophysiology of DCI, we are hopeful that we will make strides toward better outcomes for this unique patient population.

Central and Peripheral Nervous System Complications of Vasculitis Syndromes from Pathology to Bedside: Part 2-Peripheral Nervous System.

PURPOSE OF REVIEW: Peripheral nervous system vasculitides (PNSV) are a heterogeneous group of disorders with a clinical subset that may differ in prognosis and therapy. We provide a comprehensive update on the clinical assessment, diagnosis, complications, treatment, and follow-up of PNSV. RECENT FINDINGS: Progress in neuroimaging, molecular testing, and peripheral nerve biopsy has improved clinical assessment and decision-making of PNSV, also providing novel insights on how to prevent misdiagnosis and increase diagnostic certainty. Advances in imaging techniques, allowing to clearly display the vessel walls, have also enhanced the possibility to differentiate inflammatory from non-inflammatory vascular lesions, while recent histopathology data have identified the main morphological criteria for more accurate diagnosis and differential diagnoses. Overall, the identification of peculiar morphological findings tends to improve diagnostic accuracy by defining a clearer boundary between systemic and non-systemic neuropathies. Therefore, the definition of epineurium vessel wall damage, type of vascular lesion, characterization of lymphocyte populations, antibodies, and inflammatory factors, as well as the identification of direct nerve damage or degeneration, are the common goals for pathologists and clinicians, who will both benefit for data integration and findings translation. Nevertheless, to date, treatment is still largely empiric and, in some cases, unsatisfactory, thus often precluding precise prognostic prediction. In this context, new diagnostic techniques and multidisciplinary management will be essential in the proper diagnosis and prompt management of PNSV, as highlighted in the present review. Thirty to fifty percent of all patients with vasculitis have signs of polyneuropathy. Neuropathies associated with systemic vasculitis are best managed according to the guidelines of the underlying disease because appropriate workup and initiation of treatment can reduce morbidity. Steroids, or in severe or progressive cases, cyclophosphamide pulse therapy is the standard therapy in non-systemic vasculitic neuropathies. Some patients need long-term immunosuppression. The use of novel technologies for high-throughput genotyping will permit to determine the genetic influence of related phenotypes in patients with PNSV.

Ligature Mark: Crime or Suicide?

Identifying the morphological findings of vitality is crucial when determining if a lesion was inflicted in life or postmortem [...].

Glycated ACE2 reduces anti-remodeling effects of renin-angiotensin system inhibition in human diabetic hearts.

BACKGROUND: High glycated-hemoglobin (HbA1c) levels correlated with an elevated risk of adverse cardiovascular outcomes despite renin-angiotensin system (RAS) inhibition in type-2 diabetic (T2DM) patients with reduced ejection fraction. Using the routine biopsies of non-T2DM heart transplanted (HTX) in T2DM recipients, we evaluated whether the diabetic milieu modulates glycosylated ACE2 (GlycACE2) levels in cardiomyocytes, known to be affected by non-enzymatic glycosylation, and the relationship with glycemic control. OBJECTIVES: We investigated the possible effects of GlycACE2 on the anti-remodeling pathways of the RAS inhibitors by evaluating the levels of Angiotensin (Ang) 1-9, Ang 1-7, and Mas receptor (MasR), Nuclear-factor of activated T-cells (NFAT), and fibrosis in human hearts. METHODS: We evaluated 197 first HTX recipients (107 non-T2DM, 90 T2DM). All patients were treated with angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) at hospital discharge. Patients underwent clinical evaluation (metabolic status, echocardiography, coronary CT-angiography, and endomyocardial biopsies). Biopsies were used to evaluate ACE2, GlycACE2, Ang 1-9, Ang 1-7, MasR, NAFT, and fibrosis. RESULTS: GlycACE2 was higher in T2DM compared tonon-T2DM cardiomyocytes. Moreover, reduced expressions of Ang 1-9, Ang 1-7, and MasR were observed, suggesting impaired effects of RAS-inhibition in diabetic hearts. Accordingly, biopsies from T2DM recipients showed higher fibrosis than those from non-T2DM recipients. Notably, the expression of GlycACE2 in heart biopsies was strongly dependent on glycemic control, as reflected by the correlation between mean plasma HbA1c, evaluated quarterly during the 12-month follow-up, and GlycACE2 expression. CONCLUSION: Poor glycemic control, favoring GlycACE2, may attenuate the cardioprotective effects of RAS-inhibition. However, the achievement of tight glycemic control normalizes the anti-remodeling effects of RAS-inhibition. TRIAL REGISTRATION: https://clinicaltrials.gov/ NCT03546062.

A Clue on the Skin: A Systematic Review on Immunohistochemical Analyses of the Ligature Mark.

BACKGROUND: A ligature mark is a common injury in cases of hanging or strangulation. Estimation of age and vitality of the ligature mark can be crucial for differentiating antemortem and postmortem wounds and to distinguish between simulated suicidal hanging or accidental strangulation to conceal a crime and not simulated events. The immunohistochemistry has been recommended by several Authors as a reliable tool to determine whether an injury was sustained during life or not. Unfortunately, no general agreement on the immunohistochemical markers to be used has been found among the scientific community. The aim of the study was to detect the type and function of the immunohistochemical markers useful in the assessment of the vitality and age of the ligature marks for routine diagnostics. METHODS: Papers available on Pubmed, Scopus, and Web of Science were reviewed according to the PRISMA statement. RESULTS: Only eight papers satisfied all the following inclusion criteria: full texts in English dealing with human ligature marks and immunohistochemistry published on impacted or indexed scientific journals. CONCLUSIONS: The assessment of the vitality of a ligature mark is still a challenging topic in forensic science. Under ideal conditions and in compliance with autopsy protocols, the diagnosis of death by hanging or strangulation on fresh bodies can be better supported by autopsy findings other than a ligature mark. The validation of immunohistochemical markers on large series could be of help in doubtful cases and differential diagnoses.

Central and Peripheral Nervous System Complications of Vasculitis Syndromes From Pathology to Bedside: Part 1-Central Nervous System.

PURPOSE OF REVIEW: The aim of this review is to provide a comprehensive update on the clinical assessment, diagnosis, complications, and treatment of primary central nervous system vasculitis (PCNSV). RECENT FINDINGS: The developments in neuroimaging, molecular testing, and cerebral biopsy have enhanced clinical assessment and decision making, providing novel insights to prevent misdiagnosis increasing diagnostic certainty. Advances in imaging techniques visualizing the wall of intracranial vessels have improved the possibility to distinguish inflammatory from non-inflammatory vascular lesions. Large recent studies have revealed a more varied histopathological pictures and disclosed an association with amyloid angiopathy. Unfortunately, therapy remains largely empiric. PCNSV is a heterogeneous group of disorders encompassing different clinical subsets that may differ in terms of prognosis and therapy. Recent evidence has described a more benign course, with good response to therapy. New diagnostic techniques will play soon a pivotal role in the appropriate diagnosis and prompt management of PCNSV.

MED1/BDNF/TrkB pathway is involved in thalamic hemorrhage-induced pain and depression by regulating microglia.

Central post-stroke pain (CPSP) and associated depression remain poorly understood and pharmacological treatments are unsatisfactory. Recently, microglia activation was suggested to be involved in CPSP pathophysiology. The goal of this study was to investigate the effectiveness of a co-ultramicronized combination of N-palmitoylethanolamide and luteolin (PEALut) in a mouse model of thalamic hemorrhage (TH)-induced CPSP. TH was established through the collagenase-IV injection in thalamic ventral-posterolateral-nucleus. PEALut effects in CPSP-associated behaviors were evaluated during a 28-days observation period. We found that repeated administrations of co-ultra PEALut significantly reduced mechanical hypersensitivity after TH, as compared to vehicle, by reducing the early microglial activation in the perilesional site. Moreover, PEALut prevented the development of depressive-like behavior (21 days post-TH). These effects were associated with the restoration of synaptic plasticity in LEC-DG pathway and monoamines levels found impaired in TH mice. Hippocampal MED1 and TrkB expressions were significantly increased in TH compared to sham mice 21 days post-TH, whereas BDNF levels were decreased. PEALut restored MED1/TrkB/BDNF expression in mice. Remarkably, we found significant overexpression of MED1 in the human autoptic brain specimens after stroke, indicating a translational potential of our findings. These results pave the way for better-investigating depression in TH- induced CPSP, together with the involvement of MED1/TrkB/BDNF pathway, proposing PEALut as an adjuvant treatment.

Strategies and Controversies in the Treatment With Carbon Dioxide Laser of Laryngeal Hemangioma: A Case Series and Review of the Literature.

INTRODUCTION: The hemangioma is the most common vascular tumor, involving the head and neck in 60% of cases. It is rare in the larynx. In children, hemangiomas are more frequent on the subglottis, whereas in adults the most common site is the supraglottis. Laryngeal hemangioma with cavernous features isolated to the free edge of the vocal fold is a very rare clinical finding. We present 2 cases of glottic hemangioma. Both patients reported severe hoarseness. CASES: In the first patient, an extensive blue-purple mass was seen on the right vocal cord. The patient was posted for microlaryngeal surgery with carbon dioxide (CO2) laser. Second patient had a large, smooth, flesh-colored polypoid mass emanating from the left vocal cord. The patient was posted for microlaryngeal surgery. After 2 months, both patients showed a considerable voice improvement. DISCUSSION: Vocal cord hemangiomas are very rare, and they usually cause problem in the voice of the patient. A vascular lesion that may mimic a hemangioma may sometimes result from an organizing hematoma following a hemorrhage on the vocal cords due to voice abuse. Laryngeal hemangiomas also need to be distinguished pathologically from polypoidal vascular granulation tissue that may be produced by laryngeal biopsy, intubation, or trauma. Indirect endoscopy is enough to diagnosis. No active treatment is advised for adult laryngeal hemangiomas unless the lesions are symptomatic or show a tendency to involve other parts. There is no uniformly accepted treatment of head and neck hemangiomas. Surgical excision with laser CO2 microlaryngoscopic techniques gives satisfactory results.

Sodium/glucose cotransporter 2 (SGLT2) inhibitors improve cardiac function by reducing JunD expression in human diabetic hearts.

BACKGROUND: The pathogenesis of experimental diabetic cardiomyopathy may involve the activator protein 1 (AP-1) member, JunD. Using non-diabetic heart transplant (HTX) in recipients with diabetes, we examined the effects of the diabetic milieu (hyperglycemia and insulin resistance) on cardiac JunD expression over 12 months. Because sodium/glucose cotransporter-2 inhibitors (SGLT2i) significantly reverse high glucose-induced AP-1 binding in the proximal tubular cell, we investigated JunD expression in a subgroup of type 2 diabetic recipients receiving SGLT2i treatment. METHODS: We evaluated 77 first HTX recipients (40 and 37 patients with and without diabetes, respectively). Among the recipients with diabetes, 17 (45.9%) were receiving SGLT2i treatment. HTX recipients underwent standard clinical evaluation (metabolic status, echocardiography, coronary computed tomography angiography, and endomyocardial biopsy). In the biopsy samples, we evaluated JunD, insulin receptor substrates 1 and 2 (IRS1 and IRS2), peroxisome proliferator-activated receptor-γ (PPAR-γ), and ceramide levels using real-time polymerase chain reaction and immunofluorescence. The biopsy evaluations in this study were performed at 1-4 weeks (basal), 5-12 weeks (intermediate), and up to 48 weeks (final, end of 12-month follow-up) after HTX. RESULTS: There was a significant early and progressive increase in the cardiac expression of JunD/PPAR-γ and ceramide levels, along with a significant decrease in IRS1 and IRS2 in recipients with diabetes but not in those without diabetes. These molecular changes were blunted in patients with diabetes receiving SGLT2i treatment. CONCLUSION: Early pathogenesis in human diabetic cardiomyopathy is associated with JunD/PPAR-γ overexpression and lipid accumulation following HTX in recipients with diabetes. Remarkably, this phenomenon was reduced by concomitant therapy with SGLT2i, which acted directly on diabetic hearts.

Infections Are a Very Dangerous Affair: Enterobiasis and Death.

BACKGROUND: Enterobiasis or oxyuriasis from Enterobius vermicularis is an infection usually localized in the large bowel and cecum. Generally, the symptoms are characterized by anal itching, and intestinal or nervous disorders. Rarely, it is responsible for death. METHODS: A forensic autopsy of a 52-year-old white male inmate who died 5 days after hospitalization was performed. Histological and toxicological analyses were also performed. RESULTS: The death occurred by localization of Enterobius vermicularis in the duodenum and in the proximal ileum, with intestinal haemorrhage, inflammation, and peritonitis documented by histological examination. CONCLUSION: This is a common infectious disease, and can rarely occur with a fatal outcome, even in advanced populations. The lack of knowledge related to the rarity of death from enterobiasis disease can determine a dangerous concern.

Sudden Unexpected Death Caused by Cardiac Metastasization from Histiocytic Sarcoma.

BACKGROUND: Haematological malignancies, such as lymphoma and leukaemia, can have a variety of clinical manifestations. The most frequent cause of death from haematological malignancies is multiple organ failure due to neoplastic organ infiltration and/or septic shock. Histiocytic sarcoma (HS) is a rare malignant nodal or extranodal tumour with histiocytic immunophenotype that originates from a lymphohematopoietic precursor. The patients with HS usually have a poor prognosis due to its aggressive clinical behaviour. Rare cases of undiagnosed sudden HS death have been described in the literature. METHODS: A forensic autopsy of a 46-year-old white male who died at home suddenly and unexpectedly without warning conditions or known diseases. Gross analysis, histology and toxicology were also performed. RESULTS: The diagnosis of HS of the ileum with secondary nodal and cardiac metastatization was made. CONCLUSIONS: A prompt diagnosis of HS in life is paramount because it can make a difference in prognostic outcomes.

Systemic Inflammatory Response Index and Futile Recanalization in Patients with Ischemic Stroke Undergoing Endovascular Treatment.

Futile recanalization remains a significant challenge for endovascular treatment (EVT) of acute ischemic stroke (AIS). The inflammatory response that occurs after cerebral infarct plays a central role in stroke pathobiology that can influence the outcome of a recanalization procedure. The aim of this study was to evaluate the relationship between the systemic inflammatory response index (SIRI) and futile recanalization in patients with AIS. We retrospectively identified consecutive patients with ischemic stroke due to proximal arterial occlusion in the anterior circulation, who were treated with EVT and achieved near-complete or complete recanalization. Absolute neutrophil count (ANC), absolute monocyte count (AMC), and absolute lymphocyte count (ALC) were collected from admission blood work to calculate SIRI as ANC × AMC/ALC. The study outcome was futile recanalization, defined as poor functional status [modified Rankin scale (mRS) score ≥ 3] at 3 months despite complete or near-complete recanalization. A total of 184 patients were included. Futile recanalization was observed in 110 (59.8%) patients. Older patients (odds ratio (OR) = 1.07, 95% confidence interval (CI): 1.04-1.10, p < 0.001), higher admission National Institutes of Health stroke scale score (OR = 1.10, 95% CI: 1.02-1.19, p = 0.013), and higher admission SIRI (OR = 1.08, 95% CI: 1.01-1.17, p = 0.028) increased the risk of the poor outcome at 3 months despite complete or near-complete recanalization.

Pulmonary arterial hypertension (PAH) from autopsy study: T-cells, B-cells and mastocytes detection as morphological evidence of immunologically mediated pathogenesis.

BACKGROUND: Pulmonary arterial hypertension (PAH) is characterized by severe vascular remodelling, resulting in increased pulmonary vascular resistance with cardiac hypertrophy and heart failure. However, the diagnosis of PAH is often inaccurate. Many cases of PAH are incorrectly diagnosed or missed, and they are often associated with death. The aim of this study was to verify the morphological and histological criteria of fatal cases of PAH and evaluate the lymphocytic populations associated to lesions with reactive neo-angiogenesis. METHODS: Pulmonary lung sections from 10 cases of sudden unexpected death (SUD) in the absence of previously diagnosed diseases and in an apparent state of well-being, with final histological post autopsy diagnosis of PAH were collected. The pathological findings were compared using ten controls from non-pathological lung from deaths from other causes. The autopsies included 4 males (40%) and 6 females (60%) with an average age of 52.1 ± 10.1 years. Sections stained with hematoxylin and eosin (H&E) were revised for a morphological diagnosis. Subsequently, serial sections were performed and stained with immunohistochemistry for anti-CD20 (B-lymphocytes), anti-CD3 (T-lymphocytes), anti-CD4 (T-helper lumphocytes), anti-CD8 (T-cytotoxic lymphocytes) and anti-CD117/C-Kit (mast cells/MCs) to detect inflammatory infiltrate and different ratios of cell-type. Statistical analysis was conducted using a paired t-test looking at 100 cells in 3 different tissue samples representative of vascular lesion and 3 different random normal lung parenchyma fields without lesion (from 10 normal control lungs), to identify specific lymphocyte subpopulations in inflammatory infiltrates. RESULTS: There was a significant percentage increase of CD20 (p < 0.001), CD8 (p = 0.002), CD4 (p < 0.001), and CD117/C-Kit positive (C-Kit+; p < 0.001) cells mainly detected around wall vessels; while increased MCs positivity and C-Kit+ were observed especially in alveolar septa. In addition, reactive angiomatosis was observed. CONCLUSIONS: The inflammatory infiltrate should be included for a correct diagnosis of PAH besides the vascular remodelling. The inflammatory infiltrate seems to be implicated as a main factor in the pathogenesis. This finding is important to rule out secondary pulmonary hypertension, to identify SUDs of unknown causes and to add new elements to the literature that can explain the immunologically related pathogenesis of PAH.

Lysosome purinergic receptor P2X4 regulates neoangiogenesis induced by microvesicles from sarcoma patients.

The tumor microenvironment modulates cancer growth. Extracellular vesicles (EVs) have been identified as key mediators of intercellular communication, but their role in tumor growth is largely unexplored. Here, we demonstrate that EVs from sarcoma patients promote neoangiogenesis via a purinergic X receptor 4 (P2XR4) -dependent mechanism in vitro and in vivo. Using a proteomic approach, we analyzed the protein content of plasma EVs and identified critical activated pathways in human umbilical vein endothelial cells (HUVECs) and human progenitor hematopoietic cells (CD34+). We then showed that vessel formation was due to rapid mitochondrial activation, intracellular Ca2+ mobilization, increased extracellular ATP, and trafficking of the lysosomal P2XR4 to the cell membrane, which is required for cell motility and formation of stable branching vascular networks. Cell membrane translocation of P2XR4 was induced by proteins and chemokines contained in EVs (e.g. Del-1 and SDF-1). Del-1 was found expressed in many EVs from sarcoma tumors and several tumor types. P2XR4 blockade reduced EVs-induced vessels in angioreactors, as well as intratumor vascularization in mouse xenografts. Together, these findings identify P2XR4 as a key mediator of EVs-induced tumor angiogenesis via a signaling mediated by mitochondria-lysosome-sensing response in endothelial cells, and indicate a novel target for therapeutic interventions.

The Neurological Manifestations of Post-Acute Sequelae of SARS-CoV-2 infection.

PURPOSE OF REVIEW: Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global health challenge. This review aims to summarize the incidence, risk factors, possible pathophysiology, and proposed management of neurological manifestations of post-acute sequelae of SARS-CoV-2 infection (PASC) or neuro-PASC based on the published literature. RECENT FINDINGS: The National Institutes of Health has noted that PASC is a multi-organ disorder ranging from mild symptoms to an incapacitating state that can last for weeks or longer following recovery from initial infection with SARS-CoV-2. Various pathophysiological mechanisms have been proposed as the culprit for the development of PASC. These include, but are not limited to, direct or indirect invasion of the virus into the brain, immune dysregulation, hormonal disturbances, elevated cytokine levels due to immune reaction leading to chronic inflammation, direct tissue damage to other organs, and persistent low-grade infection. A multidisciplinary approach for the treatment of neuro-PASC will be required to diagnose and address these symptoms. Tailored rehabilitation and novel cognitive therapy protocols are as important as pharmacological treatments to treat neuro-PASC effectively. With recognizing the growing numbers of COVID-19 patients suffering from neuro-PASC, there is an urgent need to identify affected individuals early to provide the most appropriate and efficient treatments. Awareness among the general population and health care professionals about PASC is rising, and more efforts are needed to understand and treat this new emerging challenge. In this review, we summarize the relevant scientific literature about neuro-PASC.

Novel biomarkers useful in surveillance of graft rejection after heart transplantation.

Heart transplantation (HTx) is considered the gold-standard therapy for the treatment of advanced heart failure (HF). The long-term survival in HTx is hindered by graft failure which represents one of the major limitations of the long-term efficacy of HTx. Endomyocardial biopsy (EMB) and the evaluation of donor-specific antibodies (DSA) are currently considered the essential diagnostic tools for surveillance of graft rejection. Recently, new molecular biomarkers (including cell-free DeoxyriboNucleic Acid, exosomes, gene profiling microarray, nanostring, reverse transcriptase multiplex ligation-dependent probe amplification, proteomics and immune profiling by quantitative multiplex immunofluorescence) provide useful information on mechanisms of graft rejection. The ambitious role of a similar change of perspective is aimed at a better and longer graft preservation.