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Purpose of ReviewPeripheral 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 FindingsProgress 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.

Background DNA methylation can play a pathogenic role in the early stages of hyperglycemia linking homeostasis imbalance and vascular damage. Material and methods We investigated DNA methylome by RRBS in CD04+ and CD08+ T cells from healthy subjects (HS) to pre-diabetics (Pre-Diab) and type 2 diabetic (T2D) patients to identify early biomarkers of glucose impairment and vascular damage. Our cross-sectional study enrolled 14 individuals from HS state to increasing hyperglycemia (pilot study, PIRAMIDE trial, NCT03792607). Results Globally, differentially methylated regions (DMRs) were mostly annotated to promoter regions. Hypermethylated DMRs were greater than hypomethylated in CD04+ T cells whereas CD08+ T showed an opposite trend. Moreover, DMRs overlapping between Pre-Diab and T2D patients were mostly hypermethylated in both T cells. Interestingly, SPARC was the most hypomethylated gene in Pre-Diab and its methylation level gradually decreased in T2D patients. Besides, SPARC showed a significant positive correlation with DBP (+0.76), HDL (+0.54), Creatinine (+0.83), LVDd (+0.98), LVSD (+0.98), LAD (+0.98), LVPWd (+0.84), AODd (+0.81), HR (+0.72), Triglycerides (+0.83), LAD (+0.69) and AODd (+0.52) whereas a negative correlation with Cholesterol (−0.52) and LDL (−0.71) in T2D. Conclusion SPARC hypomethylation in CD08+ T cells may be a useful biomarker of vascular complications in Pre-Diab with a possible role for primary prevention warranting further multicenter clinical trials to validate our findings.

Dilated cardiomyopathy (DCM) represents a common genetic cause of mechanical and/or electrical dysfunction leading to heart failure (HF) onset for which truncating variants in titin (TTN) gene result in the most frequent mutations. Moreover, myocyte and endothelial cell apoptosis is a key endophenotype underlying cardiac remodelling. Therefore, a deeper knowledge about molecular networks leading to acute injury and apoptosis may reveal novel circulating biomarkers useful to better discriminate HF phenotypes, patients at risk of heart transplant as well as graft reject in order to improve personalised therapy. Remarkably, increased plasma levels of cell-free DNA (cfDNA) may reflect the extent of cellular damage, whereas circulating mitochondrial DNA (mtDNA) may be a promising biomarker of poor prognosis in patients with HF. Furthermore, some panels of circulating miRNAs may improve the stratification of natural history of disease. For example, a combination of miR-558, miR-122* and miR-520d-5p, as well as miR-125a-5p, miR-550a-5p, miR-638 and miR-190a, may aid to discriminate different phenotypes of HF ranging from preserved to reduced ejection fraction. We give update on the most relevant genetic determinants involved in DCM and discuss the putative role of non-invasive biomarkers to overcome current limitations of the reductionist approach in HF management.

The aim of this study was to characterize both by flow cytometry analysis and immunohistochemistry cervix uteri cells of nulliparous women screened for cervical intraepithelial neoplasia (CIN) in comparison to a group without CIN by using mesenchymal stem cell-like and hematopoietic lineage markers. A significant expression for CD29, CD38, HLA-I, and HLA-II was correlated positively to the CIN degree and it was more relevant in patients positive for human papilloma virus (HPV). Thus, identification and detailed characterization of pluripotent resident in uteri cells could be a promising therapeutic target.

Background: Early pathogenesis of diabetic cardiomyopathy (DMCM) may involve lipotoxicity of cardiomyocytes in the context of hyperglycemia. There are many preclinical studies of DMCM pathogenesis, but the human evidence is still poorly understood. Objectives: By using a nondiabetic mellitus (non-DM) heart transplanted (HTX) in diabetes mellitus (DM) recipients, this study conducted a serial study of human heart transplant recipients evaluating cardiac effects of diabetic milieu (hyperglycemia and insulin resistance) on lipotoxic-mediated injury. We evaluated cardiomyocyte morpho-pathology by seriated biopsies of healthy implanted hearts in DM recipients during 12-month follow-up from HTX. Because metformin reduces ectopic lipid accumulation, we evaluated the effects of the drug in a nonrandomized subgroup. Methods: The DMCM-AHEAD (Diabetes and Lipid Accumulation and Heart Transplant) prospective ongoing study (NCT03546062) evaluated 158 first HTX recipients (82 non-DM, 76 DM of whom 35 [46%] were receiving metformin). HTX recipients were undergoing clinical standard evaluation (metabolic status, echocardiography, coronary computed tomography angiography, and endomyocardial biopsies). Biopsies evaluated immune response, Oil Red-O staining, ceramide, and triacylglycerol levels. Lipotoxic factors and insulin resistance were evaluated by reverse transcriptase–polymerase chain reaction. Results: There was a significant early and progressive cardiomyocyte lipid accumulation in DM but not in non-DM recipients (p = 0.019). In the subgroup receiving metformin, independently from immunosuppressive therapy that was similar among groups, lipid accumulation was reduced in comparison with DM recipients not receiving the drug (hazard ratio: 6.597; 95% confidence interval: 2.516 to 17.296; p < 0.001). Accordingly, lipotoxic factors were increased in DM versus non-DM recipients, and, relevantly, metformin use was associated with fewer lipotoxic factors. Conclusions: Early pathogenesis of human DMCM started with cardiomyocyte lipid accumulation following HTX in DM recipients. Metformin use was associated with reduced lipid accumulation independently of immunosuppressive therapy. This may constitute a novel target for therapy of DMCM.

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.

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.

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. Summary: 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.

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.

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.

Primary percutaneous coronary intervention (PPCI) is a pivotal treatment in ST-segment elevation myocardial infarction (STEMI) patients. However, in hyperglycemic-STEMI patients, the incidence of death is still significant. Here, the involvement of sirtuin 1 (SIRT1) and miR33 on the pro-inflammatory/pro-coagulable state of the coronary thrombus was investigated. Moreover, 1-year outcomes in hyperglycemic STEMI in patients subjected to thrombus aspiration before PPCI were evaluated. Results showed that hyperglycemic thrombi displayed higher size and increased miR33, reactive oxygen species, and pro-inflammatory/pro-coagulable markers. Conversely, the hyperglycemic thrombi showed a lower endothelial SIRT1 expression. Moreover, in vitro experiments on endothelial cells showed a causal effect of SIRT1 modulation on the pro-inflammatory/pro-coagulative state via hyperglycemia-induced miR33 expression. Finally, SIRT1 expression negatively correlated with STEMI outcomes. These observations demonstrate the involvement of the miR33/SIRT1 pathway in the increased pro-inflammatory and pro-coagulable state of coronary thrombi in hyperglycemic STEMI patients.

Objective: Unusual clinical courseBackground: Schwannoma, also called neuroma or neurolemmoma, is a tumor originating from the Schwann cells surrounding the nerves. It is an isolated benign tumor and its transformation into malignant cancer is very rare. Relatively uncommon, it is only the 5% of all the tumors of soft tissues. Its localization in the head and neck region accounts for up to 25-45% of schwannomas. In the outer ear, it commonly involves the external auditory canal, while auricle and tympanic membranes are very rare localizations of schwannomas.Case Report: We report a case of a 23-year-old male with a 3-year medical history of a growing neoplasm located in the left auricle concha, which was treated with a carbon dioxide laser (CO2 laser) under local anesthesia.Conclusions: Using a CO2 laser allowed us to easily remove the tumor, reduce bleeding and surgical time, and avoid sutures and thus unsightly scars on the face. No complications and no relapse at 5 years of follow-up occurred.

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

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. Summary: 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.

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.

Background: Diagnostic criteria for electrocution related death are still a challenge in forensic pathology and it seems that the electrical mark is the only reliable evidence. Methods: A comparison of histological and morphological findings of skin and internal organs from an autopsy series of electrocution deaths with those mostly reported in literature as representative for electrocution. Results: The morphological changes of heart, brain and other main internal organs are still unspecific. Organ’s damage observed in electrocution deaths shows a wide variability, not reliable for a certain diagnosis of electrocution. The electrical mark is still the golden standard for diagnosis of electrocution. Conclusions: In electrocution related deaths, pathological findings of the main internal organs are not enough evidence to support with certainty a post-mortem diagnosis that a victim suffered an electrical damage. Although the organ histological changes are undoubtedly the starting point for a better understanding of the fatal even, the diagnosis of death from electrical damage is still a dark and unsolved chapter. The electrical mark still represents a fundamental indicator above all in the medical-legal field, but the identification of pathognomonic elements and signs not limited to the skin alone could be a valid help in the future, especially in unclear cases.

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.

Background: Neuroinvasive properties of SARS-CoV-2 have allowed the hypothesis of several pathogenic mechanisms related to acute and chronic neurological sequelae. However, neuropathological correlates have been poorly systematically investigated, being retrieved from reports of single case or limited case series still. Methods: A PubMed search was carried out to review all publications on autopsy in subjects with “COronaVIrus Disease-19” (COVID-19). Among them, we focused on histological findings of the brain, which were compared with those from the authors’ autoptic studies performed in some COVID-19 patients. Results: Only seven studies reported histological evidence of brain pathology in patients deceased for COVID-19, including three with reverse transcription–quantitative polymerase chain reaction evidence of viral infection. All these studies, in line with our experience, showed vascular-related and infection-related secondary inflammatory tissue damage due to an abnormal immune response. It is still unclear, however, whether these findings are the effect of a direct viral pathology or rather reflect a non-specific consequence of cardiovascular and pulmonary disease on the brain. Conclusions: Notwithstanding the limited evidence available and the heterogeneity of the studies, we provide a preliminary description of the relationship between SARS-CoV-2 and brain sequelae. Systematic autoptic investigations are needed for accurate detection and adequate management of these patients.

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.

Background Glycemic control is a strong predictor of long-term cardiovascular risk in patients with diabetes mellitus, and poor glycemic control influences long-term risk of cardiovascular disease even decades after optimal medical management. This phenomenon, termed glycemic memory, has been proposed to occur due to stable programs of cardiac and endothelial cell gene expression. This transcriptional remodeling has been shown to occur in the vascular endothelium through a yet undefined mechanism of cellular reprogramming. Methods In the current study, we quantified genome-wide DNA methylation of cultured human endothelial aortic cells (HAECs) via reduced-representation bisulfite sequencing (RRBS) following exposure to diabetic (250 mg/dL), pre-diabetic (125 mg/dL), or euglycemic (100 mg/dL) glucose concentrations for 72 h (n = 2). Results We discovered glucose-dependent methylation of genomic regions (DMRs) encompassing 2199 genes, with a disproportionate number found among genes associated with angiogenesis and nitric oxide (NO) signaling-related pathways. Multi-omics analysis revealed differential methylation and gene expression of VEGF (↑5.6% DMR, ↑3.6-fold expression), and NOS3 (↓20.3% DMR, ↓1.6-fold expression), nodal regulators of angiogenesis and NO signaling, respectively. Conclusion In the current exploratory study, we examine glucose-dependent and dose-responsive alterations in endothelial DNA methylation to examine a putative epigenetic mechanism underlying diabetic vasculopathy. Specifically, we uncover the disproportionate glucose-dependent methylation and gene expression of VEGF and NO signaling cascades, a physiologic imbalance known to cause endothelial dysfunction in diabetes. We therefore hypothesize that epigenetic mechanisms encode a glycemic memory within endothelial cells.

Aims Immune endothelial inflammation, underlie coronary heart disease (CHD) related phenotypes, could provide new insight into the pathobiology of the disease. We investigated DNA methylation level of the unique CpG island of HLA-G gene in CHD patients and evaluated the correlation with cardiac computed tomography angiography (CCTA) features. Methods Thirty-two patients that underwent CCTA for suspected CHD were enrolled for this study. Obstructive CHD group included fourteen patients, in which there was a stenosis greater than or equal to 50% in one or more of the major coronary arteries detected; whereas subjects with Calcium (Ca) Score=0, uninjured coronaries and with no obstructive CHD were considered as control subjects (Ctrls) (n=18). For both groups, DNA methylation profile of the whole 5'UTR-CpG island of HLA-G was measured. The plasma soluble HLA-G (sHLA-G) levels were detected in all subjects by specific ELISA assay. Statistical analysis was performed using R software. Results For the first time, our study reported that 1) a significant hypomethylation characterized three specific fragments (B, C and F) of the 5'UTR-CpG island (p=0.05) of HLA-G gene in CHD patients compared to Ctrl group; 2) hypomethylation level of one specific fragment positively correlated with coronary Ca score, a relevant parameter of CCTA (p Conclusions Our results showed that reduced levels of circulating HLA-G molecules could derive from epigenetic marks inducing hypomethylation of specific regions into 5'UTR-CpG island of HLA-G gene in CHD patients with obstructive coronary stenosis vs non critical stenosis group. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Italian Minister of Health

Objectives: To evaluate autoptic histopathological findings of arrhythmogenic ventricular cardiomyopathy (AVC) as major cause of sudden cardiac death (SCD) in young adults. Background: According to Heart Rhythm Society (HRS)’s international consensus, histological criteria for AVC diagnosis include a progressive myocardial atrophy of the right ventricle characterized by a transmural fatty or fibrofatty replacement in a segmental or diffuse pattern (residual myocytes

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.

Dyslipidemias can affect molecular networks underlying the metabolic homeostasis and vascular function leading to atherogenesis at early stages of development. Since disease-related proteins often interact with each other in functional modules, many advanced network-oriented algorithms were applied to patient-derived big data to identify the complex gene-environment interactions underlying the early pathophysiology of dyslipidemias and atherosclerosis. Both the proprotein convertase subtilisin/kexin type 7 (PCSK7) and collagen type 1 alpha 1 chain (COL1A1) genes arose from the application of TFfit and WGCNA algorithms, respectively, as potential useful therapeutic targets in prevention of dyslipidemias. Moreover, the Seed Connector algorithm (SCA) algorithm suggested a putative role of the neuropilin-1 (NRP1) protein as drug target, whereas a regression network analysis reported that niacin may provide benefits in mixed dyslipidemias. Dyslipidemias are highly heterogeneous at the clinical level; thus, it would be helpful to overcome traditional evidence-based paradigm toward a personalized risk assessment and therapy. Network Medicine uses omics data, artificial intelligence (AI), imaging tools, and clinical information to design personalized therapy of dyslipidemias and atherosclerosis. Recently, a novel non-invasive AI-derived biomarker, named Fat Attenuation Index (FAI™) has been established to early detect clinical signs of atherosclerosis. Moreover, an integrated AI-radiomics approach can detect fibrosis and microvascular remodeling improving the customized risk assessment. Here, we offer a network-based roadmap ranging from novel molecular pathways to digital therapeutics which can improve personalized therapy of dyslipidemias.

SARS-CoV-2 betacoronavirus is responsible for the Corona Virus Disease 2019 (COVID-19), which has relevant pathogenic implications for the cardiovascular system. Incidence and severity of COVID-19 syndrome are higher in the elderly population (65 years and older). This may be due to higher frequency of comorbidities, but increased frailty and immunosenescence linked with aging may also contribute. Moreover, in elderly individuals, SARS-CoV-2 may adopt different molecular strategies to strongly impact on cardiac aging that culminate in exacerbating a pro-inflammatory state (cytokine storm activation), which, in turn, may lead to pulmonary vascular endothelialitis, microangiopathy, diffuse thrombosis, myocarditis, heart failure, cardiac arrhythmias, and acute coronary syndromes. All these events are particularly relevant in elderly patients, and deserve targeted cardiovascular treatments and specific management of repurposed drugs against COVID-19. We discuss current evidence about the cardiovascular involvement during COVID-19, and elaborate on clinical implications in elderly patients., Highlights • SARS-CoV-2 infection has relevant pathogenic implications for the heart, mainly in elderly patients. • Common cardiometabolic comorbidities and aging strongly contribute to higher frequency and severity of disease in elderly. • SARS-CoV-2 may directly and indirectly damage the heart leading to multi-organ failure and death. • Network-oriented analysis are providing novel insight about SARS-CoV-2 pathogenic mechanisms and putative drug targets.

Background DNA methylation can play a pathogenic role in the early stages of hyperglycemia linking homeostasis imbalance and vascular damage. Material and methods We investigated DNA methylome by RRBS in CD04+ and CD08+ T cells from healthy subjects (HS) to pre-diabetics (Pre-Diab) and type 2 diabetic (T2D) patients to identify early biomarkers of glucose impairment and vascular damage. Our cross-sectional study enrolled 14 individuals from HS state to increasing hyperglycemia (pilot study, PIRAMIDE trial, NCT03792607). Results Globally, differentially methylated regions (DMRs) were mostly annotated to promoter regions. Hypermethylated DMRs were greater than hypomethylated in CD04+ T cells whereas CD08+ T showed an opposite trend. Moreover, DMRs overlapping between Pre-Diab and T2D patients were mostly hypermethylated in both T cells. Interestingly, SPARC was the most hypomethylated gene in Pre-Diab and its methylation level gradually decreased in T2D patients. Besides, SPARC showed a significant positive correlation with DBP (+0.76), HDL (+0.54), Creatinine (+0.83), LVDd (+0.98), LVSD (+0.98), LAD (+0.98), LVPWd (+0.84), AODd (+0.81), HR (+0.72), Triglycerides (+0.83), LAD (+0.69) and AODd (+0.52) whereas a negative correlation with Cholesterol (−0.52) and LDL (−0.71) in T2D. Conclusion SPARC hypomethylation in CD08+ T cells may be a useful biomarker of vascular complications in Pre-Diab with a possible role for primary prevention warranting further multicenter clinical trials to validate our findings., Highlights • We conducted the first methylome analysis by RRBS platform in circulating CD04+ and CD08+ T cells in increasing hyperglycemia. • This approach has revealed possible biomarkers for cardiovascular and kidney complications in prediabetes. • SPARC hypomethylation may underly a pro-fibrotic endophenotype to be validated in larger multicenter trials.

Background: Despite current intensive treatments, hyperglycemic patients have an unfavorable prognosis due to severe CHD and development of complications. The interplay between hyperglycemia and systemic inflammation can modify patterns of gene expression mainly affecting DNA methylation in promoter regions and, thus, endothelial damage. However, DNA methylome of CD04+ and CD08+ T cells, which play a relevant role in endothelial dysfunction has not been studied, especially during increasing hyperglycemia.Purpose: To identify differentially methylated regions (DRMs) in CD04 + and CD08 + T cells by comparing healthy subjects (HS) to Pre-Diab and type 2 (T2D) patients. This approach would investigate possible biomarkers useful to identify vascular damage already at Pre-Diab state.Methods: In this pilot study, we enrolled a subgroup of patients from our ongoing PIRAMIDE clinical trial (NCT03792607) including a total of 14 individuals classified in HS (n=2), Pre-Diab (n=6), and T2D (n=6). The DMRs were identified by using the reduced representation bisulfite sequencing platform (RRBS) which captures the majority of promoters and CpG islands. Big data analysis was performed by using the R package and ChromHMM algorithms.Results: Most of the total DMRs (30-35%) were in the promoter regions in increasing hyperglycemia vs HS. A global analysis of DMR-related genes overlapping between Pre-Diab and T2D patients showed a prevalence of DNA hypermethylation in both T cells. Interestingly, the secreted protein acidic and cysteine rich (SPARC) gene was annotated to the most hypomethylated-DMR in Pre-Diab and its methylation level gradually decreased in T2D patients.Conclusions: Preliminary data indicated that hypomethylation of the SPARC promoter may be a useful biomarker of vascular complications in Pre-Diab patients with a possible role for primary prevention. However, larger multicenter trials are needed to validate our epigenetic data in the clinical arena.

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.

Highlights • SARS-CoV-2 causes acute respiratory distress syndrome (ARDS) and multiple organ failure until death. • Myocarditis, acute myocardial infarction, arrhythmias thromboembolism, and disseminated intravascular coagulation (DIC) are the main complications in patients with cardiovascular comorbidities. • SARSCoV-2 can worsen the clinical status of patients with comorbidities especially pre-existing cardiovascular diseases and this may interfere with therapies., A novel coronavirus SARS-CoV-2 causes acute respiratory distress syndrome (ARDS) with cardiovascular and multiple organ failure till death. The main mechanisms of virus internalization and interaction with the host are down-regulation or upregulation of the ACE2 receptor, the surface glycoprotein competition mechanism for the binding of porphyrin to iron in heme formation as well as interference with the immune system. The interference on renin–angiotensin–aldosterone system (RAAS) activation, heme formation, and the immune response is responsible for infection diffusion, endothelial dysfunction, vasoconstriction, oxidative damage and releasing of inflammatory mediators. The main pathological findings are bilateral interstitial pneumonia with diffuse alveolar damage (DAD). Because ACE receptor is also present in the endothelium of other districts as well as in different cell types, and as porphyrins are transporters in the blood and other biological liquids of iron forming heme, which is important in the assembly of the hemoglobin, myoglobin and the cytochromes, multiorgan damage occurs both primitive and secondary to lung damage. More relevantly, myocarditis, acute myocardial infarction, thromboembolism, and disseminated intravasal coagulation (DIC) are described as complications in patients with poor outcome. Here, we investigated the role of SARSCoV-2 on the cardiovascular system and in patients with cardiovascular comorbidities, and possible drug interference on the heart.

Background: Pulmonary alveolar microlithiasis (PAM) is a rare autosomal recessive disease with a high penetrance characterized by widespread intra-alveolar accumulation of countless minute calculi called microliths. Patients with PAM may be asymptomatic, and the diagnosis is often an accidental finding during medical imaging performed for other diseases. Otherwise, it can develop into pulmonary fibrosis. In both cases, the disease can lead to respiratory and pulmonary heart failure which, though occurring rarely, may have a fatal outcome. Case presentation: We report the case of a 40-year-old male found dead in the bathroom. In the absence of trauma or other signs of injuries and in absence of a history of previous diseases, forensic autopsy was required to identify the time, cause and means of death. Our final diagnosis was death by right ventricular hypertrophy with initial signs of acute ischemia in a patient with PAM. Conclusions: This case provides insights into a pathology which is not frequent and can lead to death, besides illustrating the importance of histology in solving cases that come within a forensic setting. Therefore histology is fundamental to diagnose the cause of death, supplemented by knowledge of physiology and pathology in the cardiovascular and respiratory. Keywords: PAM, Alveolar microlithiasis, Forensic autopsy, Pulmonary hypertension

Background How metabolic impairment leads to cardiac dysfunction in diabetics is unknown. A recent theory, derived mainly from rodent models, involves lipid over-storage to cardiomyocytes. Previous human study demonstrated cardiac steatosis on explanted hearts of diabetics with heart failure. However, this study did not provide any evidence about the effects of diabetes milieu on implanted non-diabetic heart. Purpose We evaluated intramyocyte lipid infiltration in explanted heart of type 2 diabetics with end-stage heart failure. Moreover, we studied the effects of diabetic milieu on myocyte lipid infiltration and cardiac function of non-diabetic implanted hearts in type 2 diabetics one year after heart transplantation (HTx). Methods We conducted a prospective study with a follow-up of 12 months on 88 patients over 18 years of age underwent first HTX. Patients with pre-HTx diabetes duration for at least 6 months were included in the study. Patients with endomyocardial biopsy (EMB) considered positive for rejection, according to International Society for Heart Lung Transplantation (ISHLT), and with post-HTx diabetes were excluded from the study. All patients underwent immunosuppression induction according ISHLT indications. All patients were followed applying internationally accepted patient evaluations (echocardiography and metabolic control) and EMB schedules. EBM from patients without rejection evidences were evaluated for intramyocyte lipid infiltration with oil red-O staining (Or-O). Results The patients were divided in diabetics (44%, age 51.6±7.2 y, diabetes duration 11±3 y) and no-diabetics (56%, 52.1±10.9 y). The patients were matched on the basis of eligibility for a HTx. Seven patients (3 diabetics and 4 no-diabetics) died in hospital. 5 (11%) patients developed post- HTx diabetes. No differences were seen in rejection (12% vs. 10%), infection (9% vs. 10%), renal dysfunction (9% vs. 8%) or mortality (7% vs. 8%). Therefore, the study population included 23 no-diabetics and 22 diabetics. After 1 year, we evidenced an impairment of both sx and dx ventricular function as showed by a significantly reduction of ejection fraction and TAPSE in diabetic patients (Figure-A). Although diastolic function not show significant differences among groups, the E/e' ratio showed lower reduction in diabetics. Or-O evidenced that 91% of diabetic and only 2 of no-diabetic explanted hearts (9%) showed intramyocyte lipid infiltration (Figure-B). Moreover, Or-O of EMB, for monitoring heart transplant during 1 year, evidenced a progressive intramyocyte lipid infiltration in 18 diabetics (81%), whereas none of no-diabetics showed intramyocyte lipid infiltration. Conclusions Our data show that almost all of the explanted diabetic hearts had intramyocyte lipid infiltration. More interesting, we observed that healthy heart transplanted in recipients with pretransplant diabetes were affected early by metabolic disorders leading to intramyocyte lipid infiltration.

Progresses in liquid-based assays may provide novel useful non-invasive indicators of cardiovascular (CV) diseases. By analysing circulating cells or their products in blood, saliva and urine samples, we can investigate molecular changes present at specific time points in each patient allowing sequential monitoring of disease evolution. For example, an increased number of circulating endothelial cells may be a diagnostic biomarker for diabetic nephropathy and heart failure with preserved ejection fraction. The assessment of circulating cell-free DNA (cfDNA) levels may be useful to predict severity of acute myocardial infarction, as well as diagnose heart graft rejection. Remarkably, circulating epigenetic biomarkers, including DNA methylation, histone modifications and non-coding RNAs are key pathogenic determinants of CV diseases representing putative useful biomarkers and drug targets. For example, the unmethylatedFAM101Agene may specifically trace cfDNA derived from cardiomyocyte death providing a powerful diagnostic biomarker of apoptosis during ischaemia. Moreover, changes in plasma levels of circulating miR-92 may predict acute coronary syndrome onset in patients with diabetes. Now, network medicine provides a framework to analyse a huge amount of big data by describing a CV disease as a result of a chain of molecular perturbations rather than a single defect (reductionism). We outline advantages and challenges of liquid biopsy with respect to traditional tissue biopsy and summarise the main completed and ongoing clinical trials in CV diseases. Furthermore, we discuss the importance of combining fluid-based assays, big data and network medicine to improve precision medicine and personalised therapy in this field.

Intravascular large B cell lymphoma (IVLBCL) is a rare extranodal non-Hodgkin lymphoma characterized by proliferation of malignant cells within the lumen of small vessels, with a predilection for the CNS and the skin. IVLBCL clinical course is highly aggressive, clinical signs and symptoms are not specific and may consist of neurological and cognitive impairment, fever of unknown origin and cutaneous lesions, lacking of a typical neuroimaging pattern. For all these reasons the diagnosis is commonly missed and the exitus is frequent, therefore post mortem evaluation is necessary to clarify the clinical history. We present a case of IVLBCL in a 62-year-old woman with unusual symptomatology, mimicking a vascular, multi-infarctual cerebropathy. Hachinski Ischemic Score was 7 suggesting a vascular dementia. Autopsy was unable to define the nature of the disease. Immunohistochemical analysis for cluster of differentiation 20 (CD20) revealed the ubiquitous presence of malignant lymphoid B-cells into the vessel of all organs analyzed, allowing the definitive diagnosis of IVLBCL. The atypical cells expressed high levels of anti-apoptotic proteins B-cell lymphoma 2 (Bcl-2) and Galectin-3, and showed cellular myelocytomatosis (c-Myc) staining in