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Adrenomedullin (ADM) is a peptide hormone produced primarily in the adrenal glands, playing a crucial role in various physiological processes. As well as improving vascular integrity and decreasing vascular permeability, ADM acts as a vasodilator, positive inotrope, diuretic, natriuretic and bronchodilator, antagonizing angiotensin II by inhibiting aldosterone secretion. ADM also has antihypertrophic, anti-apoptotic, antifibrotic, antioxidant, angiogenic and immunoregulatory effects and antimicrobial properties. ADM expression is upregulated by hypoxia, inflammation-inducing cytokines, viral or bacterial substances, strength of shear stress, and leakage of blood vessels. These pathological conditions are established during systemic inflammation that can result from infections, surgery, trauma/accidents or burns. The ability to rapidly identify infections and the prognostic, predictive power makes it a valuable tool in severe viral and bacterial infections burdened by high incidence and mortality. This review sheds light on the pathophysiological processes that in severe viral or bacterial infections cause endothelitis up to the development of organ damage, the resulting increase in ADM levels dosed through its more stable peptide mid-regional proadrenomedullin (MR-proADM), the most significant studies that attest to its diagnostic and prognostic accuracy in highlighting the severity of viral or bacterial infections and appropriate therapeutic insights. [ABSTRACT FROM AUTHOR]

Adrenomedullin (ADM) is a peptide hormone produced primarily in the adrenal glands, playing a crucial role in various physiological processes. As well as improving vascular integrity and decreasing vascular permeability, ADM acts as a vasodilator, positive inotrope, diuretic, natriuretic and bronchodilator, antagonizing angiotensin II by inhibiting aldosterone secretion. ADM also has antihypertrophic, anti-apoptotic, antifibrotic, antioxidant, angiogenic and immunoregulatory effects and antimicrobial properties. ADM expression is upregulated by hypoxia, inflammation-inducing cytokines, viral or bacterial substances, strength of shear stress, and leakage of blood vessels. These pathological conditions are established during systemic inflammation that can result from infections, surgery, trauma/accidents or burns. The ability to rapidly identify infections and the prognostic, predictive power makes it a valuable tool in severe viral and bacterial infections burdened by high incidence and mortality. This review sheds light on the pathophysiological processes that in severe viral or bacterial infections cause endothelitis up to the development of organ damage, the resulting increase in ADM levels dosed through its more stable peptide mid-regional proadrenomedullin (MR-proADM), the most significant studies that attest to its diagnostic and prognostic accuracy in highlighting the severity of viral or bacterial infections and appropriate therapeutic insights.

Aim. To analyze the results of thrombectomy in lower-extremity ischemia in patients with coronavirus disease 2019 (COVID-19) and respiratory failure of different severity.Material and methods. This retrospective, cohort, comparative study for the period from May 1, 2020 to March 1, 2022 included 305 patients with acute lower-extremity ischemia and COVID-19. Depending on the type of oxygen support, three groups of patients were formed: group 1 (n=168) — nasal oxygen insufflation; group 2 (n=92) — non-invasive ventilation (NIV); group 3 (n=45) — artificial ventilation (AV). Thrombectomy was carried out according to the standard technique using Fogarty catheters (3F-6F — depending on the vessel size). After the diagnosis was established before and after the start of surgical treatment, all patients received the following therapy: Unfractionated IV heparin infusion at an initial rate of 1000 U/r, adjusted to maintain the activated partial thromboplastin time at 2-3 times the normal value; 2. Oral acetylsalicylic acid 125 mg; 3. Analgesics.Results. Myocardial infarction and ischemic stroke were not detected in the total sample. The highest number of deaths (group 1: 5,3%, n=9; group 2: 72,8%, n=67; group 3: 100%, n=45; p

Aims: Inflammation-driven endothelitis seems to be a hallmark of acute heart failure (AHF) and cardiogenic shock (CS). Endocan, a soluble proteoglycan secreted by the activated endothelium, contributes to inflammation and endothelial dysfunction, but has been scarcely explored in human AHF. We aimed to evaluate serum (S-Endocan) and urinary endocan (U-Endocan) profiles in AHF and CS patients and to correlate them with biomarkers/parameters of inflammation, endothelial activation, cardiovascular dysfunction and prognosis. Methods: Blood and spot urine were collected from patients with AHF (n = 23) or CS (n = 25) at days 1-2 (admission), 3-4 and 5-8 and from controls (blood donors, n = 22) at a single time point. S-Endocan, U-Endocan, serum IL-1ß, IL-6, tumour necrosis factor-a (S-TNF-a), intercellular adhesion molecule-1 (S-ICAM-1), vascular cell adhesion molecule-1 (S-VCAM-1) and E-selectin were determined by ELISA or multiplex immunoassays. Serum C-reactive protein (S-CRP), plasma B-type natriuretic peptide (P-BNP) and highsensitivity troponin I (P-hs-trop I), lactate, urea, creatinine and urinary proteins, as well as prognostic scores (APACHE II, SAPS II) and echocardiographic left ventricular ejection fraction (LVEF) were also evaluated. Results: Admission S-Endocan was higher in both patient groups, with CS presenting greater values than AHF (AHF and CS vs. Controls, p < 0.001; CS vs. AHF, p < 0.01). Admission U-Endocan was only higher in CS patients (p < 0.01 vs. Controls). At admission, S-VCAM-1, S-IL-6 and S-TNF-a were also higher in both patient groups but there were no differences in S-E-selectin and S-IL-1ß among the groups, nor in P-BNP, S-CRP or renal function between AHF and CS. Neither endocan nor other endothelial and inflammatory markers were reduced during hospitalization (p > 0.05). S-Endocan positively correlated with S-VCAM-1, S-IL-6, S-CRP, APACHE II and SAPS II scores and was positively associated with P-BNP in multivariate analyses. Admission S-Endocan raised in line with LVEF impairment (p = 0.008 for linear trend). Conclusion: Admission endocan significantly increases across AHF spectrum. The lack of reduction in endothelial and inflammatory markers throughout hospitalization suggests a perpetuation of endothelial dysfunction and inflammation. S-Endocan appears to be a biomarker of endothelitis and a putative therapeutic target in AHF and CS, given its association with LVEF impairment and P-BNP and its positive correlation with prognostic scores. [ABSTRACT FROM AUTHOR]

Mid-regional proadrenomedullin (MR-proADM) is a new biomarker of endothelial damage and its clinical use is increasing in sepsis and respiratory infections and recently in SARS-CoV-2 infection. We conducted a systematic review and meta-analysis to clarify the use of MR-proADM in severe COVID-19 disease. After Pubmed, Embase, and Scopus search, registries, and gray literature, deduplication, and selection of full-texts, we found 21 studies addressing the use of proadrenomedullin in COVID-19. All the studies were published between 2020 and 2022 from European countries. A total of 9 studies enrolled Intensive Care Unit (ICU) patients, 4 were conducted in the Emergency Department, and 8 had mixed populations. Regarding the ICU critically ill patients, 4 studies evaluating survival as primary outcome were available, of which 3 reported completed data. Combining the selected studies in a meta-analysis, a total of 252 patients were enrolled; of these, 182 were survivors and 70 were non-survivors. At the admission to the ICU, the average MR-proADM level in survivor patients was 1.01 versus 1.64 in non-survivor patients. The mean differences of MR-proADM values in survivors vs. non-survivors was −0.96 (95% CI from −1.26, to −0.65). Test for overall effect: Z = 6.19 (p < 0.00001) and heterogeneity was I2 = 0%. MR-proADM ICU admission levels seem to predict mortality among the critical COVID-19 population. Further, prospective studies, focused on critically ill patients and investigating a reliable MR-proADM cut-off, are needed to provide adequate guidance to its use in severe COVID-19. [ABSTRACT FROM AUTHOR]

Aims: Inflammation-driven endothelitis seems to be a hallmark of acute heart failure (AHF) and cardiogenic shock (CS). Endocan, a soluble proteoglycan secreted by the activated endothelium, contributes to inflammation and endothelial dysfunction, but has been scarcely explored in human AHF. We aimed to evaluate serum (S-Endocan) and urinary endocan (U-Endocan) profiles in AHF and CS patients and to correlate them with biomarkers/parameters of inflammation, endothelial activation, cardiovascular dysfunction and prognosis.Methods: Blood and spot urine were collected from patients with AHF (n = 23) or CS (n = 25) at days 1–2 (admission), 3-4 and 5-8 and from controls (blood donors, n = 22) at a single time point. S-Endocan, U-Endocan, serum IL-1β, IL-6, tumour necrosis factor-α (S-TNF-α), intercellular adhesion molecule-1 (S-ICAM-1), vascular cell adhesion molecule-1 (S-VCAM-1) and E-selectin were determined by ELISA or multiplex immunoassays. Serum C-reactive protein (S-CRP), plasma B-type natriuretic peptide (P-BNP) and high-sensitivity troponin I (P-hs-trop I), lactate, urea, creatinine and urinary proteins, as well as prognostic scores (APACHE II, SAPS II) and echocardiographic left ventricular ejection fraction (LVEF) were also evaluated.Results: Admission S-Endocan was higher in both patient groups, with CS presenting greater values than AHF (AHF and CS vs. Controls, p < 0.001; CS vs. AHF, p < 0.01). Admission U-Endocan was only higher in CS patients (p < 0.01 vs. Controls). At admission, S-VCAM-1, S-IL-6 and S-TNF-α were also higher in both patient groups but there were no differences in S-E-selectin and S-IL-1β among the groups, nor in P-BNP, S-CRP or renal function between AHF and CS. Neither endocan nor other endothelial and inflammatory markers were reduced during hospitalization (p > 0.05). S-Endocan positively correlated with S-VCAM-1, S-IL-6, S-CRP, APACHE II and SAPS II scores and was positively associated with P-BNP in multivariate analyses. Admission S-Endocan raised in line with LVEF impairment (p = 0.008 for linear trend).Conclusion: Admission endocan significantly increases across AHF spectrum. The lack of reduction in endothelial and inflammatory markers throughout hospitalization suggests a perpetuation of endothelial dysfunction and inflammation. S-Endocan appears to be a biomarker of endothelitis and a putative therapeutic target in AHF and CS, given its association with LVEF impairment and P-BNP and its positive correlation with prognostic scores.

The presence of coronavirus-associated myocarditis remains controversial despite elevations in cardiac troponin and natriuretic peptide in many patients.Aim. To assess the morphological changes in the myocardium of patients who died due to coronavirus disease 2019 (COVID-19) and compare them with the intravital level of cardiac biomarkers.Material and methods. A total of 420 hospital charts and 77 autopsies of those who died from COVID-19 were analyzed. In 15 of 77 cases (19%) with histologically suspected myocarditis, an immunohistochemical examination of the myocardium with antibodies to CD3, CD45, CD8, CD68, CD34, Ang1, VWF, VEGF, HLA-DR, MHC1, C1q, VP1 of enteroviruses was performed, and in 8 patients with immunohistochemically confirmed myocarditis (10%) — polymerase chain reaction for SARS-CoV-2.Results. Hemorrhage, intramural thrombosis, necrosis of non-coronary origin, myocardial infarction and lymphocytic myocarditis were detected in 43%, 10%, 17%, 19% and 10% of cases, respectively, without coronavirus N and E gene sequences in the myocardium. Dysplasia, hyperplasia and hypertrophy of the vascular endothelium, expression of Ang1, VWF, VEGF, MHC1, C1q, VP1 of enteroviruses were determined in 100, 100, 87, 100, 75 and 62% of cases of myocarditis, respectively. There were no significant correlations between inflammatory biomarkers and myocarditis.Conclusion. The main morphological manifestation of COVID-19 in the myocardium is the so-called endotheliitis with dysplasia and endothelial activation, leading to hemorrhages, intramural thrombosis and necrosis. There is no convincing evidence of a direct involvement of coronavirus in myocarditis induction.

Emerging evidences prove that the ongoing pandemic of coronavirus disease 2019 (COVID-19) is strictly linked to coagulopathy even if pneumonia appears as the major clinical manifestation. The exact incidence of thromboembolic events is largely unknown, so that a relative significant number of studies have been performed in order to explore thrombotic risk in COVID-19 patients. Cytokine storm, mediated by pro-inflammatory interleukins, tumor necrosis factor α and elevated acute phase reactants, is primarily responsible for COVID-19-associated hypercoagulopathy. Also comorbidities, promoting endothelial dysfunction, contribute to a higher thromboembolic risk. In this review we aim to investigate epidemiology and clarify the pathophysiological pathways underlying hypercoagulability in COVID-19 patients, providing indications on the prevention of thromboembolic events in COVID-19. Furthermore we aim to reassume the pathophysiological paths involved in COVID-19 infection.

It has been widely reported that the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) attaches human cells by using the Angiotensin Converting Enzyme 2 (ACE2) receptor, but vascular impairment described during coronavirus disease 2019 (COVID-19) infection is primarily due to the direct involvement of the endothelial cells by the virus or secondarily to the inflammatory host response is currently unknown. We therefore aimed to demonstrate in vivo the presence of endothelial dysfunction in six COVID-19 patients without cardiovascular risk factors or pre-existing cardiac condition, using the Endo-PAT 2000, a device able to measure endothelial vasodilation function in a rapid and non-invasive way. Four patients were positive for endothelial dysfunction, with RHI values between 1.13-1.56 (average value 1.32, normal values >1.67); in one of the two negative patients the reported RHI value was slightly above the cutoff (1.72). Our findings confirm that COVID-19 patients are at higher risk of developing endothelial dysfunction. In addition, our results demonstrate that endothelial impairment may occur even in the absence of cardiovascular risk factors.

• To evaluate in SARS-CoV-2 patients the behavior of MR-proADM a peptide derived from adromedullin, that maintains endothelial integrity: the endothelial dysfunction seems to be involved in the spread of the COVID-19 disease and, consequently, the increase in this biomarker concentrations allow to obtain clinically relevant prognostic informations. • To compare the informations provided by MR-proADM with those of some biomarkers routinely measured in patients suffering from multiorgan disease. • To provide additional biochemical informations in patients suffering from SARS-CoV-2 producing an outbreak of pandemic proportions. Endothelial dysfunction, a major complication of SARS-CoV-2 infectionplaying a key-role in multi-organ damage, carries high risk of mortality. To investigate the potential role of Mid-Regional pro-Adrenomedullin (MR-proADM) in detecting endothelial damage with a view to stratifying the risk of adverse events (length of stay, death, admission in Intensive Care Unit) and/or disease resolution. In 135 consecutive patients with SARS-CoV-2 infection, MR-proADM was measured in EDTA-K2 plasma samples using B.R.A.H.M.S. KRYPTOR® COMPACT Plus method (Thermo Fisher Scientific, Hennigsdorf, Germany) Patients were subdivided into three groups based on their MR-proADM value (nmol/L): 1 (n = 20, MR-proADM ≤ 0.55); 2 (n = 82, 0.55 < MR-proADM ≤ 1.50); 3 (n = 33, MR-proADM > 1.50). The higher the MR-proADM value, the greater the patients' age, the more frequent the occurrence of pneumonia, the requiring of more aggressive treatment, the longer the hospitalization and the more frequent a fatal event. Significant differences were found between the three groups for MR-proADM, White-blood cell count, Neutrophil count, D-dimer, C-reactive Protein, Procalcitonin and hs-Troponin I. At logistic regression,it was found that MR-proADM and Log 10 D-dimer were the most significant predictors of adverse events. The findings made in the present study highlight the relevance of MR-proADM values in providing clinically useful information, particularly for stratifying COVID-19 patients according to the risk of a more severe form of disease and to the development of adverse events. [ABSTRACT FROM AUTHOR]

COVID-19 primarily affects the respiratory system and may lead to severe systemic complications, such as acute respiratory distress syndrome (ARDS), multiple organ failure, cytokine storm, and thromboembolic events. Depending on the immune status of the affected individual early disease control can be reached by a robust type-I-interferon (type-I-IFN) response restricting viral replication. If type-I-IFN upregulation is impaired, patients develop severe COVID-19 that involves profound alveolitis, endothelitis, complement activation, recruitment of immune cells, as well as immunothrombosis. In patients with proper initial disease control there can be a second flare of type-I-IFN release leading to post-COVID manifestation such as chilblain-like lesions that are characterized by thrombosis of small vessels in addition to an inflammatory infiltrate resembling lupus erythematosus (LE). Mechanistically, SARS-CoV-2 invades pneumocytes and endothelial cells by acting on angiotensin-II-converting enzyme 2 (ACE2). It is hypothesized, that viral uptake might downregulate ACE2 bioavailability and enhance angiotensin-II-derived pro-inflammatory and pro-thrombotic state. Since ACE2 is encoded on the X chromosome these conditions might also be influenced by gender-specific regulation. Taken together, SARS-CoV-2 infection affects the vascular compartment leading to variable thrombogenic or inflammatory response depending on the individual immune response status. [ABSTRACT FROM AUTHOR]

There is strong evidence that COVID-19 pathophysiology is mainly driven by a spatiotemporal immune deregulation. Both its phenotypic heterogeneity, spanning from asymptomatic to severe disease/death, and its associated mortality, are dictated by and linked to maladaptive innate and adaptive immune responses against SARS-CoV-2, the etiologic factor of the disease. Deregulated interferon and cytokine responses, with the contribution of immune and cellular stress-response mediators (like cellular senescence or uncontrolled inflammatory cell death), result in innate and adaptive immune system malfunction, endothelial activation and inflammation (endothelitis), as well as immunothrombosis (with enhanced platelet activation, NET production/release and complement hyper-activation). All these factors play key roles in the development of severe COVID-19. Interestingly, another consequence of this immune deregulation, is the production of autoantibodies and the subsequent development of autoimmune phenomena observed in some COVID-19 patients with severe disease. These new aspects of the disease that are now emerging (like autoimmunity and cellular senescence), could offer us new opportunities in the field of disease prevention and treatment. Simultaneously, lessons already learned from the immunobiology of COVID-19 could offer new insights, not only for this disease, but also for a variety of chronic inflammatory responses observed in autoimmune and (auto)inflammatory diseases. [ABSTRACT FROM AUTHOR]

There is strong evidence that COVID-19 pathophysiology is mainly driven by a spatiotemporal immune deregulation. Both its phenotypic heterogeneity, spanning from asymptomatic to severe disease/death, and its associated mortality, are dictated by and linked to maladaptive innate and adaptive immune responses against SARS-CoV-2, the etiologic factor of the disease. Deregulated interferon and cytokine responses, with the contribution of immune and cellular stress-response mediators (like cellular senescence or uncontrolled inflammatory cell death), result in innate and adaptive immune system malfunction, endothelial activation and inflammation (endothelitis), as well as immunothrombosis (with enhanced platelet activation, NET production/release and complement hyper-activation). All these factors play key roles in the development of severe COVID-19. Interestingly, another consequence of this immune deregulation, is the production of autoantibodies and the subsequent development of autoimmune phenomena observed in some COVID-19 patients with severe disease. These new aspects of the disease that are now emerging (like autoimmunity and cellular senescence), could offer us new opportunities in the field of disease prevention and treatment. Simultaneously, lessons already learned from the immunobiology of COVID-19 could offer new insights, not only for this disease, but also for a variety of chronic inflammatory responses observed in autoimmune and (auto)inflammatory diseases.

Emerging evidences prove that the ongoing pandemic of coronavirus disease 2019 (COVID-19) is strictly linked to coagulopathy even if pneumonia appears as the major clinical manifestation. The exact incidence of thromboembolic events is largely unknown, so that a relative significant number of studies have been performed in order to explore thrombotic risk in COVID-19 patients. Cytokine storm, mediated by pro-inflammatory interleukins, tumor necrosis factor α and elevated acute phase reactants, is primarily responsible for COVID-19-associated hypercoagulopathy. Also comorbidities, promoting endothelial dysfunction, contribute to a higher thromboembolic risk. In this review we aim to investigate epidemiology and clarify the pathophysiological pathways underlying hypercoagulability in COVID-19 patients, providing indications on the prevention of thromboembolic events in COVID-19. Furthermore we aim to reassume the pathophysiological paths involved in COVID-19 infection. [ABSTRACT FROM AUTHOR]

Background Since the first documented outbreak of a novel severe acute respiratory syndrome inducing Coronavirus in China at the end of 2019 the virus has spread to all continents, leading the WHO to declare a pandemic in March 2020. While this virus primarily targets the alveoli in the lungs, multiple authors have described an increased rate of thrombo-embolic events in affected patients. We present this case of a myocardial infarction with no obstructive coronary atherosclerosis in an otherwise healthy 48-year-old patient. Case summary A 48-year-old female, presenting with chest pain radiating to her left shoulder with no cardiovascular risk factors other than genetic predisposition, was screened for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and tested positive. Although computed tomography angiography excluded obstructive coronary heart disease, cardiac magnetic resonance imaging showed an acute myocardial infarction with no obstructive coronary arteries of the inferior wall. The patient was treated with dual anti-platelet therapy, an angiotensin-converting-enzyme inhibitor and a statin, and assigned to a cardiac rehabilitation program. Conclusion We report a serious thrombo-embolic event during an oligosymptomatic SARS-CoV-2 infection in a healthy, young patient. While these two diseases may have occurred simultaneously, by chance, it is possible that the pro-thrombotic effects of the SARS-CoV-2 infection facilitated the infarction. This case further demonstrates the significant cardiovascular morbidity potentially caused by SARS-CoV-2. [ABSTRACT FROM AUTHOR]

The presence of stroke has been observed in young adults (under fifty years of age) without cardiovascular risk factors who are suffering from COVID-19. It is speculated that there is really a significant increase, as a few cases have yet to be described, or that the infection favors his development. Cerebrovascular events are more common in older patients with stroke risk factors, such as hypertension and diabetes mellitus, and those who have elevated fibrin D-dimers. Multiple case reports and series about cerebrovascular disease (CVD) in COVID-19 has been informed. The mechanism that causes cerebral ischemia in COVID-19 remains undiscovered. However, progressively there is increasing evidence of hypercoagulability that can be or contribute to the cause. We review the current literature about CVD both epidemiology and etiology. More studies are needed to understand.

Until less than two decades ago, all known human coronaviruses (CoV) caused diseases so mild that they did not stimulate further advanced CoV research. In 2002 and following years, the scenario changed dramatically with the advent of the new more pathogenic CoVs, including Severe Acute Respiratory Syndome (SARS-CoV-1), Middle Eastern respiratory syndrome (MERS)-CoV, and the new zoonotic SARS-CoV-2, likely originated from bat species and responsible for the present coronavirus disease (COVID-19), which to date has caused 15,581,007 confirmed cases and 635,173 deaths in 208 countries, including Italy. SARS-CoV-2 transmission is mainly airborne via droplets generated by symptomatic patients, and possibly asymptomatic individuals during incubation of the disease, although for the latter, there are no certain data yet. However, research on asymptomatic viral infection is currently ongoing worldwide to elucidate the real prevalence and mortality of the disease. From a clinical point of view, COVID-19 would be defined as “COVID Planet “ because it presents as a multifaceted disease, due to the large number of organs and tissues infected by the virus. Overall, based on the available published data, 80.9% of patients infected by SARS-CoV-2 develop a mild disease/infection, 13.8% severe pneumonia, 4.7% respiratory failure, septic shock, or multi-organ failure, and 3% of these cases are fatal, but mortality parameter is highly variable in different countries. Clinically, SARS-CoV-2 causes severe primary interstitial viral pneumonia and a “cytokine storm syndrome”, characterized by a severe and fatal uncontrolled systemic inflammatory response triggered by the activation of interleukin 6 (IL-6) with development of endothelitis and generalized thrombosis that can lead to organ failure and death. Risk factors include advanced age and comorbidities including hypertension, diabetes, and cardiovascular disease. Virus entry occurs via binding the angiotensin-converting enzyme 2 (ACE2) receptor present in almost all tissues and organs through the Spike (S) protein. Currently, SARS-CoV-2 infection is prevented by the use of masks, social distancing, and improved hand hygiene measures. This review summarizes the current knowledge on the main biological and clinical features of the SARS-CoV-2 pandemic, also focusing on the principal measures taken in some Italian regions to face the emergency and on the most important treatments used to manage the COVID-19 pandemic.

Aim. To study a vasomotor endothelial function in patients with diabetes mellitus (DM) type 1 at different stages of diabetic nephropathy (DN). Material and methods. Twenty six patients with DM type 1(11 males and 15 females, mean age 25.9 ±4.3 years, mean history of DM 12.9 + 3.4 years) entered the study. They were divided into 4 groups: group 1 -without renal affection, group 2 - with microalbuminuria (MAU), group 3 - with proteinuria (PU), group 4 - with chronic renal failure (CRF). The control group consisted of 7 healthy volunteers. Endothelium-dependent vasodilation (EDVD) was studied in the test with reactive hyperemia provoked by 4-5 min occlusion of the brachial artery by pneumocollar and subsequent assessment of arterial diameter changes after decompression using high-resolution ultrasound dopplerography. Results. Reactive hyperemia resulted in dilation of the artery in all the examinees. This dilation was maximal on second 30 after removal of the collar in the controls, group 2, 3 and 4 and reached 9.2 ± 2.9, 9.63 ± 3.62, 7.25 ± 5.23 and 4.42 ± 4.05%, respectively. Resting blood flow velocity was similar in all the groups and rose maximally by 95-150%. To estimate EDVD of the brachial artery more precisely, the coefficient of endothelial sensitivity to shift tension was calculated. It made up 0.084 ± 0.04 (control group), 0.0825 + 0.08 (group 1), 0.138 ± 0.07(group 2), 0.067 ± 0.05 (group 3) and 0.052 ± 0.04 (group 4). Conclusion. At the earliest stage of DN (stage MAU), EDVD is not affected as maximal vasodilation of the brachial artery and endothelial sensitivity to shift tension do not differ from the control values. This means that the stage of MAU is reversible in early treatment, but PU and CRF are not reversible stages associated with depletion of endothelial cells and loss of sensitivity to changing hemodynamic conditions.

This case demonstrates an unusual presentation of Herpes simplex virus (HSV) ocular infection and the challenges faced during the management of its complications. A thirty year-old lady, a steroid responder with HSV keratouveitis, was referred for non-response to treatment with the prophylactic dose of oral acyclovir and acetazolamide. She presented with large epithelial bullae, anterior chamber reaction, and raised intraocular pressure in her right eye. Initially, she responded to the therapeutic dose of oral acyclovir, but on follow-up visits, she developed high intraocular pressures of up to 45 mmHg on maximum medical therapy. Hence, trabeculectomy with mitomycin-C was performed. One year later, she developed corneal endothelial decompensation, for which a Descemet's stripping automated endothelial keratoplasty (DSAEK) was done. Eight months post-operatively, she had a best corrected visual acuity of 20/20, clear corneal graft, quiet anterior chamber, and well-controlled intraocular pressures. HSV trabeculitis is associated with inflammation of the anterior chamber, endothelitis and raised intra-ocular pressure. A combination of anti-viral, anti-inflammatory, and anti-glaucoma medications helps in the management. However, glaucoma filtration surgery is often needed to the control intra-ocular pressure. Chronic recurrent episodes eventually lead to endothelial failure and demand endothelial keratoplasty (EK). It is prudent to adopt certain measures to perform EK in these phakic eyes without causing any iatrogenic damage to the filtration bleb as well as to the clear crystalline lens. This case highlights the difficulties of treating HSV-related keratouveitis with uncontrolled glaucoma, problems of associated steroid response, and complexities in performing corneal endothelial procedures in young phakic patients especially post-trabeculectomy. • HSV infecting the uveal tract is likely to infect the endothelium and trabecula. • HSV trabeculitis is associated with endothelitis and high intraocular pressure, which is not controlled with maximum medical management. • Glaucoma filtration surgery helps in controlling intraocular pressure. • Chronic cases develop endothelial dysfunction and demand endothelial keratoplasty. • Endothelial keratoplasty in a phakic eye needs a strategical approach intra-operatively. [ABSTRACT FROM AUTHOR]

The human immune system protects the body against invasive organisms and kicks into a hyperactive mode in COVID-19 patients, particularly in those who are critically sick. Therapeutic regimens directed at the hyperactive immune system have been found to be effective in the treatment of patients with COVID-19. An evolving potential treatment option is therapy with mesenchymal stem cells (MSCs) due to their regenerative and reparative ability in epithelial cells. Clinical trials have reported the safe usage of MSC therapy. Systemic effects of MSC treatment have included a reduction in pro-inflammatory cytokines and a decrease in the levels of CRP, IL-6, and lactase dehydrogenase, which function as independent biomarkers for COVID-19 mortality and respiratory failure.

Background: The incidence of endothelitis in cardiac transplants, and the relationship to clinical symptoms and humoral rejection, is unclear. Recently, the finding of intravascular macrophages has been found to represent antibody-mediated rejection. This study investigated the role of intravascular T lymphocytes in antibody-mediated rejection. Methods: A total of 819 sequential biopsy specimens from 93 cardiac allograft recipients were prospectively studied. Rejection was graded according to International Society for Heart and Lung Transplantation (ISHLT) criteria and inflammatory infiltrates characterized by immunohistochemical staining for CD3, CD4, CD8, CD68, and CD20. Endothelitis was defined as lymphocyte and macrophage infiltrates within arteriolar, capillary, or venular walls, with endothelial swelling, in contrast to perivascular inflammation of cellular rejection. Complement C4d was identified in capillary walls by immunofluorescent staining and immunohistochemical staining on paraffin sections. Results: Endothelitis was identified in 27 specimens (3%) from 14 patients (15%). ISHLT rejection grades were 0 in 6 specimens, 1R in 20 (1A in 8; 1B in 12), and 2R (3A) in 1. In all cases, there were admixtures of macrophages and T lymphocytes. Inflammation was most prominent in venules. C4d was localized in 12 of the 27 specimens (44%). C4d was localized in 31 of 796 specimens without endothelitis (p < 0.001). The endothelial infiltrates were CD3, CD4, CD8, and CD68+. Twelve of 14 patients had > 0 panel reactive antibodies (PRA), 9 were above 10%, and 8 were above 25%; 5 patients were treated for clinical antibody-mediated rejection, and 4 had possible cardiac allograft vasculopathy by ultrasound imaging (mean follow-up, 40 months). Conclusion: Endothelitis is present in more than 10% of heart transplant recipients and is associated with complement deposition on biopsy samples. Approximately 33% of patients have clinical evidence of humoral rejection. The eventual risk for developing graft vascular disease remains undetermined. [Copyright &y& Elsevier]

Acute mesenteric ischemia is a rare but extremely severe complication of SARS-CoV-2 infection. The present review aims to document the clinical, laboratory, and imaging findings, management, and outcomes of acute intestinal ischemia in COVID-19 patients. A comprehensive search was performed on PubMed and Web of Science with the terms "COVID-19" and "bowel ischemia" OR "intestinal ischemia" OR "mesenteric ischemia" OR "mesenteric thrombosis". After duplication removal, a total of 36 articles were included, reporting data on a total of 89 patients, 63 being hospitalized at the moment of onset. Elevated D-dimers, leukocytosis, and C reactive protein (CRP) were present in most reported cases, and a contrast-enhanced CT exam confirms the vascular thromboembolism and offers important information about the bowel viability. There are distinct features of bowel ischemia in non-hospitalized vs. hospitalized COVID-19 patients, suggesting different pathological pathways. In ICU patients, the most frequently affected was the large bowel alone (56%) or in association with the small bowel (24%), with microvascular thrombosis. Surgery was necessary in 95.4% of cases. In the non-hospitalized group, the small bowel was involved in 80%, with splanchnic veins or arteries thromboembolism, and a favorable response to conservative anticoagulant therapy was reported in 38.4%. Mortality was 54.4% in the hospitalized group and 21.7% in the non-hospitalized group (p < 0.0001). Age over 60 years (p = 0.043) and the need for surgery (p = 0.019) were associated with the worst outcome. Understanding the mechanisms involved and risk factors may help adjust the thromboprophylaxis and fluid management in COVID-19 patients. [ABSTRACT FROM AUTHOR]

Abstract: The endothelium is now considered a real endocrine–paracrine organ, important not only as a structural barrier between the circulation and surrounding tissue, but also because it plays an essential role for local hemodynamics, releasing substances that modulate the vascular calibre and blood cell activation. Here, after a brief but detailed analysis of the importance of the endothelium in vascular homeostasis, in the control of coagulation and in the relations with the different blood cells, we will explain the concept of endothelial dysfunction (altered NO release) and activation (amplified adhesion molecule expression) in inflammatory, connective tissue and post-trasplantation diseases. Furthermore, this review will focus on the activity of prostacyclin and synthetic analogs, especially their ability to interact with the vasodilatation system and their role in modulating cell interaction by surface adhesion molecule expression, cytokines and growth factors release as well as gene transcription factors. Finally, we will consider the therapeutic role of prostacyclin analogs in the prevention and treatment of connective tissue diseases. [Copyright &y& Elsevier]

Acute mesenteric ischemia is a rare but extremely severe complication of SARS-CoV-2 infection. The present review aims to document the clinical, laboratory, and imaging findings, management, and outcomes of acute intestinal ischemia in COVID-19 patients. A comprehensive search was performed on PubMed and Web of Science with the terms "COVID-19" and "bowel ischemia" OR "intestinal ischemia" OR "mesenteric ischemia" OR "mesenteric thrombosis". After duplication removal, a total of 36 articles were included, reporting data on a total of 89 patients, 63 being hospitalized at the moment of onset. Elevated D-dimers, leukocytosis, and C reactive protein (CRP) were present in most reported cases, and a contrast-enhanced CT exam confirms the vascular thromboembolism and offers important information about the bowel viability. There are distinct features of bowel ischemia in non-hospitalized vs. hospitalized COVID-19 patients, suggesting different pathological pathways. In ICU patients, the most frequently affected was the large bowel alone (56%) or in association with the small bowel (24%), with microvascular thrombosis. Surgery was necessary in 95.4% of cases. In the non-hospitalized group, the small bowel was involved in 80%, with splanchnic veins or arteries thromboembolism, and a favorable response to conservative anticoagulant therapy was reported in 38.4%. Mortality was 54.4% in the hospitalized group and 21.7% in the non-hospitalized group ( p < 0.0001). Age over 60 years ( p = 0.043) and the need for surgery ( p = 0.019) were associated with the worst outcome. Understanding the mechanisms involved and risk factors may help adjust the thromboprophylaxis and fluid management in COVID-19 patients.

Until less than two decades ago, all known human coronaviruses (CoV) caused diseases so mild that they did not stimulate further advanced CoV research. In 2002 and following years, the scenario changed dramatically with the advent of the new more pathogenic CoVs, including Severe Acute Respiratory Syndome (SARS-CoV-1), Middle Eastern respiratory syndrome (MERS)-CoV, and the new zoonotic SARS-CoV-2, likely originated from bat species and responsible for the present coronavirus disease (COVID-19), which to date has caused 15,581,007 confirmed cases and 635,173 deaths in 208 countries, including Italy. SARS-CoV-2 transmission is mainly airborne via droplets generated by symptomatic patients, and possibly asymptomatic individuals during incubation of the disease, although for the latter, there are no certain data yet. However, research on asymptomatic viral infection is currently ongoing worldwide to elucidate the real prevalence and mortality of the disease. From a clinical point of view, COVID-19 would be defined as "COVID Planet " because it presents as a multifaceted disease, due to the large number of organs and tissues infected by the virus. Overall, based on the available published data, 80.9% of patients infected by SARS-CoV-2 develop a mild disease/infection, 13.8% severe pneumonia, 4.7% respiratory failure, septic shock, or multi-organ failure, and 3% of these cases are fatal, but mortality parameter is highly variable in different countries. Clinically, SARS-CoV-2 causes severe primary interstitial viral pneumonia and a "cytokine storm syndrome", characterized by a severe and fatal uncontrolled systemic inflammatory response triggered by the activation of interleukin 6 (IL-6) with development of endothelitis and generalized thrombosis that can lead to organ failure and death. Risk factors include advanced age and comorbidities including hypertension, diabetes, and cardiovascular disease. Virus entry occurs via binding the angiotensin-converting enzyme 2 (ACE2) receptor present in almost all tissues and organs through the Spike (S) protein. Currently, SARS-CoV-2 infection is prevented by the use of masks, social distancing, and improved hand hygiene measures. This review summarizes the current knowledge on the main biological and clinical features of the SARS-CoV-2 pandemic, also focusing on the principal measures taken in some Italian regions to face the emergency and on the most important treatments used to manage the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Diabetic heart disease (DHD) can be classified as a primary consequence from several pathophysiological manifestation of diabetes mellitus (DM) on cardiac tissues or secondarily in extracardiac tissues and is encountered as either primary or secondary complications of DM. Endothelitis is inflammation of the vascular endothelium and is likely to be seen in the majority of patients who start to manifest an end organ complication of DM in this case DHD. Diabetes is a leading cause for many cardiovascular syndromes and diseases including congestive heart failure (CHF) however much remains unknown about the transition from diagnosed DM to clinical state and the contribution of the various mechanical and counterregulatory systems in the manifested complaint. Diastolic heart failure or heart failure with preserved ejection fraction (DHF/HFpEF), accounts for half of all CHF presentations, has DM as a major contributor, however, there remain large gaps in clinical and pathophysiological understanding. This review aims to explore the microscopic aspects in diabetic endothelitis and provide a clinical link to with context to HFpEF., Competing Interests: Conflict-of-interest statement: All co-authors have won independent and governmental research funding. None pose a conflict of interest for this review., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

The presence of stroke has been observed in young adults (under fifty years of age) without cardiovascular risk factors who are suffering from COVID-19. It is speculated that there is really a significant increase, as a few cases have yet to be described, or that the infection favors his development. Cerebrovascular events are more common in older patients with stroke risk factors, such as hypertension and diabetes mellitus, and those who have elevated fibrin D-dimers. Multiple case reports and series about cerebrovascular disease (CVD) in COVID-19 has been informed. The mechanism that causes cerebral ischemia in COVID-19 remains undiscovered. However, progressively there is increasing evidence of hypercoagulability that can be or contribute to the cause. We review the current literature about CVD both epidemiology and etiology. More studies are needed to understand., Competing Interests: Marcos Altable and Juan Moisés de la Serna have no conflicts of interest to disclose regarding the manuscript. The authors declare that the manuscript was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (© 2020 Published by Elsevier Inc.)