The preventive effect and mechanism of Dayuanyin in hypoxic pulmonary hypertension through NF-kappaB signaling pathway.

Dayuanyin (DYY) has been shown to reduce lung inflammation in both coronavirus disease 2019 (COVID-19) and lung injury. This experiment was designed to investigate the efficacy and mechanism of action of DYY against hypoxic pulmonary hypertension (HPH) and to evaluate the effect of DYY on the protection of lung function. Animal welfare and experimental procedures are approved and in accordance with the provision of the Animal Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Science. Male C57/BL6J mice were randomly divided into 4 groups: control group, model group, DYY group (800 mg.kg-1), and positive control sildenafil group (100 mg.kg-1). The animals were given control solvents or drugs by gavage three days in advance. On day 4, the animals in the model group, DYY group and sildenafil group were kept in a hypoxic chamber containing 10% +/- 0.5% oxygen, and the animals in the control group were kept in a normal environment, and the control solvent or drugs continued to be given continuously for 14 days. The right ventricular systolic pressure, right ventricular hypertrophy index, organ indices and other metrics were measured in the experimental endpoints. Meantime, the expression levels of the inflammatory factors in mice lung tissues were measured. The potential therapeutic targets of DYY on pulmonary hypertension were predicted using network pharmacology, the expression of nuclear factor kappa B (NF- kappaB) signaling pathway-related proteins were measured by Western blot assay. It was found that DYY significantly reduced the right ventricular systolic pressure, attenuated lung injury and decreased the expression of inflammatory factors in mice. It can also inhibit hypoxia-induced activation of NF- kappaB signaling pathway. DYY has a protective effect on lung function, as demonstrated by DYY has good efficacy in HPH, and preventive administration can slow down the disease progression, and its mechanism may be related to inhibit the activation of NF-kappaB and signal transducer and activator of transcription 3 (STAT3) by DYY.Copyright © 2023, Chinese Pharmaceutical Association. All rights reserved.

Linking CT and SPECT based analysis for quantitative follow-up of vascular perfusion defects in COVID-19

COVID-19 still affects a large population worldwide with possible post-traumatic sequelae requiring long-term patient follow-up for the most severe cases. The lung is the primary target of severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) infection. In particular, the virus affects the entire pulmonary vascular tree from large vessels to capillaries probably leading to an abnormal vascular remodeling. In this study we investigated two modalities for assessing this remodeling, SPECT perfusion scintigraphy and computed tomography, the latter enabling the computation of vascular remodeling patterns. We analyzed on a cohort of 30 patients the relationship between vascular remodeling and perfusion defects in the peripheral lung area, which is a predominant focus of the COVID-19 infectious patterns. We found that such relationship exists, demonstrated by moderate significant correlations between SPECT and CT measures. In addition, a vascular remodeling index derived from the z-score normalized peripheral CT images showed a moderate significant correlation with the diffusing capacity of the lung for carbon monoxide (DLCO) measures. Altogether these results point CT scan as a good tool for a standardized, quantitative, and easy-to-use routine characterization and follow-up of COVID-19-induced vascular remodeling. An extensive validation of these results will be carried out in the near future on a larger cohort. © 2023 SPIE.

The preventive effect and mechanism of Dayuanyin in hypoxic pulmonary hypertension through NF-kappaB signaling pathway

Dayuanyin (DYY) has been shown to reduce lung inflammation in both coronavirus disease 2019 (COVID-19) and lung injury. This experiment was designed to investigate the efficacy and mechanism of action of DYY against hypoxic pulmonary hypertension (HPH) and to evaluate the effect of DYY on the protection of lung function. Animal welfare and experimental procedures are approved and in accordance with the provision of the Animal Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Science. Male C57/BL6J mice were randomly divided into 4 groups: control group, model group, DYY group (800 mg.kg-1), and positive control sildenafil group (100 mg.kg-1). The animals were given control solvents or drugs by gavage three days in advance. On day 4, the animals in the model group, DYY group and sildenafil group were kept in a hypoxic chamber containing 10% +/- 0.5% oxygen, and the animals in the control group were kept in a normal environment, and the control solvent or drugs continued to be given continuously for 14 days. The right ventricular systolic pressure, right ventricular hypertrophy index, organ indices and other metrics were measured in the experimental endpoints. Meantime, the expression levels of the inflammatory factors in mice lung tissues were measured. The potential therapeutic targets of DYY on pulmonary hypertension were predicted using network pharmacology, the expression of nuclear factor kappa B (NF- kappaB) signaling pathway-related proteins were measured by Western blot assay. It was found that DYY significantly reduced the right ventricular systolic pressure, attenuated lung injury and decreased the expression of inflammatory factors in mice. It can also inhibit hypoxia-induced activation of NF- kappaB signaling pathway. DYY has a protective effect on lung function, as demonstrated by DYY has good efficacy in HPH, and preventive administration can slow down the disease progression, and its mechanism may be related to inhibit the activation of NF-kappaB and signal transducer and activator of transcription 3 (STAT3) by DYY.Copyright © 2023, Chinese Pharmaceutical Association. All rights reserved.

Phenotypes of post covid interstitial lung disease, clinical, radiological, and pathological correlations

Introduction: The clinical-radiologic-pathologic features of post-COVID interstitial lung disease (ILD) remain to be explored. Method(s): In a prospective multicenter Italian study (PCOILS), subsequent patients seen at 4-18 months after the acute infection underwent transbronchial lung cryobiopsy and BAL if they showed a significant ILD (progressive and/or symptomatic and/or with pulmonary function impairment). Result(s): 19 patients enrolled;characteristics are summarized in Fig.2. We identified 3 post-COVID phenotypes: 1) prominent vascular changes;2) post-COVID fibrosis;3) persistent COVID. Fig. 1. Phenotype 1 was detected only in 2 cases with similar characteristics as showed in Fig. 1 Phenotype 2 was detected in 7 patients all with HRCT NSIP/OP features. Histology showed fibrotic or mixed NSIP, fibrotic OP, fibrotic DAD and bronchiolar damage. Phenotype 3 was detected only in the case reported in Fig.1.The remaining 9 patients were reclassified as known ILDs and treated according to current guidelines. Conclusion(s): We identified 3 phenotypes of postcovid damage with heterogeneous pictures and leading to differenttreatment choices.

The evolving landscape of pulmonary arterial hypertension clinical trials

Although it is a rare disease, the number of available therapeutic options for treating pulmonary arterial hypertension has increased since the late 1990s, with multiple drugs developed that are shown to be effective in phase 3 randomised controlled trials. Despite considerable advancements in pulmonary arterial hypertension treatment, prognosis remains poor. Existing therapies target pulmonary endothelial dysfunction with vasodilation and anti-proliferative effects. Novel therapies that target proliferative vascular remodelling and affect important outcomes are urgently needed. There is need for additional innovations in clinical trial design so that all emerging candidate therapies can be rigorously studied. Pulmonary arterial hypertension trial design has shifted from short-term submaximal exercise capacity as a primary endpoint, to larger clinical event-driven trial outcomes. Event-driven pulmonary arterial hypertension trials could face feasibility and efficiency issues in the future because increasing sample sizes and longer follow-up durations are needed, which would be problematic in such a rare disease. Enrichment strategies, innovative and alternative trial designs, and novel trial endpoints are potential solutions that could improve the efficiency of future pulmonary arterial hypertension trials while maintaining robustness and clinically meaningful evidence.Copyright © 2022 Elsevier Ltd

Histopathologic changes in lung tissue after Covid-19 pneumonia

Current knowledge of histopathological changes in Covid-19 pneumonia is mainly based on autopsy findings. There are few data on dynamics of lung lesions in vivo after acute phase of disease. The aim of this study was to determine histopathologic changes during the long/post-Covid stage in patients who had suffered from moderate to severe Covid-19 pneumonia. Bronchoscopy with transbronchial lung biopsy was performed in patients with HRCT lesions involving >40% of lung parenchyma, at least 4 weeks after discharge. Additional criteria were restrictive pattern in lung function tests and signed informed consent. Histopathologic analyses were performed using H&E, MSB, MOVAT, TTF1, CD34 and CD68 staining. Research was approved by the Hospital Ethical Committee. Among 26 patients that met inclusion criteria, adequate biopsy samples were obtained from 24. The mean time from the onset of disease to biopsy was 13 weeks. We found 4 histopathologic patterns: diffuse alveolar damage-DAD with vascular abnormalities, nonspecific interstitial inflammation, organizing pneumonia and interstitial fibrosis in 11, 9, 2 and 2 patients, respectively. Vascular abnormalities included capillary thrombi, dilated venules and dissection of small pulmonary arteries. Given the duration of disease, DAD and vascular abnormalities were detected up to the 12 week from the onset of symptoms. All patients biopsied after 12th weeks had some degree of tissue inflammation without vascular changes. Our findings show rather slow recovery of lung tissue after Covid-19 pneumonia. Long lasting DAD with vascular abnormalities may explain prolonged dyspnea and exercise intolerance and should be taken into consideration when planning further rehabilitation.

Uphill versus downhill high-intensity training effectiveness in preserving vascular function and exercise performance in runners who reduce their regular endurance training.

Purpose: The COVID-19 restrictions have limited outdoor physical activities. High-intensity training (HIT) may be a valid indoor alternative. We tested whether an indoor HIT is effective in maintaining vascular function and exercise performance in runners who reduce their usual endurance training, and whether a downhill HIT is as effective as an uphill one for such purposes. Methods: Sixteen runners performed the same 6-week HIT either uphill (UP, eight runners) or downhill (DOWN, eight runners). Eight runners continuing their usual endurance training acted as a control group (CON). The following data were collected before vs after our HIT: vascular conductance during rapid leg vasodilation to assess vasodilation capacity; V̇O2max through running incremental test to exhaustion; 2000 m running time; neuromuscular indexes related to lower-limb muscle strength. Results: Both uphill and downhill HIT failed in maintaining the pre-HIT leg vasodilation capacity compared to CON, which was, however, blunted more after uphill than downhill HIT. V̇O2max and 2000 m time were similar after downhill HIT compared to CON, and augmented after uphill HIT compared to CON and DOWN. Indexes of lower-limb muscle strength were similar before vs after HIT and among groups. Conclusion: Our HIT was ineffective in maintaining the pre-HIT leg vasodilation capacity compared to runners continuing their usual low-intensity endurance training, but did not lead to reductions in V̇O2max, 2000 m time performance, and indexes related to lower-limb muscle strength. Our data show an appealing potential for preserving exercise performance with low cardiorespiratory effort via downhill running.

Long-Term Adverse Effects of Mild COVID-19 Disease on Arterial Stiffness, and Systemic and Central Hemodynamics: A Pre-Post Study.

COVID-19-associated vascular disease complications are primarily associated with endothelial dysfunction; however, the consequences of disease on vascular structure and function, particularly in the long term (>7 weeks post-infection), remain unexplored. Individual pre- and post-infection changes in arterial stiffness as well as central and systemic hemodynamic parameters were measured in patients diagnosed with mild COVID-19. As part of in-laboratory observational studies, baseline measurements were taken up to two years before, whereas the post-infection measurements were made 2-3 months after the onset of COVID-19. We used the same measurement protocol throughout the study as well as linear and mixed-effects regression models to analyze the data. Patients (N = 32) were predominantly healthy and young (mean age ± SD: 36.6 ± 12.6). We found that various parameters of arterial stiffness and central hemodynamics-cfPWV, AIx@HR75, and cDBP as well as DBP and MAP-responded to a mild COVID-19 disease. The magnitude of these responses was dependent on the time since the onset of COVID-19 as well as age (pregression_models ≤ 0.013). In fact, mixed-effects models predicted a clinically significant progression of vascular impairment within the period of 2-3 months following infection (change in cfPWV by +1.4 m/s, +15% in AIx@HR75, approximately +8 mmHg in DBP, cDBP, and MAP). The results point toward the existence of a widespread and long-lasting pathological process in the vasculature following mild COVID-19 disease, with heterogeneous individual responses, some of which may be triggered by an autoimmune response to COVID-19.

Vascular phenotyping in post-COVID children and adolescents-the lico study

Background and Aim: An infection with SARS-CoV-2 is associated with systemic inflammation, that also affects the endothelium. This may result in endothelitis, which can influence vascular regulation and morphology. Until now, the specific mechanism of vessel damage after a SARS-CoV-2 infection is still unclear, especially in children and adolescents. The LICO Study (Long term impact of COVID-19) aims to investigate the long-term effects of a SARS-CoV-2 infection on vascular structure and function in chil-dren and adolescents. Method(s): Children and adolescents with confirmed evidence of survived SARS-CoV-2 infection are screened 6 +/- 3 months post-infection. Vascular function is assessed by flow-mediated vas-odilation (FMD) and aortic pulse wave velocity (PWV). Carotid intima-media thickness (cIMT) and retinal diagnostics (arteriove-nous ratio-AVR) are used to examine vascular structure. The matched control group without prior SARS-CoV-2 infection undergoes the same examination procedure. Result(s): So far, we have been able to evaluate 24 (9 post-covid) subjects (13.5 +/- 1.9 years;9 girls). Compared to the mean refer-ence values of the control group, 5 post-covid subjects have higher cIMT (0.49 +/- 0.01 mm vs. reference value 0.46 +/- 0.03 mm). Of these, 3 post-covid subjects even deviate from the norm PWV (4.96 +/- 0.16 m/sec vs. reference value 4.63 +/- 0.29 m/sec). The same 3 post-covid subjects are also below the norm FMD (2.06 +/- 1.05 % vs. reference value 4.18 +/- 7.04 %). None of the post-covid subjects deviates from the norm AVR values (refer-ence value 0.85 +/- 0.07). Conclusion(s): It is shown that infection with SARS-CoV-2 has the potential to impair vascular regulation. These initial results provide trends for early vascular changes among children and adolescents after recovered SARS-CoV-2 infection. Due to that this is an ongoing study, the results are constantly being expanded and may still change. To determine lasting changes in morphology, the examination is repeated after 6 months and the further results of this longitudinal study must be awaited.

Tissue-specific evidence for SARS-CoV-2 within intraocular tissues

Purpose : To systematically investigate ocular changes in autopsied eyes from fatal cases of Coronavirus disease 2019 (COVID-19) and to investigate the localization of severe acute respiratory syndrome coronavirus (SARS-CoV-2) within ocular structures. Methods : Macroscopic and microscopic histopathological evaluation was performed and the localization of SARS-CoV-2 RNA within ocular tissues investigated using an in situ hybridization (ISH) technique in 13 eyes. Contralateral eyes were freshly dissected, and droplet digital polymerase chain reaction (ddPCR) assay was performed on ocular fluids and tissues to quantify SARS-CoV-2 RNA. Results : A total of 21 fatal COVID-19 cases were included (mean age, 60.2 years [range, 27- 91 years];23.8% female). Histopathological abnormalities include vascular changes (61.9%), cytoid bodies (52.4%), and retinal edema (23.8%) with minimal inflammation (0.09%) were observed. Non-CMV viral inclusions were identified in one eye. No CMV positivity was detected. Of the 21 contralateral eyes tested by ddPCR, 14 tested positive for SARS-CoV-2. Using ddPCR and ISH, SARS-CoV-2 localization was observed in the following ocular tissues and fluid: cornea (27.3%), aqueous (26.3%), lens (54.5%), vitreous (15.0%), retina (22.2%), choroid/sclera (47.4%), and optic nerve (50.0%). The choroid/sclera, optic nerve and lens were the most frequent ocular structures found to be ddPCR positive. Evidence of replication was detected in four cases. Conclusions : Our results suggest that SARS-CoV-2 localizes to intraocular tissues. However, histological changes observed are likely a secondary hemodynamic change rather than primary effect of the virus.

An Update Review of the Pathogenesis Hypothesis in Preeclampsia

Objectives: Hypertensive disorders occur in approximately 12% to 22% of pregnancies and cause substantial perinatal morbidity and mortality of both mother and fetus. Hypertensive disease is directly responsible for approximately 20% of maternal deaths and can be classified as chronic hypertension, gestational hypertension, preeclampsia-eclampsia, and chronic hypertension with superimposed preeclampsia. At present, the pathogenesis of preeclampsia is still unclear, we wrote this article to make a uptodate review of this disease. Mechanism: A comprehensive search of several databases was conducted from inception up to March 2022. The searched databases were Web of Science, MEDLINE, Ovid, and Cochrane Database of Systematic Reviews. The search strategy included the combinations of the following medical terms: Hypertensive disorders;preeclampsia;mechanism;pathogenesis hypothesis. Findings in Brief: At present, the pathogenesis of preeclampsia is still unclear, the theory of Genetic, Inflammatory Response, Immune Imbalance in Maternal-Fetal Interface, Oxidative Stress, Vascular Endothelial Cell Damage are supposed involved in the progress of preeclampsia. Conclusions: Although there are various theories mentioned above, none of the hypothesis can fully explain preeclampsia. More research is needed on the mechanism of preeclampsia.

Multiparameter analysis of vascular remodeling in post-Acute sequelae of COVID-19

The COVID-19 infection, a current worldwide health concern, manifests as an alveolar-interstitial pneumonia with unknown long-Term evolution. It is also associated with vascular dysfunction and shows a vascular remodeling with a changed balance between small-and large-caliber vessels. In this study, we question the existence of residual vascular alteration in post-Acute sequelae of COVID-19 (PASC) by investigating possible associations between vascular remodeling biomarkers extracted from CT and functional, radiological and morphological parameters. The used vascular biomarkers concern the blood volume ratio of vessels with cross-section area inferior to 5 mm2 versus vessels of crosssection area inferior to 50 mm2 (BV5/BV50), an index of local peripheral vascular density and a peripheral composite vascular remodeling index, both measured in the antero-postero-lateral lung periphery (excluding mediastinal region). As a functional parameter, diffusing capacity of the lung for carbon monoxide (DLCO) is a measure depending on the vascular perfusion and the amount of interstitial thickening, a decreased DLCO value suggesting altered vascular perfusion. Imaging biomarkers can be extracted from the analysis of perfusion lung scintigraphy or CT scan. Some of them are included in our study. Radiological features include CT attenuation as a measure of persistence of ground glass opacity and development of changes suggestive to look for fibrosis, such as reticulations. As additional morphological parameter, lung deformation observed between inspiration/expiration maneuvers may be suggestive of the presence of reticulations inducing lung stiffness and breathing deficiency. The investigation of associations between vascular remodeling biomarkers obtained from CT and the above functional, radiological and morphological parameters revealed moderate to strong correlations highlighting the ability to capture the persistence of vascular alterations in PASC in relation with the development of fibrotic patterns, which is a promising direction for future research. © 2022 SPIE.

A Case-Control Autopsy Series of Liver Pathology Associated with Novel Coronavirus Disease (COVID-19)

Background: COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to be a global health emergency. Although well-known for pulmonary injury, COVID-19 is a systemic process. Previous autopsy case series have speculated about, although not clearly defined, patterns of hepatic injury, with steatosis being reported in many patients. This retrospective study is the first case-control study investigating hepatic pathology in a large cohort of deceased COVID-19 patients. Design: Consented autopsy cases at two institutions, between 4/2020 and 2/2021, were retrospectively searched for documentation of COVID-19 as a contributing cause of death. A control group of 40 consecutive consented COVID-19(-) autopsy cases during the same period was identified. The autopsy report and electronic medical records were reviewed for clinical information. H&E-stained liver sections were examined for selected histologic features. Results: 54 COVID-19(+) (mean age 72, M:F=3.2:1) were included in the study. The 40 control cases had a mean age of 64 years and a M:F=1.4:1. The study group was significantly older (p=0.0095) but there was no significant difference in sex. The control group had a higher rate of chronic alcoholism and underlying malignancy, with no difference noted in BMI or other comorbidities. The study group was more likely to have received steroid (72.2% vs. 30%, p<0.0001) and anticoagulation therapy (75.9% vs. 47.5%, p=0.009). Histologically, the study group showed a higher incidence of clinically insignificant steatosis (≤5%), (33.3% vs 12.5%;P = 0.03). Presence of clinically relevant (>5%) steatosis or zonal distribution of steatosis was not significantly different between the groups. Mild nonspecific lobular inflammation and acidophil bodies were also more common in COVID-19 cases (51.9% vs 30.0%;P = 0.04). No significant difference was noted among other histologic features, including vascular changes (Table 1). Conclusions: Mild nonspecific lobular necroinflammatory activity is a common finding in deceased COVID-19 patients, suggestive of COVID-19 hepatitis. COVID-19 is unlikely a cause of clinically significant steatosis. However, patients with COVID-19 are more likely to have low levels of steatosis (≤5%) compared to controls. The high rate of steroid therapy in this population may be a possible source of this minor component of steatosis.

Pulmonary Pathology in Post-Acute COVID-19 Syndrome Treated with Bilateral Orthotopic Lung Transplantation

Background: Lung transplantation has been performed as a life-saving treatment in a small number of post-acute COVID- 19 patients who develop severe pulmonary insufficiency. We report a detailed clinicopathologic analysis of 7 such patients that underwent bilateral orthotopic lung transplantation at our institution. Design: The time interval between initial diagnosis of Covid-19 infection and lung transplantation, other clinical findings, and imaging features of the 7 patients were reviewed. The pathologic findings in the 14 explants were assessed and histologic abnormalities were classified into parenchymal, airway and vascular changes. The extent (1+-to 4+ based on # of slides with the abnormality) and severity (mild, moderate, marked) of histologic abnormalities were recorded. Results: Patients ranged in age from 34 to 55 years old and were transplanted at 10.4 to 24 weeks after initial diagnosis of Covid- 19 (median 16 weeks). Six of these patients had been previously treated with ECMO for 82-145 days. Other clinical and imaging features are summarized in Table 1. All 14 explants showed diffuse marked interstitial fibrosis with a nonspecific interstitial pneumonia (NSIP) pattern. Other pathologic changes included extensive alveolar hemosiderosis (n=7 patients);prominent peribronchial metaplasia (n=7);focal multinucleated giant cells in either the parenchyma, vascular wall or peribronchiolar location (n=6);focal thrombosis involving medium to large vessels (n=4) and lung cysts associated with delicate calcifications and multinucleated giant cells (n=1). No diffuse alveolar damage changes (DAD) or vasculitis were identified. Conclusions: Lung explants from patients with post-acute COVID-19 syndrome show severe NSIP pattern of fibrosis and other pathologic changes that do not resemble the extensive fibrotic changes resulting from organizing phase of DAD or the extensive vascular changes seen in patients dying during the acute or subacute phases of COVID-19 infection. Further studies with lung biopsies are needed to understand the mechanism of fibrosis in post-acute COVID-19 syndrome and identify individuals who are likely to develop severe pulmonary fibrosis requiring lung transplantation.

An uncommon case of hypoxia in a pediatric patient

INTRODUCTION: Pulmonary arteriovenous malformations (PAVM) are typically associated with hereditary hemorrhagic telangiectasia. Isolated PAVM are uncommon and usually present between the 4th-6th decades of life;they are rarely seen in children and infrequently necessitate ICU admission. DESCRIPTION: A healthy 3-year-old boy presented to his pediatrician with a 3 day history of fever and rhinorrhea. He was hypoxic (SpO2=85%), so was placed on oxygen and transferred to an outside ED where he was found to have (non-COVID) coronavirus. He was admitted for supportive care but clinically deteriorated over the next 24 hours requiring intubation, ventilatory support with 100% FiO2, and inhaled nitric oxide. Despite these interventions he remained hypoxic. Echocardiogram demonstrated a structurally normal heart. Computed tomography angiogram showed multiple large peripheral PAVM in the left lower and upper lobes and no differentiation between arterial and venous phases indicating pulmonary shunting. He was transferred to our quaternary ICU for intervention. He underwent embolization of ~70% of his PAVM (limited due to contrast load). He initially improved, but 2 days post-intervention he declined with worsening hypoxia likely secondary to pulmonary vascular remodeling following intervention and residual shunt burden within the left lung. Given his instability, as well as an oxygenation index of 34, he was cannulated for venoarterial extracorporeal membrane oxygenation (ECMO). Following cannulation, his remaining PAVM were embolized. ECMO support was subsequently weaned and he was decannulated after 4 days. His ventilator support was weaned, and he was transferred back to the referring hospital on minimal settings. He was extubated the next day and quickly weaned to room air. He was discharged after 2.5 weeks and was doing well (SpO2=95%) at his pediatrician follow-up. DISCUSSION: This is the first case of a previously healthy child requiring cannulation for ECMO due to PAVM. This case is unique among patients with PAVM due to the early presentation, likely related to an acute respiratory illness disturbing previously well-compensated ventilation-perfusion mismatch. As highlighted in this case, ECMO can be used to support patients who require interventions for PAVM and during the transition to a new physiologic state.

Behavioural and psychological symptoms in dementia, often reversible conditions

Background: In the later stages of dementia some people with develops what's known as behavioural and psychological symptoms of dementia (BSPD). Symptoms of BPSD can include increased agitation, aggression, delusions, hallucinations, sleep disturbance and night-time waking. Behaviour changes could be caused by brain-related issues or from changes to someone's environment, health or medication. Methods: Dementia is an umbrella term used to describe a group of symptoms that affect brains work. Many conditions, such as stroke, depression, infections, as well as normal ageing, can cause dementia-like symptoms. We describe 120 patients that have been admitted in the emergency setting because of acute symptoms. We examined the patients to see if they have any infection, pain constipation, depression or side-effects of their medicine that could be contributing to or causing the behaviour change. Results: The mean age was 81, 68 women and 52 men. Hypertension was present in 96 and vascular changes in the brain were found in the neuroimaging. 78 patients had reversible symptoms of dementia due to such conditions: urinary infection , hydration, constipation, fever and CoViD-19 infection. Conclusions: Dementia is always changing and unique for each person. Everyday life can be a stressful ordeal for a person with a dementia-related disorder. As the disease progresses, behaviours changes can occur. The pandemic worsened such situation. It is important in the acute setting to rule out any concomitant illness that can cause or worsen behavioural and psychological symptoms in dementia.

COVID-19 and dys-regulation of pulmonary endothelium: implications for vascular remodeling.

Coronavirus disease-2019 (COVID-19), the disease caused by severe acute respiratory syndrome-coronavirus-2, has claimed more than 4.4 million lives worldwide (as of 20 August 2021). Severe cases of the disease often result in respiratory distress due to cytokine storm, and mechanical ventilation is required. Although, the lungs are the primary organs affected by the disease, more evidence on damage to the heart, kidney, and liver is emerging. A common link in these connections is the cardiovascular network. Inner lining of the blood vessels, called endothelium, is formed by a single layer of endothelial cells. Several clinical manifestations involving the endothelium have been reported, such as its activation via immunomodulation, endotheliitis, thrombosis, vasoconstriction, and distinct intussusceptive angiogenesis (IA), a unique and rapid process of blood-vessel formation by splitting a vessel into two lumens. In fact, the virus directly infects the endothelium via TMPRSS2 spike glycoprotein priming to facilitate ACE-2-mediated viral entry. Recent studies have indicated a significant increase in remodeling of the pulmonary vascular bed via intussusception in patients with COVID-19. However, the lack of circulatory biomarkers for IA limits its detection in COVID-19 pathogenesis. In this review, we describe the implications of angiogenesis in COVID-19, unique features of the pulmonary vascular bed and its remodeling, and a rapid and non-invasive assessment of IA to overcome the technical limitations in patients with COVID-19.

MDM2-Mediated Ubiquitination of Angiotensin-Converting Enzyme 2 Contributes to the Development of Pulmonary Arterial Hypertension.

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) converts angiotensin II, a potent vasoconstrictor, to angiotensin-(1-7) and is also a membrane protein that enables coronavirus disease 2019 (COVID-19) infectivity. AMP-activated protein kinase (AMPK) phosphorylation of ACE2 enhances ACE2 stability. This mode of posttranslational modification of ACE2 in vascular endothelial cells is causative of a pulmonary hypertension (PH)-protective phenotype. The oncoprotein MDM2 (murine double minute 2) is an E3 ligase that ubiquitinates its substrates to cause their degradation. In this study, we investigated whether MDM2 is involved in the posttranslational modification of ACE2 through its ubiquitination of ACE2, and whether an AMPK and MDM2 crosstalk regulates the pathogenesis of PH. METHODS: Bioinformatic analyses were used to explore E3 ligase that ubiquitinates ACE2. Cultured endothelial cells, mouse models, and specimens from patients with idiopathic pulmonary arterial hypertension were used to investigate the crosstalk between AMPK and MDM2 in regulating ACE2 phosphorylation and ubiquitination in the context of PH. RESULTS: Levels of MDM2 were increased and those of ACE2 decreased in lung tissues or pulmonary arterial endothelial cells from patients with idiopathic pulmonary arterial hypertension and rodent models of experimental PH. MDM2 inhibition by JNJ-165 reversed the SU5416/hypoxia-induced PH in C57BL/6 mice. ACE2-S680L mice (dephosphorylation at S680) showed PH susceptibility, and ectopic expression of ACE2-S680L/K788R (deubiquitination at K788) reduced experimental PH. Moreover, ACE2-K788R overexpression in mice with endothelial cell-specific AMPKα2 knockout mitigated PH. CONCLUSIONS: Maladapted posttranslational modification (phosphorylation and ubiquitination) of ACE2 at Ser-680 and Lys-788 is involved in the pathogenesis of pulmonary arterial hypertension and experimental PH. Thus, a combined intervention of AMPK and MDM2 in the pulmonary endothelium might be therapeutically effective in PH treatment.

Novel insights on the pulmonary vascular consequences of COVID-19.

In the last few months, the number of cases of a new coronavirus-related disease (COVID-19) rose exponentially, reaching the status of a pandemic. Interestingly, early imaging studies documented that pulmonary vascular thickening was specifically associated with COVID-19 pneumonia, implying a potential tropism of the virus for the pulmonary vasculature. Moreover, SARS-CoV-2 infection is associated with inflammation, hypoxia, oxidative stress, mitochondrial dysfunction, DNA damage, and lung coagulopathy promoting endothelial dysfunction and microthrombosis. These features are strikingly similar to what is seen in pulmonary vascular diseases. Although the consequences of COVID-19 on the pulmonary circulation remain to be explored, several viruses have been previously thought to be involved in the development of pulmonary vascular diseases. Patients with preexisting pulmonary vascular diseases also appear at increased risk of morbidity and mortality. The present article reviews the molecular factors shared by coronavirus infection and pulmonary vasculature defects, and the clinical relevance of pulmonary vascular alterations in the context of COVID-19.