Involvement of GPR43 Receptor in Effect of Lacticaseibacillus rhamnosus on Murine Steroid Resistant Chronic Obstructive Pulmonary Disease: Relevance to Pro-Inflammatory Mediators and Oxidative Stress in Human Macrophages.

BACKGROUND: Cytokine storm and oxidative stress are present in chronic obstructive pulmonary disease (COPD). Individuals with COPD present high levels of NF-κB-associated cytokines and pro-oxidant agents as well as low levels of Nrf2-associated antioxidants. This condition creates a steroid-resistant inflammatory microenvironment. Lacticaseibacillus rhamnosus (Lr) is a known anti-cytokine in lung diseases; however, the effect of Lr on lung inflammation and oxidative stress in steroid-resistant COPD mice remains unknown. OBJECTIVE: Thus, we investigated the Lr effect on lung inflammation and oxidative stress in mice and macrophages exposed to cigarette smoke extract (CSE) and unresponsive to steroids. METHODS: Mice and macrophages received dexamethasone or GLPG-094 (a GPR43 inhibitor), and only the macrophages received butyrate (but), all treatments being given before CSE. Lung inflammation was evaluated from the leukocyte population, airway remodeling, cytokines, and NF-κB. Oxidative stress disturbance was measured from ROS, 8-isoprostane, NADPH oxidase, TBARS, SOD, catalase, HO-1, and Nrf2. RESULTS: Lr attenuated cellularity, mucus, collagen, cytokines, ROS, 8-isoprostane, NADPH oxidase, and TBARS. Otherwise, SOD, catalase, HO-1, and Nrf2 were upregulated in Lr-treated COPD mice. Anti-cytokine and antioxidant effects of butyrate also occurred in CSE-exposed macrophages. GLPG-094 rendered Lr and butyrate less effective. CONCLUSIONS: Lr attenuates lung inflammation and oxidative stress in COPD mice, suggesting the presence of a GPR43 receptor-dependent mechanism also found in macrophages.

Alcohol Sniff Test (AST): An Important Tool for Screening Post-Viral Olfactory Loss in Acute Flu-Like Dysfunction.

Olfactory disorders have a significant impact on patients' quality of life but are often underestimated in clinical practice. Upper respiratory tract infections (URTIs) are a common cause of olfactory loss. While most cases of olfactory loss due to URTIs are conductive and reversible, post-viral olfactory dysfunction (PVOD) persists despite symptom improvement. PVOD is attributed to damage to the olfactory epithelium and nerves or central olfactory pathway lesions. The Alcohol Sniff Test (AST) has been proposed as a tool to assess olfactory function in the acute phase and aid in differentiating PVOD from conductive disorders. This study aims to evaluate the effectiveness of the AST as a predictor of post-viral olfactory loss in patients with flu-like syndrome. An observational cross-sectional study was conducted among employees with flu-like syndrome at a tertiary hospital. Three groups were formed: flu-like syndrome with conductive disorder without COVID-19 (PVOD-), flu-like syndrome with neurosensory and/or central disorder due to COVID-19 (PVOD +), and an asymptomatic control group. The Alcohol Sniff Test was performed to assess olfactory function. Statistical analysis was conducted to evaluate the AST's performance. For a cut off of 10 cm, 88.57% of PVOD + patients and 60.53% of PVOD - patients showed AST alteration, respectively (p = 0.013, OR = 5.05, 95% CI [1.48-17.25]). There was a statistically significant difference in the mean distance between the PVOD + group (4.35 ± 4.1 cm) and the control group (20 ± 4.33 cm) (p < 0.05). This relationship was also observed between the PVOD + and PVOD- groups (9 cm ± 7.5) (p < 0.05) and between the PVOD- and control groups (p < 0.05). For a cut off of 10 cm, the AST showed a sensitivity of 88% and specificity of 41%, resulting in an Odds Ratio of 9.7 (95% CI 3.3-28.1) (p < 0.001) and a Positive Predictive Value of 69.4% for PVOD. PVOD, including cases associated with COVID-19, is a prevalent cause of olfactory loss. The Alcohol Sniff Test demonstrated promising results in identifying PVOD in patients with flu-like syndrome. The test's simplicity and accessibility make it a valuable tool for early screening and identifying individuals who may benefit from prompt treatment. The Alcohol Sniff Test (AST) shows potential as an effective tool for screening post-viral olfactory loss in patients with flu-like syndrome. It can aid in early identification of PVOD cases and facilitate timely interventions to reduce the likelihood of persistent hyposmia.

Hematology and Serum Biochemistry of Coastal Seabirds Rehabilitated on the Southeastern and Southern Coast of Brazil.

Complete blood counts (n=566) and serum biochemistry (n=426) were assessed in seven coastal seabirds species that underwent rehabilitation along the southeastern and southern coast of Brazil from Saquarema, Rio de Janeiro State (22°56'16.44″S, 42°18'24.16″W) to Laguna, Santa Catarina State (28°29'43″S, 48°45'39.2″W), from August 2016 to August 2020. Blood samples were collected from four species of Charadriiformes, including Kelp Gull (Larus dominicanus, n=136), South American Tern (Sterna hirundinacea, n=25), Cabot's Tern (Thalasseus acuflavidus, n=17), and Common Tern (Sterna hirundo, n=14) as well as three species of Suliformes, the Brown Booby (Sula leucogaster, n=212), Magnificent Frigatebird (Fregata magnificens, n=104), and Neotropic Cormorant (Nannopterum brasilianum, n=58). The individuals were sampled as part of the protocol required before their release into the wild when considered healthy. This work aimed to establish the normal hematologic and biochemical reference values of those seabird species and, when possible, to analyze variations among age class and sex and to compare those with the available data in the literature. In addition, we provide the first baseline data for the South American Tern, Cabot's Tern, and Neotropic Cormorant. Baseline hematologic data are crucial for assessing health status of individuals and to support management and conservation actions, including release of seabirds into the wild.

Proteomics of serum-derived extracellular vesicles are associated with the severity and different clinical profiles of patients with COVID-19: An exploratory secondary analysis.

BACKGROUND AIMS: Coronavirus disease 2019 (COVID-19) is characterized by a broad spectrum of clinical manifestations with the potential to progress to multiple organ dysfunction in severe cases. Extracellular vesicles (EVs) carry a range of biological cargoes, which may be used as biomarkers of disease state. METHODS: An exploratory secondary analysis of the SARITA-2 and SARITA-1 datasets (randomized clinical trials on patients with mild and moderate/severe COVID-19) was performed. Serum-derived EVs were used for proteomic analysis to identify enriched biological processes and key proteins, thus providing insights into differences in disease severity. Serum-derived EVs were separated from patients with COVID-19 by size exclusion chromatography and nanoparticle tracking analysis was used to determine particle concentration and diameter. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was performed to identify and quantify protein signatures. Bioinformatics and multivariate statistical analysis were applied to distinguish candidate proteins associated with disease severity (mild versus moderate/severe COVID-19). RESULTS: No differences were observed in terms of the concentration and diameter of enriched EVs between mild (n = 14) and moderate/severe (n = 30) COVID-19. A total of 414 proteins were found to be present in EVs, of which 360 were shared while 48 were uniquely present in severe/moderate compared to mild COVID-19. The main biological signatures in moderate/severe COVID-19 were associated with platelet degranulation, exocytosis, complement activation, immune effector activation, and humoral immune response. Von Willebrand factor, serum amyloid A-2 protein, histone H4 and H2A type 2-C, and fibrinogen ß-chain were the most differentially expressed proteins between severity groups. CONCLUSION: Exploratory proteomic analysis of serum-derived EVs from patients with COVID-19 detected key proteins related to immune response and activation of coagulation and complement pathways, which are associated with disease severity. Our data suggest that EV proteins may be relevant biomarkers of disease state and prognosis.

Prospective Randomized Phase 2 Trial of Hypofractionated Stereotactic Radiation Therapy of 25 Gy in 5 Fractions Compared With 35 Gy in 5 Fractions in the Reirradiation of Recurrent Glioblastoma.

PURPOSE: The aim of this work was to investigate whether reirradiation of recurrent glioblastoma with hypofractionated stereotactic radiation therapy (HSRT) consisting of 35 Gy in 5 fractions (35 Gy/5 fx) compared with 25 Gy in 5 fractions (25 Gy/5 fx) improves outcomes while maintaining acceptable toxicity. METHODS AND MATERIALS: We conducted a prospective randomized phase 2 trial involving patients with recurrent glioblastoma (per the 2007 and 2016 World Health Organization classification). A minimum interval from first radiation therapy of 5 months and gross tumor volume of 150 cc were required. Patients were randomized 1:1 to receive HSRT alone in 25 Gy/5 fx or 35 Gy/5 fx. The primary endpoint was progression-free survival (PFS). We used a randomized phase 2 screening design with a 2-sided α of 0.15 for the primary endpoint. RESULTS: From 2011 to 2019, 40 patients were randomized and received HSRT, with 20 patients in each group. The median age was 50 years (range, 27-71); a new resection before HSRT was performed in 75% of patients. The median PFS was 4.9 months in the 25 Gy/5 fx group and 5.2 months in the 35 Gy/5 fx group (P = .23). Six-month PFS was similar at 40% (85% CI, 24%-55%) for both groups. The median overall survival (OS) was 9.2 months in the 25 Gy/5 fx group and 10 months in the 35 Gy/5 fx group (P = .201). Grade ≥3 necrosis was numerically higher in the 35 Gy/5 fx group (3 [16%] vs 1 [5%]), but the difference was not statistically significant (P = .267). In an exploratory analysis, median OS of patients who developed treatment-related necrosis was 14.1 months, and that of patients who did not was 8.7 months (P = .003). CONCLUSIONS: HSRT alone with 35 Gy/5 fx was not superior to 25 Gy/5 fx in terms of PFS or OS. Due to a potential increase in the rate of clinically meaningful treatment-related necrosis, we suggest 25 Gy/5 fx as the standard dose in HSRT alone. During follow-up, attention should be given to differentiating tumor progression from potentially manageable complications.

Hand function outcomes following surgical treatment of complete neonatal brachial plexus palsy.

PURPOSE: Although re-innervation of the hand is considered a priority in the treatment of infants with complete brachial plexus injury, there is currently a paucity of publications investigating hand function outcomes following primary nerve reconstruction in infants with neonatal brachial plexus palsy (NBPP). This study therefore aimed to evaluate hand function outcomes in a series of patients with complete NBPP. METHODS: This retrospective case series included all patients who underwent primary nerve surgery for complete neonatal brachial plexus palsy over an 8-year period. Outcomes were assessed using the Raimond Hand Scale. Classification of grade 3 or higher indicates a functional hand (assistance in bimanual activity). RESULTS: Nineteen patients with a complete NBPP underwent primary nerve reconstruction at a mean age of 3.7 months. Periodic clinical evaluations were performed until at least 4 years of age. According to the Raimondi hand scale, one patient did not recover (grade 0), three patients attained grade 1, four grade 2, ten grade 3, and in one grade 4. Overall hand functional recovery was achieved in 57.8% (11/19) of patients. CONCLUSION: Sufficient recovery of hand function to perform bimanual activity tasks in patients with complete NBPP lesions is possible and should be a priority in the surgical treatment of these infants.

Beneficial effects of empagliflozin and liraglutide on the cerebral microcirculation of diabetic rats.

OBJECTIVES: This study aimed to evaluate the effects of the antidiabetics liraglutide, a GLP-1 analog, and empagliflozin, an SGLT-2 inhibitor, on the brain microcirculation of diabetic rats. METHODS: Type 2 diabetes mellitus (DM) was experimentally induced in male Wistar rats by combining a high-fat diet and a low dose of streptozotocin (35 mg/kg). Liraglutide (100 µg/kg s.c.) and empagliflozin (10 mg/kg, oral) were administered for 5 weeks. Body weight was monitored periodically. Oral glucose tolerance, fasting glycemia, and blood triglycerides were evaluated after the treatments. Endothelial-leukocyte interactions in the brain microcirculation and structural capillary density were assessed. RESULTS: DM rats presented metabolic and cerebrovascular alterations. Liraglutide treatment decreased body weight and blood triglycerides of DM rats. Empagliflozin treatment improved glucose tolerance but only the combination therapy significantly reduced fasting blood glucose. Both treatments and their combination reduced leukocyte adhesion into the endothelium of brain venules. However, empagliflozin was more effective in preventing DM-induced microvascular rarefaction. CONCLUSION: These findings suggest that chronic treatment with SGLT2 inhibitors and GLP-1 receptor agonists may serve as potential therapeutic approaches to prevent microvascular complications associated with diabetes.

Andrology of shortnose guitarfish Zapteryx brevirostris (Müller & Henle, 1841) (Chondrichthyes, Trygonorrhinidae).

The andrological study of a species involves the macro- and microscopic analyses of the internal reproductive organs and the evaluation of seminal parameters and ultrastructural characteristics of the spermatozoa. As in other vertebrates, the male reproductive tract in chondrichthyans consists of testes and reproductive ducts (efferent duct, epididymis, Leydig's gland, ductus deferens and seminal vesicle). In this study the authors used three adult specimens of Zapteryx brevirostris from wild capture kept at the Ubatuba Aquarium, Brazil. Semen was collected by abdominal massage over the location of the seminal vesicle, preceded by ultrasonographic evaluation. The semen collected was diluted 1:200 and subject to quantitative and morphological analyses. Ultrastructural analysis was performed using transmission and scanning electron microscopy. Correlation was observed between successful collection and ultrasonographic image of an engorged seminal vesicle, as well as testicles with easily delimitable margins and higher echogenicity. It was possible to identify free spermatozoa with helical filiform appearance, as well as spermatozeugmata. The average sperm concentration resulted in 5 million packets per millilitre and 140 million spermatozoa per millilitre. The sperm nucleus is described as follows: cone shaped, parachromatin sheath less dense than the chromatin of the nucleus, smooth depression of the nuclear fossa, abaxial axoneme 9 + 2 and accessory axonemal columns in positions 3 and 8 and oval shaped, with flattened inner surface in cross-section. These results broaden the knowledge of the andrology of this species, contributing to ex situ breeding programmes.

Food-related substrate preference in juveniles seastar Echinaster (Othilia) brasiliensis (Müller & Troschel,1842) in captivity.

There are only a few studies that describe the larval development of Echinaster or aspects on culture systems for the genus. For starfishes, the choice of suitable substrates has received special attention since it could influence the acid-base balance of the water, movement capacity and predation rate. The objective of this study was to evaluate the ideal food-related substrate for the rearing of juvenile Echinaster brasiliensis. A batch of fertilized eggs released in spontaneous spawning was collected and kept in a plankton-kreisel until metamorphosis. Data on preference of food-related substrate was recorded for 10 weeks from day 58 post-release. From release to 132 days old, arm length increased from 0.81 mm to 1.31 ± 0.03 mm. Considering the sudden increase in arm length (AL), it was estimated that feeding started around 40 days of age. Regarding food-related substrate preferences, biofilm grown on "rocks" showed a significant difference among other treatments, adding up to 50% of preference (p < .05). For sponge and biofilm from bio media, there was no statistical difference for the whole period. In this study, sponges showed to be the least preferred food-related substrate for post-settlement juveniles. Considering that Echinaster and other starfish are commonly maintained on a diet of collected or cultured sponges, difficulties in sourcing a ready supply throughout the year represent limitations to their sole use within commercial or laboratory-scale production. In this sense, the use of biofilm from biological media for the feeding of juvenile starfish is not yet reported in the literature and showed to be an easy and promising option.

Microsurgical Resection of Tonsillar Arteriovenous Malformation: Operative Video.

Cerebellar arteriovenous malformation (AVM) comprises 10%-15% of intracranial AVMs.1 Rupture often leads to devastating brainstem compression, with mortality reported as high as 67%.2 AVM can be a challenging disease, especially when large in size.3 AVMs can be treated by 1 or a combination of treatment modalities, namely embolization, radiosurgery, or microsurgical resection.4,5 Arterial adhesions to tonsilobulbar and telovelonsilar segments of posterior inferior cerebellar artery (PICA) can be a challenge, increasing bleeding and ischemic risk.6 We present a 2-dimensional video case of a tonsillar AVM. The patient, a previously healthy female in her 20s, presented with a chronic headache. She had no medical history. Initial magnetic resonance imaging revealed a tonsillar AVM classified as Spetzler-Martin grade II. It received its supply from the tonsilobulbar and telovelotonsilar segments of the PICA and drained directly into the precentral vein, transverse sinus, and sigmoid sinus. An angiogram revealed severe venous engorgement-the source of the patient's headache. The AVM was partially embolized 1 month preoperatively. A medial suboccipital telovelar approach was chosen to reduce the working distance and afford a wider corridor to expose the suboccipital surface of the cerebellum.7,8 Complete resection of the AVM was achieved with no additional morbidity. Microsurgery in experienced hands offers the best chance of cure for AVMs. In Video 1, we demonstrate the relationships among the tonsila, biventral lobule, vallecula cerebelli, PICA, and cerebellomedullary fissure as an important anatomic landmark in a safe total resection of a tonsillar AVM.

Physiotherapeutic approach to the preoperative period for the anterior cruciate ligament reconstruction: A systematic review.

INTRODUCTION: The tearing of the anterior cruciate ligament (ACL) is one of the most common type of knee injury. Current evidence show that there are specific predictors for postoperative success in ACL injuries, but there is a limited number of studies on preoperative rehabilitation. Therefore, the goals of this review were to emphasize physiotherapy approaches to the preoperative period and to verify its effectiveness at the time the athlete returns to sport. METHOD: We conducted a systematic search in these databases: Medline, Scielo, Lilacs, CINAHL, Web of Science, PeDro and Cochrane Library. RESULTS: Our searches identified 553 occurences; of these, 511 titles and abstracts underwent triage after removal of duplicates. We identified 120 full texts for a stricter screening, amongst them, three studies included in the review for complying with the elegibility criteria. CONCLUSION: Physiotherapic preoperative treatment exhibits weak evidence for strength gains and pain relief, as well as strong evidence of functional improvement compared to the control group. These results were reported 4 months after the ACLR, in average.

Effects of the addition of fatty acid from soybean oil sludge in recycled asphalt mixtures.

Recycling agents provide better additions of reclaimed asphalt pavement (RAP) in the production of new asphalt mixtures. Alternative and residual materials that have the potential as asphalt binder viscosity reducers have gained visibility in the field of paving due to the perspective of circular economy in recycled mixtures. Soybean oil sludge fatty acid is a material produced from soybean oil sludge, a waste generated in the soybean oil refining step. Thus, this paper investigated the physical, chemical, and rheological effects of the asphalt binder PG 64-XX modified by the fatty acid of soybean oil sludge in the contents of 6% and 7% by weight of the binder. The modified binder samples were submitted to penetration tests, softening point, rotational viscosity, performance grade (PG), before and after short-term aging (RTFO), and multiple stress creep and recovery (MSCR). A control asphalt mixture and recycled asphalt mixtures produced with 40% RAP and fatty acid-modified binders were subjected to tensile strength, induced moisture damage, resilient modulus, and fatigue life. A Student's t statistical test verified the significance of the data, as well as the estimation of production costs of these asphalt mixtures. The use of the fatty acid significantly reduced the stiffness and viscosity of the control asphalt binder, decreasing the mixing temperatures at 14 °C and 17 °C to 6% and 7%, respectively. Using higher fatty acid contents from soybean oil sludge significantly improved the performance of recycled mixtures in tensile strength, moisture damage, and fatigue life. The production cost of recycled asphalt mixtures was lower than that of the control mixture.

Birth and growth of the shortnose guitarfish Zapteryx brevirostris (Müller & Henle, 1841) (Chondrichthyes, Rhinobatidae) in captivity.

Endemic to the south-west Atlantic Ocean, the shortnose guitarfish (Zapteryx brevirostris) is a small species, classified as endangered by the IUCN. Although reproduction in captivity has been successful for some species, a range of factors can limit the success of captive breeding programmes for elasmobranchs. In Brazil, the Ubatuba Aquarium was the first public aquarium to reproduce small-sized elasmobranchs. Since 2018, at least five parturition events have been recorded for Z. brevirostris at the institution. From a total of 13 live neonates that rearing was attempted, the mean ± standard error of weight, total length (TL) and disc width at birth were 17.47 ± 1.6 g, 13.25 ± 0.7 cm and 6.53 ± 0.2 cm, respectively. The mean weight as well as mean TL were higher for females at all births, with 26.15 g and 15.07 cm for females in comparison with 17.09 g and 13.94 cm for males. Considering the increasing risk of extinction that the species is facing, age and growth studies are fundamental for the success of conservation, improving the knowledge of Z. brevirostris life cycle so that a more efficient and sustainable management can be carried out. This study provides important data, as well as directions for captive breeding of the species.

Long-term assessment of systemic microcirculatory function and plasma cytokines after coronavirus disease 2019 (COVID-19).

Systemic microvascular dysfunction has been shown to be present in COVID-19, and serum cytokines are known to be involved in the regulation of vascular function. We sought to evaluate systemic microvascular endothelial function, with laser doppler perfusion monitoring (LDPM), and plasma levels of cytokines after acute COVID-19. Individuals admitted to a Cardiology hospital with acute COVID-19 and followed for 12-15 months after recovery underwent noninvasive evaluation of systemic endothelium-dependent microvascular reactivity by cutaneous LDPM with local thermal hyperemia (LTH). A multiplex biometric immunoassay panel was used to assess 48 serum cytokines and chemokines. Twenty patients and 14 control volunteers were enrolled. The areas under the curves of vasodilation induced by LTH were significantly increased after recovery (P=0.009) and were not different from values obtained in healthy volunteers (P = 0.85). The peak microvascular flow during LTH did also significantly increase (P = 0.02), and was not different form values obtained in healthy volunteers (P = 0.55). Several cytokines displayed significantly reduced serum concentrations after recovery from COVID-19. In conclusion, endothelium-dependent systemic microvascular reactivity improved after recovery from COVID-19 in patients with cardiovascular diseases, in parallel with a reduction in the levels of several serum cytokines and chemokines involved in the regulation of vascular function and inflammation.

The Na/K-ATPase role as a signal transducer in lung inflammation.

Acute respiratory distress syndrome (ARDS) is marked by damage to the capillary endothelium and alveolar epithelium following edema formation and cell infiltration. Currently, there are no effective treatments for severe ARDS. Pathologies such as sepsis, pneumonia, fat embolism, and severe trauma may cause ARDS with respiratory failure. The primary mechanism of edema clearance is the epithelial cells' Na/K-ATPase (NKA) activity. NKA is an enzyme that maintains the electrochemical gradient and cell homeostasis by transporting Na+ and K+ ions across the cell membrane. Direct injury on alveolar cells or changes in ion transport caused by infections decreases the NKA activity, loosening tight junctions in epithelial cells and causing edema formation. In addition, NKA acts as a receptor triggering signal transduction in response to the binding of cardiac glycosides. The ouabain (a cardiac glycoside) and oleic acid induce lung injury by targeting NKA. Besides enzymatic inhibition, the NKA triggers intracellular signal transduction, fostering proinflammatory cytokines production and contributing to lung injury. Herein, we reviewed and discussed the crucial role of NKA in edema clearance, lung injury, and intracellular signaling pathway activation leading to lung inflammation, thus putting the NKA as a protagonist in lung injury pathology.

Development and validation of liquid chromatography-tandem mass spectrometry method to quantify dasatinib in plasma and its application to a pharmacokinetic study

Abstract Dasatinib, a potent oral multi-targeted kinase inhibitor against Src and Bcr-Abl, can decrease inflammatory response in sepsis. A simple and cost-effective method for determination of an effective dose dasatinib was established. This method was validated in human plasma, with the aim of reducing the number of animals used, thus, avoiding ethical problems. Dasatinib and internal standard lopinavir were extracted from 180 uL of plasma using liquid-liquid extraction with methyl tert-butil ether, followed by liquid chromatography coupled to triple quadrupole mass spectrometry in multiple reaction monitoring mode. For the pharmacokinetic study, 1 mg/kg of dasatinib was administered to mice with and without sepsis. The method was linear over the concentration range of 1-98 ng/mL for DAS in mice and human plasma, with r2>0.99 and presented intra- and interday precision within the range of 2.3 - 6.2 and 4.3 - 7.0%, respectively. Further intra- and interday accuracy was within the range of 88.2 - 105.8 and 90.6 - 101.7%, respectively. The mice with sepsis showed AUC0-t = 2076.06 h*ng/mL and Cmax =102.73 ng/mL and mice without sepsis presented AUC0-t = 2128.46 h*ng/mL. Cmax = 164.5 ng/mL. The described analytical method was successfully employed in pharmacokinetic study of DAS in mice.

Long-term assessment of systemic microcirculatory function and plasma cytokines after coronavirus disease 2019 (COVID-19)

Abstract Systemic microvascular dysfunction has been shown to be present in COVID-19, and serum cytokines are known to be involved in the regulation of vascular function. We sought to evaluate systemic microvascular endothelial function, with laser doppler perfusion monitoring (LDPM), and plasma levels of cytokines after acute COVID-19. Individuals admitted to a Cardiology hospital with acute COVID-19 and followed for 12-15 months after recovery underwent noninvasive evaluation of systemic endothelium-dependent microvascular reactivity by cutaneous LDPM with local thermal hyperemia (LTH). A multiplex biometric immunoassay panel was used to assess 48 serum cytokines and chemokines. Twenty patients and 14 control volunteers were enrolled. The areas under the curves of vasodilation induced by LTH were significantly increased after recovery (P=0.009) and were not different from values obtained in healthy volunteers (P= 0.85). The peak microvascular flow during LTH did also significantly increase (P= 0.02), and was not different form values obtained in healthy volunteers (P= 0.55). Several cytokines displayed significantly reduced serum concentrations after recovery from COVID-19. In conclusion, endothelium-dependent systemic microvascular reactivity improved after recovery from COVID-19 in patients with cardiovascular diseases, in parallel with a reduction in the levels of several serum cytokines and chemokines involved in the regulation of vascular function and inflammation.

Age-linked suppression of lipoxin A4 associates with cognitive deficits in mice and humans.

Age increases the risk for cognitive impairment and is the single major risk factor for Alzheimer's disease (AD), the most prevalent form of dementia in the elderly. The pathophysiological processes triggered by aging that render the brain vulnerable to dementia involve, at least in part, changes in inflammatory mediators. Here we show that lipoxin A4 (LXA4), a lipid mediator of inflammation resolution known to stimulate endocannabinoid signaling in the brain, is reduced in the aging central nervous system. We demonstrate that genetic suppression of 5-lipoxygenase (5-LOX), the enzyme mediating LXA4 synthesis, promotes learning impairment in mice. Conversely, administration of exogenous LXA4 attenuated cytokine production and memory loss induced by inflammation in mice. We further show that cerebrospinal fluid LXA4 is reduced in patients with dementia and positively associated with cognitive performance, brain-derived neurotrophic factor (BDNF), and AD-linked amyloid-ß. Our findings suggest that reduced LXA4 levels may lead to vulnerability to age-related cognitive disorders and that promoting LXA4 signaling may comprise an effective strategy to prevent early cognitive decline in AD.