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1.
Wiad Lek ; 74(9 cz 1): 2039-2043, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34725273

RESUMO

OBJECTIVE: The aim: To determine the influence of obesity on cutaneous microcirculation in patients with different stages of obesity and without cardio-vascular pathologies. PATIENTS AND METHODS: Materials and methods: The 67 eligible patients with obesity were enrolled into the main group in this research. 20 healthy patients with normal body weight were included in the control group in this study. The mean age and gender were similar among the groups. Each patient underwent a clinical evaluation during the consultation, biological tests, electrocardiogram, Laser Doppler flowmetry. RESULTS: Results: There was a significant decrease in IM and σ in patients with class II obesity and class III obesity compared with control group. IV was decreased in all groups, but the significant differences were recorded only among patients with obesity and not among overweight patients. During wavelet analysis a significant decrease of the AmaxE was detected in all 4 groups (by 14,7%, 37,7%, 52,4%, 57,4% respectively, P < 0,05). The most significant changes were recorded in the heart spectrum (AmaxC). CONCLUSION: Conclusions: Overweight patients and patients with obesity without cardio-vascular pathology have initial manifestations of microcirculatory disorders, which deteriorate with an increase of BMI. Changes in microcirculation in patients with obesity characterized by the significant decrease of microvessels perfusion, decreasing endothelial and increasing heart specter modulations. Only high BMI was found to be associated with impaired microcirculation endothelial function (AmaxE B=0.446, 95% CI [0,15, 0,92]) according to the results of regression analysis.


Assuntos
Obesidade , Pele , Humanos , Fluxometria por Laser-Doppler , Microcirculação , Microvasos , Obesidade/complicações
2.
Zhonghua Zhong Liu Za Zhi ; 43(11): 1215-1221, 2021 Nov 23.
Artigo em Chinês | MEDLINE | ID: mdl-34794227

RESUMO

Objective: To discuss the diagnostic value of superb microvacular imaging (SMI) in renal solid tumors of different sizes. Methods: A total of 142 patients with 146 renal tumors detected by ultrasound in Tianjin Medical University Cancer Institute and Hospital from September 2017 to March 2019 were retrospectively analyzed. The maximum diameter of lesions was 0.8-7.3 cm, and patients were divided into the maximum diameter ≤3.0 cm group (61 patients, 64 lesions) and the maximum diameter >3.0 cm group (61 patients, 82 lesions). All of the tumors were separately evaluated by SMI and color Doppler flow imaging (CDFI) with Adler grade, vascular morphology and peripheral blood flow. Results: In the group with maximum diameter ≤3.0 cm, 50 lesions were malignant and 14 were benign. In the group with maximum diameter >3.0 cm, 62 lesions were malignant and 20 were benign. In the group with maximum diameter ≤3.0 cm, there were no significant differences in location, boundary, echo, homogeneity and small cystic area between malignant tumors and benign tumors (P>0.05). In the group with maximum diameter >3.0 cm, there were significant differences in echo, homogeneity and small cystic area between malignant tumors and benign tumors (P<0.05). For all of the benign tumors, there were no significant difference between CDFI and SMI in evaluating Adler grade, vascular morphology and peripheral blood flow (P>0.05). For malignant tumors with maximum diameter ≤3.0 cm, 43 lesions with Adler grade 2-3 were detected by SMI, which was higher than CDFI (32, P<0.05). There were 38 lesions with dendritic and irregular vascular morphology detected by SMI, which was higher than CDFI (7, P<0.05). The detected rate of peripheral annular or semi-annular blood flow in lesions was 80.0% (40/50), higher than CDFI (18/50, P<0.05). While in malignant tumors with maximum diameter >3 cm, the lesion with peripheral annular or semi-annular blood flow detected by SMI was 38, higher than 22 of CDFI (P<0.05). The area under the receiver operating characteristic (ROC) curve for CDFI and SMI diagnosis of renal solid tumors with the maximum diameter ≤3.0 cm was 0.627 (sensitivity: 54.0%, specificity: 71.4%) and 0.791 (sensitivity: 94.0%, specificity: 64.3%), respectively, with statistically significant difference (P=0.039). The area under the ROC curve for CDFI and SMI diagnosis of renal solid tumors with the maximum diameter>3.0 cm was 0.852 (sensitivity: 85.5%, specificity: 85.0%) and 0.860 (sensitivity: 91.9%, specificity: 80.0%), respectively, without statistically significance (P=0.858). Conclusions: SMI is superior to CDFI in detecting low-velocity blood flow and microvessels in both malignant and benign renal tumors, and can effectively improve the display rate of peripheral blood flow in malignant tumors. Otherwise, SMI can provide better diagnostic efficiency for renal tumors with the maximum diameter ≤3.0 cm.


Assuntos
Neoplasias Renais , Diagnóstico Diferencial , Humanos , Neoplasias Renais/diagnóstico por imagem , Microvasos/diagnóstico por imagem , Estudos Retrospectivos , Ultrassonografia , Ultrassonografia Doppler em Cores
3.
Eur Rev Med Pharmacol Sci ; 25(20): 6439-6442, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34730226

RESUMO

Arterial thromboembolic complications reported in patients with COVID-19 infection suggested that SARS-CoV-2 can trigger atherosclerotic plaque vulnerability. While endothelial cells in healthy subjects protect against thrombus formation, after injury they show prothrombotic activity. In addition, it has been hypothesized that "cytokine storm" might stimulate the production of neo-platelets triggering an abnormal "immunothrombosis" responsible for the hypercoagulable state induced in COVID-19 patients. The aim of this study is to report a case of severe COVID-19 infection characterized by the occurrence of microthrombosis in the vasa vasorum of the aorta. A 67-year-old male patient, in good health status and without comorbidities, who underwent a severe COVID-19 infection with fatal outcome, showed scattered aortic atherosclerotic plaques, characterized by multiple occlusive micro-thromboses in the vasa vasorum, spread out lymphocytic infiltrates and foci of endotheliitis and endothelial detachment. This case report confirms the previously described thrombotic involvement of vasa vasorum in COVID-19. The occurrence of the synchronous damage involving both the lumen surface (endothelial dysfunction, endotheliitis and endothelial detachment) and the adventitia (inflammation and occlusive thrombosis of vasa vasorum) could be the key points related to the fatal outcome of the SARS-CoV-2 patients. In our opinion, vasa vasorum thrombosis may thus initiate an atherogenic process that could be characterized by a much more rapid development.


Assuntos
Doenças da Aorta/complicações , COVID-19/patologia , Microvasos/patologia , Placa Aterosclerótica/patologia , Vasa Vasorum/patologia , Idoso , Doenças da Aorta/patologia , Humanos , Masculino
4.
Artigo em Inglês | MEDLINE | ID: mdl-34769880

RESUMO

Clinical treatment outcome of MRONJ (medication-related osteonecrosis of the jaw) surgery despite radical osseous removal and primary closure healing still shows differences in terms of outcome and disease recurrence. The study aims to assess the rate of angiogenesis of MRONJ lesions in order to understand the impact of angiogenesis and neoangiogenesis status on MRONJ surgical treatment outcome. This is the first study correlating microvessel density with prognosis in MRONJ surgically-treated patients. The immunohistochemical expression of CD34 and CD105 in MRONJ specimens obtained from surgically-treated patients was evaluated. The most vascularized areas detected by CD34 and CD105 were selected and the microvessel density value of the samples was registered. Samples were retrospectively divided according to the clinical outcome of MRONJ surgical treatment, dividing patients into two groups, "healed" and "not healed". Statistical analysis was performed to assess if neovessels could influence treatment outcome in patients undergoing radical surgery. In the examined cohort, this value was highly predictive of better treatment outcome after radical surgery of MRONJ. Understanding of angiogenesis-dependent factors deserves further attention as a future target for MRONJ prevention and therapies.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos , Humanos , Microvasos , Estudos Retrospectivos , Resultado do Tratamento , Cicatrização
5.
Crit Care ; 25(1): 381, 2021 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-34749792

RESUMO

BACKGROUND: COVID-19 is primarily a respiratory disease; however, there is also evidence that it causes endothelial damage in the microvasculature of several organs. The aim of the present study is to characterize in vivo the microvascular reactivity in peripheral skeletal muscle of severe COVID-19 patients. METHODS: This is a prospective observational study carried out in Spain, Mexico and Brazil. Healthy subjects and severe COVID-19 patients admitted to the intermediate respiratory (IRCU) and intensive care units (ICU) due to hypoxemia were studied. Local tissue/blood oxygen saturation (StO2) and local hemoglobin concentration (THC) were non-invasively measured on the forearm by near-infrared spectroscopy (NIRS). A vascular occlusion test (VOT), a three-minute induced ischemia, was performed in order to obtain dynamic StO2 parameters: deoxygenation rate (DeO2), reoxygenation rate (ReO2), and hyperemic response (HAUC). In COVID-19 patients, the severity of ARDS was evaluated by the ratio between peripheral arterial oxygen saturation (SpO2) and the fraction of inspired oxygen (FiO2) (SF ratio). RESULTS: Healthy controls (32) and COVID-19 patients (73) were studied. Baseline StO2 and THC did not differ between the two groups. Dynamic VOT-derived parameters were significantly impaired in COVID-19 patients showing lower metabolic rate (DeO2) and diminished endothelial reactivity. At enrollment, most COVID-19 patients were receiving invasive mechanical ventilation (MV) (53%) or high-flow nasal cannula support (32%). Patients on MV were also receiving sedative agents (100%) and vasopressors (29%). Baseline StO2 and DeO2 negatively correlated with SF ratio, while ReO2 showed a positive correlation with SF ratio. There were significant differences in baseline StO2 and ReO2 among the different ARDS groups according to SF ratio, but not among different respiratory support therapies. CONCLUSION: Patients with severe COVID-19 show systemic microcirculatory alterations suggestive of endothelial dysfunction, and these alterations are associated with the severity of ARDS. Further evaluation is needed to determine whether these observations have prognostic implications. These results represent interim findings of the ongoing HEMOCOVID-19 trial. Trial registration ClinicalTrials.gov NCT04689477 . Retrospectively registered 30 December 2020.


Assuntos
COVID-19/fisiopatologia , Unidades de Terapia Intensiva/tendências , Microvasos/fisiopatologia , Unidades de Cuidados Respiratórios/tendências , Síndrome do Desconforto Respiratório/fisiopatologia , Índice de Gravidade de Doença , Adulto , Idoso , Brasil/epidemiologia , COVID-19/diagnóstico , COVID-19/epidemiologia , Feminino , Humanos , Masculino , México/epidemiologia , Microcirculação/fisiologia , Pessoa de Meia-Idade , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/fisiopatologia , Estudos Prospectivos , Síndrome do Desconforto Respiratório/diagnóstico , Síndrome do Desconforto Respiratório/epidemiologia , Espanha/epidemiologia
6.
Medicine (Baltimore) ; 100(41): e27496, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34731131

RESUMO

ABSTRACT: Using animal models and molecular biology researches, hyperuricemia has been shown to instruct renal arteriolopathy, arterial hypertension, and microvascular injury involving the renin-angiotensin system and resulting in renal function impairment. Nevertheless, the association between uric acid levels and the development of albuminuria has been under-investigated in patients with type 2 diabetes mellitus. Patients with type 2 diabetes and regular outpatient visits were recruited from the Puli Branch of the Taichung Veterans General Hospital in Taiwan since January 2014. Demographics, lifestyle features, and medical history were gathered by well-trained interviewers. All participants underwent comprehensive physical examinations, including a biochemical assay of venous blood specimens and urine samples after an 8-hour overnight fast. Participants were followed until June 2018. The primary outcome was the albuminuria incidence. Univariable and multivariable Cox regression analysis were employed to explore the relation between uric acid and incident albuminuria. Uric acid cutoffs for incident albuminuria were determined with the receiver operator characteristic curve. We included 247 qualified subjects (mean age: 64.78 years old [standard deviation = 11.29 years]; 138 [55.87%] men). During a 4.5-year follow-up duration, 20 subjects with incident albuminuria were recognized. Serum uric acid was significantly associated with an increased risk of incident albuminuria (adjusted hazard ratio = 2.39; 95% confidence interval: 1.53-3.75; P < .001) with potential confounders adjustment. The uric acid cutoff point was 6.9 mg/dL (area under the curve 0.708, sensitivity 60.0%, specificity 84.58%) for incident albuminuria. Serum uric acid was associated with incident albuminuria among patients with type 2 diabetes.


Assuntos
Albuminúria/epidemiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/urina , Ácido Úrico/sangue , Idoso , Albuminúria/etiologia , Animais , Estudos de Coortes , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/complicações , Feminino , Humanos , Hipertensão/complicações , Hiperuricemia/complicações , Incidência , Masculino , Camundongos , Microvasos/lesões , Pessoa de Meia-Idade , Modelos Animais , Insuficiência Renal/etiologia , Sistema Renina-Angiotensina/fisiologia , Fatores de Risco , Taiwan/epidemiologia
7.
Hamostaseologie ; 41(5): 387-396, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34695855

RESUMO

Hypercoagulability and vascular injury, which characterize morbidity in COVID-19 disease, are frequently observed in the skin. Several pathomechanisms, such as inflammation caused by angiotensin-converting enzyme 2-mediated uptake into endothelial cells or SARS-CoV-2-initiated host immune responses, contribute to microthrombus formation and the appearance of vascular skin lesions. Besides pathophysiologic mechanisms observed in the skin, this review describes the clinical appearance of cutaneous vascular lesions and their association with COVID-19 disease, including acro-ischemia, reticular lesions, and cutaneous small vessel vasculitis. Clinicians need to be aware that skin manifestations may be the only symptom in SARS-CoV-2 infection, and that inflammatory and thrombotic SARS-CoV-2-driven processes observed in multiple organs and tissues appear identically in the skin as well.


Assuntos
COVID-19/complicações , SARS-CoV-2 , Pele/irrigação sanguínea , Enzima de Conversão de Angiotensina 2/fisiologia , Anticorpos Antifosfolipídeos/sangue , Transtornos da Coagulação Sanguínea/sangue , Transtornos da Coagulação Sanguínea/etiologia , Transtornos da Coagulação Sanguínea/patologia , COVID-19/patologia , COVID-19/fisiopatologia , Ativação do Complemento , Citocinas/metabolismo , Interações entre Hospedeiro e Microrganismos/imunologia , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Microvasos/imunologia , Microvasos/patologia , Microvasos/fisiopatologia , Pandemias , SARS-CoV-2/patogenicidade , SARS-CoV-2/fisiologia , Pele/imunologia , Vasculite/etiologia , Vasculite/patologia , Vasculite/fisiopatologia , Internalização do Vírus
8.
Med Sci Monit ; 27: e930776, 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34635632

RESUMO

During the coronavirus disease 2019 (COVID-19) pandemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, patients presented with COVID-19 pneumonia of varying severity. The phenomenon of severe hypoxemia without signs of respiratory distress is also known as silent or hidden hypoxemia. Although silent hypoxemia is not unique to pneumonia due to SARS-CoV-2 infection, this phenomenon is now recognized to be associated with severe COVID-19 pneumonia. Proper management of critically ill patients is the key to reducing mortality. Herein, we summarize the possible and rare factors contributing to silent hypoxemia in patients with COVID-19. Microvascular thrombosis causes dead space ventilation in the lungs, and the flow of pulmonary capillaries is reduced, which leads to an imbalance in the V/Q ratio. The dissociation curve of oxyhemoglobin shifts to the left and limits the release of oxygen to the tissue. SARS-CoV-2 interferes with the synthesis of hemoglobin and reduces the ability to carry oxygen. The accumulation of endogenous carbon monoxide and carboxyhemoglobin will reduce the total oxygen carrying capacity and interfere with pulse oxygen saturation readings. There are also some non-specific factors that cause the difference between pulse oximetry and oxygen partial pressure. We propose some potentially more effective clinical alternatives and recommendations for optimizing the clinical management processes of patients with COVID-19. This review aims to describe the prevalence of silent hypoxemia in COVID-19 pneumonia, to provide an update on what is known of the pathophysiology, and to highlight the importance of diagnosing silent hypoxemia in patients with COVID-19 pneumonia.


Assuntos
COVID-19/metabolismo , Hipóxia/virologia , Pneumonia Viral/virologia , Doenças Assintomáticas/epidemiologia , COVID-19/epidemiologia , COVID-19/virologia , Humanos , Hipóxia/epidemiologia , Hipóxia/metabolismo , Pulmão/citologia , Pulmão/metabolismo , Pulmão/virologia , Microvasos/metabolismo , Oximetria , Oxigênio/metabolismo , Pneumonia Viral/metabolismo , Prevalência , SARS-CoV-2/isolamento & purificação , Trombose/metabolismo , Trombose/virologia
9.
Int J Mol Sci ; 22(19)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34638895

RESUMO

Beta-Caryophyllene (BCP), a naturally occurring sesquiterpene abundantly found in cloves, hops, and cannabis, is the active candidate of a relatively new group of vascular-inhibiting compounds that aim to block existing tumor blood vessels. Previously, we have reported the anti-cancer properties of BCP by utilizing a series of in-vitro anti-tumor-related assays using human colorectal carcinoma cells. The present study aimed to investigate the effects of BCP on in-vitro, ex-vivo, and in-vivo models of anti-angiogenic assays and evaluate its anti-cancer activity in xenograft tumor (both ectopic and orthotopic) mice models of human colorectal cancer. Computational structural analysis and an apoptosis antibody array were also performed to understand the molecular players underlying this effect. BCP exhibited strong anti-angiogenic activity by blocking the migration of endothelial cells, tube-like network formation, suppression of vascular endothelial growth factor (VEGF) secretion from human umbilical vein endothelial cells and sprouting of rat aorta microvessels. BCP has a probable binding at Site#0 on the surface of VEGFR2. Moreover, BCP significantly deformed the vascularization architecture compared to the negative control in a chick embryo chorioallantoic membrane assay. BCP showed a remarkable reduction in tumor size and fluorescence molecular tomography signal intensity in all the mice treated with BCP, in a dose-dependent relationship, in ectopic and orthotopic tumor xenograft models, respectively. The histological analysis of the tumor from BCP-treated mice revealed a clear reduction of the density of vascularization. In addition, BCP induced apoptosis through downregulation of HSP60, HTRA, survivin, and XIAP, along with the upregulation of p21 expressions. These results suggest that BCP acts at multiple stages of angiogenesis and could be used as a promising therapeutic candidate to halt the growth of colorectal tumor cells.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias Colorretais/prevenção & controle , Neovascularização Patológica/prevenção & controle , Sesquiterpenos Policíclicos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Embrião de Galinha , Membrana Corioalantoide/irrigação sanguínea , Membrana Corioalantoide/efeitos dos fármacos , Neoplasias Colorretais/irrigação sanguínea , Células HCT116 , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino , Camundongos Nus , Microvasos/efeitos dos fármacos , Ratos Sprague-Dawley
10.
Nanoscale ; 13(41): 17254-17271, 2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34651623

RESUMO

Angiogenesis is an essential process for tumor development. Owing to the imbalance between pro- and anti-angiogenic factors, the tumor vasculature possesses the characteristics of tortuous, hyperpermeable vessels and compressive force, resulting in a reduction in the effect of traditional chemotherapy and radiotherapy. Anti-angiogenesis has emerged as a promising strategy for cancer treatment. Tumor angiogenesis, however, has been proved to be a complex process in which the tumor microenvironment (TME) plays a vital role in the initiation and development of the tumor microvasculature. The host stromal cells in the TME, such as cancer associated fibroblasts (CAFs), tumor associated macrophages (TAMs) and Treg cells, contribute to angiogenesis. Furthermore, the abnormal metabolic environment, such as hypoxia and acidosis, leads to the up-regulated expression of angiogenic factors. Indeed, normalization of the tumor microvasculature via targeting and modulating the TME has become a promising strategy for anti-angiogenesis and anti-tumor therapy. In this review, we summarize the abnormalities of the tumor microvasculature, tumor angiogenesis induced by an abnormal metabolic environment and host stromal cells, as well as drug delivery therapies to restore the balance between pro- and anti-angiogenic factors by targeting and normalizing the tumor vasculature in the TME.


Assuntos
Neoplasias , Microambiente Tumoral , Humanos , Imunoterapia , Microvasos , Neoplasias/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico
11.
Int J Mol Sci ; 22(19)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34638868

RESUMO

Mechanical unloading contributes to significant cardiovascular deconditioning. Endothelial dysfunction in the sites of microcirculation may be one of the causes of the cardiovascular degeneration induced by unloading, but the detailed mechanism is still unclear. Here, we first demonstrated that mechanical unloading inhibited brain microvascular endothelial cell proliferation and downregulated histone deacetylase 6 (HDAC6) expression. Furthermore, HDAC6 promoted microvascular endothelial cell proliferation and attenuated the inhibition of proliferation caused by clinorotation unloading. To comprehensively identify microRNAs (miRNAs) that are regulated by HDAC6, we analyzed differential miRNA expression in microvascular endothelial cells after transfection with HDAC6 siRNA and selected miR-155-5p, which was the miRNA with the most significantly increased expression. The ectopic expression of miR-155-5p inhibited microvascular endothelial cell proliferation and directly downregulated Ras homolog enriched in brain (RHEB) expression. Moreover, RHEB expression was downregulated under mechanical unloading and was essential for the miR-155-5p-mediated promotion of microvascular endothelial cell proliferation. Taken together, these results are the first to elucidate the role of HDAC6 in unloading-induced cell growth inhibition through the miR-155-5p/RHEB axis, suggesting that the HDAC6/miR-155-5p/RHEB pathway is a specific target for the preventative treatment of cardiovascular deconditioning.


Assuntos
Proliferação de Células , Células Endoteliais/metabolismo , Regulação da Expressão Gênica , Desacetilase 6 de Histona/metabolismo , MicroRNAs/biossíntese , Microvasos/metabolismo , Proteína Enriquecida em Homólogo de Ras do Encéfalo/metabolismo , Animais , Linhagem Celular , Células Endoteliais/citologia , Camundongos , Microvasos/citologia
12.
Nat Neurosci ; 24(11): 1522-1533, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34675436

RESUMO

Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in cerebral small vessels of patients with COVID-19 and elucidate potential mechanisms underlying the vascular pathology. In brains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals and animal models, we found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries. We obtained evidence that brain endothelial cells are infected and that the main protease of SARS-CoV-2 (Mpro) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, Mpro induces the death of human brain endothelial cells and the occurrence of string vessels in mice. Deletion of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood-brain barrier due to NEMO ablation. Importantly, a pharmacological inhibitor of RIPK signaling prevented the Mpro-induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.


Assuntos
Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Proteases 3C de Coronavírus/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Microvasos/metabolismo , SARS-CoV-2/metabolismo , Animais , Barreira Hematoencefálica/patologia , Encéfalo/patologia , Chlorocebus aethiops , Proteases 3C de Coronavírus/genética , Cricetinae , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Mesocricetus , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microvasos/patologia , SARS-CoV-2/genética , Células Vero
13.
Invest Ophthalmol Vis Sci ; 62(13): 27, 2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34705024

RESUMO

Purpose: To identify the presence of choroidal microvascular dropout (MvD) in nonarteritic anterior ischemic optic neuropathy (NAION) eyes and to characterize the topographical distribution for the mechanistic interpretation of MvD development. Methods: We performed optical coherence tomography angiography on 47 open-angle glaucoma (OAG) and 19 NAION eyes with ß-zone peripapillary atrophy (ßPPA). We recorded the presence of MvD and compared between the peripapillary topographical measures of MvD, retinal nerve fiber layer (RNFL) defect, and ßPPA in angular width and location. Results: MvD was present in both diseases, marginally more frequently in NAION eyes (19/19, 100.0%) than in OAG eyes (38/47, 80.6%, P = 0.050), without a discernable difference in appearance. NAION eyes also showed wider MvD and RNFL defects compared to OAG eyes (both P < 0.001). In topographical measurements, the distribution of MvD showed a strong correspondence to superimposition areas of ßPPA and RNFL defects, more distinctly than to RNFL defects (all P < 0.001). The outline of superimposition area also remarkably resembled the MvD area. Conclusions: MvD was present in both the OAG and NAION groups. The ßPPA-RNFL defect superimposition area topographically and morphologically matched MvD. Further investigations are needed to elucidate the role of RNFL defects in the pathogenesis of MvD and the clinical significance.


Assuntos
Corioide/irrigação sanguínea , Angiofluoresceinografia/métodos , Glaucoma/diagnóstico , Microvasos/patologia , Neuropatia Óptica Isquêmica/diagnóstico , Vasos Retinianos/patologia , Tomografia de Coerência Óptica/métodos , Estudos Transversais , Feminino , Seguimentos , Fundo de Olho , Glaucoma/complicações , Glaucoma/fisiopatologia , Glaucoma de Ângulo Aberto , Humanos , Pressão Intraocular , Masculino , Pessoa de Meia-Idade , Fibras Nervosas/patologia , Disco Óptico/patologia , Neuropatia Óptica Isquêmica/etiologia , Neuropatia Óptica Isquêmica/fisiopatologia , Células Ganglionares da Retina/patologia , Estudos Retrospectivos , Campos Visuais
15.
Int J Mol Sci ; 22(18)2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34576081

RESUMO

Pulmonary hypertension (PH) is a progressive cardiovascular disorder in which local vascular inflammation leads to increased pulmonary vascular remodeling and ultimately to right heart failure. The HDAC inhibitor butyrate, a product of microbial fermentation, is protective in inflammatory intestinal diseases, but little is known regarding its effect on extraintestinal diseases, such as PH. In this study, we tested the hypothesis that butyrate is protective in a Sprague-Dawley (SD) rat model of hypoxic PH. Treatment with butyrate (220 mg/kg intake) prevented hypoxia-induced right ventricular hypertrophy (RVH), hypoxia-induced increases in right ventricular systolic pressure (RVSP), pulmonary vascular remodeling, and permeability. A reversal effect of butyrate (2200 mg/kg intake) was observed on elevated RVH. Butyrate treatment also increased the acetylation of histone H3, 25-34 kDa, and 34-50 kDa proteins in the total lung lysates of butyrate-treated animals. In addition, butyrate decreased hypoxia-induced accumulation of alveolar (mostly CD68+) and interstitial (CD68+ and CD163+) lung macrophages. Analysis of cytokine profiles in lung tissue lysates showed a hypoxia-induced upregulation of TIMP-1, CINC-1, and Fractalkine and downregulation of soluble ICAM (sICAM). The expression of Fractalkine and VEGFα, but not CINC-1, TIMP-1, and sICAM was downregulated by butyrate. In rat microvascular endothelial cells (RMVEC), butyrate (1 mM, 2 and 24 h) exhibited a protective effect against TNFα- and LPS-induced barrier disruption. Butyrate (1 mM, 24 h) also upregulated tight junctional proteins (occludin, cingulin, claudin-1) and increased the acetylation of histone H3 but not α-tubulin. These findings provide evidence of the protective effect of butyrate on hypoxic PH and suggest its potential use as a complementary treatment for PH and other cardiovascular diseases.


Assuntos
Butiratos/farmacologia , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Hipóxia/complicações , Pulmão/fisiopatologia , Pneumonia/fisiopatologia , Remodelação Vascular/efeitos dos fármacos , Acetilação/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Citocinas/metabolismo , Células Endoteliais/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Hipertrofia Ventricular Direita/complicações , Hipertrofia Ventricular Direita/fisiopatologia , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Microvasos/patologia , Pneumonia/complicações , Ratos Sprague-Dawley , Sístole/efeitos dos fármacos , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Regulação para Cima/efeitos dos fármacos
17.
Diagn Interv Radiol ; 27(5): 587-594, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34559047

RESUMO

PURPOSE: The present work aims to evaluate whether dynamic contrast-enhanced magnetic resonance Imaging (DCE-MRI) can monitor non-invasively the blocking effect on microvessels of the Combretastatin-A4-phosphate (CA4P) and assess the therapeutic efficacy. METHODS: Forty rabbits were implanted the VX2 tumors specimens. Two weeks later, serial MRI (T1 weighted image, T2 weighted image and DCE) were performed at 0 h, 4 h, 24 h, 3 d and 7 d after CA4P (10 mg/kg) or saline treatment. The parameters of DCE (Ktrans, Kep, Ve and iAUC60) of enhancement tumor portions were measured. Then all the tumor samples were stained to count microvessel density (MVD). At last, two-way repeated measures ANOVA was used to analyze the difference between and within groups. The correlation between the Ktrans, Kep, Ve, iAUC60 and MVD was analyzed by using the Pearson correlation analysis and Spearman's rank correlation. RESULTS: The Ktrans and iAUC60 in the CA4P group were lower than the values of the control group at 4 h after treatment, which have significant differences (D-value: -0.133 min-1, 95%CI: -0.169~-0.097 min-1,F = 59.109, p < 0.001 for Ktrans; D-value: -10.533 mmol/sec, 95%CI: -17.147~-3.919 mmol/sec,F = 11.110, and p = 0.003 for iAUC60). In the CA4P group, the Ktrans and iAUC60 reached the minimum values at 4 h. There were significant differences between 4 h and other different time points of the Ktrans and iAUC60 in the treatment group (all p < 0.01). The parameters Ktrans (r = 0.532, P = 0.016 and r = 0.681, P = 0.001, respectively) and iAUC60 (r = 0.580, P = 0.007 and r = 0.568, P = 0.009, respectively) of 7 days showed correlation with MVD in both groups, while Kep and Ve did not show correlation with MVD (P > 0.05). CONCLUSION: The blocking effect of microvessels after CA4P treatment can be evaluated by DCE-MRI, and the parameters of quantitative Ktrans and semi- quantitative iAUC60 can assess the change of the tumor angiogenesis noninvasively.


Assuntos
Meios de Contraste , Neoplasias Hepáticas , Animais , Imageamento por Ressonância Magnética , Microvasos/diagnóstico por imagem , Neovascularização Patológica , Coelhos
18.
Cells ; 10(9)2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34571912

RESUMO

COVID-19 presents with a wide range of clinical neurological manifestations. It has been recognized that SARS-CoV-2 infection affects both the central and peripheral nervous system, leading to smell and taste disturbances; acute ischemic and hemorrhagic cerebrovascular disease; encephalopathies and seizures; and causes most surviving patients to have long lasting neurological symptoms. Despite this, typical neuropathological features associated with the infection have still not been identified. Studies of post-mortem examinations of the cerebral cortex are obtained with difficulty due to laboratory safety concerns. In addition, they represent cases with different neurological symptoms, age or comorbidities, thus a larger number of brain autoptic data from multiple institutions would be crucial. Histopathological findings described here are aimed to increase the current knowledge on neuropathology of COVID-19 patients. We report post-mortem neuropathological findings of ten COVID-19 patients. A wide range of neuropathological lesions were seen. The cerebral cortex of all patients showed vascular changes, hyperemia of the meninges and perivascular inflammation in the cerebral parenchyma with hypoxic neuronal injury. Perivascular lymphocytic inflammation of predominantly CD8-positive T cells mixed with CD68-positive macrophages, targeting the disrupted vascular wall in the cerebral cortex, cerebellum and pons were seen. Our findings support recent reports highlighting a role of microvascular injury in COVID-19 neurological manifestations.


Assuntos
COVID-19/patologia , Córtex Cerebral/patologia , Idoso , Idoso de 80 Anos ou mais , Autopsia , Encéfalo/patologia , Encéfalo/virologia , Encefalopatias/patologia , Encefalopatias/virologia , Linfócitos T CD8-Positivos/patologia , Córtex Cerebral/virologia , Feminino , Humanos , Inflamação , Macrófagos/patologia , Masculino , Microvasos/patologia , Microvasos/virologia , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/patologia , Doenças do Sistema Nervoso/virologia , SARS-CoV-2/patogenicidade
19.
Artigo em Inglês | MEDLINE | ID: mdl-34521653

RESUMO

INTRODUCTION: To evaluate effects of Ocufolin on retinal microvasculature in mild non-proliferative diabetic retinopathy patients who carried methylenetetrahydrofolate reductase (MTHFR) polymorphisms (DR+MTHFRP). RESEARCH DESIGN AND METHODS: This is a prospective cohort study. Eight DR+MTHFRP (administrated Ocufolin for 6 months) and 15 normal controls (NCs) were recruited. MTHFR polymorphisms were subtyped as normal, C677T, or A1298C. Best-corrected visual acuity (BCVA) was evaluated. Retinal vessel density (VD) and microstructure were evaluated by optical coherence tomography angiography. RESULTS: BCVA and vascular indices of DR+MTHFRP at baseline were worse than those of NC and improved. Compared with baseline, DR+MTHFRP had significantly improved BCVA during follow-up period (p<0.05). VD of superficial vascular plexus was increased at 4 months (p=0.012), while VD of retinal vascular network did not change (p>0.05). Carriers of A1298C and C677T showed statistically significant increase in VD at all layers by 6 months, while carriers of C677T alone showed no significant change and carriers of A1298C alone showed decreased density from 4 months to 6 months. Microstructure did not change during the follow-up period. CONCLUSION: A 6-month intake of Ocufolin is capable of reversing structural changes of microangiopathy in mild non-proliferative DR+MTHFRP. This suggests a novel way to address these impairments prior to catastrophic vision loss.


Assuntos
Diabetes Mellitus , Retinopatia Diabética , Suplementos Nutricionais , Metilenotetra-Hidrofolato Redutase (NADPH2) , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/genética , Angiofluoresceinografia , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Microvasos , Estudos Prospectivos , Vasos Retinianos/diagnóstico por imagem
20.
Hum Reprod ; 36(11): 2935-2947, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34492112

RESUMO

STUDY QUESTION: Can abnormalities in retinal microvasculature representing adverse microcirculatory perfusion and inflammation shed light on the pathophysiology of female fecundability? SUMMARY ANSWER: In our prospective study, abnormalities in retinal vascular geometric morphology (i.e. sparser arteriolar fractal and larger venular bifurcation) during pre-conception phase are temporarily associated with a prolonged time-to-pregnancy (TTP). WHAT IS KNOWN ALREADY: Suboptimal retinal microcirculatory morphology has been associated with obesity, psychological stress and hypertension, all of which are known risk factors for reduced female fecundability. STUDY DESIGN, SIZE, DURATION: A total of 652 women of Chinese, Malay or Indian ethnicity 18-45 years of age and planning to conceive spontaneously within the next 12 months were recruited during the pre-conception period into the Singapore PREconception Study of long-Term maternal and child Outcomes (S-PRESTO), from February 2015 to October 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: During recruitment, we collected information on socio-demographic factors, menstrual characteristics and lifestyle behaviors and made anthropometric measurements. We assessed the following retinal microvascular features: caliber, branching angle and fractal dimension. We conducted follow-up telephone surveys to track each participant's pregnancy status at 6, 9 and 12 months after enrolment. We ascertained clinical pregnancies via ultrasonography, with TTP measured by the number of menstrual cycles required to achieve a clinical pregnancy over a 1-year follow-up. Then, we performed discrete-time proportional hazards models to estimate the fecundability odds ratio (FOR) and 95% CI for each retinal microvascular feature in association with TTP, after adjusting for major confounders, including body mass index and fasting glycemic level at study entry. MAIN RESULTS AND THE ROLE OF THE CHANCE: Among 652 recruited women, 276 (42.3%) successfully conceived within 1 year of follow-up. The mean (and SD) was 1.24 (0.05) Df for retinal arteriolar dimension fraction and 78.45 (9.79) degrees for retinal venular branching angle, respectively. Non-linear relationship testing was performed before multiple adjustment in all associations and a non-monotonic association was detected between retinal venular branching angle and TTP. Compared with women in the highest tertile of retinal arteriolar fractal dimension, women in the second tertile had a prolonged TTP (FOR: 0.68; 95% CI: 0.51-0.92), as did women in the lowest tertile (FOR: 0.73; 95% CI: 0.55-0.98). Compared with women in the middle tertile of retinal venular branching angle, women in the highest tertile had a borderline prolonged TTP (FOR: 0.75; 95% CI: 0.56-1.02). No other retinal vascular features were significantly associated with TTP. LIMITATIONS, REASONS FOR CAUTION: We were unable to adjust for other potential confounding factors such as female sexual function (e.g. frequency of sexual intercourse), which might introduce a residual bias. Moreover, even though this is a prospective cohort design, our findings can identify the temporal relationship but not necessarily infer a causal relationship between maternal microvasculature and TTP. Lastly, our study involving mainly Chinese, Malay and Indian ethnicities might not be generalizable to other races or ethnicities. WIDER IMPLICATIONS OF THE FINDINGS: Suboptimal microcirculation may lead to reduced female fecundability. In the future, in addition to conventional ultrasonographic evaluation of ovarian and uterine physiological function, assessing the retinal microvasculature might be useful for assessment of ovarian age, fertility prediction and endometrial evaluation before assisted reproductive techniques for fertility treatments. STUDY FUNDING/COMPETING INTEREST(S): This research is supported by the Singapore National Research Foundation (NRF) under its Translational and Clinical Research (TCR) Flagship Programme and administered by the Singapore Ministry of Health's National Medical Research Council (NMRC) (Singapore-NMRC/TCR/004-NUS/2008; NMRC/TCR/012-NUHS/2014) and Singapore National Medical Research Council Transition Award (NMRC TA/0027/2014). The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT03531658.


Assuntos
Grupos Étnicos , Tempo para Engravidar , Criança , Feminino , Humanos , Microcirculação , Microvasos , Gravidez , Estudos Prospectivos , Singapura/epidemiologia
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