RESUMO
Approximately 70% of all strokes occur in patients over 65 years old, and stroke increases the risk of developing dementia. The circle of Willis (CoW), the ring of arteries at the base of the brain, links the intracerebral arteries to one another to maintain adequate cerebral perfusion. The CoW proteome is affected in cerebrovascular and neurodegenerative diseases, but changes related to aging have not been described. Here, we report on a quantitative proteomics analysis comparing the CoW from five young (2-3-month-old) and five aged male (18-20-month-old) mice using gene ontology (GO) enrichment, ingenuity pathway analysis (IPA), and iPathwayGuide tools. This revealed 242 proteins that were significantly dysregulated with aging, among which 189 were upregulated and 53 downregulated. GO enrichment-based analysis identified blood coagulation as the top biological function that changed with age and integrin binding and extracellular matrix constituents as the top molecular functions. Consistent with these findings, iPathwayGuide-based impact analysis revealed associations between aging and the complement and coagulation, platelet activation, ECM-receptor interaction, and metabolic process pathways. Furthermore, IPA analysis revealed the enrichment of 97 canonical pathways that contribute to inflammatory responses, as well as 59 inflammation-associated upstream regulators including 39 transcription factors and 20 cytokines. Thus, aging-associated changes in the CoW proteome in male mice demonstrate increases in metabolic, thrombotic, and inflammatory processes.
Assuntos
Envelhecimento , Círculo Arterial do Cérebro , Proteoma , Animais , Círculo Arterial do Cérebro/patologia , Envelhecimento/metabolismo , Masculino , Proteoma/metabolismo , Camundongos , Doenças Vasculares/metabolismo , Doenças Vasculares/patologia , Camundongos Endogâmicos C57BL , Proteômica/métodosRESUMO
Gain-of-function mutations in STING cause STING-associated vasculopathy with onset in infancy (SAVI) characterized by early-onset systemic inflammation, skin vasculopathy, and interstitial lung disease. Here, we report and characterize a novel STING variant (F269S) identified in a SAVI patient. Single-cell transcriptomics of patient bone marrow revealed spontaneous activation of interferon (IFN) and inflammatory pathways across cell types and a striking prevalence of circulating naïve T cells was observed. Inducible STING F269S expression conferred enhanced signaling through ligand-independent translocation of the protein to the Golgi, protecting cells from viral infections but preventing their efficient immune priming. Additionally, endothelial cell activation was promoted and further exacerbated by cytokine secretion by SAVI immune cells, resulting in inflammation and endothelial damage. Our findings identify STING F269S mutation as a novel pathogenic variant causing SAVI, highlight the importance of the crosstalk between endothelial and immune cells in the context of lung disease, and contribute to a better understanding of how aberrant STING activation can cause pathology.
Assuntos
Células Endoteliais , Proteínas de Membrana , Humanos , Lactente , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Mutação com Ganho de Função , Complexo de Golgi/metabolismo , Interferons/metabolismo , Interferons/genética , Doenças Pulmonares Intersticiais/genética , Doenças Pulmonares Intersticiais/patologia , Doenças Pulmonares Intersticiais/imunologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Mutação , Transdução de Sinais , Doenças Vasculares/genética , Doenças Vasculares/patologia , Recém-Nascido , Pré-Escolar , FemininoRESUMO
BACKGROUND: Increased arterial tortuosity has been associated with various cardiovascular complications. However, the extent and role of arterial tortuosity in non-atherosclerotic vascular diseases remain to be fully elucidated. This study aimed to assess arterial tortuosity index (ATI) in patients with non-atherosclerotic vascular diseases and the associated factors. METHODS: This is a retrospective analysis of patients with non-atherosclerotic vascular diseases referred to the Malformation and Rare Vascular Disease Center at the University Hospital in Lausanne (Switzerland). Computed tomography angiography (CTA) images performed between October 2010 and April 2022 were retrieved and the aortic tortuosity index (ATI) was calculated. Patients were classified based on diagnosis into the following groups: arterial dissection & aneurysm, arteritis & autoimmune disease, hereditary connective tissue diseases, and fibromuscular dysplasia (FMD). Univariate and multivariate logistic regression analysis was used to determine potentially relevant predictors of aortic tortuosity. RESULTS: The mean age upon computed tomography angiography (CTA) was 46.8 (standard deviation [SD] 14.6) years and 59.1% of the patients were female. Mean ATI was higher in patients over 60 years old (1.27), in those with arterial aneurysms (mean: 1.11), and in those diagnosed with hypertension (mean: 1.13). When only patients over 60 years old were considered, those diagnosed with connective tissue diseases had the highest ATI. At multivariate regression analysis, increasing age (p < 0.05), presence of arterial aneurysms (p < 0.05), and hypertension (p < 0.05) were independently associated with ATI. CONCLUSIONS: The ATI may be a promising tool in diagnostic evaluation, cardiovascular risk stratification, medical or surgical management, and prognostic assessment in several non-atherosclerotic vascular conditions. Further studies with longitudinal design and larger cohorts are needed to validate the role of ATI in the full spectrum of vascular diseases.
Assuntos
Aneurisma , Angiografia por Tomografia Computadorizada , Hipertensão , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto , Hipertensão/complicações , Aneurisma/patologia , Aneurisma/diagnóstico por imagem , Doenças Vasculares/patologia , Doenças Vasculares/diagnóstico por imagem , Idoso , Artérias/patologia , Artérias/diagnóstico por imagem , Fatores EtáriosRESUMO
Total anomalous pulmonary venous return (TAPVR) is rare (accounting for about 1% of all CHD) and can occur as a single lesion or in combination with other types of CHD (such as heterotaxy or HLHS). TAPVR is defined as an abnormal connection where all pulmonary veins do not drain into the left atrium but into the right atrium either directly or through a vein that is connected to the right atrium. TAPVR can be divided into four anatomic groups (Fig. 32.1): (1) supracardiac (about 55%), (2) cardiac (about 30%), (3) infracardiac (about 13%), and (4) mixed (very rare). In addition, it can be divided into two physiological types: nonobstructed and obstructed. Embryologically, all pulmonary veins usually connect to a pulmonary venous confluence that connects to the left atrium. If this connection does not occur, the pulmonary venous confluence connects to a systemic vein instead.
Assuntos
Cardiopatias Congênitas , Veias Pulmonares , Doenças Vasculares , Cardiopatias Congênitas/patologia , Veias Pulmonares/anormalidades , Veias Pulmonares/embriologia , Doenças Vasculares/patologiaRESUMO
Vascular disease, including heart disease, stroke, and peripheral arterial disease, is one of the leading causes of death and disability and represents a significant global health issue. Since the development of human induced pluripotent stem cells (hiPSCs) in 2007, hiPSCs have provided unique and tremendous opportunities for studying human pathophysiology, disease modeling, and drug discovery in the field of regenerative medicine. In this review, we discuss vascular physiology and related diseases, the current methods for generating vascular cells (eg, endothelial cells, smooth muscle cells, and pericytes) from hiPSCs, and describe the opportunities and challenges to the clinical applications of vascular organoids, tissue-engineered blood vessels, and vessels-on-a-chip. We then explore how hiPSCs can be used to study and treat inherited vascular diseases and discuss the current challenges and future prospects. In the future, it will be essential to develop vascularized organoids or tissues that can simultaneously undergo shear stress and cyclic stretching. This development will not only increase their maturity and function but also enable effective and innovative disease modeling and drug discovery.
Assuntos
Células-Tronco Pluripotentes Induzidas , Doenças Vasculares , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Doenças Vasculares/terapia , Doenças Vasculares/patologia , Engenharia Tecidual/métodos , Organoides , AnimaisRESUMO
Autophagy is a highly conserved cellular recycling process which enables eukaryotes to maintain both cellular and overall homeostasis through the catabolic breakdown of intracellular components or the selective degradation of damaged organelles. In recent years, the importance of autophagy in vascular endothelial cells (ECs) has been increasingly recognized, and numerous studies have linked the dysregulation of autophagy to the development of endothelial dysfunction and vascular disease. Here, we provide an overview of the molecular mechanisms underlying autophagy in ECs and our current understanding of the roles of autophagy in vascular biology and review the implications of dysregulated autophagy for vascular disease. Finally, we summarize the current state of the research on compounds to modulate autophagy in ECs and identify challenges for their translation into clinical use.
Assuntos
Autofagia , Células Endoteliais , Humanos , Autofagia/fisiologia , Células Endoteliais/metabolismo , Animais , Doenças Vasculares/patologia , Doenças Vasculares/metabolismoRESUMO
Calcium (Ca2+) is a secondary messenger that regulates various cellular processes. However, Ca2+ mishandling could lead to pathological conditions. Orai1 is a Ca2+channel contributing to the store-operated calcium entry (SOCE) and plays a critical role in Ca2+ homeostasis in several cell types. Dysregulation of Orai1 contributed to severe combined immune deficiency syndrome, some cancers, pulmonary arterial hypertension (PAH), and other cardiorespiratory diseases. During its activation process, Orai1 is mainly regulated by stromal interacting molecule (STIM) proteins, especially STIM1; however, many other regulatory partners have also been recently described. Increasing knowledge about these regulatory partners provides a better view of the downstream signalling pathways of SOCE and offers an excellent opportunity to decipher Orai1 dysregulation in these diseases. These proteins participate in other cellular functions, making them attractive therapeutic targets. This review mainly focuses on Orai1 regulatory partners in the physiological and pathological conditions of the pulmonary circulation and inflammation.
Assuntos
Proteína ORAI1 , Humanos , Proteína ORAI1/metabolismo , Animais , Moléculas de Interação Estromal/metabolismo , Sinalização do Cálcio , Cálcio/metabolismo , Doenças Vasculares/metabolismo , Doenças Vasculares/patologiaRESUMO
Chronic venous disease (CVD) comprises a spectrum of morphofunctional disorders affecting the venous system, affecting approximately 1 in 3 women during gestation. Emerging evidence highlights diverse maternofetal implications stemming from CVD, particularly impacting the placenta. While systemic inflammation has been associated with pregnancy-related CVD, preliminary findings suggest a potential link between this condition and exacerbated inflammation in the placental tissue. Inflammasomes are major orchestrators of immune responses and inflammation in different organs and systems. Notwithstanding the relevance of inflammasomes, specifically the NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3)- which has been demonstrated in the placentas of women with different obstetric complications, the precise involvement of this component in the placentas of women with CVD remains to be explored. This study employs immunohistochemistry and real-time PCR (RT-qPCR) to examine the gene and protein expression of key components in both canonical and non-canonical pathways of the NLRP3 inflammasome (NLRP3, ASC-apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain-caspase 1, caspase 5, caspase 8, and interleukin 1ß) within the placental tissue of women affected by CVD. Our findings reveal a substantial upregulation of these components in CVD-affected placentas, indicating a potential pathophysiological role of the NLRP3 inflammasome in the development of this condition. Subsequent investigations should focus on assessing translational interventions addressing this dysregulation in affected patient populations.
Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Placenta , Adulto , Feminino , Humanos , Gravidez , Doença Crônica , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Interleucina-1beta/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Placenta/metabolismo , Placenta/patologia , Complicações Cardiovasculares na Gravidez/genética , Complicações Cardiovasculares na Gravidez/patologia , Doenças Vasculares/genética , Doenças Vasculares/patologiaRESUMO
Background: Craniopharyngioma (CP), although slow growing and histologically benign, has high morbidity, mostly related to hypothalamus-pituitary dysfunction and electrolyte imbalance. Increased risk of vascular complications has been described. However, data are still poor, especially in the paediatric population. The aim of our study was to evaluate the occurrence, timing, and predisposing factors of deep venous thrombosis (DVT) and other vascular alterations in neurosurgical paediatric CP patients. Materials and Methods: In a single-centre, retrospective study, we investigated 19 CP patients (11 males, 8 females, mean age 10.5 ± 4.3 years), who underwent neurosurgery between December 2016 and August 2022, referred to Meyer Children's Hospital IRCCS in Florence. Results: Five patients (26.3%) presented vascular events, which all occurred in connection with sodium imbalances. Three DVT (two with associated pulmonary embolism, in one case leading to death) developed in the post-operative period, most frequently at 7-10 days. Elevated D-dimers, a reduced partial activated thrombin time and a prolonged C-reactive protein increase were highly related to thrombotic vascular events. One case of posterior cerebral artery pseudoaneurysm was described soon after neurosurgery, requiring vascular stenting. Superficial vein thrombophlebitis was a late complication in one patient with other predisposing factors. Conclusion: CP patients undergoing neurosurgery are at risk of developing DVT and vascular alterations, thus careful follow-up is mandatory. In our study, we found that the phase of transition from central diabetes insipidus to a syndrome of inappropriate antidiuretic hormone secretion may be a period of significant risk for DVT occurrence. Careful vascular follow-up is mandatory in CP-operated patients.
Assuntos
Craniofaringioma , Neoplasias Hipofisárias , Complicações Pós-Operatórias , Humanos , Craniofaringioma/cirurgia , Craniofaringioma/complicações , Feminino , Masculino , Criança , Estudos Retrospectivos , Neoplasias Hipofisárias/cirurgia , Neoplasias Hipofisárias/complicações , Adolescente , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/epidemiologia , Trombose Venosa/etiologia , Trombose Venosa/epidemiologia , Procedimentos Neurocirúrgicos/efeitos adversos , Pré-Escolar , Doenças Vasculares/etiologia , Doenças Vasculares/epidemiologia , Doenças Vasculares/patologia , SeguimentosRESUMO
Coronary artery dissection (CAD) is the intimal tearing of the coronary arterial wall and can be iatrogenic, spontaneous, or traumatic in origin. CAD is a rare but challenging condition that can cause significant hemodynamic compromise. Management strategies for CAD, such as the use of mechanical circulatory support devices, are available in the clinical setting. However, the incidence, etiology, and optimal management of CAD are not well-defined, emphasizing the need for adequate animal models in preclinical studies. Large animal models provide the human-like conditions necessary for testing and development of potential treatment strategies. In this chapter, we describe a method for the creation of a CAD swine model.
Assuntos
Dissecção Aórtica , Vasos Coronários , Modelos Animais de Doenças , Doenças Vasculares/congênito , Animais , Suínos , Vasos Coronários/patologia , Humanos , Anomalias dos Vasos Coronários , Doenças Vasculares/etiologia , Doenças Vasculares/patologia , Doenças Vasculares/terapia , Doença da Artéria Coronariana/patologiaRESUMO
Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), stroke, and aneurysms, are characterized by the abnormal accumulation and aggregation of disease-causing proteins in the brain and spinal cord. Recent research suggests that proteins linked to these conditions can be secreted and transferred among cells using exosomes. The transmission of abnormal protein buildup and the gradual degeneration in the brains of impacted individuals might be supported by these exosomes. Furthermore, it has been reported that neuroprotective functions can also be attributed to exosomes in neurodegenerative diseases. The potential neuroprotective functions may play a role in preventing the formation of aggregates and abnormal accumulation of proteins associated with the disease. The present review summarizes the roles of exosomes in neurodegenerative diseases as well as elucidating their therapeutic potential in AD, PD, ALS, HD, stroke, and aneurysms. By elucidating these two aspects of exosomes, valuable insights into potential therapeutic targets for treating neurodegenerative diseases may be provided.
Assuntos
Exossomos , Exossomos/metabolismo , Humanos , Animais , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Doenças Vasculares/metabolismo , Doenças Vasculares/patologia , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/patologiaRESUMO
RATIONALE: White matter lesions (WMLs) are structural changes in the brain that manifest as demyelination in the central nervous system pathologically. Vasogenic WMLs are the most prevalent type, primarily associated with advanced age and cerebrovascular risk factors. Conversely, immunogenic WMLs, typified by multiple sclerosis (MS), are more frequently observed in younger patients. It is crucial to distinguish between these 2 etiologies. Furthermore, in cases where multiple individuals exhibit WMLs within 1 family, genetic testing may offer a significant diagnostic perspective. PATIENT CONCERNS: A 25-year-old male presented to the Department of Neurology with recurrent headaches. He was healthy previously and the neurological examination was negative. Brain magnetic resonance imaging (MRI) showed widespread white matter hyperintensity lesions surrounding the ventricles and subcortical regions on T2-weighted and T2 fluid-attenuated inversion recovery images, mimicking immunogenic disease-MS. DIAGNOSES: The patient was diagnosed with a patent foramen ovale, which could explain his headache syndrome. Genetic testing unveiled a previously unidentified missense mutation in the SERPINC1 gene in the patient and his father. The specific abnormal laboratory finding was a reduction in antithrombin III activity, and the decrease may serve as the underlying cause for the presence of multiple intracranial WMLs observed in both the patient and his father. INTERVENTIONS: The patient received percutaneous patent foramen ovale closure surgery and took antiplatelet drug recommended by cardiologists and was followed up for 1 month and 6 months after operation. OUTCOMES: While the lesions on MRI remain unchanging during follow-up, the patient reported a significant relief in headaches compared to the initial presentation. LESSONS: This case introduces a novel perspective on the etiology of cerebral WMLs, suggesting that hereditary antithrombin deficiency (ATD) could contribute to altered blood composition and may serve as an underlying cause in certain individuals with asymptomatic WMLs.
Assuntos
Deficiência de Antitrombina III , Forame Oval Patente , Esclerose Múltipla , Doenças do Sistema Nervoso , Doenças Vasculares , Substância Branca , Masculino , Humanos , Adulto , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Forame Oval Patente/patologia , Antitrombina III/genética , Deficiência de Antitrombina III/complicações , Deficiência de Antitrombina III/genética , Deficiência de Antitrombina III/patologia , Encéfalo/patologia , Imageamento por Ressonância Magnética/métodos , Doenças Vasculares/patologia , Doenças do Sistema Nervoso/patologia , Esclerose Múltipla/diagnóstico , Cefaleia , Mutação , AntitrombinasRESUMO
BACKGROUND: Veterinary knowledge regarding feline heartworm has been increasing significantly over the past two decades. Necropsy surveys of shelter cats have shown feline adult heartworm infection prevalence to be 5-20% of the rate in unprotected dogs; however, other studies have shown feline heartworm antibody prevalence up to 33%, reflecting higher exposure rates and potential immature adult infections. Thus, the true prevalence of feline heartworm infection is likely underestimated due to the limitations of current diagnostic techniques, inadequate testing protocols, and the high likelihood of cats exhibiting transient clinical signs or dying without confirmation of infection. Diagnosing Feline Heartworm Disease (FHWD), also referred to as Heartworm Associated Respiratory Disease (HARD), is one of the conundrums of veterinary medicine. The purpose of this study was to evaluate and characterize the occurrence of Heartworm Associated Respiratory Disease [HARD] in shelter cats, naturally-infected with D.immitis. METHODS: Fifty shelter cats slated for euthanasia between December 2009 and June 2010 were investigated by gross necropsy, radiography, serology, and lung histopathology using techniques that have been established in experimental models of cat heartworm infection. The relationship between pulmonary vascular disease and serological markers for heartworm was also examined using correlations and statistical modeling. Serology included standard heartworm antigen test and a commonly used heartworm antibody test. Also included were heat-treated heartworm antigen test and two additional heartworm antibody tests previously evaluated on experimentally-infected cats. RESULTS: None of the cats were heartworm antibody (HW Ab) positive on a commonly used HW Ab test used by many reference laboratories even though 20% of the study cats were heartworm antigen (HW Ag) positive on heat-treated samples. Two additional HW Ab test were positive on 26% and 22% of the study cats. The combination of heat-treated HW Ag, HW Ab tests, and histopathology indicated 34% of the study cats had HARD. CONCLUSIONS: Utilizing both, the above tests, and thoracic radiographs, enhanced the ability to predict vascular disease, possibly caused by infection with immature and adult heartworms and supported the premise that cats develop heartworm disease at the same rate as dogs.
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Doenças do Gato , Dirofilaria immitis , Dirofilariose , Doenças Vasculares , Animais , Gatos , Alabama , Anticorpos Anti-Helmínticos , Doenças do Gato/diagnóstico , Doenças do Gato/epidemiologia , Doenças do Gato/patologia , Dirofilariose/diagnóstico , Dirofilariose/epidemiologia , Dirofilariose/patologia , Pulmão/patologia , Doenças Vasculares/patologiaRESUMO
The understanding of the function of perivascular adipose tissue (PVAT) in vascular aging has significantly changed due to the increasing amount of information regarding its biology. Adipose tissue surrounding blood vessels is increasingly recognized as a key regulator of vascular disorders. It has significant endocrine and paracrine effects on the vasculature and is mediated by the production of a variety of bioactive chemicals. It also participates in a number of pathological regulatory processes, including oxidative stress, immunological inflammation, lipid metabolism, vasoconstriction, and dilation. Mechanisms of homeostasis and interactions between cells at the local level tightly regulate the function and secretory repertoire of PVAT, which can become dysregulated during vascular aging. The PVAT secretion group changes from being reducing inflammation and lowering cholesterol to increasing inflammation and increasing cholesterol in response to systemic or local inflammation and insulin resistance. In addition, the interaction between the PVAT and the vasculature is reciprocal, and the biological processes of PVAT are directly influenced by the pertinent indicators of vascular aging. The architectural and biological traits of PVAT, the molecular mechanism of crosstalk between PVAT and vascular aging, and the clinical correlation of vascular age-related disorders are all summarized in this review. In addition, this paper aims to elucidate and evaluate the potential benefits of therapeutically targeting PVAT in the context of mitigating vascular aging. Furthermore, it will discuss the latest advancements in technology used for targeting PVAT.
Assuntos
Tecido Adiposo , Envelhecimento , Vasos Sanguíneos , Humanos , Tecido Adiposo/metabolismo , Tecido Adiposo/fisiologia , Animais , Envelhecimento/fisiologia , Envelhecimento/metabolismo , Vasos Sanguíneos/fisiologia , Vasos Sanguíneos/metabolismo , Doenças Vasculares/metabolismo , Doenças Vasculares/patologia , Doenças Vasculares/fisiopatologiaRESUMO
Hypertension, a disease whose prevalence increases with age, induces pathological conditions of ischemic vascular disorders such as cerebral infarction and myocardial infarction due to accelerated arteriosclerosis and circulatory insufficiency of small arteries and sometimes causes hemorrhagic conditions such as cerebral hemorrhage and ruptured aortic aneurysm. On the other hand, as it is said that aging starts with the blood vessels, impaired blood flow associated with vascular aging is the basis for the development of many pathological conditions, and ischemic changes in target organs associated with vascular disorders result in tissue dysfunction and degeneration, inducing organ hypofunction and dysfunction. Therefore, we hypothesized that hypertension is associated with all age-related vascular diseases, and attempted to review the relationship between hypertension and diseases for which a relationship has not been previously well reported. Following our review, we hope that a collaborative effort to unravel age-related diseases from the perspective of hypertension will be undertaken together with experts in various specialties regarding the relationship of hypertension to all pathological conditions.
Assuntos
Envelhecimento , Hipertensão , Humanos , Envelhecimento/patologia , Hipertensão/fisiopatologia , Doenças Vasculares/patologia , AnimaisRESUMO
Two-dimensional in vitro cultures have represented a milestone in biomedical and pharmacological research. However, they cannot replicate the architecture and interactions of in vivo tissues. Moreover, ethical issues regarding the use of animals have triggered strategies alternative to animal models. The development of three-dimensional (3D) models offers a relevant tool to investigate disease pathogenesis and treatment, modeling in vitro the in vivo environment. We aimed to develop a dynamic 3D in vitro model for culturing human endothelial cells (ECs) and skin fibroblasts, simulating the structure of the tissues mainly affected in systemic sclerosis (SSc), a prototypical autoimmune fibrotic vasculopathy. Dermal fibroblasts and umbilical vein ECs grown in scaffold or hydrogel, respectively, were housed in bioreactors under flow. Fibroblasts formed a tissue-like texture with the deposition of a new extracellular matrix (ECM) and ECs assembled tube-shaped structures with cell polarization. The fine-tuned dynamic modular system allowing 3D fibroblast/EC culture connection represents a valuable model of the in vivo interplay between the main players in fibrotic vasculopathy as SSc. This model can lead to a more accurate study of the disease's pathogenesis, avoiding the use of animals, and to the development of novel therapies, possibly resulting in improved patient management.
Assuntos
Escleroderma Sistêmico , Doenças Vasculares , Animais , Humanos , Células Endoteliais/patologia , Pele/patologia , Escleroderma Sistêmico/patologia , Fibrose , Doenças Vasculares/patologia , Fibroblastos/patologia , Células CultivadasRESUMO
Diabetes is associated with cognitive decline, but the underlying mechanisms are complex and their relationship with Alzheimer's Disease biomarkers is not fully understood. We assessed the association of small vessel disease (SVD) and amyloid burden with cognitive functioning in 47 non-demented older adults with type-2 diabetes from the Israel Diabetes and Cognitive Decline Study (mean age 78Y, 64% females). FLAIR-MRI, Vizamyl amyloid-PET, and T1W-MRI quantified white matter hyperintensities as a measure of SVD, amyloid burden, and gray matter (GM) volume, respectively. Mean hemoglobin A1c levels and duration of type-2 diabetes were used as measures of diabetic control. Cholesterol level and blood pressure were used as measures of cardiovascular risk. A broad neuropsychological battery assessed cognition. Linear regression models revealed that both higher SVD and amyloid burden were associated with lower cognitive functioning. Additional adjustments for type-2 diabetes-related characteristics, GM volume, and cardiovascular risk did not alter the results. The association of amyloid with cognition remained unchanged after further adjustment for SVD, and the association of SVD with cognition remained unchanged after further adjustment for amyloid burden. Our findings suggest that SVD and amyloid pathology may independently contribute to lower cognitive functioning in non-demented older adults with type-2 diabetes, supporting a multimodal approach for diagnosing, preventing, and treating cognitive decline in this population.
Assuntos
Doença de Alzheimer , Doenças de Pequenos Vasos Cerebrais , Transtornos Cognitivos , Disfunção Cognitiva , Diabetes Mellitus Tipo 2 , Doenças Vasculares , Feminino , Humanos , Idoso , Masculino , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Cognição , Doença de Alzheimer/patologia , Disfunção Cognitiva/patologia , Transtornos Cognitivos/patologia , Amiloide/metabolismo , Imageamento por Ressonância Magnética , Doenças Vasculares/patologia , Doenças de Pequenos Vasos Cerebrais/complicações , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Doenças de Pequenos Vasos Cerebrais/patologia , Encéfalo/metabolismoRESUMO
Vascular diseases, a leading cause of death in human, are strongly associated with pathological damage to blood vessels. The selenoprotein (Sel) have been reported to play important roles in vascular disease. However, the role of SelO in vascular disease has not been conclusively investigated. The present experiment was to investigate the regulatory mechanism of the effect of SelO on the permeability of vascular endothelial. The H.E staining, FITC-Dextran staining, Dil-AC-LDL staining and FITC-WGA staining showed that vascular structure was damaged, and intercellular junctions were disrupted with selenium (Se)-deficient. Immunohistochemistry, qPCR and Western blot revealed decreased expression of the adhesion plaque proteins vinculin, talin and paxillin, decreased expression of the vascular connectivity effector molecules connexin, claudin-1 and E-cadherin and increased expression of JAM-A and N-cadherin, as well as decreased expression of the ZO-1 signaling pathways ZO-1, Rock, rhoGEF, cingulin and MLC-2. In a screening of 24 Sel present in mice, SelO showed the most pronounced changes in vascular tissues, and a possible association between SelO and vascular intercellular junction effectors was determined using IBM SPSS Statistics 25. Silencing of SelO, vascular endothelial intercellular junction adverse effects present. The regulatory relationship between SelO and vascular endothelial intercellular junctions was determined. The results showed that Se deficiency lead to increased vascular endothelial permeability and vascular tissue damage by decreasing SelO expression, suggesting a possible role for SelO in regulating vascular endothelial permeability.
Assuntos
Selênio , Doenças Vasculares , Humanos , Animais , Camundongos , Células Endoteliais/metabolismo , Selênio/metabolismo , Doenças Vasculares/patologia , Permeabilidade , Selenoproteínas/genética , Selenoproteínas/metabolismoRESUMO
PURPOSE: To assess diagnostic performance and reproducibility of reduced bowel wall enhancement evaluated by quantitative methods using CT to identify bowel necrosis among closed-loop small bowel obstruction (CL-SBO) patients. METHODS: This retrospective single-center study included patients who diagnosed with CL-SBO caused by adhesion or internal hernia during January 2016 and May 2022. Patients were divided into necrotic group (n = 41) and non-necrotic group (n = 67) according to surgical exploration and postoperative pathology. Two doctors independently measured the attenuation of bowel wall and consensus was reached through panel discussion with a third gastrointestinal radiologist. Reduced bowel wall enhancement was assessed by four quantitative methods. Univariate analyses were used to evaluate the association between each method and bowel necrosis, and kappa/intraclass correlation coefficient values were used to assess interobserver agreement. Diagnostic performance parameters were calculated for each method. RESULTS: Reduced bowel wall enhancement in arterial phase (OR 8.98, P < 0.0001), reduced bowel wall enhancement in portal phase (OR 16.84, P < 0.001), adjusted reduced bowel wall enhancement in arterial phase (OR 29.48, P < 0.001), adjusted reduced bowel wall enhancement in portal phase (OR 145.69, P < 0.001) were significantly associated with bowel necrosis. Adjusted reduced bowel wall enhancement in portal phase had the best diagnostic performance (AUC: 0.92; Youden index: 0.84; specificity: 94.03 %) and interobserver agreement (kappa value of 0.59-0.73) to predict bowel necrosis. CONCLUSION: When assessing reduced bowel enhancement to predict bowel necrosis among CL-SBO patients, using unenhanced CT images and proximal dilated loop as standard references in portal phase is the most accurate quantitative method among those tested.
Assuntos
Traumatismos Abdominais , Obstrução Intestinal , Doenças Vasculares , Humanos , Tomografia Computadorizada por Raios X/métodos , Estudos Retrospectivos , Reprodutibilidade dos Testes , Intestino Delgado/diagnóstico por imagem , Sensibilidade e Especificidade , Obstrução Intestinal/diagnóstico por imagem , Obstrução Intestinal/cirurgia , Doenças Vasculares/patologia , Necrose/diagnóstico por imagem , Necrose/patologia , Traumatismos Abdominais/complicaçõesRESUMO
OBJECTIVE: Internal Jugular Vein Stenosis (IJVS) is hypothesized to play a role in the pathogenesis of diverse neurological diseases. We sought to evaluate differences in IJVS assessment between CT and MRI in a retrospective patient cohort. METHODS: We included consecutive patients who had both MRI of the brain and CT of the head and neck with contrast from 1 June 2021 to 30 June 2022 within the same admission. The degree of IJVS was categorized into five grades (0-IV). RESULTS: A total of 35 patients with a total of 70 internal jugular (IJ) veins were included in our analysis. There was fair intermodality agreement in stenosis grades (κ = 0.220, 95% C.I. = [0.029, 0.410]), though categorical stenosis grades were significantly discordant between imaging modalities, with higher grades more frequent in MRI (χ2 = 27.378, p = 0.002). On CT-based imaging, Grade III or IV stenoses were noted in 17/70 (24.2%) IJs, whereas on MRI-based imaging, Grade III or IV stenoses were found in 40/70 (57.1%) IJs. Among veins with Grade I-IV IJVS, MRI stenosis estimates were significantly higher than CT stenosis estimates (77.0%, 95% C.I. [35.9-55.2%] vs. 45.6%, 95% C.I. [35.9-55.2%], p < 0.001). CONCLUSION: MRI with contrast overestimates the degree of IJVS compared to CT with contrast. Consideration of this discrepancy should be considered in diagnosis and treatment planning in patients with potential IJVS-related symptoms.