The Role of Autophagy in Vascular Endothelial Cell Health and Physiology.

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.

Exacerbated Activation of the NLRP3 Inflammasome in the Placentas from Women Who Developed Chronic Venous Disease during Pregnancy.

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.

Vascular complications in craniopharyngioma-resected paediatric patients: a single-center experience.

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.

Swine Model of Coronary Artery Dissection.

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.

Antithrombin deficiency caused by SERPINC1 gene mutation in white matter lesions: A case report.

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.

Exosomes in Vascular/Neurological Disorders and the Road Ahead.

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.

Evaluation of feline heartworm disease based on gross necropsy, serology, pulmonary histopathology, and radiographic evidence in adult shelter cats in northeastern Alabama.

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.

Perivascular fat tissue and vascular aging: A sword and a shield.

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.

Hypertension facilitates age-related diseases. ~ Is hypertension associated with a wide variety of diseases?~.

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.

Fibroblasts and Endothelial Cells in Three-Dimensional Models: A New Tool for Addressing the Pathogenesis of Systemic Sclerosis as a Prototype of Fibrotic Vasculopathies.

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.

Circulating endothelial cells in pathophysiology.

PURPOSE OF REVIEW: The purpose of this review is to synthesize recent insights into the roles and importance of circulating endothelial cells (CECs) as indicators of the severity, progression, and prognosis of vascular-related diseases. RECENT FINDINGS: Recent studies have identified elevated counts of CECs in pathological conditions, notably inflammatory or cardiovascular diseases such as acute myocardial infarction and heart failure, underscoring their potential as sensitive indicators of disease. Furthermore, the rise in CEC levels in cancer patients, particularly with disease advancement, points to their role in cancer-associated angiogenesis and response to treatment. SUMMARY: This review underscores the evolving significance of CECs as markers for evaluating the gravity and advancement of diseases with vascular injury, including cardiovascular diseases, cancer, inflammatory conditions, and thromboembolic events. These last years, efforts made to standardize flow cytometry detection of CEC and the development of highly sensitive techniques to isolate, quantify or phenotype rare cells open promising avenues for clinical application. This may yield extensive knowledge regarding the mechanisms by which endothelial cells contribute to a variety of vascular-related disorders and their clinical value as emerging biomarkers.

Prediction of bowel necrosis by reduced bowel wall enhancement in closed-loop small bowel obstruction: Quantitative methods.

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.

Differential Assessment of Internal Jugular Vein Stenosis in Patients Undergoing CT and MRI with Contrast.

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.

The mechanism of selenium regulating the permeability of vascular endothelial cells through selenoprotein O.

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.

Amyloid deposition and small vessel disease are associated with cognitive function in older adults with type 2 diabetes.

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.

Poor self-rated health is associated with faster cognitive decline and greater small vessel disease in older adults with type 2 diabetes.

OBJECTIVE: Self-rated health (SRH) is a predictor for poor health outcomes and cognition. Older adults with type 2 diabetes mellitus (T2D) have multi-morbidity and greater cognitive impairment. In the present study we investigated the association of SRH with cognitive decline and brain pathology in older adults with T2D. METHODS: Participants (n = 1122) were from the Israel Diabetes and Cognitive Decline study, and SRH was categorised as low (n = 202), moderate (n = 400) or high (n = 520). Cognition was measured by four cognitive domains: episodic memory, executive functions, language, and attention/working memory. Global cognition was the average of the cognitive domains. Statistical models adjusted for sociodemographic, cardiovascular, and clinical variables. In a randomly selected subsample (n = 230) that had magnetic resonance imaging, we examined relationships between baseline SRH and brain characteristics (white matter hyperintensities [WMHs], hippocampal, and total grey matter [GM] volumes). RESULTS: Low SRH was associated with a decline in executive functions, which accelerated over time when compared to high SRH (est = -0.0036; p = <0.001). Compared to high SRH, low SRH was associated with a faster decline in global cognition (est = -0.0024; p = 0.009). Low SRH at baseline was associated with higher volumes of WMHs (est = 9.8420; p < 0.0008). SRH was not associated with other cognitive domains, or with hippocampal and total GM. CONCLUSIONS: Low SRH is associated with cognitive decline in T2D older adults and may serve as a risk assessment. WMHs may represent an underlying mechanism.

Joint diffusional kurtosis magnetic resonance imaging analysis of white matter and the thalamus to identify subcortical ischemic vascular disease.

Identifying subcortical ischemic vascular disease (SIVD) in older adults is important but challenging. Growing evidence suggests that diffusional kurtosis imaging (DKI) can detect SIVD-relevant microstructural pathology, and a systematic assessment of the discriminant power of DKI metrics in various brain tissue microstructures is urgently needed. Therefore, the current study aimed to explore the value of DKI and diffusion tensor imaging (DTI) metrics in detecting early-stage SIVD by combining multiple diffusion metrics, analysis strategies, and clinical-radiological constraints. This prospective study compared DKI with diffusivity and macroscopic imaging evaluations across the aging spectrum including SIVD, Alzheimer's disease (AD), and cognitively normal (NC) groups. Using a white matter atlas and segregated thalamus analysis with considerations of the pre-identified macroscopic pathology, the most effective diffusion metrics were selected and then examined using multiple clinical-radiological constraints in a two-group or three-group paradigm. A total of 122 participants (mean age, 74.6 ± 7.38 years, 72 women) including 42 with SIVD, 50 with AD, and 30 NC were evaluated. Fractional anisotropy, mean kurtosis, and radial kurtosis were critical metrics in detecting early-stage SIVD. The optimal selection of diffusion metrics showed 84.4-100% correct classification of the results in a three-group paradigm, with an area under the curve of .909-.987 in a two-group paradigm related to SIVD detection (all P < .001). We therefore concluded that greatly resilient to the effect of pre-identified macroscopic pathology, the combination of DKI/DTI metrics showed preferable performance in identifying early-stage SIVD among adults across the aging spectrum.

Endothelial Response to Type I Interferon Contributes to Vasculopathy and Fibrosis and Predicts Disease Progression of Systemic Sclerosis.

OBJECTIVE: Interferon (IFN)-1 signatures are a hallmark of patients with systemic sclerosis (SSc). However, its significance in clinical stratification and contribution to deterioration still need to be better understood. METHODS: For hypothesis generation, we performed single-cell RNA sequencing (scRNA-seq) on skin biopsies (four patients with SSc and two controls) using the BD Rhapsody platform. Two publicly available data sets of skin scRNA-seq were used for validation (GSE138669: 12 patients with diffuse cutaneous SSc [dcSSc] and 10 controls; GSE195452: 52 patients with dcSSc and 41 patients with limited cutaneous SSc [lcSSc] and 54 controls). The IFN-1 signature was mapped, functionally investigated in a bleomycin plus IFNα-2 adenovirus-associated virus (AAV)-induced model and verified in an SSc cohort (n = 61). RESULTS: The discovery and validation data sets showed similar findings. Endothelial cells (ECs) had the most prominent IFN-1 signature among dermal nonimmune cells. The EC IFN-1 signature was increased both in patients with SSc versus controls and in patients with dcSSc versus those with lcSSc. Among EC subclusters, the IFN-1 signature was statistically higher in the capillary ECs of patients with dcSSc, which was higher than those in patients with lcSSc, which in turn was higher than those in healthy controls (HCs). Endothelial-to-mesenchymal transition (EndoMT) scores increased in parallel. Deteriorated bleomycin-induced dermal fibrosis, EndoMT, and perivascular fibrosis and caused blood vessel loss with EC apoptosis. Vascular myxovirus resistance (MX) 1, an IFN-1 response protein, was significantly increased both in total SSc versus HC skin and in dcSSc versus lcSSc skin. Baseline vascular MX1 performed similarly to skin score in predicting disease progression over 6 to 34 months in total SSc and was superior in the dcSSc subpopulation. CONCLUSION: The EC IFN-1 signature distinguished SSc skin subtypes and disease progression and may contribute to vasculopathy and fibrosis.

Serum neurofilament light and white matter characteristics in the general population: a longitudinal analysis.

Neurofilament light polypeptide (NfL) is a component of the neuronal cytoskeleton and particularly abundant in large-caliber axons. When axonal injury occurs, NfL is released and reaches the cerebrospinal fluid and the blood. Associations between NfL and white matter alterations have previously been observed in studies based on patients with neurological diseases. The current study aimed to explore the relationship between serum NfL (sNfL) and white matter characteristics in a population-based sample. The cross-sectional associations between sNfL as dependent variable, fractional anisotropy (FA), and white matter lesion (WML) volume were analyzed with linear regression models in 307 community-dwelling adults aged between 35 and 65 years. These analyses were repeated with additional adjustment for the potential confounders age, sex, and body mass index (BMI). Longitudinal associations over a mean follow-up of 5.39 years were analyzed with linear mixed models. The unadjusted cross-sectional models yielded significant associations between sNfL, WML volume, and FA, respectively. However, after the adjustment for confounders, these associations did not reach significance. In the longitudinal analyses, the findings corroborated the baseline findings showing no significant associations between sNfL and white matter macrostructure and microstructure beyond the effects of age. In synopsis with previous studies in patients with acute neurological diseases showing a significant association of sNfL with white matter changes beyond the effects of age, the present results based on a sample from the general population suggest the perspective that changes in sNfL reflect age-related effects that also manifest in altered white matter macrostructure and microstructure.

Capillary rarefaction: a missing link in renal and cardiovascular disease?

Patients with chronic kidney disease (CKD) have an increased risk for cardiovascular morbidity and mortality. Capillary rarefaction may be both one of the causes as well as a consequence of CKD and cardiovascular disease. We reviewed the published literature on human biopsy studies and conclude that renal capillary rarefaction occurs independently of the cause of renal function decline. Moreover, glomerular hypertrophy may be an early sign of generalized endothelial dysfunction, while peritubular capillary loss occurs in advanced renal disease. Recent studies with non-invasive measurements show that capillary rarefaction is detected systemically (e.g., in the skin) in individuals with albuminuria, as sign of early CKD and/or generalized endothelial dysfunction. Decreased capillary density is found in omental fat, muscle and heart biopsies of patients with advanced CKD as well as in skin, fat, muscle, brain and heart biopsies of individuals with cardiovascular risk factors. No biopsy studies have yet been performed on capillary rarefaction in individuals with early CKD. At present it is unknown whether individuals with CKD and cardiovascular disease merely share the same risk factors for capillary rarefaction, or whether there is a causal relationship between rarefaction in renal and systemic capillaries. Further studies on renal and systemic capillary rarefaction, including their temporal relationship and underlying mechanisms are needed. This review stresses the importance of preserving and maintaining capillary integrity and homeostasis in the prevention and management of renal and cardiovascular disease.