Medical implants made of biodegradable materials could be of advantage for temporary applications such mechanical support during bone-healing or as vascular stents to keep blood vessels open. After completion of the healing process the implant would disappear, avoiding long-term side effects or the need for surgical removal. Various corrodible metal alloys based on magnesium, iron or zinc have been proposed as sturdier and potentially less inflammatory alternative to degradable organic polymers, in particular for load-bearing applications. Despite the recent introduction of magnesium-based screws the remaining hurdles to routine clinical applications are still challenging, such as limiting mechanical material characteristics or unsuitable corrosion characteristics. Here, salient features and clinical prospects of currently investigated biodegradable implant materials are summarized with a main focus on magnesium alloys. A mechanism of action for the stimulation of bone growth due to the exertion of mechanical force by magnesium corrosion products is discussed. To explain divergent in vitro and in vivo effects of magnesium a novel model for bacterial biofilm infections is proposed which predicts crucial consequences antibacterial implant strategies.

Brain metastasis is the most common intracranial malignancy in adults. The prognosis is extremely poor, partly because most patients have more than one brain lesion, and the currently available therapies are nonspecific or inaccessible to those occult metastases due to an impermeable brain-tumor-barrier (BTB). Phosphatidylserine (PS) is externalized on the surface of viable endothelial cells (ECs) in tumor blood vessels. In this study, we have applied a PS-targeting antibody to assess brain metastases in mouse models. Fluorescence microscopic imaging revealed that extensive PS exposure was found exclusively on vascular ECs of brain metastases. The highly sensitive and specific binding of the PS antibody enables individual metastases, even micrometastases containing an intact BTB, to be clearly delineated. Furthermore, conjugation of the PS antibody with a fluorescence dye, IRDye 800CW, or a radioisotope, ¹²⁵I, allowed clear visualization of individual brain metastases by optical imaging and autoradiography, respectively. In conclusion, we demonstrated a novel strategy of targeting brain metastases based on our finding that abundant PS exposure occurs on blood vessels of brain metastases but not normal brain, which may be useful for the development of imaging and targeted therapeutics for brain metastases

The aim of this study was to analyze the relationship between healthy vascular aging (HVA) and the Mediterranean diet alongside other lifestyles in a Spanish population aged 35 to 75 years without previous cardiovascular diseases. Methods: Cross-sectional descriptive study with 501 individuals aged 35 to 75 years recruited from five health centers by random sampling stratified by age and sex (55.90±14.24 years, 49.70% men). HVA was determined in two steps. Step 1: Subjects with vascular damage to the carotid arteries or peripheral arterial disease were classified as non-HVA. Step 2: The study population was classified by age and sex using the percentiles of the vascular aging index (VAI), with VAI ≤p25 considered HVA and >p25 considered non-HVA. The VAI was estimated using the following formula (VAI = (log (1.09) × 10 cIMT + log (1.14) cfPWV) × 39.1 + 4.76. Carotid-femoral pulse wave velocity (cfPWV) was measured with the SphygmoCor^® device and carotid intima-media thickness using Sonosite Micromax^® ultrasound. Mediterranean diet (MD) adherence, alcohol and tobacco use were recorded through validated questionnaires. Physical activity was assessed with the ActiGraph-GT3X^® accelerometer. Results: The mean VAI value was 61.23±12.86; (Men 63.47±13.75 and women 59.04±11.54; p<0.001). HVA was found in 18.9% (men 19.9% and women 17.8%). In the multiple regression analysis after adjusting for possible confounding factors, the mean VAI value showed a positive association with alcohol use (β=0.020) and sedentary hours per week (β=0.109), and a negative association with hours of activity per week (β=-0.102) and with the number of healthy lifestyles (β=-0.640). In the logistic regression analysis after adjusting for possible confounding factors, and compared to those classified as non-HVA, subjects classified as HVA were more likely to show adherence to MD (OR = 0.571), perform more than 26 hours per week of physical activity (OR = 1.735), spend less than 142 hours per week being sedentary (OR = 1.696), and have more than two healthy lifestyles (OR = 1.877). Conclusion: The results of this study suggest that the more time spent doing physical activity and the less time spent sitting, the lower the vascular aging index and the greater likelihood of being classified in the group of subjects showing HVA.

Abstract The aim of the present review is to discuss the roles of vitamin K and vitamin K-dependent proteins, and the combined action of the vitamins K and D, for maintenance of bone health. The most relevant vitamin K-dependent proteins in this respect are osteocalcin and matrix Gla-protein (MGP). When carboxylated these proteins appear to have the ability to chelate and import calcium from the blood to the bone, thereby reducing the risk of osteoporosis. Carboxylated osteocalcin appears to contribute directly to bone quality and strength. Adequate vitamin K status is required for carboxylation of MGP and osteocalcin. In addition, vitamin K acts on bone metabolism by other mechanism, such as a ligand for the nuclear steroid and xenobiotic receptor (SXR). In this narrative review, we examine the evidence for increased bone mineralization through dietary adequacy of vitamin K (phylloquinone or menaquinone). Summarizing the evidence for a synergistic effect of vitamin K and vitamin D3 we find that an adequate supply of vitamin K on top of an optimal vitamin D status seems to add to the benefit for maintaining bone health. More research related to synergism and possible mechanisms of vitamins D3 and K interaction in bone health is needed.

The kinase pathway plays a crucial role in blood vessel function. Particular attention is paid to VEGFR-type 2 angiogenesis and vascular morphogenesis as the tyrosin kinase pathway is preferentially activated. In silico studies were performed on several peptides that affect VEGFR2 in both stimulating and inhibitory ways. This investigation aims to examine the molecular properties of VEGFR2, a molecule primarily involved in the processes of vasculogenesis and angiogenesis. These relationships were defined by the interactions between vascular endothelial growth factor receptor 2 (VEGFR2) and the structural features of the systems. The chemical space of the inhibitory peptides and stimulators was described using topological and energetic properties. Furthermore, chimeric models of stimulating and inhibitory proteins (for VEGFR2) were computed using the protein system structures. The interaction between the chimeric proteins and VEGFR was computed. The chemical space was further characterized using complex manifolds and high-dimensional data visualization. The results show that a slightly similar chemical area is shared by VEGFR2 and is shared by stimulating and inhibitory proteins. On the other hand, the stimulator peptides and the inhibitors have distinct chemical spaces.

Unmanned aerial vehicles (UAVs), commonly known as drones, present a cost-effective solution for the swift collection of data from vast and remote areas that are otherwise difficult to access. The Mediterranean Basin, known for being a hot spot for plant biodiversity, hosts several habitats and taxa of significant naturalistic value. However, many of these areas are often inaccessible to botanists, making exploration and research challenging. The aim of this paper is to involve the utilization of drone surveys and open-source software for botanical research. Our primary goal is to show the effectiveness of these tools in the field and demonstrate their practical application in Natura 2000 sites. The protected area chosen for this research is Rocca di Novara, situated in northeastern Sicily. Thanks to our drone investigations, we were able to capture images of the mountain’s side that is inaccessible to humans. This allowed us to observe the habitat of some species in detail. One of the most fascinating discoveries was the reappearance of Saxifraga callosa subsp. australis, which had not been confirmed in this area for over 140 years. Using drones for botanical research can boost field research, making monitoring easier and more cost-effective over time, especially in Natura 2000 sites.

Rapid haemostasis during surgery is essential when one wants to reduce the duration of opera-tions, reduce the need for transfusions, and above all when one wants to achieve better patient management. The use of haemostatic agents, sealants and adhesives improves the haemostatic process by offering several advantages, especially in vascular surgery. These agents vary widely in their mechanism of action, composition, ease of application, adhesion to wet or dry tissue, im-munogenicity and cost. The most used are cyanoacrylate-based glues (Glubran 2) or polysaccharide hydrogel-microsphere powder (AristaTMAH). This work is based on a retrospective study carried out on a sample of patients with different vascular diseases (FAV, pseudoaneurysm and PICC application) in which two different haemostatic sealants were used. The aim was to assess the safety, the advantages and the ability of both sealants to activate the haemostatic process at the affected site, also in relation to their chemical-physical characteristics. The obtained results showed that the application of Glubran 2 and AristaTMAH as surgical wound closure systems is effective and safe as the success achieved was ≥94% on anastomoses of FAV; 100% on stabilization of Picc catheters; ≤95% on pseudoaneurysms.

Introduction. This retrospective study aimed to compare the risk factors for vascular calcification (VC) between pre-hemodialysis (HD) and prevalent HD adult patients while investigating associations with calcification biomarkers. Methods. Baseline data from 30 pre-HD and 85 HD patients were analyzed, including iPTH, vitamin D, FGF23, fetuinA, sclerostin, and VC scores (Adragao method). Multivariable linear regression identified VC predictors. Results: The prevalence of VC was similar in both groups, but HD patients had more pronounced VC scores ≥6. Pre-HD patients were older, with higher prevalence of Balkan endemic nephropathy, hypertension, and less frequent use of calcium phosphate binders. Both groups exhibited similar patterns of hyperphosphatemia, low vitamin D, and iPTH levels. In HD group normal phosphate was significantly common in patients with VC, whereas hyperphosphatemia was significantly common in patients without VC. Fetuin-A levels were higher in pre-HD patients, while FGF23 was elevated in HD patients. In pre-HD patients, male gender was associated with reduced VC risk, while in HD patients, malignancies and serum phosphate levels were negative VC predictors. Conclusion: Effective monitoring and tailored treatment of VC in CKD are still focused on phosphate regulation. Besides, mineral disturbances, hormones and biomarkers regulation, and patient-specific variables need to be considered.

Vasculogenic mimicry (VM), a process in which aggressive cancer cells form tube-like structures, plays a crucial role in providing nutrients and escape routes. Highly plastic tumor cells, such as those with triple-negative breast cancer (TNBC) phenotype, can develop VM. However, little is known about the interplay between cellular components of the tumor microenvironment upon TNBC cells VM-capacity. In this study, we analyzed the ability of endothelial and stromal cells to induce VM when interacting with TNBC cells, and analyzed the involvement of the FGFR/PI3K/Akt pathway in this process. VM was corroborated using fluorescently‐labeled TNBC cells. Only endothelial cells triggered VM formation, suggesting a predominant role of paracrine/ juxtacrine factors from an endothelial origin in VM development. By immunocytochemistry, qPCR and secretome analyses, we determined increased expression of proangiogenic factors as well as stemness markers in VM-forming cancer cells. Similarly, endothelial cells primed by TNBC cells showed upregulation of proangiogenic molecules, including FGF, VEGFA, and several inflammatory cytokines. The endothelium-dependent TNBC-VM formation was prevented by AZD4547 or LY294002, strongly suggesting the involvement of the FGFR/PI3K/Akt axis in this process. Given that VM is associated with poor clinical prognosis, targeting FGFR/PI3K/Akt pharmacologically may hold promise for treating and preventing VM in TNBC tumors.

Synaptic zinc ions (Zn2+) play an important role in the development of vascular dementia (VD) and Parkinson’s disease (PD). In this article, based on our study and many others, we review the mo-lecular pathways by which Zn2+ causes neurotoxicity. Zn2+ influences calcium homeostasis, energy production pathway, production of reactive oxygen species, endoplasmic reticulum stress pathway, and activated protein kinase/c-Jun amino terminal kinase (SAPK/JNK) pathway and consequently exerts neurotoxicity. Furthermore, we searched various crops for substances that protect neurones from neurotoxicity caused by Zn2+ and clarified that carnosine (β-alanylhistidine) may be a therapeutic drug for VD and PD. Here, we also review the molecular mechanisms underlying the role of carnosine as an endogenous protector and its protective effect against Zn2+-induced cyto-toxicity and discuss prospects for future neurodegenerative diseases therapeutic applications of this dipeptide.

Vascular endothelial growth factor (VEGF) is a important biomarker with significant clinical importance. It plays a key role in angiogenesis, would healing, tumor growth, lung development, and in retinal diseases. Hence, detecting and quantifying VEGF is crucial in clinical diagnosis and prognosis of various diseases. In this work, a simple but highly cost-effective platform is developed for VEGF protein detection by using commercially available interdigitated sensors that are modified through surface chemistry tagged with DNA aptamer grafting. The dielectric characteristics between the fingers of sensor is modulated by the negatively charged aptamer-VEGF capture and the impedance is estimated using impedance analyzer. Impedance spectra tests was compared between pristine unmodified, functionalized monolayer surfaces and aptamer-grafted surfaces in order to evaluate the efficacy of VEGF detection. In our results, the sensitivity experiments as conducted had shown the ability of the interdigitated sensor to detect VEGF at a low concentration of 5 pM. The specificity of the functionalized sensor in detecting VEGF is further studied by comparing the impedance to platelet-derived growth factor (PDGF), and the results confirm the specificity of the sensor. Finally, an alternative illustration of impedance spectra is also proposed to improve the data visualization, and such presentation may be potential for intelligent VEGF detection.

Three-dimensional matrices are a new strategy used to tackle type I diabetes; a chronic metabolic disease characterized by the destruction of beta pancreatic cells. Type I collagen is an abundant extracellular matrix (ECM), component that has been used to support cell growth. However, pure collagen possesses some difficulties including low stiffness and strength, and high susceptibility to cell-mediated contraction. Therefore, we developed a collagen hydrogel with a poly(ethylene glycol) diacrylate (PEGDA) interpenetrating network (IPN), functionalized with vascular endothelial growth factor (VEGF) to mimic the pancreatic environment for the sustenance of beta-pancreatic cells. We analyzed the physicochemical characteristic of the hydrogels and found that they were successfully synthesized. The mechanical behavior of the hydrogels improved with the addition of VEGF, and the swelling degree and the degradation were stable over time. In addition, it was found that 5 ng/mL VEGF-functionalized collagen/PEGDA IPN hydrogels sustained and enhanced viability, proliferation, respiratory capacity and functionality of beta pancreatic cells. Hence, this is a potential candidate for future preclinical evaluation, which may be favorable for diabetes treatment.

The neurovascular niche is crucial for constant blood supply and blood-brain barrier (BBB) function and is altered in a number of different neurological conditions, making this an intensely active field of research. Brain vasculature is unique for its tight association of endothelial cells with astrocytic endfeet processes. Separation of the vascular compartment by centrifugation-based methods confirmed enrichment of astrocytic endfeet processes, making it possible to study the entire vascular niche with such methods. Several centrifugation-based separation protocols are found in the literature; however, with some constraints which limit their applicability and the scope of the studies. Here, we describe and validate a protocol for physically separating the neurovascular niche from the parenchyma, which is optimized for smaller tissue quantities. Using endothelial, neuronal and astrocyte markers, we show that quantitative Western blot-based target detection can be performed of both the vascular and parenchymal fractions using as little as a single mouse brain hemisphere. Validation of our protocol in rodent stroke models by detecting changes in serum albumin signals and astrocyte activation, i.e. increased glial fibrillary acidic protein expression, between the ipsilateral and the lesion-free contralateral hemisphere demonstrates this protocol as a new way of detecting BBB breakdown and astrogliosis, respectively.

In atherosclerosis patients, vascular endothelial dysfunction is commonly observed with damage of vascular endothelial glycocalyx, an extracellular matrix-bound to and encapsulating the endothelial cell lining the blood vessel wall. Unfavorable lifestyle; smoking and physical inactivity, also induces glycocalyx degradation. Moreover, the vascular endothelial glycocalyx is damaged by various unfavorable disease conditions like as dehydration, acute infectious disease, trauma, sepsis, ARDS, Kawasaki disease, preeclampsia, gestational diabetes mellitus, hypertension, diabetes, chronic kidney disease, atherosclerosis, stroke, dementia, microvascular angina, acute coronary syndrome, and heart failure. The vascular endothelial glycocalyx has been shown to be important not only as a physical cytoprotective barrier for vascular endothelial cells but also as a mechanism that regulates intracellular cell signaling. Therefore, vascular endothelial glycocalyx has great potential to explore new strategies for assessing the benefit conditions of our healthy vasculature.

Cerebral blood flow (CBF) decreases across the lifespan, and chronic conditions such as dementia and stroke accelerate this decline. Impaired CBF results in reduced delivery of oxygen and nutrients, which can damage the brain over time. Thus, there is a need to identify lifestyle interventions including diet and exercise to maintain CBF with aging and in the presence of chronic disease. In the present study, we used transcranial Doppler ultrasound to record middle cerebral artery velocity (MCAv), a surrogate measure of CBF, during moderate-intensity exercise in sedentary, cognitively-normal older adults (N = 90). A multiple linear regression model (F(4, 85) = 3.21, p = 0.02) showed self-reported omega-3 supplement use significantly moderated the association between age and mean exercising MCAv in these individuals (p = 0.01). Older age was associated with lower exercising MCAv in the group not taking omega-3 supplements, while exercising MCAv showed no decline with increasing age in the group who reported omega-3 supplement use. These findings suggest omega-3 supplementation may have an important role in the preservation of CBF with aging.

Abstract: The broad clinical use of synthetic vascular grafts for vascular diseases is limited by their thrombogenicity and low patency rate, especially for vessels with a diameter inferior to 6 mm. Alternatives such as tissue-engineered blood grafts (TEBGs) have gained increasing interest. Among the different manufacturing approaches, 3D bioprinting presents numerous advantages and enables the fabrication of multi-scale, multi-material, and multicellular tissues with heterogeneous and functional intrinsic structures. Extrusion-, inkjet- and light-based 3D printing techniques have been used for the fabrication of TEBG out of hydrogels, cells, and/or solid polymers. This review discusses the state-of-the-art research on the use of 3D printing for TEBG with a focus on the biomaterials and deposition methods.

Biomarkers have the potential to aid in the study of Alzheimer’s disease (AD); unfortunately, AD biomarker values often have a high degree of overlap between healthy and AD individuals. This study investigates the potential utility of a series of novel AD biomarkers, the sixty second ¹²⁹Xe retention time, and the xenon washout parameter, based on the washout of hyperpolarized ¹²⁹Xe from the brain of AD participants following inhalation. The xenon washout parameter is influenced by cerebral perfusion, T1 relaxation of xenon, and the xenon partition coefficient, all factors influenced by AD. Participants with Alzheimer’s disease (n=4) and healthy volunteers (n=4) were imaged using hyperpolarized ¹²⁹Xe magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) to determine the amount of retain xenon in the brain. At 60 sec post breath hold, AD patients retained significantly higher amounts of ¹²⁹Xe compared to healthy controls. Data was fit to a pharmacokinetic model and the xenon washout parameter was extracted. Xenon washout in white and grey matter occurs at a slower rate in Alzheimer’s participants (¹²⁹Xe half-life time of 42s and 43s, respectively) relative to controls (20s and 16s, respectively). Following larger scale clinical trials for validation, the xenon washout parameter has the potential to become a useful biomarker for the support of an AD diagnosis.

Growth factors, chemokines and cytokines guide tissue regeneration after injuries. However, their applications as recombinant proteins are almost non-existent due to the difficulty of maintaining their bioactivity in the protease-rich milieu of injured tissues in humans. Safety concerns have ruled out their systemic administration. The vascular system provides a natural platform for circumvent the limitations of the local delivery of protein-based therapeutics. Tissue selectivity in drug accumulation can be obtained as organ-specific molecular signatures exist in the blood vessels in each tissue, essentially forming a postal code system (“vascular zip codes”) within the vasculature. These target-specific “vascular zip codes” can be exploited in regenerative medicine as the angiogenic vasculature forming in the regenerating tissues has a unique molecular signature. The identification of vascular homing peptides capable of finding these unique “vascular zip codes” after their systemic administration provides an opportunity for the target-specific delivery of therapeutics to tissue injuries. Therapeutic proteins can be “packaged” together with homing peptides by expressing them as multi-functional recombinant proteins. These multi-functional recombinant proteins provide an example how molecular engineering gives a compound an ability to home to regenerating tissue and enhance its therapeutic potential. Regenerative medicine has been dominated by the locally applied therapeutic approaches despite these therapies are not moving to clinical medicine with success. There might be a time to change the paradigm towards systemically administered, target organ-specific therapeutic molecules in future drug discovery and development for regenerative medicine

Vascular rings are a rare congenital anomaly of the aortic arch in which a ring-shaped structure forms surrounding the trachea and/or esophagus, potentially causing compression. We describe the case of a 14-month-old female patient with failure to thrive secondary to dysphagia, and a vascular ring formed by a right aortic arch, an aberrant left subclavian artery, and a left liga-mentum arteriosum. Surgical repair involved ligamentum arteriosum division, Kommerell’s di-verticulum obliteration, and left subclavian artery re-implantation into the left carotid artery. Endoscopy and EndoFLIPTM evaluated intraoperative improvement in esophageal narrowing and impedance, respectively. Postoperative period was uneventful and follow-up visits demonstrated dysphagia resolution and a patent re-implanted left subclavian artery.

Vascular anomalies are a diverse group of abnormal blood vessel developments that can occur at birth or shortly afterward. Embolization and sclerotherapy have been utilized as a treatment option for these malformations but may cause moderate to severe pain. This study aims to evaluate the utilization of peripheral nerve blocks in opioid consumption, pain scores, and length of stay. A retrospective chart review was conducted at the UPMC Children's Hospital of Pittsburgh for all patients who underwent embolization and sclerotherapy between 2011 and 2020. Patient data was collected to compare opioid consumption, pain scores, and length of stay. Eight hundred fifty-four procedures were performed on 347 patients. The morphine milligram equivalent per kilogram mean ratio between groups was 0.9 (0.86, 0.95) with a p-value of &lt;0.001. The pain score mean ratio was –1.17 (–2.2, -0.1) and a p-value of 0.027. Length of stay had a mean ratio of 0.94 (0.4, 2) and a p-value of 0.875. By decreasing opioid consumption and postoperative pain scores, peripheral nerve blocks may have utility in patients undergoing embolization and sclerotherapy while not clinically increasing the length of stay for patients. Their use should be individualized and carefully discussed with the interventional radiologist.

Photon-counting Computed Tomography (PCCT) is a promising cardiovascular-imaging technique. Using detectors that count the number and energy of photons in multiple bins, PCCT offers several advantages over conventional CT, including a higher image quality, reduced contrast agent volume, radiation doses, and artifacts. Although PCCT is well established for cardiac imaging in assessing coronary artery disease, its application in vascular imaging remains limited. This review summarizes the available literature and provides an overview of the current use of PCCT for the diagnosis of vascular conditions. Of the 13 records selected in the initial search, 7 articles were included in the present review: 6 cohort studies and 1 case report. This review synthesized the available literature on PCCT in vascular imaging, focusing mainly on endoleaks detection and characterization after endovascular aneurysm repair (EVAR), contrast dose volume, and radiation exposure reduction, particularly in patients with chronic kidney disease and in those requiring follow-up CT.

We performed a retrospective, observational study for 51 eyes of 51 treatment-naive patients with polypoidal choroidal vasculopathy (PCV), whose lesion ranged within the 6x6mm scope of optical coherence tomography angiography (OCTA). Patients were divided into two groups based on the pattern of branching vascular network (BVN) on OCTA: ill-defined group and well-defined group. BVN morphology was not related to baseline best-corrected visual acuity (BCVA). But the BCVA in the ill-defined BVN group (-0.18 [interquartile range: -0.40 to 0.00]) was significantly improved after anti-vascular endothelial growth factor (VEGF) injections, compared with that (0.00 [interquartile range: -0.18 to 0.00]) in the well-defined group (z=2.143, p=0.032). Multiple logistic regression analysis showed that male sex, smaller number of injections, and presence of polypoidal lesions on OCTA images at baseline predicted a poor prognosis of polypoidal lesions on OCTA images after anti-VEGF therapy (all p&lt;0.05). Finally, BCVA at baseline and the number of injections were protective factors for BCVA after anti-VEGF therapy (all p&lt;0.05). In contrast, history of hypertension and macular edema at baseline were risk factors for BCVA after anti-VEGF injections (all p&lt;0.05). Our results revealed the visual and morphological prognosis of patients with active subfoveal circumscribed PCV after anti-VEGF therapy.

Cell-based therapy in regenerative medicine is a powerful tool that can be used both to restore various cell lost in a wide range of human disorders, and in renewal processes. Stem cells show promise for universal use in clinical medicine, potentially enabling the regeneration of numerous organs and tissues in the human body. This is possible due to their self-renewal capacity, and their ability to differentiate into various cell types. To date, pluripotent stem cells seem to be the most promising regeneration tool. Recently, a novel stem cell niche, called multilineage-differentiating stress-enduring (Muse) cells, is emerging. These cells are of particular interest because they are pluripotent and are found in adult human mesenchymal tissues. One of their most significant features is that they can produce cells representative of all the three germ layers. Furthermore, they can be easily harvested from fat, and isolated from the mesenchymal stem cells. This makes them very promising, allowing autologous treatments and avoiding the problems of rejection, typical of transplants. Muse cells have recently been employed, with encouraging results, in numerous preclinical studies, performed to test their efficacy in the treatment of various pathologies, exploiting their regenerative potential in different tissues. This systematic review aimed to 1) highlight the specific potential of Muse cells, and provide a better understanding of this niche, and 2) originate the first organized review of already tested applications of Muse cells in regenerative medicine. The obtained results could be useful to extend the possible therapeutic applications of Muse cells.

Megalin (LRP2) is a rapidly recycling multiligand endocytic receptor, primarily expressed in polarized epithelial cells. Despite megalin could promote tumor growth and invasiveness through several mechanisms, it has been understudied in the field of molecular oncology so far. The present study aimed to evaluate the impact of megalin expression in oral squamous cell carcinoma (OSCC) on disease progression. Megalin expression was evaluated immunohistochemically in 63 OSCC specimens. Data obtained were retrospectively compared with patients’ clinicopathological features and survival. The proportion of megalin-expressing cells in primary OSCC tissue was significantly associated with metastatic spreading to lymph nodes, vascular invasion and lower overall survival rate. Results obtained by the study suggest that megalin can be considered as a novel molecule involved in OSCC pathogenesis, but also useful as a potential biomarker for cancer progression.

Type 2 Diabetes Mellitus is being increasingly associated with dysfunction of cognition. Dementia, including vascular dementia and Alzheimer’s disease, is being recognized as comorbidities of this metabolic disorder. The progressive hallmarks of this cognitive dysfunction include mild impairment of cognition and cognitive decline. Dementia and mild impairment of cognition appear in older patients primarily. Studies on risk factors, neuropathology, and brain imaging have provided important suggestions for mechanisms that lie behind the development of dementia. It is a significant challenge to understand the disease processes related to diabetes which affect the brain and lead to dementia development. The connection between Diabetes Mellitus and dysfunction of cognition has been observed in many human and animal studies that have noted mechanisms related to Diabetes Mellitus are possibly responsible for aggravating cognitive dysfunction. This article attempts to narrate the possible association between type 2 diabetes and Dementia, reviewing studies that have noted this association in vascular dementia and Alzheimer’s disease and helping to explain the potential mechanisms behind the disease process. The Google search for ‘Diabetes Mellitus and Dementia’ was carried out. Also, the search was done using ‘Diabetes Mellitus,’ ‘Vascular Dementia,’ ‘Alzheimer’s Disease.’ The literature search was done from Google Scholar, Pubmed, Embase, ScienceDirect, and MEDLINE. Keeping in mind the increasing rate of Diabetes Mellitus, it is important to establish the type 2 diabetes effect on the brain and diseases of neurodegeneration. This narrative review aims to build awareness regarding different types of dementia and their relationship with diabetes.

Type 2 diabetes (T2D) is associated with increased cardiovascular morbidity, mortality, and hospital admissions. There is variability in clinical practice. The objectives are to analyze the variability in the control of Blood Pressure (BP), HbA1c, and LDL-C in T2D patients and its influence on admissions due to cardiovascular events (CVE) Methods: We analyzed the electronic records in Primary Care Health centers in Navarra (Spain) and hospital admission for CVE. We follow 480637 people from 2012 to 2016. We calculated indicators of control of patients with T2D for each year, percentage with: HbA1c &lt; 7%; HbA1c &gt;= 9%; BP &lt;140/90 mmHg; LDL-C &lt;100 mg/dl. We used logistic and Cox regression. Results: Patients in the best control GP practices cluster are 2.5 times more likely to have HbA1c &lt;7% [OR: 2.46 (95% CI: 2.29-3.64)]. Poor HbA1c control ≥ 9% is more likely in the worst control cluster [OR: 1.73 (95% CI:1.63-1.83)]. The probability of admission for CVE increases with age, being male, low income, obesity, history of CVE, having HbA1c ≥ 9%, and belonging to a GP practice in the cluster of HbA1C ≥ 9% worst control. In contrast, it decreases in patients with HbA1c &lt;7%, BP&lt;140/90 mmHg and LDL &lt;100 mg/dl.

Abstract: Perihilar cholangiocarcinoma (phCC) is the most common type of cholangiocarcinoma, accounting for approximately 60 % of cases, followed by the distal and then the intrahepatic forms. There is not a staging system that allows comparation of all series and extract some conclusions to increase the long-survival rate in this dismal disease. The extension of the resection, which theoretically dependes on the type of phCC, is not closed subject. As surgery is the only known way to achieve a cure, many aggressive approachs have been adopted. Despite extended liver resections and even vascular resections, margins are positive in around one third of patients. In the past two decades, with advances in diagnostic and surgical techniques, the surgical outcomes and survival rates have gradually improved, although variability is the rule, with morbidity and mortality rates ranging from 14% to 76% and from 0% to 19%, respectively. Extended hepatectomies and portal vein resection even right hepatic artery reconstruction for the left side tumors are frequently needed. Salvage procedures when arterial reconstruction is not feasible, as well as hepatopancreatoduodenectomy, are still under evaluation too. In this article, we discuss the aggressive surgical approach to phCC focused on vascular resection. Disparate results on the surgical treatment of phCC made it impossible to reach clear-cut conclusions.

An abdominal aortic aneurysm (AAA) is a dilatation of the abdominal aorta that progressively grows till the rupture. Treatment is typically recommended when the diameter is more than 5 cm. The EVAR (Endovascular aneurysm repair) is a mininvasive procedure that involves the placement of an expandable stent graft within the aorta to treat aortic disease without operating directly on the aorta. For years, stent grafts' essential design was based on metallic stent frames to support the fabric. More recently, a polymer-based technology has been proposed as an alternative method to seal AAA. This review underlines the two platforms that are based on a polymer technology: 1)the polymer-filled endobags, so-called Endovascular Aneurysm Sealing (EVAS) with Nellix stent graft; and 2)the O-ring EVAR polymer-based proximal neck sealing device, so-called Ovation stent graft. Polymer characteristics for this particular aim, clinical applications, and durability results are summarized and commented critically. The platform that embraced the concept of inflating endobags filled with polymer to exclude the aneurysmal sac was not successful because of the lack of an adequate proximal fixation. The platform that used polymer to create a circumferential sealing of the aneurysmal neck has proven safe and effective.

Abstract Background Costello syndrome (CS) is a rare RASopathy caused by a mutation in the proto-oncogene gene HRAS located on chromosome 11p15.5. It is characterized by failure to thrive, intellectual disability, coarse facies, and various cardiovascular, musculoskeletal, and dermatological abnormalities. Aims This literature review describes the various dermatological manifestations of CS in hopes of guiding dermatologists to recognize this rare neurocutaneous syndrome promptly and achieving better patient outcomes. Methods PubMed, MEDLINE, and Scopus were utilized to search for articles and studies on the dermatological features and disorders present in CS. Articles were selected and screened primarily by two reviewers. In the initial article selection process, a third reviewer was included in times of contradiction between the two primary reviewers. Twenty-three articles were ultimately included for analysis. Results CS presents myriad dermatological manifestations, the most characteristic being fine, curly to wavy hair, thick, bushy eyebrows, thin but fast-growing nails, cutaneous papillomas, and loose and redundant skin. Significant cutaneous pathologies associated with CS include eczema, acanthosis nigricans, nevi, coarse facies, and hyperpigmentation. Individuals with CS are also at increased risk for heat intolerance, hyperhidrosis, and photosensitivity. Conclusions Dermatologists must be aware of CS and its dermatological manifestations to efficiently treat the comorbidities involved with this rare neurodevelopmental disorder. CS can present similarly to Cardio-facial-cutaneous syndrome, Noonan syndrome, William syndrome, and Beckwith-Wiedemann syndrome; thus, a keen understanding of the cutaneous differences amongst the syndromes may aid in accurate diagnosis.

Damage to peripheral arteries by the atherosclerotic process accounts for about 3% of the world's population, which puts this problem in the category of major social problems. Modified lipoproteins and cholesterol crystals are known to accumulate in the arterial intima and cause the formation of proatherogenic macrophages, foam cells, and inflammation. Defective efferocytosis of apoptotic foam cells leads to the formation of a necrotic core, a sign of failure to resolve inflammation. Resolution of inflammation is mediated by specialized pro-resorption lipid mediators, proteins and signaling gases. Improving the balance between pro-inflammatory and anti-inflammatory factors contributes to the reverse development of local atherogenesis. Active direct intervention in the reconstruction of the adventitial layer of the arterial wall using cholesterol-affinity polysaccharide hydrogels containing a cocktail of growth factors creates conditions for the formation of additional extracellular matrix and reversal of cholesterol mass from the subintimal zone. Creating concentration and electrostatic gradients in the adventitia zone using a hydrogel may be one of the effective ways to degrade early soft atherogenic plaques and locally restore the damaged structure of the vessel wall. Growing scientific interest in the previously insufficiently studied adventitia indicates its important role in angionesis and atherogenesis.

The promoter of the RECEPTOR-LIKE CYTOPLASMIC KINASE VI_A2 gene contains nine binding sites for the REPLUMLESS transcription factor. In agreement, the expression of the kinase gene was strongly downregulated in the rpl-4 mutant. Comparing phenotypes of loss-of-function mutants, it was revealed that both genes are involved in stem growth, phyllotaxis, organization of the vascular tissues, and the replum, highlighting potential functional interactions. Expression of the RLCKVI_A2 gene from the constitutive 35S promoter could not complement the rpl-4 phenotypes, but exhibited a dominant positive effect on stem growth and affected vascular differentiation and organization. The results also indicated that the number of vascular bundles is independently regulated from stem thickness. Although our study cannot demonstrate the direct link between the RPL and RLVKVI_A2 genes, it highlights the significance of the proper developmental regulation of the RLCKVI_A2 promoter for balanced stem development.

This retrospective study aimed to compare risk factors for vascular calcification (VC) between pre-hemodialysis (HD) and prevalent HD adult patients while investigating associations with calcification biomarkers. Baseline data from 30 pre-HD and 85 HD patients were analyzed, in-cluding iPTH, vitamin D, FGF-23, fetuin-A, sclerostin and VC scores (Adragao method). Preva-lence of VC was similar in both groups, but HD patients had more frequent VC scores ≥6. Pre-HD patients were older, with higher prevalence of hypertension and less frequent use of calcium phosphate binders. Both groups showed similar patterns of hyperphosphatemia, low vitamin D, and iPTH. Fetuin-A levels were higher in pre-HD, while FGF-23 was elevated in HD patients. Higher VC risk in pre-HD patients was associated with male gender, older age, lower fetuin-A and higher sclerostin, lower ferritin and no vitamin D treatment, while in HD patients with higher sclerostin, FGF23 and urea, and lower iPTH. Conclusion. Progression of CKD from the pre-HD to the HD stage is accompanied by a decreased effect of the inhibitor and an increase in the promoter VC. However, mineral imbalance, hormonal regulation, treatment options, and patient-specific fac-tors should be considered. Further studies are needed to elucidate the underlying pathways.

Artificial Intelligence (AI) made its first appearance in 1956, and since then it has progressively introduced itself in healthcare system and patients’ information and care. AI functions can be grouped under the following headings: Machine Learning (ML), Deep Learning (DL), Artificial Neural Network (ANN), Convolutional Neural Network (CNN), Computer Vision (CV). Chronic limb-threatening ischemia (CLTI) represents the last stage of peripheral artery disease (PAD), and has increased over recent years, together with the rise in prevalence of diabetes and population ageing. Nowadays AI grants the possibility of developing new diagnostic and treatment solutions in the vascular field, given the possibility of accessing clinical, biological, and imaging data. By assessing the vascular anatomy in every patient, as well as the burden of atherosclerosis, and classifying the level and degree of disease, sizing and planning the best endovascular treatment, defining the perioperative complications risk, integrating experiences and resources between different specialties, identifying latent PAD, thus offering evidence-based solutions and guiding surgeons in the choice of the best surgical technique, AI challenges the role of the physician’s experience in PAD treatment.

Abstract: Background: Aging is an important risk factor for cardiovascular diseases and con-vincing data has shown that chronic low-grade inflammation, which develops with advanced age, contributes significantly to cardiovascular risk. Objectives: The present study aimed to use ¹⁸F-FDG/¹⁸F-NaF-PET/CT imaging to respectively gauge arterial inflammation and microcalcifi-cation in healthy elderly and to assess the potential benefits of a tyrosol- and hydroxytyrosol-rich diet on these two markers of atherosclerotic plaque fragility. Methods: Eleven healthy partici-pants (mean age 75 ± 5.67 years) were supplemented for 6 months with high polyphenol-rich extra virgin olive oil (HP-EVOO), extra virgin olive oil (EVOO), or refined olive oil (ROO). The partic-ipants underwent PET/CT imaging with ¹⁸F-FDG and ¹⁸F-NaF radiotracers at baseline and after 6 months. ¹⁸F-FDG and ¹⁸F-NaF uptakes were quantified using standardized uptake values (SUV) and were categorized based on artery calcification and olive oil type. Results: A total of 324 slices of the aortas of the imaged participants were analyzed for arterial inflammation and 327 slices were analyzed for microcalcification. 18F-FDG uptake was significantly higher in the non-calcified segments than in the calcified segments (SUVmax = 2.70  0.62 and SUVmax = 2.54  0.44, respectively, p<0.042). Conversely, the non-calcified segments displayed significantly lower 18F-NaF uptake than the calcified segments (SUVmax = 1.90 0.37 and 2.09  0.24, respec-tively, p<0.0001). The 6-month supplementation with HP-EVOO induced a significant reduction in 18F-FDG uptake in both the non-calcified (2.93  0.23 to 2.75  0.38, p<0.004) and calcified seg-ments of the aortas (2.25  0.29 to 2.15  0.19, p<0.02). 18F-NaF uptake was also significantly low-er in patients supplemented with HP-EVOO (SUVmax = 1.98  0.33 at baseline compared to 1.85  0.28, after the 6-month supplementation, p<0.004), whereas no significant effect was observed with EVOO. Conversely, participants supplemented with ROO displayed a significant increase in 18F-NaF uptake (SUVmax = 1.78  0.34 to 1.95  0.34, p<0.0001). Conclusion: The present study confirmed that ¹⁸F-FDG/¹⁸F-NaF-PET/CT imaging is a valuable approach for assessing age-related arterial damage and demonstrated that a phenolic compound-rich diet reduces both arterial inflammation and atherosclerotic lesion microcalcification.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to an infection. Recent in-vitro studies have investigated the effects of CytoSorb hemoadsorption on endothelial function in sepsis showing a reduction in markers of endothelial dysfunction, but to this day there is a lack of clinical studies showing whether this approach could actually positively influence the disturbed vascular barrier function in septic conditions. We analyzed the data on administered fluid volumes and catecholamines to determine the potential benefit of CytoSorb hemoadsorption therapy on endothelial function in a clinical scenario. We performed a retrospective analysis of 124 septic shock patients who had undergone adjunctive treatment with CytoSorb hemadsorption therapy. We collected volume requirements, and calculated the volume balance within different time periods to obtain an assumption on the stability of the vascular barrier. We also calculated catecholamine requirements. With regard to the entire study cohort our findings revealed a significant reduction in fluid balance at 72 hours (T72) compared to both baseline (T0) and the 24-hour mark (T24). Fluid balances from T72 – T0 were significantly lower in hospital survivors compared to non-survivors. Patients who received a second catecholamine had a significantly lower in-hospital mortality. Our findings showed that use of hemoadsorption therapy results in a reduced positive fluid balance paralleled by reductions in vasopressor needs suggesting a positive effect on endothelial integrity. These results, derived from a large cohort of patients, provide valuable insights that may greatly improve our understanding of the multiple effects of hemoadsorption treatment in septic shock patients.

The coastal wetlands of the Mediterranean area are among the most vulnerable and threatened environments due to human pressure and activities. Fragmentation is generally considered as one of the most driving factors in habitats loss. In this paper, we investigated the floristic composition, structure, conservation status, and trends of the habitat types sensu 92/43EEC Directive of a coastal wetland area in south-eastern Sicily (“Saline di Priolo” SAC). Based on 128 phytosociological surveys and several plant collections, a total of 304 taxa, 28 plant communities and 16 habitats have been identified. Furthermore, three new plant associations were described, including two in the wetland and one on the rocky coasts. For the classification of plant communities and habitats, a hierarchical clustering was performed by using Euclidean coefficient and beta-flexible algorithm. The life form spectrum of the current flora highlights the dominance of therophytes and hemicryptophytes. The Mediterranean species are largely prevailing with 123 taxa. The cartographic analysis performed with ArcGis 10.3 shows a radical reduction of the wetland habitats in the last 70 years, and a strong alteration of the ecological succession of the psammophilous-hygrophilous vegetation. Moreover, landscape configuration of the coastal vegetation and habitat types was well highlighted by a set of specific landscape metrics. In particular, our outcomes identify three habitats (2110, 2210, and 5220* EU code) with bad conservation status, among which one of priority conservation (Zyziphus arborescent matorral), that requires urgent restoration measures.

Brain arteriovenous malformations (BAVMs) are a critical concern in hereditary hemorrhagic telangiectasia (HHT) patients, carrying the risk of life-threatening intracranial hemorrhage. While traditionally seen as congenital, the debate continues due to documented de novo cases. Our primary goal was to identify the precise postnatal window in which deletion of the HHT gene Endoglin (Eng) triggers BAVM development. We employed SclCreER(+);Eng2f/2f mice, enabling timed Eng gene deletion in endothelial cells via tamoxifen. Tamoxifen was given at four postnatal periods: P1-3, P8-10, P15-17, and P22-24. BAVM development was assessed at 2-3 months using latex dye perfusion. We examined angiogenic activity by assessing vascular endothelial growth factor receptor 2 (VEGFR2) expression via Western blotting and Flk1-LacZ reporter mice. Longitudinal magnetic resonance angiography (MRA) was conducted up to 9 months. BAVMs emerged in 88% (P1-3), 86% (P8-10), and 55% (P15-17) of cases, with varying localization. Notably, the P22-24 group did not develop BAVMs but exhibited skin AVMs. VEGFR2 expression peaked in the initial 2 postnatal weeks, coinciding with BAVM onset. These findings support the “second hit” theory, highlighting the role of early postnatal angiogenesis, in initiating BAVM development in HHT type I mice.

Background: As the world tends to recover from the crisis created by the COVID-19 pandemic, vaccines have served as one of the most valuable tools of combat and large-scale immunization has helped to tide over the catastrophe. However, several reports of post -vaccination neurological complications around the globe have surfaced up in recent literature. This study was conducted with an aim to describe the spectrum of neurological ailments requiring hospitalization following COVID-19 vaccination.Methods: An ambispective observational study was carried out from March 2021 to February 2022 at a tertiary care institute with 25 patients who satisfied the inclusion criteria of a new onset neurological illness requiring hospitalization within 4 days to 42 days of vaccination. The patients were duly followed upto months after discharge.Results: The median age of the sample was 36 years and the median latency of onset of neurological events was 14 days. Guillain-Barré syndrome was documented in 11 patients; majority were acute motor axonal neuropathy (45.45%) followed by acute inflammatory demyelinating polyradiculoneuropathy (36.36%) and acute motor sensory axonal neuropathy (18.18%). Central nervous system demyelination was reported in 9 patients; two patients had acute disseminated encephalomyelitis, 2 patients were diagnosed with myelin oligodendrocyte glycoprotein antibody-associated disease, one patient with aquaporin-4 positive neuromyelitis optica spectrum disorder , and the rest were labelled as seronegative central nervous system demyelination. Vascular events were noted in 5 patients comprising of 2 cases each of cerebral venous sinus thrombosis and intracerebral hemorrhage and a case of Moyamoya angiopathy. All patients were conservatively managed and had a complete to partial recovery suggestive of a favorable outcome after 3 months. Conclusion: The pathomechanisms of post -vaccination neurological complications is yet to be elucidatedand any causal association attributable to vaccination warrants further research. Compared to the enormity of the vaccinated population, the adverse effects are miniscule to hinder and discourage vaccination.

Glaucoma, a group of diseases characterized by progressive retinal ganglion cell loss, cupping of the optic disc and by a typical pattern of visual field defects, is a leading cause of severe visual impairment and blindness worldwide. Elevated intraocular pressure (IOP) is the leading risk factor for glaucoma development. However, glaucoma can also develop at normal pressure levels. An increased susceptibility of retinal ganglion cells to IOP, systemic vascular dysregulation, endothelial dysfunction and autoimmune imbalances have been suggested to play a role in the pathophysiology of normal tension glaucoma. Since inflammation and oxidative stress play a role in all forms of glaucoma, the goal of this review article is to resent an overview on the inflammatory and prooxidant mechanisms in the pathophysiology of glaucoma and to discuss immunomodulatory and antioxidant treatment approaches.

This review highlights normal and tumor tissue vasculature, immunological changes, and phenotypic alterations (VIP model) as fundamental in abscopal interaction. In the stereotactic body radiotherapy (SBRT) and immunotherapy era, we are moving toward “immunological radiation planning,” i.e., radiation scheduling with abscopal effect as a vital endpoint as well. Towards this end, this manuscript presents specific diagrammatic tumor models to optimize the outcome of abscopal response in SBRT, based on the principle of the four R’s - Repair, Redistribution, Repopulation, and Reoxygenation of radiotherapy. The article highlights the importance of restricting the dose of SBRT to < 10 Gy per fraction, appropriate use of dose painting, and concomitant/delayed SBRT boost potential. Current literature indicates that immunotherapy should not precede but follow SBRT within seven days. Included is the review of integrating “cyclical” antiangiogenics, immune adjuvants/immune-metabolites as abscopal effect enhancers with SBRT. The importance of proton, carbon-ion SBRT is dealt with briefly. Proposed six fundamental requirements for augmentation of the abscopal cascade are listed. The existing exploratory results need to develop a definitive strategy amidst complex interactions in SBRT, immunotherapy, immune-adjuvants, & abscopal effects. We now have enough literature evidence to convert “abscopal by chance” to “abscopal by design” by harmonized combinatorial approach.

The present study aims to evaluate the ability of peonidin and petunidin-3-glucoside (Peo and Pet-3-glc) and their metabolites (vanillic acid; VA and methyl-gallic acid; MetGA), to prevent monocyte (THP-1) adhesion to endothelial cells (HUVECs), and to reduce the production of VCAM-1, E-selectin and VEGF in a stimulated pro-inflammatory environment, a pivotal step of atherogenesis. Tumor necrosis factor-α (TNF-α; 100 ng mL-1) was used to stimulate the adhesion of labelled monocytes (THP-1) to endothelial cells (HUVECs). Successively, different concentrations of Peo-3-glc and Pet-3-glc (0.02, 0.2, 2 and 20 µM) and VA and MetGA (0.05, 0.5, 5 and 50 µM) were tested. After 24 h, the production of VCAM-1, E-selectin and VEGF was quantified by ELISA kits, while the adhesion process was measured spectrophotometrically. Peo-3-glc and Pet-3-glc (from 0.02 to 20 µM) significantly (p<0.0001) decreased THP-1 adhesion to HUVECs at all concentrations (-37%, -24%, -30% and -47% for Peo-3-glc; -37%, -33%, -33% and -45% for Pet-3-glc). VA, but not MetGA, reduced the adhesion process at 50 µM (-21%; p<0.001). At the same concentrations, a significant (p<0.0001) reduction of E-selectin, but not VCAM-1, was documented. In addition, anthocyanins and their metabolites significantly decreased (p<0.001) VEGF production. The present findings suggest, that while Peo-3-glc and Pet-3-glc, but not their metabolites, reduced monocyte adhesion to endothelial cells through suppression of E-selectin production, VEGF production was reduced by both anthocyanins and their metabolites suggesting a role in regulation of angiogenesis.

Backgorund and Objectives: In this study, we aimed to evaluate and compare the changes in visual and structural outcomes in patients with intravitreal aflibercept (IVA)-resistant neovascular age-related macular degeneration (nAMD) switched to either intravitreal brolucizumab (IVBr) or intravitreal faricimab (IVF) injections in a clinical setting. Materials and Methods: This obser-vational clinical study included 20 eyes of 20 patients switched to brolucizumab and 15 eyes of 14 patients switched to faricimab for aflibercept-resistant nAMD. We measured the structural outcome (central macular thickness (CMT)) and the visual outcome (best-corrected visual acuity (BCVA); logMAR) as follows: just before the most recent IVA injection (B0), one month after the most recent IVA injection (B1), just before the first IVBr or IVF injection (A0), one month after (A1) and three months after (A3) the first IVBr or IVF injection. Results: BCVA showed significant im-provement at A1 (0.25 ± 0.34) and at A3 (0.19 ± 0.24) compared to A0 (0.38 ± 0.35) in IVBr group (p = 0.0156, p = 0.0166, respectively). CMT (μm) was significantly thinner at A1 (IVBr; 240.55 ± 51.82, IVF; 234.91 ± 47.29) and at A3 (IVBr; 243.21 ± 76.15, IVF; 250.50 ± 72.61) compared to at A0 (IVBr; 303.55 ± 79.18, IVF; 270.33 ± 77.62) in IVBr group (A1; p = 0.0093, A3; p = 0.0026) and in IVF group (A1; p = 0.0161, A3; p = 0.0093). There was no significant difference in BCVA and CMT improvement observed between two groups at any time point (p > 0.05 for all). Conclusion: Switching from aflibercept to either brolucizumab or faricimab has a significant anatomical ef-fect on eyes with aflibercept-resistant nAMD and both treatments appear to be effective short-term treatment options. There is a trend towards greater visual improvements and reductions in CMT with brolucizumab.

Fundus image registration plays a crucial role in the clinical evaluation of ocular diseases, such as diabetic retinopathy and macular degeneration, necessitating meticulous monitoring. The alignment of multiple fundus images enables the longitudinal analysis of patient progression, widening the visual scope, or augmenting resolution for detailed examinations. Currently, prevalent methodologies rely on feature-based approaches for fundus registration. However, certain methods exhibit high feature point density, posing challenges in matching due to point similarity. This study introduces a novel fundus image registration technique integrating U-Net for the extraction of feature points employing FIVES for its training and evaluation, a novel and large dataset for blood vessels segmentation, prioritizing point distribution over abundance. Subsequently, the method employs medial axis transform and pattern detection to obtain feature points characterized by the Fast Retina Keypoint (FREAK) descriptor, facilitating matching for transformation matrix computation. Assessment of the vessel segmentation achieves 0.7559 for Intersection Over Union (IoU), while evaluation on the Fundus Image Registration Dataset (FIRE) demonstrates the method’s comparative performance against existing methods, yielding a registration error of 0.596 for area under the curve, refining similar earlier methods and suggesting promising performance comparable to prior methodologies.

The signs and symptoms of Long COVID can be explained by a shortage of blood in the body and a resulting deficient blood flow through nearly all organs. This shortage arose during the acute phase of COVID19 by an increased breakdown of haematocytes, to which the liver responds by reducing the production of plasma, in order to prevent a too large decrease in haematocrit. In order to ensure the perfusion of organs that are directly necessary for survival, the body takes the emergency measure of diverting blood from other organs and tissues. The perfusion of the blood-producing organs is also affected by this distribution measure, which hinders the smooth recovery of the total blood volume. The body is stuck in this vicious circle: a shortage of circulating blood hinders the recovery of blood production. This explains the long duration of Long COVID. My proposed treatment of Long COVID focuses on the recovery of the correct volume of blood in the body of the right composition by the intravenous administration of donor blood products, starting with albumin concentrate. A trial treatment can be performed in any hospital without much additional preparations, and has a lower associated risk for the patient than analysing the total blood. A diagnosis ex juvantibus, by therapeutic response, is therefore preferable. I suspect that we will find a haematocrit value at the high extreme of the reference range, and an albumin value at the low extreme of the reference range in most Long COVID patients before the start of the treatment, because the liver can not keep up with the recovery of the red bone marrow.

We compared the functional and morphologic effects in the loading dose between patients with treatment-naïve neovascular age-related macular degeneration treated with either intravitreal aflibercept (IVA) or intravitreal faricimab (IVF) injection in clinical settings. This retrospective study included 30 eyes from 28 patients who started IVA treatment between June and September 2022 and 30 eyes from 29 patients who started IVF treatment between October 2022 and March 2023. The mean best corrected visual acuity (BCVA) significantly improved from pre-treatment after loading dose in the IVA group (from 0.46 ± 0.46 to 0.36 ± 0.37, p=0.0047) and not in the IVF group (from 0.46 ± 0.41 to 0.44 ± 0.45, p=0.60). The mean central retinal thickness (CRT) significantly improved in both groups. The proportion of eyes with residual exudative change was greater in the IVF group than in the IVA group at 2 months after the first treatment. (p=0.026) We further analyzed the patients who obtained complete resolution of exudative changes after the loading dose. The IVA group had a significant improvement in BCVA, whereas the IVF group did not p=0.0047 and 0.20, respectively) Although IVA and IVF significantly improved the CRT, the BCVA improved significantly in IVA group and not in IVF group.

Curcumin is a natural dietary polyphenol which that possesses potent anti-aging and neuroprotective properties through various mechanisms and signaling pathways. This study aimed to investigate the effect of curcumin on factors involved in neurogenesis and angiogenesis in the aged brain. Old female Wistar rats were divided into three equal groups (n=7): control, sham, and curcumin (received curcumin, i.p., 30 mg/kg and 5 days/week for 8 weeks) rats. Curcumin treatment caused a significant increase in the vascular endothelial growth factor (VEGF), Brain-derived neurotrophic factor (BDNF) and anti-apoptotic protein BCl-2 in the brains of aging rats but no significant effect on anti-apoptotic Bax protein. Additionally, curcumin attenuated brain lipid peroxidation and decreased transforming growth factor β1 (TGF-β1). These results suggested that curcumin possesses neuroprotective effects against brain aging, which were mediated by improvment in neurogenesis and angiogenesis. Also, curcumin could alleviate brain aging which may be due to attenuating oxidative stress, inhibiting apoptosis and down-regulating TGF-β1, which in turn enhances VEGF and BDNF. Therefore, curcumin has potential therapeutic value in the treatment of neurological apoptosis, neurogenesis and angiogenesis changes caused by brain aging.

Lesion studies are crucial in establishing brain-behavior relationships, and accurately segmenting the lesion represents the first step in achieving this. Manual lesion segmentation is the gold standard for chronic strokes. However, it is labor-intensive, subject to bias, and limits sample size. Therefore, our objective is to develop an automatic segmentation algorithm for chronic stroke lesions on T1-weighted MR images. Methods: To train our model, we utilized an open-source dataset: ATLAS v2.0 (Anatomical Tracings of Lesions After Stroke). We partitioned the dataset of 655 T1 images with manual segmentation labels into five subsets and performed a 5-fold cross-validation to avoid overfitting of the model. We used a deep neural network (DNN) architecture for model training. Results: To evaluate the model performance, we used three metrics that pertain to diverse aspects of volumetric segmentation including shape, location, and size. The Dice similarity coefficient (DSC) compares the spatial overlap between manual and machine segmentation. The average DSC was 0.65 (0.61- 0.67; 95% bootstrapped CI). Average symmetric surface distance (ASSD) measures contour distances between the two segmentations. ASSD between manual and automatic segmentation was 12mm. Finally, we compared the total lesion volumes and the Pearson correlation coefficient (ρ) between the manual and automatically segmented lesion volumes, which was 0.97(p-value &lt; 0.001). Conclusions: We present the first automated segmentation model trained on a large multicentric dataset. This model will enable automated on-demand processing of MRI scans and quantitative chronic stroke lesion assessment.

A key feature of pulmonary arterial hypertension (PAH) is the hyperplastic proliferation exhibited by the vascular smooth muscle cells from patients (HPASMC). The growth inducers FOXM1 and PLK1 are highly upregulated in these cells. The mechanism by which these two proteins direct aberrant growth in these cells is not clear. Herein we identify cyclin dependent kinase 1 (CDK1) also termed cell division cycle protein 2 (CDC2), as having a primary role in promoting progress of the cell cycle leading to proliferation in HPASMC. HPASMC obtained from PAH patients and pulmonary arteries from Sugen/hypoxia rats were investigated for their expression of CDC2. Protein levels of CDC2 were much higher in PAH than in cells from normal donors. Knocking down FOXM1 or PLK1 protein expression with siRNA or pharmacological inhibitors lowered the cellular expression of CDC2 considerably. However, knockdown of CDC2 with siRNA or inhibiting its activity with RO-3306 did not reduce the protein expression of FOXM1 or PLK1. Expression of CDC2 and FOXM1 reached its maximum at G1/S, while PLK1 reached its maximum at G2/M phase of the cell cycle. The expression of other CDKs such as CDK2, CDK4, CDK6, CDK7 and CDK9 did not change in PAH HPASMC. Moreover, inhibition via Wee1 inhibitor adavosertib or siRNAs targeting Wee1, Myt1, CDC25A, CDC25B, or CDC25C led to dramatic decreases in CDC2 protein expression. Lastly, we found CDC2 expression at the RNA and protein level to be upregulated in pulmonary arteries during disease progression Sugen/hypoxia rats. In sum, our present results illustrate that the increased expression of FOXM1 and PLK1 in PAH leads directly to increased expression of CDC2 resulting in a potentiated growth hyperactivity of PASMC from patients with pulmonary hypertension. Our results further suggest that the regulation of CDC2, or associated regulatory proteins, will prove beneficial in the treatment of this disease.

Background: This study tested the hypothesis that treatment of symptomatic, partial-thickness rotator cuff tear (sPTRCT) with fresh, uncultured, unmodified, autologous adipose derived regenerative cells (UA-ADRCs) isolated from lipoaspirate at the point of care is safe and more effective than corticosteroid injection. Methods: Subjects aged between 30 and 75 years with sPTRCT who did not respond to physical therapy treatments for at least six weeks were randomly assigned to receive a single injection of an average 11.4×10⁶ UA-ADRCs (in 5 mL liquid; mean cell viability: 88%) (n=11; modified intention-to-treat (mITT) population) or a single injection of 80 mg of methylprednisolone (40 mg/ml; 2 mL) plus 3 mL of 0.25% bupivacaine (n=5; mITT population), respectively. Safety and efficacy were assessed using the American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES), RAND Short Form-36 Health Survey and pain visual analogue scale (VAS) at baseline (BL) as well as three weeks (W3), W6, W9, W12, W24, W32, W40 and W52 post treatment. Fat-saturated T2 weighted magnetic resonance imaging of the shoulder was performed at BL as well as at W24 and W52 post treatment. Results: No severe adverse events related to the injection of UA-ADRCs were observed in the 12 months post treatment. The risks connected with treatment of sPTRCT with UA-ADRCs were not greater than those connected with treatment of sPTRCT with corticosteroid injection. However, one subject in the corticosteroid group developed a full rotator cuff tear during the course of this pilot study. Despite the small number of subjects in this pilot study, those in the UA-ADRCs group showed statistically significantly higher mean ASES total scores at W24 and W52 post treatment than those in the corticosteroid group (p < 0.05). Discussion: This pilot study suggests that the use of UA-ADRCs in subjects with sPTRCT is safe and leads to improved shoulder function without adverse effects. To verify the results of this initial safety and feasibility pilot study in a larger patient population, a randomized controlled trial on 246 patients suffering from sPTRCT is currently ongoing.

Discovery of inhibitors for endothelial-related transcription factors can contribute to the development of angiogenic therapies that treat diseases ranging from cardiovascular to cancer. The role of transcription factor Vezf1 in vascular development and regulation of angiogenesis has been defined by several earlier studies. Through construction of a computational model for Vezf1, work here has identified a novel small molecule drug capable of inhibiting Vezf1 from binding to its cognate DNA binding site. Using structure-based design and virtual screening of the NCI Diversity Compound Library, 12 shortlisted compounds were tested for their ability to interfere with the binding of Vezf1 to DNA using electrophoretic gel mobility shift assays. We identified one compound, T4, which has an IC50 of 20uM. Using murine endothelial cells, MSS31, we tested the effect of T4 on endothelial cell viability and angiogenesis by using tube formation assay. Our data show that addition of T4 in cell culture medium does not affect cell viability at concentrations lower or equal to its IC 50 but strongly inhibits the network formation by MSS31 in the tube formation assays. Given its potential efficacy, this inhibitor has significant therapeutic potential in several human diseases raging from wound healing to cancer.

Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality worldwide, including in Croatia. Since most patients have multiple disorders and diseases caused largely by the same risk factors, and as it is essential to approach each patient as a person with all disorders, today we are talking about a new paradigm - cardio-renal-metabolic (CKM) syndrome and cardio-renal-metabolic health, which necessarily includes brain health. Elevated systolic blood pressure, LDL cholesterol, smoking, obesity, diabetes, impaired renal function or chronic kidney disease, which all stem from insufficient physical activity, unhealthy diet with excessive intake of table salt, and air pollution, are the leading causes of overall morbidity and mortality from CKM diseases, especially mortality from CVD. Experts from various fields key to CKM health have written this document with the aim of integrating it as part of the national plan for the prevention of chronic non-communicable diseases with a focus on CVD, which should become mandatory and be based on the existing guidelines of professional societies.

Traumatic vascular injuries consist in direct or indirect damage to arteries and/or veins and accounts for 3% of all traumatic injuries. Typical consequences are hemorrhage and ischemia. Extremities vascular injuries can occur isolated or in association in major trauma with other organ injuries. They account for 1-2% of patients admitted to Emergency Department, for approximately 50% of all arterial injuries. Lower extremities are more frequently injured than the upper ones in adult population. The outcome of vascular injuries is strictly correlated to the environment and the time background. Treatment can be challenging notably in polytrauma because of the dilemma of which injury should be prioritized and treatment delay can cause disability or even death especially for limb vascular injury. Our purposes are to discuss the role of Computed Tomography Angiography (CTA) in the diagnosis of vascular trauma and its optimized protocol to achieve the definitive diagnosis, and to assess the radiological signs of vascular injuries and the possible pitfalls.

Pulmonary arteriovenous malformations (PAVMs) are vascular anomalies resulting in abnormal connection between pulmonary arteries and veins. In 80% of cases, PAVMs are present from birth, but clinical manifestations are rarely seen in childhood. These congenital malformations are typically associated with Hereditary Hemorrhagic Telangiectasia (HHT), a rare disease that affects 1 in 5,000/8,000 individuals. HHT disease is frequently caused by mutations in genes involved in the TGF-β pathway. However, approximately 15% of patients do not have a genetic diagnosis and, among the genetically diagnosed, more than 33% do not meet the Curaçao Criteria. This makes clinical diagnosis even more challenging in the pediatric age group. Here, we introduce an 8 years old patient bearing a severe phenotype of multiple diffuse PAVMs caused by an unknown mutation which ended in lung transplantation. Phenotypically, the case of study follows a molecular pattern HHT-like. Therefore, molecular biology and cellular functional analysis has been performed in primary endothelial cells (ECs) isolated from the explanted lung. The findings revealed a loss of functionality in lung endothelial tissue and a stimulation of endothelial to mesenchymal transition. Understanding the molecular basis of this transition could potentially offer new therapeutic strategies to delay lung transplantation in severe cases.

Research indicates compelling evidence of SARS-CoV-2 vertical transmission as a result of placental pathology. Background: This study offers an approach on histopathological and immunohistochemical placental observations from SARS-CoV-2 positive mothers compared negative ones. Methods: Out of 44 examined placentas, 24 were collected from patients with SARS-CoV-2 infection during pregnancy and 20 without infection. Results: The disease group showed strong SARS-CoV-2 positivity of the membranes, trophoblast and fetal villous macrophages. Most infections occurred during the third trimester of pregnancy (66.6%). Pathology revealed areas consistent with avascular villi (AV), thrombi in the chorionic vessels and umbilical cord in the positive group, suggesting fetal vascular malperfusion (FVM). Other observed features included infarction (17%), perivillous fibrin deposition (29%), intervillous fibrin (25%), delayed placental maturation (8.3%), chorangiosis (13%), chorioamnionitis (8.3%) and meconium (21%). The negative control group revealed only one case of placental infarction (5%), intervillous fibrin (5%), delayed placental maturation (5%), chorioamnionitis (5%) and two cases of meconium (19%). Our results were consistent with literature. Conclusions: This study shows SARS-CoV-2 has an impact on coagulation, demonstrated by fetal thrombotic vasculopathy (p=0.01) and fibrin deposition (p=0.01). Further research is necessary to establish whether SARS-CoV-2 is the cause of vascular pathologies during pregnancy.

Background: Takayasu Arteritis (TAK) increases vascular stiffness and arterial resistance. Hypertension and atherosclerosis lead to similar changes. We investigated possible differences in cardiovascular remodeling between these diseases and whether the differences are correlated with immune cell expression. Methods: Patients with active TAK arteritis were compared with age- and sex-matched hypertensive and atherosclerotic patients. In a subpopulation of TAK patients, Treg/Th17 cells were measured before (T0) and after 18 months (T18) of infliximab treatment. Echocardiogram, supraaortic Doppler ultrasound, and lymphocytogram were performed in all patients. Histological and immunohistochemical evaluation of the vessel wall was performed to compare the in vivo results. Results: TAK patients have increased aortic valve dysfunction and diastolic dysfunction. These data have been associated with uric acid levels. A significant increase in aortic stiffness was also noted and associated with peripheral T lymphocyte levels. CD3+CD4+ cell infiltrates were detected in the vessel wall samples of these patients. They had a lower mean percentage of Tregs at T0 than controls, but levels increased significantly at T18. Opposite results were found in Th17 cells. Finally, TAK patients were found to have an increased risk of atherosclerotic cardiovascular disease (ASCVD). Conclusion: Our data suggest that different pathogenic mechanisms of vessel damage, including atherosclerosis, underlie TAK patients compared with control subjects. The increased risk of ASCVD in TAK patients correlates directly with the degree of inflammatory cell infiltration in the vessel wall. Infliximab restores the normal frequency of Tregs/Th17 in TAK patients and allows a possible reduction of steroids and immunosuppressants.

It is widely known that vitamin D receptors have been found in neurons and glial cells and their highest expression is in the hippocampus, hypothalamus, thalamus and subcortical grey nuclei, and substantia nigra. The vitamin D helps the regulation of neurotrophin, neural differentiation and maturation, through the control operation of growing factors synthesis (ie NGF and GDNF), the trafficking of the septo-hyppocampal pathway, and the control of the synthesis process of different neuromodulators (such as Ach, DA, and GABA). Based on these assumptions, we have written this review in order to summarize the potential role of vitamin D in neurological pathologies. The work could be titanic, and might result very fuzzy and even incoherent, if we would not have conjectured to taper our first intentions and devoted our interests towards three mainstreams: demyelinating pathologies, vascular syndromes and neurodegeneration. Due to the lack of effective therapeutic options, a part from the disease modifying strategies, the role of different risk factors should be investigated in neurology, as far as their correction may lead to the improvement of the cerebral conditions. We have explored the relationships between the gene-environmental influence and long term vitamin D deficiency, as a risk factor for the development of different types of neurological disorders, along with the role and the rationale of therapeutic trials with vitamin D implementation.

Specific proteolytic cleavages turn on, modify, or turn off the activity of vascular endothelial growth factors (VEGFs). Proteolysis is most prominent among the lymph­angiogenic VEGF-C and VEGF-D, which are synthesized as precursors that need to undergo enzymatic removal of their C- and N-terminal propeptides before they can activate their receptors. The activating cleavage of VEGF-C is mediated by at least five different proteases: plasmin, ADAMTS3, prostate-specific antigen, cathepsin D, and thrombin. All of these proteases except for ADAMTS3 can also activate VEGF-D. Processing by different proteases results in distinct forms of the "mature" growth factors, which differ in affinity and receptor activation potential. The “default” VEGF-C-activating enzyme ADAMTS3 does not activate VEGF-D and therefore, VEGF-C and VEGF-D do function in different contexts. VEGF-C itself is also regulated in different contexts by different proteases. During embryonic development, ADAMTS3 activates VEGF-C. In contrast, thrombin and plasmin likely activate VEGF-C/-D during tissue injury-induced lymphangiogenesis, and PSA and cathepsin D perhaps during tumor-associated pathological lymphangio­genesis. Additionally, cathepsin D from saliva might activate latent VEGF-C/-D upon wound licking, thereby accelerating healing. Similar to tyrosine kinase receptors and VEGFs themselves, these activating proteases could be targeted to modulate angiogenesis and lymphangiogenesis in relevant diseases.

Electrospun fiber scaffolds are widely used in small diameter vascular tissue engineering because they mimick organizational structure and biological function of natural extracellular matrix. However, there is still one problem of low patency rate in the long term. The main reasons are the mismatch of compliance and the easy formation of thrombus. Therefore, it is very important to promote the rapid endothelialization of small diameter tissue engineering blood vessels by regulating the topological structure and biological properties of electrospun fiber scaffolds. Firstly, crimped polylactic acid (PLA) fibers were prepared by heat treatment to mimick the crimped structure and nonlinear mechanical properties of the elastic membrane of blood vessel wall. It improved effectively the aspect ratio of human umbilical vein endothelial cells (HUVECs) and promoted lateral alignment and growth. Then, crimped PLA fibers with three levels of pore structure were prepared by thermal induced phase separation, vapor induced phase separation and laser ablation to enhance the degree of HUVECs infiltrarion and realize patterned cell growth. Crimped PLA fibers with three levels of pore structure promote rapid endothelialization of blood vessels, which is of great significance to achieve long term patency rate of small diameter tissue engineering blood vessels.

Calpain is delineated as a superfamily of cysteine proteases containing a CysPC motif within their genes. Among the fifteen species of mammalian homologs, calpain-1 and -2, which are categorized as conventional isozymes, execute limited proteolysis in a calcium-dependent fashion. Accordingly, the calpain system participates in physiological and pathological phenomena, encompassing cell migration, apoptosis, skeletal muscle integrity, and synaptic plasticity. The dysregulation of the calpain system has been inextricably linked to a multitude of diseases, such as ischemic and degenerative diseases, rendering it a subject of profound interest in the fields of basic research and pharmaceutical development aimed at therapeutic interventions. Recent investigations have unveiled the contributions of both conventional and unconventional calpains to the pathogenesis of cardiometabolic disorders, such as atherosclerosis, diabetes, and hepatic diseases. Consequently, the present review accentuates the pivotal role of calpains in the complications of cardiometabolic diseases and embarks upon a discourse regarding calpains as molecular targets.

Alzheimer’s disease (AD) and vascular dementia (VaD) together contribute to almost 90% of all dementia cases leading to major health challenges of our time with a substantial global socioeconomic burden. While in Alzheimer’s disease, the improved understanding of Amyloid beta (Aß) mismetabolism and tau hyperphosphorylation as pathophysiological hallmarks has led to significant clinical breakthroughs, similar advances in VaD are lacking. We thus highlight here the importance of shared pathomechanisms found in AD and VaD: Endothelial damage, blood brain barrier (BBB) breakdown and hypoperfusion inducing oxidative stress, inflammation and demyelination and thus trophic uncoupling in the neurovascular unit. A dysfunctional endothelium and BBB lead to the accumulation of neurotoxic molecules and Aß through impaired clearance, which in turn leads to neurodegeneration. In this context we discuss possible neuropathological parameters, which might serve as biomarkers and thus improve diagnostic accuracy or reveal targets for novel therapeutic strategies for both forms of dementia.

Patients receiving hemodialysis are at risk of vascular access infections (VAIs) and particularly vulnerable to the opportunistic pathogen Staphylococcus aureus. Hemodialysis patients were also at increased risk of infection during the COVID-19 pandemic. Therefore, this study determined the change in the molecular and antibiotic resistance profiles of S. aureus isolates from VAIs during the pandemic compared with before. 102 S. aureus isolates were collected from VAIs between November 2013 and December 2021. Before the pandemic, 69 isolates were collected, 58%, 39.1%, and 2.9% from arteriovenous grafts (AVGs), tunneled cuffed catheters (TCCs), and arteriovenous fistulas (AVFs), respectively. The prevalence of AVG and TCC isolates changed to 39.4% and 60.6%, respectively, of 33 isolates during the pandemic. Sequence type (ST)59 was the predominant clone in TCC-methicillin-resistant S. aureus (MRSA) and AVG-MRSA before the pandemic, whereas the predominant clone was ST8 in AVG-MRSA during the pandemic. ST59 carrying the ermB gene was resistant to clindamycin and erythromycin. By contrast, ST8 carrying the msrA gene was exclusively resistant to erythromycin. The ST distribution for different VAIs changed from before to during the pandemic. The change in antibiotic resistance rate for different VAIs was closely related to the distribution of specific STs.

Branching patterns are ubiquitous in nature, consequently over the years many researchers have tried to characterize the complexity of their structures. Due to their hierarchical nature and resemblance to fractal trees, they are often thought to have fractal properties, however their non-homogeneity (i.e., lack of strict self-similarity) is often ignored. In this paper we review and examine the use of the box-counting and sandbox methods to estimate the fractal dimensions of branching structures. We highlight the fact that these methods rely on an assumption of self-similarity that is not present in branching structures due to their non-homogeneous nature. Looking at the local slopes of the log-log plots used by these methods reveals the problems caused by the non-homogeneity. Finally, we examine the role of the canopies (endpoints or limit points) of branching structures in the estimation of their fractal dimensions.

Despite the important role that the GH/IGF-I axis plays in vascular homeostasis, these kind of growth factors barely appear in articles addressing the neovascularization process. Currently, the vascular endothelium has turned to be considered as an authentic gland of internal secretion due to the wide variety of released factors and functions with local effect, including the paracrine/autocrine production of GH or IGF-I, for which the endothelium has specific receptors. In this comprehensive review, it will be described the evidence involving these proangiogenic hormones in arteriogenesis dealing with the arterial occlusion and making of them a potential therapy. It will be analyzed all those elements triggering the local and systemic production of GH/IGF-I and their possible role both in physiological and pathological conditions. The whole evidence will be combined with important data from the GHAS trial, in which GH or placebo were administrated to patients suffering from critical limb ischemia with no option for revascularization. We postulate that GH, alone or in combination, should be considered as a promising therapeutic agent for helping in the approach of the ischemic disease.

The RAINBOW Phase III study established the efficacy of the combination of paclitaxel and ramucirumab, a monoclonal antibody targeting VEGF receptor-2 (VEGF-R2), as second-line therapy. We retrospectively analyzed the data of patients treated with ramucirumab plus paclitaxel at our Institution to evaluate the impact of clinical heterogeneous figures on the efficacy and safety of this combination paclitaxel/ramucirumab in a real- life cohort of patients. After a median follow-up of 10.74 months, the median progression-free survival (PFS) was 5.8 months (95% CI: 3.04 - 5,63). Disease control rate (DCR) was 61% and the median duration of response (DOR) was 5.8 months. Median overall survival (OS) was 8.3 months. A trend toward better outcome was observed in HER2 positive patients. In multivariate analysis, nutritional status (p = 0.0001) and number of metastatic sites (p = 0.0266) resulted significantly related with longer PFS. Our analysis confirmed the efficacy and safety of the combination of ramucirumab with paclitaxel also in the real-life practice and the median PFS is significantly longer than that reported for Western population in previous studies. Subgroup analysis confirms the key-role of nutritional status as prognostic factor and suggests a possible interaction between EGF and angiogenesis pathways that deserves further investigations.

The impact of systemic vascular resistance (SVR) in hypertrophic (HCM) and amyloid cardio-myopathies has been seldom investigated. We studied pressure-strain loop derived myocardial work (MW) indices and SVR in patients with either sarcomere HCM or wild type transthyretin cardiac amyloidosis (ATTR), presented with heart failure and preserved left ventricular ejection fraction (HFpEF) at the outpatient cardiology units at Messina and Catania University Hospitals (Italy). Patients were in sinus rhythm and needed to have good transthoracic ultrasound imaging quality to undergo transthoracic strain-echocardiography. Other than conventional parameters, SVR and GWI (global work index) were measured. Based on cross-tabulation (a way to assess the ventricular-arterial coupling), the patients were then classified in 4 classes according to the cut-off values suggested by previous studies of 1,440 dyne/s/cm-5 for SVR (Stefadouros et al., 1973) and 1576 mm Hg% for GWI (Olsen et al., 2022). Sixty patients, 30 in each group, aged 61±16 years, 78% males, were studied. HCM were younger than ATTR patients and in a better clinical status (23% HCM vs 77% ATTR were NYHA class 3, p<0.001). Overall, 51 patients (85%) showed high SVR, of whom 21 were HCM (70%) and 30 ATTR (100%) (p<0.005). Both, SVR and GWI were impaired (the poorest class C) in 43% HCM patients (with greater left ventricular concentric hypertrophy) vs 93% of ATTR patients (in advanced NYHA class) (p<0.001). In conclusion, assessing SVR and GWI in HFpEF patients with HCM or ATTR can help clinicians to interpret the pathophysiological and clinical features of such complex diseases.

Vascular endothelial growth factors (VEGFs) are regarded as the key vasculogenic mediators in the human body, of which VEGF-A is considered as one of the important types. It is the major growth factor possessing increasing vascular permeability as well as angiogenesis properties. This article provides intuition into the different effects of VEGF-A on vessels in ovarian hyper stimulation syndrome (OHSS) which is defined as a complication of in-vitro fertilization for infertility treatment, and obesity, a universally health problem. These are two dissimilar pathways outcomes for VEGF-A effects, thereby This article reviews updated information about the mentioned disorders and reveals that how this kind of growth factor yields different results on vasculature by activating distinct intracellular signaling in endothelial cells.

Ral-interacting protein 76 (RLIP76) is a potential factor with vascular endothelial growth factor (VEGF) in the corpus luteum and tumor angiogenesis. RLIP76, VEGF, and hypoxia-inducible factor-1 (HIF-1) are proteins that activate angiogenic functions in tumor and endothelial cells. RLIP76 is a main factor in tumor growth, and VEGF is a major endothelial cell protein for angiogenesis. Also, RLIP76 regulates a small GTPase (R-Ras, oncogene) in cell survival, spreading, and migration. HIF-1 is important in the corpus luteum, tumor angiogenesis, and tumor growth. VEGF and HIF-1 regulate the angiogenic function of RLIP76, and RLIP76 controls vascular growth in endothelial and tumor cells. RLIP76, R-Ras, VEGF, and HIF-1 may be useful in the research of corpus luteum and cancer therapy and the study of mechanisms of tumor angiogenesis. This review will help to elucidate the roles of RLIP76/R-Ras and VEGF via HIF-1 in corpus luteum and tumor angiogenesis, tumorigenesis, and the specific regulation of RLIP76 in luteal, tumor, and endothelial cells. Thus, we reviewed the angiogenesis of the corpus luteum and tumor in the ovarian and tumor microenvironment.

In the recent years, tissue engineering researchers have exploited a variety of biomaterials that can potentially mimic extracellular matrix (ECM) for tissue regeneration. Natural cellulose, mainly obtained from bacterial (BC) and plant-based (PC) sources, can serve as a high potential scaffold material for different regenerative purposes. Natural cellulose has drawn the attention of researchers due to its advantage over synthetic cellulose in terms of availability, cost-effectiveness, perfusablility, biocompatibility, negligible toxicity, mild immune response and due to imitating native tissues. In this article, we will review the recent in vivo and in vitro studies aimed to assess the potentials of natural cellulose for the purpose of soft (skin, heart, veins, nerve, among others) and hard (bone and tooth) tissue engineering.

Vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) serve an essential role in tumor angiogenesis and have emerged as potential therapeutic targets in lung cancer. This review explores the significance of serum VEGF levels as a predictive biomarker in non-small cell lung cancer (NSCLC). The VEGF family, consisting of VEGFA, VEGFB, VEGFC, VEGFD, and placenta growth factor (PlGF), engages with specific receptors, including tyrosine kinase receptors (VEGFR-1, VEGFR-2, and VEGFR-3) and neuropilin receptors (NRP-1 and NRP-2), to promote angiogenesis and lymphangiogenesis. VEGF-A, the primary component of the VEGF family, binds to VEGFR-2 to stimulate endothelial cell proliferation and migration, while VEGF-B, VEGF-C, and VEGF-D interact with VEGFR-1 and VEGFR-3 to regulate tumor angiogenesis, lymphangiogenesis, and metastasis. The VEGF/VEGFR signaling pathway activates various downstream effectors, including phospholipase Cγ1, MAPK, and PI3K/Akt, which are essential for maintaining vascular homeostasis and promoting angiogenesis. In NSCLC, elevated serum VEGF levels have been observed, and the VEGF/VEGFR axis is frequently impaired, leading to irregular blood vessel formation and metastatic spread. Despite the development of anti-VEGF therapies, their impact on lung cancer outcomes has been limited. Further research is needed to optimize the effectiveness of these treatments and elucidate the potential of serum VEGF as a predictive biomarker in NSCLC.

Neonatal rats that receive sucrose during a critical postnatal period (CP, days 12 to 28) develop hypertension by the time they reach adulthood. Changes during this period could contribute to inflammation and be associated with variations in the vascular smooth muscle (VSMC) phenotype. We studied changes in inflammatory pathways that could underlie the expressions of the secretory phenotype in the VSMC in the thoracic aorta of rats that received sucrose during CP. We analyzed histological changes in the aorta and expressions of the COX-2, TLR4, iNOS, eNOS, MMP-2, -9, β-, α-actin, and TNF-α, IL-6 and IL-1β expressions, and fatty acids by gas chromatography. The aortic wall presented disorganization, decellularization, wavy elastic fibers and increase in the lumen area. The COX-2, TLR4 expressions, TNF-α and IL-6 were increased, but iNOS, MMP-2 and -9 tended to increase and eNOS and arachidonic acid tended to decrease, con increase in oleic acid in CP in comparison with control group. There is a transient hypertension at the end of the CP that is accompanied by an inflammation and a change in the phenotype of VSMC to the secretory phenotype. The inflammatory changes could act as epigenetic signals to determine the hypertension development during adulthood.

Cerebral cavernous malformations (CCM) or familial cavernomatosis is a rare, autosomal dominant, inherited disease characterized by the presence of vascular malformations consisting of blood vessels with an abnormal structure in the form of clusters. Based on the altered gene (CCM1/Krit1, CCM2, CCM3) and its origin (spontaneous or familial), different types of this dis-ease can be found. In this work we have isolated and cultivated primary endothelial cells (ECs) from peripheral blood of a type 1 CCM patient. Differential functional and gene expression pro-file of these cells were analyzed and compared to primary ECs from a healthy donor. The muta-tion of the familial index case consisted of a heterozygous point mutation in the position +1 splicing consensus between exons 15 and 16, causing failure in RNA processing and in the final protein. Furthermore, gene expression analysis by quantitative PCR revealed a decreased ex-pression of genes involved in intercellular junction formation, angiogenesis, and vascular ho-meostasis. Cell biology analysis showed that CCM1 ECs were impaired in angiogenesis and cell migration. Taken together, the results obtained suggest that the alterations found in CCM1 ECs are already present in the heterozygous condition, suffering from vascular impairment and someway predisposed to vascular damage.

Prediabetes, a pivotal phase in glucose metabolism between normalcy and diabetes, exerts a profound influence on the aging process and the risk of age-related diseases. This comprehensive review delves into the intricate web of blood-based biomarkers that collectively expedite senescence, marking the transition from a state of health to age-related complications. Key findings underscore the significance of diverse biomarkers, such as telomere length, p16INK4a, senescence-associated secretory phenotype (SASP) factors, DNA methylation clocks, advanced glycation end products (AGEs), inflammatory and oxidative stress markers, circulating hormones, and additional factors like folate, B12, osteocalcin, and more. Not only do these biomarkers serve as indicators of senescence, but they actively fuel chronic inflammation, oxidative stress, and metabolic dysregulation, all of which contribute to accelerated aging. The implications of this understanding are profound, as prediabetes emerges as a critical period in an individual's life, influencing various physiological systems, including the vascular and neural systems, metabolic functions, hormonal regulation, and bone health. Recognizing the profound influence of prediabetes on senescence provides a foundation for personalized intervention strategies to mitigate age-related complications and promote healthy aging. Future research directions call for a more diverse array of biomarkers, in-depth exploration of their roles, and the development of tailored precision medicine strategies to ensure a holistic understanding and effective management of prediabetes-induced senescence and its implications for aging. This knowledge has far-reaching implications for public health and clinical practice, emphasizing the need for early detection and intervention in prediabetic individuals to enhance the quality of life in an aging population with diverse needs.

The plant graft healing process is an intricate development influenced by numerous endogenous and environmental factors. This process involves the histological changes, physiological and biochemical reactions, signal transduction, and hormone exchanges in the grafting junction. Studies have shown that applying exogenous plant growth regulators can effectively promote the graft healing process and improve the quality of grafted plantlets. However, the physiological and molecular mechanism of graft healing formation remains unclear. In our present study, transcriptome changes in the melon and cucurbita genomes were analyzed between control and NAA treatment, and we provided the first view of complex networks to regulate graft healing under exogenous NAA application. The results showed that the exogenous NAA application could accelerate the graft healing process of oriental melon scion grafted onto squash rootstock through histological observation, increase the SOD, POD, PAL, and PPO activities during graft union development and enhance the contents of IAA, GA3, and ZR except for the IL stage. The DEGs were identified in the plant hormone signal-transduction, phenylpropanoid biosynthesis, and phenylalanine metabolism through transcriptome analysis of CK vs. NAA at the IL, CA, and VB stage by KEGG pathway enrichment analysis. Moreover, the exogenous NAA application significantly promoted the expression of genes involved in the hormone signal-transduction pathway, ROS scavenging system, and vascular bundle formation.

In this study we discuss critical issues in modelling the structure and function of lymph nodes (LNs), with emphasis on how LN physiology is related to its multi-scale structural organization. In addition to macroscopic domains such as B-cell follicles and the T cell zone, there are vascular networks which play a key role in the delivery of information to the inner parts of the LN, i.e., the conduit and blood microvascular networks. We propose object-oriented computational algorithms to model the 3D geometry of the fibroblastic reticular cell (FRC) network and the microvasculature. Assuming that a conduit cylinder is densely packed with collagen fibers, the computational flow study predicted that the diffusion should be a dominating process in mass transport than convective flow. The geometry models are used to analyze the lymph flow properties through the conduit network in unperturbed- and damaged states of the LN. The analysis predicts that elimination of up to 60–90 % of edges is required to stop the lymph flux. This result suggests a high degree of functional robustness of the network.

The intracellular calcium dynamics in vascular endothelial cells (VECs) in response to wall shear stress (WSS) and/or adenosine triphosphate (ATP) have been commonly regarded as an important factor in regulating VEC function and behavior including proliferation, migration and apoptosis. However, the effects of time-varying ATP signals have been usually neglected in the past investigations in the field of VEC mechanobiology. In order to investigate the combined effects of WSS and dynamic ATP signals on the intracellular calcium dynamic in VECs, a Y-shaped microfluidic device, which can provide the cultured cells on the bottom of its mixing micro-channel with stimuli of WSS signal alone and different combinations of WSS and ATP signals in one single micro-channel, is proposed. Both numerical simulation and experimental studies verify the feasibility of its application. Cellular experimental results also suggest that a combination of WSS and ATP signals rather than a WSS signal alone might play a more significant role in VEC Ca²⁺ signal transduction induced by blood flow.

Age-related macular degeneration (AMD) is an eye disease and the most common cause of vision loss in the Western World. In its advanced stage, AMD occurs in two clinically distinguished forms: dry and wet, but only wet AMD is treatable. However, the treatment based on repeated injections with vascular endothelial growth factor A (VEGFA) antagonists may at best stop the disease progression and prevent or delay vision loss but without an improvement of visual dysfunction. Moreover, it is a serious mental and financial burden for patients and may be linked with some complications. The recent first success of intravitreal gene therapy with ADVM-022, which transformed retinal cells to continuous production of aflibercept, a VEGF antagonist, after a single injection, has opened a revolutionary perspective in wet AMD treatment. Promising results obtained so far in other ongoing clinical trials support this perspective. In this narrative/hypothesis review, we present basic information on wet AMD pathogenesis and treatment, the idea of gene therapy in retinal diseases, update evidence on completed and ongoing clinical trials with gene therapy for wet AMD, and perspectives on the road to the clinic of “one and done” therapy for wet AMD to replace a lifetime of injections. Gene editing targeting the VEGFA gene is also presented as another gene therapy strategy to improve wet AMD management.

A monolayer of endothelial cells (ECs) lines the lumen of blood vessels and as such provides a semi-selective barrier between the blood and the interstitial space. Compromise of the lung EC barrier due to inflammatory or toxic events may results in pulmonary edema, which is a cardinal feature of acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS). The EC functions are controlled, at least in part, via epigenetic mechanisms mediated by histone deacetylases (HDACs). Zinc-dependent HDACs represent the largest group of HDACs and are activated by Zn2+. Members of this HDAC group are involved in the epigenetic regulation primarily via modifying the structure of chromatin upon removal of acetyl groups from histones. In addition, they can deacetylate many non-histone histone proteins, including those located in extra nuclear compartments. Recently, the therapeutic potential of inhibiting zinc-dependent HDACs for EC barrier preservation has gained momentum. However, the role of specific HDAC subtypes in EC barrier regulation remains largely unknown. This review aims to provide an update on the role of zinc-dependent HDACs in endothelial dysfunction and its related diseases. We will broadly focus on biological contributions, signaling pathways and transcriptional roles of HDACs in endothelial pathobiology associated mainly with lung diseases and we will discuss the potential of their inhibitors for lung injury prevention.

Polymorphism of vitamin D3 receptor (VDR), has been associated with low bone mineral density and other immune and metabolic disorders; however, its impact on mortality of female dialysis patients is not well studied. This study aimed to identify bone mass-related factors, VDR gene polymorphism, and their interaction with morbid conditions that could influence all-cause mortality. In 246 female dialysis patients, age 43±11 years on continuous ambulatory dialysis peritoneal; 48%, haemodialysis; 23% and automated peritoneal dialysis; 29%. Tscore, Ca, PO4, albumin, hs-CRP, osteoprotegerin, fetuin, osteocalcin, iPTH, PINP and β-CTx were measured. PCR products were digested with Bsml to analyze VDR polymorphisms. Patients n=229; were followed for a median of 17 (15-31) months; 42 patients died. Bsml polymorphism, bb=64% and BB+Bb=36%. Hs-CRP was the risk of death in multivariate Cox Analysis. Patients with bb and inflammation had a higher risk of death (HR 2.48, 95% CI 1.08-5.68) persisted after adjustment for age, diabetes and iPTH (HR 2.33; 95% CI, 1.01-8.33) and after further adjustment for vintage, albumin, osteoprotegerin and vitamin D therapy (HR 3.49; 95% CI, 1.20-10.9). We may conclude that the presences of the bb genotype of VDR and inflammation have additive effects on all cause-mortality in females in CAPD, APD, and HD patients.

Tunneled central venous catheters (CVC) are mainly considered as rescue vascular access option in dialysis but still used in about one quarter of prevalent patients worldwide as being associated with poor performances and higher risks. Study design. In this retrospective single-center study, we aimed to report on clinical performances achieved with high-flow tunneled CVC (DualCath, DCath) and compared it with arteriovenous accesses (AVAs; AV fistula, AV graft, Thomas Shunt) in a hospital-based dialysis unit. Methods. Sixty-eight stage 5 chronic kidney disease dialysis dependent patients (CKD5D) receiving high volume hemodiafiltration were followed-up for 30 months. The study consisted of two phases: baseline cross-sectional and longitudinal follow-up of key performance indicators. Clinical performances consisting of effective blood flow and blood volume, recirculation, urea and ionic Kt/V and total Kt, ultrafiltration volume and percent reduction of ß2-M were measured monthly as part of quality control in our unit. Results. At baseline, effective blood flow with DCath was close to 400 ml/min, similar to AVAs. Recirculation with DCath (7%, 6-13%) was higher than AVAs. Diffusive dialysis dose delivered with DCath (spKt and eKt/V) and convective dialysis dose achieved with DCath were slightly lower than AVAs, but still much higher than recommended by guidelines. Percent reduction of ß2-M achieved with DCath was also 4 to 10% lower than AVAs. On longitudinal follow-up, main clinical performance indicators of DCath (total Kt and total ultrafiltration volume, L/session) were maintained very stable over time and close to those achieved with AVAs. Conclusions. As shown in this study, high-flow DualCath tunneled two single lumen silicone catheters may be used to deliver high volume hemodiafiltration in a reliable and consistent manner without compromising clinical performances. These results rely from the specific design of the two silicone cannulas and the strict adherence to best catheter practices.

Vascular calcification (VC) is associated with increased cardiovascular risks in patients with chronic kidney disease (CKD). Sodium-glucose cotransporter 2 inhibitors, like empagliflozin, can improve cardiovascular and renal outcomes. We assessed the expression of Runt-related transcription factor 2 (Runx2), interleukin (IL)-1β, IL-6, AMP-activated protein kinase (AMPK), nuclear factor erythroid-2-related factor (Nrf2), and heme oxygenase 1 (HO-1) in inorganic phosphate–induced VC in mouse VSMCs to investigate the mechanisms underlying empagliflozin’s therapeutic effects. We evaluated biochemical parameters, mean artery pressure (MAP), pulse wave velocity (PWV), transcutaneous glomerular filtration rate (GFR), and histology in an in vivo mouse model with VC induced by an oral high-phosphorus diet following a 5/6 nephrectomy in ApoE−/− mice. Compared to the control group, empagliflozin-treated mice showed significant reductions in blood glucose, MAP, PWV, and calcification, as well as increased calcium and GFR levels. Empagliflozin inhibited osteogenic trans-differentiation by decreasing inflammatory cytokine expression and increasing AMPK, Nrf2, and HO-1 levels. Empagliflozin mitigates high phosphate–induced calcification in mouse VSMCs through the Nrf2/HO-1 anti-inflammatory pathway by activating AMPK. Animal experiments suggested that empagliflozin reduces VC in CKD ApoE−/− mice on a high-phosphate diet.

The potentially active A subunit of coagulation factor XIII (FXIII-A) is an intracellular transglutaminase expressed in various cell types including platelets and monocytes/macrophages. It is involved in stabilizing protein structures by cross-linking through Nε-(?-L-glutamyl)-L-lysyl iso-peptide bonds. Macrophages are major cellular constituents of the atherosclerotic plaque and are important in determining its structural/functional features. Two of their important functions are the accumulation of oxidized LDL in the lipid core, and by cross-linking structural proteins they may stabilize the plaque and protect the thrombi of atherogenic origin against fibrinolytic degradation. It is important to know whether these functions operate in parallel utilizing the same cellular compartments. First, we showed that monocyte-derived human macrophages significantly increase their FXIII-A content when up-taking oxidized LDL. This phenomenon is very likely independent of the process of transformation into foam cells, as the transformation of vascular smooth muscle cells into foam cells fails to result in the expression of FXIII-A. FXIII containing macrophage-like cells are abundant in the plaque and FXIII-A is also present in the extracellular core. Several cells co-stained for FXIII-A and for Oil Red O suggest that expression of FXIII-A and lipid up-take are common features of macrophages present in the atherosclerotic plaque.

Pericytes are increasingly recognized as being important in the control of blood-brain barrier permeability and vascular flow. Research on this important cell type has been hindered by widespread confusion regarding the phenotypic identity and nomenclature of pericytes and other perivascular cell types. In addition, pericyte heterogeneity and mouse-human species differences have contributed to confusion. Herein we summarize our present knowledge on the identification of pericytes and pericyte subsets in humans, primarily focusing on recent findings in humans and nonhuman primates. Precise identification and definition of pericytes and pericyte subsets in humans may help us to better understand pericyte biology and develop new therapeutic approaches specifically targeting disease-associated pericyte subsets.

It has become practically impossible to survey the literature on cells derived from adipose tissue with the aim to apply them in regenerative medicine. The aim of this review is to provide a jump start to understanding the potential of UA-ADRCs (uncultured, unmodified, fresh, autologous adipose derived regenerative cells isolated at the point of care) in regenerative medicine. We show that serious and adequate clinical research demonstrates that tissue regeneration with UA-ADRCs is safe and effective. ADRCs are neither 'fat stem cells' nor could they exclusively be isolated from adipose tissue, as ADRCs contain the same adult (depending on the definition) pluripotent or multipotent stem cells that are ubiquitously present in the walls of small blood vessels. Of note, the specific isolation procedure used has significant impact on the number and viability of the cells and hence on safety and efficacy of UA-ADRCs. Furthermore, there is no need to further separate adipose-derived stem cells (ASCs) from ADRCs if the latter were adequately isolated from adipose tissue. Most importantly, UA-ADRCs have the physiological capacity to adequately regenerate tissue without need for manipulating, stimulating and/or (genetically) reprogramming the cells for this purpose. Tissue regeneration with UA-ADRCs fulfills the criteria of homologous use.

Pachychoroid neovasculopathy (PNV) is a pachychoroid-spectrum disease. As blood circulation throughout the choroid may be involved in PNV pathogenesis, analysis using ultra-wide-field (UWF) fundus imaging is crucial. We evaluated choroidal thickness after half-fluence photodynamic therapy (PDT) combined with intravitreal aflibercept injection for PNV using UWF swept-source optical coherence tomography. Seventeen eyes with PNV that underwent half-fluence PDT with adjuvant single intravitreal aflibercept injection were analyzed. To compare choroidal thicknesses in the central and peripheral choroids, we set subfields <3, <9, and 9–18 mm from the fovea. The <9- and 9–18-mm subfields were divided into four quadrants. Choroidal thickness in each subfield decreased significantly after half-fluence PDT (P<0.001); this reduction was more pronounced in the central area. We also investigated the relationship between the dominant side of the deep choroidal veins that harbor choroidal vein efflux from the macula. When choroidal thickness in the supratemporal and infratemporal 9x9-mm subfields were evaluated, the ratio of choroidal thickness reduction was not significantly different between the dominant and non-dominant sides. The dominant side was not associated with the extent of choroidal thickness reduction in PNV. In conclusion, half-fluence PDT caused thinning of the entire choroid, especially in the central area, in PNV.

Background: Developing an efficient and standardized method to isolate and characterize adipose-derived stem cells (ASCs) from the stromal vascular fraction (SVF) of the adipose tissue for clinical application represents one of the major challenges in cell therapy and tissue engineering. Methods: In this study, we proposed an innovative, non-enzymatic protocol to collect clinically useful ASCs within freshly isolated SVF from adipose tissue by centrifugation of the infranatant portion of lipoaspirate and to determine the characteristic cytofluorimetric pattern, prior to in vitro culture. Results: The SVF yielded a mean of 73,32 \pm\ 10,89% cell viability evaluated with CALCEINA-FITC, i.e. cell-permeant dye. The ASCs were positive for PC7-labeled mAb anti-CD34 and negative for both PE-labeled mAb anti-CD31 and APC-labeled mAb anti-CD45. The frequency of ASCs estimated according to the panel of cell surface markers used was 51,06%\ \pm 5,26% versus the unstained ASCs subpopulation that was 0,74%\pm0,84% (P<0.0001). The ASCs events/\muL were 1602,13/\muL \pm 731,87/\muL. Conclusion: Our findings suggested that ASCs found in freshly isolated adipose SVF obtained by centrifugation of lipoaspirate can be immunophenotypically identified with a basic panel of cell surface markers. These findings aimed to provide standardization and contribute to reducing the inconsistency on reported cell surface antigens of ASC derived from the existing literature.

Objective: Both conventional penile venous surgery for erection restoration and surgical therapy for penile augmentation have been controversial. Based on De Novo penile fibrovascular assembly, we report on innovative penile venous stripping (PVS) and factual penile girth enhancement (FPGE). Methods: From 2013 to 2023, 18 men underwent PVS and FPGE, all confirmed with veno-occlusive dysfunction (VOD). PVS involves stripping erection-related veins, primarily one deep dorsal vein and a pair of cavernosal veins, after ligating each emissary vein closest to the outer tunica albuginea using 6-0 nylon. FPGE was performed along the tunica albuginea bilaterally; then, the two tunic defects were repaired with a 70.0x30.0 mm venous stripe and covered with either autologous venous walls (AVW, n=10) or Surgiform (SF, n=8). The penile girth was measured, and radio-opaque contrast was used to compare intracorporeal retention. The abridged 5-item version of the International Index of Erectile Function (IIEF-5) score and the Erection Hardness Scale (EHS) were used yearly during follow-up via the Internet. Results: The follow-up period was 5.3±1.5 years. Radiopacity was consistently enhanced. Although there was indifference between AVW and SF, there was a significant improvement (both P＜ 0.01) in IIEF-5 and EHS scores (9.7±2.8 vs. 20.8±2.3; 1.7±0.6 vs. 3.2±0.2, respectively). Both the diameters of the glans and penile shaft increased (28.0±2.3mm and 28.3±2.1mm vs 35.3±2.2mm and 36.3±2.1mm respectively). The satisfaction rate was 81.3% (13/16). Conclusions: This novel combination of PVS and FPGE is promising, although further validation requires a larger sample size.

Introduction: ophthalmological assessment of the retinal circulation and the level of VEGF-A is currently considered a non-invasive and safe diagnostic tool to assess the peripheral microcircu-lation Objective: to study retinal hemodynamics and VEGF-A levels in patients with type 1 diabetes mellitus after pancreas transplantation Settings and Design: A prospective, single-stage, single-center, non-randomized clinical trial Methods: 79 patients (158 eyes) with type 1 diabetes mellitus and end-stage diabetic nephropathy participated in the study. Patients were divided into 3 groups: group 1, potential recipients of pancreas and kidney transplant from the waiting list; group 2, patients after kidney transplanta-tion; and group 3, patients after simultaneous pancreas and kidney transplantation. Ophthalmo-logical examination included measuring the macular hemoperfusion density. The level of VEGF-A was examined in the patients' tear by enzyme immunoassay. Results: retinal hemoperfusion density and VEGF-A concentration were expected to correlate with the severity of diabetic changes in the fundus of patients. A lower index of retinal hemoperfusion density and a high level of VEGF-A were noted in patients with proliferative ret-inopathy and macular oedema. Group 3 showed the lowest frequency of the active phase of the proliferative retinopathy and retinal macular oedema, characterized by a higher retinal hemoperfusion density in the foveal and the parafoveal zone of the macular region, and low VEGF-A concentration in tear. Conclusion: measurement of retinal hemoperfusion density and determination of tear VEGF-A concentration are informative objective methods for diagnosing the severity of diabetic changes of the fundus.

ABSTRACT Introduction: Traditional penile venous surgery and enhancement have been controversial. Based on De Novo penile fibrovascular assembly, we report on penile venous stripping (PVS) and factual penile girth enhancement (FPGE). Methods: From 2013 to 2023, 18 men underwent PVS and FPGE, all confirmed with veno-occlusive dysfunction (VOD). PVS involves the stripping of erection-related veins. FPGE was performed along the tunica albuginea bilaterally; then, the two tunic defects were repaired with a 70.0x30.0 mm venous stripe and covered with either autologous venous walls (AVW, n=10) or Surgiform (SF, n=8). The penile girth was measured, and radio-opaque contrast was used. The abridged 5-item version of the International Index of Erectile Function (IIEF-5) score and the Erection Hardness Scale (EHS) were used yearly during follow-up via the Internet. Results: The follow-up period was 5.3±1.5 years. Radiopacity was consistently enhanced. Although there was indifference between AVW and SF, there was a significant improvement (both P＜0.01) in IIEF-5 and EHS scores (9.7±2.8 vs. 20.8±2.3; 1.7±0.6 vs. 3.2±0.2, respectively). Both the diameters of the glans and penile shaft increased (28.0±2.3mm and 28.3±2.1mm vs 35.3±2.2mm and 36.3±2.1mm respectively). The satisfaction rate was 81.3% (13/16). Conclusions: This novel combination of PVS and FPGE is promising, although a larger sample size is needed for further validation.

Pulmonary hypertension (PH) is a severe and chronic disease characterized by increased pulmonary vascular resistance and remodeling often precipitating right-sided heart dysfunction and death. Although the condition is progressive and incurable, current therapies for the disease focus on multiple different drugs and general supportive therapies to manage symptoms and prolong survival, ranging from medications more specific to pulmonary arterial hypertension (PAH) to exercise training. Moreover, there are multiple studies exploring novel experimental drugs and therapies including unique neurostimulation, to help better manage the disease. Here we provide a narrative review focusing on current PH treatments that target multiple underlying biochemical mechanisms, including but not limited to imbalances in vasoconstrictor-vasodilator and autonomic nervous system function, inflammation, and bone morphogenic protein (BMP) signaling. We also focus on the potential of novel therapies for managing PH, focusing on multiple types of neu-rostimulation including acupuncture. Lastly, we also touch upon the disease’s different subgroups, clinical presentations and prognosis, diagnostics, demographics, and cost.

Longitudinal image registration of pulmonary computed tomography (PCT) images may serve as an essential tool for investigating the relationship between radiation dose distribution and the occurrence and phenotype of radiation-induced lung disease (RILD). Although numerous longitudinal registration algorithms have been developed for PCT, most similarity-based approaches are not suitable for PCT involving RILD due to the complex tissue variation between two PCT images. Moreover, conventional feature-based approaches might fail to find a sufficient number of matched pairs of feature points due to the disparate lung deformation caused by breathing and RILD. To overcome the challenges resulting from RILD, component structure coherence point drift (CSCPD) was proposed to establish a deformation model by decomposing the chest into several components and matching them with individual parameters based on coherence point drift (CPD). Moreover, a regional vascular point matching (RVPM) algorithm was proposed to generate a vascular subtree and to substantially increase the number of corresponding pairs between two images. Eventually, the components were recomposed and aligned by a thin plate spline algorithm. A performance assessment on 15 pairs of PCT images of patients with RILD yielded recall and precision values of 0.85 and 0.89 for RVPM, respectively. Moreover, the target registration error of CSCPD with RVPM (2.3 ± 1.79) was significantly better than that of conventional CPD with RVPM (2.95 ± 1.89) and conventional CPD (5.04 ± 2.87). Therefore, the proposed registration system is robust enough to address the disparate deformation of lungs with RILD, and it improves registration accuracy within the parenchyma.

Excessive intracellular glucose in insulin independent tissues including nerve, nephron, lens and retina invites mishandling of metabolism of glucose resulting in a background of increased oxidative stress, advanced glycation end products (AGE) formation, lipid peroxidation and failure of antioxidant defense systems in type 2 diabetes mellitus (T2DM). All these detrimental biochemical anomalies ultimately attack biological membranes and especially capillary beds of retina and glomerulus of kidney, resulting in break-down of inner blood-retinal i.e. initiation of diabetic retinopathy (DR). If these disarrays are corrected to a large extent, development of DR can be avoided or delayed. In this prospective clinical trial, 185 patients with T2DM who received B-vitamins, vitamin-C, and E along with anti-diabetic medication for five years, demonstrated a slower rate of the development of DR and reduced abnormal biochemical mediators like reactive oxygen species (ROS), malondialdehyde (MDA), AGE, and vascular endothelial growth factor (VEGF) compared to 175 T2DM individuals who were treated with only anti-hyperglycemic drugs.

This systematic examines research into patients diagnosed with retinal vascular occlusive diseases (RVODs) secondary to coronavirus disease 2019 (COVID-19) infection or vaccination. RVODs include central retinal vein occlusion, branch retinal vein occlusion, central retinal artery occlusion, and branch retinal artery occlusion. Previous studies have posited a possible link between RVODs and COVID-19. RVODs are of two types: retinal vein occlusion and retinal artery occlusion. These disorders develop when retinal blood vessels become clogged by thrombi or fat deposition. The retina is an important component of the visual apparatus. Its photoreceptors are stimulated by the light hitting the eye and record its pattern. The retina then relays this visual information to the brain. When retinal blood vessels become clogged, the damage can range from slightly reduced vision to complete blindness. COVID-19 causes endothelial dysfunction and increased levels of von Willebrand factor antigens in the blood. Elevation of von Willebrand factor activates the coagulation process and platelet aggregation. The treatment methods and visual prognosis in COVID-19-related RVODs do not differ from conventional RVODs. However, ophthalmologists need to be aware of the possible relationship and should consider RVODs when they encounter patients with vision loss following COVID-19 infection or vaccination.

Background: The ageing process starts in the center of the face, in the periocular region and around the mouth, with a combination of volume loss and tissue descent, wrinkles deepen, and loss of skin structure and quality. Recently, several studies proved the efficacy of therapies based on the autologous adipose tissue grafting that leverages the properties of stromal vascular fraction (SVF) and adipose derived mesenchymal stem cells (ADSCs) to accelerate the regenerative processes of the skin. This study aimed to verify the ability of the guided Superficial Enhanced Fluid Fat Injection (SEFFI) in the facial area to correct volume loss and skin aging and proved the very low rate of complications of this standardized procedure . Methods: we retrospectively collected data from 2,365 procedures performed in Italian centers between 2019 and 2021. Guided SEFFI was performed alone or combined with cosmetic treatments, including the use of hyaluronic acid filler, suspension threads, synthetic calcium hydroxylapatite, botulin toxin, and microneedling. Results: SEFFI was used alone in more than 60% of the patients, and in all face areas. In about one tenth of patients SEFFI was combined with botulin toxin treatment or hyaluronic acid filling. Other procedures were used more rarely. Ecchymosis in the donor or injection sites was the most frequent event, and yet observed in only 14.2% and 38.6% of patients, respectively. Conclusions: The SEFFI technique is standardized and minimally invasive, leading to very few complications. It can be a promising antiaging medical treatment that combines effectiveness, safety, and simplicity.

Current clinical treatment options for symptomatic, partial-thickness rotator cuff tear (sPTRCT) offer only limited potential for true tissue healing and improvement of clinical results. In animal models, injections of adult stem cells isolated from adipose tissue into tendon injuries evidenced histological regeneration of tendon tissue. However, it is unclear whether such beneficial effects could also be observed in a human tendon treated with fresh, uncultured, autologous, adipose derived regenerative cells (UA-ADRCs). A specific challenge in this regard is that UA-ADRCs cannot be labeled and, thus, not unequivocally identified in the host tissue. Therefore, histological regeneration of injured human tendons after injection of UA-ADRCs must be assessed using comprehensive, immunohistochemical and microscopic analysis of biopsies taken from the treated tendon a few weeks after injection of UA-ADRCs.

This study investigated subclinical atherosclerosis progression in low-risk, middle-aged adults (N=141; mean age 49.6±4.7 years) using a 5-year ultrasound follow-up. We compared in-volvement of the carotid and femoral arteries. Methods: Clinical data, risk factors, and carotid/femoral intima-media thickness (IMT) and plaque presence were analyzed. Results: Cardiovascular risk factors and scores increased significantly at follow-up. Both carotid and femoral IMT increased (p&lt;0.001) but remained within the normal range. While plaque prev-alence rose and was similar in both arteries (carotid: 4.8% to 17.9%, femoral: 3.6% to 17.7%, p&lt;0.001 for both), the progression of plaque burden was greater in femorals. Notably, carotid IMT demonstrated a faster yearly progression rate compared to femoral IMT. The age- and sex-adjusted increase in IMT was also more frequent in the carotids (52.9% to 78.8%, p&lt;0.001) compared to femorals (23.2% to 44.7%, p&lt;0.001). Conclusions: This study demonstrates significant subclinical atherosclerosis progression in low-risk middle-aged adults during 5 years. Carotid arteries showed a faster progression rate and higher prevalence of increased age- and sex-adjusted IMT compared to the femoral arteries. However, plaque burden was similar in both territories, with greater progression in femorals. Identifying carotid and femoral atherosclerosis burden may be a valuable tool for risk stratification in this population.

Tumor vasculature proliferates rapidly, generally lacks pericyte coverage, and is uniquely frag-ile making it an attractive therapeutic target. A subset of small-molecule tubulin binding agents cause disaggregation of the endothelial cytoskeleton leading to enhanced vascular permeability generating increased interstitial pressure. The resulting vascular collapse and ischemia cause downstream hypoxia, ultimately leading to cell death and necrosis. Thus, local damage gener-ates massive amplification and tumor destruction. The tumor vasculature is readily accessed and potentially a common target irrespective of disease site in the body. Development of a therapeutic approach and particularly next generation agents benefits from effective non-invasive assays. Imaging technologies offer varying degrees of sophistication and ease of implementation. This review considers technological strengths and weaknesses with examples from our own laboratory. Methods reveal vascular extent and patency, as well as insights into tissue viability, proliferation and necrosis. Spatiotemporal resolution ranges from cellular mi-croscopy to single slice tomography and full three-dimensional views of whole tumors and measurements can be sufficiently rapid to reveal acute changes or long-term outcomes. Since imaging is non-invasive, each tumor may serve as its own control making investigations par-ticularly efficient and rigorous. The concept of tumor vascular disruption was proposed over 30 years ago and it remains an active area of research.

Ecklonia cava (E.cava) can alleviate vascular dysfunction in diseases associated with poor circulation. E. cava contains various polyphenols with different functions, but few studies have compared the effects of these polyphenols. Here, we comparatively investigated four major compounds present in an ethanoic extract of E. cava. These four major compounds were isolated and their effects were examined on monocyte-associated vascular inflammation and dysfunctions. Pyrogallol-phloroglucinol-6,6-bieckol (PPB) significantly inhibited monocyte migration in vitro by reducing levels of inflammatory macrophage differentiation and of its related molecular factors. In addition, PPB protected against monocyte-associated endothelial cell death by increasing the phosphorylations of PI3K-AKT and AMPK, decreasing caspase levels, and reducing monocyte-associated vascular smooth muscle cell proliferation and migration by decreasing the phosphorylations of ERK and AKT. The results of this study show that four compounds were effective for reduction of monocyte-associated vascular inflammation and dysfunctions, but PPB might be more useful for the treatment of vascular dysfunction in diseases associated with poor circulation.

Familial Exudative Vitreoretinopathy (FEVR), Norrie disease, and persistent fetal vascular syndrome (PFVS) are extremely rare retinopathies that are clinically distinct but are unified by abnormal retinal endothelial cell function – and subsequent irregular retinal vascular development and/or aberrant inner blood-retinal-barrier (iBRB) function. The early angiogenesis of the retina and its iBRB is a delicate process that is mediated by the canonical Norrin Wnt-signaling pathway in retinal endothelial cells. Pathogenic variants in genes that play key roles within this pathway such as NDP, FZD4, TSPAN12, and LRP5, have been associated with the incidence of these retinal diseases. Recent efforts to further elucidate the etiology of these conditions have not only highlighted their multigenic nature but have also resulted in the discovery of pathological variants in additional genes such as CTNNB1, KIF11, and ZNF408, some of which operate outside of the Norrin Wnt-signaling pathway. Recent discoveries of FEVR-linked variants in two other Catenin genes (CTNND1, CTNNA1) and the Endoplasmic Reticulum Membrane Complex Subunit-1 gene (EMC1) suggest that we will continue to find additional genes that impact the neural retinal vasculature, especially in multi-syndromic conditions. The goals of this review are to briefly highlight the current understanding of the roles of their encoded proteins in retinal endothelial cells to understand the essential functional mechanisms that can be altered to cause these very rare pediatric retinal vascular diseases.

Background: Antiphospholipid antibodies (aPL) are a laboratory criterion for the classification of antiphospholipid syndrome (APS), and are known to cause clinical symptoms: vascular thrombosis or obstetric complications. It is suggested that aPL may be associated with thromboembolism in severe COVID-19 cases. Aim: to combine clinical data with aPL findings at 4 time points (admission, worsening, discharge, 3-month follow-up) in patients hospitalized with COVID-19 pneumonia. Methods: current and past history of thrombosis and obstetric complications; aPL determined at 4 time points: anticardiolipin (aCL), anti-β2-glycoprotein I (anti- β2GPI) and antiphosphatidylserine/prothrombin (aPS/PT) of the IgM, IgG or IgA isotypes. Results: 111 patients with COVID-19 pneumonia were enrolled. During hospitalization, 7 patients died, 3 of them due to pulmonary artery thromboembolism (none was aPL positive). Only one of the five who developed pulmonary artery thrombosis was aPL positive. Of 9/101 patients with a history of thrombosis, 5 had arterial thrombosis and none was aPL positive at admission and follow-up; 4 had venous thrombosis and one was aPL positive at all time points (newly diagnosed APS). Of these 9/101 patients, 55.6% were transiently aPL positive at discharge only, compared to 26.1% without history of thrombosis (p=0.05). Conclusions: aPL were not associated with fatal outcomes and vascular thrombosis; aPL were transiently positive in more than half of patients with a history of thrombosis.

The potassium-chloride cotransporter KCC2 is the main extruder of Cl- in neurons. It plays a fundamental role in the activity of the inhibitory neurotransmitters (GABA and glycine) since low levels of KCC2 promote intracellular Cl- accumulation leading to a depolarizing activity of GABA and glycine. Downregulation of this cotransporter occurs in neurological disorders characterized by hyperexcitability, such as epilepsy, neuropathic pain and spasticity. KCC2 is also downregulated after axotomy. If muscle reinnervation is allowed, KCC2 levels recover in motoneurons. Therefore, we argued that target-derived neurotrophic factors might be involved in the regulation of KCC2 expression. For this purpose, we performed the axotomy of extraocular motoneurons by monocular enucleation of adult rats, and a pellet containing either VEGF or BDNF was chronically implanted in the orbit. Double confocal immunofluorescence of ChAT and KCC2 was carried out in brainstem sections. Axotomy led to a KCC2 decrease in the neuropil and soma of extraocular motoneurons, peaking at 15 days post-lesion, with the exception of abducens motoneuron somata. VEGF administration prevented the axotomy-induced KCC2 downregulation. By contrast, BDNF either maintained or reduced KCC2 levels following axotomy suggesting BDNF is involved in the axotomy-induced KCC2 downregulation in extraocular motoneurons. The finding that VEGF prevents KCC2 decrease opens new possibilities for the treatment of neurological disorders coursing with neuronal hyperactivity due to KCC2 downregulation.