Abnormal Vessels Research Articles

Efficacy of Anti-VEGF in Treatment of Retinopathy of Prematurity

Retinopathy of prematurity (ROP) is a vasoproliferative retinal disorder that affects premature infants. Vascular endothelial growth factor (VEGF) has been implicated in the pathogenesis of ROP. Anti-VEGF agents can potentially inhibit abnormal vessel growth in ROP. This study aimed to evaluate the efficacy of anti-VEGF (bevacizumab) in treatment of ROP. A prospective study was conducted on 75 patients including 70 adults and 5 ROP babies who received intravitreal injection of bevacizumab (Avastin). Distant visual acuity, slit lamp examination, indirect ophthalmoscopy and optical coherence tomography (OCT) were assessed at baseline, immediate, 1 week and 4 weeks post injection. Statistically significant improvement was observed in distant visual acuity and reduction in macular thickness after Avastin injection. At 4 weeks, best corrected visual acuity of 6/6 was attained by 15 adults and 3 ROP babies. OCT revealed decreased macular edema with mean reduction of 115.29μm. ROP subjects showed greater visual gain (mean acuity improvement - 2.4 lines) as compared to adults (mean acuity improvement - 1.52 lines). Significant correlation was found between better visual acuity and macular thickness less than 300μm. Intravitreal Avastin resulted in rapid regression of neovascularization in ROP. No ocular or systemic complications were observed. Single injection controlled disease progression in majority of cases. Anti-VEGF agents can be considered as primary modality for treating type 1 ROP due to their safety, efficacy and long-term benefits. Larger studies are required to establish optimal dosage and long-term effects.

Cone cell dysfunction attenuates retinal neovascularization in oxygen-induced retinopathy mouse model.

Aberrant neovascularization is the most common feature in retinopathy of prematurity (ROP), which leads to the retinal detachment and visual defects in neonates with a low gestational age eventually. Understanding the regulation of inappropriate angiogenic signaling benefits individuals at-risk. Recently, neural activity originating from the specific neural activity has been considered to contribute to retinal angiogenesis. Here, we explored the impact of cone cell dysfunction on oxygen-induced retinopathy (OIR), a mouse model commonly employed to understand retinal diseases associated with abnormal blood vessel growth, using the Gnat2cpfl3 (cone photoreceptor function loss-3) strain of mice (regardless of the sex), which is known for its inherent cone cell dysfunction. We found that the retinal avascular area, hypoxic area, and neovascular area were significantly attenuated in Gnat2cpfl3 OIR mice compared to those in C57BL/6 OIR mice. Moreover, the HIF-1α/VEGF axis was also reduced in Gnat2cpfl3 OIR mice. Collectively, our results indicated that cone cell dysfunction, as observed in Gnat2cpfl3 OIR mice, leads to attenuated retinal neovascularization. This finding suggests that retinal neural activity may precede and potentially influence the onset of pathological neovascularization.

Anlotinib and anti-PD-1 mAbs perfected CIK cell therapy for lung adenocarcinoma in preclinical trials.

Murine cytokine-induced killer (CIK) cells are heterologous cells that kill various allogeneic and isogenic tumors and have functional and phenotypic characteristics of natural killer cells and T lymphocytes. However, the effect of CIK cells alone on solid tumor therapy is only limited. To enhance the therapeutic effect, it is vital to discover a mix of several therapy approaches. Immune cell function is inhibited by abnormal tumor vessels and the tumor microenvironment, which block lymphocyte entry into tumor tissue. To increase the effectiveness of CIK cells' antitumor activity, antivascular therapy and CIK cell therapy can be combined. Furthermore, anlotinib is a tiny drug with multitarget tyrosine kinase inhibitors that can block cell migration, delay angiogenesis, and decrease blood vessel density. Compared with other antiangiogenesis drugs, anlotinib stands out due to the wider target of action and lower effective dose. In this work, anlotinib and murine CIK cells were coupled to boost CD3+ T cell infiltration, CD3+CD4+ T cell infiltration, and expression of granzyme B and interferon γ from CD3+CD8+ T cells, which increased the antitumor activity. Through the generation of cytotoxic cytokines by T lymphocytes, the therapeutic group using anti-PD-1 monoclonal antibodies in conjunction with anlotinib and CIK cells was more successful than the group receiving dual therapy. The preclinical study contributes to exploring the therapeutic alternatives for patients with lung adenocarcinoma, thus prolonging their lives.

Frequency of risk factors for stroke in young Pakistani population

Background and Objective:
 There is paucity of data regarding risk factors of stroke in young Pakistanis. The objective of this study was to identify the frequency of risk factors for ischemic stroke in the young Pakistani population
 Methods:
 This was a retrospective Cross sectional study conducted at Aziz Fatima Hospital Neurology outpatient’s department between January 2022 to April 2022.bAll patients presenting with an ischemic stroke within the past month and age between 20 and 49 years were included. Data was collected from patient notes using a table which listed the patient’s demographic information and risk factors. All the patients had appropriate investigations on site to look for cardiac and vessel abnormalities along with relevant blood tests. The results were then assessed using univariate analysis to divide patients according to age, gender and prevalence of risk factors.
 Results:
 A total of 53 patient’s data was collected. The mean age was 39 years. The commonest risk factor was hypertension (58%). The other risk factors were ischemic heart disease (36%), diabetes mellitus (34%), dyslipidemia (26%), smoking (21%), obesity (19%), atrial fibrillation (2%) and vasculitis (2%). Positive family history of stroke was found in 26%.
 Conclusion:
 Hypertension was the commonest risk factor for young age group under 50 years, followed by ischemic heart disease. Our younger population also had a higher frequency of causes like diabetes mellitus, dyslipidemia and smoking.

Early Unguided Human Brain Organoid Neurovascular Niche Modeling into the Permissive Chick Embryo Chorioallantoic Membrane.

Engrafting organoids into vascularized tissues in model animals, such as the immunodeficient mouse or chick embryo chorioallantoic membrane (CAM), has proven efficient for neovascularization modeling. The CAM is a richly vascularized extraembryonic membrane, which shows limited immunoreactivity, thus becoming an excellent hosting model for human origin cell transplants. This paper describes the strategy to engraft human brain organoids differentiated at multiple maturation stages into the CAM. The cellular composition of brain organoids changes with time, reflecting the milestones of human brain development. We grafted brain organoids at relevant maturation stages: neuroepithelial expansion (18 DIV), early neurogenesis (60 DIV), and early gliogenesis (180 DIV) into the CAM of embryonic day (E)7 chicken embryos. Engrafted brain organoids were harvested 5 days later and their histological features were analyzed. No histological signs of neovascularization in the grafted organoids or abnormal blood vessels adjacent to the graftings were detected. Moreover, remarkable changes were observed in the cellular composition of the grafted organoids, namely, an increase in the number of glial fibrillary acidic protein-positive-reactive astrocytes. However, the cytoarchitectural changes were dependent on the organoid maturation stage. Altogether, these results suggest that brain organoids can grow in the CAM, and they show differences in the cytoarchitecture depending on their maturation stage at grafting.

The emerging roles of irisin in vascular calcification.

Vascular calcification is a common accompanying pathological change in many chronic diseases, which is caused by calcium deposition in the blood vessel wall and leads to abnormal blood vessel function. With the progress of medical technology, the diagnosis rate of vascular calcification has explosively increased. However, due to its mechanism's complexity, no effective drug can relieve or even reverse vascular calcification. Irisin is a myogenic cytokine regulating adipose tissue browning, energy metabolism, glucose metabolism, and other physiological processes. Previous studies have shown that irisin could serve as a predictor for vascular calcification, and protect against hypertension, diabetes, chronic kidney disease, and other risk factors for vascular calcification. In terms of mechanism, it improves vascular endothelial dysfunction and phenotypic transformation of vascular smooth muscle cells. All the above evidence suggests that irisin plays a predictive and protective role in vascular calcification. In this review, we summarize the association of irisin to the related risk factors for vascular calcification and mainly explore the role of irisin in vascular calcification.

Targeted Cyclo[8]pyrrole-Based NIR-II Photoacoustic Tomography Probe for Suppression of Orthotopic Pancreatic Tumor Growth and Intra-abdominal Metastases.

Pancreatic cancer is highly lethal. New diagnostic and treatment modalities are desperately needed. We report here that an expanded porphyrin, cyclo[8]pyrrole (CP), with a high extinction coefficient (89.16 L/g·cm) within the second near-infrared window (NIR-II), may be formulated with an αvβ3-specific targeting peptide, cyclic-Arg-Gly-Asp (cRGD), to form cRGD-CP nanoparticles (cRGD-CPNPs) with promising NIR-II photothermal (PT) therapeutic and photoacoustic (PA) imaging properties. Studies with a ring-array PA tomography system, coupled with analysis of control nanoparticles lacking a targeting element (CPNPs), revealed that cRGD conjugation promoted the delivery of the NPs through abnormal vessels around the tumor to the solid tumor core. This proved true in both subcutaneous and orthotopic pancreatic tumor mice models, as confirmed by immunofluorescent studies. In combination with NIR-II laser photoirradiation, the cRGD-CPNPs provided near-baseline tumor growth inhibition through PTT both in vitro and in vivo. Notably, the combination of the present cRGD-CPNPs and photoirradiation was found to inhibit intra-abdominal metastases in an orthotopic pancreatic tumor mouse model. The cRGD-CPNPs also displayed good biosafety profiles, as inferred from PA tomography, blood analyses, and H&E staining. They thus appear promising for use in combined PA imaging and PT therapeutic treatment of pancreatic cancer.

The Role of Ultrasonography and Magnetic Resonance Imaging in the Diagnosis of the Adherent Placenta: An Observational Study.

Introduction Placenta accreta is an important factor responsible for maternal morbidity and mortality and is commonly associated with emergent postpartum hysterectomy. The precise prenatal diagnosis of affected pregnancies allows optimal obstetric management. Ultrasonography (USG) and magnetic resonance imaging (MRI) are the only diagnostic modalities available for the prenatal diagnosis of placenta accreta. Objective This study aims to evaluate the accuracy of USG and MRI in diagnosing adherent placenta. Methods Thirty females with placenta previa or a history of previous cesarean sections were evaluated with USG at 28-30 weeks, followed by MRI. The findings of USG and MRI were compared with the intra-operative findings (gold standard) as determined at surgery and by pathological examination. Results Abnormal bridging vessel (n = 24; 80%) was the most common finding seen on USG, whereas abnormal bulge (n = 22; 73.3%) and heterogenous placenta (n = 21; 70%) were the most common findings seen on MRI. The sensitivity of USG and MRI was in the range of 86.7%-92.9% and 92.9%-100%, respectively, in diagnosing three types of adherent placenta. The positive predictive values (PPV) of USG and MRI were in the range of 86.7%-86.7%and93.8%-100%, respectively, in diagnosing three types of adherent placenta. The accuracy of USG and MRI was in the range of 86.7%-96.7% and 96.7%-100%, respectively, in diagnosing three types of adherent placenta. Conclusion MRI helps to accurately classify placental invasion according to depth, as can be seen from the results of the present study, where the MRI technique was more accurate in diagnosing three types of adherent placenta.

Abstract TMP3: Overexpression of Alk1 in Brain Endothelial Cells Alleviates the Severity of Brain Arteriovenous Malformations in Alk1 Mutant Mice

Background and purpose: Brain arteriovenous malformation (bAVM) can cause life threatening intra-cranial hemorrhage. Currently, there is no effective medical therapy available to treat bAVM patients. Mutation of activin receptor-like kinase 1 ( Alk1 also called ACVRL1 ) causes a familiar form of bAVM. Genetically overexpression of Alk1 in endothelial cells (ECs) recurs the phenotype of Alk1 deficient mice. We hypothesize that transduction of Alk1 gene into brain ECs using an adeno associated viral vector (AAV) may lead to cure of bAVM in Alk1 mutant mice. Methods: To identify a AAV capsid that can transduce brain ECs after intravenous (i.v.) delivery, several engineered AAV capsids were screened. A single-stranded CBA promoter driven tdTomato transgene was packaged in these capsids and delivered i.v. to wild-type mice. Tissues were collected 4 weeks later. After identifying a capsid, cc84, that can transduce brain ECs effectively after i.v. deliver, we package CMV-Alk1 transgene into AAV.cc84. Brain AVMs were induced on PdgfbiCre; Alk1 f/f mice through intra-brain injection of AAV1-VEGF followed by intraperitoneal injection of 1.25 mg/25g tamoxifen two weeks later. AAV.cc84-Alk1 was delivered to PdgfbiCre; Alk1 f/f mice through i.v. injection at the time of tamoxifen treatment Histological analyses were used to analyze viral transduction in the brain and liver, vessel density, and abnormal vessels in the brain and liver inflammation. Liver and kidney function were analyzed by colorimetric assays for Alkaline Phosphatase Activity (ALP), Alanine Transaminase Activity ALT), and Creatinine levels (Cr). Results: After i.v. injection, AAV-cc84 transduced a high percentage of brain ECs and a few hepatocytes. AAV.cc84-Alk1 treatment reduced vessel density (p=0.008), abnormal vessels (p=0.034), mouse mortality rates (20% vs 60% respectively) compared to the AAV.cc84-RFP (control vector) treated PdgfbiCre; Alk1 f/f mice. The levels of ALP, ALT and Cr were similar between AAV injected and uninjected mice. Conclusion: AAV.cc84 mediated EC overexpression of Alk1 reduced bAVM severity in Alk1 deficient mice indicating that AAV.cc84 is a promising gene therapy vector to treat bAVMs.

Unilateral periocular spasm.

Hemifacial spasm is an uncontrollable, recurrent facial muscular contraction that typically occurs on one side of the face, cannot be suppressed, and can last the entire day and during sleep. The most common underlying cause of facial nerve compression is an enlarged or abnormal tracking blood vessel at the brainstem level. Clinical diagnoses are frequently based on a patient's medical history and physical examination. Before deciding on a course of action, however, an electromyogram and MRI are performed to determine the underlying cause. Due to its high effectiveness (success rates of 85% to 95%) and low frequency of adverse reactions, botulinum toxin is the preferred therapy for hemifacial spasm and can provide transient symptomatic alleviation. Surgical microvascular decompression is a therapeutic approach that targets the underlying cause of this condition and has an average success rate of 85%.

Abstract WP247: Potential Predictors for Progression of Adult Moyamoya Disease: A Study From Multicenter Registry

Background and aims: Moyamoya disease refers to a chronic progressive steno-occlusive disease at the distal portion of the internal carotid arteries (ICAs) and compensatory abnormal collateral vessel formation. However, the incidence of progression and its’ related factors in adult moyamoya disease has not been well known. Our study was to investigate the prevalence of progression of steno-occlusion of intracranial vessels and clinical outcome in the patients with adult moyamoya disease. Methods: From Jan 2001 to Jun 2021, we included the patients who was diagnosed with symptomatic or asymptomatic moyamoya disease from moyamoya registries of 4 hospitals in Korea. We excluded patients who did not have any follow-up angiography more than 1 year after baseline angiography [digital subtraction angiography (DSA) or magnetic resonance angiography (MRA)]. We adopted Suzuki’s angiographic staging and MRA score for the analysis. Results: A total of 293 moyamoya patients were included, and mean follow-up period was 92.7 ±52.8 months. Among them, progression of vessel stenosis in DSA and/or MRA was found in 110 patients (37.5%). Recurrent stroke occurred in 39/183 (21.3%) in non-progression group and 40/110 (36.4%) in progression group. Clinical characteristics were not significantly different between two groups. However, previous ischemic stroke history is independently associated with angiographic progression (odds ratio, 3.384 [95% CI, 1.521-7.531]) in multivariable logistic regression analysis. Conclusions: Occlusive arterial status worsened in one-third of the patients with adult moyamoya disease during approximately 8 years of follow-up. Careful neurological and radiological follow-up would be essential to prevent additional stroke occurrence, especially in patients with a history of cerebral infarction.

Abstract TMP5: Mutation of Pdgfrβ Enhances the Severity of Brain Arteriovenous Malformation on Endoglin Mutant Mice Through Exacerbation of Angiogenesis and Inflammation

Background and Purpose: Brain arteriovenous malformations (bAVMs) are tangles of abnormal vessels shunting blood directly from arteries to veins. Reduction of pericytes is correlated with bAVM hemorrhage. The PDGFB/PDGFRβ signaling plays important roles in regulating pericyte recruitment during angiogenesis. Hypothesis: Mutation of PDGFRβ causes cerebrovascular malformation and enhances bAVM severity in endoglin ( Eng ) deficient mice. Methods: Three mouse models were used: (1) Pdgfrβ F7 (F7) mice that have mutations disrupting most Pdgfrβ signaling, (2) Pdgfb icreER; Eng f/f mice that have Pdgfb promoter driving, tamoxifen (TM) inducible cre expression in endothelial cells (ECs) and a floxed Eng gene; and (3) PdgfbicreER; Eng f/f ;F7 +/- mice were used. Brain angiogenesis was induced by intra-parenchymal injection of AAV-VEGF. BAVMs were induced in PdgfbicreER; Eng f/f and PdgfbicreER; Eng f/f ;F7 +/- mice by inducting EC Eng deletion through TM treatment and brain angiogenesis through intra-brain injection of AAV-VEGF. BAVM phenotypes were analyzed 8-weeks after model induction by latex vascular cast to detect arteriovenous shunts, immunostaining to analyze vessel morphology, Prussian blue staining to quantify microhemorrhage and RNAseq to investigate gene expression profiles. Results: Dysplastic vessels with reduced pericyte coverage were detected in the brain and brain angiogenic region of F7 +/- and F7 +/+ mice. AVM like vessels were detected in the brain of 16% F7 +/- and 66% of F7 +/+ mice. F7 mutation increases bAVM penetrance in Eng deficient mice (71% vs 50%), dysplastic vessels and microhemorrhage. RNAseq data revealed that mutation of Pdgfrb increased the expression of pro-angiogenic and endothelial cell proliferation genes and genes promote cell migration and inflammation in the bAVMs of Eng mutant mice. Conclusion: Pdgfrβ mutation exacerbates the severity of bAVM in Eng mutant mice by enhancing angiogenesis and inflammation.

CRISPR‐based gene therapy for wet age‐related macular degeneration in mouse model

AbstractWet age‐related macular degeneration (AMD) is a common cause of vision loss in the elderly. It is characterised by choroidal neovascularisation (CNV), caused by overexpression of vascular endothelial growth factor (VEGF), resulting in abnormal vessel proliferation. Current clinical management predominantly relies on anti‐VEGF agents, which require frequent and costly injections. Clustered regularly interspaced short palindromic repeats (CRISPR) technology has emerged as a promising strategy for permanently suppressing angiogenesis by targeting the VEGF‐related pathway. Increased research suggests that disrupting this pathway holds potential for preventing CNV progression. This review provides an overview of the aetiology, classification and pathophysiology of wet AMD, followed by a concise summary of current gene editing research using the CRISPR/Cas system via viral vector delivery strategies to target ocular pro‐angiogenic factors, including Hif‐1α, VEGF and VEGFR. The importance of timely targeting of VEGFA is emphasised and the challenges associated with gene editing therapies are also highlighted.

Probing the glioma microvasculature: a case series of the comparison between perfusion MRI and intraoperative high-frame-rate ultrafast Doppler ultrasound

BackgroundWe aimed to describe the microvascular features of three types of adult-type diffuse glioma by comparing dynamic susceptibility contrast (DSC) perfusion magnetic resonance imaging (MRI) with intraoperative high-frame-rate ultrafast Doppler ultrasound.MethodsCase series of seven patients with primary brain tumours underwent both DSC perfusion MRI and intra-operative high-frame-rate ultrafast Doppler ultrasound. From the ultrasound images, three-dimensional vessel segmentation was obtained of the tumour vascular bed. Relative cerebral blood volume (rCBV) maps were generated with leakage correction and normalised to the contralateral normal-appearing white matter. From tumour histograms, median, mean, and maximum rCBV ratios were extracted.ResultsLow-grade gliomas (LGGs) showed lower perfusion than high-grade gliomas (HGGs), as expected. Within the LGG subgroup, oligodendroglioma showed higher perfusion than astrocytoma. In HGG, the median rCBV ratio for glioblastoma was 3.1 while astrocytoma grade 4 showed low perfusion with a median rCBV of 1.2. On the high-frame-rate ultrafast Doppler ultrasound images, all tumours showed a range of rich and organised vascular networks with visually apparent abnormal vessels, even in LGG.ConclusionsThis unique case series revealed in vivo insights about the microvascular architecture in both LGGs and HGGs. Ultrafast Doppler ultrasound revealed rich vascularisation, also in tumours with low perfusion at DSC MRI. These findings warrant further investigations using advanced MRI postprocessing, in particular for characterising adult-type diffuse glioma.Relevance statementOur findings challenge the current assumption behind the estimation of relative cerebral blood volume that the distribution of blood vessels in a voxel is random.Key points• Ultrafast Doppler ultrasound revealed rich vascularity irrespective of perfusion dynamic susceptibility contrast MRI state.• Rich and organised vascularisation was also observed even in low-grade glioma.• These findings challenge the assumptions for cerebral blood volume estimation with MRI.Graphical

Abnormal retinal vessel filling in central retinal artery occlusion

ABSTRACT Clinical relevance Central retinal artery occlusion (CRAO) is an ophthalmic emergency with a poor prognosis. Several initial CRAO presentation factors can influence the final visual outcome. Fluorescein angiography filling of retinal vessels in CRAO has not been studied in great detail. Background The aim of this paper is to study the aberrant filling of the retinal vessels on fluorescein angiography in patients with CRAO and understand its clinical relevance. Methods Cases of CRAO diagnosed between June 2017 and May 2022 and who had undergone a fundus fluorescein angiography were included. Comparisons were made between the cases with and without aberrant filling of the retinal vessel. Results Twenty-two eyes of 22 patients (14 males and 8 females) with CRAO underwent fluorescein angiography. Ages of the patients ranged from 18 to 73 years, while time interval between development of acute onset vision problems and presentation to the retinal clinic ranged from a minimum of 1 day to a maximum of 30 days. Snellen visual acuity at presentation ranged from perception of light (PL +) to 6/6. On fluorescein angiography, aberrant flow of the fluorescein dye into the retinal vein was observed in four of the 22 (18%) eyes with CRAO. All these cases showed a patient's temporal cilioretinal artery. The cases with aberrant filling of the retinal vessels showed a better presenting visual acuity (6/6–6/60), lesser severity of inner retinal damage and a better final visual acuity (6/6–6/60) compared to CRAO cases without aberrant filling. Conclusion Aberrant filling of the retinal vein can be seen on fluorescein angiography in eyes with CRAO and a patent temporal cilioretinal artery. Such eyes with aberrant retinal vessel filling have a better visual prognosis.

Role of intraoperative entroscopy in obscure small bowel gastrointestinal bleed

ABSTRACT Obscure gastrointestinal bleed (OGIB) is defined as bleeding of unknown origin that persists or recurs after a negative initial or primary endoscopy (colonoscopy and upper gastrointestinal [GI] endoscopy) and imaging. Approximately 5% of all GI bleeding is obscure GI bleed. Abnormal blood vessels arteriovenous malformations (AVMs) cause 30%–40% of small intestinal bleeds. AVMs are the main source of bleeding in patients over the age of 50 years. Tumors (benign and malignant), polyps, Crohn’s disease, and ulcers are some of the other causes of bleeding. Various diagnostic modalities available to detect small intestinal bleed are upper GI endoscopy, colonoscopy, contrast-enhanced computed tomography scan of the abdomen with angiogram, small bowel enteroscopy, video capsule endoscopy, and scintigraphy studies. Advanced imaging/diagnostic modalities may not be available in all centers, posing a great challenge in the localization of the source of GI bleed. This series highlights the role of diagnostic laparoscopy with intraoperative enteroscope (IOE) in the management of OGIB.

Cell and molecular targeted therapies for diabetic retinopathy.

Diabetic retinopathy (DR) stands as a prevalent complication in the eye resulting from diabetes mellitus, predominantly associated with high blood sugar levels and hypertension as individuals age. DR is a severe microvascular complication of both type I and type II diabetes mellitus and the leading cause of vision impairment. The critical approach to combatting and halting the advancement of DR lies in effectively managing blood glucose and blood pressure levels in diabetic patients; however, this is seldom achieved. Both human and animal studies have revealed the intricate nature of this condition involving various cell types and molecules. Aside from photocoagulation, the sole therapy targeting VEGF molecules in the retina to prevent abnormal blood vessel growth is intravitreal anti-VEGF therapy. However, a substantial portion of cases, approximately 30-40%, do not respond to this treatment. This review explores distinctive pathophysiological phenomena of DR and identifiable cell types and molecules that could be targeted to mitigate the chronic changes occurring in the retina due to diabetes mellitus. Addressing the significant research gap in this domain is imperative to broaden the treatment options available for managing DR effectively.

Nanoparticle‐based sustained drug delivery for the treatment of ocular neovascular diseases

Aims/Purpose: Nanoparticles have shown great potential as a drug delivery system for the treatment of neovascular ocular diseases characterized by the growth of abnormal blood vessels in the retina. The current standard of therapy for neovascular ocular diseases involves administering monoclonal antibody‐based anti‐VEGF drugs via intravitreal injections on a periodic basis. The short half‐lives of these drugs necessitate frequent injections, which can limit the effectiveness of the treatments. Hence, there is a need to develop new approaches for enhanced bioavailability and sustained and long‐lasting delivery of anti‐VEGF drugs. The aim of this study was to utilize poly (glycerol sebacate) (PGS) nanoparticles to achieve an extended release of anti‐VEGF (anti‐vascular endothelial growth factor) drugs, with the objective of reducing the frequency of intravitreal injections required for treatment.Methods: Double emulsion solvent evaporation method was utilized for the synthesis of PGS nanoparticles. Nanoparticle size and polydispersity index (PDI) were determined with dynamic light scattering method.Results: Nanoparticles were synthesized with a size of approximately 150 nm and PDI less than 0.3. The encapsulation efficiency of nanoparticles loaded with anti‐VEGF drugs was found to be 74%. The 30% drug release from nanoparticles in the first 2 months indicates that nanoparticles are a promising candidate for sustained drug release applications. Cell‐viability studies showed that anti‐VEGF drug‐loaded nanoparticles did not exhibit toxicity to ARPE‐19 cells, but they did exhibit anti‐angiogenesis properties by inhibiting the growth of HUVEC cells in a concentration‐dependent manner.Conclusions: The development of new‐generation materials for the storage and preservation of anti‐VEGF drugs, as well as their enhancement with prolonged release, will considerably improve the efficacy of long‐term treatment strategies for ocular neovascular diseases.

The Arteria Lymphatica and Lymphatic Microperforators: A Dedicated Blood Supply to Collecting Lymphatics and Their Potential Implications in Lymphedema: Anatomical Description.

Lymphedema is common after lymphatic damage in cancer treatment, with negative impacts on function and quality of life. Evidence suggests that blood vessel microvasculature is sensitive to irradiation and trauma; however, despite knowledge regarding dedicated mural blood supply to arteries and veins (vasa vasorum), equivalent blood vessels supplying lymphatics have not been characterized. We studied collecting lymphatics for dedicated mural blood vessels in our series of 500 lymphaticovenous anastomosis procedures for lymphedema, and equivalent controls. Microscopic images of lymphatics from lymphedema and control patients were analyzed for lymphatic wall vascular density. Collecting lymphatics from 20 patients with lymphedema and 10 control patients were sampled for more detailed analysis (podoplanin immunostaining, light/confocal microscopy, microcomputed tomography, and transmission electron microscopy) to assess lymphatic wall ultrastructure and blood supply. Analysis revealed elaborate, dense blood microvessel networks associating with lymphatic walls in lymphedema patients and smaller equivalent vessels in controls. These vasa vasora or "arteria lymphatica" were supplied by regular axial blood vessels, parallel to lymphatic microperforators linking dermal and collecting lymphatics. Lymphatic walls were thicker in lymphedema patients than controls, with immunohistochemistry, computed tomography, transmission electron microscopy, and confocal microscopy characterizing abnormal blood vessels (altered appearance, thickened walls, elastin loss, narrow lumina, and fewer red blood cells) on these lymphatic walls. Dedicated blood vessels on lymphatics are significantly altered in lymphedema. A better understanding of the role of these vessels may reveal mechanistic clues into lymphedema pathophysiology and technical aspects of lymphedema microsurgery, and suggest potential novel therapeutic targets.

Lobectomy for Anomalous Systemic Arterial Supply to the Basal Segment of the Lung in the Second Trimester of a Pregnant Patient with Hemoptysis.

An anomalous systemic arterial supply to the basal segment of the lung (ABLL) is a rare congenital vascular anomaly. We herein report a case of ABLL in a 26-year-old pregnant woman with hemoptysis. Contrast-enhanced chest computed tomography (CT) revealed an abnormal vessel branching directly from the descending aorta and circulating to the left lower lobe while showing a normal bronchial anatomy. The patient was therefore diagnosed with ABLL. Maternal safety was a priority, and the patient underwent thoracoscopic left lower lobectomy at 19 weeks' gestation. We concluded that the hemoptysis had been caused by an increased circulating plasma volume during pregnancy.