Evidence Of Neovascularization Research Articles

PHENOTYPIC CHARACTERIZATION OF PREDICTORS FOR DEVELOPMENT AND PROGRESSION OF GEOGRAPHIC ATROPHY USING OPTICAL COHERENCE TOMOGRAPHY.

To evaluate the impact of optical coherence tomography phenotypes preceding atrophy related to age-related macular degeneration on the progression of atrophic lesions. In this observational retrospective cohort study, a total of 70 eyes of 60 consecutive patients with intermediate age-related macular degeneration with a minimum follow-up of 24 months were included. The atrophy was quantified using fundus autofluorescence, also considering the directionality of atrophy as centrifugal and centripetal progression rates. The main outcome measures were geographic atrophy (GA) progression rate (mm 2 /year) and square root transformation of GA (mm 2 /year). The best-fit model for GA (odds ratio: 1.81, P < 0.001) and square root transformation of GA (odds ratio: 1.36, P < 0.001) areas revealed that the main baseline predictor was the presence of a retinal pigment epithelium-basal lamina-Bruch membrane splitting. Large drusen at baseline appeared protective for the GA area lesion expansion over time (odds ratio: 0.52, P < 0.001) when considered with other confounders. A thin retinal pigment epithelium-basal lamina-Bruch membrane splitting without evidence of neovascularization on optical coherence tomography angiography likely represents an optical coherence tomography signature for late basal laminar deposits. Identifying this phenotype can help identify individuals with a higher risk of rapid progression and atrophy expansion.

SURGICAL MANAGEMENT OF GRANULOMA IN A 5-YEAR-OLD UDA EWE

Granuloma is a well-known inflammatory condition in veterinary and human medicine. It is a chronic inflammatory reaction triggered by a wide variety of persistent agents, characterized by the recruitment and activation of macrophages, occasionally presenting areas of central necrosis. The aim of the present report is to provide information regarding the manifestation, cytology, histology and management of granuloma in sheep. A five-year-old Uda ewe was presented to the Veterinary Teaching Hospital, University of Jos in September, 2023, with a large mass around the neck, extending towards the jugular furrow. Following cytological examination of the mass, surgical excision was undertaken under mild sedation (2% Xylazine) and local anaesthesia (1% Lidocaine hydrochloride). The mass was subjected to histopathological examination, while routine wound cleansing and care was instituted with post-operative administration of analgesic, anti-inflammatory agent, antibiotics, multivitamins and tetanus toxoid intramuscularly. Histopathological findings comprised of masses having necrotic centre with sulfur granules, area of macrophages, lymphocyte, plasma cell and zones of fibro-connective tissue with evidence of neo-vascularization and perivascular cuffing supporting the diagnosis of granuloma. Follow-up re-examinations of the Ewe were undertaken every other day with stitches removed on day 12 post-operation following complete apposition of the wound edges. After 14 days of management, the ewe was discharged following normal rectal temperature (39.0ºC), pulse rates (80.0 beats/minute) and respiratory rates (28.0 cycles/minute). Therefore, cases of granuloma could be satisfactorily managed by complete surgical excision with thorough post-operative care.

Clinical Efficacy of a Modified Surgical Procedure in the Treatment of Incompetent Great Saphenous Veins.

The aim of this study was to evaluate the clinical efficacy of a modified surgical procedure for the treatment of varicose veins. This retrospective analysis was conducted on lower extremities with symptomatic great saphenous vein (GSV) incompetence that underwent stripping from the groin to the knee, with preservation of the superficial epigastric vein (SEV), between January 2015 and April 2022. Follow-up assessments were performed using Doppler ultrasound, Venous Clinical Severity Score (VCSS), and the Aberdeen Varicose Vein Questionnaire (AVVQ) at 6 and 12 months after surgery. The study included 179 limbs from 120 patients (47 men and 73 women). The mean patient age was 56.5 years (range, 20-78 years), and the distribution of preoperative Clinical-Etiology-Anatomy-Pathophysiology clinical classes was 8% C0-C1, 88% C2, and 4% C3-C6. The preoperative diameter of the saphenofemoral confluence averaged 6.9 mm (range, 2.7-15.8 mm). After a mean postoperative follow-up period of 24 months, evidence of neovascularization around the stump of the saphenofemoral junction (SFJ) was observed in 2 limbs (1.1%). Additionally, varicose vein recurrence was found in 1 limb (0.6%) and was associated with an incompetent thigh perforator. At postoperative follow- up, both VCSS and AVVQ scores were significantly lower than the preoperative scores. Modified surgical treatment of GSV incompetence, involving preservation of the SEV and stripping of a short segment up to the knee, demonstrated favorable clinical results in terms of postoperative complication rate, neovascularization rate around the SFJ stump, varicose vein recurrence rate, and improvement in lower extremity symptoms.

Ghost cell glaucoma secondary to vitreous hemorrhage caused due to ruptured retinal artery macroaneurysm

A 59 year old diabetic and hypertensive lady with primary open angle glaucoma and past history of non ischemic central retinal vein occlusion presented with vitreous hemorrhage(VH). The VH did not resolve over a 2 month period and led to a sudden rise in intraocular pressure(IOP). Anterior chamber had 2+ khaki colored cells. Gonioscopic examination revealed open angles and no evidence of neovascularization. The IOP was controlled with medical management and vitrectomy was performed for non-resolving VH, which revealed a ruptured retinal artery macroaneurysm (RAM). Our case report contributes to the understanding of the diverse clinical spectrum of RAM.

Lipid Keratopathy: Histopathology, Major Differential Diagnoses and The Importance of Clinical Correlation.

Lipid keratopathy (LK) is a rare ophthalmological condition characterized by a progressive reduction in visual acuity caused by corneal opacification due to central lipid accumulation. LK is characterized by lipid deposits, cholesterol clefts, and neovascularization (NV) leading to disruption in corneal optical quality. LK classification includes a primary and secondary form which depend on pre-existing corneal or systemic disorders and the evidence of NV. Secondary LK is typically associated with a prior occurrence of herpetic infection, such as herpes zoster keratitis. Patients with LK usually present with progressive vision loss and dense cream-colored corneal opacification. Treatment modalities include conservative and surgical approaches focused on corneal NV elimination. When evaluating corneal lipidosis, it is crucial to consider a range of differential diagnoses, including corneal arcus, Schnyder corneal dystrophy, and other corneal deposit conditions. We report a case of a 62-year-old male with herpes zoster keratitis complicated with LK. He presented with painless progressive vision loss and corneal scarring, which raised suspicion about LK diagnosis. This paper emphasizes the importance of correlating clinical and histological findings for accurate LK diagnosis.

3D Living Dressing Improves Healing and Modulates Immune Response in a Thermal Injury Model.

Thermal injury trauma can induce a state of immunosuppression, causing wounds to become chronic in nature. Stem cell-based therapies represent a promising new approach to treat such wounds due to their capacity to self-renew and their multi-lineage potential. Mesenchymal stem cells (MSCs) are known to secrete endogenous factors that stimulate wound healing by promoting angiogenesis, extracellular matrix remodeling, skin regeneration, and by dampening down inflammation. MSC delivery in a biomaterial construct can augment their wound-healing capacity by concentrating cells at the burn site and upregulating trophic factor secretion. The work presented is the first to evaluate repair in an in vitro raft thermal injury model using a regenerative, dual cell delivery three-dimensional (3D) core/shell (c/s) "living dressing" construct. This previously characterized 3D c/s bioprinted construct, which delivers both MSCs and endothelial cells, was used to treat an in vitro 3D raft skin thermal injury wound model. The mesenchymal stromal cell line (T0523) was encapsulated within a gelatin-based shell bioink, and human umbilical vein endothelial cells within a chitosan-based core bioink to biofabricate a living dressing for enhanced thermal injury repair and regeneration. We hypothesized that the cell-laden c/s tissue engineered construct (TEC) would strengthen the wound's proangiogenic, anti-inflammatory, and skin regeneration potential. An in vitro thermal injury in a 3D raft skin model showed a slight delay in wound closure in the presence of the c/s TEC but was augmented by corresponding increases in the release of wound-healing factors, epidermal growth factor, matrix metalloproteinases-9, transforming growth factor-α, platelet-derived growth factor; a decrease in pro-inflammatory factor interleukin-6, and evidence of neovascularization.

Exudative non-neovascular age-related macular degeneration.

To describe the clinical and multimodal imaging (MMI) features of age-related macular degeneration (AMD) eyes presenting with intraretinal exudation and no evidence of neovascularization or structural alterations of native retinal vessels. This was a retrospective review of the MMI and electronic health records for 3 consecutive patients presenting with unilateral exudative non-neovascular age-related macular degeneration. MMI included confocal color fundus photography (CFP), fundus autofluorescence (FAF), fluorescein angiography (FA), spectral domain optical coherence tomography (SD-OCT), swept-source optical coherence tomography angiography (SS-OCTA), and spectral domain optical coherence tomography angiography (SD-OCTA). Dense B-scan OCTA (DB-OCTA) patterns and implemented image post-processing were used to improve spatial resolution in the OCTA analysis and remove projection artifacts. Three eyes of 3 patients (1 male and 2 females, ages 72-87) developed intraretinal fluid (IRF) producing retinal edema during regular follow-up for non-neovascular AMD. FA, SS-OCTA, and DB-OCTA demonstrated no evidence of macular neovascularization or discrete retinal vascular abnormalities that could explain the IRF accumulation. Two eyes received intravitreal anti-VEGF therapy and demonstrated prompt resolution of IRF with periodic recurrences over time. Exudative non-neovascular AMD is a novel clinical phenotype characterized by the presence of non-neovascular intraretinal exudation producing macular edema. Differentiating this condition from other manifestations of AMD requires appropriate use of MMI. Further study is needed to assess the clinical impact and optimal management of exudative non-neovascular AMD.

Retinoschisis in eyes with pachychoroid and retinal pigment epithelial atrophy.

To describe the clinical characteristics and courses for eyes with retinoschisis associated with pachychoroid. A retrospective interventional case series study. Twenty-one eyes (18 patients) with pachychoroid that showed retinoschisis without evidence of neovascularization that had been followed for 1year were included. Multimodal imaging, including fundus photography, spectral-domain optical coherence tomography (OCT) with an enhanced depth protocol, fluorescein angiography (FA), and indocyanine green angiography (ICGA), was provided and treatment outcomes were analyzed. Focal RPE atrophy was present below or adjacent to the schisis in all eyes, and the mean atrophy area was 1.38 ± 1.37mm2. Intraretinal fluids of the schisis originated from the atrophy area and involved the retinal layer which was correlated with the extent of outer retinal defect. Dilated Haller layer vessel and choroidal vascular hyperpermeability were observed under the area with atrophy in all eyes. After 1year of treatment, 11 eyes (52%) still had fluid and 7 of them had fluid at the macula. Nonetheless, the mean central macular thickness decreased (144.4 to 121.8, P < 0.001), visual acuity improved (0.65 to 0.47, P = 0.026), and subfoveal choroidal thickness decreased (442.2μm to 394.9μm, P < 0.001). Atrophy of RPE can cause retinoschisis in eyes with pachychoroid. The intraretinal fluid that originated from underlying choroid and choroidal thickness decreased as intraretinal fluid diminished.

Longitudinal Wide-Field Swept-Source OCT Angiography of Neovascularization in Proliferative Diabetic Retinopathy after Panretinal Photocoagulation

Wide-field swept-source (SS) OCT angiography (OCTA) was compared with ultrawide-field (UWF) fluorescein angiography (FA) for evaluating neovascularization (NV) before and after panretinal photocoagulation (PRP) in eyes with treatment-naive proliferative diabetic retinopathy (PDR). Prospective, observational, consecutive case series. Patients with treatment-naive PDR. Patients were imaged using the SS OCTA 12× 12-mm field of view (PLEX Elite 9000; Carl Zeiss Meditec, Inc, Dublin, CA) at baseline and at 1 week, 1 month, and 3 months after PRP. Select eyes were imaged with 5 SS OCTA 12× 12-mm scans to create posterior pole montages. Ultrawide-field fundus photography and UWF FA were obtained at baseline and 3 months after PRP. Neovascularization visualized using wide-field SS OCTA and UWF FA. From January through May 2018, wide-field SS OCTA was performed on 20 eyes with treatment-naive PDR from 15 patients. The en face SS OCTA 12× 12-mm vitreoretinal interface (VRI) slab images showed NV at baseline in 18 of 20 eyes (90%). Of the remaining 2 eyes, the posterior pole montage captured peripheral NV in one eye, and in the other eye, no evidence of NV was detected with either UWF FA or SS OCTA. After PRP, both SS OCTA and FA demonstrated similar progression or regression of NV, but SS OCTA provided more detailed visualization of the vascular changes. Neovascularization in PDR can be identified at baseline and imaged serially after PRP using wide-field SS OCTA. In patients with a high clinical suspicion for PDR, wide-field SS OCTA likely will betheonlyimaging method needed for diagnosis and longitudinal evaluation of NV.

Interpretation of Subretinal Fluid Using OCT in Intermediate Age-Related Macular Degeneration

To determine the natural history of asymptomatic, subretinal fluid (SRF) in intermediate age-related macular degeneration (iAMD) and highlight the entity of nonexudative detachment of the neurosensory retina (NEDNR). Prospective, observational case series. Cases of iAMD with bilateral drusen >125 μm who were participating in a longitudinal study, in whom spectral-domain (SD)-OCT imaging detected asymptomatic SRF. Participants underwent clinical examinations every 6 months with multimodal imaging that included infrared reflectance, fundus autofluorescence, and SD-OCT. The grading center identified eyes with SRF. Eyes with SRF ≤30 μm were monitored more regularly, whereas eyes with SRF >30 μm underwent fluorescein angiography (FA) and indocyanine green angiography (ICGA). Subretinal fluid without evidence of neovascularization or polyp was termed "NEDNR". All cases of SRF underwent swept-source OCT angiography (SS-OCTA) to determine if choroidal neovascularization (CNV) was present and were then followed prospectively. Natural history of iAMD eyes with SRF that had no evidence of neovascularization during the monitoring period of 30 to 54 months. Sixteen eyes of 12 patients with iAMD developed asymptomatic SRF over a follow-up period of 30 to 54 months. Four eyes developed occult CNV on FA and were no longer followed in this study. Four eyes developed SRF ≤30 μm, and 8 eyes developed SRF >30 μm, with 11 of the 12 eyes developing subretinal hyperreflective material (SHRM). None of these 12 eyes showed any evidence of neovascularization at the initial detection of SRF and were termed "NEDNR". During the follow-up period of 12 to 36 months after the onset of SRF, only 1 eye developed exudative CNV. The remaining 11 eyes failed to demonstrate any abnormal choroidal vasculature on SS-OCTA, including 4 eyes with cuticular drusen in which SHRM developed into a large subfoveal vitelliform-like deposit. Multimodal imaging is helpful for the interpretation and management of asymptomatic SRF in iAMD. In some eyes, all imaging, including SS-OCTA, failed to demonstrate subclinical neovascularization, and we use the acronym NEDNR to describe these cases. This phenotype within iAMD needs to be recognized and monitored to determine if and when treatment might be needed.

Proliferative retinopathy during hyperbaric oxygen treatment

A 43-year-old male with type 2 diabetes mellitus, treated with insulin for 28 years and with an HbA1c of 7.9% six months prior, suffered from bilateral plantar ulcers refractory to specialised wound care. He underwent a planned 40 sessions of treatment (HBOT) at 243 kPa for 90 minutes. Consent was given for this report. The patient's ophthalmic history included bilateral proliferative diabetic retinopathy (PDR) identified on routine diabetic eye screening three years previously. This was treated with pan-retinal photocoagulation (PRP). Three months before starting HBOT, he underwent phacoemulsification and intra-ocular lens insertion of his left eye, having had the same procedure done to his right eye a year prior, without complication. He was reviewed again one week prior to his first HBOT and fundoscopy confirmed non-proliferative diabetic retinopathy (NPDR) without evidence of PDR. The patient had a routine follow up by the ophthalmologist following his fifth HBOT when fundoscopic examination revealed pre-retinal a form of PDR, in his left eye. This was treated with PRP at the time. His visual acuity, 6⁄9 bilaterally, had not changed, nor did he describe any changes in his visual field despite these findings. He was seen three weeks later (following 12 further HBOT) when fundoscopy showed worsening proliferative changes, this time in both eyes. Bevacizumab was injected at the time and fill-in PRP performed the following week. His visual acuity remained unchanged in both eyes. At this point, HBOT was withheld to allow the proliferative phase of the patients' retinopathy to remit. The potentially effects of to the retinal vasculature of diabetic patients was postulated in 1994 following a similar experience, albeit without a baseline fundoscopic examination. In particular, the concern was of accelerating the proliferative process of retinopathy with subsequent irreversible loss of vision. Thereafter, routine screening and treatment of all diabetic patients for PDR was adopted at our facility. Until now, there have been no further cases of NPDR evolving into PDR at three-month review following HBOT. Indeed, a brief literature search using the terms retinopathy, complications, adverse effects, vitreous, hemorrhage, haemorrhage, hyperbaric and oxygen has not found any other cases described. In a double blind, randomised trial (meeting abstract only) of 15 diabetic patients with both NPDR and PDR, patients in neither the HBOT (243 kPa for 90 min) nor the control arm had evidence of neovascularisation nor worsening of their proliferative retinopathy at three-month follow up. The significance of PDR following cataract surgery has also been considered. A review article consistently found that NPDR progression occurred in up to a third of such patients. Despite this, there were no cases of NPDR progressing to PDR at 12-month follow up. Whether this patient's sudden progression to PDR was related to HBOT, recent cataract surgery or another unknown factor is unclear. However, the temporal relationship to 17 HBOT is difficult to explain and appears more rapid than available data regarding vascular regrowth in wound healing would suggest.

Study protocol: a double blind randomised control trial of high volume image guided injections in Achilles and patellar tendinopathy in a young active population

BackgroundChronic tendinopathy is a significant problem particularly in active populations limiting sporting and occupational performance. The prevalence of patellar tendinopathy in some sports is near 50% and the incidence of lower limb tendinopathy is 1.4% p.a. in the UK Military. Management includes isometric, eccentric, heavy slow resistance exercises and extracorporeal shockwave therapy (ESWT). Often these treatments are inadequate yet there is no good evidence for injection therapies and success rates from surgery can be as low as 50%.High Volume Image Guided Injection (HVIGI) proposes to strip away the neovascularity and disrupt the nerve ingrowth seen in chronic cases and has shown promising results in case series. This study aims to investigate the efficacy of HVIGI in a randomised controlled trial (RCT).MethodsRCT comparing 40ml HVIGI, with or without corticosteroid, with a 3ml local anaesthetic sham-control injection. Ninety-six participants will be recruited. Inclusion criteria: male, 18–55 years old, chronic Achilles or patellar tendinopathy of at least 6 months, failed conservative management including ESWT, and Ultrasound (US) evidence of neovascularisation, tendon thickening and echogenic changes. Outcome measures will be recorded at baseline, 6 weeks, 3, 6 and 12 months. Primary outcome measures include The Victoria Institute of Sport Assessments for Achilles and patellar tendinopathy (VISA-A and VISA-P) and VAS pain. Secondary outcome measures include Modified Ohberg score, maximum tendon diameter and assessment of hypoechoic appearance on US, and Functional Activity Assessment.DiscussionDespite previous interventional trials and reviews there is still insufficient evidence to guide injectable therapy for chronic tendinopathy that has failed conservative treatment. The scant evidence available suggests HVIGI has the greatest potential however there is no level one RCT evidence to support this. Investigating the efficacy of HVIGI against control in a RCT and separating the effect of HVIGI and corticosteroid will add high level evidence to the management of chronic tendinopathy resistant to conservative treatment.Trial RegistrationEudraCT: 2015-003587-36 3 Dec 2015

Histogenesis of cardiac myxoma: the potential role of the cardiac neural crest

Cardiac myxoma is the most common tumor of the heart. The myxoma arises in the region of the interatrial septum and the fossa ovalis, with the left atrium as the most common site of growth. The histogenesis of cardiac myxoma remains unclear. We have previously suggested that a clearer understanding of tumor origins can be achieved through a detailed investigation of heart development (1). In the heart, cardiac neural crest contributes to the septation of the outflow tract, the morphogenesis of the great arteries, and the maturation of the atrioventricular valves and the conduction system (2). We hypothesized that myxoma develops from resident cardiac neural crest cells, via a re-activation of the developmental programs that govern epithelial-mesenchymal transition. Immunohistochemical analysis for canonical markers calretinin, vimentin, α-SMA, CD31, CD34, S100, plus cardiac neural crest markers plexin A2 and semaphorin 3C was performed in one case of sporadic cardiac myxoma. Primary myxoma cell culture was obtained ex vivo via both single cell isolation and outgrowth methods. In vitro confocal microscopy confirms the presence of myxoma cells positive for calretinin, vimentin, α-SMA, CD31, CD34, S100, plexin A2 and semaphorin 3C. Expression of semaphorin 3C and plexin A2 was also confirmed by Western blot analysis. In order to characterize in vivo behaviour of cultured myxoma cells, 2,3x106 cells (cell culture passage 3) were subcutaneously inoculated in interscapular region of immunocompromised mouse. Newly formed tissue was processed for histological and immunohistochemical evaluations. Hematoxylin and eosin staining confirmed the myxoid background of the mass. Despite the presence of CD31-positive human cells, there was no evidence of neovascularization. Our preliminary findings confirm our hypothesis, suggesting that cardiac neural crest in adult heart could be involved in the pathogenesis of cardiac myxoma.

Abstract 19419: A Phase IIa Randomized Double-Blind, Placebo Controlled Study to Evaluate Plasmid Stromal Cell-Derived Factor-1 for Treatment of Critical Limb Ischemia - The STOP-CLI Trial

Background: Stromal cell-derived factor-1 (SDF-1) promotes tissue repair by increasing cell survival, endogenous stem cell recruitment and vasculogenesis. Preclinical studies demonstrated that non-viral DNA plasmid encoding human SDF-1 (pSDF-1) is safe and increased vessel density in animal models of hindlimb ischemia versus placebo. Additionally, clinical studies have demonstrated safety of pSDF-1 and evidence of neovascularization at the microvascular level. A Phase IIa multi-center double blind randomized placebo-controlled dose escalation study (STOP-CLI) was initiated to evaluate the safety and efficacy of pSDF-1 administered via direct intramuscular injection in patients with critical limb ischemia (CLI). Methods: Forty eight CLI (Rutherford 4 or 5) patients who were poor candidates for surgical revascularization on stable medical therapy with ankle systolic pressure ≤70 mmHg or toe systolic pressure ≤50 mmHg were enrolled into 4 cohorts (n=12 each). Within each cohort, subjects were randomized 3:1 to receive a single set of direct intramuscular injections (8 or 16) to the ischemic limb of escalating doses of 1 mg/ml pSDF-1 (4, 8, 8 or 16mg) or placebo and were followed for 12 months post-dosing. Efficacy endpoints include: quality of life via SF-36, visual analog scale (VAS), Rutherford class, time to first/number of amputations, wound healing, and survival. Results: Enrollment was completed in July 2013. At baseline, patients were, 58.6±13.7 years, 88% male, and had an equal number of Rutherford 4 and 5 (n=24 each). To date, 482 follow up months have been completed with 36 Serious Adverse Events reported, none drug-related. Interim 12 month efficacy results show patients who received 8 injections (8 x 1 mg) totaling 8 mg pSDF-1 improved in rest pain (VAS -3.3±2.5 cm vs. -0.8±2.4 cm; 8 x 1 mg injections vs. placebo, p=0.12) and demonstrate improvements in SF-36 Overall Physical (22.4 ± 27 vs. -2.6 ± 29.7, p=0.22) and Mental (21.0 ± 12.7 vs. 0.26 ± 28.2, p=0.16) Health. Final 12 month data will be available in September 2014. Conclusions: STOP-CLI tests the hypothesis that delivery of pSDF-1 is safe and will improve the clinical status of patients with CLI. The interim results of STOP-CLI demonstrate safety and bioactivity of pSDF-1 for treatment of CLI.

A murine macrofilaricide pre-clinical screening model for onchocerciasis and lymphatic filariasis.

BackgroundNew drugs effective against adult filariae (macrofilaricides) would accelerate the elimination of lymphatic filariasis and onchocerciasis. Anti-Onchocerca drug development is hampered by the lack of a facile model. We postulated that SCID mice could be developed as a fmacrofilaricide screening model.MethodsThe filaricides: albendazole (ABZ), diethylcarbamazine (DEC), flubendazole (FBZ), ivermectin (IVM) and the anti-Wolbachia macrofilaricide, minocycline (MIN) were tested in Brugia malayi (Bm)-parasitized BALB/c SCID mice vs vehicle control (VC). Responses were compared to BALB/c wild type (WT). Onchocerca ochengi male worms or onchocercomata were surgically implanted into BALB/c SCID, CB.17 SCID, BALB/c WT mice or Meriones gerbils. Survival was evaluated at 7–15 days. BALB/c SCID were tested to evaluate the responsiveness of pre-clinical macrofilaricides FBZ and rifapentine (RIFAP) against male Onchocerca.ResultsWT and SCID responded with >95% efficacy following ABZ or DEC treatments against Bm larvae (P < 0.0001). IVM was partially filaricidal against Bm larvae in WT and SCID (WT; 39.8%, P = 0.0356 and SCID; 56.7%, P = 0.026). SCID responded similarly to WT following IVM treatment of microfilaraemias (WT; 79%, P = 0.0194. SCID; 76%, P = 0.0473). FBZ induced a total macrofilaricidal response against adult Bm in WT and SCID (WT; P = 0.0067, SCID; P = 0.0071). MIN induced a >90% reduction in Bm Wolbachia burdens (P < 0.0001) and a blockade of microfilarial release (P = 0.0215) in SCID. Male Onchocerca survival was significantly higher in SCID vs WT mice, but not gerbils, after +15 days (60% vs 22% vs 39% P = 0.0475). Onchocercoma implants had engrafted into host tissues, with evidence of neovascularisation, after +7 days and yielded viable macro/microfilariae ex vivo. FBZ induced a macrofilaricidal effect in Onchocerca male implanted SCID at +5 weeks (FBZ; 1.67% vs VC; 43.81%, P = 0.0089). Wolbachia loads within male Onchocerca were reduced by 99% in implanted SCID receiving RIFAP for +2 weeks.ConclusionsWe have developed a ‘pan-filarial’ small animal research model that is sufficiently robust, with adequate capacity and throughput, to screen existing and future pre-clinical candidate macrofilaricides. Pilot data suggests a murine onchocercoma xenograft model is achievable.

Deletion of hemojuvelin, an iron-regulatory protein, in mice results in abnormal angiogenesis and vasculogenesis in retina along with reactive gliosis.

Loss-of-function mutations in hemojuvelin (HJV) cause juvenile hemochromatosis, an iron-overload disease. Deletion of Hjv in mice results in excessive iron accumulation and morphologic changes in the retina. Here, we studied the retinal vasculature in Hjv(-/-) mice. Age-matched wild-type and Hjv(-/-) mice were used for fluorescein angiography and preparation of retinal cryosections, flat-mounts, and trypsin-digested blood vessels. Retinal angiogenesis was monitored by immunofluorescent detection of isolectin-B4, endoglin, and VEGF. Retinal vasculogenesis was monitored by immunofluorescent detection of collagen IV. Reactive gliosis was assessed based on the expression of glial fibrillary acidic protein and vimentin and CD11b/c as markers for Müller cells and microglia. Between 18 and 24 months of age, retinas of Hjv(-/-) mice displayed marked disruptions in angiogenesis and vasculogenesis. Blood vessels in Hjv(-/-) mice were tortuous and dilated, with a decrease in the tight-junction protein occludin. There was also evidence of neovascularization in Hjv(-/-) mice with blood vessels appearing in the vitreous, which were leaky. There was reactive gliosis in these mice involving both Müller cells and microglia. Such changes were not detected at 2 weeks of age. Even at the age of 4 months, retinas of Hjv(-/-) mice were almost normal with changes just beginning to appear. Thus, the vascular changes in Hjv(-/-) mouse retinas represent an age-dependent phenomenon. Deletion of Hjv in mice leads to abnormal retinal angiogenesis/vasculogenesis, with proliferation of new, leaky blood vessels in the vitreous. These changes are accompanied with reactive gliosis involving Müller cells and microglia.

A murine macrofilaricide pre-clinical screening model for onchocerciasis and lymphatic filariasis

New drugs effective against adult filariae (macrofilaricides) would accelerate the elimination of lymphatic filariasis and onchocerciasis. Anti-Onchocerca drug development is hampered by the lack of a facile model. We postulated that SCID mice could be developed as a fmacrofilaricide screening model. The filaricides: albendazole (ABZ), diethylcarbamazine (DEC), flubendazole (FBZ), ivermectin (IVM) and the anti-Wolbachia macrofilaricide, minocycline (MIN) were tested in Brugia malayi (Bm)-parasitized BALB/c SCID mice vs vehicle control (VC). Responses were compared to BALB/c wild type (WT). Onchocerca ochengi male worms or onchocercomata were surgically implanted into BALB/c SCID, CB.17 SCID, BALB/c WT mice or Meriones gerbils. Survival was evaluated at 7–15 days. BALB/c SCID were tested to evaluate the responsiveness of pre-clinical macrofilaricides FBZ and rifapentine (RIFAP) against male Onchocerca. WT and SCID responded with >95% efficacy following ABZ or DEC treatments against Bm larvae (P < 0.0001). IVM was partially filaricidal against Bm larvae in WT and SCID (WT; 39.8%, P = 0.0356 and SCID; 56.7%, P = 0.026). SCID responded similarly to WT following IVM treatment of microfilaraemias (WT; 79%, P = 0.0194. SCID; 76%, P = 0.0473). FBZ induced a total macrofilaricidal response against adult Bm in WT and SCID (WT; P = 0.0067, SCID; P = 0.0071). MIN induced a >90% reduction in Bm Wolbachia burdens (P < 0.0001) and a blockade of microfilarial release (P = 0.0215) in SCID. Male Onchocerca survival was significantly higher in SCID vs WT mice, but not gerbils, after +15 days (60% vs 22% vs 39% P = 0.0475). Onchocercoma implants had engrafted into host tissues, with evidence of neovascularisation, after +7 days and yielded viable macro/microfilariae ex vivo. FBZ induced a macrofilaricidal effect in Onchocerca male implanted SCID at +5 weeks (FBZ; 1.67% vs VC; 43.81%, P = 0.0089). Wolbachia loads within male Onchocerca were reduced by 99% in implanted SCID receiving RIFAP for +2 weeks. We have developed a `pan-filarial’ small animal research model that is sufficiently robust, with adequate capacity and throughput, to screen existing and future pre-clinical candidate macrofilaricides. Pilot data suggests a murine onchocercoma xenograft model is achievable.

The value of coronary angiography in the work-up of atrial myxomas

Atrial myxomas are the most common primary cardiac tumors. They are highly vascular with evidence of neovascularization and a characteristic"tumor blush" in approximately half of the cases. Although the visualization of feeding vessels has several clinical and therapeutic implications, there is still no consensus on the indication of preoperative coronary angiography to assess tumor vascularity except in patients with angina or those older than 40 years to rule out coronary artery disease. Herein, I present a case of an incidentally discovered right atrial mass receiving vascular supply from the right coronary artery. The mass was successfully excised and the diagnosis of cardiac myxoma was confirmed via histopathology. A review of the value of coronary angiography in detecting myxoma neovascularization is provided, which suggests that it can offer additional valuable information that can alter the surgical approach and therefore may be considered prior to myxoma resection.

An Animal Explant Model for the Study of Human Cutaneous Squamous Cell Carcinoma

We established a human tissue explant model to facilitate study of cutaneous squamous cell carcinoma. We accomplished this by implanting debulked SCC, from surgical discard, into nude rats. Human SCC remained viable and continued to proliferate for at least 4 weeks and showed evidence of neovascularization. At 4 weeks, SCC implants showed a trend toward increased PCNA positive cells compared to fresh SCC cells/mm2 tissue) supporting continued proliferation throughout engraftment. Von Willebrand's Factor (VWF) positive cells were found within implants and likely represented rat vessel neovascularization. Human Langerhans' (Langerin+) cells, but no T cells (CD3+, CD8+, FoxP3+), macrophages (CD163), or NK cells (NKp46), were present in SCC implants at 4 weeks. These findings support the possibility that LCs fail to migrate from cutaneous SCC and thus contribute to lack of effective antitumor response. Our findings also provide a novel model system for further study of primary cutaneous SCC.

Surgical stimulation of angiogenesis

The results of surgical approaches are unsatisfactory in patients with a distal arterial bed that is ineligible for revascularization. In this retrospective study, we investigated outcomes in patients who underwent surgical interventions that are reported to induce angiogenesis. 6 patients diagnosed with thromboangiitis obliterans were included in this study. Of these 6 patients, 2 underwent femoropopliteal bypass surgery using reversed great saphenous vein as a conduit. The other 4 underwent ascending venous arterialization (bypass from the popliteal artery to the great saphenous vein at the level of medial malleolus, using reversed great saphenous vein). During the early postoperative period, all of the reversed saphenous vein grafts were occluded. The mean postoperative ankle-brachial index increased from 0.33 to 0.83. During the postoperative period, intermittent claudication disappeared in all patients. Angiograms taken during the postoperative period showed evidence of neovascularization when compared to those taken during preoperative evaluation. Wound healing is an inflammatory process that simultaneously activates angiogenesis. We propose that the improved ankle-brachial index values and neovascularization shown in our patients were associated with this inflammatory process.