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OBJECTIVE: We characterized and correlated endothelial progenitor cells (EPCs) and circulating progenitor cells (CPCs) with lack of vascular complications in the Joslin Medalist Study in patients with type 1 diabetes for 50 years or longer. RESEARCH DESIGN AND METHODS: EPC and CPC levels were ascertained by flow cytometry and compared among Medalists (n = 172) with or without diabetic retinopathy (DR; n = 84 of 162), neuropathy (n = 94 of 165), diabetic nephropathy (DN; n = 18 of 172), cardiovascular disease (CVD; n = 63 of 168), age-matched controls (n = 83), type 2 diabetic patients (n = 36), and younger type 1 diabetic patients (n = 31). Mitogens, inflammatory cytokines, and oxidative markers were measured in blood or urine. Migration of cultured peripheral blood mononuclear cells (PBMCs) from Medalists and age-matched controls were compared. RESULTS: Medalists' EPC and CPC levels equaled those of their nondiabetic age-matched controls, were 10% higher than those in younger type 1 diabetic patients, and were 20% higher than those in age-matched type 2 diabetic patients. CPC levels were 15% higher in Medalists without CVD and nephropathy than in those affected, whereas EPC levels were significantly higher in those without peripheral vascular disease (PVD) than those with PVD. Stromal-derived factor 1 (SDF-1) levels were higher in Medalists with CVD, DN, and DR than in those not affected and their controls. IGF-I levels were lower in Medalists and correlated inversely with CPC levels. Additionally, cultured PBMCs from Medalists migrated more than those from nondiabetic controls. CONCLUSIONS: Normal levels of EPC and CPC in the Medalists, unlike other groups with diabetes, especially those without CVD, support the idea that endogenous factors exist to neutralize the adverse effects of metabolic abnormalities of diabetes on vascular tissues.
PURPOSE: We characterized antigen-presenting cell (APC)-relevant chemokine receptor expression in dry eye disease (DED), and investigated the effect of topical CC chemokine receptor (CCR)-7 blockade specifically on Th17 cell immunity and dry eye disease severity. METHODS: We induced DED in female C57BL/6 mice. Chemokine receptor expression by corneal APCs was characterized using immunohistochemistry. To determine the functional role of CCR7 in DED, mice were treated topically with either anti-CCR7, a control isotype antibody, or left untreated, and clinical disease severity, Th17 responses, and molecular markers of DED were quantified. RESULTS: Frequencies of CD11b(+) cells and their chemokine expression were increased in the cornea of DED mice. Mice treated topically with anti-CCR7 antibody displayed a significant reduction in clinical disease severity and Th17 response compared to the isotype and untreated groups. Topical CCR7 blockade was effective in ameliorating DED in its acute and chronic stages. CONCLUSIONS: Our findings suggest that CCR7-mediated trafficking of APCs drives the induction and maintenance of Th17 immunity in DED and that CCR7 blockade is effective in suppressing the immunopathogenic mechanisms in DED.
OBJECTIVES: To evaluate the short-term efficacy of triamcinolone acetonide versus bevacizumab for the treatment of diabetic, clinically significant, macular edema with different optical coherence tomography findings. METHODS: Fifty eyes of 45 consecutive patients with diabetic, clinically significant, macular edema were incorporated in this prospective interventional case series. Patients were divided into 3 groups according to findings on optical coherence tomography: 1) macular edema combined with serous retinal detachment (Group 1), 2) diffused macular thickening (Group 2), and 3) cystoid macular edema (Group 3). Patients from each group were treated with a single intravitreal injection of triamcinolone (IVTA) or 2 intravitreal injections of bevacizumab (IVB) with an interval of 6 weeks. Patients were observed at 6, 12, and 24 weeks after IVTA or the first IVB injection. Best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were examined at each visit. Repeated-measures analysis of variance was used to compare the efficacy of the treatment groups. RESULTS: In Group 1, IVTA showed more favorable effects on CRT reduction and BCVA improvement compared with IVB at 6, 12, and 24 weeks (P = 0.002, 0.001, 0.027 and P = 0.036, 0.001, 0.027), respectively. In Group 2, IVB had more CRT reduction than IVTA at 6 and 12 weeks (P = 0.013 and 0.036), although there was no significant difference in BCVA improvement between the 2 groups (P > 0.05). In Group 3, IVTA and IVB did not have significant effects on CRT reduction and BCVA improvement (P > 0.05). CONCLUSION: The short-term efficacy of IVTA and IVB on treating clinically significant macular edema varied with different optical coherence tomography findings. In clinically significant macular edema combined with serous retinal detachment, IVTA may be more favorable than IVB in CRT reduction and BCVA improvement. In patients with diffused macular thickening, IVB may be better than IVTA in macular thickness reduction, although this does not translate to a significant improvement in BCVA.
In the so-called McGurk illusion, when the synchronized presentation of the visual stimulus /ga/ is paired with the auditory stimulus /ba/, people in general hear it as /da/. Multisensory integration processing underlying this illusion seems to occur within the Superior Temporal Sulcus (STS). Herein, we present evidence demonstrating that bilateral cathodal transcranial direct current stimulation (tDCS) of this area can decrease the McGurk illusion-type responses. Additionally, we show that the manipulation of this audio-visual integrated output occurs irrespective of the number of eye-fixations on the mouth of the speaker. Bilateral anodal tDCS of the Parietal Cortex also modulates the illusion, but in the opposite manner, inducing more illusion-type responses. This is the first demonstration of using non-invasive brain stimulation to modulate multisensory speech perception in an illusory context (i.e., both increasing and decreasing illusion-type responses to a verbal audio-visual integration task). These findings provide clear evidence that both the superior temporal and parietal areas contribute to multisensory integration processing related to speech perception. Specifically, STS seems fundamental for the temporal synchronization and integration of auditory and visual inputs. For its part, posterior parietal cortex (PPC) may adjust the arrival of incoming audio and visual information to STS thereby enhancing their interaction in this latter area.
PURPOSE: To determine the imaging features of common intraocular foreign bodies (IOFBs) and the ability to differentiate types of IOFBs. METHODS: Four-mm IOFBs were inserted via through pars plana approach into cadaveric lamb eyes. Six metallic (aluminum, brass, copper, silver, steel, and lead) and seven nonmetallic (plastic [CF6 spectacle plastic and polyvinyl chloride pipe], glass [bottle glass and windshield glass], wood [dry and wet poplar], and stone [slate]) IOFBs were imaged using plain film x-ray, computed tomography scan, ultrasound, and magnetic resonance imaging (T1, T2, and gradient echo sequences). RESULTS: Plain film x-ray had limited ability to differentiate most IOFBs. Computed tomography findings can be divided into low attenuation objects (wood), moderate attenuation (CF6 spectacle plastic), high attenuation without surrounding artifact (polyvinyl chloride, slate, bottle glass, windshield glass, and aluminum), high attenuation with shadow artifact and minimal edge streak artifact (steel, brass, copper), and high attenuation with significant shadow artifact and prominent streak artifact (silver and lead). Density (in Hounsfield units) aided in differentiating the types of IOFBs. Gradient echo sequences on magnetic resonance imaging also held utility. Ultrasound images had considerable overlap in appearances. CONCLUSION: Imaging techniques can significantly aid in determining the IOFBs type, with computed tomography serving as the best initial modality. X-ray holds limited utility while ultrasound and magnetic resonance imaging are best reserved as adjunctive tests.
Neuropilin-1 (NRP1) is a receptor for vascular endothelial growth factor (VEGF). A soluble isoform of Nrp1 (sNrp1) has not been described in the mouse. Our goal was to examine the expression of mouse sNrp1 during liver development and regeneration.sNrp1 was cloned from mouse liver. The expression of sNrp1 and VEGF was examined in mouse liver during post-natal development and regeneration using northern blot, western blot, in situ hybridisation, and immunohistochemical analyses. HGF/NRP1 binding was examined in vitro.A novel 588-amino acid sNrp1 isoform was found to contain the ligand binding regions of Nrp1. The adult liver expressed more sNrp1 than full-length Nrp1. In vivo, hepatocytes constitutively expressed VEGF and sNrp1 in the quiescent state. sNrp1 was highly up-regulated at P20, a time point coinciding with a plateau in liver and body weights. Following hepatectomy, endogenous levels of sNrp1 decreased during the rapid growth phase, and VEGF levels were highest just prior to and during the angiogenic phase. sNrp1 levels again rose 5-10 days post-hepatectomy, presumably to control regeneration. HGF protein bound NRP1 and binding was competed with sNRP1.We cloned a novel mouse sNrp1 isoform from liver and provide evidence that this endogenous angiogenesis inhibitor may regulate VEGF or HGF bioavailability during normal physiological growth and development as well as during liver regeneration.
PURPOSE: The purpose of this report was to describe a case of spontaneous resolution of a large postvitrectomy macular hole retinal detachment. METHODS: Case report and optical coherence tomography imaging. RESULTS: A 64-year-old man with history of macula-off retinal detachment and 4 previous vitrectomies in the left eye developed a macular hole and associated retinal detachment 3 months after his last vitreoretinal surgery. Two months later, examination revealed that the macular hole had spontaneously closed, and the retinal detachment had resolved. CONCLUSION: Spontaneous resolution of macular hole-associated retinal detachment in a previously vitrectomized eye has not been reported previously. Changes in tangential traction by the associated epiretinal membrane, improvement of the cystoid changes noted at the edge of the macular hole, and/or proliferation of glial tissue to bridge the hole, along with the absorption of the subretinal fluid by the retinal pigment epithelium pump contributed to this rare event have been hyphothesized.
PURPOSE: To investigate the expression of inflammatory cytokines in ARPE-19 cells after stimulation with cholesterol crystals. METHODS: APRE-19 cells were cultured, primed with IL-1α, and treated with cholesterol crystals under different concentrations. Inflammatory cytokines (mature-IL-1β, IL-6, and IL-8) in supernatant and inflammatory cytokines (pro-IL-1β, IL-18) in cell lysate were detected by western blot. The NF-κB pathway inhibitor BAY 11-7082 was used to determine the pathway of cytokine expression. RESULTS: Cholesterol crystals did not induce the nucleotide-binding domain leucine-rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome, but did increase pro-IL-1β expression in ARPE-19 cells. Cholesterol crystals increased pro-IL-1β expression by activating the NF-κB pathway. Cholesterol crystal activation of the NF-κB pathway also leads to increased IL-6 and IL-8 expression. CONCLUSION: Cholesterol crystals can induce inflammatory cytokine expression in ARPE-19 cells by activating the NF-κB pathway.
INTRODUCTION: Orbital lymphatic malformations (OLMs) are a unique subset of head and neck low flow vascular malformations, located either in the periorbital region or in the closed orbital cavity. We discuss our experience of minimally invasive strategies of treatment using advanced imaging and Bleomycin sclerotherapy to effectively treat these malformations. MATERIALS AND METHODS: Between 2008 and 2013, we have treated 54 cases of orbital low flow vascular malformations including 22 cases of OLMs of which 16 were treated using Bleomycin. This retrospective analysis was performed from patient charts, operative reports, operative images, pre-operative, and post-operative MR imaging. Bleomycin was used for sclerotherapy in all the cases with a maximum dose per session of treatment limited to 15 mgs. DIRECT PUNCTURE SCLEROTHERAPY TECHNIQUE: OLMs target was determined using pre-procedure MR imaging and direct puncture either per-cutaneous or per-conjunctival was achieved using ultrasound or i-guide guidance. In most lymphatic fluid was drained else the position confirmed with constrast injection under fluoroscopy. Bleomycin was used either undiluted or in various concentrations mixed with saline, or contrast material and recently we favor the use of Bleofoam mixed with 25% Human albumin and air. Microcystic LMs, were treated using gravity technique, the needle track was sealed with Surgiflo or Floseal. In cases of intra cystic or intra ocular haemorrhage with elevated orbital pressure, lateral canthotomy was performed to prevent permanent damage to vision and the contents of the orbit. Postoperatively, the patients recover in ICU and monitored for vision and orbital swelling. Bleomycin skin precautions were followed for 72 h in order to avoid skin hyperpigmentation. Optimal results were obtained at 6 to 8 weeks and assessed using follow-up MRI and ophthalmologic evaluation. RESULTS: The patient's age ranged from 1 to 45 years, with equal male to female ratio. Most cases (13/16) (80%) presented non acutely while three patients (20%) presented acutely with proptosis, visual disturbance and double vision due to haemorrhage within the malformation. Treatment completed in 14, one lost to follow up and the other is yet to be followed. The follow up period ranged from 6weeks to 6 months. 65% (9/14) needed less than three procedures while the remaining five patients needed between 3-5 procedures. All patients had improvement in proptosis; vision either remained stable or improved; volume reduction of more than 80% was noted in 57% (8/14), while the remaining patients 43% had volume reduction of 50-79%. One patient had transient mydriasis post procedure that completely recovered at three months. Another developed haemorrhage within the malformation immediate post sclerotherapy requiring lateral canthotomy, drainage and redo sclerotherapy. None of our patients developed skin pigmentation or pulmonary complication related to bleomycin usage. CONCLUSION: Bleomycin sclerotherapy combined with appropriate image guidance for precise target localization is an effective and safe treatment for OLMs. Bleomycin is a preferred sclerosant as it induces minimal inflammation and post procedure swelling. Standard precautions must be instituted to prevent cutaneous pigmentation and pulmonary fibrosis. DISCLOSURES: S. Paramasivam: None. A. Fay: None. J. Fifi: None. A. Berenstein: None.
