ABSTRACT
Myotonic dystrophy type I (DM1) exhibits distinctive disease specific phenotypes and the accelerated onset of a spectrum of age-associated pathologies. In DM1, dominant effects of expanded CUG repeats result in part from the inactivation of the muscleblind-like (MBNL) proteins. To test the role of MBNL3, we deleted Mbnl3 exon 2 (Mbnl3(ΔE2)) in mice and examined the onset of age-associated diseases over 4 to 13 months of age. Accelerated onset of glucose intolerance with elevated insulin levels, cardiac systole deficits, left ventricle hypertrophy, a predictor of a later onset of heart failure and the development of subcapsular and cortical cataracts is observed in Mbnl3(ΔE2) mice. Retention of embryonic splice isoforms in adult organs, a prominent defect in DM1, is not observed in multiple RNAs including the Insulin Receptor (Insr), Cardiac Troponin T (Tnnt2), Lim Domain Binding 3 (Ldb3) RNAs in Mbnl3(ΔE2) mice. Although rare DM1-like splice errors underlying the observed phenotypes cannot be excluded, our data in conjunction with the reported absence of alternative splice errors in embryonic muscles of a similar Mbnl3(ΔE2) mouse by RNA-seq studies, suggest that mechanisms distinct from the adult retention of embryonic splice patterns may make important contributions to the onset of age-associated pathologies in DM1.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Alternative Splicing , Carrier Proteins/physiology , LIM Domain Proteins/genetics , Muscle, Skeletal/pathology , Myotonic Dystrophy/pathology , Animals , Exons , Gene Expression Regulation, Developmental , Glucose Intolerance , Male , Mice , Mice, Knockout , Muscle, Skeletal/metabolism , Myotonic Dystrophy/etiology , Myotonic Dystrophy/metabolism , Protein Binding , RNA-Binding ProteinsABSTRACT
PURPOSE: We evaluated the effect of the renin angiotensin system (RAS) peptide NorLeu3-Angiotensin (1-7) (NLE) formulated in a viscoelastic gel (USB004) on the healing of full-thickness corneal injuries. METHODS: Dutch pigmented rabbits received conjunctival administration of 0.3% USB004, 0.03% USB004, or vehicle-control to healthy and full-thickness injured eyes administered once daily for 28 consecutive days. Safety was evaluated using IOP measurement, slit-lamp examination, and confocal microscopy. Evaluations for both efficacy studies included an oblique light examination, modified Seidel test (Seidel test with gentle ocular pressure) as well as during elevated IOP test, confocal microscopy imaging, and histologic analysis. RESULTS: Application of 0.3% USB004, 0.03% USB004, and vehicle-control was safe in healthy and incised eyes. Further, application of 0.3% and 0.03% USB004 following full-thickness corneal incision resulted in a 2-fold acceleration of resolution of edema and inflammation, reduction in duration of wound leakage on a modified Seidel test (Seidel test with gentle ocular pressure) as well as during elevated IOP test, and healing with near normal architecture without evidence of fibrosis and angiogenesis when compared to vehicle-control animals. CONCLUSIONS: Topical ocular application of 0.3% and 0.03% USB004 promotes full-thickness cornea wound healing without the evidence of fibrosis and angiogenesis. Further studies are warranted to determine the cornea-specific mechanism of action(s) that promotes regeneration leading to clear corneal healing.
Subject(s)
Angiotensin II/therapeutic use , Corneal Injuries/drug therapy , Peptide Fragments/therapeutic use , Wound Healing/drug effects , Administration, Ophthalmic , Animals , Cicatrix/prevention & control , Cornea/ultrastructure , Intraocular Pressure/drug effects , Microscopy, Confocal , Microscopy, Electron, Scanning , Rabbits , Slit LampABSTRACT
PURPOSE: To study the potential efficacy of ultrasound (US) assisted by custom liposome (CLP) destruction as an innovative thrombolytic tool for the treatment of retinal vein occlusion (RVO). METHODS: Experimental RVO was induced in the right eyes of 40 rabbits using laser photothrombosis; the US experiment took place 48 hours later. Rabbits were randomly divided into four equal groups: US+CLP group, US+saline group, CLP+sham US group, and no treatment group. The latter three groups acted as controls. Fundus fluorescein angiography and Doppler US were used to evaluate retinal blood flow. RESULTS: CLP-assisted US thrombolysis resulted in restoration of flow in seven rabbits (70%). None of the control groups showed significant restoration of retinal venous blood flow. CONCLUSIONS: US-assisted thrombolysis using liposomes resulted in a statistically significant reperfusion of retinal vessels in the rabbit experimental model of RVO. This approach might be promising in the treatment of RVO in humans. Further studies are needed to evaluate this approach in patients with RVO. Ultrasound assisted thrombolysis can be an innovative tool in management of retinal vein occlusion.
Subject(s)
Disease Models, Animal , Liposomes/administration & dosage , Retinal Vein Occlusion/therapy , Thrombolytic Therapy/methods , Ultrasonography, Interventional/methods , Animals , Blood Flow Velocity , Fluorescein Angiography , Microspheres , Rabbits , Regional Blood Flow , Reperfusion , Retinal Vein/physiology , Retinal Vein Occlusion/diagnosis , Retinal Vein Occlusion/physiopathology , Rose Bengal/administration & dosage , Treatment Outcome , Ultrasonography, DopplerABSTRACT
Optimal management of posterior segment disorders requires a high-resolution and preferably noninvasive imaging tool for better definition of diseases. High-resolution optical coherence tomography can provide noninvasive, high-definition imaging of the posterior segment, allowing earlier diagnosis, better follow-up of chronic cases, and more accurate and timely monitoring of the effect of therapeutic agents. Recent findings suggest an individualized approach to vitreoretinal and choroidal diseases is possible based not only on traditional ophthalmic investigations, but also on high-resolution optical coherence tomography. This innovative tool has the combined advantages of high speed, high resolution, and safe use.
