The Role of Hoxd10 in the Development of the Motoneurons in the Posterior Spinal Cord

Hox genes encode anterior-posterior identity during central nervous system development. Few studies have examined Hox gene function at lumbosacral (LS) levels of the spinal cord, where there is extensive information on normal development. Hoxd10 is expressed at high levels in the embryonic LS spinal cord, but not the thoracic (T) spinal cord. To test the hypothesis that restricted expression of Hoxd10 contributes to the attainment of an LS identity, and specifically an LS motoneuron identity, Hoxd10 was ectopically expressed in T segments in chick embryos via in ovo electroporation. Electroporations were carried out at early neural tube stages (stages 13-15) and at the onset of motoneuron differentiation (stages 17-18). Regional motoneuron identity was assessed after the normal period of motor column formation (stages 28-29). Subsets of motoneurons in transfected T segments developed a molecular profile normally shown by anterior LS LMCl motoneurons, including Lim 1 and RALDH2 expression. In addition, motoneurons in posterior T segments showed novel axon projections to two muscles in the anterodorsal limb, the sartorius and anterior iliotibialis muscles. These changes are accompanied by a significant reduction in the number of T motoneurons at stage 29. Analyses of Hoxd10 electroporated embryos at the onset of motor column formation (stage 18) suggest that early and high levels of Hoxd10 expression led to the death of some early differentiating motoneuron. Despite these adverse effects, our data indicate that Hoxd10 expression is sufficient to induce LS motoneuron identity and axon trajectories characteristic of motoneurons in the LS anterior spinal cord. Equivalent changes in motoneuron identity were not found with the ectopic expression of Hoxd9, a gene normally expressed in T as well as LS segments. In an additional series of experiments, Hoxd10 was overexpressed in LS segments via in ovo electroporation at early neural tube stages. Analyses at stage 29 indicated proportionate increases in LMCl (Lim 1+, RALDH2+) motoneurons, and proportionate decreases in LMCm and MMC motoneurons (Isl 1+) motoneurons. These findings suggest that Hoxd10 specifically promotes the development and/or survival of LMCl motoneurons

Biocompatible Reverse Thermal Gel Sustains the Release of Intravitreal Bevacizumab In Vivo

PURPOSE. We assessed the in vivo release profile of bevacizumab from and biocompatibility of poly(ethylene glycol)-poly-(serinol hexamethylene urethane), or ESHU, a thermoresponsive hydrogel administered intravitreally for drug delivery. METHODS. The technical feasibility of injection was assessed quantitatively via mechanical testing. For in vivo studies, New Zealand White rabbit eyes were injected intravitreally with 0.05 mL of either: ESHU dissolved in 25 mg/mL bevacizumab, ESHU dissolved in PBS, or 25 mg/mL bevacizumab. Clinical examination included IOP measurements and examination with indirect ophthalmoscopy for signs of inflammation. Additionally, eyes were examined histologically following euthanasia. To quantify bevacizumab release, aqueous humor samples were obtained via anterior chamber paracentesis and ELISA was used to determine the concentration of drug weekly. In vitro cytotoxicity testing also was performed using bovine corneal endothelial cells. RESULTS. The ESHU was injected easily through a 31-gauge needle, was well tolerated in vivo, and caused minimal cell death in vitro when compared to other common materials, such as silicone oil. The long-term presence of the gel did not affect IOP, and there was no evidence of inflammation histologically or through indirect observation. The ESHU sustained the release of bevacizumab for over 9 weeks and maintained a drug concentration that averaged 4.7 times higher than eyes receiving bolus bevacizumab injections. CONCLUSIONS. To our knowledge, this is the first report demonstrating sustained bevacizumab release in vivo from an intravitreally injected hydrogel formulation, suggesting that this delivery system may be a promising candidate for ocular drug delivery. Keywords: thermally responsive hydrogel, ocular drug delivery, sustained release, biocompatibility, injectable gel C horoidal neovascularization (CNV) is the hallmark of many blinding disorders, most notably wet age-related macular degeneration (AMD) and diabetic retinopathy. It is characterized by pathologic blood vessel growth, which originates in the choroid and progresses through the Bruch's membrane into the subretinal space. 1 These vessels are fragile and permeable, causing hemorrhage, retinal detachment, scarring, and ultimately, loss of central vision. Elevated levels of VEGF is a central cause of CNV. 2-4 Thus, intravitreal injection of anti-VEGF medications, such as bevacizumab (Avastin) or ranibizumab (Lucentis), has emerged as a leading treatment strategy. 10-13 Therefore, a delivery system that extends the presence of intravitreal drugs in the eye is highly desirable for reducing injection frequency and adverse effects, while maximizing therapeutic outcomes. A number of polymeric delivery systems have been considered by researchers for intravitreal drug delivery, including microparticles, which are well tolerated in the eye and are capable of delivering drugs over a longer period of time. 14,15 For example, microparticle-encapsulated or PEGylated bevacizumab is more effective than bevacizumab alone in treating CNV in rats

Phenotypic expansion of Bosch-Boonstra-Schaaf optic atrophy syndrome and further evidence for genotype-phenotype correlations

Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS) is an autosomal dominant neurodevelopmental disorder caused by loss-of-function variants in NR2F1 and characterized by visual impairment, developmental delay, and intellectual disability. Here we report 18 new cases, provide additional clinical information for 9 previously reported individuals, and review an additional 27 published cases to present a total of 54 patients. Among these are 22 individuals with point mutations or in-frame deletions in the DNA-binding domain (DBD), and 32 individuals with other types of variants including whole-gene deletions, nonsense and frameshift variants, and point mutations outside the DBD. We corroborate previously described clinical characteristics including developmental delay, intellectual disability, autism spectrum disorder diagnoses/features thereof, cognitive/behavioral anomalies, hypotonia, feeding difficulties, abnormal brain MRI findings, and seizures. We also confirm a vision phenotype that includes optic nerve hypoplasia, optic atrophy, and cortical visual impairment. Additionally, we expand the vision phenotype to include alacrima and manifest latent nystagmus (fusional maldevelopment), and we broaden the behavioral phenotypic spectrum to include a love of music, an unusually good long-term memory, sleep difficulties, a high pain tolerance, and touch sensitivity. Furthermore, we provide additional evidence for genotype-phenotype correlations, specifically supporting a more severe phenotype associated with DBD variants

Timing and frequency synchronization in orthogonal frequency division multiplexing broadband wireless systems

Thesis (M.Eng.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2001.Includes bibliographical references (p. 87-89).by Veeral S. Shah.M.Eng

Ain't No Sunshine When You Are Gone!

An 18 year-old Latin American female presented with progressive visual loss OD over 6 weeks.An 18 year-old Latin American female presented with progressive visual loss OD over 6 weeks. She initially had blurry vision and photophobia OD with a central scotoma OD on HVF testing. At that time, examination revealed a right swollen optic nerve with retinal hemorrhages. She was otherwise healthy, and denied any eye pain, neurological deficits, trauma medications, tobacco, alcohol, or drug use.A fat suppressed orbital MRI scan showed evidence of optic nerve enhancement OD.MRIIntracanalicular right optic nerve specimen showed dense fibrovascular tissue with macrophage infiltrates. Intracranial portion of the right optic nerve specimen revealed large pleomorphic and hyperchromatic atypical cells infiltrating the nerve. Sectioned tissue underwent immunostaining for GFAP, Ki67, Olig 2, and IDH1. These atypical cells were strongly GFAP positive, but were negative for Olig and IDH1. The Ki67 index of the posterior margin of the tissue was 4-5%.This patient was managed aggressively with surgical resection of the pre-chiasmal tumor, and treated post-operatively with Temozolomide and stereotactic radiotherapy treatment.Attache

Ain't No Sunshine When You Are Gone!

An 18 year-old Latin American female presented with progressive visual loss OD over 6 weeks.An 18 year-old Latin American female presented with progressive visual loss OD over 6 weeks. She initially had blurry vision and photophobia OD with a central scotoma OD on HVF testing. At that time, examination revealed a right swollen optic nerve with retinal hemorrhages. She was otherwise healthy, and denied any eye pain, neurological deficits, trauma medications, tobacco, alcohol, or drug use.A fat suppressed orbital MRI scan showed evidence of optic nerve enhancement OD.MRIIntracanalicular right optic nerve specimen showed dense fibrovascular tissue with macrophage infiltrates. Intracranial portion of the right optic nerve specimen revealed large pleomorphic and hyperchromatic atypical cells infiltrating the nerve. Sectioned tissue underwent immunostaining for GFAP, Ki67, Olig 2, and IDH1. These atypical cells were strongly GFAP positive, but were negative for Olig and IDH1. The Ki67 index of the posterior margin of the tissue was 4-5%.This patient was managed aggressively with surgical resection of the pre-chiasmal tumor, and treated post-operatively with Temozolomide and stereotactic radiotherapy treatment.Attache

Ain't No Sunshine When You Are Gone!

An 18 year-old Latin American female presented with progressive visual loss OD over 6 weeks.An 18 year-old Latin American female presented with progressive visual loss OD over 6 weeks. She initially had blurry vision and photophobia OD with a central scotoma OD on HVF testing. At that time, examination revealed a right swollen optic nerve with retinal hemorrhages. She was otherwise healthy, and denied any eye pain, neurological deficits, trauma medications, tobacco, alcohol, or drug use.A fat suppressed orbital MRI scan showed evidence of optic nerve enhancement OD.MRIIntracanalicular right optic nerve specimen showed dense fibrovascular tissue with macrophage infiltrates. Intracranial portion of the right optic nerve specimen revealed large pleomorphic and hyperchromatic atypical cells infiltrating the nerve. Sectioned tissue underwent immunostaining for GFAP, Ki67, Olig 2, and IDH1. These atypical cells were strongly GFAP positive, but were negative for Olig and IDH1. The Ki67 index of the posterior margin of the tissue was 4-5%.This patient was managed aggressively with surgical resection of the pre-chiasmal tumor, and treated post-operatively with Temozolomide and stereotactic radiotherapy treatment

Pediatric Neuromuscular Disorders (Slides)

Disruption of the neuromuscular transmission, either at the presynaptic or postsynaptic junction, may result in fatigability and muscle weakness that commonly affect ocular motility and lid movement. We will review several of the pediatric disorders that influence neuromuscular transmission.MGsha

2018 Generation Next Genetic Testing for Inherited Neuro-Ophthalmic Diseases Genomic Ophthalmology Workshop #1: Single Gene Testing

This CPNO event is to promote the role of practicing neuro-ophthalmologists to translate genetic testing and genomic medicine tools into management and intervention. With increasing accessibility of genetic testing, the burden of ordering, interpreting, and translating genetic testing information into clinical management, many times falls on the practicing neuro-ophthalmologist. With limited availability of a geneticist or genetic counselor, neuro-ophthalmologists may feel overwhelmed when evaluating genomic medicine data and translating this information into clinical management and genetic counseling. The purpose of this new skill transfer workshop is to introduce the use of online genomic tools and databases and to empower neuro-ophthalmologist to interpret genetic testing and translate this information into clinical management. This course will begin with a brief didactic session on genetic testing followed by a representative neuro-ophthalmology case-based presentation that applies and utilizes online-based genomic tools. At the conclusion of this course, the attendees will be able to: 1) identify candidates for genomic testing, and select the appropriate; test for a patient; 2) learn the different type of genetic testing: single-, multi-gene assays, and whole exome/genome sequencing; 3) utilize web-based databases (i.e. OMIN, ClinVar) that describe genotype, phenotype, and pathogenicity to make accurate diagnosis of genetic diseases; 4) interpret genomic medicine data and translate this information into clinical management and genetic counseling. The program's goal is to introduce a framework to evaluate genetic testing that would have broad appeal among both practicing adult and pediatric neuro-ophthalmologists.ICtestinggeneticdisorder

Pediatric Neuromuscular Disorders

Disruption of the neuromuscular transmission, either at the presynaptic or postsynaptic junction, may result in fatigability and muscle weakness that commonly affect ocular motility and lid movement. We will review several of the pediatric disorders that influence neuromuscular transmission.MGsha