Julio C. Echegoyen

Prevention of plasticity of endocannabinoid signaling inhibits persistent limbic hyperexcitability caused by developmental seizures.

Depolarization-induced suppression of inhibition (DSI) is an endocannabinoid-mediated short-term plasticity mechanism that couples postsynaptic Ca2+ rises to decreased presynaptic GABA release. Whether the gain of this retrograde synaptic mechanism is subject to long-term modulation by glutamatergic excitatory inputs is not known. Here, we demonstrate that activity-dependent long-term DSI potentiation takes place in hippocampal slices after tetanic stimulation of Schaffer collateral synapses. This activity-dependent, long-term plasticity of endocannabinoid signaling was specific to GABAergic synapses, as it occurred without increases in the depolarization-induced suppression of excitation. Induction of tetanus-induced DSI potentiation in vitro required a complex pathway involving AMPA/kainate and metabotropic glutamate receptor as well as CB1 receptor activation. Because DSI potentiation has been suggested to play a role in persistent limbic hyperexcitability after prolonged seizures in the developing brain, we used these mechanistic insights into activity-dependent DSI potentiation to test whether interference with the induction of DSI potentiation prevents seizure-induced long-term hyperexcitability. The results showed that the in vitro, tetanus-induced DSI potentiation was occluded by previous in vivo fever-induced (febrile) seizures, indicating a common pathway. Accordingly, application of CB1 receptor antagonists during febrile seizures in vivo blocked the seizure-induced persistent DSI potentiation, abolished the seizure-induced upregulation of CB1 receptors, and prevented the emergence of long-term limbic hyperexcitability. These results reveal a new form of activity-dependent, long-term plasticity of endocannabinoid signaling at perisomatic GABAergic synapses, and demonstrate that blocking the induction of this plasticity abolishes the long-term effects of prolonged febrile seizures in the developing brain.

Inclusion body myositis-like phenotype induced by transgenic overexpression of βAPP in skeletal muscle

Inclusion body myositis (IBM), the most common age-related muscle disease in the elderly population, is an incurable disorder leading to severe disability. Sporadic IBM has an unknown etiology, although affected muscle fibers are characterized by many of the pathobiochemical alterations traditionally associated with neurodegenerative brain disorders such as Alzheimers disease. Accumulation of the amyloid-β peptide, which is derived from proteolysis of the larger amyloid-β precursor protein (βAPP), seems to be an early pathological event in Alzheimers disease and also in IBM, where in the latter, it predominantly occurs intracellularly within affected myofibers. To elucidate the possible role of βAPP mismetabolism in the pathogenesis of IBM, transgenic mice were derived in which we selectively targeted βAPP overexpression to skeletal muscle by using the muscle creatine kinase promoter. Here we report that older (>10 months) transgenic mice exhibit intracellular immunoreactivity to βAPP and its proteolytic derivatives in skeletal muscle. In this transgenic model, selective overexpression of βAPP leads to the development of a subset of other histopathological and clinical features characteristic of IBM, including centric nuclei, inflammation, and deficiencies in motor performance. These results are consistent with a pathogenic role for βAPP mismetabolism in human IBM.

Homeostatic Plasticity Studied Using In Vivo Hippocampal Activity-Blockade: Synaptic Scaling, Intrinsic Plasticity and Age-Dependence

Homeostatic plasticity is thought to be important in preventing neuronal circuits from becoming hyper- or hypoactive. However, there is little information concerning homeostatic mechanisms following in vivo manipulations of activity levels. We investigated synaptic scaling and intrinsic plasticity in CA1 pyramidal cells following 2 days of activity-blockade in vivo in adult (postnatal day 30; P30) and juvenile (P15) rats. Chronic activity-blockade in vivo was achieved using the sustained release of the sodium channel blocker tetrodotoxin (TTX) from the plastic polymer Elvax 40W implanted directly above the hippocampus, followed by electrophysiological assessment in slices in vitro. Three sets of results were in general agreement with previous studies on homeostatic responses to in vitro manipulations of activity. First, Schaffer collateral stimulation-evoked field responses were enhanced after 2 days of in vivo TTX application. Second, miniature excitatory postsynaptic current (mEPSC) amplitudes were potentiated. However, the increase in mEPSC amplitudes occurred only in juveniles, and not in adults, indicating age-dependent effects. Third, intrinsic neuronal excitability increased. In contrast, three sets of results sharply differed from previous reports on homeostatic responses to in vitro manipulations of activity. First, miniature inhibitory postsynaptic current (mIPSC) amplitudes were invariably enhanced. Second, multiplicative scaling of mEPSC and mIPSC amplitudes was absent. Third, the frequencies of adult and juvenile mEPSCs and adult mIPSCs were increased, indicating presynaptic alterations. These results provide new insights into in vivo homeostatic plasticity mechanisms with relevance to memory storage, activity-dependent development and neurological diseases.

Single application of a CB1 receptor antagonist rapidly following head injury prevents long-term hyperexcitability in a rat model

Effective prophylaxis for post-traumatic epilepsy currently does not exist, and clinical trials using anticonvulsant drugs have yielded no long-term antiepileptogenic effects. We report that a single, rapid post-traumatic application of the proconvulsant cannabinoid type-1 (CB1) receptor antagonist SR141716A (Rimonabant-Acomplia) abolishes the long-term increase in seizure susceptibility caused by head injury in rats. These results indicate that, paradoxically, a seizure-enhancing drug may disrupt the epileptogenic process if applied within a short therapeutic time window.

Imaging in orbital trauma

Orbital trauma is one of the most common reasons for ophthalmology specialty consultation in the emergency department setting. We survey the literature from 1990 to present to describe the role of computed tomography (CT), magnetic resonance imaging (MRI) and their associated angiography in some of the most commonly encountered orbital trauma conditions. CT orbit can often detect certain types of foreign bodies, lens dislocation, ruptured globe, choroidal or retinal detachments, or cavernous sinus thrombosis and thus complement a bedside ophthalmic exam that can sometimes be limited in the setting of trauma. CT remains the workhorse for acute orbital trauma owing to its rapidity and ability to delineate bony abnormalities; however MRI remains an important modality in special circumstances such as soft tissue assessment or with organic foreign bodies.

Imaging of eyelid lymphatic drainage

PURPOSE Traditional descriptions of lymphatic drainage show eyelids emptying into the submandibular or preauricular basin. However recent studies based on in vivo lymphatic imaging show a possible predilection for the preauricular basin. We describe lymphoscintigraphy and report findings in patients with eyelid malignancies undergoing sentinel lymph node biopsy (SLNB). METHODS Retrospective chart review of 15 consecutive patients at a single institution with eyelid carcinoma undergoing SLNB. The primary outcome measure was primary facial lymphatic drainage site from the eyelid as determined by lymphoscintigraphy. RESULTS The preauricular basin was the site of focal radioactive uptake in all 15 patients. The location of the primary tumor was as follows: medial upper eyelid (1), medial canthus (3), medial lower eyelid (3), lateral upper eyelid (3), and lateral lower eyelid (5). The types of tumor were: invasive squamous cell carcinoma (7), malignant melanoma (3), and sebaceous cell carcinoma (2), Merkel cell carcinoma (2), and conjunctival spindle cell carcinoma (1). CONCLUSIONS Lymphoscintigraphy is increasingly used in the context of SLNB for periocular malignancy. The recent literature suggests that the preauricular lymph node basin may be the primary site of eyelid lymphatic drainage and this is corroborated by our series. Further data will elucidate the biology of eyelid lymphatic channels in humans but the preauricular basin may be the prime lymphatic metastastic site in eyelid malignancies.

Laser-Assisted Keratoplasty and Post-keratoplasty Management

Lasers have been used in ophthalmology for decades in various ways. The use of the femtosecond laser in ophthalmology was first conceptualized for corneal flaps in LASIK in the early 1990s. Since then, there has been an expansion of the use of femtosecond lasers for various applications in the cornea and more recently for cataract surgery. This is a review of the use of the femtosecond laser for keratoplasty. We start with an overview of the mechanism of femtosecond laser cuts in the cornea and then review pearls for performing femtosecond laser-enabled keratoplasty (FLEK). Next, a literature review of femtosecond lasers for penetrating and lamellar keratoplasty is discussed. Lastly, femtosecond lasers for post-keratoplasty astigmatism management are examined.

Bilateral dacryocystoceles in a pregnant woman.

The authors describe, for the first time, bilateral, sequential large dacryocystoceles during pregnancy and review the literature for this presentation. A 26-year-old, 15-week pregnant woman presented with OD epiphora, diplopia, and pain in the setting of an inferomedial orbital mass. Surgical exploration and histopathology were consistent with a dacryocystocele, and a dacryocystorhinostomy was curative. She returned at 34-week gestation, with an identical presentation on the left side. Review of the literature reveals that dacryocystoceles occasionally present in adults; however, bilateral involvement may be unusual. Bilateral dacryocystoceles have not been previously reported in a pregnant woman.