Lateral Wall Orbital Decompression: Comparison of Outcomes in Rim Sparing and Temporary Rim Removal Techniques.

PURPOSE: To compare exophthalmos reduction in lateral orbital decompressions performed via rim sparing versus temporary rim removal techniques. METHODS: The authors performed a retrospective chart review of all patients who underwent simple lateral or combined medial and lateral wall orbital decompression between 2005 and 2013 by a single surgeon. Nineteen patients (33 orbits) were identified for inclusion in the study. Decompression procedures (1 or 2 orbital walls) involved either a rim sparing or a temporary rim removal technique. Preoperatively, all patients had stable exophthalmos defined as ≤1 mm change in exophthalmos over 2 consecutive visits. Measurements were taken again at the 3 to 4 months postoperative visit. Exclusion criteria were acute or unstable exophthalmos, exophthalmos secondary to malignancy, and patients lost to follow up. RESULTS: There were no significant differences in exophthalmos reduction for rim sparing versus temporary rim removal techniques in any of the groups studied. Simple lateral decompression procedures achieved 3.7 and 4.4 mm of exophthalmos reduction in rim sparing versus temporary rim removal techniques, respectively (P = 0.49). Exophthalmos reduction in combined medial and lateral wall orbital decompression was 4.1 mm for rim sparing and 3.5 mm for temporary rim removal techniques (P = 0.75). CONCLUSION: In our experience, orbital decompression approached through rim sparing or temporary rim removal techniques achieves similar results in simple lateral and combined medial and lateral decompressions. Though these techniques generate similar outcomes, temporary rim removal provides for improved visibility and access to deep orbital structures.

Hemostasis in Orbital Surgery.

This article highlights the major vascular supply of the orbit and structures supplied by these vessels. Key anatomic principles are then reviewed as they pertain to endoscopic orbital surgery in order to avoid serious orbital hemorrhages. Next, preoperative planning and patient education are outlined as well as description of orbital compartment syndrome. This is followed by discussion of various techniques for managing orbital hemorrhage in the intraoperative and postoperative setting.

Ocular Trauma From Dog Bites: Characterization, Associations, and Treatment Patterns at a Regional Level I Trauma Center Over 11 Years.

PURPOSE: Canine bites frequently result in periocular injury. The authors aimed to further characterize the dog breeds, types of injuries inflicted, and treatment outcomes. METHODS: A retrospective chart review was performed on all dog bites recorded in the University of Washington trauma registry from 2003 to 2013. Cases involving ocular injury were further investigated to identify ocular tissues affected, treatment patterns, and outcomes. RESULTS: A total of 342 dog bite victims were identified, of whom 91 sustained ocular trauma (27%). The mean age of patients with ocular injuries was significantly lower than those without (14.1 ± 1.9 vs. 30.0 ± 1.3 years, p < 0.001). Children bitten by dogs were 4.2 times more likely to sustain ocular injuries than adults (45.2% vs. 10.8%). The most common breed of dog inflicting ocular injury was the pit bull (25%). Forty percent of patients with ocular trauma sustained canalicular lacerations and epiphora was noted in only 3 patients (8%) after repair. Three percent had orbital fractures and 2% sustained ruptured globes. Infections were rare, affecting only 2% of patients. CONCLUSIONS: To our knowledge, this study is the largest to date to report the incidence and characteristics of ocular injuries sustained from dog bites. These injuries were disproportionately more common in children and have a high incidence of canalicular laceration. Though rare, globe injuries and orbital fractures were seen in this population. Importantly, this study establishes that pit bulls are the most frequent breed associated with ocular injuries from dog bites.

Sustained interleukin-1ß overexpression exacerbates tau pathology despite reduced amyloid burden in an Alzheimer's mouse model.

Neuroinflammation is an important component of Alzheimer's disease (AD) pathogenesis and has been implicated in neurodegeneration. Interleukin-1 (IL-1), a potent inflammatory cytokine in the CNS, is chronically upregulated in human AD and believed to serve as part of a vicious inflammatory cycle that drives AD pathology. To further understand the role of IL-1ß in AD pathogenesis, we used an inducible model of sustained IL-1ß overexpression (IL-1ß(XAT)) developed in our laboratory. The triple transgenic mouse model of AD, which develops plaques and tangles later in its life cycle, was bred with IL-1ß(XAT) mice, and effects of IL-1ß overexpression on AD pathology were assessed in F1 progeny. After 1 and 3 months of transgene expression, we found robust increases in tau phosphorylation despite an ∼70-80% reduction in amyloid load and fourfold to sixfold increase in plaque-associated microglia, as well as evidence of greater microglial activation at the site of inflammation. We also found evidence of increased p38 mitogen-activated protein kinase and glycogen synthase kinase-3ß activity, which are believed to contribute to tau phosphorylation. Thus, neuroinflammation regulates amyloid and tau pathology in opposing ways, suggesting that it provides a link between amyloid accumulation and changes in tau and raising concerns about the use of immunomodulatory therapies in AD.

Adult murine hippocampal neurogenesis is inhibited by sustained IL-1ß and not rescued by voluntary running.

Acute neuroinflammation reduces adult hippocampal neurogenesis but the role of chronic neuroinflammation, which may be more representative of ongoing processes in CNS disorders, remains relatively unknown. Interleukin-1ß (IL-1ß) is a pro-inflammatory cytokine that has been shown to acutely impair neurogenesis. To further investigate the relationship between sustained IL-1ß expression and adult neurogenesis, a mouse model with an IL-1ß excisionally activated transgene, IL-1ß(XAT), was utilized. Upon exposure to Cre recombinase, IL-1ß overexpression in this model results in chronic neuroinflammation, which persists up to 12 months and causes glial activation, cellular recruitment, and deficits in learning and memory. We hypothesized that adult neurogenesis would be reduced by sustained hippocampal IL-1ß overexpression and rescued by voluntary running, which has been shown to enhance neurogenesis. Hippocampal inflammation in the IL-1ß(XAT) model severely impaired doublecortin (DCX) positive cells at 1 and 3 months after IL-1ß induction. Furthermore, BrdU labeling demonstrated a shift in cell lineage from neuronal to astroglial in the context of sustained hippocampal IL-1ß overexpression. Deletion of the IL-1 receptor prevented the decrease in DCX(+) cells. Voluntary running did not attenuate the effects of IL-1ß expression demonstrated by DCX staining. These results suggest that chronic neuroinflammation severely impairs adult hippocampal neurogenesis and voluntary running is not beneficial as a therapy to rescue these effects.

Chronic IL-1ß-mediated neuroinflammation mitigates amyloid pathology in a mouse model of Alzheimer's disease without inducing overt neurodegeneration.

Neuroinflammation is a local tissue response to injurious stimuli in the central nervous system (CNS) and is characterized by glial reactivity, induction of cytokines and chemokines, and vascular permeability. The cytokine interleukin (IL)-1ß is rapidly induced following CNS insult, and is chronically expressed in neurodegenerative disorders such as Alzheimer's disease (AD). We recently developed a novel method of sustained IL-1ß production in the brain to study the link between IL-1ß and AD pathogenesis. Utilizing this model, we have previously demonstrated reduction of plaque size and frequency accompanied by a robust neuroinflammatory response. These observations were limited to a single early time point in the course of AD plaque deposition and did not investigate other neurodegenerative endpoints. To extend these observations to other stages of disease progression and evaluate additional pathologic markers, we investigated the effects of age and duration of IL-1ß overexpression in the APPswe/PS-1dE9 AD model on a congenic C57BL/6 background. We now report that IL1ß overexpression leads to decreased 6E10 immunopositive plaque pathology regardless of age or duration. We also investigated whether IL-1ß overexpression led to neuronal apoptosis or cholinergic axonal degeneration in the context of this AD model. Although we could demonstrate apoptosis of infiltrating inflammatory cells, we found no evidence for IL-1 associated apoptosis of neurons or cholinergic axon degeneration even after 5 months of chronic neuroinflammation. Together, these observations point to a neuroprotective role for IL-1ß in AD neuropathogenesis.

Cyclooxygenase-1 mediates prostaglandin E(2) elevation and contextual memory impairment in a model of sustained hippocampal interleukin-1beta expression.

Interleukin (IL)-1beta is a proinflammatory cytokine implicated in several neurodegenerative disorders. Downstream actions of IL-1beta include production of prostaglandin (PG) E(2) by increasing expression of cyclooxygenase (COX) enzymes and prostaglandin E synthase (PGES) isoforms. We recently developed a transgenic mouse carrying a dormant human IL-1beta eXcisional Activation Transgene (XAT) for conditional and chronic up-regulation of IL-1beta in selected brain regions. This model is characterized by regionally specific glial activation, immune cell recruitment, and induction of cytokines and chemokines. Here, we aimed to elucidate the effects of long-term IL-1beta expression on the PGE(2) synthetic pathway and to determine the effects of PGs on inflammation and memory in our model. As expected, PGE(2) levels were significantly elevated after IL-1beta up-regulation. Quantitative real-time PCR analysis indicated significant induction of mRNAs for COX-1 and membranous PGES-1, but not COX-2 or other PGES isoforms. Immunohistochemistry revealed elevation of COX-1 but no change in COX-2 following sustained IL-1beta production. Furthermore, pharmacological inhibition of COX-1 and use of COX-1 knockout mice abrogated IL-1beta-mediated PGE(2) increases. Although COX-1 deficient mice did not present a dramatically altered neuroinflammatory phenotype, they did exhibit improved contextual fear memory. This data suggests a unique role for COX-1 in mediating chronic neuroinflammatory effects through PGE(2) production.

The role of interleukin-1 in neuroinflammation and Alzheimer disease: an evolving perspective.

Elevation of the proinflammatory cytokine Interleukin-1 (IL-1) is an integral part of the local tissue reaction to central nervous system (CNS) insult. The discovery of increased IL-1 levels in patients following acute injury and in chronic neurodegenerative disease laid the foundation for two decades of research that has provided important details regarding IL-1's biology and function in the CNS. IL-1 elevation is now recognized as a critical component of the brain's patterned response to insults, termed neuroinflammation, and of leukocyte recruitment to the CNS. These processes are believed to underlie IL-1's function in the setting of acute brain injury, where it has been ascribed potential roles in repair as well as in exacerbation of damage. Explorations of IL-1's role in chronic neurodegenerative disease have mainly focused on Alzheimer disease (AD), where indirect evidence has implicated it in disease pathogenesis. However, recent observations in animal models challenge earlier assumptions that IL-1 elevation and resulting neuroinflammatory processes play a purely detrimental role in AD, and prompt a need for new characterizations of IL-1 function. Potentially adaptive functions of IL-1 elevation in AD warrant further mechanistic studies, and provide evidence that enhancement of these effects may help to alleviate the pathologic burden of disease.

Chronic interleukin-1beta expression in mouse brain leads to leukocyte infiltration and neutrophil-independent blood brain barrier permeability without overt neurodegeneration.

The proinflammatory cytokine interleukin-1beta (IL-1beta) plays a significant role in leukocyte recruitment to the CNS. Although acute effects of IL-1beta signaling in the mouse brain have been well described, studies elucidating the downstream effects of sustained upregulation have been lacking. Using the recently described IL-1beta(XAT) transgenic mouse model, we triggered sustained unilateral hippocampal overexpression of IL-1beta. Transgene induction led to blood-brain barrier leakage, induction of MCP-1 (monocyte chemoattractant protein 1) (CCL2), ICAM-1 (intercellular adhesion molecule 1), and dramatic infiltration of CD45-positive leukocytes comprised of neutrophils, T-cells, macrophages, and dendritic cells. Despite prolonged cellular infiltration of the hippocampus, there was no evidence of neuronal degeneration. Surprisingly, neutrophils were observed in the hippocampal parenchyma as late as 1 year after transgene induction. Their presence was coincident with upregulation of the potent neutrophil chemotactic chemokines KC (keratinocyte-derived chemokine) (CXCL1) and MIP-2 (macrophage inflammatory protein 2) (CXCL2). Knock-out of their sole receptor CXCR2 abrogated neutrophil infiltration but failed to reduce leakage of the blood-brain barrier.

Sustained hippocampal IL-1 beta overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology.

Neuroinflammation is a conspicuous feature of Alzheimer disease (AD) pathology and is thought to contribute to the ultimate neurodegeneration that ensues. IL-1 beta has emerged as a prime candidate underlying this response. Here we describe a transgenic mouse model of sustained IL-1 beta overexpression that was capable of driving robust neuroinflammation lasting months after transgene activation. This response was characterized by astrocytic and microglial activation in addition to induction of proinflammatory cytokines. Surprisingly, when triggered in the hippocampus of the APPswe/PS1dE9 mouse model of AD, 4 weeks of IL-1 beta overexpression led to a reduction in amyloid pathology. Congophilic plaque area fraction and frequency as well as insoluble amyloid beta 40 (A beta 40) and A beta 42 decreased significantly. These results demonstrate a possible adaptive role for IL-1 beta-driven neuroinflammation in AD and may help explain recent failures of antiinflammatory therapeutics for this disease.

Amelioration of pain and histopathologic joint abnormalities in the Col1-IL-1beta(XAT) mouse model of arthritis by intraarticular induction of mu-opioid receptor into the temporomandibular joint.

OBJECTIVE: To evaluate opioid receptor function as a basis for novel antinociceptive therapy in arthritis. METHODS: We induced human mu-opioid receptor (HuMOR) expression in arthritic joints of mice, using the feline immunodeficiency virus (FIV) vector, which is capable of stably transducing dividing, growth-arrested, and terminally differentiated cells. Male and female Col1-IL-1beta(XAT)-transgenic mice developed on a C57BL/6J background and wild-type littermates were studied. RESULTS: A single injection of FIV(HuMOR) into the temporomandibular joints of Col1-IL-1beta(XAT)-transgenic mice 1 week prior to induction of arthritis prevented the development of orofacial pain and joint dysfunction, and reduced the degree of histopathologic abnormality in the joint. In addition, FIV(HuMOR) prevented the attendant sensitization of trigeminal sensory neurons and activation of astroglia in brainstem trigeminal sensory nuclei. These effects were mediated by the transduction of primary sensory neurons via transport of FIV vectors from peripheral nerve endings to sensory ganglia, as evidenced by HuMOR expression in neuronal cell bodies located in the trigeminal ganglia, as well as in their proximal and distal nerve branches located in the main sensory and subnucleus caudalis of the brainstem and joints, respectively. The presence of MOR ligands predominantly in the descending trigeminal nucleus suggested that the observed antinociception occurred at the subnucleus caudalis. Articular chondrocytes and meniscal tissue were also infected by FIV(HuMOR), which presumably exerted an antiinflammatory effect on cartilage. CONCLUSION: Our results indicate that prophylactic therapy with MOR overexpression in joints can successfully prevent the development of pain, dysfunction, and histopathologic abnormalities in the joints in arthritis. These findings may provide a basis for the future development of spatiotemporally controlled antinociceptive and antiinflammatory therapy for arthritis.

Intraarticular induction of interleukin-1beta expression in the adult mouse, with resultant temporomandibular joint pathologic changes, dysfunction, and pain.

OBJECTIVE: To examine the effects of intraarticular induction of interleukin-1beta (IL-1beta) expression in adult mice. METHODS: We used somatic mosaic analysis in a novel transgenic mouse with an inducible IL-1beta transcription unit. Transgene activation was induced by Cre recombinase in the temporomandibular joints (TMJs) of adult transgenic mice (conditional knockin model). The effects of intraarticular IL-1beta induction were subsequently evaluated at the cellular, histopathologic, and behavioral levels. RESULTS: We developed transgenic mice capable of germline transmission of a dormant transcription unit consisting of the mature form of human IL-1beta as well as the reporter gene beta-galactosidase driven by the rat procollagen 1A1 promoter. Transgene activation by a feline immunodeficiency virus Cre vector resulted in histopathologic changes, including articular surface fibrillations, cartilage remodeling, and chondrocyte cloning. We also demonstrated up-regulation of genes implicated in arthritis (cyclooxygenase 2, IL-6, matrix metalloproteinase 9). There was a lack of inflammatory cells in these joints. Behavioral changes, including increased orofacial grooming and decreased resistance to mouth opening, were used as measures of nociception and joint dysfunction, respectively. The significant increase in expression of the pain-related neurotransmitter calcitonin gene-related peptide (CGRP) in the sensory ganglia as well as the auxiliary protein CGRP receptor component protein of the calcitonin-like receptor in the brainstem further substantiated the induction of pain. CONCLUSION: Induction of IL-1beta expression in the TMJs of adult mice led to pathologic development, dysfunction, and related pain in the joints. The somatic mosaic model presented herein may prove useful in the preclinical evaluation of existing and new treatments for the management of joint pathologic changes and pain, such as in osteoarthritis.

COX-3: a splice variant of cyclooxygenase-1 in mouse neural tissue and cells.

We have detected an expressed mRNA encoding a splice variant of COX-1 in the mouse central nervous system. This isoform, referred to as COX-3, is identical in sequence to COX-1 except for the in-frame retention of intron 1. Like its counterpart COX-1, COX-3 does not generally appear to be induced by acute inflammatory stimulation.