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The authors describe a rare presentation of invasive fungal rhino-orbital cellulitis caused by Saksenaea vasiformis in an immunocompetent child. The patient was initially diagnosed and treated as Mucoraceae, which has a high mortality rate and is primarily seen in immunocompromised patients. Though of the same order, Mucorales, the families Mucoraceae and Saksenaeacae, may be difficult to differentiate on histologic examination and must be distinguished by fungal culture and speciation. Our patient responded well to sino-orbital debridement and systemic treatment with amphotericin and posaconazole.

Pathologic accumulation of abnormally phosphorylated tau in neurofibrillary tangles is a hallmark feature of Alzheimer’s disease and other tauopathies. Interleukin-1β ◻◻◻ −1β◻ is a major proinflammatory cytokine in the central nervous system that has been implicated in the pathogenesis of tauopathies as well as Alzheimer’s disease. To explore the role of chronic IL-1β overexpression in tauopathies in vivo we used an inducible model of IL-1β overexpression developed in our laboratory. The IL-1β (IL-1) mice bear a transcriptional stop flanked by LoxP elements upstream of a human IL-1β gene. Upon delivery of Cre, the IL-1 transgene is locally activated by excision of the stop sequence. The IL-1 mice were bred to JNPL3 (Tau) mice, which overexpress human tau with the P301L mutation. Expression of IL-1β was induced in the dentate gyrus of 8 to 8.5 month old progeny by stereotaxic injection of FIV-Cre. One and three months later, Tau/IL-1 mice demonstrated 2-4 fold increases in phospho-tau and glial activation. To attenuate IL-1β mediated inflammation, we reduced PGE2 production via pharmacological inhibition of cyclooxygenase-1 (COX-1) with SC560 in Tau/IL-1 mice, and observed significant reductions in phospho-tau pathology and microglial activation. Further, we found upregulation in active forms of p38MAPK, which was significantly reduced in mice receiving SC560 treatment. Our results demonstrate that IL-1β has a direct exacerbating effect on tau pathology in vivo, and inhibiting COX-1 can reverse this. COX-1 inhibition can therefore serve as a valuable therapeutic strategy for tauopathies with an advanced inflammatory component.

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.

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-1β in AD pathogenesis, we used an inducible model of sustained IL-1β overexpression (IL-1βXAT) 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-1βXATmice, and effects of IL-1β 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-3β 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.

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.

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)-1β 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-1β production in the brain to study the link between IL-1β 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-1β overexpression in the APPswe/PS-1dE9 AD model on a congenic C57BL/6 background. We now report that IL1β overexpression leads to decreased 6E10 immunopositive plaque pathology regardless of age or duration. We also investigated whether IL-1β 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 five months of chronic neuroinflammation. Together, these observations point to a neuroprotective role for IL-1β in AD neuropathogenesis.

Glial activation and neuroinflammation occur in neurodegenerative disease and brain injury, however their presence in normal brain aging suggests that chronic neuroinflammation may be a factor in age-related dementia. Few studies have investigated the impact of sustained elevation of hippocampal interleukin-1beta, a pro-inflammatory cytokine upregulated during aging and Alzheimer's disease, on cognition in mice. We utilized the IL-1beta(XAT) transgenic mouse to initiate bilateral hippocampal overexpression of interleukin-1beta to determine the influence of sustained neuroinflammation independent of disease pathology. Fourteen days following transgene induction, adult male and female IL-1beta(XAT) mice were tested on non-spatial and spatial versions of the Morris water maze. For the spatial component, one retention trial was conducted 48 h after completion of a 3 day acquisition protocol (eight trials per day). Induction of IL-1beta did not impact non-spatial learning, but was associated with delayed acquisition and decreased retention of the spatial task. These behavioral impairments were accompanied by robust reactive gliosis and elevated mRNA expression of inflammatory genes in the hippocampus. Our results suggest that prolonged neuroinflammation response per se may impact mnemonic processes and support the future application of IL-1beta(XAT) transgenic mice to investigate chronic neuroinflammation in age- and pathology-related cognitive dysfunction.

Background: Intraosseous meningiomas often display clinical and radiologic features that can be confused for fibrous dysplasia. Histopathology usually confirms the diagnosis. We present a case initially misdiagnosed as fibrous dysplasia by histopathology. Methods: A 58-year-old male presented with worsening proptosis and vision loss. He was previously diagnosed with fibrous dysplasia at an outside institution, with histologic confirmation of the diagnosis during orbital decompression. Results: On examination there was evidence of optic neuropathy and mild restriction of gaze. Imaging revealed a large ossified mass of the greater sphenoid wing. Craniotomy and surgical decompression resulted in improved vision and symptoms. Histopathology revealed meningioma with bony and dural components. Conclusions: This case emphasizes the need for a high level of suspicion and representative biopsies to reach prompt diagnosis of meningiomas in cases of recurrent or atypical fibrous dysplasia

Canine bites frequently result in periocular injury. The authors aimed to further characterize the dog breeds, types of injuries inflicted, and treatment outcomes.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.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, p0.001). 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.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.

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-1β (IL-1β) is a pro-inflammatory cytokine that has been shown to acutely impair neurogenesis. To further investigate the relationship between sustained IL-1β expression and adult neurogenesis, a mouse model with an IL-1β excisionally activated transgene, IL-1β XAT , was utilized. Upon exposure to Cre recombinase, IL-1β 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-1β overexpression and rescued by voluntary running, which has been shown to enhance neurogenesis. Hippocampal inflammation in the IL-1β XAT model severely impaired doublecortin (DCX) positive cells at 1 and 3 months after IL-1β induction. Furthermore, BrdU labeling demonstrated a shift in cell lineage from neuronal to astroglial in the context of sustained hippocampal IL-1β overexpression. Deletion of the IL-1 receptor prevented the decrease in DCX + cells. Voluntary running did not attenuate the effects of IL-1β 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.

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 proinflammatory cytokine interleukin-1β (IL-1β) plays a significant role in leukocyte recruitment to the CNS. Although acute effects of IL-1β 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-1βXATtransgenic mouse model, we triggered sustained unilateral hippocampal overexpression of IL-1β. 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.

Objective To evaluate opioid receptor function as a basis for novel antinociceptive therapy in arthritis. Methods We induced human μ-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-1βXAT–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-1βXAT–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.

Objective. To examine the effects of intraarticular induction of interleukin-1 (IL-1) expression in adult mice. Methods. We used somatic mosaic analysis in a novel transgenic mouse with an inducible IL-1 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-1 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-1 as well as the reporter gene -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-1 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.

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.

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.