Relentless placoid chorioretinitis: A review of four cases in pediatric and young adult patients with a discussion of therapeutic strategies.

Introduction: Relentless placoid chorioretinitis (RPC) is a rare, bilateral disease of the retinal pigment epithelium. The clinical course is prolonged and relapsing. No standard treatment has been established to date. The purpose of this case series is to report four cases of RPC in pediatric and young adult patients in which varying treatments were used, comparing them to previously published cases. Methods: A literature review was conducted to investigate currently published presentations and treatment options for RPC. A multicenter retrospective chart review was also performed on four consecutive patients. These patients were diagnosed with RPC because of new chorioretinitis lesions continuing to appear without or despite therapy for 5-36 months (2 patients), with a clinical course prolonged and relapsing, or because of the atypical location of the multiple lesions (>50) extending from the posterior pole to the equator and mid-peripheral retina (all four patients), which were not consistent with other entities like acute posterior multifocal placoid pigment epitheliopathy and serpiginous choroiditis. Results: All four cases of RPC received oral or IV steroids acutely, and three of these patients were transitioned to a steroid-sparing agent and biologic therapy: anti-TNF alpha or anti-IL-6. Quiescence of the chorioretinitis lesions was obtained after 7 months, 1 month, and 36 months; however, the latter had issues with treatment adherence. Mycophenolate mofetil was insufficient to control the disease in one patient, but tocilizumab and infliximab thereafter were effective after cessation of adalimumab due to side effects. Adalimumab when started the first month after the presentation was effective in controlling the disease in one patient. After the failure of interferon-alpha-2a, one patient displayed long-term control with infliximab. One patient did not require a steroid-sparing agent after oral prednisone taper as there was no evidence of progression or recurrence. Conclusion: This case series adds to the current knowledge regarding potential treatments for RPC, specifically the use of anti-TNF-alpha treatment and anti-IL-6 tocilizumab. In this case study, relapses of RPC were found among patients on mycophenolate mofetil and interferon-alpha-2a, and one case did not relapse on oral steroids without a steroid-sparing agent. Our findings suggest that adalimumab, infliximab, and tocilizumab may be useful medications to obtain quiescence of RPC.

T Cell Receptor-Independent, CD31/IL-17A-Driven Inflammatory Axis Shapes Synovitis in Juvenile Idiopathic Arthritis.

T cells are considered autoimmune effectors in juvenile idiopathic arthritis (JIA), but the antigenic cause of arthritis remains elusive. Since T cells comprise a significant proportion of joint-infiltrating cells, we examined whether the environment in the joint could be shaped through the inflammatory activation by T cells that is independent of conventional TCR signaling. We focused on the analysis of synovial fluid (SF) collected from children with oligoarticular and rheumatoid factor-negative polyarticular JIA. Cytokine profiling of SF showed dominance of five molecules including IL-17A. Cytometric analysis of the same SF samples showed enrichment of αßT cells that lacked both CD4 and CD8 co-receptors [herein called double negative (DN) T cells] and also lacked the CD28 costimulatory receptor. However, these synovial αßT cells expressed high levels of CD31, an adhesion molecule that is normally employed by granulocytes when they transit to sites of injury. In receptor crosslinking assays, ligation of CD31 alone on synovial CD28nullCD31+ DN αßT cells effectively and sufficiently induced phosphorylation of signaling substrates and increased intracytoplasmic stores of cytokines including IL-17A. CD31 ligation was also sufficient to induce RORγT expression and trans-activation of the IL-17A promoter. In addition to T cells, SF contained fibrocyte-like cells (FLC) expressing IL-17 receptor A (IL-17RA) and CD38, a known ligand for CD31. Stimulation of FLC with IL-17A led to CD38 upregulation, and to production of cytokines and tissue-destructive molecules. Addition of an oxidoreductase analog to the bioassays suppressed the CD31-driven IL-17A production by T cells. It also suppressed the downstream IL-17A-mediated production of effectors by FLC. The levels of suppression of FLC effector activities by the oxidoreductase analog were comparable to those seen with corticosteroid and/or biologic inhibitors to IL-6 and TNFα. Collectively, our data suggest that activation of a CD31-driven, αßTCR-independent, IL-17A-mediated T cell-FLC inflammatory circuit drives and/or perpetuates synovitis. With the notable finding that the oxidoreductase mimic suppresses the effector activities of synovial CD31+CD28null αßT cells and IL-17RA+CD38+ FLC, this small molecule could be used to probe further the intricacies of this inflammatory circuit. Such bioactivities of this small molecule also provide rationale for new translational avenue(s) to potentially modulate JIA synovitis.

Simultaneous recording of mouse retinal ganglion cells during epiretinal or subretinal stimulation.

We compared response patterns and electrical receptive fields (ERF) of retinal ganglion cells (RGCs) during epiretinal and subretinal electrical stimulation of isolated mouse retina. Retinas were stimulated with an array of 3200 independently controllable electrodes. Four response patterns were observed: a burst of activity immediately after stimulation (Type I cells, Vision Research (2008), 48, 1562-1568), delayed bursts beginning >25ms after stimulation (Type II), a combination of both (Type III), and inhibition of ongoing spike activity. Type I responses were produced more often by epiretinal than subretinal stimulation whereas delayed and inhibitory responses were evoked more frequently by subretinal stimulation. Response latencies were significantly shorter with epiretinal than subretinal stimulation. These data suggest that subretinal stimulation is more effective at activating intraretinal circuits than epiretinal stimulation. There was no significant difference in charge threshold between subretinal and epiretinal configurations. ERFs were defined by the stimulating array surface area that successfully stimulated spikes in an RGC. ERFs were complex in shape, similar to receptive fields mapped with light. ERF areas were significantly smaller with subretinal than epiretinal stimulation. This may reflect the greater distance between stimulating electrodes and RGCs in the subretinal configuration. ERFs for immediate and delayed responses mapped within the same Type III cells differed in shape and size, consistent with different sites and mechanisms for generating these two response types.

Premature cell senescence and T cell receptor-independent activation of CD8+ T cells in juvenile idiopathic arthritis.

OBJECTIVE: CD8+ T cells lacking CD28 were originally reported to be a characteristic feature of juvenile idiopathic arthritis (JIA), but the relevance of these unusual cells to this disease remains to be elucidated. Because of recent evidence that loss of CD28 cells is typical of terminally differentiated lymphocytes, the aim of this study was to examine functional subsets of CD8+ T cells in patients with JIA. METHODS: Blood and/or waste synovial fluid samples were collected from children with a definite diagnosis of JIA (n = 98). Deidentified peripheral blood (n = 33) and cord blood (n = 13) samples from healthy donors were also collected. CD8+ and CD4+ T cells were screened for novel receptors, and where indicated, bioassays were performed to determine the functional relevance of the identified receptor. RESULTS: JIA patients had a naive T cell compartment with shortened telomeres, and their entire T cell pool had reduced proliferative capacity. They had an overabundance of CD31+CD28(null) CD8+ T cells, which was a significant feature of oligoarticular JIA (n = 62) as compared to polyarticular JIA (n = 36). CD31+ CD28(null) CD8+ T cells had limited mitotic capacity and expressed high levels of the senescence antigens histone γH2AX and/or p16. Ligation of CD31, which was independent of the T cell receptor (TCR), sufficiently induced tyrosine phosphorylation, vesicle exocytosis, and production of interferon-γ and interleukin-10. CONCLUSION: These data provide the first evidence of cell senescence, as represented by CD31+CD28(null) CD8+ T cells, in the pathophysiology of JIA. Activation of these unusual cells in a TCR-independent manner suggests that they are maladaptive and could be potential targets for immunotherapy.

Synovial fluid proteins differentiate between the subtypes of juvenile idiopathic arthritis.

OBJECTIVE: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of inflammatory diseases, and no clinically useful prognostic markers to predict disease outcome in children with JIA are currently available. Synovial fluid likely reflects the proteins present in the inflamed synovium. The purpose of this study was to delineate the synovial fluid proteome and determine whether protein expression differs in the different subtypes of JIA. METHODS: Synovial fluid samples obtained from children with oligoarticular JIA, polyarticular JIA, or systemic JIA were compared. Two-dimensional gel electrophoresis for protein separation and matrix-assisted laser desorption ionization-time-of-flight mass spectrometry and quadripole time-of-flight mass spectrometry for protein identification were used for this study. Synovial fluid cells were analyzed by polymerase chain reaction (PCR) for the presence of haptoglobin messenger RNA (mRNA). RESULTS: The synovial fluid proteome of the samples was delineated. The majority of proteins showed overexpression in JIA synovial fluid as compared with noninflammatory control samples. There were 24 statistically significantly differentially expressed spots (>2-fold change; P < 0.05) between the subtypes of JIA. PCR analysis revealed haptoglobin mRNA, suggesting that haptoglobin is locally produced in an inflamed joint in JIA. CONCLUSION: Despite the similar histologic appearance of inflamed joints in patients with different subtypes of JIA, there are differences in protein expression according to the subtype of JIA. Haptoglobin is differentially expressed between the subtypes of JIA and is locally produced in an inflamed joint in JIA. Haptoglobin and other differentially expressed proteins may be potential biomarkers in JIA.

Systemic and localized scleroderma in children: current and future treatment options.

Scleroderma is a group of rare and complex diseases with varied clinical manifestations. The most obvious manifestation of the diseases is skin hardening and sclerosis. Scleroderma can be divided into two main subgroups: systemic and localized. The systemic form, also known as systemic sclerosis, involves diffuse skin involvement and potentially severe visceral involvement. Localized scleroderma on the other hand is more common in children and usually confined to a specific region of the body with no internal organ involvement. The juvenile forms of systemic sclerosis and localized scleroderma are important conditions in children because of the clinical severity and substantial mortality of systemic scleroderma and the major growth defects associated with childhood-onset localized disease even if the active disease itself is self-limited. The pathogenic pathways of the various forms of scleroderma are only partially defined, but the main defect in scleroderma is abnormal collagen deposition leading to eventual fibrosis in the skin as well as multiple organ systems such as the heart and lungs in juvenile systemic sclerosis. Therapeutics are divided into three main subgroups for systemic sclerosis: antifibrotics, anti-inflammatories, and vasodilators. For localized disease, anti-inflammatories, vitamin D analogs, and UV irradiation have been investigated. However, the infrequency of scleroderma in the pediatric population plus the fact that this disease is very often self-limiting makes randomized controlled trials very difficult. It is for this reason that most data on treatment modalities for this disease have been extrapolated from studies in adult patients. There is no one therapy for systemic sclerosis or localized scleroderma that has proven to be very effective or significantly disease modifying. However, current therapeutic strategies must be initiated early in the disease course for maximum beneficial clinical effects. New interventions such as autologous stem cell transplant and cytokine-directed therapies are under investigation as potential treatments for this complex disease.

TLR2 and MyD88 contribute to Lactobacillus casei extract-induced focal coronary arteritis in a mouse model of Kawasaki disease.

BACKGROUND: Kawasaki disease is the most common cause of acquired cardiac disease and acute vasculitis in children, targets the coronary arteries, and can occasionally be fatal. The pathogenesis and the molecular mechanisms remain unknown. After injection of Lactobacillus casei cell-wall extract (LCCWE), mice develop a focal coronary arteritis that histopathologically resembles Kawasaki disease, but the mechanism remains unclear. Here, we tested the hypothesis that signaling by Toll-like receptors (TLRs) through their key downstream adaptor molecule myeloid differentiation factor 88 (MyD88) is required for the cellular activation and coronary arteritis produced by LCCWE. METHODS AND RESULTS: Bone marrow-derived macrophages from TLR2- or MyD88-deficient mice were unresponsive to LCCWE-induced stimulation. In contrast, macrophages obtained from TLR4-deficient mice produced the same amount of interleukin-6 as macrophages from wild-type mice after stimulation with LCCWE. Intraperitoneal injection of LCCWE produced severe focal coronary arteritis in TLR4(-/-) and C57BL/6 control mice but not in TLR2(-/-) or MyD88(-/-) mice. Collectively, these results indicate that LCCWE is a potent inducer of nuclear factor-kappaB via TLR2 but not TLR4 and that this activation proceeds via the MyD88-dependent signaling pathway. In vivo studies suggest that TLR2(-/-) mice are protected from LCCWE-induced coronary arteritis and that this protection is mediated through the adaptor molecule MyD88. CONCLUSIONS: Our results provide important insights into the molecular signaling in this mouse model of coronary arteritis. We show here that LCCWE-induced coronary arteritis is dependent on intact TLR2 and MyD88 signaling.

Visual and electrical evoked response recorded from subdural electrodes implanted above the visual cortex in normal dogs under two methods of anesthesia.

Sensitive methods are required to record electrical evoked potentials over the visual cortex to evaluate the efficacy and safety of a retinal prosthesis before it can be implanted on the retinal surface of patients afflicted by outer retinal diseases. This study was designed to examine subdural electrodes as a mean to evaluate cortical evoked potentials in response to light and electrical stimulation of the retina in three dogs under two methods of anesthesia-halothane and propofol. Results showed that subdural electrodes could be stabilized over the visual cortex for several (3-5) months, and that they were 6.95 times more sensitive than subdermal electrodes in recording cortical visual evoked potentials (VEPs) and 4.31 times more sensitive in recording cortical electrical evoked potentials under both methods of anesthesia. The waveforms' shape changed for each electrode in the subdural array during 6/6 (100%) and 20/38 (52%) multi-channel recording sessions under halothane and propofol, respectively. This change could point to a cortical retinotopic organization versus hierarchical organization of different cortical areas for a given retinal stimulus. In summary, subdural electrodes show promising results for recording visual and electrical evoked responses (EERs) and thus for evaluation of the retinal prosthesis.

Clinical trials for pediatric scleroderma.

Progressive systemic sclerosis (PSS), or scleroderma, is a rare disease in the pediatric population. Many children with PSS have significant involvement of their internal organs, which leads to decreased survival. Because of the infrequency of the condition and delayed diagnosis, there are no large studies to evaluate therapy for PSS in children. Treatment is controversial in the adult literature, and its applicability to children is unclear. Only through collaborative efforts will researchers be able to clearly delineate the etiopathogenesis of PSS, and gather information from multicenter studies to ultimately provide appropriate and effective care for children with PSS.

Bioadhesives for intraocular use.

BACKGROUND/PURPOSE: A safe, effective adhesive could be useful in the management of retinal holes or tears and selected complicated retinal detachments, as well as for attaching a small electronic device (retinal prosthesis) to the retina. In this study, we examined nine commercially available compounds for their suitability as intraocular adhesives. METHODS: The following materials were studied: commercial fibrin sealant, autologous fibrin, Cell-Tak, three photocurable glues, and three different polyethylene glycol hydrogels. An electronic strain gauge measured the adherence forces between different glues and the retina. The stability of hydrogels at body temperature and the impermeability of the hydrogel adhesive to dextran blue were examined. Long-term biocompatibility testing of the most promising glues in terms of adhesive force, consistency, and short-term safety (hydrogels) were done in rabbits. Funduscopy, electroretinogram, and histology of the retina were performed. RESULTS: Hydrogels had 2 to 39 times more adhesive force (measured in mN) than the other glues tested. They liquefied at body temperature after 3 days to a few months. Hydrogels were impermeable to dextran blue. One type of hydrogel proved to be nontoxic to the retina. CONCLUSIONS: Hydrogels proved to be superior for intraocular use in terms of consistency, adhesiveness, stability, impermeability, and safety.

Sensory-motor transformation and motor planning in the primate frontal cortex.

To examine the role of the frontal cortex in sensory-motor processing, we trained a Rhesus monkey to perform a behavioral task with alternations between localization (LOC) and non-localization (NL) paradigms. In the LOC block, the monkey had to remember the modality and location of two sequential cues. Two different GO signals instructed the monkey to touch the memorized location of either auditory or visual spatial cues (GO-AUD or GO-VIS, respectively). In the NL paradigm the monkey received the same stimuli, but was instructed to touch a fixed target, disregarding the location and modality of the spatial and GO signals. Reaction time was significantly longer after GO-AUD signals in the LOC mode compared to the reaction time following GO-VIS signals, or in the NL mode. We examined 961 neurons in the frontal cortex and 427 parietal neurons. A group of frontal task-related neurons (72/430; 16.7%) showed evoked activity both after the visual and the GO-AUD stimuli in the LOC mode. The units did not respond to the GO-VIS signal that instructed the monkey to move to the same location, or to the identical stimuli in the NL mode. No such neurons were found in the sampled areas of the parietal cortex. Our findings suggest that the monkey initially planned a default response towards the location of the visual stimulus and immediately updated his motor plans when instructed to touch the memorized location of the auditory stimulus. We suggest that frontal activity may also be related to such modifications of sensory-motor associations.

[Familial occurrence of Ebstein anomaly].

Ebstein anomaly is a rare congenital disease which affects location, structure and mobility of the tricuspid valve, and right atrium and ventricle. Although most cases are sporadic, familial occurrence has been reported. We report 2 brothers born with Ebstein anomaly. The parents were first degree cousins and there were 8 other children. 2 daughters were born with other congenital heart anomalies, 1 with ventricular septal defect and the other with severe pulmonary artery stenosis. We suggest that in some families, Ebstein anomaly is an autosomal dominant disease with different expression in the sexes.

Spatiotemporal firing patterns in the frontal cortex of behaving monkeys.

1. Activity of up to 10 single units was recorded in parallel from frontal areas of behaving monkeys. 2. Spatiotemporal firing patterns were revealed by a method that detects all excessively repeating patterns regardless of their complexity or single-unit composition. 3. Excess of repeating patterns was found in 30-60% of the cases examined when timing jitter of 1-3 ms was allowed. 4. An independent test refuted the hypothesis that these patterns represented chance events. 5. In a given behavioral condition there were usually many different patterns, each repeating several times, and not one (or a few) pattern repeating many times. 6. In 13 out of 20 cases, when a single unit elevated its firing rate in association with an external event beyond 40/s, most of the spikes within that period were associated with excessively repeating spatiotemporal patterns. 7. Of 157 types of patterns whose excess was most marked, 107 were composed of spikes from one single unit, 45 of the patterns contained spikes from two single units, and only one was composed of spikes from three different single units. 8. These properties suggest that the patterns were generated by reverberations in a synfire mode within self-exciting cell assemblies.

Neural interactions in the frontal cortex of a behaving monkey: signs of dependence on stimulus context and behavioral state.

In order to gain an understanding of the processes taking place within and between neuronal assemblies, we made simultaneous recordings of spike trains from groups of up to 11 neurons in the frontal cortex of a rhesus monkey, that was trained to perform a sensorimotor behavioral task. We report here on preliminary results from correlation analysis of these neuronal activities, with special emphasis on signs of behaviorally induced modifications of neural interaction, possibly due to rapid modulations of discharge synchronization among the neurons. Our findings suggest that different functional groups of neurons may co-exist within each small volume of cortex, and that neurons may be dynamically recruited into such a group to fulfil a specific function.