Neutrophil extracellular trap-associated RNA and LL37 enable self-amplifying inflammation in psoriasis.

Psoriasis is an inflammatory skin disease with strong neutrophil (PMN) infiltration and high levels of the antimicrobial peptide, LL37. LL37 in complex with DNA and RNA is thought to initiate disease exacerbation via plasmacytoid dendritic cells. However, the source of nucleic acids supposed to start this initial inflammatory event remains unknown. We show here that primary murine and human PMNs mount a fulminant and self-propagating neutrophil extracellular trap (NET) and cytokine response, but independently of the canonical NET component, DNA. Unexpectedly, RNA, which is abundant in NETs and psoriatic but not healthy skin, in complex with LL37 triggered TLR8/TLR13-mediated cytokine and NET release by PMNs in vitro and in vivo. Transfer of NETs to naive human PMNs prompts additional NET release, promoting further inflammation. Our study thus uncovers a self-propagating vicious cycle contributing to chronic inflammation in psoriasis, and NET-associated RNA (naRNA) as a physiologically relevant NET component.

Platelets Aggregate With Neutrophils and Promote Skin Pathology in Psoriasis.

Psoriasis is a frequent systemic inflammatory autoimmune disease characterized primarily by skin lesions with massive infiltration of leukocytes, but frequently also presents with cardiovascular comorbidities. Especially polymorphonuclear neutrophils (PMNs) abundantly infiltrate psoriatic skin but the cues that prompt PMNs to home to the skin are not well-defined. To identify PMN surface receptors that may explain PMN skin homing in psoriasis patients, we screened 332 surface antigens on primary human blood PMNs from healthy donors and psoriasis patients. We identified platelet surface antigens as a defining feature of psoriasis PMNs, due to a significantly increased aggregation of neutrophils and platelets in the blood of psoriasis patients. Similarly, in the imiquimod-induced experimental in vivo mouse model of psoriasis, disease induction promoted PMN-platelet aggregate formation. In psoriasis patients, disease incidence directly correlated with blood platelet counts and platelets were detected in direct contact with PMNs in psoriatic but not healthy skin. Importantly, depletion of circulating platelets in mice in vivo ameliorated disease severity significantly, indicating that both PMNs and platelets may be relevant for psoriasis pathology and disease severity.

Agreement of driving simulator and on-road driving performance in patients with binocular visual field loss.

PURPOSE: On-road testing is considered the standard for assessment of driving performance; however, it lacks standardization. In contrast, driving simulators provide controlled experimental settings in a virtual reality environment. This study compares both testing conditions in patients with binocular visual field defects due to bilateral glaucomatous optic neuropathy or due to retro-chiasmal visual pathway lesions. METHODS: Ten glaucoma patients (PG), ten patients with homonymous visual field defects (PH), and 20 age- and gender-matched ophthalmologically normal control subjects (CG and CH, respectively) participated in a 40-min on-road driving task using a dual brake vehicle. A subset of this sample (8 PG, 8 PH, 8 CG, and 7 CH) underwent a subsequent driving simulator test of similar duration. For both settings, pass/fail rates were assessed by a masked driving instructor. RESULTS: For on-road driving, hemianopia patients (PH) and glaucoma patients (PG) showed worse performance than their controls (CH and CG groups): PH 40%, CH 30%, PG 60%, CG 0%, failure rate. Similar results were obtained for the driving simulator test: PH 50%, CH 29%, PG 38%, CG 0%, failure rate. Twenty-four out of 31 participants (77%) showed concordant results with regard to pass/fail under both test conditions (p > 0.05; McNemar test). CONCLUSIONS: Driving simulator testing leads to results comparable to on-road driving, in terms of pass/fail rates in subjects with binocular (glaucomatous or retro-chiasmal lesion-induced) visual field defects. Driving simulator testing seems to be a well-standardized method, appropriate for assessment of driving performance in individuals with binocular visual field loss.

Driving with Glaucoma: Task Performance and Gaze Movements.

PURPOSE: The aim of this pilot study was to assess the driving performance and the visual search behavior, that is, eye and head movements, of patients with glaucoma in comparison to healthy-sighted subjects during a simulated driving test. METHODS: Driving performance and gaze behavior of six glaucoma patients and eight healthy-sighted age- and sex-matched control subjects were compared in an advanced driving simulator. All subjects underwent a 40-minute driving test including nine hazardous situations on city and rural roads. Fitness to drive was assessed by a masked driving instructor according to the requirements of the official German driving test. Several driving performance measures were investigated: lane position, time to line crossing, and speed. Additionally, eye and head movements were tracked and analyzed. RESULTS: Three out of six glaucoma patients passed the driving test and their driving performance was indistinguishable from that of the control group. Patients who passed the test showed an increased visual exploration in comparison to patients who failed; that is, they showed increased number of head and gaze movements toward eccentric regions. Furthermore, patients who failed the test showed a rightward bias in average lane position, probably in an attempt to maximize the safety margin to oncoming traffic. CONCLUSIONS: Our study suggests that a considerable subgroup of subjects with binocular glaucomatous visual field loss shows a safe driving behavior in a virtual reality environment, because they adapt their viewing behavior by increasing their visual scanning. Hence, binocular visual field loss does not necessarily influence driving safety. We recommend that more individualized driving assessments, which will take into account the patient's ability to compensate, are required.

Homonymous Visual Field Loss and Its Impact on Visual Exploration: A Supermarket Study.

PURPOSE: Homonymous visual field defects (HVFDs) may critically interfere with quality of life. The aim of this study was to assess the impact of HVFDs on a supermarket search task and to investigate the influence of visual search on task performance. METHODS: Ten patients with HVFDs (four with a right-sided [HR] and six with a left-sided defect [HL]), and 10 healthy-sighted, sex-, and age-matched control subjects were asked to collect 20 products placed on two supermarket shelves as quickly as possible. Task performance was rated as "passed" or "failed" with regard to the time per correctly collected item (TC -failed = 4.84 seconds based on the performance of healthy subjects). Eye movements were analyzed regarding the horizontal gaze activity, glance frequency, and glance proportion for different VF areas. RESULTS: Seven of 10 HVFD patients (three HR, four HL) passed the supermarket search task. Patients who passed needed significantly less time per correctly collected item and looked more frequently toward the VFD area than patients who failed. HL patients who passed the test showed a higher percentage of glances beyond the 60° VF (P < 0.05). CONCLUSION: A considerable number of HVFD patients performed successfully and could compensate for the HVFD by shifting the gaze toward the peripheral VF and the VFD area. TRANSLATIONAL RELEVANCE: These findings provide new insights on gaze adaptations in patients with HVFDs during activities of daily living and will enhance the design and development of realistic examination tools for use in the clinical setting to improve daily functioning. (http://www.clinicaltrials.gov, NCT01372319, NCT01372332).

Binocular glaucomatous visual field loss and its impact on visual exploration--a supermarket study.

Advanced glaucomatous visual field loss may critically interfere with quality of life. The purpose of this study was to (i) assess the impact of binocular glaucomatous visual field loss on a supermarket search task as an example of everyday living activities, (ii) to identify factors influencing the performance, and (iii) to investigate the related compensatory mechanisms. Ten patients with binocular glaucoma (GP), and ten healthy-sighted control subjects (GC) were asked to collect twenty different products chosen randomly in two supermarket racks as quickly as possible. The task performance was rated as "passed" or "failed" with regard to the time per correctly collected item. Based on the performance of control subjects, the threshold value for failing the task was defined as µ+3σ (in seconds per correctly collected item). Eye movements were recorded by means of a mobile eye tracker. Eight out of ten patients with glaucoma and all control subjects passed the task. Patients who failed the task needed significantly longer time (111.47 s ±12.12 s) to complete the task than patients who passed (64.45 s ±13.36 s, t-test, p < 0.001). Furthermore, patients who passed the task showed a significantly higher number of glances towards the visual field defect (VFD) area than patients who failed (t-test, p < 0.05). According to these results, glaucoma patients with defects in the binocular visual field display on average longer search times in a naturalistic supermarket task. However, a considerable number of patients, who compensate by frequent glancing towards the VFD, showed successful task performance. Therefore, systematic exploration of the VFD area seems to be a "time-effective" compensatory mechanism during the present supermarket task.

Driving with binocular visual field loss? A study on a supervised on-road parcours with simultaneous eye and head tracking.

Post-chiasmal visual pathway lesions and glaucomatous optic neuropathy cause binocular visual field defects (VFDs) that may critically interfere with quality of life and driving licensure. The aims of this study were (i) to assess the on-road driving performance of patients suffering from binocular visual field loss using a dual-brake vehicle, and (ii) to investigate the related compensatory mechanisms. A driving instructor, blinded to the participants' diagnosis, rated the driving performance (passed/failed) of ten patients with homonymous visual field defects (HP), including four patients with right (HR) and six patients with left homonymous visual field defects (HL), ten glaucoma patients (GP), and twenty age and gender-related ophthalmologically healthy control subjects (C) during a 40-minute driving task on a pre-specified public on-road parcours. In order to investigate the subjects' visual exploration ability, eye movements were recorded by means of a mobile eye tracker. Two additional cameras were used to monitor the driving scene and record head and shoulder movements. Thus this study is novel as a quantitative assessment of eye movements and an additional evaluation of head and shoulder was performed. Six out of ten HP and four out of ten GP were rated as fit to drive by the driving instructor, despite their binocular visual field loss. Three out of 20 control subjects failed the on-road assessment. The extent of the visual field defect was of minor importance with regard to the driving performance. The site of the homonymous visual field defect (HVFD) critically interfered with the driving ability: all failed HP subjects suffered from left homonymous visual field loss (HL) due to right hemispheric lesions. Patients who failed the driving assessment had mainly difficulties with lane keeping and gap judgment ability. Patients who passed the test displayed different exploration patterns than those who failed. Patients who passed focused longer on the central area of the visual field than patients who failed the test. In addition, patients who passed the test performed more glances towards the area of their visual field defect. In conclusion, our findings support the hypothesis that the extent of visual field per se cannot predict driving fitness, because some patients with HVFDs and advanced glaucoma can compensate for their deficit by effective visual scanning. Head movements appeared to be superior to eye and shoulder movements in predicting the outcome of the driving test under the present study scenario.