Lirentelimab for severe and chronic forms of allergic conjunctivitis.

BACKGROUND: Allergic conjunctivitis (AC) is an ocular inflammatory disease with symptoms driven by eosinophils and mast cells. Allergic comorbidities are common. Current treatments are often ineffective in severe AC and limited by potential side effects. Lirentelimab is an anti-sialic acid-binding immunoglobulin-like lectin-8 mAb that depletes eosinophils and inhibits mast cells. OBJECTIVE: We sought to determine safety and preliminary efficacy of lirentelimab in an open-label, phase 1b study. METHODS: Patients with chronic, severely symptomatic atopic keratoconjunctivitis, vernal keratoconjunctivitis, and perennial AC, and who had history of topical or systemic corticosteroid use, were enrolled to receive up to 6 monthly lirentelimab infusions (dose 1: 0.3 mg/kg, dose 2: 1 mg/kg, subsequent doses: 1 or 3 mg/kg). Changes from baseline in peripheral blood eosinophils, changes in patient-reported symptoms (measured by daily Allergic Conjunctivitis Symptom Questionnaire, including atopic comorbidities), changes in investigator-reported ocular signs and symptoms (Ocular Symptom Scores), changes in quality of life, and changes in tear cytokine and chemokine levels were assessed. RESULTS: Thirty patients were enrolled (atopic keratoconjunctivitis n = 13, vernal keratoconjunctivitis n = 1, perennial AC n = 16), 87% of whom had atopic comorbidities. After lirentelimab treatment, mean improvement was observed in Allergic Conjunctivitis Symptom Questionnaire score (-61%; 95% CI, -75% to -48%) and Ocular Symptom Scores (-53%; 95% CI, -76% to -31%), consistent across atopic keratoconjunctivitis, vernal keratoconjunctivitis, and perennial AC groups. There was substantial improvement in atopic comorbidities, with -55% (95% CI, -78% to -31%), -50% (95% CI, -82% to -19%), and -63% (95% CI, -87% and -38%) reduction in symptoms of atopic dermatitis, asthma, and rhinitis, respectively. Levels of key mediators of inflammation were reduced in patient tears after lirentelimab treatment. The most common adverse effects were mild to moderate infusion-related reactions. CONCLUSIONS: Lirentelimab was well tolerated, improved severe AC and concomitant atopic symptoms, and reduced inflammatory mediators in patient tears.

A novel culture platform for fast proliferation of human annulus fibrosus cells.

Tissue engineering provides a promising approach to treat degenerative disc disease, which usually requires a large quantity of seed cells. A simple and reliable in vitro culture system to expand seed cells in a timely fashion is necessary to implement the application clinically. Here, we sought to establish a cost-effective culture system for expanding human annulus fibrosus cells using extracellular matrix (ECM) proteins as culture substrates. Cells were cultured onto a plastic surface coated with various types of ECMs, including fibronectin, vitronectin, collagen type I, gelatin and cell-free matrix deposited by human nucleus pulposus cells. AF cell morphology, growth, adhesion and phenotype (anabolic and catabolic markers) were assessed by microscopy, real-time RT-PCR, western blotting, zymography, immunofluorescence staining and biochemical assays. Fibronectin, collagen and gelatin promoted cell proliferation and adhesion in a dose-dependent manner. Fibronectin elevated mRNA expression of proteoglycan and enhanced glycosaminoglycan production. Both collagen and gelatin increased protein expression of type II collagen. Consistent with increased cell adhesion, collagen and fibronectin promoted formation of focal adhesion complexes in the cell-matrix junction, suggesting enhanced binding of the actin network with both ECM substrates. On the other hand, fibronectin, collagen and gelatin decreased expression of matrix metalloproteinase-2 and matrix metalloproteinase-9 in media. Finally, a mixture of fibronectin (1.7 µg/mL) and collagen (1.3 µg/mL) was identified as the most promising in vitro culture substrate system in promoting proliferation and maintaining anabolic-catabolic balance. Our method provides a simple and cost-effective platform for tissue engineering applications in intervertebral disc research.

Recurrent Vogt-Koyanagi-Harada disease presenting with diffuse orbital inflammation.

Purpose: To report diffuse orbital inflammation as a manifestation of recurrent inflammation in a patient with Vogt-Koyanagi-Harada (VKH) disease. Observations: 20-year-old African American male, who was previously diagnosed with VKH, presented with right eye pain, swelling, and binocular double vision. He had run out of methotrexate while on steroid taper. Neuroimaging was consistent with diffuse orbital inflammation with myositis. He was started on intravenous steroids and then transitioned to oral steroids, with complete resolution of his symptoms. Conclusions and importance: Central nervous system involvement as a manifestation of VKH has been previously reported, however, there have been no reports of orbital inflammatory syndrome resulting from VKH. Thus, in the appropriate clinical context, orbital signs may be recognized as features of recurrent VKH.

Emerging therapies targeting eosinophil-mediated inflammation in chronic allergic conjunctivitis.

Ocular allergy remains a significant burden to the population while the treatment for the severe, chronic forms of allergic conjunctivitis remains largely limited to non-specific immunosuppressants. Eosinophils are central to the pathophysiology and sustaining the immunologic response found in the chronic forms of ocular allergy such as vernal keratoconjunctivitis and atopic keratoconjunctivitis. Several mediators of eosinophil recruitment, chemotaxis, adhesion, activation, and survival have been identified that offer potential therapeutic targets for ocular allergy. Based on preclinical and clinical data available in both ocular and non-ocular allergy studies, these emerging therapies warrant further investigation in reducing the severity of disease in patients with chronic ocular allergy.

Medicolegal Characteristics of Cardiac Tamponade Litigation: A Review of the LexisNexis Academic Database.

OBJECTIVE: To review, describe, and analyze medicolegal literature involving cases of cardiac tamponade. BACKGROUND: Currently, there are no studies known to these authors assessing the outcome patterns of medicolegal cases involving patients with cardiac tamponade. This potentially lethal condition may have serious consequences on both patients and clinicians. Thus, the literature was reviewed for patterns of liability and medical outcomes in patients who developed cardiac tamponade. METHODS: Legal case opinions were reviewed from LexisNexis Academic that contained the search term "tamponade"; case characteristics, litigation outcomes, and medical outcomes were identified. RESULTS: 230 case opinions were reviewed. 143 involved cardiac tamponade. Of these cases, 77 were medical malpractice cases, 30 were criminal cases, 11 were insurance claims, and the rest were other types. In malpractice cases, 35 (45%) patients were male, 69 (90%) formally named at least one doctor as a defendant, 54 (70%) claimed iatrogenicity as a cause of tamponade, and surgeons were the most commonly named defendants at 36 cases (47%). Open surgical drainage was the most common treatment at 28 (36%) cases and death was the outcome in 60 (78%) cases. Judgements were in favor of at least one doctor in 29 (42%) cases, against at least one doctor in 13 (19%) cases, and 12 (17%) cases involved a settlement by a physician. CONCLUSIONS: This study describes previously unknown medicolegal characteristics of cardiac tamponade cases.

Hydroxylated Fullerene: A Stellar Nanomedicine to Treat Lumbar Radiculopathy via Antagonizing TNF-α-Induced Ion Channel Activation, Calcium Signaling, and Neuropeptide Production.

Current nonsurgical treatments of discogenic lumbar radiculopathy are neither effective nor safe. Our prior studies have suggested that hydroxylated fullerene (fullerol) nanomaterial could attenuate proinflammatory cytokine tumor necrosis factor alpha (TNF-α)-induced neuroinflammation and oxidative stress in mouse dorsal root ganglia (DRG) and primary neurons. Here, we aim to investigate the analgesic effect of fullerol in a clinically relevant lumbar radiculopathy mouse model and to understand its underlying molecular mechanism in mouse DRGs and neurons. Surprisingly, single and local application of fullerol solution (1 µM, 10 µL) was sufficient to alleviate ipsilateral paw pain sensation in mice up to 2 weeks postsurgery. In addition, microCT data suggested fullerol potentially promoted disc height recovery following injury-induced disc herniation. Alcian blue/picrosirius red staining also suggested that fullerol promoted regeneration of extracellular matrix proteins visualized by the presence of abundant newly formed collagen and proteoglycan in herniated discs. For in vitro DRG culture, fullerol attenuated TNF-α-elicited expression of transient receptor potential cation channel subfamily V member 1 (TRPV-1) and neuropeptides release (substance P and calcitonin gene-related peptide). In addition, fullerol suppressed TNF-α-stimulated increase in intracellular Ca2+ concentrations in primary neurons. Moreover, Western blot analysis in DRG revealed that fullerol's beneficial effects against TNF-α might be mediated through protein kinase B (AKT) and extracellular protein-regulated kinase (ERK) pathways. These TNF-α antagonizing and analgesic effects indicated therapeutic potential of fullerol in treating lumbar radiculopathy, providing solid preclinical evidence toward further translational studies.