Nivolumab-Induced Ulcerative Keratitis-A Case Report

PURPOSE: To describe a case of nivolumab-induced ulcerative keratitis rapidly recovering on topical steroid treatment and to determine changes in cytokine levels in the tear fluid caused by nivolumab. METHODS: We report a 34-year-old man receiving nivolumab for metastasized melanoma with severe dry eye symptoms and a persistent corneal epithelial defect. Levels of cytokine and matrix metalloproteinase in tear fluid were measured by multiplex immunoassays. RESULTS: The corneal epithelial defect failed to recover for antiviral and lubrication therapy but resolved within 48 hours after topical steroid therapy was initiated. No recurrence of corneal ulceration was observed with intermittent topical steroid therapy during the remaining period of nivolumab treatment. No Sjögren disease-related autoantibodies were detected in the patient's serum. The levels of inflammatory cytokines and matrix metalloproteinases in the tear fluid were markedly elevated after nivolumab treatment. CONCLUSIONS: Our observations suggest that nivolumab treatment induces a local autoimmune ocular surface disorder resulting in corneal ulceration that promptly resolves using steroid eye drops. The integrity of the corneal epithelial layer can be sustained using intermittent topical steroid therapy in patients receiving nivolumab

A brief community linkage intervention for veterans with a persistent mental illness and a co-occurring substance abuse disorder

Objective: Individuals with co-occurring psychiatric and substance abuse problems often exhibit poor outpatient treatment engagement and re-hospitalization following discharge from acute psychiatric services. Although case management can improve treatment engagement and reduce attrition, these services are often delivered indefinitely, limiting the availability of treatment slots. In an effort to reduce re-hospitalization rates and improve outcomes during the transition from inpatient to outpatient treatment, we developed and evaluated Time-Limited Case Management (TLC), an eight-week integrated mental health and substance abuse augmentation intervention. Method: Sixty-five dually diagnosed veterans admitted to inpatient psychiatric treatment were included in the program evaluation, 32 who received the TLC service in addition to Treatment as Usual (TAU) that began during inpatient treatment and continued after the transition to outpatient services, and a comparison group of 33 who received only TAU without transitional support provided through the TLC augmentation service. Results: The TLC group had fewer days and episodes of hospitalization at two and six month post-study entry. Furthermore, the TLC group exhibited greater improvements on the Global Assessment of Functioning from baseline to the six-month follow-up. Conclusion: TLC appears to be an effective transitional augmentation service with benefits that persist beyond the eight weeks of the program. Future research should include a larger and more rigorously controlled trial to confirm the efficacy and unique contributions of the intervention

A suitable protocol for measuring alveolar nitric oxide in asthma with differing severity to assess peripheral airways inflammation

OBJECTIVE: Extended nitric oxide (NO) analysis offers the partitioned monitoring of inflammation in central and peripheral airways. Different mathematical models are used to estimate pulmonary NO dynamics in asthma with variable results and limitations. We aimed to establish a protocol for extended NO analysis in patients with differing asthma severity. METHODS: Forty patients with stable asthma and twenty-five matched control subjects were recruited. Exhaled NO was measured at constant flow rates between 10 and 300 mL/s. Twelve controls performed NO measurements weekly for four weeks. RESULTS: The proportions of patients with technically acceptable measurements at 10-30-50-100-150-200-250-300 mL/s exhalation flow rates were 8-58-100-98-98-95-90-80%, respectively. Alveolar NO (CANO) and total flux of NO in the conducting airways (JawNO) were calculated with the linear method from NO values measured at 100-150-200-250 mL/s exhalation flows. The mean intra-subject bias for JawNO and CANO in controls was 0.16 nL/s and 0.85 ppb, respectively. Both JawNO (1.31 /0.83-2.97/ vs. 0.70 /0.54-0.87/ nL/s, p<0.001) and CANO (4.08 /2.63-7.16/ vs. 2.42 /1.83-2.89/ ppb, p<0.001) were increased in patients with asthma compared to controls. In patients, CANO correlated with RV/TLC (r = 0.58, p<0.001), FEF25-75% (p = 0.02, r = -0.36) and DL,CO (r = -0.46, p = 0.004). JawNO was not related to lung function parameters. CONCLUSIONS: Calculation of alveolar NO concentration with the linear method from values obtained at medium flow rates (100-250 mL/s) is feasible even in asthmatic patients with severe airflow limitation and may provide information on small airways dysfunction in asthma

Activity-dependent compartmentalization of dendritic mitochondria morphology through local regulation of fusion-fission balance in neurons in vivo

Neuronal mitochondria play important roles beyond ATP generation, including Ca2+ uptake, and therefore have instructive roles in synaptic function and neuronal response properties. Mitochondrial morphology differs significantly between the axon and dendrites of a given neuronal subtype, but in CA1 pyramidal neurons (PNs) of the hippocampus, mitochondria within the dendritic arbor also display a remarkable degree of subcellular, layer-specific compartmentalization. In the dendrites of these neurons, mitochondria morphology ranges from highly fused and elongated in the apical tuft, to more fragmented in the apical oblique and basal dendritic compartments, and thus occupy a smaller fraction of dendritic volume than in the apical tuft. However, the molecular mechanisms underlying this striking degree of subcellular compartmentalization of mitochondria morphology are unknown, precluding the assessment of its impact on neuronal function. Here, we demonstrate that this compartment-specific morphology of dendritic mitochondria requires activity-dependent, Ca2+ and Camkk2-dependent activation of AMPK and its ability to phosphorylate two direct effectors: the pro-fission Drp1 receptor Mff and the recently identified anti-fusion, Opa1-inhibiting protein, Mtfr1l. Our study uncovers a signaling pathway underlying the subcellular compartmentalization of mitochondrial morphology in dendrites of neurons in vivo through spatially precise and activity-dependent regulation of mitochondria fission/fusion balance.</p

Biphasic Synaptic Ca Influx Arising from Compartmentalized Electrical Signals in Dendritic Spines

Dendritic spines compartmentalize synaptically-evoked biochemical signals. The authors show that electrical compartmentalization provided by a spine endows the associated synapse with additional modes of calcium signaling by shaping the kinetics of synaptic calcium currents

Asthma control in patients receiving inhaled corticosteroid and long-acting beta2-agonist fixed combinations. A real-life study comparing dry powder inhalers and a pressurized metered dose inhaler extrafine formulation

<p>Abstract</p> <p>Background</p> <p>Although patients have more problems using metered dose inhalers, clinical comparisons suggest they provide similar control to dry powder inhalers. Using real-life situations this study was designed to evaluate asthma control in outpatients with moderate to severe persistent asthma and to compare efficacy of fixed combinations of inhaled corticosteroids (ICS) and long acting beta-agonists (LABA).</p> <p>Methods</p> <p>This real-life study had a cross-sectional design. Patients using fixed combinations of ICS and LABA had their asthma control and spirometry assessed during regular visits.</p> <p>Results</p> <p>111 patients were analyzed: 53 (47.7%) received maintenance therapy of extrafine beclomethasone-formoterol (BDP/F) pressurized metered dose inhaler (pMDI), 25 (22.5%) fluticasone-salmeterol (FP/S) dry powder inhaler (DPI), and 33 (29.7%) budesonide-formoterol (BUD/F) DPI. Severity of asthma at time of diagnosis, assessed by the treating physician, was comparable among groups. Asthma control was achieved by 45.9% of patients; 38.7% were partially controlled and 15.3% were uncontrolled. In the extrafine BDF/F group, asthma control total score, daytime symptom score and rescue medication use score were significantly better than those using fixed DPI combinations (5.8 ± 6.2 vs. 8.5 ± 6.8; 1.4 ± 1.8 vs. 2.3 ± 2.1; 1.8 ± 2.2 vs. 2.6 ± 2.2; p = 0.0160; p = 0.012 and p = 0.025, respectively) and the mean daily ICS dose were significantly lower.</p> <p>Conclusions</p> <p>pMDI extrafine BDP/F combination demonstrated better asthma control compared to DPIs formulated with larger particles. This could be due to the improved lung deposition of the dose or less reliance on the optimal inhalation technique or both.</p