Tear film inflammatory mediators during continuous wear of contact lenses and corneal refractive therapy

OBJECTIVES: To study changes in tear film inflammatory mediators following continuous wear of silicone-hydrogel lenses and corneal refractive therapy with reverse geometry contact lenses. DESIGN: A prospective, case-control study. METHODS: Twenty-eight subjects had worn silicone-hydrogel lenses on a 30-night continuous wear basis. Thirty-two subjects had worn corneal refractive therapy lenses on an overnight basis. Thirty-two matched control subjects were also recruited. Tear samples were obtained 12 months after initial fitting and assayed using ELISA for cytokines (interleukin (IL)-6 and IL-8), matrix metalloproteinase 9 (MMP-9) and epidermal growth factor (EGF). RESULTS: EGF was significantly increased 12 months after both interventions. IL-6, IL-8 and MMP-9 were significantly increased only after corneal refractive therapy. The inflammatory response for the corneal refractive therapy patients was found to be associated with the degree of myopia corrected and the presence of corneal staining. Moreover, an increased level of MMP-9 and EGF was found to be associated with the presence of corneal-pigmented arc in the corneal refractive therapy group. CONCLUSIONS: This research showed long-term increased tear levels of inflammatory markers in subjects wearing corneal refractive therapy lenses when compared with continuous wear of silicone-hydrogel lenses or no lens wear.This research was financed by a grant (PI-081380) from the National Institute of Health Carlos III, Madrid, Spain, Ministry of Health and Consume (General Division for Health Research Funding)

Higher expression of Toll-like receptors 2 and 4 in blood cells of Keratoconus patiens

Inflammation may play a significant role in Keratoconus (KC), but the implication of immunity on this inflammatory response is unknown. Therefore, our aim was to determine the expression levels of Toll-like receptors 2 (TLR2) and 4 (TLR4) in monocytes and neutrophils from patients with KC and control subjects for demonstrating the role of innate immunity in KC. We also study the correlation between TLR2/TLR4 expression and serum levels of proinflammatory markers (IL-1β, IL-6, TNF-α, MMP-9 and NF-κB). Forty patients with bilateral KC (55% males; mean age; 33.1 ± 10.9 years) and 20 control subjects (55% males; mean age; 30.4 ± 7.6 years) were included in the study. Our results showed that mean expression of TLR2 and TLR4 in both neutrophils and monocytes was significantly higher in patients with KC compared to control subjects (all p < 0.0001). Furthermore, KC patients also showed higher serum levels of IL-1B, IL-6, TNF-α, MMP-9 (all p < 0.0001) and NF-κB (p = 0.036). In addition, we found a strong correlation between TLR2 expression in both monocytes and neutrophils (all p < 0.0001), and TLR4 in monocytes (all p < 0.05) with serum levels of IL-1B, IL-6, TNF-α and MMP-9. In conclusion, these findings suggest that TLRs may play an important role in the pathophysiology of KC.This project has been supported by grants from the Spanish Ministry of Economy and Competitiveness (Instituto de Salud Carlos III: PI14/00247); Xunta de Galicia (Consellería de Economía e Industria: 10 PX113918156PR and Consellería de Educación: GRC2014/027) and the European Union program FEDER. T. Sobrino (CP12/03121) and F. Campos (CP14/00154) are recipients of a research contract from Miguel Servet Program of Instituto de Salud Carlos III. Likewise A. Vieites-Prado is recipient of a FPI fellow (BES-2012-056027) from the Spanish Ministry of Economy and Competitiveness; and U. Regueiro is recipient of a predoctoral Fellow from the Xunta de Galicia (ED481A-2015/001)S

Increased Endothelial Progenitor Cell Levels are Associated with Good Outcome in Intracerebral Hemorrhage

Circulating endothelial progenitor cells (EPCs) play a role in the regeneration of damaged brain tissue. However, the relationship between circulating EPC levels and functional recovery in intracerebral hemorrhage (ICH) has not yet been tested. Therefore, our aim was to study the influence of circulating EPCs on the outcome of ICH. Forty-six patients with primary ICH (males, 71.7%; age, 72.7 ± 10.8 years) were prospectively included in the study within 12 hours of symptom onset. The main outcome variable was good functional outcome at 12 months (modified Rankin scale ≤2), considering residual volume at 6 months as a secondary variable. Circulating EPC (CD34+/CD133+/KDR+) levels were measured by flow cytometry from blood samples obtained at admission, 72 hours and day 7. Our results indicate that patients with good outcome show higher EPC numbers at 72 hours and day 7 (all p < 0.001). However, only EPC levels at day 7 were independently associated with good functional outcome at 12 months (OR, 1.15; CI95%, 1.01–1.35) after adjustment by age, baseline stroke severity and ICH volume. Moreover, EPC levels at day 7 were negatively correlated to residual volume (r = −0.525; p = 0.005). In conclusion, these findings suggest that EPCs may play a role in the functional recovery of ICH patients.This study has been partially supported by grants from Instituto de Salud Carlos III (PI14/01879), Spanish Research Network on Cerebrovascular Diseases RETICS-INVICTUS (RD12/0014), Xunta de Galicia (Consellería Educación GRC2014/027) and the European Union program FEDER. Furthermore, F. Campos (CP14/00154) and T. Sobrino (CP12/03121) are recipients of a research contract from Miguel Servet Program of Instituto de Salud Carlos IIIS

Pentraxin 3 (PTX3): A Molecular Marker of Endothelial Dysfunction in Chronic Migraine

Even though endothelial dysfunction is known to play a role in migraine pathophysiology, studies regarding levels of endothelial biomarkers in migraine have controversial results. Our aim was to evaluate the role of pentraxin 3 (PTX3) and soluble tumour necrosis factor-like weak inducer of apoptosis (sTWEAK) as potential biomarkers of endothelial dysfunction in chronic migraine (CM). We performed a case-control study including 102 CM patients and 28 control subjects and measured serum levels of markers of endothelial dysfunction (PTX3 and sTWEAK) and inflammation [high-sensitivity C-reactive protein (hs-CRP)] as well as brachial artery flow-mediated dilation (FMD) during interictal periods. Interictal serum levels of PTX3 and sTWEAK were higher in CM patients than in controls (1350.6 ± 54.8 versus 476.1 ± 49.4 pg/mL, p < 0.001 and 255.7 ± 21.1 versus 26.4 ± 2.6 pg/mL, p < 0.0001; respectively). FMD was diminished in CM patients compared to controls (9.6 ± 0.6 versus 15.2 ± 0.9%, p < 0.001). Both PTX3 and sTWEAK were negatively correlated with FMD (r = −0.508, p < 0.001 and r = −0.188, p = 0.033; respectively). After adjustment of confounders, PTX3 remained significantly correlated to FMD (r = −0.250, p = 0.013). Diagnosis of CM was 68.4 times more likely in an individual with levels of PTX3 ≥ 832.5 pg/mL, suggesting that PTX3 could be a novel biomarker of endothelial dysfunction in CMThis research was funded by Spanish Ministry of Economy and Competitiveness—Institute of Health Carlos III, Grant/Award Numbers: PI15/01578S

Mild systemic inflammation enhances response to OnabotulinumtoxinA in chronic migraineurs

The anti-inflammatory effect of OnabotulinumtoxinA (OnabotA) has been a matter of discussion for many years. In chronic migraine, however, increased pro-inflammatory state is associated with good response to OnabotA. We aimed to investigate whether a mild systemic inflammatory state elicited by a common oral infection (periodontitis) could enhance treatment response to OnabotA. In this study, we included 61 chronic migraineurs otherwise healthy treated with OnabotA of which 7 were poor responders and 54 good responders. Before receiving OnabotA therapy, all participants underwent a full-mouth periodontal examination and blood samples were collected to determine serum levels of calcitonin gene-related peptide (CGRP), interleukin 6 (IL-6), IL-10 and high sensitivity C-reactive protein (hs-CRP). Periodontitis was present in 70.4% of responders and 28.6% of non-responders (P = 0.042). Responders showed greater levels of inflammation than non-responders (IL-6: 15.3 ± 8.7 vs. 9.2 ± 4.7 ng/mL, P = 0.016; CGRP: 18.8 ± 7.6 vs. 13.0 ± 3.1 pg/mL, P = 0.002; and hs-CRP: 3.9 ± 6.6 vs. 0.9 ± 0.8 mg/L, P = 0.003). A linear positive correlation was found between the amount of periodontal tissue inflamed in the oral cavity and markers of inflammation (IL-6: r = 0.270, P = 0.035; CGRP: r = 0.325, P = 0.011; and hs-CRP: r = 0.370, P = 0.003). This report shows that in presence of elevated systemic inflammatory markers related to periodontitis, OnabotA seems to reduce migraine attacks. The changes of scheduled inflammatory parameters after treatment and subsequent assessment during an adequate period still need to be doneThis study was partially supported by a grant from the Spanish Ministry of Economy and Competitiveness—Institute of Health Carlos III (PI15/01578). YL holds a Senior Clinical Research Fellowship supported by the UCL Biomedical Research Centre who receives funding from the NIHR (NIHR-INF-0387) and a research contract with Fundación Instituto de Investigación Sanitaria de Santiago de Compostela (fIDIS). TS (CPII17/00027) and FC (CP14/00154) are recipients of research contracts from Miguel Servet Program of Institute of Health Carlos IIIS

Interleukin-10 facilitates the selection of patients for systemic thrombolysis

Background Clinical-Diffusion mismatch (CDM; NIHSS score ≥8 & DWI lesion volume ≤25 mL) and Perfusion-Diffusion mismatch (PDM; difference >20% between initial DWI and MTT lesion volumes) have been proposed as surrogates for ischemic brains that are at risk of infarction. However, their utility to improve the selection of patients for thrombolytic treatment remains controversial. Our aim was to identify molecular biomarkers that can be used with neuroimaging to facilitate the selection of ischemic stroke patients for systemic thrombolysis. Methods We prospectively studied 595 patients with ischemic stroke within 12 h of the stroke onset. A total of 184 patients received thrombolytic treatment according to the SITS-MOST criteria. DWI and MTT volumes were measured at admission. The main outcome variable was good functional outcome at 3 months (modified Rankin scale <3). Serum levels of glutamate (Glu), IL-10, TNF-α, IL-6, NSE, and active MMP-9 also were determined at admission. Results Patients treated with t-PA who presented with PDM had higher IL-10 levels at admission (p < 0.0001). In contrast, patients with CDM had higher levels of IL-10 (p < 0.0001) as well as Glu and TNF-α (all p < 0.05) and lower levels of NSE and active MMP-9 (all p < 0.0001). IL-10 ≥ 30 pg/mL predicts good functional outcome at 3 months with a specificity of 88% and a sensitibity of 86%. IL-10 levels ≥30 pg/mL independently in both patients with PDM (OR, 18.9) and CDM (OR, 7.5), after an adjustment for covariates. Conclusions Serum levels of IL-10 facilitate the selection of ischemic stroke patients with CDM and PDM for systemic thrombolysis.This project has been partially supported by grants from the Spanish Ministry of Science and Innovation (Fondo de Investigaciones Sanitarias, Instituto Salud Carlos III, RETICS-RD06/0026 and PI081472) and Xunta de Galicia (Consellería de Economía e Industria: 09CSA057918PR, Consellería de Sanidade: PS09/32)S

Periodontitis is associated with subclinical cerebral and carotid atherosclerosis in hypertensive patients: A cross‑sectional study

Objective: To examine the relationship between periodontitis and subclinical intracranial atherosclerosis. The association of periodontitis with preclinical markers of atherosclerosis in other vascular territories was also explored. Material and methods: This was a cross-sectional study where 97 elderly subjects with a previous history of hypertension received an ultrasonographic evaluation to assess subclinical atherosclerosis in different vascular territories: (1) cerebral [pulsatility (PI) and resistance index (RI) of the middle cerebral artery], (2) carotid [intima-media thickness (IMT)], and (3) peripheral [ankle-brachial index (ABI)]. Additionally, participants underwent a full-mouth periodontal assessment together with blood sample collection to determine levels of inflammatory biomarkers (leukocytes, fibrinogen, and erythrocyte sedimentation rate), lipid fractions (total cholesterol and high- and low-density lipoprotein), and glucose. Results: Sixty-one individuals had periodontitis. Compared to subjects without periodontitis, those with periodontitis showed higher values of PI (1.24 ± 0.29 vs 1.01 ± 0.16), RI (0.70 ± 0.14 vs 0.60 ± 0.06), and IMT (0.94 ± 0.15 vs 0.79 ± 0.15) (all p < 0.001). No statistically significant differences were found neither for ABI or for other clinical and biochemical parameters. An independent association was found between periodontitis and increased intracranial atherosclerosis (ORadjusted = 10.16; 95% CI: 3.14-32.90, p < 0.001) and to a lesser extent with thicker carotid IMT (ORadjusted = 4.10; 95% CI: 1.61-10.48, p = 0.003). Conclusions: Periodontitis is associated with subclinical atherosclerosis in both intracranial and carotid arteries in elderly subjects with hypertension. Clinical relevance: The association of periodontitis with intracranial atherosclerosis implies that periodontitis patients might have greater chances to develop ischemic stroke in the futureOpen Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This study was partially supported by grants from the Xunta de Galicia (TS: IN607A2018/3 and TS: IN607D 2020/09), Spanish Ministry of Science (TS: RTI2018-102165-B-I00 and RTC2019-007373-1), Institute of Health Carlos III (PI22/00938), and RICOR-ICTUS Network (RD21/0006/003). Furthermore, this study was also supported by grants from the Interreg Atlantic Area (TS: EAPA_791/2018_ NeuroATLANTIC project), Interreg V-A España Portugal (POCTEP) (TS: 0624_2IQBIONEURO_6_E), and the European Regional Development Fund. YL is supported by a Sara Borrell fellowship (CD22/00051), and TS (CPII17/00027) and FC (CPII19/00020) are recipients of Miguel Servet contracts, all of them funded by the Institute of Health Carlos IIIS

Iron Deposits in Periaqueductal Gray Matter Are Associated with Poor Response to OnabotulinumtoxinA in Chronic Migraine

Previous studies have reported increased brain deposits of iron in patients with chronic migraine (CM). This study aims to determine the relation between iron deposits and outcome after treatment with OnabotulinumtoxinA (OnabotA). Demographic and clinical data were collected for this study through a prospective cohort study including 62 CM patients treated with OnabotA in the Hospital Clínico Universitario de Santiago de Compostela (Spain). Demographic and clinical variables were registered. Selected biomarkers in plasma during interictal periods (calcitonin gene-related peptide (CGRP) and pentraxin-3 (PTX3)) and neuroimaging changes (iron deposits in the red nucleus (RN), substantia nigra (SN), globus pallidus (GP), and periaqueductal gray matter (PAG), and white matter lesions (WML)) were determined. Subjects were classified in responders (≥50% reduction in headache days) or non-responders (<50%). Responders to treatment were younger (mean age difference = 12.2; 95% confidence interval (CI): 5.4–18.9, p = 0.001), showed higher serum levels of CGRP (≥50 ng/mL) and PTX3 (≥1000 pg/mL) and smaller iron deposits in the GP and PAG (mean difference = 805.0; 95% CI: 37.9–1572.1 μL, p = 0.040 and mean difference = 69.8; 95% CI: 31.0–108.6 μL, p = 0.008; respectively). Differences in PAG iron deposits remained significant after adjusting for age (mean difference = 65.7; 95% CI: 22.8–108.6 μL, p = 0.003) and were associated with poor response to OnabotA after adjustment for clinical and biochemical variables (odds ratio (OR) = 0.963; 95% CI: 0.927–0.997, p = 0.041). We conclude that larger PAG iron deposits are associated with poor response to OnabotA in CMSpanish Ministry of Economy and Competitiveness—Institute of Health Carlos III, grant/award number PI15/01578S

Temperature-Induced Changes in Reperfused Stroke: Inflammatory and Thrombolytic Biomarkers

Although hyperthermia is associated with poor outcomes in ischaemic stroke (IS), some studies indicate that high body temperature may benefit reperfusion therapies. We assessed the association of temperature with effective reperfusion (defined as a reduction of ≥8 points in the National Institute of Health Stroke Scale (NIHSS) within the first 24 h) and poor outcome (modified Rankin Scale (mRS) > 2) in 875 retrospectively-included IS patients. We also studied the influence of temperature on thrombolytic (cellular fibronectin (cFn); matrix metalloproteinase 9 (MMP-9)) and inflammatory biomarkers (tumour necrosis factor-alpha (TNF-α), interleukin 6 (IL-6)) and their relationship with effective reperfusion. Our results showed that a higher temperature at 24 but not 6 h after stroke was associated with failed reperfusion (OR: 0.373, p = 0.001), poor outcome (OR: 2.190, p = 0.005) and higher IL-6 levels (OR: 0.958, p 37.5 °C at 24 h, but not at 6 h after stroke, is correlated with reperfusion failure, poor clinical outcome, and infarct size. Mild hyperthermia (36.5–37.5 °C) in the first 6 h window might benefit drug reperfusion therapies by promoting clot lysisThis study was partially supported by grants from the Spanish Ministry of Science and Innovation (SAF2017-84267-R), Xunta de Galicia (Consellería Educación: IN607A2018/3), Instituto de Salud Carlos III (ISCIII) (PI17/00540 and PI17/01103), Spanish Research Network on Cerebrovascular Diseases RETICS-INVICTUS PLUS (RD16/0019), and by the European Union FEDER program. Furthermore, Tomás. Sobrino (CPII17/00027) and Francisco Campos (CPII19/00020) are recipients of research contracts from the Miguel Servet Program of Instituto de Salud Carlos III. María Pérez-Mato is a Sara Borrell Researcher (CD19/00033)S