PD1 inhibits PKCθ-dependent phosphorylation of cytoskeleton-related proteins and immune synapse formation.

The inhibitory cell surface receptor programmed death 1 (PD1) is a major target for antibody-based cancer immunotherapies. Nevertheless, a substantial number of patients fail to respond to the treatment or experience adverse effects. An improved understanding of intracellular pathways targeted by PD1 is thus needed to develop better predictive and prognostic biomarkers. Here, via unbiased phosphoproteome analysis of primary human T cells, we demonstrate that PD1 triggering inhibited the phosphorylation and physical association with PKC theta (PKCof a variety of cytoskeleton-related proteins. PD1 blocked activation and recruitment of PKCθ to the forming immune synapse (IS) in a SHP1/SHP2 tyrosine phosphatase-dependent manner. Consequently, PD1 engagement led to impaired synaptic phosphorylation of cytoskeleton-related proteins and formation of smaller IS. TCR-induced phosphorylation of the PKCθ substrate and binding partner Vimentin was long-lasting and it could be durably inhibited by PD1 triggering. Vimentin phosphorylation in intratumoral T cells also inversely correlated with PDL1 levels in human lung carcinoma. Thus, PKCθ and its substrate Vimentin represent important targets of PD1-mediated T-cell inhibition, and low levels of Vimentin phosphorylation may serve as a biomarker for the activation of the PD1 pathway.

Identification of Tensin-3 as a MALT1 substrate that controls B cell adhesion and lymphoma dissemination.

The protease MALT1 promotes lymphocyte activation and lymphomagenesis by cleaving a limited set of cellular substrates, most of which control gene expression. Here, we identified the integrin-binding scaffold protein Tensin-3 as a MALT1 substrate in activated human B cells. Activated B cells lacking Tensin-3 showed decreased integrin-dependent adhesion but exhibited comparable NF-κB1 and Jun N-terminal kinase transcriptional responses. Cells expressing a noncleavable form of Tensin-3, on the other hand, showed increased adhesion. To test the role of Tensin-3 cleavage in vivo, mice expressing a noncleavable version of Tensin-3 were generated, which showed a partial reduction in the T cell-dependent B cell response. Interestingly, human diffuse large B cell lymphomas and mantle cell lymphomas with constitutive MALT1 activity showed strong constitutive Tensin-3 cleavage and a decrease in uncleaved Tensin-3 levels. Moreover, silencing of Tensin-3 expression in MALT1-driven lymphoma promoted dissemination of xenografted lymphoma cells to the bone marrow and spleen. Thus, MALT1-dependent Tensin-3 cleavage reveals a unique aspect of the function of MALT1, which negatively regulates integrin-dependent B cell adhesion and facilitates metastatic spread of B cell lymphomas.

Atomic force microscopy for the evaluation of corneal surface roughness after femtosecond laser flap creation and excimer ablation.

INTRODUCTION: It is well known that the femtosecond laser lamellar cut induces some degree of surface roughness. Nevertheless, as in femtosecond laser-assisted LASIK (FS-LASIK), an excimer LASIK ablation is performed, and the post-ablation stromal bed should show some degree of smoothening. We decided to compare, using atomic force microscopy (AFM), the roughness of the corneal stromal bed, after a femtosecond lasers device flap was created with or without an excimer myopic ablation. METHODS: Using 6 freshly enucleated porcine eyes, we created in every eye a flap using a femtosecond laser. Additionally, in 3 eyes, an excimer laser ablation to correct-3 diopters (D) was made. AFM imaging of the remaining corneal stroma was performed. Ten different square areas of 20 µm x 20 µm at the central area of the stroma of each corneal sample were studied. The roughness parameters used were the root-mean-square deviation from a perfectly flat surface. RESULTS: The RMS deviation was 360 ± 120 nm in femtosecond laser only, and 110 ± 20 nm in those cases where excimer is also involved (p < 0.0001). CONCLUSIONS: Our results show that the roughness of the surface treated with excimer is clearly lower than in the group with no excimer ablation; thus, the application of laser excimer after a flap created by femtosecond laser seems to soften the nano-irregularities created by this technique.

PPAR-γ Agonist GW1929 Targeted to Macrophages with Dendrimer-Graphene Nanostars Reduces Liver Fibrosis and Inflammation.

Macrophages play essential roles during the progression of chronic liver disease. They actively participate in the response to liver damage and in the balance between fibrogenesis and regression. The activation of the PPARγ nuclear receptor in macrophages has traditionally been associated with an anti-inflammatory phenotype. However, there are no PPARγ agonists with high selectivity for macrophages, and the use of full agonists is generally discouraged due to severe side effects. We designed dendrimer-graphene nanostars linked to a low dose of the GW1929 PPARγ agonist (DGNS-GW) for the selective activation of PPARγ in macrophages in fibrotic livers. DGNS-GW preferentially accumulated in inflammatory macrophages in vitro and attenuated macrophage pro-inflammatory phenotype. The treatment with DGNS-GW in fibrotic mice efficiently activated liver PPARγ signaling and promoted a macrophage switch from pro-inflammatory M1 to anti-inflammatory M2 phenotype. The reduction of hepatic inflammation was associated with a significant reduction in hepatic fibrosis but did not alter liver function or hepatic stellate cell activation. The therapeutic antifibrotic utility of DGNS-GW was attributed to an increased expression of hepatic metalloproteinases that allowed extracellular matrix remodeling. In conclusion, the selective activation of PPARγ in hepatic macrophages with DGNS-GW significantly reduced hepatic inflammation and stimulated extracellular matrix remodeling in experimental liver fibrosis.

Association between the rs3812316 Single Nucleotide Variant of the MLXIPL Gene and Alpha-Linolenic Acid Intake with Triglycerides in Mexican Mestizo Women.

The carbohydrate response element binding protein (ChREBP) is a key transcription factor to understand the gene−diet−nutrient relationship that leads to metabolic diseases. We aimed to analyze the association between the rs17145750 and rs3812316 SNVs (single nucleotide variants) of the MLXIPL gene with dietary, anthropometric, and biochemical variables in Mexican Mestizo subjects. This is a cross-sectional study of 587 individuals. Genotyping was performed by allelic discrimination. In addition, liver and adipose tissue biopsies were obtained from a subgroup of 24 subjects to analyze the expression of the MLXIPL gene. An in silico test of the protein stability and allelic imbalance showed that rs17145750 and rs3812316 showed a high rate of joint heritability in a highly conserved area. The G allele of rs3812316 was associated with lower triglyceride levels (OR = −0.070 ± 0.027, p < 0.011, 95% CI = −0.124 to −0.016), the production of an unstable protein (ΔΔG −0.83 kcal/mol), and probably lower tissue mRNA levels. In addition, we found independent factors that also influence triglyceride levels, such as insulin resistance, HDL-c, and dietary protein intake in women. Our data showed that the association of rs3812316 on triglycerides was only observed in patients with an inadequate alpha-linolenic acid intake (1.97 ± 0.03 vs. 2.11 ± 0.01 log mg/dL, p < 0.001).

Myopic LASIK Outcomes: Comparison of Three Different Femtosecond Lasers and a Mechanical Microkeratome Using the Same Excimer Laser.

INTRODUCTION: To compare the influence of one microkeratome and three femtosecond lasers on myopic laser in situ keratomileusis (LASIK) outcomes. METHODS: Retrospective, observational cohort study. We compared 134 eyes treated with the IntraLase 60 kHz, 112 eyes treated with the Femto LDV Z6, 206 eyes treated with the FS200, and 98 eyes treated with the Hansatome zero compression microkeratome. All eyes were operated on using the same surgical protocol with the same excimer laser (Wavelight Allegretto) and were allocated to refraction-matched groups. RESULTS: One day and one week postoperatively, uncorrected distance visual acuity was significantly lower in the FS200 group compared to others (P = 0.0001). This difference disappeared at the 1- and 3-month postoperative visits. Significant differences were found among groups in terms of safety index (P = 0.0001), residual sphere (P = 0.0001), and residual cylinder (P = 0.02) at the 3-month postoperative visit. No significant differences were found in corrected distance visual acuity or efficacy index. CONCLUSION: According to our results, a slight delay in visual restoration after FS200 LASIK surgery might be expected. This delay was statistically significant at 1 day and 1 week postoperatively, but there were no differences from the 1-month visit onwards. Additionally, significant differences were found among devices in terms of safety index and the refractive results, which were found not to be clinically relevant.

Corneal Confocal Microscopy Findings in Neuro Lyme Disease: A Case Report.

Neuro Lyme disease is caused by several bacteriae of the Borreliaceae family, such as Borrelia Miyamotoi. In late stages of illness, patients with Lyme disease may develop chronic neurologic symptoms such as cognitive disturbances or small fiber peripheral neuropathy. Confocal microscopy is a non-invasive method designed to evaluate the human cornea in vivo. Thus, all the corneal layers, including the cells and the sub-basal nerve plexus, can be easily visualized and analyzed. This is the first report of the morphology of small-fiber peripheral neuropathy analyzed by confocal microscopy in a patient diagnosed of neuro Lyme disease. The decrease in the number of unmyelinated sub-basal nerve fibers with abundant presence of dendritic cells (DC) in comparison with healthy corneas strongly supports the diagnosis of small fiber peripheral neuropathy in a case of neuroborreliosis disease.

Impact of femtosecond laser-assisted in situ keratomileusis on retinal ganglion cell function.

PURPOSE: To analyse the effect of femtosecond laser-assisted in situ keratomileusis (FS-LASIK) on the electrical response of retinal ganglion cells using pattern electroretinography (pERG). METHODS: This was a longitudinal, prospective, observational pilot study. We included consecutive myopic patients who underwent FS-LASIK to correct up to 6 dioptres of myopia and up to 2 dioptres of astigmatism. Patients with excessive blinking or tearing and those with Snellen uncorrected visual acuity less than 0.9 dec on postop day 1 were excluded. Diopsys NOVA® (Diopsys Inc., NJ) pERG records, using high- and low-contrast patterns, were obtained 16 h and 1 month after FS-LASIK was performed. Magnitude (µV), Magnitude D (µV), Magnitude D/Magnitude ratio and signal-to-noise ratio (dB) were analysed. Wilcoxon test for nonparametric paired data was employed. RESULTS: pERG data from 24 eyes were analysed from 24 patients who underwent FS-LASIK. Mean age was 35.79 ± 9.86 years. Mean preoperative refraction was -2.69 ± 7.6 D (spherical) and -0.38 ± 0.40 D (cylinder). Mean surgical time was 56.88 ± 7.6 s. No statistically significant differences were obtained for any of the studied parameters when comparing 16 h with 1 month after FS-LASIK, with the exception of Magnitude with low contrast, which increased from 1.21 ± 0.2 to 1.39 ± 0.29 µV at 16 h and 1 month postoperatively, respectively (p = 0.03). CONCLUSIONS: FS-LASIK seems to induce a mild and transitory defect in retinal ganglion cell function. Only a mild decrease was detected in the magnitude value for low-contrast stimuli when pERG was performed 16 h postoperatively, and it returned to normal 1 month after surgery.

Femtosecond LASIK for the correction of low and high myopic astigmatism.

INTRODUCTION: Higher preoperative myopic astigmatism is associated with a higher probability of retreatment due to patient dissatisfaction as a result of residual cylindrical error. Nonetheless, retreatment is safe and the final clinical results are comparable to those of patients with lower preoperative astigmatism who were satisfied with the primary treatment. Our purpose is to compare the efficacy and safety of femtosecond LASIK (FS-LASIK) for the refractive correction of patients with low (< 1.5 Diopters (D) versus high (≥ 1.5 D) myopic astigmatism. METHODS: Retrospective observational study of 841 eyes of 825 eligible patients treated with FSLASIK for the correction of simple or compound myopic astigmatism. Outcome measures included residual error, best corrected and uncorrected distance visual acuity (BCVA and UCVA), efficacy and safety 3 months after the primary procedure or the retreatment. RESULTS: Of 841 eyes in total, 432 (51.37%) had < 1.5 D (Group 1) and 409 (48.63%) had ≥ 1.5 D (Group 2) preoperative myopic astigmatism. The efficacy index of primary treatment was 0.94 ± 0.18 in Group 1 and 0.89 ± 0.22 in Group 2 (P = 0.001). Of 138 eyes (16.41%) that were retreated due to dis-satisfaction related to residual refractive error, 28 belonged to Group 1 (6.5%) and 110 (26.9%) to Group 2 (P < 0.001). Following retreatment, small but statistically significant differences in the residual mean postoperative cylinder (-0.08 ± 0.24 vs -0.27 ± 0.46 D, P = 0.001) and UCVA (1.11 vs 0.96, P = 0.0001) were detected for Groups 1 and 2, respectively. However, there were no statistically significant differences in the safety and efficacy indices. CONCLUSION: Following FS-LASIK, eyes with myopic astigmatism ≥ 1.5 D have approximately four times more chances of undergoing retreatment due to dis-satisfaction caused by residual refractive error compared to eyes with myopic astigmatism < 1.5 D. However, the clinical results after retreatment are highly satisfactory and comparable in both groups.

Terapia electroconvulsiva de mantenimiento y recuperación de la disfunción cognitiva: a propósito de un caso de trastorno depresivo recurrente / Maintenance electroconvulsive therapy and cognitive disfunction recovery: A case of recurrent major depressive disorder

Objetivo: Cuestionar que la terapia electroconvulsiva (TEC) sea perjudicial a nivel cognitivo a medio y largo plazo en el trastorno depresivo recurrente.Caso clínicoSe presenta el caso de una mujer de 75 años con trastorno depresivo recurrente, resistente e intolerante a varios psicofármacos, descartada previamente para TEC por sospecha de deterioro cognitivo, pero incluida en junio de 2016 en el programa de TEC de mantenimiento (TEC-M), tras 10 sesiones de TEC aguda.ResultadosTras más de 30 sesiones de TEC-M la paciente se mantiene eutímica, recibiendo una sesión trimestral de TEC y mostrando recuperación de la disfunción cognitiva tanto en la valoración subjetiva como mediante test de screening.ConclusionesLa TEC-M es eficaz en ancianos con depresión y puede mejorar e incluso normalizar la función cognitiva. (AU)

Aim: Challenge the idea that electroconvulsive therapy (ECT) is cognitively detrimental in the medium and long term in recurrent depressive disorder.Clinical caseWe introduce the case of a 75-year-old woman with recurrent major depressive disorder, resistant and intolerant to various antidepressant drugs, previously ruled out for ECT due to suspected cognitive decline, but included in June 2016 in the maintenance-electroconvulsive therapy (M-ECT program), after 10 sessions of acute ECT.OutcomesAfter more than 30 sessions of M-ECT, the patient remains euthymic, receiving a quarterly session of ECT and showing recovery from cognitive dysfunction both in the subjective assessment and through the screening test.Main findingsM-ECT is effective in the elderly with major depression, and may improve and even normalize cognitive function. (AU)

Atomic force microscopy comparative analysis of the surface roughness of two posterior chamber phakic intraocular lens models: ICL versus IPCL.

BACKGROUND: To compare the anterior surface roughness of two commercially available posterior chamber phakic intraocular lenses (IOLs) using atomic force microscopy (AFM). METHODS: Four phakic IOLs were used for this prospective, experimental study: two Visian ICL EVO+ V5 lenses and two iPCL 2.0 lenses. All of them were brand new, were not previously implanted in humans, were monofocal and had a dioptric power of - 12 diopters (D). The anterior surface roughness was assessed using a JPK NanoWizard II® atomic force microscope in contact mode immersed in liquid. Olympus OMCL-RC800PSA commercial silicon nitride cantilever tips were used. Anterior surface roughness measurements were made in 7 areas of 10 × 10 µm at 512 × 512 point resolution. The roughness was measured using the root-mean-square (RMS) value within the given regions. RESULTS: The mean of all anterior surface roughness measurements was 6.09 ± 1.33 nm (nm) in the Visian ICL EVO+ V5 and 3.49 ± 0.41 nm in the iPCL 2.0 (p = 0.001). CONCLUSION: In the current study, we found a statistically significant smoother anterior surface in the iPCL 2.0 phakic intraocular lenses compared with the VISIAN ICL EVO+ V5 lenses when studied with atomic force microscopy.

Very early mobilization in the stroke unit: Functionality, quality of life and disability at 90 days and 1 year post-stroke.

BACKGROUND: The evidence of early mobilization after stroke is conflicting, and the recovery period is an important concern. OBJECTIVE: To analyse the functionality, quality of life and disability at 90 days and 1 year post-stroke of patients who received a Very Early Mobilization Protocol. METHODS: Prospective cohort study in a tertiary stroke unit. Consecutive patients aged≥18 years and without prior significant disability, who presented motor deficit after acute stroke, were included. A symmetry test was performed to compare the changes in the main variables: Barthel Index (BI), Functional Ambulation Category (FAC), modified Rankin Scale (mRS) and EuroQol five-dimensions three-level (EQ-5D-3L) between 90 days and 1 year post-stroke. RESULTS: A total of 123 patients were recruited. The BI reflected an improvement at 1 year in transfer to chair/bed in 25.8%(p < 0.01) of patients and in toilet use in 25.8%(p = 0.02). The FAC showed an improvement at 1 year in 44.4%(p < 0.01) of patients and the mRS in 19.1%(p = 0.01). The usual activities dimension of the EQ-5D-3L showed a clinically relevant improvement after 1 year in 15.9%(p = 0.23) of patients. CONCLUSIONS: A significant percentage of patients show improvements in some functional areas and in disability between 90 days and 1 year post-stroke.

Corneal stromal roughness after VisuMax and Intralase femtosecond laser photodisruption: An atomic force microscopy study.

PURPOSE: To compare the induced corneal stromal bed roughness measured with atomic force microscopy (AFM) after LASIK flap creation with the IntraLase 60 kHz and the VisuMax femtosecond laser platforms. METHODS: Three freshly enucleated porcine eyes were operated with each femtosecond laser in this experimental study. Standard LASIK treatment parameters were used for the experiment. After LASIK flap creation, the corneal stromal roughness was assessed using a JPK NanoWizard II® AFM in contact mode immersed in liquid. Olympus OMCL-RC800PSA commercial silicon nitride cantilever tips were used. Surface measurements were made in 10 regions of the central cornea of each sample measuring 20 x 20 microns, at 512 x 512 point resolution. Roughness was measured using the root-mean-square (RMS) value within the given regions. RESULTS: Measurements from 30 regions of the 3 eyes (10 measurements per eye) in the Intralase (FS1) group, and 30 regions of the 3 eyes (10 measurements per eye) in the VisuMax (FS2) group were analyzed. There was a statistically significant difference in mean ± standard deviation RMS values between the FS1 and the FS2 groups (360 ± 120 versus 230 ± 100 nm respectively; P< 0.00001). CONCLUSION: This AFM study indicates that the surface of the stromal bed after LASIK flap creation is smoother in the FS2 group than the FS1 group.

Measurement of the Intraocular Pressure Elevation During Laser-Assisted In Situ Keratomileusis Flap Creation Using a Femtosecond Laser Platform.

Purpose: The purpose of this study was to measure the intraocular pressure (IOP) elevation during laser assisted in situ keratomileusis (LASIK) flap creation using the WaveLight FS200 femtosecond (FS) laser platform. Methods: We conducted an ex vivo experimental study in an animal model. The WaveLight FS200 FS laser platform was used to perform the corneal LASIK flap in freshly enucleated porcine eyes. We measured the changes in IOP from the application of the suction ring (suctioning phase) through the creation of the lamellar corneal flap (cutting phase). The IOP was recorded using a manometric technique with direct cannulation to the anterior chamber. Results: Nine freshly enucleated porcine eyes were included in the study. The mean baseline IOP before the procedure was 20.33 ± 5.9 mm Hg. The mean IOP increase over baseline IOP was 32.33 ± 11.3 mm Hg at the suctioning phase, and 38.22 ± 11.3 mm Hg at the cutting phase. The total surgical time needed to complete the procedure was 29.5 ± 4.4 seconds. Conclusions: The WaveLight FS200 FS laser platform produces a low to moderate increase in IOP during LASIK flap creation. Translational Relevance: The WaveLight FS200 is a safe FS laser platform because it induces a low to moderate IOP increase during LASIK flap creation.

Effect of Laser-assisted Subepithelial Keratectomy with Mitomycin C on Corneal Optical Density Measured with Confocal Microscopy.

SIGNIFICANCE: The development of confocal microscopy allows one to obtain high-resolution corneal images like its optical density. Some studies have evaluated the optical density with Scheimpflug cameras in the early post-operative period after photorefractive keratectomy, but no studies have evaluated the long-term evolution of optical density after surface ablation when mitomycin C is used. PURPOSE: This work aimed to study the changes in corneal optical density measured with confocal microscopy in eyes treated with laser-assisted subepithelial keratectomy (LASEK) and intraoperative mitomycin C (MMC) to correct myopia. METHODS: A study of 24 consecutive myopic eyes that underwent LASEK with 0.02% MMC and a control group of 24 healthy nontreated eyes was performed. Optical density was measured using the images by the confocal microscopy of the Heidelberg Retina Tomograph II with the Rostock Cornea Module. An analysis of confocal microscopy images was performed using the ImageJ software to obtain the optical density, in gray-scale units (GSU). The optical density of the stromal bed was evaluated 3 months, 15 months, and 3 years after surgery and was compared with the optical density at the equivalent depth of the stroma in controls. RESULTS: The mean values of optical density for the LASEK group were 81.7 ± 9.7, 78.6 ± 11.7, and 73.6 ± 18.7 GSU at 3 months, 15 months, and 3 years, respectively, and it was 61.8 ± 8.2 GSU for the control group. A statistically higher optical density 3 and 15 months after LASEK with MMC was found compared with controls (P < .001). No significant difference was found in optical density at 3 years post-operatively. CONCLUSIONS: Our study suggests that, after LASEK with MMC, the anterior corneal stroma has a higher optical density at 3 and 15 months post-operatively, which gradually returns to normal values 3 years after surgery.

Effect of flap homogeneity on higher-order aberrations induction after femtosecond LASIK for myopia.

PURPOSE: To assess the relevance of the homogeneity of femtosecond laser flap thickness regarding induction of higher-order aberrations (HOAs). SETTING: Clínica Rementería & Clínica Novovisión, Madrid, Spain. DESIGN: Prospective observational study. METHODS: Two hundred thirty-one patients underwent in situ keratomileusis using 5 different femtosecond lasers. The flap thicknesses were measured using anterior segment optical coherence tomography 3 months postoperatively. The same masked observer measured 6 symmetrical points nasally and temporally 1.0 mm, 2.0 mm, and 3.0 mm from the center of the flap in each case. HOAs induced in the cornea were measured using tomography. RESULTS: Positive and significant correlations were found between HOA induction and the flap thickness heterogeneity 3.0 mm from the center of the flap. Pearson correlation coefficients for the induction of HOAs were third-order 0.17112 (P = .0224), fourth-order 0.22474 (P = .0026), fifth-order 0.16449 (P = .0282), coma-like 0.17370 (P = .0204), and total HOAs 0.18182 (P = .0151). CONCLUSIONS: The amount of flap-thickness heterogeneity at 3.0 mm from the center of the flap created using femtosecond lasers was correlated with the magnitude of the HOAs induced.

Dos años de implementacion del EIPP (Equipo de Intervención Precoz en Psicosis) del hospital universitario mutua de terrassa / No disponible

En el año 2017, el Plan director de Salud Mental y Adicciones de Catalunya, puso en marcha el Programa PAE-TPI (Programa de Atención Específica al Trastorno Psicótico Incipiente) después de unos años de corroborar la eficacia de los programas pilotos implementados desde el año 2007 en el territorio catalán. Este programa, es la propuesta de un método organizativo y de un proceso activo de gestión de la psicosis focalizada en la comunidad. Se basa en la detección precoz y la atención individualizada en la que, el vínculo, es uno de los puntos fuertes. Este artículo recoge la puesta en marcha y la preparación previa así como el tipo de intervención propuesta y realizada. También se aportarán datos descriptivos derivados del primer año de asistencia clínica. El programa abarca el área geográfica de Terrassa y Sant Cugat del Vallés

In 2017, the Master Plan for Mental Health and Addictions of Catalonia, launched the PAE-TPI Program (Program for Specific Attention to Incipient Psychotic Disorder) after a few years of corroborating the effectiveness of the pilot programs implemented since 2007 in the Catalan territory. This program is the proposal of an organizational method and a process active management of community-focused psychosis. Is based on the early detection and individualized attention in which the reliance is one of the strengths. This article includes the start-up and previous preparation as well as the type of intervention proposed and carried out. Descriptive data derived from the first year of clinical care will also be provided. The program covers the geographical area of Terrassa and Sant Cugat del Vallés