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Specialized proresolving mediators and, in particular, 5(S), (6)R, 7-trihydroxyheptanoic acid methyl ester (BML-111) emerge as new therapeutic tools to prevent cardiac dysfunction and deleterious cardiac damage associated with myocarditis progression. The cardioprotective role of BML-111 is mainly caused by the prevention of increased oxidative stress and nuclear factor erythroid-derived 2-like 2 (NRF2) down-regulation induced by myocarditis. At the molecular level, BML-111 activates NRF2 signaling, which prevents sarcoplasmic reticulum–adenosine triphosphatase 2A down-regulation and Ca2+ mishandling, and attenuates the cardiac dysfunction and tissue damage induced by myocarditis., This work was supported by the Spanish Ministry of Economy and Competitiveness and the European Regional Development Fund (SAF-2017-84777R), Instituto de Salud Carlos III (ISCIII) (PI17/01093, PI17/01344, and PI20/01482), Sociedad Española de Cardiología, Proyecto Traslacional 2019 and Asociación del Ritmo Cardiaco (SEC, España), Proyecto Asociación Insuficiencia Cardiaca (Trasplante Cardiaco) 2020, Fondo Europeo de Desarrollo Regional, Fondo Social Europeo, and CIBERCV, a network funded by ISCIII, Spanish Ministry of Science, Innovation and Universities (PGC2018-097019-B-I00), Ministerio de Economía, Industria y Competitividad/Agencia Estatal de Investigación 10.13039/501100011033 PID2020-113238RB-I00, PID2019-105600RB-I00, the Instituto de Salud Carlos III (Fondo de Investigación Sanitaria grant PRB3 [PT17/0019/0003-ISCIII-SGEFI/ERDF, ProteoRed]), and “la Caixa” Foundation (project code HR17-00247). The Centro Nacional de Investigaciones Cardiovasculares is supported by the ISCIII, the Ministerio de Ciencia, Innovación y Universidades. Dr Ruiz-Hurtado is Miguel Servet I researcher of ISCIII (CP15/00129 Carlos III Health Institute). Dr Tamayo and R.I. Jaén, and M. Gil-Fernández were or currently are PhD students funded by the Formación de Profesorado Universitario program of the Spanish Ministry of Science, Innovation and Universities (FPU17/06135; FPU16/00827, FPU1901973).

To describe the evolution of the serum levels of soluble HLA-G (s-HLA-G) during the first 12 months after heart transplantation (HT) and to correlate it with clinical outcomes.Observational study based in a single-center cohort of 59 patients who underwent HT between December-2003 and March-2010. Soluble HLA-G levels were measured from serum samples extracted before HT, and 1, 3, 6 and 12 months after HT. The cumulative burden of s-HLA-G expression during the first post-transplant year was assessed by means of the area under the curve (AUC) of s-HLA-G levels over time and correlated with the acute rejection burden -as assessed by a rejection score-, the presence of coronary allograft vasculopathy (CAV) grade ≥ 1 and infections during the first post-transplant year; as well as with long-term patient and graft survival. Mean follow-up was 12.4 years.Soluble HLA-G levels decreased over the first post-transplant year (p = 0.020). The AUC of s-HLA-G levels during the first post-transplant year was higher among patients with infections vs. those without infections (p = 0.006). No association was found between the AUC of s-HLA-G levels and the burden of acute rejection or the development of CAV. Overall long-term survival, long-term survival free of late graft failure and cancer-free survival were not significantly different in patients with an AUC of s-HLA-G levels higher or lower than the median of the study population.Soluble HLA-G levels decreased over the first year after HT. Higher HLA-G expression was associated with a higher frequency of infections, but not with the burden of acute rejection or the development of CAV, neither with long-term patient or graft survival.

espanolIntroduccion La arteritis de celulas gigantes (ACG) es una vasculitis que afecta a arterias de mediano y gran calibre. La biopsia de la arteria temporal es la tecnica diagnostica de eleccion. Atendiendo a la demanda asistencial que supone, pretendemos evaluar la utilidad de la ecografia Doppler en los pacientes con sospecha de ACG, su sensibilidad y especificidad como prueba diagnostica y si puede suplir a la biopsia. Materiales y metodos Se ha realizado un estudio prospectivo de 57 pacientes entre febrero de 2015 y julio de 2016, que han sido diagnosticados con exploracion mediante ecografia Doppler y biopsia de arteria temporal. Resultados Fueron incluidos 57 pacientes, de los cuales 3 fallecieron durante el seguimiento y una paciente fue excluida del estudio al negarse a la biopsia. Otros 21 pacientes fueron diagnosticados de ACG por un especialista reumatologo tras un minimo de 6 meses de seguimiento. Presentaron ecografia positiva 22 pacientes, de los cuales 8 fueron diagnosticados de ACG y 4 de polimialgia reumatica. En nuestro estudio, la sensibilidad de la ecografia es del 42,6% y la especificidad es del 65,7%. Otros 19 pacientes presentaron biopsia positiva: todos ellos fueron diagnosticados de ACG. La biopsia presento una sensibilidad de un 73,7% y una especificidad de un 100%. Conclusiones Segun nuestro estudio, la utilidad de la ecografia es limitada y son necesarias nuevas investigaciones para determinar su papel en esta entidad. EnglishBackground Giant cell arteritis (GCA) is a vasculitis that affects medium- and large-sized arteries. Temporal artery biopsy is the gold standard for diagnosis. In view of the high demand for temporal biopsies, the purpose of this study is to evaluate the usefulness of Doppler ultrasonography in patients with suspected giant cell arteritis, to determine its sensitivity and specificity as a diagnostic test and to determine whether it would be possible to substitute biopsy for ultrasonography. Materials and methods A prospective study was undertaken including 57 patients from February 2015 to July 2016, who have undergone both ultrasonography and temporal biopsy. Results A total of 57 patients were included, 3 of whom died during the follow-up, and a patient was excluded from the study when she refused to have the biopsy. Another 21 patients were diagnosed with GCA by a rheumatologist after a minimum of 6 months of follow-up and 22 patients had positive ultrasonography, 8 of whom were diagnosed with GCA and 4 with polymyalgia rheumatica. In our study, the sensitivity of ultrasonography was 42.6%, and the specificity was 65.7%. A total of 19 patients had a positive biopsy, all of them were diagnosed with GCA. In our study, the sensitivity of the biopsy was 73.7% and the specificity was 100%. Conclusions In view of the data from our study, the usefulness of ultrasonography is questionable, and research about the role of ultrasonography in this disease should be further studied.

Resumen Introduccion y objetivos Los valores plasmaticos de galectina-3 (Gal-3) estan elevados y se correlacionan con la mortalidad total y cardiovascular en pacientes con insuficiencia cardiaca, pero su correlacion con el pronostico tras el trasplante cardiaco (TxC) es desconocida. El objetivo fue describir la tendencia evolutiva y el valor pronostico de este biomarcador tras el TxC. Metodos Mediante enzimoinmunoensayo, se midieron las concentraciones plasmaticas de Gal-3 en muestras de suero de 122 receptores de TxC, antes y 1, 3, 6 y 12 meses despues de este. Mediante regresion de Cox se analizo el valor pronostico del valor plasmatico de Gal-3 a los 12 meses del TxC. El objetivo primario del estudio fue la variable combinada muerte o disfuncion del injerto. Resultados Las concentraciones de Gal-3 disminuyeron progresivamente durante el primer ano tras el TxC (medianas: pretrasplante, 19,1 ng/ml; 1 ano postrasplante, 14,6 ng/ml; p Conclusiones Las concentraciones plasmaticas de Gal-3 disminuyeron progresivamente durante el primer ano tras el TxC. Un valor plasmatico elevado de Gal-3 1 ano tras el TxC se correlaciono con un pronostico adverso.

[Abstract] Introduction and objectives: Circulating galectin-3 (Gal-3) is elevated and significantly correlates with all-cause and cardiovascular mortality in patients with heart failure. However, the relationship between serum Gal-3 and heart transplant (HT) outcomes is unclear. The aim of this study was to describe the longitudinal trend and prognostic value of Gal-3 levels after HT. Methods: Banked serum samples were available from 122 HT recipients, collected before transplant and at 1, 3, 6, and 12 months posttransplant. Gal-3 levels in these serum samples were measured by enzyme immune assay. Multivariable Cox regression was performed to determine the prognostic value of 12-month posttransplant Gal-3 serum levels. The primary endpoint was the composite variable all-cause death or graft failure over long-term posttransplant follow-up. Results: Circulating Gal-3 concentration steadily decreased during the first year after HT (median values: pretransplant, 19.1 ng/mL; 1-year posttransplant, 14.6 ng/mL; P

Specialized proresolving mediators and, in particular, 5(S), (6)R, 7-trihydroxyheptanoic acid methyl ester (BML-111) emerge as new therapeutic tools to prevent cardiac dysfunction and deleterious cardiac damage associated with myocarditis progression. The cardioprotective role of BML-111 is mainly caused by the prevention of increased oxidative stress and nuclear factor erythroid-derived 2-like 2 (NRF2) down-regulation induced by myocarditis. At the molecular level, BML-111 activates NRF2 signaling, which prevents sarcoplasmic reticulum-adenosine triphosphatase 2A down-regulation and Ca

[Abstract] Introduction and objectives. Light-chain amyloidosis (AL-CA) and transthyretin amyloidosis (ATTR-CA) are the most common types of cardiac amyloidosis (CA). We sought to study the clinical characteristics and prognosis of both diseases. Methods. We conducted a single-centre, retrospective review of all patients diagnosed with CA between 1998 and 2018. Clinical characteristics, complementary tests, survival and other adverse clinical events were studied. Results. We identified 105 patients with CA, 65 ATTR-CA and 40 AL-CA. Mean age was 74.4 years; 24.8% were women. In both groups, heart failure was the most frequent clinical presentation (55.2%). The most prevalent electrocardiographic findings were the pseudoinfarct pattern (68.5%) and a Sokolow-Lyon index

[Abstract] Background: Acute cellular rejection (ACR) is a major complication in heart transplantation (HTx). Endomyocardial biopsy is the reference method for early detection of ACR, but a new non-invasive approach is needed. Tentative candidates could be circulating microRNAs. This study aimed to discover and validate microRNAs in serum for ACR detection after HTx. Methods: This prospective, observational, single-center study included 121 HTx patients. ACR was graded according to International Society of Heart and Lung Transplantation classification (0R−3R). First, in the discovery phase, microRNA expression profile was carried out in serum samples from patients at pre-rejection, during, and post-rejection time (0RS1 → 2RS2 → 0RS3). Relative expression (2-ΔCq) of 179 microRNAs per sample was analyzed by reverse transcription quantitative polymerase chain reaction. Second, a microRNA with a significant rise and fall pattern during ACR was selected for the next validation phase, where it was analyzed (reverse transcription quantitative polymerase chain reaction) in serum samples from 2 groups of patients: the no-ACR group (0R grade) and the ACR group (≥2R grade). Finally, a sensitivity analysis (receiver operating characteristic curve) was done to assess microRNA accuracy for ACR detection in HTx. Results: A total of 21 ACR episodes (0RS1 → 2RS2 → 0RS3) with their respective serum samples (n = 63) were included in the discovery phase. Among the 179 microRNAs analyzed, only miR-181a-5p met the rise and fall criteria. In the validation phase, miR-181a-5p relative expression (2-ΔCq) in the ACR group (n = 45) was significantly overexpressed (p < 0.0001) vs the no-ACR group (n = 45). miR-181a-5p showed an area under the curve of 0.804 (95% confidence interval: 0.707-0.880); sensitivity and specificity of 78% and 76%, respectively; and a negative predicted value of 98%. This study received financial support from Instituto de Salud Carlos III (PI15/02224), is part of the research activities of the Centro de investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), and was cofinanced with FEDER Funds

[Abstract] Introduction and objectives. Light-chain amyloidosis (AL-CA) and transthyretin amyloidosis (ATTR-CA) are the most common types of cardiac amyloidosis (CA). We sought to study the clinical characteristics and prognosis of both diseases. Methods. We conducted a single-centre, retrospective review of all patients diagnosed with CA between 1998 and 2018. Clinical characteristics, complementary tests, survival and other adverse clinical events were studied. Results. We identified 105 patients with CA, 65 ATTR-CA and 40 AL-CA. Mean age was 74.4 years; 24.8% were women. In both groups, heart failure was the most frequent clinical presentation (55.2%). The most prevalent electrocardiographic findings were the pseudoinfarct pattern (68.5%) and a Sokolow-Lyon index

Background Acute Cellular Rejection (ACR) remains a major complication in heart transplantation (HT). Since 1970, endomyocardial biopsy (EMB) has been the gold standard for ACR early detection. However, this invasive procedure has several limitations such as risk of complications, interobserver variability, false negative results and high cost. Therefore, a new non-invasive ACR biomarker is needed. Potential candidates could be microRNAs (miRs), small regulatory RNAs whose serum expression profiling could be modified in ACR patients. The aim of this study is the identification of differentially serum miRs expression patterns in ACR after HT. Methods Among HT performed in our Hospital (2013–2018), we selected patients with following criteria: i) “0R → 2R → 0R” EMB pattern for ACR (0R=no ACR, 2R=moderate ACR); ii) no antibody mediated rejection; iii) serum collected the same day as the EMBs. The 3 serum samples per patient matched in time with EMB were called “0Rs1 → 2Rs2 → 0Rs3”. In each of these serum samples, 179 miRs expression profile according manufacturer's instructions were analysed. Global Mean (GM) method was used to normalize our results expressed as miRs relative expression [2(–ΔCq)]. Expression pattern was defined as a 2 steps process: a significative rise (0Rs1 → 2Rs2) followed by a significative fall (2Rs2 → 0Rs3), or vice versa, in miR expression. Analysis of differences between 3 groups were calculated using one-way ANOVA with matched data and post-hoc Tukey test. ROC curve was generated for selected miRNA. A two-sided p Results 21 patients and their serum “0Rs1 → 2Rs2 → 0Rs3” samples were included in the study. Among 179 miRs analysed, 5 miRs showed significative difference between 0Rs1 and 2Rs2, 3 miRs were over-expressed (miR-181a-5p, miR-339-3p, let-7f-5p) and 2 under-expressed (miR-505-3p, miR-2110). Only miR-181a-5p met significative difference between 2Rs2 and 0Rs3 showing a statistical significative rise/fall pattern. Serum miR-181a-5p ROC analysis demonstrated significant discrimination between biopsy proven ACR from no-ACR biopsy, AUC=0.692 (p=0.0335). Differentially expressed miRs Mean relative expression 2(–ΔCq) (95% CI) Adjusted p-value (ANOVA) AUC (95% CI) 0Rs1 2Rs2 0Rs3 0Rs1 vs 2Rs2 2Rs2 vs 0Rs3 0Rs1 vs 0Rs3 miR-181–5p 0.80 (0.60–1.02) 1.11 (0.90–1.31) 0.86 (0.71–1.01) 0.0194 0.0225 NS 0.692 (0.529–0,855) Relative Expression 2(–ΔCq) and AUC expressed as mean (95% Confident Interval). NS: not significative. Conclusion Our findings suggest miR-181a-5p as a novel serological biomarker for detecting ACR after HT. After this preliminary discovery phase, miR-181a-5p is currently in a new validation phase to demonstrate its diagnostic performance. Acknowledgement/Funding This work was supported by a grant from isciii (PI15/02224) and it is part of the of the “CIBERCV”. Co-financed with FEDER Funds

Only five cases of multifocal medulloblastoma in the adult have been reported to date. We present a case in a male patient in his 50th decade of life who presented with three extra-axial lesions associated with a parenchymatous lesion of the right middle cerebellar peduncle. Sputum sample examination revealed larvae compatible with strongyloides stercoralis, which was our main differential diagnosis. Histological and immunohistochemical studies revealed the existence of a desmoplastic medulloblastoma.

Regenerative medicine, based on the use of stem cells, scaffolds and growth factors, has the potential to be a good approach for restoring damaged tissues of the central nervous system. This study investigated the use of human amniotic mesenchymal stem cells (hAMSC), human amniotic epithelial stem cells (hAESC), and human Wharton's jelly mesenchymal stem cells (hWJMSC) derived from human umbilical cord as a source of stem cells, and the potential of the human amniotic membrane (HAM) as a scaffold and/or source of growth factors to promote nerve regeneration. The hAMSC and hAESC obtained from HAM and the hWJMSC from umbilical cords were cultured in induction medium to obtain neural-like cells. The morphological differentiation of hAMSC, hAESC and hWJMSC into neural-like cells was evident after 4-5 days, when they acquired an elongated and multipolar shape, and at 21 days, when they expressed neural and glial markers. On other way, the HAM was completely decellularized without affecting the components of the basement membrane or the matrix. Subsequently, hAMSC, hAESC and hWJMSC differentiated into neural-like cells were seeded onto the decellularized HAM, maintaining their morphology. Finally, conditioned media from the HAM allowed proliferation of hAMSC, hAESC and hWJMSC differentiated to neural-like cells. Both HAM and umbilical cord are biomaterials with great potential for use in regenerative medicine for the treatment of neurodegenerative diseases.

Cardiac allograft vasculopathy (CAV) is a complex disease of the vasculature of the grafted heart. It is the major cause of graft loss and mortality 1 year posttransplantation. Imaging techniques are the main tools for detecting and classifying CAV. The disease typically involves the epicardial coronary arteries and spreads into the intramyocardial branches. Pathologic features are heterogeneous and include concentric proliferative intimal lesions and vascular inflammation, which can be associated with conventional atherosclerotic plaques. The involvement of the small arteries and the microcirculation, the microvasculopathy, is responsible for structural and functional changes. Among the multiple risk factors associated with CAV, antibody-mediated rejection is currently recognized as the principle.

Background The aim of the study was to analyze the mechanism of deterioration of implanted arteries. Methods Eleven patients were included. Samples of vascular segments obtained from multiorgan donors and samples of the same vascular segments after explantation in the recipient were analyzed. Blood group, time of cold and warm ischemia, cause of death, time spent in the intensive care unit, time of storage of the cryopreserved grafts, and anatomopathological and immunohistochemical studies were analyzed using the preimplant samples obtained from the multiorgan donor. For samples obtained from the recipient, blood group, duration for which the tissue from the donor has been implanted, reason for graft explantation, and anatomopathological and immunohistochemical studies were analyzed. Results Histopathologically, the main finding has been the substitution of the muscular cap of the arterial wall by an intense fibrosis, in most of the cases, of a symmetrical nature. Besides this degeneration of myocytes, there is marked perivascular fibrosis and fibrointimal thickening also exists. The T lymphocytes suggest the importance of the immunological mechanism in the distortion of the architecture of the arteries. The atherosclerosis plays a less relevant role. Conclusions Evidence of immune-mediated injury was found, and this mechanism seems to be responsible for the degenerative process in cryopreserved homografts.

Background The indoleamine, 2-3 dioxygenase (IDO) is an inducible intracellular enzyme with immunosuppressive effects mainly on lymphocyte populations. It has been postulated that indirect determination of IDO serum activity may be a marker of renal graft rejection, but its potential usefulness in heart transplantation (HT) is unknown. Methods This longitudinal study included 98 HT patients (83% males) who survived ≥1 year. Mean age was 54.14 ± 11.57 years. Serum IDO activity was analyzed one month after HT by means of high performance liquid chromatography and correlated with the cumulative incidence of acute rejection (AR) during one-year follow-up. AR was defined as biopsy-proven ≥ ISHLT grade 2R rejection or empirically treated non-biopsy-proven rejection. The study sample was divided into two groups: AR group (n = 51), including patients who experienced at least one AR episode during the first year after HT; No-AR group (N = 47), including the remaining patients. Results Mean serum IDO activity one month after HT was significantly higher ( P = .021) in the AR group (3.32 ± 1.56) than in the no-AR group (2.62 ± 1.35). No significant association between serum IDO activity and gender (male: 3.1 ± 1.56, women: 2.43 ± 0.99, P = .092), recipient age ( r = −.07, P = .943) or donor age ( r = 0.108, P = 0.293) was observed. By means of binary logistic regression, an odds ratio of 1.4 [CI 95%: 1.033-1.876, P = .03] per unit increase of act-IDO was estimated, with no significant modification upon forced adjustment for age and sex. Mean glomerular filtration rate 1 month after HT was 67.01 ± 28.51 mL/min/m 2 . No significant correlation between this parameter and serum IDO activity was observed ( r = .160, P = .117). Conclusions Our study suggests that serum IDO activity one month after HT might be associated with a higher risk of AR during one-year follow-up. This association seems to be independent of recipient gender, age or renal function.

Fetal rhabdomyoma is a benign neoplasm of rhabdomyoblasts that is found in both children and adults. Although there is often a predilection for the head and neck region, these tumors have been identified in several anatomic sites. A primary frontonasal presentation, however, has not been described yet. We report the first case of a fetal rhabdomyoma arising in the frontonasal region of a 3-year-old girl. This rare form of presentation is very interesting because of the need for a differential diagnosis with other entities. The clinician must keep in mind other possibilities typical of frontonasal region in childhood like nasal dermal sinus, anterior cephalocele and nasal glioma. For the pathologist, the most important reason to recognize and diagnose fetal rhabdomyoma in its various forms and locations is to avoid confusion with his malignant counterpart, the rhabdomyosarcoma.

Purpose: To assess the effects of myxomavirus-derived immunomodulatory proteins (Serp-1 and M-T7), on circulating mononuclear blood cells (PBMC) isolated from cardiac transplant patients. Methods and Materials: PBMC were isolated from 21 orthotopic heart transplant patients, 16 without and 5 with documented allograft vasculopathy, ages18 66 years old; 1 to 204 months post heart transplantation; all receiving standard immunosuppression medications. Cell activation was assessed by adhesion assay with calcein cell labeling. Cell isolates were segregated into treatment groups: (1)saline for baseline control, (2)Dimethyl sulfoxide (DMSO) for vehicle control, (3)cell activation with phorbol myristate acetate (PMA), (4)Serp-1 with PMA and (5) M-T7 with PMA. The inhibitory effect of Serp-1 and M-T7 on cell activation was measured based on changes in the adherent cell counts quantified by a spectrofluorometer. Statistical analysis by ANOVA was then performed. Results: PMA treatment was unable to further activate cells from patients with diagnosed allograft vasculopathy suggesting chronic elevated activation in circulating PBMC resistant to further activationan. These cells did not respond to Serp-1 or M-T7 treatment. Cells from patients without allograft vasculopathy conversely were activated by PMA (p 0.0001). M-T7 suppressed cell activity in the patients without vasculopathy despite standard immunosuppressive regimen (p 0.0001), thus indicating that patients on full anti-rejection therapy display further responses to antiinflammatory therapy despite full therapeutic regimens. Conclusions: Patients with known cardiac allograft vasculopathy have ongoing chronic activation of circulating peripheral mononuclear cells, unresponsive to further activation or anti-inflammatory treatment. M-T7, a unique virus derived chemokine modulator, significantly suppressed cell activation in patients without vasculopathy, suggesting potential for further treatment despite current optimal medical immunosuppression.