Targeting IL-6 trans-signalling by sgp130Fc attenuates severity in SARS-CoV-2 -infected mice and reduces endotheliopathy.

BACKGROUND: SARS-CoV-2 infection is considered as a relapsing inflammatory process with a dysregulation of IL-6 signalling. Classic IL-6 signalling is thought to represent a defence mechanism against pathogens. In contrast, IL-6 trans-signalling has pro-inflammatory effects. In severe COVID-19, therapeutic strategies have focused on global inhibition of IL-6, with controversial results. We hypothesized that specific blockade of IL-6 trans-signalling could inhibit inflammatory response preserving the host defence activity inherent to IL-6 classic signalling. METHODS: To test the role of the specific IL-6 trans-signalling inhibition by sgp130Fc in short- and long-term consequences of COVID-19, we used the established K18-hACE2 transgenic mouse model. Histological as well as immunohistochemical analysis, and pro-inflammatory marker profiling were performed. To investigate IL-6 trans-signalling in human cells we used primary lung microvascular endothelial cells and fibroblasts in the presence/absence of sgp130Fc. FINDINGS: We report that targeting IL-6 trans-signalling by sgp130Fc attenuated SARS-CoV-2-related clinical symptoms and mortality. In surviving mice, the treatment caused a significant decrease in lung damage. In vitro, IL-6 trans-signalling induced strong and persisting JAK1/STAT3 activation in endothelial cells and lung fibroblasts with proinflammatory effects, which were attenuated by sgp130Fc. Our data also suggest that in those cells with scant amounts of IL-6R, the induction of gp130 and IL-6 by IL-6:sIL-6R complex sustains IL-6 trans-signalling. INTERPRETATION: IL-6 trans-signalling fosters progression of COVID-19, and suggests that specific blockade of this signalling mode could offer a promising alternative to mitigate both short- and long-term consequences without affecting the beneficial effects of IL-6 classic signalling. These results have implications for the development of new therapies of lung injury and endotheliopathy in COVID-19. FUNDING: The project was supported by ISCIII, Spain (COV-20/00792 to MB, PI23/01351 to MARH) and the European Commission-Next generation EU (European Union) (Regulation EU 2020/2094), through CSIC's Global Health Platform (PTI Salud Global, SGL2103029 to MB). PID2019-110587RB-I00 (MB) supported by MICIN/AEI/10.13039/501100011033/and PID2022-143034OB-I00 (MB) by MICIN/AEI/10.13039/501100011033/FEDER. MAR-H acknowledges support from ISCIII, Spain and the European Commission-Next generation EU (European Union), through CSIC's Global Health PTI.

Characteristics and outcomes of the Spanish registry for pediatric patients with bicuspid aortic valve (REVAB).

INTRODUCTION AND OBJECTIVES: Bicuspid aortic valve (BAV) disorder is the most common congenital heart disease. The aim of this study was to describe the characteristics of 0- to 18-year olds with BAV in a population-based registry. METHODS: Data from all pediatric patients were obtained from the Spanish registry for pediatric patients with bicuspid aortic valve (REVAB) (< 18 years). For data analysis, patients with BAV were divided into 2 groups by their features: isolated BAV and BAV with associated congenital heart disease. RESULTS: We included 1681 patients from 33 hospitals. Males accounted for 69.6% (n = 1158). Valve morphology was horizontal in 63.4% (n = 1012) and pure (Sievers type 0) in 28.4% (n=469). Isolated BAV was present in 63.7% (n=1060), and concomitant left-sided obstructive lesions in 23.4% (n=390). Interventions were required in 8.6% (n=145). CONCLUSION: These data represent the first large, population-based description of the clinical presentations and outcomes of patients enrolled in the Spanish registry for pediatric patients with bicuspid aortic valve.

Short- and long-term survival of children treated with ventricular assist devices in Spain, based on 15 years' experience.

OBJECTIVES: To describe the use of ventricular assist devices (VAD) in children in Spain and to identify variables related to survival. METHODS: This is an observational cohort study of all children younger than 18 years of age who underwent an initial implantation of a VAD at any of the 6 paediatric heart transplant centres from May 2006 to December 2020. Subjects were identified retrospectively from each hospital's database. RESULTS: Paracorporeal VADs were implanted in 118 children [pulsatile (63%), continuous (30.5%) or both types (5.9%)]. Small children (<0.7 m2 of body surface area) comprised the majority of this cohort (63.3%). Overall, 67% survived to VAD explantation, and 64.9% survived to hospital discharge. Non-central nervous system haemorrhage (39%) and stroke (38.1%) were the most common complications. Body weight <5 kg, congenital heart disease, pre-implantation bilirubin >34 µmol/l and bridge to decision strategy were associated with a higher mortality at hospital discharge and in the long-term. Interagency registry for mechanically assisted circulatory support (INTERMACS) status 1 and cardiac arrest prior to VAD implantation were related to long-term mortality, whereas pre-implantation renal replacement therapy and extracorporeal membrane oxygenation were not related to mortality. CONCLUSIONS: In Spain, 67% of the VAD-supported children have been bridged to heart transplantation or to recovery. Body weight lower than 5 kg, congenital heart disease diagnosis, cholestatic liver dysfunction, bridge to decision as VAD strategy, INTERMACS-1 status and cardiac arrest were pre-implantation variables related to mortality, whereas pre-implantation renal replacement therapy and extracorporeal membrane oxygenation were not.

Síndrome de hiperémesis por cannabis: incidencia y tratamiento con capsaicina tópica / Cannabis hyperemesis syndrome: Incidence and treatment with topical capsaicin

Introducción: Existen pocos estudios en España acerca del síndrome de hiperémesis cannabinoide (SHC), así como sobre el uso de capsaicina tópica para su tratamiento.Métodos:Estudio retrospectivo de pacientes mayores de 14 años atendidos en un servicio de urgencias hospitalario durante 2018 y 2019 con diagnóstico de SHC con base en los siguientes criterios: cuadro clínico compatible, consumo de cannabis menor de 48h y test de cannabis en orina positivo. Se recogieron variables epidemiológicas, clínicas, tiempos asistenciales y tratamiento (incluyendo el uso de capsaicina tópica al 0,075%).Resultados:Se estudiaron 59 asistencias de 29 pacientes (4,4 casos/10.000 visitas, IC 95% 2,8-4,7). Un 50% volvieron a urgencias por SHC, diferenciándose estos solo en más consumo de tabaco (p=0,01) y cocaína (p=0,031). En un 74,6% de las visitas se utilizó capsaicina. El tiempo medio de resolución de los vómitos tras su aplicación fue de 17,87min.Conclusiones:Aunque probablemente esté infradiagnosticado, el SHC presenta una incidencia baja en las urgencias en España, y con alta reincidencia de los pacientes. El uso de pomada de capsaicina es eficiente y seguro. (AU)

There are few studies in Spain on cannabinoid hyperemesis syndrome (CHS), as well as on the use of topical capsaicin as a treatment.Methods:Retrospective study of patients over 14 years of age seen in a hospital emergency department during 2018 and 2019 with a diagnosis of CHS based on the following criteria: compatible clinical picture, cannabis use less than 48h and positive urine cannabis test. Epidemiological and clinical variables, attendance times and treatment (including use of topical capsaicin 0.075%) were collected.Results:Fifty-nine attendances were studied, from 29 patients (4.4 cases/10,000 visits, 95% CI 2.8-4.7). Fifty per cent returned for CHS, differing only in more tobacco (P=.01) and cocaine (P=.031) use. Capsaicin was used in 74.6% of visits. The mean time to resolution of vomiting after application was 17.87min.Conclusions:Although probably underdiagnosed, CHS has a low incidence in the emergency department in Spain, with high patient recurrence. The use of capsaicin ointment is efficient and safe. (AU)

Identification of IL-6 Signalling Components as Predictors of Severity and Outcome in COVID-19.

IL-6 is one of the major mediators of the hyper-inflammatory responses with complex biological functions as it can signal via different modes of action. IL-6 by classical signalling has anti-inflammatory and antibacterial activities, while trans-signalling mediates pro-inflammatory effects. The net biological effect of IL-6 is established by multiple factors beyond its absolute concentration. Here, we assess the relationship between IL-6 signalling variables [IL-6, soluble IL-6R (sIL-6R) and soluble gp130 (sgp130)] and outcomes in a cohort of 366 COVID-19 patients. The potential trans-signalling was evaluated by a ratio between the pro-inflammatory binary IL-6:sIL-6R complex and the inactive ternary IL-6:sIL-6R:sgp130 complex (binary/ternary complex) and the fold molar excess of sgp130 over sIL-6R (FME). Our data provide new evidence that high levels of IL-6, sIL-6R, sgp130, binary/ternary complex ratio, and low FME are independent predictors of COVID-19 severity in survivor patients (without death), and the combination of IL-6 + sIL-6R + sgp130 exhibited the most robust classification capacity. Conversely, in a subgroup of patients with a very poor prognosis, we found that high levels of IL-6 and low levels of sIL-6R, sgp130, and binary/ternary complex ratio were predictors of death. In this context, the highest predictive capacity corresponded to the combined analysis of IL-6 + FME + lymphopenia + creatinine. Herein, we present IL-6 signalling variables as a helpful tool for the early identification and stratification of patients with clear implications for treatment and clinical decision-making.

Primary cardiac fibroma in infants: A case report and review of cases of cardiac fibroma managed through orthotopic heart transplant.

Cardiac fibromas (CF) are the second most common cardiac tumors in children. They can be aggressive tumors despite their benign histopathologic nature, accounting for the highest mortality rate among primary cardiac tumors. CF usually show a progressive growth and spontaneous regression is rare. Therefore, a complete surgical excision is the preferred therapeutic approach when patients become symptomatic or if mass-related life-threatening complications are anticipated, even in asymptomatic patients. However, some cases are not good candidates for surgical excision due to the impossibility of preserving a normal cardiac anatomy or function after the tumor resection. Orthotopic heart transplantation (OHT) can be an exceptional but adequate alternative for some giant unresectable CF in children. In this article, we report our experience with the case of a 7-month-old infant with a giant unresectable cardiac fibroma who was successfully managed through OHT.

Contaminations contaminate common databases.

The polymerase chain reaction (PCR) is a very powerful method to detect and identify pathogens. The high sensitivity of the method, however, comes with a cost; any of the millions of artificial DNA copies generated by PCR can serve as a template in a following experiment. If not identified as contaminations, these may result in erroneous conclusions on the occurrence of the pathogen, thereby inflating estimates of host range and geographic distribution. In the present paper, we evaluate whether several published records of avian haemosporidian parasites, in either unusual host species or geographical regions, might stem from PCR contaminations rather than novel biological findings. The detailed descriptions of these cases are shedding light upon the steps in the work process that might lead to PCR contaminations. By increasing the awareness of this problem, it will aid in developing procedures that keep these to a minimum. The examples in the present paper are from haemosporidians of birds, however the problem of contaminations and suggested actions should apply generally to all kinds of PCR-based identifications, not just of parasites and pathogens.

De Novo Duplication of Chromosome 9p in a Female Infant: Phenotype and Genotype Correlation.

Trisomy 9p syndrome is the fourth most frequent chromosome aberration seen in infants. Duplication of the critical region 9p22p24 leads to mental retardation, psychomotor delay, and craniofacial and digital anomalies. We report a 2-year-old Ecuadorian girl with Trisomy 9p syndrome. Although her phenotype shares characteristics of Noonan syndrome, Giemsa trypsin banding technique shows there is an extra chromosomal segment on chromosome 14, and array analysis shows that it belongs to a duplication of 38 Mb of 9p13.1p24.3. Fluorescence in situ hybridization analysis detected three signals from 9p chromosome. The duplication is de novo, being another unique case of the few reported in the literature.

The CoQH2/CoQ Ratio Serves as a Sensor of Respiratory Chain Efficiency.

Electrons feed into the mitochondrial electron transport chain (mETC) from NAD- or FAD-dependent enzymes. A shift from glucose to fatty acids increases electron flux through FAD, which can saturate the oxidation capacity of the dedicated coenzyme Q (CoQ) pool and result in the generation of reactive oxygen species. To prevent this, the mETC superstructure can be reconfigured through the degradation of respiratory complex I, liberating associated complex III to increase electron flux via FAD at the expense of NAD. Here, we demonstrate that this adaptation is driven by the ratio of reduced to oxidized CoQ. Saturation of CoQ oxidation capacity induces reverse electron transport from reduced CoQ to complex I, and the resulting local generation of superoxide oxidizes specific complex I proteins, triggering their degradation and the disintegration of the complex. Thus, CoQ redox status acts as a metabolic sensor that fine-tunes mETC configuration in order to match the prevailing substrate profile.

Primary coenzyme Q10 deficiency presenting as fatal neonatal multiorgan failure.

Coenzyme Q10 deficiency is a clinically and genetically heterogeneous disorder, with manifestations that may range from fatal neonatal multisystem failure, to adult-onset encephalopathy. We report a patient who presented at birth with severe lactic acidosis, proteinuria, dicarboxylic aciduria, and hepatic insufficiency. She also had dilation of left ventricle on echocardiography. Her neurological condition rapidly worsened and despite aggressive care she died at 23 h of life. Muscle histology displayed lipid accumulation. Electron microscopy showed markedly swollen mitochondria with fragmented cristae. Respiratory-chain enzymatic assays showed a reduction of combined activities of complex I+III and II+III with normal activities of isolated complexes. The defect was confirmed in fibroblasts, where it could be rescued by supplementing the culture medium with 10 µM coenzyme Q10. Coenzyme Q10 levels were reduced (28% of controls) in these cells. We performed exome sequencing and focused the analysis on genes involved in coenzyme Q10 biosynthesis. The patient harbored a homozygous c.545T>G, p.(Met182Arg) alteration in COQ2, which was validated by functional complementation in yeast. In this case the biochemical and morphological features were essential to direct the genetic diagnosis. The parents had another pregnancy after the biochemical diagnosis was established, but before the identification of the genetic defect. Because of the potentially high recurrence risk, and given the importance of early CoQ10 supplementation, we decided to treat with CoQ10 the newborn child pending the results of the biochemical assays. Clinicians should consider a similar management in siblings of patients with CoQ10 deficiency without a genetic diagnosis.

Haploinsufficiency of COQ4 causes coenzyme Q10 deficiency.

BACKGROUND: COQ4 encodes a protein that organises the multienzyme complex for the synthesis of coenzyme Q(10) (CoQ(10)). A 3.9 Mb deletion of chromosome 9q34.13 was identified in a 3-year-old boy with mental retardation, encephalomyopathy and dysmorphic features. Because the deletion encompassed COQ4, the patient was screened for CoQ(10) deficiency. METHODS: A complete molecular and biochemical characterisation of the patient's fibroblasts and of a yeast model were performed. RESULTS: The study found reduced COQ4 expression (48% of controls), CoQ(10) content and biosynthetic rate (44% and 43% of controls), and activities of respiratory chain complex II+III. Cells displayed a growth defect that was corrected by the addition of CoQ(10) to the culture medium. Knockdown of COQ4 in HeLa cells also resulted in a reduction of CoQ(10.) Diploid yeast haploinsufficient for COQ4 displayed similar CoQ deficiency. Haploinsufficency of other genes involved in CoQ(10) biosynthesis does not cause CoQ deficiency, underscoring the critical role of COQ4. Oral CoQ(10) supplementation resulted in a significant improvement of neuromuscular symptoms, which reappeared after supplementation was temporarily discontinued. CONCLUSION: Mutations of COQ4 should be searched for in patients with CoQ(10) deficiency and encephalomyopathy; patients with genomic rearrangements involving COQ4 should be screened for CoQ(10) deficiency, as they could benefit from supplementation.

Performance of the New INNO-LiPA HPV extra to genotype human papillomavirus in cervical cell specimens.

OBJECTIVE: It was our aim to compare the INNO-LiPA HPV Genotyping Extra (LiPA; Innogenetics) versus the Linear Array test (LA; Roche) in cervical samples. STUDY DESIGN: One hundred cervical samples were selected, obtained from a cancer prevention center. All samples were human papillomavirus (HPV) DNA positive by Hybrid Capture 2 HPV test and genotyped by LA HPV genotyping test. All data were analyzed using Cohen's κ tests. κ values ranged from poor, fair, moderate and good to very good agreement strength. RESULTS: Detection of multiple infection and HPV genotypes per sample was higher by LA than by LiPA (61.5 vs. 52.1 and 2.2 vs. 1.7%, respectively). There were concordant results in 65 samples and compatible results in 33 samples. Only 2 samples were considered as discordant. In 21 samples, additional types were detected by LA, and in 13 samples, additional types were detected by LiPA. Analyzing the κ values, we have found very good agreement for 14 genotypes (6, 16, 26, 31, 33, 35, 45, 51, 52, 53, 58, 66, 68 and 70). CONCLUSIONS: We considered that the new LiPA is highly comparable with other methods and suitable for clinical and epidemiological studies.

Umbilical cord blood transplantation using non-myeloablative conditioning: the Mexican experience.

Twenty-eight children and adults underwent transplantation with allogeneic umbilical cord blood cells (UCB) using a non-ablative conditioning regimen; there were 15 males and 13 females. Seven patients were grafted because a non-malignant condition and 21 for a malignant disease. The median age was 8 years (range 4 months-72 years). Ten UCB were obtained from Mexican cord bloods banks, five cords were from compatible siblings and the remaining 13 cords were obtained from abroad. Median time to recover >0.5 x 10(9)/l granulocytes was 24 days (range 8-32 days), whereas median time to recover >20 x 10(9)/l platelets was 26 days (range 12-50 days). Twelve recipients never engrafted and recovered subsequently endogenous hematopoiesis. The non-engraftment rate was significantly higher in patients allografted for benign conditions (71%) than in those allografted for malignant conditions (28%). The median overall post-transplant survival (SV) was 33 months and the 73-months overall SV was 39%. The cumulative incidence of grade II-IV acute GVHD and grade III-IV GVHD for the entire cohort of patients were 14 and 7%, respectively. Additional studies are needed to define if non-myeloablative conditioning is preferable over conventional conditioning in the case of UCB allografting.

Drogadicciones: estrategia de intervención en una comunidad / Drug addiction: strategy of educational intervention in a community

Se llevó a cabo un estudio de intervención dirigido a valorar los conocimientos que poseía sobre las drogadicciones un grupo poblacional de una comunidad especial perteneciente a la provincia Santiago de Cuba, durante el período comprendido de febrero a marzo del 2003. A los participantes se les aplicó una encuesta inicial, donde se hizo evidente el desconocimiento de los aspectos relacionados con el tema, por lo cual se les informó al respecto a través de conferencias, charlas, dinámicas de grupos y otras técnicas psicoterapéuticas participativas, a fin de crear situaciones problemáticas que determinaron las necesidades de aprendizaje. El trabajo educativo propuesto, con participación comunitaria, permitió evaluar y comparar el nivel cognoscitivo al comienzo de este y su efectividad al final. La investigación acentuó la importancia y asequibilidad de combinar las técnicas psicoterapéuticas, didácticas y participativas para prevenir y detener el avance de este fenómeno, que actualmente constituye un problema de salud(AU)

Costo hospitalario de pacientes diagnosticados con retraso mental / Hospital cost from patients diagnosed with mental retardation

En aras de contribuir con la atención que se le debe prestar a los aspectos económicos en el financiamiento de las actividades encaminadas a garantizar la calidad de la asistencia médica, dirigidas al desarrollo de la economía de Cuba, se determinó el costo hospitalario en 20 pacientes ingresados con el diagnóstico de retraso mental. El costo promedio de la afección en estudio en el período analizado demostró el consecuente gasto de recursos posterior a su ingreso en esta institución médica equivalente a $ 930,00. Predominaron los pacientes de 18 a 22 años de edad con un costo total de $883,50 y la estadía prevalenciente de 10 a 19 días con 13 casos representó el 65 por ciento con un costo de $ 604,50. Se logró precisar la necesidad de brindar especial atención al diagnóstico confiable de trastornos mentales específicos en las comisiones médicas con el fin de disminuir el número de ingresos y bajas médicas por dichos trastornos

Costo hospitalario de pacientes diagnosticados con retraso mental / Hospital cost from patients diagnosed with mental retardation

En aras de contribuir con la atención que se le debe prestar a los aspectos económicos en el financiamiento de las actividades encaminadas a garantizar la calidad de la asistencia médica, dirigidas al desarrollo de la economía de Cuba, se determinó el costo hospitalario en 20 pacientes ingresados con el diagnóstico de retraso mental. El costo promedio de la afección en estudio en el período analizado demostró el consecuente gasto de recursos posterior a su ingreso en esta institución médica equivalente a $ 930,00. Predominaron los pacientes de 18 a 22 años de edad con un costo total de $883,50 y la estadía prevalenciente de 10 a 19 días con 13 casos representó el 65 por ciento con un costo de $ 604,50. Se logró precisar la necesidad de brindar especial atención al diagnóstico confiable de trastornos mentales específicos en las comisiones médicas con el fin de disminuir el número de ingresos y bajas médicas por dichos trastornos(AU)