Mutation study of Spanish patients with hereditary hemorrhagic telangiectasia and expression analysis of Endoglin and ALK1

10 páginas, 2 figuras, 1 tabla -- PAGS nro. 295Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant and age-dependent vascular disorder originated by mutations in Endoglin (ENG) or activin receptor-like kinase-1 (ALK1, ACVRL1) genes. The first large series HHT analysis in Spanish population has identified mutations in 17 unrelated families. Ten different mutations in ALK1 and six in ENG genes were found. Six unrelated families had a mutation in ENG gene, four representing new mutations, p.Y258fs, pV323fs, p.F279fs (c.834_837del CTTC), and p.F279fsdupC. Eleven unrelated families harboured mutations in ALK1; ten were new mutations identified as p.H328P, p.R145fs, p.G68C, p.A377T, p.H297R, p.M376T, p.C36Y, p.H328P, p.T82del and p.R47P. Overall, ALK1 mutations (HHT2) were predominant over ENG mutations (HHT1), in agreement with data reported for other Mediterranean countries (France, Italy), but at variance with Northern Europe or North America. Endoglin expression in HHT1 or HHT2 activated monocytes and blood outgrowth endothelial cells (BOECs) from older patients was well below the theoretical 50% level expected from the HHT1 haploinsufficiency model, suggesting that the pathogenic endoglin haploinsufficiency leading to the HHT phenotype is age-dependent. Interestingly, ALK1 protein levels of HHT BOECs in some missense ALK1 mutants were similar to controls. In vitro expression of these ALK1 constructs suggests that, in addition to the haploinsufficiency model, certain ALK1 mutants may inhibit the function of the wild type alleleAuthors are indebted to Drs. Michelle Letarte and Ursula Cymerman for suggestions on methods of HHT patient sequencing, Dr. Kohei Miyazono for ALK1 constructs, Carmen Langa for technical assistance, Prof. Ginevra Guanti for hosting in her lab to A.F-L. and L.M.B., and to all the volunteers and HHT patients for their collaboration. A.F-L is a predoctoral fellow of I3P Program from Ministerio de Educación y Ciencia, SpainPeer reviewe

Obstetric outcomes of sars-cov-2 infection in asymptomatic pregnant women

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER)Around two percent of asymptomatic women in labor test positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Spain. Families and care providers face childbirth with uncertainty. We determined if SARS-CoV-2 infection at delivery among asymptomatic mothers had different obstetric outcomes compared to negative patients. This was a multicenter prospective study based on universal antenatal screening for SARS-CoV-2 infection. A total of 42 hospitals tested women admitted for delivery using polymerase chain reaction, from March to May 2020. We included positive mothers and a sample of negative mothers asymptomatic throughout the antenatal period, with 6-week postpartum follow-up. Association between SARS-CoV-2 and obstetric outcomes was evaluated by multivariate logistic regression analyses. In total, 174 asymptomatic SARS-CoV-2 positive pregnancies were compared with 430 asymptomatic negative pregnancies. No differences were observed between both groups in key maternal and neonatal outcomes at delivery and follow-up, with the exception of prelabor rupture of membranes at term (adjusted odds ratio 1.88, 95% confidence interval 1.13-3.11; p = 0.015). Asymptomatic SARS-CoV-2 positive mothers have higher odds of prelabor rupture of membranes at term, without an increase in perinatal complications, compared to negative mothers. Pregnant women testing positive for SARS-CoV-2 at admission for delivery should be reassured by their healthcare workers in the absence of symptoms

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Global economic burden of unmet surgical need for appendicitis

Background: There is a substantial gap in provision of adequate surgical care in many low-and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods: Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results: Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion: For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially

Outcomes from elective colorectal cancer surgery during the SARS-CoV-2 pandemic

This study aimed to describe the change in surgical practice and the impact of SARS-CoV-2 on mortality after surgical resection of colorectal cancer during the initial phases of the SARS-CoV-2 pandemic

Bases moleculares y celulares de la Telangiectasia Hemorragica Hereditaria

Leída en la Universidad Complutense de Madrid. Facultad de Ciencias Biológicas el 01-18-2007; 212 págs.La Telangiectasia Hemorrágica Hereditaria (HHT) es una enfermedad vascular autosómica dominante caracterizada por hemorragias espontáneas y recurrentes. Mutaciones en los genes que codifican para endoglina y ALK1 son responsables de HHT1 y HHT2, respectivamente. Ambas proteínas son componentes del complejo receptor del TGF-beta, expresadas fundamentalmente en células endoteliales. Identificamos la mutación responsable de la enfermedad en 35 familias, encontrando una prevalencia de HHT2 sobre HHT1. A partir de sangre periférica de pacientes de HHT, aislamos células endoteliales (BOECs) y estudiamos sus alteraciones funcionales en relación a células de individuos sanos. Las BOECs de pacientes de HHT, tanto HHT1 como HHT2, presentaban bajos niveles de Endoglina y ALK1, así como una señalización defectuosa de esta vía de TGF-beta. Como consecuencia, los niveles de ALK5 disminuyen dando lugar a un defecto general de la señalización de TGF-beta. La señalización defectuosa de TGF-beta conduciría alteraciones en la expresión de un gran número de genes diana, así como en las funciones en las que éstos se encuentran implicados. Así, las BOECs, de pacientes presenta alteraciones a nivel de adhesión, migración , síntesis de matriz extracelular, organización del citoesqueleto, ciclo celular o fisiología vascular, dando lugar a un defecto general en angiogénesis y una fragilidad de los capilares que explican la aparición de malformaciones vasculares. En este trabajo hemos identificado en detalle los mecanismos moleculares y celulares que conducen a las manifestaciones de la HHT y describimos un modelo celular útil para el estudio de la enfermedad y la búsqueda de nuevas dianas terapéuticas.PI020200 del Fondo de Investigación Sanitaria (FIS). Bases moleculares de la Telangiectasia Hemorrágica Hereditaria. Detección y relevancia funcional de mutaciones en el gen de endoglina. Período 2002-2005. Centro deInvestigaciones Biológicas, CSIC, Madrid. Investigador Principal: Carmelo Bernabéu Quirante. 08.4/0026.1/2003 de la Comunidad Autónoma de Madrid (CAM). Mutaciones y regulación del gen de endoglina en la HHT. Período 2003. Centro de Investigaciones Biológicas, CSIC, Madrid. Investigador Principal: Carmelo Bernabéu Quirante. SAF05-01090 del Ministerio de Educación y Ciencia, Plan Nacional de I+D: Bases moleculares de la Telangiectasia Hemorrágica Hereditaria tipo I y II en España. Período 2006-2008. Centro de Investigaciones Biológicas, CSIC, Madrid. Investigador Principal: Luisa-María Botella Cubells. HTT Foundation International, Inc., Monkton, MD, USA. Primary cultures of endothelial and monocytic cells derived from HHT patients: An open window to unravel the pathogenicity of HHT. Período Julio 2005-Julio 2006. Centro de Investigaciones Biológicas, CSIC, Madrid. Investigador Principal: Carmelo bernabéu Quirante. SAF2004-01390 del Ministerio de Educación y Ciencia, Plan Nacional de I+D: Estudios sobre engoglina, un co-receptior de TGF-beta implicado en la patología humana. Período Diciembre 2004-Diciembre 2007. Centro de Investigaciones Biológicas, CSIC, Madrid. Investigador Principal: Carmelo Bernabeú QuirantePeer reviewe

Hereditary hemorrhagic telangiectasia, a vascular dysplasia affecting the TGF-beta signaling pathway

13 páginas, 8 figuras, 2 tablas -- PAGS nros. 66-78Hereditary hemorrhagic telangiectasia (HHT) is caused by mutations in endoglin (ENG; HHT1) or ACVRL1/ALK1 (HHT2) genes and is an autosomal dominant vascular dysplasia. Clinically, HHT is characterized by epistaxis, telangiectases and arteriovenous malformations in some internal organs such as the lung, brain or liver. Endoglin and ALK1 proteins are specific endothelial receptors of the transforming growth factor (TGF)-β superfamily that are essential for vascular integrity. Genetic studies in mice and humans have revealed the pivotal role of TGF-β signaling during angiogenesis. Through binding to the TGF-β type II receptor, TGF-β can activate two distinct type I receptors (ALK1 and ALK5) in endothelial cells, each one leading to opposite effects on endothelial cell proliferation and migration. The recent isolation and characterization of circulating endothelial cells from HHT patients has revealed a decreased endoglin expression, impaired ALK1- and ALK5-dependent TGF-β signaling, disorganized cytoskeleton and the failure to form cord-like structures which may lead to the fragility of small vessels with bleeding characteristic of HHT vascular dysplasia or to disrupted and abnormal angiogenesis after injuries and may explain the clinical symptoms associated with this diseaseThis work was supported by grants from HHT Foundation International, Ministerio de Educación y Ciencia (SAF2004-01390) and Fondo de Investigación Sanitaria (PI020200) to C.B. A.F-L is a predoctoral fellow of I3P Program from Ministerio de Educación y Ciencia, SpainPeer reviewe

The TGF-β co-receptor endoglin modulates the expression and transforming potential of H-Ras

10 páginas, 6 figuras.-- El pdf del artículo es la versión pre-print.Endoglin is a coreceptor for transforming growth factor-β (TGF-β) that acts as a suppressor of malignancy during mouse skin carcinogenesis. Because in this model system H-Ras activation drives tumor initiation and progression, we have assessed the effects of endoglin on the expression of H-Ras in transformed keratinocytes. We found that TGF-β1 increases the expression of H-Ras at both messenger RNA and protein levels. The TGF-β1-induced H-Ras promoter transactivation was Smad4 independent but mediated by the activation of the TGF-β type I receptor ALK5 and the Ras-mitogen-activated protein kinase (MAPK) pathway. Endoglin attenuated stimulation by TGF-β1 of both MAPK signaling activity and H-Ras gene expression. Moreover, endoglin inhibited the Ras/MAPK pathway in transformed epidermal cells containing an H-Ras oncogene, as evidenced by the levels of Ras-guanosine triphosphate, phospho-MAPK kinase (MEK) and phospho-extracellular signal-regulated kinase (ERK) as well as the expression of c-fos, a MAPK downstream target gene. Interestingly, in spindle carcinoma cells, that have a hyperactivated Ras/MAPK pathway, endoglin inhibited ERK phosphorylation without affecting MEK or Ras activity. The mechanism for this effect is unknown but strongly depends on the endoglin extracellular domain. Because the MAPK pathway is a downstream mediator of the transforming potential of Ras, the effect of endoglin on the oncogenic function of H-Ras was assessed. Endoglin inhibited the transforming capacity of H-Ras(Q61K) and H-Ras(G12V) oncogenes in a NIH3T3 focus formation assay. The ability to interfere with the expression and oncogenic potential of H-Ras provides a new face of the suppressor role exhibited by endoglin in H-Ras-driven carcinogenesis.Spanish Ministry of Science and Innovation (SAF2007-61827 to C.B., SAF2007-63821 to M.Q.); Science and Technology of Chile (FONDECYT #1050476 to J.F.S.).Peer reviewe

Treatment of epistaxes in hereditary haemorrhagic telangiectasia (Rendu-Osler-Weber disease) with tranexamic acid

4 páginas, 3 tablas -- PAGS nros. 129-132[EN]Objective: Recurrent epistaxis is the most frequent clinical manifestation of hereditary haemorrhagic telangiectasia (HHT). Its treatment occasionally presents difficulties as there is no consensus on the appropriate therapeutic protocol. Our objective was to explore the utility of oral tranexamic acid for the treatment of epistaxes in HHT patients. Patients and method: A 3-year prospective study was carried on HHT patients with epistaxis treated with oral tranexamic acid in the HHT unit at our hospital. Results: Ten patients with HHT were treated with oral tranexamic acid during the study. Most of them improved both the frequency and severity of their epistaxis and were satisfied with the treatment. No treatment-related complications were recorded. Two patients needed more aggressive treatments to control epistaxis. Conclusions: Oral tranexamic acid is useful for achieving significant reductions in epistaxis frequency and intensity in selected patients with HHT. In those presenting severe epistaxis, however, it may need to be combined with more aggressive therapies[ES]Introducción: Las epistaxis son la manifestación clínica más frecuente en los enfermos con telangiectasia hemorrágica hereditaria (HHT). Su tratamiento es en ocasiones muy complejo, y no hay consenso sobre el protocolo terapéutico que se ha de aplicar. El objetivo de nuestro estudio fue valorar la utilidad del ácido tranexámico oral en las epistaxis secundarias a HHT. Pacientes y método: Se realizó un estudio prospectivo de pacientes con HHT tratados por epistaxis en la unidad de HHT de nuestro hospital mediante ácido tranexámico durante 3 años. Resultados: Se trató a 10 pacientes con HHT mediante ácido tranexámico oral durante el período de estudio. Todos ellos presentaron una disminución tanto en la intensidad como la frecuencia de las epistaxis. En su mayoría estaban satisfechos con los resultados del tratamiento. Ninguno presentó complicaciones relacionadas con él y 2 pacientes siguieron precisando otros tratamientos para control de las epistaxis. Conclusiones: El ácido tranexámico oral es útil en el tratamiento de las epistaxis en algunos pacientes con HHT,pues reduce de forma significativa tanto la intensidad como la frecuencia. Sin embargo, en los que presentan epistaxis severas no impide la necesidad de seguir realizando Ç otros tratamientos agresivos.Peer reviewe

Antimicrobial effects of treated olive mill waste on foodborne pathogens

This work assesses the in vitro antimicrobial activity of an aqueous olive mill waste extract (AE-2) on the growth of diverse cocktails of foodborne pathogens species (Listeria monocytogenes, Staphylococcus aureus, Escherichia coli, and Salmonella Enterica). The effects were evaluated by Response Surface Methodology, using a two-block (D optimal and full factorial) sequential design, with two independent variables (hydroxytyrosol concentration 0-3000 ppm and pH 3.5-6.5) and the percentage of inhibition (%I) as the dependent variable. S. Enterica and E. coli behaviours were similar but different from L. monocytogenes and S. aureus. The models predicted the complete inhibition of the four foodborne pathogen cocktails in the region defined by 3.80-3.87 pH and 1200-1314 ppm hydroxytyrosol. Within the experimental region, the model showed the best predictions for L. monocytogenes and the worst for S. Enterica, but the errors never exceeded 46%. This study could promote the use of olive by-products as natural preservatives in the food industry, especially in acidic matrices.ISSN:0460-1173ISSN:0023-6438ISSN:1096-112