Diabetes mellitus and intermittent claudication: a cross-sectional study of 920 claudicants

INTRODUCTION: Diabetes mellitus (DM) and intermittent claudication (IC) are frequently associated health conditions. Our hypothesis is that the nature, severity and quality of life (QoL) of patients with IC and DM are worse than those of claudicant patients without diabetes. MATERIAL AND METHODS: An observational, cross-sectional and multicentre study of 920 patients with IC, divided into two groups: diabetic (n = 477) and non-diabetic (n = 443). For each group, we examined clinical and biological characteristics (including levels of glucose and lipids), the ankle-brachial index (ABI), responses to the Walking Impairment Questionnaire (WIQ) and the European Quality of Life-5 Dimensions (EQ-5D) questionnaire. RESULTS: Compared with claudicant patients without diabetes, claudicants with diabetes were older (p < 0.001), more likely to be female (p = 0.006), with a higher BMI (p < 0.001), more likely to have a sedentary lifestyle (p < 0.001) and to be a non-smoker (p < 0.001). Claudicant patients with diabetes also had significantly more cardiovascular risk factors (p < 0.001), more frequent ischaemic cardiopathy (p = 0.023) and chronic renal failure (p = 0.002), and fewer prior ictus events (p = 0.003). No significant differences between groups were found with respect to blood pressure, levels of cholesterol or triglycerides. The mean ABI of diabetic-IC patients was slightly lower than IC patients without diabetes (p = 0.016). All WIQ subdomains scores were significantly lower (p < 0.001), indicating poorer walking ability, in claudicant and diabetic patients with compared with those without diabetes. The mean E5-QD global scores and the mean EQ-5D visual analogue scale in the whole series were 0.58 (SD = 0.21) and 55.04 (SD = 21.30), respectively. Both E5-QD scores were significantly lower, indicating poorer QoL, in claudicant patients with diabetes than claudicant patients without diabetes (p < 0.001). CONCLUSION: Patients with IC and DM had more risk cardiovascular factors, cardiovascular conditions, disability and worse haemodynamic status and QoL than claudicant patients without diabetes

A Multiple System of Radio Sources at the Core of the L723 Multipolar Outflow

We present high angular resolution Very Large Array multi-epoch continuum observations at 3.6 cm and 7 mm towards the core of the L723 multipolar outflow revealing a multiple system of four radio sources suspected to be YSOs in a region of only ~4 arcsecs (1200 AU) in extent. The 3.6 cm observations show that the previously detected source VLA 2 contains a close (separation ~0.29 arcsecs or ~90 AU) radio binary, with components (A and B) along a position angle of ~150 degrees. The northern component (VLA 2A) of this binary system is also detected in the 7 mm observations, with a positive spectral index between 3.6 cm and 7 mm. In addition, the source VLA 2A is associated with extended emission along a position angle of ~115 degrees, that we interpret as outflowing shock-ionized gas that is exciting a system of HH objects with the same position angle. A third, weak 3.6 cm source, VLA 2C, that is detected also at 7 mm, is located ~0.7 arcsecs northeast of VLA 2A, and is possibly associated with the water maser emission in the region. The 7 mm observations reveal the presence of an additional source, VLA 2D, located ~3.5 arcsecs southeast of VLA 2A, and with a 1.35 mm counterpart. All these radio continuum sources have a positive spectral index, compatible with them being YSOs. We also propose that the high velocity CO emission observed in the region could be the superposition of multiple outflows (at least three independent bipolar outflows) excited by the YSOs located at the core, instead of the previous interpretations in terms of only one or two outflows.Comment: Accepted for publication in The Astrophysical Journal (2007 December 6

Elucidating the Mechanism of Action of the Attributed Immunomodulatory Role of Eltrombopag in Primary Immune Thrombocytopenia: An In Silico Approach

Intel·ligència artificial; Eltrombopag; Trombocitopènia immune primàriaInteligencia artificial; Eltrombopag; Trombocitopenia inmune primariaArtificial intelligence; Eltrombopag; Primary immune thrombocytopeniaEltrombopag is a thrombopoietin receptor (MPL) agonist approved for the treatment of primary immune thrombocytopenia (ITP). Recent evidence shows that some patients may sustain platelet counts following eltrombopag discontinuation. The systemic immunomodulatory response that resolves ITP in some patients could result from an increase in platelet mass, caused either by the direct action of eltrombopag on megakaryocytes through MPL stimulation, or potential MPL-independent actions on other cell types. To uncover the possible mechanisms of action of eltrombopag, in silico analyses were performed, including a systems biology-based approach, a therapeutic performance mapping system, and structural analyses. Through manual curation of the available bibliography, 56 key proteins were identified and integrated into the ITP interactome analysis. Mathematical models (94.92% mean accuracy) were obtained to elucidate potential MPL-dependent pathways in non-megakaryocytic cell subtypes. In addition to the effects on megakaryocytes and platelet numbers, the results were consistent with MPL-mediated effects on other cells, which could involve interferon-gamma, transforming growth factor-beta, peroxisome proliferator-activated receptor-gamma, and forkhead box protein P3 pathways. Structural analyses indicated that effects on three apoptosis-related proteins (BCL2L1, BCL2, BAX) from the Bcl-2 family may be off-target effects of eltrombopag. In conclusion, this study proposes new hypotheses regarding the immunomodulatory functions of eltrombopag in patients with ITP.This research was funded and promoted by Novartis, which contributed to setting up fundamental questions relevant for the study and reviewing the manuscript. However, the company did not have a role on study design, data collection, analysis, or interpretation

Characterization of the platelet phenotype caused by a germline RUNX1 Variant in a CRISPR/Cas9-generated murine model

RUNX1-related disorder (RUNX1-RD) is caused by germline variants affecting the RUNX1 gene. This rare, heterogeneous disorder has no specific clinical or laboratory phenotype, making genetic diagnosis necessary. Although international recommendations have been established to classify the pathogenicity of variants, identifying the causative alteration remains a challenge in RUNX1-RD. Murine models may be useful not only for definitively settling the controversy about the pathogenicity of certain RUNX1 variants, but also for elucidating the mechanisms of molecular pathogenesis. Therefore, we developed a knock-in murine model, using the CRISPR/Cas9 system, carrying the RUNX1 p.Leu43Ser variant (mimicking human p.Leu56Ser) to study its pathogenic potential and mechanisms of platelet dysfunction. A total number of 75 mice were generated; 25 per genotype (RUNX1WT/WT, RUNX1WT/L43S, and RUNX1L43S/L43S). Platelet phenotype was assessed by flow cytometry and confocal microscopy. On average, RUNX1L43S/L43S and RUNX1WT/L43S mice had a significantly longer tail-bleeding time than RUNX1WT/WT mice, indicating the variant's involvement in hemostasis. However, only homozygous mice displayed mild thrombocytopenia. RUNX1L43S/L43S and RUNX1WT/L43S displayed impaired agonist-induced spreading and α-granule release, with no differences in δ-granule secretion. Levels of integrin αIIbβ3 activation, fibrinogen binding, and aggregation were significantly lower in platelets from RUNX1L43S/L43S and RUNX1WT/L43S using phorbol 12-myristate 13-acetate (PMA), adenosine diphosphate (ADP), and high thrombin doses. Lower levels of PKC phosphorylation in RUNX1L43S/L43S and RUNX1WT/L43S suggested that the PKC-signaling pathway was impaired. Overall, we demonstrated the deleterious effect of the RUNX1 p.Leu56Ser variant in mice via the impairment of integrin αIIbβ3 activation, aggregation, α-granule secretion, and platelet spreading, mimicking the phenotype associated with RUNX1 variants in the clinical setting.This work was partially supported by grants from Instituto de Salud Carlos III (ISCIII) and Feder (PI17/01311, PI17/01966, and CB15/00055), Fundación Séneca (19873/GERM/15), Gerencia Regional de Salud (GRS 2061A/19 and 1647/A/17), Fundación Mutua Madrileña (FMM, AP172142019), and Sociedad Española de Trombosis y Hemostasia (SETH-FETH; Premio López Borrasca 2019 and Ayuda a Grupos de Trabajo en Patología Hemorrágica 2019). The authors' research on IPDs is conducted in accordance with the aims of the Functional and Molecular Characterization of Patients with Inherited Platelet Disorders Project, which is supported by the Hemorrhagic Diathesis Working Group of the Spanish Society of Thrombosis and Haemostasis. A.M.-Q., C.F.-I., and L.H.-C. were supported by predoctoral grants from the Junta de Castilla y León, Spain. E.V. was supported by the predoctoral grant from the University of Salamanca, Spain. IG-T and RB were supported by "Contratos postdoctorales Programa II) from the University of Salamanca, Spain

Risk factors for thrombotic microangiopathy in allogeneic hematopoietic stem cell recipients receiving GVHD prophylaxis with tacrolimus plus MTX or sirolimus

Post-transplant complications.-- et al.Transplantation-associated thrombotic microangiopathy (TA-TMA) is a feared complication of allogeneic hematopoietic SCT (HSCT) owing to its high mortality rate. The use of calcineurin inhibitors or sirolimus (SIR) for GVHD prophylaxis has been suggested as a potential risk factor. However, the impact of tacrolimus (TAC) and SIR combinations on the increased risk of TA-TMA is currently not well defined. We retrospectively analyzed the incidence of TA-TMA in 102 allogeneic HSCT recipients who consecutively received TAC plus SIR (TAC/SIR) (n=68) or plus MTX (TAC/MTX)±ATG (n=34) for GVHD prophylaxis. No significant differences were observed in the incidence of TA-TMA between patients receiving TAC/SIR vs TAC/MTX±ATG (7.4% vs 8.8%, P=0.8). Only grade III-IV acute GVHD, previous HSCT and serum levels of TAC >25 ng/mL were associated with a greater risk of TA-TMA. Patients developing TA-TMA have significantly poorer survival (P<0.001); however, TA-TMA ceased to be an independent prognostic factor when it was included in a multivariate model. In conclusion, the combination of TAC/SIR does not appear to pose a higher risk of TA-TMA. By contrast, we identified three different risk groups for developing TA-TMA.Peer Reviewe

Analysis of incidence, risk factors and clinical outcome of thromboembolic and bleeding events in 431 allogeneic hematopoietic stem cell transplantation recipients

This is an open-access paper.-- et al.Allogeneic hematopoietic stem cell transplantation recipients have an increasing risk of both hemorrhagic and thrombotic complications. However, the competing risks of two of these life-threatening complications in these complex patients have still not been well defined. We retrospectively analyzed data from 431 allogeneic transplantation recipients to identify the incidence, risk factors and mortality due to thrombosis and bleeding. Significant clinical bleeding was more frequent than symptomatic thrombosis. The cumulative incidence of a bleeding episode was 30.2% at 14 years. The cumulative incidence of a venous or arterial thrombosis at 14 years was 11.8% and 4.1%, respectively. The analysis of competing factors for venous thrombosis revealed extensive chronic graft-versus-host disease to be the only independent prognostic risk factor. By contrast, six factors were associated with an increased risk of bleeding; advanced disease, ablative conditioning regimen, umbilical cord blood transplantation, anticoagulation, acute III-IV graft-versus-host disease, and transplant-associated microangiopathy. The development of thrombosis did not significantly affect overall survival (P=0.856). However, significant clinical bleeding was associated with inferior survival (P<0.001). In allogeneic hematopoietic stem cell transplantation, significant clinical bleeding is more common than thrombotic complications and affects survival.Peer Reviewe

Functional alterations involved in increased bleeding in hereditary hemorrhagic telangiectasia mouse models

16p.-7 fig.Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal-dominant genetic disorder involving defects in two predominant genes known as endoglin (ENG; HHT-1) and activin receptor-like kinase 1 (ACVRL1/ALK1; HHT-2). It is characterized by mucocutaneous telangiectases that, due to their fragility, frequently break causing recurrent epistaxis and gastrointestinal bleeding. Because of the severity of hemorrhages, the study of the hemostasis involved in these vascular ruptures is critical to find therapies for this disease. Our results demonstrate that HHT patients with high bleeding, as determined by a high Epistaxis Severity Score (ESS), do not have prolonged clotting times or alterations in clotting factors. Considering that coagulation is only one of the processes involved in hemostasis, the main objective of this study was to investigate the overall mechanisms of hemostasis in HHT-1 (Eng+/−) and HHT-2 (Alk1+/−) mouse models, which do not show HHT vascular phenotypes in the meaning of spontaneous bleeding. In Eng+/− mice, the results of in vivo and in vitro assays suggest deficient platelet-endothelium interactions that impair a robust and stable thrombus formation. Consequently, the thrombus could be torn off and dragged by the mechanical force exerted by the bloodstream, leading to the reappearance of hemorrhages. In Alk1+/− mice, an overactivation of the fibrinolysis system was observed. These results support the idea that endoglin and Alk1 haploinsufficiency leads to a common phenotype of impaired hemostasis, but through different mechanisms. This contribution opens new therapeutic approaches to HHT patients' epistaxis.This work was supported by the Junta de Castilla y León (BIO/SA70/14, GRS2135/A/2020, and GRS2314/A/2021), Fundación Mutua Madrileña (FMM AP172142019), the Instituto de Salud Carlos III (PI16/00460 and PI19/01630, co-funded by FEDER), and Consejo Superior de Investigaciones Científicas (CSIC; 201920E022 to CB). CO-I was supported by a contract from the Ministerio de Economía y Competitividad of Spain. CE-T was a fellow from the Fundación Miguel Casado San José.Peer reviewe

Introducing high-throughput sequencing into mainstream genetic diagnosis practice in inherited platelet disorders

Inherited platelet disorders are a heterogeneous group of rare diseases, caused by inherited defects in platelet production and/or function. Their genetic diagnosis would benefit clinical care, prognosis and preventative treatments. Until recently, this diagnosis has usually been performed via Sanger sequencing of a limited number of candidate genes. High-throughput sequencing is revolutionizing the genetic diagnosis of diseases, including bleeding disorders. We have designed a novel high-throughput sequencing platform to investigate the unknown molecular pathology in a cohort of 82 patients with inherited platelet disorders. Thirty-four (41.5%) patients presented with a phenotype strongly indicative of a particular type of platelet disorder. The other patients had clinical bleeding indicative of platelet dysfunction, but with no identifiable features. The high-throughput sequencing test enabled a molecular diagnosis in 70% of these patients. This sensitivity increased to 90% among patients suspected of having a defined platelet disorder. We found 57 different candidate variants in 28 genes, of which 70% had not previously been described. Following consensus guidelines, we qualified 68.4% and 26.3% of the candidate variants as being pathogenic and likely pathogenic, respectively. In addition to establishing definitive diagnoses of well-known inherited platelet disorders, high-throughput sequencing also identified rarer disorders such as sitosterolemia, filamin and actinin deficiencies, and G protein-coupled receptor defects. This included disease-causing variants in DIAPH1 (n=2) and RASGRP2 (n=3). Our study reinforces the feasibility of introducing high-throughput sequencing technology into the mainstream laboratory for the genetic diagnostic practice in inherited platelet disorders.This study was supported by research grants from the Gerencia Regional de Salud (GRS 1370/A/16), ISCIII & Feder (PI14/01956), CIBERER CB15/00055, Fundación Séneca (19873/GERM/15) and Sociedad Española de Trombosis y Hemostasia (SETH). SPW holds a British Heart Foundation chair.Peer Reviewe

Economía y finanzas sociales: avances en la investigación

Esta obra colectiva propone un cambio de paradigma en la investigación científica, financiera y económica, cuyo centro de atención es reducir las desigualdades sociales y económicas, mejorar la sostenibilidad ambiental y la creación eficiente de valor económico. Desde un punto de vista crítico y mediante diversos enfoques teóricos, metodológicos y disciplinares, los autores analizan el esquema financiero predominante en las economías de mercado, al tiempo que abordan temas como la inclusión financiera, la banca ética o las experiencias e intervenciones en y sobre la economía social.ITESO, A.C