[Design of a thromboprophylaxis care process in patients with atrial fibrillation]. / Diseño del proceso asistencial de profilaxis de la tromboembolia en pacientes con fibrilación auricular.

OBJECTIVE: To describe the milestones in the anticoagulant care process of atrial fibrillation patients (AF), as well as quality and safety indicators, in order to establish an integrated care process of these patients in the Community of Madrid. METHODS: A consensus conference technique was applied, with the participation of 21 professionals (seven in the Steering Group and 14 known experts), from the specialties of Emergency, Internal Medicine, Cardiology, Neurology, Haematology, Family Medicine, Nursing, and Quality. Hospitals and Primary Care were represented. Milestones, elements and barriers/limitations were agreed upon in the care process of anticoagulated AF patients. A minimum set of indicators were also defined to assess the quality of care. RESULTS: Four milestones (stratification of thromboembolism and bleeding risk, evaluation for anticoagulant treatment, follow-up of direct-acting oral anticoagulants, and follow-up of treatment with vitamin K antagonists) were identified. A total of 14 barriers/limitations were also prioritised. In total, six indicators were defined (two structural-related, two processes-related, and two outcomes-related). CONCLUSIONS: Milestones and critical activities, together with a set of indicators, have been agreed for the development of guidelines with which to achieve a better therapeutic approach for anticoagulated AF patients.

Unnecessary overuse. Study of "inadvisable practices" for patients with atrial fibrillation. / Sobreutilización innecesaria. Estudio de los «no hacer¼ en pacientes con fibrilación auricular.

OBJECTIVE: To identify overuse (diagnostic, therapeutic and self-care practices that represent risks that outweigh the potential benefits) in patients with atrial fibrillation. METHOD: The study was based on qualitative research techniques. Using the "Metaplan" technique, we identified and ordered potentially inappropriate, ineffective and inefficient practices. By means of a consensus conference, we then established a number of "inadvisable practice" measures (relatively common practices that should be eliminated based on the scientific evidence or clinical experience). Professionals from the specialties of cardiology, haematology, neurology, internal medicine, family medicine and nursing participated in the consensus. RESULTS: We developed a catalogue of 19 "inadvisable practices" related to the diagnosis, treatment and care of anticoagulated patients that were inappropriate, had questionable effectiveness or were ineffective, as well as 13 beliefs or behaviours for anticoagulated patients that could result in injury or were useless or inefficient. CONCLUSION: The "inadvisable practices" approach helps identify practices that represent greater risks than benefits for patients. It seems appropriate to include algorithms in the clinical decision-making support systems that consider this information for the diagnosis, treatment and for home care. For this last case, recommendations have also been prepared that define specific contents for the healthcare education of these patients.

The endocrine disruptor nonylphenol induces sublethal toxicity in vascular plant development at environmental concentrations: A risk for riparian plants and irrigated crops?

In recent years, there is a growing concern among the scientific community about the presence of the so-called emergent pollutants in waters of different countries, especially endocrine-disrupting compounds (EDCs) that have the ability to alter the hormonal system. One of the substances found almost ubiquitously and in higher concentrations is the alkylphenol nonylphenol. Albeit this compound is included in priority lists as a probable risk for human health and the environment, little is known about its effects on developing plants. The aim of this work is to assess the acute and sub-chronic toxicity of environmental concentrations of nonylphenol in riparian vascular plant development using spores of the fern Polystichum setiferum and a biomarker-based approach: mitochondrial activity (cell viability), chlorophyll (plant physiology) and DNA content (growth). Mitochondrial activity and DNA content show that nonylphenol induces acute and sub-chronic toxicity at 48 h and after 1 week, respectively. Significant effects are observed in both parameters in fern spores at ng L(-1) but chlorophyll autofluorescence shows little changes. The inhibition of germination by natural allelochemicals has been reported to be related with the active hydroxyl group of phenolic compounds and largely independent of the structural nucleus to which it is attached. Results presented in this study suggest that environmental concentrations of nonylphenol could interfere with higher plant germination development by mimicking natural allelochemicals and/or phytohormones acting as a "phytoendocrine disruptor" likely posing ecophysiological risks.

Contribution of JAK2 mutations to T-cell lymphoblastic lymphoma development.

The JAK-STAT pathway has a substantial role in lymphoid precursor cell proliferation, survival and differentiation. Nonetheless, the contribution of JAK2 to T-cell lymphoblastic lymphoma (T-LBL) development remains poorly understood. We have identified one activating TEL-JAK2 translocation and four missense mutations accumulated in 2 out of 16 T-LBL samples. Two of them are novel JAK2 mutations and the other two are reported for the first time in T-LBL. Notably, R683G and I682T might have arisen owing to RNA editing. Mutated samples showed different mutated transcripts suggesting sub-clonal heterogeneity. Functional approaches revealed that two JAK2 mutations (H574R and R683G) constitutively activate JAK-STAT signaling in γ2A cells and can drive the proliferation of BaF3-EpoR cytokine-dependent cell line. In addition, aberrant hypermethylation of SOCS3 might contribute to enhance the activation of JAK-STAT signaling. Of utmost interest is that primary T-LBL samples harboring JAK2 mutations exhibited increased expression of LMO2, suggesting a mechanistic link between JAK2 mutations and the expression of LMO2, which was confirmed for the four missense mutations in transfected γ2A cells. We therefore propose that active JAK2 contribute to T-LBL development by two different mechanisms, and that the use of pan-JAK inhibitors in combination with epigenetic drugs should be considered in future treatments.

[Vascular risk factors in patients with ischaemic stroke. Distribution according to age, sex and stroke subtype]. / Factores de riesgo vascular en pacientes con ictus isquémico. Distribución según edad, sexo y subtipo de ictus.

INTRODUCTION: Cardiovascular diseases are one of the leading health problems in developed countries. This term covers conditions such as coronary vascular disease, cerebrovascular diseases and peripheral vascular disease. Ischaemic cerebrovascular disease accounts for 80% of all cerebrovascular diseases. From a clinical point of view it is interesting to distinguish between modifiable and non-modifiable vascular risk factors. AIM: To analyse the prevalence of modifiable vascular risk factors and their different combinations in a case-control study on ischaemic cerebrovascular disease in the Spanish population, and also the differences in the distribution of the risk factors according to the type of stroke (TOAST classification), age and sex. SUBJECTS AND METHODS: The study was conducted on 308 patients with ischaemic stroke who were paired by age (+/- 5 years) and sex, with 307 controls with no prior history of thrombosis. The statistical analysis was performed using the software application SAS v. 9.1. RESULTS: The results suggest that the risk factors are subject to an adding effect, as well as pointing to the presence of a specific profile of these factors depending on the subtype of stroke that is developed. CONCLUSION: The addition of cardiovascular risk factors is associated with an increased risk of vascular events. The distribution of the modifiable vascular risk factors differs according to the type of stroke and the patient's sex and age.

JAK2 as a molecular marker in myeloproliferative diseases.

The molecular pathogenesis of the myeloproliferative disorders (MPD) is poorly understood, except for chronic myeloid leukemia (CML). Recently, several groups have discovered a novel recurrent unique acquired clonal mutation in a tyrosine-kinase JAK2 in patients with Philadelphia-negative MPD and other myeloid disorders. It consists in a guanine-to-thymine change encoding a valine to phenylalanine at codon 617 (JAK2 V617F). JAK2 and the other members of the Janus kinase family are tyrosine kinases that function as intermediates between membrane receptors and intracellular signalling molecules. The mutation occurs within the enzymatically inactive JH2 pseudo-kinase domain that regulates the active JH1 kinase domain. The JAK2 activation leads to constitutive JAK and STAT (activators of transcription) hyperactivation with induction of growth factor hypersensitivity and cell transformation. Some authors have found a higher risk of vascular thrombosis and higher platelet activation when the mutation is present. Therefore, the JAK2 mutation offers a molecular target for new drugs investigation in a similar way to bcr/abl rearrangement in CML. For all these reasons, several studies related to JAK2 have arisen in the last year. In this report, we will review the literature and discuss its possible clinical and prognostic significance.

[Reticulocyte response after immediate withdrawal of recombinant human erythropoietin in chronic hemodialysis patients]. / Respuesta reticulocitaria tras cese inmediato de administración de eritropoyetina recombinante humana en enfermos en hemodiálisis crónica. Implicaciones en la terapia de la anemia.

UNLABELLED: The sudden interruption of recombinant human erythropoietin (rHuEPO) in end-stage renal disease (ESRD) patients leads to rapid anemization. The mechanisms of this phenomenon are, however, insufficiently understood. The present study examined the response to immediate rHuEPO withdrawal in dialysis patients. METHODS: 10 chronic hemodialysis (HD) patients regularly receiving rHuEPO were studied. rHuEPO was stopped and reinitiated after 7 days. Reticulocyte profile, haemoglobin and haematocrit were measured at 0, 7 and 15 days. As a complementary study, and with the purpose of analyzying whether uremia was a relevant factor, 10 non-uremic male Wistar rats were treated with rHuEPO. After two weeks, rHuEPO was withdrawn in 5 animals, and continued for 7 additional days in the remainder. The same variables than in the human study were determined. RESULTS: Changes in reticulocyte subtypes from baseline to day 7 were: total 18.2 +/- 0.9 vs 14.3 +/- 1.8% (p < 0.06); high-fluorescence (HFR): 2.6 +/- 0.4 vs 0.75 +/- 0.2 (p < 0.001); medium-fluorescence (MFR): 13.0 +/- 1.1 vs 6.6 +/- 0.9% (p < 0.02); and low-fluorescence (LFR): 84.2 +/- 1.4 vs 92.7 +/- 1% (p NS). The baseline pattern was recovered upon 7 days of rHuEPO reinitiation (p NS). Mean hemoglobin and hematocrit decreased by day 14 (p < 0.02) in spite of rHuEPO reinitiation at day 7. In non-uremic rats, changes were similar to that in the ESRD patients. CONCLUSION: rHuEPO induces changes in the reticulocyte pattern, consisting in a reduction of immature reticulocytes. These changes appear to be independent of the presence of uremia. Accordingly, complete rHuEPO withdrawal in HD patients will cause a rapidly-developing anaemia due to an alteration in the reticulocyte maturation series; therefore, sudden rHuEPO interruption should be avoided whenever is possible. As a collateral application, the specific changes described herein have potential use for detecting illegal administration of rHuEPO.

[Prothrombotic factors in stroke]. / Factores protrombóticos en la enfermedad cerebrovascular isquémica.

INTRODUCTION: Factor V Leiden and prothrombin 20210A polymorphisms are the most common mutations related to deep vein thrombosis, however their relationship with stroke is debated. This paper studies the possible relationship between both entities. MATERIAL AND METHODS: A case-control study was conducted during 27 months to study their association. A total of 312 stroke cases were included, 73 were under 60 years. Control group was obtained from blood donors. Factor V Leiden and prothrombin 20210A polymorphism prevalence was studied. Results were analyzed according to the age and the type of stroke (TOAST classification, 1993). RESULTS: Factor V Leiden was not related to stroke in the general population (OR: 0.65; 95 % CI: 0.18-2.27). The study according to age did not show any association (younger than 60 years: OR: 1.12; 95 % CI: 0.21-5.90; older than 60 years: OR: 0.50; 95 % CI: 0.11-2.14). However, prothrombin 20210A polymorphism OR in cases under 60 was OR: 2.92; 95 % CI: 0.71-11.92 suggesting a possible association between this mutation and stroke. There was no association in the general population (OR: 2.0; 95 % CI: 0.63-6.29) or in people over 60 (OR: 1.73; 95 % CI: 0.51- 5.83). The analysis according to stroke subtype did not show any association in the distribution of any of the polymorphisms studied. CONCLUSION: This study suggests that prothrombin 20210A polymorphism may play a role in stroke under 60 years of age. Factor V Leiden does not seem to be related to stroke.

DYS19 and DYS390 Y-STR polymorphism in the Iberian Peninsula: a multivariate analysis.

Genetic polymorphism of two Y-specific short tandem repeats (DYS19 and DYS390) was investigated in six populations from the Iberian Peninsula (Andalusia, Castilla-La Mancha, Castilla-Leon, Extremadura, Galicia and South East Spain) comprising a total of 895 unrelated and native individuals, and a complete database of DYS19 and DYS390 allele frequency distributions in 34 world-wide populations collected from literature was analysed. DYS19 and DYS390 polymorphism was screened by automated fluorescence analysis of PCR-amplified labelled sample fragments performed with and ABI PRISM 377 Genetic Analyser. The degree of population differentiation was analysed using the STP Test to calculate G Statistic values. Correspondence Analysis based on the allelic frequencies of each locus and combining both was performed using the NTSYS-PC version 1.70 computer package. The diversity of the genetic profiles of gene frequencies suggests an important population heterogeneity in the Iberian Peninsula as a whole (DYS390 being particularly evident), which is corroborated after statistical analyses (G = 139.8457, p = 1.7822 x 10(-14) for DYS19, G = 116.0293, p = 4.6845 x 10(-12) for DYS390). However, multivariate analysis indicates a well defined cluster of the populations of the Central region, and sets them apart from the positions within which peripheral Iberian Peninsula populations are distributed. The Galician population shows trends which bring it closer to the positions throughout which European Atlantic populations are distributed. The results shown by the Central Iberian Peninsula seem to lend support to a model of settlement population stocks which came from the region of Castilla-Leon after the Islam invasions, whereas in the South-East populations the genetic record of Middle Eastern populations is still present, a consequence of the expansion of Islam in Southern Europe in the Middle Ages.

Report of three cases of circulating heparin-like anticoagulants.

Clinically significant endogenous circulating heparin-like anticoagulant activity has been associated with hematological malignancies, liver damage, and other pathological conditions. The source of high plasma concentrations of endogenous heparin-like anticoagulants is poorly understood. We report three cases of circulating heparin-like anticoagulants in three patients with hematological malignancies: CLL, multiple myeloma, and T-prolymphocytic leukemia. The severity of bleeding in our patients ranged from severe epistaxis and deep-site hematoma to bleeding of biopsy site and occasional ecchymosis.

Atypical chronic graft-versus-host disease following interferon therapy for chronic myeloid leukaemia relapsing after allogeneic BMT.

We report a 54-year-old woman who received interferon alpha for haematological relapse of Ph-positive CML, 7 years after allogeneic BMT from an HLA-identical brother. Eighteen months after relapse, cytogenetic and molecular remission was achieved. She received interferon therapy for 25 months and it was discontinued when she developed skin lesions on her face and trunk, dysphagia and fever with respiratory failure and bilateral patchy airspace consolidation of the lung without microbiologic findings. Histologic features showed discoid lupus erythematosis, oesophagitis with pseudomembranes and a mixed pattern of lymphocytic bronchiolitis involving the alveoli and interstitial spaces all compatible with chronic GVHD. The patient was commenced on immunosuppressive therapy with complete clinical and radiological resolution. The available evidence supports an atypical presentation of chronic GVHD and suggests a role for interferon alpha in the pathogenesis of GVHD. To the best of our knowledge, this is the first case reported of severe chronic GVHD occurring during the course of interferon therapy for relapsed CML.

Fluorescence in situ hybridization evaluation of minimal residual disease on stem-cell harvests.

The usefulness of fluorescence in situ hybridization (FISH) analysis to detect minimal residual disease (MRD) in autologous bone marrow and peripheral blood stem-cell harvests has been tested in three patients with hematologic malignancies. Conventional cytogenetics and FISH were used to characterize the leukemic clones identifying the specific chromosomal abnormalities (monosomy 7 in a myelodysplastic patient and trisomy 8 in two acute myeloid leukemic patients). Such analysis was useful to monitor the MRD persistent after treating these patients with intensive chemotherapy. The myelodysplastic patient underwent eight peripheral blood-stem cell harvests in which FISH detected the persistence of monosomy 7 cells, precluding their use for autologous transplantation. This patient relapsed and died. In two acute myeloid leukemia patients who underwent an autologous marrow harvest, FISH did not show a significant proportion of trisomy 8 cells. Nevertheless, autologous transplantation was not performed, owing to an insufficient CD34 cell content in the harvests. One of these patients relapsed with the reappearance of trisomy 8 and died. The other patient, on the contrary, is alive in complete remission 3 years after the bone marrow harvest. The usefulness and applicability of MRD quantification in stem-cell harvests is discussed on the basis of the sensitivity of the methodology applied.