Resumen ejecutivo: Documento de posicionamiento: evaluación y manejo de la hipoglucemia en el paciente con diabetes mellitus 2020. Grupo de Trabajo de Diabetes Mellitus de la Sociedad Española de Endocrinología y Nutrición / Executive summary: Position document: Evaluation and management of hypoglycemia in the patient with diabetes mellitus 2020. Diabetes Mellitus Working Group of the Spanish Society of Endocrinology and Nutrition

Proporcionar unas recomendaciones prácticas para la evaluación y el manejo de la hipoglucemia en pacientes con diabetes mellitus. Miembros del Grupo de Trabajo de Diabetes Mellitus de la Sociedad Española de Endocrinología y Nutrición (SEEN). Las recomendaciones se formularon según el sistema Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) para establecer tanto la fuerza de las recomendaciones como el grado de evidencia. Se realizó una búsqueda sistemática en MEDLINE (PubMed) de la evidencia disponible para cada tema, y se revisaron artículos escritos en inglés y castellano con fecha de inclusión hasta el 28 de febrero de 2020. En este resumen ejecutivo incluimos la evidencia reciente incorporada desde 2013. El documento establece unas recomendaciones prácticas basadas en la evidencia acerca de la evaluación y manejo de la hipoglucemia en pacientes con diabetes mellitus.

To provide practical recommendations for the evaluation and management of hypoglycemia in patients with diabetes mellitus. Members of the Diabetes Mellitus Working Group of the Spanish Society of Endocrinology and Nutrition (SEEN). The recommendations were made based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system to establish both the strength of the recommendations and the level of evidence. A systematic search was made in MEDLINE (PubMed) for the available evidence on each subject, and articles written in English and Spanish with an inclusion date up to 28 February 2020 were reviewed. This executive summary takes account of the evidence incorporated since 2013. The document establishes practical evidence-based recommendations regarding the evaluation and management of hypoglycemia in patients with diabetes mellitus.

How societal responses to COVID-19 could contribute to child neglect.

BACKGROUND: The ecosystemic approach to children's needs demands a cohesive response from societies, communities, and families. During the COVID-19 pandemic, the choices societies made to protect their community members from the virus could have created contexts of child neglect. With the closure of services and institutions, societies were no longer available to help meet the needs of children. OBJECTIVE: The purpose of this study is to examine parents' reports on the response their children received to their needs during the COVID-19 crisis. METHODS: During the period of the spring 2020 lockdown, 414 parents in the province of Quebec, Canada, completed an online questionnaire about the impact of the crisis on the response their children received to their needs. RESULTS: Compared to parents of younger children, parents of older children reported less fulfillment of their child's needs in three measured domains, namely cognitive and affective, security, and basic care needs. CONCLUSION: These results are discussed in light of the policies and the resources societies have put in place during the crisis to help families meet the needs of their children. Societies must learn from this crisis to put children at the top of their priorities in the face of a societal crisis. Thoughtful discussions and energy must be given to ensure that, while facing a crisis, the developmental trajectories of children are not sacrificed.

Cytoreductive treatment in patients with CALR-mutated essential thrombocythaemia: a study comparing indications and efficacy among genotypes from the Spanish Registry of Essential Thrombocythaemia.

The present study assessed the criteria for initiating cytoreduction and response to conventional therapies in 1446 patients with essential thrombocythemia (ET), 267 (17%) of which were CALR-mutated. In low risk patients, time from diagnosis to cytoreduction was shorter in CALR-positive than in the other genotypes (2·8, 3·2, 7·4 and 12·5 years for CALR, MPL, JAK2V617F and TN, respectively, P < 0·0001). A total of 1104 (76%) patients received cytoreductive treatment with hydroxycarbamide (HC) (n = 977), anagrelide (n = 113), or others (n = 14). The estimated cumulative rates of complete haematological response (CR) at 12 months were 40 % and 67% in CALR and JAK2V617F genotypes, respectively. Median time to CR was 192 days for JAK2V617F, 343 for TN, 433 for MPL, and 705 for CALR genotypes (P < 0·0001). Duration of CR was shorter in CALR-mutated ET than in the remaining patients (P = 0·003). In CALR-positive patients, HC and anagrelide had similar efficacy in terms of response rates and duration. CALR-mutated patients developed resistance/intolerance to HC more frequently (5%, 23%, 27% and 15% for JAK2V617F, CALR, MPL and TN, respectively; P < 0·0001). In conclusion, conventional cytoreductive agents are less effective in CALR-mutated ET, highlighting the need for new treatment modalities and redefinition of haematologic targets for patients with this genotype.

SARS-CoV-2: what it is, how it acts, and how it manifests in imaging studies. / SARS-CoV-2: cómo es, cómo actúa y cómo se expresa en la imagen.

COVID-19 is a disease with many clinical, biochemical, and radiological signs that has a predilection for the lungs, probably because of the high number of ACE-2 receptors in this organ. The infection of cells activates proinflammatory substances, causing diffuse alveolar damage, which is the histopathological basis of ARDS. The exudative phase would manifest as ground-glass opacities and consolidation, and the proliferative phase would manifest as a tendency toward a more linear morphology. Both CT and PET/CT findings support the inflammatory character of the lung lesions in the initial phase of the disease and in patients with mild-moderate disease. Severe cases have pulmonary hypoperfusion that is likely due to abnormal alveolar ventilation and perfusion. On the other hand, a prothrombotic state increases the risk of thromboembolic disease through the activation of coagulation and platelet pathways with the production of fibrin degradation products (D-dimer) and consumption of platelets.

SARS-CoV-2: cómo es, cómo actúa y cómo se expresa en la imagen / SARS-CoV-2: what it is, how it acts, and how it manifests in imaging studies

La COVID-19 es una enfermedad con una gran semiología clínica, bioquímica y radiológica, que tiene una afectación preferente por el pulmón, probablemente debido a un mayor número de receptores ECA-2. La infección celular activa sustancias proinflamatorias y provoca un daño alveolar difuso, que es la base histopatológica del distrés respiratorio del adulto. La fase exudativa explicaría las imágenes "en vidrio deslustrado" y consolidación, mientras que la tendencia hacia una morfología más lineal representa la fase proliferativa. Tanto la tomografía computarizada (TC) como la tomografía por emisión de positrones/ tomografía computarizada (PET/TC) apoyan el carácter inflamatorio de las lesiones pulmonares cuando la enfermedad está en fase inicial o es leve-moderada. Los casos graves muestran una hipoperfusión pulmonar que se explicaría por una alteración de la ventilación-perfusión alveolar (V/Q). Por otro lado, un estado protrombótico conlleva mayor probabilidad de enfermedad tromboembólica por la activación de la vía de la coagulación y plaquetaria, con la producción de sustancia de degradación de la fibrina (dímero D) así como el consumo de plaquetas

COVID-19 is a disease with many clinical, biochemical, and radiological signs that has a predilection for the lungs, probably because of the high number of ACE-2 receptors in this organ. The infection of cells activates proinflammatory substances, causing diffuse alveolar damage, which is the histopathological basis of ARDS. The exudative phase would manifest as ground-glass opacities and consolidation, and the proliferative phase would manifest as a tendency toward a more linear morphology. Both CT and PET/CT findings support the inflammatory character of the lung lesions in the initial phase of the disease and in patients with mild-moderate disease. Severe cases have pulmonary hypoperfusion that is likely due to abnormal alveolar ventilation and perfusion. On the other hand, a prothrombotic state increases the risk of thromboembolic disease through the activation of coagulation and platelet pathways with the production of fibrin degradation products (D-dimer) and consumption of platelets

Natural history of polycythemia vera and essential thrombocythemia presenting with splanchnic vein thrombosis.

Patients with polycythemia vera (PV) or essential thrombocythemia (ET) presenting with splanchnic vein thrombosis (SVT) might have a specific clinico-biological profile. To investigate this hypothesis, 3705 PV/ET patients from three national registers, 118 of them presenting with SVT, were reviewed. After correction for age and sex, PV/ET patients with SVT showed an increased risk of death (HR 2.47, 95% CI 1.5-4.01, p < 0.001), venous thrombosis (IRR 3.4, 95%CI 2.1-5.5, p < 0.001), major bleeding (IRR 3.6, 95%CI 2.3-5.5, p < 0.001), and second cancer (IRR 2.37, 95%CI 1.4-4.1, p = 0.002). No case of acute leukemia was documented among patients with PV/ET presenting with SVT and seven of them (6%) progressed to myelofibrosis. SVT was not associated with lower risk of MF after correction by age and sex. Patients with SVT more frequently died from complications related to hepatic disease, major bleeding, or second cancer, resulting in a 5-year reduction of age- and sex-adjusted median survival. In conclusion, PV and ET patients presenting with SVT have shorter survival than patients with PV and ET of the same age and sex. This excess mortality is related to liver disease, major bleeding, and second cancer rather than to the natural evolution of the MPN.

miR-146a rs2431697 identifies myeloproliferative neoplasm patients with higher secondary myelofibrosis progression risk.

Myelofibrosis (MF) occurs as part of the natural history of polycythemia vera (PV) and essential thrombocythemia (ET), and remarkably shortens survival. Although JAK2V617F and CALR allele burden are the main transformation risk factors, inflammation plays a critical role by driving clonal expansion toward end-stage disease. NF-κB is a key mediator of inflammation-induced carcinogenesis. Here, we explored the involvement of miR-146a, a brake in NF-κB signaling, in MPN susceptibility and progression. rs2910164 and rs2431697, that affect miR-146a expression, were analyzed in 967 MPN (320 PV/333 ET/314 MF) patients and 600 controls. We found that rs2431697 TT genotype was associated with MF, particularly with post-PV/ET MF (HR = 1.5; p < 0.05). Among 232 PV/ET patients (follow-up time=8.5 years), 18 (7.8%) progressed to MF, being MF-free-survival shorter for rs2431697 TT than CC + CT patients (p = 0.01). Multivariate analysis identified TT genotype as independent predictor of MF progression. In addition, TT (vs. CC + CT) patients showed increased plasma inflammatory cytokines. Finally, miR-146a-/- mice showed significantly higher Stat3 activity with aging, parallel to the development of the MF-like phenotype. In conclusion, we demonstrated that rs2431697 TT genotype is an early predictor of MF progression independent of the JAK2V617F allele burden. Low levels of miR-146a contribute to the MF phenotype by increasing Stat3 signaling.

Fungal endophytes from arid areas of Andalusia: high potential sources for antifungal and antitumoral agents.

Native plant communities from arid areas present distinctive characteristics to survive in extreme conditions. The large number of poorly studied endemic plants represents a unique potential source for the discovery of novel fungal symbionts as well as host-specific endophytes not yet described. The addition of adsorptive polymeric resins in fungal fermentations has been seen to promote the production of new secondary metabolites and is a tool used consistently to generate new compounds with potential biological activities. A total of 349 fungal strains isolated from 63 selected plant species from arid ecosystems located in the southeast of the Iberian Peninsula, were characterized morphologically as well as based on their ITS/28S ribosomal gene sequences. The fungal community isolated was distributed among 19 orders including Basidiomycetes and Ascomycetes, being Pleosporales the most abundant order. In total, 107 different genera were identified being Neocamarosporium the genus most frequently isolated from these plants, followed by Preussia and Alternaria. Strains were grown in four different media in presence and absence of selected resins to promote chemical diversity generation of new secondary metabolites. Fermentation extracts were evaluated, looking for new antifungal activities against plant and human fungal pathogens, as well as, cytotoxic activities against the human liver cancer cell line HepG2. From the 349 isolates tested, 126 (36%) exhibited significant bioactivities including 58 strains with exclusive antifungal properties and 33 strains with exclusive activity against the HepG2 hepatocellular carcinoma cell line. After LCMS analysis, 68 known bioactive secondary metabolites could be identified as produced by 96 strains, and 12 likely unknown compounds were found in a subset of 14 fungal endophytes. The chemical profiles of the differential expression of induced activities were compared. As proof of concept, ten active secondary metabolites only produced in the presence of resins were purified and identified. The structures of three of these compounds were new and herein are elucidated.

Successful lichen translocation on disturbed gypsum areas: A test with adhesives to promote the recovery of biological soil crusts.

The loss of biological soil crusts represents a challenge for the restoration of disturbed environments, specifically in particular substrates hosting unique lichen communities. However, the recovery of lichen species affected by mining is rarely addressed in restoration projects. Here, we evaluate the translocation of Diploschistes diacapsis, a representative species of gypsum lichen communities affected by quarrying. We tested how a selection of adhesives could improve thallus attachment to the substrate and affect lichen vitality (as CO2 exchange and fluorescence) in rainfall-simulation and field experiments. Treatments included: white glue, water, hydroseeding stabiliser, gum arabic, synthetic resin, and a control with no adhesive. Attachment differed only in the field, where white glue and water performed best. Adhesives altered CO2 exchange and fluorescence yield. Notably, wet spoils allowed thalli to bind to the substrate after drying, revealing as the most suitable option for translocation. The satisfactory results applying water on gypsum spoils are encouraging to test this methodology with other lichen species. Implementing these measures in restoration projects would be relatively easy and cost-effective. It would help not only to recover lichen species in the disturbed areas but also to take advantage of an extremely valuable biological material that otherwise would be lost.

Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study.

The single-arm, phase 2 ENESTfreedom trial assessed the potential for treatment-free remission (TFR; i.e., the ability to maintain a molecular response after stopping therapy) following frontline nilotinib treatment. Patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase with MR4.5 (BCR-ABL1⩽0.0032% on the International Scale (BCR-ABL1IS)) and ⩾2 years of frontline nilotinib therapy were enrolled. Patients with sustained deep molecular response during the 1-year nilotinib consolidation phase were eligible to stop treatment and enter the TFR phase. Patients with loss of major molecular response (MMR; BCR-ABL1IS⩽0.1%) during the TFR phase reinitiated nilotinib. In total, 215 patients entered the consolidation phase, of whom 190 entered the TFR phase. The median duration of nilotinib before stopping treatment was 43.5 months. At 48 weeks after stopping nilotinib, 98 patients (51.6%; 95% confidence interval, 44.2-58.9%) remained in MMR or better (primary end point). Of the 86 patients who restarted nilotinib in the treatment reinitiation phase after loss of MMR, 98.8% and 88.4%, respectively, regained MMR and MR4.5 by the data cutoff date. Consistent with prior reports of imatinib-treated patients, musculoskeletal pain-related events were reported in 24.7% of patients in the TFR phase (consolidation phase, 16.3%).

Gestión cardiovascular de los pacientes con leucemia mieloide crónica desde una perspectiva multidisciplinar, y propuesta de protocolo de actuación por reunión de consenso / Cardiovascular management of patients with chronic myeloid leukemia from a multidisciplinary perspective, and proposing action protocol by consensus meeting

Introducción y objetivos: Los inhibidores de la tirosina cinasa (ITC) denominados de segunda generación (dasatinib y nilotinib) empleados en el tratamiento de la leucemia mieloide crónica (LMC) han demostrado un beneficio frente a imatinib en respuestas alcanzadas y progresiones de la enfermedad. No obstante, estos inhibidores se han relacionado con alguna forma de toxicidad cardiovascular, ocurriendo en su mayor parte en pacientes con factores de riesgo cardiovasculares (FRCV). El control de los FRCV se debe considerar por tanto imprescindible para un tratamiento adecuado de la LMC. En la actualidad, debido a la falta de recomendaciones en pacientes con LMC, el tratamiento de los FRCV se realiza de forma muy heterogénea. El objetivo de este trabajo es elaborar recomendaciones sobre la prevención y el seguimiento de episodios cardiovasculares (ECV) en pacientes con LMC tratados con ITC. Material y métodos: Expertos del Grupo Español de Leucemia Mieloide Crónica, junto con expertos en riesgo cardiovascular, hemos elaborado, con base en una reunión de consenso, recomendaciones de prevención y seguimiento de ECV en pacientes con LMC tratados con ITC. Resultados: En este documento se muestran las recomendaciones de consenso con respecto a la información necesaria a recoger en la historia clínica, la toma de decisiones terapéuticas, así como el tratamiento y el seguimiento de los FRCV. Conclusiones: El tratamiento con ITC requiere un manejo integral del paciente que deberá realizarse desde un abordaje multidisciplinar, en el que tanto la prevención como el tratamiento de los FRCV es fundamental (AU)

Introduction and objectives: The second generation tyrosine kinase inhibitors (TKI, dasatinib and nilotinib) used in chronic myeloid leukemia (CML) treatment have shown a benefit compared to imatinib in responses achieved and disease progression. However, both have been related to some cardiovascular toxicity, being more frequent in patients with cardiovascular risk factors (CVRFs). Nowadays, due to the lack of recommendations for CML patients, CVRF management is carried out heterogeneously. The aim of this work is to develop recommendations on the prevention and monitoring of cardiovascular events (CVD) in patients with CML treated with TKIs. Material and methods:Experts from the Spanish Group of Chronic Myeloid Leukemia together with experts in cardiovascular risk have elaborated, after a consensus meeting, recommendations for the prevention and follow-up of CVE in patients with CML treated with TKI. Results: Recommendations regarding the necessary information to be collected on clinical history, treatment decisions, as well as treatment and monitoring of CVRFs are shown in this document. Conclusions: TKI treatment requires comprehensive patient management from a multidisciplinary approach, in which both the prevention and management of CVRFs are essential (AU)

[Cardiovascular management of patients with chronic myeloid leukemia from a multidisciplinary perspective, and proposing action protocol by consensus meeting]. / Gestión cardiovascular de los pacientes con leucemia mieloide crónica desde una perspectiva multidisciplinar, y propuesta de protocolo de actuación por reunión de consenso.

INTRODUCTION AND OBJECTIVES: The second generation tyrosine kinase inhibitors (TKI, dasatinib and nilotinib) used in chronic myeloid leukemia (CML) treatment have shown a benefit compared to imatinib in responses achieved and disease progression. However, both have been related to some cardiovascular toxicity, being more frequent in patients with cardiovascular risk factors (CVRFs). Nowadays, due to the lack of recommendations for CML patients, CVRF management is carried out heterogeneously. The aim of this work is to develop recommendations on the prevention and monitoring of cardiovascular events (CVD) in patients with CML treated with TKIs. MATERIAL AND METHODS: Experts from the Spanish Group of Chronic Myeloid Leukemia together with experts in cardiovascular risk have elaborated, after a consensus meeting, recommendations for the prevention and follow-up of CVE in patients with CML treated with TKI. RESULTS: Recommendations regarding the necessary information to be collected on clinical history, treatment decisions, as well as treatment and monitoring of CVRFs are shown in this document. CONCLUSIONS: TKI treatment requires comprehensive patient management from a multidisciplinary approach, in which both the prevention and management of CVRFs are essential.

Frequency and prognostic value of resistance/intolerance to hydroxycarbamide in 890 patients with polycythaemia vera.

The clinical significance of resistance/intolerance to hydroxycarbamide (HC) was assessed in a series of 890 patients with polycythaemia vera (PV). Resistance/intolerance to HC was recorded in 137 patients (15·4%), consisting of: need for phlebotomies (3·3%), uncontrolled myeloproliferation (1·6%), failure to reduce massive splenomegaly (0·8%), development of cytopenia at the lowest dose of HC to achieve a response (1·7%) and extra-haematological toxicity (9%). With a median follow-up of 4·6 years, 99 patients died, resulting in a median survival of 19 years. Fulfilling any of the resistance/intolerance criteria had no impact on survival but when the different criteria were individually assessed, an increased risk of death was observed in patients developing cytopenia [Hazard ratio (HR): 3·5, 95% confidence interval (CI): 1·5-8·3, P = 0·003]. Resistance/intolerance had no impact in the rate of thrombosis or bleeding. Risk of myelofibrotic transformation was significantly higher in those patients developing cytopenia (HR: 5·1, 95% CI: 1·9-13·7, P = 0·001) and massive splenomegaly (HR: 9·1, 95% CI: 2·3-35·9, P = 0·002). Cytopenia at the lowest dose required to achieve a response was also an independent risk factor for transformation to acute leukaemia (HR: 20·3, 95% CI: 5·4-76·5, P < 0·001). In conclusion, the unified definition of resistance/intolerance to HC delineates a heterogeneous group of PV patients, with those developing cytopenia being associated with an adverse outcome.

Función sistólica del ventrículo izquierdo: cómo comprenderla y analizarla / Left ventricular systolic function: How to understand it and analyze it

En los estudios de resonancia magnética cardíaca, la función sistólica del ventrículo izquierdo suele calcularse automáticamente. Entender cómo se obtiene cada parámetro de la función y el por qué de las diferencias que pueden existir entre los valores obtenidos con dos técnicas, por ejemplo ecografía y resonancia magnética, es fundamental para comprenderlas e interpretarlas adecuadamente. En este artículo se detalla el análisis habitual de la función sistólica desde un punto de vista cuantitativo y cualitativo, y se explican otros métodos que no requieren un software específico. Hemos diseñado (y lo aportamos para que pueda usarse libremente) un fichero que, empleando el programa Microsoft Excel®, permite analizar la función sistólica sencilla e intuitivamente (AU)

In cardiac magnetic resonance imaging studies, left ventricular systolic function is usually calculated automatically. To understand and interpret parameters of left ventricular systolic function correctly, it is fundamental to understand how each parameter is obtained and why values obtained with different techniques, for example, ultrasonography and magnetic resonance imaging, can differ. This article provides details about the usual analysis of systolic function from the quantitative and qualitative points of view; it also explains other methods that do not require specific software. Moreover, we provide a file that we designed for use with Microsoft Excel® to enable simple, intuitive analysis of systolic function. Readers can use this file freely (AU)

Influencia de la edad en la enfermedad neumocócica invasiva y en la resistencia a antimicrobianos / Influence of age on the clinical manifestations of invasive pneumococcal disease and antibiotic resistance rates

Fundamento y objetivo: La enfermedad invasiva por Streptococcus pneumoniae (EISP) presenta variaciones epidemiológicas en relación con la edad y el serotipo de neumococo aislado. Los objetivos del trabajo fueron analizar las formas clínicas y la mortalidad de EISP, los serotipos aislados y la tasa de resistencia a antimicrobianos en diferentes grupos de edad. Pacientes y método: Se estudiaron 141 pacientes con EISP diagnosticados entre 2002 y 2008 y se clasificaron en 4 grupos: ≤ 2 años, 3-14 años, 15-64 años y ≥ 65 años. Resultados: La neumonía que la manifestación más frecuente (71%) en todos los grupos de edad. En el grupo ≤ 2 años destacó una mayor prevalencia de meningitis (28 frente a 9%, p = 0,054) y en el grupo 3-14 años el empiema fue más frecuente (31 frente a 5%, p < 0,001). La mortalidad se asoció con la edad ≥ 65 años (odds ratio [OR] 7, intervalo de confianza del 95% [IC 95%] 1,9-28,9), la bacteriemia primaria (OR 7, IC 95% 1,9-28,9) y la intubación orotraqueal (OR 9, IC 95% 1,9-41,1). Los serotipos más prevalentes en ≤ 2 años fueron 14, 19A y 19F, el serotipo 1 en el grupo 3-14 años y el 3 en ≥ 65 años. En la población pediátrica se observó una mayor tasa de cepas no sensibles a penicilina (42 frente a 18%, p = 0,007). Conclusiones: La edad se relacionó con las formas clínicas, la mortalidad y la resistencia a antimicrobianos. La bacteriemia primaria constituyó uno de los factores asociados con una mayor mortalidad (AU)

Background and objective: Invasive pneumococcal disease (IPD) shows different epidemiological characteristics depending on age and pneumococcus serotype. The aims of the work were to analyze the clinical manifestations and mortality associated with IPD, the serotype isolated and the antibiotic resistance rates in different age groups. Patients and method: Retrospectively, 141 patients with IPD diagnosed between 2002 and 2008 were studied. Patients were classified in 4 age groups: 2 year-old, 3-14 year-old, 15-64 year-old and 65 year-old. Results: Pneumonia was the most common manifestation in all age groups (71%). Pneumococcal meningitis was more prevalent in patients 2 year-old (28 vs. 9%, P = .054) and empyema was more frequent in those between 3-14 year-old (31 vs. 5%, P < .001). Mortality was associated with age 65 year-old (odds ratio [OR] 7, 95% confidence interval [95% CI] 1.9-28.9), primary bacteremia (OR 7, 95% CI 1.9-28.9) and orotracheal intubation (OR 9, 95% CI 1.9-41.1). The more prevalent serotypes among patients 2 year-old were 14, 19A and 19F. The serotype 1 was most common in patients between 3-14 year-old and serotype 3 in those 65 year-old. A higher rate of non-susceptible penicillin strains was observed in pediatric population (42 vs. 19%, P = .007). Conclusions: Age was related to the clinical manifestations, mortality and antibiotic resistance rates. Primary bacteremia was one of the risk factors of mortality (AU)

High p27 protein levels in chronic lymphocytic leukemia are associated to low Myc and Skp2 expression, confer resistance to apoptosis and antagonize Myc effects on cell cycle.

Myc (c-Myc) counteracts p27 effects, and low p27 usually correlates with high Myc expression in human cancer. However there is no information on the co-expression of both genes in chronic lymphocytic leukemia (CLL). We found a lack of correlation between RNA and protein levels of p27 and Myc in CLL cells, so we determined the protein levels by immunoblot in 107 cases of CLL. We observed a high p27 protein expression in CLL compared to normal B cells. Ectopic p27 expression in a CLL-derived cell line resulted in cell death resistance. Surprisingly, Myc expression was very low or undetectable in most CLL cases analyzed, with a clear correlation between high p27 and low Myc protein levels. This was associated with low Skp2 expression, which is consistent with the Skp2 role in p27 degradation and with SKP2 being a Myc target gene. High Myc expression did not correlate with leukemia progression, despite that cell cycle-related Myc target genes were upregulated. However, biochemical analysis showed that the high p27 levels inhibited cyclin-Cdk complexes even in Myc expressing CLL cells. Our data suggest that the combination of high p27 and low Myc is a marker of CLL cells which is mediated by Skp2.

Busulfan in patients with polycythemia vera or essential thrombocythemia refractory or intolerant to hydroxyurea.

Therapeutic options for patients with polycythemia vera (PV) and essential thrombocythemia (ET) resistant or intolerant to hydroxyurea are limited. Busulfan is effective as first-line therapy, but there is scarce information on this drug as second-line treatment. The efficacy of busulfan in patients with advanced PV or ET refractory or intolerant to hydroxyurea was assessed in 36 patients (PV n = 15, ET n = 21) treated for a median of 256 days. Complete hematological response (CHR) was achieved in 83 % of patients, after a median time of 203 days (range 92-313). The probability of sustained CHR at 1 and 2 years was 87 and 62 %, respectively. Time to CHR was shorter in patients treated with ≥14 mg of busulfan per week than with lower doses (141 versus 336 days, p = 0.01). Partial molecular response was achieved in three out of nine (33 %) patients. Busulfan was stopped in 27 patients (75 %) due to CHR achievement in 18 cases (67 %), hematological toxicity in 8 cases (30 %), and disease transformation in 1 case. With a median follow-up of 721 days, six patients have died, with the probability of survival at 2 years being 85 %. The probability of thrombosis at 2 years was 11 %. Transformation into acute leukemia or myelodysplastic syndrome was observed in three cases, all of them in a JAK2V617F-negative clone carrying additional mutations. Busulfan, at a dose of 2 mg/day, is an effective option for elderly patients with PV or ET who fail to hydroxyurea, but a significant rate of transformation was observed.