Osteogenic differentiation of human mesenchymal stem cells on electroactive substrates.

This study investigates the effect of electroactivity and electrical charge distribution on the biological response of human bone marrow stem cells (hBMSCs) cultured in monolayer on flat poly(vinylidene fluoride), PVDF, substrates. Differences in cell behaviour, including proliferation, expression of multipotency markers CD90, CD105 and CD73, and expression of genes characteristic of different mesenchymal lineages, were observed both during expansion in basal medium before reaching confluence and in confluent cultures in osteogenic induction medium. The crystallisation of PVDF in the electrically neutral α-phase or in the electroactive phase ß, both unpoled and poled, has been found to have an important influence on the biological response. In addition, the presence of a permanent positive or negative surface electrical charge distribution in phase ß substrates has also shown a significant effect on cell behaviour.

When to shear dairy ewes: before breeding, during pregnancy or let them unshorn?

Shearing dairy ewes may improve their fitness and heat tolerance during late pregnancy, with positive effects on lambs and lactation performances. To test this hypothesis, two Mediterranean breeds (MN, Manchega, n = 43; LC, Lacaune, n = 28), differing in lactation performances and fleece traits, were submitted to three shearing strategies: (i) shorn before breeding (SBB), (ii) shorn at day 100 of pregnancy (S100) and (iii) unshorn (CO). Ewes were bred in spring and gestated during summer. Fleece traits and respiratory rate were measured on pregnant (107-121 days) resting ewes at different barn temperatures. Blood and colostrum were sampled at lambing. Ewes suckled their lambs (28 days) and were machine-milked until 180 days of lactation. Lamb and ewe weights, and condition score of the ewes, were recorded throughout the experiment. Milk yield was assessed during suckling (fortnightly) and milking (daily), and milk was sampled for composition (fortnightly). Fleece extension and wool weight at S100 were 13 and 45% greater in MN than in LC ewes, respectively, but the ewe's respiration rate at late pregnancy, between 20 and 25 °C, did not vary among shearing treatments nor breeds. Nevertheless, S100 ewes had a 37% lower respiration rate than SBB and CO ewes at 28 °C. At lambing, SBB and S100 ewes had 86% higher glycaemia than CO in MN, but LC ewes did not vary. Shearing treatment had no effect in plasma insulin, ß-hydroxybutyrate or non-esterified fatty acids (NEFAs) at lambing in both breeds. Lamb's birthweight and growth during suckling did not differ by shearing treatment in both breeds. Colostrum composition and milk yield during suckling were not modified by shearing treatment in either breed, although S100 suckling milk composition increased in MN (protein and casein, 6%) and LC ewes (total solids, 8%; fat, 18%), compared to CO and SBB. No effects were detected in milk yield or composition during milking, but S100 tended to yield 28% more milk than CO in the LC ewes. The S100 treatment improved the body reserves in late pregnancy, when compared to CO and SBB in both breeds. In conclusion, shearing dairy ewes in late pregnancy was a recommendable management practice under summer conditions, because alleviated heat stress and improved the weight of the ewes, without detrimental effects on lambing and lactational performances, the last tending to increase milk yield in high-yielding dairy ewes.

Recomendaciones para la administración de antineoplásicos e inmunomoduladores orales por sonda enteral en oncohematología / Recommendations for using oral antineoplastic and immunomodulating agents in oncohematology by enteral tube administration

Introducción y objetivo: en los últimos años, el número de fármacos antineoplásicos e inmunomoduladores orales (ANIOS) ha crecido enormemente. Con frecuencia, estos fármacos deben administrarse por sonda enteral (SE) o a pacientes con problemas de deglución, planteando un problema respecto a su manipulación (muchos pertenecen al grupo de medicamentos peligrosos). Además, también pueden presentar interacciones cuando se administran con la nutrición enteral (NE). El objetivo ha sido analizar y actualizar las recomendaciones de administración y manipulación de los ANIOS. Métodos: se creó un Grupo de Trabajo formado por farmacéuticos del Grupo de Farmacia de la Sociedad Española de Nutrición Clínica y Metabolismo (SENPE) y del Grupo de Nutrición Clínica de la Sociedad Española de Farmacia Hospitalaria (SEFH). Se realizó una revisión bibliográfica entre 2015 y 2020 de las condiciones de manipulación y administración de los ANIOS en oncohematología, elaborando una tabla que recoge especialidades farmacéuticas, dosis, presentación, nombre comercial, instrucciones para la administración oral y por SE, interacciones con la NE, precauciones y observaciones para su manipulación y administración. Resultados: se elaboró una tabla con 77 principios activos y 84 formas farmacéuticas, recogiendo recomendaciones e instrucciones para su administración por vía oral, sonda nasogástrica y gastrostomía, para la correcta manipulación y para la administración junto a la NE. Conclusiones: la información sobre cómo administrar y manipular los ANIOS en personas con accesos enterales o problemas de deglución es escasa. Consideramos importante incluir en los estudios poscomercialización una investigación dirigida a responder a estas cuestiones para garantizar una administración segura y eficaz de los medicamentos a estos pacientes (AU)

Introduction and objective: in recent years, the number of oral antineoplastic and immunomodulating drugs in oncohematology has increased enormously. Often, these drugs must be administered to patients with enteral tube feeding or swallowing disorders, which causes safety problems when handling these drugs (many of them are classified as hazardous drugs). In addition, it is important to note that the administration of these drugs can also interact with enteral nutrition (EN). The objective of this study was to review and update the recommendations for the administration and handling of oral antineoplastic and immunomodulating drugs. Methods: a Working Group made up of pharmacists from the Pharmacy Group of The Spanish Society of Clinical Nutrition and Metabolism (SENPE) and the Clinical Nutrition Group of The Spanish Society of Hospital Pharmacy (SEFH) was created. A bibliographic review was carried out between 2015 and 2020 on the administration and handling of oral antineoplastic and immunomodulating drugs in oncohematology. The information about pharmaceutical specialties, dosage, presentation, brand names, instructions for oral or enteral tube administration, interactions with EN, precautions, and remarks for handling and administration was analyzed. Results: a total of 77 active principles and 84 pharmaceutical forms were included. Recommendations and instructions for oral, nasogastric tube, and gastrostomy administration, handling of the antineoplastic and immunomodulating drugs, and interactions with EN were described. Conclusions: the handling and administration information about the oral antineoplastic and immunomodulating drugs currently used in oncohematology for people with enteral accesses or swallowing disorders is limited. It is important to perform post-marketing studies to ensure a safe and effective administration of these drugs (AU)

Successful desensitization to cloxacillin in a patient with sepsis, with infective endocarditis and clinical suspicion of hypersensitivity to penicillins, a case report.

WHAT IS KNOWN AND OBJECTIVE: Beta-lactam antibiotic (BLA) therapy is frequently needed to treat infective endocarditis (IE). Hypersensitive reactions to BLA restrict BLA therapy in allergic patients. In the current case, we aim to describe the utility of desensitization (DS) in this context. Although the evidence is limited, DS is recommended. CASE DESCRIPTION: This case report deals with a 79-year-old woman with a clinical suspicion of allergy to BLA and a methicillin-sensitive Staphylococcus aureus (MSSA) IE. A cloxacillin DS protocol was developed to enable treatment with cloxacillin. WHAT IS NEW AND CONCLUSION: Alternative antibiotic treatments may be less effective or not available in MSSA IE. In this case report, DS allowed optimal cloxacillin treatment.

Prognostic value of antigen expression in multiple myeloma: a PETHEMA/GEM study on 1265 patients enrolled in four consecutive clinical trials.

Persistence of minimal residual disease (MRD) after treatment for myeloma predicts inferior outcomes, but within MRD-positive patients there is great heterogeneity with both early and very late relapses. Among different MRD techniques, flow cytometry provides additional information about antigen expression on tumor cells, which could potentially contribute to stratify MRD-positive patients. We investigated the prognostic value of those antigens required to monitor MRD in 1265 newly diagnosed patients enrolled in the GEM2000, GEM2005MENOS65, GEM2005MAS65 and GEM2010MAS65 protocols. Overall, CD19pos, CD27neg, CD38lo, CD45pos, CD81pos, CD117neg and CD138lo expression predicted inferior outcomes. Through principal component analysis, we found that simultaneous CD38lowCD81posCD117neg expression emerged as the most powerful combination with independent prognostic value for progression-free survival (HR:1.69; P=0.002). This unique phenotypic profile retained prognostic value among MRD-positive patients. We then used next-generation flow to determine antigen stability throughout the course of the disease, and found that the expression of antigens required to monitor MRD is mostly stable from diagnosis to MRD stages, except for CD81 whose expression progressively increased from baseline to chemoresistant tumor cells (14 vs 28%). Altogether, we showed that the phenotypic profile of tumor cells provides additional prognostic information, and could be used to further predict risk of relapse among MRD-positive patients.

Human Mesenchymal Stem Cells Growth and Osteogenic Differentiation on Piezoelectric Poly(vinylidene fluoride) Microsphere Substrates.

The aim of this work was to determine the influence of the biomaterial environment on human mesenchymal stem cell (hMSC) fate when cultured in supports with varying topography. Poly(vinylidene fluoride) (PVDF) culture supports were prepared with structures ranging between 2D and 3D, based on PVDF films on which PVDF microspheres were deposited with varying surface density. Maintenance of multipotentiality when cultured in expansion medium was studied by flow cytometry monitoring the expression of characteristic hMSCs markers, and revealed that cells were losing their characteristic surface markers on these supports. Cell morphology was assessed by scanning electron microscopy (SEM). Alkaline phosphatase activity was also assessed after seven days of culture on expansion medium. On the other hand, osteoblastic differentiation was monitored while culturing in osteogenic medium after cells reached confluence. Osteocalcin immunocytochemistry and alizarin red assays were performed. We show that flow cytometry is a suitable technique for the study of the differentiation of hMSC seeded onto biomaterials, giving a quantitative reliable analysis of hMSC-associated markers. We also show that electrosprayed piezoelectric poly(vinylidene fluoride) is a suitable support for tissue engineering purposes, as hMSCs can proliferate, be viable and undergo osteogenic differentiation when chemically stimulated.

Differentiation stage of myeloma plasma cells: biological and clinical significance.

The notion that plasma cells (PCs) are terminally differentiated has prevented intensive research in multiple myeloma (MM) about their phenotypic plasticity and differentiation. Here, we demonstrated in healthy individuals (n=20) that the CD19-CD81 expression axis identifies three bone marrow (BM)PC subsets with distinct age-prevalence, proliferation, replication-history, immunoglobulin-production, and phenotype, consistent with progressively increased differentiation from CD19+CD81+ into CD19-CD81+ and CD19-CD81- BMPCs. Afterwards, we demonstrated in 225 newly diagnosed MM patients that, comparing to normal BMPC counterparts, 59% had fully differentiated (CD19-CD81-) clones, 38% intermediate-differentiated (CD19-CD81+) and 3% less-differentiated (CD19+CD81+) clones. The latter patients had dismal outcome, and PC differentiation emerged as an independent prognostic marker for progression-free (HR: 1.7; P=0.005) and overall survival (HR: 2.1; P=0.006). Longitudinal comparison of diagnostic vs minimal-residual-disease samples (n=40) unraveled that in 20% of patients, less-differentiated PCs subclones become enriched after therapy-induced pressure. We also revealed that CD81 expression is epigenetically regulated, that less-differentiated clonal PCs retain high expression of genes related to preceding B-cell stages (for example: PAX5), and show distinct mutation profile vs fully differentiated PC clones within individual patients. Together, we shed new light into PC plasticity and demonstrated that MM patients harbouring less-differentiated PCs have dismal survival, which might be related to higher chemoresistant potential plus different molecular and genomic profiles.

A multiparameter flow cytometry immunophenotypic algorithm for the identification of newly diagnosed symptomatic myeloma with an MGUS-like signature and long-term disease control.

Achieving complete remission (CR) in multiple myeloma (MM) translates into extended survival, but two subgroups of patients fall outside this paradigm: cases with unsustained CR, and patients that do not achieve CR but return into a monoclonal gammopathy of undetermined significance (MGUS)-like status with long-term survival. Here, we describe a novel automated flow cytometric classification focused on the analysis of the plasma-cell compartment to identify among newly diagnosed symptomatic MM patients (N=698) cases with a baseline MGUS-like profile, by comparing them to MGUS (N=497) patients and validating the classification model in 114 smoldering MM patients. Overall, 59 symptomatic MM patients (8%) showed an MGUS-like profile. Despite achieving similar CR rates after high-dose therapy/autologous stem cell transplantation vs other MM patients, MGUS-like cases had unprecedented longer time-to-progression (TTP) and overall survival (OS; ~60% at 10 years; P<0.001). Importantly, MGUS-like MM patients failing to achieve CR showed similar TTP (P=0.81) and OS (P=0.24) vs cases attaining CR. This automated classification also identified MGUS patients with shorter TTP (P=0.001, hazard ratio: 5.53) and ultra-high-risk smoldering MM (median TTP, 15 months). In summary, we have developed a biomarker that identifies a subset of symptomatic MM patients with an occult MGUS-like signature and an excellent outcome, independently of the depth of response.

Síndrome neuroléptico maligno y síndrome serotoninérgico: a propósito de dos casos / Malignant neuroleptic syndrome and serotoninergic syndrome: two cases

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[Left atrial myxoma presenting as angor pectoris]. / Mixoma auricular izquierdo como forma de presentación de una angina de esfuerzo.

A 73 years old woman without cardiovascular risk factors presented physical exercise angina and dyspnea since 8 months ago. The caused of the disease was a left atrial myxoma which entering in left ventricle. The patient was free of coronary injured.

[Chagasic myocardiopathy: an infectious etiology of congestive heart failure]. / Miocardiopatía chagásica: una causa de insuficiencia cardiaca de origen infeccioso.

We present a case report of a Latin-American patient with dilated cardiomyopathy due to chronic Chagas disease satisfactorily treated with usual cardiologic support. We report a new aetiology of heart failure which is uncommon in our country but could rise due to immigration from endemic countries.