Adoptive immunotherapy with antiviral T cells: Methods and results. / Inmunoterapia adoptiva con linfocitos antivirales: métodos y resultados.

Viral infections and reactivations are one of the main causes of morbidity and mortality in patients who undergo allogeneic haematopoietic progenitor cell transplantation. Adoptive immunotherapy with virus-specific Tcells (from donor to patient) has shown efficacy in the antiviral treatment of patients who have undergone transplantation and whose immune system has not yet been reconstituted. Currently, and according to the requirements of the corresponding agencies that regulate the production of these advanced personalised therapies, the production and application of these cell products are being optimised in such a way that they comply with good manufacturing practice standards and are safe and effective for treating patients. To facilitate their implementation, we need to understand the foundations of producing and using virus-specific Tcells. This study reviews the evolution of the methodology for producing antiviral Tcells and the studies that support their therapeutic efficacy. The study covers up to the current production platforms, whose commercialisation has begun in Spain. These platforms will help obtain virus-specific Tcells and chimeric antigen receptor Tcells, among others, in a completely automated manner and under good manufacturing practice conditions. The implementation of these new methodologies in the Spanish healthcare system will undoubtedly facilitate patients' access to a new repertoire of advanced therapies.

Agreements and uncertainties in autologous haematopoietic stem cell mobilization and collection. A Spanish consensus document.

Although many experts position statements on autologous stem cell mobilization have been published, there are some aspects that are still under discussion. A Spanish Hematologist expert group was summoned to settle on agreements and uncertainties on PBSCs mobilization, including factors not always considered; as apheresis and cytometry key factors that determine a successful PBSC collection. This document reviews critical factors that define poor mobilizer patients and the tools to better collect the desired stem cells for a successful autologous haematopoietic stem cell transplant.

Genomic full-length sequence of two new HLA-C alleles, HLA-C*04:239 and HLA-C*05:137.

Two novel HLA-C alleles, C*04:239 and C*05:137, were characterized in Spanish individuals.

Human toll-like receptor 1 T1805G polymorphism and susceptibility to pulmonary tuberculosis in northern Spain.

Toll-like receptors (TLRs) are key sensors of mycobacterial infections and play a crucial role in the initiation and coordination of the antimycobacterial innate immune response. T1805G, a functional TLR1 single nucleotide polymorphism (SNP), has been associated with susceptibility to pulmonary tuberculosis (PTB), but contradictory results among different populations have been reported. Our objective was to study this SNP in a genetically homogeneous population to evaluate its role in conferring susceptibility or resistance to PTB. In our population, the 1805G allele and the GG genotype (OR 2.04, 95%CI 1.26-3.31) influence susceptibility to PTB, in contrast with data observed in other populations.

Is it possible to increase bioavailability but not environmental risk of PAHs in bioremediation?

The current poor predictability of end points associated with the bioremediation of polycyclic aromatic hydrocarbons (PAHs) is a large limitation when evaluating its viability for treating contaminated soils and sediments. However, we have seen a wide range of innovations in recent years, such as an the improved use of surfactants, the chemotactic mobilization of bacterial inoculants, the selective biostimulation at pollutant interfaces, rhizoremediation and electrobioremediation, which increase the bioavailability of PAHs but do not necessarily increase the risk to the environment. The integration of these strategies into practical remediation protocols would be beneficial to the bioremediation industry, as well as improve the quality of the environment.

Effect of interface fertilization on biodegradation of polycyclic aromatic hydrocarbons present in nonaqueous-phase liquids.

The main goal of this study was to use an oleophilic biostimulant (S-200) to target possible nutritional limitations for biodegradation of polycyclic aromatic hydrocarbons (PAHs) at the interface between nonaqueous-phase liquids (NAPLs) and the water phase. Biodegradation of PAHs present in fuel-containing NAPLs was slow and followed zero-order kinetics, indicating bioavailability restrictions. The biostimulant enhanced the biodegradation, producing logistic (S-shaped) kinetics and 10-fold increases in the rate of mineralization of phenanthrene, fluoranthene, and pyrene. Chemical analysis of residual fuel oil also evidenced an enhanced biodegradation of the alkyl-PAHs and n-alkanes. The enhancement was not the result of an increase in the rate of partitioning of PAHs into the aqueous phase, nor was it caused by the compensation of any nutritional deficiency in the medium. We suggest that biodegradation of PAH by bacteria attached to NAPLs can be limited by nutrient availability due to the simultaneous consumption of NAPL components, but this limitation can be overcome by interface fertilization.

Glial reactivity after antipsychotic treatment. An experimental study in rats and its implications for psychiatry.

INTRODUCTION: The importance of the glial cells in the function of the nervous system and in its pathology has been the object of multiple studies in the last years. Specifically, their role in the action of the antipsychotics is debated. Our study has analyzed glial reactivity in rats treated with antipsychotics. METHODOLOGY: In a first ultrastructural study of the arcuate nucleus of the hypothalamus, the animals were treated with chlorpromazine for 40 days, and were sacrificed at the end of the treatment, after 20 days of rest without treatment. In another series of studies, with the light microscope and immunohistochemistry we evaluated the immunoreactivity of the glial fibrillary acidic protein (GFAP) in six regions of the central nervous system of rats treated with typical and atypical antipsychotics. RESULTS: With the electron microscope, the animals treated with chlorpromazine showed a significant reduction of the axosomatic synapses on the neurons of the hypothalamic arcuate nucleus and an increase of glial presence, as noted by the greater amount of astrocyte processes. The mentioned modifications were reversible, tending to normalize in a group of animals sacrificed 20 days after completion of the treatment. In the immunohistochemical study, the glial reaction was important in the territory of the nucleus accumbens with all the antipsychotics, moderate in the cingulate cortex, although only with atypical antipsychotics, and scarcely significant in the rest of the regions. CONCLUSIONS: Our results confirm that the glial cells are targets of the antipsychotic action, and this will allow us to better understand the action of these drugs and the role of the glial cells in the normal function of the nervous system and in the mental disease.

Reactividad glial tras el tratamiemto con antipsicóticos. Estudio experimental en ratas e implicaciones para la psiquiatría / Glial reactivity after antipsychotic treatment. An experimental study in rats and its implications for psychiatry

Introducción. La importancia de las células gliales en la función del sistema nervioso y en su patología ha sido objeto de múltiples estudios en los últimos años. Concretamente se debate su papel en la acción de los antipsicóticos. Nuestro estudio analiza la reactividad glial en ratas tratadas con antipsicóticos. Metodología. En un primer estudio ultraestructural del núcleo arcuato del hipotálamo, los animales fueron tratados con clorpromacina durante 40 días, sacrificándose al final del tratamiento y tras 20 días de descanso. En otra serie de estudios, con el microscopio de luz y con técnicas inmunohistoquímicas valoramos la reacción a la proteína glial fibrilar ácida (GFAP) en seis regiones del sistema nervioso central de ratas tratadas con antipsicóticos típicos y atípicos. Resultados. Con el microscopio electrónico, las ratas tratadas mostraron una reducción significativa de las sinapsis axosomáticas sobre las neuronas del núcleo arcuato del hipotálamo, así como un incremento de la presencia glial evidenciable por la mayor cantidad de laminillas de astrocitos. Las modificaciones mencionadas son reversibles, tendiendo a normalizarse en los animales sacrificados a los 20 días de finalizado el tratamiento. En el estudio inmunohistoquímico la reacción astrocitaria fue muy importante en el territorio del núcleo accumbens con todos los antipsicóticos, moderada en la corteza cingular, aunque sólo con los atípicos, y discreta en el resto de las regiones. Conclusiones. Nuestros resultados confirman que las células gliales son diana de los antipsicóticos, lo que ha de contribuir a entender mejor la acción de estos fármacos y el papel de las células gliales en el normal funcionamiento del sistema nervioso y en la enfermedad mental (AU)

Introduction. The importance of the glial cells in the function of the nervous system and in its pathology has been the object of multiple studies in the last years. Specifically, their role in the action of the antipsychoticsis debated. Our study has analyzed glial reactivity in rats treated with antipsychotics. Methodology. In a first ultrastructural study of the arcuate nucleus of the hypothalamus, the animals were treated with chlorpromazine for 40 days, and were sacrificed at the end of the treatment, after 20 days of rest without treatment. In another series of studies, with the light microscope and immunohistochemistry we evaluated the immunoreactivity of the glial fibrillary acidic protein (GFAP) in six regions of the central nervous system ofrats treated with typical and atypical antipsychotics. Results. With the electron microscope, the animals treated with chlorpromazine showed a significant reduction of the axosomatic synapses on the neurons of the hypothalamic arcuate nucleus and an increase of glial presence, as noted by the greater amount of astrocyte processes. The mentioned modifications were reversible, tending to normalize in a group of animals sacrificed 20 days after completion of the treatment. In the immunohistochemical study, the glial reaction was important in the territory of the nucleus accumbens with all the antipsychotics, moderate in the cingulate cortex, although only with atypical antipsychotics, and scarcely significant in the rest of the regions. Conclusions. Our results confirm that the glial cells are targets of the antipsychotic action, and this will allow us to better understand the action of these drugs and the role of the glial cells in the normal function of the nervous system and in the mental disease (AU)

ADAMTS-13 activity and von Willebrand factor levels in methylene-blue photo-inactivated plasma processed by either the Springe method or an 'in house' system.

BACKGROUND AND OBJECTIVES: Methylene blue photo-inactivated plasma (MBPIP) has been reported to be less effective than fresh-frozen plasma (FFP) in the treatment of thrombotic thrombocytopenic purpura, which suggests a reduced content of the von Willebrand factor metalloprotease ADAMTS-13 in MBPIP. MATERIALS AND METHODS: ADAMTS-13 activity and von Willebrand factor antigen (vWF:Ag) levels were measured in plasma before and after photo-oxidation by either the Springe method or a commercial 'in house' system as well as in cryoprecipitate-poor plasma (CPP) and FFP (20 units each). RESULTS: Levels of ADAMTS-13 activity in MBPIP processed by the Springe method or the commercial 'in house' system were comparable to one another and did not significantly differ from levels found in FFP [median (range): 114% (57-139%), 99% (74-123%), and 106% (70-130%), respectively]. ADAMTS-13 activity was significantly reduced in CPP [median (range): 87% (70-107%) as compared with FFP (P < 0.05). Levels of vWF:Ag decreased after photo-oxidation by both methods. CONCLUSION: In vitro ADAMTS-13 activity was conserved in MBPIP processed by the two photo-oxidation methods analysed and did not significantly differ from levels found in FFP.

An active haemovigilance programme characterizing the safety profile of 7437 platelet transfusions prepared with amotosalen photochemical treatment.

BACKGROUND: An active haemovigilance programme was implemented to survey adverse events (AE) associated with transfusion of platelets photochemically treated with amotosalen and ultraviolet A (PCT-PLT). The results of 5106 transfusions have already been reported. Here we report the results of an additional 7437 PCT-PLT transfusions. METHODS: The focus of this ongoing haemovigilance programme is to document all AEs associated with PCT-PLT transfusion. Data collected for AEs include: time of event after starting transfusion, clinical descriptions, vital signs, results from radiographs and bacterial cultures, event severity (Grade 0-4) and causal relationship to PCT-PLT transfusion. RESULTS: One thousand four hundred patients (mean 60 years, range 1-96) received PCT-PLT transfusions. The majority of the patients (53.4%) had haematology-oncology diseases and required conventional chemotherapy (44.8%) or stem cell transplantation (8.6%). Sixty-eight PCT-PLT transfusions were associated with AE. Acute transfusion reactions (ATR), classified as an AE possibly related, probably related, or related to PCT-PLT transfusions were infrequent (n = 55, 55/7437 = 0.7%) and most were of Grade 1 severity. Thirty-nine patients (39/1400 = 2.8%) experienced one or more ATRs. The most frequently reported signs/symptoms were chills, fever, urticaria, dyspnoea, nausea and vomiting. Five AEs were considered severe (> or = Grade 2); however, no causal relationship to PCT-PLT transfusion was found. Repeated exposure to PCT-PLT did not increase the likelihood of an ATR. No cases of transfusion-related acute lung injury and no deaths due to PCT-PLT transfusions were reported. CONCLUSIONS: Routine transfusion of PCT-PLT is well-tolerated in a wide range of patients. ATRs related to PCT-PLT transfusion were infrequent and most were of mild severity.

Evaluation of a CD61 MoAb method for enumeration of platelets in thrombocytopenic patients and its impact on the transfusion decision-making process.

BACKGROUND: Almost all automated hematology cell analyzers use methods based on either the impedance (PLTi) or the optical (PLTo) properties of the cells for performing platelet counts. To improve the accuracy of platelet counts in peripheral blood (PB), the use of CD61 (GPIIIa) MoAbs (ImmunoPLT method) has recently been introduced in an automated hematology blood-analyzer system (Cell-Dyn 4000, Abbott Diagnostics). STUDY DESIGN AND METHODS: A comparative evaluation was made of the accuracy and precision of the three methods currently available in the Cell-Dyn 4000 automated hematology cell analyzer for counting the number of platelets per microliter of PB in a total of 47 patients with chemotherapy-induced thrombocytopenia. A flow cytometric PB platelet count was also performed in parallel and used as an external reference. RESULTS: PB platelet counts showed a good correlation among the PLTo, CD61-ImmunoPLT, and flow cytometric methods. In contrast, the PLTi procedure usually provided an overestimation of the number of platelets per microliter. Although a good correlation was observed between the flow cytometric reference method and both the ImmunoPLT and PLTo methods, the highest degree of agreement was found for the ImmunoPLT techniques (94% vs. 67%). A comparative analysis of the PLTo and CD61-ImmunoPLT methods with regard to their value for predicting platelet transfusion needs on the basis of specific flow cytometric platelet count thresholds showed a good correlation when the cutoff level of 10,000 platelets per microL was used. In contrast, at the threshold of 20,000 platelets per microL, slight differences were observed between the PLTo and CD61-ImmunoPLT procedures for predicting transfusion needs. CONCLUSION: Such results indicate that, if the CD61-ImmunoPLT method is used in the platelet transfusion decision-making process, unnecessary platelet transfusions could be avoided in up to 17.5 percent of persons with a PLTo count of <20,000 platelets per microL.

Cidofovir treatment of human polyomavirus-associated acute haemorrhagic cystitis.

We report the case of an 18-year-old patient who received an allogeneic bone marrow transplant from an HLA-identical unrelated donor for a Ph+ acute lymphoblastic leukemia, in his third complete remission. Cyclophosphamide and busulfan were used as conditioning treatment. Acute graft-versus-host disease developed on day +9, and the response to adequate treatment (steroids) was favourable. On day +45 the patient developed an acute severe haemorhragic cystitis, and BK polyomavirus was demonstrated in urine samples using electron microscopy and polymerase chain reaction. Urinary symptoms did not improve in spite of palliative treatment, but a response was evident after 2 weeks of cidofovir treatment.

Allogeneic peripheral stem cell transplantation in a case of hereditary sideroblastic anaemia.

We report on a case of pyridoxine refractory hereditary sideroblastic anaemia (HSA) in a 19-year-old man who underwent peripheral blood stem cell transplantation (PBSCT) from his HLA-identical brother. By using short tandem repeat polymorphism, 100% donor cells were observed in peripheral blood on day +21; bone marrow showed mixed chimaerism from day +21 to day +221, when 100% cells of donor origin were observed. The patient developed extensive chronic graft-versus-host disease with favourable response to treatment. When the haemoglobin range was normal, a programme of phlebotomies reduced serum ferritin levels. Three years after transplantation, the patient has an ECOG rating of 0, with completely normal haemoglobin values (15 g/dl). To our knowledge, this is the first PBSCT reported in a case of hereditary sideroblastic anaemia.

Randomized study of aprotinin and DDAVP to reduce postoperative bleeding after cardiopulmonary bypass surgery.

BACKGROUND: Patients on cardiopulmonary bypass (CPB) have an increased susceptibility to postoperative bleeding. Previous reports using desmopressin acetate (DDAVP) for the prevention of postoperative bleeding have given contradictory results, whereas the protease inhibitor aprotinin has been shown to reduce blood loss after this type of surgery. This randomized study was performed to assess the efficacy of DDAVP versus aprotinin in the prevention of bleeding after CPB. METHODS AND RESULTS: One hundred nine of 122 eligible patients were randomized to four different groups: Group A (n = 28) received aprotinin starting with a bolus of 2 x 10(6) KIU followed by a continuous infusion of 0.5 x 10(6) KIU/h until the end of surgery; group B (n = 25) received of DDAVP 0.3 micrograms/kg i.v. on completion of CPB; group C (n = 28) received two doses of DDAVP, the first as in group B and an additional dose 6 hours after surgery; group D (n = 28) received no treatment. There was a marked reduction of postoperative blood loss either at 12 hours (P < .01) or 72 hours (P < .02) in the aprotinin group compared with all other groups, whereas no significant effect was observed in either of the two DDAVP regimens. A significant reduction in the amount of blood used was observed only in the aprotinin group (P < .01). Of the plasma fibrinolytic components assayed, there was a significant reduction of the fibrin degradation product generation in the aprotinin group (P < .001), whereas a significant systemic hyperfibrinolysis was observed in both DDAVP-treated groups and the control group. No side effects related to the study drugs were observed in any patient. CONCLUSIONS: Aprotinin inhibited fibrinolysis; this correlated with a significant reduction of postoperative blood loss and need for blood replacement after CPB. Neither one nor two doses of DDAVP had a beneficial effect. Aprotinin offers a better alternative than DDAVP in the prevention of bleeding after CPB.