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.

Developmental changes of the GABA-immunoreactive fibers in the lamprey spinal cord.

The changes in distribution and number of GABA immunoreactive (GABA-ir) fibers from postembryonic stages to adulthood in the lamprey spinal cord white matter were studied by using immunocytochemical techniques. From prolarvae to adult spawning animals there was an increase of the number of GABA-ir fibers. Three phases can be distinguished: (a) from prolarvae to middle size larvae (around 50 mm in body length) an increase in the number of GABA-ir fibers per section is observed. Furthermore, an adult-like pattern of GABA-ir fibers distribution is established during this phase. (b) Then, the number of GABA-ir fibers remains stable until metamorphosis, the end of the larval period. (c) Finally, in young postmetamorphic and adult animals the number of GABA-ir fibers is higher than in larvae. These observations, joined to the changes previously reported in the GABA-ir neurons, indicate that at least parts of the GABA inhibitory component of the spinal locomotor network is reorganized during the lamprey life cycle and it may indicate different inhibitory requirements in the locomotor network.

Immunocytochemical localization of calretinin in the olfactory system of the adult lamprey, Lampetra fluviatilis.

The distribution of calretinin immunoreactive (CR-ir) structures in the adult lamprey (Lampetra fluviatilis) olfactory system was studied by using immunocytochemical techniques. In the olfactory epithelium, a subpopulation of olfactory receptor cells was CR-ir. In the olfactory bulbs, three different cell populations were observed. Large CR-ir cells (mitral cells) were located medially to the olfactory glomeruli and occasionally between them. In the inner cellular layer, two types of CR-ir perikarya were found: numerous small CR-ir cells (granule cells) and some medium-sized CR-ir cells (putative displaced periglomerular cells). In addition, different intensities of CR-ir fibers were present in particular rootlets of the olfactory nerves, as well as in particular glomeruli. The presence of CR-ir cells and fibers in all layers of the lamprey olfactory bulbs supports the idea that this protein is present in pathways underlying the processing of sensory information throughout evolution.

Uso de contenciones mecánicas en unidades de cuidados críticos: caracterización, estándares de aplicación y factores relacionados. Resultados de un estudio multicéntrico / The use of mechanical restraint in critical care units: Characterisation, application standards and related factors. Results of a multicentre study

Objetivos: Describir y caracterizar el uso de contenciones mecánicas (CM) en unidades de cuidados críticos (UCC) en términos de frecuencia y calidad de aplicación y analizar su relación con la monitorización del dolor/agitación-sedación/delirio, la ratio enfermera:paciente y la implicación institucional. Método: Estudio observacional multicéntrico realizado en 17 UCC entre febrero y mayo del año 2016. El tiempo de observación por UCC fue de 96h. Las principales variables fueron la prevalencia de contenciones, el grado de adherencia a las recomendaciones de uso de CM, la monitorización del dolor/agitación-sedación/delirio y la implicación institucional (protocolos y formación de los profesionales). Resultados: Se incluyeron 1.070 pacientes. La prevalencia general de contenciones fue del 19,11%, en pacientes con tubo endotraqueal (TET) del 42,10% y en pacientes sin TET ni vía aérea artificial del 13,92%. Se obtuvieron valores de adherencia entre el 0 y el 40% para las recomendaciones relacionadas con manejo no farmacológico y entre el 0 y el 100% para las relacionadas con la vigilancia de aspectos ético-legales. La menor prevalencia de contenciones se correlacionó con una adecuada monitorización del dolor en pacientes no comunicativos (p<0,001) y con la impartición de formación a los profesionales (p=0,020). Se halló correlación inversa entre la calidad de aplicación de CM y su prevalencia, tanto en el grupo general de pacientes ingresados en las UCC (r=−0,431) como en el subgrupo de pacientes con TET (r=−0,521). Conclusiones: Las contenciones son especialmente frecuentes en pacientes con TET/vía aérea artificial, pero también están presentes en otros pacientes que a priori no responden al perfil de uso atribuido. Las alternativas no farmacológicas al uso de CM, la vigilancia de aspectos éticos y legales y la implicación institucional presentan un amplio margen de mejora.(AU)

Objectives: To describe and characterise the use of mechanical restraint (MR) in critical care units (CCU) in terms of frequency and quality of application and to study its relationship with pain/agitation-sedation/delirium, nurse:patient ratio and institutional involvement. Method: Multicentre observational study conducted in 17 CCUs between February and May 2016. The observation time per CCU was 96h. The main variables were the prevalence of restraint, the degree of adherence to MR recommendations, pain/agitation-sedation/delirium monitoring and institutional involvement (protocols and training of professionals). Results: A total of 1070 patients were included. The overall prevalence of restraint was 19.11%, in patients with endotracheal tube (ETT) 42.10% and in patients without ETT or artificial airway it was 13.92%. Adherence rates between 0% and 40% were obtained for recommendations related to non-pharmacological management and between 0% and 100% for those related to monitoring of ethical-legal aspects. The lower prevalence of restraint was correlated with adequate pain monitoring in non-communicative patients (P<.001) and with the provision of training for professionals (P=.020). An inverse correlation was found between the quality of the use of MR and its prevalence, both in the general group of patients admitted to CCU (r=−.431) and in the subgroup of patients with ETT (r=−.521). Conclusions: Restraint is especially frequently used in patients with ETT/artificial airway, but is also used in other patients who may not meet the use profile. There is wide room for improvement in non-pharmacological alternatives to the use of MC, ethical and legal vigilance, and institutional involvement. Better interpretation of patient behaviour with validated tools may help limit use of MR.(AU)