An MDS-specific frailty index based on cumulative deficits adds independent prognostic information to clinical prognostic scoring.

The frailty index (FI) is based on the principle that the more deficits an individual has, the greater their risk of adverse outcomes. It is expressed as a ratio of the number of deficits present to the total number of deficits considered. We developed an MDS-specific FI using a prospective MDS registry and assessed its ability to add prognostic power to conventional prognostic scores in MDS. The 42 deficits included in this FI included measurements of physical performance, comorbidities, laboratory values, instrumental activities of daily living, quality of life and performance status. Of 644 patients, 440 were eligible for FI calculation. The median FI score was 0.25 (range 0.05-0.67), correlated with age and IPSS/IPSS-R risk scores and discriminated overall survival. With a follow-up of 20 months, survival was 27 months (95% CI 24-30.4). By multivariate analysis, age >70, FI, transfusion dependence, and IPSS were significant covariates associated with OS. The incremental discrimination improvement of the frailty index was 37%. We derived a prognostic score with five risk groups and distinct survivals ranging from 7.4 months to not yet reached. If externally validated, the MDS-FI could be used as a tool to refine the risk stratification of current clinical prognostication models.

Prophylactic RhCE and Kell antigen matching: impact on alloimmunization in transfusion-dependent patients with myelodysplastic syndromes.

BACKGROUND AND OBJECTIVES: Thirty to 80 per cent of patients with myelodysplastic syndromes (MDS) become transfusion-dependent and are at risk for red blood cell (RBC) alloimmunization. This study compared alloimmunization rates in transfusion-dependent patients with MDS at an institution with a policy of prophylactic antigen matching for RhCE and K (PAM) with those transfused at institutions without such a policy (non-PAM). MATERIALS AND METHODS: Transfusion records were retrospectively reviewed to determine total number of RBC transfusions received, whether RBC phenotyping was performed, the type and date of first alloantibody development and receipt of prophylactic antigen matching for RhCE and K. RESULTS: In 176 transfusion-dependent patients with MDS, the overall rate of new alloimmunization was 17%; the majority of patients (87%) developed at least one alloantibody to Rh or Kell antigens. The alloimmunization rate at the institution with a PAM policy was 11% compared with 23% at non-PAM institutions (P = 0·06). The rate of Rh/K alloimmunization was 7 vs. 22%, respectively (P = 0·008). No patient who received PAM developed a Rh/K alloantibody. CONCLUSION: The rate of alloimmunization was 11% at an institution with a PAM policy which was non-significantly lower than 23% at institutions without a PAM policy. However, rates of Rh/K alloimmunization were significantly lower. Such a policy should be considered in transfusion-dependent patients with MDS, although further studies on cost-effectiveness and careful consideration of resource availability in the local context are required.

Detection of control or idle state with a likelihood ratio test in asynchronous SSVEP-based brain-computer interface systems.

We consider the detection of the control or idle state in an asynchronous Steady-state visually evoked potential (SSVEP)-based brain computer interface system. We propose a likelihood ratio test using Canonical Correlation Analysis (CCA) scores calculated from the EEG measurements. The test exploits the state-specific distributions of CCA scores. The algorithm was tested on offline measurements from 42 participants and the results should a significant improvement in detection error rate over the support vector machine classifier. The proposed test is also shown to be robust against training sample size.

Valproate reduces CHOP levels and preserves oligodendrocytes and axons after spinal cord injury.

Spinal cord injury (SCI) is a major cause of disability to which there are not yet effective treatments. We previously reported that degeneration of oligodendrocytes and neurons that occurs after SCI is associated with the development of endoplasmic reticulum (ER) stress and the progressive accumulation of the pro-apoptotic factor CHOP. Since following ER stress, the balance between the pro-survival chaperone BiP and CHOP drives the cell destiny, we aimed to find drugs that modulate this ratio in favour of the former. We found that valproate (VPA) induced a significant reduction of CHOP levels after ER stress in an organotypic-based culture of spinal cord in vitro. We then administered different doses of VPA to rats following spinal cord contusion, and found that the treatment caused a marked reduction of CHOP levels early after the lesion. In addition, VPA administration partially prevented cord tissue, myelin and axonal loss, and significantly increased the relative number of surviving oligodendrocytes in the damaged spinal cord. Besides, VPA-treated rats showed better recovery of the locomotor activity than vehicle-treated rats after SCI. Since VPA is a drug already in clinical use, these results open the avenue for its therapeutical use in SCI as well as in demyelinating disorders.

Estudio farmacocinético de la asociación atorvastatina 40 mg + ezetimibe 10 mg tabletas / I study farmacocinetico of the association of atorvastatina 40 mg ezetimibe of 10 mg tablets

Determinar la Biodisponibilidad en una dosis única, de Atorvastatina 40 mg + Ezetimibe 10 mg tabletas, con evaluación de los parámetros farmacocinéticos de concentración máxima en el organismo (C Máx), área bajo la curva de los niveles en el organismo (AUC 0→t y AUC 0 →∞)tiempo en alcanzar la concentración máxima (T Máx), tiempo de vida media (t 1/ 2) y constante de eliminación (Ke). El estudio de Biodisponibilidad se desarrolló mediante la determinación de la magnitud y la velocidad de la absorción “in vivo” de la asociación Atorvastatina 40 mg + Ezetimibe 10 mg tabletas, fabricadopor Laboratorios La Santé S.A, en voluntarios sanos. 12 voluntarios sanos, hombres y mujeres, con edades comprendidas entre los 18 y 55 años, con un peso de ± 15% del apropiado según la edad y la talla, que cumplieron a cabalidad con todos los exámenes clínicos efectuados antes del estudio para su selección y que no presentaron alguna anomalía en su historia médica, recibieron una dosis única de la asociación 40 mg de Atorvastatina + 10 mg de Ezetimibe tabletas, fabricado por Laboratorios La Santé S.A. vía oral con administración de 240 mL de agua. Después de su administración se tomaron muestras de sangre de cada voluntario a los siguientes tiempos: 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 36.0, 48.0 y 72.0 horas. El análisis de las muestras se realizó por Cromatografía Líquida de Alta Resolución (HPLC) con detección UV, previa extracción de los analitos (extracción líquido/líquido), en el Laboratorio bioanalítico de Delivery Technologies. La determinación de la magnitud y la velocidad de la absorción “in vivo” de Atorvastatina 40 mg + Ezetimibe 10 mg tabletas, se evaluó comparando con los parámetros farmacocinéticos ya reportados en estudios previos de estos principios activos por separados...

To determine the bioavailability in a single dose of Atorvastatin 40 mg + Ezetimibe 10 mg tablets, with assessment of pharmacokinetic parameters of maximum concentration body (C max), area under the curve of the levels in the organism (AUC 0 → t and AUC 0 → ∞), time to reach maximum concentration (T max), half-life (t 1 / 2) and elimination constant (Ke). The bioavailability study was conducted by  determining the magnitude and rate of absorption in vivo of the association Atorvastatin 40 mg + Ezetimibe 10 mg tablets manufactured by Laboratorios La Sante SA, in healthy volunteers. 12 healthy volunteers, men and women, aged between 18 and 55, with a weight of ± 15%  according to the age and size, which fully met  with all the clinical examinations performed prior to study and not presenting any anomaly in these tests, received a single dose of the association Atorvastatin 40 mg + Ezetimibe 10 mg tablets, manufactured by Laboratorios La Santé SA, with oral administration of 240 mL of water. After administration of the drug. blood samples were taken from each volunteer at the following times: 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 36.0, 48.0 and 72.0 hours. The sample analysis was performed by High Resolution liquid chromatography (HPLC) with UV detection after extraction of analytes (liquid-liquid extraction) in the bioanalytical laboratory of Delivery Technologies. The determination of the magnitude and absorption rate in vivo of Atorvastatin 40 mg + Ezetimibe 10 mg tablets, was evaluated by comparing with the Pharmacokinetic parameters reported in previous studies of these drug by separate. Adverse Events Report: In general, there were no serious adverse events during the course of this study. According to the results and considering the pharmacokinetic parameters reflecting the amount of Atorvastatin and Ezetimibe absorbed bythe body and the speed...

Selective sigma receptor agonist 2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate (PRE084) promotes neuroprotection and neurite elongation through protein kinase C (PKC) signaling on motoneurons.

Neuronal loss and interruption of axonal pathways are occurring after spinal cord injury. This is initiated by the mechanical damage and propagated by secondary events that include the fast rise of glutamate concentration and the subsequent over-activation of glutamate receptors, triggering noxious processes to the cell. Excitotoxic processes are also observed in degenerative diseases that involve motoneuron loss. Sigma-1 receptors (Sig-1Rs) are expressed in the CNS and their ligands have been shown to prevent neuronal death associated to glutamate toxicity. In the present study, we used organotypic cultures of spinal cord slices and dorsal root ganglia (DRG) explants from 7-8 days old postnatal rats to assess whether the agonist of the Sig-1R, 2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate (PRE084), protects the spinal cord against glutamate excitotoxicity and promotes neurite elongation. The results showed that PRE084 exerted a bell-shape dose-dependent protective response of the motoneurons, with a significant neuroprotection obtained with 10 microM PRE084. PRE084 also caused an increase in the length of neurites in both motoneurons and neurons in DRG explants. Both effects were abrogated with the addition of BD 1063, an antagonist of Sig-1R, and the use of chelerythrine, a protein kinase C (PKC) pan-inhibitor indicating that PKC is implicated in the observed effects. These results suggest the use of PRE084 as a neuroprotective agent for spinal cord damage.

Analysis of FK506-mediated protection in an organotypic model of spinal cord damage: heat shock protein 70 levels are modulated in microglial cells.

Functional loss after spinal cord injuries is originated by primary and secondary injury phases whose underlying mechanisms include massive release of excitatory amino acids to cytotoxic levels that contribute to neural death. Attenuation of this excitotoxicity is a key point for improving the functional outcome after injury. One of the drugs with potential neuroprotective actions is FK506, a molecule widely used as an immunosuppressant. FK506 may exert neuroprotection via inhibition of calcineurin by binding the FKBP12, or by binding other immunophilins such as FKBP52, leading to modulation of heat shock proteins (Hsp) 90 and 70. In the present study, we used an in vitro model of organotypic culture of rat spinal cord slices to assess whether FK506 is able to protect them against glutamate excitotoxicity. The results showed that FK506 promoted a significant protective effect on the spinal cord tissue at concentrations of 50 and 100 nM. Hsp70 induction was restricted to microglial cells in spinal cord slices treated with either glutamate or FK506. In contrast, the combination of both agents led to a transient reduction in Hsp70 levels in parallel to a marked reduction in IL-1beta precursor production by glial cells. The use of geldanamycin, which promotes persistent induction of Hsp70 in these cells as well as in motoneurons, did not produce tissue neuroprotection. These observations suggest that FK506 might protect spinal cord tissue by targeting on microglial cells and that transient downregulation of Hsp70 on these cells after excitotoxicity is a relevant mechanism of action of FK506.