The membrane-permeable calmodulin inhibitors (W-7/W-13) bind to membranes changing the electrostatic surface potential. Dual effect of W-13 on EGFR activation

Membrane-permeable calmodulin inhibitors, such as the napthalenesulfonamide derivatives W-7/W-13, trifluoperazine, and calmidazolium, are used widely to investigate the role of calcium/calmodulin (Ca2+/CaM) in living cells. If two chemically different inhibitors (e.g. W-7 and trifluoperazine) produce similar effects, investigators often assume the effects are due to CaM inhibition. Zeta potential measurements, however, show that these amphipathic weak bases bind to phospholipid vesicles at the same concentrations as they inhibit Ca 2 /CaM; this suggests that they also bind to the inner leaflet of the plasma membrane, reducing its negative electrostatic surface potential. This change will cause electrostatically bound clusters of basic residues on peripheral (e.g. Src and K-Ras4B) and integral (e.g. epidermal growth factor receptor (EGFR)) proteins to translocate from the membrane to the cytoplasm. We measured inhibitor-mediated translocation of a simple basic peptide corresponding to the calmodulin-binding juxtamembrane region of the EGFR on model membranes; W-7/W-13 causes translocation of this peptide from membrane to solution, suggesting that caution must be exercised when interpreting the results obtained with these inhibitors in living cells. We present evidence that they exert dual effects on autophosphorylation of EGFR;W-13 inhibits epidermal growth factordependent EGFR autophosphorylation under different experimental conditions, but in the absence of epidermal growth factor, W-13 stimulates autophosphorylation of the receptor in four different cell types. Our interpretation is that the former effect is due toW-13inhibition of Ca 2 /CaM, but thelatter results could be due to binding of W-13 to the plasma membrane.

Development of an instrument to measure the degree of critical patient's satisfaction with nursing care: research protocol

Aim: To investigate and understand patient's satisfaction with nursing care in the intensive care unit to identify the dimensions of the concept of"satisfaction" from the patient's point of view. To design and validate a questionnaire that measures satisfaction levels in critical patients. Background: There are many instruments capable of measuring satisfaction with nursing care; however, they do not address the reality for critical patients nor are they applicable in our context. Design: A dual approach study comprising: a qualitative phase employing Grounded Theory and a quantitative and descriptive phase to prepare and validate the questionnaire. Methods: Data collection in the qualitative phase will consist of: in-depth interview after theoretical sampling, on-site diary and expert discussion group. The sample size will depend on the expected theoretical saturation n = 27-36. Analysis will be based on Grounded Theory. For the quantitative phase, the sampling will be based on convenience (n = 200). A questionnaire will be designed on the basis of qualitative data. Descriptive and inferential statistics will be used. The validation will be developed on the basis of the validity of the content, the criteria of the construct and reliability of the instrument by the Cronbach's alpha and test-retest approach. Approval date for this protocol was November 2010. Discussion: Self-perceptions, beliefs, experiences, demographic, socio-cultural epistemological and political factors are determinants for satisfaction, and these should be taken into account when compiling a questionnaire on satisfaction with nursing care among critical patients.

Performance of mechanical ventilators at the patient's home: a multicentric quality control study

Background: Quality control procedures vary considerably among the providers of equipment for home mechanical ventilation (HMV). Methods: A multicentre quality control survey of HMV was performed at the home of 300 patients included in the HMV programmes of four hospitals in Barcelona. It consisted of three steps: (1) the prescribed ventilation settings, the actual settings in the ventilator control panel, and the actual performance of the ventilator measured at home were compared; (2) the different ventilator alarms were tested; and (3) the effect of differences between the prescribed settings and the actual performance of the ventilator on non-programmed readmissions of the patient was determined. Results: Considerable differences were found between actual, set, and prescribed values of ventilator variables; these differences were similar in volume and pressure preset ventilators. The percentage of patients with a discrepancy between the prescribed and actual measured main ventilator variable (minute ventilation or inspiratory pressure) of more than 20% and 30% was 13% and 4%, respectively. The number of ventilators with built in alarms for power off, disconnection, or obstruction was 225, 280 and 157, respectively. These alarms did not work in two (0.9%), 52 (18.6%) and eight (5.1%) ventilators, respectively. The number of non-programmed hospital readmissions in the year before the study did not correlate with the index of ventilator error. Conclusions: This study illustrates the current limitations of the quality control of HMV and suggests that improvements should be made to ensure adequate ventilator settings and correct ventilator performance and ventilator alarm operation.

Psychometric characteristics of the Spanish version of instruments to measure neck pain disability

Background: The NDI, COM and NPQ are evaluation instruments for disability due to NP. There was no Spanish version of NDI or COM for which psychometric characteristics were known. The objectives of this study were to translate and culturally adapt the Spanish version of the Neck Disability Index Questionnaire (NDI), and the Core Outcome Measure (COM), to validate its use in Spanish speaking patients with non-specific neck pain (NP), and to compare their psychometric characteristics with those of the Spanish version of the Northwick Pain Questionnaire (NPQ).Methods: Translation/re-translation of the English versions of the NDI and the COM was done blindly and independently by a multidisciplinary team. The study was done in 9 primary care Centers and 12 specialty services from 9 regions in Spain, with 221 acute, subacute and chronic patients who visited their physician for NP: 54 in the pilot phase and 167 in the validation phase. Neck pain (VAS), referred pain (VAS), disability (NDI, COM and NPQ), catastrophizing (CSQ) and quality of life (SF-12) were measured on their first visit and 14 days later. Patients' self-assessment was used as the external criterion for pain and disability. In the pilot phase, patients' understanding of each item in the NDI and COM was assessed, and on day 1 test-retest reliability was estimated by giving a second NDI and COM in which the name of the questionnaires and the order of the items had been changed.Results: Comprehensibility of NDI and COM were good. Minutes needed to fill out the questionnaires [median, (P25, P75)]: NDI. 4 (2.2, 10.0), COM: 2.1 (1.0, 4.9). Reliability: [ICC, (95%CI)]: NDI: 0.88 (0.80, 0.93). COM: 0.85 (0.75,0.91). Sensitivity to change: Effect size for patients having worsened, not changed and improved between days 1 and 15, according to the external criterion for disability: NDI: -0.24, 0.15, 0.66; NPQ: -0.14, 0.06, 0.67; COM: 0.05, 0.19, 0.92. Validity: Results of NDI, NPQ and COM were consistent with the external criterion for disability, whereas only those from NDI were consistent with the one for pain. Correlations with VAS, CSQ and SF-12 were similar for NDI and NPQ (absolute values between 0.36 and 0.50 on day 1, between 0.38 and 0.70 on day 15), and slightly lower for COM (between 0.36 and 0.48 on day 1, and between 0.33 and 0.61 on day 15). Correlation between NDI and NPQ: r = 0.84 on day 1, r = 0.91 on day 15. Correlation between COM and NPQ: r = 0.63 on day 1, r = 0.71 on day 15.Conclusion: Although most psychometric characteristics of NDI, NPQ and COM are similar, those from the latter one are worse and its use may lead to patients' evolution seeming more positive than it actually is. NDI seems to be the best instrument for measuring NP-related disability, since its results are the most consistent with patient's assessment of their own clinical status and evolution. It takes two more minutes to answer the NDI than to answer the COM, but it can be reliably filled out by the patient without assistance.

Creation and Validation of Chronojump-Boscosystem: A Free Tool to Measure Vertical Jumps

Measuring the height of the vertical jump is an indicator of the strength and power of the lower body. The technological tools available to measure the vertical jump are black boxes and are not open to third-party verification or adaptation. We propose the creation of a measurement system called Chronojump-Boscosystem, consisting of open hardware and free software. Methods: A microcontroller was created and validated using a square wave generator and an oscilloscope. Two types of contact platforms were developed using different materials. These platforms were validated by the minimum pressure required for activation at different points by a strain gauge, together with the on/off time of our platforms in respect of the Ergojump-Boscosystem platform by a sample of 8 subjects performing submaximal jumps with one foot on each platform. Agile methodologies were used to develop and validate the software. Results: All the tools fall under the free software / open hardware guidelines and are, in that sense, free. The microcontroller margin of error is 0.1%. The validity of the fiberglass platform is 0.95 (ICC). The management software contains nearly 113.000 lines of code and is available in 7 languages.

A Threat to a Virtual Hand Elicits Motor Cortex Activation

We report an experiment where participants observed an attack on their virtual body as experienced in an immersive virtual reality (IVR) system. Participants sat by a table with their right hand resting upon it. In IVR, they saw a virtual table that was registered with the real one, and they had a virtual body that substituted their real body seen from a first person perspective. The virtual right hand was collocated with their real right hand. Event-related brain potentials were recorded in two conditions, one where the participant"s virtual hand was attacked with a knife and a control condition where the knife only struck the virtual table. Significantly greater P450 potentials were obtained in the attack condition confirming our expectations that participants had a strong illusion of the virtual hand being their own, which was also strongly supported by questionnaire responses. Higher levels of subjective virtual hand ownership correlated with larger P450 amplitudes. Mu-rhythm event-related desynchronization in the motor cortex and readiness potential (C3C4) negativity were clearly observed when the virtual hand was threatened as would be expected, if the real hand was threatened and the participant tried to avoid harm. Our results support the idea that event-related potentials may provide a promising non-subjective measure of virtual embodiment. They also support previous experiments on pain observation and are placed into context of similar experiments and studies of body perception and body ownership within cognitive neuroscience.

Patient with hepatocellular carcinoma related to prior acute arsenic intoxication and occult HBV: epidemiological, clinical and therapeutic results after 14 years of follow-up

Little is known about the long-term survivors of acute arsenic intoxication. We present here a clinical case report of a man with chronic hepatitis B virus (HBV) infection who developed hepatocellular carcinoma four years after acute arsenic poisoning. HBsAg was detected in serum in 1990 when he voluntarily donated blood. In 1991, the patient suffered from severe psychological depression that led him to attempt suicide by massive ingestion of an arsenic-containing rodenticide. He survived with polyneuropathy and paralysis of the lower limbs, and has been wheelchair-bound since then. During participation in a follow-up study conducted among HBV carriers, abdominal ultrasound detected a two-centimeter liver mass consistent with hepatocellular carcinoma. The tumor was confirmed by computed tomography (CT) and magnetic resonance image (MRI). Because of his significant comorbidity, the patient received palliative treatment with transarterial lipiodol chemoembolization (TACE) on three occasions (1996, 1997 and 1999). At his most recent visit in May 2005, the patient was asymptomatic, liver enzymes were normal and the tumor was in remission on ultrasound.

Effect of temperature and moisture on the dormancy and activation pattern of Oxalis latifolia bulbs

Con objeto de buscar información para un mejor control de Oxalis latifolia Kunth, se ha estudiado el efecto que presentan la temperatura y la humedad sobre la activación de sus bulbos, tanto en la forma común como en la forma Cornwall de la misma. Los bulbos de la mala hierba se mantuvieron en un refrigerador a +4°C durante 13, 20, 27, 41, 48 y 55 días. Se sacaron tres grupos de 30 bulbos de cada forma en cada fecha de muestreo y se colocaron a 21°C; 15 de ellos se mantuvieron en condiciones de sequía —no se regaron— y otros 15 en condiciones de humedad —añadiendo el agua necesaria—. Los resultados muestran que la activación ocurre durante un período prolongado de tiempo en ambas formas, tanto en seco como en húmedo. También se observó que los bulbos secos se activaron antes que los húmedos y los de la forma común antes que los Cornwall. Se observaron dos patrones de activación: los bulbos secos de la forma común generalmente presentaron una activación que sigue un patrón logarítmico, mientras que sus bulbos humedecidos mostraron una tendencia linear; los bulbos Cornwall se activaron con una tendencia exponencial en la mayoría de los casos. El tiempo medio requerido para la activación después del almacenamiento en frío fue constante en la forma común, sin embargo la activación de Cornwall fue más rápida cuanto más tiempo permanecieron almacenados en frío.

Activation of p53 by nutlin-3a induces apoptosis and cellular senescence in human glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults. Despite concerted efforts to improve current therapies and develop novel clinical approaches, patient survival remains poor. As such, increasing attention has focused on developing new therapeutic strategies that specifically target the apoptotic pathway in order to improve treatment responses. Recently, nutlins, small-molecule antagonists of MDM2, have been developed to inhibit p53-MDM2 interaction and activate p53 signaling in cancer cells. Glioma cell lines and primary cultured glioblastoma cells were treated with nutlin-3a. Nutlin-3a induced p53-dependent G1- and G2-M cell cycle arrest and apoptosis in glioma cell lines with normal TP53 status. In addition, nutlin-arrested glioma cells show morphological features of senescence and persistent induction of p21 protein. Furthermore, senescence induced by nutlin-3a might be depending on mTOR pathway activity. In wild-type TP53 primary cultured cells, exposure to nutlin-3a resulted in variable degrees of apoptosis as well as cellular features of senescence. Nutlin-3a-induced apoptosis and senescence were firmly dependent on the presence of functional p53, as revealed by the fact that glioblastoma cells with knockdown p53 with specific siRNA, or cells with mutated or functionally impaired p53 pathway, were completely insensitive to the drug. Finally, we also found that nutlin-3a increased response of glioma cells to radiation therapy. The results provide a basis for the rational use of MDM2 antagonists as a novel treatment option for glioblastoma patients.

Activation of p53 by nutlin-3a induces apoptosis and cellular senescence in human glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults. Despite concerted efforts to improve current therapies and develop novel clinical approaches, patient survival remains poor. As such, increasing attention has focused on developing new therapeutic strategies that specifically target the apoptotic pathway in order to improve treatment responses. Recently, nutlins, small-molecule antagonists of MDM2, have been developed to inhibit p53-MDM2 interaction and activate p53 signaling in cancer cells. Glioma cell lines and primary cultured glioblastoma cells were treated with nutlin-3a. Nutlin-3a induced p53-dependent G1- and G2-M cell cycle arrest and apoptosis in glioma cell lines with normal TP53 status. In addition, nutlin-arrested glioma cells show morphological features of senescence and persistent induction of p21 protein. Furthermore, senescence induced by nutlin-3a might be depending on mTOR pathway activity. In wild-type TP53 primary cultured cells, exposure to nutlin-3a resulted in variable degrees of apoptosis as well as cellular features of senescence. Nutlin-3a-induced apoptosis and senescence were firmly dependent on the presence of functional p53, as revealed by the fact that glioblastoma cells with knockdown p53 with specific siRNA, or cells with mutated or functionally impaired p53 pathway, were completely insensitive to the drug. Finally, we also found that nutlin-3a increased response of glioma cells to radiation therapy. The results provide a basis for the rational use of MDM2 antagonists as a novel treatment option for glioblastoma patients.

A Threat to a virtual hand elicits motor cortex activation

We report an experiment where participants observed an attack on their virtual body as experienced in an immersive virtual reality (IVR) system. Participants sat by a table with their right hand resting upon it. In IVR, they saw a virtual table that was registered with the real one, and they had a virtual body that substituted their real body seen from a first person perspective. The virtual right hand was collocated with their real right hand. Event-related brain potentials were recorded in two conditions, one where the participant"s virtual hand was attacked with a knife and a control condition where the knife only struck the virtual table. Significantly greater P450 potentials were obtained in the attack condition confirming our expectations that participants had a strong illusion of the virtual hand being their own, which was also strongly supported by questionnaire responses. Higher levels of subjective virtual hand ownership correlated with larger P450 amplitudes. Mu-rhythm event-related desynchronization in the motor cortex and readiness potential (C3-C4) negativity were clearly observed when the virtual hand was threatened as would be expected, if the real hand was threatened and the participant tried to avoid harm. Our results support the idea that event-related potentials may provide a promising non-subjective measure of virtual embodiment. They also support previous experiments on pain observation and are placed into context of similar experiments and studies of body perception and body ownership within cognitive neuroscience.

A Threat to a virtual hand elicits motor cortex activation

We report an experiment where participants observed an attack on their virtual body as experienced in an immersive virtual reality (IVR) system. Participants sat by a table with their right hand resting upon it. In IVR, they saw a virtual table that was registered with the real one, and they had a virtual body that substituted their real body seen from a first person perspective. The virtual right hand was collocated with their real right hand. Event-related brain potentials were recorded in two conditions, one where the participant"s virtual hand was attacked with a knife and a control condition where the knife only struck the virtual table. Significantly greater P450 potentials were obtained in the attack condition confirming our expectations that participants had a strong illusion of the virtual hand being their own, which was also strongly supported by questionnaire responses. Higher levels of subjective virtual hand ownership correlated with larger P450 amplitudes. Mu-rhythm event-related desynchronization in the motor cortex and readiness potential (C3-C4) negativity were clearly observed when the virtual hand was threatened as would be expected, if the real hand was threatened and the participant tried to avoid harm. Our results support the idea that event-related potentials may provide a promising non-subjective measure of virtual embodiment. They also support previous experiments on pain observation and are placed into context of similar experiments and studies of body perception and body ownership within cognitive neuroscience.

Estimation of lung cancer diagnosis and treatment costs based on a patient-level analysis in Catalonia (Spain)

Background: Assessing of the costs of treating disease is necessary to demonstrate cost-effectiveness and to estimate the budget impact of new interventions and therapeutic innovations. However, there are few comprehensive studies on resource use and costs associated with lung cancer patients in clinical practice in Spain or internationally. The aim of this paper was to assess the hospital cost associated with lung cancer diagnosis and treatment by histology, type of cost and stage at diagnosis in the Spanish National Health Service. Methods: A retrospective, descriptive analysis on resource use and a direct medical cost analysis were performed. Resource utilisation data were collected by means of patient files from nine teaching hospitals. From a hospital budget impact perspective, the aggregate and mean costs per patient were calculated over the first three years following diagnosis or up to death. Both aggregate and mean costs per patient were analysed by histology, stage at diagnosis and cost type. Results: A total of 232 cases of lung cancer were analysed, of which 74.1% corresponded to non-small cell lung cancer (NSCLC) and 11.2% to small cell lung cancer (SCLC); 14.7% had no cytohistologic confirmation. The mean cost per patient in NSCLC ranged from 13,218 Euros in Stage III to 16,120 Euros in Stage II. The main cost components were chemotherapy (29.5%) and surgery (22.8%). Advanced disease stages were associated with a decrease in the relative weight of surgical and inpatient care costs but an increase in chemotherapy costs. In SCLC patients, the mean cost per patient was 15,418 Euros for limited disease and 12,482 Euros for extensive disease. The main cost components were chemotherapy (36.1%) and other inpatient costs (28.7%). In both groups, the Kruskall-Wallis test did not show statistically significant differences in mean cost per patient between stages. Conclusions: This study provides the costs of lung cancer treatment based on patient file reviews, with chemotherapy and surgery accounting for the major components of costs. This cost analysis is a baseline study that will provide a useful source of information for future studies on cost-effectiveness and on the budget impact of different therapeutic innovations in Spain.