Histology-driven data mining of lipid signatures from multiple imaging mass spectrometry analyses: application to human colorectal cancer liver metastasis biopsies.

Imaging mass spectrometry (IMS) represents an innovative tool in the cancer research pipeline, which is increasingly being used in clinical and pharmaceutical applications. The unique properties of the technique, especially the amount of data generated, make the handling of data from multiple IMS acquisitions challenging. This work presents a histology-driven IMS approach aiming to identify discriminant lipid signatures from the simultaneous mining of IMS data sets from multiple samples. The feasibility of the developed workflow is evaluated on a set of three human colorectal cancer liver metastasis (CRCLM) tissue sections. Lipid IMS on tissue sections was performed using MALDI-TOF/TOF MS in both negative and positive ionization modes after 1,5-diaminonaphthalene matrix deposition by sublimation. The combination of both positive and negative acquisition results was performed during data mining to simplify the process and interrogate a larger lipidome into a single analysis. To reduce the complexity of the IMS data sets, a sub data set was generated by randomly selecting a fixed number of spectra from a histologically defined region of interest, resulting in a 10-fold data reduction. Principal component analysis confirmed that the molecular selectivity of the regions of interest is maintained after data reduction. Partial least-squares and heat map analyses demonstrated a selective signature of the CRCLM, revealing lipids that are significantly up- and down-regulated in the tumor region. This comprehensive approach is thus of interest for defining disease signatures directly from IMS data sets by the use of combinatory data mining, opening novel routes of investigation for addressing the demands of the clinical setting.

Predictive ability of an early diagnostic guess in patients presenting with chest pain; a longitudinal descriptive study.

ABSTRACT: BACKGROUND: The intuitive early diagnostic guess could play an important role in reaching a final diagnosis. However, no study to date has attempted to quantify the importance of general practitioners' (GPs) ability to correctly appraise the origin of chest pain within the first minutes of an encounter. METHODS: The validation study was nested in a multicentre cohort study with a one year follow-up and included 626 successive patients who presented with chest pain and were attended by 58 GPs in Western Switzerland. The early diagnostic guess was assessed prior to a patient's history being taken by a GP and was then compared to a diagnosis of chest pain observed over the next year. RESULTS: Using summary measures clustered at the GP's level, the early diagnostic guess was confirmed by further investigation in 51.0% (CI 95%; 49.4% to 52.5%) of patients presenting with chest pain. The early diagnostic guess was more accurate in patients with a life threatening illness (65.4%; CI 95% 64.5% to 66.3%) and in patients who did not feel anxious (62.9%; CI 95% 62.5% to 63.3%). The predictive abilities of an early diagnostic guess were consistent among GPs. CONCLUSIONS: The GPs early diagnostic guess was correct in one out of two patients presenting with chest pain. The probability of a correct guess was higher in patients with a life-threatening illness and in patients not feeling anxious about their pain.

PigCampa : Portal web de comunicació i col·laboració amb un entorn intranet de gestió del coneixement per a Associacions de Mares i Pares d'Alumnes

Aquest projecte aborda la qüestió d'implementar i implantar un sistema informàtic general i homogeni, que faciliti la gestió del coneixement, per a Associacions de Mares i Pares d'Alumnes (AMPA), des d'una aproximació a la seva modelització organitzacional.

Responsiveness of the Multiple Sclerosis International Quality of Life questionnaire to disability change: a longitudinal study.

BACKGROUND Responsiveness, defined as the ability to detect a meaningful change, is a core psychometric property of an instrument measuring quality of life (QoL) rarely reported in multiple sclerosis (MS) studies. OBJECTIVE To assess the responsiveness of the Multiple Sclerosis International Quality of Life (MusiQoL) questionnaire to change in disability over 24 months, defined by change in the Expanded Disability Status Scale (EDSS) score. METHODS Patients with MS were enrolled into a multicenter, longitudinal observational study. QoL was assessed using both the MusiQoL and the 36-Item Short-Form (SF-36) instruments at baseline and every 6 months thereafter up to month 24; neurological assessments, including EDSS score, were performed at each evaluation. RESULTS The 24-month EDSS was available for 524 patients. In the 107 worsened patients, two specific dimensions of MusiQoL, the sentimental and sexual life and the relationships with health care system dimensions, and 'physical' scores of SF-36 showed responsiveness. CONCLUSIONS Whereas specific dimensions of MusiQoL identified EDSS changes, the MusiQoL index did not detect disability changes in worsened MS patients in a 24-month observational study. Future responsiveness validation studies should include longer follow-up and more representative samples.

Cost-effectiveness of full-course oral levofloxacin in severe community-acquired pneumonia.

Oral levofloxacin is as efficient as sequential antibiotic treatment in community-acquired pneumonia (CAP). The current authors assessed whether oral levofloxacin treatment of patients with severe CAP, followed-up for 30 days, would save money. Over a 12-month period, 129 hospitalised patients with severe non-intensive care unit CAP were randomly assigned to receive either oral levofloxacin or sequential antibiotic treatment. Direct and indirect costs were compared over a 30-day period from several perspectives. CAP resolved in 71 out of 77 oral levofloxacin (92%) and in 34 out of 37 sequential antibiotic treatment patients (92%). Patients' characteristics, treatment duration, hospital length of stay and mortality were similar in both groups. Drug acquisition costs were 1.7-times smaller in oral levofloxacin patients, who were less often transferred to rehabilitation centres, but they used more physicians' visits during follow-up and their total costs were lower. As only a minority of patients was still active, inability to work and, hence, indirect costs were similar in both groups. In this study, oral levofloxacin for severe non-intensive care unit community-acquired pneumonia was equally effective as sequential antibiotic treatment, but did not lead to major costs savings except for drug acquisition costs. External factors linked with patients' characteristics and/or medical practice are likely to play a role and should be addressed.

Minimization of calcineurin inhibitors to improve long-term outcomes in kidney transplantation.

Long-term outcomes after kidney transplantation remain suboptimal, despite the great achievements observed in recent years with the use of modern immunosuppressive drugs. Currently, the calcineurin inhibitors (CNI) cyclosporine and tacrolimus remain the cornerstones of immunosuppressive regimens in many centers worldwide, regardless of their well described side-effects, including nephrotoxicity. In this article, we review recent CNI-minimization strategies in kidney transplantation, while emphasizing on the importance of long-term follow-up and patient monitoring. Finally, accumulating data indicate that low-dose CNI-based regimens would provide an interesting balance between efficacy and toxicity.

The succession process at social enterprises in Brazil

This research was based on a study of social enterprises in Brazil, to find out if and how these organizations plan and manage the succession process for their senior positions. The study investigated the subset of the associations dedicated to collectively producing goods and services, because they are formally set up and aimed at speeding up the dynamism of local development. The empirical research consisted of two stages. The first was a survey covering a sample of 378 organizations, to find out which of those had already undergone or were undergoing a succession process. The second interviewed the main manager of 32 organizations, to obtain a description of their succession experience. In this stage, the research aimed to analyze how the Individual, Organization and Environment dimensions interact to configure the succession process, identifying which factors of each of these dimensions can facilitate or limit this process. The following guiding elements were taken as the analytical basis: Individual dimension - leadership roles, skill and styles; Organization dimension - structure, planning, advisory boards, communication (transparency), control and evaluation; and Environment dimension - influence of the stakeholders (community, suppliers, clients, and business partners) on the succession process. The results indicated that succession in the researched associations is in the construction stage: it adapts to the requirements of current circumstances but is evidently in need of improvement in order for more effective planning and shared management of the process to be achieved.

Implementation of zonal control algorithms in adaptive optical systems with sparse control matrices

Miralls deformables més i més grans, amb cada cop més actuadors estan sent utilitzats actualment en aplicacions d'òptica adaptativa. El control dels miralls amb centenars d'actuadors és un tema de gran interès, ja que les tècniques de control clàssiques basades en la seudoinversa de la matriu de control del sistema es tornen massa lentes quan es tracta de matrius de dimensions tan grans. En aquesta tesi doctoral es proposa un mètode per l'acceleració i la paral.lelitzacó dels algoritmes de control d'aquests miralls, a través de l'aplicació d'una tècnica de control basada en la reducció a zero del components més petits de la matriu de control (sparsification), seguida de l'optimització de l'ordenació dels accionadors de comandament atenent d'acord a la forma de la matriu, i finalment de la seva posterior divisió en petits blocs tridiagonals. Aquests blocs són molt més petits i més fàcils de fer servir en els càlculs, el que permet velocitats de càlcul molt superiors per l'eliminació dels components nuls en la matriu de control. A més, aquest enfocament permet la paral.lelització del càlcul, donant una com0onent de velocitat addicional al sistema. Fins i tot sense paral. lelització, s'ha obtingut un augment de gairebé un 40% de la velocitat de convergència dels miralls amb només 37 actuadors, mitjançant la tècnica proposada. Per validar això, s'ha implementat un muntatge experimental nou complet , que inclou un modulador de fase programable per a la generació de turbulència mitjançant pantalles de fase, i s'ha desenvolupat un model complert del bucle de control per investigar el rendiment de l'algorisme proposat. Els resultats, tant en la simulació com experimentalment, mostren l'equivalència total en els valors de desviació després de la compensació dels diferents tipus d'aberracions per als diferents algoritmes utilitzats, encara que el mètode proposat aquí permet una càrrega computacional molt menor. El procediment s'espera que sigui molt exitós quan s'aplica a miralls molt grans.

Absence of the fourth cranial nerve in congenital Brown syndrome.

PURPOSE: To elucidate the aetiology of congenital Brown syndrome. METHODS: Four consecutive patients diagnosed with unilateral congenital Brown syndrome had a comprehensive standardized ocular motility examination. Any compensatory head posture was measured. Brain magnetic resonance imaging (MRI) with regard for the IV cranial nerve (CN) was performed in all patients. Orbital MRI was performed in 2/4 patients, with images acquired in eight directions of gaze and superior oblique (SO) muscle areas compared. RESULTS: CN IV could not be identified bilaterally in two patients, but was absent only on the side of the Brown syndrome in the two other patients. On the normal side, orbital MRI revealed a smaller SO muscle area in upgaze than in downgaze, demonstrating normal actions of this muscle. On the side of the Brown syndrome, the SO area remained the same in upgaze and in downgaze and approximately symmetric to the area of SO in downgaze on the normal side. CONCLUSIONS: These cases add further anatomical support to the theory of paradoxical innervation in congenital Brown syndrome. CN IV was absent in two patients on the side of the Brown syndrome, but without muscle hypoplasia. SO muscle size did not vary in up- and downgaze, which we interpreted as a sign of constant innervation through branches of CN III.

Image quality assessment in digital mammography: part I. Technical characterization of the systems.

In many European countries, image quality for digital x-ray systems used in screening mammography is currently specified using a threshold-detail detectability method. This is a two-part study that proposes an alternative method based on calculated detectability for a model observer: the first part of the work presents a characterization of the systems. Eleven digital mammography systems were included in the study; four computed radiography (CR) systems, and a group of seven digital radiography (DR) detectors, composed of three amorphous selenium-based detectors, three caesium iodide scintillator systems and a silicon wafer-based photon counting system. The technical parameters assessed included the system response curve, detector uniformity error, pre-sampling modulation transfer function (MTF), normalized noise power spectrum (NNPS) and detective quantum efficiency (DQE). Approximate quantum noise limited exposure range was examined using a separation of noise sources based upon standard deviation. Noise separation showed that electronic noise was the dominant noise at low detector air kerma for three systems; the remaining systems showed quantum noise limited behaviour between 12.5 and 380 µGy. Greater variation in detector MTF was found for the DR group compared to the CR systems; MTF at 5 mm(-1) varied from 0.08 to 0.23 for the CR detectors against a range of 0.16-0.64 for the DR units. The needle CR detector had a higher MTF, lower NNPS and higher DQE at 5 mm(-1) than the powder CR phosphors. DQE at 5 mm(-1) ranged from 0.02 to 0.20 for the CR systems, while DQE at 5 mm(-1) for the DR group ranged from 0.04 to 0.41, indicating higher DQE for the DR detectors and needle CR system than for the powder CR phosphor systems. The technical evaluation section of the study showed that the digital mammography systems were well set up and exhibiting typical performance for the detector technology employed in the respective systems.

Esfingolipids i senyal•lització cel.lular: l'(E)-2-hexadecenal com a possible lípid bioactiu

L’esfingosina-1-fosfat (S1P) és un lípid bioactiu amb funcions crucials en la biologia cel•lular. Entre aquestes, la seva activitat mitogènica i citoprotectora són les més estudiades. L’S1P és catabolitzada intracel•lularment mitjançant l’esfingosina-1-fosfat liasa (SGPL1) per generar (E)-2-hexadecenal i fosforiletanolamina. L’objectiu d’aquest projecte és explorar si l’(E)-2-hexadecenal és realment un catabòlit innocu o bé si, pel seu caràcter acceptor de Michael, és capaç de reaccionar amb pèptids o proteïnes específics. Aquesta interacció podria traduïr-se en funcions biològiques determinades, algunes de les quals són possiblement atribuïdes a l’esfingosina-1-fosfat com a tal. Per poder explorar el potencials adductes proteïcs amb l’aldehid, s’han emprat, sobre cèl•lules HeLa que sobreexpressen SGPL1, sondes anàlegs a esfingosina i esfinganina (i els seus derivats fosforil•lats) que presenten una funció azida en la posició omega de la cadena esfingoide. Aquestes, mitjançant química click sense coure, s’han fet reaccionar amb una molècula que presenta un dibenzociclooctí unit a biotina DBCObiotina). Després d’aïllar les proteïnes així biotinilades amb una reïna d’estreptavidina, aquestes es van separar per electroforesi. Les bandes proteïques observades es van extreure del gel i es van digerir amb tripsina, per posteriorment analitzar els pèptids per MALDI-TOF, el que permetria l’identificació de proteïnes a partir de “peptide mass fingerprinting”. Lamentablement, a la fi d’aquest contracte, encara no s’ha pogut identificar cap proteïna que s’uneixi a l’aldehid alliberat per la reacció de l’esfingosina-1- fosfat liasa. No obstant, durant aquest temps s’ha millorat el mètode per detectar aquests adductes proteïcs. Per això, si la recerca continua en aquesta línia, properament es podria saber amb certesa si existeixen o no aquestes interaccions covalents entre determinades proteïnes i l’(E)-2-hexadecenal.

Reversed shoulder arthroplasty baseplate fixed according to the three major columns principle

Introduction: Glenoid bone volume and bone quality can render the fixation of a reversed shoulder arthroplasty (RSA) basis plate hazardous. Cadaveric study at our institution has demonstrated that optimal baseplate fixation could be achieved with screws in three major columns. Our aim is to review our early rate of aseptic glenoid loosening in a series of baseplates fixed according to this principle. Methods: Between 2005 and 2008, 48 consecutive RSA (Reversed Aequalis) were implanted in 48 patients with an average age of 74.4 years (range, 56 to 86 years). There were 37 women and 11 men. Twenty-seven primary RSAs were performed for cuff tear arthropathy, 3 after failed rotator cuff surgery, 6 for failed arthroplasties, 7 for acute fractures and 5 after failed ORIF. All baseplate fixations were done using a nonlocking posterior screw in the scapular spine, a nonlocking anterior screw in the glenoid body, a locking superior screw in the coracoid and a locking inferior screw in the pillar. All patients were reviewed with standardized radiographs. We reported the positions of the screws in relation to the scapular spine and the coracoid process in two different views. We defined screw positions as totally, partially or out of the target. Finally, we reported aseptic glenoid loosening which was defined as implant subsidence. Results: Four patients were lost to follow-up. Thus 44 shoulders could be reviewed after a mean follow-up of 16 months (range, 9 to 32 months). Thirty-seven (84%) screws were either partially or totally in the spine. Thus, 7 (16%) scapular spine screws were out of the target. No coracoid screw was out of the target. At final follow-up control, we reported no glenoid loosening. Conclusion: Early glenoid loosening occurred before the two years follow-up and is most of time related to technical problems and/or insufficient glenoid bone stock and bone quality. Our study demonstrate that baseplate fixation of a RSA according to the three columns principle is a reproducible technique and a valuable way to prevent early glenoid loosening.

Brain energetics (thought needs food).

PURPOSE OF REVIEW: Almost 15 years after its initial proposal, the astrocyte-neuron lactate shuttle hypothesis still occupies the center stage in research on brain energetics. Recent developments have provided further evidence for its validity and have extended its application to different areas of neuroscience. RECENT FINDINGS: Description of cell-specific metabolic characteristics have reinforced the view that a prominent conversion of glucose into lactate takes place in astrocytes, whereas neurons preferentially take up and oxidize lactate over glucose-derived pyruvate. Indeed, specific mechanisms are activated by glutamatergic activity to favor such a net lactate transfer between the two cell types. Moreover, demonstration in vivo of the existence and implication of the astrocyte-neuron lactate shuttle hypothesis for particular neurophysiological processes is beginning to appear. SUMMARY: Brain energetics has undertaken its revolution. A new concept based on metabolic compartmentalization between astrocytes and neurons is establishing itself as the leading paradigm that opens new perspectives in areas such as functional brain imaging and regulation of energy homeostasis.

Pitfalls to Avoid when Measuring Institutions: Is 'Doing Business' Damaging Business?

Over recent years, both governments and international aid organizations have been devoting large amounts of resources to "simplifying" the procedures for setting up and formalizing firms. Many of these actions have focused on reducing the initial costs of setting up the firm, disregarding the more important role of business registers as a source of reliable information for judges, government departments and, above all, other firms. This reliable information is essential for reducing transaction costs in future dealings with all sorts of economic agents, both public and private. The priorities of reform policies should therefore be thoroughly reviewed, stressing the value of the legal institutions rather than trivializing them as is often the case.

Clinical consequences of imatinib plasma concentrations variability in hemato-oncologic patients

Background: Imatinib has revolutionized the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST). Considering the large inter-individual differences in the function of the systems involved in its disposition, exposure to imatinib can be expected to vary widely among patients. This observational study aimed at describing imatinib pharmacokinetic variability and its relationship with various biological covariates, especially plasma alpha1-acid glycoprotein (AGP), and at exploring the concentration-response relationship in patients. Methods: A population pharmacokinetic model (NONMEM) including 321 plasma samples from 59 patients was built up and used to derive individual post-hoc Bayesian estimates of drug exposure (AUC; area under curve). Associations between AUC and therapeutic response or tolerability were explored by ordered logistic regression. Influence of the target genotype (i.e. KIT mutation profile) on response was also assessed in GIST patients. Results: A one-compartment model with first-order absorption appropriately described the data, with an average oral clearance of 14.3 L/h (CL) and volume of distribution of 347 L (Vd). A large inter-individual variability remained unexplained, both on CL (36%) and Vd (63%), but AGP levels proved to have a marked impact on total imatinib disposition. Moreover, both total and free AUC correlated with the occurrence and number of side effects (e.g. OR 2.9±0.6 for a 2-fold free AUC increase; p<0.001). Furthermore, in GIST patients, higher free AUC predicted a higher probability of therapeutic response (OR 1.9±0.5; p<0.05), notably in patients with tumor harboring an exon 9 mutation or wild-type KIT, known to decrease tumor sensitivity towards imatinib. Conclusion: The large pharmacokinetic variability, associated to the pharmacokinetic-pharmacodynamic relationship uncovered are arguments to further investigate the usefulness of individualizing imatinib prescription based on TDM. For this type of drug, it should ideally take into consideration either circulating AGP concentrations or free drug levels, as well as KIT genotype for GIST.