Integrating novel agents into multiple myeloma treatment - current status in Switzerland and treatment recommendations.

The treatment of multiple myeloma has undergone significant changes in the recent past. The arrival of novel agents, especially thalidomide, bortezomib and lenalidomide, has expanded treatment options and patient outcomes are improving significantly. This article summarises the discussions of an expert meeting which was held to debate current treatment practices for multiple myeloma in Switzerland concerning the role of the novel agents and to provide recommendations for their use in different treatment stages based on currently available clinical data. Novel agent combinations for the treatment of newly diagnosed, as well as relapsed multiple myeloma are examined. In addition, the role of novel agents in patients with cytogenetic abnormalities and renal impairment, as well as the management of the most frequent side effects of the novel agents are discussed. The aim of this article is to assist in treatment decisions in daily clinical practice to achieve the best possible outcome for patients with multiple myeloma.

Nitric oxide activity through guanylate cyclase and phosphodiesterase modulation is impaired in fetal lambs with congenital diaphragmatic hernia.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is associated with pulmonary hypertension and death. Administration of nitric oxide (NO) alone remains ineffective in CDH cases. We investigated in near full-term lambs with and without CDH the role of guanylate cyclase (GC), the enzyme activated by NO in increasing cyclic 3'-5'-guanylosine monophosphate, and the role of phosphodiesterase (PDE) 5, the enzyme-degrading cyclic 3'-5'-guanylosine monophosphate. METHODS: Congenital diaphragmatic hernia was surgically created in fetal lambs at 85 days of gestation. Pulmonary hemodynamics were assessed by means of pressure and blood flow catheters (135 days). In vitro, we tested drugs on rings of isolated pulmonary vessels. RESULTS: In vivo, sodium nitroprusside, a direct NO donor, and methyl-2(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5 trimethoxyphenyl)-3-isoquinoline carboxylate sulfate (T-1032) and Zaprinast, both PDE 5 blockers, reduced pulmonary vascular resistance in CDH and non-CDH animals. The activation of GC by sodium nitroprusside and the inhibition of PDE 5 by T-1032 were less effective in CDH animals. In vitro, the stimulation of GC by 3(5'hydroxymethyl-2'furyl)-1-benzyl indazole (YC-1) (a benzyl indazole derivative) and the inhibition of PDE 5 by T-1032 were less effective in pulmonary vascular rings from CDH animals. The YC-1-induced vasodilation in rings from CDH animals was higher when associated with the PDE 5 inhibitor T-1032. CONCLUSIONS: Guanylate cyclase and PDE 5 play a role in controlling pulmonary vascular tone in fetal lambs with or without CDH. Both enzymes seem to be impaired in fetal lambs with CDH.

Consultoria del procés de logística interna del laboratori d'anàlisis clíniques a l'Hospital General de Vic

Com a resultat de les politiques i estratègies de col·laboració entre la universitat de Vic i de l’hospital i de la voluntat de realitzar activitats formatives conjuntes , s’estableix un línia de treball orientada a l’estudi i anàlisi de la situació logística interna actual del laboratori d’anàlisis clíniques de l’Hospital General de Vic. El treball es centra en el procés intern del laboratori i l’abast de l’estudi es troba limitat a les àrees especifiques d’hematologia i coagulació i bioquímica. D’aquestes dues àrees el treball realitza un estudi exhaustiu del seu procés intern, identifica les seves activitats i la seva metodologia de treball amb l’objectiu d’elaborar el Value Stream Map de cadascuna de les àrees. Les àrees de Microbiologia, Banc de Sang i Urgències resten fora d’aquest estudi exhaustiu tot i que són presents en el treball per la inevitable interacció que tenen en la globalitat del procés. El treball es centra bàsicament en els processos automatitzats tot i que els processos que es duen a terme en el laboratori són tant automatitzats com manuals. També es limita al sistema productiu intern del laboratori tot i la interacció que té aquest sistema intern amb altres centres productius del sistema com ara són els centres d’atenció primària, els diversos hospitals i centres d’atenció sociosanitària. El laboratori es troba immers en el moment de l’elaboració d’aquest treball en un situació de canvi i millora del seus processos interns que consisteixen principalment en la substitució de part la maquinària actual que obliguen a la definició d’un nou layout i d’una nova distribució de la producció a cada màquina. A nivell extern també s’estan produint millores en el sistema informàtic de gestió que afecten a part del seu procés. L’objectiu del treball és donar visibilitat total al procés de logística interna actual del laboratori, identificant clarament com són i quina seqüència tenen els processos logístics interns i els mètodes de treball actuals, tant de recursos màquina com recursos persona, per poder identificar sota una perspectiva de generació de valor, aquells punts concrets de la logística interna que poden ser millorats en quant a eficiència i productivitat amb l’objectiu que un cop identificats es puguin emprendre accions i/o projectes de millora. El treball finalitza amb un anàlisis final del procés logística interna des d’una òptica Lean. Per fer-ho, identifica aquelles activitats que no aporten valor al procés o MUDA i les classifica en set categories i es realitzen diverses propostes de millora com són la implantació d’un flux continu , anivellat i basat en un concepte pull , identifica activitats que poden ser estandarditzades i/o simplificades i proposa modificacions en les infraestructures físiques per donar major visibilitat al procés. L’aspecte humà del procés es planteja des d’un punt de vist de metodologia, formació, comunicació i aplicació de les 5S.

Clinical review: Update on neurally adjusted ventilatory assist - report of a round-table conference.

ABSTRACT: Conventional mechanical ventilators rely on pneumatic pressure and flow sensors and controllers to detect breaths. New modes of mechanical ventilation have been developed to better match the assistance delivered by the ventilator to the patient's needs. Among these modes, neurally adjusted ventilatory assist (NAVA) delivers a pressure that is directly proportional to the integral of the electrical activity of the diaphragm recorded continuously through an esophageal probe. In clinical settings, NAVA has been chiefly compared with pressure-support ventilation, one of the most popular modes used during the weaning phase, which delivers a constant pressure from breath to breath. Comparisons with proportional-assist ventilation, which has numerous similarities, are lacking. Because of the constant level of assistance, pressure-support ventilation reduces the natural variability of the breathing pattern and can be associated with asynchrony and/or overinflation. The ability of NAVA to circumvent these limitations has been addressed in clinical studies and is discussed in this report. Although the underlying concept is fascinating, several important questions regarding the clinical applications of NAVA remain unanswered. Among these questions, determining the optimal NAVA settings according to the patient's ventilatory needs and/or acceptable level of work of breathing is a key issue. In this report, based on an investigator-initiated round table, we review the most recent literature on this topic and discuss the theoretical advantages and disadvantages of NAVA compared with other modes, as well as the risks and limitations of NAVA.

Reconeixement de veu mitjançant xarxes neuronals

La interacció home-màquina per mitjà de la veu cobreix moltes àrees d’investigació. Es destaquen entre altres, el reconeixement de la parla, la síntesis i identificació de discurs, la verificació i identificació de locutor i l’activació per veu (ordres) de sistemes robòtics. Reconèixer la parla és natural i simple per a les persones, però és un treball complex per a les màquines, pel qual existeixen diverses metodologies i tècniques, entre elles les Xarxes Neuronals. L’objectiu d’aquest treball és desenvolupar una eina en Matlab per al reconeixement i identificació de paraules pronunciades per un locutor, entre un conjunt de paraules possibles, i amb una bona fiabilitat dins d’uns marges preestablerts. El sistema és independent del locutor que pronuncia la paraula, és a dir, aquest locutor no haurà intervingut en el procés d’entrenament del sistema. S’ha dissenyat una interfície que permet l’adquisició del senyal de veu i el seu processament mitjançant xarxes neuronals i altres tècniques. Adaptant una part de control al sistema, es podria utilitzar per donar ordres a un robot com l’Alfa6Uvic o qualsevol altre dispositiu.

p53 and cyclooxygenase-2 expression are directly associated with cyclin D1 expression in radical prostatectomy specimens of patients with hormone-naïve prostate cancer.

Prostate cancer (PCa) is a potentially curable disease when diagnosed in early stages and subsequently treated with radical prostatectomy (RP). However, a significant proportion of patients tend to relapse early, with the emergence of biochemical failure (BF) as an established precursor of progression to metastatic disease. Several candidate molecular markers have been studied in an effort to enhance the accuracy of existing predictive tools regarding the risk of BF after RP. We studied the immunohistochemical expression of p53, cyclooxygenase-2 (COX-2) and cyclin D1 in a cohort of 70 patients that underwent RP for early stage, hormone naïve PCa, with the aim of prospectively identifying any possible interrelations as well as correlations with known prognostic parameters such as Gleason score, pathological stage and time to prostate-specific antigen (PSA) relapse. We observed a significant (p = 0.003) prognostic role of p53, with high protein expression correlating with shorter time to BF (TTBF) in univariate analysis. Both p53 and COX-2 expression were directly associated with cyclin D1 expression (p = 0.055 and p = 0.050 respectively). High p53 expression was also found to be an independent prognostic factor (p = 0.023). Based on previous data and results provided by this study, p53 expression exerts an independent negative prognostic role in localized prostate cancer and could therefore be evaluated as a useful new molecular marker to be added in the set of known prognostic indicators of the disease. With respect to COX-2 and cyclin D1, further studies are required to elucidate their role in early prediction of PCa relapse after RP.

An Efficient Segmentation Method for Ultrasound Images based on a Semi-supervised Approach and Patch-based Features

Segmenting ultrasound images is a challenging problemwhere standard unsupervised segmentation methods such asthe well-known Chan-Vese method fail. We propose in thispaper an efficient segmentation method for this class ofimages. Our proposed algorithm is based on asemi-supervised approach (user labels) and the use ofimage patches as data features. We also consider thePearson distance between patches, which has been shown tobe robust w.r.t speckle noise present in ultrasoundimages. Our results on phantom and clinical data show avery high similarity agreement with the ground truthprovided by a medical expert.

Preoperative percutaneous galactography : P23

Purpose: To describe the technique of preoperative percutaneous galactography (PPG) in patients with ductal pathology without nipple discharge or when standard preoperative galactography was not possible. Methods and materials: All patients from 2000 to 2008 in whom PPG was performed were retrospectively reviewed. The technique of PPG will be described. Indications, feasibility, performance, complications and results are assessed. In all patients surgical correlation has been performed. Results: PPG was performed under ultrasound guidance in 12 patients. First the pathologic duct was punctured with a 25 G needle and distended with saline. Then a mixture of blue dye and iodinated contrast material or only blue dye were injected. When a mixture of blue dye and iodinated contrast material was injected a mammographic control was performed. 9 patients had no nipple discharge. 3 patients had nipple discharge but standard preoperative galactography was not possible. PPG was possible in all patients with no complications. Indications for PPG were a suspected papilloma in 10 patients, a history of bloody discharge with a dilated duct in one patient and recurrent abscesses with a dilated duct in one patient. Of the 10 patients with a suspected papilloma, a papilloma was surgically confirmed in 9. Conclusion: Preoperative percutaneous galactography is a easy and accurate technique in patients with ductal pathology where standard preoperative galactography is not possible.

Les set vides del paper: formats de presentació i models de distribució en línia dels treballs publicats en revistes científiques digitals

Study of the publication models and the means of accessing scientific literature in the current environment of digital communication and the web. The text introduces the concept of journal article as a well-defined and stable unit within the publishing world, and as a nucleus on which professional and scholarly communication has been based since its beginnings in the 17th century. The transformation of scientific communication that the digital world has enabled is analysed. Descriptions are provided of some of the practices undertaken by authors, research organisations, publishers and library-related institutions as a response to the new possibilities being unveiled for articles, both as products as well as for their creation and distribution processes. These transformations affect the very nature of articles as a minimal unit -both unique and stable- of scientific communication. The article concludes by noting that under varying documentary forms of publisher aggregation and bibliographic control -sometimes simultaneously and, even, apparently contradictory- there flourishes a more pluralistic type of scientific communication. This pluralism offers: more possibilities for communication among authors; fewer levels of intermediaries such as agents that intervene and provide added value to the products; greater availability for users both economically speaking and from the point of view of access; and greater interaction and wealth of contents, thanks to the new hypertext and multimedia possibilities.

Novel methods improve prediction of species' distributions from occurrence data

Prediction of species' distributions is central to diverse applications in ecology, evolution and conservation science. There is increasing electronic access to vast sets of occurrence records in museums and herbaria, yet little effective guidance on how best to use this information in the context of numerous approaches for modelling distributions. To meet this need, we compared 16 modelling methods over 226 species from 6 regions of the world, creating the most comprehensive set of model comparisons to date. We used presence-only data to fit models, and independent presence-absence data to evaluate the predictions. Along with well-established modelling methods such as generalised additive models and GARP and BIOCLIM, we explored methods that either have been developed recently or have rarely been applied to modelling species' distributions. These include machine-learning methods and community models, both of which have features that may make them particularly well suited to noisy or sparse information, as is typical of species' occurrence data. Presence-only data were effective for modelling species' distributions for many species and regions. The novel methods consistently outperformed more established methods. The results of our analysis are promising for the use of data from museums and herbaria, especially as methods suited to the noise inherent in such data improve.

A modular magnetic anastomotic device for minimally invasive digestive anastomosis: proof of concept and preliminary data in the pig model.

BACKGROUND: The aim of our study was to assess the feasibility of minimally invasive digestive anastomosis using a modular flexible magnetic anastomotic device made up of a set of two flexible chains of magnetic elements. The assembly possesses a non-deployed linear configuration which allows it to be introduced through a dedicated small-sized applicator into the bowel where it takes the deployed form. A centering suture allows the mating between the two parts to be controlled in order to include the viscerotomy between the two magnetic rings and the connected viscera. METHODS AND PROCEDURES: Eight pigs were involved in a 2-week survival experimental study. In five colorectal anastomoses, the proximal device was inserted by a percutaneous endoscopic technique, and the colon was divided below the magnet. The distal magnet was delivered transanally to connect with the proximal magnet. In three jejunojejunostomies, the first magnetic chain was injected in its linear configuration through a small enterotomy. Once delivered, the device self-assembled into a ring shape. A second magnet was injected more distally through the same port. The centering sutures were tied together extracorporeally and, using a knot pusher, magnets were connected. Ex vivo strain testing to determine the compression force delivered by the magnetic device, burst pressure of the anastomosis, and histology were performed. RESULTS: Mean operative time including endoscopy was 69.2 ± 21.9 min, and average time to full patency was 5 days for colorectal anastomosis. Operative times for jejunojejunostomies were 125, 80, and 35 min, respectively. The postoperative period was uneventful. Burst pressure of all anastomoses was ≥ 110 mmHg. Mean strain force to detach the devices was 6.1 ± 0.98 and 12.88 ± 1.34 N in colorectal and jejunojejunal connections, respectively. Pathology showed a mild-to-moderate inflammation score. CONCLUSIONS: The modular magnetic system showed enormous potential to create minimally invasive digestive anastomoses, and may represent an alternative to stapled anastomoses, being easy to deliver, effective, and low cost.

Conditional BDNF release under pathological conditions improves Huntington's disease pathology by delaying neuronal dysfunction

Background Brain-Derived Neurotrophic Factor (BDNF) is the main candidate for neuroprotective therapy for Huntington's disease (HD), but its conditional administration is one of its most challenging problems. Results Here we used transgenic mice that over-express BDNF under the control of the Glial Fibrillary Acidic Protein (GFAP) promoter (pGFAP-BDNF mice) to test whether up-regulation and release of BDNF, dependent on astrogliosis, could be protective in HD. Thus, we cross-mated pGFAP-BDNF mice with R6/2 mice to generate a double-mutant mouse with mutant huntingtin protein and with a conditional over-expression of BDNF, only under pathological conditions. In these R6/2:pGFAP-BDNF animals, the decrease in striatal BDNF levels induced by mutant huntingtin was prevented in comparison to R6/2 animals at 12 weeks of age. The recovery of the neurotrophin levels in R6/2:pGFAP-BDNF mice correlated with an improvement in several motor coordination tasks and with a significant delay in anxiety and clasping alterations. Therefore, we next examined a possible improvement in cortico-striatal connectivity in R62:pGFAP-BDNF mice. Interestingly, we found that the over-expression of BDNF prevented the decrease of cortico-striatal presynaptic (VGLUT1) and postsynaptic (PSD-95) markers in the R6/2:pGFAP-BDNF striatum. Electrophysiological studies also showed that basal synaptic transmission and synaptic fatigue both improved in R6/2:pGAP-BDNF mice. Conclusions These results indicate that the conditional administration of BDNF under the GFAP promoter could become a therapeutic strategy for HD due to its positive effects on synaptic plasticity.

Plaque characteristics and arterial remodeling in coronary and peripheral arterial systems.

BACKGROUND: Few studies have examined plaque characteristics among multiple arterial beds in vivo. The purpose of this study was to compare the plaque morphology and arterial remodeling between coronary and peripheral arteries using gray-scale and radiofrequency intravascular ultrasound (IVUS) at clinical presentation. METHODS AND RESULTS: IVUS imaging was performed in 68 patients with coronary and 93 with peripheral artery lesions (29 carotid, 50 renal, and 14 iliac arteries). Plaques were classified as fibroatheroma (VH-FA) (further subclassified as thin-capped [VH-TCFA] and thick-capped [VH-ThCFA]), fibrocalcific plaque (VH-FC) and pathological intimal thickening (VH-PIT). Plaque rupture (13% of coronary, 7% of carotid, 6% of renal, and 7% of iliac arteries; P = NS) and VH-TCFA (37% of coronary, 24% of carotid, 16% of renal, and 7% of iliac arteries; P = 0.02) were observed in all arteries. Compared with coronary arteries, VH-FA was less frequently observed in renal (P < 0.001) and iliac arteries (P < 0.006). Lesions with positive remodeling demonstrated more characteristics of VH-FA in coronary (84% vs. 25%, P < 0.001), carotid (72% vs. 20%, P = 0.001), and renal arteries (42% vs. 4%, P = 0.001) compared with those with intermediate/negative remodeling. There was positive relationship between remodeling index and percent necrotic area in all four arteries. CONCLUSIONS: Atherosclerotic plaque phenotypes were heterogeneous among four different arteries; renal and iliac arteries had more stable phenotypes compared with coronary artery. In contrast, the associations of remodeling pattern with plaque phenotype and composition were similar among the various arterial beds.