Population pharmacokinetics of imatinib in CML and GIST patients under long-term treatment

Imatinib (Glivec®) has transformed the treatment and short-term prognosis of chronic myeloid leukaemia (CML) and gastro-intestinal stromal tumour (GIST). However, the treatment must be taken indefinitely, it is not devoid of inconvenience and toxicity. Moreover, resistance or escape from disease control occur in a significant number of patients. Imatinib is a substrate of the cytochromes P450 CYP3A4/5 and of the multidrug transporter P glycoprotein (product of the MDR1 gene). Considering the large inter-individual differences in the expression and function of those systems, the disposition and clinical activity of imatinib can be expected to vary widely among patients, calling for dosage individualisation. The aim of this exploratory study was to determine the average pharmacokinetic parameters characterizing the disposition of imatinib in the target population, to assess their inter-individual variability, and to identify influential factors affecting them. A total of 321 plasma concentrations, taken at various sampling times after latest dose, were measured in 59 patients receiving Glivec® at diverse regimens, using a validated chromatographic method (HPLC-UV) developed for this study. The results were analysed by non-linear mixed effect modelling (NONMEM). A one- compartment model with first-order absorption appeared appropriate to describe the data, with an average apparent clearance of 12.4 l/h, a distribution volume of 268 l and an absorption constant of 0.47 h-1. The clearance was affected by body weight, age and sex. No influences of interacting drugs were found. DNA samples were used for pharmacogenetic explorations. The MDR1 polymorphism 3435C>T appears to affect the disposition of imatinib. Large inter-individual variability remained unexplained by the demographic covariates considered, both on clearance (40%) and distribution volume (71%). Together with intra-patient variability (34%), this translates into an 8-fold width of the 90%-prediction interval of plasma concentrations expected under a fixed dosing regimen ! This is a strong argument to further investigate the possible usefulness of a therapeutic drug monitoring programme for imatinib. It may help to individualise the dosing regimen before overt disease progression or observation of treatment toxicity, thus improving both the long-term therapeutic effectiveness and tolerability of this drug.

Long-term complete responses after 131I-tositumomab therapy for relapsed or refractory indolent non-Hodgkin's lymphoma.

We present the long-term results of 18 chemotherapy relapsed indolent (N = 12) or transformed (N = 6) NHL patients of a phase II anti-CD20 (131)I-tositumomab (Bexxar) therapy study. The biphasic therapy included two injections of 450 mg unlabelled antibody combined with (131)I-tositumomab once as dosimetric and once as therapeutic activity delivering 75 or 65 cGy whole-body radiation dose to patients with normal or reduced platelet counts, respectively. Two patients were not treated due to disease progression during dosimetry. The overall response rate was 81% in the 16 patients treated, including 50% CR/CRu and 31% PR. Median progression free survival of the 16 patients was 22.5 months. Median overall survival has not been reached after a median observation of 48 months. Median PFS of complete responders (CR/CRu) has not been reached and will be greater than 51 months. Short-term side effects were mainly haematological and transient. Among the relevant long-term side effects, one patient previously treated with CHOP chemotherapy died from secondary myelodysplasia. Four patients developed HAMA. In conclusion, (131)I-tositumomab RIT demonstrated durable responses especially in those patients who achieved a complete response. Six of eight CR/CRu are ongoing after 46-70 months.

A short motif in Drosophila SECIS Binding Protein 2 provides differential binding affinity to SECIS RNA hairpins

Selenoproteins contain the amino acid selenocysteine which is encoded by a UGA Sec codon. Recoding UGA Sec requires a complex mechanism, comprising the cis-acting SECIS RNA hairpin in the 3′UTR of selenoprotein mRNAs, and trans-acting factors. Among these, the SECIS Binding Protein 2 (SBP2) is central to the mechanism. SBP2 has been so far functionally characterized only in rats and humans. In this work, we report the characterization of the Drosophila melanogaster SBP2 (dSBP2). Despite its shorter length, it retained the same selenoprotein synthesis-promoting capabilities as the mammalian counterpart. However, a major difference resides in the SECIS recognition pattern: while human SBP2 (hSBP2) binds the distinct form 1 and 2 SECIS RNAs with similar affinities, dSBP2 exhibits high affinity toward form 2 only. In addition, we report the identification of a K (lysine)-rich domain in all SBP2s, essential for SECIS and 60S ribosomal subunit binding, differing from the well-characterized L7Ae RNA-binding domain. Swapping only five amino acids between dSBP2 and hSBP2 in the K-rich domain conferred reversed SECIS-binding properties to the proteins, thus unveiling an important sequence for form 1 binding.

Long-term cerebral plasticity-related gene expression : a study of the respective role of CBP and CRTC1 in CREB transcriptional activation

1.1 AbstractThe treatment of memory disorders and cognitive deficits in various forms of mental retardation may greatly benefit from a better understanding of the molecular and cellular mechanisms of memory formation. Different forms of memory have distinct molecular requirements.Short-term memory (STM) is thought to be mediated by covalent modifications of existing synaptic molecules, such as phosphorylation or dephosphorylation of enzymes, receptors or ion channels. In contrast, long-term memoiy (LTM) is thought to be mediated by growth of new synapses and restructuring of existing synapses. There is extensive evidence that changes in gene expression and de novo protein synthesis are key processes for LTM formation. In this context, the transcription factor CREB (cAMP-response element-binding protein) was shown to be crucial. Activation of CREB requires phosphorylation of a serine residue (Ser-133), and the subsequent recruitment of a coactivator called CREB-binding protein (CBP). Moreover, we have recently shown that another coactivator called CREB Regulated Transcription Coactivator 1 (CRTC1) functions as a calcium- and cAMP-sensitive coincidence detector in neurons, and is involved in hippocampal long-term synaptic plasticity. Given the importance of cAMP and calcium signaling for plasticity-related gene expression in neurons and in astrocytes, we sought to determine the respective involvement of the CREB coactivators CBP and CRTC1 in CREB-mediated transcription.We developed various strategies to selectively interfere with these CREB coactivators in mouse primary neurons and in astrocytes in vitro. However, despite several pieces of evidence implicating CBP and/or CRTC1 in the regulation of neuronal plasticity genes, we could not clearly determine the respective requirement of these coactivators for the activation of these genes. Nevertheless, we showed that calcineurin activity, which is important for CRTC1 nuclear translocation, is necessary for the expression of some CREB-regulated plasticity genes. We associated this phenomena to physiopathological conditions observed in Down's syndrome. In addition, we demonstrated that in astrocytes, noradrenaline stimulates CREB-target gene expression through β-adrenergic receptor activation, intracellular cAMP pathway activation, and CRTC-induced CREB transactivation.Defining the respective role of CREB and its coactivators CBP and CRTC1 in neuronal and astrocytic cultures in vitro sets the stage for future in vivo studies and for the possible development of new therapeutic strategies to improve the treatment of memoiy and cognitive disorders.1.2 RésuméUne meilleure connaissance des mécanismes moléculaires et cellulaires responsables de la formation de la mémoire pourrait grandement améliorer le traitement des troubles de la mémoire ainsi que des déficits cognitifs observés dans différentes formes de pathologies psychiatriques telles que le retard mental. Les différentes formes de mémoire dépendent de processus moléculaires différents.La mémoire à court terme (STM) semble prendre forme suite à des modifications covalentes de molécules synaptiques préexistantes, telles que la phosphorylation ou la déphosphorylation d'enzymes, de récepteurs ou de canaux ioniques. En revanche, la mémoire à long terme (LTM) semble être due à la génération de nouvelles synapses et à la restructuration des synapses existantes. De nombreuses études ont permis de démontrer que les changements dans l'expression des gènes et la synthèse de protéine de novo sont des processus clés pour la formation de la LTM. Dans ce contexte, le facteur de transcription CREB (cAMP-response element-binding protein) s'est avéré être un élément crucial. L'activation de CREB nécessite la phosphorylation d'un résidu sérine (Ser-133), et le recrutement d'un coactivateur nommé CBP (CREB binding protein). En outre, nous avons récemment démontré qu'un autre coactivateur de CREB nommé CRTC1 (CREB Regulated Transcription Coactivator 1) agit comme un détecteur de coïncidence de l'AMP cyclique (AMPc) et du calcium dans les neurones et qu'il est impliqué dans la formation de la plasticité synaptique à long terme dans l'hippocampe. Etant donné l'importance des voies de l'AMPc et du calcium dans l'expression des gènes impliqués dans la plasticité cérébrale, nous voulions déterminer le rôle respectif des coactivateurs de CREB, CBP et CRTC1.Nous avons développé diverses stratégies pour interférer de façon sélective avec les coactivateurs de CREB dans les neurones et dans les astrocytes chez la souris in vitro. Nos résultats indiquent que CBP et CRTC1 sont tous deux impliqués dans la transcription dépendante de CREB induite par l'AMPc et le calcium dans les neurones. Cependant, malgré plusieurs évidences impliquant CBP et/ou CRTC1 dans l'expression de gènes de plasticité neuronale, nous n'avons pas pu déterminer clairement leur nécessité respective pour l'activation de ces gènes. Toutefois, nous avons montré que l'activité de la calcineurine, dont dépend la translocation nucléaire de CRTC1, est nécessaire à l'expression de certains de ces gènes. Nous avons pu associer ce phénomène à une condition physiopathologique observée dans le syndrome de Down. Nous avons également montré que dans les astrocytes, la noradrénaline stimule l'expression de gènes cibles de CREB par une activation des récepteurs β- adrénergiques, l'activation de la voie de l'AMPc et la transactivation de CREB par les CRTCs.Définir le rôle respectif de CREB et de ses coactivateurs CBP et CRTC1 dans les neurones et dans les astrocytes in vitro permettra d'acquérir les connaissances nécessaires à de futures études in vivo et, à plus long terme d'éventuellement développer des stratégies thérapeutiques pour améliorer les traitements des troubles cognitifs.

Civil conflict and human capital accumulation: The long-term effects of political violence in Perú

This paper provides empirical evidence of the persistent effect of exposure to political violence on humancapital accumulation. I exploit the variation in conflict location and birth cohorts to identify the longandshort-term effects of the civil war on educational attainment. Conditional on being exposed toviolence, the average person accumulates 0.31 less years of education as an adult. In the short-term,the effects are stronger than in the long-run; these results hold when comparing children within thesame household. Further, exposure to violence during early childhood leads to permanent losses. I alsoexplore the potential causal mechanisms.

Risk management under a two-factor model of the term structure of interest rates

This paper presents several applications to interest rate risk managementbased on a two-factor continuous-time model of the term structure of interestrates previously presented in Moreno (1996). This model assumes that defaultfree discount bond prices are determined by the time to maturity and twofactors, the long-term interest rate and the spread (difference between thelong-term rate and the short-term (instantaneous) riskless rate). Several newmeasures of ``generalized duration" are presented and applied in differentsituations in order to manage market risk and yield curve risk. By means ofthese measures, we are able to compute the hedging ratios that allows us toimmunize a bond portfolio by means of options on bonds. Focusing on thehedging problem, it is shown that these new measures allow us to immunize abond portfolio against changes (parallel and/or in the slope) in the yieldcurve. Finally, a proposal of solution of the limitations of conventionalduration by means of these new measures is presented and illustratednumerically.

Transcatheter aortic valve implantation (TAVI): state of the art techniques and future perspectives.

Transcatheter aortic valve therapies are the newest established techniques for the treatment of high risk patients affected by severe symptomatic aortic valve stenosis. The transapical approach requires a left anterolateral mini-thoracotomy, whereas the transfemoral method requires an adequate peripheral vascular access and can be performed fully percutaneously. Alternatively, the trans-subclavian access has been recently proposed as a third promising approach. Depending on the technique, the fine stent-valve positioning can be performed with or without contrast injections. The transapical echo-guided stent-valve implantation without angiography (the Lausanne technique) relies entirely on transoesophageal echocardiogramme imaging for the fine stent-valve positioning and it has been proved that this technique prevents the onset of postoperative contrast-related acute kidney failure. Recent published reports have shown good hospital outcomes and short-term results after transcatheter aortic valve implantation, but there are no proven advantages in using the transfemoral or the transapical technique. In particular, the transapical series have a higher mean logistic Euroscore of 27-35%, a procedural success rate above 95% and a mean 30-day mortality between 7.5 and 17.5%, whereas the transfemoral results show a lower logistic Euroscore of 23-25.5%, a procedural success rate above 90% and a 30-day mortality of 7-10.8%. Nevertheless, further clinical trials and long-term results are mandatory to confirm this positive trend. Future perspectives in transcatheter aortic valve therapies would be the development of intravascular devices for the ablation of the diseased valve leaflets and the launch of new stent-valves with improved haemodynamic, different sizes and smaller delivery systems.

Long-term treatment of eosinophilic esophagitis esophagitis with budesonide

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic-inflammatory disease of the esophagus, characterized by esophagus-related symptoms and a dense tissue eosinophilia, both refractory to proton pump inhibitors. Topical corticosteroids have proven effective in inducing clinical and histologic remission. However, a long-term strategy for the management of this chronic disease is not yet defined. METHODS: In a randomized, double-blind, placebocontrolled, long-term trial, we evaluated the efficacy of twice-daily 0.25 mg swallowed budesonide in maintaining a remission in adult EoE with prior response to induction therapy. Pre- and post-treatment disease activity was assessed clinically, endoscopically, histologically, by immunofluorescence and by high-resolution endosonography. The primary end point was the ability to maintain histologic remission (<5 eos/hpf) of EoE in. Secondary end points were the efficacy on symptom control and on tissue remodeling as well as the determination of the safety of long-term esophageal administration of topical corticosteroids. RESULTS: During a 50-week therapy of quiescent EoE with low-dose budesonide the esophageal eosinophil load (ECP staining) increased from 1.1 to 29.9 eos/hpf, but under placebo the increase was significantly larger (0.5 to 51.1 eos/hpf; p=0.01). At the end of the studyperiod, 35.7% (5/14) of the budesonide patients were in complete and 14.3% (2/14) in partial histologic remission; with placebo no patient was in complete and 28.6% (4/14) were in partial remission (p=0.0647). The increase of the symptom score was markedly lower in budesonide- (0.79 to 2.29 points) than in placebo-patients (0.71 to 4.00 points; p=0.0875). The median time to relapse of symptoms was >125 days in the budesonide and 95 days in the placebo group (p = 0.14). Measured by high-resolution endosonography, all EoE patients had pre-treatment a highly thickened esophageal wall compared with healthy controls (3.05±1.08 mm vs. 2.18±0.35 mm; p<0.0001). Long-term topical budesonide reduced mainly the thickness of the superficial wall layers (mucosa, 0.75 mm to 0.45 mm; p=0.025) whereas the response of the deeper layers was less pronounced (submucosa 1.31 to 1.08 mm; p=0.19 and muscularis 0.82 to 0.76 mm; p=0.72). Budesonide did not evoke any mucosal atrophy. CONCLUSIONS: This study clearly demonstrates that 1) Untreated eosinophil inflammation results in an impressive remodeling of the esophagus; 2) A therapy is therefore needed; 3) The high relapse rate after short-term therapy requires a long-term management and 4) Maintenance treatment with budesonide is well tolerated and keeps half of the patients in remission.

Spaced training facilitates long-term retention of place navigation in adult but not in adolescent rats

Young and adult Long Evans rats were tested in the water maze according to two different procedures: half of the subjects were given one session of four trials a day for 6 days, whereas the other subjects had the same amount of training massed in 1 day. For both conditions, a 14-day retention interval was then introduced to test long-term memory. This was followed by a four-trial reversal session. All groups showed a significant learning curve, but escape latencies were shorter for the adult than for the young rats, without differential effect of the training procedure. A first probe trial (PT1) confirmed similar accurate short-term retention in all the groups. But unimpaired long-term memory was only seen in the adult rats trained with the spaced procedure. The young rats trained over 1 day also showed some retention of the platform location after 14 days, but not the other two groups. Reversal acquisition of the new platform location was rapid in the four groups. These results indicate that although accurate short-term spatial memory in the water maze is seen after a 1-day massed training in both age groups, unimpaired long-term retention is only observed in adult rats trained with 24-h inter-session intervals.

Metacognitive training for schizophrenia: a multicentre randomised controlled trial.

A psychotherapeutic approach for schizophrenia is now recommended as an adjuvant for psychopharmacology, since antipsychotic medications only have a partial impact especially as regards positive symptoms and insight. In addition, cognitive distortions and the lack of metacognitive skills might increase positive symptoms leading to poor social functioning. This underlines the need for specific approaches which target cognitive processes relevant for insight, and abilities in metacognition. Metacognitive training (MCT) is a structured group intervention, which enhances a patient's reflection on cognitive biases and improves problem-solving. The aim of our study was to assess MCTs' short term impact on insight, symptoms and quality of life. Fifty patients with schizophrenia or schizoaffective disorders and persistent positive symptoms (delusions or hallucinations) were enrolled in the study. After baseline assessment participants were randomised either to supportive therapy or MCT. Both groups used the same design (1h-session twice a week during 8weeks) although the basic knowledge given to participants was different between interventions. Participants were assessed at eight weeks based on the Scale to Assess Unawareness of Mental Disorder, Positive and Negative Syndrome Scale (PANSS), Psychotic Symptom Rating Scales, the Calgary Depression Scale for Schizophrenia and the Quality of Life Scale. Between-group differences were significant in favour of MCT on the PANSS positive scale. Between-group differences in post- and pre-test values showed a trend in favour of MCT for insight on hallucinations. Results of our study indicate that the MCT has an effect on reducing positive symptomatology, and a trend impact on insight and social functioning.

Medication use in pregnancy: a cross-sectional, multinational web-based study.

OBJECTIVES: Intercountry comparability between studies on medication use in pregnancy is difficult due to dissimilarities in study design and methodology. This study aimed to examine patterns and factors associated with medications use in pregnancy from a multinational perspective, with emphasis on type of medication utilised and indication for use. DESIGN: Cross-sectional, web-based study performed within the period from 1 October 2011 to 29 February 2012. Uniform collection of drug utilisation data was performed via an anonymous online questionnaire. SETTING: Multinational study in Europe (Western, Northern and Eastern), North and South America and Australia. PARTICIPANTS: Pregnant women and new mothers with children less than 1 year of age. PRIMARY AND SECONDARY OUTCOME MEASURES: Prevalence of and factors associated with medication use for acute/short-term illnesses, chronic/long-term disorders and over-the-counter (OTC) medication use. RESULTS: The study population included 9459 women, of which 81.2% reported use of at least one medication (prescribed or OTC) during pregnancy. Overall, OTC medication use occurred in 66.9% of the pregnancies, whereas 68.4% and 17% of women reported use of at least one medication for treatment of acute/short-term illnesses and chronic/long-term disorders, respectively. The extent of self-reported medicated illnesses and types of medication used by indication varied across regions, especially in relation to urinary tract infections, depression or OTC nasal sprays. Women with higher age or lower educational level, housewives or women with an unplanned pregnancy were those most often reporting use of medication for chronic/long-term disorders. Immigrant women in Western (adjusted OR (aOR): 0.55, 95% CI 0.34 to 0.87) and Northern Europe (aOR: 0.50, 95% CI 0.31 to 0.83) were less likely to report use of medication for chronic/long-term disorders during pregnancy than non-immigrants. CONCLUSIONS: In this study, the majority of women in Europe, North America, South America and Australia used at least one medication during pregnancy. There was a substantial inter-region variability in the types of medication used.

Astrocyte-neuron lactate transport is required for long-term memory formation.

We report that, in the rat hippocampus, learning leads to a significant increase in extracellular lactate levels that derive from glycogen, an energy reserve selectively localized in astrocytes. Astrocytic glycogen breakdown and lactate release are essential for long-term but not short-term memory formation, and for the maintenance of long-term potentiation (LTP) of synaptic strength elicited in vivo. Disrupting the expression of the astrocytic lactate transporters monocarboxylate transporter 4 (MCT4) or MCT1 causes amnesia, which, like LTP impairment, is rescued by L-lactate but not equicaloric glucose. Disrupting the expression of the neuronal lactate transporter MCT2 also leads to amnesia that is unaffected by either L-lactate or glucose, suggesting that lactate import into neurons is necessary for long-term memory. Glycogenolysis and astrocytic lactate transporters are also critical for the induction of molecular changes required for memory formation, including the induction of phospho-CREB, Arc, and phospho-cofilin. We conclude that astrocyte-neuron lactate transport is required for long-term memory formation.

Deficit in memory consolidation (abnormal forgetting rate) in childhood temporal lobe epilepsy. Pre and postoperative long-term observation.

Deficits in memory consolidation have been reported in adult patients with epilepsy but, not to our knowledge, in children. We report the long-term follow-up (9 y. o. to 18 y. o.) of a boy who suffered from temporal lobe epilepsy and underwent a left temporal lobectomy with amygdalo-hippocampal resection at the age of 10. He showed an abnormal forgetting rate when trying to encode new information and a significant deficit for retrieving remote episodic memories (when compared with his twin brother), both consistent with a consolidation disorder. His memory condition slightly improved after cessation of the epilepsy, nevertheless did not normalize. No standard memory assessment could pinpoint his memory problem, hence an adapted methodology was needed. We discuss the nature of the memory deficit, its possible causes and its clinical implications.

How Does Addressing Patient's Defenses Help to Repair Alliance Ruptures in Psychodynamic Psychotherapy?: An Exploratory Study.

Interpreting or addressing defenses is an important aspect of psychoanalytic technique. Previous research has shown that therapist addressing defenses (TADs) can produce a positive effect on alliance. The potential value of TADs during the process of alliance rupture and resolution has not yet been documented. We selected patients (n = 17) undertaking a short-term dynamic psychotherapy in which the therapeutic alliance, measured with the Helping Alliance Questionnaire and monitored after each session, showed a pattern of rupture and resolution. Two control sessions (5 and 15) were also selected. Presence of TADs was examined in each therapist interpretation. Compared with control sessions, rupture sessions were characterized by fewer TADs and especially fewer TADs addressing specifically intermediate-essentially neurotic-defenses. Resolution sessions were characterized by more TADs addressing specifically intermediate defenses. This confirms the link between therapist technique and alliance process in psychodynamic psychotherapy.

Tuloskortti, strategia ja tavoitteet, Case: TeliaSonera Finland Oyj, Verkot ja tuotanto -divisioona

Tuloskortti on mittaristo, jonka avulla yritystä johdetaan, tuloksia mitataan, luodaan yrityksen strategia ja asetetaan sekä pitkän että lyhyen aikavälin tavoitteet. Se toimii myös raportoinnin välineenä. Tutkielman teoreettinen tavoite on selvittää miten tuloskorttia voi hyödyntää yrityksen strategian implementoinnissa ja sitä kauttayrityksen sille asettamiin tavoitteisiin pääsemisessä. Tuloskortin avulla ohjataan liiketoimintaa sekä organisaation nykyistä ja tulevaisuuden suorituskykyä. Tuloskortin mittariston tavoitteet johdetaan strategiasta ja toisaalta strategia johdetaan tuloskortin tavoitteista. Hyvätuloskortti kertoo tarinan yrityksen strategiasta ja visiosta. Tutkielman empiirinen osa liittyy caseyrityksen TeliaSonera Finland Oyj:n Verkot ja tuotanto - divisioonassa suoritettuun kyselytutkimukseen. Empiirisenä tavoitteena on tutkia, miten työntekijän asema organisaatiossa vaikuttaa suhtautumisessa tuloskorttiin ja sen avulla suoritettavaan työn ohjaukseen. Miten vastaajat kokevat tuloskortin avulla asetetun yrityksen suunnan sekä tuloksellisuuden mittauksen? Onko näkemyseroja esimiesten ja asiantuntijoiden välillä? Kirjoittaja havaitsi, että kyseiset luokat suhtautuvat varsin yhteneväisesti kysymyksiin. Näkemyseroa ilmenee lähinnä siinä, miten tuloskortin avulla voidaan vaikuttaa ja miten tärkeää se on. Tuloskortti koetaan myös tärkeänä sitouttamisen sekä palkitsemisen välineenä.