Prospective assessment of trocar-specific morbidity in laparoscopy.

BACKGROUND: The purpose of the present study was to challenge the hypothetical advantage of single port laparoscopy (SPL) over conventional laparoscopy by measuring prospectively the morbidity specifically related to conventional trocar sites (TS). METHODS: From November 2010 to December 2011, 300 patients undergoing various laparoscopic procedures were enrolled. Patient, surgery, and trocar characteristics were recorded. We evaluated at three time points (in-hospital and at 1 and 6 months postoperatively) specifically for each TS, pain (Visual Analog Scale), morbidity (infection, hematoma, hernia), and cosmesis (Patient Scar Assessment Score; PSAS). Patients designated their "worst TS," and a composite endpoint "bad TS" was defined to include any adverse outcome at a TS. RESULTS: We analyzed 1,074 TS. Follow-up was >90 %. Pain scores of >3/10 at 1 and 6 months postoperatively, were reported by 3 and 1 % of patients at the 5 mm TS and by 9 and 1 % at the larger TS, respectively (5 mm TS vs larger TS; p = 0.001). Pain was significantly lower for TS located in the lower abdomen than for the upper abdomen or the umbilicus (p = 0.001). The overall complication rate was <1 % and significantly lower for the 5 mm TS (hematoma p = 0.046; infection p = 0.0001). No hernia was found. The overall PSAS score was low and significantly lower for the 5 mm TS (p = 0.0001). Significant predictors of "bad TS" were larger TS (p = 0.001), umbilical position (p = 0.0001), emergency surgery (p = 0.0001), accidental trocar exit (p = 0.022), fascia closure (p = 0.006), and specimen extraction site (p = 0.0001). CONCLUSIONS: Specific trocar morbidity is low and almost negligible for 5 mm trocars. The umbilicus appears to be an unfavorable TS.

Traitement de la dépression résistante par l'association citalopram-lithium. Méthodologie d'une étude multicentrique en double aveugle et résultats préliminaires [Treatment of resistant depression with the citalopram-lithium combination. Methodology of a double-blind multicenter study and preliminary results].

Citalopram, a new bicyclic antidepressant, is the most selective serotonin reuptake inhibitor. In a number of double-blind controlled studies, citalopram was compared to placebo and to known tricyclic antidepressants. These studies have shown their efficacy and good safety. The inefficacy of a psychotropic treatment in at least 20% of depressives has led a number of authors to propose original drug combinations and associations, like antidepressant/lithium (Li), antidepressant/sleep deprivation (agrypnia), antidepressant/ECT, or antidepressant/LT3. The aim of this investigation is to evaluate the clinical effectiveness and safety of a combined citalopram/lithium treatment in therapy-resistant patients, taking account of serotonergic functions, as tested by the fenfluramine/prolactin test, and of drug pharmacokinetics and pharmacogenetics of metabolism. DESIGN OF THE STUDY: A washout period of 3 days before initiating the treatment is included. After an open treatment phase of 28 days (D) with citalopram (20 mg D1-D3; 40 mg D4-D14; 40 or 60 mg D15-D28; concomitant medication allowed: chloral, chlorazepate), the nonresponding patients [less than 50% improvement in the total score on the 21 item-Hamilton Depression Rating Scale (HDRS)] are selected and treated with or without Li (randomized in double-blind conditions: citalopram/Li or citalopram/placebo) during the treatment (D29-D35). Thereafter, all patients included in the double-blind phase subsequently receive an open treatment with citalopram/Li for 7 days (D36-D42). The hypothesis of a relationship between serotoninergic functions in patients using the fenfluramine/prolactin test (D1) and the clinical response to citalopram (and Li) is assessed. Moreover, it is evaluated whether the pharmacogenetic status of the patients, as determined by the mephenytoin/dextromethorphan test (D0-D28), is related to the metabolism of fenfluramine and citalopram, and also to the clinical response. CLINICAL ASSESSMENT: Patients with a diagnosis of major depressive disorders according to DSM III are submitted to a clinical assessment of D1, D7, D14, D28, D35, D42: HDRS, CGI (clinical global impression), VAS (visual analog scales for self-rating of depression), HDRS (Hamilton depression rating scale, 21 items), UKU (side effects scale), and to clinical laboratory examens, as well as ECG, control of weight, pulse, blood pressure at D1, D28, D35. Fenfluramine/prolactin test: A butterfly needle is inserted in a forearm vein at 7 h 45 and is kept patent with liquemine. Samples for plasma prolactin, and d- and l-fenfluramine determinations are drawn at 8 h 15 (base line). Patients are given 60 mg fenfluramine (as a racemate) at 8 h 30. Kinetic points are determined at 9 h 30, 10 h 30, 11 h 30, 12 h 30, 13 h 30. Plasma levels of d- and l-fenfluramine are determined by gas chromatography and prolactin by IRNA. Mephenytoin/dextromethorphan test: Patients empty their bladders before the test; they are then given 25 mg dextropethorphan and 100 mg mephenytoin (as a racemate) at 8 h 00. They collect all urines during the following 8 hours. The metabolic ratio is determined by gas chromatography (metabolic ratio dextromethorphan/dextrorphan greater than 0.3 = PM (poor metabolizer); mephenytoin/4-OH-mephenytoin greater than 5.6, or mephenytoin S/R greater than 0.8 = PM). Citalopram plasma levels: Plasma levels of citalopram, desmethylcitalopram and didesmethylcitalopram are determined by gas chromatography--mass spectrometry. RESULTS OF THE PILOT STUDY. The investigation has been preceded by a pilot study including 14 patients, using the abovementioned protocol, except that all nonresponders were medicated with citalopram/Li on D28 to D42. The mean total score (n = 14) on the 21 item Hamilton scale was significantly reduced after the treatment, ie from 26.93 +/- 5.80 on D1 to 8.57 +/- 6.90 on D35 (p less than 0.001). A similar patCitalopram, a new bicyclic antidepressant, is the most selective serotonin reu

Extreme self-monitoring, fear of hypoglycemia and obsessive-compulsive disorder in type 1 diabetes mellitus: when less is better

Background: Pre-existing psychological factors can strongly influence coping with type 1 diabetes mellitus and interfere with self-monitoring. Psychiatric disorders seem to be positively associated with poor metabolic control. We present a case of extreme compulsive blood testing due to obsessive fear of hypoglycemia in an adolescent with type 1 diabetes mellitus. Case report: Type 1 diabetes mellitus (anti GAD-antibodies 2624 U/l, norm < 9.5) was diagnosed in a boy aged 14.3 years [170 cm (+ 0.93 SDS), weight 50.5 kg (+ 0.05 SDS)]. Laboratory work-up showed no evidence for other autoimmune disease. Family and past medical history were unremarkable. Growth and developmental milestones were normal. Insulin-analog based basal-bolus regime was initiated, associated to standard diabetic education. Routine psychological evaluation performed at the onset of diabetes revealed intermittent anxiety and obsessivecompulsive traits. Accordingly, a close psychiatric follow-up was initiated for the patient and his family. An adequate metabolic control (HbA1c drop from >14 to 8%) was achieved within 3 months, attributed to residual -cell function. In the following 6 months, HbA1c rose unexpectedly despite seemingly adequate adaptations of insulin doses. Obsessive fear of hypoglycemia leading to a severe compulsive behavior developed progressively with as many as 68 glycemia measurements per day (mean over 1 week). The patient reported that he could not bear leaving home with glycemia < 15 mmol/l, ending up with school eviction and severe intra-familial conflict. Despite intensive psychiatric outpatient support, HbA1c rose rapidly to >14% with glycemia-testing reaching peaks of 120 tests/day. The situation could only be discontinued through psychiatric hospitalization with intensive behavioral training. As a result, adequate metabolic balance was restored (HbA1c value: 7.1 %) with acceptable 10-15 daily glycemia measurements. Discussion: The association of overt psychiatric disorders to type 1 diabetes mellitus is very rare in the pediatric age group. It can lead to a pathological behavior with uncontrolled diabetes. Such exceptional situations require long-term admissions with specialized psychiatric care. Slow acceptation of a "less is better" principle in glycemia testing and amelioration of metabolic control are difficult to achieve.

Fine structural variations of alphabeta TCRs selected by vaccination with natural versus altered self-antigen in melanoma patients

Immunotherapy of cancer is often performed with altered "analog" peptide Ags optimized for HLA class I binding, resulting in enhanced immunogenicity, but the induced T cell responses require further evaluation. Recently, we demonstrated fine specificity differences and enhanced recognition of naturally presented Ag by T cells after vaccination with natural Melan-A/MART-1 peptide, as compared with analog peptide. In this study, we compared the TCR primary structures of 1489 HLA-A*0201/Melan-A26-35-specific CD8 T cells derived from both cohorts of patients. Although a strong preference for TRAV12-2 segment usage was present in nearly all patients, usage of particular TRAJ gene segments and CDR3 composition differed slightly after vaccination with natural vs analog peptide. Moreover, TCR β-chain repertoires were broader after natural than analog peptide vaccination. In all patients, we observed a marked conservation of the CDR3β amino acid composition with recurrent sequences centered on a glycyl-leucyl/valyl/alanyl-glycyl motif. In contrast to viral-specific TCR repertoires, such "public" motifs were primarily expressed by nondominant T cell clonotypes, which contrasted with "private" CDR3β signatures frequently found in T cell clonotypes that dominated repertoires of individual patients. Interestingly, no differences in functional avidity were observed between public and private T cell clonotypes. Collectively, our data indicate that T cell repertoires generated against natural or analog Melan-A peptide exhibited slightly distinct but otherwise overlapping and structurally conserved TCR features, suggesting that the differences in binding affinity/avidity of TCRs toward pMHC observed in the two cohorts of patients are caused by subtle structural TCR variations.

A wearable system to time gate crossing during alpine skiing slalom

INTRODUCTION: In alpine skiing, chronometry analysis is currently the most common tool to assess performance. It is widely used to rank competitors during races, as well as to manage athletes training and to evaluate material. Usually, this measurement is accurately realized using timing cells. Nevertheless, these devices are too complex and expensive to allow chronometry of every gates crossing. On the other side, differential GPS can be used for measuring gate crossing time (Waegli et al). However, this is complex (e.g. recording gate position with GPS) and mainly used in research applications. The aim of the study was to propose a wearable system to time gates crossing during alpine skiing slalom (SL), which is suitable for routine uses. METHODS: The proposed system was composed of a 3D accelerometer (ADXL320®, Analog Device, USA) placed at the sacrum of the athlete, a matrix of force sensors (Flexiforce®, Tekscan, USA) fixed on the right shin guard and a data logger (Physilog®, BioAGM, Switzerland). The sensors were sampled at 500 Hz. The crossing time were calculated in two phases. First, the accelerometer was used to detect the curves by considering the maximum of the mediolateral peak acceleration. Then, the force sensors were used to detect the impacts with the gates by considering maximum force variation. In case of non impact, the detection was realized based on the acceleration and features measured at the other gates. In order to assess the efficiency of the system, two different SL were monitored twice for two world cup level skiers, a male SL expert and a female downhill expert. RESULTS AND DISCUSSION: The combination of the accelerometer and force sensors allowed to clearly identify the gate crossing times. When comparing the runs of the SL expert and the downhill expert, we noticed that the SL expert was faster. For example for the first SL, the overall difference between the best run of each athlete was of 5.47s. At each gate, the SL expert increased the time difference slower at the beginning (0.27s/gate) than at the end (0.34s/gate). Furthermore, when comparing the runs of the SL expert, a maximum time difference of 20ms at each gate was noticed. This showed high repeatability skills of the SL expert. In opposite, the downhill expert with a maximum difference time of 1s at each gate was clearly less repeatable. Both skiers were not disturbed by the system. CONCLUSION: This study proposed a new wearable system to automatically time gates crossing during alpine skiing slalom combining force and accelerometer sensors. The system was evaluated with two professional world cup skiers and showed a high potential. This system could be extended to time other parameters. REFERENCES Waegli A, Skaloud J (2007). Inside GNSS, Spring, 24-34.

Comments on "On resistor-induced thermal noise in linear circuits"

Correspondència referida a l'article de R. Giannetti, publicat ibid. vol.49 p.87-88

Disseny d’un circuit analògic reconfigurable

En l’actualitat, l’electrònica digital s’està apoderant de la majoria de camps de desenvolupament, ja que ofereix un gran ventall de possibilitats que permeten fer front a gran quantitat de problemàtiques. Poc a Poc s’ha anat prescindint el màxim possible de l’electrònica analògica i en el seu lloc s’han utilitzat sistemes microprocessats, PLDs o qualsevol altre dispositiu digital, que proporciona beneficis enlluernadors davant la fatigosa tasca d’implementar una solució analògica.Tot i aquesta tendència, és inevitable la utilització de l’electrònica analògica, ja que el mon que ens envolta és l’entorn en el que han de proporcionar servei els diferents dissenys que es realitzen, i aquest entorn no és discret sinó continu. Partint d’aquest punt ben conegut hem de ser conscients que com a mínim els filtres d’entrada i sortida de senyal juntament amb els convertidors D/A A/D mai desapareixeran.Així doncs, aquests circuits analògics, de la mateixa forma que els digitals, han de sercomprovats un cop dissenyats, és en aquest apartat on el nostre projecte desenvoluparà un paper protagonista, ja que serà la eina que ha de permetre obtenir les diferents senyals característiques d’un determinat circuit, per posteriorment realitzar els tests que determinaran si es compleix el rang de correcte funcionament, i en cas de no complir, poder concretar quin paràmetre és el causant del defecte

Appropriateness of therapy for active Crohn's disease: results of a multidisciplinary international expert panel-EPACT II

The increasing number of trials testing management strategies for luminal Crohn's disease (CD) has not fitted all the gaps in our knowledge and thus, in clinical. practice, many decisions for CD patients have to be taken without the benefit of high-quality evidence. Methods: A multidisciplinary European expert panel used the RAND Appropriateness Method to develop and rate explicit criteria for the management of individual patients with active, steroid-dependent (ST-D) and steroid-refractory (ST-R) CD. Results: Overall., 296 indications pertaining to mild-to-moderate, severe, ST-D, and ST-R CD were rated. In anti-TNF naive patients, budesonide and prednisone were found to be appropriate for mild-moderate CD, and infliximab (IFX) was appropriate when these had previously failed or had not been tolerated. In patients with a prior successful treatment by IFX, this drug, with or without co-administration of a thiopurine analog, was favoured. Other anti-TNFs were appropriate in the presence of intolerance or resistance to IFX. High-dose steroids, IFX or adlimumab were appropriate in severe active CD. For the 105 indications for ST-D or ST-R disease, the panel considered the thiopurine analogs, methotrexate, IFX, adalimumab, and surgery for limited resection, to be appropriate, depending on the outcome of prior therapies. Anti-TNFs were generally considered appropriate in ST-R. Conclusion: Steroids, including budesonide for mild-to-moderate CD, remain the first-line therapy for active luminal CD. Anti-TNFs, in particular IFX as shown by the amount of available evidence, remain the second-line therapy for most indications. Thiopurine analogs, methotrexate and anti-TNFs are favoured in ST-D patients and ST-R patients. (C) 2009 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

The use of positional scanning synthetic combinatorial libraries (PS-SCL) to study T Lympohcyte specificity and degeneracy

Les cellules CD8? T cytolytiques (CTL) sont les principaux effecteurs du système immunitaire adaptatif contre les infections et les tumeurs. La récente identification d?antigènes tumoraux humains reconnus par des cellules T cytolytiques est la base pour le, développement des vaccins antigène spécifiques contre le cancer. Le nombre d?antigènes tumoraux reconnus par des CTL que puisse être utilisé comme cible pour la vaccination des patients atteints du cancer est encore limité. Une nouvelle technique, simple et rapide, vient d?être proposée pour l?identification d?antigènes reconnus par des CTL. Elle se base sur l?utilisation de librairies combinatoriales de peptides arrangées en un format de "scanning" ou balayage par position (PS-SCL). La première partie de cette étude a consisté à valider cette nouvelle technique par une analyse détaillée de la reconnaissance des PS-SCL par différents clones de CTL spécifiques pour des antigènes associés à la tumeur (TAA) connus ainsi que par des clones de spécificité inconnue. Les résultats de ces analyses révèlent que pour tous les clones, la plupart des acides aminés qui composent la séquence du peptide antigénique naturel ont été identifiés par l?utilisation des PS-SCL. Les résultats obtenus ont permis d?identifier des peptides analogues ayant une antigènicité augmentée par rapport au peptide naturel, ainsi que des peptides comportant de multiples modifications de séquence, mais présentant la même réactivité que le peptide naturel. La deuxième partie de cette étude a consisté à effectuer des analyses biométriques des résultats complexes générés par la PS-SCL. Cette approche a permis l?identification des séquences correspondant aux épitopes naturels à partir de bases de données de peptides publiques. Parmi des milliers de peptides, les séquences naturelles se trouvent comprises dans les 30 séquences ayant les scores potentiels de stimulation les plus élevés pour chaque TAA étudié. Mais plus important encore, l?utilisation des PS-SCL avec un clone réactif contre des cellules tumorales mais de spécificité inconnue nous a permis d?identifier I?epitope reconnu par ce clone. Les données présentées ici encouragent l?utilisation des PS-SCL pour l?identification et l?optimisation d?épitopes pour des CTL réactifs anti-tumoraux, ainsi que pour l?étude de la reconnaissance dégénérée d?antigènes par les CTL.<br/><br/>CD8+ cytolytic T lymphocytes (CTL) are the main effector cells of the adaptive immune system against infection and tumors. The recent identification of moleculariy defined human tumor Ags recognized by autologous CTL has opened new opportunities for the development of Ag-specific cancer vaccines. Despite extensive work, however, the number of CTL-defined tumor Ags that are suitable targets for the vaccination of cancer patients is still limited, especially because of the laborious and time consuming nature of the procedures currentiy used for their identification. The use of combinatorial peptide libraries in positionai scanning format (Positional Scanning Synthetic Combinatorial Libraries, PS-SCL)' has recently been proposed as an alternative approach for the identification of these epitopes. To validate this approach, we analyzed in detail the recognition of PS-SCL by tumor-reactive CTL clones specific for multiple well-defined tumor-associated Ags (TAA) as well as by tumor-reactive CTL clones of unknown specificity. The results of these analyses revealed that for all the TAA-specific clones studied most of the amino acids composing the native antigenic peptide sequences could be identified through the use of PS-SCL. Based on the data obtained from the screening of PS-SCL, we could design peptide analogs of increased antigenicity as well as cross-reactive analog peptides containing multiple amino acid substitutions. In addition, the resuits of PS-SCL-screening combined with a recently developed biometric data analysis (PS-SCL-based biometric database analysis) allowed the identification of the native peptides in public protein databases among the 30 most active sequences, and this was the case for all the TAA studied. More importantiy, the screening of PS- SCL with a tumor-reactive CTL clone of unknown specificity resulted in the identification of the actual epitope. Overall, these data encourage the use of PS-SCL not oniy for the identification and optimization of tumor-associated CTL epitopes, but also for the analysis of degeneracy in T lymphocyte receptor (TCR) recognition of tumor Ags.<br/><br/>Les cellules T CD8? cytolytiques font partie des globules blancs du sang et sont les principales responsables de la lutte contre les infections et les tumeurs. Les immunologistes cherchent depuis des années à identifier des molécules exprimées et présentées à la surface des tumeurs qui puissent être reconnues par des cellules T CD8? cytolytiques capables ensuite de tuer ces tumeurs de façon spécifique. Ce type de molécules représente la base pour le développement de vaccins contre le cancer puisqu?elles pourraient être injectées aux patients afin d?induire une réponse anti- tumorale. A présent, il y a très peu de molécules capables de stimuler le système immunitaire contre les tumeurs qui sont connues parce que les techniques développées à ce jour pour leur identification sont complexes et longues. Une nouvelle technique vient d?être proposée pour l?identification de ce type de molécules qui se base sur l?utilisation de librairies de peptides. Ces librairies représentent toutes les combinaisons possibles des composants de base des molécules recherchées. La première partie de cette étude a consisté à valider cette nouvelle technique en utilisant des cellules T CD8? cytolytiques capables de tuer des cellules tumorales en reconnaissant une molécule connue présente à leur surface. On a démontré que l?utilisation des librairies permet d?identifier la plupart des composants de base de la molécule reconnue par les cellules T CD8? cytolytiques utilisées. La deuxième partie de cette étude a consisté à effectuer une recherche des molécules potentiellement actives dans des protéines présentes dans des bases des données en utilisant un programme informatique qui permet de classer les molécules sur la base de leur activité biologique. Parmi des milliers de molécules de la base de données, celles reconnues par nos cellules T CD8? cytolytiques ont été trouvées parmi les plus actives. Plus intéressant encore, la combinaison de ces deux techniques nous a permis d?identifier la molécule reconnue par une population de cellules T CD8? cytolytiques ayant une activité anti-tumorale, mais pour laquelle on ne connaissait pas la spécificité. Nos résultats encouragent l?utilisation des librairies pour trouver et optimiser des molécules reconnues spécifiquement par des cellules T CD8? cytolytiques capables de tuer des tumeurs.

Glutathione deficit in schizophrenia: strategies to increase glutathione levels in " in vitro " and clinical studies

Summary: Decrease in glutathione (GSH) levels was observed in cerebrospinal fluid, prefrontal cortex and post-mortem striatum of schizophrenia patients. Evidences suggest a defect in GSH synthesis at the levels of the rate-limiting synthesizing enzyme, glutamate cysteine ligase (GCL). Indeed, polymorphisms in the gene of the modifier subunit of GCL (GCLM) was shown to be associated with the disease in three different populations, GCLM gene expression is decreaséd in fibroblasts from patients and the increase in GCL activity induced by an oxidative stress is lower in patients' fibroblasts compared to controls. GSH being a major antioxydant and redox regulator, its presence is of high importance for protecting cells against oxidative stress. The aim of the present work was to use various substances to increase GSH levels by diverse strategies. Since the synthesizing enzyme GCL is defective, bypassing this enzyme was the first strategy we used. GSH ethyl ester (GSHEE), a membrane permeable analog of GSH, succeeded in replenishing GSH levels in cultured neurons and astrocytes previously depleted in GSH by L-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of GCL. GSHEE also abolished dopamine-induced decrease of NMDA-mediated calcium response observed in BSO-treated neurons. y-Glutamylcysteine ethyl ester (GCSE), a membrane permeable analog of the product of GCL, increased GSH levels only in astrocytes. The second strategy was to boost the defective enzyme GCL. While quercetin (flavonoid) could increase GSH levels only in astrocytes, curcumin (polyphenol) and tertbutylhydroquinone (quinone) were successful in both neurons and astrocytes, via an increase in the gene expression of the two subunits of GCL and, consequently, an increase in the activity of the enzyme. However, FK506, an immunosupressant, was unefficient. Treating astrocytes from GCLM KO mice showed that the modulatory subunit is necessary for the action of the substances. Finally, since cysteine is the limiting precursor in the synthesis of GSH, we hypothesized that we could increase GSH levels by providing more of this precursor. N-acetyl-cysteine (NAC), a cysteine donor, was administered to schizophrenia patients, using adouble-blind and cross-over protocol. NAC significantly improved the mismatch negativity (MMN), a component of the auditory evoked potentials, thought to reflect selective current flowing through open, unblocked NMDA channels. Considering that NMDA function is reduced when GSH levels are low, increasing these levels with NAC could improve NMDA function as reflected by the improvement in the generation of the MMN. Résumé: Les taux de glutathion (GSH) dans le liquide céphalo-rachidien, le cortex préfrontal ainsi que le striatum post-mortem de patients schizophrènes, sont diminués. L'enzyme limitante dans la synthèse du GSH, la glutamyl-cysteine ligase (GCL), est défectueuse. En effet, des polymorphismes dans le gène de la sous-unité modulatrice de GCL (GCLM) sont associés à la maladie, l'expression du gène GCLM est diminuée dans les fibroblastes de patients et, lors d'un stress oxidative, l'augmentation de l'activité de GCL est plus faible chez les patients que chez les contrôles. Le GSH étant un important antioxydant et régulateur du status redox, sa présence est primordiale afin de protéger les cellules contre les stress oxydatifs. Au cours du présent travail, une variété de substances ont été utilisées dans le but d'augmenter les taux de GSH. Passer outre l'enzyme de synthèse GCL qui est défectueuse fut la première stratégie utilisée. L'éthylester de GSH (GSHEE), un analogue du GSH qui pénètre la membrane cellulaire, a augmenté les taux de GSH dans des neurones et des astrocytes déficitaires en GSH dû au L-buthionine-(S,R)-sulfoximine (BSO), un inhibiteur du GCL. Dans ces neurones, le GSHEE a aussi aboli la diminution de la réponse NMDA, induite parla dopamine. L'éthyl-ester de y-glutamylcysteine (GCEE), un analogue du produit de la GCL qui pénètre la membrane cellulaire, a augmenté les taux de GSH seulement dans les astrocytes. La seconde stratégie était d'augmenter l'activité de l'enzyme GCL. Tandis que la quercétine (flavonoïde) n'a pu augmenter les taux de GSH que dans les astrocytes, la curcumin (polyphénol) et le tert-butylhydroquinone (quinone) furent efficaces dans les deux types de cellules, via une augmentation de l'expression des gènes des deux sous-unités de GCL et de l'activité de l'enzyme. Le FK506 (immunosupresseur) n' a démontré aucune efficacité. Traiter des astrocytes provenant de souris GCLM KO a permis d'observer que la sous-unité modulatoire est nécessaire à l'action des substances. Enfin, puisque la cysteine est le substrat limitant dans la synthèse du GSH, fournir plus de ce présurseur pourrait augmenter les taux de GSH. Nacétyl-cystéine (NAC), un donneur de cystéine, a été administrée à des schizophrènes, lors d'une étude en double-aveugle et cross-over. NAC a amélioré le mismatch negativity (MMN), un composant des potentials évoqués auditifs, qui reflète le courant circulant via les canaux NMDA. Puisque la fonctionnalité des R-NMDA est diminuée lorsque les taux de GSH sont bas, augmenter ces taux avec NAC pourrait améliorer la fonction des R-NMDA, réflété par une augmentation de l'amplitude du MMN.

FPGA-Based Control Design for Power Electronic Applications

Tehoelektoniikkalaitteella tarkoitetaan ohjaus- ja säätöjärjestelmää, jolla sähköä muokataan saatavilla olevasta muodosta haluttuun uuteen muotoon ja samalla hallitaan sähköisen tehon virtausta lähteestä käyttökohteeseen. Tämä siis eroaa signaalielektroniikasta, jossa sähköllä tyypillisesti siirretään tietoa hyödyntäen eri tiloja. Tehoelektroniikkalaitteita vertailtaessa katsotaan yleensä niiden luotettavuutta, kokoa, tehokkuutta, säätötarkkuutta ja tietysti hintaa. Tyypillisiä tehoelektroniikkalaitteita ovat taajuudenmuuttajat, UPS (Uninterruptible Power Supply) -laitteet, hitsauskoneet, induktiokuumentimet sekä erilaiset teholähteet. Perinteisesti näiden laitteiden ohjaus toteutetaan käyttäen mikroprosessoreja, ASIC- (Application Specific Integrated Circuit) tai IC (Intergrated Circuit) -piirejä sekä analogisia säätimiä. Tässä tutkimuksessa on analysoitu FPGA (Field Programmable Gate Array) -piirien soveltuvuutta tehoelektroniikan ohjaukseen. FPGA-piirien rakenne muodostuu erilaisista loogisista elementeistä ja niiden välisistä yhdysjohdoista.Loogiset elementit ovat porttipiirejä ja kiikkuja. Yhdysjohdot ja loogiset elementit ovat piirissä kiinteitä eikä koostumusta tai lukumäärää voi jälkikäteen muuttaa. Ohjelmoitavuus syntyy elementtien välisistä liitännöistä. Piirissä on lukuisia, jopa miljoonia kytkimiä, joiden asento voidaan asettaa. Siten piirin peruselementeistä voidaan muodostaa lukematon määrä erilaisia toiminnallisia kokonaisuuksia. FPGA-piirejä on pitkään käytetty kommunikointialan tuotteissa ja siksi niiden kehitys on viime vuosina ollut nopeaa. Samalla hinnat ovat pudonneet. Tästä johtuen FPGA-piiristä on tullut kiinnostava vaihtoehto myös tehoelektroniikkalaitteiden ohjaukseen. Väitöstyössä FPGA-piirien käytön soveltuvuutta on tutkittu käyttäen kahta vaativaa ja erilaista käytännön tehoelektroniikkalaitetta: taajuudenmuuttajaa ja hitsauskonetta. Molempiin testikohteisiin rakennettiin alan suomalaisten teollisuusyritysten kanssa soveltuvat prototyypit,joiden ohjauselektroniikka muutettiin FPGA-pohjaiseksi. Lisäksi kehitettiin tätä uutta tekniikkaa hyödyntävät uudentyyppiset ohjausmenetelmät. Prototyyppien toimivuutta verrattiin vastaaviin perinteisillä menetelmillä ohjattuihin kaupallisiin tuotteisiin ja havaittiin FPGA-piirien mahdollistaman rinnakkaisen laskennantuomat edut molempien tehoelektroniikkalaitteiden toimivuudessa. Työssä on myösesitetty uusia menetelmiä ja työkaluja FPGA-pohjaisen säätöjärjestelmän kehitykseen ja testaukseen. Esitetyillä menetelmillä tuotteiden kehitys saadaan mahdollisimman nopeaksi ja tehokkaaksi. Lisäksi työssä on kehitetty FPGA:n sisäinen ohjaus- ja kommunikointiväylärakenne, joka palvelee tehoelektroniikkalaitteiden ohjaussovelluksia. Uusi kommunikointirakenne edistää lisäksi jo tehtyjen osajärjestelmien uudelleen käytettävyyttä tulevissa sovelluksissa ja tuotesukupolvissa.

MANAGING STRATEGIC CHANGE:New Business Models Applying Wireless Technology as a Source of Competitive Edge

The diffusion of mobile telephony began in 1971 in Finland, when the first car phones, called ARP1 were taken to use. Technologies changed from ARP to NMT and later to GSM. The main application of the technology, however, was voice transfer. The birth of the Internet created an open public data network and easy access to other types of computer-based services over networks. Telephones had been used as modems, but the development of the cellular technologies enabled automatic access from mobile phones to Internet. Also other wireless technologies, for instance Wireless LANs, were also introduced. Telephony had developed from analog to digital in fixed networks and allowed easy integration of fixed and mobile networks. This development opened a completely new functionality to computers and mobile phones. It also initiated the merger of the information technology (IT) and telecommunication (TC) industries. Despite the arising opportunity for firms' new competition the applications based on the new functionality were rare. Furthermore, technology development combined with innovation can be disruptive to industries. This research focuses on the new technology's impact on competition in the ICT industry through understanding the strategic needs and alternative futures of the industry's customers. The change speed inthe ICT industry is high and therefore it was valuable to integrate the DynamicCapability view of the firm in this research. Dynamic capabilities are an application of the Resource-Based View (RBV) of the firm. As is stated in the literature, strategic positioning complements RBV. This theoretical framework leads theresearch to focus on three areas: customer strategic innovation and business model development, external future analysis, and process development combining these two. The theoretical contribution of the research is in the development of methodology integrating theories of the RBV, dynamic capabilities and strategic positioning. The research approach has been constructive due to the actual managerial problems initiating the study. The requirement for iterative and innovative progress in the research supported the chosen research approach. The study applies known methods in product development, for instance, innovation process in theGroup Decision Support Systems (GDSS) laboratory and Quality Function Deployment (QFD), and combines them with known strategy analysis tools like industry analysis and scenario method. As the main result, the thesis presents the strategic innovation process, where new business concepts are used to describe the alternative resource configurations and scenarios as alternative competitive environments, which can be a new way for firms to achieve competitive advantage in high-velocity markets. In addition to the strategic innovation process as a result, thestudy has also resulted in approximately 250 new innovations for the participating firms, reduced technology uncertainty and helped strategic infrastructural decisions in the firms, and produced a knowledge-bank including data from 43 ICT and 19 paper industry firms between the years 1999 - 2004. The methods presentedin this research are also applicable to other industries.

A parameterization method for the computation of invariant tori and their whiskers in quasi-periodic maps: explorations and mechanisms for the breakdown of hyperbolicity

In two previous papers [J. Differential Equations, 228 (2006), pp. 530 579; Discrete Contin. Dyn. Syst. Ser. B, 6 (2006), pp. 1261 1300] we have developed fast algorithms for the computations of invariant tori in quasi‐periodic systems and developed theorems that assess their accuracy. In this paper, we study the results of implementing these algorithms and study their performance in actual implementations. More importantly, we note that, due to the speed of the algorithms and the theoretical developments about their reliability, we can compute with confidence invariant objects close to the breakdown of their hyperbolicity properties. This allows us to identify a mechanism of loss of hyperbolicity and measure some of its quantitative regularities. We find that some systems lose hyperbolicity because the stable and unstable bundles approach each other but the Lyapunov multipliers remain away from 1. We find empirically that, close to the breakdown, the distances between the invariant bundles and the Lyapunov multipliers which are natural measures of hyperbolicity depend on the parameters, with power laws with universal exponents. We also observe that, even if the rigorous justifications in [J. Differential Equations, 228 (2006), pp. 530-579] are developed only for hyperbolic tori, the algorithms work also for elliptic tori in Hamiltonian systems. We can continue these tori and also compute some bifurcations at resonance which may lead to the existence of hyperbolic tori with nonorientable bundles. We compute manifolds tangent to nonorientable bundles.

Mitta-anturin mittauselektroniikan kehittäminen teräksen puutislepinnoituksen ohjaukseen

Työn tarkoituksena oli kehittää mittauselektroniikka puutislepinnoitusprosessin ohjaukseen. Mittauselektroniikalla on tarkoitus mitata pikoampeeriluokan virtoja mittaanturilta, jossa virtaa kuuma, noin 250 ºC asteinen kaasu. Mitta-anturin toiminta perustuu ioniliikkuvuusspektrometriaan. Työssä tutkitaan pikoampeeriluokan virtojen mittaamista sekä mittauskytkennöissä käytetyn virta-jännitemuuntimen ominaisuuksia ja mitoittamista. Työ tarkastelee myös T-kytkennän käyttöä vahvistimen takaisinkytkennässä. Jännitekertojakytkentöjä käsitellään teoreettisesti mitta-anturin biasjännitteiden luomiseksi vähäisellä piirilevypinta-alalla. Työssä suunniteltiin mittauselektroniikan esivahvistinprototyypit sekä mitta-anturin biasjännitekytkentä. Mitta-anturin kuumien olosuhteiden vuoksi on mittauselektroniikka siirrettävä etäämmäksi mitta-anturista. Prototyyppikytkennöillä sekä laboratoriomittauksilla selvitettiin mittauselektroniikan esivahvistimien siirtämiseen liittyviä ongelmia. Biasjännitekytkennän suunnittelussa pyrittiin kytkentä toteuttamaan mahdollisimman vähällä piirilevypinta-alalla. Mittauselektroniikka todettiin laboratoriomittausten perusteella toimivaksi puutislepinnoitusprosessissa suoritettavia koemittauksia varten.

Sulautetun moniprosessorijärjestelmän suunnittelu sähkömoottorien ohjaus- ja valvontatarpeisiin

Universal Converter (UNICON) –projektin osana suunniteltiin sähkömoottorikäyttöjen ohjaukseen ja mittaukseen soveltuva digitaaliseen signaaliprosessoriin (DSP) pohjautuva sulautettu järjestelmä. Riittävän laskentatehon varmistamiseksi päädyttiin käyttämään moniprosessorijärjestelmää. Prosessorijärjestelmässä käytettävää DSP-piiriä valittaessa valintaperusteina olivat piirien tarjoama prosessointiteho ja moniprosessorituki. Analog Devices:n SHARC-sarjan DSP-piirit täyttivät parhaiten asetetut vaatimukset: Ne tarjoavat tehokkaan käskykannan lisäksi suuren sisäisen muistin ja sisäänrakennetun moniprosessorituen. Järjestelmän mittalaiteluonteisuudesta johtuen keskeinen suunnitteluparametri oli luoda nopeat tiedonsiirtoyhteydet mittausantureilta DSP-järjestelmään. Tämä toteutettiin käyttäen ohjelmointavia FPGA-logiikkapiirejä digitaalimuotoisen mittausdatan vastaanotossa ja esikäsittelyssä. Tiedonsiirtoyhteys PC-tietokoneelle toteutettiin käyttäen erityistä liityntäkorttia DSP-järjestelmän ja PC-tietokoneen välillä. Liityntäkortin päätehtävänä on puskuroida siirrettävä data. Järjestelyllä estetään PC-tietokoneen vaikutus DSP-järjestelmän toimintaan, jotta kyetään takaamaan järjestelmän reaaliaikainen toiminta kaikissa olosuhteissa.