Endogeneizing know-how flows through the nature of R&D investments

In this paper we carefully link knowledge flows to and from a firm s innovation process with this firm s investment decisions. Three types of investments are considered: investments in applied research, investments in basic research, and investments in intellectual property protection. Only when basic research is performed, can the firm effectively access incoming knowledge flows and these incoming spillovers serve to increase the efficiency of own applied research. The firm can at the same time influence outgoing knowledge flows, improving appropriability of its innovations, by investing in protection. Our results indicate that firms with small budgets for innovation will not invest in basic research. This occurs in the short run, when the budget for know-how creation is restricted, or in the long-run, when market opportunities are low, when legal protection is not very important, or, when the pool of accessible and relevant external know-how is limited. The ratio of basic to applied research is non-decreasing in the size of the pool of accessible external know-how, the size and opportunity of the market, and, the effectiveness of intellectual property rights protection. This indicates the existence of economies of scale in basic research due to external market related factors. Empirical evidence from a sample of innovative manufacturing firms in Belgium confirms the economies of scale in basic research as a consequence of the firm s capacity to access external knowledge flows and to protectintellectual property, as well as the complementarity between legal and strategic investments.

Un projet multicentrique suisse pour améliorer la prévention et la récidive après un syndrome coronarien aigu [A Swiss multicentric project to improve the prevention of cardiovascular event recurrence after acute coronary syndromes].

Recurrence of cardiovascular events and mortality remain high after acute coronary syndromes. A Swiss multicentric study, "Inflammation and acute coronary syndromes (ACS)--Novel strategies for prevention and clinical managements", is currently underway with the support of the Swiss National Science Foundation. The study includes a clinical research subproject of which the aim is to assess the impact of the ELIPS program (multi-dimEnsionaL prevention Program after acute coronary Syndrome) on the recurrence of cardiovascular events after an ACS. The basic research sub-projects aim to investigate novel cardiovascular risk biomarkers and genetic determinants of recurrence and to study the role of stem cells after an ACS. Another sub-project will evaluate intracoronary imaging techniques and the efficacy of different types of stents.

Defining substance use disorders: do we really need more than heavy use?

AIMS: The aim of the study was to explore whether the concept of heavy substance use over time can be used as definition of substance use disorder. METHODS: Narrative review. RESULTS: Heavy use over time clearly underlies the neurobiological changes associated with current thinking of substance use disorders. In addition, there is evidence that heavy use over time can explain the majority of social problems and of burden of disease (morbidity and mortality). A definition of substance use disorders via heavy use over time would avoid some of the problems of current conceptualizations, for instance the cultural specificity of concepts such as loss of control. Finally, stressing the continuum of use may avoid the high level of stigmatization currently associated with substance use disorders. CONCLUSION: 'Heavy substance use over time' seems to be a definition of substance use disorders in line with results of basic research and epidemiology. Additionally, it reduces stigmatization. This approach should thus be further explored.

Sustained antipsychotic effect of metacognitive training in psychosis: a randomized-controlled study.

Persistent psychotic symptoms represent a major challenge for psychiatric care. Basic research has shown that psychotic symptoms are associated with cognitive biases. Metacognitive training (MCT) aims at helping patients to become aware of these biases and to improve problem-solving. Fifty-two participants fulfilling diagnostic criteria of schizophrenia or schizoaffective disorders and persistent delusions and stabilized antipsychotic medication were enrolled in this study. Following baseline assessment patients were randomized either to treatment as usual (TAU) conditions or TAU+MCT. The intervention consisted of eight weekly 1-hour sessions (maximum: 8 hours). Participants were assessed at 8 weeks and 6-months later by blind assessors. Participants were assessed with the Psychotic Symptoms Rating Scales (PSYRATS) and the positive subscale of the PANSS. Between-group differences in post- and pre-test values were significant at a medium effect size in favor of the MCT for the PSYRATS delusion scale and the positive scale of the PANSS both at post and follow-up. The results of this study indicate that MCT training has a surplus antipsychotic effect for patients suffering from schizophrenia-related disorders who demonstrate only a partial response to antipsychotic treatment and that the effect of the intervention persists for at least 6 months after the intervention.

High-grade meningiomas: new avenues for drug treatment?

PURPOSE OF REVIEW: For standard first-line treatment of high-grade meningiomas, surgical resection and radiotherapy are regarded as standard of care. In the recurrent setting after exhaustion of all local treatment options, no effective therapies are known and several drugs have failed to show efficacy, but novel compounds may offer hope for better disease control. RECENT FINDINGS: Upregulation of proangiogenic molecules and dysregulation of some signaling pathways such as the platelet-derived growth factor and mammalian target of rapamycin are recurrently found in high-grade meningiomas. Furthermore, in-vitro studies and single patient experience indicate that trabectedin may be an effective therapy in this tumor type. Unfortunately, so far there is a lack of conclusive clinical trials to draw definite conclusions of efficacy of these approaches. SUMMARY: There remains a significant unmet need for defining the role of medical therapy in recurrent high-grade meningioma, and more basic research and multicentric well designed trials are needed in this rare and devastating tumor type. Potentially promising novel therapeutics include antiangiogenic drugs, molecular inhibitors of signaling cascades, immunotherapeutics or trabectedin. However, more basic research is required to identify more promising drug targets. VIDEO ABSTRACT AVAILABLE: See the Video Supplementary Digital Content 1 (http://links.lww.com/CONR/A22).

Stabilised beta-catenin in postnatal ventricular myocardium leads to dilated cardiomyopathy and premature death.

Beta-catenin is a component of the intercalated disc in cardiomyocytes, but can also be involved in signalling and activation of gene transcription. We wanted to determine how long-term changes in beta-catenin expression levels would affect mature cardiomyocytes. Conditional transgenic mice that either lacked beta-catenin or that expressed a non-degradable form of beta-catenin in the adult ventricle were created. While mice lacking beta-catenin in the ventricle do not have an overt phenotype, mice expressing a non-degradable form develop dilated cardiomyopathy and do not survive beyond 5 months. A detailed analysis could reveal that this phenotype is correlated with a distinct localisation of beta-catenin in adult cardiomyocytes, which cannot be detected in the nucleus, no matter how much protein is present. Our report is the first study that addresses long-term effects of either the absence of beta-catenin or its stabilisation on ventricular cardiomyocytes and it suggests that beta-catenin's role in the nucleus may be of little significance in the healthy adult heart.

Assessment of systolic and diastolic LV function by MR myocardial tagging.

Heart failure has been divided into several different forms depending on etiology, clinical course and pathophysiology of left ventricular (LV) dysfunction. Systolic and diastolic dysfunction are characterized by a reduced cardiac output with normal (= diastolic dysfunction) or depressed (= systolic dysfunction) LV pump function. New diagnostic techniques such as magnetic resonance imaging (MRI) allow to determine noninvasively LV 3D motion by labelling specific myocardial regions (= myocardial "tagging") with a rectangular or radial grid. From the deformation of this grid rotational and translational motion of the heart can be derived. A "wringing" motion of the left ventricle has been described during systole which includes a clockwise rotation at the base and a counterclockwise rotation at the apex. During diastole, an "untwisting" motion has been demonstrated. In the normal heart, diastolic "untwisting" occurs primarily during isovolumic relaxation, analogous to the systolic "wringing" which takes place mainly during isovolumic contraction. A prolongation of the "untwisting" motion was found in the hypertrophied (aortic stenosis) and hibernating myocardium. Thus, heart failure is associated with profound alterations in the mechanical function of the heart which are manifested by changes in systolic "wringing" and diastolic "untwisting" motion.

Dextramers: new generation of fluorescent MHC class I/peptide multimers for visualization of antigen-specific CD8+ T cells.

Direct identification as well as isolation of antigen-specific T cells became possible since the development of "tetramers" based on avidin-fluorochrome conjugates associated with mono-biotinylated class I MHC-peptide monomeric complexes. In principle, a series of distinct class I MHC-peptide tetramers, each labelled with a different fluorochrome, would allow to simultaneously enumerate as many unique antigen-specific CD8(+) T cells. Practically, however, only phycoerythrin and allophycocyanin conjugated tetramers have been generally available, imposing serious constraints for multiple labeling. To overcome this limitation, we have developed dextramers which are multimers based on a dextran backbone bearing multiple fluorescein and streptavidin moieties. Here we demonstrate the functionality and optimization of these new probes on human CD8(+) T cell clones with four independent antigen specificities. Their applications to the analysis of relatively low frequency antigen-specific T cells in peripheral blood, as well as their use in fluorescence microscopy, are demonstrated. The data show that dextramers produce a stronger signal than their fluoresceinated tetramer counterparts. Thus, these could become the reagents of choice as the antigen-specific T cell labeling transitions from basic research to clinical application.

Of flies, mice and men: a systematic approach to understanding the early life origins of chronic lung disease.

Despite intensive research efforts, the aetiology of the majority of chronic lung diseases (CLD) in both, children and adults, remains elusive. Current therapeutic options are limited, providing only symptomatic relief, rather than treating the underlying condition, or preventing its development in the first place. Thus, there is a strong and unmet clinical need for the development of both, novel effective therapies and preventative strategies for CLD. Many studies suggest that modifications of prenatal and/or early postnatal lung development will have important implications for future lung function and risk of CLD throughout life. This view represents a fundamental change of current pathophysiological concepts and treatment paradigms, and holds the potential to develop novel preventative and/or therapeutic strategies. However, for the successful development of such approaches, key questions, such as a clear understanding of underlying mechanisms of impaired lung development, the identification and validation of relevant preclinical models to facilitate translational research, and the development of concepts for correction of aberrant development, all need to be solved. Accordingly, a European Science Foundation Exploratory Workshop was held where clinical, translational and basic research scientists from different disciplines met to discuss potential mechanisms of developmental origins of CLD, and to identify major knowledge gaps in order to delineate a roadmap for future integrative research.

STAT3α interacts with nuclear GSK3beta and cytoplasmic RISK pathway and stabilizes rhythm in the anoxic-reoxygenated embryonic heart.

Activation of the Janus Kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) pathway is known to play a key role in cardiogenesis and to afford cardioprotection against ischemia-reperfusion in adult. However, involvement of JAK2/STAT3 pathway and its interaction with other signaling pathways in developing heart transiently submitted to anoxia remains to be explored. Hearts isolated from 4-day-old chick embryos were submitted to anoxia (30 min) and reoxygenation (80 min) with or without the antioxidant MPG, the JAK2/STAT3 inhibitor AG490 or the PhosphoInositide-3-Kinase (PI3K)/Akt inhibitor LY-294002. Time course of phosphorylation of STAT3α(tyrosine705) and Reperfusion Injury Salvage Kinase (RISK) proteins [PI3K, Akt, Glycogen Synthase Kinase 3beta (GSK3beta), Extracellular signal-Regulated Kinase 2 (ERK2)] was determined in homogenate and in enriched nuclear and cytoplasmic fractions of the ventricle. STAT3 DNA-binding was determined. The chrono-, dromo- and inotropic disturbances were also investigated by electrocardiogram and mechanical recordings. Phosphorylation of STAT3α(tyr705) was increased by reoxygenation, reduced (~50%) by MPG or AG490 but not affected by LY-294002. STAT3 and GSK3beta were detected both in nuclear and cytoplasmic fractions while PI3K, Akt and ERK2 were restricted to cytoplasm. Reoxygenation led to nuclear accumulation of STAT3 but unexpectedly without DNA-binding. AG490 decreased the reoxygenation-induced phosphorylation of Akt and ERK2 and phosphorylation/inhibition of GSK3beta in the nucleus, exclusively. Inhibition of JAK2/STAT3 delayed recovery of atrial rate, worsened variability of cardiac cycle length and prolonged arrhythmias as compared to control hearts. Thus, besides its nuclear translocation without transcriptional activity, oxyradicals-activated STAT3α can rapidly interact with RISK proteins present in nucleus and cytoplasm, without dual interaction, and reduce the anoxia-reoxygenation-induced arrhythmias in the embryonic heart.

EH-myomesin splice isoform is a novel marker for dilated cardiomyopathy.

The M-band is the prominent cytoskeletal structure that cross-links the myosin and titin filaments in the middle of the sarcomere. To investigate M-band alterations in heart disease, we analyzed the expression of its main components, proteins of the myomesin family, in mouse and human cardiomyopathy. Cardiac function was assessed by echocardiography and compared to the expression pattern of myomesins evaluated with RT-PCR, Western blot, and immunofluorescent analysis. Disease progression in transgenic mouse models for dilated cardiomyopathy (DCM) was accompanied by specific M-band alterations. The dominant splice isoform in the embryonic heart, EH-myomesin, was strongly up-regulated in the failing heart and correlated with a decrease in cardiac function (R = -0.86). In addition, we have analyzed the expressions of myomesins in human myocardial biopsies (N = 40) obtained from DCM patients, DCM patients supported by a left ventricular assist device (LVAD), hypertrophic cardiomyopathy (HCM) patients and controls. Quantitative RT-PCR revealed that the EH-myomesin isoform was up-regulated 41-fold (P < 0.001) in the DCM patients compared to control patients. In DCM hearts supported by a LVAD and HCM hearts, the EH-myomesin expression was comparable to controls. Immunofluorescent analyses indicate that EH-myomesin was enhanced in a cell-specific manner, leading to a higher heterogeneity of the myocytes' cytoskeleton through the myocardial wall. We suggest that the up-regulation of EH-myomesin denotes an adaptive remodeling of the sarcomere cytoskeleton in the dilated heart and might serve as a marker for DCM in mouse and human myocardium.

Cibles rétiniennes d'action des médicaments [Retinal drug targets].

Retinal effects of systemically administered drugs are rare due to the hematoretinal barriers that protect the retina from circulating active principles. However, some compounds may have direct or indirect toxic effects on the retina through direct interaction with a specific receptor or due to their accumulation within pigment of uveal cells. In the latter case, toxicity is dose-dependent and may be observed years after cessation of medication, as observed with antimalarial drugs. Anti-infective and anti-inflammatory agents, particularly glucocorticoids, are currently injected peri- or intraocularly. The mechanisms and the exact toxicity of glucocorticoids on the retina remain poorly understood. More recently, anti-VEGF has been specifically developed for the treatment of retinal diseases. However, the long-term blockade of VEGF on normal retinal physiology should be determined taking into account VEGF and VEGF receptors expression in the normal and pathologic retina. Whilst enormous advances are made in the treatment of retinal diseases, basic research is still required to define more accurately the molecular targets of drugs to improve their benefits and reduce their potential side effects.

Angiotensin converting enzyme inhibitor induced angio-oedema: a review of the pathophysiology and risk factors.

Angio-oedema (AE) is a known adverse effect of angiotensin converting enzyme inhibitor (ACE-I) therapy. Over the past several decades, evidence of failure to diagnose this important and potentially fatal reaction is commonly found in the literature. Because this reaction is often seen first in the primary care setting, a review was undertaken to analyse and document the keys to both diagnostic criteria as well as to investigate potential risk factors for ACE-I AE occurrence. A general review of published literature was conducted through Medline, EMBASE, and the Cochrane Database, targeting ACE-I-related AE pathomechanism, diagnosis, epidemiology, risk factors, and clinical decision making and treatment. The incidence and severity of AE appears to be on the rise and there is evidence of considerable delay in diagnosis contributing to significant morbidity and mortality for patients. The mechanism of AE due to ACE-I drugs is not fully understood, but some genomic and metabolomic information has been correlated. Additional epidemiologic data and clinical treatment outcome predictors have been evaluated, creating a basis for future work on the development of clinical prediction tools to aid in risk identification and diagnostic differentiation. Accurate recognition of AE by the primary care provider is essential to limit the rising morbidity associated with ACE-I treatment-related AE. Research findings on the phenotypic indicators relevant to this group of patients as well as basic research into the pathomechanism of AE are available, and should be used in the construction of better risk analysis and clinical diagnostic tools for ACE-I AE.

Interaktiivisen oppimisympäristön kehittäminen sähkötekniikan laboratoriotyöskentelyyn

Teklab is a manufacturer of electrical workstations. One major client group for the workstations is schools.Recently Teklab has started to concentrate on offering laboratory packages instead of single workstations. Laboratory packages include e.g. workstations, furniture, assembly and maintenance program. Teklab is looking for ideas to create more value for the laboratory package. One possibility is to design an educationalintroduction package to electric laboratories. In this thesis basic research isdone by studying the teaching methods in use today. Also modern education technology is presented. The thesis analyses different technologies for the laboratory introduction package. The technologies are analysed e.g. by applicability and feasibility. As a result of the work, the introduction has been done using an interactive presentation system. The presentation uses a software program and wireless student handsets designed by Dolphin Interactive. As a part of the work, also the recreation of the Teklab devices' instruction manuals has been started. For the future work, a digital learning object is under work, and a laboratory test is planned.

ELEKTRONIIKKATEHTAAN PAIKALLISESTIVALMISTETTUJEN KOMPONENTTIEN HANKINTAKETJUN KEHITTÄMINEN

Varastojen vähentämiseksi ehdotetaan usein eräkokojen pienentämistä. Tämä sopii sellaiseen toimintaympäristöön, jossa voidaan ostaa nimikkeitä oman valmistuksen ja myynnin tahdissa. Kun kiihkeärytmisessä elektroniikkabisneksessä alihankkijoilta ja varustetoimittajilta sitovasti tilataan hyvin lyhyellä toimitusajalla, ei oston eräkokojen pienentäminen kevennä materiaalivirtaa. Täytyy ottaa löysät pois hankintaketjun toimitusajoista. Monessa toimitusketjussa jalostava työ vaatii vain murto-osan toimitusajasta, ja loppuaika kuluu varastoissa odotteluun, kuljettamiseen ja moninkertaiseen tarkastamiseen. Hukka-ajan leikkaamisen ohessa haetaan muita kustannussäästöjä. Korkeiden työvoimakustannusten rasittama teollisuus on pyrkinyt teknisillä ratkaisuilla korvaamaan palkkatyövoiman erilaisilla mekaanisilla järjestelmillä. Pisimmällä ollaan pienerä- ja yksittäisvalmistusta harjoittavissa konepajoissa, joissa on investoitu FM-järjestelmiin. Diplomityössä on esitetty kaksi nivoutuvaa tutkimusprojektia, joista ensimmäinen keskittyy miehittämättömän käytön kehittämiseen ja toinen keventää hankintaketjun materiaalivirtaa. Ensin esiteltävä projekti on elektroniikkateollisuudelle uusi aluevaltaus. Siksi asiassa on jouduttu tekemään runsaasti perustutkimusta ja etenemään etappi kerrallaan. Projektin tuloksena on saatu aikaan automaattinen, joustava kuljetin, joka yksinään pystyy toimimaan ilman työvoimaa niin pitkään kunnes sen akut pitää ladata. Joustavan kuljettimen sisältävän järjestelmän muita elementtejä ei projektissa nostettu samalle miehittämättömän käytön tasolle, vaan ensin päätettiin hankkia kokemuksia kuljettimen toiminnasta. Toinen projekti syventää yhteistyötä yrityksen alihankkijan kanssa. Alihankkija on yksi harvojen Suomesta hankittavien komponenttien toimittaja. Siksi on pidetty tärkeänä tiivistää toimitusaikaa lähemmäs yrityksen sitovan tilauskannan pituutta. Tutkittavaksi valittiin mahdollisuus siirtää alihankkijan tuotantolaite yrityksen välittömään läheisyyteen, jolloin yrityksen tuotanto voisi tilata komponenttierän alihankkijan koneelta, kun se lähtötilanteessa tilataan komponenttivarastosta. Ennusteen perusteella tilattaisiin vain raaka-aine, mutta arvoa lisäävä työ tehtäisiin vain ja ainoastaan tilauksen mukaisesti.