The need for combination antihypertensive therapy to reach target blood pressures: what has been learned from clinical practice and morbidity-mortality trials?

Pharmacological treatment of hypertension represents a cost-effective way for preventing cardiovascular and renal complications. To benefit maximally from antihypertensive treatment blood pressure (BP) should be brought to below 140/90 mmHg in every hypertensive patient, and even lower (< 130/80 mmHg) if diabetes or renal disease co-exists. Most of the time such targets cannot be reached using monotherapies. This is especially true in patients who exhibit a high cardiovascular risk. The co-administration of two agents acting by different mechanisms considerably increases BP control. Such preparations are not only efficacious, but also well tolerated, and some fixed low-dose combinations have a tolerability profile similar to placebo. This is for instance the case for the preparation containing the angiotensin-converting enzyme inhibitor perindopril (2 mg) and the diuretic indapamide (0.625 mg), a fixed low-dose combination that has recently been shown in controlled interventional trials to be more effective than monotherapies in reducing albuminuria, regressing cardiac hypertrophy and improving macrovascular stiffness. Fixed-dose combinations are becoming more and more popular and are even proposed by current hypertension guidelines as a first-line option to treat hypertensive patients.

Occasional adnominal idiom modification : a cognitive linguistic approach

abstract:occasional Adnominal Idiom Modification - A Cognitive Linguistic Approach From a cognitive-linguistic perspective, this paper explores alternative types of adnoniinal modification in occasional variants of English verbal idioms. Being discussed against data extracted from the British National Corpiis (BNC), the model claims that in idioni-production idiomatic constructions are activated as complex linguistic schemas to code a context-specific target-conceptualisation. Adnominal pre- and postmodifications are one specific form of creative alteration to adapt the idiom for this purpose. Semantically, idiom-interna1 NPextension is not a uniforni process. It is necessary to distinguish two systematic types of adnominal modification: external and internal modification (Ernst 1981). While external NPmodification has adverbial function, ¡.e. it modifies the idiom as a unit, internal modification directly applies to the head-noun and thus depends on the degree of motivation and analysability of a given idiom. Following the cognitive-linguistic framework, these dimensions of idiom-transparency result from the language user's ability to remotivate the bipartite semantic structure by conceptual metaphors and metonymies.

Liiketoimintasuunnitelman laatiminen katsastusalan yritykselle

Tämän diplomityön päätavoitteena oli laatia katsastusalan yritykselle liiketoimintasuunnitelma, joka luo perustan yrityksen johtamiselle ja jatkokehittämiselle.Katsastus Kovalainen Oy tarvitsee jatkuvaan käyttöönsä yrityksen toimintaa ohjaavan viitekehyksen. Ensimmäisenä alaongelmana oli selvittää, mitä liiketoiminnaneri osa-alueita liiketoimintasuunnitelma käsittelee? Onnistuneen liiketoimintasuunnitelman yhtenä peruspilarina voidaan pitää sitä, kuinka hyvin se soveltuu kohdeyrityksen käyttöön ja onko sen sisältämä tieto oleellista juuri kohdeyritykselle? Toinen alaongelma ratkaistiin vastaamalla kysymykseen: Millä tavoin yrityksestä ja sen toimintaympäristöstä kyetään erottamaan juuri se oleellisin tieto liiketoimintasuunnitelman luomiseksi? Kolmanneksi alaongelmaksi muodostui kysymys siitä, kuinka liiketoimintasuunnitelman viitekehys ja empiirinen tieto yhdistetään toimivaksi kokonaisuudeksi, jota yritys voi hyödyntää. Työn teoriaosuus on tehty kirjallisuustutkimuksena ja siinä esitellään liiketoimintasuunnitelmaan kuuluvat osa-alueet teorian näkökulmasta. Empiirisen osuuden tiedot on kerätty pääasiassa haastatteluiden avulla. Empiiristä aineistoa on kerätty myös käyttämällä hyväksi jo olemassa olevaa dokumentoitua tietoa yrityksestä, kuten yrityksen tilinpäätös- ja markkinaosuusraportteja. Liiketoimintasuunnitelmaan kuuluva yrityksen sisäinen analyysi auttoi yrityksen johtoa identifioimaan ja priorisoimaan ne toiminnot ja tekijät, jotka eniten vaikuttavat yrityksen menestymiseen ja kilpailukykyyn. Kyseisen analysoinnin avulla huomattiin, että suurimmat puutteet ja kehitystoimenpiteet koskivat Katsastus Kovalaisen markkinointia ja katsastustiloja.Toimintaympäristön analysoinnin tuloksena huomattiin, että Katsastus Kovalaisenmarkkinaosuus on jo 40 prosenttia, jota voidaan pitää sen verran suurena, että tärkeimmäksi tekijäksi tulevaisuudessa katsottiin nykyisen markkinaosuuden säilyttäminen muun muassa pitämällä nykyiset asiakkaat tyytyväisenä.

Pauson-Khand reaction of internal dissymmetric trifluoromethyl alkynes. influence of the alkene on the regioselectivity

Abstract: The scope of the Pauson-Khand reaction (PKR) of internal trifluoromethyl alkynes, previously described with norbornadiene, is expanded to norbornene and ethylene. A thorough structural analysis of the resulting PK adducts has been carried out to unveil that α-trifluoromethylcyclopentenones are preferred in all cases, independently of the electronic properties of the alkyne. The regioselectivity observed with norbornadiene and ethylene is higher than in the case of norbornene.

egr-4, a target of EGFR signaling, is required for the formation of the brian primordial and head regeneration in planarians

During the regeneration of freshwater planarians, polarity and patterning programs play essential roles in determining whether a head or a tail regenerates at anterior or posterior-facing wounds. This decision is made very soon after amputation. The pivotal role of the Wnt/β-catenin and Hh signaling pathways in re-establishing anterior-posterior (AP) polarity has been well documented. However, the mechanisms that control the growth and differentiation of the blastema in accordance with its AP identity are less well understood. Previous studies have described a role of Smed-egfr-3, a planarian epidermal growth factor receptor, in blastema growth and differentiation. Here, we identify Smed-egr-4, a zinc-finger transcription factor belonging to the early growth response gene family, as a putative downstream target of Smed-egfr-3. Smed-egr-4 is mainly expressed in the central nervous system and its silencing inhibits anterior regeneration without affecting the regeneration of posterior regions. Single and combinatorial RNA interference to target different elements of the Wnt/β-catenin pathway, together with expression analysis of brain- and anterior-specific markers, revealed that Smed-egr-4: (1) is expressed in two phases - an early Smed-egfr-3-independent phase and a late Smed-egfr-3-dependent phase; (2) is necessary for the differentiation of the brain primordia in the early stages of regeneration; and (3) that it appears to antagonize the activity of the Wnt/β-catenin pathway to allow head regeneration. These results suggest that a conserved EGFR/egr pathway plays an important role in cell differentiation during planarian regeneration and indicate an association between early brain differentiation and the proper progression of head regeneration.

Kansainvälisten yhtiöiden yritysostot Venäjän elintarviketeollisuudessa

Tässä työssä tutkittiin Venäjän elintarviketeollisuuteen vuosina 1992 - 2004 investoineitakansainvälisiä yhtiöitä, niiden käyttämiä investointitapoja ja yritysostojen motiiveja. Viime vuosina Venäjän bruttokansantuote kasvoi yli 4 % vuodessa. Venäjän ostovoima kasvoi talouden mukana. Venäjän elintarviketeollisuudella on vieläkin kasvupotentiaalia. Paikallinen elintarvikevalmistus on varteenotettava vaihtoehto, jota kannattaa harkita. Vuosina 1992 - 2004 meijeri- ja virvoitusjuomateollisuudessa uusien tehtaiden rakentajia oli enemmän kuin tehtaiden ostajia. Panimoteollisuudessa oli enemmän yritysostojen käyttäjiä kuin uuden tehtaan rakentajia. Konditoriateollisuudessa ja kaikilla tutkituilla sektoreilla yhteensä yritysostojen käyttäjiä oli saman verran kuin uusien tehtaiden rakentajia. Tärkeimmät ulkoiset syyt yritysostoihin Venäjällä olivat markkinoiden koko, hallituspolitiikka ja säädökset, ostettavan kohdeyrityksen tuotemerkki ja kohdeyrityksen markkinaosuus. Tärkeimmät sisäiset syyt yritysostoihin olivat ulkomaan markkinoiden rooli strategiassa, tuotteen sopeuttamisen tarve ja yrityksen omat vapaat resurssit.

Using the balanced scorecard as a tool for procurement strategy implementation

Tavoitteena diplomityössä oli tutkia, miten hankintastrategiaa saataisiin paremmin toteutettua jokapäiväisessä työssä. Strategian implementointiin käytettiin strategiakarttaa sekä balanced scorecard -mittareita. Tutkimus toteutettiin hankintaosastolla Vaasan & Vaasan Oy:ssä, joka toimii leipomotoimialalla viidessä maassa Itämeren alueella. Hankinnan strategiakartta ja balanced scorecard -mittarit laadittiin olemassa olevan hankintastrategian pohjalta. Perinteisiä balanced scorecard -näkökulmia muokattiin paremmin hankintatoimeen sopiviksi. Malliin lisättiin toimittajanäkökulma ja hankinnan rooli pääprosessien tukifunktiona otettiin huomioon muuttamalla balanced scorecardin asiakasnäkökulma sisäisen asiakkaan näkökulmaksi. Strategiakartta myös laadittiin niin, että hankinnan sisäisten asiakkaiden odotukset ovat kartassa tasavertaisina taloudellistentavoitteiden kanssa. Balanced scorecard -mittareiden määrä pidettiin pienenä, jotta niiden toimintaa ohjaava vaikutus olisi mahdollisimman suuri. Mittareita voidaan vaihtaa strategian muuttuessa. Työssä todettiin, että strategiakartta ja balanced scorecard ovat hyviä välineitä strategian muuttamiseen konkreettisiksi toimenpiteiksi myös tukifunktiossa, kun esimerkiksi mallin näkökulmia muokataan tapauskohtaisesti. Strategiakartat ja balanced scorecard tulisi kytkeä osaksi koko yrityksen strategista suunnittelua. Strategiakartan ja balanced scorecardin käytöstä on hankinnalle monia hyötyjä. Työntekijät hahmottavat paremmin oman panoksensa yrityksen tavoitteiden saavuttamisessa. Käytetyt työkalut voivat tukea myös konsernin yksiköiden hankintojen keskittämiskehitystä.

Prosessijohtamisen soveltaminen energialaitoksen kunnossapidossa

Diplomityössä tarkastellaan prosessijohtamista energialaitoksen kunnossapidossa. Tarkastelun kohteena on Helsingin Energian voimalaitosten kunnossapito. Asioita tarkastellaan kunnossapitoliiketoiminnon näkökulmasta. Työ kertoo tapahtuneista muutoksista, nykyisestä toimintatavasta ja tulevaisuuden kehitystarpeista. Työn lähtökohtana ovat energia-alalla tapahtuneet toimintaympäristön muutokset ja yrityksen organisaation muutos. Yrityksen organisaatio on muutettu funktionaalisesta organisaatiosta liiketoimintopohjaiseksi, joka toi mukanaan sisäisen kaupankäynnin. Kunnossapidon toimittamiseen asiakkaalle sovelletaan prosessijohtamista. Prosessin kehittyminen on hidasta ja vaatii määrätietoista työtä edistyäkseen. Prosessit on kuvattava ja otettava käyttöön, jonka jälkeen voidaan tunnistaa kehityskohteita. Kunnossapitoprosessi ylittää liiketoimintojen välisen rajan, jonka toimivuus on ratkaisevaa prosessin suorituskyvylle. Prosessijohtamisen edistämiseksi on tunnistettu tärkeimmiksi kehityskohteiksi kunnossapitostrategian kehittäminen, rajapinnan selkiyttäminen ja prosessin mittaaminen.

IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis.

XIAP prevents apoptosis by binding to and inhibiting caspases, and this inhibition can be relieved by IAP antagonists, such as Smac/DIABLO. IAP antagonist compounds (IACs) have therefore been designed to inhibit XIAP to kill tumor cells. Because XIAP inhibits postmitochondrial caspases, caspase 8 inhibitors should not block killing by IACs. Instead, we show that apoptosis caused by an IAC is blocked by the caspase 8 inhibitor crmA and that IAP antagonists activate NF-kappaB signaling via inhibtion of cIAP1. In sensitive tumor lines, IAP antagonist induced NF-kappaB-stimulated production of TNFalpha that killed cells in an autocrine fashion. Inhibition of NF-kappaB reduced TNFalpha production, and blocking NF-kappaB activation or TNFalpha allowed tumor cells to survive IAC-induced apoptosis. Cells treated with an IAC, or those in which cIAP1 was deleted, became sensitive to apoptosis induced by exogenous TNFalpha, suggesting novel uses of these compounds in treating cancer.

Novel insulated gamma and lentis retroviral vectors towards safer genetic modification of stem cells

In otherwise successful gene therapy trials insertional mutagenesis has resulted in leukemia. The identification of new short synthetic genetic insulator elements (GIE) which would both prevent such activation effects and shield the transgene from silencing, is a main challenge. Previous attempts with e.g. b-globin HS4, have met with poor efficacy and genetic instability. We have investigated potential improvement with two new candidate synthetic GIEs in SIN-gamma and lentiviral vectors. With each constructs two internal promoters have been tested: either the strong Fr- MuLV-U3 or the housekeeping hPGK.We could identify a specific combination of insulator 2 repeats which translates into best functional activity, high titers and boundary effect in both gammaretro and lentivectors. In target cells a dramatic shift of expression is observed with an homogenous profile the level of which strictly depends on the promoter strength. These data remain stable in both HeLa cells over three months and cord blood HSCs for two months, irrespective of the multiplicity of infection (MOI). In comparison, control native and SIN vectors expression levels show heterogeneous, depend on the MOI and prove unstable. We have undertaken genotoxicity assessment in comparing integration patterns ingenuity in human target cells sampled over three months using high-throughput pyro-sequencing. Data will be presented. Further genotoxicity assessment will include in vivo studies. We have established insulated vectors which harbour both boundary and enhancer-blocking effect and show stable in prolonged in vitro culture conditions. Work performed with support of EC-DG research FP6-NoE, CLINIGENE: LSHB-CT-2006-018933

Basin-internal derivation of hydrocarbons in the Witwatersrand Basin, South Africa: evidence from bulk and molecular δ13C data

Gold in the quartz-pebble conglomerates of the late Archean Witwatersrand Basin, South Africa, is often intimately associated with carbonaceous matter of organic/biogenic origin which occurs in the form of stratiform carbon seams and paragenetically late bitumen nodules. Both carbon forms are believed to be formed by solidification of migrating hydrocarbons. This paper presents bulk and molecular chemical and stable carbon isotope data for the carbonaceous matter, all of which are used to provide a clue to the source of the hydrocarbons. These data are compared with those from intra-basinal shales and overlying dolostone of the Transvaal Supergroup. The delta C-13 values of the extracts from the Witwatersrand carbonaceous material show small differences (up to 2.4 parts per thousand) compared to the associated insoluble organic matter. This suggests that the auriferous rocks were stained by mobile hydrocarbons produced by thermal and oxidative alteration of indigenous bitumens, a contribution from hydrocarbons derived from intra-basinal Witwatersrand shales cannot be excluded. Individual aliphatic hydrocarbons of the various carbonaceous materials were subjected to compound specific isotope analysis using on-line gas chromatography/combustion/stable isotope ratio mass spectrometry (GC/C/IRMS). The limited variability of the molecular parameters and uniform delta C-13 values of individual n-alkanes (-31.1 +/- 1.7 parts per thousand) and isoprenoids (-30.7 +/- 1.1 parts per thousand) in the Witwatersrand samples exclude the mixing of oils from different sources. Carbonaceous matter in the dolostones shows distinctly different bulk and molecular isotope characteristics and thus cannot have been the source of the hydrocarbons in the Witwatersrand deposits. All the various forms of Witwatersrand carbon appear indigenous to the Witwatersrand Basin, and the differences between them are explained by variable, in general probably short (centimeter- to meter-scale) hydrocarbon migration during diagenesis and subsequent hydrothermal infiltration. (C) 2001 Elsevier Science B.V. All rights reserved.

Raeder's paratrigeminal syndrome due to spontaneous dissection of the cervical and petrous internal carotid artery.

The combination of pain, ipsilateral oculosympathetic defect (ptosis and miosis), and ipsilateral trigeminal dysfunction constitutes Raeder's syndrome. We describe a patient with an acute presentation of Raeder's syndrome due to spontaneous internal carotid artery dissection. True trigeminal dysfunction due to carotid dissection is rare, and the potential mechanisms for its involvement are reviewed in this paper. Finally, we remind clinicians to consider dissection in the differential diagnosis of Raeder's syndrome because of its potential for ischemic cerebral neurologic sequelae and suggest early cranial and neck imaging in the evaluation of such patients.

Genomic determinants of the efficiency of internal ribosomal entry sites of viral and cellular origin

Variation in cellular gene expression levels has been shown to be inherited. Expression is controlled at transcriptional and post-transcriptional levels. Internal ribosome entry sites (IRES) are used by viruses to bypass inhibition of cap-dependent translation, and by eukaryotic cells to control translation under conditions when protein synthesis is inhibited. We aimed at identifying genomic determinants of variability in IRES-mediated translation of viral [Encephalomyocarditis virus (EMCV)] and cellular IRES [X-linked inhibitor-of-apoptosis (XIAP) and c-myc]. Bicistronic lentiviral constructs expressing two fluorescent reporters were used to transduce laboratory and B lymphoblastoid cell lines [15 CEPH pedigrees (n = 205) and 50 unrelated individuals]. IRES efficiency varied according to cell type and among individuals. Control of IRES activity has a significant genetic component (h(2) of 0.47 and 0.36 for EMCV and XIAP, respectively). Quantitative linkage analysis identified a suggestive locus (LOD 2.35) on chromosome 18q21.2, and genome-wide association analysis revealed of a cluster of SNPs on chromosome 3, intronic to the FHIT gene, marginally associated (P = 5.9E-7) with XIAP IRES function. This study illustrates the in vitro generation of intermediate phenotypes by using cell lines for the evaluation of genetic determinants of control of elements such as IRES.

Synthesis and multi-target biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents

We have synthesized a family of rheinhuprine hybrids to hit several key targets for Alzheimer"s disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase butyrylcholinesterase, and BACE-1, dual Aβ42 and tau anti-aggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and ()-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction , preventing the loss of synaptic proteins and/or have a positive effect on the induction of long term potentiation. In vivo studies in APP-PS1 transgenic mice treated i.p. for 4 weeks with (+)- and ()-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and ()-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.

Synthesis and multi-target biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents

We have synthesized a family of rheinhuprine hybrids to hit several key targets for Alzheimer"s disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase butyrylcholinesterase, and BACE-1, dual Aβ42 and tau anti-aggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and ()-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction , preventing the loss of synaptic proteins and/or have a positive effect on the induction of long term potentiation. In vivo studies in APP-PS1 transgenic mice treated i.p. for 4 weeks with (+)- and ()-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and ()-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.