Interplay of oxidative, nitrosative/nitrative stress, inflammation, cell death and autophagy in diabetic cardiomyopathy.

Diabetes is a recognized risk factor for cardiovascular diseases and heart failure. Diabetic cardiovascular dysfunction also underscores the development of diabetic retinopathy, nephropathy and neuropathy. Despite the broad availability of antidiabetic therapy, glycemic control still remains a major challenge in the management of diabetic patients. Hyperglycemia triggers formation of advanced glycosylation end products (AGEs), activates protein kinase C, enhances polyol pathway, glucose autoxidation, which coupled with elevated levels of free fatty acids, and leptin have been implicated in increased generation of superoxide anion by mitochondria, NADPH oxidases and xanthine oxidoreductase in diabetic vasculature and myocardium. Superoxide anion interacts with nitric oxide forming the potent toxin peroxynitrite via diffusion limited reaction, which in concert with other oxidants triggers activation of stress kinases, endoplasmic reticulum stress, mitochondrial and poly(ADP-ribose) polymerase 1-dependent cell death, dysregulates autophagy/mitophagy, inactivates key proteins involved in myocardial calcium handling/contractility and antioxidant defense, activates matrix metalloproteinases and redox-dependent pro-inflammatory transcription factors (e.g. nuclear factor kappaB) promoting inflammation, AGEs formation, eventually culminating in myocardial dysfunction, remodeling and heart failure. Understanding the complex interplay of oxidative/nitrosative stress with pro-inflammatory, metabolic and cell death pathways is critical to devise novel targeted therapies for diabetic cardiomyopathy, which will be overviewed in this brief synopsis. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases.

Pro-inflammatory cytokines induce the transcription factors C/EBPbeta and C/EBPdelta in astrocytes.

The transcription factors CCAAT/enhancer binding protein (C/EBP)-beta and -delta are key regulators for the expression of the acute phase genes in the liver, such as complement component C3 and antichymotrypsin. In the brain, these acute phase proteins are produced in response to pro-inflammatory cytokines by the reactive astrocytes, in particular those surrounding the amyloid plaques of Alzheimer's disease brains. Here we show that lipopolysaccharides (LPS), IL-1beta, and TNFalpha induce the expression of the c/ebpbeta and -delta genes in mouse primary astrocytes. This induction precedes the expression of the acute phase genes coding for the complement component C3 and the mouse homologue of antichymotrypsin. The induction of these two acute phase genes by LPS is blocked by cycloheximide, whereas this protein synthesis inhibitor does not affect the expression of the c/ebp genes. Altogether, our data support a role as immediate-early genes for c/ebpbeta and -delta, whose expression is induced by pro-inflammatory cytokines in mouse cortical astrocytes. In the liver, these transcription factors are known to play an important role in inflammation and energy metabolism regulation. Therefore, C/EBPbeta and -delta could be pivotal transcription factors involved in brain inflammation, in addition to their previously demonstrated role in brain glycogen metabolism regulation (Cardinaux and Magistretti. J Neurosci 16:919-929, 1996).

ZigBee/ZigBee PRO security assessment based on compromised cryptographic keys

Sensor networks have many applications in monitoring and controlling of environmental properties such as sound, acceleration, vibration and temperature. Due to limitedresources in computation capability, memory and energy, they are vulnerable to many kinds of attacks. The ZigBee specification based on the 802.15.4 standard, defines a set of layers specifically suited to sensor networks. These layers support secure messaging using symmetric cryptographic. This paper presents two different ways for grabbing the cryptographic key in ZigBee: remote attack and physical attack. It also surveys and categorizes some additional attacks which can be performed on ZigBee networks: eavesdropping, spoofing, replay and DoS attacks at different layers. From this analysis, it is shown that some vulnerabilities still in the existing security schema in ZigBee technology.

Patent foramen ovale in patients with ischaemic stroke of unknown cause: to close? "pro closure" position

There is ample epidemiological and anecdotal evidence that a PFO increases the risk of stroke both in young and elderly patients, although only in a modest way: PFOs are more prevalent in patients with cryptogenic (unexplained) stroke than in healthy subjects, and are more prevalent in cryptogenic stroke than in strokes of other causes. Furthermore, multiple case series confirm an association of paradoxical embolism across a PFO in patients with deep vein thrombosis and/or pulmonary emboli.2. Is stroke recurrence risk in PFO-patients really not elevated when compared to PFO-free patients, as suggested by traditional observational studies? This finding is an epidemiological artifact called "the paradox of recurrence risk research" (Dahabreh & Kent, JAMA 2011) and is due to one (minor) risk factor, such as PFO, being wiped out by other, stronger risk factors in the control population.3. Having identified PFO as a risk factor for a first stroke and probably also for recurrences, we have to treat it, because treating risk factors always has paid off. No one would nowadays question the aggressive treatment of other risk factors of stroke such as hypertension, atrial fibrillation, smoking, or hyperlipidemia.4. In order to be effective, the preventive treatment has to control the risk factor (i.e. close effectively the PFO), and has to have little or no side effects. Both these conditions are now fulfilled thanks to increasing expertise of cardiologists with technically advanced closure devices and solid back up by multidisciplinary stroke teams.5. Closing a PFO does not dispense us from treating other stroke risk factors aggressively, given that these are cumulative with PFO.6. The most frequent reason why patients have a stroke recurrence after PFO closure is not that closure is ineffective, but that the initial stroke etiology is insufficiently investigated and not PFO related, and that the recurrence is due to another mechanism because of poor risk factor control.7. Similarly, the randomized CLOSURE study was negative because a) patients were included who had a low chance that their initial event was due to the PFO, b) patients were selected with a low chance that a PFO-related recurrence would occur, c) there was an unacceptable high rate of closure-related side effects, and d) the number of randomized patients was too small for a prevention trial.8. It is only a question of time until a sufficiently large randomized clinical trial with true PFO-related stroke patients and a high PFO-related recurrence risk will be performed and show the effectiveness of this closure9. PFO being a rather modest risk factor for stroke does not mean we should prevent our patients from getting the best available prevention by the best physicians in the best stroke centers Therefore, a PFO-closure performed by an excellent cardiologist following the recommendation of an expert neurovascular specialist after a thorough workup in a leading stroke center is one of the most effective stroke prevention treatments available in 2011.

Typpeä sisältävien jätevesien käsittely 2-n-PRO menetelmällä

Työssä tutkittiin kaksivaiheisen typenpoistoprosessin (2-N-PRO) soveltuvuutta Joutsenon Kukkuroinmäen aluejätekeskuksen kompostointilaitoksen jätevesille pilot-kokein 12.1.- 5.4.2006. Kompostilaitoksella on jätevesien esikäsittelytarve korkeista ammoniumtyppipitoisuuksista johtuen. Pilot-laitteisto koostuu sekoitussäiliöstä, strippaustornista ja katalyyttipolttimesta. Käsiteltävän jäteveden pH nostetaan korkealle tasolle, jolloin ammoniumtyppi muuttuu ammoniakiksi. Vesi johdetaan strippaustorniin, jossa se sadetetaan tornin pohjalle. Ammoniakki erottuu sadetuksessa ilmaan, joka imetään katalyyttipolttimelle. Katalyyttinen poltin käsittelee ammoniakkia typpikaasuksi. Pilot-kokeet suoritettiin jatkuvatoimisesti. Laitteisto pystyy erottamaan jätevedestä ammoniumtyppeä ammoniakiksi ja käsittelemään ammoniakin pääosin typpikaasuksi. Lisäksi suoritettiin panoskoe, jonka tulokset tukevat jatkuvatoimisesta käytöstä saatuja tuloksia.

[Magnificentiores selectioresque Urbis Venetiarum prospectus quos olim Michael Marieschi, Venetus pictor et architectus in plerisque tabulis depinxit, nunc vero ab ipsomet acurate delineante, incidente, tyspisque mandante, iterum in sexdecim aereis tabulis in lucem aeduntur]. [3], Foscarorum ades ad levam, et e conspectu altera Balborum ambo praeter canalem magnum ; ubi etiam solemne nauticum certamen, et maxima prequentia cymbarum vel auro vel argento vel alio ornatu obductarum, fictasque formas exhibentium cernuntur, nec non lintres naviculariorum pro brabrio certantium. Inter easdem aedes exornata ad maiorem spectaculi dignitatm meta super acquas erigitur. : [estampe] / Mich.l Marieschi del.t et inci.t

Référence bibliographique : Toledano, Marieschi, 35d

Specific targeting of pro-death NMDA receptor signals with differing reliance on the NR2B PDZ ligand.

NMDA receptors (NMDARs) mediate ischemic brain damage, for which interactions between the C termini of NR2 subunits and PDZ domain proteins within the NMDAR signaling complex (NSC) are emerging therapeutic targets. However, expression of NMDARs in a non-neuronal context, lacking many NSC components, can still induce cell death. Moreover, it is unclear whether targeting the NSC will impair NMDAR-dependent prosurvival and plasticity signaling. We show that the NMDAR can promote death signaling independently of the NR2 PDZ ligand, when expressed in non-neuronal cells lacking PSD-95 and neuronal nitric oxide synthase (nNOS), key PDZ proteins that mediate neuronal NMDAR excitotoxicity. However, in a non-neuronal context, the NMDAR promotes cell death solely via c-Jun N-terminal protein kinase (JNK), whereas NMDAR-dependent cortical neuronal death is promoted by both JNK and p38. NMDAR-dependent pro-death signaling via p38 relies on neuronal context, although death signaling by JNK, triggered by mitochondrial reactive oxygen species production, does not. NMDAR-dependent p38 activation in neurons is triggered by submembranous Ca(2+), and is disrupted by NOS inhibitors and also a peptide mimicking the NR2B PDZ ligand (TAT-NR2B9c). TAT-NR2B9c reduced excitotoxic neuronal death and p38-mediated ischemic damage, without impairing an NMDAR-dependent plasticity model or prosurvival signaling to CREB or Akt. TAT-NR2B9c did not inhibit JNK activation, and synergized with JNK inhibitors to ameliorate severe excitotoxic neuronal loss in vitro and ischemic cortical damage in vivo. Thus, NMDAR-activated signals comprise pro-death pathways with differing requirements for PDZ protein interactions. These signals are amenable to selective inhibition, while sparing synaptic plasticity and prosurvival signaling.

Emerging paradigms and questions on pro-angiogenic bone marrow-derived myelomonocytic cells.

Cancer-related inflammation has emerged in recent years as a major event contributing to tumor angiogenesis, tumor progression and metastasis formation. Bone marrow-derived and inflammatory cells promote tumor angiogenesis by providing endothelial progenitor cells that differentiate into mature endothelial cells, and by secreting pro-angiogenic factors and remodeling the extracellular matrix to stimulate angiogenesis though paracrine mechanisms. Several bone marrow-derived myelonomocytic cells, including monocytes and macrophages, have been identified and characterized by several laboratories in recent years. While the central role of these cells in promoting tumor angiogenesis, tumor progression and metastasis is nowadays well established, many questions remain open and new ones are emerging. These include the relationship between their phenotype and function, the mechanisms of pro-angiogenic programming, their contribution to resistance to anti-angiogenic treatments and to metastasis and their potential clinical use as biomarkers of angiogenesis and anti-angiogenic therapies. Here, we will review phenotypical and functional aspects of bone marrow-derived myelonomocytic cells and discuss some of the current outstanding questions.

Programa de Càlcul Nutricional Professional (PCN Pro)

Aplicació de càlcul nutricional que permet les següents funcionalitats: Gestió d’Individus/Pacients permet organitzar els pacients en carpetes i subcarpetes, podent incorporar un històric de dades antropomètriques i dietètic i calcular els següents dades: IMC (Índex de Massa Corporal), Índex Cintura / Maluc, Estima el pes ideal orientatiu, Estimació de Despesa Energètica per: Harris-Benedict, FAO-OMS, Mifflin-St. Jeor. En base a la informació introduïda a la pestanya Activitat Física estima també la despesa energètica tenint en compte l’activitat física realitzada per l’individu (permet estimar la despesa energètica per 605 activitats).Estimació de necessitats energètiques en malalts per Long et al. i Ireton-Jones amb la base del càlcul del Metabolisme Basal de Harris-Benedict. Introduint els plecs (Plec Pectoral, Plec Bíceps, Plec Abdominal, Plec Supraespinal, Plec Cuixa anterior, Plec Cama medial, Plec Subescapular, Plec Tricipital), els diàmetres (Diàmetre Antero-Posterior Tòrax, Diàmetre Sagital, Diàmetre Húmer, Diàmetre Fèmur, Diàmetre Biacromial, Diàmetre Transversal Tòrax, Diàmetre Biileocrestal) i els perímetres (Perímetre Braç flexionat, Perímetre Braç, Perímetre Canell, Perímetre Cuixa, Perímetre Cama, Perímetre Tòrax) el programa és capaç de calcular el % de greix, massa òssia, massa muscular i massa residual per diferents fórmules (% Gas Yuhasz, % Gras Faulkner, % Gras Siri, % Gras Brozek, Distribució corporal de Drinkwater). També calcula el perímetre muscular del braç i la cama. També calcula el Pes Objectiu en relació a un % Greix objectiu, calculant quin pes hauria de tenir el pacient per un % de Greix donat.

Common Variants of TLR1 Associate with Organ Dysfunction and Sustained Pro- Inflammatory Responses during Sepsis

Background: Toll-like receptors (TLRs) are critical components for host pathogen recognition and variants in genes participating in this response influence susceptibility to infections. Recently, TLR1 gene polymorphisms have been found correlated with whole blood hyper-inflammatory responses to pathogen-associated molecules and associated with sepsis-associated multiorgan dysfunction and acute lung injury (ALI). We examined the association of common variants of TLR1 gene with sepsis-derived complications in an independent study and with serum levels for four inflammatory biomarker among septic patients. Methodology/Principal Findings: Seven tagging single nucleotide polymorphisms of the TLR1 gene were genotyped in samples from a prospective multicenter case-only study of patients with severe sepsis admitted into a network of intensive care units followed for disease severity. Interleukin (IL)-1 b, IL-6, IL-10, and C-reactive protein (CRP) serum levels were measured at study entry, at 48 h and at 7th day. Alleles -7202G and 248Ser, and the 248Ser-602Ile haplotype were associated with circulatory dysfunction among severe septic patients (0.001<=p <= 0.022), and with reduced IL-10 (0.012<= p <=0.047) and elevated CRP (0.011<= p <=0.036) serum levels during the first week of sepsis development. Additionally, the -7202GG genotype was found to be associated with hospital mortality (p =0.017) and ALI (p =0.050) in a combined analysis with European Americans, suggesting common risk effects among studies Conclusions/Significance: These results partially replicate and extend previous findings, supporting that variants of TLR1 gene are determinants of severe complications during sepsis.

Internationalization of Experience Pro concept

Diplomityö on tehty STTF:lle (Software Technology Transfer Finland), joka pyrkii kansainvälisille markkinoille Experience Pro -tuotekonseptillaan. Kansainvälistyminen on haasteellinen prosessi pk-yritykselle, ja haastetta haluttiin lähestyä strategisella suunnittelulla. Työn tavoitteena oli teoriatiedon ja löydettyjen kansainvälistymisesimerkkien avulla tuottaa STTF:lle kansainvälistymissuunnitelma strategiaan pohjautuen.Kaksi merkittävintä strategista valintaa STTF:n kansainvälistymisessä olivat kohdemaiden ja operaatiomuodon valinnat. Päätökset tehtiin strategisten analyysien perusteella. Analyysien avulla määritettiin myös yrityksen kilpailuedut. Löydettyjä vahvuuksia pyrittiin hyödyntämään myöhemmin kansainvälistymisen osastrategioita rakennettaessa. Tavoitteiden asettaminen ja markkinointi-mix:n kehittäminen olivat keskeisimmät osat markkinoinnin osastrategiassa. Jakelukanavan merkitystä korostettiin STTF:n kansainvälistymisessä ja yhteistyölle pyrittiin luomaan hyvät edellytykset. Strategia konkretisoitiin luomalla operatiiviset suunnitelmat markkinoinnin tukimateriaalien tuottamiseksi ja yhteistyökumppanien etsimiseksi. Markkinatutkimuksen perusteella potentiaaliset kohdemaat Experience Pro -konseptille olivat Australia, Hollanti, Irlanti, Iso-Britannia, Norja, Ruotsi, Saksa ja Tanska. STTF:llä on muutama sopiva vaihtoehtoinen operaatiomuoto valittavanaan riippuen kohdemaasta. Suomen maine vakaana, korkean teknologian maana voidaan nähdä maaetuna STTF:lle ja muita vahvuuksia ovat STTF:n teknologinen osaaminen, tuotteeseen liittyvät palvelut ja henkilökohtaiset kontaktit. SWOT-analyysi paljasti STTF:n heikkouksia voitettaviksi.Tulevaisuudessa STTF voi jatkaa kansainvälistymistään suunnitelman mukaisesti. Tavoitteiden saavuttaminen vaatii sitoutumista, aktiivista yhteistyökumppanien etsimistä ja jatkuvaa prosessien kehittämistä vastaamaan kansainvälisten markkinoiden vaatimuksia.