Prevalence of Acute Coronary Syndrome in Patients Suspected for Pulmonary Embolism or Acute Aortic Syndrome: Rationale for the Triple Rule-out Concept.

BACKGROUND: The aims of the study were to evaluate the prevalence of acute coronary syndrome (ACS) among patients presenting with atypical chest pain who are evaluated for acute aortic syndrome (AAS) or pulmonary embolism (PE) with computed tomoangiography (CTA) and discuss the rationale for the use of triple rule-out (TRO) protocol for triaging these patients. METHODS: This study is a retrospective analysis of patients presenting with atypical chest pain and evaluated with thoracic (CTA), for suspicion of AAS/PE. Two physicians reviewed patient files for demographic characteristics, initial CT and final clinical diagnosis. Patients were classified according to CTA finding into AAS, PE and other diagnoses and according to final clinical diagnosis into AAS, PE, ACS and other diagnoses. RESULTS: Four hundred and sixty-seven patients were evaluated: 396 (84.8%) patients for clinical suspicion of PE and 71 (15.2%) patients for suspicion of AAS. The prevalence of ACS and AAS was low among the PE patients: 5.5% and 0.5% respectively (P = 0.0001), while the prevalence of ACS and PE was 18.3% and 5.6% among AAS patients (P = 0.14 and P = 0.34 respectively). CONCLUSION: The prevalence of ACS and AAS among patients suspected clinically of having PE is limited while the prevalence of ACS and PE among patients suspected clinically of having AAS is significant. Accordingly patients suspected for PE could be evaluated with dedicated PE CTA while those suspected for AAS should still be triaged using TRO protocol.

Role of basic calcium phosphate crystals in osteoarthritis

L'arthrose est une maladie dégénérative des articulations due à une dégradation progressive du cartilage. La calcification de l'articulation (essentiellement due à des dépôts de cristaux de phosphate de calcium basique -cristaux BCP-) est une caractéristique de cette maladie. Cependant, le rôle des cristaux BCP reste à déterminer. Nous avons tout d'abord déterminé en utilisant des cultures primaires de chondrocytes que les cristaux de BCP induisaient la production de la cytokine IL-6, via une signalisation intracellulaire implicant les kinase Syk, PI3 et Jak et Stat3. Les cristaux de BCP induisent également la perte de protéoglycanes et l'expression de IL-6 dans des explants de cartlage humain et ces deux effets peuvent être bloqués par un inhibiteur de IL-6, le Tocilizumab. Par ailleurs, nous avons trouvé que l'IL-6 ajouté à des chondrocytes, favorisait la formation de cristax de BCP et augmentait l'expression de gènes impliqués dans le processus de minéralisation : Ank (codant pour un transporteur de pyrophooshate), Annexin5 (codant pour un canal calcique) et Pit-1 (codant pour un transporteur de phoshate). In vivo, les cristaux de BCP injectés dans l'articulation de souris induisent une érosion du cartilage. Dans un modèle murin d'arthrose du genou induit par ménisectomie, nous avons observé la formation progressive de cristaux de BCP. Fait intéressant, la présence de ces cristaux dans l'articulation précédait la destruction du cartilage. Un agent susceptible de bloquer les calcifications tel que le sodium thiosulfate (STS), administré à des souris ménisectomisées, inhibait le dépôt intra-articulaire de ces cristaux ainsi que l'érosion du cartilage. Nous avons identifié ainsi un cercle vicieux dans l'arthrose, les cristaux induisant l'interleukine-6 et l'interleukine-6 induisant la formation de ces cristaux. Nous avons étudié si on pouvait bloquer cette boucle cristaux de BCP-IL6 soit par des agents décalcifiants, soit par des inhibiteurs d'IL-6. In vitro, des anticorps anti IL- 6 ou des inhibiteurs de signalisation, inhibaient significativement IL-6 et la minéralisation induite par IL-6. De même le STS inhibait la formation de ces cristaux et la production de l'IL-6. Tout récemment, nous avons trouvé que des inhibiteurs de la xanthine oxidoréductase étaient aussi capables d'inhiber à la fois la production d'IL-6 et la minéralization des chondrocytes. Finalement, nous avons pu exclure un rôle du système IL-1 dans le modèle d'arthrose induite par ménisectomie, les souris déficientes pour IL-1a/ß, MyD88 et l'inflammasome NLRP3 n'étant pas protégées dans ce modèle d'arthrose. L'ensemble de nos résultats montre que les cristaux BCP sont pathogéniques dans l'arthrose et qu'un inhibiteur de minéralisation tel que le STS ou un inhibiteur de l'interleukine-6 constitueraient des nouvelles thérapies pour l'arthrose. -- Osteoarthritis (OA), the most common degenerative disorder of the joints, results from an imbalance between the breakdown and repair of the cartilage and surrounding articular structures. Joint calcification (essentially due to basic calcium phosphate (BCP) crystal deposition) is a characteristic feature of OA. However, the role of BCP crystal deposition in the pathogenesis of OA remains unclear[1][1]. We first demonstrated that in primary murine chondrocytes exogenous BCP crystals led to IL-6 up-modulation and that BCP crystal signaling pathways involved Syk and PI3 kinases, and also gp130 associated molecules, Jak2 and Stat3. BCP crystals also induced proteoglycan loss and IL-6 expression in human cartilage expiants, (which were significantly reduced by an IL-6 inhibitor). In addition, we found that in chondrocytes exogenous IL-6 promoted calcium-containing crystal formation and up- regulation of genes codifying for proteins involved in the calcification process: the inorganic pyrophosphate transport channel Ank, the calcium channel Annexinö and the sodium/phosphate cotransporter Piti. In vivo, BCP crystals injected into murine knee joints induced cartilage erosion. In the menisectomy model, increasing deposits, identified as BCP crystals, were progressively observed around the joint before cartilage erosion. These deposits strongly correlated with cartilage degradation and IL-6 expression. These results demonstrated that BCP crystals deposition and IL-6 production are mutually reinforcing in the osteoarthritic pathogenic process. We then investigated if we could block the BCP-IL6 loop by either targeting IL-6 production or BCP crystal deposits. Treatment of chondrocytes with anti-IL-6 antibodies or inhibitors of IL-6- signaling pathway significantly inhibited IL-6-induced crystal formation. Similarly, sodium thiosulfate (STS), a well-known systemic calcification inhibitor, decreased crystal deposition as well as HA-induced IL-6 secretion in chondrocytes and, in vivo, it decreased crystal deposits size and cartilage erosion in menisectomized knees. Interestingly, we also found that xanthine-oxidoreductase (XO) inhibitors inhibited both IL-6 production and calcium crystal depositis in chondrocytes. We began to unravel the mechanisms involved in this coordinate modulation of IL-6 and mineralization. STS inhibited Reactive Oxygen Species (ROS) generation and we are currently investigating whether XO represents a major source of ROS in chondrocyte mineralization. Finally, we ruled out that IL-1 activation/signaling plays a role in the murine model of OA induced by menisectomy, as IL-1a/ß, the IL-1 R associated molecule MyD88 and NLRP3 inflammasome deficient mice were not protected in this model of OA. Moreover TLR-1, -2, -4,-6 deficient mice had a phenotype similar to that of wild-type mice. Altogether our results demonstrated a self-amplification loop between BCP crystals deposition and IL-6 production, which represents an aggravating process in OA pathogenesis. As currently prescribed OA drugs are addressing OA symptoms,our results highlight a potential novel treatment strategy whereby inhibitors of calcium- containing crystal formation and IL-6 could be combined to form the basis of a disease modifying treatment and alter the course of OA.

Creatine deficiency syndomes : a new model of partial GAMT deficiency affecting brain cell development

Les syndromes de déficiences cérébrales en créatine (CCDS) sont dus à des mutations dans les gènes GATM et G AMT (codant pour les enzymes AGAT et G AMT de la voie de synthèse de créatine) ainsi que SLC6A8 (transporteur de créatine), et génèrent une absence ou une très forte baisse de créatine (Cr) dans le cerveau, mesurée par spectroscopic de résonance magnétique. Les patients CCDS développent des handicaps neurologiques sévères. Les patients AGAT et GAMT peuvent être traités avec des doses importantes de Cr, mais gardent dans la plupart des cas des séquelles neurologiques irréversibles. Aucun traitement efficace n'existe à ce jour pour la déficience en SLC6A8. Bien que de nombreux modèles aient été développés pour comprendre la Cr cérébrale en conditions physiologiques, les pathomécanismes des CCDS ne sont pas encore compris. Des souris transgéniques pour les gènes Gatm, Gamt et Slc6a8 ont été générées, mais elles ne miment que partiellement la pathologie humaine. Parmi les CCDS, la déficience en GAMT est la plus sévère, en raison de l'accumulation cérébrale de l'intermédiaire guanidinoacétate (GAA). Alors que la toxicité cérébrale du GAA a été étudiée par exposition directe au GAA d'animaux adultes sains, les mécanismes de la toxicité du GAA en condition de déficience en GAMT dans le cerveau en développement sont encore inconnus. Le but de ce projet était donc de développer un modèle de déficience en GAMT dans des cultures 3D primaires de cellules nerveuses de rat en agrégats par knock-down du gène GAMT, en utilisant un virus adéno-associé (AAV) induisant le mécanisme d'interférence à l'ARN (RNAi). Le virus scAAV2, à la multiplicité d'infection de 1000, s'est révélé le plus efficace pour transduire tous les types de cellules nerveuses des cultures (neurones, astrocytes, oligodendrocytes), et générer un knock-down maximal de la protéine GAMT de 85% (jour in vitro 18). Cette déficience partielle en GAMT s'est révélée insuffisante pour générer une déficience en Cr, mais a causé l'accumulation attendue de GAA, à des doses comparables aux niveaux observés dans le LCR des patients GAMT. Le GAA a induit une croissance axonale anarchique accompagnée d'une baisse de l'apoptose naturelle, suivis par une induction tardive de mort cellulaire non-apoptotique. Le co-traitement par la Cr a prévenu tous les effets toxiques du GAA. Ce travail montre que l'accumulation de GAA en absence de déficience en Cr est suffisante pour affecter le développement du tissu nerveux, et suggère que des formes de déficiences en GAMT supplémentaires, ne présentant pas de déficiences en Cr, pourraient être découvertes par mesure du GAA, en particulier à travers les programmes récemment proposés de dépistage néonatal de la déficience en GAMT. -- Cerebral creatine deficiency syndromes (CCDS) are caused by mutations in the genes GATM and GAMT (respectively coding for the two enzymes of the creatine synthetic pathway, AGAT and GAMT) as well as SLC6A8 (creatine transporter), and lead to the absence or very strong decrease of creatine (Cr) in the brain when measured by magnetic resonance spectroscopy. Affected patients show severe neurological impairments. While AGAT and GAMT deficient patients can be treated with high dosages of Cr, most remain with irreversible brain sequelae. No treatment has been successful so far for SLC6A8 deficiency. While many models have helped understanding the cerebral Cr pathways in physiological conditions, the pathomechanisms underlying CCDS are yet to be elucidated. Transgenic mice carrying mutations in the Gatm, Gamt and Slc6a8 genes have been developed, but only partially mimic the human pathology. Among CCDS, GAMT deficiency is the most severe, due to the CNS accumulation of the guanidinoacetate (GAA) intermediate. While brain toxicity of GAA has been explored through direct GAA exposure of adult healthy animals, the mechanisms underlying GAA toxicity in GAMT deficiency conditions on the developing CNS are yet unknown. The aim of this project was thus to develop and characterize a GAMT deficiency model in developing brain cells by gene knockdown, by adeno-associated virus (AAV)-driven RNA interference (RNAi) in rat 3D organotypic primary brain cell cultures in aggregates. scAAV2 with a multiplicity of infection of 1000 was shown as the most efficient serotype, was able to transduce all brain cell types (neurons, astrocytes, oligodendrocytes) and to induce a maximal GAMT protein knockdown of 85% (day in vitro 18). Metabolite analysis showed that partial GAMT knockdown was insufficient to induce Cr deficiency but generated the awaited GAA accumulation at concentrations comparable to the levels observed in cerebrospinal fluid of GAMT-deficient patients. Accumulated GAA induced axonal hypersprouting paralleled with inhibition of natural apoptosis, followed by a later induction in non-apoptotic cell death. Cr supplementation led to the prevention of all GAA-induced toxic effects. This work shows that GAA accumulation without Cr deficiency is sufficient to affect CNS development, and suggests that additional partial GAMT deficiencies, which may not show the classical brain Cr deficiency, may be discovered through GAA measurement including by recently proposed neonatal screening programs for GAMT deficiency.

Singling out individual inventors from patent data

An increasing number of studies in recent years have sought to identify individual inventors from patent data. A variety of heuristics have been proposed for using the names and other information disclosed in patent documents to establish who is who in patents. This paper contributes to this literature by describing a methodology for identifying inventors using patents applied to the European Patent Office, EPO hereafter. As in much of this literature, we basically follow a threestep procedure : 1- the parsing stage, aimed at reducing the noise in the inventor’s name and other fields of the patent; 2- the matching stage, where name matching algorithms are used to group similar names; and 3- the filtering stage, where additional information and various scoring schemes are used to filter out these similarlynamed inventors. The paper presents the results obtained by using the algorithms with the set of European inventors applying to the EPO over a long period of time.

Aetiologies of pulseless electrical activity in out-of-hospital cardiac arrests:A retrospective study and analysis of specific causes

Background: Pulseless electrical activity (PEA) cardiac arrest is defined as a cardiac arrest (CA) presenting with a residual organized electrical activity on the electrocardiogram. In the last decades, the incidence of PEA has regularly increased, compared to other types of CA like ventricular fibrillation or pulseless ventricular tachycardia. PEA is frequently induced by reversible conditions. The "4 (or 5) H" & "4 (or 5) T" are proposed as a mnemonic to asses for Hypoxia, Hypovolemia, Hypo- /Hyperkalaemia, Hypothermia, Thrombosis (cardiac or pulmonary), cardiac Tamponade, Toxins, and Tension pneumothorax. Other pathologies (intracranial haemorrhage, severe sepsis, myocardial contraction dysfunction) have been identified as potential causes for PEA, but their respective probability and frequencies are unclear and they are not yet included into the resuscitation guidelines. The aim of this study was to analyse the aetiologies of PEA out-of-hospital CA, in order to evaluate the relative frequencies of each cause and therefore to improve the management of patients suffering a PEA cardiac arrest. Method: This retrospective study was based on data routinely and prospectively collected for each PEMS intervention. All adult patients treated from January 1st 2002 to December 2012 31st by the PEMS for out-of-hospital cardiac arrest, with PEA as the first recorded rhythm, and admitted to the emergency department (ED) of the Lausanne University Hospital were included. The aetiologies of PEA cardiac arrest were classified into subgroups, based on the classical H&T's classification, supplemented by four other subgroups analysis: trauma, intra-cranial haemorrhage (ICH), non-ischemic cardiomyopathy (NIC) and undetermined cause. Results: 1866 OHCA were treated by the PEMS. PEA was the first recorded rhythm in 240 adult patients (13.8 %). After exclusion of 96 patients, 144 patients with a PEA cardiac arrest admitted to the ED were included in the analysis. The mean age was 63.8 ± 20.0 years, 58.3% were men and the survival rate at 48 hours was 29%. 32 different causes of OHCA PEA were established for 119 patients. For 25 patients (17.4 %), we were unable to attribute a specific cause for the PEA cardiac arrest. Hypoxia (23.6 %), acute coronary syndrome (12.5%) and trauma (12.5 %) were the three most frequent causes. Pulmonary embolism, Hypovolemia, Intoxication and Hyperkaliemia occurs in less than 10% of the cases (7.6 %, 5.6 %, 3.5%, respectively 2.1 %). Non ischemic cardiomyopathy and intra-cranial haemorrhage occur in 8.3 % and 6.9 %, respectively. Conclusions: According to our results, intra-cranial haemorrhage and non-ischemic cardiomyopathy represent noticeable causes of PEA in OHCA, with a prevalence equalling or exceeding the frequency of classical 4 H's and 4 T's aetiologies. These two pathologies are potentially accessible to simple diagnostic procedures (native CT-scan or echocardiography) and should be included into the 4 H's and 4 T's mnemonic.

Validation of plant dynamic model by online and laboratory measurements – a tool to predict online COD loads out of production of mechanical printing papers

COD discharges out of processes have increased in line with elevating brightness demands for mechanical pulp and papers. The share of lignin-like substances in COD discharges is on average 75%. In this thesis, a plant dynamic model was created and validated as a means to predict COD loading and discharges out of a mill. The assays were carried out in one paper mill integrate producing mechanical printing papers. The objective in the modeling of plant dynamics was to predict day averages of COD load and discharges out of mills. This means that online data, like 1) the level of large storage towers of pulp and white water 2) pulp dosages, 3) production rates and 4) internal white water flows and discharges were used to create transients into the balances of solids and white water, referred to as “plant dynamics”. A conversion coefficient was verified between TOC and COD. The conversion coefficient was used for predicting the flows from TOC to COD to the waste water treatment plant. The COD load was modeled with similar uncertainty as in reference TOC sampling. The water balance of waste water treatment was validated by the reference concentration of COD. The difference of COD predictions against references was within the same deviation of TOC-predictions. The modeled yield losses and retention values of TOC in pulping and bleaching processes and the modeled fixing of colloidal TOC to solids between the pulping plant and the aeration basin in the waste water treatment plant were similar to references presented in literature. The valid water balances of the waste water treatment plant and the reduction model of lignin-like substances produced a valid prediction of COD discharges out of the mill. A 30% increase in the release of lignin-like substances in the form of production problems was observed in pulping and bleaching processes. The same increase was observed in COD discharges out of waste water treatment. In the prediction of annual COD discharge, it was noticed that the reduction of lignin has a wide deviation from year to year and from one mill to another. This made it difficult to compare the parameters of COD discharges validated in plant dynamic simulation with another mill producing mechanical printing papers. However, a trend of moving from unbleached towards high-brightness TMP in COD discharges was valid.

Most of the Abundant Protein Fractions of Embryonic Cerebrospinal Fluid are Produced Out of the Brain Anlagen

The microenvironment of the central nervous system is important for neuronal function and development. During the early stages of embryo development the cephalic vesicles are filled by embryonic cerebrospinal fluid, a complex fluid containing different protein fractions, which contributes to the regulation of the survival, proliferation and neurogenesis of neuroectodermal stem cells. The protein content of embryonic cerebrospinal fluid from chick and rat embryos at the start of neurogenesis has already been determined. Most of the identified gene products are thought to be involved in the regulation of developmental processes during embryogenesis. However, due to the crucial roles played by embryonic cerebrospinal fluid during brain development, the embryological origin of the gene products it contains remains an intriguing question. According to the literature most of these products are synthesised in embryonic tissues other than the neuroepithelium. In this study we examined the embryological origin of the most abundant embryonic cerebrospinal fluid protein fractions by means of slot-blot analysis and by using several different embryonic and extraembryonic protein extracts, immunodetected with polyclonal antibodies. This first attempt to elucidate their origin is not based on the proteins identified by proteomic methods, but rather on crude protein fractions detected by SDS-PAGE analysis and to which polyclonal antibodies were specifically generated. Despite some of the limitations of this study, i.e. that one protein fraction may contain more than one gene product, and that a specific gene product may be contained in different protein fractions depending on post-translational modifications, our results show that most of the analysed protein fractions are not produced by the cephalic neuroectoderm but are rather stored in the egg reservoir; furthermore, few are produced by embryo tissues, thus indicating that they must be transported from their production or storage sites to the cephalic cavities, most probably via embryonic serum. These results raise the question as to whether the transfer of proteins from these two embryo compartments is regulated at this early developmental stage.