Embodied Autonomy in Digital Ecosystems: From Bio-Inspired Agents to Cognitive Systems

This paper proposes to promote autonomy in digital ecosystems so that it provides agents with information to improve the behavior of the digital ecosystem in terms of stability. This work proposes that, in digital ecosystems, autonomous agents can provide fundamental services and information. The final goal is to run the ecosystem, generate novel conditions and let agents exploit them. A set of evaluation measures must be defined as well. We want to provide an outline of some global indicators, such as heterogeneity and diversity, and establish relationships between agent behavior and these global indicators to fully understand interactions between agents, and to understand the dependence and autonomy relations that emerge between the interacting agents. Individual variations, interaction dependencies, and environmental factors are determinants of autonomy that would be considered. The paper concludes with a discussion of situations when autonomy is a milestone

Gender differences in HIV-positive persons in use of cardiovascular disease-related interventions : D:A:D study

INTRODUCTION: There is a lack of data on potential gender differences in the use of interventions to prevent and treat cardiovascular disease (CVD) in HIV-positive individuals. We investigated whether such differences exist in the D:A:D study. MATERIALS AND METHODS: Follow-up was from 01/02/99 until the earliest of death, 6 months after last visit or 01/02/13. Rates of initiation of lipid-lowering drugs (LLDs), angiotensin-converting enzyme inhibitors (ACEIs), anti-hypertensives and receipt of invasive cardiovascular procedures (ICPs; bypass, angioplasty, endarterectomy) were calculated in those without a myocardial infarction (MI) or stroke at baseline, overall and in groups known to be at higher CVD risk: (i) age >50, (ii) total cholesterol >6.2 mmol/l, (iii) triglyceride >2.3 mmol/l, (iv) hypertension, (v) previous MI, (vi) diabetes, or (vii) predicted 10-year CVD risk >10%. Poisson regression was used to assess whether rates of initiation were higher in men than women, after adjustment for these factors. RESULTS: At enrolment, women (n=13,039; median (interquartile range) 34 (29-40) years) were younger than men (n=36,664, 39 (33-46) years, p=0.001), and were less likely to be current smokers (29% vs. 39%, p=0.0001), to have diabetes (2% vs. 3%, p=0.0001) or to have hypertension (7% vs. 11%, p=0.0001). Of 49,071 individuals without a MI/stroke at enrolment, 0.6% women vs. 2.1% men experienced a MI while 0.8% vs. 1.3% experienced a stroke. Overall, women received ICPs at a rate of 0.07/100 person-years (PYRS) compared to 0.29/100 PYRS in men. Similarly, the rates of initiation of LLDs (1.28 vs. 2.46), anti-hypertensives (1.11 vs. 1.38) and ACEIs (0.82 vs. 1.37) were all significantly lower in women than men (Table 1). As expected, initiation rates of each intervention were higher in the groups determined to be at moderate/high CVD risk; however, within each high-risk group, initiation rates of most interventions (with the exception of anti-hypertensives) were generally lower in women than men. These gender differences persisted after adjustment for potential confounders (Table 1). CONCLUSION: Use of most CVD interventions was lower among women than men in the D:A:D study. Our findings suggest that actions should be taken to ensure that both men and women are monitored for CVD and, if eligible, receive appropriate CVD interventions.

Diabétologie : nouveautés en médecine 2007 [Trends in diabetes]

Une méta-analyse concernant l'utilisation de la rosiglitazone chez les diabétiques de type 2 a révélé une augmentation significative du risque d'infarctus du myocarde et une tendance à la surmortalité cardiovasculaire. La méthodologie de cette étude ainsi que ses conclusions ont été beaucoup critiquées. Cette étude montre les limites des méta-analyses auxquelles on prête un rang manifestement trop élevé dans la hiérarchie des niveaux de preuve. L'étude 4T a évalué trois schémas d'insuline dans le traitement du diabète de type 2. Les résultats à un an montrent que seule une minorité des patients atteignent les objectifs. Post-Steno 2 a été présenté au congrès européen du diabète. Ces nouvelles données confirment que le traitement intensifié de tous les facteurs de risque cardiovasculaire permet une réduction majeure de la mortalité cardiovasculaire après 13,3 ans. A recent meta-analysis on the rosiglitazone in the treatment of type 2 diabetes revealed a significant increased risk of myocardial infarction and a trend to a higher cardiovascular mortality. In the following month after this publication, the methodology as its conclusions were criticized. This study shows the limits of the meta-analyses to which one lends a row obviously too high in the hierarchy of the levels of evidence. The study 4T evaluated 3 insulin strategies in the treatment of the type 2 diabetes. The results at one year show that only a minority of the patients achieve the goals. Post-Steno 2 was presented at the European congress diabetes. These new data confirm that the intensified treatment of all cardiovascular factors risk allows a major reduction of cardiovascular mortality after 13.3 years

Peripheral arterial disease in HIV patients older than 50 years of age

Our objective was to analyze the prevalence of peripheral arterial disease (PAD) in HIV patients at risk and to compare them with the general population. All HIV patients older than 50 years who attended our unit from October 2005-July 2006 and all persons attending for an annual medical checkup at an employees' insurance association during the same period were invited to participate in the study. Of the latter (n = 407), a person of the same sex and age (+/-5 years) was included for each HIV patient. PAD was assessed by the ankle-brachial index (ABI) in all subjects, and all completed the Edinburgh questionnaire. Ninety-nine HIV patients and 99 persons from the general population of the same age and sex were included in the study. The HIV patients had a greater prevalence of dyslipidemia, diabetes, and PAD, which was symptomatic in five of them and in one subject from the general population. Patients with HIV infection older than 50 had a high prevalence of PAD, and as it was asymptomatic in half the cases, an ABI may be performed in this population to actively look for PAD. Control of cardiovascular risk factors and the use of such drugs as platelet antiaggregation agents should therefore be optimized in this population.

Evaluation of the synergistic potential of vancomycin combined with other antimicrobial agents against methicillin-resistant Staphylococcus aureus and coagulase-negative Staphylococcus spp strains

Methicillin-resistant Staphylococcus aureus (MRSA) and coagulase-negative Staphylococcus spp (CNS) are the most common pathogens that cause serious long term infections in patients. Despite the existence of new antimicrobial agents, such as linezolid, vancomycin (VAN) remains the standard therapy for the treatment of infections caused by these multidrug-resistant strains. However, the use of VAN has been associated with a high frequency of therapeutic failures in some clinical scenarios, mainly with decreasing concentration of VAN. This work aims to evaluate the synergic potential of VAN plus sulfamethoxazole/trimethoprim (SXT), VAN plus rifampin (RIF) and VAN plus imipenem (IPM) in sub-minimum inhibitory concentrations against 22 clinical strains of MRSA and CNS. The checkerboard method showed synergism of VAN/RIF and VAN/SXT against two and three of the 22 strains, respectively. The combination of VAN with IPM showed synergistic effects against 21 out of 22 strains by the E-test method. Four strains were analyzed by the time-kill curve method and synergistic activity was observed with VAN/SXT, VAN/RIF and especially VAN/IPM in sub-inhibitory concentrations. It would be interesting to determine if synergy occurs in vivo. Evidence of in vivo synergy could lead to a reduction of the standard VAN dosage or treatment time.

PsyCoLaUS: santé mentale et maladies cardiovasculaires: association fortuite [PsyCoLaus: mental disorders and cardiovascular diseases: spurious association?].

Cardio-vascular diseases (CVD), their well established risk factors (CVRF) and mental disorders are common and co-occur more frequently than would be expected by chance. However, the mechanisms underlying this association are still poorly understood. The main study questions of PsyCoLaus, the psychiatric arm of CoLaus, are: 1) Do mental disorders increase vulnerability to CVRF and CVD? 2) Do CVRF and CVD promote the development of mental disorders? 3) Do CVRF/ CVD and mental disorders share common pathogenetic processes? The longitudinal project adds a comprehensive psychiatric evaluation to the CoLaus investigation. A better understanding of the psychological, physiological and behavioral links underlying CVD/ CVRF and mental disorders will result in the development of more specific and efficient strategies of prevention and treatment for both psychiatric and CVD/CVRF, two major elements of burden of disease.

Prevention of the renarrowing of coronary arteries using drug-eluting stents in the perioperative period: an update.

The management of patients scheduled for surgery with a coronary stent, and receiving 1 or more antiplatelet drugs, has many controversies. The premature discontinuation of antiplatelet drugs substantially increases the risk of stent thrombosis (ST), myocardial infarction, and cardiac death, and surgery under an altered platelet function could also lead to an increased risk of bleeding in the perioperative period. Because of the conflict in the recommendations, this article reviews the current antiplatelet protocols after positioning a coronary stent, the evidence of increased risk of ST associated with the withdrawal of antiplatelet drugs and increased bleeding risk associated with its maintenance, the different perioperative antiplatelet protocols when patients are scheduled for surgery or need an urgent operation, and the therapeutic options if excessive bleeding occurs.

The renin-angiotensin system and arterial wall behavior.

To assess the behavior of the arterial wall in hypertensive patients, we developed a noninvasive ultrasonic device. Simultaneous recordings of internal diameter and blood pressure over the whole cardiac cycle are used to establish compliance-pressure curves. Blood pressure, which is a co-determinant of compliance, is thus taken into account. This method allows one to compare arteries from patients with different blood pressures. Arterial compliance and distensibility were first investigated in healthy young volunteers administered either lisinopril (20 mg), atenolol (100 mg) or nitrendipine (20 mg) once a day. After 8 days of treatment, only lisinopril was found to increase arterial compliance. Subsequently, we compared arterial diameter- and distensibility-pressure curves from newly diagnosed and untreated hypertensive patients with those of matched normotensive control patients. Diameter-pressure curves did not differ significantly between the groups and distensibility was not reduced. Similar findings were later obtained in an animal model, when mechanical properties of carotid arteries were compared between spontaneously hypertensive rats and normotensive counterparts (Wistar-Kyoto rats). These results, although interesting by providing noninvasive information on the elastic response of the wall, call for further development of the technique to be able to measure arterial wall thickness. Stress-strain relationship could ultimately be established to thoroughly characterize physical properties of blood vessel walls.

Effects of MDL 100,240, a dual inhibitor of angiotensin-converting enzyme and neutral endopeptidase on the vasopressor response to exogenous angiotensin I and angiotensin II challenges in healthy volunteers.

MDL 100,240, a dual inhibitor of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), was administered intravenously to two panels of four healthy males in a four-period, dose-increasing (0, 1.56, 6.25, and 25 mg, and 0, 3.13, 12.5, and 50 mg, respectively) double-blind, placebo-controlled study. Plasma ACE activity and blood-pressure response to exogenous angiotensin I and angiotensin II i.v. challenges and safety and tolerance were assessed over a 24-h period. MDL 100,240 induced a rapid, dose-related, and sustained inhibition of ACE (>70% over 24 h at doses > or =12.5 mg). The time integral of ACE inhibition was related to the dose but with near-maximal values already attained at doses > or =12.5 mg. Systolic and diastolic blood-pressure responses to exogenous angiotensin I challenges were inhibited in a dose-dependent fashion, whereas the effects of angiotensin II remained unaffected. Mean supine blood pressure decreased transiently (3 h) at doses > or =3.125 mg and < or =24 h with the 25- and 50-mg doses, but not significantly. MDL 100,240 was well tolerated. In healthy subjects, MDL 100,240 exerts a dose-dependent and long-lasting ACE-blocking activity, also expressed by the inhibition of the pressor responses to exogenous angiotensin I challenges. The baroreceptor reflex, assessed by the response to exogenous angiotensin II challenge, remains unaltered.

Improving anemia management with less frequently dosed erythropoiesis stimulating agents

Introduction and Aims: The process of delivering erythropoiesis stimulating agents (ESAs) to hemodialysis patients (HD) is complex. Many European countries are requiring centers to document this process. To date, there has not been any comprehensive description of the operational aspects of ESA delivery in Europe. The objective of the Mercurius study was to describe the entire process of ESA delivery in dialysis centers. In addition, we explored the benefits of less frequent dosing. Methods: A conceptual model was developed to classify the sub-processes in the pharmacy, dialysis unit, waste unit, and back office. Within each dialysis unit activities associated with dose determination, ordering procedures, receipt and storage of ESAs, and ESA administration were measured. Within the pharmacy, ordering from supplier, receiving and storing, and delivering ESA to the dialysis unit were measured. The amount of time and materials associated with waste disposal and back office activities were also observed. We also evaluated the impact of less frequent dosing on the resources required to perform anemia management for HD patients. Structured interviews with staff were used to develop a comprehensive list of processes, sub-processes, and activities that are routinely followed to order, register, administer, and dispose of waste associated with ESAs. Each activity was evaluated to determine if less frequent dosing influenced the amount of resources required. A model was developed to estimate the change in resources consumed using less frequent dosing regimens. Results: Eight centers from 5 European countries (Belgium, France, Italy, Sweden, and Switzerland) participated in the study. The number of HD patients in each center ranged from 42 to 707 (mean=175). Across all of the centers, patients received a variety of dosing regimens (eg, TIW, BIW, QW and Q2W). The mean (±SD) time spent for the pharmacy to order an ESA from the supplier was 6.1 (±8.7) minutes; time spent in the dialysis unit and pharmacy for receiving and storing ESPs was 5.3 (±5.3) and 10.0 (±10.9) minutes, respectively; and time spent administering each injection was 6.4 (±6.5) minutes. Switching from current dosing practices to Q2W could decrease the mean number of syringes used from 12,420 to 5,085 per year. We estimate a reduction in the number of disinfective tissues and liquids of 58% and 71%, respectively by switching from current practice to dosing ESAs Q2W. Conclusions: There was significant variation in the time that it takes to perform routine ESA activities. We estimate that a reduction in resources required to manage anemia can be obtained by reducing the frequency of administration from the current mix of ESAs. These resources could be redeployed for patient care.

Anàlisi de la imatge turística percebuda pels agents orgànics: El cas de Girona

Anàlisi empírica de la imatge turística de la ciutat de Girona que transmeten els agents orgànics mitjançant els blogs d’Internet i, a partir d’aquí, deducció de quina és la imatge percebuda pels turistes potencials

Genotypes of Cryptococcus neoformans and Cryptococcus gattii as agents of endemic cryptococcosis in Teresina, Piauí (northeastern Brazil)

Throughout Brazil, Cryptococcus neoformans is the cause of cryptococcosis, whereas Cryptococcus gattii is endemic to the northern and northeastern states. In this study, the molecular types of 63 cryptococcal isolates recovered from the cerebrospinal fluid of meningitis patients diagnosed between 2008-2010 in Teresina, Piauí, Brazil, were analysed. Out of the 63 patients, 37 (58.7%) were human immunodeficiency virus (HIV)-positive and 26 (41.3%) were HIV-negative. URA5-restriction fragment length polymorphism analysis identified 37/63 (58.7%) isolates as the C. neoformans VNI genotype, predominantly in HIV-positive patients (32/37, 86.5%), and 24/63 (38.1%) as the C. gattii VGII genotype, mostly in HIV-negative patients (21/26, 80.8%). The occurrence of C. gattii VGII in six apparently healthy children and in seven adolescents/young adults in this region reaffirms the endemic occurrence of C. gattii VGII-induced primary cryptococcosis and early cryptococcal infection. Lethality occurred in 18/37 (48.6%) of the HIV-positive subjects and in 13/26 (50%) of the HIV-negative patients. Our results provide new information on the molecular epidemiology of C. neoformans and C. gattii in Brazilian endemic areas.

Analysis of GPCR properties of Frizzled receptors and establishment of the "in vitro" platform for screening of Frizzled agonists/antagonists as potential therapeutic agents

Morphogens of the Wnt protein family are the secreted lipoglycoprotein ligands which initiate several pathways heavily involved in the coordination of various developmental stages of organisms in the majority of animal species. Deregulation of these pathways in the adult leads to formation and sustaining of multiple types of cancer. The latter notion is reinforced by the fact that the very discovery of the first Wnt ligand was due to its role as the causative factor of carcinogenic transformation (Nusse and Varmus, 1982). Nowadays our knowledge on Wnt signaling has "moved with the times" and these pathways were identified to be often crucial for tumor formation, its interactions with the microenvironment, and promotion of the metastases (Huang and Du, 2008; Zerlin et al., 2008; Jessen, 2009). Thus the relevance of the pathway as the target for drug development has further increased in the light of modern paradigms of the complex cancer treatments which target also spreading and growth- promoting factors of tumors by specific and highly efficient substances (Pavet et al., 2010). Presently the field of the Wnt-targeting drug research is almost solely dominated by assays based on transcriptional activation induced by the signaling. This approach resulted in development of a number of promising substances (Lee et al., 2011). Despite its effectiveness, the method nevertheless suffers from several drawbacks. Among the major ones is the fact that this approach is prone to identify compounds targeting rather downstream effectors of the pathway, which are indiscriminately used by all the subtypes of the Wnt signaling. Additionally, proteins which are involved in several signaling cascades and not just the Wnt pathway turn out as targets of the new compounds. These issues increase risks of side effects due to off-target interactions and blockade of the pathway in healthy cells. In the present work we put forward a novel biochemical approach for drug development on the Wnt pathway. It targets Frizzleds (Fzs) - a family of 7-transmbembrane proteins which serve as receptors for Wnt ligands. They offer unique properties for the development of highly specific and effective drugs as they control all branches of the Wnt signaling. Recent advances in the understanding of the roles of heterotrimeric G proteins downstream from Fzs (Katanaev et al., 2005; Liu et al., 2005; Jernigan et al., 2010) suggest application of enzymatic properties of these effectors to monitor the receptor-mediated events. We have applied this knowledge in practice and established a specific and efficient method based on utilization of a novel high-throughput format of the GTP-binding assay to follow the activation of Fzs. This type of assay is a robust and well-established technology for the research and screenings on the GPCRs (Harrison and Traynor, 2003). The conventional method of detection involves the radioactively labeled non-hydrolysable GTP analog [35S]GTPyS. Its application in the large-scale screenings is however problematic which promoted development of the novel non-radioactive GTP analog GTP-Eu. The new molecule employs phenomenon of the time-resolved fluorescence to provide sensitivity comparable to the conventional radioactive substance. Initially GTP-Eu was tested only in one of many possible types of GTP-binding assays (Frang et al., 2003). In the present work we expand these limits by demonstrating the general comparability of the novel label with the radioactive method in various types of assays. We provide a biochemical characterization of GTP-Eu interactions with heterotrimeric and small GTPases and a comparative analysis of the behavior of the new label in the assays involving heterotrimeric G protein effectors. These developments in the GTP-binding assay were then applied to monitor G protein activation by the Fz receptors. The data obtained in mammalian cultured cell lines provides for the first time an unambiguous biochemical proof for direct coupling of Fzs with G proteins. The specificity of this interaction has been confirmed by the experiments with the antagonists of Fz and by the pertussis toxin-mediated deactivation. Additionally we have identified the specificity of Wnt3a towards several members of the Fz family and analyzed the properties of human Fz-1 which was found to be the receptor coupled to the Gi/o family of G proteins. Another process playing significant role in the functioning of every GPCR is endocytosis. This phenomenon can also be employed for drug screenings on GPCRs (Bickle, 2010). In the present work we have demonstrated that Drosophila Fz receptors are involved in an unusual for many GPCRs manifestation of the receptor-mediated internalization. Through combination of biochemical approaches and studies on Drosophila as the model organism we have shown that direct interactions of the Fzs and the α-subunit of the heterotrimeric G protein Go with the small GTPase Rab5 regulate internalization of the receptor in early endosomes. We provide data uncovering the decisive role of this self-promoted endocytosis in formation of a proper signaling output in the canonical as well as planar cell polarity (PCP) pathways regulated by Fz. The results of this work thus establish a platform for the high-throughput screening to identify substances active in the cancer-related Wnt pathways. This methodology has been adjusted and applied to provide the important insights in Fz functioning and will be instrumental for further investigations on the Wnt-mediated pathways.