Coexistence of antibodies to tick-borne agents of babesiosis and Lyme borreliosis in patients from Cotia county, State of São Paulo, Brazil

This paper reports a case of coinfection caused by pathogens of Lyme disease and babesiosis in brothers. This was the first case of borreliosis in Brazil, acquired in Cotia County, State of São Paulo, Brazil. Both children had tick bite history, presented erythema migrans, fever, arthralgia, mialgia, and developed positive serology (ELISA and Western-blotting) directed to Borrelia burgdorferi G 39/40 and Babesia bovis antigens, mainly of IgM class antibodies, suggestive of acute disease. Also, high frequencies of antibodies to B. bovis was observed in a group of 59 Brazilian patients with Lyme borreliosis (25.4%), when compared with that obtained in a normal control group (10.2%) (chi-square = 5.6; p < 0.05). Interestingly, both children presented the highest titers for IgM antibodies directed to both infective diseases, among all patients with Lyme borreliosis.

Interfície de control de dades en una fàbrica

Aquest treball tracta de l'estudi i creació de la interfície d'una aplicació que reculli les dades de control generades en un procés productiu real en una petita planta de fabricació amb cinc treballadors.

Therapeutic Drug Monitoring of the new targeted anticancer agents imatinib, nilotinib, dasatinib, sunitinib, sorafenib and lapatinib by LC tandem mass spectrometry.

The treatment of some cancer patients has shifted from traditional, non-specific cytotoxic chemotherapy to chronic treatment with molecular targeted therapies. Imatinib mesylate, a selective inhibitor of tyrosine kinases (TKIs) is the most prominent example of this new era and has opened the way to the development of several additional TKIs, including sunitinib, nilotinib, dasatinib, sorafenib and lapatinib, in the treatment of various hematological malignancies and solid tumors. All these agents are characterized by an important inter-individual pharmacokinetic variability, are at risk for drug interactions, and are not devoid of toxicity. Additionally, they are administered for prolonged periods, anticipating the careful monitoring of their plasma exposure via Therapeutic Drug Monitoring (TDM) to be an important component of patients' follow-up. We have developed a liquid chromatography-tandem mass spectrometry method (LC-MS/MS) requiring 100 microL of plasma for the simultaneous determination of the six major TKIs currently in use. Plasma is purified by protein precipitation and the supernatant is diluted in ammonium formate 20 mM (pH 4.0) 1:2. Reverse-phase chromatographic separation of TKIs is obtained using a gradient elution of 20 mM ammonium formate pH 2.2 and acetonitrile containing 1% formic acid, followed by rinsing and re-equilibration to the initial solvent composition up to 20 min. Analyte quantification, using matrix-matched calibration samples, is performed by electro-spray ionization-triple quadrupole mass spectrometry by selected reaction monitoring detection using the positive mode. The method was validated according to FDA recommendations, including assessment of extraction yield, matrix effects variability (<9.6%), overall process efficiency (87.1-104.2%), as well as TKIs short- and long-term stability in plasma. The method is precise (inter-day CV%: 1.3-9.4%), accurate (-9.2 to +9.9%) and sensitive (lower limits of quantification comprised between 1 and 10 ng/mL). This is the first broad-range LC-MS/MS assay covering the major currently in-use TKIs. It is an improvement over previous methods in terms of convenience (a single extraction procedure for six major TKIs, reducing significantly the analytical time), sensitivity, selectivity and throughput. It may contribute to filling the current knowledge gaps in the pharmacokinetics/pharmacodynamics relationships of the latest TKIs developed after imatinib and better define their therapeutic ranges in different patient populations in order to evaluate whether a systematic TDM-guided dose adjustment of these anticancer drugs could contribute to minimize the risk of major adverse reactions and to increase the probability of efficient, long lasting, therapeutic response.

Fast subplasma membrane Ca2+ transients control exo-endocytosis of synaptic-like microvesicles in astrocytes

Astrocytes are the most abundant glial cell type in the brain. Although not apposite for long-range rapid electrical communication, astrocytes share with neurons the capacity of chemical signaling via Ca(2+)-dependent transmitter exocytosis. Despite this recent finding, little is known about the specific properties of regulated secretion and vesicle recycling in astrocytes. Important differences may exist with the neuronal exocytosis, starting from the fact that stimulus-secretion coupling in astrocytes is voltage independent, mediated by G-protein-coupled receptors and the release of Ca(2+) from internal stores. Elucidating the spatiotemporal properties of astrocytic exo-endocytosis is, therefore, of primary importance for understanding the mode of communication of these cells and their role in brain signaling. We here take advantage of fluorescent tools recently developed for studying recycling of glutamatergic vesicles at synapses (Voglmaier et al., 2006; Balaji and Ryan, 2007); we combine epifluorescence and total internal reflection fluorescence imaging to investigate with unprecedented temporal and spatial resolution, the stimulus-secretion coupling underlying exo-endocytosis of glutamatergic synaptic-like microvesicles (SLMVs) in astrocytes. Our main findings indicate that (1) exo-endocytosis in astrocytes proceeds with a time course on the millisecond time scale (tau(exocytosis) = 0.24 +/- 0.017 s; tau(endocytosis) = 0.26 +/- 0.03 s) and (2) exocytosis is controlled by local Ca(2+) microdomains. We identified submicrometer cytosolic compartments delimited by endoplasmic reticulum tubuli reaching beneath the plasma membrane and containing SLMVs at which fast (time-to-peak, approximately 50 ms) Ca(2+) events occurred in precise spatial-temporal correlation with exocytic fusion events. Overall, the above characteristics of transmitter exocytosis from astrocytes support a role of this process in fast synaptic modulation.

Fast analysis of doping agents in urine by ultra-high-pressure liquid chromatography-quadrupole time-of-flight mass spectrometry. II: Confirmatory analysis.

For doping control, analyses of samples are generally achieved in two steps: a rapid screening and, in the case of a positive result, a confirmatory analysis. A two-step methodology based on ultra-high-pressure liquid chromatography coupled to a quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) was developed to screen and confirm 103 doping agents from various classes (e.g., beta-blockers, stimulants, diuretics, and narcotics). The screening method was presented in a previous article as part I (i.e., Fast analysis of doping agents in urine by ultra-high-pressure liquid chromatography-quadrupole time-of-flight mass spectrometry. Part I: screening analysis). For the confirmatory method, basic, neutral and acidic compounds were extracted by a dedicated solid-phase extraction (SPE) in a 96-well plate format and detected by MS in the tandem mode to obtain precursor and characteristic product ions. The mass accuracy and the elemental composition of precursor and product ions were used for compound identification. After validation including matrix effect determination, the method was considered reliable to confirm suspect results without ambiguity according to the positivity criteria established by the World Anti-Doping Agency (WADA). Moreover, an isocratic method was developed to separate ephedrine from its isomer pseudoephedrine and cathine from phenylpropanolamine in a single run, what allowed their direct quantification in urine.

An overview of the effects of annexin 1 on cells involved in the inflammatory process

The concept of anti-inflammation is currently evolving with the definition of several endogenous inhibitory circuits that are important in the control of the host inflammatory response. Here we focus on one of these pathways, the annexin 1 (ANXA1) system. Originally identified as a 37 kDa glucocorticoid-inducible protein, ANXA1 has emerged over the last decade as an important endogenous modulator of inflammation. We review the pharmacological effects of ANXA1 on cell types involved in inflammation, from blood-borne leukocytes to resident cells. This review reveals that there is scope for more research, since most of the studies have so far focused on the effects of the protein and its peptido-mimetics on neutrophil recruitment and activation. However, many other cells central to inflammation, e.g. endothelial cells or mast cells, also express ANXA1: it is foreseen that a better definition of the role(s) of the endogenous protein in these cells will open the way to further pharmacological studies. We propose that a more systematic analysis of ANXA1 physio-pharmacology in cells involved in the host inflammatory reaction could aid in the design of novel anti-inflammatory therapeutics based on this endogenous mediator.

Tobacco Control Briefing

The Tobacco Control briefing is part of the South East Public Heath Group's Information Series of briefings. The Information Series is a set of briefings on a variety of public health topics. Their purpose is to inform partners about public health issues. In particular they can be used to inform the Local Area Agreement process. The series is evolving and comments and suggestions are welcome.

Struggles for meaning and struggles for control: the diffusion of bandwagon technology in two institutional environments

In this thesis, I examine the diffusion process for a complex medical technology, the PET scanner, in two different health care systems, one of which is more market-oriented (Switzerland) and the other more centrally managed by a public agency (Quebec). The research draws on institutional and socio-political theories of the diffusion of innovations to examine how institutional contexts affect processes of diffusion. I find that diffusion proceeds more rapidly in Switzerland than in Quebec, but that processes in both jurisdictions are characterized by intense struggles among providers and between providers and public agencies. I show that the institutional environment influences these processes by determining the patterns of material resources and authority available to actors in their struggles to strategically control the technology, and by constituting the discursive resources or institutional logics on which actors may legitimately draw in their struggles to give meaning to the technology in line with their interests and values. This thesis illustrates how institutional structures and meanings manifest themselves in the context of specific decisions within an organizational field, and reveals the ways in which governance structures may be contested and realigned when they conflict with interests that are legitimized by dominant institutional logics. It is argued that this form of contestation and readjustment at the margins constitutes one mechanism by which institutional frameworks are tested, stretched and reproduced or redefined.

Characterization of the gene expression related to the process of DNA damage tolerance in Schistosoma mansoni

In the course of its complex life cycle, the parasite Schistosoma mansoni need to adapt to distinct environments, and consequently is exposed to various DNA damaging agents. The Schistosoma genome sequencing initiative has uncovered sequences from genes and transcripts related to the process of DNA damage tolerance as the enzymes UBC13, MMS2, and RAD6. In the present work, we evaluate the importance of this process in different stages of the life cycle of this parasite. The importance is evidenced by expression and phylogenetic profiles, which show the conservation of this pathway from protozoa to mammalians on evolution.

Análisis y diseño de una aplicación control de inventarios de una empresa lechera. "Holandesa"

El present treball consisteix en un sistema per a una empresa de producció i distribució de productes làctics basat en l'anàlisi i disseny amb les noves tecnologies. L'aplicació, que es dirà Control d'Inventaris, durà a terme la gestió del procés de revisió d'inventaris en magatzems registrant l'entrada de productes per a l'elaboració i la producció dels diferents productes. També realitzarà la gestió de reserves de comandes per a la seva cartera de clients.

Issues in blood pressure control and the potential role of single-pill combination therapies.

Hypertension (HTN) is a major risk factor for cardiovascular mortality, yet only a small proportion of hypertensive individuals receive appropriate therapy and achieve target blood pressure (BP) values. Factors influencing the success of antihypertensive therapy include physicians' acceptance of guideline BP targets, the efficacy and tolerability of the drug regimen, and patient compliance and persistence with therapy. It is now well recognised that most hypertensive patients require at least two antihypertensive agents to achieve their target BP. However, complicated treatment regimens are a major contributory factor to poor patient compliance. The use of combination therapy for HTN offers a number of advantages over the use of monotherapy, including improved efficacy, as drug combinations with a synergistic mechanism of action can be used. This additive effect means that lower doses of the individual components can be used, which may translate into a decreased likelihood of adverse events. The use of single-pill combination therapy, in which two or more agents are combined in a single dosage form, offers all the benefits of free combination therapy (improved efficacy and tolerability over monotherapy) together with the added benefit of improved patient compliance because of the simplified treatment regimen. The use of single-pill combination therapy may also be associated with cost savings compared with the use of free combinations for reasons of cheaper drug costs, fewer physician visits and fewer hospitalisations for uncontrolled HTN and cardiovascular events. Thus, the use of single-pill combination therapy for HTN should help improve BP goal attainment through improved patient compliance, leading to reduced costs for cardiovascular-related care.

FGF receptors control vitamin D and phosphate homeostasis by mediating renal FGF-23 signaling and regulating FGF-23 expression in bone.

The functional interaction between fibroblast growth factor 23 (FGF-23) and Klotho in the control of vitamin D and phosphate homeostasis is manifested by the largely overlapping phenotypes of Fgf23- and Klotho-deficient mouse models. However, to date, targeted inactivation of FGF receptors (FGFRs) has not provided clear evidence for an analogous function of FGFRs in this process. Here, by means of pharmacologic inhibition of FGFRs, we demonstrate their involvement in renal FGF-23/Klotho signaling and elicit their role in the control of phosphate and vitamin D homeostasis. Specifically, FGFR loss of function counteracts renal FGF-23/Klotho signaling, leading to deregulation of Cyp27b1 and Cyp24a1 and the induction of hypervitaminosis D and hyperphosphatemia. In turn, this initiates a feedback response leading to high serum levels of FGF-23. Further, we show that FGFR inhibition blocks Fgf23 transcription in bone and that this is dominant over vitamin D-induced Fgf23 expression, ultimately impinging on systemic FGF-23 protein levels. Additionally, we identify Fgf23 as a specific target gene of FGF signaling in vitro. Thus, in line with Fgf23- and Klotho-deficient mouse models, our study illustrates the essential function of FGFRs in the regulation of vitamin D and phosphate levels. Further, we reveal FGFR signaling as a novel in vivo control mechanism for Fgf23 expression in bone, suggesting a dual function of FGFRs in the FGF-23/Klotho pathway leading to vitamin D and phosphate homeostasis.

Impact of standardised review of intravenous antibiotic therapy 72 hours after prescription in two internal medicine wards.

Post-prescription review of hospital antibiotic therapy may contribute to more appropriate use. We estimated the impact of a standardised review of intravenous antibiotic therapy three days after prescription in two internal medicine wards of a university hospital. In one ward, we assessed the charts of patients under intravenous antibiotic therapy using a standardised review process and provided feedback to the prescriber. There was no intervention in the other ward. After six months we crossed the allocation between the two wards. In all, 204 courses of antibiotic therapy were included in the intervention periods and 226 in the control periods. Post-prescription review led to proposals for modification in 46% of antibiotic courses. Time to treatment modification was 22% shorter in the intervention periods compared with the control periods (3.9+/-5.2 days vs 5.0+/-6.0 days, P=0.007). Patients included in the intervention group had lower antibiotic consumption than patients in the control group, but the intervention had no significant impact on the overall antibiotic consumption of the two wards.

El proceso en España de la adopción de una legislación eficaz para la prevención del tabaquismo

The prevention movement has been the key agent involved in smoking control policies. This study describes the context and the process in which Law 28/2005 was passed in Spain with a synthesis of its substance. It provides the background of the events leading up to Spain's current smoking control law in addition to an analysis of the role played by the different social actors in the process and the arguments and strategies employed in opposition by the tobacco industry. A review is also provided of the political agents, highlighting that decentralized countries have further problems in enforcing regulations. This case offers lessons for the future.

Management of bleeding following major trauma: a European guideline

INTRODUCTION Evidence-based recommendations can be made with respect to many aspects of the acute management of the bleeding trauma patient, which when implemented may lead to improved patient outcomes. METHODS The multidisciplinary Task Force for Advanced Bleeding Care in Trauma was formed in 2005 with the aim of developing guidelines for the management of bleeding following severe injury. Recommendations were formulated using a nominal group process and the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) hierarchy of evidence and were based on a systematic review of published literature. RESULTS Key recommendations include the following: The time elapsed between injury and operation should be minimised for patients in need of urgent surgical bleeding control, and patients presenting with haemorrhagic shock and an identified source of bleeding should undergo immediate surgical bleeding control unless initial resuscitation measures are successful. A damage control surgical approach is essential in the severely injured patient. Pelvic ring disruptions should be closed and stabilised, followed by appropriate angiographic embolisation or surgical bleeding control, including packing. Patients presenting with haemorrhagic shock and an unidentified source of bleeding should undergo immediate further assessment as appropriate using focused sonography, computed tomography, serum lactate, and/or base deficit measurements. This guideline also reviews appropriate physiological targets and suggested use and dosing of blood products, pharmacological agents, and coagulation factor replacement in the bleeding trauma patient. CONCLUSION A multidisciplinary approach to the management of the bleeding trauma patient will help create circumstances in which optimal care can be provided. By their very nature, these guidelines reflect the current state-of-the-art and will need to be updated and revised as important new evidence becomes available.