The Second Transmembrane Domain of P2X7 Contributes to Dilated Pore Formation

Activation of the purinergic receptor P2X7 leads to the cellular permeability of low molecular weight cations. To determine which domains of P2X7 are necessary for this permeability, we exchanged either the C-terminus or portions of the second transmembrane domain (TM2) with those in P2X1 or P2X4. Replacement of the C-terminus of P2X7 with either P2X1 or P2X4 prevented surface expression of the chimeric receptor. Similarly, chimeric P2X7 containing TM2 from P2X1 or P2X4 had reduced surface expression and no permeability to cationic dyes. Exchanging the N-terminal 10 residues or C-terminal 14 residues of the P2X7 TM2 with the corresponding region of P2X1 TM2 partially restored surface expression and limited pore permeability. To further probe TM2 structure, we replaced single residues in P2X7 TM2 with those in P2X1 or P2X4. We identified multiple substitutions that drastically changed pore permeability without altering surface expression. Three substitutions (Q332P, Y336T, and Y343L) individually reduced pore formation as indicated by decreased dye uptake and also reduced membrane blebbing in response to ATP exposure. Three others substitutions, V335T, S342G, and S342A each enhanced dye uptake, membrane blebbing and cell death. Our results demonstrate a critical role for the TM2 domain of P2X7 in receptor function, and provide a structural basis for differences between purinergic receptors. © 2013 Sun et al

Impact of Safety-Related Dose Reductions or Discontinuations on Sustained Virologic Response in HCV-Infected Patients: Results from the GUARD-C Cohort.

BACKGROUND: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. METHODS: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. RESULTS: SVR24 rates were 46.1% (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1, 2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced ≥1 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with ≥1 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not ≥5. CONCLUSIONS: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginterferon alfa-2a/ribavirin.This study was sponsored by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Support for third-party writing assistance for this manuscript, furnished by Blair Jarvis MSc, ELS, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd, Basel, Switzerland

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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Synopsys of the 3rd National Congress of Tropical Medicine and 1st Lusophone Congress of Vector-Borne Diseases

A medicina tropical tem vindo a assumir, cada vez mais, uma dimensão global. As patologias referidas como tropicais e restritas, durante muitos anos, a territórios tropicais têm vindo gradualmente a conquistar, cada vez mais, espaço geográfico em áreas anteriormente consideradas isentas destes flagelos. Atualmente, a Europa e os EUA debatem-se com surtos epidémicos de infeções por microrganismos patogénicos considerados tropicais e o impacto das doenças transmitidas por vetores na Saúde humana e veterinária encontra-se cada vez mais disseminado. O Instituto de Higiene e Medicina Tropical da Universidade NOVA de Lisboa organizou o 3º Congresso Nacional de Medicina Tropical e o 1º Congresso Lusófono de Doenças Transmitidas por Vetores, nos dias 20 e 21 de abril de 2015, tendo sido a maior parte dedicado às doenças transmitidas por vetores. A iniciativa contou com cerca de 300 participantes (oriundos de países da Lusofonia e ainda de outros centros científicos internacionais), com 57 comunicações orais e 41 posters. Este encontro teve como objetivo criar um espaço para a discussão e apresentação de trabalhos, desenvolvidos a nível nacional e internacional, nomeadamente sobre a prevenção, o controlo e a eliminação, assim como os vários desafios associados ao desenvolvimento de novas metodologias aplicadas ao diagnóstico e tratamento das doenças transmitidas por vetores. Currently, Tropical Medicine emerged as both an important medical specialty and scientific discipline assuming a preponderant global dimension. Until a few years ago, several tropical pathologies, which were exclusively associated with tropical regions, have been gradually expanding to other geographic areas previously considered free of these infections. Vector-borne diseases are included among this group of infections. Actually, Europe and the US struggle with disease outbreaks caused by pathogens primarily associated with tropical regions. In fact, the impact of vector-borne diseases in human and veterinary health is increasingly being disseminated worldwide. The Institute of Hygiene and Tropical Medicine, University NOVA of Lisbon organized the 3rd National Congress of Tropical Medicine and the 1st Congress of Portuguese Speaking Countries on Vector-borne Diseases, on 20th - 21st of April, 2015, dedicated to vector-borne diseases topics. The meeting was attended by about 300 participants from Portugal, Portuguese speaking countries, and other international scientific centers. Overall, 57 oral communications and 41 posters were presented on sessions that promoted great interest and scientific discussion, about the control, elimination, as well as the challenges associated with the development of novel methodologies applied to the diagnosis and treatment of several vector-borne diseases.publishersversionpublishe

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Governmental surveillance system of healthcare-associated infection in Brazil

Objective: This study aimed to describe the structure of governmental surveillance systems for Healthcare Associated Infection (HAI) in the Brazilian Southeastern and Southern States. Method: A cross-sectional, descriptive and exploratory study, with data collection by means of two-phases: characterization of the healthcare structure and of the HAI surveillance system. Results: The governmental teams for prevention and control of HAI in each State ranged from one to six members, having at least one nurse. All States implemented their own surveillance system. The information systems were classified into chain (n=2), circle (n=4) or wheel (n=1). Conclusion: Were identified differences in the structure and information flow from governmental surveillance systems, possibly limiting a nationwide standardization. The present study points to the need for establishing minimum requirements in public policies, in order to guide the development of HAI surveillance systems

Experimental Ehrlichia canis infection changes acute-phase proteins

Early diagnosis of canine ehrlichiosis favors prompt institution of treatment and improves the prognosis for the animal, since this disease causes mortality among dogs. Studies have shown that determining the concentration of acute-phase proteins (APPs) may contribute towards early detection of disease and aid in predicting the prognosis. This study aimed to evaluate the APP profile in dogs experimentally infected with Ehrlichia canis, at the start of the infection and after treatment. It also investigated whether any correlation between APP levels and the clinical and laboratory alterations over the course of the disease would be possible. The results obtained showed abnormal levels of all the APPs on the third day after infection (D3), with the highest levels being reached on D18, with the exception of ceruloplasmin and acid glycoprotein, which presented their peaks on D6 and D12 respectively. We concluded that assessment of APP levels could contribute towards establishing an early diagnosis of canine ehrlichiosis, particularly regarding acid glycoprotein and ceruloplasmin, since these proteins were detected at increased levels even before the onset of clinical and laboratory findings of the disease.O diagnóstico precoce da erliquiose canina favorece a pronta instituição do tratamento e melhora o prognóstico do animal, pois se trata de uma doença de alta mortalidade em cães. Estudos têm apontado que a determinação da concentração de proteínas de fase aguda (PFA) pode contribuir para detecção precoce de doenças e auxiliar na predição do prognóstico. O presente estudo objetivou avaliar o perfil de proteínas de fase aguda (PFA) em cães experimentalmente infectados com Ehrlichia canis, no início da infecção e após o tratamento. Além disso, se seria possível associá-las com as alterações clínico-laboratoriais durante o curso da doença. Os resultados obtidos evidenciaram que todas as PFA estudadas alteraram suas concentrações em D3 (dia 3), comparadas ao D0, atingindo concentrações máximas em D18, com exceção da ceruloplasmina e da glicoproteína ácida, cujos picos foram observados em D6 e D12, respectivamente. Concluímos que a avaliação das concentrações de PFA poderiam contribuir para o diagnóstico precoce da erliquiose canina, principalmente com relação à ceruloplasmina e glicoproteína ácida, pois seus aumentos foram anteriores ao aparecimento dos sinais clínicos e das alterações laboratoriais da doença