A critical role of autophagy in antileukemia/lymphoma effects of APO866, an inhibitor of NAD biosynthesis.

APO866, an inhibitor of NAD biosynthesis, exhibits potent antitumor properties in various malignancies. Recently, it has been shown that APO866 induces apoptosis and autophagy in human hematological cancer cells, but the role of autophagy in APO866-induced cell death remains unclear. Here, we report studies on the molecular mechanisms underlying APO866-induced cell death with emphasis on autophagy. Treatment of leukemia and lymphoma cells with APO866 induced both autophagy, as evidenced by an increase in autophagosome formation and in SQSTM1/p62 degradation, but also increased caspase activation as revealed by CASP3/caspase 3 cleavage. As an underlying mechanism, APO866-mediated autophagy was found to deplete CAT/catalase, a reactive oxygen species (ROS) scavenger, thus promoting ROS production and cell death. Inhibition of autophagy by ATG5 or ATG7 silencing prevented CAT degradation, ROS production, caspase activation, and APO866-induced cell death. Finally, supplementation with exogenous CAT also abolished APO866 cytotoxic activity. Altogether, our results indicated that autophagy is essential for APO866 cytotoxic activity on cells from hematological malignancies and also indicate an autophagy-dependent CAT degradation, a novel mechanism for APO866-mediated cell killing. Autophagy-modulating approaches could be a new way to enhance the antitumor activity of APO866 and related agents.

Monte Carlo simulation of a clearance box monitor used for nuclear power plant decommissioning.

When decommissioning a nuclear facility it is important to be able to estimate activity levels of potentially radioactive samples and compare with clearance values defined by regulatory authorities. This paper presents a method of calibrating a clearance box monitor based on practical experimental measurements and Monte Carlo simulations. Adjusting the simulation for experimental data obtained using a simple point source permits the computation of absolute calibration factors for more complex geometries with an accuracy of a bit more than 20%. The uncertainty of the calibration factor can be improved to about 10% when the simulation is used relatively, in direct comparison with a measurement performed in the same geometry but with another nuclide. The simulation can also be used to validate the experimental calibration procedure when the sample is supposed to be homogeneous but the calibration factor is derived from a plate phantom. For more realistic geometries, like a small gravel dumpster, Monte Carlo simulation shows that the calibration factor obtained with a larger homogeneous phantom is correct within about 20%, if sample density is taken as the influencing parameter. Finally, simulation can be used to estimate the effect of a contamination hotspot. The research supporting this paper shows that activity could be largely underestimated in the event of a centrally-located hotspot and overestimated for a peripherally-located hotspot if the sample is assumed to be homogeneously contaminated. This demonstrates the usefulness of being able to complement experimental methods with Monte Carlo simulations in order to estimate calibration factors that cannot be directly measured because of a lack of available material or specific geometries.

Post-mortem cardiac 3-T magnetic resonance imaging: visualization of sudden cardiac death?

OBJECTIVES: This study aimed to investigate post-mortem magnetic resonance imaging (pmMRI) for the assessment of myocardial infarction and hypointensities on post-mortem T2-weighted images as a possible method for visualizing the myocardial origin of arrhythmic sudden cardiac death. BACKGROUND: Sudden cardiac death has challenged clinical and forensic pathologists for decades because verification on post-mortem autopsy is not possible. pmMRI as an autopsy-supporting examination technique has been shown to visualize different stages of myocardial infarction. METHODS: In 136 human forensic corpses, a post-mortem cardiac MR examination was carried out prior to forensic autopsy. Short-axis and horizontal long-axis images were acquired in situ on a 3-T system. RESULTS: In 76 cases, myocardial findings could be documented and correlated to the autopsy findings. Within these 76 study cases, a total of 124 myocardial lesions were detected on pmMRI (chronic: 25; subacute: 16; acute: 30; and peracute: 53). Chronic, subacute, and acute infarction cases correlated excellently to the myocardial findings on autopsy. Peracute infarctions (age range: minutes to approximately 1 h) were not visible on macroscopic autopsy or histological examination. Peracute infarction areas detected on pmMRI could be verified in targeted histological investigations in 62.3% of cases and could be related to a matching coronary finding in 84.9%. A total of 15.1% of peracute lesions on pmMRI lacked a matching coronary finding but presented with severe myocardial hypertrophy or cocaine intoxication facilitating a cardiac death without verifiable coronary stenosis. CONCLUSIONS: 3-T pmMRI visualizes chronic, subacute, and acute myocardial infarction in situ. In peracute infarction as a possible cause of sudden cardiac death, it demonstrates affected myocardial areas not visible on autopsy. pmMRI should be considered as a feasible post-mortem investigation technique for the deceased patient if no consent for a clinical autopsy is obtained.

Renal function in patients with HIV starting therapy with tenofovir and either efavirenz, lopinavir or atazanavir.

BACKGROUND: Tenofovir is associated with reduced renal function, but it is not clear whether there is a greater decline in renal function when tenofovir is co-administered with a boosted protease inhibitor rather than with a nonnucleoside reverse transcriptase inhibitor (NNRTI). METHODS: We calculated the estimated glomerular filtration rate (eGFR) for patients in the Swiss HIV Cohort Study. We estimated the difference in eGFR over time between first therapies containing tenofovir and either the NNRTI efavirenz or the protease inhibitors lopinavir (LPV/r) or atazanavir (ATV/r), both boosted with ritonavir. RESULTS: Patients on a first therapy of tenofovir co-administered with efavirenz (n  = 484), LPV/r (n = 269) and ATV/r (n =  187) were followed for a median of 1.7, 1.2 and 1.3 years, respectively. Relative to tenofovir and efavirenz, the estimated difference in eGFR for tenofovir and LPV/r was -2.6 ml/min per 1.73 m [95% confidence interval (CI) -7.3 to 2.2) during the first 6 months of therapy, then followed by a difference of 0.0 ml/min per 1.73 m (95% CI -1.1 to 1.1) for each additional 6 months of therapy. Relative to tenofovir and efavirenz, the estimated difference in eGFR for tenofovir and ATV/r was -7.6 ml/min per 1.73 m (95% CI -11.8 to -3.4) during the first 6 months of therapy, then followed by a difference of -0.5 ml/min per 1.73 m (95% CI -1.6 to 0.7) for each additional 6 months of therapy. CONCLUSION: Tenofovir with either boosted protease inhibitor leads to a greater initial decline in eGFR than tenofovir with efavirenz; this decline may be worse with ATV/r than with LPV/r.

Toxicokinetic modeling of folpet fungicide and its ring-biomarkers of exposure in humans.

A human in vivo toxicokinetic model was built to allow a better understanding of the toxicokinetics of folpet fungicide and its key ring biomarkers of exposure: phthalimide (PI), phthalamic acid (PAA) and phthalic acid (PA). Both PI and the sum of ring metabolites, expressed as PA equivalents (PAeq), may be used as biomarkers of exposure. The conceptual representation of the model was based on the analysis of the time course of these biomarkers in volunteers orally and dermally exposed to folpet. In the model, compartments were also used to represent the body burden of folpet and experimentally relevant PI, PAA and PA ring metabolites in blood and in key tissues as well as in excreta, hence urinary and feces. The time evolution of these biomarkers in each compartment of the model was then mathematically described by a system of coupled differential equations. The mathematical parameters of the model were then determined from best fits to the time courses of PI and PAeq in blood and urine of five volunteers administered orally 1 mg kg(-1) and dermally 10 mg kg(-1) of folpet. In the case of oral administration, the mean elimination half-life of PI from blood (through feces, urine or metabolism) was found to be 39.9 h as compared with 28.0 h for PAeq. In the case of a dermal application, mean elimination half-life of PI and PAeq was estimated to be 34.3 and 29.3 h, respectively. The average final fractions of administered dose recovered in urine as PI over the 0-96 h period were 0.030 and 0.002%, for oral and dermal exposure, respectively. Corresponding values for PAeq were 24.5 and 1.83%, respectively. Finally, the average clearance rate of PI from blood calculated from the oral and dermal data was 0.09 ± 0.03 and 0.13 ± 0.05 ml h(-1) while the volume of distribution was 4.30 ± 1.12 and 6.05 ± 2.22 l, respectively. It was not possible to obtain the corresponding values from PAeq data owing to the lack of blood time course data.

1010-005 Bloody Run Creek Watershed Final Report

The City of Marquette lies in the 65,000 acre Mississippi River watershed, and is surrounded by steep bluffs. Though scenic, controlling water runoff during storm events presents significant challenges. Flash-flooding from the local watershed has plagued the city for decades. The people of Marquette have committed to preserve the water quality of key natural resources in the area including the Bloody Run Creek and associated wetlands by undertaking projects to control the spread of debris and sediment caused by excess runoff during area storm events. Following a July 2007 storm (over 8” of rain in 24 hours) which caused unprecedented flood damage, the City retained an engineering firm to study the area and provide recommendations to eliminate or greatly reduce uncontrolled runoff into the Bloody Run Creek wetland, infrastructure damage and personal property loss. Marquette has received Iowa Great Places designation, and has demonstrated its commitment to wetland preservation with the construction of Phase I of this water quality project. The Bench Area Storm Water Management Plan prepared by the City in 2008 made a number of recommendations to mitigate flash flooding by improving storm water conveyance paths, detention, and infrastructure within the Bench area. Due to steep slopes and rocky geography, infiltration based systems, though desirable, would not be an option over surface based systems. Runoff from the 240 acre watershed comes primarily from large, steep drainage areas to the south and west, flowing to the Bench area down three hillside routes; designated as South East, South Central and South West. Completion of Phase I, which included an increased storage capacity of the upper pond, addressed the South East and South Central areas. The increased upper pond capacity will now allow Phase II to proceed. Phase II will address runoff from the South West drainage area; which engineers have estimated to produce as much water volume as the South Central and South East areas combined. Total costs for Phase I are $1.45 million, of which Marquette has invested $775,000, and IJOBS funding contributed $677,000. Phase II costs are estimated at $617,000. WIRB funding support of $200,000 would expedite project completion, lessen the long term debt impact to the community and aid in the preservation of the Bloody Run Creek and adjoining wetlands more quickly than Marquette could accomplish on its own.

Country actions to meet UN commitments on non-communicable diseases: a stepwise approach.

Strong leadership from heads of state is needed to meet national commitments to the UN political declaration on non-communicable diseases (NCDs) and to achieve the goal of a 25% reduction in premature NCD mortality by 2025 (the 25 by 25 goal). A simple, phased, national response to the political declaration is suggested, with three key steps: planning, implementation, and accountability. Planning entails mobilisation of a multisectoral response to develop and support the national action plan, and to build human, financial, and regulatory capacity for change. Implementation of a few priority and feasible cost-effective interventions for the prevention and treatment of NCDs will achieve the 25 by 25 goal and will need only few additional financial resources. Accountability incorporates three dimensions: monitoring of progress, reviewing of progress, and appropriate responses to accelerate progress. A national NCD commission or equivalent, which is independent of government, is needed to ensure that all relevant stakeholders are held accountable for the UN commitments to NCDs.

Características fenológicas e físicas e perfil de ácidos graxos em oliveiras no sul de Minas Gerais

O objetivo deste trabalho foi avaliar as características fenológicas e físicas, o teor lipídico e o perfil de ácidos graxos dos frutos de cultivares de oliveira, da Serra da Mantiqueira, sul do Estado de Minas Gerais. Foram avaliadas as cultivares Alto D'Ouro, Arbequina, Galega, Grappolo 541, Grappolo 561, Grappolo 575, Negroa, Penafiel, Ropades 392 e Santa Catalina, nos anos agrícolas 2008/2009, 2009/2010 e 2010/2011. Extraiu-se o óleo bruto das cultivares ricas em lipídeos, para a avaliação do perfil de ácidos graxos. O florescimento ocorre de julho a outubro, e a colheita de janeiro a março. A cultivar mais precoce é a Arbequina, e as mais tardias são Galega, Grappolo 575 e Santa Catalina. 'Grappolo 561' apresenta frutos de maior diâmetro transversal, e 'Grappolo 541' frutos de maior massa total. 'Arbequina' e 'Grappolo 561' apresentam maior teor de lipídeos.

Influencia del contenido de oxigeno sobre la ductilidad del hierro de granos ultra finos obtenido por compactación en caliente

Sabiendo que las propiedades mecánicas de un metal están gobernadas por sumicroestructura y más precisamente por su tamaño de grano, la industria busca desarrollarmateriales con un tamaño de grano nanométrico que tengan comportamientos mecánicosinteresantes: alto limite elástico y ductilidad aceptable.Este proyecto trata de la influencia del oxigeno sobre un material nanoestructurado obtenidopor compactación en caliente de polvo molido de hierro. Con este objetivo, se ha realizadodos polvo de hierro conteniendo cada uno una concentración en oxigeno diferente (0.238 y0.634% másico). Se los han compactado a diferentes temperaturas (575, 600, 625y 650°C).Se ha realizado diferentes pruebas sobre los consolidados: medición de la densidad,dureza, determinación del tamaño de grano, resistencia mecánica y ductilidad medianteensayo de tracción.Las piezas consolidadas con un porcentaje bajo de carbono muestran una buena resistenciacon porcentajes de alargamiento bajos pero suficientes. Para las piezas con altoscontenidos de oxígeno, se ha demostrado que el oxigeno fragiliza el material formandoóxidos que ralentizan el crecimiento de grano a alta temperatura y que dificultan suconsolidación. De esta manera, estas piezas tienen una resistencia teórica mucho mayorpero rompen por rotura frágil.

Influencia del contenido de oxigeno sobre la ductilidad del hierro de granos ultra finos obtenido por compactación en caliente

Sabiendo que las propiedades mecánicas de un metal están gobernadas por sumicroestructura y más precisamente por su tamaño de grano, la industria busca desarrollarmateriales con un tamaño de grano nanométrico que tengan comportamientos mecánicosinteresantes: alto limite elástico y ductilidad aceptable.Este proyecto trata de la influencia del oxigeno sobre un material nanoestructurado obtenidopor compactación en caliente de polvo molido de hierro. Con este objetivo, se ha realizadodos polvo de hierro conteniendo cada uno una concentración en oxigeno diferente (0.238 y0.634% másico). Se los han compactado a diferentes temperaturas (575, 600, 625y 650°C).Se ha realizado diferentes pruebas sobre los consolidados: medición de la densidad,dureza, determinación del tamaño de grano, resistencia mecánica y ductilidad medianteensayo de tracción.Las piezas consolidadas con un porcentaje bajo de carbono muestran una buena resistenciacon porcentajes de alargamiento bajos pero suficientes. Para las piezas con altoscontenidos de oxígeno, se ha demostrado que el oxigeno fragiliza el material formandoóxidos que ralentizan el crecimiento de grano a alta temperatura y que dificultan suconsolidación. De esta manera, estas piezas tienen una resistencia teórica mucho mayorpero rompen por rotura frágil.

Evaluation of an intravitreal fluocinolone acetonide implant versus standard systemic therapy in noninfectious posterior uveitis.

PURPOSE: To evaluate the safety and efficacy of an intravitreal fluocinolone acetonide (FA) implant compared with standard therapy in subjects with noninfectious posterior uveitis (NIPU). DESIGN: Randomized, controlled, phase 2b/3, open-label, multicenter superiority trial. PARTICIPANTS: Subjects with unilateral or bilateral NIPU. METHODS: One hundred forty subjects received either a 0.59-mg FA intravitreal implant (n = 66) or standard of care (SOC; n = 74) with either systemic prednisolone or equivalent corticosteroid as monotherapy (> or =0.2 mg/kg daily) or, if judged necessary by the investigator, combination therapy with an immunosuppressive agent plus a lower dose of prednisolone or equivalent corticosteroid (> or =0.1 mg/kg daily). MAIN OUTCOME MEASURES: Time to first recurrence of uveitis. RESULTS: Eyes that received the FA intravitreal implant experienced delayed onset of observed recurrence of uveitis (P<0.01) and a lower rate of recurrence of uveitis (18.2% vs. 63.5%; P< or =0.01) compared with SOC study eyes. Adverse events frequently observed in implanted eyes included elevated intraocular pressure (IOP) requiring IOP-lowering surgery (occurring in 21.2% of implanted eyes) and cataracts requiring extraction (occurring in 87.8% of phakic implanted eyes). No treatment-related nonocular adverse events were observed in the implant group, whereas such events occurred in 25.7% of subjects in the SOC group. CONCLUSIONS: The FA intravitreal implant provided better control of inflammation in patients with uveitis compared with systemic therapy. Intraocular pressure and lens clarity of implanted eyes need close monitoring in patients receiving the FA intravitreal implant.

Unilateral ureteropelvic junction obstruction in children: long-term followup after unilateral pyeloplasty.

PURPOSE: The benefit of surgery on renal function in unilateral ureteropelvic junction stenosis (UPJS) is still debated. We evaluated renal function outcome after unilateral pyeloplasty in 53 children. MATERIALS AND METHODS: We retrospectively reviewed 123I-hippuran renography performed at diagnosis and 5 to 15 years (mean +/- SD 7 +/- 3 years) after successful pyeloplasty. UPJS was prenatally detected in 26 children because of urinary tract infection in 17 and miscellaneous reasons in 10. Relative function (RF) and absolute function were measured on background corrected renograms. Absolute function of the affected and contralateral kidneys was determined by an accumulation index (AI), representing the percent injected dose extracted by each kidney 30 to 90 seconds after the heart peak. RESULTS: Preoperatively 33 of the 53 UPJS kidneys had a decreased AI but only 8 had a RF of less than 40%, which was improved in 7 at followup. In addition, the AI improved in 29 kidneys, of which 19 (36%) normalized. Of the UPJS kidneys 14 had an initially decreased AI that remained abnormal at followup. In these kidneys preoperative RF was less than 40% in all. At followup RF was greater than 40% in 4 children, in whom the AI of the UPJS kidney did not improve but the AI of the contralateral one decreased from supranormal to normal. Seven contralateral kidneys had a supranormal AI, whereas the AI remained normal in 3, of which the RF in the UPJS kidney remained at less than 40%. The AI and RF were normal in 20 UPJS kidneys and remained normal. CONCLUSIONS: When normal, the AI and RF reflected renal function outcome similarly. The AI added relevant information in UPJS kidneys with impaired function, showing compensation of the contralateral kidney.