Differential Internalization of Amphotericin B - Conjugated Nanoparticles in Human Cells and the Expression of Heat Shock Protein 70

Although a variety of nanoparticles (NPs) functionalized with amphotericin B, an antifungal agent widely used in the clinic, have been studied in the last years their cytotoxicity profile remains elusive. Here we show that human endothelial cells take up high amounts of silica nanoparticles (SNPs) conjugated with amphotericin B (AmB) (SNP-AmB) (65.4 12.4 pg of Si per cell) through macropinocytosis while human fibroblasts internalize relatively low amounts (2.3 0.4 pg of Si per cell) because of their low capacity for macropinocytosis. We further show that concentrations of SNP-AmB and SNP up to 400 mg/mL do not substantially affect fibroblasts. In contrast, endothelial cells are sensitive to low concentrations of NPs (above 10 mg/mL), in particular to SNP-AmB. This is because of their capacity to internalize high concentration of NPs and high sensitivity of their membrane to the effects of AmB. Low-moderate concentrations of SNP-AmB (up to 100 mg/mL) induce the production of reactive oxygen species (ROS), LDH release, high expression of pro-inflammatory cytokines and chemokines (IL-8, IL-6, G-CSF, CCL4, IL-1b and CSF2) and high expression of heat shock proteins (HSPs) at gene and protein levels. High concentrations of SNP-AmB (above 100 ug/mL) disturb membrane integrity and kill rapidly human cells(60% after 5 h). This effect is higher in SNP-AmB than in SNP

An empirical evaluation of imputation accuracy for association statistics reveals increased type-I error rates in genome-wide associations

<p>Abstract</p> <p>Background</p> <p>Genome wide association studies (GWAS) are becoming the approach of choice to identify genetic determinants of complex phenotypes and common diseases. The astonishing amount of generated data and the use of distinct genotyping platforms with variable genomic coverage are still analytical challenges. Imputation algorithms combine directly genotyped markers information with haplotypic structure for the population of interest for the inference of a badly genotyped or missing marker and are considered a near zero cost approach to allow the comparison and combination of data generated in different studies. Several reports stated that imputed markers have an overall acceptable accuracy but no published report has performed a pair wise comparison of imputed and empiric association statistics of a complete set of GWAS markers.</p> <p>Results</p> <p>In this report we identified a total of 73 imputed markers that yielded a nominally statistically significant association at <it>P </it>< 10 ^-5for type 2 Diabetes Mellitus and compared them with results obtained based on empirical allelic frequencies. Interestingly, despite their overall high correlation, association statistics based on imputed frequencies were discordant in 35 of the 73 (47%) associated markers, considerably inflating the type I error rate of imputed markers. We comprehensively tested several quality thresholds, the haplotypic structure underlying imputed markers and the use of flanking markers as predictors of inaccurate association statistics derived from imputed markers.</p> <p>Conclusions</p> <p>Our results suggest that association statistics from imputed markers showing specific MAF (Minor Allele Frequencies) range, located in weak linkage disequilibrium blocks or strongly deviating from local patterns of association are prone to have inflated false positive association signals. The present study highlights the potential of imputation procedures and proposes simple procedures for selecting the best imputed markers for follow-up genotyping studies.</p

Spatial patterns and temporal variability of drought in Western Iran

An analysis of drought in western Iran from 1966 to 2000 is presented using monthly precipitation data observed at 140 gauges uniformly distributed over the area. Drought conditions have been assessed by means of the Standardized Precipitation Index (SPI). To study the long-term drought variability the principal component analysis was applied to the SPI field computed on 12-month time scale. The analysis shows that applying an orthogonal rotation to the first two principal component patterns, two distinct sub-regions having different climatic variability may be identified. Results have been compared to those obtained for the largescale using re-analysis data suggesting a satisfactory agreement. Furthermore, the extension of the large-scale analysis to a longer period (1948–2007) shows that the spatial patterns and the associated time variability of drought are subjected to noticeable changes. Finally, the relationship between hydrological droughts in the two sub-regions and El Niño Southern Oscillation events has been investigated finding that there is not clear evidence for a link between the two phenomen

Gravitational collapse with tachyon field and barotropic fluid

A particular class of space-time, with a tachyon field, \phi, and a barotropic fluid constituting the matter content, is considered herein as a model for gravitational collapse. For simplicity, the tachyon potential is assumed to be of inverse square form i.e., V(\phi) \sim \phi^{-2}. Our purpose, by making use of the specific kinematical features of the tachyon, which are rather different from a standard scalar field, is to establish the several types of asymptotic behavior that our matter content induces. Employing a dynamical system analysis, complemented by a thorough numerical study, we find classical solutions corresponding to a naked singularity or a black hole formation. In particular, there is a subset where the fluid and tachyon participate in an interesting tracking behaviour, depending sensitively on the initial conditions for the energy densities of the tachyon field and barotropic fluid. Two other classes of solutions are present, corresponding respectively, to either a tachyon or a barotropic fluid regime. Which of these emerges as dominant, will depend on the choice of the barotropic parameter, \gamma. Furthermore, these collapsing scenarios both have as final state the formation of a black hole.Comment: 18 pages, 7 figures. v3: minor changes. Final version to appear in GR

Doppler and birth weight Z score: predictors for adverse neonatal outcome in severe fetal compromise

BACKGROUND: An adequate placental perfusion is crucial for the normal growth and well being of the fetus and newborn. The blood flow through the placenta can be compromised in a variety of clinical situations, always causing important damage to the gestation. Our objective is to identify significant predictors for adverse neonatal outcome in severe fetal compromise. METHODS: Consecutive premature fetuses at between 25 and 32 weeks with severe placental insufficiency were examined prospectively. Inclusion criteria were: (i) singletons (ii) normal anatomy; (iii) abnormal umbilical artery Doppler pulsatility index (PI); (iv) abnormal cerebroplacental ratio; (v) middle cerebral artery (MCA) PI < - 2SD ("brain sparing"); (vi) last Doppler examination performed within 24 hours prior to delivery. All 46 patients that met criteria and started the study were followed to the end. We considered as independent potential predicting variables: absent or reversed end diastolic flow in umbilical artery, abnormal ductus venosus S/A ratio, absent or reversed flow during atrial contraction in the ductus venosus and birth weight Z score. Outcome parameters were: neonatal mortality and severe neonatal morbidity. RESULTS: Backward stepwise logistic regression analysis was used to determine the optimal model for the prediction of neonatal mortality and severe neonatal morbidity. In this analysis birth weight Z score index showed the strongest association OR = 1,87 [1,17-2,99] with all neonatal outcome, all other independent variables were excluded for the optimal model. There was no mortality for the group with normal birth weight Z score. CONCLUSION: Our study suggests that birth weight Z score is the strongest predictor of adverse neonatal outcome in severe placental insufficiencies. Such use of Z scores, allowing to get rid of gestational age or sex covariates could be extended to estimated fetal weight and might help in making important decisions in the management of compromised pregnancies

Changes in medicine course curricula in Brazil encouraged by the Program for the Promotion of Medical School Curricula (PROMED)

<p>Abstract</p> <p>Background</p> <p>The Program for the Promotion of Changes in Medical School Curricula (PROMED) was developed by the Brazilian Ministries of Health and Education. The objective of this program was to finance the implementation of changes to the curricula of medical schools directed towards the Brazilian national healthcare system (SUS). This paper reports research carried out together with the coordinators responsible for the PROMED of each medical school approved, in which interviews were used to evaluate whether this financial support succeeded in stimulating changes. The aim of this study was to evaluate the impact of this program three years after implementation in the universities that received funding.</p> <p>Methods</p> <p>The 19 course coordinators of the medical schools in which the PROMED project was implemented were interviewed using a questionnaire containing 12 questions for qualitative analysis. This paper focuses partially on the reports of the results of this qualitative analysis. Laurence Bardin's.</p> <p>Results</p> <p>The universities interviewed were found to have some common concerns: the decoupling of basic and professional training difficulties in achieving proximity to the network of services; insufficient funding; and the emphasis of most teachers being on teaching hospitals and specialization. These findings indicate that the direction of curriculum reform (PROMED) is toward providing a targeted training for this system.</p> <p>Conclusion</p> <p>The interviewees were aware that this program would trigger future changes in all aspects of healthcare and represents an ongoing challenge to the academic field. PROMED provided the momentum for change in the nature of medical training in Brazil and was seen as powerful enough to override other processes and as a basis for guidance regarding the methodology, pedagogical approach and scenarios of practical experience.</p

Evaluation of objective and subjective indicators of death in a period of one year in a sample of prevalent patients under regular hemodialysis

<p>Abstract</p> <p>Background</p> <p>To identify objective and subjective indicators of death in prevalent hemodialysis (HD) patients in a follow-up study of 12 months.</p> <p>Methods</p> <p>The study included end-stage renal disease patients undergoing HD and analyzed demographic and laboratory data from the dialysis unit's records. Baseline data concerning socioeconomic status, comorbidity, quality of life level, coping style and depression were also assessed. For variables that differed in the comparison between survivors and non-survivors, Cox proportional hazards for death were calculated.</p> <p>Results</p> <p>The mortality rate was 13.0%. Non-survivors differed in age, comorbidity, inclusion on the transplant waiting list and physical functioning score. The hazard ratios of death were 8.958 (2.843-28.223; <it>p </it>< 0.001) for comorbidity, 3.992 (1.462-10.902; <it>p </it>= 0.007) for not being on the transplant waiting list, 1.038 (1.012-1.066; <it>p </it>= 0.005) for age, and 0.980 (0.964-0.996; <it>p </it>= 0.014) for physical functioning.</p> <p>Conclusions</p> <p>Comorbidity, not being on the transplant waiting list, age and physical functioning, which reflects physical status, must be seen as risk indicators of death among patients undergoing HD.</p

Salvage for cervical recurrences of head and neck cancer with dissection and interstitial high dose rate brachytherapy

Salvage therapy in head and neck cancer (HNC) is a controversy issue and the literature is scarce regarding the use of interstitial high-dose rate brachytherapy (I-HDR) in HNC. We evaluated the long-term results of a treatment policy combining salvage surgery and I-HDR for cervical recurrences of HNC. Charts of 21 patients treated from 1994 to 2004 were reviewed. The crude local control rate for all patients was 52.4%. The 5- and 8-years overall (OS) and local relapse-free survival (LRFS) rates were 50%, 42.9%, 42.5% and 28.6%, respectively. The only predictive factor associated to LFRS and OS was negative margin status (p = 0.0007 and p = 0.0002). We conclude that complete surgery is mandatory for long term control and the doses given by brachytherapy are not high enough to compensate for microscopic residual disease after surgery