Direct powder extrusion 3d printing of praziquantel to overcome neglected disease formulation challenges in paediatric populations

For the last 40 years, praziquantel has been the standard treatment for schistosomiasis, a neglected parasitic disease affecting more than 250 million people worldwide. However, there is no suitable paediatric formulation on the market, leading to off-label use and the splitting of commercial tablets for adults. In this study, we use a recently available technology, direct powder extrusion (DPE) three-dimensional printing (3DP), to prepare paediatric Printlets™ (3D printed tablets) of amorphous solid dispersions of praziquantel with Kollidon® VA 64 and surfactants (Span™ 20 or Kolliphor® SLS). Printlets were successfully printed from both pellets and powders obtained from extrudates by hot melt extrusion (HME). In vitro dissolution studies showed a greater than four-fold increase in praziquantel release, due to the formation of amorphous solid dispersions. In vitro palatability data indicated that the printlets were in the range of praziquantel tolerability, highlighting the taste masking capabilities of this technology without the need for additional taste masking excipients. This work has demonstrated the possibility of 3D printing tablets using pellets or powder forms obtained by HME, avoiding the use of filaments in fused deposition modelling 3DP. Moreover, the main formulation hurdles of praziquantel, such as low drug solubility, inadequate taste, and high and variable dose requirements, can be overcome using this technology

Reducing occurrence of Giardia duodenalis in children living in semiarid regions: impact of a large scale rainwater harvesting initiative.

BACKGROUND: In Brazil, about two million people living in rural semiarid regions were benefited with the construction of rainwater cement cisterns, as an initiative from the program "One Million Cisterns" (P1MC). Nevertheless, few epidemiological studies have been conducted to assess health risks or protection effects associated with consumption of this water source. The aim of this study was to evaluate whether access to rainwater harvesting cisterns is associated with the decrease in the occurrence of Giardia duodenalis infections in children, compared to other children living in households supplied by other water sources. METHODOLOGY/PRINCIPAL FINDINGS: A quasi-experimental study with two concurrent cohorts was developed in two rural municipalities of the semiarid region of Brazil. A sample of 664 children, aged between 4 months and 5 years old, was followed up, of which 332 had access to rainwater cisterns (cistern group) and 332 did not, having water supplied from alternative sources (comparison group). In a period of approximately one year (2010) intestinal parasites were investigated in feces three times. The prevalence of G. duodenalis in children from the cistern group ranged from 4.8 to 10.5%, while the prevalence in the comparison group ranged from 7.6 to 16.7%. Multivariate analysis (GEE) showed a higher risk of G. duodenalis infection in children who did not have access to rainwater cisterns, when compared to children who did (OR 1.72; 95% CI 1.14-2.59). The other variables associated with G. duodenalis infection were: number of rooms per house (OR 0.89; 95% CI 0.80-0.99); family income (OR0.48; 95% CI 0.26-0.88); birth order (OR 1.72; 95% CI 1.17-2.51); preterm children (OR 1.70; 95% CI 1.19-2.43); and improper hand hygiene prior to food preparation (OR 4.78; 95% CI 1.95-11.76). CONCLUSIONS/SIGNIFICANCE: Ownership of a rainwater cistern is associated with a lower prevalence of G. duodenalis infection in children after adjustment for environmental and family-related factors. Nevertheless, the study suggests the necessity to complement physical interventions with actions related to personal and domestic hygiene to enable further reductions in parasite infections affecting mainly the underprivileged populations

Identification of a cytokine network sustaining neutrophil and Th17 activation in untreated early rheumatoid arthritis

© 2010 Cascão et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by sustained synovitis. Recently, several studies have proposed neutrophils and Th17 cells as key players in the onset and perpetuation of this disease. The main goal of this work was to determine whether cytokines driving neutrophil and Th17 activation are dysregulated in very early rheumatoid arthritis patients with less than 6 weeks of disease duration and before treatment (VERA). Methods: Cytokines related to neutrophil and Th17 activation were quantified in the serum of VERA and established RA patients and compared with other very early arthritis (VEA) and healthy controls. Synovial fluid (SF) from RA and osteoarthritis (OA) patients was also analyzed. Results: VERA patients had increased serum levels of cytokines promoting Th17 polarization (IL-1b and IL-6), as well as IL-8 and Th17-derived cytokines (IL-17A and IL-22) known to induce neutrophil-mediated inflammation. In established RA this pattern is more evident within the SF. Early treatment with methotrexate or corticosteroids led to clinical improvement but without an impact on the cytokine pattern. Conclusions: VERA patients already display increased levels of cytokines related with Th17 polarization and neutrophil recruitment and activation, a dysregulation also found in SF of established RA. 0 Thus, our data suggest that a cytokine-milieu favoring Th17 and neutrophil activity is an early event in RA pathogenesis.This work was supported by a grant from Sociedade Portuguesa de Reumatologia/Schering-Plough 2005. RAM and RC were funded by Fundação para a Ciência e a Tecnologia (FCT) SFRH/BD/30247/2006 and SFRH/BD/40513/2007, respectively. MMS-C was funded by Marie Curie Intra-European Fellowship PERG-2008-239422 and a EULAR Young Investigator Award

Entanglement Content of Quantum Particle Excitations I. Free Field Theory

We evaluate the entanglement entropy of a single connected region in excited states of one-dimensional massive free theories with finite numbers of particles, in the limit of large volume and region length. For this purpose, we use finite-volume form factor expansions of branch-point twist field two-point functions. We find that the additive contribution to the entanglement due to the presence of particles has a simple "qubit" interpretation, and is largely independent of momenta: it only depends on the numbers of groups of particles with equal momenta. We conjecture that at large momenta, the same result holds for any volume and region lengths, including at small scales. We provide accurate numerical verifications

The effectiveness of public health interventions to reduce the health impact of climate change:a systematic review of systematic reviews

Climate change is likely to be one of the most important threats to public health in the coming years. Yet despite the large number of papers considering the health impact of climate change, few have considered what public health interventions may be of most value in reducing the disease burden. We aimed to evaluate the effectiveness of public health interventions to reduce the disease burden of high priority climate sensitive diseases

School performance of international adoptees better than expected from cognitive test results

Objective: To investigate school performance of international adoptees in relation to their cognitive competence. Method: From the population of all male Swedish residents born 1973–1976, registered in the census 1985 and with complete test scores from military conscription, the following study groups were identified: Korean adoptees (n = 320), non-Korean adoptees (n = 1,125), siblings (children born by adoptive parents, n = 190) and Swedish majority comparisons (n = 142,024). Global scores from intelligence tests at conscription were compared with grade points from the last compulsory school year (year 9). Linear and logistic regression was applied in statistical analyses. Results: The mean grade points in theoretical subjects were lower in non-Korean adoptees than in the majority population, but when global test scores from military conscription were adjusted for, outcomes were significantly better, equal for physics, than in the majority population. The grade points of Korean adoptees were higher than in the majority population and the same held true after adjusting for global test scores. When SES was taken into account, the risk of poor school performance (only completed lower subject levels) increased in non-Korean adoptees compared to models only adjusted for age and sex. Conclusion: Male international adoptees generally perform better in school than expected by their cognitive competence. A cognitive evaluation is important in the assessment of adoptees with learning difficulties

Effect of voriconazole on Candida tropicalis biofilms: Relation with ERG genes expression

Candida tropicalis has emerged as the third most prevalent fungal pathogens and its ability to form biofilms has been considered one of the most important virulence factors, since biofilms represent high tolerance to antifungal agents. However, the mechanisms of C. tropicalis biofilm resistance to antifungals remain poorly understood. Thus, the main aim of this work was to infer about the effect of voriconazole on the formation and control of C. tropicalis biofilms and disclose its relationship with ERG genes' expression. Planktonic cells tolerance of several C. tropicalis clinical isolates to voriconazole was determined through of antifungal susceptibility test, and the effect of this azole against C. tropicalis biofilm formation and pre-formed biofilms was evaluated by cultivable cells determination and total biomass quantification. ERG genes expression was analyzed by quantitative real-time polymerase chain reaction. This work showed that C. tropicalis resistance to voriconazole is strain dependent and that voriconazole was able to partially control biofilm formation, but was unable to eradicate C. tropicalis pre-formed biofilms. Moreover, C. tropicalis biofilms resistance to voriconazole seems to be associated with alterations of sterol content in the cell membrane, resulting in ERG genes overexpression. Voriconazole is unable to control C. tropicalis biofilms, and the overexpression of ERG genes is a possible mechanism of biofilm resistance.TheauthorsthanktheFCTfortheStrategic Project of the UID/BIO/04469/2013 unit, FCT and European Union funds (FEDER/COMPETE) for the project RECI/BBBEBI/0179/2012 (FCOMP-01-0124-FEDER-027462). We also would like to acknowledge Pfizer , S.A. for the kindly donation of voriconazole

Genotypic classification of patients with Wolfram syndrome: insights into the natural history of the disease and correlation with phenotype

Purpose: Wolfram syndrome is a degenerative, recessive rare disease with an onset in childhood. It is caused by mutations in WFS1 or CISD2 genes. More than 200 different variations in WFS1 have been described in patients with Wolfram syndrome, which complicates the establishment of clear genotype-phenotype correlation. The purpose of this study was to elucidate the role of WFS1 mutations and update the natural history of the disease. Methods: This study analyzed clinical and genetic data of 412 patients with Wolfram syndrome published in the last 15 years. Results: (i) 15% of published patients do not fulfill the current ­inclusion criterion; (ii) genotypic prevalence differences may exist among countries; (iii) diabetes mellitus and optic atrophy might not be the first two clinical features in some patients; (iv) mutations are nonuniformly distributed in WFS1; (v) age at onset of diabetes mellitus, hearing defects, and diabetes insipidus may depend on the patient"s genotypic class; and (vi) disease progression rate might depend on genotypic class. Conclusion: New genotype-phenotype correlations were established, disease progression rate for the general population and for the genotypic classes has been calculated, and new diagnostic criteria have been proposed. The conclusions raised could be important for patient management and counseling as well as for the development of treatments for Wolfram syndrome