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Sample records for improved cftr delivery

  1. Interaction between a novel TGFB1 haplotype and CFTR genotype is associated with improved lung function in cystic fibrosis.

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    Bremer, Lindsay A; Blackman, Scott M; Vanscoy, Lori L; McDougal, Kathryn E; Bowers, Amanda; Naughton, Kathleen M; Cutler, David J; Cutting, Garry R

    2008-07-15

    Cystic fibrosis (CF), the most common lethal single gene disorder in Caucasians, is due to mutations in the CFTR gene. Twin and sibling analysis indicates that modifier genes, rather than allelic variation in CFTR, are responsible for most of the variability in severity of lung disease, the major cause of mortality in CF patients. We used a family-based approach to test for association between lung function and two functional SNPs (rs1800469, '-509' and rs1982073, 'codon 10') in the 5' region of transforming growth factor-beta1 (TGFB1), a putative CF modifier gene. Quantitative transmission disequilibrium testing of 472 CF patient-parent-parent trios revealed that both TGFB1 SNPs showed significant transmission distortion when patients were stratified by CFTR genotype. Although lung function and nutritional status are correlated in CF patients, there was no evidence of association between the TGFB1 SNPs and variation in nutritional status. Additional tagging SNPs (rs8179181, rs2278422, rs8110090, rs4803455 and rs1982072) that capture most of the diversity in TGFB1 were also typed but none showed association with variation in lung function. However, a haplotype composed of the -509 C and codon 10 T alleles along with the C allele of the 3' SNP rs8179181 was highly associated with increased lung function in patients grouped by CFTR genotype. These results demonstrate that TGFB1 is a modifier of CF lung disease and reveal a previously unrecognized beneficial effect of TGFB1 variants upon the pulmonary phenotype.

  2. The CFTR-Associated Ligand Arrests the Trafficking of the Mutant ΔF508 CFTR Channel in the ER Contributing to Cystic Fibrosis

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    Emily Bergbower

    2018-01-01

    Full Text Available Background/Aims: The CFTR-Associated Ligand (CAL, a PDZ domain containing protein with two coiled-coil domains, reduces cell surface WT CFTR through degradation in the lysosome by a well-characterized mechanism. However, CAL’s regulatory effect on ΔF508 CFTR has remained almost entirely uninvestigated. Methods: In this study, we describe a previously unknown pathway for CAL by which it regulates the membrane expression of ΔF508 CFTR through arrest of ΔF508 CFTR trafficking in the endoplasmic reticulum (ER using a combination of cell biology, biochemistry and electrophysiology. Results: We demonstrate that CAL is an ER localized protein that binds to ΔF508 CFTR and is degraded in the 26S proteasome. When CAL is inhibited, ΔF508 CFTR retention in the ER decreases and cell surface expression of mature functional ΔF508 CFTR is observed alongside of enhanced expression of plasma membrane scaffolding protein NHERF1. Chaperone proteins regulate this novel process, and ΔF508 CFTR binding to HSP40, HSP90, HSP70, VCP, and Aha1 changes to improve ΔF508 CFTR cell surface trafficking. Conclusion: Our results reveal a pathway in which CAL regulates the cell surface availability and intracellular retention of ΔF508 CFTR.

  3. Regulatory crosstalk by protein kinases on CFTR trafficking and activity

    Science.gov (United States)

    Farinha, Carlos Miguel; Swiatecka-Urban, Agnieszka; Brautigan, David; Jordan, Peter

    2016-01-01

    Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is a member of the ATP binding cassette (ABC) transporter superfamily that functions as a cAMP-activated chloride ion channel in fluid-transporting epithelia. There is abundant evidence that CFTR activity (i.e. channel opening and closing) is regulated by protein kinases and phosphatases via phosphorylation and dephosphorylation. Here, we review recent evidence for the role of protein kinases in regulation of CFTR delivery to and retention in the plasma membrane. We review this information in a broader context of regulation of other transporters by protein kinases because the overall functional output of transporters involves the integrated control of both their number at the plasma membrane and their specific activity. While many details of the regulation of intracellular distribution of CFTR and other transporters remain to be elucidated, we hope that this review will motivate research providing new insights into how protein kinases control membrane transport to impact health and disease.

  4. Delivery improvements for CANDU projects

    International Nuclear Information System (INIS)

    Stephen Yu; Ken Hedges

    1998-01-01

    Future CANDU design will continue to meet emerging design and performance requirements as expected by the operating utilities, and will integrate new technologies into both the product features and work processes. Elements of this risk reduction strategy include feedback of lessons learned from operating plants, project experiences from previous projects, and replication of successful systems and equipment. Project implementation risk is minimized by up-front engineering and licensing prior to contract start. Enhanced competitiveness of the CANDU products is ensured by incorporating improvements based on updated technology. This paper summarizes the strategy used to enhance competitiveness of the CANDU products and the measures introduced to minimize risk during project implementation. This strategy provides a balance between innovation and proven designs; and between the desire for safety and operational improvements and the cost to achieve the improvements

  5. Targeting the intracellular environment in cystic fibrosis: restoring autophagy as a novel strategy to circumvent the CFTR defect

    Directory of Open Access Journals (Sweden)

    Valeria Rachela Villella

    2013-01-01

    Full Text Available Cystic fibrosis (CF patients harboring the most common deletion mutation of the cystic fibrosis transmembrane conductance regulator (CFTR, F508del, are poor responders to potentiators of CFTR channel activity which can be used to treat a small subset of CF patients who genetically carry plasma membrane-resident CFTR mutants. The misfolded F508del-CFTR protein is unstable in the plasma membrane even if rescued by pharmacological agents that prevent its intracellular retention and degradation. CF is a conformational disease in which defective CFTR induces an impressive derangement of general proteostasis resulting from disabled autophagy. In this review, we discuss how rescuing Beclin 1 (BECN1, a major player of autophagosome formation, either by means of direct gene transfer or indirectly by administration of proteostasis regulators, could stabilize F508del-CFTR at the plasma membrane. We focus on the relationship between the improvement of peripheral proteostasis and CFTR plasma membrane stability in F508del-CFTR homozygous bronchial epithelia or mouse lungs. Moreover, this article reviews recent preclinical evidence indicating that targeting the intracellular environment surrounding the misfolded mutant CFTR instead of protein itself could constitute an attractive therapeutic option to sensitize patients carrying the F508del-CFTR mutation to the beneficial action of CFTR potentiators on lung inflammation.

  6. Targeting the Intracellular Environment in Cystic Fibrosis: Restoring Autophagy as a Novel Strategy to Circumvent the CFTR Defect

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    Villella, Valeria Rachela; Esposito, Speranza; Bruscia, Emanuela M.; Maiuri, Maria Chiara; Raia, Valeria; Kroemer, Guido; Maiuri, Luigi

    2013-01-01

    Cystic fibrosis (CF) patients harboring the most common deletion mutation of the CF transmembrane conductance regulator (CFTR), F508del, are poor responders to potentiators of CFTR channel activity which can be used to treat a small subset of CF patients who genetically carry plasma membrane (PM)-resident CFTR mutants. The misfolded F508del-CFTR protein is unstable in the PM even if rescued by pharmacological agents that prevent its intracellular retention and degradation. CF is a conformational disease in which defective CFTR induces an impressive derangement of general proteostasis resulting from disabled autophagy. In this review, we discuss how rescuing Beclin 1 (BECN1), a major player of autophagosome formation, either by means of direct gene transfer or indirectly by administration of proteostasis regulators, could stabilize F508del-CFTR at the PM. We focus on the relationship between the improvement of peripheral proteostasis and CFTR PM stability in F508del-CFTR homozygous bronchial epithelia or mouse lungs. Moreover, this article reviews recent pre-clinical evidence indicating that targeting the intracellular environment surrounding the misfolded mutant CFTR instead of protein itself could constitute an attractive therapeutic option to sensitize patients carrying the F508del-CFTR mutation to the beneficial action of CFTR potentiators on lung inflammation. PMID:23346057

  7. From the endoplasmic reticulum to the plasma membrane: mechanisms of CFTR folding and trafficking.

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    Farinha, Carlos M; Canato, Sara

    2017-01-01

    CFTR biogenesis starts with its co-translational insertion into the membrane of endoplasmic reticulum and folding of the cytosolic domains, towards the acquisition of a fully folded compact native structure. Efficiency of this process is assessed by the ER quality control system that allows the exit of folded proteins but targets unfolded/misfolded CFTR to degradation. If allowed to leave the ER, CFTR is modified at the Golgi and reaches the post-Golgi compartments to be delivered to the plasma membrane where it functions as a cAMP- and phosphorylation-regulated chloride/bicarbonate channel. CFTR residence at the membrane is a balance of membrane delivery, endocytosis, and recycling. Several adaptors, motor, and scaffold proteins contribute to the regulation of CFTR stability and are involved in continuously assessing its structure through peripheral quality control systems. Regulation of CFTR biogenesis and traffic (and its dysregulation by mutations, such as the most common F508del) determine its overall activity and thus contribute to the fine modulation of chloride secretion and hydration of epithelial surfaces. This review covers old and recent knowledge on CFTR folding and trafficking from its synthesis to the regulation of its stability at the plasma membrane and highlights how several of these steps can be modulated to promote the rescue of mutant CFTR.

  8. Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation.

    Science.gov (United States)

    De Stefano, Daniela; Villella, Valeria R; Esposito, Speranza; Tosco, Antonella; Sepe, Angela; De Gregorio, Fabiola; Salvadori, Laura; Grassia, Rosa; Leone, Carlo A; De Rosa, Giuseppe; Maiuri, Maria C; Pettoello-Mantovani, Massimo; Guido, Stefano; Bossi, Anna; Zolin, Anna; Venerando, Andrea; Pinna, Lorenzo A; Mehta, Anil; Bona, Gianni; Kroemer, Guido; Maiuri, Luigi; Raia, Valeria

    2014-01-01

    Restoration of BECN1/Beclin 1-dependent autophagy and depletion of SQSTM1/p62 by genetic manipulation or autophagy-stimulatory proteostasis regulators, such as cystamine, have positive effects on mouse models of human cystic fibrosis (CF). These measures rescue the functional expression of the most frequent pathogenic CFTR mutant, F508del, at the respiratory epithelial surface and reduce lung inflammation in Cftr(F508del) homozygous mice. Cysteamine, the reduced form of cystamine, is an FDA-approved drug. Here, we report that oral treatment with cysteamine greatly reduces the mortality rate and improves the phenotype of newborn mice bearing the F508del-CFTR mutation. Cysteamine was also able to increase the plasma membrane expression of the F508del-CFTR protein in nasal epithelial cells from F508del homozygous CF patients, and these effects persisted for 24 h after cysteamine withdrawal. Importantly, this cysteamine effect after washout was further sustained by the sequential administration of epigallocatechin gallate (EGCG), a green tea flavonoid, both in vivo, in mice, and in vitro, in primary epithelial cells from CF patients. In a pilot clinical trial involving 10 F508del-CFTR homozygous CF patients, the combination of cysteamine and EGCG restored BECN1, reduced SQSTM1 levels and improved CFTR function from nasal epithelial cells in vivo, correlating with a decrease of chloride concentrations in sweat, as well as with a reduction of the abundance of TNF/TNF-alpha (tumor necrosis factor) and CXCL8 (chemokine [C-X-C motif] ligand 8) transcripts in nasal brushing and TNF and CXCL8 protein levels in the sputum. Altogether, these results suggest that optimal schedules of cysteamine plus EGCG might be used for the treatment of CF caused by the F508del-CFTR mutation.

  9. Dendrimer-based selective autophagy-induction rescues ΔF508-CFTR and inhibits Pseudomonas aeruginosa infection in cystic fibrosis.

    Directory of Open Access Journals (Sweden)

    Scott Mackenzie Brockman

    Full Text Available Cystic Fibrosis (CF is a genetic disorder caused by mutation(s in the CF-transmembrane conductance regulator (Cftr gene. The most common mutation, ΔF508, leads to accumulation of defective-CFTR protein in aggresome-bodies. Additionally, Pseudomonas aeruginosa (Pa, a common CF pathogen, exacerbates obstructive CF lung pathology. In the present study, we aimed to develop and test a novel strategy to improve the bioavailability and potentially achieve targeted drug delivery of cysteamine, a potent autophagy-inducing drug with anti-bacterial properties, by developing a dendrimer (PAMAM-DEN-based cysteamine analogue.We first evaluated the effect of dendrimer-based cysteamine analogue (PAMAM-DENCYS on the intrinsic autophagy response in IB3-1 cells and observed a significant reduction in Ub-RFP and LC3-GFP co-localization (aggresome-bodies by PAMAM-DENCYS treatment as compared to plain dendrimer (PAMAM-DEN control. Next, we observed that PAMAM-DENCYS treatment shows a modest rescue of ΔF508-CFTR as the C-form. Moreover, immunofluorescence microscopy of HEK-293 cells transfected with ΔF508-CFTR-GFP showed that PAMAM-DENCYS is able to rescue the misfolded-ΔF508-CFTR from aggresome-bodies by inducing its trafficking to the plasma membrane. We further verified these results by flow cytometry and observed significant (p<0.05; PAMAM-DEN vs. PAMAM-DENCYS rescue of membrane-ΔF508-CFTR with PAMAM-DENCYS treatment using non-permeabilized IB3-1 cells immunostained for CFTR. Finally, we assessed the autophagy-mediated bacterial clearance potential of PAMAM-DENCYS by treating IB3-1 cells infected with PA01-GFP, and observed a significant (p<0.01; PAMAM-DEN vs. PAMAM-DENCYS decrease in intracellular bacterial counts by immunofluorescence microscopy and flow cytometry. Also, PAMAM-DENCYS treatment significantly inhibits the growth of PA01-GFP bacteria and demonstrates potent mucolytic properties.We demonstrate here the efficacy of dendrimer-based autophagy

  10. CORK Study in Cystic Fibrosis: Sustained Improvements in Ultra-Low-Dose Chest CT Scores After CFTR Modulation With Ivacaftor.

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    Ronan, Nicola J; Einarsson, Gisli G; Twomey, Maria; Mooney, Denver; Mullane, David; NiChroinin, Muireann; O'Callaghan, Grace; Shanahan, Fergus; Murphy, Desmond M; O'Connor, Owen J; Shortt, Cathy A; Tunney, Michael M; Eustace, Joseph A; Maher, Michael M; Elborn, J Stuart; Plant, Barry J

    2018-02-01

    Ivacaftor produces significant clinical benefit in patients with cystic fibrosis (CF) with the G551D mutation. Prevalence of this mutation at the Cork CF Centre is 23%. This study assessed the impact of cystic fibrosis transmembrane conductance regulator modulation on multiple modalities of patient assessment. Thirty-three patients with the G551D mutation were assessed at baseline and prospectively every 3 months for 1 year after initiation of ivacaftor. Change in ultra-low-dose chest CT scans, blood inflammatory mediators, and the sputum microbiome were assessed. Significant improvements in FEV 1 , BMI, and sweat chloride levels were observed post-ivacaftor treatment. Improvement in ultra-low-dose CT imaging scores were observed after treatment, with significant mean reductions in total Bhalla score (P < .01), peribronchial thickening (P = .035), and extent of mucous plugging (P < .001). Reductions in circulating inflammatory markers, including interleukin (IL)-1β, IL-6, and IL-8 were demonstrated. There was a 30% reduction in the relative abundance of Pseudomonas species and an increase in the relative abundance of bacteria associated with more stable community structures. Posttreatment community richness increased significantly (P = .03). Early and sustained improvements on ultra-low-dose CT scores suggest it may be a useful method of evaluating treatment response. It paralleled improvement in symptoms, circulating inflammatory markers, and changes in the lung microbiota. Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

  11. CFTR Modulators: Shedding Light on Precision Medicine for Cystic Fibrosis

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    Lopes-Pacheco, Miquéias

    2016-01-01

    Cystic fibrosis (CF) is the most common life-threatening monogenic disease afflicting Caucasian people. It affects the respiratory, gastrointestinal, glandular and reproductive systems. The major cause of morbidity and mortality in CF is the respiratory disorder caused by a vicious cycle of obstruction of the airways, inflammation and infection that leads to epithelial damage, tissue remodeling and end-stage lung disease. Over the past decades, life expectancy of CF patients has increased due to early diagnosis and improved treatments; however, these patients still present limited quality of life. Many attempts have been made to rescue CF transmembrane conductance regulator (CFTR) expression, function and stability, thereby overcoming the molecular basis of CF. Gene and protein variances caused by CFTR mutants lead to different CF phenotypes, which then require different treatments to quell the patients’ debilitating symptoms. In order to seek better approaches to treat CF patients and maximize therapeutic effects, CFTR mutants have been stratified into six groups (although several of these mutations present pleiotropic defects). The research with CFTR modulators (read-through agents, correctors, potentiators, stabilizers and amplifiers) has achieved remarkable progress, and these drugs are translating into pharmaceuticals and personalized treatments for CF patients. This review summarizes the main molecular and clinical features of CF, emphasizes the latest clinical trials using CFTR modulators, sheds light on the molecular mechanisms underlying these new and emerging treatments, and discusses the major breakthroughs and challenges to treating all CF patients. PMID:27656143

  12. IMPROVEMENTS IN THE QUALITY OF COURIER DELIVERY

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    Jacek Karcz

    2016-06-01

    Full Text Available The functioning of courier companies is a vital component of modern trade. E-commerce services are changing the way of shopping. Along with them, also courier services change and become more advance. Customers of courier companies become more aware of quality, which they should expect from supplier of these services. The article presents the result of the research of the effectiveness and the timelines of deliveries realized by one of the terminals of a leading courier operator in Poland. The survey involved 55 courier routes over the course of 10 business days. The author analyses weak points of the supply chain and presents two solutions, which may improve quality of delivery processes.

  13. Improving the delivery of preventive care services.

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    Hung, Dorothy Y

    2007-05-01

    Performance of preventive services is an important indicator of high-quality health care, but many recommended services are not regularly offered in primary care practices. Health risk assessments, counseling, and referral to community-based programs help address risk behaviors, many of which are leading causes of preventable death and disability in the United States. This study examined various influences on the delivery of preventive services designed to address smoking, excessive consumption of alcohol, unhealthy diets, and sedentary lifestyles. More than 300 health care providers in 52 practices nationwide have contributed data to this study. Staff participation in quality improvement enhanced work relationships and also diminished the effect of practice size on the performance of preventive care. The use of nurse practitioners, allied health professionals, clinician reminders, and patient registries were positively associated with care delivery.

  14. Improving Service Delivery of the Finance and Budget Section ...

    African Journals Online (AJOL)

    dell

    Action research was conducted in May and June 2004 aimed at improving service delivery of ... improve service delivery. (Quinby,1985). Furthermore, the intervention stage in which the development of ..... Educational leadership,. 42, 17-21.

  15. Manipulating proteostasis to repair the F508del-CFTR defect in cystic fibrosis.

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    Esposito, Speranza; Tosco, Antonella; Villella, Valeria R; Raia, Valeria; Kroemer, Guido; Maiuri, Luigi

    2016-12-01

    Cystic fibrosis (CF) is a lethal monogenic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that entails the (diagnostic) increase in sweat electrolyte concentrations, progressive lung disease with chronic inflammation and recurrent bacterial infections, pancreatic insufficiency, and male infertility. Therapies aimed at restoring the CFTR defect have emerged. Thus, a small molecule which facilitates chloride channel opening, the potentiator Ivacaftor, has been approved for the treatment of CF patients bearing a particular class of rare CFTR mutations. However, small molecules that directly target the most common misfolded CFTR mutant, F508del, and improve its intracellular trafficking in vitro, have been less effective than expected when tested in CF patients, even in combination with Ivacaftor. Thus, new strategies are required to circumvent the F508del-CFTR defect. Airway and intestinal epithelial cells from CF patients bearing the F508del-CFTR mutation exhibit an impressive derangement of cellular proteostasis, with oxidative stress, overactivation of the tissue transglutaminase (TG2), and disabled autophagy. Proteostasis regulators such as cysteamine can rescue and stabilize a functional F508del-CFTR protein through suppressing TG2 activation and restoring autophagy in vivo in F508del-CFTR homozygous mice, in vitro in CF patient-derived cell lines, ex vivo in freshly collected primary patient's nasal cells, as well as in a pilot clinical trial involving homozygous F508del-CFTR patients. Here, we discuss how the therapeutic normalization of defective proteostasis can be harnessed for the treatment of CF patients with the F508del-CFTR mutation.

  16. Improving the delivery of global tobacco control.

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    Bitton, Asaf; Green, Carol; Colbert, James

    2011-01-01

    Tobacco control must remain a critical global health priority given the growing burden of tobacco-induced disease in the developing world. Insights from the emerging field of global health delivery suggest that tobacco control could be improved through a systematic, granular analysis of the processes through which it is promoted, implemented, and combated. Using this framework, a critical bottleneck to the delivery of proven health promotion emerges in the role that the tobacco industry plays in promoting tobacco use and blocking effective tobacco-control policies. This "corporate bottleneck" can also be understood as a root cause of massive disease and suffering upon vulnerable populations worldwide, for the goal of maximizing corporate profit. Naming, understanding, and responding to this corporate bottleneck is crucial to the success of tobacco-control policies. Three case studies of tobacco-control policy--South Africa, the Framework Convention on Tobacco Control, and Uruguay--are presented to explore and understand the implications of this analysis. © 2011 Mount Sinai School of Medicine.

  17. Improved overall delivery documentation following implementation of a standardized shoulder dystocia delivery form

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    Moragianni, Vasiliki A.; Hacker, Michele R.; Craparo, Frank J.

    2013-01-01

    Objective Our objective was to evaluate whether using a standardized shoulder dystocia delivery form improved documentation. A standardized delivery form was added to our institution’s obstetrical record in August 2003. Methods A retrospective cohort study was conducted comparing 100 vaginal deliveries complicated by shoulder dystocia before, and 81 after implementation of the standardized delivery form. The two groups were compared in terms of obstetric characteristics, neonatal outcomes and documentation components. Results Charts that included the standardized delivery form were more likely to contain documentation of estimated fetal weight (82.7% vs. 39.0% without the form, Pdystocia, and second stage duration. Conclusions Inclusion of a standardized form in the delivery record improves the rate of documentation of both shoulder dystocia-specific and general delivery components. PMID:22017330

  18. From service delivery to solution delivery: commissioning for health improvement.

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    Shircore, Richard; Ladbury, Patrick

    2009-11-01

    The further division of responsibilities between commissioners and providers in England will have far-reaching consequences and opportunities for developing and enhancing health improvement. Commissioners will have the opportunity to craft local solutions to local issues. To be effective, these local responses need to tackle the core determinants of health and to build the social capital that is at the heart of all communities that enjoy high standards of health. This paper argues that the new arrangements mark an evolution of the Beveridge model of healthcare (centralized, top down and professionally prescribed) to a post-Beveridge model characterized by it being decentralized, localized and utilizing professional skills in the pursuit of client and community satisfaction and engagement rather than a narrowly defined professional perspective. This paper indicates some of the key conceptual changes commissioners need to employ to take advantage of the emerging opportunities. It is argued that the new arrangements will only be fully effective if commissioners of health improvement programmes ensure they factor in health promotion and social marketing expertise, both in the strategic and operational phases of commissioning. Finally, predictions are made about changes in the values and characteristics of current health improvement organizations.

  19. The hypertonic environment differentially regulates wild-type CFTR and TNR-CFTR chloride channels.

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    Lassance-Soares, Roberta M; Cheng, Jie; Krasnov, Kristina; Cebotaru, Liudmila; Cutting, Garry R; Souza-Menezes, Jackson; Morales, Marcelo M; Guggino, William B

    2010-01-01

    This study tested the hypotheses that the hypertonic environment of the renal medulla regulates the expression of cystic fibrosis transmembrane conductance regulator protein (CFTR) and its natural splice variant, TNR-CFTR. To accomplish this, Madin-Darby canine kidney (MDCK) stable cell lines expressing TNR-CFTR or CFTR were used. The cells were treated with hypertonic medium made with either NaCl or urea or sucrose (480 mOsm/kg or 560 mOsm/kg) to mimic the tonicity of the renal medulla environment. Western blot data showed that CFTR and TNR-CFTR total cell protein is increased by hypertonic medium, but using the surface biotinylation technique, only CFTR was found to be increased in cell plasma membrane. Confocal microscopy showed TNR-CFTR localization primarily at the endoplasmic reticulum and plasma membrane. In conclusion, CFTR and TNR-CFTR have different patterns of distribution in MDCK cells and they are modulated by a hypertonic environment, suggesting their physiological importance in renal medulla. Copyright © 2010 S. Karger AG, Basel.

  20. Optimizing nasal potential difference analysis for CFTR modulator development: assessment of ivacaftor in CF subjects with the G551D-CFTR mutation.

    Directory of Open Access Journals (Sweden)

    Steven M Rowe

    Full Text Available Nasal potential difference (NPD is used as a biomarker of the cystic fibrosis transmembrane conductance regulator (CFTR and epithelial sodium channel (ENaC activity. We evaluated methods to detect changes in chloride and sodium transport by NPD based on a secondary analysis of a Phase II CFTR-modulator study. Thirty-nine subjects with CF who also had the G551D-CFTR mutation were randomized to receive ivacaftor (Kalydeco™; also known as VX-770 in four doses or placebo twice daily for at least 14 days. All data were analyzed by a single investigator who was blinded to treatment assignment. We compared three analysis methods to determine the best approach to quantify changes in chloride and sodium transport: (1 the average of both nostrils; (2 the most-polarized nostril at each visit; and (3 the most-polarized nostril at screening carried forward. Parameters of ion transport included the PD change with zero chloride plus isoproterenol (CFTR activity, the basal PD, Ringer's PD, and change in PD with amiloride (measurements of ENaC activity, and the delta NPD (measuring CFTR and ENaC activity. The average and most-polarized nostril at each visit were most sensitive to changes in chloride and sodium transport, whereas the most-polarized nostril at screening carried forward was less discriminatory. Based on our findings, NPD studies should assess both nostrils rather than a single nostril. We also found that changes in CFTR activity were more readily detected than changes in ENaC activity, and that rigorous standardization was associated with relatively good within-subject reproducibility in placebo-treated subjects (± 2.8 mV. Therefore, we have confirmed an assay of reasonable reproducibility for detecting chloride-transport improvements in response to CFTR modulation.

  1. Assessment of Extension Service Delivery on Improved Cassava ...

    African Journals Online (AJOL)

    Extension service delivery is too often merely seen as a vehicle for spreading scientific and technical progress and technology transfer. In the real sense, however, dissemination of knowledge is not a one way affair from scientists to producers. The study was conducted to assess extension service delivery on improved ...

  2. Buccal Transmucosal Delivery System of Enalapril for Improved ...

    African Journals Online (AJOL)

    Purpose: To prepare and characterize buccal transmucosal delivery system of enalapril maleate for overcoming its low bioavailability, and hence provide improved therapeutic efficacy and patient compliance. Methods: Transmucosal drug delivery systems of enalapril maleate were formulated as buccal films by solvent ...

  3. How can innovative project delivery systems improve the overall efficiency of GDOT in transportation project delivery?

    Science.gov (United States)

    2013-04-01

    The USDOT and Federal Highway Administration (FHWA) recommend the smart use of innovative project : delivery systems, such as design-build, to improve efficiency and effectiveness of developing transportation : projects. Although design-build provide...

  4. Characterization of nasal potential difference in cftr knockout and F508del-CFTR mice.

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    Emilie Lyne Saussereau

    Full Text Available BACKGROUND: Treatments designed to correct cystic fibrosis transmembrane conductance regulator (CFTR defects must first be evaluated in preclinical experiments in the mouse model of cystic fibrosis (CF. Mice nasal mucosa mimics the bioelectric defect seen in humans. The use of nasal potential difference (V(TE to assess ionic transport is a powerful test evaluating the restoration of CFTR function. Nasal V(TE in CF mice must be well characterized for correct interpretation. METHODS: We performed V(TE measurements in large-scale studies of two mouse models of CF--B6;129 cftr knockout and FVB F508del-CFTR--and their respective wild-type (WT littermates. We assessed the repeatability of the test for cftr knockout mice and defined cutoff points distinguishing between WT and F508del-CFTR mice. RESULTS: We determined the typical V(TE values for CF and WT mice and demonstrated the existence of residual CFTR activity in F508del-CFTR mice. We characterized intra-animal variability in B6;129 mice and defined the cutoff points for F508del-CFTR chloride secretion rescue. Hyperpolarization of more than -2.15 mV after perfusion with a low-concentration Cl(- solution was considered to indicate a normal response. CONCLUSIONS: These data will make it possible to interpret changes in nasal V(TE in mouse models of CF, in future preclinical studies.

  5. Improvement of different vaccine delivery systems for cancer therapy

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    Safaiyan Shima

    2011-01-01

    Full Text Available Abstract Cancer vaccines are the promising tools in the hands of the clinical oncologist. Many tumor-associated antigens are excellent targets for immune therapy and vaccine design. Optimally designed cancer vaccines should combine the best tumor antigens with the most effective immunotherapy agents and/or delivery strategies to achieve positive clinical results. Various vaccine delivery systems such as different routes of immunization and physical/chemical delivery methods have been used in cancer therapy with the goal to induce immunity against tumor-associated antigens. Two basic delivery approaches including physical delivery to achieve higher levels of antigen production and formulation with microparticles to target antigen-presenting cells (APCs have demonstrated to be effective in animal models. New developments in vaccine delivery systems will improve the efficiency of clinical trials in the near future. Among them, nanoparticles (NPs such as dendrimers, polymeric NPs, metallic NPs, magnetic NPs and quantum dots have emerged as effective vaccine adjuvants for infectious diseases and cancer therapy. Furthermore, cell-penetrating peptides (CPP have been known as attractive carrier having applications in drug delivery, gene transfer and DNA vaccination. This review will focus on the utilization of different vaccine delivery systems for prevention or treatment of cancer. We will discuss their clinical applications and the future prospects for cancer vaccine development.

  6. Curcumin/poly(2-methyl-2-oxazoline-b-tetrahydrofuran-b-2-methyl-2-oxazoline) formulation: An improved penetration and biological effect of curcumin in F508del-CFTR cell lines.

    Science.gov (United States)

    Gonçalves, Cristine; Gomez, Jean-Pierre; Même, William; Rasolonjatovo, Bazoly; Gosset, David; Nedellec, Steven; Hulin, Philippe; Huin, Cécile; Le Gall, Tony; Montier, Tristan; Lehn, Pierre; Pichon, Chantal; Guégan, Philippe; Cheradame, Hervé; Midoux, Patrick

    2017-08-01

    Neutral amphiphilic triblock ABA copolymers are of great interest to solubilize hydrophobic drugs. We reported that a triblock ABA copolymer consisting of methyl-2-oxazoline (MeOx) and tetrahydrofuran (THF) (MeOx 6 -THF 19 -MeOx 6 ) (TBCP2) can solubilize curcumin (Cur) a very hydrophobic molecule exhibiting multiple therapeutic effects but whose insolubility and low stability in water is a major drawback for clinical applications. Here, we provide evidences by flow cytometry and confocal microscopy that Cur penetration in normal and ΔF508-CFTR human airway epithelial cell lines is facilitated by TBCP2. When used on ΔF508-CFTR cell lines, the Cur/TBCP2 formulation promotes the restoration of the expression of the CFTR protein in the plasma membrane. Furthermore, patch-clamp and MQAE fluorescence experiments show that this effect is associated with a correction of a Cl - selective current at the membrane surface of F508del-CFTR cells. The results show the great potential of the neutral amphiphilic triblock copolymer MeOx 6 -THF 19 -MeOx 6 as carrier for curcumin in a Cystic Fibrosis context. We anticipate that other MeOx n -THF m -MeOx n copolymers could have similar behaviours for other highly insoluble therapeutic drugs or cosmetic active ingredients. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. An improved delivery system for bladder irrigation.

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    Moslemi, Mohammad K; Rajaei, Mojtaba

    2010-10-05

    Occasionally, urologists may see patients requiring temporary bladder irrigation at hospitals without stocks of specialist irrigation apparatus. One option is to transfer the patient to a urology ward, but often there are outstanding medical issues that require continued specialist input. Here, we describe an improved system for delivering temporary bladder irrigation by utilizing readily available components and the novel modification of a sphygmomanometer blub. This option is good for bladder irrigation in patients with moderate or severe gross hematuria due to various causes. In this prospective study from March 2007 to April 2009, we used our new system in eligible cases. In this system, an irrigant bag with 1 L of normal saline was suspended 80 cm above the indwelled 3-way Foley catheter, and its drainage tube was inserted into the irrigant port of the catheter. To increase the flow rate of the irrigant system, we inserted a traditional sphygmomanometer bulb at the top of the irrigant bag. This closed system was used for continuous bladder irrigation (CBI) in patients who underwent open prostatectomy, transurethral resection of the prostate (TURP), or transurethral resection of the bladder (TURB). This high-pressure system is also used for irrigation during cystourethroscopy, internal urethrotomy, and transurethral lithotripsy. Our 831 eligible cases were divided into two groups: group 1 were endourologic cases and group 2 were open prostatectomy, TURP, and TURB cases. The maximum and average flow rates were evaluated. The efficacy of our new system was compared prospectively with the previous traditional system used in 545 cases. In group 1, we had clear vision at the time of endourologic procedures. The success rate of this system was 99.5%. In group 2, the incidence of clot retention decreased two fold in comparison to traditional gravity-dependent bladder flow system. These changes were statistically significant (P = 0.001). We did not observe any adverse

  8. Crystallographic and single-particle analyses of native- and nucleotide-bound forms of the cystic fibrosis transmembrane conductance regulator (CFTR) protein.

    Science.gov (United States)

    Awayn, N H; Rosenberg, M F; Kamis, A B; Aleksandrov, L A; Riordan, J R; Ford, R C

    2005-11-01

    Cystic fibrosis, one of the major human inherited diseases, is caused by defects in the CFTR (cystic fibrosis transmembrane conductance regulator), a cell-membrane protein. CFTR acts as a chloride channel which can be opened by ATP. Low-resolution structural studies of purified recombinant human CFTR are described in the present paper. Localization of the C-terminal decahistidine tag in CFTR was achieved by Ni2+-nitriloacetate nanogold labelling, followed by electron microscopy and single-particle analysis. The presence of the gold label appears to improve the single-particle-alignment procedure. Projection structures of CFTR from two-dimensional crystals analysed by electron crystallography displayed two alternative conformational states in the presence of nucleotide and nanogold, but only one form of the protein was observed in the quiescent (nucleotide-free) state.

  9. Decentralisation in Uganda: Prospects for Improved Service Delivery

    African Journals Online (AJOL)

    Financial decentralisation, on the other hand, attempted to assign responsibilities and taxes between the centre and local governments, to enable the transfer of grants and other resources to different parts of the country, and to improve service delivery. This paper will review different government, public and academic ...

  10. Improved Ant Colony Optimization for Seafood Product Delivery Routing Problem

    Directory of Open Access Journals (Sweden)

    Baozhen Yao

    2014-02-01

    Full Text Available This paper deals with a real-life vehicle delivery routing problem, which is a seafood product delivery routing problem. Considering the features of the seafood product delivery routing problem, this paper formulated this problem as a multi-depot open vehicle routing problem. Since the multi-depot open vehicle routing problem is a very complex problem, a method is used to reduce the complexity of the problem by changing the multi-depot open vehicle routing problem into an open vehicle routing problem with a dummy central depot in this paper. Then, ant colony optimization is used to solve the problem. To improve the performance of the algorithm, crossover operation and some adaptive strategies are used. Finally, the computational results for the benchmark problems of the multi-depot vehicle routing problem indicate that the proposed ant colony optimization is an effective method to solve the multi-depot vehicle routing problem. Furthermore, the computation results of the seafood product delivery problem from Dalian, China also suggest that the proposed ant colony optimization is feasible to solve the seafood product delivery routing problem.

  11. A little CFTR goes a long way: CFTR-dependent sweat secretion from G551D and R117H-5T cystic fibrosis subjects taking ivacaftor.

    Directory of Open Access Journals (Sweden)

    Jessica E Char

    Full Text Available To determine if oral dosing with the CFTR-potentiator ivacaftor (VX-770, Kalydeco improves CFTR-dependent sweating in CF subjects carrying G551D or R117H-5T mutations, we optically measured sweat secretion from 32-143 individually identified glands in each of 8 CF subjects; 6 F508del/G551D, one G551D/R117H-5T, and one I507del/R117H-5T. Two subjects were tested only (- ivacaftor, 3 only (+ ivacaftor and 3 (+/- ivacaftor (1-5 tests per condition. The total number of gland measurements was 852 (- ivacaftor and 906 (+ ivacaftor. A healthy control was tested 4 times (51 glands. For each gland we measured both CFTR-independent (M-sweat and CFTR-dependent (C-sweat; C-sweat was stimulated with a β-adrenergic cocktail that elevated [cAMP]i while blocking muscarinic receptors. Absent ivacaftor, almost all CF glands produced M-sweat on all tests, but only 1/593 glands produced C-sweat (10 tests, 5 subjects. By contrast, 6/6 subjects (113/342 glands produced C-sweat in the (+ ivacaftor condition, but with large inter-subject differences; 3-74% of glands responded with C/M sweat ratios 0.04%-2.57% of the average WT ratio of 0.265. Sweat volume losses cause proportionally larger underestimates of CFTR function at lower sweat rates. The losses were reduced by measuring C/M ratios in 12 glands from each subject that had the highest M-sweat rates. Remaining losses were estimated from single channel data and used to correct the C/M ratios, giving estimates of CFTR function (+ ivacaftor  = 1.6%-7.7% of the WT average. These estimates are in accord with single channel data and transcript analysis, and suggest that significant clinical benefit can be produced by low levels of CFTR function.

  12. Overcoming cellular and tissue barriers to improve liposomal drug delivery

    Science.gov (United States)

    Kohli, Aditya G.

    Forty years of liposome research have demonstrated that the anti-tumor efficacy of liposomal therapies is, in part, driven by three parameters: 1) liposome formulation and lipid biophysics, 2) accumulation and distribution in the tumor, and 3) release of the payload at the site of interest. This thesis outlines three studies that improve on each of these delivery steps. In the first study, we engineer a novel class of zwitterlipids with an inverted headgroup architecture that have remarkable biophysical properties and may be useful for drug delivery applications. After intravenous administration, liposomes accumulate in the tumor by the enhanced permeability and retention effect. However, the tumor stroma often limits liposome efficacy by preventing distribution into the tumor. In the second study, we demonstrate that depletion of hyaluronan in the tumor stroma improves the distribution and efficacy of DoxilRTM in murine 4T1 tumors. Once a liposome has distributed to the therapeutic site, it must release its payload over the correct timescale. Few facile methods exist to quantify the release of liposome therapeutics in vivo. In the third study, we outline and validate a simple, robust, and quantitative method for tracking the rate and extent of release of liposome contents in vivo. This tool should facilitate a better understanding of the pharmacodynamics of liposome-encapsulated drugs in animals. This work highlights aspects of liposome behavior that have prevented successful clinical translation and proposes alternative approaches to improve liposome drug delivery.

  13. CFTR-France, a national relational patient database for sharing genetic and phenotypic data associated with rare CFTR variants.

    Science.gov (United States)

    Claustres, Mireille; Thèze, Corinne; des Georges, Marie; Baux, David; Girodon, Emmanuelle; Bienvenu, Thierry; Audrezet, Marie-Pierre; Dugueperoux, Ingrid; Férec, Claude; Lalau, Guy; Pagin, Adrien; Kitzis, Alain; Thoreau, Vincent; Gaston, Véronique; Bieth, Eric; Malinge, Marie-Claire; Reboul, Marie-Pierre; Fergelot, Patricia; Lemonnier, Lydie; Mekki, Chadia; Fanen, Pascale; Bergougnoux, Anne; Sasorith, Souphatta; Raynal, Caroline; Bareil, Corinne

    2017-10-01

    Most of the 2,000 variants identified in the CFTR (cystic fibrosis transmembrane regulator) gene are rare or private. Their interpretation is hampered by the lack of available data and resources, making patient care and genetic counseling challenging. We developed a patient-based database dedicated to the annotations of rare CFTR variants in the context of their cis- and trans-allelic combinations. Based on almost 30 years of experience of CFTR testing, CFTR-France (https://cftr.iurc.montp.inserm.fr/cftr) currently compiles 16,819 variant records from 4,615 individuals with cystic fibrosis (CF) or CFTR-RD (related disorders), fetuses with ultrasound bowel anomalies, newborns awaiting clinical diagnosis, and asymptomatic compound heterozygotes. For each of the 736 different variants reported in the database, patient characteristics and genetic information (other variations in cis or in trans) have been thoroughly checked by a dedicated curator. Combining updated clinical, epidemiological, in silico, or in vitro functional data helps to the interpretation of unclassified and the reassessment of misclassified variants. This comprehensive CFTR database is now an invaluable tool for diagnostic laboratories gathering information on rare variants, especially in the context of genetic counseling, prenatal and preimplantation genetic diagnosis. CFTR-France is thus highly complementary to the international database CFTR2 focused so far on the most common CF-causing alleles. © 2017 Wiley Periodicals, Inc.

  14. Operations and quality management for public service delivery improvement.

    Directory of Open Access Journals (Sweden)

    Paulin Mbecke

    2014-10-01

    Full Text Available Public service management reforms have not yet contributed to poverty eradication and generally socio-economic development of many African countries. The reforms suggested and implemented to date still prove to be weak in addressing the many challenges faced by the public service in delivering goods and services to the population. The failure of the current public service management calls for a consideration of business-driven approaches and practices that facilitate effectiveness, efficiency, competitiveness and flexibility in goods and services provision. The critical social theory methodology and the literature review technique described and raised awareness on service delivery chaos in South Africa. A public service reform that focuses on operations and quality management is one of the ways of improving and sustaining service delivery in South Africa. Operations management is an essential tool for the planning, execution, control, monitoring and evaluation of production processes. Quality management, in the other hand, is essential to ensure best quality of goods and services produced by the public service within acceptable time and available resources to meet or exceed people’s expectations. The operations and quality management framework proposed in this article is a potential alternative to the current service delivery crisis in South Africa.

  15. Managerial process improvement: a lean approach to eliminating medication delivery.

    Science.gov (United States)

    Hussain, Aftab; Stewart, LaShonda M; Rivers, Patrick A; Munchus, George

    2015-01-01

    Statistical evidence shows that medication errors are a major cause of injuries that concerns all health care oganizations. Despite all the efforts to improve the quality of care, the lack of understanding and inability of management to design a robust system that will strategically target those factors is a major cause of distress. The paper aims to discuss these issues. Achieving optimum organizational performance requires two key variables; work process factors and human performance factors. The approach is that healthcare administrators must take in account both variables in designing a strategy to reduce medication errors. However, strategies that will combat such phenomena require that managers and administrators understand the key factors that are causing medication delivery errors. The authors recommend that healthcare organizations implement the Toyota Production System (TPS) combined with human performance improvement (HPI) methodologies to eliminate medication delivery errors in hospitals. Despite all the efforts to improve the quality of care, there continues to be a lack of understanding and the ability of management to design a robust system that will strategically target those factors associated with medication errors. This paper proposes a solution to an ambiguous workflow process using the TPS combined with the HPI system.

  16. Nanostructured delivery systems with improved leishmanicidal activity: a critical review.

    Science.gov (United States)

    Bruni, Natascia; Stella, Barbara; Giraudo, Leonardo; Della Pepa, Carlo; Gastaldi, Daniela; Dosio, Franco

    2017-01-01

    Leishmaniasis is a vector-borne zoonotic disease caused by protozoan parasites of the genus Leishmania , which are responsible for numerous clinical manifestations, such as cutaneous, visceral, and mucocutaneous leishmaniasis, depending on the site of infection for particular species. These complexities threaten 350 million people in 98 countries worldwide. Amastigotes living within macrophage phagolysosomes are the principal target of antileishmanial treatment, but these are not an easy target as drugs must overcome major structural barriers. Furthermore, limitations on current therapy are related to efficacy, toxicity, and cost, as well as the length of treatment, which can increase parasitic resistance. Nanotechnology has emerged as an attractive alternative as conventional drugs delivered by nanosized carriers have improved bioavailability and reduced toxicity, together with other characteristics that help to relieve the burden of this disease. The significance of using colloidal carriers loaded with active agents derives from the physiological uptake route of intravenous administered nanosystems (the phagocyte system). Nanosystems are thus able to promote a high drug concentration in intracellular mononuclear phagocyte system (MPS)-infected cells. Moreover, the versatility of nanometric drug delivery systems for the deliberate transport of a range of molecules plays a pivotal role in the design of therapeutic strategies against leishmaniasis. This review discusses studies on nanocarriers that have greatly contributed to improving the efficacy of antileishmaniasis drugs, presenting a critical review and some suggestions for improving drug delivery.

  17. Nanoemulsifying drug delivery system to improve the bioavailability of piroxicam.

    Science.gov (United States)

    Motawea, Amira; Borg, Thanaa; Tarshoby, Manal; Abd El-Gawad, Abd El-Gawad H

    2017-05-01

    The aim of this study is to develop and characterize self-nanoemulsifying drug delivery system (SNEDDS) of piroxicam in liquid and solid forms to improve its dissolution, absorption and therapeutic efficacy. The generation of liquid SNEDDS (L-SNEDDS) was composed of soybean or coconut oil/Tween 80/Transcutol HP (12/80/8%w/w) and it was selected as the optimized formulation based on the solubility study and pseudo-ternary phase diagram. Optimized L-SNEDDS and liquid supersaturatable SNEDDS (L-sSNEDDS) preparations were then adsorbed onto adsorbents and formulated as directly compressed tablets. The improved drug dissolution rate in the solid supersaturatable preparation (S-sSNEDDS) may be due to the formation of a nanoemulsion and the presence of drug in an amorphous state with hydrogen bond interaction between the drug and SNEDDS components. In vivo pharmacokinetic studies on eight healthy human volunteers showed a significant improvement in the oral bioavailability of piroxicam from S-sSNEDDS (F12) compared with both the pure drug (PP) and its commercial product (Feldene ® ) (commercial dosage form (CD)). The relative bioavailability of S-sSNEDDS (F12) relative to PP or CD was about 151.01 and 98.96%, respectively. The obtained results ratify that S-sSNEDDS is a promising drug delivery system to enhance the oral bioavailability of piroxicam.

  18. Microparticle-mediated transfer of the viral receptors CAR and CD46, and the CFTR channel in a CHO cell model confers new functions to target cells.

    Directory of Open Access Journals (Sweden)

    Gaëlle Gonzalez

    Full Text Available Cell microparticles (MPs released in the extracellular milieu can embark plasma membrane and intracellular components which are specific of their cellular origin, and transfer them to target cells. The MP-mediated, cell-to-cell transfer of three human membrane glycoproteins of different degrees of complexity was investigated in the present study, using a CHO cell model system. We first tested the delivery of CAR and CD46, two monospanins which act as adenovirus receptors, to target CHO cells. CHO cells lack CAR and CD46, high affinity receptors for human adenovirus serotype 5 (HAdV5, and serotype 35 (HAdV35, respectively. We found that MPs derived from CHO cells (MP-donor cells constitutively expressing CAR (MP-CAR or CD46 (MP-CD46 were able to transfer CAR and CD46 to target CHO cells, and conferred selective permissiveness to HAdV5 and HAdV35. In addition, target CHO cells incubated with MP-CD46 acquired the CD46-associated function in complement regulation. We also explored the MP-mediated delivery of a dodecaspanin membrane glycoprotein, the CFTR to target CHO cells. CFTR functions as a chloride channel in human cells and is implicated in the genetic disease cystic fibrosis. Target CHO cells incubated with MPs produced by CHO cells constitutively expressing GFP-tagged CFTR (MP-GFP-CFTR were found to gain a new cellular function, the chloride channel activity associated to CFTR. Time-course analysis of the appearance of GFP-CFTR in target cells suggested that MPs could achieve the delivery of CFTR to target cells via two mechanisms: the transfer of mature, membrane-inserted CFTR glycoprotein, and the transfer of CFTR-encoding mRNA. These results confirmed that cell-derived MPs represent a new class of promising therapeutic vehicles for the delivery of bioactive macromolecules, proteins or mRNAs, the latter exerting the desired therapeutic effect in target cells via de novo synthesis of their encoded proteins.

  19. Analysis and Improvement of Healthcare Delivery Processes in ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    ... delivery processes given the district's limited human and financial resources. ... Throughout this period of instability and unrest, Lacor Hospital has delivered critical ... and; strengthen the hospital's decision-making around healthcare delivery ...

  20. Predominant constitutive CFTR conductance in small airways

    Directory of Open Access Journals (Sweden)

    Lytle Christian

    2005-01-01

    Full Text Available Abstract Background The pathological hallmarks of chronic obstructive pulmonary disease (COPD are inflammation of the small airways (bronchiolitis and destruction of lung parenchyma (emphysema. These forms of disease arise from chronic prolonged infections, which are usually never present in the normal lung. Despite the fact that primary hygiene and defense of the airways presumably requires a well controlled fluid environment on the surface of the bronchiolar airway, very little is known of the fluid and electrolyte transport properties of airways of less than a few mm diameter. Methods We introduce a novel approach to examine some of these properties in a preparation of minimally traumatized porcine bronchioles of about 1 mm diameter by microperfusing the intact bronchiole. Results In bilateral isotonic NaCl Ringer solutions, the spontaneous transepithelial potential (TEP; lumen to bath of the bronchiole was small (mean ± sem: -3 ± 1 mV; n = 25, but when gluconate replaced luminal Cl-, the bionic Cl- diffusion potentials (-58 ± 3 mV; n = 25 were as large as -90 mV. TEP diffusion potentials from 2:1 NaCl dilution showed that epithelial Cl- permeability was at least 5 times greater than Na+ permeability. The anion selectivity sequence was similar to that of CFTR. The bionic TEP became more electronegative with stimulation by luminal forskolin (5 μM+IBMX (100 μM, ATP (100 μM, or adenosine (100 μM, but not by ionomycin. The TEP was partially inhibited by NPPB (100 μM, GlyH-101* (5–50 μM, and CFTRInh-172* (5 μM. RT-PCR gave identifying products for CFTR, α-, β-, and γ-ENaC and NKCC1. Antibodies to CFTR localized specifically to the epithelial cells lining the lumen of the small airways. Conclusion These results indicate that the small airway of the pig is characterized by a constitutively active Cl- conductance that is most likely due to CFTR.

  1. Statewide Quality Improvement Initiative to Reduce Early Elective Deliveries and Improve Birth Registry Accuracy.

    Science.gov (United States)

    Kaplan, Heather C; King, Eileen; White, Beth E; Ford, Susan E; Fuller, Sandra; Krew, Michael A; Marcotte, Michael P; Iams, Jay D; Bailit, Jennifer L; Bouchard, Jo M; Friar, Kelly; Lannon, Carole M

    2018-04-01

    To evaluate the success of a quality improvement initiative to reduce early elective deliveries at less than 39 weeks of gestation and improve birth registry data accuracy rapidly and at scale in Ohio. Between February 2013 and March 2014, participating hospitals were involved in a quality improvement initiative to reduce early elective deliveries at less than 39 weeks of gestation and improve birth registry data. This initiative was designed as a learning collaborative model (group webinars and a single face-to-face meeting) and included individual quality improvement coaching. It was implemented using a stepped wedge design with hospitals divided into three balanced groups (waves) participating in the initiative sequentially. Birth registry data were used to assess hospital rates of nonmedically indicated inductions at less than 39 weeks of gestation. Comparisons were made between groups participating and those not participating in the initiative at two time points. To measure birth registry accuracy, hospitals conducted monthly audits comparing birth registry data with the medical record. Associations were assessed using generalized linear repeated measures models accounting for time effects. Seventy of 72 (97%) eligible hospitals participated. Based on birth registry data, nonmedically indicated inductions at less than 39 weeks of gestation declined in all groups with implementation (wave 1: 6.2-3.2%, Pinitiative, they saw significant decreases in rates of early elective deliveries as compared with wave 3 (control; P=.018). All waves had significant improvement in birth registry accuracy (wave 1: 80-90%, P=.017; wave 2: 80-100%, P=.002; wave 3: 75-100%, Pinitiative enabled statewide spread of change strategies to decrease early elective deliveries and improve birth registry accuracy over 14 months and could be used for rapid dissemination of other evidence-based obstetric care practices across states or hospital systems.

  2. From Data to Improved Decisions: Operations Research in Healthcare Delivery.

    Science.gov (United States)

    Capan, Muge; Khojandi, Anahita; Denton, Brian T; Williams, Kimberly D; Ayer, Turgay; Chhatwal, Jagpreet; Kurt, Murat; Lobo, Jennifer Mason; Roberts, Mark S; Zaric, Greg; Zhang, Shengfan; Schwartz, J Sanford

    2017-11-01

    The Operations Research Interest Group (ORIG) within the Society of Medical Decision Making (SMDM) is a multidisciplinary interest group of professionals that specializes in taking an analytical approach to medical decision making and healthcare delivery. ORIG is interested in leveraging mathematical methods associated with the field of Operations Research (OR) to obtain data-driven solutions to complex healthcare problems and encourage collaborations across disciplines. This paper introduces OR for the non-expert and draws attention to opportunities where OR can be utilized to facilitate solutions to healthcare problems. Decision making is the process of choosing between possible solutions to a problem with respect to certain metrics. OR concepts can help systematically improve decision making through efficient modeling techniques while accounting for relevant constraints. Depending on the problem, methods that are part of OR (e.g., linear programming, Markov Decision Processes) or methods that are derived from related fields (e.g., regression from statistics) can be incorporated into the solution approach. This paper highlights the characteristics of different OR methods that have been applied to healthcare decision making and provides examples of emerging research opportunities. We illustrate OR applications in healthcare using previous studies, including diagnosis and treatment of diseases, organ transplants, and patient flow decisions. Further, we provide a selection of emerging areas for utilizing OR. There is a timely need to inform practitioners and policy makers of the benefits of using OR techniques in solving healthcare problems. OR methods can support the development of sustainable long-term solutions across disease management, service delivery, and health policies by optimizing the performance of system elements and analyzing their interaction while considering relevant constraints.

  3. CFTR-dependent chloride efflux in cystic fibrosis mononuclear cells is increased by ivacaftor therapy.

    Science.gov (United States)

    Guerra, Lorenzo; D'Oria, Susanna; Favia, Maria; Castellani, Stefano; Santostasi, Teresa; Polizzi, Angela M; Mariggiò, Maria A; Gallo, Crescenzio; Casavola, Valeria; Montemurro, Pasqualina; Leonetti, Giuseppina; Manca, Antonio; Conese, Massimo

    2017-07-01

    The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) potentiator ivacaftor (Kalydeco®) improves clinical outcome in G551D cystic fibrosis (CF) patients. Here, we have investigated whether ivacaftor has a clinical impact on non-G551D gating mutations and function of circulating leukocytes as well. Seven patients were treated with ivacaftor and evaluated at baseline, and at 1-3 and 6 months. Besides clinical and systemic inflammatory parameters, circulating mononuclear cells (MNC) were evaluated for CFTR-dependent chloride efflux by spectrofluorimetry, neutrophils for oxidative burst by cytofluorimetry and HVCN1 mRNA expression by real time PCR. Ivacaftor determined a significant decrease in sweat chloride concentrations at all time points during treatment. Body mass index (BMI), FEV 1 , and FVC showed an increasing trend. While C-reactive protein decreased significantly at 2 months, the opposite behavior was noticed for circulating monocytes. CFTR activity in MNC was found to increase significantly at 3 and 6 months. Neutrophil oxidative burst peaked at 2 months and then decreased to baseline. HVCN1 mRNA expression was significantly higher than baseline at 1-3 months and decreased after 6 months of treatment. The chloride efflux in MNC correlated positively with both FEV 1 and FVC. On the other hand, sweat chloride correlated positively with CRP and WBC, and negatively with both respiratory function tests. A cluster analysis confirmed that sweat chloride, FEV 1 , FVC, BMI, and MNC chloride efflux behaved as a single entity over time. In patients with non-G551D mutations, ivacaftor improved both chloride transport in sweat ducts and chloride efflux in MNC, that is, functions directly imputed to CFTR. © 2017 Wiley Periodicals, Inc.

  4. Buccal Transmucosal Delivery System of Enalapril for Improved ...

    African Journals Online (AJOL)

    Methods: Transmucosal drug delivery systems of enalapril maleate were ... Index Medicus, JournalSeek, Journal Citation Reports/Science Edition, Directory of Open Access Journals. (DOAJ) ... investigated for various drugs including protein.

  5. Improving Financial Service Delivery to Communities through Micro ...

    African Journals Online (AJOL)

    ... through Micro-finance Institutions in Uganda; the case of Pride Micro-finance ... This data was analysed qualitatively and the results of the analysis indicated that ... a number of challenges in financial service delivery; like inability to reach out ...

  6. Understanding the queuing theory for improved service delivery: an ...

    African Journals Online (AJOL)

    The methodology adopted in this paper, therefore is to describe queuing theory and its associated terminologies in relation to service delivery. In view of this, the paper presented a simplified exposition of queuing theory and management of waiting lines as it affects entrepreneurial drive for more business growth and ...

  7. Improvement of arbutin trans-epidermal delivery using ...

    African Journals Online (AJOL)

    Purpose: To assess the ability of radiofrequency (RF) microporation to promote trans-epidermal delivery of arbutin. Methods: To investigate the enhancing effect of RF microchannels on skin permeation of arbutin, in vitro skin permeability studies were performed with RF microporation-treated Hartley albino guinea pig skin ...

  8. Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial.

    Science.gov (United States)

    Alton, Eric W F W; Armstrong, David K; Ashby, Deborah; Bayfield, Katie J; Bilton, Diana; Bloomfield, Emily V; Boyd, A Christopher; Brand, June; Buchan, Ruaridh; Calcedo, Roberto; Carvelli, Paula; Chan, Mario; Cheng, Seng H; Collie, D David S; Cunningham, Steve; Davidson, Heather E; Davies, Gwyneth; Davies, Jane C; Davies, Lee A; Dewar, Maria H; Doherty, Ann; Donovan, Jackie; Dwyer, Natalie S; Elgmati, Hala I; Featherstone, Rosanna F; Gavino, Jemyr; Gea-Sorli, Sabrina; Geddes, Duncan M; Gibson, James S R; Gill, Deborah R; Greening, Andrew P; Griesenbach, Uta; Hansell, David M; Harman, Katharine; Higgins, Tracy E; Hodges, Samantha L; Hyde, Stephen C; Hyndman, Laura; Innes, J Alastair; Jacob, Joseph; Jones, Nancy; Keogh, Brian F; Limberis, Maria P; Lloyd-Evans, Paul; Maclean, Alan W; Manvell, Michelle C; McCormick, Dominique; McGovern, Michael; McLachlan, Gerry; Meng, Cuixiang; Montero, M Angeles; Milligan, Hazel; Moyce, Laura J; Murray, Gordon D; Nicholson, Andrew G; Osadolor, Tina; Parra-Leiton, Javier; Porteous, David J; Pringle, Ian A; Punch, Emma K; Pytel, Kamila M; Quittner, Alexandra L; Rivellini, Gina; Saunders, Clare J; Scheule, Ronald K; Sheard, Sarah; Simmonds, Nicholas J; Smith, Keith; Smith, Stephen N; Soussi, Najwa; Soussi, Samia; Spearing, Emma J; Stevenson, Barbara J; Sumner-Jones, Stephanie G; Turkkila, Minna; Ureta, Rosa P; Waller, Michael D; Wasowicz, Marguerite Y; Wilson, James M; Wolstenholme-Hogg, Paul

    2015-09-01

    Lung delivery of plasmid DNA encoding the CFTR gene complexed with a cationic liposome is a potential treatment option for patients with cystic fibrosis. We aimed to assess the efficacy of non-viral CFTR gene therapy in patients with cystic fibrosis. We did this randomised, double-blind, placebo-controlled, phase 2b trial in two cystic fibrosis centres with patients recruited from 18 sites in the UK. Patients (aged ≥12 years) with a forced expiratory volume in 1 s (FEV1) of 50-90% predicted and any combination of CFTR mutations, were randomly assigned, via a computer-based randomisation system, to receive 5 mL of either nebulised pGM169/GL67A gene-liposome complex or 0.9% saline (placebo) every 28 days (plus or minus 5 days) for 1 year. Randomisation was stratified by % predicted FEV1 (<70 vs ≥70%), age (<18 vs ≥18 years), inclusion in the mechanistic substudy, and dosing site (London or Edinburgh). Participants and investigators were masked to treatment allocation. The primary endpoint was the relative change in % predicted FEV1. The primary analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT01621867. Between June 12, 2012, and June 24, 2013, we randomly assigned 140 patients to receive placebo (n=62) or pGM169/GL67A (n=78), of whom 116 (83%) patients comprised the per-protocol population. We noted a significant, albeit modest, treatment effect in the pGM169/GL67A group versus placebo at 12 months' follow-up (3.7%, 95% CI 0.1-7.3; p=0.046). This outcome was associated with a stabilisation of lung function in the pGM169/GL67A group compared with a decline in the placebo group. We recorded no significant difference in treatment-attributable adverse events between groups. Monthly application of the pGM169/GL67A gene therapy formulation was associated with a significant, albeit modest, benefit in FEV1 compared with placebo at 1 year, indicating a stabilisation of lung function in the treatment group. Further improvements in

  9. Improving Government service delivery with private sector intermediaries

    OpenAIRE

    Klievink, B.; Janssen, M.

    2008-01-01

    Government organizations operate a variety of channels to interact with citizens and businesses. Advances in information and communication technology enabled an online presence and more direct interactions. A focus on efficiency makes organizations encourage the use of electronic channels over traditional channels. Also, intermediaries in the service delivery chain are cut out in favor of direct interactions. This strategy of disintermediation finds its rationale in the transaction costs theo...

  10. Incidence and Carrier Frequency of CFTR Gene Mutations in Pregnancies With Echogenic Bowel in Nova Scotia and Prince Edward Island.

    Science.gov (United States)

    Miller, Michelle E; Allen, Victoria M; Brock, Jo-Ann K

    2018-03-01

    Fetal echogenic bowel (echogenic bowel) is associated with cystic fibrosis (CF), with a reported incidence ranging from 1% to 13%. Prenatal testing for CF in the setting of echogenic bowel can be done by screening parental or fetal samples for pathogenic CFTR variants. If only one pathogenic variant is identified, sequencing of the CFTR gene can be undertaken, to identify a second pathogenic variant not covered in the standard screening panel. Full gene sequencing, however, also introduces the potential to identify variants of uncertain significance (VUSs) that can create counselling challenges and cause parental anxiety. To provide accurate counselling for families in the study population, the incidence of CF associated with echogenic bowel and the carrier frequency of CFTR variants were investigated. All pregnancies for which CF testing was undertaken for the indication of echogenic bowel (from Nova Scotia and Prince Edward Island) were identified (January 2007-July 2017). The CFTR screening and sequencing results were reviewed, and fetal outcomes related to CF were assessed. A total of 463 pregnancies with echogenic bowel were tested. Four were confirmed to be affected with CF, giving an incidence of 0.9% in this cohort. The carrier frequency of CF among all parents in the cohort was 5.0% (1 in 20); however, when excluding parents of affected fetuses, the carrier frequency for the population was estimated at 4.1% (1 in 25). CFTR gene sequencing identified an additional VUS in two samples. The incidence of CF in pregnancies with echogenic bowel in Nova Scotia and Prince Edward Island is 0.9%, with an estimated population carrier frequency of 4.1%. These results provide the basis for improved counselling to assess the risk of CF in the pregnancy, after parental carrier screening, using Bayesian probability. Counselling regarding VUSs should be undertaken before gene sequencing. Copyright © 2017 Society of Obstetricians and Gynaecologists of Canada. Published by

  11. Improving drug delivery technology for treating neurodegenerative diseases.

    Science.gov (United States)

    Choonara, Yahya E; Kumar, Pradeep; Modi, Girish; Pillay, Viness

    2016-07-01

    Neurodegenerative diseases (NDs) represent intricate challenges for efficient uptake and transport of drugs to the brain mainly due to the restrictive blood-brain barrier (BBB). NDs are characterized by the loss of neuronal subtypes as sporadic and/or familial and several mechanisms of neurodegeneration have been identified. This review attempts to recap, organize and concisely evaluate the advanced drug delivery systems designed for treating common NDs. It highlights key research gaps and opinionates on new neurotherapies to overcome the BBB as an addition to the current treatments of countering oxidative stress, inflammation and apoptotic mechanisms. Current treatments do not fully address the biological, drug and therapeutic factors faced. This has led to the development of vogue treatments such as nose-to-brain technologies, bio-engineered systems, fusion protein chaperones, stem cells, gene therapy, use of natural compounds, neuroprotectants and even vaccines. However, failure of these treatments is mainly due to the BBB and non-specific delivery in the brain. In order to increase neuroavailability various advanced drug delivery systems provide promising alternatives that are able to augment the treatment of Alzheimer's disease and Parkinson's disease. However, much work is still required in this field beyond the preclinical testing phase.

  12. How can lipid nanocarriers improve transdermal delivery of olanzapine?

    Science.gov (United States)

    Iqbal, Nimra; Vitorino, Carla; Taylor, Kevin M G

    2017-06-01

    The development of a transdermal nanocarrier drug delivery system with potential for the treatment of psychiatric disorders, such as schizophrenia and bipolar disorder, is described. Lipid nanocarriers (LN), encompassing various solid:liquid lipid compositions were formulated and assessed as potential nanosystems for transdermal delivery of olanzapine. A previously optimized method of hot high pressure homogenization (HPH) was adopted for the production of the LN, which comprised solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC) and nanoemulsions (NE). Precirol  ® was selected as the solid lipid for progression of studies. SLN exhibited the best performance for transdermal delivery of olanzapine, based on in vitro release and permeation studies, coupled with results from physicochemical characterization of several solid:liquid lipid formulations. Stability tests, performed to give an indication of long-term storage behavior of the formulations, were in good agreement with previous studies for the best choice of solid:liquid lipid ratio. Overall, these findings highlight the SLN-based formulation as promising for the further inclusion in and production of transdermal patches, representing an innovative therapeutic approach.

  13. Steviol reduces MDCK Cyst formation and growth by inhibiting CFTR channel activity and promoting proteasome-mediated CFTR degradation.

    Directory of Open Access Journals (Sweden)

    Chaowalit Yuajit

    Full Text Available Cyst enlargement in polycystic kidney disease (PKD involves cAMP-activated proliferation of cyst-lining epithelial cells and transepithelial fluid secretion into the cyst lumen via cystic fibrosis transmembrane conductance regulator (CFTR chloride channel. This study aimed to investigate an inhibitory effect and detailed mechanisms of steviol and its derivatives on cyst growth using a cyst model in Madin-Darby canine kidney (MDCK cells. Among 4 steviol-related compounds tested, steviol was found to be the most potent at inhibiting MDCK cyst growth. Steviol inhibition of cyst growth was dose-dependent; steviol (100 microM reversibly inhibited cyst formation and cyst growth by 72.53.6% and 38.2±8.5%, respectively. Steviol at doses up to 200 microM had no effect on MDCK cell viability, proliferation and apoptosis. However, steviol acutely inhibited forskolin-stimulated apical chloride current in MDCK epithelia, measured with the Ussing chamber technique, in a dose-dependent manner. Prolonged treatment (24 h with steviol (100 microM also strongly inhibited forskolin-stimulated apical chloride current, in part by reducing CFTR protein expression in MDCK cells. Interestingly, proteasome inhibitor, MG-132, abolished the effect of steviol on CFTR protein expression. Immunofluorescence studies demonstrated that prolonged treatment (24 h with steviol (100 microM markedly reduced CFTR expression at the plasma membrane. Taken together, the data suggest that steviol retards MDCK cyst progression in two ways: first by directly inhibiting CFTR chloride channel activity and second by reducing CFTR expression, in part, by promoting proteasomal degradation of CFTR. Steviol and related compounds therefore represent drug candidates for treatment of polycystic kidney disease.

  14. 21 CFR 866.5900 - Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation detection system.

    Science.gov (United States)

    2010-04-01

    ... regulator (CFTR) gene mutation detection system. 866.5900 Section 866.5900 Food and Drugs FOOD AND DRUG...) gene mutation detection system. (a) Identification. The CFTR gene mutation detection system is a device... Guidance Document: CFTR Gene Mutation Detection System.” See § 866.1(e) for the availability of this...

  15. CFTR is a tumor suppressor gene in murine and human intestinal cancer

    NARCIS (Netherlands)

    Than, B. L. N.; Linnekamp, J. F.; Starr, T. K.; Largaespada, D. A.; Rod, A.; Zhang, Y.; Bruner, V.; Abrahante, J.; Schumann, A.; Luczak, T.; Niemczyk, A.; O'Sullivan, M. G.; Medema, J. P.; Fijneman, R. J. A.; Meijer, G. A.; van den Broek, E.; Hodges, C. A.; Scott, P. M.; Vermeulen, L.; Cormier, R. T.

    2016-01-01

    CFTR, the cystic fibrosis (CF) gene, encodes for the CFTR protein that plays an essential role in anion regulation and tissue homeostasis of various epithelia. In the gastrointestinal (GI) tract CFTR promotes chloride and bicarbonate secretion, playing an essential role in ion and acid-base

  16. A multistate quality improvement program to decrease elective deliveries before 39 weeks of gestation.

    Science.gov (United States)

    Oshiro, Bryan T; Kowalewski, Leslie; Sappenfield, William; Alter, Caroline C; Bettegowda, Vani R; Russell, Rebecca; Curran, John; Reeves, Lori; Kacica, Marilyn; Andino, Nelson; Mason-Marti, Peyton; Crouse, Dennis; Knight, Susan; Littlejohn, Karen; Malatok, Sharyn; Dudley, Donald J; Berns, Scott D

    2013-05-01

    Nonmedically indicated (elective) deliveries before 39 weeks of gestation result in unnecessary neonatal morbidity. We sought to determine whether implementation of a process improvement program will decrease the rate of elective scheduled singleton early-term deliveries (37 0/7-38 6/7 weeks of gestation) in a group of diverse community and academic hospitals. Policies and procedures for scheduling inductions and cesarean deliveries were implemented and patient and health care provider education was provided. Outcomes for scheduled singleton deliveries at 34 weeks of gestation or higher were submitted through a web-based data entry system. The rate of scheduled singleton elective early-term deliveries as well as the rates of early-term medically indicated and unscheduled deliveries, neonatal intensive care unit admissions, and singleton term fetal mortality rate were evaluated. A total of 29,030 scheduled singletons at 34 weeks of gestation or higher were delivered in 26 participating hospitals between January 2011 and December 2011. Elective scheduled early-term deliveries decreased from 27.8% in the first month to 4.8% in the 12th month (Pscheduled singleton early-term inductions (72%, P=.029) and cesarean deliveries (84%; Pscheduled early-term singletons decreased nonsignificantly from 1.5% to 1.2% (P=.24). There was no increase in the term fetal mortality rate. A rapid-cycle process improvement program substantially decreased elective scheduled early-term deliveries to less than 5% in a group of diverse hospitals across multiple states. III.

  17. West Virginia Peer Exchange : Streamlining Highway Safety Improvement Program Project Delivery - An RSPCB Peer Exchange

    Science.gov (United States)

    2014-09-01

    The West Virginia Division of Highways (WV DOH) hosted a Peer Exchange to share information and experiences for streamlining Highway Safety Improvement Program (HSIP) project delivery. The event was held September 23 to 24, 2014 in Charleston, West V...

  18. West Virginia peer exchange : streamlining highway safety improvement program project delivery.

    Science.gov (United States)

    2015-01-01

    The West Virginia Division of Highways (WV DOH) hosted a Peer Exchange to share information and experiences : for streamlining Highway Safety Improvement Program (HSIP) project delivery. The event was held September : 22 to 23, 2014 in Charleston, We...

  19. 76 FR 24339 - Streamlining Service Delivery and Improving Customer Service

    Science.gov (United States)

    2011-05-02

    ... accessed by the Internet or mobile phone and improved processes that deliver services faster and more... ``Conversations with America'' to Further Improve Customer Service). However, with advances in technology and... major initiative (signature initiative) that will use technology to improve the customer experience; (b...

  20. CFTR, Mucins, and Mucus Obstruction in Cystic Fibrosis

    Science.gov (United States)

    Kreda, Silvia M.; Davis, C. William; Rose, Mary Callaghan

    2012-01-01

    Mucus pathology in cystic fibrosis (CF) has been known for as long as the disease has been recognized and is sometimes called mucoviscidosis. The disease is marked by mucus hyperproduction and plugging in many organs, which are usually most fatal in the airways of CF patients, once the problem of meconium ileus at birth is resolved. After the CF gene, CFTR, was cloned and its protein product identified as a cAMP-regulated Cl− channel, causal mechanisms underlying the strong mucus phenotype of the disease became obscure. Here we focus on mucin genes and polymeric mucin glycoproteins, examining their regulation and potential relationships to a dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR). Detailed examination of CFTR expression in organs and different cell types indicates that changes in CFTR expression do not always correlate with the severity of CF disease or mucus accumulation. Thus, the mucus hyperproduction that typifies CF does not appear to be a direct cause of a defective CFTR but, rather, to be a downstream consequence. In organs like the lung, up-regulation of mucin gene expression by inflammation results from chronic infection; however, in other instances and organs, the inflammation may have a non-infectious origin. The mucus plugging phenotype of the β-subunit of the epithelial Na+ channel (βENaC)-overexpressing mouse is proving to be an archetypal example of this kind of inflammation, with a dehydrated airway surface/concentrated mucus gel apparently providing the inflammatory stimulus. Data indicate that the luminal HCO3 − deficiency recently described for CF epithelia may also provide such a stimulus, perhaps by causing a mal-maturation of mucins as they are released onto luminal surfaces. In any event, the path between CFTR dysfunction and mucus hyperproduction has proven tortuous, and its unraveling continues to offer its own twists and turns, along with fascinating glimpses into biology. PMID:22951447

  1. Transmembrane helical interactions in the CFTR channel pore.

    Directory of Open Access Journals (Sweden)

    Jhuma Das

    2017-06-01

    Full Text Available Mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR gene affect CFTR protein biogenesis or its function as a chloride channel, resulting in dysregulation of epithelial fluid transport in the lung, pancreas and other organs in cystic fibrosis (CF. Development of pharmaceutical strategies to treat CF requires understanding of the mechanisms underlying channel function. However, incomplete 3D structural information on the unique ABC ion channel, CFTR, hinders elucidation of its functional mechanism and correction of cystic fibrosis causing mutants. Several CFTR homology models have been developed using bacterial ABC transporters as templates but these have low sequence similarity to CFTR and are not ion channels. Here, we refine an earlier model in an outward (OWF and develop an inward (IWF facing model employing an integrated experimental-molecular dynamics simulation (200 ns approach. Our IWF structure agrees well with a recently solved cryo-EM structure of a CFTR IWF state. We utilize cysteine cross-linking to verify positions and orientations of residues within trans-membrane helices (TMHs of the OWF conformation and to reconstruct a physiologically relevant pore structure. Comparison of pore profiles of the two conformations reveal a radius sufficient to permit passage of hydrated Cl- ions in the OWF but not the IWF model. To identify structural determinants that distinguish the two conformations and possible rearrangements of TMHs within them responsible for channel gating, we perform cross-linking by bifunctional reagents of multiple predicted pairs of cysteines in TMH 6 and 12 and 6 and 9. To determine whether the effects of cross-linking on gating observed are the result of switching of the channel from open to close state, we also treat the same residue pairs with monofunctional reagents in separate experiments. Both types of reagents prevent ion currents indicating that pore blockage is primarily responsible.

  2. Collaborative Practice Model: Improving the Delivery of Bad News.

    Science.gov (United States)

    Bowman, Pamela N; Slusser, Kim; Allen, Deborah

    2018-02-01

    Ideal bad news delivery requires skilled communication and team support. The literature has primarily focused on patient preferences, impact on care decisions, healthcare roles, and communication styles, without addressing systematic implementation. This article describes how an interdisciplinary team, led by advanced practice nurses, developed and implemented a collaborative practice model to deliver bad news on a unit that had struggled with inconsistencies. Using evidence-based practices, the authors explored current processes, role perceptions and expectations, and perceived barriers to developing the model, which is now the standard of care and an example of interprofessional team collaboration across the healthcare system. This model for delivering bad news can be easily adapted to meet the needs of other clinical units.
.

  3. New heavy crude oil flow improver increases delivery : application scenarios

    Energy Technology Data Exchange (ETDEWEB)

    Pierce, J.; Johnston, R.; Lauzon, P. [ConocoPhillips Specialty Products Inc., Houston, TX (United States)

    2009-07-01

    Flow improvers or drag reducing agents have been used for over 25 years as a method to increase fluid flow in hydrocarbon pipelines. The technology is effective in refined projects, light and medium crude oils. This paper presented a new development in flow improver technology that allows treatment of heavy crude oil slates. It discussed case studies of flow improver treatment of heavy oils in various pipeline system as well as factors that affect commercial success. tabs., figs.

  4. Improving communication between obstetric and neonatology teams for high-risk deliveries: a quality improvement project.

    Science.gov (United States)

    Sundgren, Nathan C; Kelly, Frances C; Weber, Emily M; Moore, Merle L; Gokulakrishnan, Ganga; Hagan, Joseph L; Brand, M Colleen; Gallegos, Jennifer O; Levy, Barbara E; Fortunov, Regine M

    2017-01-01

    Summoning is a key component of communication between obstetrics and neonatal resuscitation team (NRT) in advance of deliveries. A paging system is a commonly used summoning tool. The timeliness and information contained in the page help NRT to optimally prepare for postdelivery infant care. Our aim was to increase the frequency that summoning pages contained gestational age and reason for NRT attendance to >90%. At baseline, 8% of pages contained gestational age and 33% of pages contained a reason for NRT attendance. Sequential Plan-Do-Study-Act cycles were used as our model for quality improvement. During the 8-month improvement period, the per cent of pages increased to 97% for gestational age and 97% for reason for NRT attendance. Measures of page timeliness, our balancing measure, did not change. Summoning communication between obstetric and NRT is crucial for optimal perinatal outcomes. The active involvement of all stakeholders throughout the project resulted in the development of a standardised paging tool and a more informative paging process, which is a key communication tool used in many centres.

  5. Assessment of Extension Service Delivery on Improved Cassava ...

    African Journals Online (AJOL)

    SH

    credit facilities, improved planting materials and marketing. The mean ... (2010), and to surpass 250 million metric tons for ... the effectiveness of the research system, a number ... link is an effective agricultural system to ..... Strategy for poverty.

  6. Improvement of buccal delivery of morphine using the prodrug approach

    DEFF Research Database (Denmark)

    Christrup, Lona Louring; Jørgensen, A.; Christensen, C.B.

    1997-01-01

    relationship to the lipophilicity of the compounds. In the in vitro studies the optimal permeation was achieved for the prodrug morphine-3-propionate having a log P value of approximately 0.7. In contrast to that optimal in vivo absorption was obtained for the prodrug morphine-3-acetate having a log P value...... Improved by using ester prodrugs with higher lipophilicity than morphine itself. However, the enzymatic stability of the prodrugs in saliva also play an important role for the overall improvement in absorption properties....

  7. Activation of CFTR by ASBT-mediated bile salt absorption

    NARCIS (Netherlands)

    Bijvelds, MJC; Jorna, H; Verkade, HJ; Bot, AGM; Hofmann, F; Agellon, LB; Sinaasappel, M; de Jonge, HR

    2005-01-01

    In cholangiocytes, bile salt (BS) uptake via the apical sodium-dependent bile acid transporter (ASBT) may evoke ductular flow by enhancing cAMP-mediated signaling to the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. We considered that ASBT-mediated BS uptake in the distal

  8. Improvement of Arbutin Trans-Epidermal Delivery Using ...

    African Journals Online (AJOL)

    Furthermore, improved depigmentation effects in brown guinea pig in vivo after ... microporation technology was initially developed to remove .... using an isocratic mobile phase consisting of ... acetonitrile (92:8, v/v) at a flow rate of 1.0. μL/min.

  9. Generic project definitions for improvement of health care delivery: A case-base approach

    NARCIS (Netherlands)

    Niemeijer, G.C.; Does, R.J.M.M.; de Mast, J.; Trip, A.; van den Heuvel, J.

    2011-01-01

    Background: The purpose of this article is to create actionable knowledge, making the definition of process improvement projects in health care delivery more effective. Methods: This study is a retrospective analysis of process improvement projects in hospitals, facilitating a case-based reasoning

  10. Insulin-like growth factor 1 (IGF-1 enhances the protein expression of CFTR.

    Directory of Open Access Journals (Sweden)

    Ha Won Lee

    Full Text Available Low levels of insulin-like growth factor 1 (IGF-1 have been observed in the serum of cystic fibrosis (CF patients. However, the effects of low serum IGF-1 on the cystic fibrosis transmembrane conductance regulator (CFTR, whose defective function is the primary cause of cystic fibrosis, have not been studied. Here, we show in human cells that IGF-1 increases the steady-state levels of mature wildtype CFTR in a CFTR-associated ligand (CAL- and TC10-dependent manner; moreover, IGF-1 increases CFTR-mediated chloride transport. Using an acceptor photobleaching fluorescence resonance energy transfer (FRET assay, we have confirmed the binding of CAL and CFTR in the Golgi. We also show that CAL overexpression inhibits forskolin-induced increases in the cell-surface expression of CFTR. We found that IGF-1 activates TC10, and active TC10 alters the functional association between CAL and CFTR. Furthermore, IGF-1 and active TC10 can reverse the CAL-mediated reduction in the cell-surface expression of CFTR. IGF-1 does not increase the expression of ΔF508 CFTR, whose processing is arrested in the ER. This finding is consistent with our observation that IGF-1 alters the functional interaction of CAL and CFTR in the Golgi. However, when ΔF508 CFTR is rescued with low temperature or the corrector VRT-325 and proceeds to the Golgi, IGF-1 can increase the expression of the rescued ΔF508 CFTR. Our data support a model indicating that CAL-CFTR binding in the Golgi inhibits CFTR trafficking to the cell surface, leading CFTR to the degradation pathway instead. IGF-1-activated TC10 changes the interaction of CFTR and CAL, allowing CFTR to progress to the plasma membrane. These findings offer a potential strategy using a combinational treatment of IGF-1 and correctors to increase the post-Golgi expression of CFTR in cystic fibrosis patients bearing the ΔF508 mutation.

  11. Sphingosine-1-Phosphate Is a Novel Regulator of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR Activity.

    Directory of Open Access Journals (Sweden)

    Firhan A Malik

    Full Text Available The cystic fibrosis transmembrane conductance regulator (CFTR attenuates sphingosine-1-phosphate (S1P signaling in resistance arteries and has emerged as a prominent regulator of myogenic vasoconstriction. This investigation demonstrates that S1P inhibits CFTR activity via adenosine monophosphate-activated kinase (AMPK, establishing a potential feedback link. In Baby Hamster Kidney (BHK cells expressing wild-type human CFTR, S1P (1μmol/L attenuates forskolin-stimulated, CFTR-dependent iodide efflux. S1P's inhibitory effect is rapid (within 30 seconds, transient and correlates with CFTR serine residue 737 (S737 phosphorylation. Both S1P receptor antagonism (4μmol/L VPC 23019 and AMPK inhibition (80μmol/L Compound C or AMPK siRNA attenuate S1P-stimluated (i AMPK phosphorylation, (ii CFTR S737 phosphorylation and (iii CFTR activity inhibition. In BHK cells expressing the ΔF508 CFTR mutant (CFTRΔF508, the most common mutation causing cystic fibrosis, both S1P receptor antagonism and AMPK inhibition enhance CFTR activity, without instigating discernable correction. In summary, we demonstrate that S1P/AMPK signaling transiently attenuates CFTR activity. Since our previous work positions CFTR as a negative S1P signaling regulator, this signaling link may positively reinforce S1P signals. This discovery has clinical ramifications for the treatment of disease states associated with enhanced S1P signaling and/or deficient CFTR activity (e.g. cystic fibrosis, heart failure. S1P receptor/AMPK inhibition could synergistically enhance the efficacy of therapeutic strategies aiming to correct aberrant CFTR trafficking.

  12. Choosing Wisely: Opportunities for Improving Value in Cancer Care Delivery?

    Science.gov (United States)

    Rocque, Gabrielle B; Williams, Courtney P; Jackson, Bradford E; Wallace, Audrey S; Halilova, Karina I; Kenzik, Kelly M; Partridge, Edward E; Pisu, Maria

    2017-01-01

    Patients, providers, and payers are striving to identify where value in cancer care can be increased. As part of the Choosing Wisely (CW) campaign, ASCO and the American Society for Therapeutic Radiology and Oncology have recommended against specific, yet commonly performed, treatments and procedures. We conducted a retrospective analysis of Medicare claims data to examine concordance with CW recommendations across 12 cancer centers in the southeastern United States. Variability for each measure was evaluated on the basis of patient characteristics and site of care. Hierarchical linear modeling was used to examine differences in average costs per patient by concordance status. Potential cost savings were estimated on the basis of a potential 95% adherence rate and average cost difference. The analysis included 37,686 patients with cancer with Fee-for-Service Medicare insurance. Concordance varied by CW recommendation from 39% to 94%. Patient characteristics were similar for patients receiving concordant and nonconcordant care. Significant variability was noted across centers for all recommendations, with as much as an 89% difference. Nonconcordance was associated with higher costs for every measure. If concordance were to increase to 95% for all measures, we would estimate a $19 million difference in total cost of care per quarter. These results demonstrate ample room for reduction of low-value care and corresponding costs associated with the CW recommendations. Because variability in concordance was driven primarily by site of care, rather than by patient factors, continued education about these low-value services is needed to improve the value of cancer care.

  13. Sweat chloride as a biomarker of CFTR activity: proof of concept and ivacaftor clinical trial data.

    Science.gov (United States)

    Accurso, Frank J; Van Goor, Fredrick; Zha, Jiuhong; Stone, Anne J; Dong, Qunming; Ordonez, Claudia L; Rowe, Steven M; Clancy, John Paul; Konstan, Michael W; Hoch, Heather E; Heltshe, Sonya L; Ramsey, Bonnie W; Campbell, Preston W; Ashlock, Melissa A

    2014-03-01

    We examined data from a Phase 2 trial {NCT00457821} of ivacaftor, a CFTR potentiator, in cystic fibrosis (CF) patients with aG551D mutation to evaluate standardized approaches to sweat chloride measurement and to explore the use of sweat chloride and nasal potential difference (NPD) to estimate CFTR activity. Sweat chloride and NPD were secondary endpoints in this placebo-controlled, multicenter trial. Standardization of sweat collection, processing,and analysis was employed for the first time. Sweat chloride and chloride ion transport (NPD) were integrated into a model of CFTR activity. Within-patient sweat chloride determinations showed sufficient precision to detect differences between dose-groups and assess ivacaftor treatment effects. Analysis of changes in sweat chloride and NPD demonstrated that patients treated with ivacaftor achieved CFTR activity equivalent to approximately 35%–40% of normal. Sweat chloride is useful in multicenter trials as a biomarker of CFTR activity and to test the effect of CFTR potentiators.

  14. Improved Prediction of Preterm Delivery Using Empirical Mode Decomposition Analysis of Uterine Electromyography Signals.

    Directory of Open Access Journals (Sweden)

    Peng Ren

    Full Text Available Preterm delivery increases the risk of infant mortality and morbidity, and therefore developing reliable methods for predicting its likelihood are of great importance. Previous work using uterine electromyography (EMG recordings has shown that they may provide a promising and objective way for predicting risk of preterm delivery. However, to date attempts at utilizing computational approaches to achieve sufficient predictive confidence, in terms of area under the curve (AUC values, have not achieved the high discrimination accuracy that a clinical application requires. In our study, we propose a new analytical approach for assessing the risk of preterm delivery using EMG recordings which firstly employs Empirical Mode Decomposition (EMD to obtain their Intrinsic Mode Functions (IMF. Next, the entropy values of both instantaneous amplitude and instantaneous frequency of the first ten IMF components are computed in order to derive ratios of these two distinct components as features. Discrimination accuracy of this approach compared to those proposed previously was then calculated using six differently representative classifiers. Finally, three different electrode positions were analyzed for their prediction accuracy of preterm delivery in order to establish which uterine EMG recording location was optimal signal data. Overall, our results show a clear improvement in prediction accuracy of preterm delivery risk compared with previous approaches, achieving an impressive maximum AUC value of 0.986 when using signals from an electrode positioned below the navel. In sum, this provides a promising new method for analyzing uterine EMG signals to permit accurate clinical assessment of preterm delivery risk.

  15. Frequency of common CFTR gene mutations in Venezuelan patients with cystic fibrosis

    OpenAIRE

    Sánchez, Karen; Arcia, Orlando; Matute, Xiorama; Mindiola, Luz; Chaustre, Ismenia; Takiff, Howard

    2014-01-01

    Mutations in the CFTR gene in Cystic Fibrosis (CF) patients have geographic differences and there is scant data on their prevalence in Venezuelan patients. This study determined the frequency of common CFTR gene mutations in these patients. We amplified and sequenced exons 7, 10, 11, 19, 20 and 21, which contain the most common CFTR mutations, from 105 Venezuelan patients in the National CF Program. Eleven different mutations were identified, four with frequencies greater than 1%: p.Phe508del...

  16. Determination of CFTR densities in erythrocyte plasma membranes using recognition imaging

    Energy Technology Data Exchange (ETDEWEB)

    Ebner, Andreas; Hinterdorfer, Peter [Institute for Biophysics, University of Linz, A-4040 Linz (Austria); Nikova, Dessy; Lange, Tobias; Bruns, Reimer; Oberleithner, Hans; Schillers, Hermann [Institute of Physiology II, University of Muenster, D-48149 Muenster (Germany); Haeberle, Johannes; Falk, Sabine; Duebbers, Angelika [Department of Pediatrics, University Hospitals of Muenster, D-48149 Muenster (Germany)], E-mail: schille@uni-muenster.de

    2008-09-24

    CFTR (cystic fibrosis transmembrane conductance regulator) is a cAMP-regulated chloride (Cl{sup -}) channel that plays an important role in salt and fluid movement across epithelia. Cystic fibrosis (CF), the most common genetic disease among Caucasians, is caused by mutations in the gene encoding CFTR. The most predominant mutation, F508del, disturbs CFTR protein trafficking, resulting in a reduced number of CFTR in the plasma membrane. Recent studies indicate that CFTR is not only found in epithelia but also in human erythrocytes. Although considerable attempts have been made to quantify CFTR in cells, conclusions on numbers of CFTR molecules localized in the plasma membrane have been drawn indirectly. AFM has the power to provide the needed information, since both sub-molecular spatial resolution and direct protein recognition via antibody-antigen interaction can be observed. We performed a quantification study of the CFTR copies in erythrocyte membranes at the single molecule level, and compared the difference between healthy donors and CF patients. We detected that the number of CFTR molecules is reduced by 70% in erythrocytes of cystic fibrosis patients.

  17. Determination of CFTR densities in erythrocyte plasma membranes using recognition imaging

    International Nuclear Information System (INIS)

    Ebner, Andreas; Hinterdorfer, Peter; Nikova, Dessy; Lange, Tobias; Bruns, Reimer; Oberleithner, Hans; Schillers, Hermann; Haeberle, Johannes; Falk, Sabine; Duebbers, Angelika

    2008-01-01

    CFTR (cystic fibrosis transmembrane conductance regulator) is a cAMP-regulated chloride (Cl - ) channel that plays an important role in salt and fluid movement across epithelia. Cystic fibrosis (CF), the most common genetic disease among Caucasians, is caused by mutations in the gene encoding CFTR. The most predominant mutation, F508del, disturbs CFTR protein trafficking, resulting in a reduced number of CFTR in the plasma membrane. Recent studies indicate that CFTR is not only found in epithelia but also in human erythrocytes. Although considerable attempts have been made to quantify CFTR in cells, conclusions on numbers of CFTR molecules localized in the plasma membrane have been drawn indirectly. AFM has the power to provide the needed information, since both sub-molecular spatial resolution and direct protein recognition via antibody-antigen interaction can be observed. We performed a quantification study of the CFTR copies in erythrocyte membranes at the single molecule level, and compared the difference between healthy donors and CF patients. We detected that the number of CFTR molecules is reduced by 70% in erythrocytes of cystic fibrosis patients

  18. Lumacaftor/ivacaftor, a novel agent for the treatment of cystic fibrosis patients who are homozygous for the F580del CFTR mutation.

    Science.gov (United States)

    Bulloch, Marilyn N; Hanna, Cameron; Giovane, Richard

    2017-10-01

    Cystic Fibrosis (CF) is an autosomal recessive disease affecting up to 90,000 people worldwide. Approximately 73% of patients are homozygous for the F508del cystic fibrosis transmembrane conductance regulator [CFTR] mutation. Traditionally treatment has only included supportive care. Therefore, there is a need for safe and effective novel therapies targeting the underlying molecular defects seen with CF. Areas covered: In 2016, the Food and Drug Administration and the European Commission approved LUM/IVA (Orkambi), a CFTR modulator that includes both a CFTR corrector and potentiator, for CF patients homozygous for the F508del CFTR mutation. This article reviews the pharmacologic features, clinical efficacy, and safety of LUM/IVA and summarize the available pre-clinical and clinical data of LUM/IVA use. Expert commentary: LUM/IVA showed modest, but significant improvements from baseline in percent predicted FEV 1 (ppFEV 1 ) as well as a reduction in pulmonary exacerbations by 35% It was shown to be safe for short- and long-term use. Currently, LUM/IVA is the only oral agent in its class available and represents a milestone the development of therapies for the management of CF. Nonetheless, pharmacoeconomic data are necessary to justify its high cost before is use becomes standard of care.

  19. Osteoblast CFTR inactivation reduces differentiation and osteoprotegerin expression in a mouse model of cystic fibrosis-related bone disease.

    Directory of Open Access Journals (Sweden)

    Michael S Stalvey

    Full Text Available Low bone mass and increased fracture risk are recognized complications of cystic fibrosis (CF. CF-related bone disease (CFBD is characterized by uncoupled bone turnover--impaired osteoblastic bone formation and enhanced osteoclastic bone resorption. Intestinal malabsorption, vitamin D deficiency and inflammatory cytokines contribute to CFBD. However, epidemiological investigations and animal models also support a direct causal link between inactivation of skeletal cystic fibrosis transmembrane regulator (CFTR, the gene that when mutated causes CF, and CFBD. The objective of this study was to examine the direct actions of CFTR on bone. Expression analyses revealed that CFTR mRNA and protein were expressed in murine osteoblasts, but not in osteoclasts. Functional studies were then performed to investigate the direct actions of CFTR on osteoblasts using a CFTR knockout (Cftr-/- mouse model. In the murine calvarial organ culture assay, Cftr-/- calvariae displayed significantly less bone formation and osteoblast numbers than calvariae harvested from wildtype (Cftr+/+ littermates. CFTR inactivation also reduced alkaline phosphatase expression in cultured murine calvarial osteoblasts. Although CFTR was not expressed in murine osteoclasts, significantly more osteoclasts formed in Cftr-/- compared to Cftr+/+ bone marrow cultures. Indirect regulation of osteoclastogenesis by the osteoblast through RANK/RANKL/OPG signaling was next examined. Although no difference in receptor activator of NF-κB ligand (Rankl mRNA was detected, significantly less osteoprotegerin (Opg was expressed in Cftr-/- compared to Cftr+/+ osteoblasts. Together, the Rankl:Opg ratio was significantly higher in Cftr-/- murine calvarial osteoblasts contributing to a higher osteoclastogenesis potential. The combined findings of reduced osteoblast differentiation and lower Opg expression suggested a possible defect in canonical Wnt signaling. In fact, Wnt3a and PTH-stimulated canonical Wnt

  20. CFTR mutation analysis and haplotype associations in CF patients☆

    OpenAIRE

    Cordovado, S.K.; Hendrix, M.; Greene, C.N.; Mochal, S.; Earley, M.C.; Farrell, P.M.; Kharrazi, M.; Hannon, W.H.; Mueller, P.W.

    2011-01-01

    Most newborn screening (NBS) laboratories use second-tier molecular tests for cystic fibrosis (CF) using dried blood spots (DBS). The Centers for Disease Control and Prevention’s NBS Quality Assurance Program offers proficiency testing (PT) in DBS for CF transmembrane conductance regulator (CFTR) gene mutation detection. Extensive molecular characterization on 76 CF patients, family members or screen positive newborns was performed for quality assurance. The coding, regulatory regions and por...

  1. CFTR mediates noradrenaline-induced ATP efflux from DRG neurons.

    Science.gov (United States)

    Kanno, Takeshi; Nishizaki, Tomoyuki

    2011-09-24

    In our earlier study, noradrenaline (NA) stimulated ATP release from dorsal root ganglion (DRG) neurons as mediated via β(3) adrenoceptors linked to G(s) protein involving protein kinase A (PKA) activation, to cause allodynia. The present study was conducted to understand how ATP is released from DRG neurons. In an outside-out patch-clamp configuration from acutely dissociated rat DRG neurons, single-channel currents, sensitive to the P2X receptor inhibitor PPADS, were evoked by approaching the patch-electrode tip close to a neuron, indicating that ATP is released from DRG neurons, to activate P2X receptor. NA increased the frequency of the single-channel events, but such NA effect was not found for DRG neurons transfected with the siRNA to silence the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In the immunocytochemical study using acutely dissociated rat DRG cells, CFTR was expressed in neurons alone, but not satellite cells, fibroblasts, or Schwann cells. It is concluded from these results that CFTR mediates NA-induced ATP efflux from DRG neurons as an ATP channel.

  2. A Journey to Improved Inpatient Glycemic Control by Redesigning Meal Delivery and Insulin Administration.

    Science.gov (United States)

    Engle, Martha; Ferguson, Allison; Fields, Willa

    2016-01-01

    The purpose of this quality improvement project was to redesign a hospital meal delivery process in order to shorten the time between blood glucose monitoring and corresponding insulin administration and improve glycemic control. This process change redesigned the workflow of the dietary and nursing departments. Modifications included nursing, rather than dietary, delivering meal trays to patients receiving insulin. Dietary marked the appropriate meal trays and phoned each unit prior to arrival on the unit. The process change was trialed on 2 acute care units prior to implementation hospital wide. Elapsed time between blood glucose monitoring and insulin administration was analyzed before and after process change as well as evaluation of glucometrics: percentage of patients with blood glucose between 70 and 180 mg/dL (percent perfect), blood glucose greater than 300 mg/dL (extreme hyperglycemia), and blood glucose less than 70 mg/dL (hypoglycemia). Percent perfect glucose results improved from 45% to 53%, extreme hyperglycemia (blood glucose >300 mg/dL) fell from 11.7% to 5%. Hypoglycemia demonstrated a downward trend line, demonstrating that with improving glycemic control hypoglycemia rates did not increase. Percentage of patients receiving meal insulin within 30 minutes of blood glucose check increased from 35% to 73%. In the hospital, numerous obstacles were present that interfered with on-time meal insulin delivery. Establishing a meal delivery process with the nurse performing the premeal blood glucose check, delivering the meal, and administering the insulin improves overall blood glucose control. Nurse-led process improvement of blood glucose monitoring, meal tray delivery, and insulin administration does lead to improved glycemic control for the inpatient population.

  3. Improving aerosol drug delivery during invasive mechanical ventilation with redesigned components.

    Science.gov (United States)

    Longest, P Worth; Azimi, Mandana; Golshahi, Laleh; Hindle, Michael

    2014-05-01

    Patients receiving invasive mechanical ventilation with an endotracheal tube (ETT) can often benefit from pharmaceutical aerosols; however, drug delivery through the ventilator circuit is known to be very inefficient. The objective of this study was to improve the delivery of aerosol through an invasive mechanical ventilation system by redesigning circuit components using a streamlining approach. Redesigned components were the T-connector interface between the nebulizer and ventilator line and the Y-connector leading to the ETT. The streamlining approach seeks to minimize aerosol deposition and loss by eliminating sharp changes in flow direction and tubing diameter that lead to flow disruption. Both in vitro experiments and computational fluid dynamic (CFD) simulations were applied to analyze deposition and emitted dose of drug for multiple droplet size distributions, flows, and ETT sizes used in adults. The experimental results demonstrated that the streamlined components improved delivery through the circuit by factors ranging from 1.3 to 1.5 compared with a commercial system for adult ETT sizes of 8 and 9 mm. The overall delivery efficiency was based on the bimodal aspect of the aerosol distributions and could not be predicted by median diameter alone. CFD results indicated a 20-fold decrease in turbulence in the junction region for the streamlined Y resulting in a maximum 9-fold decrease in droplet deposition. The relative effectiveness of the streamlined designs was found to increase with increasing particle size and increasing flow, with a maximum improvement in emitted dose of 1.9-fold. Streamlined components can significantly improve the delivery of pharmaceutical aerosols during mechanical ventilation based on an analysis of multiple aerosol generation devices, ETT sizes, and flows.

  4. Nanocrystal: a novel approach to overcome skin barriers for improved topical drug delivery.

    Science.gov (United States)

    Patel, Viral; Sharma, Om Prakash; Mehta, Tejal

    2018-04-01

    Skin is an important route of drug delivery for the treatment of various dermatological conditions. The advent of nanotechnology is paving the roadmaps for topical drug delivery by providing sustained release as well as maintaining a localized effect, outweighing the toxicity concern. Area covered: This review highlighted the morphology of skin, its barrier nature as well as drug penetration pathways after topical application of formulations. The existing methods to improve topical drug delivery, by infringing or permeating the skin barriers, are discussed. This context concretes the foundation to accentuate the need for the development of nanocrystal-based topical formulation. The mechanism of drug release, immediate as well as sustained release, after topical administration of drug nanocrystals is also elaborated. The special emphasis is given on the breakthrough achieved, in topical drug delivery using drug nanocrystals, so far in the plethora of literature, patents, and products, under clinical trial as well as in the market. Expert opinion: The current research on nanocrystals for topical drug delivery is highlighting the breakthroughs achieved so far. The output of these research envisages that topical nanocrystals based formulations can be a novel strategy for the drugs which are facing solubility, bioavailability and toxicity concerns.

  5. An Improved Method for Magnetic Nanocarrier Drug Delivery across the Cell Membrane

    Directory of Open Access Journals (Sweden)

    Behzad Mehrafrooz

    2018-01-01

    Full Text Available One of the crucial issues in the pharmacological field is developing new drug delivery systems. The main concern is to develop new methods for improving the drug delivery efficiencies such as low disruptions, precise control of the target of delivery and drug sustainability. Nowadays, there are many various methods for drug delivery systems. Carbon-based nanocarriers are a new efficient tool for translocating drug into the defined area or cells inside the body. These nanocarriers can be functionalized with proteins, peptides and used to transport their freight to cells or defined areas. Since functionalized carbon-based nanocarriers show low toxicity and high biocompatibility, they are used in many nanobiotechnology fields. In this study, different shapes of nanocarrier are investigated, and the suitable magnetic field, which is applied using MRI for the delivery of the nanocarrier, is proposed. In this research, based on the force required to cross the membrane and MD simulations, the optimal magnetic field profile is designed. This optimal magnetic force field is derived from the mathematical model of the system and magnetic particle dynamics inside the nanocarrier. The results of this paper illustrate the effects of the nanocarrier’s shapes on the percentage of success in crossing the membrane and the optimal required magnetic field.

  6. Investigating CFTR and KCa3.1 Protein/Protein Interactions.

    Directory of Open Access Journals (Sweden)

    Hélène Klein

    Full Text Available In epithelia, Cl- channels play a prominent role in fluid and electrolyte transport. Of particular importance is the cAMP-dependent cystic fibrosis transmembrane conductance regulator Cl- channel (CFTR with mutations of the CFTR encoding gene causing cystic fibrosis. The bulk transepithelial transport of Cl- ions and electrolytes needs however to be coupled to an increase in K+ conductance in order to recycle K+ and maintain an electrical driving force for anion exit across the apical membrane. In several epithelia, this K+ efflux is ensured by K+ channels, including KCa3.1, which is expressed at both the apical and basolateral membranes. We show here for the first time that CFTR and KCa3.1 can physically interact. We first performed a two-hybrid screen to identify which KCa3.1 cytosolic domains might mediate an interaction with CFTR. Our results showed that both the N-terminal fragment M1-M40 of KCa3.1 and part of the KCa3.1 calmodulin binding domain (residues L345-A400 interact with the NBD2 segment (G1237-Y1420 and C- region of CFTR (residues T1387-L1480, respectively. An association of CFTR and F508del-CFTR with KCa3.1 was further confirmed in co-immunoprecipitation experiments demonstrating the formation of immunoprecipitable CFTR/KCa3.1 complexes in CFBE cells. Co-expression of KCa3.1 and CFTR in HEK cells did not impact CFTR expression at the cell surface, and KCa3.1 trafficking appeared independent of CFTR stimulation. Finally, evidence is presented through cross-correlation spectroscopy measurements that KCa3.1 and CFTR colocalize at the plasma membrane and that KCa3.1 channels tend to aggregate consequent to an enhanced interaction with CFTR channels at the plasma membrane following an increase in intracellular Ca2+ concentration. Altogether, these results suggest 1 that the physical interaction KCa3.1/CFTR can occur early during the biogenesis of both proteins and 2 that KCa3.1 and CFTR form a dynamic complex, the formation of which

  7. Biophysical characterisation of calumenin as a charged F508del-CFTR folding modulator.

    Directory of Open Access Journals (Sweden)

    Rashmi Tripathi

    Full Text Available The cystic fibrosis transmembrane regulator (CFTR is a cyclic-AMP dependent chloride channel expressed at the apical surface of epithelial cells lining various organs such as the respiratory tract. Defective processing and functioning of this protein caused by mutations in the CFTR gene results in loss of ionic balance, defective mucus clearance, increased proliferation of biofilms and inflammation of human airways observed in cystic fibrosis (CF patients. The process by which CFTR folds and matures under the influence of various chaperones in the secretory pathway remains incompletely understood. Recently, calumenin, a secretory protein, belonging to the CREC family of low affinity calcium binding proteins has been identified as a putative CFTR chaperone whose biophysical properties and functions remain uncharacterized. We compared hydropathy, instability, charge, unfoldability, disorder and aggregation propensity of calumenin and other CREC family members with CFTR associated chaperones and calcium binding proteins, wild-type and mutant CFTR proteins and intrinsically disordered proteins (IDPs. We observed that calumenin, along with other CREC proteins, was significantly more charged and less folded compared to CFTR associated chaperones. Moreover like IDPs, calumenin and other CREC proteins were found to be less hydrophobic and aggregation prone. Phylogenetic analysis revealed a close link between calumenin and other CREC proteins indicating how evolution might have shaped their similar biophysical properties. Experimentally, calumenin was observed to significantly reduce F508del-CFTR aggregation in a manner similar to AavLEA1, a well-characterized IDP. Fluorescence microscopy based imaging analysis also revealed altered trafficking of calumenin in bronchial cells expressing F508del-CFTR, indicating its direct role in the pathophysiology of CF. In conclusion, calumenin is characterized as a charged protein exhibiting close similarity with

  8. Mechanisms of CFTR Functional Variants That Impair Regulated Bicarbonate Permeation and Increase Risk for Pancreatitis but Not for Cystic Fibrosis

    OpenAIRE

    LaRusch, Jessica; Jung, Jinsei; General, Ignacio J.; Lewis, Michele D.; Park, Hyun Woo; Brand, Randall E.; Gelrud, Andres; Anderson, Michelle A.; Banks, Peter A.; Conwell, Darwin; Lawrence, Christopher; Romagnuolo, Joseph; Baillie, John; Alkaade, Samer; Cote, Gregory

    2014-01-01

    CFTR is a dynamically regulated anion channel. Intracellular WNK1-SPAK activation causes CFTR to change permeability and conductance characteristics from a chloride-preferring to bicarbonate-preferring channel through unknown mechanisms. Two severe CFTR mutations (CFTRsev ) cause complete loss of CFTR function and result in cystic fibrosis (CF), a severe genetic disorder affecting sweat glands, nasal sinuses, lungs, pancreas, liver, intestines, and male reproductive system. We hypothesize tha...

  9. Asymmetric fan beams (AFB) for improvement of the craniocaudal dose distribution in helical tomotherapy delivery

    International Nuclear Information System (INIS)

    Gladwish, Adam; Kron, Tomas; McNiven, Andrea; Bauman, Glenn; Van Dyk, Jake

    2004-01-01

    Helical tomotherapy (HT) is a novel radiotherapy technique that utilizes intensity modulated fan beams that deliver highly conformal dose distributions in a helical beam trajectory. The most significant limitation in dose delivery with a constant fan beam thickness (FBT) is the penumbra width of the dose distribution in the craniocaudal direction, which is equivalent to the FBT. We propose to employ a half-blocked fan beam at start and stop location to reduce the penumbra width by half. By opening the jaw slowly during the helical delivery until the desired FBT is achieved it is possible to create a sharper edge in the superior and inferior direction from the target. The technique was studied using a tomotherapy beam model implemented on a commercial treatment planning system (Theraplan Plus V3.0). It was demonstrated that the dose distribution delivered using a 25 mm fan beam can be improved significantly, to reduce the dose to normal structures located superiorly and inferiorly of the target. Dosimetry for this technique is straightforward down to a FBT of 15 mm and implementation should be simple as no changes in couch movement are required compared to a standard HT delivery. We conclude that the use of asymmetric collimated fan beams for the start and stop of the helical tomotherapeutic dose delivery has the potential of significantly improving the dose distribution in helical tomotherapy

  10. The Dilemma of Accountability and Good Governance for Improved Public Service Delivery in Nigeria

    Directory of Open Access Journals (Sweden)

    Kehinde David Adejuwon

    2012-12-01

    Full Text Available The public sector in Nigeria is irrefutably beset with gross  incompetence and ineffective management. Perplexing difficulties endure in the Nigerian public sector in spite of a number of reform programmes that have been designed to enhance efficient and effective service delivery for almost two decades. The fact that public service has failed dismally to achieve its laudable objectives is the reason for the vote of no confidence passed on its administrators by majority of the Nigerian populace. The article examines the dilemma of accountability and good governance in Nigeria and demonstrates that the critical point in achieving meaningful developments in the country intrinsically lay with improved service delivery in the public sector. The basic reason why the public service has become the scorn of the people is because for too long, both the government and public servants have paid lip service to the crucial issue of effective and efficient service delivery. The article argues that improved service delivery will improve both the performance and the image of public service and re-awaken the citizens’ interest and trust in them to do business with public servants. It suggests that  in order to bring sanity back to the Nigerian Public Service,  all unprofessional tendencies such as ethnicity bias and nepotism in appointments and promotions, lack of security of tenure of office, and appointment of non-career public servants into key positions in the public service must stop. Also,  effective service delivery must be tailored to the circumstances of Nigeria. The study made use of secondary data obtained from various sources. It therefore concludes that without a reawakening of the culture of accountability and transparency lost over the years, the trusting relationship needed to forge between the government and the governed for the actualization of good governance will not materialize.

  11. Applying Toyota production system techniques for medication delivery: improving hospital safety and efficiency.

    Science.gov (United States)

    Newell, Terry L; Steinmetz-Malato, Laura L; Van Dyke, Deborah L

    2011-01-01

    The inpatient medication delivery system used at a large regional acute care hospital in the Midwest had become antiquated and inefficient. The existing 24-hr medication cart-fill exchange process with delivery to the patients' bedside did not always provide ordered medications to the nursing units when they were needed. In 2007 the principles of the Toyota Production System (TPS) were applied to the system. Project objectives were to improve medication safety and reduce the time needed for nurses to retrieve patient medications. A multidisciplinary team was formed that included representatives from nursing, pharmacy, informatics, quality, and various operational support departments. Team members were educated and trained in the tools and techniques of TPS, and then designed and implemented a new pull system benchmarking the TPS Ideal State model. The newly installed process, providing just-in-time medication availability, has measurably improved delivery processes as well as patient safety and satisfaction. Other positive outcomes have included improved nursing satisfaction, reduced nursing wait time for delivered medications, and improved efficiency in the pharmacy. After a successful pilot on two nursing units, the system is being extended to the rest of the hospital. © 2010 National Association for Healthcare Quality.

  12. Enhancement techniques for improving 5-aminolevulinic acid delivery through the skin

    Directory of Open Access Journals (Sweden)

    Li-Wen Zhang

    2011-03-01

    Full Text Available Photodynamic therapy (PDT is a popular technique for skin cancer treatment. Protoporphyrin IX, which is a photosensitizing agent, converted enzymatically from the prodrug 5-aminolevulinic acid (ALA, is used as a photosensitizer in PDT for cancer. However, ALA penetrates with difficulty through intact skin; therefore, improving delivery systems for ALA in the skin will play an important role in ALA-PDT. Enhancement of ALA skin penetration can be achieved by physical methods, such as iontophoresis, laser, microneedles, ultrasound, and by adding chemical penetration enhancers, such as, dimethyl sulfoxide, oleic acid, and others, whereas some researches used lipophilic ALA derivatives and different vehicles to improve the transdermal delivery of ALA. This review introduces several enhancement techniques for increasing ALA permeation through the skin.

  13. Optimizing hyaluronidase dose and plasmid DNA delivery greatly improves gene electrotransfer efficiency in rat skeletal muscle

    DEFF Research Database (Denmark)

    Åkerström, Thorbjörn; Vedel, Kenneth; Needham Andersen, Josefine

    2015-01-01

    Transfection of rat skeletal muscle in vivo is a widely used research model. However, gene electrotransfer protocols have been developed for mice and yield variable results in rats. We investigated whether changes in hyaluronidase pre-treatment and plasmid DNA delivery can improve transfection...... with a homogenous distribution. We also show that transfection was stable over five weeks of regular exercise or inactivity. Our findings show that species-specific plasmid DNA delivery and hyaluronidase pre-treatment greatly improves transfection efficiency in rat skeletal muscle....... efficiency in rat skeletal muscle. We found that pre-treating the muscle with a hyaluronidase dose suitable for rats (0.56. U/g b.w.) prior to plasmid DNA injection increased transfection efficiency by >200% whereas timing of the pre-treatment did not affect efficiency. Uniformly distributing plasmid DNA...

  14. Improving fiber-optic laser beam delivery by incorporating GRADIUM optics

    International Nuclear Information System (INIS)

    Hunter, B.V.; Leong, K.H.

    1997-01-01

    The performance of a fiber-optic laser beam delivery system strongly depends on the fiber and the optics used to image the fiber face on the workpiece. We have compared off-the-shelf homogenous (BK7) and GRADIUM (axial-gradient) singlets to determine what improvement the GRADIUM offers in practice to the typical laser user. The realized benefit for this application, although significant, is much smaller than would be realized by a conventional imaging application. The figure of merit for laser-based materials processing is the 86% energy-enclosure radius, which is not directly supported by commerical ray-tracing software. Therefore empirical rules of thumb are presented to understand when GRADIUM (or any other well-corrected optics) will yield meaningful improvement to the beam delivery system. copyright 1997 Optical Society of America

  15. In-flight food delivery and waste collection service: the passengers’ perspective and potential improvement

    Science.gov (United States)

    Romli, F. I.; Rahman, K. Abdul; Ishak, F. D.

    2016-10-01

    Increased competition in the commercial air transportation industry has made service quality of the airlines as one of the key competitive measures to attract passengers against their rivals. In-flight services, particularly food delivery and waste collection, have a notable impact on perception of the overall airline's service quality because they are directly and interactively provided to passengers during flight. An online public survey is conducted to explore general passengers' perception of current in-flight food delivery and waste collection services, and to identify potential rooms for improvement. The obtained survey results indicate that in-flight service does have an effect on passengers' choice of airlines. Several weaknesses of the current service method and possible improvements have been established from the collected responses.

  16. Cftr Modulates Wnt/β-Catenin Signaling and Stem Cell Proliferation in Murine Intestine

    Directory of Open Access Journals (Sweden)

    Ashlee M. Strubberg

    2018-01-01

    Conclusions: CF intestine shows increased ISC proliferation and Wnt/β-catenin signaling. Loss of Cftr increases pHi in ISCs, which stabilizes the plasma membrane association of the Wnt transducer Dvl, likely facilitating Wnt/β-catenin signaling. Absence of Cftr-dependent suppression of ISC proliferation in the CF intestine may contribute to increased risk for intestinal tumors.

  17. Rescuing mutant CFTR: a multi-task approach to a better outcome in treating cystic fibrosis.

    Science.gov (United States)

    Amaral, Margarida D; Farinha, Carlos M

    2013-01-01

    Correcting multiple defects of mutant CFTR with small molecule compounds has been the goal of an increasing number of recent Cystic Fibrosis (CF) drug discovery programmes. However, the mechanism of action (MoA) by which these molecules restore mutant CFTR is still poorly understood, in particular of CFTR correctors, i.e., compounds rescuing to the cells surface the most prevalent mutant in CF patients--F508del-CFTR. However, there is increasing evidence that to fully restore the multiple defects associated with F508del-CFTR, different small molecules with distinct corrective properties may be required. Towards this goal, a better insight into MoA of correctors is needed and several constraints should be addressed. The methodological approaches to achieve this include: 1) testing the combined effect of compounds with that of other (non-pharmacological) rescuing strategies (e.g., revertants or low temperature); 2) assessing effects in multiple cellular models (non-epithelial vs epithelial, non-human vs human, immortalized vs primary cultures, polarized vs non polarized, cells vs tissues); 3) assessing compound effects on isolated CFTR domains (e.g., compound binding by surface plasmon resonance, assessing effects on domain folding and aggregation); and finally 4) assessing compounds specificity in rescuing different CFTR mutants and other mutant proteins. These topics are reviewed and discussed here so as to provide a state-of-the art review on how to combine multiple ways of rescuing mutant CFTR to the ultimate benefit of CF patients.

  18. Evaluation of potential regulatory elements identified as DNase I hypersensitive sites in the CFTR gene

    DEFF Research Database (Denmark)

    Phylactides, M.; Rowntree, R.; Nuthall, H.

    2002-01-01

    hypersensitive sites (DHS) within the locus. We previously identified at least 12 clusters of DHS across the CFTR gene and here further evaluate DHS in introns 2,3,10,16,17a, 18, 20 and 21 to assess their functional importance in regulation of CFTR gene expression. Transient transfections of enhancer/reporter...

  19. Improving IMRT delivery efficiency with reweighted L1-minimization for inverse planning

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Hojin [Department of Radiation Oncology, Stanford University, Stanford, California 94305-5847 and Department of Electrical Engineering, Stanford University, Stanford, California 94305-9505 (United States); Becker, Stephen [Laboratoire Jacques-Louis Lions, Universite Pierre et Marie Curie, Paris 6, 75005 France (France); Lee, Rena; Lee, Soonhyouk [Department of Radiation Oncology, School of Medicine, Ewha Womans University, Seoul 158-710 (Korea, Republic of); Shin, Sukyoung [Medtronic CV RDN R and D, Santa Rosa, California 95403 (United States); Candes, Emmanuel [Department of Statistics, Stanford University, Stanford, California 94305-4065 (United States); Xing Lei; Li Ruijiang [Department of Radiation Oncology, Stanford University, Stanford, California 94305-5304 (United States)

    2013-07-15

    Purpose: This study presents an improved technique to further simplify the fluence-map in intensity modulated radiation therapy (IMRT) inverse planning, thereby reducing plan complexity and improving delivery efficiency, while maintaining the plan quality.Methods: First-order total-variation (TV) minimization (min.) based on L1-norm has been proposed to reduce the complexity of fluence-map in IMRT by generating sparse fluence-map variations. However, with stronger dose sparing to the critical structures, the inevitable increase in the fluence-map complexity can lead to inefficient dose delivery. Theoretically, L0-min. is the ideal solution for the sparse signal recovery problem, yet practically intractable due to its nonconvexity of the objective function. As an alternative, the authors use the iteratively reweighted L1-min. technique to incorporate the benefits of the L0-norm into the tractability of L1-min. The weight multiplied to each element is inversely related to the magnitude of the corresponding element, which is iteratively updated by the reweighting process. The proposed penalizing process combined with TV min. further improves sparsity in the fluence-map variations, hence ultimately enhancing the delivery efficiency. To validate the proposed method, this work compares three treatment plans obtained from quadratic min. (generally used in clinic IMRT), conventional TV min., and our proposed reweighted TV min. techniques, implemented by a large-scale L1-solver (template for first-order conic solver), for five patient clinical data. Criteria such as conformation number (CN), modulation index (MI), and estimated treatment time are employed to assess the relationship between the plan quality and delivery efficiency.Results: The proposed method yields simpler fluence-maps than the quadratic and conventional TV based techniques. To attain a given CN and dose sparing to the critical organs for 5 clinical cases, the proposed method reduces the number of segments

  20. Improving IMRT delivery efficiency with reweighted L1-minimization for inverse planning

    International Nuclear Information System (INIS)

    Kim, Hojin; Becker, Stephen; Lee, Rena; Lee, Soonhyouk; Shin, Sukyoung; Candès, Emmanuel; Xing Lei; Li Ruijiang

    2013-01-01

    Purpose: This study presents an improved technique to further simplify the fluence-map in intensity modulated radiation therapy (IMRT) inverse planning, thereby reducing plan complexity and improving delivery efficiency, while maintaining the plan quality.Methods: First-order total-variation (TV) minimization (min.) based on L1-norm has been proposed to reduce the complexity of fluence-map in IMRT by generating sparse fluence-map variations. However, with stronger dose sparing to the critical structures, the inevitable increase in the fluence-map complexity can lead to inefficient dose delivery. Theoretically, L0-min. is the ideal solution for the sparse signal recovery problem, yet practically intractable due to its nonconvexity of the objective function. As an alternative, the authors use the iteratively reweighted L1-min. technique to incorporate the benefits of the L0-norm into the tractability of L1-min. The weight multiplied to each element is inversely related to the magnitude of the corresponding element, which is iteratively updated by the reweighting process. The proposed penalizing process combined with TV min. further improves sparsity in the fluence-map variations, hence ultimately enhancing the delivery efficiency. To validate the proposed method, this work compares three treatment plans obtained from quadratic min. (generally used in clinic IMRT), conventional TV min., and our proposed reweighted TV min. techniques, implemented by a large-scale L1-solver (template for first-order conic solver), for five patient clinical data. Criteria such as conformation number (CN), modulation index (MI), and estimated treatment time are employed to assess the relationship between the plan quality and delivery efficiency.Results: The proposed method yields simpler fluence-maps than the quadratic and conventional TV based techniques. To attain a given CN and dose sparing to the critical organs for 5 clinical cases, the proposed method reduces the number of segments

  1. Multilayered pyramidal dissolving microneedle patches with flexible pedestals for improving effective drug delivery.

    Science.gov (United States)

    Lau, Shinying; Fei, Jie; Liu, Haoran; Chen, Weixing; Liu, Ran

    2017-11-10

    Dissolving microneedles have been employed as a safe and convenient transdermal delivery system for drugs and vaccines. To improve effective drug delivery, a multilayered pyramidal dissolving microneedle patch, composed of silk fibroin tips with the ability of robust mechanical strength, rapid dissolution and drug release supported on a flexible polyvinyl alcohol (PVA) pedestal is reported. To show the utility of this approach the ability of the fabricated microneedles to deliver insulin is demonstrated. The dissolving microneedles have sufficient mechanical strength to be inserted into abdomen skin of mice to a depth of approximately 150μm, and release their encapsulated insulin into the skin to cause a hypoglycemic effect. The fabrication of microneedles avoids high temperature which benefits storage stability at room temperature for 20d. This result indicates >99.4% of insulin remained in the microneedles. In comparison to traditional needle-based administration, the proposed multilayered pyramidal dissolving microneedle patches enable self-administration, miniaturization, pain-free administration, drug delivery and drug stability, all being important features in needle free drug delivery. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Generic project definitions for improvement of health care delivery: a case-based approach.

    Science.gov (United States)

    Niemeijer, Gerard C; Does, Ronald J M M; de Mast, Jeroen; Trip, Albert; van den Heuvel, Jaap

    2011-01-01

    The purpose of this article is to create actionable knowledge, making the definition of process improvement projects in health care delivery more effective. This study is a retrospective analysis of process improvement projects in hospitals, facilitating a case-based reasoning approach to project definition. Data sources were project documentation and hospital-performance statistics of 271 Lean Six Sigma health care projects from 2002 to 2009 of general, teaching, and academic hospitals in the Netherlands and Belgium. Objectives and operational definitions of improvement projects in the sample, analyzed and structured in a uniform format and terminology. Extraction of reusable elements of earlier project definitions, presented in the form of 9 templates called generic project definitions. These templates function as exemplars for future process improvement projects, making the selection, definition, and operationalization of similar projects more efficient. Each template includes an explicated rationale, an operationalization in the form of metrics, and a prototypical example. Thus, a process of incremental and sustained learning based on case-based reasoning is facilitated. The quality of project definitions is a crucial success factor in pursuits to improve health care delivery. We offer 9 tried and tested improvement themes related to patient safety, patient satisfaction, and business-economic performance of hospitals.

  3. Cellular chloride and bicarbonate retention alters intracellular pH regulation in Cftr KO crypt epithelium

    Science.gov (United States)

    Walker, Nancy M.; Liu, Jinghua; Stein, Sydney R.; Stefanski, Casey D.; Strubberg, Ashlee M.

    2015-01-01

    Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR), an anion channel providing a major pathway for Cl− and HCO3− efflux across the apical membrane of the epithelium. In the intestine, CF manifests as obstructive syndromes, dysbiosis, inflammation, and an increased risk for gastrointestinal cancer. Cftr knockout (KO) mice recapitulate CF intestinal disease, including intestinal hyperproliferation. Previous studies using Cftr KO intestinal organoids (enteroids) indicate that crypt epithelium maintains an alkaline intracellular pH (pHi). We hypothesized that Cftr has a cell-autonomous role in downregulating pHi that is incompletely compensated by acid-base regulation in its absence. Here, 2′,7′-bis(2-carboxyethyl)-5(6)-carboxyfluorescein microfluorimetry of enteroids showed that Cftr KO crypt epithelium sustains an alkaline pHi and resistance to cell acidification relative to wild-type. Quantitative real-time PCR revealed that Cftr KO enteroids exhibit downregulated transcription of base (HCO3−)-loading proteins and upregulation of the basolateral membrane HCO3−-unloader anion exchanger 2 (Ae2). Although Cftr KO crypt epithelium had increased Ae2 expression and Ae2-mediated Cl−/HCO3− exchange with maximized gradients, it also had increased intracellular Cl− concentration relative to wild-type. Pharmacological reduction of intracellular Cl− concentration in Cftr KO crypt epithelium normalized pHi, which was largely Ae2-dependent. We conclude that Cftr KO crypt epithelium maintains an alkaline pHi as a consequence of losing both Cl− and HCO3− efflux, which impairs pHi regulation by Ae2. Retention of Cl− and an alkaline pHi in crypt epithelium may alter several cellular processes in the proliferative compartment of Cftr KO intestine. PMID:26542396

  4. Rab4GTPase modulates CFTR function by impairing channel expression at plasma membrane

    International Nuclear Information System (INIS)

    Saxena, Sunil K.; Kaur, Simarna; George, Constantine

    2006-01-01

    Cystic fibrosis (CF), an autosomal recessive disorder, is caused by the disruption of biosynthesis or the function of a membrane cAMP-activated chloride channel, CFTR. CFTR regulatory mechanisms include recruitment of channel proteins to the cell surface from intracellular pools and by protein-protein interactions. Rab proteins are small GTPases involved in regulated trafficking controlling vesicle docking and fusion. Rab4 controls recycling events from endosome to the plasma membrane, fusion, and degradation. The colorectal cell line HT-29 natively expresses CFTR and responds to cAMP stimulation with an increase in CFTR-mediated currents. Rab4 over-expression in HT-29 cells inhibits both basal and cAMP-stimulated CFTR-mediated currents. GTPase-deficient Rab4Q67L and GDP locked Rab4S22N both inhibit channel activity, which appears characteristically different. Active status of Rab4 was confirmed by GTP overlay assay, while its expression was verified by Western blotting. The pull-down and immunoprecipitation experiments suggest that Rab4 physically interacts with CFTR through protein-protein interaction. Biotinylation with cell impermeant NHS-Sulfo-SS-Biotin implies that Rab4 impairs CFTR expression at cell surface. The enhanced cytosolic CFTR indicates that Rab4 expression restrains CFTR appearance at the cell membrane. The study suggests that Rab4 regulates the channel through multiple mechanisms that include protein-protein interaction, GTP/GDP exchange, and channel protein trafficking. We propose that Rab4 is a dynamic molecule with a significant role in CFTR function

  5. Cellular chloride and bicarbonate retention alters intracellular pH regulation in Cftr KO crypt epithelium.

    Science.gov (United States)

    Walker, Nancy M; Liu, Jinghua; Stein, Sydney R; Stefanski, Casey D; Strubberg, Ashlee M; Clarke, Lane L

    2016-01-15

    Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR), an anion channel providing a major pathway for Cl(-) and HCO3 (-) efflux across the apical membrane of the epithelium. In the intestine, CF manifests as obstructive syndromes, dysbiosis, inflammation, and an increased risk for gastrointestinal cancer. Cftr knockout (KO) mice recapitulate CF intestinal disease, including intestinal hyperproliferation. Previous studies using Cftr KO intestinal organoids (enteroids) indicate that crypt epithelium maintains an alkaline intracellular pH (pHi). We hypothesized that Cftr has a cell-autonomous role in downregulating pHi that is incompletely compensated by acid-base regulation in its absence. Here, 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein microfluorimetry of enteroids showed that Cftr KO crypt epithelium sustains an alkaline pHi and resistance to cell acidification relative to wild-type. Quantitative real-time PCR revealed that Cftr KO enteroids exhibit downregulated transcription of base (HCO3 (-))-loading proteins and upregulation of the basolateral membrane HCO3 (-)-unloader anion exchanger 2 (Ae2). Although Cftr KO crypt epithelium had increased Ae2 expression and Ae2-mediated Cl(-)/HCO3 (-) exchange with maximized gradients, it also had increased intracellular Cl(-) concentration relative to wild-type. Pharmacological reduction of intracellular Cl(-) concentration in Cftr KO crypt epithelium normalized pHi, which was largely Ae2-dependent. We conclude that Cftr KO crypt epithelium maintains an alkaline pHi as a consequence of losing both Cl(-) and HCO3 (-) efflux, which impairs pHi regulation by Ae2. Retention of Cl(-) and an alkaline pHi in crypt epithelium may alter several cellular processes in the proliferative compartment of Cftr KO intestine. Copyright © 2016 the American Physiological Society.

  6. Improving Staff Communication and Transitions of Care Between Obstetric Triage and Labor and Delivery.

    Science.gov (United States)

    O'Rourke, Kathleen; Teel, Joseph; Nicholls, Erika; Lee, Daniel D; Colwill, Alyssa Covelli; Srinivas, Sindhu K

    2018-03-01

    To improve staff perception of the quality of the patient admission process from obstetric triage to the labor and delivery unit through standardization. Preassessment and postassessment online surveys. A 13-bed labor and delivery unit in a quaternary care, Magnet Recognition Program, academic medical center in Pennsylvania. Preintervention (n = 100), postintervention (n = 52), and 6-month follow-up survey respondents (n = 75) represented secretaries, registered nurses, surgical technicians, certified nurse-midwives, nurse practitioners, maternal-fetal medicine fellows, anesthesiologists, and obstetric and family medicine attending and resident physicians from triage and labor and delivery units. We educated staff and implemented interventions, an admission huddle and safety time-out whiteboard, to standardize the admission process. Participants were evaluated with the use of preintervention, postintervention, and 6-month follow-up surveys about their perceptions regarding the admission process. Data tracked through the electronic medical record were used to determine compliance with the admission huddle and whiteboards. A 77% reduction (decrease of 49%) occurred in the perception of incomplete patient admission processes from baseline to 6-month follow-up after the intervention. Postintervention and 6-month follow-up survey results indicated that 100% of respondents responded strongly agree/agree/neutral that the new admission process improved communication surrounding care for patients. Data in the electronic medical record indicated that compliance with use of admission huddles and whiteboards increased from 50% to 80% by 6 months. The new patient admission process, including a huddle and safety time-out board, improved staff perception of the quality of admission from obstetric triage to the labor and delivery unit. Copyright © 2018 AWHONN, the Association of Women's Health, Obstetric and Neonatal Nurses. Published by Elsevier Inc. All rights reserved.

  7. Efficacy of a process improvement intervention on delivery of HIV services to offenders: a multisite trial.

    Science.gov (United States)

    Pearson, Frank S; Shafer, Michael S; Dembo, Richard; Del Mar Vega-Debién, Graciela; Pankow, Jennifer; Duvall, Jamieson L; Belenko, Steven; Frisman, Linda K; Visher, Christy A; Pich, Michele; Patterson, Yvonne

    2014-12-01

    We tested a modified Network for the Improvement of Addiction Treatment (NIATx) process improvement model to implement improved HIV services (prevention, testing, and linkage to treatment) for offenders under correctional supervision. As part of the Criminal Justice Drug Abuse Treatment Studies, Phase 2, the HIV Services and Treatment Implementation in Corrections study conducted 14 cluster-randomized trials in 2011 to 2013 at 9 US sites, where one correctional facility received training in HIV services and coaching in a modified NIATx model and the other received only HIV training. The outcome measure was the odds of successful delivery of an HIV service. The results were significant at the .05 level, and the point estimate for the odds ratio was 2.14. Although overall the results were heterogeneous, the experiments that focused on implementing HIV prevention interventions had a 95% confidence interval that exceeded the no-difference point. Our results demonstrate that a modified NIATx process improvement model can effectively implement improved rates of delivery of some types of HIV services in correctional environments.

  8. SUPPORTIVE SUPERVISION AS A TECHNOLOGY OF IMPROVING THE QUALITY OF HOSPITAL CARE DELIVERY

    Directory of Open Access Journals (Sweden)

    Svetlana A. Mukhortova

    2017-01-01

    Full Text Available Improving the quality of medical care is a priority in countries with developed and developing health care system. There are various approaches to improve the quality and safety of patient’s care, as well as various strategies to encourage hospitals to achieve this goal. The purpose of the presented literature review was to analyze existing experience of the implementation of technology of supportive supervision in health care facilities to improve the quality of hospital care delivery. The data sources for publication were obtained from the following medical databases: PubMed, Cochrane Library, Medscape, e-library, and books on the topic of the review written by experts. The article discusses the results of the research studies demonstrating the successes and failures of supportive supervision technology application. Implementation of supportive supervision in medical facilities based on generalized experience of different countries is a promising direction in improving the quality of medical care delivery. This technology opens up opportunities to improve skills and work quality of the staff at pediatric hospitals in the Russian Federation.

  9. Functionally engineered nanosized particles in pharmaceutics: improved oral delivery of poorly water-soluble drugs.

    Science.gov (United States)

    Ozeki, Tetsuya; Tagami, Tatsuaki

    2013-01-01

    The development of drug nanoparticles has attracted substantial attention because of their potential to improve the dissolution rate and oral availability of poorly water-soluble drugs. This review summarizes the recent articles that discussed nanoparticle-based oral drug delivery systems. The preparation methods were categorized as top-down and bottom-up methods, which are common methods for preparing drug nanoparticles. In addition, methods of handling drug nanoparticles (e.g., one-step preparation of nanocomposites which are microparticles containing drug nanoparticles) were introduced for the effective preservation of drug nanoparticles. The carrier-based preparation of drug nanoparticles was also introduced as a potentially promising oral drug delivery system.

  10. Mobile phones as a health communication tool to improve skilled attendance at delivery in Zanzibar

    DEFF Research Database (Denmark)

    Lund, S; Hemed, M; Nielsen, Bb

    2012-01-01

    Please cite this paper as: Lund S, Hemed M, Nielsen B, Said A, Said K, Makungu M, Rasch V. Mobile phones as a health communication tool to improve skilled attendance at delivery in Zanzibar: a cluster-randomised controlled trial. BJOG 2012; DOI: 10.1111/j.1471-0528.2012.03413.x. Objective......  To examine the association between a mobile phone intervention and skilled delivery attendance in a resource-limited setting. Design  Pragmatic cluster-randomised controlled trial with primary healthcare facilities as the unit of randomisation. Setting  Primary healthcare facilities in Zanzibar. Population...... for study participation. Methods  Twenty-four primary healthcare facilities in six districts in Zanzibar were allocated by simple randomisation to either mobile phone intervention (n = 12) or standard care (n = 12). The intervention consisted of a short messaging service (SMS) and mobile phone voucher...

  11. Delivery of viral vectors to tumor cells: extracellular transport, systemic distribution, and strategies for improvement.

    Science.gov (United States)

    Wang, Yong; Yuan, Fan

    2006-01-01

    It is a challenge to deliver therapeutic genes to tumor cells using viral vectors because (i) the size of these vectors are close to or larger than the space between fibers in extracellular matrix and (ii) viral proteins are potentially toxic in normal tissues. In general, gene delivery is hindered by various physiological barriers to virus transport from the site of injection to the nucleus of tumor cells and is limited by normal tissue tolerance of toxicity determined by local concentrations of transgene products and viral proteins. To illustrate the obstacles encountered in the delivery and yet limit the scope of discussion, this review focuses only on extracellular transport in solid tumors and distribution of viral vectors in normal organs after they are injected intravenously or intratumorally. This review also discusses current strategies for improving intratumoral transport and specificity of viral vectors.

  12. Action research to improve methods of delivery and feedback in an Access Grid Room environment

    Science.gov (United States)

    McArthur, Lynne C.; Klass, Lara; Eberhard, Andrew; Stacey, Andrew

    2011-12-01

    This article describes a qualitative study which was undertaken to improve the delivery methods and feedback opportunity in honours mathematics lectures which are delivered through Access Grid Rooms. Access Grid Rooms are facilities that provide two-way video and audio interactivity across multiple sites, with the inclusion of smart boards. The principal aim was to improve the student learning experience, given the new environment. The specific aspects of the course delivery that the study focused on included presentation of materials and provision of opportunities for interaction between the students and between students and lecturers. The practical considerations in the delivery of distance learning are well documented in the literature, and similar problems arise in the Access Grid Room environment; in particular, those of limited access to face-to-face interaction and the reduction in peer support. The nature of the Access Grid Room classes implies that students studying the same course can be physically situated in different cities, and possibly in different countries. When studying, it is important that students have opportunity to discuss new concepts with others; particularly their peers and their lecturer. The Access Grid Room environment also presents new challenges for the lecturer, who must learn new skills in the delivery of materials. The unique nature of Access Grid Room technology offers unprecedented opportunity for effective course delivery and positive outcomes for students, and was developed in response to a need to be able to interact with complex data, other students and the instructor, in real-time, at a distance and from multiple sites. This is a relatively new technology and as yet there has been little or no studies specifically addressing the use and misuse of the technology. The study found that the correct placement of cameras and the use of printed material and smart boards were all crucial to the student experience. In addition, the

  13. Partnership working and improved service delivery: views of staff providing sexual health services.

    Science.gov (United States)

    Pow, Janette; Elliott, Lawrie; Raeside, Robert; Themessl-Huber, Markus; Claveirole, Anne

    2013-07-01

    Successful partnership working has theoretically been linked to improvements in service delivery and is dependent on the strength of the partnership, trust, communication, professional roles and resource sharing. Empirical evidence to confirm the relationships between these factors and improved service provision, however, is lacking. Our aim was to assess the views of staff as to the conditions required for partnership working. This study was a cross-sectional survey of 687 staff offering sexual health education, information or support to young people in the Healthy Respect intervention area in Scotland. Views of each variable were scored and structural equation modelling was used to assess the theoretical model. Responses were received from 284 (41%) staff. Greater strength of partnership was directly associated with increasing the number of referrals. Establishing professional roles between organizations was also associated with increasing the number of referrals. Strength of partnership was indirectly associated with working more effectively with young people and this relationship depended on clear communication, trust, established professional roles and shared resources. Effective partnership working depends on a number of interdependent relationships between organizations, which act synergistically to improve organizational outcomes. Effective partnership working leads to improved service delivery though there is a need for better controlled studies which demonstrate the effect on health outcomes.

  14. Strategies for improving chemotherapeutic delivery to solid tumors mediated by vascular permeability modulation

    Science.gov (United States)

    Roy Chaudhuri, Tista

    An essential mode of distribution of blood-borne chemotherapeutic agents within a solid tumor is via the micro-circulation. Poor tumor perfusion, because of a lack of functional vasculature or a lack of microvessels, as well as low tumor vascular permeability, can prevent adequate deposition of even low molecular-weight agents into the tumor. The modulation of tumor vascular function and density can provides numerous strategies for improving intratumor deposition of chemotherapeutic agents. Here we investigated strategies to improve drug delivery to two tumor types that share in common poor drug delivery, but differ in the underlying cause. First, in an angiogenesis-driven brain tumor model of Glioblastoma, the vascular permeability barrier, along with poorly-functional vasculature, hinders drug delivery. A strategy of nanoparticle-based tumor 'priming' to attack the vascular permeability barrier, employing sterically stabilized liposomal doxorubicin (SSL-DXR), was investigated. Functional and histological evaluation of tumor vasculature revealed that after an initial period of depressed vascular permeability and vascular pruning 3--4 days after SSL-DXR administration, vascular permeability and perfusion were restored and then elevated after 5--7 days. As a result of tumor priming, deposition of subsequently-administered nanoparticles was enhanced, and the efficacy of temozolomide (TMZ), if administered during the window of elevated permeability, was increased. The sequenced regimen resulted in a persistent reduction of the tumor proliferative index and a 40% suppression of tumor volume, compared to animals that received both agents simultaneously. Second, in a hypovascular, pancreatic ductal adenocarcinoma model, disruption of tumor-stromal communication via sonic hedgehog (sHH) signaling pathway inhibition mediated an indirect vascular proliferation and a more than 2-fold increase in intratumor nanoparticle deposition. Enhanced delivery of SSL-DXR in tumors pre

  15. The HDAC inhibitor SAHA does not rescue CFTR membrane expression in Cystic Fibrosis.

    Science.gov (United States)

    Bergougnoux, Anne; Petit, Aurélie; Knabe, Lucie; Bribes, Estelle; Chiron, Raphaël; De Sario, Albertina; Claustres, Mireille; Molinari, Nicolas; Vachier, Isabelle; Taulan-Cadars, Magali; Bourdin, Arnaud

    2017-07-01

    The development of suitable Cystic Fibrosis (CF) models for preclinical bench tests of therapeutic candidates is challenging. Indeed, the validation of molecules to rescue the p.Phe508del-CFTR channel (encoded by the Cystic Fibrosis Transmembrane conductance Regulator gene carrying the p.Phe508del mutation) requires taking into account their overall effects on the epithelium. Suberoylanilide Hydroxamic Acid (SAHA), a histone deacetylase inhibitor (HDACi), was previously shown to be a CFTR corrector via proteostasis modulation in CFTR-deficient immortalized cells. Here, we tested SAHA effects on goblet cell metaplasia using an ex vivo model based on the air-liquid interface (ALI) culture of differentiated airway epithelial cells obtained by nasal scraping from CF patients and healthy controls. Ex vivo epithelium grew successfully in ALI cultures with significant rise in the expression of CFTR and of markers of airway epithelial differentiation compared to monolayer cell culture. SAHA decreased CFTR transcript and protein levels in CF and non-CF epithelia. Whereas SAHA induced lysine hyperacetylation, it did not change histone modifications at the CFTR promoter. SAHA reduced MUC5AC and MUC5B expression and inhibited goblet epithelial cell differentiation. Similar effects were obtained in CF and non-CF epithelia. All the effects were fully reversible within five days from SAHA withdrawal. We conclude that, ex vivo, SAHA modulate the structure of airway epithelia without specific effect on CFTR gene and protein suggesting that HDACi cannot be useful for CF treatment. Copyright © 2017. Published by Elsevier Ltd.

  16. The cystic fibrosis transmembrane recruiter the alter ego of CFTR as a multi-kinase anchor.

    Science.gov (United States)

    Mehta, Anil

    2007-11-01

    This review focuses on a newly discovered interaction between protein kinases involved in cellular energetics, a process that may be disturbed in cystic fibrosis for unknown reasons. I propose a new model where kinase-mediated cellular transmission of energy provides mechanistic insight to a latent role of the cystic fibrosis transmembrane conductance regulator (CFTR). I suggest that CFTR acts as a multi-kinase recruiter to the apical epithelial membrane. My group finds that, in the cytosol, two protein kinases involved in cell energy homeostasis, nucleoside diphosphate kinase (NDPK) and AMP-activated kinase (AMPK), bind one another. Preliminary data suggest that both can also bind CFTR (function unclear). The disrupted role of this CFTR-kinase complex as 'membrane transmitter to the cell' is proposed as an alternative paradigm to the conventional ion transport mediated and CFTR/chloride-centric view of cystic fibrosis pathogenesis. Chloride remains important, but instead, chloride-induced control of the phosphohistidine content of one kinase component (NDPK, via a multi-kinase complex that also includes a third kinase, CK2; formerly casein kinase 2). I suggest that this complex provides the necessary near-equilibrium conditions needed for efficient transmission of phosphate energy to proteins controlling cellular energetics. Crucially, a new role for CFTR as a kinase controller is proposed with ionic concentration acting as a signal. The model posits a regulatory control relay for energy sensing involving a cascade of protein kinases bound to CFTR.

  17. Local delivery of FTY720 in PCL membrane improves SCI functional recovery by reducing reactive astrogliosis.

    Science.gov (United States)

    Wang, Junjuan; Wang, Jiaqiu; Lu, Ping; Cai, Youzhi; Wang, Yafei; Hong, Lan; Ren, Hao; Heng, Boon Chin; Liu, Hua; Zhou, Jing; Ouyang, Hongwei

    2015-09-01

    FTY720 has recently been approved as an oral drug for treating relapsing forms of multiple sclerosis, and exerts its therapeutic effect by acting as an immunological inhibitor targeting the sphingosine-1-phosphate (S1P) receptor subtype (S1P1) of T cells. Recently studies demonstrated positive efficacy of this drug on spinal cord injury (SCI) in animal models after systemic administration, albeit with significant adverse side effects. We hereby hypothesize that localized delivery of FTY720 can promote SCI recovery by reducing pathological astrogliosis. The mechanistic functions of FTY720 were investigated in vitro and in vivo utilizing immunofluorescence, histology, MRI and behavioral analysis. The in vitro study showed that FTY720 can reduce astrocyte migration and proliferation activated by S1P. FTY720 can prolong internalization of S1P1 and exert antagonistic effects on S1P1. In vivo study of SCI animal models demonstrated that local delivery of FTY720 with polycaprolactone (PCL) membrane significantly decreased S1P1 expression and glial scarring compared with the control group. Furthermore, FTY720-treated groups exhibited less cavitation volume and neuron loss, which significantly improved recovery of motor function. These findings demonstrated that localized delivery of FTY720 can promote SCI recovery by targeting the S1P1 receptor of astrocytes, provide a new therapeutic strategy for SCI treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. Technical Improvement and Application of Hydrodynamic Gene Delivery in Study of Liver Diseases

    Directory of Open Access Journals (Sweden)

    Mei Huang

    2017-08-01

    Full Text Available Development of an safe and efficient in vivo gene delivery method is indispensable for molecular biology research and the progress in the following gene therapy. Over the past few years, hydrodynamic gene delivery (HGD with naked DNA has drawn increasing interest in both research and potential clinic applications due to its high efficiency and low risk in triggering immune responses and carcinogenesis in comparison to viral vectors. This method, involving intravenous injection (i.v. of massive DNA in a short duration, gives a transient but high in vivo gene expression especially in the liver of small animals. In addition to DNA, it has also been shown to deliver other substance such as RNA, proteins, synthetic small compounds and even viruses in vivo. Given its ability to robustly mimic in vivo hepatitis B virus (HBV production in liver, HGD has become a fundamental and important technology on HBV studies in our group and many other groups. Recently, there have been interesting reports about the applications and further improvement of this technology in other liver research. Here, we review the principle, safety, current application and development of hydrodynamic delivery in liver disease studies, and discuss its future prospects, clinical potential and challenges.

  19. The custodian administered research extract server: "improving the pipeline" in linked data delivery systems.

    Science.gov (United States)

    Eitelhuber, Tom; Davis, Geoff

    2014-01-01

    At Western Australia's Data Linkage Branch (DLB) the extraction of linked data has become increasingly complex over the past decade and classical methods of data delivery are unsuited to the larger extractions which have become the norm. The Custodian Administered Research Extract Server (CARES) is a fast, accurate and predictable approach to linked data extraction. The Data Linkage Branch (DLB) creates linkage keys within and between datasets. To comply with the separation principal, these keys are sent to applicable data collection agencies for extraction. Routing requests through multiple channels is inefficient and makes it hard to monitor work and predict delivery times. CARES was developed to address these shortcomings and involved ongoing consultation with the Custodians and staff of collections, plus challenges of hardware, programming, governance and security. The introduction of CARES has reduced the workload burden of linked data extractions, while improving the efficiency, stability and predictability of turnaround times. As the scope of a linkage system broadens, challenges in data delivery are inevitable. CARES overcomes multiple obstacles with no sacrifice to the integrity, confidentiality or security of data. CARES is a valuable component of linkage infrastructure that is operable at any scale and adaptable to many data environments.

  20. Recommendations to support nurses and improve the delivery of oncology and palliative care in India

    Directory of Open Access Journals (Sweden)

    Virginia T LeBaron

    2017-01-01

    Full Text Available Context: Nurses in India often practice in resource-constrained settings and care for cancer patients with high symptom burden yet receive little oncology or palliative care training. Aim: The aim of this study is to explore challenges encountered by nurses in India and offer recommendations to improve the delivery of oncology and palliative care. Methods: Qualitative ethnography. Setting: The study was conducted at a government cancer hospital in urban South India. Sample: Thirty-seven oncology/palliative care nurses and 22 others (physicians, social workers, pharmacists, patients/family members who interact closely with nurses were included in the study. Data Collection: Data were collected over 9 months (September 2011– June 2012. Key data sources included over 400 hours of participant observation and 54 audio-recorded semi-structured interviews. Analysis: Systematic qualitative analysis of field notes and interview transcripts identified key themes and patterns. Results: Key concerns of nurses included safety related to chemotherapy administration, workload and clerical responsibilities, patients who died on the wards, monitoring family attendants, and lack of supplies. Many participants verbalized distress that they received no formal oncology training. Conclusions: Recommendations to support nurses in India include: prioritize safety, optimize role of the nurse and explore innovative models of care delivery, empower staff nurses, strengthen nurse leadership, offer relevant educational programs, enhance teamwork, improve cancer pain management, and engage in research and quality improvement projects. Strong institutional commitment and leadership are required to implement interventions to support nurses. Successful interventions must account for existing cultural and professional norms and first address safety needs of nurses. Positive aspects from existing models of care delivery can be adapted and integrated into general nursing

  1. Advancing clinical development pathways for new CFTR modulators in cystic fibrosis.

    Science.gov (United States)

    Mayer-Hamblett, Nicole; Boyle, Michael; VanDevanter, Donald

    2016-05-01

    Cystic fibrosis (CF) is a life-shortening genetic disease affecting approximately 70,000 individuals worldwide. Until recently, drug development efforts have emphasised therapies treating downstream signs and symptoms resulting from the underlying CF biological defect: reduced function of the CF transmembrane conductance regulator (CFTR) protein. The current CF drug development landscape has expanded to include therapies that enhance CFTR function by either restoring wild-type CFTR protein expression or increasing (modulating) the function of mutant CFTR proteins in cells. To date, two systemic small-molecule CFTR modulators have been evaluated in pivotal clinical trials in individuals with CF and specific mutant CFTR genotypes that have led to regulatory review and/or approval. Advances in the discovery of CFTR modulators as a promising new class of therapies have been impressive, yet work remains to develop highly effective, disease-modifying modulators for individuals of all CF genotypes. The objectives of this review are to outline the challenges and opportunities in drug development created by systemic genotype-specific CFTR modulators, highlight the advantages of sweat chloride as an established biomarker of CFTR activity to streamline early-phase development and summarise options for later phase clinical trial designs that respond to the adoption of approved genotype-specific modulators into standard of care. An optimal development framework will be needed to move the most promising therapies efficiently through the drug development pipeline and ultimately deliver efficacious and safe therapies to all individuals with CF. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  2. Cholesterol modulates CFTR confinement in the plasma membrane of primary epithelial cells.

    Science.gov (United States)

    Abu-Arish, Asmahan; Pandzic, Elvis; Goepp, Julie; Matthes, Elizabeth; Hanrahan, John W; Wiseman, Paul W

    2015-07-07

    The cystic fibrosis transmembrane conductance regulator (CFTR) is a plasma-membrane anion channel that, when mutated, causes the disease cystic fibrosis. Although CFTR has been detected in a detergent-resistant membrane fraction prepared from airway epithelial cells, suggesting that it may partition into cholesterol-rich membrane microdomains (lipid rafts), its compartmentalization has not been demonstrated in intact cells and the influence of microdomains on CFTR lateral mobility is unknown. We used live-cell imaging, spatial image correlation spectroscopy, and k-space image correlation spectroscopy to examine the aggregation state of CFTR and its dynamics both within and outside microdomains in the plasma membrane of primary human bronchial epithelial cells. These studies were also performed during treatments that augment or deplete membrane cholesterol. We found two populations of CFTR molecules that were distinguishable based on their dynamics at the cell surface. One population showed confinement and had slow dynamics that were highly cholesterol dependent. The other, more abundant population was less confined and diffused more rapidly. Treatments that deplete the membrane of cholesterol caused the confined fraction and average number of CFTR molecules per cluster to decrease. Elevating cholesterol had the opposite effect, increasing channel aggregation and the fraction of channels displaying confinement, consistent with CFTR recruitment into cholesterol-rich microdomains with dimensions below the optical resolution limit. Viral infection caused the nanoscale microdomains to fuse into large platforms and reduced CFTR mobility. To our knowledge, these results provide the first biophysical evidence for multiple CFTR populations and have implications for regulation of their surface expression and channel function. Copyright © 2015 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  3. Evidence that CFTR is expressed in rat tracheal smooth muscle cells and contributes to bronchodilation

    Directory of Open Access Journals (Sweden)

    Mettey Yvette

    2006-08-01

    Full Text Available Abstract Background The airway functions are profoundly affected in many diseases including asthma, chronic obstructive pulmonary disease (COPD and cystic fibrosis (CF. CF the most common lethal autosomal recessive genetic disease is caused by mutations of the CFTR gene, which normally encodes a multifunctional and integral membrane protein, the CF transmembrane conductance regulator (CFTR expressed in airway epithelial cells. Methods To demonstrate that CFTR is also expressed in tracheal smooth muscle cells (TSMC, we used iodide efflux assay to analyse the chloride transports in organ culture of rat TSMC, immunofluorescence study to localize CFTR proteins and isometric contraction measurement on isolated tracheal rings to observe the implication of CFTR in the bronchodilation. Results We characterized three different pathways stimulated by the cAMP agonist forskolin and the isoflavone agent genistein, by the calcium ionophore A23187 and by hypo-osmotic challenge. The pharmacology of the cAMP-dependent iodide efflux was investigated in detail. We demonstrated in rat TSMC that it is remarkably similar to that of the epithelial CFTR, both for activation (using three benzo [c]quinolizinium derivatives and for inhibition (glibenclamide, DPC and CFTRinh-172. Using rat tracheal rings, we observed that the activation of CFTR by benzoquinolizinium derivatives in TSMC leads to CFTRinh-172-sensitive bronchodilation after constriction with carbachol. An immunolocalisation study confirmed expression of CFTR in tracheal myocytes. Conclusion Altogether, these observations revealed that CFTR in the airways of rat is expressed not only in the epithelial cells but also in tracheal smooth muscle cells leading to the hypothesis that this ionic channel could contribute to bronchodilation.

  4. Essential medicines in Tanzania: does the new delivery system improve supply and accountability?

    Science.gov (United States)

    Mikkelsen-Lopez, Inez; Cowley, Peter; Kasale, Harun; Mbuya, Conrad; Reid, Graham; de Savigny, Don

    2014-02-01

    Objective : Assess whether reform in the Tanzanian medicines delivery system from a central 'push' kit system to a decentralized 'pull' Integrated Logistics System (ILS) has improved medicines accountability. Methods : Rufiji District in Tanzania was used as a case study. Data on medicines ordered and patients seen were compiled from routine information at six public health facilities in 1999 under the kit system and in 2009 under the ILS. Three medicines were included for comparison: an antimalarial, anthelmintic and oral rehydration salts (ORS). Results : The quality of the 2009 data was hampered by incorrect quantification calculations for orders, especially for antimalarials. Between the periods 1999 and 2009, the percent of unaccounted antimalarials fell from 60 to 18%, while the percent of unaccounted anthelmintic medicines went from 82 to 71%. Accounting for ORS, on the other hand, did not improve as the unaccounted amounts increased from 64 to 81% during the same period. Conclusions : The ILS has not adequately addressed accountability concerns seen under the kit system due to a combination of governance and system-design challenges. These quantification weaknesses are likely to have contributed to the frequent periods of antimalarial stock-out experienced in Tanzania since 2009. We propose regular reconciliation between the health information system and the medicines delivery system, thereby improving visibility and guiding interventions to increase the availability of essential medicines.

  5. Learning to Learn: towards a Relational and Transformational Model of Learning for Improved Integrated Care Delivery

    Directory of Open Access Journals (Sweden)

    John Diamond

    2013-06-01

    Full Text Available Health and social care systems are implementing fundamental changes to organizational structures and work practices in an effort to achieve integrated care. While some integration initiatives have produced positive outcomes, many have not. We reframe the concept of integration as a learning process fueled by knowledge exchange across diverse professional and organizational communities. We thus focus on the cognitive and social dynamics of learning in complex adaptive systems, and on learning behaviours and conditions that foster collective learning and improved collaboration. We suggest that the capacity to learn how to learn shapes the extent to which diverse professional groups effectively exchange knowledge and self-organize for integrated care delivery.

  6. Endovascular aneurysm repair delivery redesign leads to quality improvement and cost reduction.

    Science.gov (United States)

    Warner, Courtney J; Horvath, Alexander J; Powell, Richard J; Columbo, Jesse A; Walsh, Teri R; Goodney, Philip P; Walsh, Daniel B; Stone, David H

    2015-08-01

    Endovascular aneurysm repair (EVAR) is now a mainstay of therapy for abdominal aortic aneurysm, although it remains associated with significant expense. We performed a comprehensive analysis of EVAR delivery at an academic medical center to identify targets for quality improvement and cost reduction in light of impending health care reform. All infrarenal EVARs performed from April 2011 to March 2012 were identified (N = 127). Procedures were included if they met standard commercial instructions for use guidelines, used a single manufacturer, and were billed to Medicare diagnosis-related group 238 (n = 49). By use of DMAIC (define, measure, analyze, improve, and control) quality improvement methodology (define, measure, analyze, improve, control), targets for EVAR quality improvement were identified and high-yield changes were implemented. Procedure technical costs were calculated before and after process redesign. Perioperative services and clinic visits were identified as targets for quality improvement efforts and cost reduction. Mean technical costs before the intervention were $31,672, with endograft implants accounting for 52%. Pricing redesign in collaboration with hospital purchasing reduced mean EVAR technical costs to $28,607, a 10% reduction in overall cost, with endograft implants now accounting for 46%. Perioperative implementation of instrument tray redesign reduced instrument use by 32% (184 vs 132 instruments), saving $50,000 annually. Unnecessary clinic visits were reduced by 39% (1.6 vs 1.1 clinic visits per patient) through implementation of a preclinic imaging protocol. There was no difference in mean length of stay after the intervention. Comprehensive EVAR delivery redesign leads to cost reduction and waste elimination while preserving quality. Future efforts to achieve more competitive and transparent device pricing will make EVAR more cost neutral and enhance its financial sustainability for health care systems. Copyright © 2015 Society for

  7. NM23 proteins: innocent bystanders or local energy boosters for CFTR?

    Science.gov (United States)

    Muimo, Richmond; Alothaid, Hani Mm; Mehta, Anil

    2018-03-01

    NM23 proteins NDPK-A and -B bind to the cystic fibrosis (CF) protein CFTR in different ways from kinases such as PKA, CK2 and AMPK or linkers to cell calcium such as calmodulin and annexins. NDPK-A (not -B) interacts with CFTR through reciprocal AMPK binding/control, whereas NDPK-B (not -A) binds directly to CFTR. NDPK-B can activate G proteins without ligand-receptor coupling, so perhaps NDPK-B's binding influences energy supply local to a nucleotide-binding site (NBD1) needed for CFTR to function. Curiously, CFTR (ABC-C7) is a member of the ATP-binding cassette (ABC) protein family that does not obey 'clan rules'; CFTR channels anions and is not a pump, regulates disparate processes, is itself regulated by multiple means and is so pleiotropic that it acts as a hub that orchestrates calcium signaling through its consorts such as calmodulin/annexins. Furthermore, its multiple partners make CFTR dance to different tunes in different cellular and subcellular locations as it recycles from the plasma membrane to endosomes. CFTR function in airway apical membranes is inhibited by smoking which has been dubbed 'acquired CF'. CFTR alone among family members possesses a trap for other proteins that it unfurls as a 'fish-net' and which bears consensus phosphorylation sites for many protein kinases, with PKA being the most canonical. Recently, the site of CFTR's commonest mutation has been proposed as a knock-in mutant that alters allosteric control of kinase CK2 by log orders of activity towards calmodulin and other substrates after CFTR fragmentation. This link from CK2 to calmodulin that binds the R region invokes molecular paths that control lumen formation, which is incomplete in the tracheas of some CF-affected babies. Thus, we are poised to understand the many roles of NDPK-A and -B in CFTR function and, especially lumen formation, which is defective in the gut and lungs of many CF babies.

  8. CFTR Genotype and Maximal Exercise Capacity in Cystic Fibrosis: A Cross-sectional Study.

    Science.gov (United States)

    Radtke, Thomas; Hebestreit, Helge; Gallati, Sabina; Schneiderman, Jane E; Braun, Julia; Stevens, Daniel; Hulzebos, Erik Hj; Takken, Tim; Boas, Steven R; Urquhart, Don S; Lands, Larry C; Tejero, Sergio; Sovtic, Aleksandar; Dwyer, Tiffany; Petrovic, Milos; Harris, Ryan A; Karila, Chantal; Savi, Daniela; Usemann, Jakob; Mei-Zahav, Meir; Hatziagorou, Elpis; Ratjen, Felix; Kriemler, Susi

    2018-02-01

    Cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in human skeletal muscle cells. Variations of CFTR dysfunction among patients with cystic fibrosis may be an important determinant of maximal exercise capacity in cystic fibrosis. Previous studies on the relationship between CFTR genotype and maximal exercise capacity are scarce and contradictory. This study was designed to explore factors influencing maximal exercise capacity, expressed as peak oxygen uptake (V.O2peak), with a specific focus on CFTR genotype in children and adults with cystic fibrosis. In an international, multicenter, cross-sectional study, we collected data on CFTR genotype and cardiopulmonary exercise tests in patients with cystic fibrosis who were ages 8 years and older. CFTR mutations were classified into functional classes I–V. The final analysis included 726 patients (45% females; age range, 8–61 yr; forced expiratory volume in 1 s, 16 to 123% predicted) from 17 cystic fibrosis centers in North America, Europe, Australia, and Asia, all of whom had both valid maximal cardiopulmonary exercise tests and complete CFTR genotype data. Overall, patients exhibited exercise intolerance (V.O2peak, 77.3 ± 19.1% predicted), but values were comparable among different CFTR classes. We did not detect an association between CFTR genotype functional classes I–III and either V.O2peak (percent predicted) (adjusted β = −0.95; 95% CI, −4.18 to 2.29; P = 0.57) or maximum work rate (Wattmax) (adjusted β = −1.38; 95% CI, −5.04 to 2.27; P = 0.46) compared with classes IV–V. Those with at least one copy of a F508del-CFTR mutation and one copy of a class V mutation had a significantly lower V.O2peak (β = −8.24%; 95% CI, −14.53 to −2.99; P = 0.003) and lower Wattmax (adjusted β = −7.59%; 95% CI, −14.21 to −0.95; P = 0.025) than those with two copies of a class II mutation. On the basis of linear regression analysis adjusted for

  9. Closing the delivery gaps in pediatric HIV care in Togo, West Africa: using the care delivery value chain framework to direct quality improvement.

    Science.gov (United States)

    Fiori, Kevin; Schechter, Jennifer; Dey, Monica; Braganza, Sandra; Rhatigan, Joseph; Houndenou, Spero; Gbeleou, Christophe; Palerbo, Emmanuel; Tchangani, Elfamozo; Lopez, Andrew; Bensen, Emily; Hirschhorn, Lisa R

    2016-03-01

    Providing quality care for all children living with HIV/AIDS remains a global challenge and requires the development of new healthcare delivery strategies. The care delivery value chain (CDVC) is a framework that maps activities required to provide effective and responsive care for a patient with a particular disease across the continuum of care. By mapping activities along a value chain, the CDVC enables managers to better allocate resources, improve communication, and coordinate activities. We report on the successful application of the CDVC as a strategy to optimize care delivery and inform quality improvement (QI) efforts with the overall aim of improving care for Pediatric HIV patients in Togo, West Africa. Over the course of 12 months, 13 distinct QI activities in Pediatric HIV/AIDS care delivery were monitored, and 11 of those activities met or exceeded established targets. Examples included: increase in infants receiving routine polymerase chain reaction testing at 2 months (39-95%), increase in HIV exposed children receiving confirmatory HIV testing at 18 months (67-100%), and increase in patients receiving initial CD4 testing within 3 months of HIV diagnosis (67-100%). The CDVC was an effective approach for evaluating existing systems and prioritizing gaps in delivery for QI over the full cycle of Pediatric HIV/AIDS care in three specific ways: (1) facilitating the first comprehensive mapping of Pediatric HIV/AIDS services, (2) identifying gaps in available services, and (3) catalyzing the creation of a responsive QI plan. The CDVC provided a framework to drive meaningful, strategic action to improve Pediatric HIV care in Togo.

  10. Improving immunization delivery using an electronic health record: the ImmProve project.

    Science.gov (United States)

    Bundy, David G; Persing, Nichole M; Solomon, Barry S; King, Tracy M; Murakami, Peter N; Thompson, Richard E; Engineer, Lilly D; Lehmann, Christoph U; Miller, Marlene R

    2013-01-01

    Though an essential pediatric preventive service, immunizations are challenging to deliver reliably. Our objective was to measure the impact on pediatric immunization rates of providing clinicians with electronic health record-derived immunization prompting. Operating in a large, urban, hospital-based pediatric primary care clinic, we evaluated 2 interventions to improve immunization delivery to children ages 2, 6, and 13 years: point-of-care, patient-specific electronic clinical decision support (CDS) when children overdue for immunizations presented for care, and provider-specific bulletins listing children overdue for immunizations. Overall, the proportion of children up to date for a composite of recommended immunizations at ages 2, 6, and 13 years was not different in the intervention (CDS active) and historical control (CDS not active) periods; historical immunization rates were high. The proportion of children receiving 2 doses of hepatitis A immunization before their second birthday was significantly improved during the intervention period. Human papillomavirus (HPV) immunization delivery was low during both control and intervention periods and was unchanged for 13-year-olds. For 14-year-olds, however, 4 of the 5 highest quarterly rates of complete HPV immunization occurred in the final year of the intervention. Provider-specific bulletins listing children overdue for immunizations increased the likelihood of identified children receiving catch-up hepatitis A immunizations (hazard ratio 1.32; 95% confidence interval 1.12-1.56); results for HPV and the composite of recommended immunizations were of a similar magnitude but not statistically significant. In our patient population, with high baseline uptake of recommended immunizations, electronic health record-derived immunization prompting had a limited effect on immunization delivery. Benefit was more clearly demonstrated for newer immunizations with lower baseline uptake. Copyright © 2013 Academic

  11. Point-of-care technology: integration for improved delivery of care.

    Science.gov (United States)

    Gregory, Debbie; Buckner, Martha

    2014-01-01

    The growing complexity of technology, equipment, and devices involved in patient care delivery can be staggering and overwhelming. Technology is intended to be a tool to help clinicians, but it can also be a frustrating hindrance if not thoughtfully planned and strategically aligned. Critical care nurses are key partners in the collaborations needed to improve safety and quality through health information technology (IT). Nurses must advocate for systems that are interoperable and adapted to the context of care experiences. The involvement and collaboration between clinicians, information technology specialists, biomedical engineers, and vendors has never been more relevant and applicable. Working together strategically with a shared vision can effectively provide a seamless clinical workflow, maximize technology investments, and ultimately improve patient care delivery and outcomes. Developing a strategic integrated clinical and IT roadmap is a critical component of today's health care environment. How can technology strategy be aligned from the executive suite to the bedside caregiver? What is the model for using clinical workflows to drive technology adoption? How can the voice of the critical care nurse strengthen this process? How can success be assured from the initial assessment and selection of technology to a sustainable support model? What is the vendor's role as a strategic partner and "co-caregiver"?

  12. Nanoparticle tumor localization, disruption of autophagosomal trafficking, and prolonged drug delivery improve survival in peritoneal mesothelioma.

    Science.gov (United States)

    Liu, Rong; Colby, Aaron H; Gilmore, Denis; Schulz, Morgan; Zeng, Jialiu; Padera, Robert F; Shirihai, Orian; Grinstaff, Mark W; Colson, Yolonda L

    2016-09-01

    The treatment outcomes for malignant peritoneal mesothelioma are poor and associated with high co-morbidities due to suboptimal drug delivery. Thus, there is an unmet need for new approaches that concentrate drug at the tumor for a prolonged period of time yielding enhanced antitumor efficacy and improved metrics of treatment success. A paclitaxel-loaded pH-responsive expansile nanoparticle (PTX-eNP) system is described that addresses two unique challenges to improve the outcomes for peritoneal mesothelioma. First, following intraperitoneal administration, eNPs rapidly and specifically localize to tumors. The rate of eNP uptake by tumors is an order of magnitude faster than the rate of uptake in non-malignant cells; and, subsequent accumulation in autophagosomes and disruption of autophagosomal trafficking leads to prolonged intracellular retention of eNPs. The net effect of these combined mechanisms manifests as rapid localization to intraperitoneal tumors within 4 h of injection and persistent intratumoral retention for >14 days. Second, the high tumor-specificity of PTX-eNPs leads to delivery of greater than 100 times higher concentrations of drug in tumors compared to PTX alone and this is maintained for at least seven days following administration. As a result, overall survival of animals with established mesothelioma more than doubled when animals were treated with multiple doses of PTX-eNPs compared to equivalent dosing with PTX or non-responsive PTX-loaded nanoparticles. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Liposomal buccal mucoadhesive film for improved delivery and permeation of water-soluble vitamins.

    Science.gov (United States)

    Abd El Azim, Heba; Nafee, Noha; Ramadan, Alyaa; Khalafallah, Nawal

    2015-07-05

    This study aims at improving the buccal delivery of vitamin B6 (VB6) as a model highly water-soluble, low permeable vitamin. Two main strategies were combined; first VB6 was entrapped in liposomes, which were then formulated as mucoadhesive film. Both plain and VB6-loaded liposomes (LPs) containing Lipoid S100 and propylene glycol (∼ 200 nm) were then incorporated into mucoadhesive film composed of SCMC and HPMC. Results showed prolonged release of VB6 (72.65%, T50% diss 105 min) after 6h from LP-film compared to control film containing free VB6 (96.37%, T50% diss 30 min). Mucoadhesion was assessed both ex vivo on chicken pouch and in vivo in human. Mucoadhesive force of 0.2N and residence time of 4.4h were recorded. Ex vivo permeation of VB6, across chicken pouch mucosa indicated increased permeation from LP-systems compared to corresponding controls. Interestingly, incorporation of the vesicles in mucoadhesive film reduced the flux by 36.89% relative to LP-dispersion. Meanwhile, both films provided faster initial permeation than the liquid forms. Correlating the cumulative percent permeated ex vivo with the cumulative percent released in vitro indicated that LPs retarded VB6 release but improved permeation. These promising results represent a step forward in the field of buccal delivery of water-soluble vitamins. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. A survey of detergents for the purification of stable, active human cystic fibrosis transmembrane conductance regulator (CFTR).

    Science.gov (United States)

    Hildebrandt, Ellen; Zhang, Qinghai; Cant, Natasha; Ding, Haitao; Dai, Qun; Peng, Lingling; Fu, Yu; DeLucas, Lawrence J; Ford, Robert; Kappes, John C; Urbatsch, Ina L

    2014-11-01

    Structural knowledge of the cystic fibrosis transmembrane conductance regulator (CFTR) requires developing methods to purify and stabilize this aggregation-prone membrane protein above 1mg/ml. Starting with green fluorescent protein- and epitope-tagged human CFTR produced in mammalian cells known to properly fold and process CFTR, we devised a rapid tandem affinity purification scheme to minimize CFTR exposure to detergent in order to preserve its ATPase function. We compared a panel of detergents, including widely used detergents (maltosides, neopentyl glycols (MNG), C12E8, lysolipids, Chaps) and innovative detergents (branched alkylmaltosides, facial amphiphiles) for CFTR purification, function, monodispersity and stability. ATPase activity after reconstitution into proteoliposomes was 2-3 times higher when CFTR was purified using facial amphiphiles. ATPase activity was also demonstrated in purified CFTR samples without detergent removal using a novel lipid supplementation assay. By electron microscopy, negatively stained CFTR samples were monodisperse at low concentration, and size exclusion chromatography showed a predominance of monomer even after CFTR concentration above 1mg/ml. Rates of CFTR aggregation quantified in an electrophoretic mobility shift assay showed that detergents which best preserved reconstituted ATPase activity also supported the greatest stability, with CFTR monomer half-lives of 6-9days in MNG or Chaps, and 12-17days in facial amphiphile. Cryoelectron microscopy of concentrated CFTR in MNG or facial amphiphile confirmed mostly monomeric protein, producing low resolution reconstructions in conformity with similar proteins. These protocols can be used to generate samples of pure, functional, stable CFTR at concentrations amenable to biophysical characterization. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Process improvement program evolves into compliance program at an integrated delivery system.

    Science.gov (United States)

    Tyk, R C; Hylton, P G

    1998-09-01

    An integrated delivery system discovered questionable practices when it undertook a process-improvement initiative for its revenue-to-cash cycle. These discoveries served as a wake-up call to the organization that it needed to develop a comprehensive corporate compliance program. The organization engaged legal counsel to help it establish such a program. A corporate compliance officer was hired, and a compliance committee was set up. They worked with counsel to develop the structure and substance of the program and establish a corporate code of conduct that became a part of the organization's policies and procedures. Teams were formed in various areas of the organization to review compliance-related activities and suggest improvements. Clinical and nonclinical staff attended mandatory educational sessions about the program. By approaching compliance systematically, the organization has put itself in an excellent position to avoid fraudulent and abusive activities- and the government scrutiny they invite.

  16. Using information technology for an improved pharmaceutical care delivery in developing countries. Study case: Benin.

    Science.gov (United States)

    Edoh, Thierry Oscar; Teege, Gunnar

    2011-10-01

    One of the problems in health care in developing countries is the bad accessibility of medicine in pharmacies for patients. Since this is mainly due to a lack of organization and information, it should be possible to improve the situation by introducing information and communication technology. However, for several reasons, standard solutions are not applicable here. In this paper, we describe a case study in Benin, a West African developing country. We identify the problem and the existing obstacles for applying standard ECommerce solutions. We develop an adapted system approach and describe a practical test which has shown that the approach has the potential of actually improving the pharmaceutical care delivery. Finally, we consider the security aspects of the system and propose an organizational solution for some specific security problems.

  17. Side chain and backbone contributions of Phe508 to CFTR folding

    Energy Technology Data Exchange (ETDEWEB)

    Thibodeau, Patrick H.; Brautigam, Chad A.; Machius, Mischa; Thomas, Philip J. (U. of Texas-SMED)

    2010-12-07

    Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), an integral membrane protein, cause cystic fibrosis (CF). The most common CF-causing mutant, deletion of Phe508, fails to properly fold. To elucidate the role Phe508 plays in the folding of CFTR, missense mutations at this position were generated. Only one missense mutation had a pronounced effect on the stability and folding of the isolated domain in vitro. In contrast, many substitutions, including those of charged and bulky residues, disrupted folding of full-length CFTR in cells. Structures of two mutant nucleotide-binding domains (NBDs) reveal only local alterations of the surface near position 508. These results suggest that the peptide backbone plays a role in the proper folding of the domain, whereas the side chain plays a role in defining a surface of NBD1 that potentially interacts with other domains during the maturation of intact CFTR.

  18. Purification and crystallization of the cystic fibrosis transmembrane conductance regulator (CFTR).

    Science.gov (United States)

    Rosenberg, Mark F; Kamis, Alhaji Bukar; Aleksandrov, Luba A; Ford, Robert C; Riordan, John R

    2004-09-10

    The cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein that is mutated in patients suffering from cystic fibrosis. Here we report the purification and first crystallization of wild-type human CFTR. Functional characterization of the material showed it to be highly active. Electron crystallography of negatively stained two-dimensional crystals of CFTR has revealed the overall architecture of this channel for two different conformational states. These show a strong structural homology to two conformational states of another eukaryotic ATP-binding cassette transporter, P-glycoprotein. In contrast to P-glycoprotein, however, both conformational states can be observed in the presence of a nucleotide, which may be related to the role of CFTR as an ion channel rather than a transporter. The hypothesis that the two conformations could represent the "open" and "closed" states of the channel is considered.

  19. Postoperative Irradiation of Gynecologic Malignancies: Improving Treatment Delivery Using Aperture-Based Intensity-Modulated Radiotherapy

    International Nuclear Information System (INIS)

    Nadeau, Sylvain; Bouchard, Myriam; Germain, Isabelle; Raymond, Paul-Emile; Beaulieu, Frederic; Beaulieu, Luc; Roy, Rene; Gingras, Luc

    2007-01-01

    Purpose: To evaluate dosimetric and treatment delivery advantages of aperture-based intensity-modulated radiotherapy (AB-IMRT) for the treatment of patients receiving whole pelvic radiotherapy for gynecologic malignancies. Methods and Materials: Nineteen patients undergoing pelvic radiotherapy after resection of endometrial cancers were selected. A 45-Gy dose was prescribed to the target volume delineated on a planning CT scan. An in-house inverse planning system, Ballista, was used to develop a treatment plan using aperture-based multileaf collimator segments. This approach was compared with conventional four-field, enlarged four-field, and static beamlet-based IMRT (BB-IMRT) techniques in terms of target coverage, dose-volume histogram statistics for surrounding normal tissues, and numbers of segments and monitor units (MU). Results: Three quarters (76.4%) of the planning target volume received the prescription dose with conventional four-field plans. With adequate target coverage, the Ballista plans significantly reduced the volume of bowel and bladder irradiated at the prescribed dose (p < 0.001), whereas the two approaches provided equivalent results for the rectum (p 0.5). On the other hand, AB-IMRT and BB-IMRT plans showed only small differences in dose-volume histogram statistics of unknown clinical impact, whereas Ballista plan delivery required on average 73% and 59% fewer segments and MU, respectively. Conclusion: With respect to conventional techniques, AB-IMRT for the treatment of gynecologic malignancies provides dosimetric advantages similar to those with BB-IMRT but with clear treatment delivery improvements

  20. Genomic sequencing in cystic fibrosis newborn screening: what works best, two-tier predefined CFTR mutation panels or second-tier CFTR panel followed by third-tier sequencing?

    Science.gov (United States)

    Currier, Robert J; Sciortino, Stan; Liu, Ruiling; Bishop, Tracey; Alikhani Koupaei, Rasoul; Feuchtbaum, Lisa

    2017-10-01

    PurposeThe purpose of this study was to model the performance of several known two-tier, predefined mutation panels and three-tier algorithms for cystic fibrosis (CF) screening utilizing the ethnically diverse California population.MethodsThe cystic fibrosis transmembrane conductance regulator (CFTR) mutations identified among the 317 CF cases in California screened between 12 August 2008 and 18 December 2012 were used to compare the expected CF detection rates for several two- and three-tier screening approaches, including the current California approach, which consists of a population-specific 40-mutation panel followed by third-tier sequencing when indicated.ResultsThe data show that the strategy of using third-tier sequencing improves CF detection following an initial elevated immunoreactive trypsinogen and detection of only one mutation on a second-tier panel.ConclusionIn a diverse population, the use of a second-tier panel followed by third-tier CFTR gene sequencing provides a better detection rate for CF, compared with the use of a second-tier approach alone, and is an effective way to minimize the referrals of CF carriers for sweat testing. Restricting screening to a second-tier testing to predefined mutation panels, even broad ones, results in some missed CF cases and demonstrates the limited utility of this approach in states that have diverse multiethnic populations.

  1. Transporter-Guided Delivery of Nanoparticles to Improve Drug Permeation across Cellular Barriers and Drug Exposure to Selective Cell Types

    Directory of Open Access Journals (Sweden)

    Longfa Kou

    2018-01-01

    Full Text Available Targeted nano-drug delivery systems conjugated with specific ligands to target selective cell-surface receptors or transporters could enhance the efficacy of drug delivery and therapy. Transporters are expressed differentially on the cell-surface of different cell types, and also specific transporters are expressed at higher than normal levels in selective cell types under pathological conditions. They also play a key role in intestinal absorption, delivery via non-oral routes (e.g., pulmonary route and nasal route, and transfer across biological barriers (e.g., blood–brain barrier and blood–retinal barrier. As such, the cell-surface transporters represent ideal targets for nano-drug delivery systems to facilitate drug delivery to selective cell types under normal or pathological conditions and also to avoid off-target adverse side effects of the drugs. There is increasing evidence in recent years supporting the utility of cell-surface transporters in the field of nano-drug delivery to increase oral bioavailability, to improve transfer across the blood–brain barrier, and to enhance delivery of therapeutics in a cell-type selective manner in disease states. Here we provide a comprehensive review of recent advancements in this interesting and important area. We also highlight certain key aspects that need to be taken into account for optimal development of transporter-assisted nano-drug delivery systems.

  2. Computational design of a PDZ domain peptide inhibitor that rescues CFTR activity.

    Directory of Open Access Journals (Sweden)

    Kyle E Roberts

    Full Text Available The cystic fibrosis transmembrane conductance regulator (CFTR is an epithelial chloride channel mutated in patients with cystic fibrosis (CF. The most prevalent CFTR mutation, ΔF508, blocks folding in the endoplasmic reticulum. Recent work has shown that some ΔF508-CFTR channel activity can be recovered by pharmaceutical modulators ("potentiators" and "correctors", but ΔF508-CFTR can still be rapidly degraded via a lysosomal pathway involving the CFTR-associated ligand (CAL, which binds CFTR via a PDZ interaction domain. We present a study that goes from theory, to new structure-based computational design algorithms, to computational predictions, to biochemical testing and ultimately to epithelial-cell validation of novel, effective CAL PDZ inhibitors (called "stabilizers" that rescue ΔF508-CFTR activity. To design the "stabilizers", we extended our structural ensemble-based computational protein redesign algorithm K* to encompass protein-protein and protein-peptide interactions. The computational predictions achieved high accuracy: all of the top-predicted peptide inhibitors bound well to CAL. Furthermore, when compared to state-of-the-art CAL inhibitors, our design methodology achieved higher affinity and increased binding efficiency. The designed inhibitor with the highest affinity for CAL (kCAL01 binds six-fold more tightly than the previous best hexamer (iCAL35, and 170-fold more tightly than the CFTR C-terminus. We show that kCAL01 has physiological activity and can rescue chloride efflux in CF patient-derived airway epithelial cells. Since stabilizers address a different cellular CF defect from potentiators and correctors, our inhibitors provide an additional therapeutic pathway that can be used in conjunction with current methods.

  3. CFTR chloride channel as a molecular target of anthraquinone compounds in herbal laxatives

    Science.gov (United States)

    Yang, Hong; Xu, Li-na; He, Cheng-yan; Liu, Xin; Fang, Rou-yu; Ma, Tong-hui

    2011-01-01

    Aim: To clarify whether CFTR is a molecular target of intestinal fluid secretion caused by the anthraquinone compounds from laxative herbal plants. Methods: A cell-based fluorescent assay to measure I− influx through CFTR chloride channel. A short-circuit current assay to measure transcellular Cl− current across single layer FRT cells and freshly isolated colon mucosa. A closed loop experiment to measure colon fluid secretion in vivo. Results: Anthraquinone compounds rhein, aloe-emodin and 1,8-dihydroxyanthraquinone (DHAN) stimulated I− influx through CFTR chloride channel in a dose-dependent manner in the presence of physiological concentration of cAMP. In the short-circuit current assay, the three compound enhanced Cl− currents in epithelia formed by CFTR-expressing FRT cells with EC50 values of 73±1.4, 56±1.7, and 50±0.5μmol/L, respectively, and Rhein also enhanced Cl− current in freshly isolated rat colonic mucosa with a similar potency. These effects were completely reversed by the CFTR selective blocker CFTRinh-172. In in vivo closed loop experiments, rhein 2 mmol/L stimulated colonic fluid accumulation that was largely blocked by CFTRinh-172. The anthraquinone compounds did not elevate cAMP level in cultured FRT cells and rat colonic mucosa, suggesting a direct effect on CFTR activity. Conclusion: Natural anthraquinone compounds in vegetable laxative drugs are CFTR potentiators that stimulated colonic chloride and fluid secretion. Thus CFTR chloride channel is a molecular target of vegetable laxative drugs. PMID:21602836

  4. Design and optimization of self-nanoemulsifying drug delivery systems for improved bioavailability of cyclovirobuxine D

    Directory of Open Access Journals (Sweden)

    Ke ZC

    2016-06-01

    Full Text Available Zhongcheng Ke,1–3 Xuefeng Hou,4 Xiao-bin Jia31Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 2Huangshan University, Huangshan, Anhui, 3Third Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 4Anhui University of Chinese Medicine, Hefei, Anhui, People’s Republic of ChinaBackground: The main purpose of this research was to design a self-nanoemulsifying drug delivery system (SNEDDS for improving the bioavailability of cyclovirobuxine D as a poorly water-soluble drug.Materials and methods: Solubility trials, emulsifying studies, and pseudo-ternary phase diagrams were used to screen the SNEDDS formulations. The optimized drug-loaded SNEDDS was prepared at a mass ratio of 3:24:38:38 for cyclovirobuxine D, oleic acid, Solutol SH15, and propylene glycol, respectively. The optimized formulation was characterized in terms of physicochemical and pharmacokinetic parameters compared with marketed cyclovirobuxine D tablets.Results: The optimized cyclovirobuxine-D-loaded SNEDDS was spontaneously dispersed to form a nanoemulsion with a globule size of 64.80±3.58 nm, which exhibited significant improvement of drug solubility, rapid absorption rate, and enhanced area under the curve, together with increased permeation and decreased efflux. Fortunately, there was a nonsignificant cytotoxic effect toward Caco-2 cells. The relative bioavailability of SNEDDS was 200.22% in comparison with market tablets, in rabbits.Conclusion: SNEDDS could be a potential candidate for an oral dosage form of cyclovirobuxine D with improved bioavailability.Keywords: self-nanoemulsifying drug delivery, bioavailability, cyclovirobuxine D

  5. Spectrum of CFTR gene mutations in Ecuadorian cystic fibrosis patients: the second report of the p.H609R mutation.

    Science.gov (United States)

    Ortiz, Sofía C; Aguirre, Santiago J; Flores, Sofía; Maldonado, Claudio; Mejía, Juan; Salinas, Lilian

    2017-11-01

    High heterogeneity in the CFTR gene mutations disturbs the molecular diagnosis of cystic fibrosis (CF). In order to improve the diagnosis of CF in our country, the present study aims to define a panel of common CFTR gene mutations by sequencing 27 exons of the gene in Ecuadorian Cystic Fibrosis patients. Forty-eight Ecuadorian individuals with suspected/confirmed CF diagnosis were included. Twenty-seven exons of CFTR gene were sequenced to find sequence variations. Prevalence of pathogenic variations were determined and compared with other countries' data. We found 70 sequence variations. Eight of these are CF-causing mutations: p.F508del, p.G85E, p.G330E, p.A455E, p.G970S, W1098X, R1162X, and N1303K. Also this study is the second report of p.H609R in Ecuadorian population. Mutation prevalence differences between Ecuadorian population and other Latin America countries were found. The panel of mutations suggested as an initial screening for the Ecuadorian population with cystic fibrosis should contain the mutations: p.F508del, p.G85E, p.G330E, p.A455E, p.G970S, W1098X, R1162X, and N1303K. © 2017 NETLAB Laboratorios Especializados. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

  6. Improved oral bioavailability of glyburide by a self-nanoemulsifying drug delivery system.

    Science.gov (United States)

    Liu, Hongzhuo; Shang, Kuimao; Liu, Weina; Leng, Donglei; Li, Ran; Kong, Ying; Zhang, Tianhong

    2014-01-01

    The present study aimed at the development and characterisation of self-nanoemulsifying drug delivery system (SNEDDS) to improve the oral bioavailability of poorly soluble glyburide. The solubility of glyburide was determined in various oils, surfactants and co-surfactants which were grouped into two different combinations to construct ternary phase diagrams. The formulations were evaluated for emulsification time, droplet size, zeta-potential, electrical conductivity and stability of nanoemulsions. The optimised SNEDDS loading with 5 mg/g glyburide comprised 55% Cremophor® RH 40, 15% propanediol and 30% Miglyol® 812, which rapidly formed fine oil-in-water nanoemulsions with 46 ± 4 nm particle size. Compared with the commercial micronised tablets (Glynase®PresTab®), enhanced in vitro release profiles of SNEDDS were observed, resulting in the 1.5-fold increase of AUC following oral administration of SNEDDS in fasting beagle dogs. These results indicated that SNEDDS is a promising drug delivery system for increasing the oral bioavailability of glyburide.

  7. Microemulsion-loaded hydrogel formulation of butenafine hydrochloride for improved topical delivery.

    Science.gov (United States)

    Pillai, Anilkumar B; Nair, Jyothilaksmi V; Gupta, Nishant Kumar; Gupta, Swati

    2015-09-01

    Topical microemulsion systems for the antifungal drug, butenafine hydrochloride (BTF) were designed and developed to overcome the problems associated with the cutaneous delivery due to poor water solubility. The solubility of BTF in oils, surfactants and co-surfactants was evaluated to screen the components of the microemulsion. Isopropyl palmitate was used as the oil phase, aerosol OT as the surfactant and sorbitan monooleate as co-surfactant. The pseudoternary diagrams were constructed to identify the area of microemulsion existence and optimum systems were designed. The systems were assessed for drug-loading efficiency and characterized for pH, robustness to dilution, globule size, drug content and stability. Viscosity analysis, spreadability, drug content assay, ex vivo skin permeation study and antifungal activity assay were performed for the optimized microemulsion-loaded hydrogel. The optimized BTF microemulsion had a small and uniform globule size. The incorporation of microemulsion system into Carbopol 940 gel was found to be better as compared to sodium alginate or hydroxyl propyl methyl cellulose (HPMC K4 M) gel. The developed gel has shown better ex vivo skin permeation and antifungal activity when compared to marketed BTF cream. Thus, the results provide a basis for the successful delivery of BTF from microemulsion-loaded hydrogel formulation, which resulted in improved penetration of drug and antifungal activity in comparison with commercial formulation of BTF.

  8. Novel flurbiprofen derivatives with improved brain delivery: synthesis, in vitro and in vivo evaluations.

    Science.gov (United States)

    Zheng, Dan; Shuai, Xiao; Li, Yanping; Zhou, Peng; Gong, Tao; Sun, Xun; Zhang, Zhirong

    2016-09-01

    Tarenflurbil (R-flurbiprofen) was acknowledged as a promising candidate in Alzheimer's disease (AD) therapy. However, the Phase III study of tarenflurbil was extremely restricted by its poor delivery efficiency to the brain. To tackle this problem, the novel carriers for tarenflurbil, racemic flurbiprofen (FLU) derivatives (FLU-D1 and FLU-D2) modified by N,N-dimethylethanolamine-related structures were synthesized and characterized. These derivatives showed good safety level in vitro and they possessed much higher cellular uptake efficiency in brain endothelial cells than FLU did. More importantly, the uptake experiments suggested that they were internalized via active transport mechanisms. Biodistribution studies in rats also illustrated a remarkably enhanced accumulation of these derivatives in the brain. FLU-D2, the ester linkage form of these derivatives, achieved a higher brain-targeting efficiency. Its C max and AUC 0- t were enhanced by 12.09-fold and 4.61-fold, respectively compared with those of FLU. Additionally, it could be hydrolyzed by esterase in the brain to release the parent FLU, which might facilitate its therapeutic effect. These in vitro and in vivo results highlighted the improvement of the brain-targeted delivery of FLU by making use of N,N-dimethylethanolamine ligand, with which an active transport mechanism was involved.

  9. New delivery systems for amphotericin B applied to the improvement of leishmaniasis treatment

    Directory of Open Access Journals (Sweden)

    Miguel Angel Chávez-Fumagalli

    2015-06-01

    Full Text Available Leishmaniasis is one of the six major tropical diseases targeted by the World Health Organization. It is a life-threatening disease of medical, social and economic importance in endemic areas. No vaccine is yet available for human use, and chemotherapy presents several problems. Pentavalent antimonials have been the drugs of choice to treat the disease for more than six decades; however, they exhibit high toxicity and are not indicated for children, for pregnant or breastfeeding women or for chronically ill patients. Amphotericin B (AmpB is a second-line drug, and although it has been increasingly used to treat visceral leishmaniasis (VL, its clinical use has been hampered due to its high toxicity. This review focuses on the development and in vivo usage of new delivery systems for AmpB that aim to decrease its toxicity without altering its therapeutic efficacy. These new formulations, when adjusted with regard to their production costs, may be considered new drug delivery systems that promise to improve the treatment of leishmaniasis, by reducing the side effects and the number of doses while permitting a satisfactory cost-benefit ratio.

  10. Biocompatible Nanoemulsions for Improved Aceclofenac Skin Delivery: Formulation Approach Using Combined Mixture-Process Experimental Design.

    Science.gov (United States)

    Isailović, Tanja; Ðorđević, Sanela; Marković, Bojan; Ranđelović, Danijela; Cekić, Nebojša; Lukić, Milica; Pantelić, Ivana; Daniels, Rolf; Savić, Snežana

    2016-01-01

    We aimed to develop lecithin-based nanoemulsions intended for effective aceclofenac (ACF) skin delivery utilizing sucrose esters [sucrose palmitate (SP) and sucrose stearate (SS)] as additional stabilizers and penetration enhancers. To find the suitable surfactant mixtures and levels of process variables (homogenization pressure and number of cycles - high pressure homogenization manufacturing method) that result in drug-loaded nanoemulsions with minimal droplet size and narrow size distribution, a combined mixture-process experimental design was employed. Based on optimization data, selected nanoemulsions were evaluated regarding morphology, surface charge, drug-excipient interactions, physical stability, and in vivo skin performances (skin penetration and irritation potential). The predicted physicochemical properties and storage stability were proved satisfying for ACF-loaded nanoemulsions containing 2% of SP in the blend with 0%-1% of SS and 1%-2% of egg lecithin (produced at 50°C/20 cycles/800 bar). Additionally, the in vivo tape stripping demonstrated superior ACF skin absorption from these nanoemulsions, particularly from those containing 2% of SP, 0.5% of SS, and 1.5% of egg lecithin, when comparing with the sample costabilized by conventional surfactant - polysorbate 80. In summary, the combined mixture-process experimental design was shown as a feasible tool for formulation development of multisurfactant-based nanosized delivery systems with potentially improved overall product performances.

  11. A host defense mechanism involving CFTR-mediated bicarbonate secretion in bacterial prostatitis.

    Directory of Open Access Journals (Sweden)

    Chen Xie

    Full Text Available BACKGROUND: Prostatitis is associated with a characteristic increase in prostatic fluid pH; however, the underlying mechanism and its physiological significance have not been elucidated. METHODOLOGY/PRINCIPAL FINDINGS: In this study a primary culture of rat prostatic epithelial cells and a rat prostatitis model were used. Here we reported the involvement of CFTR, a cAMP-activated anion channel conducting both Cl(- and HCO(3(-, in mediating prostate HCO(3(- secretion and its possible role in bacterial killing. Upon Escherichia coli (E. coli-LPS challenge, the expression of CFTR and carbonic anhydrase II (CA II, along with several pro-inflammatory cytokines was up-regulated in the primary culture of rat prostate epithelial cells. Inhibiting CFTR function in vitro or in vivo resulted in reduced bacterial killing by prostate epithelial cells or the prostate. High HCO(3(- content (>50 mM, rather than alkaline pH, was found to be responsible for bacterial killing. The direct action of HCO(3(- on bacterial killing was confirmed by its ability to increase cAMP production and suppress bacterial initiation factors in E. coli. The relevance of the CFTR-mediated HCO(3(- secretion in humans was demonstrated by the upregulated expression of CFTR and CAII in human prostatitis tissues. CONCLUSIONS/SIGNIFICANCE: The CFTR and its mediated HCO(3(- secretion may be up-regulated in prostatitis as a host defense mechanism.

  12. High Level Waste Feed Delivery AZ-101 Batch Transfer to the Private Contractor Transfer and Mixing Process Improvements

    International Nuclear Information System (INIS)

    DUNCAN, G.P.

    2000-01-01

    The primary purpose of this business case is to provide Operations and Maintenance with a detailed transfer process review for the first High Level Waste (HLW) feed delivery to the Privatization Contractor (PC), AZ-101 batch transfer to PC. The Team was chartered to identify improvements that could be implemented in the field. A significant penalty can be invoked for not providing the quality, quantity, or timely delivery of HLW feed to the PC

  13. Aligning health information technologies with effective service delivery models to improve chronic disease care.

    Science.gov (United States)

    Bauer, Amy M; Thielke, Stephen M; Katon, Wayne; Unützer, Jürgen; Areán, Patricia

    2014-09-01

    Healthcare reforms in the United States, including the Affordable Care and HITECH Acts, and the NCQA criteria for the Patient Centered Medical Home have promoted health information technology (HIT) and the integration of general medical and mental health services. These developments, which aim to improve chronic disease care, have largely occurred in parallel, with little attention to the need for coordination. In this article, the fundamental connections between HIT and improvements in chronic disease management are explored. We use the evidence-based collaborative care model as an example, with attention to health literacy improvement for supporting patient engagement in care. A review of the literature was conducted to identify how HIT and collaborative care, an evidence-based model of chronic disease care, support each other. Five key principles of effective collaborative care are outlined: care is patient-centered, evidence-based, measurement-based, population-based, and accountable. The potential role of HIT in implementing each principle is discussed. Key features of the mobile health paradigm are described, including how they can extend evidence-based treatment beyond traditional clinical settings. HIT, and particularly mobile health, can enhance collaborative care interventions, and thus improve the health of individuals and populations when deployed in integrated delivery systems. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. Nanoparticle delivery of chemosensitizers improve chemotherapy efficacy without incurring additional toxicity

    Science.gov (United States)

    Caster, Joseph M.; Sethi, Manish; Kowalczyk, Sonya; Wang, Edina; Tian, Xi; Nabeel Hyder, Sayed; Wagner, Kyle T.; Zhang, Ying-Ao; Kapadia, Chintan; Man Au, Kin; Wang, Andrew Z.

    2015-01-01

    Chemosensitizers can improve the therapeutic index of chemotherapy and overcome treatment resistance. Successful translation of chemosensitizers depends on the development of strategies that can preferentially deliver chemosensitizers to tumors while avoiding normal tissue. We hypothesized that nanoparticle (NP) formulation of chemosensitizers can improve their delivery to tumors which can in turn improve their therapeutic index. To demonstrate the proof of principle of this approach, we engineered NP formulations of two chemosensitizers, the PI3-kindase inhibitor wortmanin (Wtmn) and the PARP inhibitor olaparib. NP Wtmn and NP olaparib were evaluated as chemosensitizers using lung cancer cells and breast cancer cells respectively. We found Wtmn to be an efficient chemosensitizer in all tested lung-cancer cell lines reducing tumor cell growth between 20 and 60% compared to drug alone. NP formulation did not decrease its efficacy in vitro. Olaparib showed less consistent chemosensitization as a free drug or in NP formulation. NP Wtmn was further evaluated as a chemosensitizer using mouse models of lung cancer. We found that NP Wtmn is an effective chemosensitizer and more effective than free Wtmn showing a 32% reduction in tumor growth compared to free Wtmn when given with etoposide. Importantly, NP Wtmn was able to sensitize the multi-drug resistant H69AR cells to etoposide. Additionally, the combination of NP Wtmn and etoposide chemotherapy did not significantly increase toxicity. The present study demonstrates the proof of principle of using NP formulation of chemosensitizing drugs to improve the therapeutic index of chemotherapy.

  15. Severe postpartum haemorrhage after vaginal delivery: a statistical process control chart to report seven years of continuous quality improvement.

    Science.gov (United States)

    Dupont, Corinne; Occelli, Pauline; Deneux-Tharaux, Catherine; Touzet, Sandrine; Duclos, Antoine; Bouvier-Colle, Marie-Hélène; Rudigoz, René-Charles; Huissoud, Cyril

    2014-07-01

    Severe postpartum haemorrhage after vaginal delivery: a statistical process control chart to report seven years of continuous quality improvement To use statistical process control charts to describe trends in the prevalence of severe postpartum haemorrhage after vaginal delivery. This assessment was performed 7 years after we initiated a continuous quality improvement programme that began with regular criteria-based audits Observational descriptive study, in a French maternity unit in the Rhône-Alpes region. Quarterly clinical audit meetings to analyse all cases of severe postpartum haemorrhage after vaginal delivery and provide feedback on quality of care with statistical process control tools. The primary outcomes were the prevalence of severe PPH after vaginal delivery and its quarterly monitoring with a control chart. The secondary outcomes included the global quality of care for women with severe postpartum haemorrhage, including the performance rate of each recommended procedure. Differences in these variables between 2005 and 2012 were tested. From 2005 to 2012, the prevalence of severe postpartum haemorrhage declined significantly, from 1.2% to 0.6% of vaginal deliveries (pcontrol limits, that is, been out of statistical control. The proportion of cases that were managed consistently with the guidelines increased for all of their main components. Implementation of continuous quality improvement efforts began seven years ago and used, among other tools, statistical process control charts. During this period, the prevalence of severe postpartum haemorrhage after vaginal delivery has been reduced by 50%. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  16. Improving consistency and quality of service delivery: implications for the addiction treatment field.

    Science.gov (United States)

    Knott, Anne Marie; Corredoira, Rafael; Kimberly, John

    2008-09-01

    Addiction treatment providers face serious problems in delivering consistent, high-quality services over time. Among those providers with multiple treatment sites, there is also intersite variability. This is a serious problem in the addiction field, likely to be made worse as new technologies are introduced and/or as there is industry consolidation (Corredoira, R., Kimberly, J. (2006) Industry evolution through consolidation: Implications for addiction treatment. Journal of Substance Abuse Treatment 31, 255-265.). Although serious, these problems in managing and monitoring to assure consistent service quality have been faced by many other industries. Here, we review evidence from research in other industries regarding three different forms of management (vertical integration, franchising, and licensing) across a chain of individual service providers. We show how each management form affects the level, consistency, and improvement of service delivery over time. In addition, we discuss how such performance advantages affect customer demand as well as regulatory endorsement of the consolidated firm and its approach.

  17. Human gene therapy: novel approaches to improve the current gene delivery systems.

    Science.gov (United States)

    Cucchiarini, Magali

    2016-06-01

    Even though gene therapy made its way through the clinics to treat a number of human pathologies since the early years of experimental research and despite the recent approval of the first gene-based product (Glybera) in Europe, the safe and effective use of gene transfer vectors remains a challenge in human gene therapy due to the existence of barriers in the host organism. While work is under active investigation to improve the gene transfer systems themselves, the use of controlled release approaches may offer alternative, convenient tools of vector delivery to achieve a performant gene transfer in vivo while overcoming the various physiological barriers that preclude its wide use in patients. This article provides an overview of the most significant contributions showing how the principles of controlled release strategies may be adapted for human gene therapy.

  18. Improving the delivery of care and reducing healthcare costs with the digitization of information.

    Science.gov (United States)

    Noffsinger, R; Chin, S

    2000-01-01

    In the coming years, the digitization of information and the Internet will be extremely powerful in reducing healthcare costs while assisting providers in the delivery of care. One example of healthcare inefficiency that can be managed through information digitization is the process of prescription writing. Due to the handwritten and verbal communication surrounding prescription writing, as well as the multiple tiers of authorizations, the prescription drug process causes extensive financial waste as well as medical errors, lost time, and even fatal accidents. Electronic prescription management systems are being designed to address these inefficiencies. By utilizing new electronic prescription systems, physicians not only prescribe more accurately, but also improve formulary compliance thereby reducing pharmacy utilization. These systems expand patient care by presenting proactive alternatives at the point of prescription while reducing costs and providing additional benefits for consumers and healthcare providers.

  19. Improvement in transdermal drug delivery performance by graphite oxide/temperature-responsive hydrogel composites with micro heater

    International Nuclear Information System (INIS)

    Yun, Jumi; Lee, Dae Hoon; Im, Ji Sun; Kim, Hyung-Il

    2012-01-01

    Transdermal drug delivery system (TDDS) was prepared with temperature-responsive hydrogel. The graphite was oxidized and incorporated into hydrogel matrix to improve the thermal response of hydrogel. The micro heater was fabricated to control the temperature precisely by adopting a joule heating method. The drug in hydrogel was delivered through a hairless mouse skin by controlling temperature. The efficiency of drug delivery was improved obviously by incorporation of graphite oxide due to the excellent thermal conductivity and the increased interfacial affinity between graphite oxide and hydrogel matrix. The fabricated micro heater was effective in controlling the temperature over lower critical solution temperature of hydrogel precisely with a small voltage less than 1 V. The cell viability test on graphite oxide composite hydrogel showed enough safety for using as a transdermal drug delivery patch. The performance of TDDS could be improved noticeably based on temperature-responsive hydrogel, thermally conductive graphite oxide, and efficient micro heater. - Graphical abstract: The high-performance transdermal drug delivery system could be prepared by combining temperature-responsive hydrogel, thermally conductive graphite oxide with improved interfacial affinity, and efficient micro heater fabricated by a joule heating method. Highlights: ► High performance of transdermal drug delivery system with an easy control of voltage. ► Improved thermal response of hydrogel by graphite oxide incorporation. ► Efficient micro heater fabricated by a joule heating method.

  20. Improvement in transdermal drug delivery performance by graphite oxide/temperature-responsive hydrogel composites with micro heater

    Energy Technology Data Exchange (ETDEWEB)

    Yun, Jumi [Department of Fine Chemical Engineering and Applied Chemistry, BK21-E2M, Chungnam National University, Daejeon 305-764 (Korea, Republic of); Lee, Dae Hoon [Environment Research Division, Korea Institute of Machinery and Materials, 171 Jang-dong, Yusong-gu, Daejeon 305-343 (Korea, Republic of); Im, Ji Sun [Department of Fine Chemical Engineering and Applied Chemistry, BK21-E2M, Chungnam National University, Daejeon 305-764 (Korea, Republic of); Kim, Hyung-Il, E-mail: hikim@cnu.ac.kr [Department of Fine Chemical Engineering and Applied Chemistry, BK21-E2M, Chungnam National University, Daejeon 305-764 (Korea, Republic of)

    2012-08-01

    Transdermal drug delivery system (TDDS) was prepared with temperature-responsive hydrogel. The graphite was oxidized and incorporated into hydrogel matrix to improve the thermal response of hydrogel. The micro heater was fabricated to control the temperature precisely by adopting a joule heating method. The drug in hydrogel was delivered through a hairless mouse skin by controlling temperature. The efficiency of drug delivery was improved obviously by incorporation of graphite oxide due to the excellent thermal conductivity and the increased interfacial affinity between graphite oxide and hydrogel matrix. The fabricated micro heater was effective in controlling the temperature over lower critical solution temperature of hydrogel precisely with a small voltage less than 1 V. The cell viability test on graphite oxide composite hydrogel showed enough safety for using as a transdermal drug delivery patch. The performance of TDDS could be improved noticeably based on temperature-responsive hydrogel, thermally conductive graphite oxide, and efficient micro heater. - Graphical abstract: The high-performance transdermal drug delivery system could be prepared by combining temperature-responsive hydrogel, thermally conductive graphite oxide with improved interfacial affinity, and efficient micro heater fabricated by a joule heating method. Highlights: Black-Right-Pointing-Pointer High performance of transdermal drug delivery system with an easy control of voltage. Black-Right-Pointing-Pointer Improved thermal response of hydrogel by graphite oxide incorporation. Black-Right-Pointing-Pointer Efficient micro heater fabricated by a joule heating method.

  1. Constraints in animal health service delivery and sustainable improvement alternatives in North Gondar, Ethiopia

    Directory of Open Access Journals (Sweden)

    Hassen Kebede

    2014-11-01

    Full Text Available Poor livestock health services remain one of the main constraints to livestock production in many developing countries, including Ethiopia. A study was carried out in 11 districts of North Gondar, from December 2011 to September 2012, with the objective of identifying the existing status and constraints of animal health service delivery, and thus recommending possible alternatives for its sustainable improvement. Data were collected by using pre-tested questionnaires and focus group discussion. Findings revealed that 46.34% of the responding farmers had taken their animals to government veterinary clinics after initially trying treatments with local medication. More than 90.00% of the clinical cases were diagnosed solely on clinical signs or even history alone. The antibacterial drugs found in veterinary clinics were procaine penicillin (with or without streptomycin, oxytetracycline and sulphonamides, whilst albendazole, tetramisole and ivermectin were the only anthelmintics. A thermometer was the only clinical aid available in all clinics, whilst only nine (45.00% clinics had a refrigerator. In the private sector, almost 95.00% were retail veterinary pharmacies and only 41.20% fulfilled the requirement criteria set. Professionals working in the government indicated the following problems: lack of incentives (70.00%, poor management and lack of awareness (60.00% and inadequate budget (40.00%. For farmers, the most frequent problems were failure of private practitioners to adhere to ethical procedures (74.00% and lack of knowledge of animal diseases and physical distance from the service centre (50.00%. Of all responding farmers, 58.54% preferred the government service, 21.14% liked both services equally and 20.33% preferred the private service. Farmers’ indiscriminate use of drugs from the black market (23.00% was also mentioned as a problem by private practitioners. Sustainable improvement of animal health service delivery needs increased

  2. Constraints in animal health service delivery and sustainable improvement alternatives in North Gondar, Ethiopia.

    Science.gov (United States)

    Kebede, Hassen; Melaku, Achenef; Kebede, Elias

    2014-11-12

    Poor livestock health services remain one of the main constraints to livestock production in many developing countries, including Ethiopia. A study was carried out in 11 districts of North Gondar, from December 2011 to September 2012, with the objective of identifying the existing status and constraints of animal health service delivery, and thus recommending possible alternatives for its sustainable improvement. Data were collected by using pre-tested questionnaires and focus group discussion. Findings revealed that 46.34% of the responding farmers had taken their animals to government veterinary clinics after initially trying treatments with local medication. More than 90.00% of the clinical cases were diagnosed solely on clinical signs or even history alone. The antibacterial drugs found in veterinary clinics were procaine penicillin (with or without streptomycin), oxytetracycline and sulphonamides, whilst albendazole, tetramisole and ivermectin were the only anthelmintics. A thermometer was the only clinical aid available in all clinics, whilst only nine (45.00%) clinics had a refrigerator. In the private sector, almost 95.00% were retail veterinary pharmacies and only 41.20% fulfilled the requirement criteria set. Professionals working in the government indicated the following problems: lack of incentives (70.00%), poor management and lack of awareness (60.00%) and inadequate budget (40.00%). For farmers, the most frequent problems were failure of private practitioners to adhere to ethical procedures (74.00%) and lack of knowledge of animal diseases and physical distance from the service centre (50.00%). Of all responding farmers, 58.54% preferred the government service, 21.14% liked both services equally and 20.33% preferred the private service. Farmers' indiscriminate use of drugs from the black market (23.00%) was also mentioned as a problem by private practitioners. Sustainable improvement of animal health service delivery needs increased awareness for all

  3. Involvement of the Cdc42 pathway in CFTR post-translational turnover and in its plasma membrane stability in airway epithelial cells.

    Directory of Open Access Journals (Sweden)

    Romain Ferru-Clément

    Full Text Available Cystic fibrosis transmembrane conductance regulator (CFTR is a chloride channel that is expressed on the apical plasma membrane (PM of epithelial cells. The most common deleterious allele encodes a trafficking-defective mutant protein undergoing endoplasmic reticulum-associated degradation (ERAD and presenting lower PM stability. In this study, we investigated the involvement of the Cdc42 pathway in CFTR turnover and trafficking in a human bronchiolar epithelial cell line (CFBE41o- expressing wild-type CFTR. Cdc42 is a small GTPase of the Rho family that fulfils numerous cell functions, one of which is endocytosis and recycling process via actin cytoskeleton remodelling. When we treated cells with chemical inhibitors such as ML141 against Cdc42 and wiskostatin against the downstream effector N-WASP, we observed that CFTR channel activity was inhibited, in correlation with a decrease in CFTR amount at the cell surface and an increase in dynamin-dependent CFTR endocytosis. Anchoring of CFTR to the cortical cytoskeleton was then presumably impaired by actin disorganization. When we performed siRNA-mediated depletion of Cdc42, actin polymerization was not impacted, but we observed actin-independent consequences upon CFTR. Total and PM CFTR amounts were increased, resulting in greater activation of CFTR. Pulse-chase experiments showed that while CFTR degradation was slowed, CFTR maturation through the Golgi apparatus remained unaffected. In addition, we observed increased stability of CFTR in PM and reduction of its endocytosis. This study highlights the involvement of the Cdc42 pathway at several levels of CFTR biogenesis and trafficking: (i Cdc42 is implicated in the first steps of CFTR biosynthesis and processing; (ii it contributes to the stability of CFTR in PM via its anchoring to cortical actin; (iii it promotes CFTR endocytosis and presumably its sorting toward lysosomal degradation.

  4. New nanomicelle curcumin formulation for ocular delivery: improved stability, solubility, and ocular anti-inflammatory treatment.

    Science.gov (United States)

    Li, Mengshuang; Xin, Meng; Guo, Chuanlong; Lin, Guiming; Wu, Xianggen

    2017-11-01

    A stable topical ophthalmic curcumin formulation with high solubility, stability, and efficacy is needed for pharmaceutical use in clinics. The objective of this article was to describe a novel curcumin containing a nanomicelle formulation using a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (PVCL-PVA-PEG) graft copolymer. Nanomicelle curcumin was formulated and optimized and then further evaluated for in vitro cytotoxicity/in vivo ocular irritation, in vitro cellular uptake/in vivo corneal permeation, and in vitro antioxidant activity/in vivo anti-inflammatory efficacy. The solubility, chemical stability, and antioxidant activity were greatly improved after the encapsulation of the PVCL-PVA-PEG nanomicelles. The nanomicelle curcumin ophthalmic solution was simple to prepare and the nanomicelles are stable to the storage conditions, and it had good cellular tolerance. Nanomicelle curcumin also had excellent ocular tolerance in rabbits. The use of nanomicelles significantly improved in vitro cellular uptake and in vivo corneal permeation as well as improved anti-inflammatory efficacy when compared with a free curcumin solution. These findings indicate that nanomicelles could be promising topical delivery systems for the ocular administration of curcumin.

  5. Design and optimization of self-nanoemulsifying drug delivery systems for improved bioavailability of cyclovirobuxine D.

    Science.gov (United States)

    Ke, Zhongcheng; Hou, Xuefeng; Jia, Xiao-Bin

    2016-01-01

    The main purpose of this research was to design a self-nanoemulsifying drug delivery system (SNEDDS) for improving the bioavailability of cyclovirobuxine D as a poorly water-soluble drug. Solubility trials, emulsifying studies, and pseudo-ternary phase diagrams were used to screen the SNEDDS formulations. The optimized drug-loaded SNEDDS was prepared at a mass ratio of 3:24:38:38 for cyclovirobuxine D, oleic acid, Solutol SH15, and propylene glycol, respectively. The optimized formulation was characterized in terms of physicochemical and pharmacokinetic parameters compared with marketed cyclovirobuxine D tablets. The optimized cyclovirobuxine-D-loaded SNEDDS was spontaneously dispersed to form a nanoemulsion with a globule size of 64.80±3.58 nm, which exhibited significant improvement of drug solubility, rapid absorption rate, and enhanced area under the curve, together with increased permeation and decreased efflux. Fortunately, there was a nonsignificant cytotoxic effect toward Caco-2 cells. The relative bioavailability of SNEDDS was 200.22% in comparison with market tablets, in rabbits. SNEDDS could be a potential candidate for an oral dosage form of cyclovirobuxine D with improved bioavailability.

  6. Group interventions to improve health outcomes: a framework for their design and delivery

    Directory of Open Access Journals (Sweden)

    Avenell Alison

    2010-12-01

    Full Text Available Abstract Background Delivering an intervention to a group of patients to improve health outcomes is increasingly popular in public health and primary care, yet "group" is an umbrella term which encompasses a complex range of aims, theories, implementation processes and evaluation methods. We propose a framework for the design and process evaluation of health improvement interventions occurring in a group setting, which will assist practitioners, researchers and policy makers. Methods We reviewed the wider literature on health improvement interventions delivered to patient groups and identified a gap in the literature for designing, evaluating and reporting these interventions. We drew on our experiences conducting systematic reviews, intervention, mixed method and ethnographic studies of groups for breastfeeding and weight management. A framework for health improvement group design and delivery evolved through an iterative process of primary research, reference to the literature and research team discussion. Results Although there is an extensive literature on group processes in education, work, politics and psychological therapies, far less is known about groups where the aim is health improvement. Theories of behaviour change which are validated for individual use are often assumed to be generalisable to group settings, without being rigorously tested. Health improvement or behaviour change interventions delivered in a group setting are complex adaptive social processes with interactions between the group leader, participants, and the wider community and environment. Ecological models of health improvement, which embrace the complex relationship between behaviour, systems and the environment may be more relevant than an individual approach to behaviour change. Conclusion The evidence for effectiveness and cost-effectiveness of group compared with one-to-one interventions for many areas of health improvement in public health and primary care is

  7. Integration of social media with healthcare big data for improved service delivery

    Directory of Open Access Journals (Sweden)

    Sibulela Mgudlwa

    2018-04-01

    Full Text Available Background: In the last decade, social media users across the world have crossed 1 billion, making it one of the fastest growing sources of big data. Also, people needing healthcare continue to increase in every society. Through accessibility, communication and interaction between health practitioners and patients, this type of ever-growing, social media subscriber–based platform can be of significant use in improving healthcare delivery to society. However, users encounter serious challenges in their attempts to make use of social media and big data for health-related services. The challenges are primarily caused by factors such as integration, complexity, security and privacy. The challenges are mainly owing to the sensitive nature of the healthcare environment, as a result of personalisation and privacy of information.   Objectives: The objectives of the study were to examine and gain a better understanding of the complexities that are associated with the use of social media and healthcare big data, through influencing factors, and to develop a framework that can be used to improve health-related services to the patients.   Methods: The interpretivist approach was employed, within which qualitative data were collected. This included documents and existing literature in the areas of social media and healthcare big data. To have a good spread of both previous and current state of events within the phenomena being studied, literature published between 2006 and 2016 were gathered. The data were interpretively analysed.   Results: Based on the analysis of the data, factors of influence were found, which were used to develop a model. The model illustrates how the factors of influence can enable and at the same time constrain the use of social media for healthcare services. The factors were interpreted from which a framework was developed. The framework is intended to guide integration of social media with healthcare big data through which

  8. Improving efficiency and safety in external beam radiation therapy treatment delivery using a Kaizen approach.

    Science.gov (United States)

    Kapur, Ajay; Adair, Nilda; O'Brien, Mildred; Naparstek, Nikoleta; Cangelosi, Thomas; Zuvic, Petrina; Joseph, Sherin; Meier, Jason; Bloom, Beatrice; Potters, Louis

    Modern external beam radiation therapy treatment delivery processes potentially increase the number of tasks to be performed by therapists and thus opportunities for errors, yet the need to treat a large number of patients daily requires a balanced allocation of time per treatment slot. The goal of this work was to streamline the underlying workflow in such time-interval constrained processes to enhance both execution efficiency and active safety surveillance using a Kaizen approach. A Kaizen project was initiated by mapping the workflow within each treatment slot for 3 Varian TrueBeam linear accelerators. More than 90 steps were identified, and average execution times for each were measured. The time-consuming steps were stratified into a 2 × 2 matrix arranged by potential workflow improvement versus the level of corrective effort required. A work plan was created to launch initiatives with high potential for workflow improvement but modest effort to implement. Time spent on safety surveillance and average durations of treatment slots were used to assess corresponding workflow improvements. Three initiatives were implemented to mitigate unnecessary therapist motion, overprocessing of data, and wait time for data transfer defects, respectively. A fourth initiative was implemented to make the division of labor by treating therapists as well as peer review more explicit. The average duration of treatment slots reduced by 6.7% in the 9 months following implementation of the initiatives (P = .001). A reduction of 21% in duration of treatment slots was observed on 1 of the machines (P Kaizen approach has the potential to improve operational efficiency and safety with quick turnaround in radiation therapy practice by addressing non-value-adding steps characteristic of individual department workflows. Higher effort opportunities are identified to guide continual downstream quality improvements. Copyright © 2017 American Society for Radiation Oncology. Published by

  9. Whiteboard Use in Labor and Delivery: A Tool to Improve Patient Knowledge of the Name of the Delivery Provider and Satisfaction with Care.

    Science.gov (United States)

    Pimentel, Verónica Maria; Sun, Mengyang; Bernstein, Peter S; Ferzli, Myriam; Kim, Mimi; Goffman, Dena

    2018-04-01

    Introduction The impact of whiteboard use in labor rooms has not previously been studied. This quality improvement study aimed to evaluate patient knowledge of their delivering physician's name and the change in patient satisfaction after the implementation of a whiteboard in labor rooms. Methods A multidisciplinary team designed a dry-erase whiteboard prompting care providers to record their names, roles and patient care information. A questionnaire was administered to patients before and after the whiteboard implementation. Patients who had a planned cesarean or vaginal birth within 1 h of admission were excluded. Categorical variables were compared using Chi square and Fisher's exact tests. A multivariable logistic regression was performed to control for confounders. Results 191 patients completed the questionnaires. Although patients were not randomized, the pre-and post-intervention groups were similar. Post-intervention, we found a significant increase in recalling the delivery resident's name [21/101 (20.8%) vs. 33/90 (36.7%), p = 0.016] and a non-significant increase in recalling the name of the attending and nurse [19/101 (18.8%) vs. 23/90 (25.6%), p = 0.296; 46/101 (45.5%) vs. 53/90 (58.9%), p = 0.082]. Post-intervention, patient satisfaction with care was significantly higher [83/101 (82.2%) vs. 83/89 (93.3%), p = 0.028]. Knowledge of the delivery resident's name was associated with higher patient satisfaction [115/137 (84%) vs. 51/53 (96%), p = 0.03] and attendance of the postpartum care visit [50.4% (69/137) vs. 64.8% (35/54), p = 0.049]. Discussion The use of a well-designed whiteboard increases laboring patients' knowledge of their delivery physician's name and may improve patient satisfaction with care on Labor and Delivery.

  10. Molecular mechanisms of reduced glutathione transport: role of the MRP/CFTR/ABCC and OATP/SLC21A families of membrane proteins

    International Nuclear Information System (INIS)

    Ballatori, Nazzareno; Hammond, Christine L.; Cunningham, Jennifer B.; Krance, Suzanne M.; Marchan, Rosemarie

    2005-01-01

    The initial step in reduced glutathione (GSH) turnover in all mammalian cells is its transport across the plasma membrane into the extracellular space; however, the mechanisms of GSH transport are not clearly defined. GSH export is required for the delivery of its constituent amino acids to other tissues, detoxification of drugs, metals, and other reactive compounds of both endogenous and exogenous origin, protection against oxidant stress, and secretion of hepatic bile. Recent studies indicate that some members of the multidrug resistance-associated protein (MRP/CFTR or ABCC) family of ATP-binding cassette (ABC) proteins, as well as some members of the organic anion transporting polypeptide (OATP or SLC21A) family of transporters contribute to this process. In particular, five of the 12 members of the MRP/CFTR family appear to mediate GSH export from cells namely, MRP1, MRP2, MRP4, MRP5, and CFTR. Additionally, two members of the OATP family, rat Oatp1 and Oatp2, have been identified as GSH transporters. For the Oatp1 transporter, efflux of GSH may provide the driving force for the uptake of extracellular substrates. In humans, OATP-B and OATP8 do not appear to transport GSH; however, other members of this family have yet to be characterized in regards to GSH transport. In yeast, the ABC proteins Ycf1p and Bpt1p transport GSH from the cytosol into the vacuole, whereas Hgt1p mediates GSH uptake across the plasma membrane. Because transport is a key step in GSH homeostasis and is intimately linked to its biological functions, GSH export proteins are likely to modulate essential cellular functions

  11. Performance-based financing for improving HIV/AIDS service delivery: a systematic review.

    Science.gov (United States)

    Suthar, Amitabh B; Nagata, Jason M; Nsanzimana, Sabin; Bärnighausen, Till; Negussie, Eyerusalem K; Doherty, Meg C

    2017-01-04

    Although domestic HIV/AIDS financing is increasing, international HIV/AIDS financing has plateaued. Providing incentives for the health system (i.e. performance-based financing [PBF]) may help countries achieve more with available resources. We systematically reviewed effects of PBF on HIV/AIDS service delivery to inform WHO guidelines. PubMed, WHO Index Medicus, conference databases, and clinical trial registries were searched in April 2015 for randomised trials, comparative contemporaneous studies, or time-series studies. Studies evaluating PBF in people with HIV were included when they reported service quality, access, or cost. Meta-analyses were not possible due to limited data. This study is registered with PROSPERO, number CRD42015023207. Four studies, published from 2009 to 2015 and including 173,262 people, met the eligibility criteria. All studies were from Sub-Saharan Africa. PBF did not improve individual testing coverage (relative risk [RR], 1.00, 95% confidence interval [CI] 0.89 to 1.13), improved couples testing coverage (RR 1.11, 95% CI 1.02 to 1.20), and improved pregnant women testing coverage (RR 1.29, 95% CI 1.28-1.30). PBF improved coverage of antiretrovirals in pregnant women (RR 1.55, 95% CI 1.50 to 1.59), infants (RR 1.92, 95% CI 1.84 to 2.01), and adults (RR 1.74, 1.64 to 1.85). PBF reduced attrition (RR 0.84, 95% CI 0.74 to 0.96) and treatment failure (odds ratio 0.55, 95% CI 0.32 to 0.97). Potential harms were not reported. Although the limited data suggests PBF positively affected HIV service access and quality, critical health system and governance knowledge gaps remain. More research is needed to inform national policymaking.

  12. Digesting a Path Forward: The Utility of Collagenase Tumor Treatment for Improved Drug Delivery.

    Science.gov (United States)

    Dolor, Aaron; Szoka, Francis C

    2018-06-04

    Collagen and hyaluronan are the most abundant components of the extracellular matrix (ECM) and their overexpression in tumors is linked to increased tumor growth and metastasis. These ECM components contribute to a protective tumor microenvironment by supporting a high interstitial fluid pressure and creating a tortuous setting for the convection and diffusion of chemotherapeutic small molecules, antibodies, and nanoparticles in the tumor interstitial space. This review focuses on the research efforts to deplete extracellular collagen with collagenases to normalize the tumor microenvironment. Although collagen synthesis inhibitors are in clinical development, the use of collagenases is contentious and clinically untested in cancer patients. Pretreatment of murine tumors with collagenases increased drug uptake and diffusion 2-10-fold. This modest improvement resulted in decreased tumor growth, but the benefits of collagenase treatment are confounded by risks of toxicity from collagen breakdown in healthy tissues. In this review, we evaluate the published in vitro and in vivo benefits and limitations of collagenase treatment to improve drug delivery.

  13. Investigating Engineered Ribonucleoprotein Particles to Improve Oral RNAi Delivery in Crop Insect Pests

    Directory of Open Access Journals (Sweden)

    François-Xavier Gillet

    2017-04-01

    Full Text Available Genetically modified (GM crops producing double-stranded RNAs (dsRNAs are being investigated largely as an RNA interference (RNAi-based resistance strategy against crop insect pests. However, limitations of this strategy include the sensitivity of dsRNA to insect gut nucleases and its poor insect cell membrane penetration. Working with the insect pest cotton boll weevil (Anthonomus grandis, we showed that the chimeric protein PTD-DRBD (peptide transduction domain—dsRNA binding domain combined with dsRNA forms a ribonucleoprotein particle (RNP that improves the effectiveness of the RNAi mechanism in the insect. The RNP slows down nuclease activity, probably by masking the dsRNA. Furthermore, PTD-mediated internalization in insect gut cells is achieved within minutes after plasma membrane contact, limiting the exposure time of the RNPs to gut nucleases. Therefore, the RNP provides an approximately 2-fold increase in the efficiency of insect gene silencing upon oral delivery when compared to naked dsRNA. Taken together, these data demonstrate the role of engineered RNPs in improving dsRNA stability and cellular entry, representing a path toward the design of enhanced RNAi strategies in GM plants against crop insect pests.

  14. Investigating Engineered Ribonucleoprotein Particles to Improve Oral RNAi Delivery in Crop Insect Pests.

    Science.gov (United States)

    Gillet, François-Xavier; Garcia, Rayssa A; Macedo, Leonardo L P; Albuquerque, Erika V S; Silva, Maria C M; Grossi-de-Sa, Maria F

    2017-01-01

    Genetically modified (GM) crops producing double-stranded RNAs (dsRNAs) are being investigated largely as an RNA interference (RNAi)-based resistance strategy against crop insect pests. However, limitations of this strategy include the sensitivity of dsRNA to insect gut nucleases and its poor insect cell membrane penetration. Working with the insect pest cotton boll weevil ( Anthonomus grandis ), we showed that the chimeric protein PTD-DRBD (peptide transduction domain-dsRNA binding domain) combined with dsRNA forms a ribonucleoprotein particle (RNP) that improves the effectiveness of the RNAi mechanism in the insect. The RNP slows down nuclease activity, probably by masking the dsRNA. Furthermore, PTD-mediated internalization in insect gut cells is achieved within minutes after plasma membrane contact, limiting the exposure time of the RNPs to gut nucleases. Therefore, the RNP provides an approximately 2-fold increase in the efficiency of insect gene silencing upon oral delivery when compared to naked dsRNA. Taken together, these data demonstrate the role of engineered RNPs in improving dsRNA stability and cellular entry, representing a path toward the design of enhanced RNAi strategies in GM plants against crop insect pests.

  15. Self-microemulsifying drug delivery system for improved oral bioavailability of dipyridamole: preparation and evaluation.

    Science.gov (United States)

    Guo, Feng; Zhong, Haijun; He, Jing; Xie, Baogang; Liu, Fen; Xu, Helin; Liu, Minmin; Xu, Chunlian

    2011-07-01

    Dipyridamole shows poor and variable bioavailability after oral administration due to pHdependent solubility, low biomembrane permeability as well as being a substrate of P-glycoprotein. In order to improve the oral absorption of dipyridamole, a self-microemulsifying drug delivery system (SMEDDS) for dipyridamole was prepared and evaluated in vitro and in vivo. The optimum formulation was 18% oleic acid, 12% Labrafac lipophile WL 1349, 42% Solutol HS 15 and 28% isopropyl alcohol. It was found that the performance of self-microemulsification with the combination of oleic acid and Labrafac lipophile WL 1349 increased compared with just one oil. The results obtained from an in vitro dissolution assay indicated that dipyridamole in SMEDDS dissolved rapidly and completely in pH 6.8 aqueous media, while the commercial drug tablet was less soluble. An oral bioavailability study in rats showed that dipyridamole in the SMEDDS formulation had a 2.06-fold increased absorption compared with the simple drug suspension. It was evident that SMEDDS may be an effective approach to improve the oral absorption for drugs having pH-dependent solubility.

  16. Value-based contracting innovated Medicare advantage healthcare delivery and improved survival.

    Science.gov (United States)

    Mandal, Aloke K; Tagomori, Gene K; Felix, Randell V; Howell, Scott C

    2017-02-01

    In Medicare Advantage (MA) with its CMS Hierarchical Condition Categories (CMS-HCC) payment model, CMS reimburses private plans (Medicare Advantage Organizations [MAOs]) with prospective, monthly, health-based or risk-adjusted, capitated payments. The effect of this payment methodology on healthcare delivery remains debatable. How value-based contracting generates cost efficiencies and improves clinical outcomes in MA is studied. A difference in contracting arrangements between an MAO and 2 provider groups facilitated an intervention-control, preintervention-postintervention, difference-in-differences approach among statistically similar, elderly, community-dwelling MA enrollees within one metropolitan statistical area. Starting in 2009, for intervention-group MA enrollees, the MAO and a provider group agreed to full-risk capitation combined with a revenue gainshare. The gainshare was based on increases in the Risk Adjustment Factor (RAF), which modified the CMS-HCC payments. For the control group, the MAO continued to reimburse another provider group through fee-for-service. RAF, utilization, and survival were followed until December 31, 2012. The intervention group's mean RAF increased significantly (P based visits (P based care for these MA enrollees with multiple comorbidities, a 6% survival benefit with a 32.8% lower hazard of death (P Value-based contracting can drive utilization patterns and improve clinical outcomes among chronically ill, elderly MA members.

  17. Delivery of Flightless I Neutralizing Antibody from Porous Silicon Nanoparticles Improves Wound Healing in Diabetic Mice.

    Science.gov (United States)

    Turner, Christopher T; McInnes, Steven J P; Melville, Elizabeth; Cowin, Allison J; Voelcker, Nicolas H

    2017-01-01

    Flightless I (Flii) is elevated in human chronic wounds and is a negative regulator of wound repair. Decreasing its activity improves healing responses. Flii neutralizing antibodies (FnAbs) decrease Flii activity in vivo and hold significant promise as healing agents. However, to avoid the need for repeated application in a clinical setting and to protect the therapeutic antibody from the hostile environment of the wound, suitable delivery vehicles are required. In this study, the use of porous silicon nanoparticles (pSi NPs) is demonstrated for the controlled release of FnAb to diabetic wounds. We achieve FnAb loading regimens exceeding 250 µg antibody per mg of vehicle. FnAb-loaded pSi NPs increase keratinocyte proliferation and enhance migration in scratch wound assays. Release studies confirm the functionality of the FnAb in terms of Flii binding. Using a streptozotocin-induced model of diabetic wound healing, a significant improvement in healing is observed for mice treated with FnAb-loaded pSi NPs compared to controls, including FnAb alone. FnAb-loaded pSi NPs treated with proteases show intact and functional antibody for up to 7 d post-treatment, suggesting protection of the antibodies from proteolytic degradation in wound fluid. pSi NPs may therefore enable new therapeutic approaches for the treatment of diabetic ulcers. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Identification of Technical Requirement for Improving Quality of Local Online Food Delivery Service in Yogyakarta

    OpenAIRE

    Elvandari, , Cecilia Desvita Ratna; Sukartiko, Anggoro Cahyo; Nugrahini, Arita Dewi

    2017-01-01

    Increased internet usage and fast-paced consumer’s demands have created business opportunities, including online food delivery services. However, competition with similar national-scale businesses allegedly contributed to the decline in the number of XYZ company orders, one of the food-delivery service providers in Yogyakarta. Therefore, this study aimed to identify the need’s attributes of the daring food delivery service consumers, to find out the service-quality satisfaction level, and to ...

  19. Nutritional Status Improved in Cystic Fibrosis Patients with the G551D Mutation After Treatment with Ivacaftor

    NARCIS (Netherlands)

    Borowitz, Drucy; Lubarsky, Barry; Wilschanski, Michael; Munck, Anne; Gelfond, Daniel; Bodewes, Frank; Schwarzenberg, Sarah Jane

    The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gating mutation G551D prevents sufficient ion transport due to reduced channel-open probability. Ivacaftor, an oral CFTR potentiator, increases the channel-open probability. To further analyze improvements in weight and body mass

  20. Social Insurance for Delivery (Jampersal Policy in Indonesia: Culture-Based Approach for Improving Delivery by Health Workers in Rural Areas

    Directory of Open Access Journals (Sweden)

    Riswati Riswati

    2015-06-01

    Full Text Available Background: Jampersal program was launched in Indonesia in January of 2011 by Permenkes No.631/Menkes/PER/III/2011. The aim was to improve the coverage of antenatal care, delivery, postpartum care, postnatal, and family planning by health professionals free of charge. After over a year Jampersal program runs, The ANC figures of Jampersal utilization were still very low. Methods:Quantitative and qualitative research on socio- cultural factors in relation to the selection of health personnel by utilizing Jampersal conducted in 2012 which was then followed by a round table discussion to review the policy options related to the Jampersal utilization of the 6 rural districts. Results: Policy options suggested in Jampersal socialization activities need Intersectoral Commitment:The Ministry of Home Affairs, Ministry of Religious Affairs, and BKKBN, followed by a clear and decisive political commitment. They need active partnerships of the midwives, TBAs and cadres in Jampersal socialization. Midwives in the health center level should be prohibited from private practice, but the total amount of compensation of midwife in helping delivery should be adjusted. Regulations are required and procedures should be set for Jamkesnas, Jamkesda, and Jampersal; They need regulation on cooperation between the health centers staffs and village chiefs to further reinforce ID requirement;The transportation cost to refferal unit; TBAs services (division of task and cost; Financial restrictions to cover by Jampersal on second or third delivery. Additionally need a regulation of reward and punishment for midwives,TBAs and cadres involvement in serving pregnancy and delivery. In village level, they need to establish regulation, that TbaS AND Cadres should write the pregnat women data at the board office of village chiefts. Lastly, MoU between head of district health center and midwife assosiation related to midwife understanding of cultural approaches and on

  1. Genotype-phenotype correlation and functional studies in patients with cystic fibrosis bearing CFTR complex alleles.

    Science.gov (United States)

    Terlizzi, Vito; Castaldo, Giuseppe; Salvatore, Donatello; Lucarelli, Marco; Raia, Valeria; Angioni, Adriano; Carnovale, Vincenzo; Cirilli, Natalia; Casciaro, Rosaria; Colombo, Carla; Di Lullo, Antonella Miriam; Elce, Ausilia; Iacotucci, Paola; Comegna, Marika; Scorza, Manuela; Lucidi, Vincenzina; Perfetti, Anna; Cimino, Roberta; Quattrucci, Serena; Seia, Manuela; Sofia, Valentina Maria; Zarrilli, Federica; Amato, Felice

    2017-04-01

    The effect of complex alleles in cystic fibrosis (CF) is poorly defined for the lack of functional studies. To describe the genotype-phenotype correlation and the results of either in vitro and ex vivo studies performed on nasal epithelial cells (NEC) in a cohort of patients with CF carrying cystic fibrosis transmembrane conductance regulator ( CFTR ) complex alleles. We studied 70 homozygous, compound heterozygous or heterozygous for CFTR mutations: p.[Arg74Trp;Val201Met;Asp1270Asn], n=8; p.[Ile148Thr;Ile1023_Val1024del], n=5; p.[Arg117Leu;Leu997Phe], n=6; c.[1210-34TG[12];1210-12T[5];2930C>T], n=3; p.[Arg74Trp;Asp1270Asn], n=4; p.Asp1270Asn, n=2; p.Ile148Thr, n=6; p.Leu997Phe, n=36. In 39 patients, we analysed the CFTR gating activity on NEC in comparison with patients with CF (n=8) and carriers (n=4). Finally, we analysed in vitro the p.[Arg74Trp;Val201Met;Asp1270Asn] complex allele. The p.[Ile148Thr;Ile1023_Val1024del] caused severe CF in five compound heterozygous with a class I-II mutation. Their CFTR activity on NEC was comparable with patients with two class I-II mutations (mean 7.3% vs 6.9%). The p.[Arg74Trp;Asp1270Asn] and the p.Asp1270Asn have scarce functional effects, while p.[Arg74Trp;Val201Met;Asp1270Asn] caused mild CF in four of five subjects carrying a class I-II mutation in trans , or CFTR-related disorders (CFTR-RD) in three having in trans a class IV-V mutation. The p.[Arg74Trp;Val201Met;Asp1270Asn] causes significantly (pT] and a class I-II mutation had mild CF or CFTR-RD (gating activity: 18.5-19.0%). The effect of complex alleles partially depends on the mutation in trans . Although larger studies are necessary, the CFTR activity on NEC is a rapid contributory tool to classify patients with CFTR dysfunction. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  2. Altered intestinal bile salt biotransformation in a cystic fibrosis (Cftr-/-) mouse model with hepato-biliary pathology.

    Science.gov (United States)

    Bodewes, Frank A J A; van der Wulp, Mariëtte Y M; Beharry, Satti; Doktorova, Marcela; Havinga, Rick; Boverhof, Renze; James Phillips, M; Durie, Peter R; Verkade, Henkjan J

    2015-07-01

    Cftr(-/-tm1Unc) mice develop progressive hepato-biliary pathology. We hypothesize that this liver pathology is related to alterations in biliary bile hydrophobicity and bile salt metabolism in Cftr(-/-tm1Unc) mice. We determined bile production, biliary and fecal bile salt- and lipid compositions and fecal bacterial composition of C57BL/6J Cftr(-/-tm1Unc) and control mice. We found no differences between the total biliary bile salt or lipid concentrations of Cftr(-/-) and controls. Compared to controls, Cftr(-/-) mice had a ~30% higher bile production and a low bile hydrophobicity, related to a ~7 fold higher concentration of the choleretic and hydrophilic bile salt ursocholate. These findings coexisted with a significantly smaller quantity of fecal Bacteroides bacteria. Liver pathology in Cftr(-/-tm1Unc) is not related to increased bile hydrophobicity. Cftr(-/-) mice do however display a biliary phenotype characterized by increased bile production and decreased biliary hydrophobicity. Our findings suggest Cftr dependent, alterations in intestinal bacterial biotransformation of bile salts. Copyright © 2014. Published by Elsevier B.V.

  3. Self-microemulsifying drug delivery system for improving the bioavailability of huperzine A by lymphatic uptake

    Directory of Open Access Journals (Sweden)

    Fang Li

    2017-05-01

    Full Text Available Huperzine A (Hup-A is a poorly water-soluble drug with low oral bioavailability. A self-microemulsifying drug delivery system (SMEDDS was used to enhance the oral bioavailability and lymphatic uptake and transport of Hup-A. A single-pass intestinal perfusion (SPIP technique and a chylomicron flow-blocking approach were used to study its intestinal absorption, mesenteric lymph node distribution and intestinal lymphatic uptake. The value of the area under the plasma concentration–time curve (AUC of Hup-A SMEDDS was significantly higher than that of a Hup-A suspension (P<0.01. The absorption rate constant (Ka and the apparent permeability coefficient (Papp for Hup-A in different parts of the intestine suggested a passive transport mechanism, and the values of Ka and Papp of Hup-A SMEDDS in the ileum were much higher than those in other intestinal segments. The determination of Hup-A concentration in mesenteric lymph nodes can be used to explain the intestinal lymphatic absorption of Hup-A SMEDDS. For Hup-A SMEDDS, the values of AUC and maximum plasma concentration (Cmax of the blocking model were significantly lower than those of the control model (P<0.05. The proportion of lymphatic transport of Hup-A SMEDDS and Hup-A suspension were about 40% and 5%, respectively, suggesting that SMEDDS can significantly improve the intestinal lymphatic uptake and transport of Hup-A.

  4. Experiences of practice facilitators working on the Improved Delivery of Cardiovascular Care project: Retrospective case study.

    Science.gov (United States)

    Liddy, Clare; Rowan, Margo; Valiquette-Tessier, Sophie-Claire; Drosinis, Paul; Crowe, Lois; Hogg, William

    2018-01-01

    To examine the barriers to and facilitators of practice facilitation experienced by participants in the Improving Delivery of Cardiovascular Care (IDOCC) project. Case studies of practice facilitators' narrative reports. Eastern Ontario. Primary care practices that participated in the IDOCC project. Cases were identified by calculating sum scores in order to determine practices' performance relative to their peers. Two case exemplars were selected that scored within ± 1 SD of the total mean score, and a qualitative analysis of practice facilitators' narrative reports was conducted using a 5-factor implementation framework to identify barriers and facilitators. Narratives were divided into 3 phases: planning, implementation, and sustainability. Barriers and facilitators fluctuated over the intervention's 3 phases. Site A reported more barriers (n = 47) than facilitators (n = 38), while site B reported a roughly equal number of barriers (n = 144) and facilitators (n = 136). In both sites, the most common barriers involved organizational and provider factors and the most common facilitators were associated with innovation and structural factors. Both practices encountered various barriers and facilitators throughout the IDOCC's 3 phases. The case studies reveal the complex interactions of these factors over time, and provide insight into the implementation of practice facilitation programs. Copyright© the College of Family Physicians of Canada.

  5. Global Lessons In Frugal Innovation To Improve Health Care Delivery In The United States.

    Science.gov (United States)

    Bhatti, Yasser; Taylor, Andrea; Harris, Matthew; Wadge, Hester; Escobar, Erin; Prime, Matt; Patel, Hannah; Carter, Alexander W; Parston, Greg; Darzi, Ara W; Udayakumar, Krishna

    2017-11-01

    In a 2015 global study of low-cost or frugal innovations, we identified five leading innovations that scaled successfully in their original contexts and that may provide insights for scaling such innovations in the United States. We describe common themes among these diverse innovations, critical factors for their translation to the United States to improve the efficiency and quality of health care, and lessons for the implementation and scaling of other innovations. We highlight promising trends in the United States that support adapting these innovations, including growing interest in moving care out of health care facilities and into community and home settings; the growth of alternative payment models and incentives to experiment with new approaches to population health and care delivery; and the increasing use of diverse health professionals, such as community health workers and advanced practice providers. Our findings should inspire policy makers and health care professionals and inform them about the potential for globally sourced frugal innovations to benefit US health care.

  6. A comparative study on the nanoparticles for improved drug delivery systems.

    Science.gov (United States)

    Mahmoodi, Nosrat O; Ghavidast, Atefeh; Amirmahani, Najmeh

    2016-09-01

    Nanoparticles have attracted considerable recent interest for diverse biomedical applications because of the unique properties of the nanomaterials. It is already known that one of the major advances in the relative application of nanoparticles is the recognition of the steric stabilization which can increase the particle stability in the biological environment and provide the opportunities of the application of nanoparticles in the development of drug delivery systems (DDSs) for achieving drug targeting and controlled drug release. To facilitate their use in such applications, the appropriate design of surface ligands on these nanoparticles is necessary. In view of these, functionalized nanoparticles through surface modification can be utilized to specifically interact with the target molecules on the cell membrane or intracellular ones. This review briefly presents self-assembled nanoparticles with molecules of therapeutic significance with two strategies. The first strategy attempts to improve the placement of the drugs using conjugating the appropriate ligands or adding targeting moieties to the DDS. The second strategy utilizes trigger-controlled drug-release, which restricts drug release at the targeted site to kill cancer cells by externally controlled mechanisms. Among external stimulations, conveniently light has attracted much interest because it, as an orthogonal external stimulus, gives spatiotemporal control of payload release. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Single chain Fc-dimer-human growth hormone fusion protein for improved drug delivery.

    Science.gov (United States)

    Zhou, Li; Wang, Hsuan-Yao; Tong, Shanshan; Okamoto, Curtis T; Shen, Wei-Chiang; Zaro, Jennica L

    2017-02-01

    Fc fusion protein technology has been successfully used to generate long-acting forms of several protein therapeutics. In this study, a novel Fc-based drug carrier, single chain Fc-dimer (sc(Fc) 2 ), was designed to contain two Fc domains recombinantly linked via a flexible linker. Since the Fc dimeric structure is maintained through the flexible linker, the hinge region was omitted to further stabilize it against proteolysis and reduce FcγR-related effector functions. The resultant sc(Fc) 2 candidate preserved the neonatal Fc receptor (FcRn) binding. sc(Fc) 2 -mediated delivery was then evaluated using a therapeutic protein with a short plasma half-life, human growth hormone (hGH), as the protein drug cargo. This novel carrier protein showed a prolonged in vivo half-life and increased hGH-mediated bioactivity compared to the traditional Fc-based drug carrier. sc(Fc) 2 technology has the potential to greatly advance and expand the use of Fc-technology for improving the pharmacokinetics and bioactivity of protein therapeutics. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. An integrated methodology for process improvement and delivery system visualization at a multidisciplinary cancer center.

    Science.gov (United States)

    Singprasong, Rachanee; Eldabi, Tillal

    2013-01-01

    Multidisciplinary cancer centers require an integrated, collaborative, and stream-lined workflow in order to provide high quality of patient care. Due to the complex nature of cancer care and continuing changes to treatment techniques and technologies, it is a constant struggle for centers to obtain a systemic and holistic view of treatment workflow for improving the delivery systems. Project management techniques, Responsibility matrix and a swim-lane activity diagram representing sequence of activities can be combined for data collection, presentation, and evaluation of the patient care. This paper presents this integrated methodology using multidisciplinary meetings and walking the route approach for data collection, integrated responsibility matrix and swim-lane activity diagram with activity time for data representation and 5-why and gap analysis approach for data analysis. This enables collection of right detail of information in a shorter time frame by identifying process flaws and deficiencies while being independent of the nature of the patient's disease or treatment techniques. A case study of a multidisciplinary regional cancer centre is used to illustrate effectiveness of the proposed methodology and demonstrates that the methodology is simple to understand, allowing for minimal training of staff and rapid implementation. © 2011 National Association for Healthcare Quality.

  9. Efficient Gene Delivery to Pig Airway Epithelia and Submucosal Glands Using Helper-Dependent Adenoviral Vectors

    Directory of Open Access Journals (Sweden)

    Huibi Cao

    2013-01-01

    Full Text Available Airway gene delivery is a promising strategy to treat patients with life-threatening lung diseases such as cystic fibrosis (CF. However, this strategy has to be evaluated in large animal preclinical studies in order to translate it to human applications. Because of anatomic and physiological similarities between the human and pig lungs, we utilized pig as a large animal model to examine the safety and efficiency of airway gene delivery with helper-dependent adenoviral vectors. Helper-dependent vectors carrying human CFTR or reporter gene LacZ were aerosolized intratracheally into pigs under bronchoscopic guidance. We found that the LacZ reporter and hCFTR transgene products were efficiently expressed in lung airway epithelial cells. The transgene vectors with this delivery can also reach to submucosal glands. Moreover, the hCFTR transgene protein localized to the apical membrane of both ciliated and nonciliated epithelial cells, mirroring the location of wild-type CF transmembrane conductance regulator (CFTR. Aerosol delivery procedure was well tolerated by pigs without showing systemic toxicity based on the limited number of pigs tested. These results provide important insights into developing clinical strategies for human CF lung gene therapy.

  10. The promise of multimedia technology for STI/HIV prevention: frameworks for understanding improved facilitator delivery and participant learning.

    Science.gov (United States)

    Khan, Maria R; Epperson, Matthew W; Gilbert, Louisa; Goddard, Dawn; Hunt, Timothy; Sarfo, Bright; El-Bassel, Nabila

    2012-10-01

    There is increasing excitement about multimedia sexually transmitted infection (STI) and HIV prevention interventions, yet there has been limited discussion of how use of multimedia technology may improve STI/HIV prevention efforts. The purpose of this paper is to describe the mechanisms through which multimedia technology may work to improve the delivery and uptake of intervention material. We present conceptual frameworks describing how multimedia technology may improve intervention delivery by increasing standardization and fidelity to the intervention material and the participant's ability to learn by improving attention, cognition, emotional engagement, skills-building, and uptake of sensitive material about sexual and drug risks. In addition, we describe how the non-multimedia behavioral STI/HIV prevention intervention, Project WORTH, was adapted into a multimedia format for women involved in the criminal justice system and provide examples of how multimedia activities can more effectively target key mediators of behavioral change in this intervention.

  11. Improving the Lung Delivery of Nasally Administered Aerosols During Noninvasive Ventilation—An Application of Enhanced Condensational Growth (ECG)

    Science.gov (United States)

    Tian, Geng; Hindle, Michael

    2011-01-01

    Abstract Background Aerosol drug delivery during noninvasive ventilation (NIV) is known to be inefficient due to high depositional losses. To improve drug delivery efficiency, the concept of enhanced condensational growth (ECG) was recently proposed in which a submicrometer or nanoaerosol reduces extrathoracic deposition and subsequent droplet size increase promotes lung retention. The objective of this study was to provide proof-of-concept that the ECG approach could improve lung delivery of nasally administered aerosols under conditions consistent with NIV. Methods Aerosol deposition and size increase were evaluated in an adult nose–mouth–throat (NMT) replica geometry using both in vitro experiments and CFD simulations. For the ECG delivery approach, separate streams of a submicrometer aerosol and warm (39°C) saturated air were generated and delivered to the right and left nostril inlets, respectively. A control case was also considered in which an aerosol with a mass median aerodynamic diameter (MMAD) of 4.67 μm was delivered to the model. Results In vitro experiments showed that the ECG approach significantly reduced the drug deposition fraction in the NMT geometry compared with the control case [14.8 (1.83)%—ECG vs. 72.6 (3.7)%—control]. Aerosol size increased from an initial MMAD of 900 nm to a size of approximately 2 μm at the exit of the NMT geometry. Results of the CFD model were generally in good agreement with the experimental findings. Based on CFD predictions, increasing the delivery temperature of the aerosol stream from 21 to 35°C under ECG conditions further reduced the total NMT drug deposition to 5% and maintained aerosol growth by ECG to approximately 2 μm. Conclusions Application of the ECG approach may significantly improve the delivery of pharmaceutical aerosols during NIV and may open the door for using the nasal route to routinely deliver pulmonary medications. PMID:21410327

  12. First functional polymorphism in CFTR promoter that results in decreased transcriptional activity and Sp1/USF binding

    International Nuclear Information System (INIS)

    Taulan, M.; Lopez, E.; Guittard, C.; Rene, C.; Baux, D.; Altieri, J.P.; DesGeorges, M.; Claustres, M.; Romey, M.C.

    2007-01-01

    Growing evidences show that functionally relevant polymorphisms in various promoters alter both transcriptional activity and affinities of existing protein-DNA interactions, and thus influence disease progression in humans. We previously reported the -94G>T CFTR promoter variant in a female CF patient in whom any known disease-causing mutation has been detected. To investigate whether the -94G>T could be a regulatory variant, we have proceeded to in silico analyses and functional studies including EMSA and reporter gene assays. Our data indicate that the promoter variant decreases basal CFTR transcriptional activity in different epithelial cells and alters binding affinities of both Sp1 and USF nuclear proteins to the CFTR promoter. The present report provides evidence for the first functional polymorphism that negatively affects the CFTR transcriptional activity and demonstrates a cooperative role of Sp1 and USF transcription factors in transactivation of the CFTR gene promoter

  13. Simulation training improves medical students' learning experiences when performing real vaginal deliveries.

    Science.gov (United States)

    Dayal, Ashlesha K; Fisher, Nelli; Magrane, Diane; Goffman, Dena; Bernstein, Peter S; Katz, Nadine T

    2009-01-01

    To determine the relationship between simulation training for vaginal delivery maneuvers and subsequent participation in live deliveries during the clinical rotation and to assess medical students' performance and confidence in vaginal delivery maneuvers with and without simulation training. Medical students were randomized to receive or not to receive simulation training for vaginal delivery maneuvers on a mannequin simulator at the start of a 6-week clerkship. Both groups received traditional didactic and clinical teaching. One researcher, blinded to randomization, scored student competence of delivery maneuvers and overall delivery performance on simulator. Delivery performance was scored (1-5, with 5 being the highest) at weeks 1 and 5 of the clerkship. Students were surveyed to assess self-confidence in the ability to perform delivery maneuvers at weeks 1 and 5, and participation in live deliveries was evaluated using student obstetric patient logs. Thirty-three students were randomized, 18 to simulation training [simulation group (SIM)] and 15 to no simulation training [control group (CON)]. Clerkship logs demonstrated that SIM students participated in more deliveries than CON students (9.8 +/- 3.7 versus 6.2 +/- 2.8, P < 0.005). SIM reported increased confidence in ability to perform a vaginal delivery, when compared with CON at the end of the clerkship (3.81 +/- 0.83 versus 3.00 +/- 1.0, respectively, P < 0.05). The overall delivery performance score was significantly higher in SIM, when compared with CON at week 1 (3.94 +/- 0.94 versus 2.07 +/- 1.22, respectively, P < 0.001) and week 5 (4.88 +/- 0.33 versus 4.31 +/- 0.63, P < 0.001) in the simulated environment. Students who receive simulation training participate more actively in the clinical environment during the course of the clerkship. Student simulation training is beneficial to learn obstetric skills in a minimal risk environment, demonstrate competency with maneuvers, and translate this competence

  14. Exploring advantages/disadvantages and improvements in overcoming gene delivery barriers of amino acid modified trimethylated chitosan.

    Science.gov (United States)

    Zheng, Hao; Tang, Cui; Yin, Chunhua

    2015-06-01

    Present study aimed at exploring advantages/disadvantages of amino acid modified trimethylated chitosan in conquering multiple gene delivery obstacles and thus providing comprehensive understandings for improved transfection efficiency. Arginine, cysteine, and histidine modified trimethyl chitosan were synthesized and employed to self-assemble with plasmid DNA (pDNA) to form nanocomplexes, namely TRNC, TCNC, and THNC, respectively. They were assessed by structural stability, cellular uptake, endosomal escape, release behavior, nuclear localization, and in vitro and in vivo transfection efficiencies. Besides, sodium tripolyphosphate (TPP) was added into TRNC to compromise certain disadvantageous attributes for pDNA delivery. Optimal endosomal escape ability failed to bring in satisfactory transfection efficiency of THNC due to drawbacks in structural stability, cellular uptake, pDNA liberation, and nuclear distribution. TCNC evoked the most potent gene expression owing to multiple advantages including sufficient stability, preferable uptake, efficient pDNA release, and high nucleic accumulation. Undesirable stability and insufficient pDNA release adversely affected TRNC-mediated gene transfer. However, incorporation of TPP could improve such disadvantages and consequently resulted in enhanced transfection efficiencies. Coordination of multiple contributing effects to conquer all delivery obstacles was necessitated for improved transfection efficiency, which would provide insights into rational design of gene delivery vehicles.

  15. Co-delivery of resveratrol and docetaxel via polymeric micelles to improve the treatment of drug-resistant tumors

    DEFF Research Database (Denmark)

    Guo, Xiong; Zhao, Zhiyue; Chen, Dawei

    2018-01-01

    Co-delivery of anti-cancer drugs is promising to improve the efficacy of cancer treatment. This study was aiming to investigate the potential of concurrent delivery of resveratrol (RES) and docetaxel (DTX) via polymeric nanocarriers to treat breast cancer. To this end, methoxyl poly(ethylene glycol...... profiles, and enhanced cytotoxicity in vitro against MCF-7 cells. The AUC(0→t) of DTX and RES in mPEG-PDLA micelles after i.v. administration to rats were 3.0-fold and 1.6-fold higher than that of i.v. injections of the individual drugs. These findings indicated that the co-delivery of RES and DTX using m...

  16. Ribosomal Stalk Protein Silencing Partially Corrects the ΔF508-CFTR Functional Expression Defect.

    Directory of Open Access Journals (Sweden)

    Guido Veit

    2016-05-01

    Full Text Available The most common cystic fibrosis (CF causing mutation, deletion of phenylalanine 508 (ΔF508 or Phe508del, results in functional expression defect of the CF transmembrane conductance regulator (CFTR at the apical plasma membrane (PM of secretory epithelia, which is attributed to the degradation of the misfolded channel at the endoplasmic reticulum (ER. Deletion of phenylalanine 670 (ΔF670 in the yeast oligomycin resistance 1 gene (YOR1, an ABC transporter of Saccharomyces cerevisiae phenocopies the ΔF508-CFTR folding and trafficking defects. Genome-wide phenotypic (phenomic analysis of the Yor1-ΔF670 biogenesis identified several modifier genes of mRNA processing and translation, which conferred oligomycin resistance to yeast. Silencing of orthologues of these candidate genes enhanced the ΔF508-CFTR functional expression at the apical PM in human CF bronchial epithelia. Although knockdown of RPL12, a component of the ribosomal stalk, attenuated the translational elongation rate, it increased the folding efficiency as well as the conformational stability of the ΔF508-CFTR, manifesting in 3-fold augmented PM density and function of the mutant. Combination of RPL12 knockdown with the corrector drug, VX-809 (lumacaftor restored the mutant function to ~50% of the wild-type channel in primary CFTRΔF508/ΔF508 human bronchial epithelia. These results and the observation that silencing of other ribosomal stalk proteins partially rescue the loss-of-function phenotype of ΔF508-CFTR suggest that the ribosomal stalk modulates the folding efficiency of the mutant and is a potential therapeutic target for correction of the ΔF508-CFTR folding defect.

  17. Resveratrol increases F508del-CFTR dependent salivary secretion in cystic fibrosis mice

    Directory of Open Access Journals (Sweden)

    Barbara Dhooghe

    2015-07-01

    Full Text Available Cystic fibrosis (CF is a fatal genetic disease associated with widespread exocrine gland dysfunction. Studies have suggested activating effects of resveratrol, a naturally-occurring polyphenol compound with antioxidant and anti-inflammatory properties, on CF transmembrane conductance regulator (CFTR protein function. We assayed, in F508del-CFTR homozygous (CF and in wild-type mice, the effect of resveratrol on salivary secretion in basal conditions, in response to inhibition by atropine (basal β-adrenergic-dependent component and to stimulation by isoprenaline (CFTR-dependent component. Both components of the salivary secretion were smaller in CF mice than in controls. Two hours after intraperitoneal administration of resveratrol (50 mg/kg dissolved in DMSO, the compound was detected in salivary glands. As in both CF and in wild-type mice, DMSO alone increased the response to isoprenaline in males but not in females, the effect of resveratrol was only measured in females. In wild-type mice, isoprenaline increased secretion by more than half. In CF mice, resveratrol rescued the response to isoprenaline, eliciting a 2.5-fold increase of β-adrenergic-stimulated secretion. We conclude that the salivary secretion assay is suitable to test DMSO-soluble CFTR modulators in female mice. We show that resveratrol applied in vivo to mice reaches salivary glands and increases β-adrenergic secretion. Immunolabelling of CFTR in human bronchial epithelial cells suggests that the effect is associated with increased CFTR protein expression. Our data support the view that resveratrol is beneficial for treating CF. The salivary secretion assay has a potential application to test efficacy of novel CF therapies.

  18. Toward improved target conformity for two spot scanning proton therapy delivery systems using dynamic collimation

    Science.gov (United States)

    Moignier, Alexandra; Gelover, Edgar; Smith, Blake R.; Wang, Dongxu; Flynn, Ryan T.; Kirk, Maura L.; Lin, Liyong; Solberg, Timothy D.; Lin, Alexander; Hyer, Daniel E.

    2016-01-01

    Purpose: To quantify improvement in target conformity in brain and head and neck tumor treatments resulting from the use of a dynamic collimation system (DCS) with two spot scanning proton therapy delivery systems (universal nozzle, UN, and dedicated nozzle, DN) with median spot sizes of 5.2 and 3.2 mm over a range of energies from 100 to 230 MeV. Methods: Uncollimated and collimated plans were calculated with both UN and DN beam models implemented within our in-house treatment planning system for five brain and ten head and neck datasets in patients previously treated with spot scanning proton therapy. The prescription dose and beam angles from the clinical plans were used for both the UN and DN plans. The average reduction of the mean dose to the 10-mm ring surrounding the target between the uncollimated and collimated plans was calculated for the UN and the DN. Target conformity was analyzed using the mean dose to 1-mm thickness rings surrounding the target at increasing distances ranging from 1 to 10 mm. Results: The average reductions of the 10-mm ring mean dose for the UN and DN plans were 13.7% (95% CI: 11.6%–15.7%; p < 0.0001) and 11.5% (95% CI: 9.5%–13.5%; p < 0.0001) across all brain cases and 7.1% (95% CI: 4.4%–9.8%; p < 0.001) and 6.3% (95% CI: 3.7%–9.0%; p < 0.001), respectively, across all head and neck cases. The collimated UN plans were either more conformal (all brain cases and 60% of the head and neck cases) than or equivalent (40% of the head and neck cases) to the uncollimated DN plans. The collimated DN plans offered the highest conformity. Conclusions: The DCS added either to the UN or DN improved the target conformity. The DCS may be of particular interest for sites with UN systems looking for a more economical solution than upgrading the nozzle to improve the target conformity of their spot scanning proton therapy system. PMID:26936726

  19. Improving drug delivery strategies for lymphatic filariasis elimination in urban areas in Ghana.

    Directory of Open Access Journals (Sweden)

    Nana-Kwadwo Biritwum

    2017-05-01

    Full Text Available The Global Program to Eliminate Lymphatic Filariasis (GPELF advocates for the treatment of entire endemic communities, in order to achieve its elimination targets. LF is predominantly a rural disease, and achieving the required treatment coverage in these areas is much easier compared to urban areas that are more complex. In Ghana, parts of the Greater Accra Region with Accra as the capital city are also endemic for LF. Mass Drug Administration (MDA in Accra started in 2006. However, after four years of treatment, the coverage has always been far below the 65% epidemiologic coverage for interrupting transmission. As such, there was a need to identify the reasons for poor treatment coverage and design specific strategies to improve the delivery of MDA. This study therefore set out to identify the opportunities and barriers for implementing MDA in urban settings, and to develop appropriate strategies for MDA in these settings. An experimental, exploratory study was undertaken in three districts in the Greater Accra region. The study identified various types of non-rural settings, the social structures, stakeholders and resources that could be employed for MDA. Qualitative assessment such as in-depth interviews (IDIs and focus group discussions (FGDs with community leaders, community members, health providers, NGOs and other stakeholders in the community was undertaken. The study was carried out in three phases: pre-intervention, intervention and post-intervention phases, to assess the profile of the urban areas and identify reasons for poor treatment coverage using both qualitative and quantitative research methods. The outcomes from the study revealed that, knowledge, attitudes and practices of community members to MDA improved slightly from the pre-intervention phase to the post-intervention phase, in the districts where the interventions were readily implemented by health workers. Many factors such as adequate leadership, funding, planning and

  20. Impact of the CFTR-potentiator ivacaftor on airway microbiota in cystic fibrosis patients carrying a G551D mutation.

    Directory of Open Access Journals (Sweden)

    Cédric Bernarde

    Full Text Available Airway microbiota composition has been clearly correlated with many pulmonary diseases, and notably with cystic fibrosis (CF, an autosomal genetic disorder caused by mutation in the CF transmembrane conductance regulator (CFTR. Recently, a new molecule, ivacaftor, has been shown to re-establish the functionality of the G551D-mutated CFTR, allowing significant improvement in lung function.The purpose of this study was to follow the evolution of the airway microbiota in CF patients treated with ivacaftor, using quantitative PCR and pyrosequencing of 16S rRNA amplicons, in order to identify quantitative and qualitative changes in bacterial communities. Three G551D children were followed up longitudinally over a mean period of more than one year covering several months before and after initiation of ivacaftor treatment.129 operational taxonomy units (OTUs, representing 64 genera, were identified. There was no significant difference in total bacterial load before and after treatment. Comparison of global community composition found no significant changes in microbiota. Two OTUs, however, showed contrasting dynamics: after initiation of ivacaftor, the relative abundance of the anaerobe Porphyromonas 1 increased (p<0.01 and that of Streptococcus 1 (S. mitis group decreased (p<0.05, possibly in relation to the anti-Gram-positive properties of ivacaftor. The anaerobe Prevotella 2 correlated positively with the pulmonary function test FEV-1 (r=0.73, p<0.05. The study confirmed the presumed positive role of anaerobes in lung function.Several airway microbiota components, notably anaerobes (obligate or facultative anaerobes, could be valuable biomarkers of lung function improvement under ivacaftor, and could shed light on the pathophysiology of lung disease in CF patients.

  1. Nanoscale Nutrient Delivery Systems for Food Applications: Improving Bioactive Dispersibility, Stability, and Bioavailability.

    Science.gov (United States)

    McClements, David Julian

    2015-07-01

    There has been a surge of interest in the development of nanoscale systems for the encapsulation, protection, and delivery of lipophilic nutrients, vitamins, and nutraceuticals. This review article highlights the challenges associated with incorporating these lipophilic bioactive components into foods, and then discusses potential nanoscale delivery systems that can be used to overcome these challenges. In particular, the desirable characteristics required for any nanoscale delivery system are presented, as well as methods of fabricating them and of characterizing them. An overview of different delivery systems is given, such as microemulsions, nanoemulsions, emulsions, microgels, and biopolymer nanoparticles, and their potential applications are discussed. Nanoscale delivery systems have considerable potential within the food industry, but they must be carefully formulated to ensure that they are safe, economically viable, and effective. Nanoscale delivery systems have numerous potential applications in the food industry for encapsulating, protecting, and releasing bioactive agents, such as nutraceuticals and vitamins. This review article highlights methods for designing, fabricating, characterizing, and utilizing edible nanoparticles from a variety of different food-grade ingredients. © 2015 Institute of Food Technologists®

  2. Functional interaction between CFTR and the sodium-phosphate co-transport type 2a in Xenopus laevis oocytes.

    Directory of Open Access Journals (Sweden)

    Naziha Bakouh

    Full Text Available A growing number of proteins, including ion transporters, have been shown to interact with Cystic Fibrosis Transmembrane conductance Regulator (CFTR. CFTR is an epithelial chloride channel that is involved in Cystic Fibrosis (CF when mutated; thus a better knowledge of its functional interactome may help to understand the pathophysiology of this complex disease. In the present study, we investigated if CFTR and the sodium-phosphate co-transporter type 2a (NPT2a functionally interact after heterologous expression of both proteins in Xenopus laevis oocytes.NPT2a was expressed alone or in combination with CFTR in X. laevis oocytes. Using the two-electrode voltage-clamp technique, the inorganic phosphate-induced current (IPi was measured and taken as an index of NPT2a activity. The maximal IPi for NPT2a substrates was reduced when CFTR was co-expressed with NPT2a, suggesting a decrease in its expression at the oolemna. This was consistent with Western blot analysis showing reduced NPT2a plasma membrane expression in oocytes co-expressing both proteins, whereas NPT2a protein level in total cell lysate was the same in NPT2a- and NPT2a+CFTR-oocytes. In NPT2a+CFTR- but not in NPT2a-oocytes, IPi and NPT2a surface expression were increased upon PKA stimulation, whereas stimulation of Exchange Protein directly Activated by cAMP (EPAC had no effect. When NPT2a-oocytes were injected with NEG2, a short amino-acid sequence from the CFTR regulatory domain that regulates PKA-dependent CFTR trafficking to the plasma membrane, IPi values and NPT2a membrane expression were diminished, and could be enhanced by PKA stimulation, thereby mimicking the effects of CFTR co-expression.We conclude that when both CFTR and NPT2a are expressed in X. laevis oocytes, CFTR confers to NPT2a a cAMPi-dependent trafficking to the membrane. This functional interaction raises the hypothesis that CFTR may play a role in phosphate homeostasis.

  3. Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis.

    Science.gov (United States)

    LaRusch, Jessica; Jung, Jinsei; General, Ignacio J; Lewis, Michele D; Park, Hyun Woo; Brand, Randall E; Gelrud, Andres; Anderson, Michelle A; Banks, Peter A; Conwell, Darwin; Lawrence, Christopher; Romagnuolo, Joseph; Baillie, John; Alkaade, Samer; Cote, Gregory; Gardner, Timothy B; Amann, Stephen T; Slivka, Adam; Sandhu, Bimaljit; Aloe, Amy; Kienholz, Michelle L; Yadav, Dhiraj; Barmada, M Michael; Bahar, Ivet; Lee, Min Goo; Whitcomb, David C

    2014-07-01

    CFTR is a dynamically regulated anion channel. Intracellular WNK1-SPAK activation causes CFTR to change permeability and conductance characteristics from a chloride-preferring to bicarbonate-preferring channel through unknown mechanisms. Two severe CFTR mutations (CFTRsev) cause complete loss of CFTR function and result in cystic fibrosis (CF), a severe genetic disorder affecting sweat glands, nasal sinuses, lungs, pancreas, liver, intestines, and male reproductive system. We hypothesize that those CFTR mutations that disrupt the WNK1-SPAK activation mechanisms cause a selective, bicarbonate defect in channel function (CFTRBD) affecting organs that utilize CFTR for bicarbonate secretion (e.g. the pancreas, nasal sinus, vas deferens) but do not cause typical CF. To understand the structural and functional requirements of the CFTR bicarbonate-preferring channel, we (a) screened 984 well-phenotyped pancreatitis cases for candidate CFTRBD mutations from among 81 previously described CFTR variants; (b) conducted electrophysiology studies on clones of variants found in pancreatitis but not CF; (c) computationally constructed a new, complete structural model of CFTR for molecular dynamics simulation of wild-type and mutant variants; and (d) tested the newly defined CFTRBD variants for disease in non-pancreas organs utilizing CFTR for bicarbonate secretion. Nine variants (CFTR R74Q, R75Q, R117H, R170H, L967S, L997F, D1152H, S1235R, and D1270N) not associated with typical CF were associated with pancreatitis (OR 1.5, p = 0.002). Clones expressed in HEK 293T cells had normal chloride but not bicarbonate permeability and conductance with WNK1-SPAK activation. Molecular dynamics simulations suggest physical restriction of the CFTR channel and altered dynamic channel regulation. Comparing pancreatitis patients and controls, CFTRBD increased risk for rhinosinusitis (OR 2.3, p<0.005) and male infertility (OR 395, p<0.0001). WNK1-SPAK pathway-activated increases in CFTR

  4. Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis.

    Directory of Open Access Journals (Sweden)

    Jessica LaRusch

    2014-07-01

    Full Text Available CFTR is a dynamically regulated anion channel. Intracellular WNK1-SPAK activation causes CFTR to change permeability and conductance characteristics from a chloride-preferring to bicarbonate-preferring channel through unknown mechanisms. Two severe CFTR mutations (CFTRsev cause complete loss of CFTR function and result in cystic fibrosis (CF, a severe genetic disorder affecting sweat glands, nasal sinuses, lungs, pancreas, liver, intestines, and male reproductive system. We hypothesize that those CFTR mutations that disrupt the WNK1-SPAK activation mechanisms cause a selective, bicarbonate defect in channel function (CFTRBD affecting organs that utilize CFTR for bicarbonate secretion (e.g. the pancreas, nasal sinus, vas deferens but do not cause typical CF. To understand the structural and functional requirements of the CFTR bicarbonate-preferring channel, we (a screened 984 well-phenotyped pancreatitis cases for candidate CFTRBD mutations from among 81 previously described CFTR variants; (b conducted electrophysiology studies on clones of variants found in pancreatitis but not CF; (c computationally constructed a new, complete structural model of CFTR for molecular dynamics simulation of wild-type and mutant variants; and (d tested the newly defined CFTRBD variants for disease in non-pancreas organs utilizing CFTR for bicarbonate secretion. Nine variants (CFTR R74Q, R75Q, R117H, R170H, L967S, L997F, D1152H, S1235R, and D1270N not associated with typical CF were associated with pancreatitis (OR 1.5, p = 0.002. Clones expressed in HEK 293T cells had normal chloride but not bicarbonate permeability and conductance with WNK1-SPAK activation. Molecular dynamics simulations suggest physical restriction of the CFTR channel and altered dynamic channel regulation. Comparing pancreatitis patients and controls, CFTRBD increased risk for rhinosinusitis (OR 2.3, p<0.005 and male infertility (OR 395, p<<0.0001. WNK1-SPAK pathway-activated increases in

  5. A New Concept of a Drug Delivery System with Improved Precision and Patient Safety Features

    Directory of Open Access Journals (Sweden)

    Florian Thoma

    2014-12-01

    Full Text Available This paper presents a novel dosing concept for drug delivery based on a peristaltic piezo-electrically actuated micro membrane pump. The design of the silicon micropump itself is straight-forward, using two piezoelectrically actuated membrane valves as inlet and outlet, and a pump chamber with a piezoelectrically actuated pump membrane in-between. To achieve a precise dosing, this micropump is used to fill a metering unit placed at its outlet. In the final design this metering unit will be made from a piezoelectrically actuated inlet valve, a storage chamber with an elastic cover membrane and a piezoelectrically actuated outlet valve, which are connected in series. During a dosing cycle the metering unit is used to adjust the drug volume to be dispensed before delivery and to control the actually dispensed volume. To simulate the new drug delivery concept, a lumped parameter model has been developed to find the decisive design parameters. With the knowledge taken from the model a drug delivery system is designed that includes a silicon micro pump and, in a first step, a silicon chip with the storage chamber and two commercial microvalves as a metering unit. The lumped parameter model is capable to simulate the maximum flow, the frequency response created by the micropump, and also the delivered volume of the drug delivery system.

  6. Home grocery delivery improves the household food environments of behavioral weight loss participants: results of an 8-week pilot study.

    Science.gov (United States)

    Gorin, Amy A; Raynor, Hollie A; Niemeier, Heather M; Wing, Rena R

    2007-11-14

    Household food availability is consistently linked to dietary intake; yet behavioral weight control treatment includes only minimal instruction on how to change the home environment to support dietary goals. This pilot study examined whether it is feasible to change the household food environments of behavioral weight loss participants through the use of a commercially available grocery home delivery service. Overweight participants (N = 28; BMI = 31.7 +/- 3.6 kg/m2; 89.3% women, 47.9 +/- 9.5 years) were randomly assigned to 8-weeks of standard behavioral weight loss (SBT) or to SBT plus home food delivery (SBT+Home). SBT+Home participants were instructed to do their household grocery shopping via an online service affiliated with a regional supermarket chain and were reimbursed for delivery charges. Compared to SBT, SBT+Home produced significantly greater reductions in the total number of foods in the home (p = .01) and number of foods that were high in fat (p = .002). While the groups did not differ in 8-week weight losses, within SBT+Home there was a trend for the number of home deliveries to be associated with weight loss (p = .08). Participants reported that the home delivery service was easy to use and that it helped decrease impulse purchases and lead to healthier choices; however, few planned to continue using the service after the study. Encouraging weight loss participants to use a commercially available online grocery ordering and home delivery service reduces the overall number of food items in the home and decreases access to high-fat food choices. More research is needed to determine whether this is a viable strategy to strengthen stimulus control and improve weight loss outcomes.

  7. Home grocery delivery improves the household food environments of behavioral weight loss participants: Results of an 8-week pilot study

    Directory of Open Access Journals (Sweden)

    Niemeier Heather M

    2007-11-01

    Full Text Available Abstract Background Household food availability is consistently linked to dietary intake; yet behavioral weight control treatment includes only minimal instruction on how to change the home environment to support dietary goals. This pilot study examined whether it is feasible to change the household food environments of behavioral weight loss participants through the use of a commercially available grocery home delivery service. Methods Overweight participants (N = 28; BMI = 31.7 ± 3.6 kg/m2; 89.3% women, 47.9 ± 9.5 years were randomly assigned to 8-weeks of standard behavioral weight loss (SBT or to SBT plus home food delivery (SBT+Home. SBT+Home participants were instructed to do their household grocery shopping via an online service affiliated with a regional supermarket chain and were reimbursed for delivery charges. Results Compared to SBT, SBT+Home produced significantly greater reductions in the total number of foods in the home (p = .01 and number of foods that were high in fat (p = .002. While the groups did not differ in 8-week weight losses, within SBT+Home there was a trend for the number of home deliveries to be associated with weight loss (p = .08. Participants reported that the home delivery service was easy to use and that it helped decrease impulse purchases and lead to healthier choices; however, few planned to continue using the service after the study. Conclusion Encouraging weight loss participants to use a commercially available online grocery ordering and home delivery service reduces the overall number of food items in the home and decreases access to high-fat food choices. More research is needed to determine whether this is a viable strategy to strengthen stimulus control and improve weight loss outcomes.

  8. The human CFTR protein expressed in CHO cells activates aquaporin-3 in a cAMP-dependent pathway: study by digital holographic microscopy

    KAUST Repository

    Jourdain, P.

    2013-12-11

    The transmembrane water movements during cellular processes and their relationship to ionic channel activity remain largely unknown. As an example, in epithelial cells it was proposed that the movement of water could be directly linked to cystic fibrosis transmembrane conductance regulator (CFTR) protein activity through a cAMP-stimulated aqueous pore, or be dependent on aquaporin. Here, we used digital holographic microscopy (DHM) an interferometric technique to quantify in situ the transmembrane water fluxes during the activity of the epithelial chloride channel, CFTR, measured by patch-clamp and iodide efflux techniques. We showed that the water transport measured by DHM is fully inhibited by the selective CFTR blocker CFTRinh172 and is absent in cells lacking CFTR. Of note, in cells expressing the mutated version of CFTR (F508del-CFTR), which mimics the most common genetic alteration encountered in cystic fibrosis, we also show that the water movement is profoundly altered but restored by pharmacological manipulation of F508del-CFTR-defective trafficking. Importantly, whereas activation of this endogenous water channel required a cAMP-dependent stimulation of CFTR, activation of CFTR or F508del-CFTR by two cAMP-independent CFTR activators, genistein and MPB91, failed to trigger water movements. Finally, using a specific small-interfering RNA against the endogenous aquaporin AQP3, the water transport accompanying CFTR activity decreased. We conclude that water fluxes accompanying CFTR activity are linked to AQP3 but not to a cAMP-stimulated aqueous pore in the CFTR protein.

  9. Strategies to improve drug delivery across the blood-brain barrier.

    Science.gov (United States)

    de Boer, Albertus G; Gaillard, Pieter J

    2007-01-01

    The blood-brain barrier (BBB), together with the blood-cerebrospinal-fluid barrier, protects and regulates the homeostasis of the brain. However, these barriers also limit the transport of small-molecule and, particularly, biopharmaceutical drugs such as proteins, genes and interference RNA to the brain, thereby limiting the treatment of many brain diseases. As a result, various drug delivery and targeting strategies are currently being developed to enhance the transport and distribution of drugs into the brain. In this review, we discuss briefly the biology and physiology of the BBB as the most important barrier for drug transport to the brain and, in more detail, the possibilities for delivering large-molecule drugs, particularly genes, by receptor-mediated nonviral drug delivery to the (human) brain. In addition, the systemic and intracellular pharmacokinetics of nonviral gene delivery, together with targeted brain imaging, are reviewed briefly.

  10. Does teaching of documentation of shoulder dystocia delivery through simulation result in improved documentation in real life?

    Science.gov (United States)

    Comeau, Robyn; Craig, Catherine

    2014-03-01

    Documentation of deliveries complicated by shoulder dystocia is a valuable communication skill necessary for residents to attain during residency training. Our objective was to determine whether the teaching of documentation of shoulder dystocia in a simulation environment would translate to improved documentation of the event in an actual clinical situation. We conducted a cohort study involving obstetrics and gynaecology residents in years 2 to 5 between November 2010 and December 2012. Each resident participated in a shoulder dystocia simulation teaching session and was asked to write a delivery note immediately afterwards. They were given feedback regarding their performance of the delivery and their documentation of the events. Following this, dictated records of shoulder dystocia deliveries immediately before and after the simulation session were identified through the Meditech system. An itemized checklist was used to assess the quality of residents' dictated documentation before and after the simulation session. All eligible residents (18) enrolled in the study, and 17 met the inclusion criteria. For 10 residents (59%) documentation of a delivery with shoulder dystocia was present before and after the simulation session, for five residents (29%) it was only present before the session, and for two residents (18%) it was only present after the session. When residents were assessed as a group, there were no differences in the proportion of residents recording items on the checklist before and after the simulation session (P > 0.05 for all). Similarly, analysis of the performance of the10 residents who had dictated documentation both before and after the session showed no differences in the number of elements recorded on dictations done before and after the simulation session (P > 0.05 for all). The teaching of shoulder dystocia documentation through simulation did not result in a measurable improvement in the quality of documentation of shoulder dystocia in

  11. Improved cytotoxicity of paclitaxel loaded in nanosized lipid carriers by intracellular delivery

    Energy Technology Data Exchange (ETDEWEB)

    Miao, Jing, E-mail: joemj1005@163.com, E-mail: miaojing@zju.edu.cn [Zhejiang University, Department of Pharmacy, the First Affiliated Hospital, College of Medicine (China); Du, Yongzhong; Yuan, Hong [Zhejiang University, College of Pharmaceutical Sciences (China); Zhang, Xingguo; Li, Qian; Rao, Yuefeng [Zhejiang University, Department of Pharmacy, the First Affiliated Hospital, College of Medicine (China); Zhao, Mengdan [Zhejiang University, Women’s Hospital, College of Medicine (China); Hu, Fuqiang, E-mail: hufq@zju.edu.cn [Zhejiang University, College of Pharmaceutical Sciences (China)

    2015-01-15

    Nanosized lipid carriers (NLC) can improve the limited drug-loading (DL) capacity and drug expulsion during storage, and adjust the drug release profile of solid lipid nanoparticles (SLN). In this study, Paclitaxel (PTX)-loaded NLC were prepared by solvent diffusion method using monostearin as solid lipid and oleic acid (OA) as liquid lipid matrix. The blank NLC with different OA content (the size range was from 89.5 ± 7.4 to 160.2 ± 34.6 nm) showed smaller size than the blank SLN (the size was 272.7 ± 43.6 nm), while the PTX-loaded NLC (the size range was from 481.3 ± 29.8 to 561.7 ± 38.3 nm) showed little bigger size, higher DL capacity, and faster drug in vitro release rate comparing with SLN (the size was 437.3 ± 68.2 nm). The 50 % cellular growth inhibitions (IC{sub 50}) of PTX-loaded NLC with 0, 5, 10, and 20 wt % OA were 0.92 ± 0.06, 0.69 ± 0.04, 0.25 ± 0.02, and 0.12 ± 0.02 µg mL{sup −1}, respectively, while the IC{sub 50} of Taxol{sup TM} was 1.72 ± 0.09 µg mL{sup −1}. For analyzing cellular drug effect, cellular uptakes of fluorescent NLC and intracellular drug concentration were investigated. As the incorporation of OA into solid lipid matrix could accelerate both the cellular uptake and the PTX delivery, loaded by NLC, the cytotoxicity of PTX could be enhanced, and further enhanced by increasing OA content in NLC.

  12. Improved cytotoxicity of paclitaxel loaded in nanosized lipid carriers by intracellular delivery

    International Nuclear Information System (INIS)

    Miao, Jing; Du, Yongzhong; Yuan, Hong; Zhang, Xingguo; Li, Qian; Rao, Yuefeng; Zhao, Mengdan; Hu, Fuqiang

    2015-01-01

    Nanosized lipid carriers (NLC) can improve the limited drug-loading (DL) capacity and drug expulsion during storage, and adjust the drug release profile of solid lipid nanoparticles (SLN). In this study, Paclitaxel (PTX)-loaded NLC were prepared by solvent diffusion method using monostearin as solid lipid and oleic acid (OA) as liquid lipid matrix. The blank NLC with different OA content (the size range was from 89.5 ± 7.4 to 160.2 ± 34.6 nm) showed smaller size than the blank SLN (the size was 272.7 ± 43.6 nm), while the PTX-loaded NLC (the size range was from 481.3 ± 29.8 to 561.7 ± 38.3 nm) showed little bigger size, higher DL capacity, and faster drug in vitro release rate comparing with SLN (the size was 437.3 ± 68.2 nm). The 50 % cellular growth inhibitions (IC 50 ) of PTX-loaded NLC with 0, 5, 10, and 20 wt % OA were 0.92 ± 0.06, 0.69 ± 0.04, 0.25 ± 0.02, and 0.12 ± 0.02 µg mL −1 , respectively, while the IC 50 of Taxol TM was 1.72 ± 0.09 µg mL −1 . For analyzing cellular drug effect, cellular uptakes of fluorescent NLC and intracellular drug concentration were investigated. As the incorporation of OA into solid lipid matrix could accelerate both the cellular uptake and the PTX delivery, loaded by NLC, the cytotoxicity of PTX could be enhanced, and further enhanced by increasing OA content in NLC

  13. Analysis of Y chromosome microdeletions and CFTR gene mutations as genetic markers of infertility in Serbian men

    Directory of Open Access Journals (Sweden)

    Dinić Jelena

    2007-01-01

    Full Text Available Background/Aim. Impaired fertility of a male partner is the main cause of infertility in up to one half of all infertile couples. At the genetic level, male infertility can be caused by chromosome aberrations or gene mutations. The presence and types of Y chromosome microdeletions and cystic fybrosis transmembrane conductance regulator (CFTR gene mutations as genetic cause of male infertility was tested in Serbian men. The aim of this study was to analyze CFTR gene mutations and Y chromosome microdelations as potential causes of male infertility in Serbian patients, as well as to test the hypothesis that CFTR mutations in infertile men are predominantly located in the several last exons of the gene. Methods. This study has encompassed 33 men with oligo- or azoospermia. The screening for Y chromosome microdeletions in the azoospermia factor (AZF region was performed by multiplex PCR analysis. The screening of the CFTR gene was performed by denaturing gradient gel electrophoresis (DGGE method. Results. Deletions on Y chromosome were detected in four patients, predominantly in AZFc region (four of total six deletions. Mutations in the CFTR gene were detected on eight out of 66 analyzed chromosomes of infertile men. The most common mutation was F508del (six of total eight mutations. Conclusion. This study confirmed that both Y chromosome microdeletions and CFTR gene mutations played important role in etiology of male infertility in Serbian infertile men. Genetic testing for Y chromosome microdeletions and CFTR gene mutations has been introduced in routine diagnostics and offered to couples undergoing assisted reproduction techniques. Considering that both the type of Y chromosome microdeletion and the type of CFTR mutation have a prognostic value, it is recommended that AZF and CFTR genotyping should not only be performed in patients with reduced sperm quality before undergoing assisted reproduction, but also for the purpose of preimplantation and

  14. A Study to Assess the Role of Educational Intervention in Improving the Delivery of Routine Immunization Services

    Directory of Open Access Journals (Sweden)

    Bhatia M

    2015-10-01

    Full Text Available Background: Immunization has been regarded as the most cost-effective intervention for child health promotion. Even after improvements, the developing countries are still struggling with low coverage rates, immunization failure, high rates of adverse events following immunization (AEFI etc. The present study was conducted to assess the role of educational intervention in improving immunization delivery services. Methodology: It was a pre-post intervention observational study carried out in immunization clinics of two tertiary care hospitals. The data from pre and post educational intervention assessment was compared and analyzed using SPSS 10.0. Results: At both clinics there was 40% and 45% increase in cleaning of the spoon used for administration of vitamin A. Post-intervention there was 40% increase in use of hub cutter at both the centres. After intervention, there was 30% and 35% increase in the delivery of four key messages by staff nurse. Conclusion: Unlike Doctors, the health staff is not motivated for regular touch with the theory part of their work field and continued knowledge up-gradation. This strategy of periodic re-orientation of the topic in the form of educational intervention may help in improving service delivery to the beneficiaries. Further research is required in this aspect.

  15. The effect of NO-donors on chloride efflux, intracellular Ca(2+) concentration and mRNA expression of CFTR and ENaC in cystic fibrosis airway epithelial cells.

    Science.gov (United States)

    Oliynyk, Igor; Hussain, Rashida; Amin, Ahmad; Johannesson, Marie; Roomans, Godfried M

    2013-06-01

    Since previous studies showed that the endogenous bronchodilator, S-nitrosglutathione (GSNO), caused a marked increase in CFTR-mediated chloride (Cl(-)) efflux and improved the trafficking of CFTR to the plasma membrane, and that also the nitric oxide (NO)-donor GEA3162 had a similar, but smaller, effect on Cl(-) efflux, it was investigated whether the NO-donor properties of GSNO were relevant for its effect on Cl(-) efflux from airway epithelial cells. Hence, the effect of a number of other NO-donors, sodium nitroprusside (SNP), S-nitroso-N-acetyl-DL-penicillamine (SNAP), diethylenetriamine/nitric oxide adduct (DETA-NO), and diethylenetriamine/nitric oxide adduct (DEA-NONOate) on Cl(-) efflux from CFBE (∆F508/∆F508-CFTR) airway epithelial cells was tested. Cl(-) efflux was determined using the fluorescent N-(ethoxycarbonylmethyl)-6-methoxyquinoliniu bromide (MQAE)-technique. Possible changes in the intracellular Ca(2+) concentration were tested by the fluorescent fluo-4 method in a confocal microscope system. Like previously with GSNO, after 4 h incubation with the NO-donor, an increased Cl(-) efflux was found (in the order SNAP>DETA-NO>SNP). The effect of DEA-NONOate on Cl(-) efflux was not significant, and the compound may have (unspecific) deleterious effects on the cells. Again, as with GSNO, after a short (5 min) incubation, SNP had no significant effect on Cl(-) efflux. None of the NO-donors that had a significant effect on Cl(-) efflux caused significant changes in the intracellular Ca(2+) concentration. After 4 h preincubation, SNP caused a significant increase in the mRNA expression of CFTR. SNAP and DEA-NONOate decreased the mRNA expression of all ENaC subunits significantly. DETA-NO caused a significant decrease only in α-ENaC expression. After a short preincubation, none of the NO-donors had a significant effect, neither on the expression of CFTR, nor on that of the ENaC subunits in the presence and absence of L-cysteine. It can be concluded that

  16. Applicability and Efficiency of NGS in Routine Diagnosis: In-Depth Performance Analysis of a Complete Workflow for CFTR Mutation Analysis.

    Directory of Open Access Journals (Sweden)

    Adrien Pagin

    Full Text Available Actually, about 2000 sequence variations have been documented in the CFTR gene requiring extensive and multi-step genetic testing in the diagnosis of cystic fibrosis and CFTR-related disorders. We present a two phases study, with validation and performance monitoring, of a single experiment methodology based on multiplex PCR and high throughput sequencing that allows detection of all variants, including large rearrangements, affecting the coding regions plus three deep intronic loci.A total of 340 samples, including 257 patients and 83 previously characterized control samples, were sequenced in 17 MiSeq runs and analyzed with two bioinformatic pipelines in routine diagnostic conditions. We obtained 100% coverage for all the target regions in every tested sample.We correctly identified all the 87 known variants in the control samples and successfully confirmed the 62 variants identified among the patients without observing false positive results. Large rearrangements were identified in 18/18 control samples. Only 17 patient samples showed false positive signals (6.6%, 12 of which showed a borderline result for a single amplicon. We also demonstrated the ability of the assay to detect allele specific dropout of amplicons when a sequence variation occurs at a primer binding site thus limiting the risk for false negative results.We described here the first NGS workflow for CFTR routine analysis that demonstrated equivalent diagnostic performances compared to Sanger sequencing and multiplex ligation-dependent probe amplification. This study illustrates the advantages of NGS in term of scalability, workload reduction and cost-effectiveness in combination with an improvement of the overall data quality due to the simultaneous detection of SNVs and large rearrangements.

  17. A New Targeted CFTR Mutation Panel Based on Next-Generation Sequencing Technology.

    Science.gov (United States)

    Lucarelli, Marco; Porcaro, Luigi; Biffignandi, Alice; Costantino, Lucy; Giannone, Valentina; Alberti, Luisella; Bruno, Sabina Maria; Corbetta, Carlo; Torresani, Erminio; Colombo, Carla; Seia, Manuela

    2017-09-01

    Searching for mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) is a key step in the diagnosis of and neonatal and carrier screening for cystic fibrosis (CF), and it has implications for prognosis and personalized therapy. The large number of mutations and genetic and phenotypic variability make this search a complex task. Herein, we developed, validated, and tested a laboratory assay for an extended search for mutations in CFTR using a next-generation sequencing-based method, with a panel of 188 CFTR mutations customized for the Italian population. Overall, 1426 dried blood spots from neonatal screening, 402 genomic DNA samples from various origins, and 1138 genomic DNA samples from patients with CF were analyzed. The assay showed excellent analytical and diagnostic operative characteristics. We identified and experimentally validated 159 (of 188) CFTR mutations. The assay achieved detection rates of 95.0% and 95.6% in two large-scale case series of CF patients from central and northern Italy, respectively. These detection rates are among the highest reported so far with a genetic test for CF based on a mutation panel. This assay appears to be well suited for diagnostics, neonatal and carrier screening, and assisted reproduction, and it represents a considerable advantage in CF genetic counseling. Copyright © 2017 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

  18. Increasing the density of nanomedicines improves their ultrasound-mediated delivery to tumours

    Czech Academy of Sciences Publication Activity Database

    Mo, S.; Carlisle, R.; Laga, Richard; Myers, R.; Graham, S.; Cawood, R.; Ulbrich, Karel; Seymour, L.; Coussios, C. C.

    2015-01-01

    Roč. 210, 28 July (2015), s. 10-18 ISSN 0168-3659 R&D Projects: GA MŠk(CZ) EE2.3.30.0029 Institutional support: RVO:61389013 Keywords : delivery * density * tumour Subject RIV: CE - Biochemistry Impact factor: 7.441, year: 2015

  19. Improving Service Delivery: Investigating the Role of Information Sharing, Job Characteristics, and Employee Satisfaction

    Science.gov (United States)

    Bontis, Nick; Richards, David; Serenko, Alexander

    2011-01-01

    Purpose: The purpose of this study is to propose and test a model designed to investigate the impact of job characteristics, employee satisfaction, and information sharing on two key indicators of quality service delivery, such as worker perceptions of their efficiency and customer focus. Design/methodology/approach: During the project, 9,060…

  20. Improving the Quality and Cost of Healthcare Delivery: The Potential of Radio Frequency Identification (RFID) Technology

    Science.gov (United States)

    Vilamovska, Anna-Marie

    2010-01-01

    The study investigated whether an upcoming class of health information technology (HIT) can be used to address currently outstanding issues in the quality and cost of healthcare delivery. Expert interviews and a literature review were used to describe the 2009 universe of in- and outpatient healthcare RFID applications and to identify those…

  1. Efficient intracellular delivery and improved biocompatibility of colloidal silver nanoparticles towards intracellular SERS immuno-sensing.

    Science.gov (United States)

    Bhardwaj, Vinay; Srinivasan, Supriya; McGoron, Anthony J

    2015-06-21

    High throughput intracellular delivery strategies, electroporation, passive and TATHA2 facilitated diffusion of colloidal silver nanoparticles (AgNPs) are investigated for cellular toxicity and uptake using state-of-art analytical techniques. The TATHA2 facilitated approach efficiently delivered high payload with no toxicity, pre-requisites for intracellular applications of plasmonic metal nanoparticles (PMNPs) in sensing and therapeutics.

  2. Improved oral bioavailability of poorly water-soluble indirubin by a supersaturatable self-microemulsifying drug delivery system

    Directory of Open Access Journals (Sweden)

    Chen ZQ

    2012-02-01

    Full Text Available Zhi-Qiang Chen, Ying Liu, Ji-Hui Zhao, Lan Wang, Nian-Ping FengSchool of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of ChinaBackground: Indirubin, isolated from the leaves of the Chinese herb Isatis tinctoria L, is a protein kinase inhibitor and promising antitumor agent. However, the poor water solubility of indirubin has limited its application. In this study, a supersaturatable self-microemulsifying drug delivery system (S-SMEDDS was developed to improve the oral bioavailability of indirubin.Methods: A prototype S-SMEDDS was designed using solubility studies and phase diagram construction. Precipitation inhibitors were selected from hydrophilic polymers according to their crystallization-inhibiting capacity through in vitro precipitation tests. In vitro release of indirubin from S-SMEDDS was examined to investigate its likely release behavior in vivo. The in vivo bioavailability of indirubin from S-SMEDDS and from SMEDDS was compared in rats.Results: The prototype formulation of S-SMEDDS comprised Maisine™ 35-1:Cremophor® EL:Transcutol® P (15:40:45, w/w/w. Polyvinylpyrrolidone K17, a hydrophilic polymer, was used as a precipitation inhibitor based on its better crystallization-inhibiting capacity compared with polyethylene glycol 4000 and hydroxypropyl methylcellulose. In vitro release analysis showed more rapid drug release from S-SMEDDS than from SMEDDS. In vivo bioavailability analysis in rats indicated that improved oral absorption was achieved and that the relative bioavailability of S-SMEDDS was 129.5% compared with SMEDDS.Conclusion: The novel S-SMEDDS developed in this study increased the dissolution rate and improved the oral bioavailability of indirubin in rats. The results suggest that S-SMEDDS is a superior means of oral delivery of indirubin.Keywords: supersaturatable self-microemulsifying drug delivery system, indirubin, bioavailability, oral drug delivery, hydrophilic polymer

  3. Important role of platelets in modulating endotoxin-induced lung inflammation in CFTR-deficient mice.

    Directory of Open Access Journals (Sweden)

    Caiqi Zhao

    Full Text Available Mutation of CFTR (cystic fibrosis transmembrane conductance regulator leads to cystic fibrosis (CF. Patients with CF develop abnormalities of blood platelets and recurrent lung inflammation. However, whether CFTR-mutated platelets play a role in the development of lung inflammation is elusive. Therefore, we intratracheally challenged wildtype and F508del (a common type of CFTR mutation mice with LPS to observe changes of F508del platelets in the peripheral blood and indexes of lung inflammation (BAL neutrophils and protein levels. Furthermore, we investigated whether or not and how F508del platelets modulate the LPS-induced acute lung inflammation by targeting anti-platelet aggregation, depletion of neutrophils, reconstitution of bone marrow or neutrophils, blockade of P-selectin glycoprotein ligand-1 (PSGL-1, platelet activating factor (PAF, and correction of mutated CFTR trafficking. We found that LPS-challenged F508del mice developed severe thrombocytopenia and had higher levels of plasma TXB2 coincided with neutrophilic lung inflammation relative to wildtype control. Inhibition of F508del platelet aggregation or depletion of F508del neutrophils diminished the LPS-induced lung inflammation in the F508del mice. Moreover, wildtype mice reconstituted with either F508del bone marrow or neutrophils developed worse thrombocytopenia. Blocking PSGL-1, platelet activating factor (PAF, or rectifying trafficking of mutated CFTR in F508del mice diminished and alveolar neutrophil transmigration in the LPS-challenged F508del mice. These findings suggest that F508del platelets and their interaction with neutrophils are requisite for the development of LPS-induced lung inflammation and injury. As such, targeting platelets might be an emerging strategy for dampening recurrent lung inflammation in cystic fibrosis patients.

  4. Captopril improves tumor nanomedicine delivery by increasing tumor blood perfusion and enlarging endothelial gaps in tumor blood vessels.

    Science.gov (United States)

    Zhang, Bo; Jiang, Ting; Tuo, Yanyan; Jin, Kai; Luo, Zimiao; Shi, Wei; Mei, Heng; Hu, Yu; Pang, Zhiqing; Jiang, Xinguo

    2017-12-01

    Poor tumor perfusion and unfavorable vessel permeability compromise nanomedicine drug delivery to tumors. Captopril dilates blood vessels, reducing blood pressure clinically and bradykinin, as the downstream signaling moiety of captopril, is capable of dilating blood vessels and effectively increasing vessel permeability. The hypothesis behind this study was that captopril can dilate tumor blood vessels, improving tumor perfusion and simultaneously enlarge the endothelial gaps of tumor vessels, therefore enhancing nanomedicine drug delivery for tumor therapy. Using the U87 tumor xenograft with abundant blood vessels as the tumor model, tumor perfusion experiments were carried out using laser Doppler imaging and lectin-labeling experiments. A single treatment of captopril at a dose of 100 mg/kg significantly increased the percentage of functional vessels in tumor tissues and improved tumor blood perfusion. Scanning electron microscopy of tumor vessels also indicated that the endothelial gaps of tumor vessels were enlarged after captopril treatment. Immunofluorescence-staining of tumor slices demonstrated that captopril significantly increased bradykinin expression, possibly explaining tumor perfusion improvements and endothelial gap enlargement. Additionally, imaging in vivo, imaging ex vivo and nanoparticle distribution in tumor slices indicated that after a single treatment with captopril, the accumulation of 115-nm nanoparticles in tumors had increased 2.81-fold with a more homogeneous distribution pattern in comparison to non-captopril treated controls. Finally, pharmacodynamics experiments demonstrated that captopril combined with paclitaxel-loaded nanoparticles resulted in the greatest tumor shrinkage and the most extensive necrosis in tumor tissues among all treatment groups. Taken together, the data from the present study suggest a novel strategy for improving tumor perfusion and enlarging blood vessel permeability simultaneously in order to improve

  5. Design and development of microemulsion drug delivery system of acyclovir for improvement of oral bioavailability

    OpenAIRE

    Ghosh, Pradip Kumar; Majithiya, Rita J.; Umrethia, Manish L.; Murthy, Rayasa S. R.

    2006-01-01

    The main purpose of this work was to develop an oral microemulsion formulation for enhancing the bioavailability of acyclovir. A Labrafac-based microemulsion formulation with Labrasol as surfactant and Plurol Oleique as cosurfactant was developed for oral delivery of acyclovir. Phase behavior and solubilization capacity of the microemulsion system were characterized, and in vivo oral absorption of acyclovir from the microemulsion was investigated in rats. A single isotropic region, which was ...

  6. Polyethylenimine-modified Pluronics (PCMs) Improve Morpholino Oligomer Delivery in Cell Culture and Dystrophic mdx Mice

    OpenAIRE

    Wang, Mingxing; Wu, Bo; Lu, Peijuan; Cloer, Caryn; Tucker, Jay D; Lu, Qilong

    2012-01-01

    We investigated a series of small-sized polyethylenimine (PEI, 0.8/1.2 k)-conjugated pluronic copolymers (PCMs) for their potential to enhance delivery of an antisense phosphorodiamidate morpholino oligomer (PMO) in vitro and in dystrophic mdx mice. PCM polymers containing pluronics of molecular weight (Mw) ranging 2–6 k, with hydrophilic-lipophilic balance (HLB) 7–23, significantly enhanced PMO-induced exon-skipping in a green fluorescent protein (GFP) reporter-based myoblast culture system....

  7. Self-Micro Emulsifying Drug Delivery Systems: a Strategy to Improve Oral Bioavailability

    Directory of Open Access Journals (Sweden)

    Vijay K. Sharma

    Full Text Available Aim: Oral route has always been the favorite route of drug administration in many diseases and till today it is the first way investigated in the development of new dosage forms. The major problem in oral drug formulations is low and erratic bioavailability, which mainly results from poor aqueous solubility, thereby pose problems in their formulation. For the therapeutic delivery of lipophilic active moieties (BCS class II drugs, lipid based formulations are inviting increasing attention. Methods: To that aim, from the web sites of PubMed, HCAplus, Thomson, and Registry were used as the main sources to perform the search for the most significant research articles published on the subject. The information was then carefully analyzed, highlighting the most important results in the formulation and development of self-micro emulsifying drug delivery systems as well as its therapeutic activity. Results: Self-emulsifying drug delivery system (SMEDDS has gained more attention due to enhanced oral bio-availability enabling reduction in dose, more consistent temporal profiles of drug absorption, selective targeting of drug(s toward specific absorption window in GIT, and protection of drug(s from the unreceptive environment in gut. Conclusions: This article gives a complete overview of SMEDDS as a promising approach to effectively deal with the problem of poorly soluble molecules.

  8. Vented spikes improve delivery from intravenous bags with no air headspace.

    Science.gov (United States)

    Galush, William J; Horst, Travis A

    2015-07-01

    Flexible plastic bags are the container of choice for most intravenous (i.v.) infusions. Under certain circumstances, however, the air-liquid interface present in these i.v. bags can lead to physical instability of protein biopharmaceuticals, resulting in product aggregation. In principle, the air headspace present in the bags can be removed to increase drug stability, but experiments described here show that this can result in incomplete draining of solution from the bag using gravity delivery, or generation of negative pressure in the bag when an infusion pump is used. It is expected that these issues could lead to incomplete delivery of medication to patients or pump-related problems, respectively. However, here it is shown that contrary to the standard pharmacy practice of using nonvented spikes with i.v. bags, the use of vented spikes with i.v. bags that lack air headspace allows complete delivery of the dose solution without impacting the physical stability of a protein-based drug. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  9. Platelet-Rich Plasma in Bone Regeneration: Engineering the Delivery for Improved Clinical Efficacy

    Directory of Open Access Journals (Sweden)

    Isaac A. Rodriguez

    2014-01-01

    Full Text Available Human bone is a tissue with a fairly remarkable inherent capacity for regeneration; however, this regenerative capacity has its limitations, and defects larger than a critical size lack the ability to spontaneously heal. As such, the development and clinical translation of effective bone regeneration modalities are paramount. One regenerative medicine approach that is beginning to gain momentum in the clinical setting is the use of platelet-rich plasma (PRP. PRP therapy is essentially a method for concentrating platelets and their intrinsic growth factors to stimulate and accelerate a healing response. While PRP has shown some efficacy in both in vitro and in vivo scenarios, to date its use and delivery have not been optimized for bone regeneration. Issues remain with the effective delivery of the platelet-derived growth factors to a localized site of injury, the activation and temporal release of the growth factors, and the rate of growth factor clearance. This review will briefly describe the physiological principles behind PRP use and then discuss how engineering its method of delivery may ultimately impact its ability to successfully translate to widespread clinical use.

  10. Using Quality Improvement Methods and Time-Driven Activity-Based Costing to Improve Value-Based Cancer Care Delivery at a Cancer Genetics Clinic.

    Science.gov (United States)

    Tan, Ryan Y C; Met-Domestici, Marie; Zhou, Ke; Guzman, Alexis B; Lim, Soon Thye; Soo, Khee Chee; Feeley, Thomas W; Ngeow, Joanne

    2016-03-01

    To meet increasing demand for cancer genetic testing and improve value-based cancer care delivery, National Cancer Centre Singapore restructured the Cancer Genetics Service in 2014. Care delivery processes were redesigned. We sought to improve access by increasing the clinic capacity of the Cancer Genetics Service by 100% within 1 year without increasing direct personnel costs. Process mapping and plan-do-study-act (PDSA) cycles were used in a quality improvement project for the Cancer Genetics Service clinic. The impact of interventions was evaluated by tracking the weekly number of patient consultations and access times for appointments between April 2014 and May 2015. The cost impact of implemented process changes was calculated using the time-driven activity-based costing method. Our study completed two PDSA cycles. An important outcome was achieved after the first cycle: The inclusion of a genetic counselor increased clinic capacity by 350%. The number of patients seen per week increased from two in April 2014 (range, zero to four patients) to seven in November 2014 (range, four to 10 patients). Our second PDSA cycle showed that manual preappointment reminder calls reduced the variation in the nonattendance rate and contributed to a further increase in patients seen per week to 10 in May 2015 (range, seven to 13 patients). There was a concomitant decrease in costs of the patient care cycle by 18% after both PDSA cycles. This study shows how quality improvement methods can be combined with time-driven activity-based costing to increase value. In this paper, we demonstrate how we improved access while reducing costs of care delivery. Copyright © 2016 by American Society of Clinical Oncology.

  11. Improving service delivery of water, sanitation, and hygiene in primary schools: a cluster-randomized trial in western Kenya.

    Science.gov (United States)

    Alexander, Kelly T; Dreibelbis, Robert; Freeman, Matthew C; Ojeny, Betty; Rheingans, Richard

    2013-09-01

    Water, sanitation, and hygiene (WASH) programs in schools have been shown to improve health and reduce absence. In resource-poor settings, barriers such as inadequate budgets, lack of oversight, and competing priorities limit effective and sustained WASH service delivery in schools. We employed a cluster-randomized trial to examine if schools could improve WASH conditions within existing administrative structures. Seventy schools were divided into a control group and three intervention groups. All intervention schools received a budget for purchasing WASH-related items. One group received no further intervention. A second group received additional funding for hiring a WASH attendant and making repairs to WASH infrastructure, and a third group was given guides for student and community monitoring of conditions. Intervention schools made significant improvements in provision of soap and handwashing water, treated drinking water, and clean latrines compared with controls. Teachers reported benefits of monitoring, repairs, and a WASH attendant, but quantitative data of WASH conditions did not determine whether expanded interventions out-performed our budget-only intervention. Providing schools with budgets for WASH operational costs improved access to necessary supplies, but did not ensure consistent service delivery to students. Further work is needed to clarify how schools can provide WASH services daily.

  12. Improved Treatment of Pancreatic Cancer With Drug Delivery Nanoparticles Loaded With a Novel AKT/PDK1 Inhibitor.

    Science.gov (United States)

    Kobes, Joseph E; Daryaei, Iman; Howison, Christine M; Bontrager, Jordan G; Sirianni, Rachael W; Meuillet, Emmanuelle J; Pagel, Mark D

    2016-09-01

    This research study sought to improve the treatment of pancreatic cancer by improving the drug delivery of a promising AKT/PDK1 inhibitor, PHT-427, in poly(lactic-co-glycolic) acid (PLGA) nanoparticles. PHT-427 was encapsulated in single-emulsion and double-emulsion PLGA nanoparticles (SE-PLGA-427 and DE-PLGA-427). The drug release rate was evaluated to assess the effect of the second PLGA layer of DE-PLGA-427. Ex vivo cryo-imaging and drug extraction from ex vivo organs was used to assess the whole-body biodistribution in an orthotopic model of MIA PaCa-2 pancreatic cancer. Anatomical magnetic resonance imaging (MRI) was used to noninvasively assess the effects of 4 weeks of nanoparticle drug treatment on tumor size, and diffusion-weighted MRI longitudinally assessed changes in tumor cellularity. DE-PLGA-427 showed delayed drug release and longer drug retention in the pancreas relative to SE-PLGA-427. Diffusion-weighted MRI indicated a consistent decrease in cellularity during drug treatment with both types of drug-loaded nanoparticles. Both SE- and DE-PLGA-427 showed a 6-fold and 4-fold reduction in tumor volume relative to untreated tumors and an elimination of primary pancreatic tumor in 68% of the mice. These results indicated that the PLGA nanoparticles improved drug delivery of PHT-427 to pancreatic tumors, which improved the treatment of MIA PaCa-2 pancreatic cancer.

  13. Improving the Simplified Acquisition of Base Engineering Requirements (SABER) Delivery Order Award Process: Results of a Process Improvement Plan

    Science.gov (United States)

    1991-09-01

    putting all tasks directed towsrds achieving an outcome in aequence. The tasks can be viewed as steps in the process (39:2.3). Using this...improvement opportunity is investigated. A plan is developed, root causes are identified, and solutions are tested and implemented. The process is... solutions , check for actual improvement, and integrate the successful improvements into the process. ?UP 7. Check Improvement Performance. Finally, the

  14. Towards comprehensive early abortion service delivery in high income countries: insights for improving universal access to abortion in Australia

    Directory of Open Access Journals (Sweden)

    Angela Dawson

    2016-10-01

    Full Text Available Abstract Background Improving access to safe abortion is an essential strategy in the provision of universal access to reproductive health care. Australians are largely supportive of the provision of abortion and its decriminalization. However, the lack of data and the complex legal and service delivery situation impacts upon access for women seeking an early termination of pregnancy. There are no systematic reviews from a health services perspective to help direct health planners and policy makers to improve access comprehensive medical and early surgical abortion in high income countries. This review therefore aims to identify quality studies of abortion services to provide insight into how access to services can be improved in Australia. Methods We undertook a structured search of six bibliographic databases and hand-searching to ascertain peer reviewed primary research in English between 2005 and 2015. Qualitative and quantitative study designs were deemed suitable for inclusion. A deductive content analysis methodology was employed to analyse selected manuscripts based upon a framework we developed to examine access to early abortion services. Results This review identified the dimensions of access to surgical and medical abortion at clinic or hospital-outpatient based abortion services, as well as new service delivery approaches utilising a remote telemedicine approach. A range of factors, mostly from studies in the United Kingdom and United States of America were found to facilitate improved access to abortion, in particular, flexible service delivery approaches that provide women with cost effective options and technology based services. Standards, recommendations and targets were also identified that provided services and providers with guidance regarding the quality of abortion care. Conclusions Key insights for service delivery in Australia include the: establishment of standards, provision of choice of procedure, improved provider

  15. Natural products to improve quality of life targeting for colon drug delivery.

    Science.gov (United States)

    Kim, Hyunjo

    2012-03-01

    The colon is largely being investigated as a site for administration of protein and peptides, which are degraded by digestive enzymes in the upper GIT. Also for local diseases of the colon such as inflammatory bowel disease, colorectal cancer and ameobiasis, drug administration to the site of action can not only reduce the dose to be administered, but also decrease the side effects. Inflammatory Bowel Disease (IBD) such as Ulcerative colitis and Crohn's disease are characterized by chronic intestinal inflammation. Intestinal bacteria initiate the activation of intestinal inflammatory processes, which are mediated by pro-inflammatory cytokines and chemokine. Increased chemokine expression has also been observed in epithelial cells, endothelial cells, and smooth muscle cells. Future trials of specific agents capable of inhibiting chemokine synthesis and secretion or blocking chemokine-chemokine receptor interaction will be important to study in patients with ulcerative colitis and Crohn's disease. Many important bioactive compounds have been discovered from natural sources using bioactivity directed fractionation and isolation (BDFl) Continuing discovery has also been facilitated by the recent development of new bioassay methods. These bioactive compounds are mostly plant secondary metabolites, and many naturally occurring pure compounds have become medicines, dietary supplements, and other useful commercial products. The present review includes various approaches investigated for colon drug delivery and their site specificity. To achieve successful colonic delivery, a drug needs to be protected from absorption and the environment of the upper gastrointestinal tract and then be abruptly released into the proximal colon, which is considered the optimum site for colon targeted delivery of drugs.

  16. Quality improvement in healthcare delivery utilizing the patient-centered medical home model.

    Science.gov (United States)

    Akinci, Fevzi; Patel, Poonam M

    2014-01-01

    Despite the fact that the United States dedicates so much of its resources to healthcare, the current healthcare delivery system still faces significant quality challenges. The lack of effective communication and coordination of care services across the continuum of care poses disadvantages for those requiring long-term management of their chronic conditions. This is why the new transformation in healthcare known as the patient-centered medical home (PCMH) can help restore confidence in our population that the healthcare services they receive is of the utmost quality and will effectively enhance their quality of life. Healthcare using the PCMH model is delivered with the patient at the center of the transformation and by reinvigorating primary care. The PCMH model strives to deliver effective quality care while attempting to reduce costs. In order to relieve some of our healthcare system distresses, organizations can modify their delivery of care to be patient centered. Enhanced coordination of services, better provider access, self-management, and a team-based approach to care represent some of the key principles of the PCMH model. Patients that can most benefit are those that require long-term management of their conditions such as chronic disease and behavioral health patient populations. The PCMH is a feasible option for delivery reform as pilot studies have documented successful outcomes. Controversy about the lack of a medical neighborhood has created concern about the overall sustainability of the medical home. The medical home can stand independently and continuously provide enhanced care services as a movement toward higher quality care while organizations and government policy assess what types of incentives to put into place for the full collaboration and coordination of care in the healthcare system.

  17. Modulation of electrostatic interactions to improve controlled drug delivery from nanogels

    Energy Technology Data Exchange (ETDEWEB)

    Mauri, Emanuele; Chincarini, Giulia M.F.; Rigamonti, Riccardo; Magagnin, Luca; Sacchetti, Alessandro, E-mail: alessandro.sacchetti@polimi.it; Rossi, Filippo, E-mail: filippo.rossi@polimi.it

    2017-03-01

    The synthesis of nanogels as devices capable to maintain the drug level within a desired range for a long and sustained period of time is a leading strategy in controlled drug delivery. However, with respect to the good results obtained with antibodies and peptides there are a lot of problems related to the quick and uncontrolled diffusion of small hydrophilic molecules through polymeric network pores. For these reasons research community is pointing toward the use of click strategies to reduce release rates of the linked drugs to the polymer chains. Here we propose an alternative method that considers the electrostatic interactions between polymeric chains and drugs to tune the release kinetics from nanogel network. The main advantage of these systems lies in the fact that the carried drugs are not modified and no chemical reactions take place during their loading and release. In this work we synthesized PEG-PEI based nanogels with different protonation degrees and the release kinetics with charged and uncharged drug mimetics (sodium fluorescein, SF, and rhodamine B, RhB) were studied. Moreover, also the effect of counterion used to induce protonation was taken into account in order to build a tunable drug delivery system able to provide multiple release rates with the same device. - Highlights: • The design of nanogels as drug delivery systems based on electrostatic interaction among drug and polymers is proposed. • Nanogels can be synthetized tuning their positive charge density, according to the protonation of PEI at different pH. • No biorthogonal chemistry strategies are applied to the polymers or drugs. • Drug release is efficiently modulated by charge density of PEI chains. • The effect of counterion on nanogel synthesis is investigated and allows controlling the drug release.

  18. Novel designed polyoxyethylene nonionic surfactant with improved safety and efficiency for anticancer drug delivery

    Directory of Open Access Journals (Sweden)

    Li C

    2014-04-01

    Full Text Available Chang Li,1 Chunmeng Sun,1 Shasha Li,1 Peng Han,2 Huimin Sun,3 Ammar Ouahab,1 Yan Shen,1 Yourui Xu,1 Yerong Xiong,1 Jiasheng Tu11State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 2Chinese Pharmacopoeia Commission, Beijing, 3National Institute for Food and Drug Control, Beijing, People's Republic of ChinaAbstract: In order to limit the adverse reactions caused by polysorbate 80 in Taxotere®, a widely used formulation of docetaxel, a safe and effective nanocarrier for this drug has been developed based on micelles formed by a new class of well-defined polyoxyethylene sorbitol oleate (PSO with sorbitol as the matrix in aqueous solution. The physicochemical properties of the amphiphilic surfactant and the resulting micelles can be easily fine-tuned by the homogeneous sorbitol matrix and pure oleic acid. Composition, critical micelle concentration, and entrapment efficiency were investigated by ultraviolet visible spectroscopy, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, fluorospectrophotometry, and high-performance liquid chromatography. In vitro and in vivo evaluation revealed that PSO had exceptionally low hemolysis and histamine release rates compared with commercial polysorbate 80. Moreover, the tumor targeting delivery of PSO was investigated by in vivo imaging in S180 tumor-bearing mice. The results suggest that this novel delivery system, PSO, provides an acceptable alternative to polysorbate 80 for delivery of docetaxel. Further, due to the hypoallergenic nature of PSO, the mechanism of pseudoallergy caused by the polyoxyethylene nonionic surfactant was investigated. Based on in vitro cell analysis, it was assumed that the initial contact of polyoxyethylene nonionic surfactant with mast cells provoked pseudoallergy via polyamine receptor-mediated endocytosis.Keywords: polyoxyethylene nonionic surfactant, sorbitol, isosorbide, pseudoallergy

  19. Improving the Delivery of SOD1 Antisense Oligonucleotides to Motor Neurons Using Calcium Phosphate-Lipid Nanoparticles

    Directory of Open Access Journals (Sweden)

    Liyu Chen

    2017-08-01

    P-lipid NPs could be an effective and safe delivery system for the improved delivery of SOD1 ASOs to motor neurons. Further in vivo evaluation in transgenic mouse models of SOD1 ALS are therefore warranted.

  20. Attitudinal orientation of first level managers for improvement of municipal service delivery: Experience of training intervention in Kolkata

    Directory of Open Access Journals (Sweden)

    Uttam Kumar Roy

    2010-07-01

    Full Text Available This paper discusses a program of attitudinal orientation courses provided for functionaries of a large municipal corporation in India. Almost 450 Assistant Managers from the Kolkata Municipal Corporation took part in the training, which was held at the Administrative Training Institute (ATI of the Government of West Bengal, India. Under the 74th Constitutional Amendment Act, Indian Municipalities/Corporations (Urban Local Bodies are empowered and entrusted to perform planning, development and governance for the city/ town and to provide services to the citizens. The change in outlook towards the local government reflected in the Act has highlighted the need for greater awareness and a better attitude amongst municipal staff as well as elected representatives towards service delivery. Good governance can be achieved through the overall performance of officials of an organization, provided they possess the necessary knowledge, skills, attitudes and competencies. For historical reasons, knowledge, skills and attitudes amongst officials of Urban Local Bodies (ULBs in India have been traditionally of a low standard. Willingness to perform better in the role of municipal service delivery is not common. Therein lies the need for training for improvement in service delivery, especially for organizations like large municipal corporations and municipalities.

  1. A Blockchain Ecosystem for Digital Identity: Improving Service Delivery in Canada’s Public and Private Sectors

    Directory of Open Access Journals (Sweden)

    Greg Wolfond

    2017-10-01

    Full Text Available Blockchain-based solutions have the potential to make government operations more efficient and improve the delivery of services in the public and private sectors. Identity verification and authentication technologies, as one of the applications of blockchain-based solutions – and the focus of our own efforts at SecureKey Technologies – have been critical components in service delivery in both sectors due to their power to increase trust between citizens and the services they access. To convert trust into solid value added, identities must be validated through highly-reliable technologies, such as blockchain, that have the capacity to reduce cost and fraud and to simplify the experience for customers while also keeping out the bad actors. With identities migrating to digital platforms, organizations and citizens need to be able to transact with reduced friction even as more counter-bound services move to online delivery. In this article, drawing on our own experiences with an ecosystem approach to digital identity, we describe the potential value of using blockchain technology to address the present and future challenges of identity verification and authentication within a Canadian context.

  2. Current insights into the role of PKA phosphorylation in CFTR channel activity and the pharmacological rescue of cystic fibrosis disease-causing mutants.

    Science.gov (United States)

    Chin, Stephanie; Hung, Maurita; Bear, Christine E

    2017-01-01

    Cystic fibrosis transmembrane conductance regulator (CFTR) channel gating is predominantly regulated by protein kinase A (PKA)-dependent phosphorylation. In addition to regulating CFTR channel activity, PKA phosphorylation is also involved in enhancing CFTR trafficking and mediating conformational changes at the interdomain interfaces of the protein. The major cystic fibrosis (CF)-causing mutation is the deletion of phenylalanine at position 508 (F508del); it causes many defects that affect CFTR trafficking, stability, and gating at the cell surface. Due to the multiple roles of PKA phosphorylation, there is growing interest in targeting PKA-dependent signaling for rescuing the trafficking and functional defects of F508del-CFTR. This review will discuss the effects of PKA phosphorylation on wild-type CFTR, the consequences of CF mutations on PKA phosphorylation, and the development of therapies that target PKA-mediated signaling.

  3. Analysis of cystic fibrosis gener product (CFTR) function in patients with pancreas divisum and recurrent acute pancreatitis.

    Science.gov (United States)

    Gelrud, Andres; Sheth, Sunil; Banerjee, Subhas; Weed, Deborah; Shea, Julie; Chuttani, Ram; Howell, Douglas A; Telford, Jennifer J; Carr-Locke, David L; Regan, Meredith M; Ellis, Lynda; Durie, Peter R; Freedman, Steven D

    2004-08-01

    The mechanism by which pancreas divisum may lead to recurrent episodes of acute pancreatitis in a subset of individuals is unknown. Abnormalities of the cystic fibrosis gene product (CFTR) have been implicated in the genesis of idiopathic chronic pancreatitis. The aim of this study was to determine if CFTR function is abnormal in patients with pancreas divisum and recurrent acute pancreatitis (PD/RAP). A total of 69 healthy control subjects, 12 patients with PD/RAP, 16 obligate heterozygotes with a single CFTR mutation, and 95 patients with cystic fibrosis were enrolled. CFTR function was analyzed by nasal transepithelial potential difference testing in vivo. The outcomes of the PD/RAP patients following endoscopic and surgical treatments were concomitantly analyzed. Direct measurement of CFTR function in nasal epithelium in response to isoproterenol demonstrated that the values for PD/RAP were intermediate between those observed for healthy controls and cystic fibrosis patients. The median value was 13 mV for PD/RAP subjects, which was statistically different from healthy controls (22 mV, p= 0.001) and cystic fibrosis pancreatic sufficient (-1 mV, p < 0.0001) and pancreatic insufficient (-3 mV, p < 0.0001) patients. These results suggest a link between CFTR dysfunction and recurrent acute pancreatitis in patients with pancreas divisum and may explain why a subset of patients with pancreas divisum develops recurrent acute pancreatitis. Copyright 2004 American College of Gastroenterology

  4. CFTR mutations spectrum and the efficiency of molecular diagnostics in Polish cystic fibrosis patients.

    Directory of Open Access Journals (Sweden)

    Ewa Ziętkiewicz

    Full Text Available Cystic fibrosis (CF is caused by mutations in the cystic fibrosis transmembrane regulator gene (CFTR. In light of the strong allelic heterogeneity and regional specificity of the mutation spectrum, the strategy of molecular diagnostics and counseling in CF requires genetic tests to reflect the frequency profile characteristic for a given population. The goal of the study was to provide an updated comprehensive estimation of the distribution of CFTR mutations in Polish CF patients and to assess the effectiveness of INNOLiPA_CFTR tests in Polish population. The analyzed cohort consisted of 738 patients with the clinically confirmed CF diagnosis, prescreened for molecular defects using INNOLiPA_CFTR panels from Innogenetics. A combined efficiency of INNOLiPA CFTR_19 and CFTR_17_TnUpdate tests was 75.5%; both mutations were detected in 68.2%, and one mutation in 14.8% of the affected individuals. The group composed of all the patients with only one or with no mutation detected (109 and 126 individuals, respectively was analyzed further using a mutation screening approach, i.e. SSCP/HD (single strand conformational polymorphism/heteroduplex analysis of PCR products followed by sequencing of the coding sequence. As a result, 53 more mutations were found in 97 patients. The overall efficiency of the CF allele detection was 82.5% (7.0% increase compared to INNOLiPA tests alone. The distribution of the most frequent mutations in Poland was assessed. Most of the mutations repetitively found in Polish patients had been previously described in other European populations. The most frequent mutated allele, F508del, represented 54.5% of Polish CF chromosomes. Another eight mutations had frequencies over 1%, 24 had frequencies between 1 and 0.1%; c.2052-2053insA and c.3468+2_3468+3insT were the most frequent non-INNOLiPA mutations. Mutation distribution described herein is also relevant to the Polish diaspora. Our study also demonstrates that the reported

  5. Pluronic-Functionalized Silica-Lipid Hybrid Microparticles: Improving the Oral Delivery of Poorly Water-Soluble Weak Bases.

    Science.gov (United States)

    Rao, Shasha; Richter, Katharina; Nguyen, Tri-Hung; Boyd, Ben J; Porter, Christopher J H; Tan, Angel; Prestidge, Clive A

    2015-12-07

    A Pluronic-functionalized silica-lipid hybrid (Plu-SLH) microparticle system for the oral delivery of poorly water-soluble, weak base drugs is reported for the first time. A highly effective Plu-SLH microparticle system was composed of Labrasol as the lipid phase, Pluronic F127 as the polymeric precipitation inhibitor (PPI), and silica nanoparticles as the solid carrier. For the model drug cinnarizine (CIN), the Plu-SLH delivery system was shown to offer significant biopharmaceutical advantages in comparison with unformulated drug and drug in the silica-lipid hybrid (SLH) system. In vitro two-phase dissolution studies illustrated significantly reduced pH provoked CIN precipitation and an 8- to 14-fold improvement in the extent of dissolution in intestinal conditions. In addition, under simulated intestinal digesting conditions, the Plu-SLH provided approximately three times more drug solubilization than the SLH. Oral administration in rats resulted in superior bioavailability for Plu-SLH microparticles, i.e., 1.6- and 2.1-fold greater than the SLH and the unformulated CIN, respectively. A physical mixture of Pluronic and SLH (Plu&SLH), having the same composition as Plu-SLH, was also evaluated, but showed no significant increase in CIN absorption when compared to unmodified CIN or SLH. This work represents the first study where different methods of incorporating PPI to formulate solid-state lipid-based formulations were compared for the impact on the biopharmaceutical performance. The data suggest that the novel physicochemical properties and structure of the fabricated Plu-SLH microparticle delivery system play an important role in facilitating the synergistic advantage of Labrasol and Pluronic F127 in preventing drug precipitation, and the Plu-SLH provides efficient oral delivery of poorly water-soluble weak bases.

  6. End-Tidal CO2-Guided Chest Compression Delivery Improves Survival in a Neonatal Asphyxial Cardiac Arrest Model.

    Science.gov (United States)

    Hamrick, Justin T; Hamrick, Jennifer L; Bhalala, Utpal; Armstrong, Jillian S; Lee, Jeong-Hoo; Kulikowicz, Ewa; Lee, Jennifer K; Kudchadkar, Sapna R; Koehler, Raymond C; Hunt, Elizabeth A; Shaffner, Donald H

    2017-11-01

    To determine whether end-tidal CO2-guided chest compression delivery improves survival over standard cardiopulmonary resuscitation after prolonged asphyxial arrest. Preclinical randomized controlled study. University animal research laboratory. 1-2-week-old swine. After undergoing a 20-minute asphyxial arrest, animals received either standard or end-tidal CO2-guided cardiopulmonary resuscitation. In the standard group, chest compression delivery was optimized by video and verbal feedback to maintain the rate, depth, and release within published guidelines. In the end-tidal CO2-guided group, chest compression rate and depth were adjusted to obtain a maximal end-tidal CO2 level without other feedback. Cardiopulmonary resuscitation included 10 minutes of basic life support followed by advanced life support for 10 minutes or until return of spontaneous circulation. Mean end-tidal CO2 at 10 minutes of cardiopulmonary resuscitation was 34 ± 8 torr in the end-tidal CO2 group (n = 14) and 19 ± 9 torr in the standard group (n = 14; p = 0.0001). The return of spontaneous circulation rate was 7 of 14 (50%) in the end-tidal CO2 group and 2 of 14 (14%) in the standard group (p = 0.04). The chest compression rate averaged 143 ± 10/min in the end-tidal CO2 group and 102 ± 2/min in the standard group (p tidal CO2-guided chest compression delivery. The response of the relaxation arterial pressure and cerebral perfusion pressure to the initial epinephrine administration was greater in the end-tidal CO2 group than in the standard group (p = 0.01 and p = 0.03, respectively). The prevalence of resuscitation-related injuries was similar between groups. End-tidal CO2-guided chest compression delivery is an effective resuscitation method that improves early survival after prolonged asphyxial arrest in this neonatal piglet model. Optimizing end-tidal CO2 levels during cardiopulmonary resuscitation required that chest compression delivery rate exceed current guidelines

  7. Delivery of adipose-derived stem cells in poloxamer hydrogel improves peripheral nerve regeneration.

    Science.gov (United States)

    Allbright, Kassandra O; Bliley, Jacqueline M; Havis, Emmanuelle; Kim, Deok-Yeol; Dibernardo, Gabriella A; Grybowski, Damian; Waldner, Matthias; James, Isaac B; Sivak, Wesley N; Rubin, J Peter; Marra, Kacey G

    2018-02-06

    Peripheral nerve damage is associated with high long-term morbidity. Because of beneficial secretome, immunomodulatory effects, and ease of clinical translation, transplantation with adipose-derived stem cells (ASC) represents a promising therapeutic modality. Effect of ASC delivery in poloxamer hydrogel was assessed in a rat sciatic nerve model of critical-sized (1.5 cm) peripheral nerve injury. Nerve/muscle unit regeneration was assessed via immunostaining explanted nerve, quantitative polymerase chain reaction (qPCR), and histological analysis of reinnervating gastrocnemius muscle. On the basis of viability data, 10% poloxamer hydrogel was selected for in vivo study. Six weeks after transection and repair, the group treated with poloxamer delivered ASCs demonstrated longest axonal regrowth. The qPCR results indicated that the inclusion of ASCs appeared to result in expression of factors that aid in reinnervating muscle tissue. Delivery of ASCs in poloxamer addresses multiple facets of the complexity of nerve/muscle unit regeneration, representing a promising avenue for further study. Muscle Nerve, 2018. © 2018 Wiley Periodicals, Inc.

  8. Modulation of electrostatic interactions to improve controlled drug delivery from nanogels.

    Science.gov (United States)

    Mauri, Emanuele; Chincarini, Giulia M F; Rigamonti, Riccardo; Magagnin, Luca; Sacchetti, Alessandro; Rossi, Filippo

    2017-03-01

    The synthesis of nanogels as devices capable to maintain the drug level within a desired range for a long and sustained period of time is a leading strategy in controlled drug delivery. However, with respect to the good results obtained with antibodies and peptides there are a lot of problems related to the quick and uncontrolled diffusion of small hydrophilic molecules through polymeric network pores. For these reasons research community is pointing toward the use of click strategies to reduce release rates of the linked drugs to the polymer chains. Here we propose an alternative method that considers the electrostatic interactions between polymeric chains and drugs to tune the release kinetics from nanogel network. The main advantage of these systems lies in the fact that the carried drugs are not modified and no chemical reactions take place during their loading and release. In this work we synthesized PEG-PEI based nanogels with different protonation degrees and the release kinetics with charged and uncharged drug mimetics (sodium fluorescein, SF, and rhodamine B, RhB) were studied. Moreover, also the effect of counterion used to induce protonation was taken into account in order to build a tunable drug delivery system able to provide multiple release rates with the same device. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Can delivery systems use cost-effectiveness analysis to reduce healthcare costs and improve value?

    Science.gov (United States)

    Savitz, Lucy A; Savitz, Samuel T

    2016-01-01

    Understanding costs and ensuring that we demonstrate value in healthcare is a foundational presumption as we transform the way we deliver and pay for healthcare in the U.S. With a focus on population health and payment reforms underway, there is increased pressure to examine cost-effectiveness in healthcare delivery. Cost-effectiveness analysis (CEA) is a type of economic analysis comparing the costs and effects (i.e. health outcomes) of two or more treatment options. The result is expressed as a ratio where the denominator is the gain in health from a measure (e.g. years of life or quality-adjusted years of life) and the numerator is the incremental cost associated with that health gain. For higher cost interventions, the lower the ratio of costs to effects, the higher the value. While CEA is not new, the approach continues to be refined with enhanced statistical techniques and standardized methods. This article describes the CEA approach and also contrasts it to optional approaches, in order for readers to fully appreciate caveats and concerns. CEA as an economic evaluation tool can be easily misused owing to inappropriate assumptions, over reliance, and misapplication. Twelve issues to be considered in using CEA results to drive healthcare delivery decision-making are summarized. Appropriately recognizing both the strengths and the limitations of CEA is necessary for informed resource allocation in achieving the maximum value for healthcare services provided.

  10. Biomimickry of UPEC Cytoinvasion: A Novel Concept for Improved Drug Delivery in UTI

    Directory of Open Access Journals (Sweden)

    Clara Maria Pichl

    2016-02-01

    Full Text Available Urinary tract infections (UTIs are among the most common bacterial infections. In an increasing number of cases, pathogen (multi-resistance hampers durable treatment success via the standard therapies. On the functional level, the activity of urinary excreted antibiotics is compromized by the efficient tissue colonization mechanism of uropathogenic Escherichia coli (UPEC. Advanced drug delivery systems aim at exploiting a glycan-mediated targeting mechanism, similar to the UPEC invasion pathway, to increase bioavailability. This may be realized by conjugation of intravesically applied drugs or drug carriers to chosen plant lectins. Higher local drug concentrations in or nearby bacterial reservoirs may be gained, with higher chances for complete eradication. In this study, preliminary parameters to clarify the potential of this biorecognitive approach were evaluated. Glycan-triggered interaction cascades and uptake processes of several plant lectins with distinct carbohydrate specificities were characterized, and wheat germ agglutinin (WGA could be identified as the most promising targeter for crossing the urothelial membrane barrier. In partially differentiated primary cells, intracellular accumulation sites were largely identical for GlcNAc- and Mannose-specific lectins. This indicates that WGA-mediated delivery may also enter host cells via the FimH-dependent uptake pathway.

  11. Sustained reductions in time to antibiotic delivery in febrile immunocompromised children: results of a quality improvement collaborative.

    Science.gov (United States)

    Dandoy, Christopher E; Hariharan, Selena; Weiss, Brian; Demmel, Kathy; Timm, Nathan; Chiarenzelli, Janis; Dewald, Mary Katherine; Kennebeck, Stephanie; Langworthy, Shawna; Pomales, Jennifer; Rineair, Sylvia; Sandfoss, Erin; Volz-Noe, Pamela; Nagarajan, Rajaram; Alessandrini, Evaline

    2016-02-01

    Timely delivery of antibiotics to febrile immunocompromised (F&I) paediatric patients in the emergency department (ED) and outpatient clinic reduces morbidity and mortality. The aim of this quality improvement initiative was to increase the percentage of F&I patients who received antibiotics within goal in the clinic and ED from 25% to 90%. Using the Model of Improvement, we performed Plan-Do-Study-Act cycles to design, test and implement high-reliability interventions to decrease time to antibiotics. Pre-arrival interventions were tested and implemented, followed by post-arrival interventions in the ED. Many processes were spread successfully to the outpatient clinic. The Chronic Care Model was used, in addition to active family engagement, to inform and improve processes. The study period was from January 2010 to January 2015. Pre-arrival planning improved our F&I time to antibiotics in the ED from 137 to 88 min. This was sustained until October 2012, when further interventions including a pre-arrival huddle decreased the median time to antibiotics within 60 min to >90%. In September 2014, we implemented a rapid response team to improve reliable venous access in the ED, which increased our mean percentage of patients receiving timely antibiotics to its highest rate (95%). This stepwise approach with pre-arrival planning using the Chronic Care Model, followed by standardisation of processes, created a sustainable improvement of timely antibiotic delivery in F&I patients. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  12. Improvement of drug delivery by hyperthermia treatment using magnetic cubic cobalt ferrite nanoparticles

    Energy Technology Data Exchange (ETDEWEB)

    Dey, Chaitali, E-mail: chaitalidey29@gmail.com [Centre for Research in Nanoscience & Nanotechnology, Block-JD-2, Sector-III, Salt Lake, Kolkata 700106 (India); Baishya, Kaushik [S.N. Bose National Centre for Basic Sciences, Block-JD, Sector-III, Salt Lake, Kolkata 700106 (India); Ghosh, Arup [S.N. Bose National Centre for Basic Sciences, Block-JD, Sector-III, Salt Lake, Kolkata 700106 (India); Department of Physics, Indian Institute of Science Education and Research (IISER) Pune, Dr. Homi Bhabha Road, Pashan, Pune 411008 (India); Goswami, Madhuri Mandal, E-mail: madhuri@bose.res.in [S.N. Bose National Centre for Basic Sciences, Block-JD, Sector-III, Salt Lake, Kolkata 700106 (India); Ghosh, Ajay [Dept. of Applied Optics and Photonics, University of Calcutta, Block-JD-2, Sector-III, Salt Lake, Kolkata 700106 (India); Mandal, Kalyan [S.N. Bose National Centre for Basic Sciences, Block-JD, Sector-III, Salt Lake, Kolkata 700106 (India)

    2017-04-01

    In this study, we report a novel synthesis method, characterization and application of a new class of ferromagnetic cubic cobalt ferrite magnetic nanoparticles (MNPs) for hyperthermia therapy and temperature triggered drug release. The MNPs are characterized by XRD, TEM, FESEM, AC magnetic hysteresis and VSM. These MNPs were coated with folic acid and loaded with an anticancer drug. The drug release studies were done at two different temperatures (37 °C and 44 °C) with progress of time. It was found that higher release of drug took place at elevated temperature (44 °C). We have developed a temperature sensitive drug delivery system which releases the heat sensitive drug selectively as the particles are heated up under AC magnetic field and controlled release is possible by changing the external AC magnetic field.

  13. Improved survival for elderly married glioblastoma patients. Better treatment delivery, less toxicity, and fewer disease complications

    International Nuclear Information System (INIS)

    Putz, Florian; Goerig, Nicole; Knippen, Stefan; Gryc, Thomas; Semrau, Sabine; Lettmaier, Sebastian; Fietkau, Rainer; Putz, Tobias; Eyuepoglu, Ilker; Roessler, Karl

    2016-01-01

    Marital status is a well-described prognostic factor in patients with gliomas but the observed survival difference is unexplained in the available population-based studies. A series of 57 elderly glioblastoma patients (≥70 years) were analyzed retrospectively. Patients received radiotherapy or chemoradiation with temozolomide. The prognostic significance of marital status was assessed. Disease complications, toxicity, and treatment delivery were evaluated in detail. Overall survival was significantly higher in married than in unmarried patients (median, 7.9 vs. 4.0 months; p = 0.006). The prognostic significance of marital status was preserved in the multivariate analysis (HR, 0.41; p = 0.011). Married patients could receive significantly higher daily temozolomide doses (mean, 53.7 mg/m"2 vs. 33.1 mg/m"2; p = 0.020), were more likely to receive maintenance temozolomide (45.7 % vs. 11.8 %; p = 0.016), and had to be hospitalized less frequently during radiotherapy (55.0 % vs. 88.2 %; p = 0.016). Of the patients receiving temozolomide, married patients showed significantly lower rates of hematologic and liver toxicity. Most complications were infectious or neurologic in nature. Complications of any grade were more frequent in unmarried patients (58.8 % vs. 30.0 %; p = 0.041) with the incidence of grade 3-5 complications being particularly elevated (47.1 % vs. 15.0 %; p = 0.004). We found poorer treatment delivery as well as an unexpected severe increase in toxicity and disease complications in elderly unmarried glioblastoma patients. Marital status may be an important predictive factor for clinical decision-making and should be addressed in further studies. (orig.) [de

  14. Improved survival for elderly married glioblastoma patients : Better treatment delivery, less toxicity, and fewer disease complications.

    Science.gov (United States)

    Putz, Florian; Putz, Tobias; Goerig, Nicole; Knippen, Stefan; Gryc, Thomas; Eyüpoglu, Ilker; Rössler, Karl; Semrau, Sabine; Lettmaier, Sebastian; Fietkau, Rainer

    2016-11-01

    Marital status is a well-described prognostic factor in patients with gliomas but the observed survival difference is unexplained in the available population-based studies. A series of 57 elderly glioblastoma patients (≥70 years) were analyzed retrospectively. Patients received radiotherapy or chemoradiation with temozolomide. The prognostic significance of marital status was assessed. Disease complications, toxicity, and treatment delivery were evaluated in detail. Overall survival was significantly higher in married than in unmarried patients (median, 7.9 vs. 4.0 months; p = 0.006). The prognostic significance of marital status was preserved in the multivariate analysis (HR, 0.41; p = 0.011). Married patients could receive significantly higher daily temozolomide doses (mean, 53.7 mg/m² vs. 33.1 mg/m²; p = 0.020), were more likely to receive maintenance temozolomide (45.7 % vs. 11.8 %; p = 0.016), and had to be hospitalized less frequently during radiotherapy (55.0 % vs. 88.2 %; p = 0.016). Of the patients receiving temozolomide, married patients showed significantly lower rates of hematologic and liver toxicity. Most complications were infectious or neurologic in nature. Complications of any grade were more frequent in unmarried patients (58.8 % vs. 30.0 %; p = 0.041) with the incidence of grade 3-5 complications being particularly elevated (47.1 % vs. 15.0 %; p = 0.004). We found poorer treatment delivery as well as an unexpected severe increase in toxicity and disease complications in elderly unmarried glioblastoma patients. Marital status may be an important predictive factor for clinical decision-making and should be addressed in further studies.

  15. CFTR depletion results in changes in fatty acid composition and promotes lipogenesis in intestinal Caco 2/15 cells.

    Directory of Open Access Journals (Sweden)

    Geneviève Mailhot

    2010-05-01

    Full Text Available Abnormal fatty acid composition (FA in plasma and tissue lipids frequently occurs in homozygous and even in heterozygous carriers of cystic fibrosis transmembrane conductance regulator (CFTR mutations. The mechanism(s underlying these abnormalities remained, however, poorly understood despite the potentially CFTR contributing role.The aim of the present study was to investigate the impact of CFTR depletion on FA uptake, composition and metabolism using the intestinal Caco-2/15 cell line. shRNA-mediated cftr gene silencing induced qualitative and quantitative modifications in FA composition in differentiated enterocytes as determined by gas-liquid chromatography. With the cftr gene disruption, there was a 1,5 fold increase in the total FA amount, largely attributable to monounsaturated and saturated FA compared to controls. The activity of delta-7 desaturase, estimated by the 16:1(n-7/16:0, was significantly higher in knockdown cells and consistent with the striking elevation of the n-7 FA family. When incubated with [14C]-oleic acid, CFTR-depleted cells were capable of quick incorporation and export to the medium concomitantly with the high protein expression of L-FABP known to promote intracellular FA trafficking. Accordingly, lipoprotein vehicles (CM, VLDL, LDL and HDL, isolated from CFTR knockdown cells, exhibited higher levels of radiolabeled FA. Moreover, in the presence of [14C]-acetate, knockdown cells exhibited enhanced secretion of newly synthesized phospholipids, triglycerides, cholesteryl esters and free FA, thereby suggesting a stimulation of the lipogenic pathway. Conformably, gene expression of SREBP-1c, a key lipogenic transcription factor, was increased while protein expression of the phosphorylated and inactive form of acetylCoA carboxylase was reduced, confirming lipogenesis induction. Finally, CFTR-depleted cells exhibited lower gene expression of transcription factors (PPARalpha, LXRalpha, LXRbeta and RXRalpha

  16. An injectable hybrid nanoparticle-in-oil-in-water submicron emulsion for improved delivery of poorly soluble drugs

    Science.gov (United States)

    Wang, Shuo; Wang, Hua; Liang, Wenquan; Huang, Yongzhuo

    2012-04-01

    Poor drugability problems are commonly seen in a class of chemical entities with poor solubility in water and oil, and moreover, physicochemical instability of these compounds poses extra challenges in design of dosage forms. Such problems contribute a significant high failure rate in new drug development. A hybrid nanoparicle-in-oil-in-water (N/O/W) submicron emulsion was proposed for improved delivery of poorly soluble and unstable drugs (e.g., dihydroartemisinin (DHA)). DHA is known for its potent antimalarial effect and antitumor activity. However, its insolubility and instability impose big challenges for formulations, and so far, no injectable dosage forms are clinically available yet. Therefore, an injectable DHA N/O/W system was developed. Unlike other widely-explored systems (e.g., liposomes, micelles, and emulsions), in which low drug load and only short-term storage are often found, the hybrid submicron emulsion possesses three-fold higher drug-loading capacity than the conventional O/W emulsion. Of note, it can be manufactured into a freeze-drying form and can render its storage up to 6 months even in room temperature. The in vivo studies demonstrated that the PK profiles were significantly improved, and this injectable system was effective in suppressing tumor growth. The strategy provides a useful solution to effective delivery of such a class of drugs.

  17. Improving family planning services delivery and uptake: experiences from the "Reversing the Stall in Fertility Decline in Western Kenya Project".

    Science.gov (United States)

    Amo-Adjei, Joshua; Mutua, Michael; Athero, Sherine; Izugbara, Chimaraoke; Ezeh, Alex

    2017-10-10

    In this paper, we reflect on our experiences of implementing a multipronged intervention to improve sexual and reproductive health outcomes. The project used family planning as its entry point and was implemented in two high fertility counties-Busia and Siaya in Kenya. The intervention, implemented by a seven-member consortium, involved: family planning services delivery; regular training of service providers to deliver high quality services; monitoring and evaluation; strengthening of commodity chain delivery and forecasting; school-based and out-of-school based sexuality education; and advocacy and stakeholder engagements at the community, county and national levels. Over a 5-year period, the project contributed to raising demand for family planning considerably, evidenced in fertility decline. It also improved the capacity of family planning services providers, increased commitment and awareness of county government and other community stakeholders on the importance of investments in family planning. Our collaborations with organisations interested in sexual and reproductive health issues substantially enhanced the consortium's ability to increase demand for, and supply of family planning commodities. These collaborations are proving useful in the continuity and sustainability of project achievements.

  18. F508del-CFTR rescue: a matter of cell stress response.

    Science.gov (United States)

    Nieddu, Erika; Pollarolo, Benedetta; Merello, Luisa; Schenone, Silvia; Mazzei, Mauro

    2013-01-01

    Cystic fibrosis (CF) is a common inherited fatal disease affecting 70,000 people worldwide, with a median predicted age of survival of approximately 38 years. The deletion of Phenylalanine in position 508 of the Cystic Fibrosis Transmembrane conductance Regulator (F508del-CFTR) is the most common mutation in CF patients: the deleted protein, not properly folded, is degraded. To date no commercial drugs are available. Low temperature, some osmolytes and conditions able to induce heat shock protein 70 (Hsp70) expression and heat shock cognate 70 (Hsc70) inhibition result in F508del-CFTR rescue, hence restoring its physiological function: this review sheds light on the correlation between these several evidences. Interestingly, all these approaches have a role in the cell stress response (CSR), a set of cell reactions to stress. In addition, unpredictably, F508del-CFTR rescue has to be considered in the frame of CSR: entities that induce - or are induced during - the CSR are, in general, also able to correct trafficking defect of CFTR. Specifically, the low temperature induces, by definition, a CSR; osmolytes, such as glycerol and trimethylamine N-oxide (TMAO), are products of the CSR; pharmacological correctors, such as Matrine and 4-phenylbutirric acid (4PBA), down-regulate the constitutive Hsc70 in favor of an up-regulation of the inducible chaperone Hsp70, another component of the CSR. The identification of a common mechanism of action for different types of correctors could drive the discovery of new active molecules in CF, overcoming methods clinically inapplicable, such as the low temperature.

  19. Stimulation of Intestinal Cl- Secretion Through CFTR by Caffeine Intake in Salt-Sensitive Hypertensive Rats

    Directory of Open Access Journals (Sweden)

    Xiao Wei

    2018-03-01

    Full Text Available Background/Aims: High salt consumption is a major risk factor for hypertension, and sodium homeostasis is regulated by both intestinal sodium absorption and urinary sodium excretion. Chronic caffeine intake has been reported to attenuate salt-sensitive hypertension by promoting urinary sodium excretion; however, its exact role in intestinal sodium absorption remains unknown. Here, we investigated whether and how chronic caffeine consumption antagonizes salt-sensitive hypertension by inhibiting intestinal sodium absorption. Methods: Dahl salt-sensitive rats were fed 8% NaCl chow and 0.1% caffeine in their drinking water for 15 days. The blood pressure and fecal sodium content were measured. The effect of caffeine on the movement of Cl- in enterocyte cells was determined with the Ussing chamber assay. Results: Rats that were treated with caffeine displayed significantly lower mean blood pressure and higher fecal sodium content than the controls. Consistent with these findings, caffeine intake decreased fluid absorption by the intestine in the fluid perfusion experiment. Further, the results from the Ussing chamber assay indicated that caffeine promoted Cl- secretion through enterocyte apical cystic fibrosis transmembrane conductance regulator (CFTR, and thus inhibited sodium absorption. Moreover, depletion of cAMP or inhibition of CFTR completely abolished the effect of caffeine on Cl- secretion. Conclusion: The results indicate that chronic caffeine consumption reduces sodium absorption by promoting CFTR-mediated Cl- secretion in the intestine, which contributes to the anti-hypertensive effect of caffeine in salt-sensitive rats.

  20. CFTR-dependent defect in alternatively-activated macrophages in cystic fibrosis.

    Science.gov (United States)

    Tarique, Abdullah A; Sly, Peter D; Holt, Patrick G; Bosco, Anthony; Ware, Robert S; Logan, Jayden; Bell, Scott C; Wainwright, Claire E; Fantino, Emmanuelle

    2017-07-01

    The role of the macrophages in cystic fibrosis (CF) lung disease has been poorly studied. We hypothesized that alternatively activated M2 macrophages are abnormal in CF lung disease. Blood samples were collected from adults (n=13) children (n=27) with CF on admission for acute pulmonary exacerbation and when clinically stable. Monocytes were differentiated into macrophages and polarized into classical (M1) and alternatively-activated (M2) phenotypes, function determined ex-vivo and compared with healthy controls. In the absence of functional cystic fibrosis trans-membrane conductance regulator (CFTR), either naturally in patients with CF or induced with CFTR inhibitors, monocyte-derived macrophages do not respond to IL-13/IL-4, fail to polarize into M2s associated with a post-transcriptional failure to produce and express IL-13Rα1 on the macrophage surface Polarization to the M1 phenotype was unaffected. CFTR-dependent imbalance of macrophage phenotypes and functions could contribute to the exaggerated inflammatory response seen in CF lung disease. Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

  1. Antibodies to the CFTR modulate the turgor pressure of guard cell protoplasts via slow anion channels.

    Science.gov (United States)

    Leonhardt, N; Bazin, I; Richaud, P; Marin, E; Vavasseur, A; Forestier, C

    2001-04-06

    The plasma membrane guard cell slow anion channel is a key element at the basis of water loss control in plants allowing prolonged osmolite efflux necessary for stomatal closure. This channel has been extensively studied by electrophysiological approaches but its molecular identification is still lacking. Recently, we described that this channel was sharing some similarities with the mammalian ATP-binding cassette protein, cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel [Leonhardt, N. et al. (1999) Plant Cell 11, 1141-1151]. Here, using the patch-clamp technique and a bioassay, consisting in the observation of the change in guard cell protoplasts volume, we demonstrated that a functional antibody raised against the mammalian CFTR prevented ABA-induced guard cell protoplasts shrinking and partially inhibited the slow anion current. Moreover, this antibody immunoprecipitated a polypeptide from guard cell protein extracts and immunolabeled stomata in Vicia faba leaf sections. These results indicate that the guard cell slow anion channel is, or is closely controlled by a polypeptide, exhibiting one epitope shared with the mammalian CFTR.

  2. A new compound heterozygous CFTR mutation in a Chinese family with cystic fibrosis.

    Science.gov (United States)

    Xie, Yingjun; Huang, Xueqiong; Liang, Yujian; Xu, Lingling; Pei, Yuxin; Cheng, Yucai; Zhang, Lidan; Tang, Wen

    2017-11-01

    Cystic fibrosis (CF) is the most common autosomal recessive disease among Caucasians but is rarer in the Chinese population, because mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. To elucidate the causative role of a novel compound heterozygous mutation of CF. In this study, clinical samples were obtained from two siblings with recurrent airway infections, clubbed fingers, salt-sweat and failure to gain weight in a non-consanguineous Chinese family. Next-generation sequencing was performed on the 27 coding exons of CFTR in both children, with confirmation by Sanger sequencing. Next-generation sequencing showed the same compound heterozygous CFTR mutation (c.865A>T p.Arg289X and c.3651_3652insAAAT p.Tyr1219X) in both children. As this mutation is consistent with the clinical manifestations of CF and no other mutations were detected after scanning the gene sequence, we suggest that the CF phenotype is caused by compound heterozygosity for c.865A>T and c.3651_3652insAAAT. As c865A>T is not currently listed in the "Cystic Fibrosis Mutation Database", this information about CF in a Chinese population is of interest. © 2015 John Wiley & Sons Ltd.

  3. Longevity and plasticity of CFTR provide an argument for noncanonical SNP organization in hominid DNA.

    Directory of Open Access Journals (Sweden)

    Aubrey E Hill

    Full Text Available Like many other ancient genes, the cystic fibrosis transmembrane conductance regulator (CFTR has survived for hundreds of millions of years. In this report, we consider whether such prodigious longevity of an individual gene--as opposed to an entire genome or species--should be considered surprising in the face of eons of relentless DNA replication errors, mutagenesis, and other causes of sequence polymorphism. The conventions that modern human SNP patterns result either from purifying selection or random (neutral drift were not well supported, since extant models account rather poorly for the known plasticity and function (or the established SNP distributions found in a multitude of genes such as CFTR. Instead, our analysis can be taken as a polemic indicating that SNPs in CFTR and many other mammalian genes may have been generated--and continue to accrue--in a fundamentally more organized manner than would otherwise have been expected. The resulting viewpoint contradicts earlier claims of 'directional' or 'intelligent design-type' SNP formation, and has important implications regarding the pace of DNA adaptation, the genesis of conserved non-coding DNA, and the extent to which eukaryotic SNP formation should be viewed as adaptive.

  4. Title IV Quality Control Project, Stage II. Management Option II: Delivery System Quality Improvements.

    Science.gov (United States)

    Advanced Technology, Inc., Reston, VA.

    Stage Two of the Title IV Quality Control Project is an integrated study of quality in five related Federal financial aid programs for postsecondary students. Section 1 of the paper establishes a framework for defining quality improvements, in order to identify the types of changes that would tend to improve quality across all facets of the…

  5. Realist synthesis of educational interventions to improve nutrition care competencies and delivery by doctors and other healthcare professionals

    Science.gov (United States)

    Mogre, Victor; Scherpbier, Albert J J A; Stevens, Fred; Aryee, Paul; Cherry, Mary Gemma; Dornan, Tim

    2016-01-01

    Objective To determine what, how, for whom, why, and in what circumstances educational interventions improve the delivery of nutrition care by doctors and other healthcare professionals work. Design Realist synthesis following a published protocol and reported following Realist and Meta-narrative Evidence Synthesis: Evolving Standards (RAMESES) guidelines. A multidisciplinary team searched MEDLINE, CINAHL, ERIC, EMBASE, PsyINFO, Sociological Abstracts, Web of Science, Google Scholar and Science Direct for published and unpublished (grey) literature. The team identified studies with varied designs; appraised their ability to answer the review question; identified relationships between contexts, mechanisms and outcomes (CMOs); and entered them into a spreadsheet configured for the purpose. The final synthesis identified commonalities across CMO configurations. Results Over half of the 46 studies from which we extracted data originated from the USA. Interventions that improved the delivery of nutrition care improved skills and attitudes rather than just knowledge; provided opportunities for superiors to model nutrition care; removed barriers to nutrition care in health systems; provided participants with local, practically relevant tools and messages; and incorporated non-traditional, innovative teaching strategies. Operating in contexts where student and qualified healthcare professionals provided nutrition care in developed and developing countries, these interventions yielded health outcomes by triggering a range of mechanisms, which included feeling competent, feeling confident and comfortable, having greater self-efficacy, being less inhibited by barriers in healthcare systems and feeling that nutrition care was accepted and recognised. Conclusions These findings show how important it is to move education for nutrition care beyond the simple acquisition of knowledge. They show how educational interventions embedded within systems of healthcare can improve

  6. Preparation and characterization of docetaxel self-nanoemulsifying powders (SNEPs): A strategy for improved oral delivery

    Energy Technology Data Exchange (ETDEWEB)

    Sunkavalli, Sharath; Eedara, Basanth Babu; Janga, Karthik Yadav; Velpula, Ashok; Jukanti, Raju; Bandari, Suresh [St. Peter' s Institute of Pharmaceutical Sciences, Warangal (India)

    2016-03-15

    Liquid self-nanoemulsifying drug delivery systems (L-SNEDDS) of docetaxel were prepared using varying ratios of Capmul PG 8 NF (oil), Cremophor EL (surfactant) and Transcutol-P (co-surfactant). The optimized L-SNEDDS (L{sub 11}) was transformed into self-nanoemulsifying powder (SNEP) by physical adsorption on to Neusilin US2 and evaluated for dissolution behavior, in vitro cytotoxicity and in vivo oral bioavailability. Optimized L-SNEDDS (L{sub 11}) composed of 50% of oil, 41.7% of surfactant and 8.3% co-surfactant produced stable emulsion with smaller globules (43±3 nm). In vitro dissolution studies showed the rapid drug release within 5min (95.42±1%) from SNEP{sub N}. In vitro cytotoxicity assessed by the MTT assay using MCF-7 human breast cancer cell lines revealed that L-SNEDDS significantly reduced the IC{sub 50} value and was 2.3 times lower than the pure docetaxel. Further, the oral bioavailability studies in male Wistar rats showed higher C{sub max} values following treatment with SNEP{sub N} (0.98±0.13 μg/mL) and L-SNEDDS (1.09± 0.06 μg/mL) compared to pure docetaxel (0.37±0.04 μg/mL).

  7. Improvement of interaction between PVA and chitosan via magnetite nanoparticles for drug delivery application.

    Science.gov (United States)

    Shagholani, Hamidreza; Ghoreishi, Sayed Mehdi; Mousazadeh, Mohammad

    2015-01-01

    Magnetite nanoparticles were synthesized by coprecipitation under ultrasonication followed by coating with chitosan. Polyvinyl alcohol (PVA) is then combined with the chitosan that coated the magnetite nanoparticles. The combination occurs by hydrogen binding and ionic cross-linking of the amino and hydroxyl groups of chitosan and PVA respectively. The magnetite nanoparticles have an average size of 10.62 nm that was confirmed by TEM. The VSM measurements showed that nanoparticles were superparamagnetic. The coatings on the core nanoparticles were estimated by AAS and the attachments of coating to the nanoparticles were confirmed by FT-IR analysis. Physicochemical properties of nanoparticles were measured by DLS and zeta potential. Naked magnetite, chitosan and PVA coating have zeta potential of +36.4, +48.1 and -12.5 mV respectively. The unspecific adsorption and interaction between nanoparticles and bovine serum albumin (BSA) were investigated systematically by UV-vis spectroscopy method. The nanoparticles that were modified by PVA present low protein adsorption, which makes them a practical choice for preventing opsonization in clinical application and drug delivery. Copyright © 2015. Published by Elsevier B.V.

  8. Bone regeneration: Biomaterials as local delivery systems with improved osteoinductive properties.

    Science.gov (United States)

    Martin, Victor; Bettencourt, Ana

    2018-01-01

    Bone is a mineralized conjunctive tissue, with a unique trauma healing capability. However, the replacement or regeneration of lost bone is not always successful and becomes more difficult the wider the bone defect. A significant growth in the demand for orthopedic and maxillofacial surgical procedures as a result of population aging and increase in chronic diseases as diabetes is a fact and successful approaches for bone regeneration are still needed. Until today, autogenous bone graft continues to be the best solution even with important limitations, as quantity and the requirement of a donator area. Alternatively, local delivery systems combining an osteoconductive biomaterial with osteoinductive compounds as hormones, growth factors or drugs is a popular approach aiming to replace the need for autogenous bone grafts. Nevertheless, in spite of the intense research in the area, presently there is no system that can mimic all the biological functions of the autogenous bone grafts. In this context, the present work provides an overview of the most recent advances in the field of synthetic bone grafts. The opportunities and limitations are detailed along with the remaining gaps in the research that are still preventing the successful translation of more products into the market able to be a valuable option in comparison to the autogenous bone grafts. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Alendronate-Loaded Modified Drug Delivery Lipid Particles Intended for Improved Oral and Topical Administration

    Directory of Open Access Journals (Sweden)

    Lacramioara Ochiuz

    2016-06-01

    Full Text Available The present paper focuses on solid lipid particles (SLPs, described in the literature as the most effective lipid drug delivery systems that have been introduced in the last decades, as they actually combine the advantages of polymeric particles, hydrophilic/lipophilic emulsions and liposomes. In the current study, we present our most recent advances in the preparation of alendronate (AL-loaded SLPs prepared by hot homogenization and ultrasonication using various ratios of a self-emulsifying lipidic mixture of Compritol 888, Gelucire 44/14, and Cremophor A 25. The prepared AL-loaded SLPs were investigated for their physicochemical, morphological and structural characteristics by dynamic light scattering, differential scanning calorimetry, thermogravimetric and powder X-ray diffraction analysis, infrared spectroscopy, optical and scanning electron microscopy. Entrapment efficacy and actual drug content were assessed by a validated HPLC method. In vitro dissolution tests performed in simulated gastro-intestinal fluids and phosphate buffer solution pH 7.4 revealed a prolonged release of AL of 70 h. Additionally, release kinetics analysis showed that both in simulated gastrointestinal fluids and in phosphate buffer solution, AL is released from SLPs based on equal ratios of lipid excipients following zero-order kinetics, which characterizes prolonged-release drug systems.

  10. Floating Microparticulate Oral Diltiazem Hydrochloride Delivery ...

    African Journals Online (AJOL)

    Delivery System for Improved Delivery to Heart ... Conclusion: Microparticulate floating (gastroretentive) oral drug delivery system of diltiazem prepared ..... treatment of cardiac disease. ... hydrochloride-loaded mucoadhesive microspheres.

  11. How to improve the validity of sexual behaviour reporting: systematic review of questionnaire delivery modes in developing countries.

    Science.gov (United States)

    Langhaug, Lisa F; Sherr, Lorraine; Cowan, Frances M

    2010-03-01

    To systematically review comparative research from developing countries on the effects of questionnaire delivery mode. We searched Medline, EMbase and PsychINFO and ISSTDR conference proceedings. Randomized control trials and quasi-experimental studies were included if they compared two or more questionnaire delivery modes, were conducted in a developing country, reported on sexual behaviours and occurred after 1980. A total of 28 articles reporting on 26 studies met the inclusion criteria. Heterogeneity of reported trial outcomes between studies made it inappropriate to combine trial outcomes. Eighteen studies compared audio computer-assisted survey instruments (ACASI) or its derivatives [personal digital assistant (PDA) or computer-assisted personal interview (CAPI)] against another self-administered questionnaires, face-to-face interviews or random response technique. Despite wide variation in geography and populations sampled, there was strong evidence that computer-assisted interviews lowered item-response rates and raised rates of reporting sensitive behaviours. ACASI also improved data entry quality. A wide range of sexual behaviours were reported including vaginal, oral, anal and/or forced sex, age of sexual debut, condom use at first and/or last sex. Validation of self-reports using biomarkers was rare. These data reaffirm that questionnaire delivery modes do affect self-reported sexual behaviours and that use of ACASI can significantly reduce reporting bias. Its acceptability and feasibility in developing country settings should encourage researchers to consider its use when conducting sexual health research. Triangulation of self-reported data using biomarkers is recommended. Standardizing sexual behaviour measures would allow for meta-analysis.

  12. Nanoparticle-based drug delivery to improve the efficacy of antiretroviral therapy in the central nervous system

    Directory of Open Access Journals (Sweden)

    Gomes MJ

    2014-04-01

    Full Text Available Maria João Gomes,1 José das Neves,1,2 Bruno Sarmento1,2 1Instituto de Engenharia Biomédica (INEB, Porto, Portugal; 2Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde (IINFACTS, Instituto Superior de Ciências da Saúde-Norte, CESPU, Gandra, Portugal Abstract: Antiretroviral drug therapy plays a cornerstone role in the treatment of human immunodeficiency virus (HIV/acquired immunodeficiency syndrome patients. Despite obvious advances over the past 3 decades, new approaches toward improved management of infected individuals are still required. Drug distribution to the central nervous system (CNS is required in order to limit and control viral infection, but the presence of natural barrier structures, in particular the blood–brain barrier, strongly limits the perfusion of anti-HIV compounds into this anatomical site. Nanotechnology-based approaches may help providing solutions for antiretroviral drug delivery to the CNS by potentially prolonging systemic drug circulation, increasing the crossing and reducing the efflux of active compounds at the blood–brain barrier, and providing cell/tissue-targeting and intracellular drug delivery. After an initial overview on the basic features of HIV infection of the CNS and barriers to active compound delivery to this anatomical site, this review focuses on recent strategies based on antiretroviral drug-loaded solid nanoparticles and drug nanosuspensions for the potential management of HIV infection of the CNS. Keywords: HIV/AIDS, blood–brain barrier, protease inhibitors, efflux transporters, drug targeting

  13. Improved mucoadhesion and cell uptake of chitosan and chitosan oligosaccharide surface-modified polymer nanoparticles for mucosal delivery of proteins.

    Science.gov (United States)

    Dyawanapelly, Sathish; Koli, Uday; Dharamdasani, Vimisha; Jain, Ratnesh; Dandekar, Prajakta

    2016-08-01

    The main aim of the present study was to compare mucoadhesion and cellular uptake efficiency of chitosan (CS) and chitosan oligosaccharide (COS) surface-modified polymer nanoparticles (NPs) for mucosal delivery of proteins. We have developed poly (D, L-lactide-co-glycolide) (PLGA) NPs, surface-modified COS-PLGA NPs and CS-PLGA NPs, by using double emulsion solvent evaporation method, for encapsulating bovine serum albumin (BSA) as a model protein. Surface modification of NPs was confirmed using physicochemical characterization methods such as particle size and zeta potential, SEM, TEM and FTIR analysis. Both surface-modified PLGA NPs displayed a slow release of protein compared to PLGA NPs. Furthermore, we have explored the mucoadhesive property of COS as a material for modifying the surface of polymeric NPs. During in vitro mucoadhesion test, positively charged COS-PLGA NPs and CS-PLGA NPs exhibited enhanced mucoadhesion, compared to negatively charged PLGA NPs. This interaction was anticipated to improve the cell interaction and uptake of NPs, which is an important requirement for mucosal delivery of proteins. All nanoformulations were found to be safe for cellular delivery when evaluated in A549 cells. Moreover, intracellular uptake behaviour of FITC-BSA loaded NPs was extensively investigated by confocal laser scanning microscopy and flow cytometry. As we hypothesized, positively charged COS-PLGA NPs and CS-PLGA NPs displayed enhanced intracellular uptake compared to negatively charged PLGA NPs. Our results demonstrated that CS- and COS-modified polymer NPs could be promising carriers for proteins, drugs and nucleic acids via nasal, oral, buccal, ocular and vaginal mucosal routes.

  14. Stimulation of wild-type, F508del- and G551D-CFTR chloride channels by non toxic modified pyrrolo[2,3-b]pyrazine derivatives

    Directory of Open Access Journals (Sweden)

    Luc eDannhoffer

    2011-08-01

    Full Text Available Cystic Fibrosis is a major inherited disorder involving abnormalities of fluid and electrolyte transport in a number of different organs due to abnormal function of Cystic Fibrosis Transmembrane conductance Regulator (CFTR protein. We recently identified a family of CFTR activators, which contains the hit: RP107 [7-n-butyl-6-(4-hydroxyphenyl[5H]-pyrrolo[2,3-b]pyrazine]. Here, we further evaluated the effect of the chemical modifications of the RP107-OH radical on CFTR activation. The replacement of the OH radical by a fluorine atom at position 2 (RP193 or 4 (RP185 significantly decreased the toxicity of the compounds without altering the ability to activate CFTR, especially for RP193. The non-toxic compound RP193 has no effect on cAMP production but stimulates the channel activity of wild-type CFTR in stably transfected CHO cells, in human bronchial epithelial NuLi-1 cells and in primary culture of human bronchial epithelial cells. Whole cell and single patch clamp recordings showed that RP193 induced a linear, time and voltage-independent current, which was fully inhibited by two different and selective CFTR inhibitors (CFTRinh-172 and GPinh-5a. Moreover, RP193 stimulates CFTR in temperature-rescued CuFi-1 (F508del/F508del human bronchial epithelial cells and in CHO cells stably expressing G551D-CFTR. This study shows that it is feasible to reduce cytotoxicity of chemical compounds without affecting their potency to activate CFTR and to rescue the class 2 F508del-CFTR and class 3 G551D-CFTR CF mutant activities.

  15. Improved oral bioavailability of poorly water-soluble indirubin by a supersaturatable self-microemulsifying drug delivery system.

    Science.gov (United States)

    Chen, Zhi-Qiang; Liu, Ying; Zhao, Ji-Hui; Wang, Lan; Feng, Nian-Ping

    2012-01-01

    Indirubin, isolated from the leaves of the Chinese herb Isatis tinctoria L, is a protein kinase inhibitor and promising antitumor agent. However, the poor water solubility of indirubin has limited its application. In this study, a supersaturatable self-microemulsifying drug delivery system (S-SMEDDS) was developed to improve the oral bioavailability of indirubin. A prototype S-SMEDDS was designed using solubility studies and phase diagram construction. Precipitation inhibitors were selected from hydrophilic polymers according to their crystallization-inhibiting capacity through in vitro precipitation tests. In vitro release of indirubin from S-SMEDDS was examined to investigate its likely release behavior in vivo. The in vivo bioavailability of indirubin from S-SMEDDS and from SMEDDS was compared in rats. The prototype formulation of S-SMEDDS comprised Maisine™ 35-1:Cremophor(®) EL:Transcutol(®) P (15:40:45, w/w/w). Polyvinylpyrrolidone K17, a hydrophilic polymer, was used as a precipitation inhibitor based on its better crystallization-inhibiting capacity compared with polyethylene glycol 4000 and hydroxypropyl methylcellulose. In vitro release analysis showed more rapid drug release from S-SMEDDS than from SMEDDS. In vivo bioavailability analysis in rats indicated that improved oral absorption was achieved and that the relative bioavailability of S-SMEDDS was 129.5% compared with SMEDDS. The novel S-SMEDDS developed in this study increased the dissolution rate and improved the oral bioavailability of indirubin in rats. The results suggest that S-SMEDDS is a superior means of oral delivery of indirubin.

  16. Improved survival for elderly married glioblastoma patients. Better treatment delivery, less toxicity, and fewer disease complications

    Energy Technology Data Exchange (ETDEWEB)

    Putz, Florian; Goerig, Nicole; Knippen, Stefan; Gryc, Thomas; Semrau, Sabine; Lettmaier, Sebastian; Fietkau, Rainer [Friedrich-Alexander-University Erlangen-Nuremberg, Department of Radiation Oncology, Erlangen (Germany); Putz, Tobias [University of Bamberg, Professorship of Demography, Bamberg (Germany); Eyuepoglu, Ilker; Roessler, Karl [Friedrich-Alexander-University Erlangen-Nuremberg, Department of Neurosurgery, Erlangen (Germany)

    2016-11-15

    Marital status is a well-described prognostic factor in patients with gliomas but the observed survival difference is unexplained in the available population-based studies. A series of 57 elderly glioblastoma patients (≥70 years) were analyzed retrospectively. Patients received radiotherapy or chemoradiation with temozolomide. The prognostic significance of marital status was assessed. Disease complications, toxicity, and treatment delivery were evaluated in detail. Overall survival was significantly higher in married than in unmarried patients (median, 7.9 vs. 4.0 months; p = 0.006). The prognostic significance of marital status was preserved in the multivariate analysis (HR, 0.41; p = 0.011). Married patients could receive significantly higher daily temozolomide doses (mean, 53.7 mg/m{sup 2} vs. 33.1 mg/m{sup 2}; p = 0.020), were more likely to receive maintenance temozolomide (45.7 % vs. 11.8 %; p = 0.016), and had to be hospitalized less frequently during radiotherapy (55.0 % vs. 88.2 %; p = 0.016). Of the patients receiving temozolomide, married patients showed significantly lower rates of hematologic and liver toxicity. Most complications were infectious or neurologic in nature. Complications of any grade were more frequent in unmarried patients (58.8 % vs. 30.0 %; p = 0.041) with the incidence of grade 3-5 complications being particularly elevated (47.1 % vs. 15.0 %; p = 0.004). We found poorer treatment delivery as well as an unexpected severe increase in toxicity and disease complications in elderly unmarried glioblastoma patients. Marital status may be an important predictive factor for clinical decision-making and should be addressed in further studies. (orig.) [German] Fuer verheiratete Patienten mit malignen Gliomen ist ein verbessertes Gesamtueberleben gut beschrieben. Die zugrunde liegenden Mechanismen konnten bislang jedoch in den verfuegbaren bevoelkerungsbezogenen Arbeiten nicht erklaert werden. Eine Serie von 57 aelteren Patienten mit

  17. Improving access to skilled attendance at delivery: a policy brief for Uganda.

    Science.gov (United States)

    Nabudere, Harriet; Asiimwe, Delius; Amandua, Jacinto

    2013-04-01

    This study describes the process of production, findings for a policy brief on Increasing Access to Skilled Birth Attendance, and subsequent use of the report by policy makers and others from the health sector in Uganda. The methods used to prepare the policy brief use the SUPPORT Tools for evidence-informed health policy making. The problem that this evidence brief addresses was identified through an explicit priority setting process involving policy makers and other stakeholders, further clarification with key informant interviews of relevant policy makers, and review of relevant documents. A working group of national stakeholder representatives and external reviewers commented on and contributed to successive drafts of the report. Research describing the problem, policy options, and implementation considerations was identified by reviewing government documents, routinely collected data, electronic literature searches, contact with key informants, and reviewing the reference lists of relevant documents that were retrieved. The proportion of pregnant women delivering from public and private non-profit facilities was low at 34 percent in 2008/09. The three policy options discussed in the report could be adopted independently or complementary to the other to increase access to skilled care. The Ministry of Health in deliberating to provide intrapartum care at first level health facilities from the second level of care, requested for research evidence to support these decisions. Maternal waiting shelters and working with the private-for-profit sector to facilitate deliveries in health facilities are promising complementary interventions that have been piloted in both the public and private health sector. A combination of strategies is needed to effectively implement the proposed options as discussed further in this article. The policy brief report was used as a background document for two stakeholder dialogue meetings involving members of parliament, policy makers

  18. From Demonstration System to Prototype: ShakeAlert Beta Users Provide Feedback to Improve Alert Delivery

    Science.gov (United States)

    Strauss, J. A.; Vinci, M.; Steele, W. P.; Allen, R. M.; Hellweg, M.

    2013-12-01

    Earthquake Early Warning (EEW) is a system that can provide a few to tens of seconds to minutes of warning prior to ground shaking at a given location. The goal and purpose of such a system is to reduce the damage, costs, and casualties resulting from an earthquake. A prototype earthquake early warning system (ShakeAlert) is in development by the UC Berkeley Seismological Laboratory, Caltech, ETH Zurich, University of Washington, and the USGS. Events are published to the UserDisplay--ShakeAlert's Java based graphical interface, which is being tested by a small group of beta users throughout California. The beta users receive earthquake alerts in real-time and are providing feedback on their experiences. For early warning alerts to be useful, people, companies, and institutions must know beforehand what actions they will perform when they receive the information. Beta user interactions allow the ShakeAlert team to discern: which alert delivery options are most effective, what changes would make the UserDisplay more useful in a pre-disaster situation, and most importantly, what actions users plan to take for various scenarios. We also collect feedback detailing costs of implementing actions and challenges within the beta user organizations, as well as anticipated benefits and savings. Thus, creating a blueprint for a fully operational system that will meet the needs of the public. New California users as well as the first group of Pacific Northwest users are slated to join the ShakeAlert beta test group in the fall of 2013.

  19. A conceptual model of physician work intensity: guidance for evaluating policies and practices to improve health care delivery.

    Science.gov (United States)

    Horner, Ronnie D; Matthews, Gerald; Yi, Michael S

    2012-08-01

    Physician work intensity, although a major factor in determining the payment for medical services, may potentially affect patient health outcomes including quality of care and patient safety, and has implications for the redesign of medical practice to improve health care delivery. However, to date, there has been minimal research regarding the relationship between physician work intensity and either patient outcomes or the organization and management of medical practices. A theoretical model on physician work intensity will provide useful guidance to such inquiries. To describe an initial conceptual model to facilitate further investigations of physician work intensity. A conceptual model of physician work intensity is described using as its theoretical base human performance science relating to work intensity. For each of the theoretical components, we present relevant empirical evidence derived from a review of the current literature. The proposed model specifies that the level of work intensity experienced by a physician is a consequence of the physician performing the set of tasks (ie, demands) relating to a medical service. It is conceptualized that each medical service has an inherent level of intensity that is experienced by a physician as a function of factors relating to the physician, patient, and medical practice environment. The proposed conceptual model provides guidance to researchers as to the factors to consider in studies of how physician work intensity impacts patient health outcomes and how work intensity may be affected by proposed policies and approaches to health care delivery.

  20. Improvement of Transdermal Delivery of Exendin-4 Using Novel Tip-Loaded Microneedle Arrays Fabricated from Hyaluronic Acid.

    Science.gov (United States)

    Liu, Shu; Wu, Dan; Quan, Ying-Shu; Kamiyama, Fumio; Kusamori, Kosuke; Katsumi, Hidemasa; Sakane, Toshiyasu; Yamamoto, Akira

    2016-01-04

    The purpose of this study was to evaluate the characteristics of exendin-4 tip-loaded microneedle arrays and to compare their acute efficacy with subcutaneous injections in type 2 diabetic GK/Slc rats. Fluorescein isothiocyanate labeled dextran with an average molecular weight of 4,000 (FD4) was selected as a model drug, and FD4 tip-loaded microneedle arrays were prepared in this study. In addition, intraperitoneal glucose tolerance tests after application of exendin-4 tip-loaded microneedle arrays were also compared with those after subcutaneous injection in type 2 diabetic GK/Slc rats. The release of FD4 from the tip-loaded microneedle arrays was very rapid, particularly in the initial 30 s, and most of the FD4 was released within 5 min. In addition, glucose tolerance was improved and the insulin secretion was enhanced after application of exendin-4 tip-loaded microneedle arrays, and these effects were comparable to those after subcutaneous injection of exendin-4. Similar plasma concentration profiles were seen after application of exendin-4 tip-loaded microneedle arrays, as was the case with subcutaneous injection in type 2 diabetic GK/Slc rats. These findings indicate that exendin-4 tip-loaded microneedle arrays can be used as an alternative to achieve sufficient delivery of exendin-4 for treatment of type 2 diabetes. To our knowledge, this is the first report of transdermal exendin-4 delivery using tip-loaded microneedle arrays.

  1. HLW Feed Delivery AZ101 Batch Transfer to the Private Contractor Transfer and Mixing Process Improvements [Initial Release at Rev 2

    Energy Technology Data Exchange (ETDEWEB)

    DUNCAN, G.P.

    2000-02-28

    The primary purpose of this business case is to provide Operations and Maintenance with a detailed transfer process review for the first High Level Waste (HLW) feed delivery to the Privatization Contractor (PC), AZ-101 batch transfer to PC. The Team was chartered to identify improvements that could be implemented in the field. A significant penalty can be invoked for not providing the quality, quantity, or timely delivery of HLW feed to the PC.

  2. Improving supply chain performance : real-time demand information and flexible deliveries

    NARCIS (Netherlands)

    Shang, K.H.; Zhou, S.X.; Houtum, van G.J.J.A.N.

    2010-01-01

    In some supply chains, materials are ordered periodically according to local information. This paper investigates how to improve the performance of such a supply chain. Specifically, we consider a serial inventory system in which each stage implements a local reorder interval policy; i.e., each

  3. Improving supply chain performance : real-time demand information and responsive deliveries

    NARCIS (Netherlands)

    Shang, K.H.; Zhou, S.Y.; Houtum, van G.J.J.A.N.

    2008-01-01

    In some supply chains, materials are ordered periodically according to local information. This paper investigates how to improve the performance of such a supply chain. Specifically, we consider a serial inventory system in which each stage implements a local reorder interval policy, i.e., each

  4. 205_WS: Improving the Delivery of Primary Care Through Risk Stratification

    DEFF Research Database (Denmark)

    Kinder, Karen; Kristensen, Troels; Abrams, Chad

    . Content The workshop will open with an introductory presentation on the numerous applications of risk stratification within the integrated and primary care sectors. The workshop will then focus on individual sessions based on three applications: – Case Management. – Improving Coordination...

  5. Improving CT quality with optimized image parameters for radiation treatment planning and delivery guidance

    Directory of Open Access Journals (Sweden)

    Guang-Pei Chen

    2017-10-01

    Conclusion: CT image quality can be improved with the IQE protocols created in this study, to provide better soft tissue contrast, which would be beneficial for use in radiation therapy, e.g., for planning data acquisition or for IGRT for hypo-fractionated treatments.

  6. Gene delivery to the lungs: pulmonary gene therapy for cystic fibrosis.

    Science.gov (United States)

    Villate-Beitia, Ilia; Zarate, Jon; Puras, Gustavo; Pedraz, José Luis

    2017-07-01

    Cystic fibrosis (CF) is a monogenic autosomal recessive disorder where the defective gene, the cystic fibrosis transmembrane conductance regulator (CFTR), is well identified. Moreover, the respiratory tract can be targeted through noninvasive aerosolized formulations for inhalation. Therefore, gene therapy is considered a plausible strategy to address this disease. Conventional gene therapy strategies rely on the addition of a correct copy of the CFTR gene into affected cells in order to restore the channel activity. In recent years, genome correction strategies have emerged, such as zinc-finger nucleases, transcription activator-like effector nucleases and clustered regularly interspaced short palindromic repeats associated to Cas9 nucleases. These gene editing tools aim to repair the mutated gene at its original genomic locus with high specificity. Besides, the success of gene therapy critically depends on the nucleic acids carriers. To date, several clinical studies have been carried out to add corrected copies of the CFTR gene into target cells using viral and non-viral vectors, some of them with encouraging results. Regarding genome editing systems, preliminary in vitro studies have been performed in order to repair the CFTR gene. In this review, after briefly introducing the basis of CF, we discuss the up-to-date gene therapy strategies to address the disease. The review focuses on the main factors to take into consideration when developing gene delivery strategies, such as the design of vectors and plasmid DNA, in vitro/in vivo tests, translation to human use, administration methods, manufacturing conditions and regulatory issues.

  7. Xanthan gum stabilized PEGylated gold nanoparticles for improved delivery of curcumin in cancer

    Science.gov (United States)

    Swami Muddineti, Omkara; Kumari, Preeti; Ajjarapu, Srinivas; Manish Lakhani, Prit; Bahl, Rishabh; Ghosh, Balaram; Biswas, Swati

    2016-08-01

    In recent years, gold nanoparticles (AuNPs) have received immense interest in various biomedical applications including drug delivery, photothermal ablation of cancer and imaging agent for cancer diagnosis. However, the synthesis of AuNPs poses challenges due to the poor reproducibility and stability of the colloidal system. In the present work, we developed a one step, facile procedure for the synthesis of AuNPs from hydrogen tetrachloroaurate (III) hydrate (HAuCl4. 3H2O) by using ascorbic acid and xanthan gum (XG) as reducing agent and stabilizer, respectively. The effect of concentrations of HAuCl4, 3H2O, ascorbic acid and methoxy polyethylene glycol-thiol (mPEG800-SH) were optimized and it was observed that stable AuNPs were formed at concentrations of 0.25 mM, 50 μM and 1 mM for HAuCl4.3H2O, ascorbic acid, and mPEG800-SH, respectively. The XG stabilized, deep red wine colored AuNPs (XG-AuNPs) were obtained by drop-wise addition of aqueous solution of ascorbic acid (50 mM) and XG (1.5 mg ml-1). Synthesized XG-AuNPs showed λmax at 540 nm and a mean hydrodynamic diameter of 80 ± 3 nm. PEGylation was performed with mPEG800-SH to obtain PEGylated XG-AuNPs (PX-AuNPs) and confirmed by Ellman’s assay. No significant shift observed in λmax and hydrodynamic diameter between XG-AuNPs and PX-AuNPs. Colloidal stability of PX-AuNPs was studied in normal saline, buffers within a pH range of 1.2-7.4, DMEM complete medium and in normal storage condition at 4 ˚C. Further, water soluble curcumin was prepared using PVP-K30 as solid dispersion and loaded on to PX-AuNPs (CPX-AuNPs), and evaluated for cellular uptake and cytotoxicity in Murine melanoma (B16F10) cells. Time and concentration dependent studies using CPX-AuNPs showed efficient uptake and decreased cell viability compared to free curcumin.

  8. Delivery of maternal health care in Indigenous primary care services: baseline data for an ongoing quality improvement initiative

    Directory of Open Access Journals (Sweden)

    Kwedza Ru K

    2011-03-01

    Full Text Available Abstract Background Australia's Aboriginal and Torres Strait Islander (Indigenous populations have disproportionately high rates of adverse perinatal outcomes relative to other Australians. Poorer access to good quality maternal health care is a key driver of this disparity. The aim of this study was to describe patterns of delivery of maternity care and service gaps in primary care services in Australian Indigenous communities. Methods We undertook a cross-sectional baseline audit for a quality improvement intervention. Medical records of 535 women from 34 Indigenous community health centres in five regions (Top End of Northern Territory 13, Central Australia 2, Far West New South Wales 6, Western Australia 9, and North Queensland 4 were audited. The main outcome measures included: adherence to recommended protocols and procedures in the antenatal and postnatal periods including: clinical, laboratory and ultrasound investigations; screening for gestational diabetes and Group B Streptococcus; brief intervention/advice on health-related behaviours and risks; and follow up of identified health problems. Results The proportion of women presenting for their first antenatal visit in the first trimester ranged from 34% to 49% between regions; consequently, documentation of care early in pregnancy was poor. Overall, documentation of routine antenatal investigations and brief interventions/advice regarding health behaviours varied, and generally indicated that these services were underutilised. For example, 46% of known smokers received smoking cessation advice/counselling; 52% of all women received antenatal education and 51% had investigation for gestational diabetes. Overall, there was relatively good documentation of follow up of identified problems related to hypertension or diabetes, with over 70% of identified women being referred to a GP/Obstetrician. Conclusion Participating services had both strengths and weaknesses in the delivery of maternal

  9. Improved Oral Bioavailability Using a Solid Self-Microemulsifying Drug Delivery System Containing a Multicomponent Mixture Extracted from Salvia miltiorrhiza

    Directory of Open Access Journals (Sweden)

    Xiaolin Bi

    2016-04-01

    Full Text Available The active ingredients of salvia (dried root of Salvia miltiorrhiza include both lipophilic (e.g., tanshinone IIA, tanshinone I, cryptotanshinone and dihydrotanshinone I and hydrophilic (e.g., danshensu and salvianolic acid B constituents. The low oral bioavailability of these constituents may limit their efficacy. A solid self-microemulsifying drug delivery system (S-SMEDDS was developed to load the various active constituents of salvia into a single drug delivery system and improve their oral bioavailability. A prototype SMEDDS was designed using solubility studies and phase diagram construction, and characterized by self-emulsification performance, stability, morphology, droplet size, polydispersity index and zeta potential. Furthermore, the S-SMEDDS was prepared by dispersing liquid SMEDDS containing liposoluble extract into a solution containing aqueous extract and hydrophilic polymer, and then freeze-drying. In vitro release of tanshinone IIA, salvianolic acid B, cryptotanshinone and danshensu from the S-SMEDDS was examined, showing approximately 60%–80% of each active component was released from the S-SMEDDS in vitro within 20 min. In vivo bioavailability of these four constituents indicated that the S-SMEDDS showed superior in vivo oral absorption to a drug suspension after oral administration in rats. It can be concluded that the novel S-SMEDDS developed in this study increased the dissolution rate and improved the oral bioavailability of both lipophilic and hydrophilic constituents of salvia. Thus, the S-SMEDDS can be regarded as a promising new method by which to deliver salvia extract, and potentially other multicomponent drugs, by the oral route.

  10. Improving patient experience in a pediatric ambulatory clinic: a mixed method appraisal of service delivery

    Directory of Open Access Journals (Sweden)

    Soeteman M

    2015-03-01

    Full Text Available Marijn Soeteman,1 Vera Peters,2 Jamiu O Busari1,3 1Department of Pediatrics, Atrium Medical Center, Heerlen, 2Faculty of Health, Medicine and Life Sciences, 3Department of Educational Development and Research, Faculty of Health, Medicine and Life Sciences, University of Maastricht, Maastricht, the Netherlands Objective: In 2013, customer satisfaction surveys showed that patients were unhappy with the services provided at our ambulatory clinic. In response, we performed an appraisal of our services, which resulted in the development of a strategy to reduce waiting time and improve quality of service. Infrastructural changes to our clinic’s waiting room, consultation rooms, and back offices were performed, and schedules were redesigned to reduce wait time to 10 minutes and increase consultation time to 20 minutes. Our objective was to identify if this would improve 1 accessibility to caregivers and 2 quality of service and available amenities. Design: We conducted a multi-method survey using 1 a patient flow analysis to analyze the flow of service and understand the impact of our interventions on patient flow and 2 specially designed questionnaires to investigate patients’ perceptions of our wait time and how to improve our services. Results: The results showed that 79% of our respondents were called in to see a doctor within 20 minutes upon arrival. More patients (55% felt that 10–20 minutes was an acceptable wait time. We also observed a perceived increase in satisfaction with wait time (94%. Finally, a large number of patients (97% were satisfied with the quality of service and with the accessibility to caregivers (94%. Conclusion: The majority of our patients were satisfied with the accessibility to our ambulatory clinics and with the quality of services provided. The appraisal of our operational processes using a patient flow analysis also demonstrated how this strategy could effectively be applied to investigate and improve quality of

  11. Partnerships and the good-governance agenda: improving service delivery through state-NGO collaborations

    OpenAIRE

    Bano, M

    2018-01-01

    First under the Millennium Development Goals (MDGs) and now under the Sustainable Development Goals (SDGs), partnerships for development, especially between state and NGOs, remain a valued goal. Partnerships are argued to improve provision of basic social services to the poor: the state is viewed as providing scale, with NGOs ensuring good governance. Close study of three leading partnership arrangements in Pakistan (privatization of basic health units, an 'adopt a school' program, and low-co...

  12. Does a voucher program improve reproductive health service delivery and access in Kenya?

    Science.gov (United States)

    Njuki, Rebecca; Abuya, Timothy; Kimani, James; Kanya, Lucy; Korongo, Allan; Mukanya, Collins; Bracke, Piet; Bellows, Ben; Warren, Charlotte E

    2015-05-23

    Current assessments on Output-Based Aid (OBA) programs have paid limited attention to the experiences and perceptions of the healthcare providers and facility managers. This study examines the knowledge, attitudes, and experiences of healthcare providers and facility managers in the Kenya reproductive health output-based approach voucher program. A total of 69 in-depth interviews with healthcare providers and facility managers in 30 voucher accredited facilities were conducted. The study hypothesized that a voucher program would be associated with improvements in reproductive health service provision. Data were transcribed and analyzed by adopting a thematic framework analysis approach. A combination of inductive and deductive analysis was conducted based on previous research and project documents. Facility managers and providers viewed the RH-OBA program as a feasible system for increasing service utilization and improving quality of care. Perceived benefits of the program included stimulation of competition between facilities and capital investment in most facilities. Awareness of family planning (FP) and gender-based violence (GBV) recovery services voucher, however, remained lower than the maternal health voucher service. Relations between the voucher management agency and accredited facilities as well as existing health systems challenges affect program functions. Public and private sector healthcare providers and facility managers perceive value in the voucher program as a healthcare financing model. They recognize that it has the potential to significantly increase demand for reproductive health services, improve quality of care and reduce inequities in the use of reproductive health services. To improve program functioning going forward, there is need to ensure the benefit package and criteria for beneficiary identification are well understood and that the public facilities are permitted greater autonomy to utilize revenue generated from the voucher program.

  13. A European regulatory perspective on cystic fibrosis: current treatments, trends in drug development and translational challenges for CFTR modulators.

    Science.gov (United States)

    Ponzano, Stefano; Nigrelli, Giulia; Fregonese, Laura; Eichler, Irmgard; Bertozzi, Fabio; Bandiera, Tiziano; Galietta, Luis J V; Papaluca, Marisa

    2018-06-30

    In this article we analyse the current authorised treatments and trends in early drug development for cystic fibrosis (CF) in the European Union for the time period 2000-2016. The analysis indicates a significant improvement in the innovation and development of new potential medicines for CF, shifting from products that act on the symptoms of the disease towards new therapies targeting the cause of CF. However, within these new innovative medicines, results for CF transmembrane conductance regulator (CFTR) modulators indicate that one major challenge for turning a CF concept product into an actual medicine for the benefit of patients resides in the fact that, although pre-clinical models have shown good predictability for certain mutations, a good correlation to clinical end-points or biomarkers ( e.g. forced expiratory volume in 1 s and sweat chloride) for all mutations has not yet been achieved. In this respect, the use of alternative end-points and innovative nonclinical models could be helpful for the understanding of those translational discrepancies. Collaborative endeavours to promote further research and development in these areas as well as early dialogue with the regulatory bodies available at the European competent authorities are recommended. Copyright ©ERS 2018.

  14. Spherical agglomerates of pure drug nanoparticles for improved pulmonary delivery in dry powder inhalers

    International Nuclear Information System (INIS)

    Hu Jun; Dong Yuancai; Pastorin, Giorgia; Ng, Wai Kiong; Tan, Reginald B. H.

    2013-01-01

    The aim of this study was to produce micron-sized spherical agglomerates of pure drug nanoparticles to achieve improved aerosol performance in dry powder inhalers (DPIs). Sodium cromoglicate was chosen as the model drug. Pure drug nanoparticles were prepared through a bottom-up particle formation process, liquid antisolvent precipitation, and then rapidly agglomerated into porous spherical microparticles by immediate (on-line) spray drying. Nonporous spherical drug microparticles with similar geometric size distribution were prepared by conventional spray drying of the aqueous drug solution, which together with the mechanically micronized drug particles were used as the control samples. The three samples were characterized by field emission scanning electron microscopy, laser diffraction, Brunauer–Emmett–Teller analysis, density measurement, powder X-ray diffraction, and in vitro aerosol deposition measurement with a multistage liquid impinger. It was found that drug nanoparticles with a diameter of ∼100 nm were precipitated and agglomerated into highly porous spherical microparticles with a volume median diameter (D 50% ) of 2.25 ± 0.08 μm and a specific surface area of 158.63 ± 3.27 m 2 /g. In vitro aerosol deposition studies showed the fine particle fraction of such spherical agglomerates of drug nanoparticles was increased by more than 50 % in comparison with the control samples, demonstrating significant improvements in aerosol performance. The results of this study indicated the potential of the combined particle engineering process of liquid antisolvent precipitation followed by immediate (on-line) spray drying in the development of novel DPI drug products with improved aerosol performance.

  15. Spherical agglomerates of pure drug nanoparticles for improved pulmonary delivery in dry powder inhalers

    Energy Technology Data Exchange (ETDEWEB)

    Hu Jun; Dong Yuancai [Institute of Chemical and Engineering Sciences (Singapore); Pastorin, Giorgia, E-mail: phapg@nus.edu.sg [National University of Singapore, Department of Pharmacy (Singapore); Ng, Wai Kiong, E-mail: ng_wai_kiong@ices.a-star.edu.sg; Tan, Reginald B. H. [Institute of Chemical and Engineering Sciences (Singapore)

    2013-04-15

    The aim of this study was to produce micron-sized spherical agglomerates of pure drug nanoparticles to achieve improved aerosol performance in dry powder inhalers (DPIs). Sodium cromoglicate was chosen as the model drug. Pure drug nanoparticles were prepared through a bottom-up particle formation process, liquid antisolvent precipitation, and then rapidly agglomerated into porous spherical microparticles by immediate (on-line) spray drying. Nonporous spherical drug microparticles with similar geometric size distribution were prepared by conventional spray drying of the aqueous drug solution, which together with the mechanically micronized drug particles were used as the control samples. The three samples were characterized by field emission scanning electron microscopy, laser diffraction, Brunauer-Emmett-Teller analysis, density measurement, powder X-ray diffraction, and in vitro aerosol deposition measurement with a multistage liquid impinger. It was found that drug nanoparticles with a diameter of {approx}100 nm were precipitated and agglomerated into highly porous spherical microparticles with a volume median diameter (D{sub 50%}) of 2.25 {+-} 0.08 {mu}m and a specific surface area of 158.63 {+-} 3.27 m{sup 2}/g. In vitro aerosol deposition studies showed the fine particle fraction of such spherical agglomerates of drug nanoparticles was increased by more than 50 % in comparison with the control samples, demonstrating significant improvements in aerosol performance. The results of this study indicated the potential of the combined particle engineering process of liquid antisolvent precipitation followed by immediate (on-line) spray drying in the development of novel DPI drug products with improved aerosol performance.

  16. Fabrication and characterization of nuclear localization signal-conjugated glycol chitosan micelles for improving the nuclear delivery of doxorubicin

    Directory of Open Access Journals (Sweden)

    Zhao J

    2012-09-01

    Full Text Available Jingmou Yu,1 Xin Xie,1 Meirong Zheng,1 Ling Yu,2 Lei Zhang,1 Jianguo Zhao,1 Dengzhao Jiang,1 Xiangxin Che11Key Laboratory of Systems Biology Medicine of Jiangxi Province, College of Basic Medical Science, Jiujiang University, Jiujiang, 2Division of Nursing, 2nd Affiliated Hospital, Yichun University, Yichun, People's Republic of ChinaBackground: Supramolecular micelles as drug-delivery vehicles are generally unable to enter the nucleus of nondividing cells. In the work reported here, nuclear localization signal (NLS-modified polymeric micelles were studied with the aim of improving nuclear drug delivery.Methods: In this research, cholesterol-modified glycol chitosan (CHGC was synthesized. NLS-conjugated CHGC (NCHGC was synthesized and characterized using proton nuclear magnetic resonance spectroscopy, dynamic light scattering, and fluorescence spectroscopy. Doxorubicin (DOX, an anticancer drug with an intracellular site of action in the nucleus, was chosen as a model drug. DOX-loaded micelles were prepared by an emulsion/solvent evaporation method. The cellular uptake of different DOX formulations was analyzed by flow cytometry and confocal laser scanning microscopy. The cytotoxicity of blank micelles, free DOX, and DOX-loaded micelles in vitro was investigated by 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay in HeLa and HepG2 cells.Results: The degree of substitution was 5.9 cholesterol and 3.8 NLS groups per 100 sugar residues of the NCHGC conjugate. The critical aggregation concentration of the NCHGC micelles in aqueous solution was 0.0209 mg/mL. The DOX-loaded NCHGC (DNCHGC micelles were observed as being almost spherical in shape under transmission electron microscopy, and the size was determined as 248 nm by dynamic light scattering. The DOX-loading content of the DNCHGC micelles was 10.1%. The DOX-loaded micelles showed slow drug-release behavior within 72 hours in vitro. The DNCHGC micelles exhibited greater

  17. Improved intracellular delivery of glucocerebrosidase mediated by the HIV-1 TAT protein transduction domain

    International Nuclear Information System (INIS)

    Lee, Kyun Oh; Luu, Nga; Kaneski, Christine R.; Schiffmann, Raphael; Brady, Roscoe O.; Murray, Gary J.

    2005-01-01

    Enzyme replacement therapy (ERT) for Gaucher disease designed to target glucocerebrosidase (GC) to macrophages via mannose-specific endocytosis is very effective in reversing hepatosplenomegaly, and normalizing hematologic parameters but is less effective in improving bone and lung involvement and ineffective in brain. Recombinant GCs containing an in-frame fusion to the HIV-1 trans-activator protein transduction domain (TAT) were expressed in eukaryotic cells in order to obtain active, normally glycosylated GC fusion proteins for enzyme uptake studies. Despite the absence of mannose-specific endocytic receptors on the plasma membranes of various fibroblasts, the recombinant GCs with C-terminal TAT fusions were readily internalized by these cells. Immunofluorescent confocal microscopy demonstrated the recombinant TAT-fusion proteins with a mixed endosomal and lysosomal localization. Thus, TAT-modified GCs represent a novel strategy for a new generation of therapeutic enzymes for ERT for Gaucher disease

  18. Using screen-based simulation of inhaled anaesthetic delivery to improve patient care.

    Science.gov (United States)

    Philip, J H

    2015-12-01

    Screen-based simulation can improve patient care by giving novices and experienced clinicians insight into drug behaviour. Gas Man(®) is a screen-based simulation program that depicts pictorially and graphically the anaesthetic gas and vapour tension from the vaporizer to the site of action, namely the brain and spinal cord. The gases and vapours depicted are desflurane, enflurane, ether, halothane, isoflurane, nitrogen, nitrous oxide, sevoflurane, and xenon. Multiple agents can be administered simultaneously or individually and the results shown on an overlay graph. Practice exercises provide in-depth knowledge of the subject matter. Experienced clinicians can simulate anaesthesia occurrences and practices for application to their clinical practice, and publish the results to benefit others to improve patient care. Published studies using this screen-based simulation have led to a number of findings, as follows: changing from isoflurane to desflurane toward the end of anaesthesia does not accelerate recovery in humans; vital capacity induction can produce loss of consciousness in 45 s; simulated context-sensitive decrement times explain recovery profiles; hyperventilation does not dramatically speed emergence; high fresh gas flow is wasteful; fresh gas flow and not the vaporizer setting should be reduced during intubation; re-anaesthetization can occur with severe hypoventilation after extubation; and in re-anaesthetization, the anaesthetic redistributes from skeletal muscle. Researchers using screen-based simulations can study fewer subjects to reach valid conclusions that impact clinical care. © The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  19. Nanopolymers improve delivery of exon skipping oligonucleotides and concomitant dystrophin expression in skeletal muscle of mdx mice

    Directory of Open Access Journals (Sweden)

    Sirsi Shashank R

    2008-04-01

    Full Text Available Abstract Background Exon skipping oligonucleotides (ESOs of 2'O-Methyl (2'OMe and morpholino chemistry have been shown to restore dystrophin expression in muscle fibers from the mdx mouse, and are currently being tested in phase I clinical trials for Duchenne Muscular Dystrophy (DMD. However, ESOs remain limited in their effectiveness because of an inadequate delivery profile. Synthetic cationic copolymers of poly(ethylene imine (PEI and poly(ethylene glycol (PEG are regarded as effective agents for enhanced delivery of nucleic acids in various applications. Results We examined whether PEG-PEI copolymers can facilitate ESO-mediated dystrophin expression after intramuscular injections into tibialis anterior (TA muscles of mdx mice. We utilized a set of PEG-PEI copolymers containing 2 kDa PEI and either 550 Da or 5 kDa PEG, both of which bind 2'OMe ESOs with high affinity and form stable nanoparticulates with a relatively low surface charge. Three weekly intramuscular injections of 5 μg of ESO complexed with PEI2K-PEG550 copolymers resulted in about 500 dystrophin-positive fibers and about 12% of normal levels of dystrophin expression at 3 weeks after the initial injection, which is significantly greater than for injections of ESO alone, which are known to be almost completely ineffective. In an effort to enhance biocompatibility and cellular uptake, the PEI2K-PEG550 and PEI2K-PEG5K copolymers were functionalized by covalent conjugation with nanogold (NG or adsorbtion of colloidal gold (CG, respectively. Surprisingly, using the same injection and dosing regimen, we found no significant difference in dystrophin expression by Western blot between the NG-PEI2K-PEG550, CG-PEI2K-PEG5K, and non-functionalized PEI2K-PEG550 copolymers. Dose-response experiments using the CG-PEI2K-PEG5K copolymer with total ESO ranging from 3–60 μg yielded a maximum of about 15% dystrophin expression. Further improvements in dystrophin expression up to 20% of normal

  20. Self-assembled liquid crystalline nanoparticles as a novel ophthalmic delivery system for dexamethasone: Improving preocular retention and ocular bioavailability.

    Science.gov (United States)

    Gan, Li; Han, Shun; Shen, Jinqiu; Zhu, Jiabi; Zhu, Chunliu; Zhang, Xinxin; Gan, Yong

    2010-08-30

    The object of this study was to design novel self-assembled liquid crystalline nanoparticles (cubosomes) as an ophthalmic delivery system for dexamethasone (DEX) to improve its preocular retention and ocular bioavailability. DEX cubosome particles were produced by fragmenting a cubic crystalline phase of monoolein and water in the presence of stabilizer Poloxamer 407. Small angle X-ray diffraction (SAXR) profiles revealed its internal structure as Pn3m space group, indicating the diamond cubic phase. In vitro, the apparent permeability coefficient of DEX administered in cubosomes exhibited a 4.5-fold (F1) and 3.5-fold (F2) increase compared to that of Dex-Na phosphate eye drops. Preocular retention studies revealed that the retention of cubosomes was significantly longer than that of solution and carbopol gel, with AUC(0-->180min) of Rh B cubosomes being 2-3-fold higher than that of the other two formulations. In vivo pharmacokinetics in aqueous humor was evaluated by microdialysis, which indicated a 1.8-fold (F1) increase in AUC(0-->240min) of DEX administered in cubosomes relative to that of Dex-Na phosphate eye drops, with about an 8-fold increase compared to that of DEX suspension. Corneal cross-sections after incubation with DEX cubosomes demonstrated an unaffected corneal structure and tissue integrity, which indicated the good biocompatibility of DEX cubosomes. In conclusion, self-assembled liquid crystalline nanoparticles might represent a promising vehicle for effective ocular drug delivery. Crown Copyright 2010. Published by Elsevier B.V. All rights reserved.

  1. Reduction-sensitive lipopolyamines as a novel nonviral gene delivery system for modulated release of DNA with improved transgene expression.

    Science.gov (United States)

    Byk, G; Wetzer, B; Frederic, M; Dubertret, C; Pitard, B; Jaslin, G; Scherman, D

    2000-11-16

    We have designed and synthesized original cationic lipids for modulated release of DNA from cationic lipid/DNA complexes. Our rationale was that modulated degradation of the lipids during or after penetration into the cell could improve the trafficking of DNA to the nucleus resulting in increased transgene expression. The new reduction-sensitive lipopolyamines (RSL) harbor a disulfide bridge within different positions in the backbone of the lipids as biosensitive function. A useful synthetic method was developed to obtain, with very good yields and reproducibility, unsymmetrical disulfide-bridged molecules, starting from symmetrical disulfides and thiols. The new lipopolyamines are good candidates as carriers of therapeutic genes for in vivo gene delivery. To optimize the transfection efficiency in these novel series, we have carried out structure-activity relationship studies by placing the disulfide bridge at different positions in the backbone of the cationic lipid and by systematic variation of lipid chain length. Results indicate that the transfection level can be modulated as a function of the location of the disulfide bridge in the molecule. We suggest that an early release of DNA during or after penetration into the cell, probably promoted by reduction of a disulfide bridge placed between the polyamine and the lipid, implies a total loss of transfection efficiency. On the other hand, proper modulation of DNA release by inserting the disulfide bridge between one lipid chain and the rest of the molecule brings about increased transfection efficiency as compared to previously described nondegradable lipopolyamine analogues. Finally, preliminary physicochemical characterization of the complexes demonstrates that DNA release from complexes can be modulated as a function of the surrounding reducing conditions of the complexes and of the localization of the disulfide bridge within the lipopolyamine. Our results suggest that RSL is a promising new approach for gene

  2. S737F is a new CFTR mutation typical of patients originally from the Tuscany region in Italy.

    Science.gov (United States)

    Terlizzi, Vito; Di Lullo, Antonella Miriam; Comegna, Marika; Centrone, Claudia; Pelo, Elisabetta; Castaldo, Giuseppe; Raia, Valeria; Braggion, Cesare

    2018-01-03

    An increasing number of patients have been described as having a number of Cystic Fibrosis Transmembrane conductance Regulator (CFTR) variants for which it lacks a clear genotype-phenotype correlation. We assesses the clinical features of patients bearing the S737F (p.Ser737Phe) CFTR missense variant and evaluated the residual function of CFTR protein on nasal epithelial cells (NEC). A retrospective database was performed from individuals homozygous or compound heterozygous for the S737F variant followed in the Cystic Fibrosis (CF) Centre of Florence. We performed a nasal brushing in cooperating patients and compared the results with those of patients followed in the pediatric CF Centre of Naples. 9/295 (3%) subjects carrying at least S737F CFTR variant on one allele were identified. Patients were diagnosed in 7/9 cases by newborn screening and in two cases for dehydration with hypochloremic metabolic alkalosis; at diagnosis sweat chloride levels (SCL) were in the pathological range in only one case. After a mean follow up of 8,6 years (range 0,5-15,8), SCL were in the pathological range in 8/9 cases (mean age at CF diagnosis: 1,5 years), all patients were pancreatic sufficiency and respiratory function was normal. The gating activity on NEC was 15.6% and 12.7% in two patients compound heterozygous for W1282X and DelE22_24, while it was ranged between 6,2% and 9,8% in CF patients. S737F is a CFTR mutation associated to hypochloremic alkalosis in childhood, mild CF phenotype in teenage years and a residual function of CFTR protein.

  3. Using process elicitation and validation to understand and improve chemotherapy ordering and delivery.

    Science.gov (United States)

    Mertens, Wilson C; Christov, Stefan C; Avrunin, George S; Clarke, Lori A; Osterweil, Leon J; Cassells, Lucinda J; Marquard, Jenna L

    2012-11-01

    Chemotherapy ordering and administration, in which errors have potentially severe consequences, was quantitatively and qualitatively evaluated by employing process formalism (or formal process definition), a technique derived from software engineering, to elicit and rigorously describe the process, after which validation techniques were applied to confirm the accuracy of the described process. The chemotherapy ordering and administration process, including exceptional situations and individuals' recognition of and responses to those situations, was elicited through informal, unstructured interviews with members of an interdisciplinary team. The process description (or process definition), written in a notation developed for software quality assessment purposes, guided process validation (which consisted of direct observations and semistructured interviews to confirm the elicited details for the treatment plan portion of the process). The overall process definition yielded 467 steps; 207 steps (44%) were dedicated to handling 59 exceptional situations. Validation yielded 82 unique process events (35 new expected but not yet described steps, 16 new exceptional situations, and 31 new steps in response to exceptional situations). Process participants actively altered the process as ambiguities and conflicts were discovered by the elicitation and validation components of the study. Chemotherapy error rates declined significantly during and after the project, which was conducted from October 2007 through August 2008. Each elicitation method and the subsequent validation discussions contributed uniquely to understanding the chemotherapy treatment plan review process, supporting rapid adoption of changes, improved communication regarding the process, and ensuing error reduction.

  4. Improving health-care delivery in low-resource settings with nanotechnology

    Directory of Open Access Journals (Sweden)

    James J Abbas

    2017-03-01

    Full Text Available In the two decades after 1990, the rates of child and maternal mortality dropped by over 40% and 47%, respectively. Despite these improvements, which are in part due to increased access to medical technologies, profound health disparities exist. In 2015, a child born in a developing region is nearly eight times as likely to die before the age of 5 than one born in a developed region and developing regions accounted for nearly 99% of the maternal deaths. Recent developments in nanotechnology, however, have great potential to ameliorate these and other health disparities by providing new cost-effective solutions for diagnosis or treatment of a variety of medical conditions. Affordability is only one of the several challenges that will need to be met to translate new ideas into a medical product that addresses a global health need. This article aims to describe some of the other challenges that will be faced by nanotechnologists who seek to make an impact in low-resource settings across the globe.

  5. The Green Roof Microbiome: Improving Plant Survival for Ecosystem Service Delivery

    Directory of Open Access Journals (Sweden)

    Roberta Fulthorpe

    2018-02-01

    Full Text Available Plants are key contributors to ecosystem services delivered by green roofs in cities including stormwater capture, temperature regulation, and wildlife habitat. As a result, current research has primarily focused on their growth in relationship to extensive green roof (e.g., substrates <15 cm depth ecosystem services. Green roofs are exposed to a variety of harsh abiotic factors such as intense solar radiation, wind, and isolation from ground-level habitats, making survival exceedingly difficult. Plants in natural habitats benefit from a variety of interactions with fungi and bacteria. These plant-microbial interactions improve mechanisms of survival and productivity; however, many green roof substrates are sterilized prior to installation and lack microbial communities with unstudied consequences for green roof plant health and subsequent survival and performance. In this paper, we present six hypotheses on the positive role of microbes in green roof applications. In natural and experimental systems, microbial interactions have been linked to plant (1 drought tolerance, (2 pathogen protection, (3 nutrient availability, (4 salt tolerance, (5 phytohormone production, and (6 substrate stabilization, all of which are desirable properties of green roof ecosystems. As few studies exist that directly examine these relationships on green roofs, we explore the existing ecological literature on these topics to unravel the mechanisms that could support more complex green roof ecosystem and lead to new insight into the design, performance, and broader applications in green infrastructure.

  6. Persurf, a new method to improve surfactant delivery: a study in surfactant depleted rats.

    Directory of Open Access Journals (Sweden)

    Wolfram Burkhardt

    Full Text Available PURPOSE: Exogenous surfactant is not very effective in adults with ARDS, since surfactant does not reach atelectatic alveoli. Perfluorocarbons (PFC can recruit atelectatic areas but do not replace impaired endogenous surfactant. A surfactant-PFC-mixture could combine benefits of both therapies. The aim of the proof-of-principal-study was to produce a PFC-in-surfactant emulsion (Persurf and to test in surfactant depleted Wistar rats whether Persurf achieves I. a more homogenous pulmonary distribution and II. a more homogenous recruitment of alveoli when compared with surfactant or PFC alone. METHODS: Three different PFC were mixed with surfactant and phospholipid concentration in the emulsion was measured. After surfactant depletion, animals either received 30 ml/kg of PF5080, 100 mg/kg of stained (green dye Curosurf™ or 30 ml/kg of Persurf. Lungs were fixated after 1 hour of ventilation and alveolar aeration and surfactant distribution was estimated by a stereological approach. RESULTS: Persurf contained 3 mg/ml phospholipids and was stable for more than 48 hours. Persurf-administration improved oxygenation. Histological evaluation revealed a more homogenous surfactant distribution and alveolar inflation when compared with surfactant treated animals. CONCLUSIONS: In surfactant depleted rats administration of PFC-in-surfactant emulsion leads to a more homogenous distribution and aeration of the lung than surfactant alone.

  7. Nanocrystals of medium soluble actives--novel concept for improved dermal delivery and production strategy.

    Science.gov (United States)

    Zhai, Xuezhen; Lademann, Jürgen; Keck, Cornelia M; Müller, Rainer H

    2014-08-15

    After use in oral pharmaceutical products, nanocrystals are meanwhile applied to improve the dermal penetration of cosmetic actives (e.g. rutin, hesperidin) and of drugs. By now, nanocrystals are only dermally applied made from poorly soluble actives. The novel concept is to formulate nanocrystals also from medium soluble actives, and to apply a dermal formulation containing additionally nanocrystals. The nanocrystals should act as fast dissolving depot, increase saturation solubility and especially accumulate in the hair follicles, to further increase skin penetration. Caffeine was used as model compound with relevance to market products, and a particular process was developed for the production of caffeine nanocrystals to overcome the supersaturation related effect of crystal growth and fiber formation - typical with medium soluble compounds. It is based on low energy milling (pearl milling) in combination with low dielectric constant dispersion media (water-ethanol or ethanol-propylene glycol mixtures) and optimal stabilizers. Most successful was Carbopol(®) 981 (e.g. 20% caffeine in ethanol-propylene glycol 3:7 with 2% Carbopol, w/w). Nanocrystals with varied sizes can now be produced in a controlled process e.g. 660 nm (optimal for hair follicle accumulation) to 250 nm (optimal for fast dissolution). The short term test proved stability over 2 months of the present formulation being sufficient to perform in vivo testing of the novel concept. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. Managing the interface with marketing to improve delivery of pharmacovigilance within the pharmaceutical industry.

    Science.gov (United States)

    Edwards, Brian

    2004-01-01

    The pharmaceutical industry is under pressure to improve the scientific quality of its decisions concerning the benefit and risks of its products while ensuring compliance with acceptable standards of marketing. All those in a pharmaceutical company who currently work within pharmacovigilance should be encouraged to lead from the front to examine ongoing marketing activities to see how they can be adapted more towards pharmacovigilance and risk management. The current irony is that the personnel who have the greatest influence on benefit-risk decisions of a product are not necessarily those who acknowledge that they are performing pharmacovigilance. Indeed, for all concerned, whether their orientation is scientific and commercial, effective communication with prescribers and consumers usually underpins product success. Also, a substantial 'marketing' budget is culturally acceptable for the pharmaceutical industry so it is logical to assume that resource for postmarketing activity is often made available. Given these realities, I suggest we should strive for an integrated marketing and risk-management plan based on the best available evidence and that being fully aware and in control of the safety issues for your products is the best way to commercialise them successfully. This approach can still be consistent with other corporate responsibilities such as trying to reduce the financial burden of product development. If this article stimulates further debate about how the pharmaceutical industry can more effectively organise resources and operations to support pharmacovigilance, risk management, and marketing, then it will have achieved its purpose.

  9. Solid formulation of a supersaturable self-microemulsifying drug delivery system for valsartan with improved dissolution and bioavailability.

    Science.gov (United States)

    Yeom, Dong Woo; Chae, Bo Ram; Kim, Jin Han; Chae, Jun Soo; Shin, Dong Jun; Kim, Chang Hyun; Kim, Sung Rae; Choi, Ji Ho; Song, Seh Hyon; Oh, Dongho; Sohn, Se Il; Choi, Young Wook

    2017-11-07

    In order to improve the dissolution and oral bioavailability of valsartan (VST), and reduce the required volume for treatment, we previously formulated a supersaturable self-microemulsifying drug delivery system (SuSMEDDS) composed of VST (80 mg), Capmul ® MCM (13.2 mg), Tween ® 80 (59.2 mg), Transcutol ® P (59.2 mg), and Poloxamer 407 (13.2 mg). In the present study, by using Florite ® PS-10 (119.1 mg) and Vivapur ® 105 (105.6 mg) as solid carriers, VST-loaded solidified SuSMEDDS (S-SuSMEDDS) granules were successfully developed, which possessed good flow properties and rapid drug dissolution. By introducing croscarmellose sodium (31 mg) as a superdisintegrant, S-SuSMEDDS tablets were also successfully formulated, which showed fast disintegration and high dissolution efficiency. Preparation of granules and tablets was successfully optimized using D-optimal mixture design and 3-level factorial design, respectively, resulting in percentage prediction errors of <10%. In pharmacokinetic studies in rats, the relative bioavailability of the optimized granules was 107% and 222% of values obtained for SuSMEDDS and Diovan ® powder, respectively. Therefore, we conclude that novel S-SuSMEDDS formulations offer great potential for developing solid dosage forms of a liquefied formulation such as SuSMEDDS, while improving oral absorption of drugs with poor water solubility.

  10. The effectiveness of service delivery initiatives at improving patients' waiting times in clinical radiology departments: a systematic review.

    Science.gov (United States)

    Olisemeke, B; Chen, Y F; Hemming, K; Girling, A

    2014-12-01

    We reviewed the literature for the impact of service delivery initiatives (SDIs) on patients' waiting times within radiology departments. We searched MEDLINE, EMBASE, CINAHL, INSPEC and The Cochrane Library for relevant articles published between 1995 and February, 2013. The Cochrane EPOC risk of bias tool was used to assess the risk of bias on studies that met specified design criteria. Fifty-seven studies met the inclusion criteria. The types of SDI implemented included extended scope practice (ESP, three studies), quality management (12 studies), productivity-enhancing technologies (PETs, 29 studies), multiple interventions (11 studies), outsourcing and pay-for-performance (one study each). The uncontrolled pre- and post-intervention and the post-intervention designs were used in 54 (95%) of the studies. The reporting quality was poor: many of the studies did not test and/or report the statistical significance of their results. The studies were highly heterogeneous, therefore meta-analysis was inappropriate. The following type of SDIs showed promising results: extended scope practice; quality management methodologies including Six Sigma, Lean methodology, and continuous quality improvement; productivity-enhancing technologies including speech recognition reporting, teleradiology and computerised physician order entry systems. We have suggested improved study design and the mapping of the definitions of patient waiting times in radiology to generic timelines as a starting point for moving towards a situation where it becomes less restrictive to compare and/or pool the results of future studies in a meta-analysis.

  11. An immortal cell line to study the role of endogenous CFTR in electrolyte absorption.

    Science.gov (United States)

    Bell, C L; Quinton, P M

    1995-01-01

    The intact human reabsorptive sweat duct (RD) has been a reliable model for investigations of the functional role of "endogenous" CFTR (cystic fibrosis transmembrane conductance regulator) in normal and abnormal electrolyte absorptive function. But to overcome the limitations imposed by the use of fresh, intact tissue, we transformed cultured RD cells using the chimeric virus Ad5/SV40 1613 ori-. The resultant cell line, RD2(NL), has remained differentiated forming a polarized epithelium that expressed two fundamental components of absorption, a cAMP activated Cl- conductance (GCl) and an amiloride-sensitive Na+ conductance (GNa). In the unstimulated state, there was a low level of transport activity; however, addition of forskolin (10(-5) M) significantly increased the Cl- diffusion potential (Vt) generated by a luminally directed Cl- gradient from -15.3 +/- 0.7 mV to -23.9 +/- 1.1 mV, n = 39; and decreased the transepithelial resistance (Rt) from 814.8 +/- 56.3 omega.cm2 to 750.5 +/- 47.5 omega.cm2, n = 39, (n = number of cultures). cAMP activation, anion selectivity (Cl- > I- > gluconate), and a dependence upon metabolic energy (metabolic poisoning inhibited GCl), all indicate that the GCl expressed in RD2(NL) is in fact CFTR-GCl. The presence of an apical amiloride-sensitive GNa was shown by the amiloride (10(-5) M) inhibition of GNa as indicated by a reduction of Vt and equivalent short circuit current by 78.0 +/- 3.1% and 77.9 +/- 2.6%, respectively, and an increase in Rt by 7.2 +/- 0.8%, n = 36. In conclusion, the RD2(NL) cell line presents the first model system in which CFTR-GCl is expressed in a purely absorptive tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

  12. Association between F508 deletion in CFTR and chronic pancreatitis risk.

    Science.gov (United States)

    Zhao, Dong; Xu, Yanzhen; Li, Jiatong; Fu, Shien; Xiao, Feifan; Song, Xiaowei; Xie, Zhibin; Jiang, Min; He, Yan; Liu, Chengwu; Wen, Qiongxian; Yang, Xiaoli

    2017-09-01

    The cystic fibrosis transmembrane conductance regulator (CFTR) has been reported to influence individual susceptibility to chronic pancreatitis (CP), but the results of previous studies are controversial. We performed a study to demonstrate the relationship between CFTR and CP. We searched PubMed, Scopus, and Embase for studies of patients with CP. Seven studies from 1995 to 2016 were identified, and included 64,832 patients. Pooled prevalence and 95% confidence intervals (CIs) were calculated. F508 deletion in CFTR was significantly positively associated with CP risk in the overall analysis (odds ratio [OR]=3.20, 95% CI: 2.30-4.44, I 2 =31.7%). In subgroup analysis stratified by ethnicity, F508 deletion was significantly associated with CP risk in Indian populations, using a fixed effects model (ORs=5.45, 95% CI: 2.52-11.79, I 2 =0.0%), and in non-Indian populations, using a random effects model (ORs=3.59, 95% CI: 1.73-7.48, I 2 =60.9%). At the same time, we found that Indians with F508 deletion had much higher CP prevalence than non-Indians. Interestingly, F508 deletion was also associated with CP and idiopathic CP risk in subgroup analysis stratified by aeitiology, using the fixed effects model. Based on current evidence, F508 deletion is a risk factor for CP, and Indians with F508 deletion have much higher CP morbidity. Copyright © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  13. Liposomal Encapsulation for Systemic Delivery of Propranolol via Transdermal Iontophoresis Improves Bone Microarchitecture in Ovariectomized Rats.

    Science.gov (United States)

    Teong, Benjamin; Kuo, Shyh Ming; Tsai, Wei-Hsin; Ho, Mei-Ling; Chen, Chung-Hwan; Huang, Han Hsiang

    2017-04-13

    The stimulatory effects of liposomal propranolol (PRP) on proliferation and differentiation of human osteoblastic cells suggested that the prepared liposomes-encapsulated PRP exerts anabolic effects on bone in vivo. Iontophoresis provides merits such as sustained release of drugs and circumvention of first pass metabolism. This study further investigated and evaluated the anti-osteoporotic effects of liposomal PRP in ovariectomized (OVX) rats via iontophoresis. Rats subjected to OVX were administered with pure or liposomal PRP via iontophoresis or subcutaneous injection twice a week for 12 weeks. Changes in the microarchitecture at the proximal tibia and the fourth lumbar spine were assessed between pure or liposomal PRP treated and non-treated groups using micro-computed tomography. Administration of liposomal PRP at low dose (0.05 mg/kg) via iontophoresis over 2-fold elevated ratio between bone volume and total tissue volume (BV/TV) in proximal tibia to 9.0% whereas treatment with liposomal PRP at low and high (0.5 mg/kg) doses via subcutaneous injection resulted in smaller increases in BV/TV. Significant improvement of BV/TV and bone mineral density (BMD) was also found in the fourth lumbar spine when low-dose liposomal PRP was iontophoretically administered. Iontophoretic low-dose liposomal PRP also elevated trabecular numbers in tibia and trabecular thickness in spine. Enhancement of bone microarchitecture volumes has highlighted that liposomal formulation with transdermal iontophoresis is promising for PRP treatment at the lower dose and with longer duration than its clinical therapeutic range and duration to exhibit optimal effects against bone loss in vivo.

  14. Local myocardial insulin-like growth factor 1 (IGF-1) delivery with biotinylated peptide nanofibers improves cell therapy for myocardial infarction

    Science.gov (United States)

    Davis, Michael E.; Hsieh, Patrick C. H.; Takahashi, Tomosaburo; Song, Qing; Zhang, Shuguang; Kamm, Roger D.; Grodzinsky, Alan J.; Anversa, Piero; Lee, Richard T.

    2006-05-01

    Strategies for cardiac repair include injection of cells, but these approaches have been hampered by poor cell engraftment, survival, and differentiation. To address these shortcomings for the purpose of improving cardiac function after injury, we designed self-assembling peptide nanofibers for prolonged delivery of insulin-like growth factor 1 (IGF-1), a cardiomyocyte growth and differentiation factor, to the myocardium, using a "biotin sandwich" approach. Biotinylated IGF-1 was complexed with tetravalent streptavidin and then bound to biotinylated self-assembling peptides. This biotin sandwich strategy allowed binding of IGF-1 but did not prevent self-assembly of the peptides into nanofibers within the myocardium. IGF-1 that was bound to peptide nanofibers activated Akt, decreased activation of caspase-3, and increased expression of cardiac troponin I in cardiomyocytes. After injection into rat myocardium, biotinylated nanofibers provided sustained IGF-1 delivery for 28 days, and targeted delivery of IGF-1 in vivo increased activation of Akt in the myocardium. When combined with transplanted cardiomyocytes, IGF-1 delivery by biotinylated nanofibers decreased caspase-3 cleavage by 28% and increased the myocyte cross-sectional area by 25% compared with cells embedded within nanofibers alone or with untethered IGF-1. Finally, cell therapy with IGF-1 delivery by biotinylated nanofibers improved systolic function after experimental myocardial infarction, demonstrating how engineering the local cellular microenvironment can improve cell therapy. engineering | maturation | scaffold

  15. The role of team climate in improving the quality of chronic care delivery: a longitudinal study among professionals working with chronically ill adolescents in transitional care programmes.

    Science.gov (United States)

    Cramm, Jane M; Strating, Mathilde M H; Nieboer, Anna P

    2014-05-22

    This study aimed to (1) evaluate the effectiveness of implementing transition programmes in improving the quality of chronic care delivery and (2) identify the predictive role of (changes in) team climate on the quality of chronic care delivery over time. This longitudinal study was undertaken with professionals working in hospitals and rehabilitation units that participated in the transition programme 'On Your Own Feet Ahead!' in the Netherlands. A total of 145/180 respondents (80.6%) filled in the questionnaire at the beginning of the programme (T1), and 101/173 respondents (58.4%) did so 1 year later at the end of the programme (T2). A total of 90 (52%) respondents filled in the questionnaire at both time points. Two-tailed, paired t tests were used to investigate improvements over time and multilevel analyses to investigate the predictive role of (changes in) team climate on the quality of chronic care delivery. Transition programme. Quality of chronic care delivery measured with the Assessment of Chronic Illness Care Short version (ACIC-S). The overall ACIC-S score at T1 was 5.90, indicating basic or intermediate support for chronic care delivery. The mean ACIC-S score at T2 significantly improved to 6.70, indicating advanced support for chronic care. After adjusting for the quality of chronic care delivery at T1 and significant respondents' characteristics, multilevel regression analyses showed that team climate at T1 (pteam climate (pteam climate to enhance the quality of chronic care delivery to chronically ill adolescents. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  16. Distribution of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR Mutations in a Cohort of Patients Residing in Palestine.

    Directory of Open Access Journals (Sweden)

    Issa Siryani

    Full Text Available Cystic fibrosis (CF is an autosomal recessive inherited life-threatening disorder that causes severe damage to the lungs and the digestive system. In Palestine, mutations in the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR that contributes to the clinical presentation of CF are ill defined. A cohort of thirty three clinically diagnosed CF patients from twenty one different Palestinian families residing in the central and southern part of Palestine were incorporated in this study. Sweat chloride testing was performed using the Sweat Chek Conductivity Analyzer (ELITECH Group, France to confirm the clinical diagnosis of CF. In addition, nucleic acid from the patients' blood samples was extracted and the CFTR mutation profiles were assessed by direct sequencing of the CFTR 27 exons and the intron-exon boundaries. For patient's DNA samples where no homozygous or two heterozygous CFTR mutations were identified by exon sequencing, DNA samples were tested for deletions or duplications using SALSA MLPA probemix P091-D1 CFTR assay. Sweat chloride testing confirmed the clinical diagnosis of CF in those patients. All patients had NaCl conductivity >60 mmol/l. In addition, nine different CFTR mutations were identified in all 21 different families evaluated. These mutations were c.1393-1G>A, F508del, W1282X, G85E, c.313delA, N1303K, deletion exons 17a-17b-18, deletion exons 17a-17b and Q1100P. c.1393-1G>A was shown to be the most frequent occurring mutation among tested families. We have profiled the underling mutations in the CFTR gene of a cohort of 21 different families affected by CF. Unlike other studies from the Arab countries where F508del was reported to be the most common mutation, in southern/central Palestine, the c.1393-1G>A appeared to be the most common. Further studies are needed per sample size and geographic distribution to account for other possible CFTR genetic alterations and their frequencies. Genotype

  17. Self-nanoemulsifying drug delivery system for enhanced bioavailability and improved hepatoprotective activity of biphenyl dimethyl dicarboxylate.

    Science.gov (United States)

    El-Laithy, Hanan M

    2008-07-01

    Biphenyl Dimethyl Dicarboxylate (BDD) is insoluble in aqueous solution and the bioavailability after oral administration is low. Self-nanoemulsifying drug delivery system (SNEDDS) containing BDD has been successfully prepared using carefully selected ingredients which are less affected by pH and ionic strength changes to improve its bioavailability. SNEDDS is an isotropic mixture of lipid, surfactant, and cosurfactant which are spontaneously emulsified in aqueous medium under gentle digestive motility in the gastrointestinal tract. Pseudo ternary phase diagrams composed of various excipients were plotted to identify self -nano -emulsifying area. Droplet size changes upon dilution with aqueous media and in vitro release of BDD from SNEDDS in 0.1N HCl and phosphate buffer (pH 7.4) were studied and compared with commercial chinese pilules and Pennel capsules. The hepatoprotective activity upon oral administration of SNEDDS against carbon tetrachloride-induced oxidative stress in albino rats was assessed by measuring biochemical parameters like serum glutamic oxalacetate transaminase (SGOT), serum glutamic pyruvate transaminase (SGPT) and lactate dehydrogenase (LDH). Results showed that using a proper ratio of Tween 80 to Transcutol as surfactant and co-surfactant respectively and Miglyol 812 as oil to surfactants mixture resulted in production of infinitely diluted formulations in nano droplet size range. BDD self nano emulsified formula composed of 20% Miglyol 812, 60% Tween 80 and 20% Transcutol released 99% of the drug very rapidly within 10-15 minutes regardless of the pH condition. The oral absorption and bioavailability of BDD self nano emulsified formula in albino rats were significantly enhanced (P<0.01) with an average improvement of 1.7 and 6-folds that of commercial chinese pilules and Pennel capsules respectively. This improvement was also confirmed histopathologically in chemically injured rats and by the significant decrease in elevated liver enzymes

  18. Reducing Bottlenecks to Improve the Efficiency of the Lung Cancer Care Delivery Process: A Process Engineering Modeling Approach to Patient-Centered Care.

    Science.gov (United States)

    Ju, Feng; Lee, Hyo Kyung; Yu, Xinhua; Faris, Nicholas R; Rugless, Fedoria; Jiang, Shan; Li, Jingshan; Osarogiagbon, Raymond U

    2017-12-01

    The process of lung cancer care from initial lesion detection to treatment is complex, involving multiple steps, each introducing the potential for substantial delays. Identifying the steps with the greatest delays enables a focused effort to improve the timeliness of care-delivery, without sacrificing quality. We retrospectively reviewed clinical events from initial detection, through histologic diagnosis, radiologic and invasive staging, and medical clearance, to surgery for all patients who had an attempted resection of a suspected lung cancer in a community healthcare system. We used a computer process modeling approach to evaluate delays in care delivery, in order to identify potential 'bottlenecks' in waiting time, the reduction of which could produce greater care efficiency. We also conducted 'what-if' analyses to predict the relative impact of simulated changes in the care delivery process to determine the most efficient pathways to surgery. The waiting time between radiologic lesion detection and diagnostic biopsy, and the waiting time from radiologic staging to surgery were the two most critical bottlenecks impeding efficient care delivery (more than 3 times larger compared to reducing other waiting times). Additionally, instituting surgical consultation prior to cardiac consultation for medical clearance and decreasing the waiting time between CT scans and diagnostic biopsies, were potentially the most impactful measures to reduce care delays before surgery. Rigorous computer simulation modeling, using clinical data, can provide useful information to identify areas for improving the efficiency of care delivery by process engineering, for patients who receive surgery for lung cancer.

  19. Improving clinical research and cancer care delivery in community settings: evaluating the NCI community cancer centers program

    Directory of Open Access Journals (Sweden)

    Fennell Mary L

    2009-09-01

    Full Text Available Abstract Background In this article, we describe the National Cancer Institute (NCI Community Cancer Centers Program (NCCCP pilot and the evaluation designed to assess its role, function, and relevance to the NCI's research mission. In doing so, we describe the evolution of and rationale for the NCCCP concept, participating sites' characteristics, its multi-faceted aims to enhance clinical research and quality of care in community settings, and the role of strategic partnerships, both within and outside of the NCCCP network, in achieving program objectives. Discussion The evaluation of the NCCCP is conceptualized as a mixed method multi-layered assessment of organizational innovation and performance which includes mapping the evolution of site development as a means of understanding the inter- and intra-organizational change in the pilot, and the application of specific evaluation metrics for assessing the implementation, operations, and performance of the NCCCP pilot. The assessment of the cost of the pilot as an additional means of informing the longer-term feasibility and sustainability of the program is also discussed. Summary The NCCCP is a major systems-level set of organizational innovations to enhance clinical research and care delivery in diverse communities across the United States. Assessment of the extent to which the program achieves its aims will depend on a full understanding of how individual, organizational, and environmental factors align (or fail to align to achieve these improvements, and at what cost.

  20. Improving clinical research and cancer care delivery in community settings: evaluating the NCI community cancer centers program.

    Science.gov (United States)

    Clauser, Steven B; Johnson, Maureen R; O'Brien, Donna M; Beveridge, Joy M; Fennell, Mary L; Kaluzny, Arnold D

    2009-09-26

    In this article, we describe the National Cancer Institute (NCI) Community Cancer Centers Program (NCCCP) pilot and the evaluation designed to assess its role, function, and relevance to the NCI's research mission. In doing so, we describe the evolution of and rationale for the NCCCP concept, participating sites' characteristics, its multi-faceted aims to enhance clinical research and quality of care in community settings, and the role of strategic partnerships, both within and outside of the NCCCP network, in achieving program objectives. The evaluation of the NCCCP is conceptualized as a mixed method multi-layered assessment of organizational innovation and performance which includes mapping the evolution of site development as a means of understanding the inter- and intra-organizational change in the pilot, and the application of specific evaluation metrics for assessing the implementation, operations, and performance of the NCCCP pilot. The assessment of the cost of the pilot as an additional means of informing the longer-term feasibility and sustainability of the program is also discussed. The NCCCP is a major systems-level set of organizational innovations to enhance clinical research and care delivery in diverse communities across the United States. Assessment of the extent to which the program achieves its aims will depend on a full understanding of how individual, organizational, and environmental factors align (or fail to align) to achieve these improvements, and at what cost.

  1. Dual-drug delivery by porous silicon nanoparticles for improved cellular uptake, sustained release, and combination therapy.

    Science.gov (United States)

    Wang, Chang-Fang; Mäkilä, Ermei M; Kaasalainen, Martti H; Hagström, Marja V; Salonen, Jarno J; Hirvonen, Jouni T; Santos, Hélder A

    2015-04-01

    Dual-drug delivery of antiangiogenic and chemotherapeutic drugs can enhance the therapeutic effect for cancer therapy. Conjugation of methotrexate (MTX) to porous silicon (PSi) nanoparticles (MTX-PSi) with positively charged surface can improve the cellular uptake of MTX and inhibit the proliferation of cancer cells. Herein, MTX-PSi conjugates sustained the release of MTX up to 96 h, and the released fragments including MTX were confirmed by mass spectrometry. The intracellular distribution of the MTX-PSi nanoparticles was confirmed by transmission electron microscopy. Compared to pure MTX, the MTX-PSi achieved similar inhibition of cell proliferation in folate receptor (FR) over-expressing U87 MG cancer cells, and a higher effect in low FR-expressing EA.hy926 cells. Nuclear fragmentation analysis demonstrated programmed cell apoptosis of MTX-PSi in the high/low FR-expressing cancer cells, whereas PSi alone at the same dose had a minor effect on cell apoptosis. Finally, the porous structure of MTX-PSi enabled a successful concomitant loading of another anti-angiogenic hydrophobic drug, sorafenib, and considerably enhanced the dissolution rate of sorafenib. Overall, the MTX-PSi nanoparticles can be used as a platform for combination chemotherapy by simultaneously enhancing the dissolution rate of a hydrophobic drug and sustaining the release of a conjugated chemotherapeutic drug. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  2. Caring Wisely: A Program to Support Frontline Clinicians and Staff in Improving Healthcare Delivery and Reducing Costs.

    Science.gov (United States)

    Gonzales, Ralph; Moriates, Christopher; Lau, Catherine; Valencia, Victoria; Imershein, Sarah; Rajkomar, Alvin; Prasad, Priya; Boscardin, Christy; Grady, Deborah; Johnston, S

    2017-08-01

    We describe a program called "Caring Wisely"®, developed by the University of California, San Francisco's (UCSF), Center for Healthcare Value, to increase the value of services provided at UCSF Health. The overarching goal of the Caring Wisely® program is to catalyze and advance delivery system redesign and innovations that reduce costs, enhance healthcare quality, and improve health outcomes. The program is designed to engage frontline clinicians and staff-aided by experienced implementation scientists-to develop and implement interventions specifically designed to address overuse, underuse, or misuse of services. Financial savings of the program are intended to cover the program costs. The theoretical underpinnings for the design of the Caring Wisely® program emphasize the importance of stakeholder engagement, behavior change theory, market (target audience) segmentation, and process measurement and feedback. The Caring Wisely® program provides an institutional model for using crowdsourcing to identify "hot spot" areas of low-value care, inefficiency and waste, and for implementing robust interventions to address these areas. © 2017 Society of Hospital Medicine.

  3. Is congenital bilateral absence of vas deferens a primary form of cystic fibrosis? Analyses of the CFTR gene in 67 patients

    Energy Technology Data Exchange (ETDEWEB)

    Mercier, B.; Verlingue, C.; Audrezet, M.P.; Ferec, C. [Centre de Biogenetique C.D.T.S., Brest (France); Lissens, W.; Bonduelle, M. [University Hospital VUB, Brussels (United Kingdom); Silber, S.J. [St. Luke`s Hospital, St. Louis, MO (United States); Novelli, G. [Catholic Univ. of Rome (Italy)

    1995-01-01

    Congenital bilateral absence of the vas deferens (CBAVD) is an important cause of sterility in men. Although the genetic basis of this condition is still unclear, it has been shown recently that some of these patients carry mutations in their cystic fibrosis transmembrane conductance regulator (CFTR) genes. To extend this observation, we have analyzed the entire coding sequence of the CFTR gene in a cohort of 67 men with CBAVD, who are otherwise healthy. We have identified four novel missense mutations (A800G, G149R, R258G, and E193K). We have shown that 42% of subjects were carriers of one CFTR allele and that 24% are compound heterozygous for CFTR alleles. Thus, we have been unable to identify 76% of these patients as carrying two CFTR mutations. Furthermore, we have described the segregation of CFTR haplotypes in the family of one CBAVD male; in this family are two male siblings, with identical CFTR loci but displaying different phenotypes, one of them being fertile and the other sterile. The data presented in this family, indicating a discordance between the CBAVD phenotype and a marked carrier ({delta}F508) chromosome, support the involvement of another gene(s), in the etiology of CBAVD. 35 refs., 2 figs., 1 tab.

  4. Improved bioavailability of targeted Curcumin delivery efficiently regressed cardiac hypertrophy by modulating apoptotic load within cardiac microenvironment

    International Nuclear Information System (INIS)

    Ray, Aramita; Rana, Santanu; Banerjee, Durba; Mitra, Arkadeep; Datta, Ritwik; Naskar, Shaon; Sarkar, Sagartirtha

    2016-01-01

    Cardiomyocyte apoptosis acts as a prime modulator of cardiac hypertrophy leading to heart failure, a major cause of human mortality worldwide. Recent therapeutic interventions have focussed on translational applications of diverse pharmaceutical regimes among which, Curcumin (from Curcuma longa) is known to have an anti-hypertrophic potential but with limited pharmacological efficacies due to low aqueous solubility and poor bioavailability. In this study, Curcumin encapsulated by carboxymethyl chitosan (CMC) nanoparticle conjugated to a myocyte specific homing peptide was successfully delivered in bioactive form to pathological myocardium for effective regression of cardiac hypertrophy in a rat (Rattus norvegicus) model. Targeted nanotization showed higher cardiac bioavailability of Curcumin at a low dose of 5 mg/kg body weight compared to free Curcumin at 35 mg/kg body weight. Moreover, Curcumin/CMC-peptide treatment during hypertrophy significantly improved cardiac function by downregulating expression of hypertrophy marker genes (ANF, β-MHC), apoptotic mediators (Bax, Cytochrome-c) and activity of apoptotic markers (Caspase 3 and PARP); whereas free Curcumin in much higher dose showed minimal improvement during compromised cardiac function. Targeted Curcumin treatment significantly lowered p53 expression and activation in diseased myocardium via inhibited interaction of p53 with p300-HAT. Thus attenuated acetylation of p53 facilitated p53 ubiquitination and reduced the apoptotic load in hypertrophied cardiomyocytes; thereby limiting cardiomyocytes' need to enter the regeneration cycle during hypertrophy. This study elucidates for the first time an efficient targeted delivery regimen for Curcumin and also attributes towards probable mechanistic insight into its therapeutic potential as a cardio-protective agent for regression of cardiac hypertrophy. - Highlights: • Cardiomyocyte targeted Curcumin/CMC-peptide increases bioavailability of the drug.

  5. Polyelectrolyte Complex Based Interfacial Drug Delivery System with Controlled Loading and Improved Release Performance for Bone Therapeutics

    Directory of Open Access Journals (Sweden)

    David Vehlow

    2016-03-01

    Full Text Available An improved interfacial drug delivery system (DDS based on polyelectrolyte complex (PEC coatings with controlled drug loading and improved release performance was elaborated. The cationic homopolypeptide poly(l-lysine (PLL was complexed with a mixture of two cellulose sulfates (CS of low and high degree of substitution, so that the CS and PLL solution have around equal molar charged units. As drugs the antibiotic rifampicin (RIF and the bisphosphonate risedronate (RIS were integrated. As an important advantage over previous PEC systems this one can be centrifuged, the supernatant discarded, the dense pellet phase (coacervate separated, and again redispersed in fresh water phase. This behavior has three benefits: (i Access to the loading capacity of the drug, since the concentration of the free drug can be measured by spectroscopy; (ii lower initial burst and higher residual amount of drug due to removal of unbound drug and (iii complete adhesive stability due to the removal of polyelectrolytes (PEL excess component. It was found that the pH value and ionic strength strongly affected drug content and release of RIS and RIF. At the clinically relevant implant material (Ti40Nb similar PEC adhesive and drug release properties compared to the model substrate were found. Unloaded PEC coatings at Ti40Nb showed a similar number and morphology of above cultivated human mesenchymal stem cells (hMSC compared to uncoated Ti40Nb and resulted in considerable production of bone mineral. RIS loaded PEC coatings showed similar effects after 24 h but resulted in reduced number and unhealthy appearance of hMSC after 48 h due to cell toxicity of RIS.

  6. Effectiveness of community based intervention on improvement of pregnancy and delivery process in district 4 of Tehran

    Directory of Open Access Journals (Sweden)

    Mamak Shariat

    2015-10-01

    Full Text Available Background: To reduce cesarean section rate, we need complex interventions to modify related behavior. We aimed to identify the effectiveness of a community-based intervention on prenatal care status, delivery and decline of cesarean section rate. Methods: A quasi-experimental study was carried out on mothers residing in Khak Sefid and Javadiyeh in Tehran from January 2011 to September 2014. Study population was 274 mothers; attending in health centers for first vaccination of their neonates. Mothers' demographic data were recorded in some questionnaires. One year interventions including; consultation, distribution of educational package and training courses (for mothers, fathers and their families, educational programs for midwives, obstetricians and gynecologist, residents, medical students, accomplishment of 10 steps baby-friendly principles and provision adequate personnel in labor-delivery room were implemented in community, hospitals and health centers. After intervention, 250 mothers who were attending in health centers for vaccination of 2 months aged neonates were assessed and their data were recorded in the same questionnaires. The effectiveness of intervention on cesarean section rate and cesarean tendency in before and after intervention groups were compared. P< 0.05 was considered as level of significance. Results: Of 274 mothers in "before intervention" group 193 (70.44% and of 250 mothers in "after intervention", 169 subjects (67.6% had cesarean section. Although a significant decline was seen in cesarean tendency in "after intervention" group (P= 0.034, no significant difference was seen between 2 groups' cesarean section rates (P= 0.48. In "after intervention" group episiotomy, induction of labor rate and maternal morbidity were significantly lower than "before intervention" group (P= 0.0001, 0.0001, 0.01. Although no significant difference was seen between two groups neonatal birth weight (P= 0.69, a significant difference was

  7. Restoration of CFTR Activity in Ducts Rescues Acinar Cell Function and Reduces Inflammation in Pancreatic and Salivary Glands of Mice.

    Science.gov (United States)

    Zeng, Mei; Szymczak, Mitchell; Ahuja, Malini; Zheng, Changyu; Yin, Hongen; Swaim, William; Chiorini, John A; Bridges, Robert J; Muallem, Shmuel

    2017-10-01

    Sjögren's syndrome and autoimmune pancreatitis are disorders with decreased function of salivary, lacrimal glands, and the exocrine pancreas. Nonobese diabetic/ShiLTJ mice and mice transduced with the cytokine BMP6 develop Sjögren's syndrome and chronic pancreatitis and MRL/Mp mice are models of autoimmune pancreatitis. Cystic fibrosis transmembrane conductance regulator (CFTR) is a ductal Cl -  channel essential for ductal fluid and HCO 3 - secretion. We used these models to ask the following questions: is CFTR expression altered in these diseases, does correction of CFTR correct gland function, and most notably, does correcting ductal function correct acinar function? We treated the mice models with the CFTR corrector C18 and the potentiator VX770. Glandular, ductal, and acinar cells damage, infiltration, immune cells and function were measured in vivo and in isolated duct/acini. In the disease models, CFTR expression is markedly reduced. The salivary glands and pancreas are inflamed with increased fibrosis and tissue damage. Treatment with VX770 and, in particular, C18 restored salivation, rescued CFTR expression and localization, and nearly eliminated the inflammation and tissue damage. Transgenic overexpression of CFTR exclusively in the duct had similar effects. Most notably, the markedly reduced acinar cell Ca 2+ signaling, Orai1, inositol triphosphate receptors, Aquaporin 5 expression, and fluid secretion were restored by rescuing ductal CFTR. Our findings reveal that correcting ductal function is sufficient to rescue acinar cell function and suggests that CFTR correctors are strong candidates for the treatment of Sjögren's syndrome and pancreatitis. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

  8. Development of allele-specific multiplex PCR to determine the length of poly-T in intron 8 of CFTR

    Directory of Open Access Journals (Sweden)

    Neng Chen

    2014-07-01

    Full Text Available Cystic fibrosis transmembrane conductance regulator (CFTR gene mutation analysis has been implemented for Cystic Fibrosis (CF carrier screening, and molecular diagnosis of CF and congenital bilateral absence of the vas deferens (CBAVD. Although poly-T allele analysis in intron 8 of CFTR is required when a patient is positive for R117H, it is not recommended for routine carrier screening. Therefore, commercial kits for CFTR mutation analysis were designed either to mask the poly-T allele results, unless a patient is R117H positive, or to have the poly-T analysis as a standalone reflex test using the same commercial platform. There are other standalone assays developed to detect poly-T alleles, such as heteroduplex analysis, High Resolution Melting (HRM curve analysis, allele-specific PCR (AS-PCR and Sanger sequencing. In this report, we developed a simple and easy-to-implement multiplex AS-PCR assay using unlabeled standard length primers, which can be used as a reflex or standalone test for CFTR poly-T track analysis. Out of 115 human gDNA samples tested, results from our new AS-PCR matched to the previous known poly-T results or results from Sanger sequencing.

  9. Gq activity- and β-arrestin-1 scaffolding-mediated ADGRG2/CFTR coupling are required for male fertility

    Science.gov (United States)

    Lin, Hui; Li, Rui-Rui; Liang, Zong-Lai; Gao, Yuan; Yang, Zhao; He, Dong-Fang; Lin, Amy; Mo, Hui; Lu, Yu-Jing; Li, Meng-Jing; Kong, Wei; Chung, Ka Young; Yi, Fan; Li, Jian-Yuan; Qin, Ying-Ying; Li, Jingxin; Thomsen, Alex R B; Kahsai, Alem W; Chen, Zi-Jiang; Xu, Zhi-Gang; Liu, Mingyao

    2018-01-01

    Luminal fluid reabsorption plays a fundamental role in male fertility. We demonstrated that the ubiquitous GPCR signaling proteins Gq and β-arrestin-1 are essential for fluid reabsorption because they mediate coupling between an orphan receptor ADGRG2 (GPR64) and the ion channel CFTR. A reduction in protein level or deficiency of ADGRG2, Gq or β-arrestin-1 in a mouse model led to an imbalance in pH homeostasis in the efferent ductules due to decreased constitutive CFTR currents. Efferent ductule dysfunction was rescued by the specific activation of another GPCR, AGTR2. Further mechanistic analysis revealed that β-arrestin-1 acts as a scaffold for ADGRG2/CFTR complex formation in apical membranes, whereas specific residues of ADGRG2 confer coupling specificity for different G protein subtypes, this specificity is critical for male fertility. Therefore, manipulation of the signaling components of the ADGRG2-Gq/β-arrestin-1/CFTR complex by small molecules may be an effective therapeutic strategy for male infertility. PMID:29393851

  10. TRANSDERMAL DRUG DELIVERY SYSTEM: REVIEW

    OpenAIRE

    Vishvakarama Prabhakar; Agarwal Shivendra; Sharma Ritika; Saurabh Sharma

    2012-01-01

    Various new technologies have been developed for the transdermal delivery of some important drugs. Today about 74% of drugs are taken orally and are found not to be as effective as desired. To improve such characters transdermal drug delivery system was emerged. Drug delivery through the skin to achieve a systemic effect of a drug is commonly known as transdermal drug delivery and differs from traditional topical drug delivery. Transdermal drug delivery systems (TDDS) are dosage forms involve...

  11. A systematic review of interventions to improve prevention of mother-to-child HIV transmission service delivery and promote retention.

    Science.gov (United States)

    Ambia, Julie; Mandala, Justin

    2016-01-01

    The success of prevention of mother-to-child transmission of HIV (PMTCT) is dependent upon high retention of mother-infant pairs within these programmes. This is a systematic review to evaluate the effectiveness of interventions that aim to improve PMTCT service delivery and promote retention throughout the PMTCT steps. Selected databases were searched for studies published in English (up to September 2015). Outcomes of interest included antiretroviral (ARV) drugs or antiretroviral therapy (ART) initiation among HIV-positive pregnant and/or breastfeeding women and their infants, retention into PMTCT programs, the uptake of early infant diagnosis (EID) of HIV and infant HIV status. Risk ratios and random-effect meta-analysis were used in the analysis. Interventions assessed in the 34 identified studies included male partner involvement in PMTCT, peer mentoring, the use of community health workers (CHWs), mobile phone-based reminders, conditional cash transfer, training of midwives, integration of PMTCT services and enhanced referral. Five studies (two randomized) that evaluated mobile phone-based interventions showed a statistically significant increase (pooled RR 1.18; 95% CI 1.05 to 1.32, I(2)=83%) in uptake of EID of HIV at around six weeks postpartum. Male partner involvement in PMTCT was associated with reductions in infant HIV transmission (pooled RR 0.61; 95% CI 0.39 to 0.94, I(2)=0%) in four studies (one randomized). Four studies (three randomized) that were grounded on psychological interventions reported non-significant results (pooled RR 1.01; 95% CI 0.93 to 1.09, I(2)=69%) in increasing ARV/ART uptake among HIV-positive pregnant and/or breastfeeding women and infant HIV testing (pooled RR 1.00; 95% CI 0.94 to 1.07, I(2)=45%). The effect of the other interventions on the effectiveness of improving PMTCT uptake was unclear. Heterogeneity of interventions limits these findings. Our findings indicate that mobile phone-based reminders may increase the uptake

  12. Lipid nanoparticles of zaleplon for improved oral delivery by Box-Behnken design: optimization, in vitro and in vivo evaluation.

    Science.gov (United States)

    Dudhipala, Narendar; Janga, Karthik Yadav

    2017-07-01

    Zaleplon (ZL) is a hypnotic drug prescribed for the management of insomnia and convulsions. The oral bioavailability of ZL was low (∼30%) owing to poor water solubility and hepatic first-pass metabolism. The cornerstone of this investigation is to develop and optimize solid lipid nanoparticles (SLNs) of ZL with the aid of Box-Behnken design (BBD) to improve the oral bioavailability. A design space with three formulation variables at three levels were evaluated in BBD. Amount of lipid (A 1 ), amount of surfactant (A 2 ) and concentration of co-surfactant (%) (A 3 ) were selected as independent variables, whereas, particle size (B 1 ), entrapment efficiency (B 2 ) and zeta potential (ZP, B 3 ) as responses. ZL-SLNs were prepared by hot homogenization with ultrasonication method and evaluated for responses to obtain optimized formulation. Morphology of nanoparticles was observed under SEM. DSC and XRD studies were examined to understand the native crystalline behavior of drug in SLN formulations. Further, in vivo studies were performed in Wistar rats. The optimized formulation with 132.89 mg of lipid, 106.7 mg of surfactant and 0.2% w/v of co-surfactant ensued in the nanoparticles with 219.9 ± 3.7 nm of size, -25.66 ± 2.83 mV surface charge and 86.83 ± 2.65% of entrapment efficiency. SEM studies confirmed the spherical shape of SLN formulations. The DSC and XRD studies revealed the transformation of crystalline drug to amorphous form in SLN formulation. In conclusion, in vivo studies in male Wistar rats demonstrated an improvement in the oral bioavailability of ZL from SLN over control ZL suspension. The enhancement in the oral bioavailability of ZL from SLNs, developed with the aid of BBD, explicated the potential of lipid-based nanoparticles as a potential carrier in improving the oral delivery of this poorly soluble drug.

  13. Cystic fibrosis transmembrane conductance regulator (CFTR allelic variants relate to shifts in faecal microbiota of cystic fibrosis patients.

    Directory of Open Access Journals (Sweden)

    Serena Schippa

    Full Text Available INTRODUCTION: In this study we investigated the effects of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR gene variants on the composition of faecal microbiota, in patients affected by Cystic Fibrosis (CF. CFTR mutations (F508del is the most common lead to a decreased secretion of chloride/water, and to mucus sticky secretions, in pancreas, respiratory and gastrointestinal tracts. Intestinal manifestations are underestimated in CF, leading to ileum meconium at birth, or small bowel bacterial overgrowth in adult age. METHODS: Thirty-six CF patients, fasting and under no-antibiotic treatment, were CFTR genotyped on both alleles. Faecal samples were subjected to molecular microbial profiling through Temporal Temperature Gradient Electrophoresis and species-specific PCR. Ecological parameters and multivariate algorithms were employed to find out if CFTR variants could be related to the microbiota structure. RESULTS: Patients were classified by two different criteria: 1 presence/absence of F508del mutation; 2 disease severity in heterozygous and homozygous F508del patients. We found that homozygous-F508del and severe CF patients exhibited an enhanced dysbiotic faecal microbiota composition, even within the CF cohort itself, with higher biodiversity and evenness. We also found, by species-specific PCR, that potentially harmful species (Escherichia coli and Eubacterium biforme were abundant in homozygous-F508del and severe CF patients, while beneficial species (Faecalibacterium prausnitzii, Bifidobacterium spp., and Eubacterium limosum were reduced. CONCLUSIONS: This is the first report that establishes a link among CFTR variants and shifts in faecal microbiota, opening the way to studies that perceive CF as a 'systemic disease', linking the lung and the gut in a joined axis.

  14. Cystic fibrosis transmembrane conductance regulator (CFTR) allelic variants relate to shifts in faecal microbiota of cystic fibrosis patients.

    Science.gov (United States)

    Schippa, Serena; Iebba, Valerio; Santangelo, Floriana; Gagliardi, Antonella; De Biase, Riccardo Valerio; Stamato, Antonella; Bertasi, Serenella; Lucarelli, Marco; Conte, Maria Pia; Quattrucci, Serena

    2013-01-01

    In this study we investigated the effects of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene variants on the composition of faecal microbiota, in patients affected by Cystic Fibrosis (CF). CFTR mutations (F508del is the most common) lead to a decreased secretion of chloride/water, and to mucus sticky secretions, in pancreas, respiratory and gastrointestinal tracts. Intestinal manifestations are underestimated in CF, leading to ileum meconium at birth, or small bowel bacterial overgrowth in adult age. Thirty-six CF patients, fasting and under no-antibiotic treatment, were CFTR genotyped on both alleles. Faecal samples were subjected to molecular microbial profiling through Temporal Temperature Gradient Electrophoresis and species-specific PCR. Ecological parameters and multivariate algorithms were employed to find out if CFTR variants could be related to the microbiota structure. Patients were classified by two different criteria: 1) presence/absence of F508del mutation; 2) disease severity in heterozygous and homozygous F508del patients. We found that homozygous-F508del and severe CF patients exhibited an enhanced dysbiotic faecal microbiota composition, even within the CF cohort itself, with higher biodiversity and evenness. We also found, by species-specific PCR, that potentially harmful species (Escherichia coli and Eubacterium biforme) were abundant in homozygous-F508del and severe CF patients, while beneficial species (Faecalibacterium prausnitzii, Bifidobacterium spp., and Eubacterium limosum) were reduced. This is the first report that establishes a link among CFTR variants and shifts in faecal microbiota, opening the way to studies that perceive CF as a 'systemic disease', linking the lung and the gut in a joined axis.

  15. Combined local and systemic antibiotic delivery improves eradication of wound contamination: An animal experimental model of contaminated fracture.

    Science.gov (United States)

    Rand, B C C; Penn-Barwell, J G; Wenke, J C

    2015-10-01

    Systemic antibiotics reduce infection in open fractures. Local delivery of antibiotics can provide higher doses to wounds without toxic systemic effects. This study investigated the effect on infection of combining systemic with local antibiotics via polymethylmethacrylate (PMMA) beads or gel delivery. An established Staphylococcus aureus contaminated fracture model in rats was used. Wounds were debrided and irrigated six hours after contamination and animals assigned to one of three groups, all of which received systemic antibiotics. One group had local delivery via antibiotic gel, another PMMA beads and the control group received no local antibiotics. After two weeks, bacterial levels were quantified. Combined local and systemic antibiotics were superior to systemic antibiotics alone at reducing the quantity of bacteria recoverable from each group (p = 0.002 for gel; p = 0.032 for beads). There was no difference in the bacterial counts between bead and gel delivery (p = 0.62). These results suggest that local antibiotics augment the antimicrobial effect of systemic antibiotics. Although no significant difference was found between vehicles, gel delivery offers technical advantages with its biodegradable nature, ability to conform to wound shape and to deliver increased doses. Further study is required to see if the gel delivery system has a clinical role. ©2015 The British Editorial Society of Bone & Joint Surgery.

  16. Novel solid self-emulsifying drug delivery system of coenzyme Q₁₀ with improved photochemical and pharmacokinetic behaviors.

    Science.gov (United States)

    Onoue, Satomi; Uchida, Atushi; Kuriyama, Kazuki; Nakamura, Tatsuya; Seto, Yoshiki; Kato, Masashi; Hatanaka, Junya; Tanaka, Toshiyuki; Miyoshi, Hiroyuki; Yamada, Shizuo

    2012-08-15

    The present study was undertaken to develop a solid self-emulsifying drug delivery system of coenzyme Q(10) (CoQ(10)/s-SEDDS) with high photostability and oral bioavailability. The CoQ(10)/s-SEDDS was prepared by spray-drying an emulsion preconcentrate containing CoQ(10), medium-chain triglyceride, sucrose ester of fatty acid, and hydroxypropyl cellulose, and its physicochemical, photochemical, and pharmacokinetic properties were evaluated. The CoQ(10)/s-SEDDS powder with a diameter of ca. 15 μm was obtained by spray-drying, in which the CoQ(10) was mostly amorphized. The CoQ(10)/s-SEDDS exhibited immediate self-emulsification when introduced to aqueous media under gentle agitation, forming uniform fine droplets with a mean diameter of ca. 280 nm. There was marked generation of reactive oxygen species, in particular superoxide, from CoQ(10) exposed to simulated sunlight (250W/m(2)), suggesting potent photoreactivity. Nano-emulsified solution of CoQ(10) under light exposure underwent photodegradation with 22-fold higher degradation kinetics than crystalline CoQ(10), although the CoQ(10)/s-SEDDS was less photoreactive. After the oral administration of CoQ(10)/s-SEDDS (100 mg-CoQ(10)/kg) in rats, enhanced exposure of CoQ(10) was observed with increases in both C(max) and AUC of ca. 5-fold in comparison with those of orally administered crystalline CoQ(10). From the improved physicochemical and pharmacokinetic data, the s-SEDDS approach upon spray-drying might be a suitable dosage option for enhancing nutraceutical and pharmaceutical values of CoQ(10). Copyright © 2012 Elsevier B.V. All rights reserved.

  17. Submicron-bubble-enhanced focused ultrasound for blood-brain barrier disruption and improved CNS drug delivery.

    Directory of Open Access Journals (Sweden)

    Ching-Hsiang Fan

    Full Text Available The use of focused ultrasound (FUS with microbubbles has been proven to induce transient blood-brain barrier opening (BBB-opening. However, FUS-induced inertial cavitation of microbubbles can also result in erythrocyte extravasations. Here we investigated whether induction of submicron bubbles to oscillate at their resonant frequency would reduce inertial cavitation during BBB-opening and thereby eliminate erythrocyte extravasations in a rat brain model. FUS was delivered with acoustic pressures of 0.1-4.5 MPa using either in-house manufactured submicron bubbles or standard SonoVue microbubbles. Wideband and subharmonic emissions from bubbles were used to quantify inertial and stable cavitation, respectively. Erythrocyte extravasations were evaluated by in vivo post-treatment magnetic resonance susceptibility-weighted imaging, and finally by histological confirmation. We found that excitation of submicron bubbles with resonant frequency-matched FUS (10 MHz can greatly limit inertial cavitation while enhancing stable cavitation. The BBB-opening was mainly caused by stable cavitation, whereas the erythrocyte extravasation was closely correlated with inertial cavitation. Our technique allows extensive reduction of inertial cavitation to induce safe BBB-opening. Furthermore, the safety issue of BBB-opening was not compromised by prolonging FUS exposure time, and the local drug concentrations in the brain tissues were significantly improved to 60 times (BCNU; 18.6 µg versus 0.3 µg by using chemotherapeutic agent-loaded submicron bubbles with FUS. This study provides important information towards the goal of successfully translating FUS brain drug delivery into clinical use.

  18. Thermodynamic study of the native and phosphorylated regulatory domain of the CFTR

    Energy Technology Data Exchange (ETDEWEB)

    Marasini, Carlotta, E-mail: marasini@ge.ibf.cnr.it [Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Via De Marini 6, 16149 Genova (Italy); Galeno, Lauretta; Moran, Oscar [Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Via De Marini 6, 16149 Genova (Italy)

    2012-07-06

    Highlights: Black-Right-Pointing-Pointer CFTR mutations produce cystic fibrosis. Black-Right-Pointing-Pointer Chloride transport depends on the regulatory domain phosphorylation. Black-Right-Pointing-Pointer Regulatory domain is intrinsically disordered. Black-Right-Pointing-Pointer Secondary structure and protein stability change upon phosphorylation. -- Abstract: The regulatory domain (RD) of the cystic fibrosis transmembrane conductance regulator (CFTR), the defective protein in cystic fibrosis, is the region of the channel that regulates the CFTR activity with multiple phosphorylation sites. This domain is an intrinsically disordered protein, characterized by lack of stable or unique tertiary structure. The disordered character of a protein is directly correlated with its function. The flexibility of RD may be important for its regulatory role: the continuous conformational change may be necessary for the progressive phosphorylation, and thus activation, of the channel. However, the lack of a defined and stable structure results in a considerable limitation when trying to in build a unique molecular model for the RD. Moreover, several evidences indicate significant structural differences between the native, non-phosphorylated state, and the multiple phosphorylated state of the protein. The aim of our work is to provide data to describe the conformations and the thermodynamic properties in these two functional states of RD. We have done the circular dichroism (CD) spectra in samples with a different degree of phosphorylation, from the non-phosphorylated state to a bona fide completely phosphorylated state. Analysis of CD spectra showed that the random coil and {beta}-sheets secondary structure decreased with the polypeptide phosphorylation, at expenses of an increase of {alpha}-helix. This observation lead to interpret phosphorylation as a mechanism favoring a more structured state. We also studied the thermal denaturation curves of the protein in the two

  19. Thermodynamic study of the native and phosphorylated regulatory domain of the CFTR

    International Nuclear Information System (INIS)

    Marasini, Carlotta; Galeno, Lauretta; Moran, Oscar

    2012-01-01

    Highlights: ► CFTR mutations produce cystic fibrosis. ► Chloride transport depends on the regulatory domain phosphorylation. ► Regulatory domain is intrinsically disordered. ► Secondary structure and protein stability change upon phosphorylation. -- Abstract: The regulatory domain (RD) of the cystic fibrosis transmembrane conductance regulator (CFTR), the defective protein in cystic fibrosis, is the region of the channel that regulates the CFTR activity with multiple phosphorylation sites. This domain is an intrinsically disordered protein, characterized by lack of stable or unique tertiary structure. The disordered character of a protein is directly correlated with its function. The flexibility of RD may be important for its regulatory role: the continuous conformational change may be necessary for the progressive phosphorylation, and thus activation, of the channel. However, the lack of a defined and stable structure results in a considerable limitation when trying to in build a unique molecular model for the RD. Moreover, several evidences indicate significant structural differences between the native, non-phosphorylated state, and the multiple phosphorylated state of the protein. The aim of our work is to provide data to describe the conformations and the thermodynamic properties in these two functional states of RD. We have done the circular dichroism (CD) spectra in samples with a different degree of phosphorylation, from the non-phosphorylated state to a bona fide completely phosphorylated state. Analysis of CD spectra showed that the random coil and β-sheets secondary structure decreased with the polypeptide phosphorylation, at expenses of an increase of α-helix. This observation lead to interpret phosphorylation as a mechanism favoring a more structured state. We also studied the thermal denaturation curves of the protein in the two conditions, monitoring the changes of the mean residue ellipticity measured at 222 nm as a function of temperature

  20. Improving the effectiveness of service delivery in the public healthcare sector: the case of ophthalmology services in Malaysia.

    Science.gov (United States)

    Foo, Chee Yoong; Lim, Ka Keat; Sivasampu, Sheamini; Dahian, Kamilah Binti; Goh, Pik Pin

    2015-08-28

    Rising demand of ophthalmology care is increasingly straining Malaysia's public healthcare sector due to its limited human and financial resources. Improving the effectiveness of ophthalmology service delivery can promote national policy goals of population health improvement and system sustainability. This study examined the performance variation of public ophthalmology service in Malaysia, estimated the potential output gain and investigated several factors that might explain the differential performance. Data for 2011 and 2012 on 36 ophthalmology centres operating in the Ministry of Health hospitals were used in this analysis. We first consulted a panel of ophthalmology service managers to understand the production of ophthalmology services and to verify the production model. We then assessed the relative performance of these centres using Data Envelopment Analysis (DEA). Efficiency scores (ES) were decomposed into technical, scale, and congestion component. Potential increase in service output was estimated. Sensitivity analysis of model changes was performed and stability of the result was assessed using bootstrap approach. Second stage Tobit regression was conducted to determine if hospital type, availability of day services and population characteristics were related to the DEA scores. In 2011, 33% of the ophthalmology centres were found to have ES > 1 (mean ES = 1.10). Potential output gains were 10% (SE ± 2.92), 7.4% (SE ± 2.06), 6.9% (SE ± 1.97) if the centres could overcome their technical, scale and congestion inefficiencies. More centres moved to the performance frontier in 2012 (mean ES = 1.07), with lower potential output gain. The model used has good stability. Robustness checks show that the DEA correctly identified low performing centres. Being in state hospital was significantly associated with better performance. Using DEA to benchmarking service performance of ophthalmology care could provide insights for policy

  1. Improving access to emergency contraception pills through strengthening service delivery and demand generation: a systematic review of current evidence in low and middle-income countries.

    Directory of Open Access Journals (Sweden)

    Angela Dawson

    Full Text Available Emergency contraception pills (ECP are among the 13 essential commodities in the framework for action established by the UN Commission on Life-Saving Commodities for Women and Children. Despite having been on the market for nearly 20 years, a number of barriers still limit women's access to ECP in low- and middle-income countries (LMIC including limited consumer knowledge and poor availability. This paper reports the results of a review to synthesise the current evidence on service delivery strategies to improve access to ECP.A narrative synthesis methodology was used to examine peer reviewed research literature (2003 to 2013 from diverse methodological traditions to provide critical insights into strategies to improve access from a service delivery perspective. The studies were appraised using established scoring systems and the findings of included papers thematically analysed and patterns mapped across all findings using concept mapping.Ten papers were included in the review. Despite limited research of adequate quality, promising strategies to improve access were identified including: advance provision of ECP; task shifting and sharing; intersectoral collaboration for sexual assault; m-health for information provision; and scale up through national family planning programs.There are a number of gaps in the research concerning service delivery and ECP in LMIC. These include a lack of knowledge concerning private/commercial sector contributions to improving access, the needs of vulnerable groups of women, approaches to enhancing intersectoral collaboration, evidence for social marketing models and investment cases for ECP.

  2. Improving Access to Emergency Contraception Pills through Strengthening Service Delivery and Demand Generation: A Systematic Review of Current Evidence in Low and Middle-Income Countries

    Science.gov (United States)

    Dawson, Angela; Tran, Nguyen-Toan; Westley, Elizabeth; Mangiaterra, Viviana; Festin, Mario

    2014-01-01

    Objectives Emergency contraception pills (ECP) are among the 13 essential commodities in the framework for action established by the UN Commission on Life-Saving Commodities for Women and Children. Despite having been on the market for nearly 20 years, a number of barriers still limit women's access to ECP in low- and middle-income countries (LMIC) including limited consumer knowledge and poor availability. This paper reports the results of a review to synthesise the current evidence on service delivery strategies to improve access to ECP. Methods A narrative synthesis methodology was used to examine peer reviewed research literature (2003 to 2013) from diverse methodological traditions to provide critical insights into strategies to improve access from a service delivery perspective. The studies were appraised using established scoring systems and the findings of included papers thematically analysed and patterns mapped across all findings using concept mapping. Findings Ten papers were included in the review. Despite limited research of adequate quality, promising strategies to improve access were identified including: advance provision of ECP; task shifting and sharing; intersectoral collaboration for sexual assault; m-health for information provision; and scale up through national family planning programs. Conclusion There are a number of gaps in the research concerning service delivery and ECP in LMIC. These include a lack of knowledge concerning private/commercial sector contributions to improving access, the needs of vulnerable groups of women, approaches to enhancing intersectoral collaboration, evidence for social marketing models and investment cases for ECP. PMID:25285438

  3. The importance of functional tests to assess the effect of a new CFTR variant when genotype-phenotype correlation is not possible.

    Science.gov (United States)

    Hinzpeter, Alexandre; Reboul, Marie-Pierre; Callebaut, Isabelle; Zordan, Cécile; Costes, Bruno; Guichoux, Julie; Iron, Albert; Lacombe, Didier; Martin, Natacha; Arveiler, Benoit; Fanen, Pascale; Fergelot, Patricia; Girodon, Emmanuelle

    2017-05-01

    In vitro functional tests aimed to investigate CFTR dysfunction appear critical to help elucidate the functional impact of new variants of uncertain clinical significance and solve inconclusive cases, especially in early deceased newborns.

  4. Self-Nanoemulsifying Drug Delivery System of Coenzyme (Q10) with Improved Dissolution, Bioavailability, and Protective Efficiency on Liver Fibrosis.

    Science.gov (United States)

    Khattab, Abeer; Hassanin, Lobna; Zaki, Nashwah

    2017-07-01

    The aim of our investigation is to develop and characterize self-nanoemulsifying drug delivery systems (SNEDDS) of CoQ 10 to improve its water solubility, dissolution rate, and bioavailability, and then evaluate its biochemical and physiological effect on liver cirrhosis in rats compared with CoQ 10 powder. SNEDDS are isotropic and thermodynamically stable mixture of oil, surfactant, co-surfactant, and drug that form an oil/water nanoemulsion when added to aqueous phases with soft agitation. Upon administration, self-nanoemulsifying system becomes in contact with gastrointestinal fluid and forms o/w nanoemulsion by the aid of gastrointestinal motility. When the nanoemulsion is formed in the gastrointestinal tract, it presents the drug in a solubilized form inside small nano-sized droplets that provide a large surface area for enhancing the drug release and absorption. Solubility of CoQ 10 in various oils, surfactants, and co-surfactants were studied to identify the components of SNEDDS; pseudo-ternary phase diagrams were plotted to identify the efficient self-emulsifying regions. CoQ 10 -loaded SNEDDS were prepared using isopropyl myristate as oil; Cremophor El, Labrasol, or Tween80 as surfactant; and Transcutol as co-surfactant. The amount of CoQ 10 in each vehicle was 3%. The formulations that passed thermostability evaluation test were assessed for particle size analysis, morphological characterization, refractive index, zeta potential, viscosity, electroconductivity, drug release profile, as well as ex vivo permeability. Pharmacokinetics and hepatoprotective efficiency of the optimized SNEDDS of CoQ 10 compared with CoQ 10 suspension were performed. Results showed that all optimized formulae have the ability to form a good and stable nanoemulsion when diluted with water; the mean droplet size of all formulae was in the nanometric range (11.7-13.5 nm) with optimum polydispersity index values (0.2-0.21). All formulae showed negative zeta potential (-11.3 to -17

  5. Lipoxin A4 and platelet activating factor are involved in E. coli or LPS-induced lung inflammation in CFTR-deficient mice.

    Directory of Open Access Journals (Sweden)

    Haiya Wu

    Full Text Available CFTR (cystic fibrosis transmembrane conductance regulator is expressed by both neutrophils and platelets. Lack of functional CFTR could lead to severe lung infection and inflammation. Here, we found that mutation of CFTR (F508del or inhibition of CFTR in mice led to more severe thrombocytopenia, alveolar neutrocytosis and bacteriosis, and lower lipoxin A4/MIP-2 (macrophage inhibitory protein-2 or lipoxin A4/neutrophil ratios in the BAL (bronchoalveolar lavage during acute E. coli pneumonia. In vitro, inhibition of CFTR promotes MIP-2 production in LPS-stimulated neutrophils; however, lipoxin A4 could dose-dependently suppress this effect. In LPS-induced acute lung inflammation, blockade of PSGL-1 (P-selectin glycoprotein ligand-1 or P-selectin, antagonism of PAF by WEB2086, or correction of mutated CFTR trafficking by KM11060 could significantly increase plasma lipoxin A4 levels in F508del relevant to wildtype mice. Concurrently, F508del mice had higher plasma platelet activating factor (PAF levels and PAF-AH activity compared to wildtype under LPS challenge. Inhibiting hydrolysis of PAF by a specific PAF-AH (PAF-acetylhydrolase inhibitor, MAFP, could worsen LPS-induced lung inflammation in F508del mice compared to vehicle treated F508del group. Particularly, depletion of platelets in F508del mice could significantly decrease plasma lipoxin A4 and PAF-AH activity and deteriorate LPS-induced lung inflammation compared to control F508del mice. Taken together, lipoxin A4 and PAF are involved in E. coli or LPS-induced lung inflammation in CFTR-deficient mice, suggesting that lipoxin A4 and PAF might be therapeutic targets for ameliorating CFTR-deficiency deteriorated lung inflammation.

  6. Combined Bicarbonate Conductance-Impairing Variants in CFTR and SPINK1 Are Associated with Chronic Pancreatitis in Patients without Cystic Fibrosis

    Science.gov (United States)

    Schneider, Alexander; LaRusch, Jessica; Sun, Xiumei; Aloe, Amy; Lamb, Janette; Hawes, Robert; Cotton, Peter; Brand, Randall E.; Anderson, Michelle A.; Money, Mary E.; Banks, Peter A.; Lewis, Michele D.; Baillie, John; Sherman, Stuart; DiSario, James; Burton, Frank R.; Gardner, Timothy B.; Amann, Stephen T.; Gelrud, Andres; George, Ryan; Kassabian, Sirvart; Martinson, Jeremy; Slivka, Adam; Yadav, Dhiraj; Oruc, Nevin; Barmada, M. Michael; Frizzell, Raymond; Whitcomb, David C.

    2010-01-01

    Background & Aims Idiopathic chronic pancreatitis (ICP) is a complex inflammatory disorder associated with multiple genetic and environmental factors. In individuals without cystic fibrosis (CF), variants of CFTR that inhibit bicarbonate conductance but maintain chloride conductance might selectively impair secretion of pancreatic juice, leading to trypsin activation and pancreatitis. We investigated whether sequence variants in the gene encoding the pancreatic secretory trypsin inhibitor, SPINK1, further increase the risk of pancreatitis in these patients. Methods We screened patients with ICP (sporadic or familial) and controls for variants in SPINK1 associated with chronic pancreatitis (CP) risk (in exon 3) and in all 27 exons of CFTR. The final study group included 53 patients with sporadic ICP, 27 probands with familial ICP, and 150 unrelated controls, plus 503 controls for limited genotyping. CFTR wild-type (wt) and p.R75Q were cloned and expressed in HEK293 cells and relative conductances of HCO3− and Cl− were measured. Results SPINK1 variants were identified in 36% of subjects and 3% controls (odds ratio [OR]=16.5). One variant of CFTR that has not been associated with CF, p.R75Q, was found in 16% of subjects and 5.4% controls (OR=3.4). Co-inheritance of CFTR p.R75Q and SPINK1 variants occurred in 8.75% of patients and 0.15% controls (OR=62.5). Patch-clamp recordings of cells that expressed CFTR p.R75Q demonstrated normal chloride currents but significantly reduced bicarbonate currents (P=0.0001). Conclusions The CFTR variant p.R75Q causes a selective defect in bicarbonate conductance and increases risk for pancreatitis. Co-inheritance of CF-associated, and some not associated, CFTR variants with SPINK1 variants significantly increase risk of ICP. PMID:20977904

  7. Delivery presentations

    Science.gov (United States)

    Pregnancy - delivery presentation; Labor - delivery presentation; Occiput posterior; Occiput anterior; Brow presentation ... The mother can walk, rock, and try different delivery positions during labor to help encourage the baby ...

  8. Stable Dispersions of Covalently Tethered Polymer Improved Graphene Oxide Nanoconjugates as an Effective Vector for siRNA Delivery.

    Science.gov (United States)

    Yadav, Nisha; Kumar, Naveen; Prasad, Peeyush; Shirbhate, Shivani; Sehrawat, Seema; Lochab, Bimlesh

    2018-05-02

    Conjugates of poly(amidoamine) (PAMAM) with modified graphene oxide (GO) are attractive nonviral vectors for gene-based cancer therapeutics. GO protects siRNA from enzymatic cleavage and showed reasonable transfection efficiency along with simultaneous benefits of low cost and large scale production. PAMAM is highly effective in siRNA delivery but suffers from high toxicity with poor in vivo efficacy. Co-reaction of GO and PAMAM led to aggregation and more importantly, have detrimental effect on stability of dispersion at physiological pH preventing their exploration at clinical level. In the current work, we have designed, synthesized, characterized and explored a new type of hybrid vector (GPD), using GO synthesized via improved method which was covalently tethered with poly(ethylene glycol) (PEG) and PAMAM. The existence of covalent linkage, relative structural changes and properties of GPD is well supported by Fourier transform infrared (FTIR), UV-visible (UV-vis), Raman, X-ray photoelectron (XPS), elemental analysis, powder X-ray diffraction (XRD), thermogravimetry analysis (TGA), dynamic light scattering (DLS), and zeta potential. Scanning electron microscopy (SEM), and transmission electron microscopy (TEM) of GPD showed longitudinally aligned columnar self-assembled ∼10 nm thick polymeric nanoarchitectures onto the GO surface accounting to an average size reduction to ∼20 nm. GPD revealed an outstanding stability in both phosphate buffer saline (PBS) and serum containing cell medium. The binding efficiency of EPAC1 siRNA to GPD was supported by gel retardation assay, DLS, zeta potential and photoluminescence (PL) studies. A lower cytotoxicity with enhanced cellular uptake and homogeneous intracellular distribution of GPD/siRNA complex is confirmed by imaging studies. GPD exhibited a higher transfection efficiency with remarkable inhibition of cell migration and lower invasion than PAMAM and Lipofectamine 2000 suggesting its role in prevention of breast

  9. Gap Junctions Are Involved in the Rescue of CFTR-Dependent Chloride Efflux by Amniotic Mesenchymal Stem Cells in Coculture with Cystic Fibrosis CFBE41o- Cells

    Directory of Open Access Journals (Sweden)

    Annalucia Carbone

    2018-01-01

    Full Text Available We previously found that human amniotic mesenchymal stem cells (hAMSCs in coculture with CF immortalised airway epithelial cells (CFBE41o- line, CFBE on Transwell® filters acquired an epithelial phenotype and led to the expression of a mature and functional CFTR protein. In order to explore the role of gap junction- (GJ- mediated intercellular communication (GJIC in this rescue, cocultures (hAMSC : CFBE, 1 : 5 ratio were studied for the formation of GJIC, before and after silencing connexin 43 (Cx43, a major component of GJs. Functional GJs in cocultures were inhibited when the expression of the Cx43 protein was downregulated. Transfection of cocultures with siRNA against Cx43 resulted in the absence of specific CFTR signal on the apical membrane and reduction in the mature form of CFTR (band C, and in parallel, the CFTR-dependent chloride channel activity was significantly decreased. Cx43 downregulation determined also a decrease in transepithelial resistance and an increase in paracellular permeability as compared with control cocultures, implying that GJIC may regulate CFTR expression and function that in turn modulate airway epithelium tightness. These results indicate that GJIC is involved in the correction of CFTR chloride channel activity upon the acquisition of an epithelial phenotype by hAMSCs in coculture with CF cells.

  10. Gap Junctions Are Involved in the Rescue of CFTR-Dependent Chloride Efflux by Amniotic Mesenchymal Stem Cells in Coculture with Cystic Fibrosis CFBE41o- Cells.

    Science.gov (United States)

    Carbone, Annalucia; Zefferino, Roberto; Beccia, Elisa; Casavola, Valeria; Castellani, Stefano; Di Gioia, Sante; Giannone, Valentina; Seia, Manuela; Angiolillo, Antonella; Colombo, Carla; Favia, Maria; Conese, Massimo

    2018-01-01

    We previously found that human amniotic mesenchymal stem cells (hAMSCs) in coculture with CF immortalised airway epithelial cells (CFBE41o- line, CFBE) on Transwell® filters acquired an epithelial phenotype and led to the expression of a mature and functional CFTR protein. In order to explore the role of gap junction- (GJ-) mediated intercellular communication (GJIC) in this rescue, cocultures (hAMSC : CFBE, 1 : 5 ratio) were studied for the formation of GJIC, before and after silencing connexin 43 (Cx43), a major component of GJs. Functional GJs in cocultures were inhibited when the expression of the Cx43 protein was downregulated. Transfection of cocultures with siRNA against Cx43 resulted in the absence of specific CFTR signal on the apical membrane and reduction in the mature form of CFTR (band C), and in parallel, the CFTR-dependent chloride channel activity was significantly decreased. Cx43 downregulation determined also a decrease in transepithelial resistance and an increase in paracellular permeability as compared with control cocultures, implying that GJIC may regulate CFTR expression and function that in turn modulate airway epithelium tightness. These results indicate that GJIC is involved in the correction of CFTR chloride channel activity upon the acquisition of an epithelial phenotype by hAMSCs in coculture with CF cells.

  11. An effective tumor-targeting strategy utilizing hypoxia-sensitive siRNA delivery system for improved anti-tumor outcome.

    Science.gov (United States)

    Kang, Lin; Fan, Bo; Sun, Ping; Huang, Wei; Jin, Mingji; Wang, Qiming; Gao, Zhonggao

    2016-10-15

    Hypoxia is a feature of most solid tumors, targeting hypoxia is considered as the best validated yet not extensively exploited strategy in cancer therapy. Here, we reported a novel tumor-targeting strategy using a hypoxia-sensitive siRNA delivery system. In the study, 2-nitroimidazole (NI), a hydrophobic component that can be converted to hydrophilic 2-aminoimidazole (AI) through bioreduction under hypoxic conditions, was conjugated to the alkylated polyethyleneimine (bPEI1.8k-C6) to form amphiphilic bPEI1.8k-C6-NI polycations. bPEI1.8k-C6-NI could self-assemble into micelle-like aggregations in aqueous, which contributed to the improved stability of the bPEI1.8k-C6-NI/siRNA polyplexes, resulted in increased cellular uptake. After being transported into the hypoxic tumor cells, the selective nitro-to-amino reduction would cause structural change and elicit a relatively loose structure to facilitate the siRNA dissociation in the cytoplasm, for enhanced gene silencing efficiency ultimately. Therefore, the conflict between the extracellular stability and the intracellular siRNA release ability of the polyplexes was solved by introducing the hypoxia-responsive unit. Consequently, the survivin-targeted siRNA loaded polyplexes shown remarkable anti-tumor effect not only in hypoxic cells, but also in tumor spheroids and tumor-bearing mice, indicating that the hypoxia-sensitive siRNA delivery system had great potential for tumor-targeted therapy. Hypoxia is one of the most remarkable features of most solid tumors, and targeting hypoxia is considered as the best validated strategy in cancer therapy. However, in the past decades, there were few reports about using this strategy in the drug delivery system, especially in siRNA delivery system. Therefore, we constructed a hypoxia-sensitive siRNA delivery system utilizing a hypoxia-responsive unit, 2-nitroimidazole, by which the unavoidable conflict between improved extracellular stability and promoted intracellular si

  12. Mannosylated Chitosan Nanoparticles Based Macrophage-Targeting Gene Delivery System Enhanced Cellular Uptake and Improved Transfection Efficiency.

    Science.gov (United States)

    Peng, Yixing; Yao, Wenjun; Wang, Bo; Zong, Li

    2015-04-01

    Gene transfer mediated by mannosylated chitosan (MCS) is a safe and promising approach for gene and vaccine delivery. MCS nanoparticles based gene delivery system showed high in vivo delivery efficiency and elicited strong immune responses in mice. However, little knowledge about the cell binding, transfection efficiency and intracellular trafficking of MCS nanoparticles had been acquired. In this study, using gastrin-releasing peptide as a model plasmid (pGRP), the binding of MCS/pGRP nanoparticles to macrophages and the intracellular trafficking of MCS/pGRP nanoparticles in macrophages were investigated. MCS-mediated transfection efficiency in macrophages was also evaluated using pGL-3 as a reporter gene. The results showed that the binding and transfection efficiency of MCS nanoparticles in macrophages was higher than that of CS, which was attributed to the interaction between mannose ligands in MCS and mannose receptors on the surface of macrophages. Observation with a confocal laser scanning microscope indicated the cellular uptake of MCS/pGRP nanoparticles were more than that of CS/pGRP nanoparticles in macrophages. MCS/pGRP nanoparticles were taken up by macrophages and most of them were entrapped in endosomal/lysosomal compartments. After the nanoparticles escaping from endosomal/lysosomal compartments, naked pGRP entered the nucleus, and a few MCS might enter the nucleus in terms of nanoparticles. Overall, MCS has the potential to be an excellent macrophage-targeting gene delivery carrier.

  13. A poly(ether-ester) copolymer for the preparation of nanocarriers with improved degradation and drug delivery kinetics

    Energy Technology Data Exchange (ETDEWEB)

    Gagliardi, M., E-mail: mariacristina.gagliardi@iit.it [Center for Micro Bio-Robotics @SSSA, Istituto Italiano di Tecnologia, Viale Rinaldo Piaggio 34, 56025 Pontedera (Italy); Bertero, A. [Department of Biology, Unit of Cellular and Developmental Biology, University of Pisa, S.S.12 Abetone e Brennero 4, 56127 Pisa (Italy); Center for Neuroscience and Cognitive Systems @UNITN, Istituto Italiano di Tecnologia, Corso Bettini 31, 38068 Rovereto (Italy); Bardi, G. [Center for Bio-Molecular Nanotechnologies @UniLe, Istituto Italiano di Tecnologia, Via Barsanti, 73010 Arnesano (Italy); Bifone, A. [Center for Neuroscience and Cognitive Systems @UNITN, Istituto Italiano di Tecnologia, Corso Bettini 31, 38068 Rovereto (Italy)

    2016-02-01

    This paper reports the synthesis and the physicochemical, functional and biological characterisations of nanocarriers made of a novel di-block biodegradable poly(ether-ester) copolymer. This material presents tunable, fast biodegradation rates, but its products are less acidic than those of other biosorbable polymers like PLGA, thus presenting a better biocompatibility profile and the possibility to carry pH-sensitive payloads. A method for the production of monodisperse and spherical nanoparticles is proposed; drug delivery kinetics and blood protein adsorption were measured to evaluate the functional properties of these nanoparticles as drug carriers. The copolymer was labelled with a fluorescent dye for internalisation tests, and rhodamine B was used as a model cargo to study transport and release inside cultured cells. Biological tests demonstrated good cytocompatibility, significant cell internalisation and the possibility to vehiculate non-cell penetrating moieties into endothelial cells. Taken together, these results support the potential use of this nanoparticulate system for systemic administration of drugs. - Highlights: • We propose a novel biodegradable nanocarrier for intracellular drug delivery. • Biodegradation rates can be finely tuned by controlling copolymer composition. • Degradation products are less acidic, thus enabling delivery of pH-sensitive cargoes. • We demonstrate intracellular delivery of a non-cell-penetrating model drug. • No significant membrane damage by the polymer nanocarriers is observed.

  14. A poly(ether-ester) copolymer for the preparation of nanocarriers with improved degradation and drug delivery kinetics

    International Nuclear Information System (INIS)

    Gagliardi, M.; Bertero, A.; Bardi, G.; Bifone, A.

    2016-01-01

    This paper reports the synthesis and the physicochemical, functional and biological characterisations of nanocarriers made of a novel di-block biodegradable poly(ether-ester) copolymer. This material presents tunable, fast biodegradation rates, but its products are less acidic than those of other biosorbable polymers like PLGA, thus presenting a better biocompatibility profile and the possibility to carry pH-sensitive payloads. A method for the production of monodisperse and spherical nanoparticles is proposed; drug delivery kinetics and blood protein adsorption were measured to evaluate the functional properties of these nanoparticles as drug carriers. The copolymer was labelled with a fluorescent dye for internalisation tests, and rhodamine B was used as a model cargo to study transport and release inside cultured cells. Biological tests demonstrated good cytocompatibility, significant cell internalisation and the possibility to vehiculate non-cell penetrating moieties into endothelial cells. Taken together, these results support the potential use of this nanoparticulate system for systemic administration of drugs. - Highlights: • We propose a novel biodegradable nanocarrier for intracellular drug delivery. • Biodegradation rates can be finely tuned by controlling copolymer composition. • Degradation products are less acidic, thus enabling delivery of pH-sensitive cargoes. • We demonstrate intracellular delivery of a non-cell-penetrating model drug. • No significant membrane damage by the polymer nanocarriers is observed.

  15. Improving Student Employee Training: A Study of Web 2.0 Social Media Tools as a Delivery Model

    Science.gov (United States)

    Smith, Sharon D.

    2012-01-01

    Training student employees in Educational Outreach and Student Services (EOSS) at Arizona State University's West campus is important to maintaining a knowledgeable and productive workforce. This dissertation describes the results of an action research study in which social media tools were utilized as a delivery mechanism for training student…

  16. Accelerating delivery of trauma-sensitive care: Using multilevel stakeholder engagement to improve care for women veterans.

    Science.gov (United States)

    Yano, Elizabeth M; Hamilton, Alison B

    2017-09-01

    Engaging women Veterans with trauma histories in the design of innovations for their own care in partnership with providers and staff and other multilevel stakeholders holds promise for accelerating delivery of trauma-sensitive care. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  17. Mutations in CFTR gene and clinical correlation in Argentine patients with congenital bilateral absence of the vas deferens Correlación de las características clínicas con mutaciones del gen CFTR en pacientes argentinos con ausencia bilateral congénita de vasos deferentes

    Directory of Open Access Journals (Sweden)

    Estrella M Levy

    2004-06-01

    Full Text Available Congenital bilateral absence of the vas deferens (CBAVD is a form of male infertility in which mutations in the cystic fibrosis transmembrane conductance regulator (CFTR gene have been identified. Here we identify different mutations of CFTR and the poly-T variant of intron 8 (IVS8 in Argentine patients and analyze sweat test values and clinical characteristic related to Cystic Fibrosis (CF. For counseling purposes the two most frequent mutations in Argentine CF population: DF508 and G542X were screened in wives. In all cases, it was possible to reduce the risk of CF/CBAVD descendants in these couples because none of the mutation were found in the 36 samples. Eight patients (23% showed abnormal chloride values (> 60 mmol/l. A second group of 6 patients (18% had borderline values of sweat chloride (40-59 mmol/l. We defined another group with 6 patients (18%, with normal sweat chloride levels (30-39 mmo/l and a fourth group of 14 (41% patients with sweat chloride below 30 mmol/l. DF508, the most frequent CF mutation in the Argentine population, was found on 15 of the 72 chromosomes (21%, R117H mutation was detected on 2 of 62 chromosomes (3%. Only one R347P allele was found on 28 chromosomes analyzed (2%. On a sample of 27 patients, IVS8 analysis showed a frequency of 6/56 chromosomes (11% of 5T allele. Even though these findings present an improvement in the detection of mutations related to clinical correlations in Argentine CBAVD population, the search for other common and uncommon mutations should be continued.La ausencia bilateral congénita de vasos deferentes (CBAVD es una forma de infertilidad masculina en la que se han identificado mutaciones en el gen de la conductancia transmembrana de la fibrosis quística (CFTR. Hemos estudiado en pacientes argentinos diferentes mutaciones en el CFTR y la variante poli T del intron 8 (IVS8 y analizado los valores de test del sudor y las características clínicas relacionadas a la Fibrosis Qu

  18. Les vésicules extracellulaires comme vecteurs de macromolécules bioactives : modèle du transporteur ABCC7 (CFTR) et application à la biothérapie de la mucoviscidose

    OpenAIRE

    Vituret , Cyrielle

    2015-01-01

    Cystic fibrosis is a genetic disease in which its prognosis depends on the lung damage. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR), resulting in a dysfunctional CFTR protein normally located at the plasma membrane of epithelial cells. This thesis is a study of a novel therapeutic approach to use extracellular vesicles (EVs), microvesicles and exosomes, as transfer vectors for CFTR mRNA and protein to target cells. The proof of concept for ...

  19. Premature delivery

    Directory of Open Access Journals (Sweden)

    Bernardita Donoso Bernales

    2012-09-01

    Full Text Available Preterm delivery is the single most important cause of perinatal morbidity and mortality. In Chile, preterm births have increased in the past decade, although neonatal morbidity and mortality attributable to it shows a downward trend, thanks to improvements in neonatal care of premature babies, rather than the success of obstetric preventive and therapeutic strategies. This article describes clinical entities, disease processes and conditions that constitute predisposing factors of preterm birth, as well as an outline for the prevention and clinical management of women at risk of preterm birth.

  20. From concept to application: the impact of a community-wide intervention to improve the delivery of preventive services to children.

    Science.gov (United States)

    Margolis, P A; Stevens, R; Bordley, W C; Stuart, J; Harlan, C; Keyes-Elstein, L; Wisseh, S

    2001-09-01

    To improve health outcomes of children, the US Maternal and Child Health Bureau has recommended more effective organization of preventive services within primary care practices and more coordination between practices and community-based agencies. However, applying these recommendations in communities is challenging because they require both more complex systems of care delivery within organizations and more complex interactions between them. To improve the way that preventive health care services are organized and delivered in 1 community, we designed, implemented, and assessed the impact of a health care system-level approach, which involved addressing multiple care delivery processes, at multiple levels in the community, the practice, and the family. Our objective was to improve the processes of preventive services delivery to all children in a defined geographic community, with particular attention to health outcomes for low-income mothers and infants. Observational intervention study in 1 North Carolina county (population 182 000) involving low- income pregnant mothers and their infants, primary care practices, and departments of health and mental health. An interrupted time-series design was used to assess rates of preventive services in office practices before and after the intervention, and a historical cohort design was used to compare maternal and child health outcomes for women enrolled in an intensive home visiting program with women who sought prenatal care during the 9 months before the program's initiation. Outcomes were assessed when the infants reached 12 months of age. Our primary objective was to achieve changes in the process of care delivery at the level of the clinical interaction between care providers and patients that would lead to improved health and developmental outcomes for families. We selected interventions that were directed toward major risk factors (eg, poverty, ineffective care systems for preventive care in office practices) and

  1. Using program impact pathways to understand and improve program delivery, utilization, and potential for impact of Helen Keller International's homestead food production program in Cambodia.

    Science.gov (United States)

    Olney, Deanna K; Vicheka, Sao; Kro, Meng; Chakriya, Chhom; Kroeun, Hou; Hoing, Ly Sok; Talukder, Aminzzaman; Quinn, Victoria; Iannotti, Lora; Becker, Elisabeth; Roopnaraine, Terry

    2013-06-01

    Evidence of the impact of homestead food production programs on nutrition outcomes such as anemia and growth is scant. In the absence of information on program impact pathways, it is difficult to understand why these programs, which have been successful in increasing intake of micronutrient-rich foods, have had such limited documented impact on nutrition outcomes. To conduct a process evaluation of Helen Keller International's (HKI's) homestead food production program in Cambodia to assess whether the program was operating as planned (in terms of design, delivery, and utilization) and to identify ways in which the program might need to be strengthened in order to increase its potential for impact. A program theory framework, which laid out the primary components along the hypothesized program impact pathways, was developed in collaboration with HKI and used to design the research. Semistructured interviews and focus group discussions with program beneficiaries (n = 36 and 12, respectively), nonbeneficiaries (n = 12), and program implementers (n = 17 and 2, respectively) and observations of key program delivery points, including health and nutrition training sessions (n = 6), village model farms (n = 6), and household gardens of beneficiaries (n = 36) and nonbeneficiaries (n = 12), were conducted to assess the delivery and utilization of the primary program components along the impact pathways. The majority of program components were being delivered and utilized as planned. However, challenges with some of the key components posited to improve outcomes such as anemia and growth were noted. Among these were a gap in the expected pathway from poultry production to increased intake of eggs and poultry meat, and some weaknesses in the delivery of the health and nutrition training sessions and related improvements in knowledge among the village health volunteers and beneficiaries. Although the program has been successful in delivering the majority of the program

  2. Microneedle arrays coated with charge reversal pH-sensitive copolymers improve antigen presenting cells-homing DNA vaccine delivery and immune responses.

    Science.gov (United States)

    Duong, Huu Thuy Trang; Kim, Nak Won; Thambi, Thavasyappan; Giang Phan, V H; Lee, Min Sang; Yin, Yue; Jeong, Ji Hoon; Lee, Doo Sung

    2018-01-10

    Successful delivery of a DNA vaccine to antigen-presenting cells and their subsequent stimulation of CD4 + and CD8 + T cell immunity remains an inefficient process. In general, the delivery of prophylactic vaccines is mainly mired by low transfection efficacy, poor immunogenicity, and safety issues from the materials employed. Currently, several strategies have been exploited to improve immunogenicity, but an effective strategy for safe and pain-free delivery of DNA vaccines is complicated. Herein, we report the rapid delivery of polyplex-based DNA vaccines using microneedle arrays coated with a polyelectrolyte multilayer assembly of charge reversal pH-responsive copolymer and heparin. The charge reversal pH-responsive copolymer, composed of oligo(sulfamethazine)-b-poly(ethylene glycol)-b-poly(amino urethane) (OSM-b-PEG-b-PAEU), was used as a triggering layer in the polyelectrolyte multilayer assembly on microneedles. Charge reversal characteristics of this copolymer, that is, the OSM-b-PEG-b-PAEU copolymer exhibit, positive charge at low pH (pH4.03) and becoming negative charge when exposed to physiological pH conditions (pH7.4), allowing the facile assembly and disassembly of polyelectrolyte multilayers. The electrostatic repulsion between heparin and OSM-b-PEG-b-PAEU charge reversal copolymer triggered the release of DNA vaccines. DNA vaccines laden on microneedles are effectively transfected into RAW 264.7 macrophage cells in vitro. Vaccination of BALB/c mice by DNA vaccine-loaded microneedle arrays coated with a polyelectrolyte multilayer generated antigen-specific robust immune responses. These findings provide potential strategy of charge reversal pH-responsive copolymers coated microneedles for DNA vaccine delivery. Copyright © 2017. Published by Elsevier B.V.

  3. Sweat chloride and immunoreactive trypsinogen in infants carrying two CFTR mutations and not affected by cystic fibrosis.

    Science.gov (United States)

    Castellani, Carlo; Tridello, Gloria; Tamanini, Anna; Assael, Baroukh M

    2017-07-01

    Newborns with raised immunotrypsinogen levels who have non-pathological sweat chloride values and carry two cystic fibrosis transmembrane regulator ( CFTR ) mutations of which at least one is not acknowledged to be cystic fibrosis (CF)-causing are at risk of developing clinical manifestations consistent with CFTR-related disorders or even CF. It is not known whether newborns with similar genotypes and normal immunoreactive trypsinogen (IRT) may share the same risk. This study found that newborns with these characteristics and normal IRT have lower sweat chloride values than those with raised IRT (p=0.007). Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  4. Paying for performance to improve the delivery of health interventions in low- and middle-income countries .

    Science.gov (United States)

    Witter, Sophie; Fretheim, Atle; Kessy, Flora L; Lindahl, Anne Karin

    2012-02-15

    There is a growing interest in paying for performance as a means to align the incentives of health workers and health providers with public health goals. However, there is currently a lack of rigorous evidence on the effectiveness of these strategies in improving health care and health, particularly in low- and middle-income countries. Moreover, paying for performance is a complex intervention with uncertain benefits and potential harms. A review of evidence on effectiveness is therefore timely, especially as this is an area of growing interest for funders and governments. To assess the current evidence for the effects of paying for performance on the provision of health care and health outcomes in low- and middle-income countries. We searched more than 15 databases in 2009, including the Cochrane Effective Practice and Organisation of Care Group Specialised Register (searched 3 March 2009), CENTRAL (2009, Issue 1) (searched 3 March 2009), MEDLINE, Ovid (1948 to present) (searched 24 June 2011), EMBASE, Ovid (1980 to 2009 Week 09) (searched 2 March 2009), EconLit, Ovid (1969 to February 2009) (searched 5 March 2009), as well as the Social Sciences Citation Index, ISI Web of Science (1975 to present) (searched 8 September 2010). We also searched the websites and online resources of numerous international agencies, organisations and universities to find relevant grey literature and contacted experts in the field. We carried out an updated search on the Results-Based Financing website in April 2011, and re-ran the MEDLINE search in June 2011. Pay for performance refers to the transfer of money or material goods conditional on taking a measurable action or achieving a predetermined performance target. To be included, a study had to report at least one of the following outcomes: changes in targeted measures of provider performance, such as the delivery or utilisation of healthcare services, or patient outcomes, unintended effects and/or changes in resource use. Studies

  5. Intra-individual biological variation in sweat chloride concentrations in CF, CFTR dysfunction, and healthy pediatric subjects.

    Science.gov (United States)

    Cirilli, Natalia; Raia, Valeria; Rocco, Ilaria; De Gregorio, Fabiola; Tosco, Antonella; Salvadori, Laura; Sepe, Angela Ornella; Buzzetti, Roberto; Minicuci, Nadia; Castaldo, Giuseppe

    2018-04-02

    The sweat test is one of the main diagnostic tools used in newborn screening programs and as a confirmatory test, in case of suspect of Cystic Fibrosis (CF). Since sweat chloride (Cl) concentration is also considered an appropriate parameter to explore the efficacy of CFTR modulators in clinical trials, it is crucial to evaluate the biological variability of this test in healthy and pathological conditions. The aim of this pilot study was to determine the intra-individual biological variability of sweat Cl, both in healthy individuals and CF patients and to assess its correlation with diet, season, and menstrual cycle. Thirty-five out of 36 selected subjects (6-18 years) were enrolled by 2 CF care centers and assigned to 3 cohorts: CF, CFTR-related disorder (CFTR-RD) and healthy volunteers. Each participant was subjected to eight sweat tests in different conditions and time of the year. Data were analyzed using linear mixed effects models for repeated measures, taking also into account intra-individual correlations. We observed a high intra-individual variability of sweat Cl, with the lowest mean CV% values among CF patients (20.21 in CF, 29.74 in CFTR-RD, and 31.15 in healthy subjects). Gender and diet had no influence on sweat Cl variability, nor had pubertal age and menstrual phase. Results of this pilot study confirmed that sweat Cl variability is high in CF patients, although non-CF individuals displayed even higher mean CV% values. Season significantly influenced sweat test values only in CF patients, likely due to changes in their hydration status. © 2018 Wiley Periodicals, Inc.

  6. Analysis of the CFTR gene in Venezuelan cystic fibrosis patients, identification of six novel cystic fibrosis-causing genetic variants

    OpenAIRE

    Sánchez, Karen; De Mendonca,Elizabeth; Matute,Xiorama; Chaustre,Ismenia; Villalon,Marlene; Takiff,Howard

    2016-01-01

    Karen Sánchez,1 Elizabeth de Mendonca,1 Xiorama Matute,2 Ismenia Chaustre,2 Marlene Villalón,3 Howard Takiff4 1Unit of Genetic and Forensic Studies, Venezuelan Institute for Scientific Research (IVIC), 2Hospital JM de los Ríos, 3Hospital José Ignacio Baldo, Algodonal, National Reference Unit, 4Laboratory of Molecular Genetics, Venezuelan Institute for Scientific Research (IVIC), Caracas, Venezuela. Abstract: The mutations in the CFTR gene found in ...

  7. Development and characterization of glutathione-conjugated albumin nanoparticles for improved brain delivery of hydrophilic fluorescent marker.

    Science.gov (United States)

    Patel, Prerak J; Acharya, Niyati S; Acharya, Sanjeev R

    2013-01-01

    The glutathione-conjugated bovine serum albumin (BSA) nanoparticles were constructed in the present exploration as a novel biodegradable carrier for brain-specific drug delivery with evaluation of its in vitro and in vivo delivery properties. BSA nanocarriers were activated and conjugated to the distal amine functions of the glutathione via carbodiimide chemistry using EDAC as a mediator. These nanoparticles were characterized for particle shape, average size, SPAN value, drug entrapment and in vitro drug release. Further, presence of glutathione on the surface of BSA nanoparticles was confirmed by Ellman's assay, which has suggested that approximately 750 units of glutathione were conjugated per BSA nanoparticle. To evaluate the brain delivery properties of the glutathione-conjugated BSA nanoparticles fluorescein sodium was used as a model hydrophilic compound. Permeability and neuronal uptake properties of developed formulations were evaluated against the MDCK-MDR1 endothelial and neuro-glial cells, respectively. The permeability of glutathione-conjugated BSA nanoparticles across the monolayer of MDCK-MDR1 endothelial tight junction was shown significantly higher than that of unconjugated nanoparticles and fluorescein sodium solution. Similarly, glutathione-conjugated nanoparticles exhibited considerably higher uptake by neuro-glial cells which was inferred by high fluorescence intensity under microscope in comparison to unconjugated nanoparticles and fluorescein sodium solution. Following an intravenous administration, nearly three folds higher fluorescein sodium was carried to the rat brain by glutathione-conjugated nanoparticles as compared to unconjugated nanoparticles. The significant in vitro and in vivo results suggest that glutathione-conjugated BSA nanoparticles is a promising brain drug delivery system with low toxicity.

  8. Functional Expression of P-glycoprotein and Organic Anion Transporting Polypeptides at the Blood-Brain Barrier: Understanding Transport Mechanisms for Improved CNS Drug Delivery?

    Science.gov (United States)

    Abdullahi, Wazir; Davis, Thomas P; Ronaldson, Patrick T

    2017-07-01

    Drug delivery to the central nervous system (CNS) is greatly limited by the blood-brain barrier (BBB). Physical and biochemical properties of the BBB have rendered treatment of CNS diseases, including those with a hypoxia/reoxygenation (H/R) component, extremely difficult. Targeting endogenous BBB transporters from the ATP-binding cassette (ABC) superfamily (i.e., P-glycoprotein (P-gp)) or from the solute carrier (SLC) family (i.e., organic anion transporting polypeptides (OATPs in humans; Oatps in rodents)) has been suggested as a strategy that can improve delivery of drugs to the brain. With respect to P-gp, direct pharmacological inhibition using small molecules or selective regulation by targeting intracellular signaling pathways has been explored. These approaches have been largely unsuccessful due to toxicity issues and unpredictable pharmacokinetics. Therefore, our laboratory has proposed that optimization of CNS drug delivery, particularly for treatment of diseases with an H/R component, can be achieved by targeting Oatp isoforms at the BBB. As the major drug transporting Oatp isoform, Oatp1a4 has demonstrated blood-to-brain transport of substrate drugs with neuroprotective properties. Furthermore, our laboratory has shown that targeting Oatp1a4 regulation (i.e., TGF-β signaling mediated via the ALK-1 and ALK-5 transmembrane receptors) represents an opportunity to control Oatp1a4 functional expression for the purpose of delivering therapeutics to the CNS. In this review, we will discuss limitations of targeting P-gp-mediated transport activity and the advantages of targeting Oatp-mediated transport. Through this discussion, we will also provide critical information on novel approaches to improve CNS drug delivery by targeting endogenous uptake transporters expressed at the BBB.

  9. Analysis of the CFTR gene in Venezuelan cystic fibrosis patients, identification of six novel cystic fibrosis-causing genetic variants.

    Science.gov (United States)

    Sánchez, Karen; de Mendonca, Elizabeth; Matute, Xiorama; Chaustre, Ismenia; Villalón, Marlene; Takiff, Howard

    2016-01-01

    The mutations in the CFTR gene found in patients with cystic fibrosis (CF) have geographic differences, but there are scant data on their prevalence in Venezuelan patients. This study determined the frequency of common CFTR gene mutations in a group of Venezuelan patients with CF. The 27 exons of the CFTR gene from 110 Venezuelan patients in the National CF Program were amplified and sequenced. A total of 36 different mutations were identified, seven with frequencies greater than 1%: p.Phe508del (27.27%), p.Gly542* (3.18%), c.2988+1G>A (3.18%), p.Arg334Trp (1.36%), p.Arg1162* (1.36%), c.1-8G>C (1.36%), and p.[Gly628Arg;Ser1235Arg](1.36). In 40% of patients, all with a clinical diagnosis of CF, no mutations were found. This report represents the largest cohort of Venezuelan patients with CF ever examined, and includes a wider mutation panel than has been previously studied in this population. Mutations common in Southern European populations predominate, and several new mutations were discovered, but no mutations were found in 40% of the cohort.

  10. Improved delivery of cardiovascular care (IDOCC through outreach facilitation: study protocol and implementation details of a cluster randomized controlled trial in primary care

    Directory of Open Access Journals (Sweden)

    Akbari Ayub

    2011-09-01

    Full Text Available Abstract Background There is a need to find innovative approaches for translating best practices for chronic disease care into daily primary care practice routines. Primary care plays a crucial role in the prevention and management of cardiovascular disease. There is, however, a substantive care gap, and many challenges exist in implementing evidence-based care. The Improved Delivery of Cardiovascular Care (IDOCC project is a pragmatic trial designed to improve the delivery of evidence-based care for the prevention and management of cardiovascular disease in primary care practices using practice outreach facilitation. Methods The IDOCC project is a stepped-wedge cluster randomized control trial in which Practice Outreach Facilitators work with primary care practices to improve cardiovascular disease prevention and management for patients at highest risk. Primary care practices in a large health region in Eastern Ontario, Canada, were eligible to participate. The intervention consists of regular monthly meetings with the Practice Outreach Facilitator over a one- to two-year period. Starting with audit and feedback, consensus building, and goal setting, the practices are supported in changing practice behavior by incorporating chronic care model elements. These elements include (a evidence-based decision support for providers, (b delivery system redesign for practices, (c enhanced self-management support tools provided to practices to help them engage patients, and (d increased community resource linkages for practices to enhance referral of patients. The primary outcome is a composite score measured at the level of the patient to represent each practice's adherence to evidence-based guidelines for cardiovascular care. Qualitative analysis of the Practice Outreach Facilitators' written narratives of their ongoing practice interactions will be done. These textual analyses will add further insight into understanding critical factors impacting

  11. Conserved allosteric hot spots in the transmembrane domains of cystic fibrosis transmembrane conductance regulator (CFTR) channels and multidrug resistance protein (MRP) pumps.

    Science.gov (United States)

    Wei, Shipeng; Roessler, Bryan C; Chauvet, Sylvain; Guo, Jingyu; Hartman, John L; Kirk, Kevin L

    2014-07-18

    ATP-binding cassette (ABC) transporters are an ancient family of transmembrane proteins that utilize ATPase activity to move substrates across cell membranes. The ABCC subfamily of the ABC transporters includes active drug exporters (the multidrug resistance proteins (MRPs)) and a unique ATP-gated ion channel (cystic fibrosis transmembrane conductance regulator (CFTR)). The CFTR channel shares gating principles with conventional ligand-gated ion channels, but the allosteric network that couples ATP binding at its nucleotide binding domains (NBDs) with conformational changes in its transmembrane helices (TMs) is poorly defined. It is also unclear whether the mechanisms that govern CFTR gating are conserved with the thermodynamically distinct MRPs. Here we report a new class of gain of function (GOF) mutation of a conserved proline at the base of the pore-lining TM6. Multiple substitutions of this proline promoted ATP-free CFTR activity and activation by the weak agonist, 5'-adenylyl-β,γ-imidodiphosphate (AMP-PNP). TM6 proline mutations exhibited additive GOF effects when combined with a previously reported GOF mutation located in an outer collar of TMs that surrounds the pore-lining TMs. Each TM substitution allosterically rescued the ATP sensitivity of CFTR gating when introduced into an NBD mutant with defective ATP binding. Both classes of GOF mutations also rescued defective drug export by a yeast MRP (Yor1p) with ATP binding defects in its NBDs. We conclude that the conserved TM6 proline helps set the energy barrier to both CFTR channel opening and MRP-mediated drug efflux and that CFTR channels and MRP pumps utilize similar allosteric mechanisms for coupling conformational changes in their translocation pathways to ATP binding at their NBDs. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  12. Novel CFTR missense mutations in Brazilian patients with congenital absence of vas deferens: counseling issues Mutações novas no gene CFTR de pacientes brasileiros portadores de agenesia dos vasos deferentes: dificuldades no aconselhamento

    Directory of Open Access Journals (Sweden)

    Patricia de Campos Pieri

    2007-01-01

    Full Text Available PURPOSE: Screening for mutations in the entire Cystic Fibrosis gene (CFTR of Brazilian infertile men with congenital absence of vas deferens, in order to prevent transmission of CFTR mutations to offspring with the use of assisted reproductive technologies. METHOD: Specific polymerase chain reaction (PCR primers were designed to each of the 27 exons and splicing sites of interest followed by single strand conformational polymorphism and Heteroduplex Analysis (SSCP-HA in precast 12.5% polyacrylamide gels at 7ºC and 20ºC. Fragments with abnormal SSCP migration pattern were sequenced. RESULTS: Two novel missense mutations (S753R and G149W were found in three patients (two brothers together with the IVS8-5T allele in hetrozygosis. CONCLUSION: The available screenings for CF mutations do not include the atypical mutations associated to absence of vas deferens and thus, when these tests fail to find mutations, there is still a genetic risk of affected children with the help of assisted reproduction. We recommend the screening of the whole CFTR gene for these infertile couples, as part of the work-up before assisted reproduction.OBJETIVO: Pesquisar mutações em toda a extensão do gene que causa a Fibrose Cística (CFTR de homens brasileiros inférteis por agenesia congênita dos vasos deferentes, com a finalidade de prevenir a transmissão de mutações em CFTR à prole com o uso das tecnologias de reprodução assistida. MÉTODOS: Foram desenhados oligonucleotídeos específicos para realização de reação de polimerização em cadeia (PCR para cada um dos 27 exons e sítios de processamento de interesse no gene CFTR. O PCR foi seguido pela técnica de SSCP-HA (polimorfismos de conformação no DNA de fita simples e na formação de heteroduplexes em géis pré-fabricados de poliacrilamida a 12,5% em duas temperaturas, 7ºC e 20ºC. Os fragmentos com padrão alterado na migração do SSCP foram submetidos a seqüenciamento automatizado

  13. An innovation for improving maternal, newborn and child health (MNCH) service delivery in Jigawa State, northern Nigeria: a qualitative study of stakeholders' perceptions about clinical mentoring.

    Science.gov (United States)

    Okereke, Ekechi; Tukur, Jamilu; Aminu, Amina; Butera, Jean; Mohammed, Bello; Tanko, Mustapha; Yisa, Ibrahim; Obonyo, Benson; Egboh, Mike

    2015-02-15

    An effective capacity building process for healthcare workers is required for the delivery of quality health care services. Work-based training can be applied for the capacity building of health care workers while causing minimum disruption to service delivery within health facilities. In 2012, clinical mentoring was introduced into the Jigawa State Health System through collaboration between the Jigawa State Ministry of Health and the Partnership for Transforming Health Systems Phase 2 (PATHS2). This study evaluates the perceptions of different stakeholders about clinical mentoring as a strategy for improving maternal, newborn and child health service delivery in Jigawa State, northern Nigeria. Interviews were conducted in February 2013 with different stakeholders within Jigawa State in Northern Nigeria. There were semi-structured interviews with 33 mentored health care workers as well as the health facility departmental heads for Obstetrics and Pediatrics in the selected clinical mentoring health facilities. In-depth interviews were also conducted with the clinical mentors and two senior government health officials working within the Jigawa State Ministry of Health. The qualitative data were audio-recorded; transcribed and thematically analysed. The study findings suggest that clinical mentoring improved service delivery within the clinical mentoring health facilities. Significant improvements in the professional capacity of mentored health workers were observed by clinical mentors, heads of departments and the mentored health workers. Best practices were introduced with the support of the clinical mentors such as appropriate baseline investigations for pediatric patients, the use of magnesium sulphate and misoprostol for the management of eclampsia and post-partum hemorrhage respectively. Government health officials indicate that clinical mentoring has led to more emphasis on the need for the provision of better quality health services. Stakeholders report that

  14. siRNA as a tool to improve the treatment of brain diseases: Mechanism, targets and delivery.

    Science.gov (United States)

    Gomes, Maria João; Martins, Susana; Sarmento, Bruno

    2015-05-01

    As the population ages, brain pathologies such as neurodegenerative diseases and brain cancer increase their incidence, being the need to find successful treatments of upmost importance. Drug delivery to the central nervous system (CNS) is required in order to reach diseases causes and treat them. However, biological barriers, mainly blood-brain barrier (BBB), are the key obstacles that prevent the effectiveness of possible treatments due to their ability to strongly limit the perfusion of compounds into the brain. Over the past decades, new approaches towards overcoming BBB and its efflux transporters had been proposed. One of these approaches here reviewed is through small interfering RNA (siRNA), which is capable to specifically target one gene and silence it in a post-transcriptional way. There are different possible functional proteins at the BBB, as the ones responsible for transport or just for its tightness, which could be a siRNA target. As important as the effective silence is the way to delivery siRNA to its anatomical site of action. This is where nanotechnology-based systems may help, by protecting siRNA circulation and providing cell/tissue-targeting and intracellular siRNA delivery. After an initial overview on incidence of brain diseases and basic features of the CNS, BBB and its efflux pumps, this review focuses on recent strategies to reach brain based on siRNA, and how to specifically target these approaches in order to treat brain diseases. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Funciones de los canales iónicos CFTR y ENAC en la fibrosis quística

    Directory of Open Access Journals (Sweden)

    Alejandra G. Palma

    2014-04-01

    Full Text Available La fibrosis quística se debe a la ausencia o defecto del canal transmembrana regulador de la fibrosis quística (CFTR, un canal de cloruro codificado en el gen cftr que juega un papel clave en la homeostasis del agua e iones. El CFTR es activado por el AMPc y se localiza en las membranas apicales y basolaterales de las vías aéreas, intestino y glándulas exocrinas. Una de sus funciones primarias en los pulmones es mantener la capa de líquido superficial a través de su función de canal y regular el canal epitelial de sodio sensible al amiloride (ENaC. Se han identificado más de 1900 mutaciones en el gen cftr. La enfermedad se caracteriza por secreciones viscosas en las glándulas exocrinas y por niveles elevados de cloruro de sodio en el sudor. En la fibrosis quística el CFTR no funciona y el ENaC está desregulado; el resultado es un aumento en la reabsorción de sodio y agua con la formación de un líquido viscoso. En las glándulas sudoríparas tanto el Na+ como el Cl- se retienen en el lumen causando una pérdida de electrolitos durante la sudoración y el NaCl se elimina al sudor. Así, los niveles elevados de NaCl son la base del test del sudor inducido por pilocarpina, un método de diagnóstico para la enfermedad. En esta revisión se discuten los movimientos de Cl- y Na+ en las glándulas sudoríparas y pulmón así como el papel del ENaC en la patogénesis de la enfermedad.

  16. Design and evaluation of mPEG-PLA micelles functionalized with drug-interactive domains as improved drug carriers for docetaxel delivery.

    Science.gov (United States)

    Qi, Dingqing; Gong, Feirong; Teng, Xin; Ma, Mingming; Wen, Huijing; Yuan, Weihao; Cheng, Yi; Lu, Chong

    2017-10-01

    Polymeric micelles are very attractive drug delivery systems for hydrophobic agents, owing to their readily tailorable chemical structure and ease for scale-up preparation. However, the intrinsic poor stability of drug-loaded micelles presents one of the major challenges for most micellar systems in the translation to clinical applications. In this study, a simple, well-defined, and easy-to-scale up 9-Fluorenylmethoxycarbonyl (Fmoc) and tert-butoxycarbonyl (Boc) containing lysine dendronized mPEG-PLA (mPEG-PLA-Lys(FB) 2 ) micellar formulation was designed and prepared for docetaxel (DTX) delivery, in an effort to improve the stability of the micelles, and its physicochemical properties, pharmacokinetics, and anti-tumor efficacy against SKOV-3 ovarian cancer were evaluated. MPEG-PLA-Lys(FB) 2 was synthesized via a three-step synthetic route, and it actively interacted with DTX in aqueous media to form stable micelles with small particle sizes (~17-19 nm) and narrow size distribution (PI PLA-Lys(FB) 2 micelles achieved delayed and sustained release manner of DTX in comparison with mPEG-PLA micelles. Further in vivo xenograft tumor model in nude mice DTX/mPEG-PLA-Lys(FB) 2 micelles demonstrated significantly higher inhibitory effect on tumor growth than the marketed formulation Taxotere. Thus, our system may hold promise as a simple and effective delivery system for DTX with a potential for translation into clinical study.

  17. Conjugated and Entrapped HPMA-PLA Nano-Polymeric Micelles Based Dual Delivery of First Line Anti TB Drugs: Improved and Safe Drug Delivery against Sensitive and Resistant Mycobacterium Tuberculosis.

    Science.gov (United States)

    Upadhyay, Seema; Khan, Iliyas; Gothwal, Avinash; Pachouri, Praveen K; Bhaskar, N; Gupta, Umesh D; Chauhan, Devendra S; Gupta, Umesh

    2017-09-01

    First line antiTB drugs have several physical and toxic manifestations which limit their applications. RIF is a hydrophobic drug and has low water solubility and INH is hepatotoxic. The main objective of the study was to synthesize, characterize HPMA-PLA co-polymeric micelles for the effective dual delivery of INH and RIF. HPMA-PLA co-polymer and HPMA-PLA-INH (HPI) conjugates were synthesized and characterized by FT-IR and 1 H-NMR spectroscopy. Later on RIF loaded HPMA-PLA-INH co-polymeric micelles (PMRI) were formulated and characterized for size, zeta potential and surface morphology (SEM, TEM) as well as critical micellar concentration. The safety was assessed through RBC's interaction study. The prepared PMRI were evaluated through MABA assay against sensitive and resistant strains of M. Tuberculosis. Size, zeta and entrapment efficiency for RIF loaded HPMA-PLA-INH polymeric micelles (PMRI) was 87.64 ± 1.98 nm, -19 ± 1.93 mV and 97.2 ± 1.56%, respectively. In vitro release followed controlled and sustained delivery pattern. Sustained release was also supported by release kinetics. Haemolytic toxicity of HPI and PMRI was 8.57 and 7.05% (p PLA polymeric micelles (PMRI) were more effective against sensitive and resistant M tuberculosis. The developed approach can lead to improved patient compliance and reduced dosing in future, offering improved treatment of tuberculosis.

  18. Improving health related quality of life among rural hypertensive patients through the integrative strategy of health services delivery: a quasi-experimental trial from Chongqing, China.

    Science.gov (United States)

    Miao, Yudong; Zhang, Liang; Sparring, Vibeke; Sandeep, Sandeep; Tang, Wenxi; Sun, Xiaowei; Feng, Da; Ye, Ting

    2016-08-23

    Integrative strategy of health services delivery has been proven to be effective in economically developed countries, where the healthcare systems have enough qualified primary care providers. However rural China lacks such providers to act as gatekeeper, besides, Chinese rural hypertensive patients are usually of old age, more likely to be exposed to health risk factors and they experience a greater socio-economic burden. All these Chinese rural setting specific features make the effectiveness of integrative strategy of health services in improving health related quality of life among Chinese rural hypertensive patients uncertain. In order to assess the impact of integrative strategy of health services delivery on health related quality of life among Chinese rural hypertensive patients, a two-year quasi-experimental trial was conducted in Chongqing, China. At baseline the sample enrolled 1006 hypertensive patients into intervention group and 420 hypertensive patients into control group. Physicians from village clinics, town hospitals and county hospitals worked collaboratively to deliver multidisciplinary health services for the intervention group, while physicians in the control group provided services without cooperation. The quality of life was studied by SF-36 Scale. Blood pressures were reported by town hospitals. The Difference-in-Differences model was used to estimate the differences in SF-36 score and blood pressure of both groups to assess the impact. The study showed that at baseline there was no statistical difference in SF-36 scores between both groups. While at follow-up the intervention group scored higher in overall SF-36, Role Physical, Body Pain, Social Functioning and Role Emotional than the control group. The Difference-in-Differences result demonstrated that there were statistical differences in SF-36 total score (p = 0.011), Role Physical (p = 0.027), Social Functioning (p = 0.000), Role Emotional (p = 0.002) between both

  19. Improving arteriovenous fistula patency: Transdermal delivery of diclofenac reduces cannulation-dependent neointimal hyperplasia via AMPK activation.

    Science.gov (United States)

    MacAskill, Mark G; Watson, David G; Ewart, Marie-Ann; Wadsworth, Roger; Jackson, Andrew; Aitken, Emma; MacKenzie, Graeme; Kingsmore, David; Currie, Susan; Coats, Paul

    2015-08-01

    Creation of an autologous arteriovenous fistula (AVF) for vascular access in haemodialysis is the modality of choice. However neointimal hyperplasia and loss of the luminal compartment result in AVF patency rates of ~60% at 12months. The exact cause of neointimal hyperplasia in the AVF is poorly understood. Vascular trauma has long been associated with hyperplasia. With this in mind in our rabbit model of AVF we simulated cannulation autologous to that undertaken in vascular access procedures and observed significant neointimal hyperplasia as a direct consequence of cannulation. The neointimal hyperplasia was completely inhibited by topical transdermal delivery of the non-steroidal anti-inflammatory (NSAID) diclofenac. In addition to the well documented anti-inflammatory properties we have identified novel anti-proliferative mechanisms demonstrating diclofenac increases AMPK-dependent signalling and reduced expression of the cell cycle protein cyclin D1. In summary prophylactic transdermal delivery of diclofenac to the sight of AVF cannulation prevents adverse neointimal hyperplasic remodelling and potentially offers a novel treatment option that may help prolong AVF patency and flow rates. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  20. Improving arteriovenous fistula patency: Transdermal delivery of diclofenac reduces cannulation-dependent neointimal hyperplasia via AMPK activation

    Science.gov (United States)

    MacAskill, Mark G.; Watson, David G.; Ewart, Marie-Ann; Wadsworth, Roger; Jackson, Andrew; Aitken, Emma; MacKenzie, Graeme; Kingsmore, David; Currie, Susan; Coats, Paul

    2015-01-01

    Creation of an autologous arteriovenous fistula (AVF) for vascular access in haemodialysis is the modality of choice. However neointimal hyperplasia and loss of the luminal compartment result in AVF patency rates of ~ 60% at 12 months. The exact cause of neointimal hyperplasia in the AVF is poorly understood. Vascular trauma has long been associated with hyperplasia. With this in mind in our rabbit model of AVF we simulated cannulation autologous to that undertaken in vascular access procedures and observed significant neointimal hyperplasia as a direct consequence of cannulation. The neointimal hyperplasia was completely inhibited by topical transdermal delivery of the non-steroidal anti-inflammatory (NSAID) diclofenac. In addition to the well documented anti-inflammatory properties we have identified novel anti-proliferative mechanisms demonstrating diclofenac increases AMPK-dependent signalling and reduced expression of the cell cycle protein cyclin D1. In summary prophylactic transdermal delivery of diclofenac to the sight of AVF cannulation prevents adverse neointimal hyperplasic remodelling and potentially offers a novel treatment option that may help prolong AVF patency and flow rates. PMID:25866325

  1. Development of PEGylated PLGA nanoparticle for controlled and sustained drug delivery in cystic fibrosis

    Directory of Open Access Journals (Sweden)

    Mazur Steven

    2010-09-01

    Full Text Available Abstract Background The mutation in the cystic fibrosis transmembrane conductance regulator (CFTR gene results in CF. The most common mutation, ΔF508-CFTR, is a temperature-sensitive, trafficking mutant with reduced chloride transport and exaggerated immune response. The ΔF508-CFTR is misfolded, ubiquitinated, and prematurely degraded by proteasome mediated- degradation. We recently demonstrated that selective inhibition of proteasomal pathway by the FDA approved drug PS-341 (pyrazylcarbonyl-Phe-Leuboronate, a.k.a. Velcade or bortezomib ameliorates the inflammatory pathophysiology of CF cells. This proteasomal drug is an extremely potent, stable, reversible and selective inhibitor of chymotryptic threonine protease-activity. The apprehension in considering the proteasome as a therapeutic target is that proteasome inhibitors may affect proteostasis and consecutive processes. The affect on multiple processes can be mitigated by nanoparticle mediated PS-341 lung-delivery resulting in favorable outcome observed in this study. Results To overcome this challenge, we developed a nano-based approach that uses drug loaded biodegradable nanoparticle (PLGA-PEGPS-341 to provide controlled and sustained drug delivery. The in vitro release kinetics of drug from nanoparticle was quantified by proteasomal activity assay from days 1-7 that showed slow drug release from day 2-7 with maximum inhibition at day 7. For in vivo release kinetics and biodistribution, these drug-loaded nanoparticles were fluorescently labeled, and administered to C57BL6 mice by intranasal route. Whole-body optical imaging of the treated live animals demonstrates efficient delivery of particles to murine lungs, 24 hrs post treatment, followed by biodegradation and release over time, day 1-11. The efficacy of drug release in CF mice (Cftr-/- lungs was determined by quantifying the changes in proteasomal activity (~2 fold decrease and ability to rescue the Pseudomonas aeruginosa LPS (Pa

  2. Managing Quality by Action Research--Improving Quality Service Delivery in Higher Education as a Marketing Strategy.

    Science.gov (United States)

    Corbitt, Brian

    1998-01-01

    Describes two action research projects undertaken at an Australian university to improve quality of services to foreign students and improve the institution's image through word of mouth, or informal marketing. Each project, although small, facilitated changes or improvements to a targeted service. The role of management in empowering employees…

  3. The ichthyotoxic alga Chattonella marina induces Na+, K+-ATPase, and CFTR proteins expression in fish gill chloride cells in vivo

    International Nuclear Information System (INIS)

    Tang, Janet Y.M.; Wong, Chris K.C.; Au, Doris W.T.

    2007-01-01

    Our previous studies demonstrated that the ichthyotoxic Chattonella marina stimulated proliferation of branchial chloride cell (CC) and induced osmotic distress akin to hyperactive elimination of ions in fish (Rhabdosargus sarba). To ascertain the in vivo effects of C. marina on key CC ion transporters, the localization and expression of Na + , K + -ATPase (NKA) and cystic fibrosis transmembrane conductance regulator (CFTR) proteins in response to C. marina exposure were investigated, using a quantitative immunocytochemical approach. The polarized distributions of NKA (α subunit) and CFTR proteins in branchial CCs of R. sarba remained unchanged under C. marina exposure. However, significant inductions of these two ion-transporters were detected in CCs of fish after 6 h exposure. By real-time PCR, no significant changes in gill NKA and CFTR mRNA expressions were detected, suggesting a post-transcriptional pathway is likely involved in regulating the ion transporters abundance. This study is the first to demonstrate the in vivo effects of harmful algal toxin on NKA and CFTR protein expressions in gill transepithelial cells. Taken together, an augmentation of branchial CCs together with hyper-stimulation of NKA and CFTR in CCs attribute to the rapid development of osmotic distress in C. marina susceptible fish

  4. Clinical expression of patients with the D1152H CFTR mutation.

    Science.gov (United States)

    Terlizzi, Vito; Carnovale, Vincenzo; Castaldo, Giuseppe; Castellani, Carlo; Cirilli, Natalia; Colombo, Carla; Corti, Fabiola; Cresta, Federico; D'Adda, Alice; Lucarelli, Marco; Lucidi, Vincenzina; Macchiaroli, Annamaria; Madarena, Elisa; Padoan, Rita; Quattrucci, Serena; Salvatore, Donatello; Zarrilli, Federica; Raia, Valeria

    2015-07-01

    Discordant results were reported on the clinical expression of subjects bearing the D1152H CFTR mutation, and also for the small number of cases reported so far. A retrospective review of clinical, genetic and biochemical data was performed from individuals homozygous or compound heterozygous for the D1152H mutation followed in 12 Italian cystic fibrosis (CF) centers. 89 subjects carrying at least D1152H on one allele were identified. 7 homozygous patients had very mild clinical expression. Over half of the 74 subjects compound heterozygous for D1152H and a I-II-III class mutation had borderline or pathological sweat test and respiratory or gastrointestinal symptoms; one third had pulmonary bacteria colonization and 10/74 cases had complications (i.e. diabetes, allergic bronchopulmonary aspergillosis, and hemoptysis). However, their clinical expression was less severe as compared to a group of CF patients homozygous for the F508del mutation. Finally, 8 subjects compound heterozygous for D1152H and a IV-V class mutation showed very mild disease. The natural history of subjects bearing the D1152H mutation is widely heterogeneous and is influenced by the mutation in trans. Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

  5. Sonication-Based Improvement of the Physicochemical Properties of Guar Gum as a Potential Substrate for Modified Drug Delivery Systems

    Directory of Open Access Journals (Sweden)

    Siddique Akber Ansari

    2013-01-01

    Full Text Available Guar Gum is a natural polysaccharide that, due to its physicochemical properties, is extensively investigated for biomedical applications as a matrix for modified drug delivery, but it is also used in the food industry as well as in cosmetics. A commercial sample of Guar Gum was sonicated for different periods of time, and the reduction in the average molecular weight was monitored by means of viscometric measurements. At the same time, the rheological behaviour was also followed, in terms of viscoelasticity range, flow curves, and mechanical spectra. Sonicated samples were used for the preparation of gels in the presence of borate ions. The effect of borax on the new samples was investigated by recording mechanical spectra, flow curves, and visible absorption spectra of complexes with Congo Red. The anisotropic elongation, observed in previous studies with tablets of Guar Gum and borax, was remarkably reduced when the sonicated samples were used for the preparation of the gels.

  6. Polysaccharides as Bacterial Antiadhesive Agents and "Smart" Constituents for Improved Drug Delivery Systems Against Helicobacter pylori Infection.

    Science.gov (United States)

    Menchicchi, Bianca; Hensel, Andreas; Goycoolea, Francisco M

    2015-01-01

    The standard eradication treatment of the hostile Helicobacter pylori (H. pylori) stomach infection is facing increasing alarming antibiotic resistance worldwide and calls for alternative strategies to the use of antibiotics. One new perspective in this direction is cytoprotective compounds for targeted prevention of the adhesion of the bacteria to the stomach host cell and to inhibit the bacterial cell-cell communication via quorum sensing by specific inhibitors. Bacterial adhesion of H. pylori to the host cells is mainly mediated by carbohydrate-protein interactions. Therefore, the use of polyvalent carbohydrates, (e.g. plant-derived polysaccharides), as potential antiadhesive compounds, seems to be a promising tool to prevent the initial docking of the bacterium to the stomach cells. Polysaccharides are common constituents of daily food, either as starch or as dietary fiber and often also function as excipients for galenic drug-delivery formulations. In addition, polysaccharides with defined pharmacodynamics action against bacterial outer membrane proteins can have potential as therapeutic tools in the treatment of bacterial infections. Some polysaccharides are known to possess antibacterial properties against gram-positive bacteria, others to inhibit bacterial colonization by blocking specific carbohydrate receptors involved in host-bacteria interaction. This mode of action is advocated as alternative antiadhesion therapy. Ongoing research is also seeking for polysaccharide-based nanoformulations with potential for local drug delivery at the stomach as novel H. pylori therapies. These approaches pose challenges concerned with the stability of the nanomaterials in the harsh conditions of the gastric environment and their capacity to adhere to the stomach mucosa. In a global scenario, geographical diversity and social habits, namely lifestyle and dietary factors, influence the prevalence of the H. pylori-associated diseases and their severity. In this context

  7. Localized Intrathecal Delivery of Mesenchymal Stromal Cells Conditioned Medium Improves Functional Recovery in a Rat Model of Spinal Cord Injury

    Directory of Open Access Journals (Sweden)

    Dasa Cizkova

    2018-03-01

    Full Text Available It was recently shown that the conditioned medium (CM of mesenchymal stem cells can enhance viability of neural and glial cell populations. In the present study, we have investigated a cell-free approach via CM from rat bone marrow stromal cells (MScCM applied intrathecally (IT for spinal cord injury (SCI recovery in adult rats. Functional in vitro test on dorsal root ganglion (DRG primary cultures confirmed biological properties of collected MScCM for production of neurosphere-like structures and axon outgrowth. Afterwards, rats underwent SCI and were treated with IT delivery of MScCM or vehicle at postsurgical Days 1, 5, 9, and 13, and left to survive 10 weeks. Rats that received MScCM showed significantly higher motor function recovery, increase in spared spinal cord tissue, enhanced GAP-43 expression and attenuated inflammation in comparison with vehicle-treated rats. Spared tissue around the lesion site was infiltrated with GAP-43-labeled axons at four weeks that gradually decreased at 10 weeks. Finally, a cytokine array performed on spinal cord extracts after MScCM treatment revealed decreased levels of IL-2, IL-6 and TNFα when compared to vehicle group. In conclusion, our results suggest that molecular cocktail found in MScCM is favorable for final neuroregeneration after SCI.

  8. Simulation model of converging-diverging (CD) nozzle to improve particle delivery system of deoxyribonucleic acid (DNA)

    Science.gov (United States)

    Sumarsono, Danardono A.; Ibrahim, Fera; Santoso, Satria P.; Sari, Gema P.

    2018-02-01

    Gene gun is a mechanical device which has been used to deliver DNA vaccine into the cells and tissues by increasing the uptake of DNA plasmid so it can generate a high immune response with less amount of DNA. Nozzle is an important part of the gene gun which used to accelerate DNA in particle form with a gas flow to reach adequate momentum to enter the epidermis of human skin and elicit immune response. We developed new designs of nozzle for gene gun to make DNA uptake more efficient in vaccination. We used Computational Fluid Dynamics (CFD) by Autodesk® Simulation 2015 to simulate static fluid pressure and velocity contour of supersonic wave and parametric distance to predict the accuracy of the new nozzle. The result showed that the nozzle could create a shockwave at the distance parametric to the object from 4 to 5 cm using fluid pressure varied between 0.8-1.2 MPa. This is indication a possibility that the DNA particle could penetrate under the mammalian skin. For the future research step, this new nozzle model could be considered for development the main component of the DNA delivery system in vaccination in vivo

  9. Recirculating cardiac delivery of AAV2/1SERCA2a improves myocardial function in an experimental model of heart failure in large animals.

    Science.gov (United States)

    Byrne, M J; Power, J M; Preovolos, A; Mariani, J A; Hajjar, R J; Kaye, D M

    2008-12-01

    Abnormal excitation-contraction coupling is a key pathophysiologic component of heart failure (HF), and at a molecular level reduced expression of the sarcoplasmic reticulum (SR) Ca(2+) ATPase (SERCA2a) is a major contributor. Previous studies in small animals have suggested that restoration of SERCA function is beneficial in HF. Despite this promise, the means by which this information might be translated into potential clinical application remains uncertain. Using a recently established cardiac-directed recirculating method of gene delivery, we administered adeno-associated virus 2 (AAV2)/1SERCA2a to sheep with pacing-induced HF. We explored the effects of differing doses of AAV2/1SERCA2a (low 1 x 10(10) d.r.p.; medium 1 x 10(12) d.r.p. and high 1 x 10(13) d.r.p.) in conjunction with an intra-coronary delivery group (2.5 x 10(13) d.r.p.). At the end of the study, haemodynamic, echocardiographic, histopathologic and molecular biologic assessments were performed. Cardiac recirculation delivery of AAV2/1SERCA2a elicited a dose-dependent improvement in cardiac performance determined by left ventricular pressure analysis, (+d P/d t(max); low dose -220+/-70, P>0.05; medium dose 125+/-53, P0.05; medium dose 1+/-2, P>0.05; high dose 6.5+/-3.9, Preversal of the HF molecular phenotype. In contrast, direct intra-coronary infusion did not elicit any effect on ventricular function. As such, AAV2/1SERCA2a elicits favourable functional and molecular actions when delivered in a mechanically targeted manner in an experimental model of HF. These observations lay a platform for potential clinical translation.

  10. Mercury toxicity in the shark (Squalus acanthias) rectal gland: apical CFTR chloride channels are inhibited by mercuric chloride.

    Science.gov (United States)

    Ratner, Martha A; Decker, Sarah E; Aller, Stephen G; Weber, Gerhard; Forrest, John N

    2006-03-01

    In the shark rectal gland, basolateral membrane proteins have been suggested as targets for mercury. To examine the membrane polarity of mercury toxicity, we performed experiments in three preparations: isolated perfused rectal glands, primary monolayer cultures of rectal gland epithelial cells, and Xenopus oocytes expressing the shark cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. In perfused rectal glands we observed: (1) a dose-dependent inhibition by mercury of forskolin/3-isobutyl-1-methylxanthine (IBMX)-stimulated chloride secretion; (2) inhibition was maximal when mercury was added before stimulation with forskolin/IBMX; (3) dithiothrietol (DTT) and glutathione (GSH) completely prevented inhibition of chloride secretion. Short-circuit current (Isc) measurements in monolayers of rectal gland epithelial cells were performed to examine the membrane polarity of this effect. Mercuric chloride inhibited Isc more potently when applied to the solution bathing the apical vs. the basolateral membrane (23 +/- 5% and 68 +/- 5% inhibition at 1 and 10 microM HgCl2 in the apical solution vs. 2 +/- 0.9% and 14 +/- 5% in the basolateral solution). This inhibition was prevented by pre-treatment with apical DTT or GSH; however, only the permeant reducing agent DTT reversed mercury inhibition when added after exposure. When the shark rectal gland CFTR channel was expressed in Xenopus oocytes and chloride conductance was measured by two-electrode voltage clamping, we found that 1 microM HgCl2 inhibited forskolin/IBMX conductance by 69.2 +/- 2.0%. We conclude that in the shark rectal gland, mercury inhibits chloride secretion by interacting with the apical membrane and that CFTR is the likely site of this action. Copyright 2006 Wiley-Liss, Inc.

  11. Implementation of cooperative learning through collaboration with foreign lecturer to improve students' understanding and soft skills in the course of drug delivery system

    Science.gov (United States)

    Syukri, Yandi; Nugroho, Bambang Hernawan

    2017-03-01

    The course of Drug Delivery Systems is an elective that supports the development of new products in pharmaceutical industry. The existing learning process has been in the form of one-direction face-to-face lecturing. During the lecture, students find it difficult to follow or understand the materials, so they become passive. Also, class effectiveness is low because it cannot develop students' active participation during the learning process. To improve the learning outcomes and to achieve the desired competence, innovations in the learning process should be attempted. This learning model aimed to improve students' understanding of and soft skills in the course of Drug Delivery Systems through a cooperative learning method and collaboration with foreign lecturers. The order of cooperative learning included explaining the desired learning outcomes of each topic, providing reading materials for students to learn when preparing their papers, instructing students to work on group assignments and to help each other to master the lesson through question-answer sessions and discussions among group members, encouraging group presentations, and evaluating through quizzes. The foreign lecturers played a role in enriching teaching materials and providing an international class atmosphere. The students' hard skills assessed from the quiz, midterm exam, and final semester exam showed a minimum score of 70 > 80% in the quiz and final semester exam components, while the midterm exam value with a minimum of 70 > 80% was only 6%. The assessment of soft skills obtained from the students' independence in constructing knowledge to complete assignments and resolve problems indicated such outcomes as each group's better ability to access relevant journals, their active participation in group discussions, discipline to submit assignments, discipline to be punctual, and good communication skills. It can be concluded that cooperative learning method could improve the soft skills of students

  12. Improving the Availability and Delivery of Critical Information for Tight Gas Resource Development in the Appalachian Basin

    Energy Technology Data Exchange (ETDEWEB)

    Mary Behling; Susan Pool; Douglas Patchen; John Harper

    2008-12-31

    To encourage, facilitate and accelerate the development of tight gas reservoirs in the Appalachian basin, the geological surveys in Pennsylvania and West Virginia collected widely dispersed data on five gas plays and formatted these data into a large database that can be accessed by individual well or by play. The database and delivery system that were developed can be applied to any of the 30 gas plays that have been defined in the basin, but for this project, data compilation was restricted to the following: the Mississippian-Devonian Berea/Murrysville sandstone play and the Upper Devonian Venango, Bradford and Elk sandstone plays in Pennsylvania and West Virginia; and the 'Clinton'/Medina sandstone play in northwestern Pennsylvania. In addition, some data were collected on the Tuscarora Sandstone play in West Virginia, which is the lateral equivalent of the Medina Sandstone in Pennsylvania. Modern geophysical logs are the most common and cost-effective tools for evaluating reservoirs. Therefore, all of the well logs in the libraries of the two surveys from wells that had penetrated the key plays were scanned, generating nearly 75,000 scanned e-log files from more than 40,000 wells. A standard file-naming convention for scanned logs was developed, which includes the well API number, log curve type(s) scanned, and the availability of log analyses or half-scale logs. In addition to well logs, other types of documents were scanned, including core data (descriptions, analyses, porosity-permeability cross-plots), figures from relevant chapters of the Atlas of Major Appalachian Gas Plays, selected figures from survey publications, and information from unpublished reports and student theses and dissertations. Monthly and annual production data from 1979 to 2007 for West Virginia wells in these plays are available as well. The final database also includes digitized logs from more than 800 wells, sample descriptions from more than 550 wells, more than 600

  13. pH-Dependent dissolving nano- and microparticles for improved peroral delivery of a highly lipophilic compound in dogs.

    Science.gov (United States)

    De Jaeghere, F; Allémann, E; Cerny, R; Galli, B; Steulet, A F; Müller, I; Schütz, H; Doelker, E; Gurny, R

    2001-01-01

    RR01, a new highly lipophilic drug showing extremely low water solubility and poor oral bioavailability, has been incorporated into pH-dependent dissolving particles made of a poly(methacrylic acid-co-ethylacrylate) copolymer. The physicochemical properties of the particles were determined using laser-light-scattering techniques, scanning electron microscopy, high-performance liquid chromatography, and x-ray powder diffraction. Suspension of the free drug in a solution of hydroxypropylcellulose (reference formulation) and aqueous dispersions of pH-sensitive RR01-loaded nanoparticles or microparticles were administered orally to Beagle dogs according to a 2-block Latin square design (n = 6). Plasma samples were obtained over the course of 48 hours and analyzed by gas chromatography/mass spectrometry. The administration of the reference formulation resulted in a particularly high interindividual variability of pharmacokinetic parameters, with low exposure to compound RR01 (AUC0-48h of 6.5 microg x h/mL and coefficient of variation (CV) of 116%) and much higher Tmax, as compared to both pH-sensitive formulations. With respect to exposure and interindividual variability, nanoparticles were superior to microparticles (AUC0-48h of 27.1 microg x h/mL versus 17.7 microg x h/mL with CV of 19% and 40%, respectively), indicating that the particle size may play an important role in the absorption of compound RR01. The performance of pH-sensitive particles is attributed to their ability to release the drug selectively in the upper part of the intestine in a molecular or amorphous form. In conclusion, pH-dependent dissolving particles have a great potential as oral delivery systems for drugs with low water solubility and acceptable permeation properties.

  14. Improving the delivery of veterinary services in Africa: insights from the empirical application of transaction costs theory in Uganda and Kenya.

    Science.gov (United States)

    Ilukor, J

    2017-04-01

    This paper presents a summary of findings from a research project that examined institutional arrangements for providing animal health services in Uganda and Kenya. Given the need to find solutions to the pervasive governance challenges encountered in the delivery of veterinary services in Africa, the study applied transaction economics theory to generate recommendations on how to improve the delivery of these services and minimise livestock production risks, including those that pose a risk to human health, e.g. zoonoses. The most notable recommendations are as follows: i) lower- and middle-income countries should invest in creating an enabling environment that supports the relationship between professional veterinarians and para-professionals, to ensure the timely reporting, treatment and control of animal diseases; ii) the provision of veterinary extension services should not focus solely on household 'heads', but also on other household members, such as wives and children, and on herdsmen; iii) strong government engagement is required in the provision of veterinary services for pastoral or extensive livestock production systems, because normal market forces have failed to attract professional veterinarians and trained para-professionals from the private sector to work in these sectors; iv) farmers must be empowered to hold service providers accountable, by the development and trialling of tools that would enable them to measure the quality of services that they receive and to verify the qualifications of different service providers; v) investment in veterinary education is vital, to ensure that enough qualified veterinary staff are available to offer veterinary services to farmers.

  15. Performance evaluation of an improved optical computed tomography polymer gel dosimeter system for 3D dose verification of static and dynamic phantom deliveries

    International Nuclear Information System (INIS)

    Lopatiuk-Tirpak, O.; Langen, K. M.; Meeks, S. L.; Kupelian, P. A.; Zeidan, O. A.; Maryanski, M. J.

    2008-01-01

    The performance of a next-generation optical computed tomography scanner (OCTOPUS-5X) is characterized in the context of three-dimensional gel dosimetry. Large-volume (2.2 L), muscle-equivalent, radiation-sensitive polymer gel dosimeters (BANG-3) were used. Improvements in scanner design leading to shorter acquisition times are discussed. The spatial resolution, detectable absorbance range, and reproducibility are assessed. An efficient method for calibrating gel dosimeters using the depth-dose relationship is applied, with photon- and electron-based deliveries yielding equivalent results. A procedure involving a preirradiation scan was used to reduce the edge artifacts in reconstructed images, thereby increasing the useful cross-sectional area of the dosimeter by nearly a factor of 2. Dose distributions derived from optical density measurements using the calibration coefficient show good agreement with the treatment planning system simulations and radiographic film measurements. The feasibility of use for motion (four-dimensional) dosimetry is demonstrated on an example comparing dose distributions from static and dynamic delivery of a single-field photon plan. The capability to visualize three-dimensional dose distributions is also illustrated

  16. Process improvement for the safe delivery of multidisciplinary-executed treatments-A case in Y-90 microspheres therapy.

    Science.gov (United States)

    Cai, Bin; Altman, Michael B; Garcia-Ramirez, Jose; LaBrash, Jason; Goddu, S Murty; Mutic, Sasa; Parikh, Parag J; Olsen, Jeffrey R; Saad, Nael; Zoberi, Jacqueline E

    To develop a safe and robust workflow for yttrium-90 (Y-90) radioembolization procedures in a multidisciplinary team environment. A generalized Define-Measure-Analyze-Improve-Control (DMAIC)-based approach to process improvement was applied to a Y-90 radioembolization workflow. In the first DMAIC cycle, events with the Y-90 workflow were defined and analyzed. To improve the workflow, a web-based interactive electronic white board (EWB) system was adopted as the central communication platform and information processing hub. The EWB-based Y-90 workflow then underwent a second DMAIC cycle. Out of 245 treatments, three misses that went undetected until treatment initiation were recorded over a period of 21 months, and root-cause-analysis was performed to determine causes of each incident and opportunities for improvement. The EWB-based Y-90 process was further improved via new rules to define reliable sources of information as inputs into the planning process, as well as new check points to ensure this information was communicated correctly throughout the process flow. After implementation of the revised EWB-based Y-90 workflow, after two DMAIC-like cycles, there were zero misses out of 153 patient treatments in 1 year. The DMAIC-based approach adopted here allowed the iterative development of a robust workflow to achieve an adaptable, event-minimizing planning process despite a complex setting which requires the participation of multiple teams for Y-90 microspheres therapy. Implementation of such a workflow using the EWB or similar platform with a DMAIC-based process improvement approach could be expanded to other treatment procedures, especially those requiring multidisciplinary management. Copyright © 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

  17. Mucosal Immunity and Protective Efficacy of Intranasal Inactivated Influenza Vaccine Is Improved by Chitosan Nanoparticle Delivery in Pigs

    Directory of Open Access Journals (Sweden)

    Santosh Dhakal

    2018-05-01

    Full Text Available Annually, swine influenza A virus (SwIAV causes severe economic loss to swine industry. Currently used inactivated SwIAV vaccines administered by intramuscular injection provide homologous protection, but limited heterologous protection against constantly evolving field viruses, attributable to the induction of inadequate levels of mucosal IgA and cellular immune responses in the respiratory tract. A novel vaccine delivery platform using mucoadhesive chitosan nanoparticles (CNPs administered through intranasal (IN route has the potential to elicit strong mucosal and systemic immune responses in pigs. In this study, we evaluated the immune responses and cross-protective efficacy of IN chitosan encapsulated inactivated SwIAV vaccine in pigs. Killed SwIAV H1N2 (δ-lineage antigens (KAg were encapsulated in chitosan polymer-based nanoparticles (CNPs-KAg. The candidate vaccine was administered twice IN as mist to nursery pigs. Vaccinates and controls were then challenged with a zoonotic and virulent heterologous SwIAV H1N1 (γ-lineage. Pigs vaccinated with CNPs-KAg exhibited an enhanced IgG serum antibody and mucosal secretory IgA antibody responses in nasal swabs, bronchoalveolar lavage (BAL fluids, and lung lysates that were reactive against homologous (H1N2, heterologous (H1N1, and heterosubtypic (H3N2 influenza A virus strains. Prior to challenge, an increased frequency of cytotoxic T lymphocytes, antigen-specific lymphocyte proliferation, and recall IFN-γ secretion by restimulated peripheral blood mononuclear cells in CNPs-KAg compared to control KAg vaccinates were observed. In CNPs-KAg vaccinated pigs challenged with heterologous virus reduced severity of macroscopic and microscopic influenza-associated pulmonary lesions were observed. Importantly, the infectious SwIAV titers in nasal swabs [days post-challenge (DPC 4] and BAL fluid (DPC 6 were significantly (p < 0.05 reduced in CNPs-KAg vaccinates but not in KAg vaccinates when compared

  18. Mucosal Immunity and Protective Efficacy of Intranasal Inactivated Influenza Vaccine Is Improved by Chitosan Nanoparticle Delivery in Pigs.

    Science.gov (United States)

    Dhakal, Santosh; Renu, Sankar; Ghimire, Shristi; Shaan Lakshmanappa, Yashavanth; Hogshead, Bradley T; Feliciano-Ruiz, Ninoshkaly; Lu, Fangjia; HogenEsch, Harm; Krakowka, Steven; Lee, Chang Won; Renukaradhya, Gourapura J

    2018-01-01

    Annually, swine influenza A virus (SwIAV) causes severe economic loss to swine industry. Currently used inactivated SwIAV vaccines administered by intramuscular injection provide homologous protection, but limited heterologous protection against constantly evolving field viruses, attributable to the induction of inadequate levels of mucosal IgA and cellular immune responses in the respiratory tract. A novel vaccine delivery platform using mucoadhesive chitosan nanoparticles (CNPs) administered through intranasal (IN) route has the potential to elicit strong mucosal and systemic immune responses in pigs. In this study, we evaluated the immune responses and cross-protective efficacy of IN chitosan encapsulated inactivated SwIAV vaccine in pigs. Killed SwIAV H1N2 (δ-lineage) antigens (KAg) were encapsulated in chitosan polymer-based nanoparticles (CNPs-KAg). The candidate vaccine was administered twice IN as mist to nursery pigs. Vaccinates and controls were then challenged with a zoonotic and virulent heterologous SwIAV H1N1 (γ-lineage). Pigs vaccinated with CNPs-KAg exhibited an enhanced IgG serum antibody and mucosal secretory IgA antibody responses in nasal swabs, bronchoalveolar lavage (BAL) fluids, and lung lysates that were reactive against homologous (H1N2), heterologous (H1N1), and heterosubtypic (H3N2) influenza A virus strains. Prior to challenge, an increased frequency of cytotoxic T lymphocytes, antigen-specific lymphocyte proliferation, and recall IFN-γ secretion by restimulated peripheral blood mononuclear cells in CNPs-KAg compared to control KAg vaccinates were observed. In CNPs-KAg vaccinated pigs challenged with heterologous virus reduced severity of macroscopic and microscopic influenza-associated pulmonary lesions were observed. Importantly, the infectious SwIAV titers in nasal swabs [days post-challenge (DPC) 4] and BAL fluid (DPC 6) were significantly ( p  influenza nanovaccine may be an ideal candidate vaccine for use in pigs, and pig is a

  19. Improving Transportation Services for the University of the Thai Chamber of Commerce: A Case Study on Solving the Mixed-Fleet Vehicle Routing Problem with Split Deliveries

    Science.gov (United States)

    Suthikarnnarunai, N.; Olinick, E.

    2009-01-01

    We present a case study on the application of techniques for solving the Vehicle Routing Problem (VRP) to improve the transportation service provided by the University of The Thai Chamber of Commerce to its staff. The problem is modeled as VRP with time windows, split deliveries, and a mixed fleet. An exact algorithm and a heuristic solution procedure are developed to solve the problem and implemented in the AMPL modeling language and CPLEX Integer Programming solver. Empirical results indicate that the heuristic can find relatively good solutions in a small fraction of the time required by the exact method. We also perform sensitivity analysis and find that a savings in outsourcing cost can be achieved with a small increase in vehicle capacity.

  20. Improved MECP2 Gene Therapy Extends the Survival of MeCP2-Null Mice without Apparent Toxicity after Intracisternal Delivery

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    Sarah E. Sinnett

    2017-06-01

    Full Text Available Intravenous administration of adeno-associated virus serotype 9 (AAV9/hMECP2 has been shown to extend the lifespan of Mecp2−/y mice, but this delivery route induces liver toxicity in wild-type (WT mice. To reduce peripheral transgene expression, we explored the safety and efficacy of AAV9/hMECP2 injected into the cisterna magna (ICM. AAV9/hMECP2 (1 × 1012 viral genomes [vg]; ICM extended Mecp2−/y survival but aggravated hindlimb clasping and abnormal gait phenotypes. In WT mice, 1 × 1012 vg of AAV9/hMECP2 induced clasping and abnormal gait. A lower dose mitigated these adverse phenotypes but failed to extend survival of Mecp2−/y mice. Thus, ICM delivery of this vector is impractical as a treatment for Rett syndrome (RTT. To improve the safety of MeCP2 gene therapy, the gene expression cassette was modified to include more endogenous regulatory elements believed to modulate MeCP2 expression in vivo. In Mecp2−/y mice, ICM injection of the modified vector extended lifespan and was well tolerated by the liver but did not rescue RTT behavioral phenotypes. In WT mice, these same doses of the modified vector had no adverse effects on survival or neurological phenotypes. In summary, we identified limitations of the original vector and demonstrated that an improved vector design extends Mecp2−/y survival, without apparent toxicity.

  1. Liquid and solid self-microemulsifying drug delivery systems for improving the oral bioavailability of andrographolide from a crude extract of Andrographis paniculata.

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    Sermkaew, Namfa; Ketjinda, Wichan; Boonme, Prapaporn; Phadoongsombut, Narubodee; Wiwattanapatapee, Ruedeekorn

    2013-11-20

    The purpose of this study was to develop self-microemulsifying formulations of an Andrographis paniculata extract in liquid and pellet forms for an improved oral delivery of andrographolide. The optimized liquid self-microemulsifying drug delivery system (SMEDDS) was composed of A. paniculata extract (11.1%), Capryol 90 (40%), Cremophor RH 40 (40%) and Labrasol (8.9%). This liquid SMEDDS was further adsorbed onto colloidal silicon dioxide and microcrystalline cellulose, and converted to SMEDDS pellets by the extrusion/spheronization technique. The microemulsion droplet sizes of the liquid and pellet formulations after dilution with water were in the range of 23.4 and 30.3 nm. The in vitro release of andrographolide from the liquid SMEDDS and SMEDDS pellets was 97.64% (SD 1.97%) and 97.74% (SD 3.36%) within 15 min, respectively while the release from the initial extract was only 10%. The oral absorption of andrographolide was determined in rabbits. The C(max) value of andrographolide from the A. paniculata extract liquid SMEDDS and SMEDDS pellet formulations (equivalent to 17.5mg/kg of andrographolide) was 6-fold and 5-fold greater than the value from the initial extract in aqueous suspension (equivalent to 35 mg/kg of andrographolide), respectively. In addition, the AUC(0-12h) was increased 15-fold by the liquid SMEDDS and 13-fold by the SMEDDS pellets compared to the extract in aqueous suspension, respectively. The results clearly indicated that the liquid and solid SMEDDS could be effectively used to improve the dissolution and oral bioavailability that would also enable a reduction in the dose of the poorly water soluble A. paniculata extract. Copyright © 2013 Elsevier B.V. All rights reserved.

  2. Fostering maternal and newborn care in India the Yashoda way: does this improve maternal and newborn care practices during institutional delivery?

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    Beena Varghese

    Full Text Available BACKGROUND: The Yashoda program, named after a legendary foster-mother in Indian mythology, under the Norway-India Partnership Initiative was launched as a pilot program in 2008 to improve the quality of maternal and neonatal care at facilities in select districts of India. Yashodas were placed mainly at district hospitals, which are high delivery load facilities, to provide support and care to mothers and newborns during their stay at these facilities. This study presents the results from the evaluation of this intervention in two states in India. METHODS: Data collection methods included in-depth interviews with healthcare providers and mothers and a survey of mothers who had recently delivered within a quasi-experimental design. Fifty IDIs were done and 1,652 mothers who had delivered in the past three months were surveyed during 2010 and 2011. RESULTS: A significantly higher proportion of mothers at facilities with Yashodas (55 percent to 97 percent received counseling on immunization, breastfeeding, family planning, danger signs, and nutrition compared to those in control districts (34 percent to 66 percent. Mothers in intervention facilities were four to five times more likely to receive postnatal checks than mothers in control facilities. Among mothers who underwent cesarean sections, initiation of breastfeeding within five hours was 50 percent higher in intervention facilities. Mothers and families also reported increased support, care and respect at intervention facilities. CONCLUSION: Yashoda as mothers' aide thus seems to be an effective intervention to improve quality of maternal and newborn care in India. Scaling up of this intervention is recommended in district hospitals and other facilities with high volume of deliveries.

  3. Cationic lipid-coated PEI/DNA polyplexes with improved efficiency and reduced cytotoxicity for gene delivery into mesenchymal stem cells

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    Song HM

    2012-08-01

    Full Text Available Hongmei Song, Gang Wang, Bin He, Li Li, Caixia Li, Yusi Lai, Xianghui Xu, Zhongwei GuNational Engineering Research Center for Biomaterials, Sichuan University, Chengdu, Sichuan, People's Republic of ChinaBackground: Effective gene transfection without serum deprivation is a prerequisite for successful stem cell-based gene therapy. Polyethylenimine (PEI is an efficient nonviral gene vector, but its application has been hindered by serum sensitivity and severe cytotoxicity.Methods: To solve this problem, a new family of lipopolyplexes was developed by coating PEI/DNA polyplexes with three serum-resistant cationic lipids, namely, lysinylated, histidylated, and arginylated cholesterol. The physical properties, transfection efficiency, cellular uptake, subcellular distribution, and cytotoxicity of the lipopolyplexes was investigated.Results: The outer coat composed of lysinylated or histidylated cholesterol remarkably improved the transfection efficiency of the polyplex with a low PEI/DNA ratio of 2 in the presence of serum. The resulting lysinylated and histidylated cholesterol lipopolyplexes were even more efficient than the best performing polyplex with a high PEI/DNA ratio of 10. Results from cellular uptake and subcellular distribution studies suggest that their higher transfection efficiency may result from accelerated DNA nuclear localization. The superiority of the lipopolyplexes over the best performing polyplex was also confirmed by delivering the therapeutic gene, hVEGF165. Equally importantly, the lipid coating removed the necessity of introducing excess free PEI chains into the transfection solution for higher efficiency, generating lipopolyplexes with no signs of cytotoxicity.Conclusion: Noncovalent modification of polyplexes with lysinylated and histidylated cholesterol lipids can simultaneously improve efficiency and reduce the toxicity of gene delivery under serum conditions, showing great promise for genetic modification of bone

  4. Potential use of mobile phones in improving animal health service delivery in underserved rural areas: experience from Kilosa and Gairo districts in Tanzania.

    Science.gov (United States)

    Karimuribo, Esron D; Batamuzi, Emmanuel K; Massawe, Lucas B; Silayo, Richard S; Mgongo, Frederick O K; Kimbita, Elikira; Wambura, Raphael M

    2016-10-07

    Sub-optimal performance of the animal health delivery system in rural areas is common in developing countries including Tanzania. However, penetration of mobile phones and availability of good road network and public transport systems offer opportunities for improving the access of rural communities to diagnostic and advisory services from facilities and expertise located in urban areas. A questionnaire survey on possession and use of mobile phones by pastoral and agro-pastoral communities in Kilosa and Gairo districts was carried out between November and December 2015. A total number of 138 livestock keepers from three villages of Chakwale (54), Mvumi (41) and Parakuyo (43) participated in the study. An e-based system was designed and tested to link rural communities with urban diagnostic facilities. It was observed that the average number of phones possessed by individuals interviewed and household families was 1.1 ± 0.26 (1-2) and 3.5 ± 2.23 (1-10), respectively. It was further observed that out of 138 livestock keepers interviewed, 133 (96.4 %) had feature phones while 10 (7.2 %) of them possessed smartphones. Mobile phone is currently used to support livestock production by communicating on animal health in Parakuyo (18, 41.9 %), Mvumi (18, 43.9 %) and Chakwale (14, 25.9 %). Other contributions of mobile phones in livestock and crop agriculture observed in the study area include: exchange of livestock price information, crop price information, communicating on plant health/diseases, livestock extension and advisory services as well as crop farming extension and advisory services. We also designed and tested an e-based SUAVetDiag® system to support timely diagnosis of infectious disease conditions and prompt advice on case management in veterinary underserved areas. Availability of mobile phones in rural areas, in combination with supporting infrastructure and facilities in urban areas, has potential to stimulate local development and improving

  5. Improving preventive service delivery at adult complete health check-ups: the Preventive health Evidence-based Recommendation Form (PERFORM cluster randomized controlled trial

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    Moineddin Rahim

    2006-07-01

    Full Text Available Abstract Background To determine the effectiveness of a single checklist reminder form to improve the delivery of preventive health services at adult health check-ups in a family practice setting. Methods A prospective cluster randomized controlled trial was conducted at four urban family practice clinics among 38 primary care physicians affiliated with the University of Toronto. Preventive Care Checklist Forms© were created to be used by family physicians at adult health check-ups over a five-month period. The sex-specific forms incorporate evidence-based recommendations on preventive health services and documentation space for routine procedures such as physical examination. The forms were used in two intervention clinics and two control clinics. Rates and relative risks (RR of the performance of 13 preventive health maneuvers at baseline and post-intervention and the percentage of up-to-date preventive health services delivered per patient were compared between the two groups. Results Randomly-selected charts were reviewed at baseline (n = 509 and post-intervention (n = 608. Baseline rates for provision of preventive health services ranged from 3% (fecal occult blood testing to 93% (blood pressure measurement, similar to other settings. The percentage of up-to-date preventive health services delivered per patient at the end of the intervention was 48.9% in the control group and 71.7% in the intervention group. This is an overall 22.8% absolute increase (p = 0.0001, and 46.6% relative increase in the delivery of preventive health services per patient in the intervention group compared to controls. Eight of thirteen preventive health services showed a statistically significant change (p Conclusion This simple, low cost, clinically relevant intervention improves the delivery of preventive health services by prompting physicians of evidence-based recommendations in a checklist format that incorporates existing practice patterns. Periodic updates

  6. Melt dispersion granules: formulation and evaluation to improve oral delivery of poorly soluble drugs - a case study with valsartan.

    Science.gov (United States)

    Chella, Naveen; Tadikonda, Ramarao

    2015-06-01

    Solid dispersion (SD) technique is a promising strategy to improve the solubility and dissolution of BCS class II drugs. However, only few products are marketed till today based on SD technology due to poor flow properties and stability. The present work was intended to solve these problems by using combination approach, melt dispersion and surface adsorption technologies. The main aim of the present work is to improve the absorption in the stomach (at lower pH) where the absorption window exists for the drug by improving the dissolution, resulting in the enhancement of oral bioavailability of poorly soluble, weakly acidic drug with pH dependant solubility, i.e. valsartan. Melt dispersion granules were prepared in different ratios using different carriers (Gelucire 50/13, PEG 8000 and Pluronic F-68) and lactose as an adsorbent. Similarly, physical mixtures were also prepared at corresponding ratios. The prepared dispersion granules and physical mixtures were characterized by FTIR, DSC and in vitro dissolution studies. DSC studies revealed reduction in the crystallinity with a possibility of presence of amorphous character of drug in the dispersion granules. From dissolution studies, valsartan Gelucire dispersion (GSD4; 1:4 ratio) showed complete drug release in 30 min against the plain drug which showed only 11.31% of drug release in 30 min. Pharmacokinetic studies of optimized formulation in male Wistar rats showed 2.65-fold higher bioavailability and 1.47-fold higher Cmax compared to pure drug. The melt dispersion technology has the potential to improve dissolution and the bioavailability of BCS class II drugs.

  7. PHACES (Photographs of Academic Clinicians and Their Educational Status): a tool to improve delivery of family-centered care.

    Science.gov (United States)

    Dudas, Robert A; Lemerman, Hanna; Barone, Michael; Serwint, Janet R

    2010-01-01

    The aim of this study was to determine if an information sheet containing photographs and explanations of the training level of medical providers could enhance a parent's ability to identify their child's providers and whether this would impact parental attitudes toward trainee involvement and patient satisfaction. This was a prospective, mixed methods study of parent-child dyads admitted to an academic general pediatric inpatient service. The intervention group received a photo information sheet (Photographs of Academic Clinicians and Their Educational Status [PHACES] tool) consisting of passport-sized photos of the medical team along with information regarding their training. Parents were asked to name their child's providers, were surveyed about their attitudes toward trainees, participated in a brief, semistructured interview and completed the patient satisfaction questionnaire (ABIM-PSQ). Comparing intervention with control parents, 40 of 49 (82%) versus 19 of 51 (37%) were able to name at least one provider (adjusted odds ratio 8.0; P < .01). Parents who received the intervention were more likely to correctly match the face with the name of the medical student (67% vs 14%; P < .01) and attending (80% vs 24%; P < .01). Parents who received the intervention were more likely to report acceptance of the involvement of medical students and house staff as well as an improved understanding of their roles. Parents who received the intervention scored higher on the ABIM-PSQ (mean 48.3 vs 45.4; P = .008). An information sheet containing the photographs of health care providers along with an explanation of their training improves recognition of the health care team members, improves acceptance of trainee involvement, and improves satisfaction with care delivered by physicians in training. Copyright 2010 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.

  8. Improving DNA double-strand repair inhibitor KU55933 therapeutic index in cancer radiotherapy using nanoparticle drug delivery

    Science.gov (United States)

    Tian, Xi; Lara, Haydee; Wagner, Kyle T.; Saripalli, Srinivas; Hyder, Syed Nabeel; Foote, Michael; Sethi, Manish; Wang, Edina; Caster, Joseph M.; Zhang, Longzhen; Wang, Andrew Z.

    2015-11-01

    Radiotherapy is a key component of cancer treatment. Because of its importance, there has been high interest in developing agents and strategies to further improve the therapeutic index of radiotherapy. DNA double-strand repair inhibitors (DSBRIs) are among the most promising agents to improve radiotherapy. However, their clinical translation has been limited by their potential toxicity to normal tissue. Recent advances in nanomedicine offer an opportunity to overcome this limitation. In this study, we aim to demonstrate the proof of principle by developing and evaluating nanoparticle (NP) formulations of KU55933, a DSBRI. We engineered a NP formulation of KU55933 using nanoprecipitation method with different lipid polymer nanoparticle formulation. NP KU55933 using PLGA formulation has the best loading efficacy as well as prolonged drug release profile. We demonstrated that NP KU55933 is a potent radiosensitizer in vitro using clonogenic assay and is more effective as a radiosensitizer than free KU55933 in vivo using mouse xenograft models of non-small cell lung cancer (NSCLC). Western blots and immunofluorescence showed NP KU55933 exhibited more prolonged inhibition of DNA repair pathway. In addition, NP KU55933 leads to lower skin toxicity than KU55933. Our study supports further investigations using NP to deliver DSBRIs to improve cancer radiotherapy treatment.

  9. Use of facility assessment data to improve reproductive health service delivery in the Democratic Republic of the Congo

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    Aveledi Blandine

    2009-12-01

    Full Text Available Abstract Background Prolonged exposure to war has severely impacted the provision of health services in the Democratic Republic of the Congo (DRC. Health infrastructure has been destroyed, health workers have fled and government support to health care services has been made difficult by ongoing conflict. Poor reproductive health (RH indicators illustrate the effect that the prolonged crisis in DRC has had on the on the reproductive health (RH of Congolese women. In 2007, with support from the RAISE Initiative, the International Rescue Committee (IRC and CARE conducted baseline assessments of public hospitals to evaluate their capacities to meet the RH needs of the local populations and to determine availability, utilization and quality of RH services including emergency obstetric care (EmOC and family planning (FP. Methods Data were collected from facility assessments at nine general referral hospitals in five provinces in the DRC during March, April and November 2007. Interviews, observation and clinical record review were used to assess the general infrastructure, EmOC and FP services provided, and the infection prevention environment in each of the facilities. Results None of the nine hospitals met the criteria for classification as an EmOC facility (either basic or comprehensive. Most facilities lacked any FP services. Shortage of trained staff, essential supplies and medicines and poor infection prevention practices were consistently documented. All facilities had poor systems for routine monitoring of RH services, especially with regard to EmOC. Conclusions Women's lives can be saved and their well-being improved with functioning RH services. As the DRC stabilizes, IRC and CARE in partnership with the local Ministry of Health and other service provision partners are improving RH services by: 1 providing necessary equipment and renovations to health facilities; 2 improving supply management systems; 3 providing comprehensive competency

  10. Two Salt Bridges Differentially Contribute to the Maintenance of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Channel Function*

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    Cui, Guiying; Freeman, Cody S.; Knotts, Taylor; Prince, Chengyu Z.; Kuang, Christopher; McCarty, Nael A.

    2013-01-01

    Previous studies have identified two salt bridges in human CFTR chloride ion channels, Arg352-Asp993 and Arg347-Asp924, that are required for normal channel function. In the present study, we determined how the two salt bridges cooperate to maintain the open pore architecture of CFTR. Our data suggest that Arg347 not only interacts with Asp924 but also interacts with Asp993. The tripartite interaction Arg347-Asp924-Asp993 mainly contributes to maintaining a stable s2 open subconductance state. The Arg352-Asp993 salt bridge, in contrast, is involved in stabilizing both the s2 and full (f) open conductance states, with the main contribution being to the f state. The s1 subconductance state does not require either salt bridge. In confirmation of the role of Arg352 and Asp993, channels bearing cysteines at these sites could be latched into a full open state using the bifunctional cross-linker 1,2-ethanediyl bismethanethiosulfonate, but only when applied in the open state. Channels remained latched open even after washout of ATP. The results suggest that these interacting residues contribute differently to stabilizing the open pore in different phases of the gating cycle. PMID:23709221

  11. Does interprofessional collaboration between care levels improve following the creation of an integrated delivery organisation? The Bidasoa case in the Basque Country

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    Roberto Nuño Solinís

    2013-09-01

    Full Text Available Introduction: This article explores the impact of the creation of a new integrated delivery organisation on the evolution of interprofessional collaboration between primary and secondary care levels. In particular, the case of the Bidasoa Integrated Healthcare Organisation is analysed.Theory and methods: The evolution of interprofessional collaboration is measured through a validated Spanish questionnaire, with 10 items and a 5-point Likert scale, based on the D’Amour’s model of collaboration [20]. The final sample included 146 observations (doctors and nurses.   Results: The questionnaire identified a significant improvement on the mean scores for interprofessional collaboration of 0.57 points before and after the intervention. A significant improvement was also found in the two dimensions of the measure of interprofessional collaboration used, with the size of the change being higher for the dimension related to the organisational setting (0.63 than for interpersonal relationships (0.47.Conclusions: Before and after the creation of the Bidasoa Integrated Healthcare Organisation, an improvement in the perceived degree of interprofessional collaboration between primary and secondary care levels was observed. This finding supports the benefit of a multilevel and multidimensional approach to integration, as in the described Bidasoa case.Discussion: Results on the two dimensions of the measure of interprofessional collaboration used, seem to point to the longer time required for interpersonal relationships to change, compared to the organisational setting.

  12. Does interprofessional collaboration between care levels improve following the creation of an integrated delivery organisation? The Bidasoa case in the Basque Country

    Directory of Open Access Journals (Sweden)

    Roberto Nuño Solinís

    2013-09-01

    Full Text Available Introduction: This article explores the impact of the creation of a new integrated delivery organisation on the evolution of interprofessional collaboration between primary and secondary care levels. In particular, the case of the Bidasoa Integrated Healthcare Organisation is analysed. Theory and methods: The evolution of interprofessional collaboration is measured through a validated Spanish questionnaire, with 10 items and a 5-point Likert scale, based on the D’Amour’s model of collaboration [20]. The final sample included 146 observations (doctors and nurses.    Results: The questionnaire identified a significant improvement on the mean scores for interprofessional collaboration of 0.57 points before and after the intervention. A significant improvement was also found in the two dimensions of the measure of interprofessional collaboration used, with the size of the change being higher for the dimension related to the organisational setting (0.63 than for interpersonal relationships (0.47. Conclusions: Before and after the creation of the Bidasoa Integrated Healthcare Organisation, an improvement in the perceived degree of interprofessional collaboration between primary and secondary care levels was observed. This finding supports the benefit of a multilevel and multidimensional approach to integration, as in the described Bidasoa case. Discussion: Results on the two dimensions of the measure of interprofessional collaboration used, seem to point to the longer time required for interpersonal relationships to change, compared to the organisational setting.

  13. Disulfide-crosslinked nanomicelles confer cancer-specific drug delivery and improve efficacy of paclitaxel in bladder cancer

    Science.gov (United States)

    Pan, Amy; Zhang, Hongyong; Li, Yuanpei; Lin, Tzu-yin; Wang, Fuli; Lee, Joyce; Cheng, Mingshan; Dall'Era, Marc; Li, Tianhong; deVere White, Ralph; Pan, Chong-Xian; Lam, Kit S.

    2016-10-01

    Chemotherapy commonly used in the treatment of advanced bladder cancer is only moderately effective and associated with significant toxicity. There has been no appreciable improvement in overall survival over the last three decades. The goal of this project is to develop and characterize bladder cancer-specific nanometer-scale micelles loaded with the chemotherapeutic drug paclitaxel (PTX) and determine the anti-tumor activity and toxicity. Micelle-building-material telodendrimers were synthesized through the stepwise conjugation of eight cholic acid units at one terminus of polyethylene glycol (PEG) and a bladder cancer-specific targeting peptide named PLZ4 at the other terminus. To synthesize disulfide-crosslinked PLZ4 nanomicelles (DC-PNM), cysteine was introduced between the cholic acid and PEG. DC-PNM-PTX was synthesized through the evaporation method by loading PTX in the core. The loading capacity of PTX in DC-PNM was 25% (W/W). The loading efficiency was over 99%. DC-PNM-PTX was spherical with the median size of 25 nm. The stability of DC-PNM-PTX was determined in a solution containing sodium docecyl sulfate (SDS). It was stable in a SDS solution, but dissolved within 5 min after the addition of glutathione at the physiological intracellular concentration of 10 mM. In vivo targeting and anti-tumor activity were determined in immunodeficient mice carrying patient-derived bladder cancer xenografts (PDXs). After intravenous administration, DC-PNM specifically targeted the bladder cancer PDXs, but very little to the lung cancer xenografts in the same mice (p < 0.001). DC-PNM loaded with PTX overcame cisplatin resistance, and improved the median survival from 55 d with free PTX to 69.5 d (p = 0.03) of mice carrying PDXs. In conclusion, DC-PNM remained stable in the SDS solution, specifically targeted the bladder cancer xenografts in vivo, and improved the anti-cancer efficacy of PTX.

  14. Sildenafil citrate improves the delivery and anticancer activity of doxorubicin formulations in a mouse model of breast cancer.

    Science.gov (United States)

    Greish, Khaled; Fateel, Maryam; Abdelghany, Sara; Rachel, Nanitha; Alimoradi, Houman; Bakhiet, Moiz; Alsaie, Ahmed

    2017-11-21

    Sildenafil is an approved drug for the treatment of erectile dysfunction. The drug exerts its action through the relaxation of smooth muscles and the modulation of vascular endothelial permeability. In this work, we tested whether the aforementioned effects of sildenafil on tumour vasculatures could result in an improvement of anticancer drug concentration in tumour tissues and hence improves its anticancer effect. Sildenafil when added to doxorubicin showed synergistic anticancer activity against 4T1 breast cancer cells in vitro. Adding 1, 30 and 100 μM of Viagra to 1 μM of doxorubicin resulted in 1.8-fold, 6.2-fold and 21-fold statistically significant increases in its cytotoxic effect, respectively. As a result, 4T1 tumour-bearing mice showed up to 2.7-fold increase in drug concentrations of the fluorescent Dye DiI and doxorubicin in tumour tissues, as well as their nanoformulations. Animals treated with the combinations of both Sildenafil citrate and doxorubicin showed a statistically significant 4.7-fold reduction in tumour size compared to doxorubicin alone. This work highlights the effect of Sildenafil on tumour vasculatures and provides a rational for further testing the combination on breast cancer patients.

  15. The 2D Hyperlink/Geocaching hybrid as a New Method for Improving Communication and Educational Delivery in Environmental Science

    Science.gov (United States)

    Graham, J.; Byrne, J. M.

    2009-12-01

    Geocaching is a game of hiding and locating caches (treasures), usually with the aid of a GPS-enabled device, and then posting the locations online for others to discover. Its remarkable success as a cultural phenomenon - transcending the traditional boundaries of age, gender, race and culture, while seamlessly combining the elements of technology, mental challenge, travel, geography, orienteering and entertainment - has been well documented. One would expect, therefore, that something so accessible and so physically, mentally and technologically engaging could also have great potential as an educational tool; specifically for the teaching of environmental science in situ. The attempts to date, however, have been disappointing. It will be the purpose of this poster to demonstrate a new and effective approach to educational environmental science-based geocaching; one which treats discreet elements of the living landscape as caches (rather than obstacles), and which combines several commonly available technologies so as to create a rich, immersive experience for viewers of many ages and backgrounds. Specifically, our poster will demonstrate how traditional geocaching methods can be dramatically improved, for the purposes of education, by combining it with 2D hyperlinking technologies in such a way as to allow the viewer to access a variety of different online and/or offline media elements - documentaries, texts, websites, animations, and images, while immersed in the physical environment to which they relate. It will be shown that this site-specific approach to environmental education has considerable potential for improving the meaningful dialogue between environmental scientists and the general public.

  16. The prevention of mother-to-child transmission of HIV cascade analysis tool: supporting health managers to improve facility-level service delivery.

    Science.gov (United States)

    Gimbel, Sarah; Voss, Joachim; Mercer, Mary Anne; Zierler, Brenda; Gloyd, Stephen; Coutinho, Maria de Joana; Floriano, Florencia; Cuembelo, Maria de Fatima; Einberg, Jennifer; Sherr, Kenneth

    2014-10-21

    The objective of the prevention of Mother-to-Child Transmission (pMTCT) cascade analysis tool is to provide frontline health managers at the facility level with the means to rapidly, independently and quantitatively track patient flows through the pMTCT cascade, and readily identify priority areas for clinic-level improvement interventions. Over a period of six months, five experienced maternal-child health managers and researchers iteratively adapted and tested this systems analysis tool for pMTCT services. They prioritized components of the pMTCT cascade for inclusion, disseminated multiple versions to 27 health managers and piloted it in five facilities. Process mapping techniques were used to chart PMTCT cascade steps in these five facilities, to document antenatal care attendance, HIV testing and counseling, provision of prophylactic anti-retrovirals, safe delivery, safe infant feeding, infant follow-up including HIV testing, and family planning, in order to obtain site-specific knowledge of service delivery. Seven pMTCT cascade steps were included in the Excel-based final tool. Prevalence calculations were incorporated as sub-headings under relevant steps. Cells not requiring data inputs were locked, wording was simplified and stepwise drop-offs and maximization functions were included at key steps along the cascade. While the drop off function allows health workers to rapidly assess how many patients were lost at each step, the maximization function details the additional people served if only one step improves to 100% capacity while others stay constant. Our experience suggests that adaptation of a cascade analysis tool for facility-level pMTCT services is feasible and appropriate as a starting point for discussions of where to implement improvement strategies. The resulting tool facilitates the engagement of frontline health workers and managers who fill out, interpret, apply the tool, and then follow up with quality improvement activities. Research on

  17. Cysteamine re-establishes the clearance of Pseudomonas aeruginosa by macrophages bearing the cystic fibrosis-relevant F508del-CFTR mutation.

    Science.gov (United States)

    Ferrari, Eleonora; Monzani, Romina; Villella, Valeria R; Esposito, Speranza; Saluzzo, Francesca; Rossin, Federica; D'Eletto, Manuela; Tosco, Antonella; De Gregorio, Fabiola; Izzo, Valentina; Maiuri, Maria C; Kroemer, Guido; Raia, Valeria; Maiuri, Luigi

    2017-01-12

    Cystic fibrosis (CF), the most common lethal monogenic disease in Caucasians, is characterized by recurrent bacterial infections and colonization, mainly by Pseudomonas aeruginosa, resulting in unresolved airway inflammation. CF is caused by mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which functions as a chloride channel in epithelial cells, macrophages, and other cell types. Impaired bacterial handling by macrophages is a feature of CF airways, although it is still debated how defective CFTR impairs bacterial killing. Recent evidence indicates that a defective autophagy in CF macrophages leads to alterations of bacterial clearance upon infection. Here we use bone marrow-derived macrophages from transgenic mice to provide the genetic proof that defective CFTR compromises both uptake and clearance of internalized Pseudomonas aeruginosa. We demonstrate that the proteostasis regulator cysteamine, which rescues the function of the most common F508del-CFTR mutant and hence reduces lung inflammation in CF patients, can also repair the defects of CF macrophages, thus restoring both bacterial internalization and clearance through a process that involves upregulation of the pro-autophagic protein Beclin 1 and re-establishment of the autophagic pathway. Altogether these results indicate that cysteamine restores the function of several distinct cell types, including that of macrophages, which might contribute to its beneficial effects on CF.

  18. Clusters of Cl- channels in CFTR-expressing em>Sf>9 cells switch spontaneously between slow and fast gating modes

    DEFF Research Database (Denmark)

    Larsen, Erik Hviid; Price, E. M.; Gabriel, S. E.

    1996-01-01

    channel. Excised outside-out patches of CFTR-infected and forskolin-stimulated cells exhibited wave-like gating kinetics of well-resolved current transitions. All-point Gaussian distributions revealed contributions from several (five to nine) identical channels. Such channels, in excised outside...

  19. Structures of a minimal human CFTR first nucleotide-binding domain as a monomer, head-to-tail homodimer, and pathogenic mutant

    Energy Technology Data Exchange (ETDEWEB)

    Atwell, Shane; Brouillette, Christie G.; Conners, Kris; Emtage, Spencer; Gheyi, Tarun; Guggino, William B.; Hendle, Jorg; Hunt, John F.; Lewis, Hal A.; Lu, Frances; Protasevich, Irina I.; Rodgers, Logan A.; Romero, Rich; Wasserman, Stephen R.; Weber, Patricia C.; Wetmore, Diana; Zhang, Feiyu F.; Zhao, Xun (Cystic); (UAB); (JHU); (Columbia); (Lilly)

    2010-04-26

    Upon removal of the regulatory insert (RI), the first nucleotide binding domain (NBD1) of human cystic fibrosis transmembrane conductance regulator (CFTR) can be heterologously expressed and purified in a form that remains stable without solubilizing mutations, stabilizing agents or the regulatory extension (RE). This protein, NBD1 387-646({Delta}405-436), crystallizes as a homodimer with a head-to-tail association equivalent to the active conformation observed for NBDs from symmetric ATP transporters. The 1.7-{angstrom} resolution X-ray structure shows how ATP occupies the signature LSGGQ half-site in CFTR NBD1. The {Delta}F508 version of this protein also crystallizes as a homodimer and differs from the wild-type structure only in the vicinity of the disease-causing F508 deletion. A slightly longer construct crystallizes as a monomer. Comparisons of the homodimer structure with this and previously published monomeric structures show that the main effect of ATP binding at the signature site is to order the residues immediately preceding the signature sequence, residues 542-547, in a conformation compatible with nucleotide binding. These residues likely interact with a transmembrane domain intracellular loop in the full-length CFTR channel. The experiments described here show that removing the RI from NBD1 converts it into a well-behaved protein amenable to biophysical studies yielding deeper insights into CFTR function.

  20. Purinergic regulation of CFTR and Ca2+ -activated Cl- channels and K+ channels in human pancreatic duct epithelium

    DEFF Research Database (Denmark)

    Wang, Jing; Haanes, Kristian A; Novak, Ivana

    2013-01-01

    mutated CFTR, basolateral ATP and UTP had negligible effects. In addition to Cl(-) transport in Capan-1 cells, the effects of 5,6-dichloro-1-ethyl-1,3-dihydro-2H-benzimidazol-2-one (DC-EBIO) and clotrimazole indicated functional expression of the intermediate conductance K(+) channels (IK, KCa3...

  1. Fractional non-ablative laser-assisted drug delivery leads to improvement in male and female pattern hair loss.

    Science.gov (United States)

    Bertin, Ana Carina Junqueira; Vilarinho, Adriana; Junqueira, Ana Lúcia Ariano

    2018-02-16

    Androgenetic alopecia, also known as male and female pattern hair loss, is a very prevalent condition; however, approved therapeutic options are limited. Fractionated laser has been proposed to assist in penetration of topical medications to the cutaneous tissue. We present four cases of androgenetic alopecia that underwent treatment with a non-ablative erbium glass fractional laser followed by the application of topical finasteride 0,05% and growth factors including basic fibroblast growth factor, insulin-like growth factor, vascular endothelial growth factor, and copper peptide 1%. During all laser treatment sessions, eight passes were performed, at 7 mJ, 3-9% of coverage and density of 120 mzt/cm 2 . A positive response was observed in all of the four patients. Photographs taken 2 weeks after the last session showed improvement in hair regrowth and density. No significant side effects were observed.

  2. Local delivery of glial cell line-derived neurotrophic factor improves facial nerve regeneration after late repair.

    Science.gov (United States)

    Barras, Florian M; Kuntzer, Thierry; Zurn, Anne D; Pasche, Philippe

    2009-05-01

    Facial nerve regeneration is limited in some clinical situations: in long grafts, by aged patients, and when the delay between nerve lesion and repair is prolonged. This deficient regeneration is due to the limited number of regenerating nerve fibers, their immaturity and the unresponsiveness of Schwann cells after a long period of denervation. This study proposes to apply glial cell line-derived neurotrophic factor (GDNF) on facial nerve grafts via nerve guidance channels to improve the regeneration. Two situations were evaluated: immediate and delayed grafts (repair 7 months after the lesion). Each group contained three subgroups: a) graft without channel, b) graft with a channel without neurotrophic factor; and c) graft with a GDNF-releasing channel. A functional analysis was performed with clinical observation of facial nerve function, and nerve conduction study at 6 weeks. Histological analysis was performed with the count of number of myelinated fibers within the graft, and distally to the graft. Central evaluation was assessed with Fluoro-Ruby retrograde labeling and Nissl staining. This study showed that GDNF allowed an increase in the number and the maturation of nerve fibers, as well as the number of retrogradely labeled neurons in delayed anastomoses. On the contrary, after immediate repair, the regenerated nerves in the presence of GDNF showed inferior results compared to the other groups. GDNF is a potent neurotrophic factor to improve facial nerve regeneration in grafts performed several months after the nerve lesion. However, GDNF should not be used for immediate repair, as it possibly inhibits the nerve regeneration.

  3. Conjugation of cell-penetrating peptides with poly(lactic-co-glycolic acid-polyethylene glycol nanoparticles improves ocular drug delivery

    Directory of Open Access Journals (Sweden)

    Vasconcelos A

    2015-01-01

    Full Text Available Aimee Vasconcelos,1 Estefania Vega,2 Yolanda Pérez,3 María J Gómara,1 María Luisa García,2 Isabel Haro1 1Unit of Synthesis and Biomedical Applications of Peptides, Department of Biomedical Chemistry, Institute for Advanced Chemistry of Catalonia, Consejo Superior de Investigaciones Científicas (IQAC-CSIC, 2Department of Physical Chemistry, Institute of Nanoscience and Nanotechnology, Faculty of Pharmacy, University of Barcelona, 3Nuclear Magnetic Resonance Unit, IQAC-CSIC, Barcelona, Spain Abstract: In this work, a peptide for ocular delivery (POD and human immunodeficiency virus transactivator were conjugated with biodegradable poly(lactic-co-glycolic acid (PGLA–polyethylene glycol (PEG-nanoparticles (NPs in an attempt to improve ocular drug bioavailability. The NPs were prepared by the solvent displacement method following two different pathways. One involved preparation of PLGA NPs followed by PEG and peptide conjugation (PLGA-NPs-PEG-peptide; the other involved self-assembly of PLGA-PEG and the PLGA-PEG-peptide copolymer followed by NP formulation. The conjugation of the PEG and the peptide was confirmed by a colorimetric test and proton nuclear magnetic resonance spectroscopy. Flurbiprofen was used as an example of an anti-inflammatory drug. The physicochemical properties of the resulting NPs (morphology, in vitro release, cell viability, and ocular tolerance were studied. In vivo anti-inflammatory efficacy was assessed in rabbit eyes after topical instillation of sodium arachidonate. Of the formulations developed, the PLGA-PEG-POD NPs were the smaller particles and exhibited greater entrapment efficiency and more sustained release. The positive charge on the surface of these NPs, due to the conjugation with the positively charged peptide, facilitated penetration into the corneal epithelium, resulting in more effective prevention of ocular inflammation. The in vitro toxicity of the NPs developed was very low; no ocular irritation

  4. Beyond coverage: improving the quality of antenatal care delivery through integrated mentorship and quality improvement at health centers in rural Rwanda.

    Science.gov (United States)

    Manzi, Anatole; Nyirazinyoye, Laetitia; Ntaganira, Joseph; Magge, Hema; Bigirimana, Evariste; Mukanzabikeshimana, Leoncie; Hirschhorn, Lisa R; Hedt-Gauthier, Bethany

    2018-02-23

    Inadequate antenatal care (ANC) can lead to missed diagnosis of danger signs or delayed referral to emergency obstetrical care, contributing to maternal mortality. In developing countries, ANC quality is often limited by skill and knowledge gaps of the health workforce. In 2011, the Mentorship, Enhanced Supervision for Healthcare and Quality Improvement (MESH-QI) program was implemented to strengthen providers' ANC performance at 21 rural health centers in Rwanda. We evaluated the effect of MESH-QI on the completeness of danger sign assessments. Completeness of danger sign assessments was measured by expert nurse mentors using standardized observation checklists. Checklists completed from October 2010 to May 2011 (n = 330) were used as baseline measurement and checklists completed between February and November 2012 (12-15 months after the start of MESH-QI implementation) were used for follow-up. We used a mixed-effects linear regression model to assess the effect of the MESH-QI intervention on the danger sign assessment score, controlling for potential confounders and the clustering of effect at the health center level. Complete assessment of all danger signs improved from 2.1% at baseline to 84.2% after MESH-QI (p ANC screening items. After controlling for potential confounders, the improvement in danger sign assessment score was significant. However, the effect of the MESH-QI was different by intervention district and type of observed ANC visit. In Southern Kayonza District, the increase in the danger sign assessment score was 6.28 (95% CI: 5.59, 6.98) for non-first ANC visits and 5.39 (95% CI: 4.62, 6.15) for first ANC visits. In Kirehe District, the increase in danger sign assessment score was 4.20 (95% CI: 3.59, 4.80) for non-first ANC visits and 3.30 (95% CI: 2.80, 3.81) for first ANC visits. Assessment of critical danger signs improved under MESH-QI, even when controlling for nurse-mentees' education level and previous training in focused ANC. MESH

  5. Integration of research and practice to improve public health and healthcare delivery through a collaborative 'Health Integration Team' model - a qualitative investigation.

    Science.gov (United States)

    Redwood, Sabi; Brangan, Emer; Leach, Verity; Horwood, Jeremy; Donovan, Jenny L

    2016-06-22

    Economic considerations and the requirement to ensure the quality, safety and integration of research with health and social care provision have given rise to local developments of collaborative organisational forms and strategies to span the translational gaps. One such model - the Health Integration Team (HIT) model in Bristol in the United Kingdom (UK) - brings together National Health Service (NHS) organisations, universities, local authorities, patients and the public to facilitate the systematic application of evidence to promote integration across healthcare pathways. This study aimed to (1) provide empirical evidence documenting the evolution of the model; (2) to identify the social and organisational processes and theory of change underlying healthcare knowledge and practice; and (3) elucidate the key aspects of the HIT model for future development and translation to other localities. Contemporaneous documents were analysed, using procedures associated with Framework Analysis to produce summarised data for descriptive accounts. In-depth interviews were undertaken with key informants and analysed thematically. Comparative methods were applied to further analyse the two data sets. One hundred forty documents were analysed and 10 interviews conducted with individuals in leadership positions in the universities, NHS commissioning and provider organisations involved in the design and implementation of the HIT model. Data coalesced around four overarching themes: 'Whole system' engagement, requiring the active recruitment of all those who have a stake in the area of practice being considered, and 'collaboration' to enable coproduction were identified as 'process' themes. System-level integration and innovation were identified as potential 'outcomes' with far-reaching impacts on population health and service delivery. The HIT model emerged as a particular response to the perceived need for integration of research and practice to improve public health and

  6. Compounds that correct F508del-CFTR trafficking can also correct other protein trafficking diseases: an in vitro study using cell lines

    Directory of Open Access Journals (Sweden)

    Sampson Heidi M

    2013-01-01

    Full Text Available Abstract Background Many genetic diseases are due to defects in protein trafficking where the mutant protein is recognized by the quality control systems, retained in the endoplasmic reticulum (ER, and degraded by the proteasome. In many cases, the mutant protein retains function if it can be trafficked to its proper cellular location. We have identified structurally diverse correctors that restore the trafficking and function of the most common mutation causing cystic fibrosis, F508del-CFTR. Most of these correctors do not act directly as ligands of CFTR, but indirectly on other pathways to promote folding and correction. We hypothesize that these proteostasis regulators may also correct other protein trafficking diseases. Methods To test our hypothesis, we used stable cell lines or transient transfection to express 2 well-studied trafficking disease mutations in each of 3 different proteins: the arginine-vasopressin receptor 2 (AVPR2, also known as V2R, the human ether-a-go-go-related gene (KCNH2, also known as hERG, and finally the sulfonylurea receptor 1 (ABCC8, also known as SUR1. We treated cells expressing these mutant proteins with 9 structurally diverse F508del-CFTR correctors that function through different cellular mechanisms and assessed whether correction occurred via immunoblotting and functional assays. Results were deemed significantly different from controls by a one-way ANOVA (p  Results Here we show that F508del-CFTR correctors RDR1, KM60 and KM57 also correct some mutant alleles of other protein trafficking diseases. We also show that one corrector, the cardiac glycoside ouabain, was found to alter the glycosylation of all mutant alleles tested. Conclusions Correctors of F508del-CFTR trafficking might have broader applications to other protein trafficking diseases.

  7. Cell-laden hydrogel/titanium microhybrids: Site-specific cell delivery to metallic implants for improved integration.

    Science.gov (United States)

    Koenig, Geraldine; Ozcelik, Hayriye; Haesler, Lisa; Cihova, Martina; Ciftci, Sait; Dupret-Bories, Agnes; Debry, Christian; Stelzle, Martin; Lavalle, Philippe; Vrana, Nihal Engin

    2016-03-01

    Porous titanium implants are widely used in dental, orthopaedic and otorhinolaryngology fields to improve implant integration to host tissue. A possible step further to improve the integration with the host is the incorporation of autologous cells in porous titanium structures via cell-laden hydrogels. Fast gelling hydrogels have advantageous properties for in situ applications such as localisation of specific cells and growth factors at a target area without dispersion. The ability to control the cell types in different regions of an implant is important in applications where the target tissue (i) has structural heterogeneity (multiple cell types with a defined spatial configuration with respect to each other); (ii) has physical property gradients essential for its function (such as in the case of osteochondral tissue transition). Due to their near immediate gelation, such gels can also be used for site-specific modification of porous titanium structures, particularly for implants which would face different tissues at different locations. Herein, we describe a step by step design of a model system: the model cell-laden gel-containing porous titanium implants in the form of titanium microbead/hydrogel (maleimide-dextran or maleimide-PVA based) microhybrids. These systems enable the determination of the effect of titanium presence on gel properties and encapsulated cell behaviour as a miniaturized version of full-scale implants, providing a system compatible with conventional analysis methods. We used a fibroblast/vascular endothelial cell co-cultures as our model system and by utilising single microbeads we have quantified the effect of gel microenvironment (degradability, presence of RGD peptides within gel formulation) on cell behaviour and the effect of the titanium presence on cell behaviour and gel formation. Titanium presence slightly changed gel properties without hindering gel formation or affecting cell viability. Cells showed a preference to move towards

  8. Are written information or counseling (WOMAN-PRO II program) able to improve patient satisfaction and the delivery of health care of women with vulvar neoplasms? Secondary outcomes of a multicenter randomized controlled trial

    Science.gov (United States)

    Gehrig, Larissa; Kobleder, Andrea; Werner, Birgit; Denhaerynck, Kris; Senn, Beate

    2017-01-01

    Background: Patients with vulvar neoplasms report a lack of information, missing support in self-management and a gap in delivery of health care. Aim: The aim of the study was to investigate if written information or counseling based on the WOMAN-PRO II program are able to improve patient satisfaction and the delivery of health care from the health professional's perspective of women with vulvar neoplasms. Method: Patient satisfaction and the delivery of health care have been investigated as two secondary outcomes in a multicenter randomized controlled parallel-group phase II study (Clinical Trial ID: NCT01986725). In total, 49 women, from four hospitals (CH, AUT), completed the questionnaire PACIC-S11 after written information (n = 13) and counseling (n = 36). The delivery of health care was evaluated by ten Advanced Practice Nurses (APNs) by using the G-ACIC before and after implementing counseling based on the WOMAN-PRO II program. Results: There were no significant differences between the two groups identified (p = 0.25). Only few aspects were rated highly by all women, such as the overall satisfaction (M = 80.3 %) and satisfaction with organization of care (M = 83.0 %). The evaluation of delivery of health care by APNs in women who received counseling improved significantly (p = 0.031). Conclusions: There are indications, that the practice of both interventions might have improved patient satisfaction and counseling the delivery of health care. The aspects that have been rated low in the PACIC-S11 and G-ACIC indicate possibilities to optimize the delivery of health care.

  9. N- and C-alkylation of seven-membered iminosugars generates potent glucocerebrosidase inhibitors and F508del-CFTR correctors.

    Science.gov (United States)

    Désiré, J; Mondon, M; Fontelle, N; Nakagawa, S; Hirokami, Y; Adachi, I; Iwaki, R; Fleet, G W J; Alonzi, D S; Twigg, G; Butters, T D; Bertrand, J; Cendret, V; Becq, F; Norez, C; Marrot, J; Kato, A; Blériot, Y

    2014-11-28

    The glycosidase inhibitory properties of synthetic C-alkyl and N-alkyl six-membered iminosugars have been extensively studied leading to therapeutic candidates. The related seven-membered iminocyclitols have been less examined despite the report of promising structures. Using an in house ring enlargement/C-alkylation as well as cross-metathesis methodologies as the key steps, we have undertaken the synthesis and biological evaluation of a library of fourteen 2C- and eight N-alkyl tetrahydroxylated azepanes starting from an easily available glucopyranose-derived azidolactol. Four, six, nine and twelve carbon atom alkyl chains have been introduced. The study of two distinct D-gluco and L-ido stereochemistries for the tetrol pattern as well as R and S configurations for the C-2 carbon bearing the C-alkyl chain is reported. We observed that C-alkylation of the L-ido tetrahydroxylated azepane converts it from an α-L-fucosidase to a β-glucosidase and β-galactosidase inhibitor while N-alkylation of the D-gluco iminosugar significantly improves its inhibition profile leading to potent β-glucosidase, β-galactosidase, α-L-rhamnosidase and β-glucuronidase inhibitors whatever the stereochemistry of the alkyl chain. Interestingly, the N-alkyl chain length usually parallels the azepane inhibitor potency as exemplified by the identification of a potent glucocerebrosidase inhibitor (Ki 1 μM) bearing a twelve carbon atom chain. Additionally, several C-alkyl azepanes demonstrated promising F508del-CFTR correction unlike the parent tetrahydroxyazepanes. None of the C-alkyl and N-alkyl azepanes did inhibit ER α-glucosidases I or II.

  10. After Delivery

    Science.gov (United States)

    ... Rights Employment Discrimination Health Care Professionals Law Enforcement Driver's License For Lawyers Food & Fitness Home Food MyFoodAdvisor ... A Listen En Español After Delivery After your baby arrives, your body begins to recover from the ...

  11. Improved Insulin Pharmacokinetics Using a Novel Microneedle Device for Intradermal Delivery in Patients with Type 2 Diabetes.

    Science.gov (United States)

    Kochba, Efrat; Levin, Yotam; Raz, Itamar; Cahn, Avivit

    2016-09-01

    Currently available short-acting insulin analogs have slower absorption compared with endogenous insulin occasionally resulting in immediate postprandial hyperglycemia. Intradermal (ID) injection facilitates faster drug absorption and may result in improved insulin pharmacokinetics. Seventeen patients with type 2 diabetes were included in this single-center, pilot, open-label crossover study. Patients received 0.2 U/kg Insulin aspart ID injections using a MicronJet (MJ) needle and subcutaneous (SC) injections, using a conventional needle in a crossover design. Thirteen patients were studied under fasting conditions and four before a standard meal test. The pharmacokinetic/pharmacodynamic (PK/PD) profile, as well as the safety and tolerability of injections, was compared. Fourteen patients completed the study per-protocol. ID versus SC injection demonstrated significantly shorter Tmax (median 35 vs. 87.5 min [P < 0.001]), while the Cmax did not significantly differ (median 80 vs. 55 μU/mL [P = 0.085]). Median insulin area under the curve (AUC; 360 min) did not differ between the groups (9914 vs. 10,936 μU/mL/min [p = 0.077]), yet 0-60 min insulin AUC was higher with ID versus SC injection (mean ± SD 3821 ± 1429 vs. 2534 ± 737 μU/mL/min [p = 0.01]) and 4-6 h AUC was lower with ID versus SC injection (mean ± SD 2054 ± 858 vs. 2929 ± 1412 μU/mL/min [p = 0.02]). The relative bioavailability of the ID versus the SC insulin (AUCID/AUCSC) was similar (median 0.91 [95% confidence interval 0.73-1.27]). ID insulin injection delivered through an MJ needle demonstrated superior PK profile compared with conventional SC administration, including shorter Tmax and higher early and lower late exposure in patients with type 2 diabetes. This may help achieve better insulin coverage of meals and lower postprandial glucose excursions.

  12. Structure and Dynamics of NBD1 from CFTR Characterized Using Crystallography and Hydrogen/Deuterium Exchange Mass Spectrometry

    Energy Technology Data Exchange (ETDEWEB)

    Lewis, H.A.; Wang, C.; Zhao, X.; Hamuro, Y.; Conners, K.; Kearins, M.C.; Lu, F.; Sauder, J.M.; Molnar, K.S.; Coales, S.J.; Maloney, P.C.; Guggino, W.B.; Wetmore, D.R.; Weber, P.C.; Hunt, J.F. (SGX); (ExSAR); (Cystic); (JHU-MED); (Columbia)

    2012-04-30

    The {Delta}F508 mutation in nucleotide-binding domain 1 (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR) is the predominant cause of cystic fibrosis. Previous biophysical studies on human F508 and {Delta}F508 domains showed only local structural changes restricted to residues 509-511 and only minor differences in folding rate and stability. These results were remarkable because {Delta}F508 was widely assumed to perturb domain folding based on the fact that it prevents trafficking of CFTR out of the endoplasmic reticulum. However, the previously reported crystal structures did not come from matched F508 and {Delta}F508 constructs, and the {Delta}F508 structure contained additional mutations that were required to obtain sufficient protein solubility. In this article, we present additional biophysical studies of NBD1 designed to address these ambiguities. Mass spectral measurements of backbone amide {sup 1}H/{sup 2}H exchange rates in matched F508 and {Delta}F508 constructs reveal that {Delta}F508 increases backbone dynamics at residues 509-511 and the adjacent protein segments but not elsewhere in NBD1. These measurements also confirm a high level of flexibility in the protein segments exhibiting variable conformations in the crystal structures. We additionally present crystal structures of a broader set of human NBD1 constructs, including one harboring the native F508 residue and others harboring the {Delta}F508 mutation in the presence of fewer and different solubilizing mutations. The only consistent conformational difference is observed at residues 509-511. The side chain of residue V510 in this loop is mostly buried in all non-{Delta}F508 structures but completely solvent exposed in all {Delta}F508 structures. These results reinforce the importance of the perturbation {Delta}F508 causes in the surface topography of NBD1 in a region likely to mediate contact with the transmembrane domains of CFTR. However, they also suggest that increased

  13. The effectiveness of mobile-health technologies to improve health care service delivery processes: a systematic review and meta-analysis.

    Science.gov (United States)

    Free, Caroline; Phillips, Gemma; Watson, Louise; Galli, Leandro; Felix, Lambert; Edwards, Phil; Patel, Vikram; Haines, Andy

    2013-01-01

    Mobile health interventions could have beneficial effects on health care delivery processes. We aimed to conduct a systematic review of controlled trials of mobile technology interventions to improve health care delivery processes. We searched for all controlled trials of mobile technology based health interventions using MEDLINE, EMBASE, PsycINFO, Global Health, Web of Science, Cochrane Library, UK NHS HTA (Jan 1990-Sept 2010). Two authors independently extracted data on allocation concealment, allocation sequence, blinding, completeness of follow-up, and measures of effect. We calculated effect estimates and we used random effects meta-analysis to give pooled estimates. We identified 42 trials. None of the trials had low risk of bias. Seven trials of health care provider support reported 25 outcomes regarding appropriate disease management, of which 11 showed statistically significant benefits. One trial reported a statistically significant improvement in nurse/surgeon communication using mobile phones. Two trials reported statistically significant reductions in correct diagnoses using mobile technology photos compared to gold standard. The pooled effect on appointment attendance using text message (short message service or SMS) reminders versus no reminder was increased, with a relative risk (RR) of 1.06 (95% CI 1.05-1.07, I(2) = 6%). The pooled effects on the number of cancelled appointments was not significantly increased RR 1.08 (95% CI 0.89-1.30). There was no difference in attendance using SMS reminders versus other reminders (RR 0.98, 95% CI 0.94-1.02, respectively). To address the limitation of the older search, we also reviewed more recent literature. The results for health care provider support interventions on diagnosis and management outcomes are generally consistent with modest benefits. Trials using mobile technology-based photos reported reductions in correct diagnoses when compared to the gold standard. SMS appointment reminders have modest

  14. The Role of Team Climate in Improving the Quality of Chronic Care Delivery: A Longitudinal Study among Professionals Working with Chronically Ill Adolescents in Transitional Care Programmes

    NARCIS (Netherlands)

    J.M. Cramm (Jane); M.M.H. Strating (Mathilde); A.P. Nieboer (Anna)

    2014-01-01

    markdownabstractAbstract Objectives:This study aimed to (1) evaluate the effectiveness of implementing transition programmes inimproving the quality of chronic care delivery and(2) identify the predictive role of (changes in) teamclimate on the quality of chronic care delivery over time.

  15. A large-scale study of the random variability of a coding sequence: a study on the CFTR gene.

    Science.gov (United States)

    Modiano, Guido; Bombieri, Cristina; Ciminelli, Bianca Maria; Belpinati, Francesca; Giorgi, Silvia; Georges, Marie des; Scotet, Virginie; Pompei, Fiorenza; Ciccacci, Cinzia; Guittard, Caroline; Audrézet, Marie Pierre; Begnini, Angela; Toepfer, Michael; Macek, Milan; Ferec, Claude; Claustres, Mireille; Pignatti, Pier Franco

    2005-02-01

    Coding single nucleotide substitutions (cSNSs) have been studied on hundreds of genes using small samples (n(g) approximately 100-150 genes). In the present investigation, a large random European population sample (average n(g) approximately 1500) was studied for a single gene, the CFTR (Cystic Fibrosis Transmembrane conductance Regulator). The nonsynonymous (NS) substitutions exhibited, in accordance with previous reports, a mean probability of being polymorphic (q > 0.005), much lower than that of the synonymous (S) substitutions, but they showed a similar rate of subpolymorphic (q < 0.005) variability. This indicates that, in autosomal genes that may have harmful recessive alleles (nonduplicated genes with important functions), genetic drift overwhelms selection in the subpolymorphic range of variability, making disadvantageous alleles behave as neutral. These results imply that the majority of the subpolymorphic nonsynonymous alleles of these genes are selectively negative or even pathogenic.

  16. Synthesis and evaluation of mesoporous carbon/lipid bilayer nanocomposites for improved oral delivery of the poorly water-soluble drug, nimodipine.

    Science.gov (United States)

    Zhang, Yanzhuo; Zhao, Qinfu; Zhu, Wufu; Zhang, Lihua; Han, Jin; Lin, Qisi; Ai, Fengwei

    2015-07-01

    A novel mesoporous carbon/lipid bilayer nanocomposite (MCLN) with a core-shell structure was synthesized and characterized as an oral drug delivery system for poorly water-soluble drugs. The objective of this study was to investigate the potential of MCLN-based formulation to modulate the in vitro release and in vivo absorption of a model drug, nimodipine (NIM). NIM-loaded MCLN was prepared by a procedure involving a combination of thin-film hydration and lyophilization. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), specific surface area analysis, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were employed to characterize the NIM-loaded MCLN formulation. The effect of MCLN on cell viability was assessed using the MTT assay. In addition, the oral bioavailability of NIM-loaded MCLN in beagle dogs was compared with that of the immediate-release formulation, Nimotop®. Our results demonstrate that the NIM-loaded MCLN formulation exhibited a typical sustained release pattern. The NIM-loaded MCLN formulation achieved a greater degree of absorption and longer lasting plasma drug levels compared with the commercial formulation. The relative bioavailability of NIM for NIM-loaded MCLN was 214%. MCLN exhibited negligible toxicity. The data reported herein suggest that the MCLN matrix is a promising carrier for controlling the drug release rate and improving the oral absorption of poorly water-soluble drugs.

  17. Delivery of Bone Marrow-Derived Mesenchymal Stem Cells Improves Tear Production in a Mouse Model of Sjögren’s Syndrome

    Directory of Open Access Journals (Sweden)

    Hema S. Aluri

    2017-01-01

    Full Text Available The purpose of the present study was to test the potential of mouse bone marrow-derived mesenchymal stem cells (BD-MSCs in improving tear production in a mouse model of Sjögren’s syndrome dry eye and to investigate the underlying mechanisms involved. NOD mice (n=20 were randomized to receive i.p. injection of sterile phosphate buffered saline (PBS, control or murine BD-MSCs (1 × 106 cells. Tears production was measured at baseline and once a week after treatment using phenol red impregnated threads. Cathepsin S activity in the tears was measured at the end of treatment. After 4 weeks, animals were sacrificed and the lacrimal glands were excised and processed for histopathology, immunohistochemistry, and RNA analysis. Following BD-MSC injection, tears production increased over time when compared to both baseline and PBS injected mice. Although the number of lymphocytic foci in the lacrimal glands of treated animals did not change, the size of the foci decreased by 40.5% when compared to control animals. The mRNA level of the water channel aquaporin 5 was significantly increased following delivery of BD-MSCs. We conclude that treatment with BD-MSCs increases tear production in the NOD mouse model of Sjögren’s syndrome. This is likely due to decreased inflammation and increased expression of aquaporin 5.

  18. Combination of argan oil and phospholipids for the development of an effective liposome-like formulation able to improve skin hydration and allantoin dermal delivery.

    Science.gov (United States)

    Manca, Maria Letizia; Matricardi, Pietro; Cencetti, Claudia; Peris, Josè Esteban; Melis, Virginia; Carbone, Claudia; Escribano, Elvira; Zaru, Marco; Fadda, Anna Maria; Manconi, Maria

    2016-05-30

    Allantoin is traditionally employed in the treatment of skin ulcers and hypertrophic scars. In the present work, to improve its local deposition in the skin and deeper tissues, allantoin was incorporated in conventional liposomes and in new argan oil enriched liposomes. In both cases, obtained vesicles were unilamellar, as confirmed by cryo-TEM observation, but the addition of argan oil allowed a slight increase of the mean diameter (∼130nm versus ∼85nm). The formulations, especially those containing argan oil, favoured the allantoin accumulation in the skin, in particular in the dermis (∼8.7μg/cm(2)), and its permeation through the skin (∼33μg/cm(2)). The performances of vesicles as skin delivery systems were compared with those obtained by water dispersion of allantoin and the commercial gel, Sameplast(®). Moreover, in this work, for the first time, the elastic and viscous moduli of the skin were measured, underlining the different hydrating/moisturizing effects of the formulations. The application of ARG liposomes seems to provide a softening and relaxing effect on the skin, thus facilitating the drug accumulation and passage into and trough it. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. The CFTR Met 470 allele is associated with lower birth rates in fertile men from a population isolate.

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    Gülüm Kosova

    2010-06-01

    Full Text Available Although little is known about the role of the cystic fibrosis transmembrane regulator (CFTR gene in reproductive physiology, numerous variants in this gene have been implicated in etiology of male infertility due to congenital bilateral absence of the vas deferens (CBAVD. Here, we studied the fertility effects of three CBAVD-associated CFTR polymorphisms, the (TGm and polyT repeat polymorphisms in intron 8 and Met470Val in exon 10, in healthy men of European descent. Homozygosity for the Met470 allele was associated with lower birth rates, defined as the number of births per year of marriage (P = 0.0029. The Met470Val locus explained 4.36% of the phenotypic variance in birth rate, and men homozygous for the Met470 allele had 0.56 fewer children on average compared to Val470 carrier men. The derived Val470 allele occurs at high frequencies in non-African populations (allele frequency = 0.51 in HapMap CEU, whereas it is very rare in African population (Fst = 0.43 between HapMap CEU and YRI. In addition, haplotypes bearing Val470 show a lack of genetic diversity and are thus longer than haplotypes bearing Met470 (measured by an integrated haplotype score [iHS] of -1.93 in HapMap CEU. The fraction of SNPs in the HapMap Phase2 data set with more extreme Fst and iHS measures is 0.003, consistent with a selective sweep outside of Africa. The fertility advantage conferred by Val470 relative to Met470 may provide a selective mechanism for these population genetic observations.

  20. Invariant TAD Boundaries Constrain Cell-Type-Specific Looping Interactions between Promoters and Distal Elements around the CFTR Locus.

    Science.gov (United States)

    Smith, Emily M; Lajoie, Bryan R; Jain, Gaurav; Dekker, Job

    2016-01-07

    Three-dimensional genome structure plays an important role in gene regulation. Globally, chromosomes are organized into active and inactive compartments while, at the gene level, looping interactions connect promoters to regulatory elements. Topologically associating domains (TADs), typically several hundred kilobases in size, form an intermediate level of organization. Major questions include how TADs are formed and how they are related to looping interactions between genes and regulatory elements. Here we performed a focused 5C analysis of a 2.8 Mb chromosome 7 region surrounding CFTR in a panel of cell types. We find that the same TAD boundaries are present in all cell types, indicating that TADs represent a universal chromosome architecture. Furthermore, we find that these TAD boundaries are present irrespective of the expression and looping of genes located between them. In contrast, looping interactions between promoters and regulatory elements are cell-type specific and occur mostly within TADs. This is exemplified by the CFTR promoter that in different cell types interacts with distinct sets of distal cell-type-specific regulatory elements that are all located within the same TAD. Finally, we find that long-range associations between loci located in different TADs are also detected, but these display much lower interaction frequencies than looping interactions within TADs. Interestingly, interactions between TADs are also highly cell-type-specific and often involve loci clustered around TAD boundaries. These data point to key roles of invariant TAD boundaries in constraining as well as mediating cell-type-specific long-range interactions and gene regulation. Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  1. Multiseed liposomal drug delivery system using micelle gradient as driving force to improve amphiphilic drug retention and its anti-tumor efficacy.

    Science.gov (United States)

    Zhang, Wenli; Li, Caibin; Jin, Ya; Liu, Xinyue; Wang, Zhiyu; Shaw, John P; Baguley, Bruce C; Wu, Zimei; Liu, Jianping

    2018-11-01

    To improve drug retention in carriers for amphiphilic asulacrine (ASL), a novel active loading method using micelle gradient was developed to fabricate the ASL-loaded multiseed liposomes (ASL-ML). The empty ML were prepared by hydrating a thin film with empty micelles. Then the micelles in liposomal compartment acting as 'micelle pool' drove the drug to be loaded after the outer micelles were removed. Some reasoning studies including critical micelle concentration (CMC) determination, influencing factors tests on entrapment efficiency (EE), structure visualization, and drug release were carried out to explore the mechanism of active loading, ASL location, and the structure of ASL-ML. Comparisons were made between pre-loading and active loading method. Finally, the extended drug retention capacity of ML was evaluated through pharmacokinetic, drug tissue irritancy, and in vivo anti-tumor activity studies. Comprehensive results from fluorescent and transmission electron microscope (TEM) observation,