Nanocarriers for DNA Vaccines: Co-Delivery of TLR-9 and NLR-2 Ligands Leads to Synergistic Enhancement of Proinflammatory Cytokine Release

Adjuvants enhance immunogenicity of vaccines through either targeted antigen delivery or stimulation of immune receptors. Three cationic nanoparticle formulations were evaluated for their potential as carriers for a DNA vaccine, and muramyl dipeptide (MDP) as immunostimulatory agent, to induce and increase immunogenicity of Mycobacterium tuberculosis antigen encoding plasmid DNA (pDNA). The formulations included (1) trimethyl chitosan (TMC) nanoparticles, (2) a squalene-in-water nanoemulsion, and (3) a mineral oil-in-water nanoemulsion. The adjuvant effect of the pDNA-nanocomplexes was evaluated by serum antibody analysis in immunized mice. All three carriers display a strong adjuvant effect, however, only TMC nanoparticles were capable to bias immune responses towards Th1. pDNA naturally contains immunostimulatory unmethylated CpG motifs that are recognized by Toll-like receptor 9 (TLR-9). In mechanistic in vitro studies, activation of TLR-9 and the ability to enhance immunogenicity by simultaneously targeting TLR-9 and NOD-like receptor 2 (NLR-2) was determined by proinflammatory cytokine release in RAW264.7 macrophages. pDNA in combination with MDP was shown to significantly increase proinflammatory cytokine release in a synergistic manner, dependent on NLR-2 activation. In summary, novel pDNA-Ag85A loaded nanoparticle formulations, which induce antigen specific immune responses in mice were developed, taking advantage of the synergistic combinations of TLR and NLR agonists to increase the adjuvanticity of the carriers used.

SPIRONOLACTONE FOR NONRESOLVING CENTRAL SEROUS CHORIORETINOPATHY: A Randomized Controlled Crossover Study.

PURPOSE: To evaluate the effect of spironolactone, a mineralocorticoid receptor antagonist, for nonresolving central serous chorioretinopathy. METHODS: This is a prospective, randomized, double-blinded, placebo-controlled crossover study. Sixteen eyes of 16 patients with central serous chorioretinopathy and persistent subretinal fluid (SRF) for at least 3 months were enrolled. Patients were randomized to receive either spironolactone 50 mg or placebo once a day for 30 days, followed by a washout period of 1 week and then crossed over to either placebo or spironolactone for another 30 days. The primary outcome measure was the changes from baseline in SRF thickness at the apex of the serous retinal detachment. Secondary outcomes included subfoveal choroidal thickness and the ETDRS best-corrected visual acuity. RESULTS: The mean duration of central serous chorioretinopathy before enrollment in study eyes was 10 ± 16.9 months. Crossover data analysis showed a statistically significant reduction in SRF in spironolactone treated eyes as compared with the same eyes under placebo (P = 0.04). Secondary analysis on the first period (Day 0-Day 30) showed a significant reduction in subfoveal choroidal thickness in treated eyes as compared with placebo (P = 0.02). No significant changes were observed in the best-corrected visual acuity. There were no complications related to treatment observed. CONCLUSION: In eyes with persistent SRF due to central serous chorioretinopathy, spironolactone significantly reduced both the SRF and the subfoveal choroidal thickness as compared with placebo.

Animal modelling for inherited central vision loss.

Disease-causing variants of a large number of genes trigger inherited retinal degeneration leading to photoreceptor loss. Because cones are essential for daylight and central vision such as reading, mobility, and face recognition, this review focuses on a variety of animal models for cone diseases. The pertinence of using these models to reveal genotype/phenotype correlations and to evaluate new therapeutic strategies is discussed. Interestingly, several large animal models recapitulate human diseases and can serve as a strong base from which to study the biology of disease and to assess the scale-up of new therapies. Examples of innovative approaches will be presented such as lentiviral-based transgenesis in pigs and adeno-associated virus (AAV)-gene transfer into the monkey eye to investigate the neural circuitry plasticity of the visual system. The models reported herein permit the exploration of common mechanisms that exist between different species and the identification and highlighting of pathways that may be specific to primates, including humans.

Retinal damage induced by commercial light emitting diodes (LEDs).

Spectra of "white LEDs" are characterized by an intense emission in the blue region of the visible spectrum, absent in daylight spectra. This blue component and the high intensity of emission are the main sources of concern about the health risks of LEDs with respect to their toxicity to the eye and the retina. The aim of our study was to elucidate the role of blue light from LEDs in retinal damage. Commercially available white LEDs and four different blue LEDs (507, 473, 467, and 449nm) were used for exposure experiments on Wistar rats. Immunohistochemical stain, transmission electron microscopy, and Western blot were used to exam the retinas. We evaluated LED-induced retinal cell damage by studying oxidative stress, stress response pathways, and the identification of cell death pathways. LED light caused a state of suffering of the retina with oxidative damage and retinal injury. We observed a loss of photoreceptors and the activation of caspase-independent apoptosis, necroptosis, and necrosis. A wavelength dependence of the effects was observed. Phototoxicity of LEDs on the retina is characterized by a strong damage of photoreceptors and by the induction of necrosis.

Posterior Sub-Tenon Triamcinolone Injection for Chronic Macular Oedema Associated With Non-Ischemic Branch or Central Retinal Vein Occlusion

Aims: To evaluate the effectiveness and safety of Posterior Sub-Tenon (PST) Triamcinolone Acetonide (TA) injection for persistent macular oedema associated with non-ischemic Central Retinal Vein Occlusion (CRVO) or Branch Retinal Vein Occlusion (BRVO) in non-vitrectomized eye. Methods: Fourteen consecutive eyes of 14 patients characterized by macular oedema lasting more than 3 months and with a visual acuity of less than 20/40 were enrolled. Six eyes presented with BRVO, 8 eyes with CRVO. PST injection of 40 mg TA was performed in topical anaesthesia. All patients were phakic, and followed for at least 6 months. Snellen visual acuity converted to LogMAR units and anatomic responses were evaluated before, and at 1, 3, 6, and 12 (if required) months after injections and re-injection considered. Results: In the BRVO group, mean foveal thickness was 548.2±49.50 μm preoperatively, and 452.8±56.2 μm and 280.8±62.5 μm at 1 and 12 month follow-up, respectively. Statistical analysis showed significant differences between preoperative and postoperative measurements (P<.05, paired t test) 3 months after injections. Improvement of visual acuity by at least 0.2 LogMAR was seen in 3(50%) of the 6 eyes. No re-injection was needed. In the CRVO group, mean foveal thickness was 543.7±34.4 μm preoperatively, and 283.0±29.0 μm and 234.8±23.6 μm at 1 and 12 month follow-up, respectively. Statistical analysis showed significant differences between preoperative and postoperative measurements (P<.05, paired t test). Improvement of visual acuity by at least 0.2 LogMAR was seen in 7 eyes (88%). Mean number of re-injection was of 2.1±0.3. Intraocular pressure elevation of 22 mm Hg or higher was found in 2/14 eyes (14%). Cataract progression was noted in 5/14 eyes (36%). Conclusions: PST injection of TA appears to be as safe and effective treatment for chronic macular oedema associated due to both non-ischemic BRVO or CRVO, with a better efficacy in BRVO.

Targeting iron-mediated retinal degeneration by local delivery of transferrin.

Iron is essential for retinal function but contributes to oxidative stress-mediated degeneration. Iron retinal homeostasis is highly regulated and transferrin (Tf), a potent iron chelator, is endogenously secreted by retinal cells. In this study, therapeutic potential of a local Tf delivery was evaluated in animal models of retinal degeneration. After intravitreal injection, Tf spread rapidly within the retina and accumulated in photoreceptors and retinal pigment epithelium, before reaching the blood circulation. Tf injected in the vitreous prior and, to a lesser extent, after light-induced retinal degeneration, efficiently protected the retina histology and function. We found an association between Tf treatment and the modulation of iron homeostasis resulting in a decrease of iron content and oxidative stress marker. The immunomodulation function of Tf could be seen through a reduction in macrophage/microglial activation as well as modulated inflammation responses. In a mouse model of hemochromatosis, Tf had the capacity to clear abnormal iron accumulation from retinas. And in the slow P23H rat model of retinal degeneration, a sustained release of Tf in the vitreous via non-viral gene therapy efficently slowed-down the photoreceptors death and preserved their function. These results clearly demonstrate the synergistic neuroprotective roles of Tf against retinal degeneration and allow identify Tf as an innovative and not toxic therapy for retinal diseases associated with oxidative stress.

Référentiel de pratiques professionnelles: soins et surveillance des accès veineux centraux de l'adulte pour la nutrition parentérale [Formative assessment in clinical nutrition: Care management of parenteral nutrition central venous access]

Les voies veineuses centrales (VVC) sont essentielles pour l'administration de la nutrition parentérale. Le risque de complications est dépendant de la qualité des soins apportés à la VVC qui influence de ce fait la qualité de vie des patients et le coût des soins. Beaucoup de complications des VVC, infectieuses ou non, peuvent être prévenues par l'existence de protocoles de soins appropriés et standardisés. L'information sur les soins des VVC et les éventuelles complications est essentielle pour le dépistage et le traitement précoce de ces complications ; elle doit faire l'objet de protocoles partagés entre les patients et les soignants. Cet article décrit une évaluation des pratiques professionnelles sous la forme d'un audit clinique destiné à améliorer la qualité de soins des patients en nutrition parentérale porteurs de VVC. Central venous access devices (CVAD) are essential for the administration of parenteral nutrition. The quality of the care of CVAD influences the risk of complications and so the quality of life of the patients and the costs of care. Numerous infectious or non-infectious complications of CVAD can be prevented by appropriate, standardized protocols of care. Information about the care of CVAD and complications is essential for the early recognition and treatment of complications and should be shared between patients and caregivers. This article describes an audit for CAVD care that can be used to improve quality of care in a professional practice evaluation program.

Development of the Positive Emotions Program for Schizophrenia (PEPS): an intervention to improve pleasure and motivation in schizophrenia

Objectives: The efficacy of drug-based treatments and psychological interventions on the primary negative symptoms of schizophrenia remains limited. Recent literature has distinguished negative symptoms associated with a diminished capacity to experience, from those associated with a limited capacity for expression. The positive emotions program for schizophrenia (PEPS) is a new method that specifically aims to reduce the syndrome of a diminished capacity to experience. Methods: The intervention's vital ingredients were identified through a literature review of emotion in schizophrenia and positive psychology. The program has been beta-tested on various groups of health-care professionals. Results: A detailed description of the final version of PEPS is presented here. The French version of the program is freely downloadable. Conclusion: PEPS is a specific, short, easy to use, group-based intervention to improve pleasure, and motivation in schizophrenia. It was built considering a recovery-oriented approach to schizophrenia.

Care delivery value chains for ophthalmic clinics in Switzerland

Perceived patient value is often not aligned with the emerging expenses for health care services. In other words, the costs are often supposed as rising faster than the actual value for the patients. This fact is causing major concerns to governments, health plans, and individuals. Attempts to solve the problem have habitually been on the operational effectiveness side: increasing patient volume, minimizing costs, rationing, or closing hospitals, usually resulting in a zero-sum game. Only few approaches come from the strategic positioning side and "competition" among hospitals is still perceived rather as a danger than as a chance to create a positive-sum game and stimulate patient value. In their 2006 book, "Redefining Health Care", the renowned Harvard strategy professor Michael E. Porter and hospital management expert Professor Elizabeth Olmsted Teisberg approach the challenge from the positive-sum perspective: they propose to form Integrated Practice Units (IPUs) and manage hospitals in a modern, patient value oriented way. They argue that creating value-based competition on results should have the same effect on the health care sector like transparency and competition turned other industries with out-dated management models (like recently the inert telecommunication industry) into highly competitive and customer value creating businesses. The objective of this paper is to elaborate Care Delivery Value Chains for Integrated Practice Units in ophthalmic clinics and gather a first feedback from Swiss hospital managers, ophthalmologists, and patients, if such an approach could be a realistic way to improve health care management. First, Porter's definition of competitiveness (distinction between operational effectiveness and strategic positioning) is explained. Then, the Care Delivery Value Chain is introduced as a key element for understanding value-based management, followed by three practice examples for ophthalmic clinics. Finally, recommendations are given how the Care Delivery Value Chain can be managed efficiently and how the obstacles of becoming a patient-oriented organization can be overcome. The conclusion is that increased transparency and value-based competition on results has the potential to change the mindset of hospital managers-which will align patient value with the emerging health care expenses. Early adapters of this management approach will gain a competitive advantage. [Author, p. 6]

Automobile Corporate Networks in Europe : Sectoral Specialization of Central and Eastern European Cities

The global automobile industry is made up of very large corporations and their various subsidiaries containing different functions that create complex locational structures. The networks formed by the 19 largest automobile transnational corporations constitute an automobile "oligopoly" representing more than 90% (OICA, 2012) of the world's production. Since the mid-1990s, Central and Eastern European cities have become attractive for transnational corporations and particularly for the production functions in the automobile sector. This leads to a crucial question. Are strategic functions (such as R&D) within these networks also located in Central and Eastern Europe, or is the region still manufacturing-oriented in the automobile industry? This paper focuses on the patterns and the main factors influencing the role of some of these new central and Eastern European cities that have become integrated in the global value chain of the automobile industry. By analysing the various locations of the specialized functions within the corporations, this study aims to extend the research on global value chains (Gereffi and Korzeniewicz; 1994, Sturgeon, 2000; Krätke, 2014). The spatial patterns of the various functions and the ownerships networks of the automobile industry are constructed in order to identify the cities supporting it. In particular, the way that national metropolises bring their national territories into the globalization of the automobile industry is addressed. For example, are there some specific advantages of capital cities compared to cities that have less integration in globalization terms?

Interdisciplinary Medication Adherence Program: The Example of a University Community Pharmacy in Switzerland.

The Community Pharmacy of the Department of Ambulatory Care and Community Medicine (Policlinique Médicale Universitaire, PMU), University of Lausanne, developed and implemented an interdisciplinary medication adherence program. The program aims to support and reinforce medication adherence through a multifactorial and interdisciplinary intervention. Motivational interviewing is combined with medication adherence electronic monitors (MEMS, Aardex MWV) and a report to patient, physician, nurse, and other pharmacists. This program has become a routine activity and was extended for use with all chronic diseases. From 2004 to 2014, there were 819 patient inclusions, and 268 patients were in follow-up in 2014. This paper aims to present the organization and program's context, statistical data, published research, and future perspectives.