A new poly(ortho ester)-based drug delivery system as an adjunct treatment in filtering surgery.

PURPOSE: Pharmacologic modulation of wound healing after glaucoma filtering surgery remains a major clinical challenge in ophthalmology. Poly(ortho ester) (POE) is a bioerodible and biocompatible viscous polymer potentially useful as a sustained drug delivery system that allows the frequency of intraocular injections to be reduced. The purpose of this study was to determine the efficacy of POE containing a precise amount of 5-fluorouracil (5-FU) in an experimental model of filtering surgery in the rabbit. METHODS: Trabeculectomy was performed in pigmented rabbit eyes. An ointmentlike formulation of POE containing 1% wt/wt 5-FU was injected subconjunctivally at the site of surgery, during the procedure. Intraocular pressure (IOP), bleb persistence, and ocular inflammatory reaction were monitored until postoperative day 30. Quantitative analysis of 5-FU was performed in the anterior chamber. Histologic analysis was used to assess the appearance of the filtering fistula and the polymer's biocompatibility. RESULTS: The decrease in IOP from baseline and the persistence of the filtering bleb were significantly more marked in the 5-FU-treated eyes during postoperative days 9 through 28. Corneal toxicity triggered by 5-FU was significantly lower in the group that received 5-FU in POE compared with a 5-FU tamponade. Histopathologic evaluation showed that POE was well tolerated, and no fibrosis occurred in eyes treated with POE containing 5-FU. CONCLUSIONS: In this rabbit model of trabeculectomy, the formulation based on POE and containing a precise amount of 5-FU reduced IOP and prolonged bleb persistence in a way similar to the conventional method of a 5-FU tamponade, while significantly reducing 5-FU toxicity.

Influence of infusion line compliance on drug delivery rate during acute line loop formation.

OBJECTIVE: To determine whether infusion line compliance contributes to irregular drug delivery during vertical displacement of syringe pumps. DESIGN: Five different commercially available infusion lines were studied at infusion rates of 0.5, 1.0, and 1.5 ml/h. Zero drug delivery time was measured after acute line loop formation (70 cm) using an electronic balance. Compliance of each infusion line was calculated using a pressure transducer and measurement of the occlusion release bolus at 300 mmHg occlusion pressure. Finally, the influence of infusion line compliance on drug delivery during acute lowering of the syringe pump was studied using low- and high-compliance infusion lines. RESULTS: Acute line loop formation resulted in zero drug delivery time from 5.1 +/- 1.5 to 44.0 +/- 6.8 s at flow rates of 0.5 ml/h. Increased flow rates significantly reduced loop-induced flow variability. A close correlation was found between zero drug delivery time and calculated infusion line compliance at 0.5 ml/h (linear regression R2 = 0.79). Lowering of the syringe pump 50 cm prolonged zero drug delivery time from 295.8 +/- 20.7 s with the low-compliance tube to 463.3 +/- 24.0 s with the high-compliance infusion line. CONCLUSIONS: Infusion line compliance contributes to irregular drug delivery associated with vertical displacement of syringe pumps. Siphoning of the infusion line during patient care should be avoided, and flow rates of 1 ml/h or higher are recommended. Low-compliance infusion lines are indicated whenever highly short-acting vasoactive drugs at low delivery rates are administered.

Intraocular implants for extended drug delivery: therapeutic applications.

An overview of ocular implants with therapeutic application potentials is provided. Various types of implants can be used as slow release devices delivering locally the needed drug for an extended period of time. Thus, multiple periocular or intraocular injections of the drug can be circumvented and secondary complications minimized. The various compositions of polymers fulfilling specific delivery goals are described. Several of these implants are undergoing clinical trials while a few are already commercialized. Despite the paramount progress in design, safety and efficacy, the place of these implants in our clinical therapeutic arsenal remains limited. Miniaturization of the implants allowing for their direct injection without the need for a complicated surgery is a necessary development avenue. Particulate systems which can be engineered to target specifically certain cells or tissues are another promising alternative. For ocular diseases affecting the choroid and outer retina, transscleral or intrasscleral implants are gaining momentum.

Role of CD4+CD25+ regulatory T cells in the antigen specific induction of tolerance "via" the nasal route

ABSTRACT Asthma is a complex inflammatory syndrome caused by environmental factors in predisposed individuals (atopics). Its severity correlates with the presence of activated T lymphocytes and eosinophils in the bronchoalveolar lavage fluid (BALF). Induction of tolerance via the nasal route results in reduced recruitment of eosinophils into BALF upon challenge, inhibition of TH2 pro-inflammatory cytokine secretion and T cell hyporesponsiveness. Recently, CD4+CD25+ natural regulatory T cells (Treg) were proposed as key players in controlling the development of asthma and allergic disease. The objective of the present study is to investigate the role of CD4+CD25+ regulatory T cells in the mechanisms leading to tolerance in an established model of asthma. In this goal we depleted CD4+CD25+ T cells at different times during asthma and tolerance induction protocol in mice and looked at efficiency of tolerization (intranasal application of high dose of allergen) in the absence of natural Tregs. First, ovalbumin-sensitized mice were depleted of CD25+ T cells by intraperitoneal injection of anti-CD25 mAb (PC61) either for along-term (repeated injections of anti-CD25 from day 31 until the end of the protocol) or a short-term period (single injection of anti-CD25 before or after tolerance induction). We demonstrated that the long-term depletion of CD4+CD25+ T cells severely hampered tolerance induction (marked enhancement in eosinophil recruitment into BALF and a vigorous antigen specific T cell response to OVA upon allergen challenge) whereas transient depletions were not sufficient to do so. We then characterized T cell subsets by flow cytometry and observed that a large part of CD4+CD25+ T cells express Foxp3, an established marker of regulatory T cells. We also tested in-vitro suppressor activity of CD4+CD25+ T cells from tolerized mice by cell proliferation assay in coculture and observed a strong suppressive activity. Our data suggest that CD4+CD25+ T cells with regulatory properties play a crucial role in the induction of tolerance via the nasal route. The relationship between CD25+ natural Treg and inducible IL-10+ TRl-type Treg will have to be defined. RESUME L'asthme est un syndrome inflammatoire complexe provoqué par des facteurs environnementaux chez des individus génétiquement prédisposés (atopiques). Sa sévérité corrèle avec la présence des lymphocytes T activés et d'éosinophiles dans le lavage bronchoalvéolaire (BAL). L'induction de la tolérance par la voie nasale résulte en une diminution du recrutement des eosinophils dans le BAL, une inhibition de la sécrétion de cytokines pro-inflammatoires de type TH2 et de l'hypo-réponse des cellules T à l'allergène. Récemment, les cellules régulatrices «naturelles » de type CD4+CD25+ T (Tregs) ont été proposées comme acteurs essentiels dans le développement de l'asthme et de l'allergie. L'objectif de cette étude est d'étudier le rôle des cellules régulatrices CD4+CD25+ T dans les mécanismes menant à la tolérance dans un modèle établi d'asthme. Dans ce but nous avons déplété les cellules de CD4+CD25+ T à différents temps au cours du protocole d'induction d'asthme et de tolérance et nous avons regardé l'efficacité de l'induction de tolérance (application intranasale d'une dose importante d'allergène) en l'absence de Tregs. Dans un premier temps des souris sensibilisées à l'ovalbumine (OVA) ont été déplétées en cellules CD25+ T par l'injection intrapéritonéale d'anti-CD25 mAb (PC61) pour une longue période (injections répétées d'anti-CD25 du jour 31 jusqu'à la fin du protocole) ou pour une courte période (injection unique d'anti-CD25 avant ou après l'induction de tolérance). Nous avons démontré que la déplétion à long t erme des cellules de CD4+CD25+ T a empêché l'induction de tolérance (recrutement accru d'éosinophiles dans le BAL et une réponse vigoureuse des cellules T spécifiques de l'antigène après exposition à l'allergène) tandis des déplétions à court-terme n'ont pas cet effet. Nous avons ensuite caractérisé des sous-populations de cellules T par cytométrie de flux. Nous avons observé que la majorité des cellules CD4+CD25+ T expriment Foxp3, un marqueur établi des cellules régulatrices. Nous avons également examiné in vitro l'activité régulatrice des cellules T CD4+CD25+ issues de souris tolérisées. La prolifération de cellules T en coculture a démontré une forte activité suppressive des cellules CD4+CD25+. Nos données suggèrent que des cellules T CD4+CD25+ ayant des propriétés régulatrices jouent un rôle crucial dans l'induction de la tolérance par la voie nasale. Le rapport entre les cellules régulatrices naturelles CD4+CD25+ et les cellules régulatrices inductible de type TR1 I1-10+ devra être défini. RESUME DESTINE A UN LARGE PUBLIC L'asthme est une maladie inflammatoire des bronches, caractérisée par des crises de dyspnée (gêne respiratoire) témoignant d'une activation brutale des muscles bronchoconstricteurs, auxquelles s'associent un oedème et une hypersécrétion des muqueuses des voies aériennes ainsi qu'une importante production d'anticorps de l'allergie (IgE). Chez la plupart des enfants atteints et chez près de la moitié des adultes concernés par l'asthme, c'est une allergie à des substances présentes dans l'air environnant (acariens, pollens ou poils d'animaux) qui est à l'origine de la maladie. . Le traitement actuel de l'asthme repose d'une part sur le soulagement des symptômes grâce à des produits à base de stéroïdes ou des bronchodilatateurs. D'autre part, l'immunothérapie spécifique (aussi appelée désensibilisation) permet d'améliorer l'asthme et de «reprogrammer» le système immunitaire. C'est à ce jour, le seul moyen connu de faire régresser une allergie. Cependant l'immunothérapie prend beaucoup de temps (3 à 5 ans) et ne marche pas à tous les coups ni pour tous les antigènes. Il est donc important de mieux comprendre les mécanismes impliqués lors d'un tel traitement afin d'en améliorer l'efficacité. Af n de pouvoir investiguer en détail ces mécanismes des modèles d'immunothérapie ont été mis au point chez la souris. Notre étude se base sur un modèle d'asthme allergique chez la souris. Des souris sont rendues allergiques à l'ovalbumine (OVA) et présentent alors les caractéristiques majeures de l'asthme humain (recrutement de cellules inflammatoires dans les poumons, augmentation de la production d'IgE et de la résistance des bronches aux flux respiratoires). Ces souris asthmatiques une fois traitées par l'application nasale d'OVA (forme d'immunothérapie muqueuse) ne développent plus de réaction allergique lors d'une ré-exposition à l'allergène. Notre hypothèse est que cette «guérison» (tolérance) est liée à l'action de cellules (lymphocytes T CD4) dites «régulatrices» et caractérisées par le marqueur CD25. Pour le démontrer, nous avons éliminé ces cellules «régulatrices» CD25 de nos souris asthmatiques grâce à un anticorps monoclonal spécifique. Nous n'avons dès lors plus été en mesure d'induire une tolérance à l'allergène. Ceci suggère donc un rôle clé des cellules «régulatrices» T CD4+CD25+ dans la réussite de l'immunothérapie nasale dans notre modèle. Nos résultats n'excluent pas la participation d'autres cellules telles que les lymphocytes producteurs d'IL-10 (lymphocytes régulateurs induits). Le rôle respectif de ces sous-populations régulatrices devra être examiné dans les études à venir. Une meilleure maîtrise des mécanismes de régulation pourrait s'avérer cruciale pour améliorer les thérapies de l'asthme.

Delayed delivery of second twin: a multicentre study of 35 cases.

OBJECTIVE: The aim of this study was to conduct a statistical analysis to determine the outcome of conservative treatment after delivery of a first fetus in multiple pregnancy and thus define new prognostic factors. STUDY DESIGN: Multicentre retrospective study involving 12 centers over a 10-year period. RESULTS: Twenty-eight twin pregnancies and seven triplet pregnancies which were managed conservatively. In twin pregnancies, 79% of the delayed-delivery fetuses survived; only 7% of the first delivered fetuses survived. The mean interval between deliveries was 47 days. No statistical difference was found concerning cerclage, antibiotic therapy, tocolysis and hospitalization. Earlier delivery of the first twin and premature rupture of membranes for the second twin were significantly related to a longer interval between deliveries. CONCLUSION: Delayed delivery in multifetal pregnancies can be successful if there are no contraindications and these pregnancies are managed in a tertiary perinatal center. Publications limited to successful cases have undoubtedly introduced some bias in assessment.

The impact of information on patient preferences in different delivery patterns: a contingent valuation study of prescription versus OTC drugs.

OBJECTIVES: Our analysis assessed the impact of information on patients' preferences in prescription versus over-the-counter (OTC) delivery systems. METHODS: A contingent valuation (CV) study was implemented, randomly assigning 534 lay people into the receipt of limited or extended information concerning new influenza drugs. In each information arm, people answered two questions: the first asked about willingness to pay (WTP) for the new prescription drug; the second asked about WTP for the same drug sold OTC. RESULTS: We show that WTP is higher for the OTC scenario and that the level of information plays a significant role in the evaluation of the OTC scenario, with more information being associated with an increase in the WTP. In contrast, the level of information provided has no impact on WTP for prescription medicine. Thus, for the kind of drug considered here (i.e. safe, not requiring medical supervision), a switch to OTC status can be expected to be all the more beneficial, as the patient is provided with more information concerning the capability of the drug. CONCLUSIONS: Our results shed light on one of the most challenging issues that health policy makers are currently faced with, namely the threat of a bird flu pandemic. Drug delivery is a critical component of pandemic influenza preparedness. Furthermore, the congruence of our results with the agency and demand theories provides an important test of the validity of using WTP based on CV methods.

Global Distributed Delivery Model for Internet Service Provider

Globaalin talouden rakenteet muuttuvat jatkuvasti. Yritykset toimivat kansainvälisillä markkinoilla aiempaa enemmän. Tuotannon lisäämiseksi monet yritykset ovat ulkoistaneet tuotteidensa tuki- ja ylläpitotoiminnot halvan työvoiman maihin. Yritykset voivat tällöin keskittää toimintansa ydinosamiseensa. Vapautuneita resursseja voidaan käyttää yrityksen sisäisessä tuotekehityksessä ja panostaa seuraavan sukupolven tuotteiden ja teknologioiden kehittämiseen. Diplomityö esittelee Globaalisti hajautetun toimitusmallin Internet-palveluntarjoajalle jossa tuotteiden tuki- ja ylläpito on ulkoistettu Intiaan. Teoriaosassa esitellään erilaisia toimitusmalleja ja keskitytään erityisesti hajautettuun toimitusmalliin. Tämän lisäksi luetellaan valintakriteerejä joilla voidaan arvioida projektin soveltuvuutta ulkoistettavaksi sekä esitellään mahdollisuuksia ja uhkia jotka sisältyvät globaaliin ulkoistusprosessiin. Käytäntöosassa esitellään globaali palvelun toimittamisprosessi joka on kehitetty Internet-palveluntarjoajan tarpeisiin.

Delivery of antisense oligonucleotide to the cornea by iontophoresis.

We wished to evaluate the potential of iontophoresis to promote the delivery of antisense oligonucleotides (ODN) directed at the vascular endothelial growth factor (VEGF)-R2 receptor (KDR/Flk) to the cornea of the rat eye. Fluorescence (CY5)-labeled ODNs in phosphate-buffered saline (PBS) (20 microM) were locally administered to rat eyes, and their fate within the anterior segment was studied. Thirty-four male, 5-week-old Wistar rats were used for all experiments. The rats were divided in four groups. In group I (12 rats, 12 eyes), the ODNs (20 microM) were delivered by iontophoresis (300 microA for 5 minutes) using a specially designed corneal applicator. In group II (12 rats, 12 eyes), the ODNs (20 microM) were delivered using the same applicator, but no electrical current was applied. In group III (6 rats, 6 eyes), a corneal neovascular reaction was induced prior to the application of ODNs (20 microM), and iontophoresis electrical current was delivered as for group I rats. Group IV (4 rats, 4 eyes) received ODN (60 microM) iontophoresis application (300 microA for 5 minutes) and were used for ODN integrity studies. The animals were killed 5 minutes, 90 minutes, and 24 hours after a single ODN application and studied. Topically applied ODNs using the same iontophoresis applicator but without current do not penetrate the cornea and remain confined to the superficial epithelial layer. ODNs delivered with transcorneoscleral iontophoresis penetrate into all corneal layers and are also detected in the iris. In corneas with neovascularization, ODNs were particularly localized within the vascular endothelial cells of the stroma. ODNs extracted from eye tissues 24 hours after iontophoresis remained unaltered. The iontophoresis current did not cause any detectable ocular damage under these conditions. Iontophoresis promotes the delivery of ODNs to the anterior segment of the eye, including all corneal layers. Iontophoresis of ODNs directed at VEGF-R2 may be used for the design of specific antiangiogenic strategy in diseases of the cornea.

Development of Order-Delivery Process in Purchasing

Diplomityön tavoitteena oli kehittää Fazer Suklaan oston tilaus-toimitusprosesseja, jotta raaka-aineet ja pakkausmateriaalit pystytään hoitamaan mahdollisimman tehokkaasti. Ensin selvitettiin kirjallisuuden avulla tilaus-toimitusprosessin päävaiheet ja niihin vaikuttavat tekijät. Empiirisessä osassa lähdettiin liikkeelle käymällä läpi Fazer Suklaan oston nykytilanne, joka tehtiin ostajille suunnatun aikaselvityksen, haastatteluiden ja nykyisten tilaus-toimitusprosessien kuvaamisen avulla. Tavoitetilanteen rakentaminen aloitettiin ostettavien materiaalien ja toimittajien luokittelemisella. Tämän perusteella nämä materiaalit voitiin jakaa kolmen eri tilaus toimitusprosessin alle. Automaattisessa tilaus-toimitusprosessissa eri vaiheet automatisoidaan yhdessäavain toimittajien kanssa. Puoliautomaattinen prosessi perustuu systeemiin, jossa toimittaja näkee internetin kautta Fazerin tuotantosuunnitelman ja tekee tämän perusteella materiaalien täydennykset. Yksinkertaisessa prosessissa ostoarvoltaan alhaiset materiaalit hoidetaan mahdollisimman lähellä käyttöpistettä ja prosessin vaiheet tehdään mandollisimman pienellä työmäärällä. Tavoiteprosessien implementoinnilla todettiin suurimmiksi eduiksi prosessivaiheiden vähentyminen ja manuaalisen työn automatisoituminen. Tätä kautta saatiin prosessin eri vaiheiden työmäärää vähennettyä, sekä alennettua varastotasoja ja näin tilaus toimitusprosessin kokonaiskustannuksia pystyttiin pienentämään.

Performance measurement oforder-delivery chain in SMEs: Case study

Tutkimus pyrkii selvittämään, kuinka tehokas suorituskykymittaristo voidaan parhaiten suunnitella pk-yrityksessä. Tutkimuksen tavoitteena on luoda suorituskykymittaristo pienen kohdeyrityksen johtajien tarpeisiin. Päähuomion kohteena on yrityksen tilaus-toimitusketju ja arvoverkko. Työ on luonteeltaan kvalitatiivinen toimintatutkimus, joka noudattaa toiminta-analyyttista tutkimusotetta. Työn teoriaosassa selvitetään, kuinka suorituskyvyn mittaaminen sekä materiaali-, tieto- ja rahavirtojen hallinta on kehittynyt viime vuosina pk-yrityksen näkökulmasta. Mittariston suunnittelu aloitetaan kohdeyrityksen perusteellisella analyysilla. Tämän pohjalta määritellään yrityksen kriittiset menestystekijät, joista lopulta johdetaan suorituskykymittarit. Tutkimuksen perusteella voidaan todeta, että yleinen asenne mittaamista kohtaan, strategian huomioinnin puute sekä tietojärjestelmien rajoitteet ovat päähaasteita pk-yrityksen suorituskyvyn mittaamisessa. Mittareiden tuleekin olla melko yksinkertaisia ja helppoja käyttää, jotta mittaamisen ei koettaisi kuluttavan rajallisia resursseja liikaa. Mittariston tulee kuitenkin antaa kokonaisvaltainen kuva yrityksen suorituskyvystä, johon vaikuttavat kaikki arvoverkon osapuolet ja heidän yhteistyö toistensa kanssa.

Effects of nasal continuous airway pressure on pulmonary and systemic output in preterm infants

Objective: Respiratory assistance with nasal continuous positive airway pressure (n-CPAP) is an effective treatment in premature newborns presenting respiratory distress. The aim of the study was to depict cardiac function, systemic (Qs) and pulmonary output (Qp) by echocardiography in stable premature infants requiring prolonged n-CPAP. Our hypothesis was that n-CPAP could reduce pulmonary blood flow. Patients and methods: All premature infants < 32 weeks gestation, > 7 days-old, requiring n-CPAP without severe respiratory compromise nor need for additional oxygen were prospectively included. Every patient had a first echocardiography while on n-CPAP. N-CPAP was then discontinued for two hours and a second echocardiography was performed. Results: 17 premature infants were included. Mean gestational age was 28 ± 2 weeks and mean weight 1.1 ± 0.3 kg. Following retrieval of n-CPAP we observed an increase in Qp of 53 ml/kg/min (95% CI 19-87 ml/kg/min), but no significant change in Qs. Consecutively a significant increase in Qp/Qs ratio of 16% was found (95% CI 7-29%). Conclusions: Nasal continuous positive airway pressure has hemodynamic effects in preterm infants in stable pulmonary and cardiac conditions. It reduces pulmonary output without interference with systemic output.

Cultural Biases in Public Service Delivery : Evidence from a Regression Discontinuity Approach

What determines the share of public employment, at a given size of the State, in countries of similar levels of economic development? While the theoretical and empirical literature on this issue has mostly considered technical dimensions (efficiency and political considerations), this paper emphasizes the role of culture and quantifies it. We build a representative database for contracting choices of municipalities in Switzerland and exploit the discontinuity at the Swiss language border at identical actual set of policies and institutions to analyze the causal e↵ect of culture on the choice of how public services are provided. We find that French-speaking border municipalities are 50% less likely to contract with the private sector than their German-speaking adjacent municipalities. Technical dimensions are much smaller by comparison. This result points out that culture is a source of a potential bias that distorts the optimal choice for public service delivery. Systematic differences in the level of confidence in public administration and private companies potentially explain this discrepancy in private sector participation in public services provision.