Clinical and immunohistochemical assessment of vulval intraepithelial neoplasia following photodynamic therapy using a novel bioadhesive patch-type system loaded with 5-aminolevulinic acid

Background: The work in this study appraised photodynamic treatment (PDT) as a treatment method for vulval intraepithelial neoplasia (VIN) using a novel bioadhesive patch to deliver aminolevulinic acid. An analysis of changes in expression of apoptotic and cell cycle proteins (p53, p21, Mdm2, Blc-2, Bax, Ki-67) in response to PDT was evaluated. Methods: PDT was performed using non-laser light, either as a one or two-cycle treatment, with clinical and pathological assessment following after 6 weeks. Twenty-three patients with 25 VIN lesions underwent 49 cycles of PDT Patches were designed to conform to uneven vulval skin and contained 38 mg cm(-2) aminolevulinic acid. Assessment was carried out at 6 weeks post-treatment. Patient-based treatment assessment, along with clinical and pathological changes, were monitored. Immunohistochemical staining was used to elucidate a possible biomolecular basis for induced cellular changes. Results: Most patients (52%) reported a symptomatic response, with normal pathology restored in 38% of lesions. The patch was easy to apply and remove, causing minimal discomfort. Fluorescence inspection confirmed protoporphyrin accumulation. Pain during implementation of PDT was problematic, necessitating some form of local analgesia. Changes in expression of cell cycle and apoptotic-related proteins suggested involvement of apoptotic pathways. Down regulation of p21 and inverse changes in Bcl-2 and Bax were key findings. Conclusion: Treatment of VIN lesions using a novel bioadhesive patch induced changes in cell cycle and apoptotic proteins in response to PDT with possible utilisation of apoptotic pathways. The efficacy of PDT in treating VIN could be improved by a better understanding of these apoptotic mechanisms, the influence of factors, such as HPV status, and of the need for effective pain management.

Renal responses to three types of renin-angiotensin system blockers in patients with diabetes mellitus on a high-salt diet: a need for higher doses in diabetic patients?

Objective Activation of the renal renin-angiotensin system in patients with diabetes mellitus appears to contribute to the risk of nephropathy. Recently, it has been recognized than an elevation of prorenin in plasma also provides a strong indication of risk of nephropathy. This study was designed to examine renin-angiotensin system control mechanisms in the patient with diabetes mellitus.Methods We enrolled 43 individuals with type 2 diabetes mellitus. All individuals were on a high-salt diet to minimize the contribution of the systemic renin-angiotensin system. After an acute exposure to captopril (25 mg), they were randomized to treatment with either irbesartan (300 mg) or aliskiren (300 mg) for 2 weeks.Results All agents acutely lowered blood pressure and plasma aldosterone, and increased renal plasma flow and glomerular filtration rate. Yet, only captopril and aliskiren acutely increased plasma renin and decreased plasma angiotensin II, whereas irbesartan acutely affected neither renin nor angiotensin II. Plasma renin and angiotensin II subsequently did increase upon chronic irbesartan treatment. When given on day 14, irbesartan and aliskiren again induced the above hemodynamic, renal and adrenal effects, yet without significantly changing plasma renin. Irbesartan at that time did not affect plasma angiotensin II, whereas aliskiren lowered it to almost zero.Conclusion The relative resistance of the renal renin response to acute (irbesartan) and chronic (irbesartan and aliskiren) renin-angiotensin system blockade supports the concept of an activated renal renin-angiotensin system in diabetes, particularly at the level of the juxtaglomerular cell, and implies that diabetic patients might require higher doses of renin-angiotensin system blockers to fully suppress the renal renin-angiotensin system. J Hypertens 29: 2454-2461 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

The Effects of Pro-inflammatory Cytokines on the L-type Calcium Current in Mouse Ventricular Myocytes

L’inflammation: Une réponse adaptative du système immunitaire face à une insulte est aujourd’hui reconnue comme une composante essentielle à presque toutes les maladies infectieuses ou autres stimuli néfastes, tels les dommages tissulaires incluant l’infarctus du myocarde et l’insuffisance cardiaque. Dans le contexte des maladies cardiovasculaires, l’inflammation se caractérise principalement par une activation à long terme du système immunitaire, menant à une faible, mais chronique sécrétion de peptides modulateurs, appelés cytokines pro-inflammatoires. En effet, la littérature a montré à plusieurs reprises que les patients souffrant d’arythmies et de défaillance cardiaque présentent des taux élevés de cytokines pro-inflammatoires tels le facteur de nécrose tissulaire alpha (TNFα), l’interleukine 1β (IL-1β) et l’interleukine 6. De plus, ces patients souffrent souvent d’une baisse de la capacité contractile du myocarde. Le but de notre étude était donc de déterminer si un lien de cause à effet existe entre ces phénomènes et plus spécifiquement si le TNFα, l’IL-1β et l’IL-6 peuvent affecter les propriétés électriques et contractiles du cœur en modulant le courant Ca2+ de type L (ICaL) un courant ionique qui joue un rôle primordial au niveau de la phase plateau du potentiel d’action ainsi qu’au niveau du couplage excitation-contraction. Les possibles méchansimes par lesquels ces cytokines exercent leurs effets seront aussi explorés. Pour ce faire, des cardiomyocytes ventriculaires de souris nouveau-nées ont été mis en culture et traités 24 heures avec des concentrations pathophysiologiques (30 pg/mL) de TNFα, IL-1β ou IL-6. Des enregistrements de ICaL réalisés par la technique du patch-clamp en configuration cellule entière ont été obtenus par la suite et les résultats montrent que le TNFα n’affecte pas ICaL, même à des concentrations plus élevées (1 ng/mL). En revanche, l’IL-1β réduisait de près de 40% la densité d’ICaL. Afin d’examiner si le TNFα et l’IL-1β pouvaient avoir un effet synergique, les cardiomyocytes ont été traité avec un combinaison des deux cytokines. Toutefois aucun effet synergique sur ICaL n’a été constaté. En outre, l’IL-6 réduisait ICaL significativement, cependant la réduction de 20% était moindre que celle induite par IL-1β. Afin d’élucider les mécanismes sous-jacents à la réduction de ICaL après un traitement avec IL-1β, l’expression d’ARNm de CaV1.2, sous-unité α codante pour ICaL, a été mesurée par qPCR et les résultats obtenus montrent aucun changement du niveau d’expression. Plusieurs études ont montré que l’inflammation et le stress oxydatif vont de pair. En effet, l’imagerie confocale nous a permis de constater une augmentation accrue du stress oxydatif induit par IL-1β et malgré un traitement aux antioxydants, la diminution de ICaL n’a pas été prévenue. Cette étude montre qu’IL-1β et IL-6 réduisent ICaL de façon importante et ce indépendamment d’une régulation transcriptionelle ou du stress oxydatif. De nouvelles données préliminaires suggèrent que ICaL serait réduit suite à l’activation des protéines kinase C mais des études additionelles seront nécessaires afin d’étudier cette avenue. Nos résultats pourraient contribuer à expliquer les troubles du rythme et de contractilité observés chez les patients souffrant de défaillance cardiaque.

A ‘Boscastle-type’ quasi-stationary convective system over the UK Southwest Peninsula

An investigation is presented of a quasi-stationary convective system (QSCS) which occurred over the UK Southwest Peninsula on 21 July 2010. This system was remarkably similar in its location and structure to one which caused devastating flash flooding in the coastal village of Boscastle, Cornwall on 16 August 2004. However, in the 2010 case rainfall accumulations were around four times smaller and no flooding was recorded. The more extreme nature of the Boscastle case is shown to be related to three factors: (1) higher rain rates, associated with a warmer and moister tropospheric column and deeper convective clouds; (2) a more stationary system, due to slower evolution of the large-scale flow; and (3) distribution of the heaviest precipitation over fewer river catchments. Overall, however, the synoptic setting of the two events was broadly similar, suggesting that such conditions favour the development of QSCSs over the Southwest Peninsula. A numerical simulation of the July 2010 event was performed using a 1.5-km grid length configuration of the Met Office Unified Model. This reveals that convection was repeatedly initiated through lifting of low-level air parcels along a quasi-stationary coastal convergence line. Sensitivity tests are used to show that this convergence line was a sea breeze front which temporarily stalled along the coastline due to the retarding influence of an offshore-directed background wind component. Several deficiencies are noted in the 1.5-km model’s representation of the storm system, including delayed convective initiation; however, significant improvements are observed when the grid length is reduced to 500 m. These result in part from an improved representation of the convergence line, which enhances the associated low-level ascent allowing air parcels to more readily reach their level of free convection. The implications of this finding for forecasting convective precipitation are discussed.

Exploring S-type orbits in the Pluto-Charon binary system

This work generates, through a sample of numerical simulations of the restricted three-body problem, diagrams of semimajor axis and eccentricity which defines stable and unstable zones for particles in S-type orbits around Pluto and Charon. Since we consider initial conditions with 0 <= e <= 0.99, we found several new stable regions. We also identified the nature of each one of these newly found stable regions. They are all associated to families of periodic orbits derived from the planar circular restricted three-body problem. We have shown that a possible eccentricity of the Pluto-Charon system slightly reduces, but does not destroy, any of the stable regions.

Clinical microscopic analysis of protaper retreatment system efficacy considering root canal thirds using three endodontic sealers

To evaluate the efficacy of ProTaper Universal rotary retreatment system and the influence of sealer type on the presence of filling debris in the reinstrumented canals viewed in an operative clinical microscope. Forty-five palatal root canals of first molars were filled with gutta-percha and one of the following sealers: G1, EndoFill; G2, AH Plus; G3, Sealapex. The canals were then reinstrumented with ProTaper Universal rotary system. Roots were longitudinally sectioned and examined under an operative clinical microscope (10x), and the amount of filling debris on canal walls was analyzed using the AutoCAD 2004 software. A single operator used a specific software tool to outline the canal area and the filling debris area in each third (cervical, middle, and apical), as well as the total canal area. Data were analyzed by Kruskal-Wallis test and Tukey test at P < 0.05. Sealapex demonstrated significant differences in the average of filling debris area/canal among the 3 thirds. This group revealed that apical third showed more debris than the both cervical and middle third (P < 0.0001). Endofill presented significantly more filling debris than Sealapex in the cervical third (P < 0.05). In the middle (P = 0.12) and apical third (P = 0.10), there were no differences amongst groups. Debris was left in all canal thirds, regardless of the retreatment technique. The greatest differences between techniques and sealers were found in the cervical third. Microsc. Res. Tech. 75:12331236, 2012. (C) 2012 Wiley Periodicals, Inc.

Effect of adhesive system type and tooth region on the bond strength to dentin

Purpose: This study evaluated the bond strength of two etch-and-rinse adhesive systems (two- and three-step) and a self-etching system to Coronal and root canal dentin.Materials and Methods: The root canals of 30 human incisors and canines were instrumented and prepared with burs. The posts used for luting were duplicated with dual resin cement (Duo-link) inside Aestheti Plus #2 molds. Thus, three groups were formed (n = 10) according to the adhesive system employed: All-Bond 2 (TE3) + resin cement post (rcp) + Duo-link (DI); One-Step Plus (TE2) + rcp + DI; Tyrian/One-Step Plus (SE) + rcp + DI. Afterwards, 8 transverse sections (1.5 mm) were cut from 4 mm above the CEJ up to 4 mm short of the root canal apex, comprising coronal and root canal dentin. The sections were submitted to push-out testing in a universal testing machine EMIC (1 mm/min). Bond strength data were analyzed with two-way repeated measures ANOVA and Tukey's test (p < 0.05).Results: The relationship between the adhesives was not the same in the different regions (p < 0.05). Comparison of the means achieved with the adhesives in each region (Tukey; p < 0.05) revealed that TE3 (mean standard deviation: 5.22 +/- 1.70) was higher than TE2 (2.60 +/- 1.74) and SE (1.68 +/- 1.85).Conclusion: Under the experimental conditions, better bonding to dentin was achieved using the three-step etch-and-rinse system, especially in the coronal region. Therefore, the traditional etch-and-rinse three-step adhesive system seems to be the best choice for teeth needing adhesive endodontic restorations.

Floral biology and breeding system of three Ipomoea weeds

A biologia floral de Ipomoea cairica, I. grandifolia e I. nil - plantas daninhas da família Convolvulaceae - foi estudada em Botucatu e Jaboticabal, Estado de São Paulo, Brasil. As três espécies são melitófilas, apresentando conjuntos de visitantes florais bastante diversificados, embora haja alguma sobreposição entre eles. Com relação aos visitantes florais, a análise de agrupamento, empregando-se o índice de similaridade de Jaccard, indicou maior similaridade entre diferentes espécies de Ipomoea ocorrentes no mesmo local do que entre populações da mesma espécie em diferentes localidades. O caráter promíscuo e oportunista da adaptação à polinização, presente nessas espécies, foi demonstrado, sendo essa adaptação vantajosa para plantas daninhas, uma vez que em ambientes ruderais a disponibilidade de polinizadores é imprevisível.

Clinical microscopic analysis of protaper retreatment system efficacy considering root canal thirds using three endodontic sealers

To evaluate the efficacy of ProTaper Universal rotary retreatment system and the influence of sealer type on the presence of filling debris in the reinstrumented canals viewed in an operative clinical microscope. Forty-five palatal root canals of first molars were filled with gutta-percha and one of the following sealers: G1, EndoFill; G2, AH Plus; G3, Sealapex. The canals were then reinstrumented with ProTaper Universal rotary system. Roots were longitudinally sectioned and examined under an operative clinical microscope (10x), and the amount of filling debris on canal walls was analyzed using the AutoCAD 2004 software. A single operator used a specific software tool to outline the canal area and the filling debris area in each third (cervical, middle, and apical), as well as the total canal area. Data were analyzed by Kruskal-Wallis test and Tukey test at P < 0.05. Sealapex demonstrated significant differences in the average of filling debris area/canal among the 3 thirds. This group revealed that apical third showed more debris than the both cervical and middle third (P < 0.0001). Endofill presented significantly more filling debris than Sealapex in the cervical third (P < 0.05). In the middle (P = 0.12) and apical third (P = 0.10), there were no differences amongst groups. Debris was left in all canal thirds, regardless of the retreatment technique. The greatest differences between techniques and sealers were found in the cervical third. Microsc. Res. Tech. 75:12331236, 2012. (C) 2012 Wiley Periodicals, Inc.

Cost-effectiveness and budget impact of saxagliptine as additional therapy to metformin for the treatment of diabetes mellitus type 2 in the Brazilian private health system

Cost-effectiveness and budget impact of saxagliptine as additional therapy to metformin for the treatment of diabetes mellitus type 2 in the Brazilian private health system Objectives: To compare costs and clinical benefits of three additional therapies to metformin (MF) for patients with diabetes mellitus type 2 (DM2). Methods: A discrete event simulation model seas built to estimate the cost-utility ratio (cost per quality-adjusted life years [QALY)) of saxagliptine as an additional therapy to MF when compared to rosiglitazone or pioglitazone. A budget impact model (BIM) was built to simulate the economic impact of saxagliptine use in the context of the Brazilian private health system. Results: The acquiring medication costs for the hypothetical patient group analyzed in a time frame of three years, were R$ 10,850,185, R$ 14,836,265 and R$ 14,679,099 for saxagliptine, pioglitazone and rosiglitazone, respectively. Saxagliptine showed lower costs and greater effectiveness in both comparisons, with projected savings for the first three years of R$ 3,874 and R$ 3,996, respectively. The BIM estimated cumulative savings of R$ 417,958 with the repayment of saxagliptine in three years from the perspective of a health plan with 1,000,000 covered individuals. Conclusion: From the perspective of private paying source, the projection is that adding saxagliptine with MF save costs when compared with the addition of rosiglitazone or pioglitazone in patients with DM2 that have not reached the HbA1c goal with metformin monotherapy. The BIM of including saxagliptine in the reimbursement lists of health plans indicated significant savings on the three-year horizon.

Finite element methods for the Stokes system based on a Zienkiewicz type N-simplex

Hermite interpolation is increasingly showing to be a powerful numerical solution tool, as applied to different kinds of second order boundary value problems. In this work we present two Hermite finite element methods to solve viscous incompressible flows problems, in both two- and three-dimension space. In the two-dimensional case we use the Zienkiewicz triangle to represent the velocity field, and in the three-dimensional case an extension of this element to tetrahedra, still called a Zienkiewicz element. Taking as a model the Stokes system, the pressure is approximated with continuous functions, either piecewise linear or piecewise quadratic, according to the version of the Zienkiewicz element in use, that is, with either incomplete or complete cubics. The methods employ both the standard Galerkin or the Petrov–Galerkin formulation first proposed in Hughes et al. (1986) [18], based on the addition of a balance of force term. A priori error analyses point to optimal convergence rates for the PG approach, and for the Galerkin formulation too, at least in some particular cases. From the point of view of both accuracy and the global number of degrees of freedom, the new methods are shown to have a favorable cost-benefit ratio, as compared to velocity Lagrange finite elements of the same order, especially if the Galerkin approach is employed.

Interleaved multi-cell isolated three-phase PWM rectifier system for aircraft applications

Recently there has been an important increase in electric equipment, as well as, electric power demand in aircrafts applications. This prompts to the necessity of efficient, reliable, and low-weight converters, especially rectifiers from 115VAC to 270VDC because these voltages are used in power distribution. In order to obtain a high efficiency, in aircraft application where the derating in semiconductors is high, normally several semiconductors are used in parallel to decrease the conduction losses. However, this is in conflict with high reliability. To match both goals of high efficiency and reliability, this work proposes an interleaved multi-cell rectifier system, employing several converter cells in parallel instead of parallel-connected semiconductors. In this work a 10kW multi-cell isolated rectifier system has been designed where each cell is composed of a buck type rectifier and a full bridge DC-DC converter. The implemented system exhibits 91% of efficiency, high power density (10kW/10kg), low THD (2.5%), and n−1 fault tolerance which complies, with military aircraft standards.

A comparison of the anterior adhesive system in the oncomiracidium and adult of the monogenean parasite Merizocotyle icopae (Monocotylidae)

The anterior adhesive system of the oncomiracidium and adult of Merizocotyle icopae (Monogenea: Monocotylidae) were compared. The oncomiracidium has one ventrally placed aperture on either side of the head near the anterior extremity. In the adult, there are three ventrally placed apertures on either side of the head region. Both systems have three types of electron-dense secretory bodies opening into each aperture. A rod-shaped secretion (S1) and a small electron dense ovoid secretion (S2) are common to larvae and adults. The third secretion type differs: in adults, it is a large, spherical (S3) type but in larvae, it is an ovoid (S4) body. S4 bodies do occur in adults, but appear to be secreted as a general body secretion. An additional anteromedian secretion (S5) is also present in the oncomiracidium, but is not secreted into the anterior apertures. Homology and function of secretions are discussed.

A type system with usage aspects

Linear typing schemes can be used to guarantee non-interference and so the soundness of in-place update with respect to a functional semantics. But linear schemes are restrictive in practice, and more restrictive than necessary to guarantee soundness of in-place update. This limitation has prompted research into static analysis and more sophisticated typing disciplines to determine when in-place update may be safely used, or to combine linear and non-linear schemes. Here we contribute to this direction by defining a new typing scheme that better approximates the semantic property of soundness of in-place update for a functional semantics. We begin from the observation that some data are used only in a read-only context, after which it may be safely re-used before being destroyed. Formalising the in-place update interpretation in a machine model semantics allows us to refine this observation, motivating three usage aspects apparent from the semantics that are used to annotate function argument types. The aspects are (1) used destructively, (2), used read-only but shared with result, and (3) used read-only and not shared with the result. The main novelty is aspect (2), which allows a linear value to be safely read and even aliased with a result of a function without being consumed. This novelty makes our type system more expressive than previous systems for functional languages in the literature. The system remains simple and intuitive, but it enjoys a strong soundness property whose proof is non-trivial. Moreover, our analysis features principal types and feasible type reconstruction, as shown in M. Konen'y (In TYPES 2002 workshop, Nijmegen, Proceedings, Springer-Verlag, 2003).

Insulin sensitivity and secretion in obese Type 2 diabetic women after various bariatric operations

Objective: To compare the effects of biliopancreatic diversion (BPD) and laparoscopic gastric banding (LAGB) on insulin sensitivity and secretion with the effects of laparoscopic gastric plication (P). Methods: A total of 52 obese women (age 30-66 years) suffering from type 2 diabetes mellitus (T2DM) were prospectively recruited into three study groups: 16 BPD; 16 LAGB, and 20 P. Euglycemic clamps and mixed meal tolerance tests were performed before, at 1 month and at 6 months after bariatric surgery. Beta cell function derived from the meal test parameters was evaluated using mathematical modeling. Results: Glucose disposal per kilogram of fat free mass (a marker of peripheral insulin sensitivity) increased significantly in all groups, especially after 1 month. Basal insulin secretion decreased significantly after all three types of operations, with the most marked decrease after BPD compared with P and LAGB. Total insulin secretion decreased significantly only following the BPD. Beta cell glucose sensitivity did not change significantly post-surgery in any of the study groups. Conclusion: We documented similar improvement in insulin sensitivity in obese T2DM women after all three study operations during the 6-month postoperative follow-up. Notably, only BPD led to decreased demand on beta cells (decreased integrated insulin secretion), but without increasing the beta cell glucose sensitivity.