Efeito de vernizes à base de copolímeros do polimetacrilato na proteção contra o desgaste dental erosivo / Effect of varnishes based on polymethacrylate copolymers on protection against erosive dental wear

O aumento da prevalência de desgaste dental erosivo nos últimos anos, que apresenta uma etiologia multifatorial, se deve principalmente à mudança no estilo de vida das populações em geral. Assim, o diagnóstico precoce e a adoção de medidas preventivas são essenciais para o controle deste problema. Os copolímeros do polimetacrilato apresentaram um promissor potencial anti-erosivo associado a soluções fluoretadas em estudos prévios de nosso grupo de pesquisa. Abordagens adicionais envolvem o uso de agentes aplicados em consultório, que podem estar associados a concentrações mais elevadas de agentes fluoretados. Assim, o objetivo deste trabalho foi investigar a efetividade de uma nova formulação experimental com agentes formadores de película bioadesiva à base de copolímeros do polimetacrilato, bem como a associação destes ao fluoreto de sódio (F) em proteger o esmalte dental frente a desafios erosivos e abrasivos. Amostras de esmalte bovino polidas foram preparadas e os perfis superficiais iniciais determinados por meio de um perfilômetro de contato. Foi realizada então a desmineralização do esmalte (ácido cítrico 0,3%, pH 2,6- 5 min) para simulação da erosão inicial e nova leitura de perfil. Os espécimes foram estratificados para receberem os tratamentos de acordo com os seguintes grupos (n= 15): Controle negativo (água ultrapura); verniz comercial (Duraphat ­ NaF ­ 22600 ppm F-); formulação experimental à base de copolímero catiônico aminometacrilato (AMC) (Eudragit E100 ­ 15%); formulação experimental à base de copolímero aniônico metilmetacrilato (MMC) (Eudragit L100- 15%). As formulações experimentais foram ainda testadas associadas ao fluoreto de sódio (NaF ­ 22600 ppm F-). Os produtos foram aplicados sobre a superfície dos espécimes e foi realizada novamente a leitura do perfil para mensuração da espessura da camada de tratamento aplicada sobre o esmalte. Estes foram então armazenados em saliva artificial por 6 h. Foi então realizada a ciclagem erosiva-abrasiva, com imersão em ácido cítrico a 0,3% (5 min) intercalado com saliva artificial (1h). A abrasão foi realizada após o primeiro e último desafio erosivo diários. Foram realizadas leituras de perfil após o 1º, 3º, 5º, 7º e 9º dias de ciclagem para determinação da perda do esmalte (em µm), comparando-se os perfis obtidos após a erosão inicial e após a ciclagem. Adicionalmente, foi mensurada em espécimes adicionais tratados, a quantidade de flúor fracamente adsorvido à superfície do esmalte (solúvel em KOH), utilizando eletrodo específico (dados em µg/cm²). Foram utilizados os testes ANOVA e Tukey (5%) para os dados medidos ao final da ciclagem. Os dados de perda superficial (média±desvio-padrão) obtidos com os copolímeros AMC (-11,23 ± 3,50)b e MMC (-11,26 ± 2,38)b mostraram potencial protetor significantemente maior do que o controle negativo (-18,31±2,62)a. Os menores valores de perda de esmalte foram observados para os grupos Duraphat (-4,56±1,78)c, AMC+F (-6,26±1,79)c e MMC+F (-7,03±2,49)c, sem diferença significante entre eles (p<0,05). Para o teste adicional de concentração de flúor solúvel em KOH, foram aplicados os testes não paramétricos de Kruskal Wallis e de comparações múltiplas de Dunn (5%). O controle negativo apresentou valores (mediana / distância interquartil) significantemente menores de flúor adsorvido ao esmalte (0,90 / 0,43-1,04)a comparado aos demais. Observou-se maior valor de mediana para o grupo MMC+F (27,42 / 18,30-29,73)b do que para o AMC+F (6,50 / 5,48-8,71)c e o valor obtido para o Duraphat foi intermediário (9,15 / 7,97-14,95)bc. Concluiu-se que os copolímeros do polimetacrilato foram capazes de diminuir a perda do esmalte, apresentando potencial protetor similar ao do Duraphat quando associados ao fluoreto de sódio. O copolímero aniônico (MMC) proporcionou formação de maior quantidade de flúor adsorvido ao esmalte do que o copolímero catiônico (AMC), sendo ambos similares ao verniz comercial Duraphat.

The increase in the prevalence of erosive tooth wear in the last years, which has a multifactorial etiology, is mainly due to the changes in the lifestyle of populations in general. Thus, early diagnosis and the adoption of preventive measures are essential for controlling this problem. Polymethacrylate copolymers showed promising antierosion potential associates with fluoride solutions in previous studies conducted by our research group. Additional approaches involve the use of office-applied agents containing higher concentrations of fluorides. Thus, the aim of this study was to investigate the efficacy of a new formulation with bioadhesive film forming agents based on polymethacrylate copolymers, as well as its association with sodium fluoride (F) in protecting dental enamel against erosive and abrasive challenges. Polished bovine enamel samples were used and surface profiles was determined with a contact profilometer. Then, demineralization of enamel (0,3% citric acid pH 2,6-5 min) was performed to simulate the initial erosion and a new profile reading was made. The specimens were randomized to receive treatments according to the following groups (n=15): Negative control (ultrapure water); commercial varnish (Duraphat- NaF-22600 ppm F- ); experimental formulation based on cationic polymethacrylate copolymer (Eudragit E100 ­ 15%); experimental formulation based on anionic polymethacrylate copolymer (Eudragit L100 ­ 15%). The experimental formulations were also tested in association with sodium fluoride (NaF ­ 22600 ppm F- ). The surface profile of the specimens was read again to observe the thickness of the treatment layer applied to the enamel. These were then stored in artificial saliva for 6 h. Erosive-abrasive cycling was then carried out, with immersion in 0,3% citric acid (5 min) interspersed with artificial saliva (1h). Abrasion was carried out after the first and last daily erosive challenge. Profile readings were performed after the 1st, 3rd, 5th , 7th and 9th cycling days to determine the enamel loss (in µm), comparing the profiles obtained after initial erosion and after cycling. Additionally, the amount of fluoride weakly adsorbed to the enamel surface (soluble in KOH) was measured in additional treated specimens, using a specific electrode (data in µg/cm2 ). ANOVA and Tukey tests (5%) were used for the data measured at the end of the cycle. The surface loss data (mean ± standard deviation) obtained with the AMC (-11.23 ± 3.50)b and MMC (-11.26 ± 2.38)b copolymers showed significantly greater protective potential than the negative control (-18.31 ± 2.62)a. The lowest values of enamel loss were observed for the groups Duraphat (-4.56 ± 1.78), AMC +F (-6.26 ± 1.79)c and MMC +F (-7.03 ± 2.49)c, with no significant difference between them (p<0.05). For the additional KOH- soluble fluoride concentration test, Kruskal Wallis non-parametric tests and Dunn´s multiple comparisons tests (5%) were applied. The negative control showed significantly lower values (median/ interquartile distance) of fluoride adsorbed to the enamel (0.90 / 0.43-1.04)a compared to the others. A higher median values was observed for the MMC+F (27.42/18.30-29.73)b group than for the AMC+F (6.50 / 5.48-8.71)c and the value obtained for Duraphat was intermediate (9.15 / 7.97-14.95)bc. It was concluded that the polymethacrylate copolymers were able to reduce enamel loss, presenting a protective potential similar to that of Duraphat when associated with sodium fluoride. The anionic copolymer (MMC) provided formation of a greater amount of fluoride adsorbed to the enamel than the cationic copolymer (AMC), both being similar to the commercial varnish Duraphat.

[Modeling and theoretical analysis of ring specific mimicry in view of isomerism within medicinal promising oligomers of "DIVEMA"]. / Raschetno-teoreticheskii analiz izomerizatsonnoi tsiklomimikrii lekarstvenno-perspektivnykh oligomerov "DIVÉMA" v protsesse ikh svobodno-radikal'nogo sinteza.

The furan or pyran related hetero cycles play basic role in structural units of nucleic acids (NA) and polysaccharides (PS), significantly predetermining their functional specifics. Some of such properties, in great relevancy for medicine, can be imitated through mimicry of polymers synthetic. Particularly, a formation of similar cycloisomeric chains is possible in process of free-radical cyclocopolymerization of divinyl ether (DVE) and maleic anhydride (MA). The products yielded (DVEMA) of general formula [DVE(MA)-alt-MA]n become precursors for a broad family of water-soluble derivatives capable of wide spectrum of bioactivity, including induction of interferon, immune-stimulated and direct antiviral protection. In this connection, the knowledge: what is content of different heterocyclic isomers in backbone of the preparations and what their partial contributions in promotion of the certain bioactivities observed, are in great importance. Available experimental data (NMR, IR, etc.), controversial for interpretations, didn't elucidate a required estimation of the DVEMA isomerism. The current work represents an independent exploration of the problem via quantum chemistry-based analysis of kinetic (activation barriers) and thermodynamic (enthalpies) priorities in competition between variable isomerism within the chain synthesis. The system is considered in maximal range of hypothetically allowable variations of two levels for double regioselective bifurcations: there are four competitive ways, each of which involves a sequence of four type elementary reactions for a diverse-isomeric formation of chain units. A genesis of six chiral centers (62 stereoisomers permitted) per every of the four part ways was accounted in view for up to 256 isomeric variations in total. The required time-minimized but precisely accurate computations were conducted via B3LYP/6-31G(d), M06-2X/6-311+G(d), M06-2X/6-31+G(2df,p) techniques, which were preselected through model test-systems. As a result, the mechanisms, crucial points and factors for the process-permitted regulation of isomeric content of DVEMA were studied in details. The narrow enough set of most probable enantiomers within highly competitive 5-exo- and 6-endo- ring closing sub-ways was revealed. The results obtained are very actual for an adequate modeling (docking / molecular dynamics) of DVEMA derivatives in their interactions with biopolymer targets, in search for purposed advancement of current background in design and synthesis of highly effective agents for combined antiviral protection (against HIV, flu, herpes, and other infections).

Efectos inmunomoduladores del glatirámero acetato y su potencial papel en la reactivación de la tuberculosis pulmonar / Immunomodulating effects of glatiramer acetate and its potential role in pulmonary tuberculosis reactivation

No disponible

Development of a fluorescence-based in vivo phagocytosis assay to measure mononuclear phagocyte system function in the rat.

The mononuclear phagocyte system (MPS) which provides protection against infection is made up of phagocytic cells that engulf and digest bacteria or other foreign substances. Suppression of the MPS may lead to decreased clearance of pathogenic microbes. Drug delivery systems and immunomodulatory therapeutics that target phagocytes have a potential to inhibit MPS function. Available methods to measure inhibition of MPS function use uptake of radioactively-labeled cells or labor-intensive semi-quantitative histologic techniques. The objective of this work was to develop a non-radioactive quantitative method to measure MPS function in vivo by administering heat-killed E. coli conjugated to a pH-sensitive fluorescent dye (Bioparticles(®)). Fluorescence of the Bioparticles(®) is increased at low pH when they are in phagocytic lysosomes. The amount of Bioparticles(®) phagocytosed by MPS organs in rats was determined by measuring fluorescence intensity in livers and spleens ex vivo using an IVIS(®) Spectrum Pre-clinical In Vivo Imaging System. Phagocytosis of the particles by peripheral blood neutrophils was measured by flow cytometry. To assess method sensitivity, compounds likely to suppress the MPS [clodronate-containing liposomes, carboxylate-modified latex particles, maleic vinyl ether (MVE) polymer] were administered to rats prior to injection of the Bioparticles(®). The E. coli particles consistently co-localized with macrophage markers in the liver but not in the spleen. All of the compounds tested decreased phagocytosis in the liver, but had no consistent effects on phagocytic activity in the spleen. In addition, administration of clodronate liposomes and MVE polymer increased the percentage of peripheral blood neutrophils that phagocytosed the Bioparticles(®). In conclusion, an in vivo rat model was developed that measures phagocytosis of E. coli particles in the liver and may be used to assess the impact of test compounds on MPS function. Still, the detection of inhibition of splenic macrophage function will require further assay development.

Synthesis of Cis-fused pyran indolocarbazole derivatives that inhibit FLT3 kinase and the DNA damage kinase, checkpoint kinase 1.

Protein kinases are important enzymes in solid tumour and leukaemia pathologies. Their structures are well understood at the atomic level and their key role in the progression of certain cancers makes them valuable targets for anti-cancer therapy. Through medicinal chemical approaches, we developed an efficient preparative stereospecific synthesis of N12, N13 pyran-bridged indolocarbazoles that opens access to functional diversity within this previously challenging series. We focused upon the indolocarbazole class of chemical inhibitors, which includes S27888, an inhibitor we previously identified. We used biochemical and cell-based assays to identify small molecule inhibitors of Checkpoint kinase 1 (Chk1), a serine/threonine protein kinase that is activated when cancer cells are treated with genotoxic agents. These compounds show a promising inhibitory profile on Chk1. Furthermore, these compounds are active against FLT3, which is a tyrosine kinase that is frequently activated in human leukaemias. These data suggest that this chemical class may provide a source of therapeutic compounds for a broad range of human cancers.

Potential drug delivery system: study of the association of a model nitroimidazole drug with aggregates of amphiphilic polymers on aqueous solution

This study evaluated the association of N-hexyl-2-methyl-4-nitroimidazol, a model drug, to aggregates formed by anionic polyelectrolytes on aqueous solution. The alternating copolymers of maleic anhydride and N-vinyl-2-pyrrolidone were synthesized and then modified by reaction of the anhydride groups with aliphatic amines and alcohols of varying length of the alkyl chain. The partition of the model drug between water and the hydrophobic microdomains provided by the copolymers was studied using the pseudo-phase model to determinate the distribution coefficient K S, and the standard free energy of transfer ∆µ°t. The results indicate that all copolymers assessed are potential pharmaceutical reservoirs of the model drug. Nevertheless, the solubility of N-hexyl-2-methyl-4-nitroimidazol on the polymeric solutions is independent from the length of the alkyl chain of the copolymer.

Realizou-se estudo sobre a associação da N-hexil-2-metil-4-nitroimidazol, fármaco modelo, aos agregados formados por polieletrólitos aniônicos em solução aquosa. Os copolímeros alternados de anidrido maléico e N-vinil-2-pirrolidona foram sintetizados e, em seguida, modificados pela reação dos grupos de anidrido com aminas e álcoois alifáticos de duração variável da cadeia alquílica. A partição do fármaco modelo entre a água e os microdomínios hidrofóbicos fornecido pelos copolímeros foi estudada usando o modelo de pseudo-fase, a fim de determinar a distribuição do coeficiente K S e a energia livre padrão de transferência ∆µ°t. Os resultados indicam que todos os copolímeros avaliados são potenciais reservatórios farmacêuticos do fármaco. No entanto, a solubilidade do N-hexil-2-metil-4-nitroimidazol sobre as soluções poliméricas é independente do comprimento da cadeia alquílica do copolímero.

Development of miniaturized immunoassay: influence of surface chemistry and comparison with enzyme-linked immunosorbent assay and Western blot.

Protein microarray technology provides a useful approach for the simultaneous serodetection of various antibodies in low sample volumes. To implement functional protein microarrays, appropriate surface chemistry must be designed so that both the protein structure and the biological activity can be retained. In the current study, two surface chemistries for protein microarrays and immunofluorescent assays were developed. Glass slides were functionalized with N-hydroxysuccinimide (NHS) ester via a monofunctional silane or maleic anhydride-alt-methyl vinyl ether (MAMVE) copolymer to allow covalent grafting of histone proteins. Analytical performance of these microarrays was then evaluated for the detection of anti-histone autoantibodies present in the sera of patients suffering from a systemic autoimmune disease, namely systemic lupus erythematosus (SLE), and the results were compared with those of the classical enzyme-linked immunosorbent assay (ELISA) and Western blot. The detection limit of our MAMVE copolymer microarrays was 50-fold lower than that of the classical ELISA. Furthermore, 100-fold less volume of biological samples was required with these miniaturized immunoassays.

Tratamiento endoscópico del reflujo vesicoureteral: hallazgos histológicos / Endoscopic treatment of vesicoureteral reflux: histologic findings

Objetivo: El reflujo vesicoureteral es una patología con diferentes formas de manejo terapéutico, una de las cuales es la inyección vía endoscópica de diferentes materiales. Mostramos algunos cambios histológicos que producen estos materiales en la pared vesical. Métodos: Estudiamos 3 muestras de uréter intravesical en 3 niños afectos de reflujo vesicoureteral. Las muestras se obtuvieron durante la reimplantación de los uréteres, extirpando la porción más distal de los uréteres. Resultados: Mostramos los cambios encontrados con los diferentes materiales estudiados (politetrafluoroetileno, polidimetilsiloxano, copolímero de dextranómero y ácido hialurónico) observando una menor formación de tejido conjuntivo con los 2 últimos. Conclusiones: Se describen migraciones y granulomas con diferentes materiales y se constata la reacción de cuerpo extraño y fibrosis en la pared vesical. Son necesarios más estudios en humanos para determinar el mejor producto de inyección endoscópica (AU)

Objectives: Vesicoureteral reflux is a pathologic entity with different forms of therapeutic management, one of which is endoscopic injection of various materials. We show some histological changes produced by these materials in the bladder wall. Methods: We study three samples of intravesical ureter from three children suffering vesicoureteral reflux. The ureters were obtained during ureteral reimplantation surgery. Results: We show the changes found with various materials under study (polytetrafluorethylene, polydimethylsiloxane, hyaluronic acid and dextranomer copolimer) observing less conjunctive tissue with the two latter and with the more encapsulated hyaluronic acid - dextranomer copolimer. Conclusions: Migrations and granulomas are described with various materials and we ascertained the presence of foreign body reaction and fibrosis within the bladder wall. More studies in human beings are required to determine the best product for endoscopic injection (AU)

Tratamiento de reflujo vesicoureteral / The treatment of vesicoureteral reflux

Objetivo: El reflujo vesicoureteral (RVU) es una patología frecuente, con una incidencia de 29/50% en niños estudiados por infección del tracto urinario (ITU) y de 20% en recién nacidos con diagnóstico pre-natal de hidronefrosis. A lo largo de los años, la terapéutica ha sido motivo de muchas reuniones, de muchos trabajos de investigación y continúa siendo un tema discutido. Con el desarrollo de técnicas endoscópicas de mínima invasión, por inyección sub-ureteral de “bulking agents”, el grupo de candidatos a tratamiento quirúrgico aumentó. Presentamos los resultados del tratamiento quirúrgico de RVU de 2001 a 2006. Métodos: Se realizó un estudio retrospectivo de tratamiento endoscópico de RVU con inyección sub-ureteral de copolimero de dextranomero ácido hialurónico (Copol-Dx/AH). Se incluyeron todos los niños tratadas en el periodo comprendido entre 1/ Julio/ 2001 a 30/ Diciembre/ 2006. El tratamiento se realizó en niños con un reflujo mínimo de grado II o superior. Se consideró tratados a los pacientes que presentaban una CUMS de control sin reflujo o con reflujo vesico ureteral grado I, proponiéndose en estos casos la suspensión de la profilaxis antibiótica de ITU. Resultados: Se trataron 661 niños, 607 por vía endoscopia y 54 por técnica de Cohen. De los niños tratados endoscopicamente, 437 eran de sexo femenino y 170 de sexo masculino. El RVU era bilateral en 37,7% de los casos, siendo el grado II el más frecuente (40% en el sexo masculino y 57% en el femenino). La tasa global de éxito fue de 70% después del primer tratamiento, de 75% después del segundo tratamiento y subió para 78% después del tercero. Conclusiones: La inyección sub-ureteral de copolímero de dextranomero ácido hialurónico es un tratamiento eficaz en niños con RVU, con indiferencia del grado de reflujo. Es un procedimiento sencillo, seguro, bien tolerado y con baja morbilidad. Es, en este momento, el tratamiento quirúrgico de elección en la mayor parte de los pacientes con RVU (AU)

Objectives: Vesicoureteral reflux (VUR) is a frequent pathology, with an incidence of 29/50% in children studied for urinary tract infection (UTI) and 20% of newborns with the diagnosis of prenatal hydronephrosis. Over the years, the treatment has been the subject of many meetings, many research studies, and continues being a topic under discussion. The number of candidates for surgical treatment increased with the development of minimally invasive endoscopic techniques by subureteral injection of bulking agents. We present the results of the surgical treatment of VUR between 2001 and 2006. Methods: We performed a retrospective study of the endoscopic treatment of VUR by subureteral injection of Dextranomer and hyaluronic acid copolymer (Copol-Dx/AH). All children undergoing treatment between July 1st 2001 and December 30th 2006 were included in this study. Treatment was performed in children with VUR grade II or greater. All patients presenting no reflux or grade I VUR on control VCUG were considered cured; stopping antibiotic prophylaxis was proposed in these cases. Results: 661 children underwent treatment, 607 endoscopic and 54 with the Cohen technique. Among children treated endoscopically, 437 where females and 170 males. VUR was bilateral in 37.7% of the cases, with grade II being the most frequent (40% in males and 57% in females). Overall success rate was 70% after first treatment, 75% after second treatment and increased to 78% after the third. Conclusions: Subureteral injection of dextranomer and hyaluronic acid copolymer is an effective treatment in children with VUR, independently of the grade. It is a simple, safe, well tolerated procedure with low associated morbidity. Currently, it is the surgical treatment of choice in most patients with VUR (AU)

Endoscopic treatment of vesicoureteral reflux in the previously reimplanted ureter: technical aspects and results / Tratamiento endoscópico del reflujo vesicoureteral en el uréter previamente reimplantado: aspectos técnicos y resultados

Objectives: To assess the feasibility and results of the endoscopic treatment of vesicoureteral reflux (VUR) after a failed ureteral reimplantation. Methods: From January 1996 to October 2006, 28 patients underwent endoscopic treatment for VUR grade II to V persisting after open ureteral reimplantation. VUR was bilateral in 11 patients, for a total of 39 ureteral units (UU) treated. The endoscopic treatment was performed 1 to 7 years after surgery (average 2.5 years). Dextranomer/Hyaluronic acid Copolymer (Dx/HA) was used as injectable material. The amount of injected material ranged from 0.5 to 2.8 ml (average: 1.2 ml). Some technical refinements were required to increase the success of the procedures. Patients were followed up from 2.5 to 17 years. Voiding cystourethrogram (VCUG) was performed at 6 months and MAG3 renal scan with voiding phase at 24 months. Results were compared with the outcome of the endoscopic treatment in patients treated by the same surgeons for primary VUR, matched for grade (control group). Results: All treatments were performed as one-day procedure. No complications were observed. Success was achieved in 22/28 patients (78.5%) and in 30/39 UU (76.9 %) after failed ureteral reimplantation. No significant difference in success rate was found from the control group (p= ns). Conclusions: Endoscopic treatment of VUR after a failed reimplantion can be a challenging procedure, for a skilled endoscopists. Nonetheless it can achieve successful results in a high percentage of patients with minimal morbidity and a minimal invasiveness; it should thus be recommended for these patients (AU)

Objetivo: Evaluar la viabilidad y resultados del tratamiento endoscópico del reflujo vesicoureteral (RVU) después del fracaso del reimplante ureteral. Métodos: Entre enero de 1996 y octubre del 2006, 28 pacientes fueron sometidos a tratamiento endoscópico del RVU persistente grados II a V después de reimplante ureteral. El RVU era bilateral en 11 pacientes, con un total de 39 uréteres tratados. El tratamiento endoscópico se realizó entre 1 y 7 años después de la cirugía (media 2,5 años). Como material inyectable se utilizó copolímero de ácido hialurónico/dextranomero. La cantidad de material inyectado varió entre 0,5 y 2,8 ml (media 1,2 ml). Fue necesaria alguna finura técnica para aumentar el éxito de los procedimientos. Los pacientes fueron seguidos entre 2,5 y 17 años. Se realizó cistouretrografía miccional seriada (CUMS) a los seis meses y gammagrafía renal MAG3 con fase miccional a los 24 meses. Los resultados se compararon con los de un grupo control de tratamiento endoscópico en pacientes con RVU primario tratados por los mismos cirujanos, emparejados según el grado. Resultados: Todos los tratamientos fueron realizados de forma ambulatoria. No se observaron complicaciones. Se obtuvo el éxito en 22/28 pacientes (78 .5%) y en 30/39 uréteres (76. 9%) después de un reimplante fallido. No hubo diferencias significativas en las tasas de éxitos comparando con el grupo control (p =ns). Conclusiones: El tratamiento endoscópico del RVU después del fracaso de un reimplante puede ser un desafío para un endoscopista experto. Sin embargo puede conseguir resultados exitosos en un alto porcentaje de pacientes con mínima morbilidad en pasividad. Por tanto, debería recomendarse en estos pacientes (AU)

Modification of the sting procedure for vesicoureteral reflux: ureteral repositioning and injection / Modificación del procedimiento de inyección subureteral estándar (STING) para el reflujo vesico ureteral: reposicionamiento ureteral e inyección

Objetive: Over the past 20 years endoscopic treatment (ET) of vesicoureteral reflux (VUR) has changed the algorithm of reflux management. We describe a modification of the standard subureteral injection (STING) that has contributed to the increased success rate of this procedure. Methods: Between January 2006 and December 2006 192 children, 5 months to 10 years old (mean age 2.8 years) underwent endoscopic treatment for VUR, with injection of dextranomer/hyaluronic acid copolymer (Dx/HA). Standard STING procedure was used in 165 patients (235 ureters). A modified STING procedure, here described as “ureteral repositioning and injection” (URI) was used in 27 patients (38 ureters). In the URI technique, the needle was inserted as for standard STING; subsequently the distal part of the ureter was raised and levered towards the lumen of the bladder; Dx/HA was then injected. Renal/bladder ultrasound was performed 1 month after treatment and a voiding cystourethrogram (VCUG) at 4-6 months. Results: After a single injection the VCUG showed no reflux in 203 ureters of STING group (86%) and in 34 ureters of URI group (91%). Mean injected volume of Dx/HA was 0.7 ml (0.3 - 1.8 ml) for STING and 0.4 ml (0.3 - 0.8 ml) for URI. Conclusion: The modified STING we have proposed, presents some advantages. It is very easy to perform and needs less material to inject. The ureteral repositioning into the bladder, with the support of the implanted material, may reconstruct a true flap-valve mechanism, without the risk of ureteral obstruction (AU)

Objetivo: Durante los últimos 20 años el tratamiento endoscópico del reflujo vesicoureteral (RVU) ha cambiado el algoritmo del manejo de esta entidad. Describimos una modificación de la inyección subureteral estándar (STING) que ha contribuido a aumentar el porcentaje de éxitos de este procedimiento. Métodos: Entre enero y diciembre del 2006, 192 niños, entre cinco meses y diez años de edad (edad mediana 2,8 años), fueron sometidos a tratamiento endoscópico del reflujo vesico ureteral con inyección de copolímero de dextranomero/ácido hialurónico (DX/HA). El procedimiento STING estándar se utilizó en 165 pacientes (235 uréteres). Un procedimiento STING modificado, descrito aquí como “reposicionamiento ureteral e inyección” (RUI) se utilizó en 27 pacientes (38 uréteres). En la técnica de reposicionamiento ureteral e inyección se inserta la aguja como para un procedimiento STING estándar y posteriormente se eleva la porción distal del uréter haciendo palanca hacia la luz vesical y entonces se inyecta el DX/HA. Se realizó ecografía renal/vesical un mes después del tratamiento y una cistouretrografía miccional seriada (CUMS) a los 4-6 meses. Resultados: Después de una única inyección la CUMS mostró ausencia de reflujo en 203 uréteres del grupo STING (86%) y 34 uréteres del grupo RUI (91%).El volumen medio de DX/HA inyectado fue de 0,7 ml (0,3-1,8 ml) en el STING y 0,4 ml (0,3-0,8 ml) en el RUI. Conclusiones: La modificación del STING que proponemos tiene algunas ventajas. Es muy fácil de realizar y necesita menos material inyectable. El reposicionamiento ureteral hacia la vejiga, con el apoyo del material implantado, puede reconstruir un auténtico mecanismo de válvula-flap sin riesgo de obstrucción ureteral (AU)

Vantris®, a biocompatible, synthetic, non-biodegradable, easy-to-onject bulking substance. Evaluation of local tissular reaction, localized migration and long-distance migration / Vantris® una sustancia inyectable biocompatible, sintética, no biodegradable y fácil de aplicar: Evaluación de la reacción tisular local, y de la migración local y a larga distancia

Biodegradable injectable bulking agents of animal origin present a fast rate of bio-reabsorption and may cause an allergic reaction. Biodegradable elements of synthetic origin have a high rate of reabsorption after a year. Non-biodegradable agents of synthetic origin lead to the formation of a fibrotic capsule, giving stability and long-term permanence. VANTRIS® is categorized into this last group; it belongs to the family of Acrylics, particles of polyacrylate polyalcohol copolymer immersed in a glycerol and physiological solution carrier. Molecular mass is very high. When injected in soft tissues, this material causes a bulkiness that remains stable through time. The carrier is a 40% glycerol solution with a pH of 6. Once injected, the carrier is eliminated by the reticular system through the kidneys, without metabolizing. Particles of this polyacrylate polyalcohol with glycerol are highly deformable by compression, and may be injected using a 23-gauge needle. The average of particles size is 320 mm. Once implanted, particles are covered by a fibrotic capsule of up to 70 microns. Particles of this new material are anionic with high superficial electronegativity, thus promoting a low cellular interaction and low fibrotic growth. The new polyacrylate polyalcohol copolymer with glycerol was tested for biocompatibility according to ISO 10993-1:2003 in vitro, showing that they are not mutagenic for the Salmonella T. strains analyzed. The extract turned out to be non-cytotoxic for cell lines in culture and non-genotoxic for mice. In in vivo studies, acrylate did not cause sensitization in mice. The macroscopic reaction of tissue irritation was not significant in subcutaneous implants and in urethras of rabbits. Seven female dogs were injected transurethrally with VANTRIS® to evaluate short and long-term migration (13 weeks and 12 months respectively). No particles or signs of inflammation or necrosis are observed in any of the organs examined 13 weeks and 12 months after implantation. To conclude, this new material meets the conditions of ideal tissue bulking material (AU)

Los agentes inyectables biodegradables de origen animal presentan una tasa rápida de bioreabsorción y pueden provocar reacciones alérgicas. Los elementos biodegradables de origen sintético tienen una alta tasa de reabsorción después de un año. Los agentes no-biodegradables de origen sintético dan lugar a la formación de una cápsula fibrótica, dando estabilidad y permanencia a largo plazo. VANTRIS® se clasifica en este último grupo; pertenece a la familia de los acrílicos, partículas de copolímero poliacrida polialcohol inmersas en una solución vehiculante de glicerol y fisiológico. Su masa molecular es muy alta. Cuando se inyecta en tejidos blandos, este material produce un abultamiento que permanece estable a lo largo del tiempo. El vehículo contiene un 40% de solución de glicerol con un pH de 6. Una vez inyectada, el vehículo es eliminado por el sistema reticular a través de los riñones, sin metabólizar. Las partículas de este poliacrilato polialcohol con glicerol son altamente deformables por compresión, y pueden inyectarse utilizando una aguja del 23 Gauge. El tamaño medio de las partículas es de 320 mm. Una vez implantadas, las partículas se recubren de una cápsula fibrótica de hasta 70 micrones. Las partículas de este nuevo material son aniónicas y tienen una gran electronegatividad en superficie, promoviendo así una baja interacción celular y un bajo crecimiento fibrótico. El nuevo copolímero de poliacrilato polialcohol con glicerol fue sometido a pruebas de biocompatibilidad in vitro de acuerdo con la normal ISO 10993-1:2003, mostrando que no es mutagénico para las cepas de salmonela T. analizadas. El extracto no fue citotóxico en cultivos de líneas celulares ni en ratones. En los estudios in vivo, el acrilato no produjo sensibilización en ratones. Los implantes subcutáneos y en uretra de conejos no produjeron reacción de irritación tisular macroscópica significativa. Para evaluar la migración a corto y largo plazo se inyectó Vantris® por vía transuretral en siete hembras de perro (13 semanas y 12 meses respectivamente). No se observaron partículas o signos de inflamación con necrosis en ninguno de los órganos examinados ni a las 13 semanas ni a las 12 meses del implante. En conclusión, este nuevo material cumple con las condiciones del material inyectable tisular ideal

Tratamiento endoscópico del reflujo vésicoureteral en pacientes pediátricos diagnosticados de vejiga neurógena. Resultados y evolución a largo plazo / Endoscopic treatment of vesicoureteral reflux in pediatric patients with the diagnosis of neurogenic bladder. Results and long-term outcome

Objetivo: Conocer los resultados, complicaciones y la evolución de ocho pacientes diagnosticados de Vejiga neurógena (VN), intervenidos de Reflujo vesicoureteral (RVU) mediante la inyección subureteral de sustancias inertes, intentando precisar su indicación en el esquema terapéutico de la alteración vesical neurógena. Métodos: Revisión retrospectiva de los resultados obtenidos y de las complicaciones evidenciadas durante los controles evolutivos efectuados a ocho pacientes en edad pediátrica con VN secundaria a diferentes patologías, diagnosticados de RVU, tratado mediante inyección subureteral de pasta de teflón (1 caso), polidimetilsiloxano (6) y copolímero de dextranómero y ácido hialurónico (1). Resultados: De los 11 uréteres tratados en 8 (72.7%) el RVU curó después de la primera inyección. De los 3 uréteres con persistencia del RVU, en dos cesó después del segundo tratamiento endoscópico (TE). La eficacia del TE después de la segunda inyección alcanzó el 90.9%. En dos casos unilaterales evidenciamos RVU contralateral que curó mediante TE en uno siguiendo pauta conservadora el segundo. Durante el periodo de seguimiento (tiempo medio: 51.8 +/- 28.5 meses) presentaron complicaciones 4 casos. Reapareció el RVU en dos, observamos RVU contralateral en uno a los 19 meses del primer tratamiento y en otro evidenciamos ureterohidronefrosis bilateral con infecciones urinarias recurrentes que precisó de cistoplastia de aumento. Conclusiones: El TE es una opción eficaz cuando se decide el tratamiento quirúrgico del RVU en un paciente con vejiga neurógena. Es necesario seguir la evolución a largo plazo de los pacientes intervenidos, sobre todo aquellos con capacidad y acomodación vesical alterada y uretra activa o disinérgica, ante la posibilidad de aparición del RVU ya curado (AU)

Objectives: To know the results, complications and outcomes of eight patients with the diagnosis of neurogenic bladder (NB) who underwent vesicoureteral reflux surgery by subureteral injection of inert substances, trying to precise its indication in the therapeutic scheme for neurogenic bladder dysfunction. Methods: Retrospective review of the results and complications recorded during follow-up in eight pediatric patients with NB secondary to various pathologies and the diagnosis of VUR treated by subureteral injection of Teflon paste (1 case), polydimethylsiloxane (6) and dextranomer/hyaluronic acid copolymer (1). Results: In 8 (72.7%) of the 11 ureters treated VUR was cured after first injection. VUR stopped after second endoscopic treatment in 2 of the 3 ureters with persistent VUR. The efficacy of endoscopic treatment after second injection achieved 90.9%. In 2 unilateral cases we observed contralateral VUR, which cured in one case after endoscopic treatment and the other one followed a conservative scheme. Over the follow-up period (Mean FU time 51.8+/- 28.5 months) 4 cases presented complications. VUR recurred in two: in one contralateral VUR was detected 19 months after first treatment, the other one presented bilateral ureterohydronephrosis with recurrent urinary tract infections and required augmentation cystoplasty. Conclusions: Endoscopic treatment is an effective option when choosing surgical treatment for VUR in a patient with neurogenic bladder. It is necessary to follow the long-term outcome of patients after surgery, mainly those with abnormal bladder capacity and compliance and active or dyssynergic urethra due to the possibility of recurrence of the VUR (AU)

Eficacia del tratamiento endoscópico del reflujo vesicoureteral secundario. Análisis de una serie de 142 casos / The efficacy of endoscopic treatment for secondary vesicoureteral reflux. Analysis of a series of 142 cases

Objetivo: Analizar la proporción de reflujos vesicoureterales secundarios o complicados del total de reflujos vesicoureterales tratados en nuestro centro. Determinar la eficacia del tratamiento endoscópico en dicho tipo de reflujo según la etiología que lo produce y según el grado. Método: Revisamos nuestra serie desde que iniciamos el tratamiento endoscópico del reflujo en el año 1992 hasta diciembre del 2006, empleando tres materiales distintos: pasta de politetrafluoroetileno (Teflon®), polidimetilsiloxano (Macroplastique®) y dextranómero-copolímero de ácido hialurónico (Deflux®). Hemos tratado a 402 pacientes y 479 unidades excretoras, de los que 124 pacientes y 142 unidades excretoras correspondían a una etiología secundaria. Se han seguido de forma sistemática mediante ecografía y CUMS o cistografía isotópica. Definimos el éxito del tratamiento como la desaparición del RVU o el descenso a grado I sin ITU tras retirar la profilaxis antibiótica. Resultados: Se resolvieron en el primer intento el 71,13% de los reflujos secundarios, mejorando al 85,92% en el segundo intento y al 90,14% en el tercero. El volumen medio inyectado ha sido de 0,65 ml. La tasa de complicaciones ha sido del 0%. Conclusiones: El tratamiento endoscópico del reflujo vesicoureteral secundario es un procedimiento minimamente invasivo, que puede realizarse en regimen ambulatorio, técnicamente algo más difícil que en los casos de reflujo vesicoureteral primario, pero con muy baja morbilidad y muy eficaz en casos seleccionados, por lo que pensamos que debe ser considerado la primera opción de tratamiento. La menor eficacia la hemos obtenido en los casos de reflujos secundarios a vejiga neurógena, probablemente en relación a un mal control de las altas presiones vesicales (AU)

Objectives: To evaluate the rate of secondary or complicated vesicoureteral reflux (VUR) among the total number of VUR cases treated in our institution. To determine the efficacy of the endoscopic treatment in secondary or complicated VUR depending on etiology and grade. Method: We review our experience with endoscopic treatment for VUR from 1992 to 2006. We have used three different materials: polytetrafluoroethylen (Teflon®), polydimethylsiloxane(Macroplastique®) and dextranomer/hyaluronic acid copolymer (Deflux®). 479 ureters with VUR were treated in 402 patients ; 124 patients and 142 ureters of them were secondary or complicated VUR cases. All patients were followed up with urinary tract ultrasound and radiological or isotopic voiding cystogram. Success is defined as VUR disappearance or improvement to grade I VUR without urinary infection after removing antibiotic prophylaxis. Results: The success rate has been 71.13% after the first injection, 85.92% after the second injection and 90.14% after the third injection. Mean subureteral dose has been 0.65 ml. The complications rate has been 0%. Conclusions: The endoscopic treatment in secondary or complicated VUR is a minimally invasive procedure. It seems to be more difficult than in primary VUR cases, but its low morbidity and efficacy indicate this may be a proper first option in selected patients. In cases of VUR secondary to neurogenic bladder dysfunction it seems to be less successful, probably because of a worse control of the high bladder pressure (AU)

Una buena solución para un mal caso / A good solution for a bad case

Se presenta el caso de un varón afecto de reflujo, después de haber realizado un reimplante ureteral y aún después de haberle realizado un tratamiento endoscópico adicional. Al realizar una segunda cistoscopia para practicar un nuevo tratamiento endoscópico, se descubrió un orificio en el tercio medio del túnel del reimplante ureteral previo que actuaba de «shunt» y mantenía el reflujo. El paciente fue tratado exitosamente mediante la oclusión del orificio que mantenía este reflujo con una nueva inyección de «Dextranómero/Nasha» (AU)

We present the case of a child presenting vesicoureteral reflux after ureteral reimplantation and endoscopic treatment. In a second cistoscopy to repeat endoscopic treatment a new orifice in the medium third of the tunnel of the previous ureteral reimplantation was discovered. This orifice acted as a shunt and maintained reflux. The patient was treated by further occlusion of the orifice with another injection of «tranómero/Nasha» (AU)

[Structure and antiviral activity of adamantane-containing polymer preparation]. / Struktura i antivirusnaia aktivnost' adamantansoderzhashchikh polimernykh preparatov.

New water-soluble antiviral chemical agents, containing 10 to 30% of adamantane derivatives (amino-, aminopropyl-adamantane-, aminomethyl- and rimantadine), which were conjugated with polycarboxylic matrixes of the divinyl ether and maleic anhydride copolymers (DIVEMA), were developed. The polymeric drugs exhibited a low cytotoxicity (4 to 10 times less than rimantadine) and a wide spectrum of antiviral activity against influenza viruses, including both the remantadine-resistant strains of A/PR/8/34 (H1N1) and the B/Saint-Petersburg strain/71/77 as well as against herpes viruses of type 1, parainfluenza viruses of types 1 and 3 and RS-virus. A reduction of the viral infection titer in their reproduction in sensitive cells' cultures was more than 2.0 Ig ID50. Complete inhibition of viral-specific syntheses, registered by immune-enzyme assay (IEA) and by hemagglutination test was observed at low infection doses ranging from 1 to 100 ID50. The efficiency of the antiviral effect depends on a drug's molecular weight and a structure of chemical bonds between the adamantane nucleus and the polymeric matrix.

Nonspecific stimulation of the maternal immune system. I. Effects On teratogen-induced fetal malformations.

BACKGROUND: Maternal immune stimulation has reported, but unconfirmed, efficacy for reducing chemical-induced morphologic defects in mice. METHODS: Teratogenic chemicals (2,3,7, 8-tetrachlorodibenzo-p-dioxin [TCDD], ethyl carbamate [urethane], methylnitrosourea [MNU], or valproic acid [VA]) were given to pregnant mice to induce cleft palate (TCDD, urethane), digital defects (urethane, MNU), or exencephaly (VA). Before teratogen administration, the immune system of female mice was stimulated by intraperitoneal (IP) administration of pyran copolymer or attenuated bacillus Calmette Guérin (BCG), or by footpad injection with Freund's complete adjuvant (FCA). RESULTS: Fetal defects caused by all four chemicals studied were reduced by maternal immunostimulation, sometimes dramatically. In addition to reducing VA-induced exencephaly, immunostimulation with FCA resulted in fetal mice displaying anury (absence of tails). Activated maternal immune cells could not be detected in fetal circulation using flow cytometry and a fluorescent cell-tracking probe. CONCLUSIONS: For the chemicals tested, maternal immune stimulation has efficacy in reducing fetal defects. Immune protection against teratogenesis may be an indirect effect of maternal immune cell activation.

Effectiveness of a simply designed tumor vaccine in prevention of malignant melanoma development.

We investigated the efficacy of a simple syngeneic tumor vaccine to induce specific antitumor immunity in female C57Bl/6 mice. Tumor vaccine was prepared by mixing irradiated B-16 melanoma tumor cells with the pleiotropic biological response modifier-maleic anhydride divinyl ether (MVE-2). Experimental animals were pretreated with the vaccine in order to prevent the development of intraperitoneal (i.p.) B-16 melanoma tumors after inoculation of viable tumor cells. More than 40% of prevaccinated animals challenged i.p. with 5 x 10(5) viable tumor cells were completely protected from tumor development and remained tumor-free 100 days after tumor cell inoculation. The percentage of tumor-free animals (survivors) rose to as much as 90% when the application of tumor vaccine was repeated two weeks after the first vaccination (i.e. one week after the inoculation of viable tumor cells). The induced antitumor response depended predominantly upon macrophage function, since vaccinated animals which were depleted of peritoneal macrophages died within the same time range as animals in the control group. Also, tumor-type specificity of the vaccine was confirmed by the fact that the animals vaccinated with B-16 melanoma vaccine were not protected from the development of another type of tumor. In conclusion, comparison of the experimental data with the data from the literature suggests that our simple tumor vaccine may be as effective as genetically engineered tumor vaccines. At the same time, this kind of vaccine is easier to control and thus safer to apply in humans when compared to genetically engineered vaccines.

Prevention of hepatic ischemia-reperfusion injury by SOD-DIVEMA conjugate.

A protective effect of the SOD (superoxide dismutase)-DIVEMA (divinyl ether and maleic anhydride) conjugate on I-R (ischemia-reperfusion) liver injury was demonstrated. Twenty minutes of normothermic hepatic ischemia was induced by clamping the portal triad of Sprague-Dawley rats. Five minutes before the end of ischemia, SOD, SOD-DIVEMA, or NaCl (0.9%) was given intravenously. Using intravital fluorescence microscopy, hepatic microvascular perfusion was analyzed before ischemia and repeatedly during the 120-min reperfusion period. SOD-DIVEMA significantly restored the sinusoidal perfusion rate (control, 98.0 +/- 0.5; NaCl, 65.5 +/- 7. 7; SOD, 81.5 +/- 8.2; SOD-DIVEMA, 95.8 +/- 0.7%) and reduced the number of leukocytes stagnant in acini (control, 4.4 +/- 0.9; NaCl, 36.6 +/- 6.3; SOD, 27.7 +/- 6.8; SOD-DIVEMA, 12.3 +/- 3.3 cells/lobule) and adherent in postsinusoidal venules (control, 55.0 +/- 24; NaCl, 417 +/- 63; SOD, 253 +/- 58; SOD-DIVEMA, 40.0 +/- 14 cells/mm2). In addition, SOD-DIVEMA maintained postischemic hepatocellular integrity. The SOD-DIVEMA-treated group revealed higher serum SOD enzyme activity compared to the SOD group after 120 min of reperfusion (SOD-DIVEMA, 33.0 +/- 5.9; SOD, 8.6 +/- 3.1 U/ml). The beneficial effect of SOD-DIVEMA was most prominent after 120 min of reperfusion, indicating a longer intravascular half-life of SOD-DIVEMA.

An effective tumor vaccine against malignant melanoma: irradiated autologous tumor cells admixed with MVE-2.

The aim of this study was to develop as effective as possible autologous tumor vaccine which would be at the same time easy to produce, highly controllable, and without undesired side effects on normal tissue. Therefore, irradiated autologous - syngeneic B-16 tumor cells admixed with a non-specific immunomodulator MVE-2 (a polymer fraction of 1,2-co-polymer of divinyl ether and maleic anhydride) were used for subcutaneous (s.c.). or intraperitoneal (i.p.) prevaccination of experimental mice. Compared to the control mice, a statistically significant delay in tumor development of s.c. tumors was achieved in prevaccinated mice (p<0.05). An even better effect was observed in mice challenged i.p. with viable tumor cells. Using a single prevaccination complete protection was obtained in between 40-85% of the experimental mice. When the survivors from the groups injected once with the tumor vaccine were rechallenged with viable tumor cells (101 day after the first tumor challenge, no additional prevaccination), 15.7% remained free of tumor, while the survivors from the groups injected with the tumor vaccine twice and 101 day later rechallenged with viable tumor cells remained free of tumor in 60% of the cases. Based on these results we can postulate that our vaccine is effective for prevention of tumor development. The achieved protection can be augmented with serial vaccinations and can be maintained for a longer period of time.