Preclinical evaluation of common markers and iohexol for the development of intestinal permeability tests in dogs : Studies on laboratory Beagle dogs and Sprague-Dawley rats

Intestinal permeability testing is the specific method to assess for a defective intestinal epithelial barrier. Intestinal permeability measurements are considered helpful and non-invasive means to evaluate intestinal mucosal damage for both scientific (particularly) and clinical purposes, and have been widely used in laboratory rodents and humans. Despite their many advantages, permeability tests have not gained widespread use as a testing option for the detection and management of canine intestinal disorders in veterinary clinical research. The main reasons for this may include the lack of an optimal biomarker for permeability testing, impracticalities involving current testing methodologies, and inconsistencies in test results that have been found by investigators using these tests. Chromium 51-labeled ethylenediamine tetra-acetic acid (51Cr-EDTA) is widely considered the most accurate intestinal permeability probe, but the use of radioactivity is a major drawback. Sugar biomarkers such as lactulose and rhamnose have been more commonly used in the recent years, but they have been associated with marked inconsistencies in the test results. Iohexol is a contrast medium commonly used in radiology for diagnostic purposes in human and veterinary patients, but this molecule has more recently been successfully used for the screening of gut mucosal damage in laboratory rats and humans. The main advantage of iohexol is that its use does not involve radioactivity, nor is it degraded in the intestinal lumen. Furthermore, it has the potential to be quantified by different analytical techniques. The main objective of this project was to improve the methodology of the intestinal permeability tests in dogs in order to make the testing simpler, more practical and accurate for veterinarians and researchers using this approach to investigate intestinal mucosal damage and disorders associated with a defective intestinal epithelial barrier. An additional objective was to preliminarily assess the use of iohexol as a novel intestinal permeability marker for use in dogs. The work consisted of preclinical comparisons of the most relevant intestinal permeability markers including 51Cr-EDTA, lactulose and rhamnose, and iohexol performed in both urine and blood tests using laboratory dog and rat models. In conclusion, studies on the percentage urinary recovery of 51Cr-EDTA, lactulose, and rhamnose, as well as D-xylose, 3-O-methyl-D-glucose, and sucrose after their oral simultaneous administration provided normative data for healthy adult male Beagle dogs. The analysis revealed a discrepancy in the percentage urinary recovery between 51Cr-EDTA and lactulose, suggesting that these two markers are not as equivalent as has so far been believed based on previous studies in humans and cats. It was also concluded that the use of a single marker provides comparable test results to the use of two markers, as evidenced by a comparison of recovery values from 51Cr-EDTA and lactulose versus their correspondent ratio against rhamnose. This supports the hypothesis that, in contrast to the dual sugar test, the use of one inert larger probe may be sufficient for permeability testing, and the testing procedure may consequently be considerably simplified. The studies also demonstrated that the 51Cr-EDTA permeability blood test based on the collection of at least two serum or plasma specimens gives comparable results to the 6-h cumulative urine test. The blood approach is much easier than the urine-based test, as it avoids the constraints associated with urine collection in dogs. Iohexol was shown to have a clear relationship with 51Cr-EDTA in serum levels when they were simultaneously administered to Beagle dogs. When it was used as an intestinal permeability probe in laboratory rats before and after the induction of a well-characterized experimental form of inflammatory bowel disease, it was also possible to clearly discriminate between healthy animals and rats with intestinal mucosal damage. The iohexol blood test can therefore be considered a promising tool for assessing canine intestinal permeability in veterinary clinical research. Nevertheless, further studies using iohexol as intestinal permeability blood marker, particularly in diseased dogs, are warranted before firm conclusions can be made on the validity of this test.Yleisten merkkiaineiden ja joheksolin laboratorioarviointi ja koiran suolen läpäisevyystutkimusten kehittäminen beaglekoirilla ja Sprague–Dawley-rotilla. Suolen läpäisevyystesteillä tutkitaan, onko suolen pintaepiteelissä vaurio. Näitä testejä on käytetty runsaasti laboratoriojyrsijöillä ja ihmisillä ja ne ovat hyödyllisiä ja kajoamattomia suolen limakalvovaurion tutkimuskeinoja sekä (etenkin) tutkimuksessa että hoidossa. Monista eduista huolimatta näitä testejä ei vielä käytetä laajasti koirien suolistosairauksien diagnosointiin ja hoitoon. Tämä johtunee lähinnä siitä, että testaukseen sopivaa optimaalista biomarkkeria ei ole, nykyiset testausmenetelmät ovat hankalia ja tulosten on huomattu vaihtelevan. 51Cr-EDTAa pidetään tarkimpana suolen läpäisevyyden markkerina, mutta se on radioaktiivista. Sokeribiomarkkereiden kuten laktuloosin ja ramnoosin käyttö on laajentunut viime vuosina, mutta testitulokset ovat vaihdelleet huomattavasti. Joheksoli on ihmisillä ja eläimillä yleisesti käytetty röntgenvarjoaine, jota on käytetty myös suolen limakalvovaurioiden seulontaan laboratoriorotilla ja ihmisillä. Joheksoli ei ole radioaktiivista eikä hajoa suolessa, ja sen määrä pystytään mittaamaan eri tekniikoilla. Tutkimuksen päätavoitteena oli kehittää suolen läpäisevyystestausta, jotta koirat voitaisiin tutkia aiempaa helpommin, kätevämmin ja tarkemmin suolen limakalvovaurioiden ja suolen epiteeliä vaurioittavien tautien varalta. Tutkimuksessa arvioitiin myös alustavasti joheksolin käyttöä uutena suolen läpäisevyyden merkki-aineena koirilla. Tutkimuksessa verrattiin prekliinisesti tärkeimpiä suolen läpäisevyyden merkkiaineita, mm. 51Cr-EDTAa, laktuloosia, ramoosia ja joheksolia, laboratoriokoirien ja rottien virtsa- ja verinäytteiden avulla. Tulokset 51Cr-EDTAn, laktuloosin, ramnoosin, D-ksyloosin, 3-O-metyyli-D-glukoosin ja sakkaroosin erittymisestä virtsaan tuottivat tietoa terveiden aikuisten urosbeaglejen viitearvoista. 51Cr-EDTAn ja laktuloosin prosentuaalisessa erittymisessä virtsaan havaittiin eroja, joten nämä merkkiaineet saattavat erota toisistaan enemmän kuin ihmis- ja kissakokeiden perusteella on luultu. 51Cr-EDTAn ja laktuloosin erittymisen ja niiden ja ramnoosin erittymissuhteen vertailu osoitti, että yhdellä merkkiaineella saadaan yhtä hyvät tulokset kuin kahdella. Tämä tukee käsitystä, että testaus voidaan toteuttaa kahden sokerin sijasta vain yhdellä inertillä, suurimolekyylisellä merkkiaineella, mikä voi helpottaa suuresti testausta. Tutkimukset osoittivat myös, että 51Cr-EDTAn määritys vähintään kahdesta verinäytteestä tuottaa yhtä hyvät tulokset kuin 6 tunnin virtsankeräykseen perustuva koe. Veritestaus on huomattavasti helpompaa kuin koirien virtsan kerääminen ja testaus. Seerumin joheksoli- ja 51Cr-EDTA-pitoisuuksien todettiin korreloivan selvästi, kun beagleille annettiin molempia. Kun laboratoriorottien suolen läpäisevyyttä tutkittiin joheksolilla sekä ennen kokeellisen tulehduksellisen suolistosairauden induktiota ja sen jälkeen, tuloksista nähtiin selvästi, oliko suolen limakalvo terve vai vaurioitunut. Joheksoliverikoe on siis lupaava työkalu koiran suolen läpäisevyyden arviointiin. Joheksoliverikokeen käyttöä suolen läpäisevyyden tutkimiseen on silti hyvä arvioida tarkemmin etenkin sairailla koirilla ennen kuin kokeen luotettavuudesta tehdään varmoja johtopäätöksiä

Rompendo as ondas e os estereótipos: o surf feminino não é apenas esporte, mas movimento social e insulto às culturas

The purpose of this paper is to demonstrate the theoretical background for phenomena occurring in modern female surfing. It describes the barriers (not only religious or cultural) encountered by women wishing to surf today, which we know from the media. Female surfers not only break the waves but also many socio-cultural barriers and stereotypes. We characterize barriers that can also be found in regions where surfing is treated as a national good or as a good way for healthy lifestyle.El objetivo de este artículo es demostrar los fundamentos teóricos de los fenómenos que ocurren en el surf femenino moderno. Describe las barreras (no solo religiosas o culturales) que enfrentan las mujeres que desean surfear hoy, lo que sabemos por los medios de comunicación. Los surfistas no solo rompen las olas, sino también muchas barreras y estereotipos socioculturales. Caracterizamos las barreras que también se pueden encontrar en las regiones donde el surf es tratado como un activo nacional o un estilo de vida saludable.O objetivo deste artigo é demonstrar os fundamentos teóricos dos fenômenos que ocorrem no surf feminino moderno. Ele descreve as barreiras (não apenas religiosas ou culturais) encontradas pelas mulheres que desejam surfar hoje, as quais conhecemos da mídia. As surfistas não apenas quebram as ondas, mas também muitas barreiras e estereótipos socioculturais. Nós caracterizamos barreiras que também podem ser encontradas em regiões onde o surf é tratado como um bem nacional ou como um bom caminho para um estilo de vida saudável

Betões com incorporação de agregados cerâmicos reciclados

Observa-se atualmente uma preocupação crescente com a preservação dos recursos naturais, a gestão e controlo da sua extração do meio ambiente. A crescente produção de resíduos de construção e demolição (RCD) e os constrangimentos ambientais que isso acarreta, é cada vez mais um problema com proporções a nível mundial. A vontade de contribuir com uma solução para este problema originou a realização deste estudo, focado na avaliação da viabilidade da reutilização dos RCD cerâmicos como agregados no fabrico do betão. A literatura já existente sobre o fabrico de betão com RCD cerâmicos, revelou que os agregados reciclados cerâmicos (ARC) quando substituídos em grande quantidade no betão, originam uma diminuição na resistência do betão, quando comparado com um betão constituído apenas com agregados naturais (AN). Contudo existe uma lacuna na literatura no que respeita a betões realizados com substituição abaixo dos 25% de AN por ARC. Nesta dissertação realizou-se um estudo experimental destinado a apresentar a trabalhabilidade e a resistência à compressão de betões, quando estes são realizados com uma substituição de ARC de 10, 15% e 20% nos AN da sua composição. Os resultados deste estudo mostraram que betões com incorporação de ARC com taxa de substituição de 20% e associados a uma relação água/cimento calculada com base em três critérios, apresentam bons valores, tanto quanto à trabalhabilidade como à resistência à compressão. Estes resultados permitiram concluir a viabilidade da utilização em obra de betões com ARC como substitutos do betão convencional. Este estudo tem uma contribuição teórica e prática para a área de Engenharia Civil

Gestão de Recursos Humanos Satisfação dos Agentes face aos Comandantes de Esquadra

O desempenho de qualquer organização reflecte a contribuição dada pelas pessoas que a constituem, sendo que acrescenta o autor que esta contribuição resulta da gestão dessas mesmas pessoas e do investimento que é feito no seu desenvolvimento (Gomes, 2008). Perante isto podemos afirmar que numa organização encontramos vários elementos que se afirmam como determinantes para a concretização dos objectivos traçados. No entanto existe um que se assume mais importante que todos os outros: as pessoas. Sendo a Polícia de Segurança Pública constituída por cerca de 23000 elementos (à data actual), esta importância do factor humano é evidente. A satisfação e motivação de todas estas pessoas torna-se primordial para a materialização de uma missão institucional definida. Na concepção de Marques (2009) esta satisfação no trabalho é fruto da percepção que cada indivíduo tem do universo organizacional. Os objectivos deste estudo são avaliar o grau de satisfação dos agentes, os quais têm atribuído a árdua tarefa executiva, de carácter operacional. Para esta avaliação recorremos a aplicação de questionários e entrevistas, com o objectivo de revelar não só o nível de satisfação destes elementos, como também clarificar os comportamentos adoptados pelos comandantes de esquadra, em matéria de gestão de pessoas. A nível metodológico, os resultados atingidos decorreram directamente da aplicação do questionário baseado no modelo de “Escala de avaliação do estilo gerencial” (Melo, 2004). Estes resultados foram consolidados através do aprofundamento qualitativo baseado na técnica de entrevista, entroncado a montante na discussão teórica e conceptual mantida, e na sua análise crítica subsequente. Como resultados esperados salienta-se a percepção do nível de satisfação dos agentes face ao seu comandante de esquadra. Para além deste resultado procurámos ainda trabalhar o desenho do perfil comportamental de cada comandante.The performance of any organization reflects the contribution made by the people who constitute it. Moreover, the author states that this has resulted in the management of those same people and the investment made in their development (Gomes,2008). Given this fact, we can say that in an organization we find several elements that are determinant in the achievement of their objectives, however there is one that is more important than the others: the people. Being Polícia de Segurança Pública composed by 23000 elements (up to this date / until present), this importance of the human factor is evident. Satisfaction and motivation of all these people becomes paramount for the realization of a defined institutional mission. In Marques’s (2009) conception, job satisfaction is the result of the perception that each individual has of the organizational universe. The objective of this study is to evaluate/ assess the degree of satisfaction of Agents, which have been assigned the arduous executive task of operational character. For this evaluation, we resorted to the use of questionnaires and interviews, with the aim of revealing not only the level of satisfaction of these elements, as well as/ but also clarifying the behaviors adopted by Police Station Commanders in the field of people management. Methodologically, these results derived directly from the questionnaire based on the model presented by Melo (2004), entitled “Escala de avaliação do estilo gerencial” (“Evaluation scale for management style”). These results were consolidated by qualitative analysis, based on the interview technique, rooted in theoretical discussion and conceptually maintained, and its subsequent critical analysis. As expected results we would like to highlight the perceived level of satisfaction of Agents regarding their Police Station Commander. Beyond this result, we also tried to work the design of the behavioral profile of each commander

Intestinal permeability to iohexol as an in vivo marker of chemotherapy-induced gastrointestinal toxicity in Sprague-Dawley rats

Gastrointestinal toxicity is the most common adverse effect of chemotherapy. Chemotherapeutic drugs damage the intestinal mucosa and increase intestinal permeability. Intestinal permeability is one of the key markers of gastrointestinal function and measuring intestinal permeability could serve as a useful tool for assessing the severity of chemotherapy-induced gastrointestinal toxicity.Peer reviewe

International scientific collaboration in HIV and HPV: a network analysis.

Research endeavours require the collaborative effort of an increasing number of individuals. International scientific collaborations are particularly important for HIV and HPV co-infection studies, since the burden of disease is rising in developing countries, but most experts and research funds are found in developed countries, where the prevalence of HIV is low. The objective of our study was to investigate patterns of international scientific collaboration in HIV and HPV research using social network analysis. Through a systematic review of the literature, we obtained epidemiological data, as well as data on countries and authors involved in co-infection studies. The collaboration network was analysed in respect to the following: centrality, density, modularity, connected components, distance, clustering and spectral clustering. We observed that for many low- and middle-income countries there were no epidemiological estimates of HPV infection of the cervix among HIV-infected individuals. Most studies found only involved researchers from the same country (64%). Studies derived from international collaborations including high-income countries and either low- or middle-income countries had on average three times larger sample sizes than those including only high-income countries or low-income countries. The high global clustering coefficient (0.9) coupled with a short average distance between researchers (4.34) suggests a "small-world phenomenon." Researchers from high-income countries seem to have higher degree centrality and tend to cluster together in densely connected communities. We found a large well-connected community, which encompasses 70% of researchers, and 49 other small isolated communities. Our findings suggest that in the field of HIV and HPV, there seems to be both room and incentives for researchers to engage in collaborations between countries of different income-level. Through international collaboration resources available to researchers in high-income countries can be efficiently used to enroll more participants in low- and middle-income countries

Urinary Excretion of Iohexol as a Permeability Marker in a Mouse Model of Intestinal Inflammation: Time Course, Performance and Welfare Considerations

Intestinal permeability (IP) tests are used to assess intestinal damage in patients and research models. The probe iohexol has shown advantages compared to 51Cr-EDTA or absorbable/nonabsorbable sugars. During IP tests, animals are housed in metabolic cages (MCs) to collect urine. We examined the performance of an iohexol IP test in mice. Rag1-/- (C57BL/6) mice of both sexes were divided into controls or treatment groups, the latter receiving injections of effector/memory T cells to induce intestinal inflammation. After two, four and five weeks (W), a single dose of iohexol was orally administered. Urine was collected seven times over 24 h in MCs. Iohexol concentration was measured by ELISA. Intestinal histological damage was scored in duodenal sections. In control and treated mice of both sexes, urinary excretion of iohexol peaked at 4 h. From W2 to W4/W5, urinary iohexol excretion increased in treated mice of both sexes, consistent with development of duodenitis in this model. Positive correlations were observed between the urinary excretion of iohexol in W4/W5 and the histological severity of duodenitis in treated male mice. We conclude that a 6 h cumulative urine sample appears sufficient to evaluate small IP to iohexol in this mouse model, improving animal welfare by reducing cage periods

Urinary Excretion of Iohexol as a Permeability Marker in a Mouse Model of Intestinal Inflammation: Time Course, Performance and Welfare Considerations

Intestinal permeability (IP) tests are used to assess intestinal damage in patients and research models. The probe iohexol has shown advantages compared to 51Cr-EDTA or absorbable/nonabsorbable sugars. During IP tests, animals are housed in metabolic cages (MCs) to collect urine. We examined the performance of an iohexol IP test in mice. Rag1-/- (C57BL/6) mice of both sexes were divided into controls or treatment groups, the latter receiving injections of effector/memory T cells to induce intestinal inflammation. After two, four and five weeks (W), a single dose of iohexol was orally administered. Urine was collected seven times over 24 h in MCs. Iohexol concentration was measured by ELISA. Intestinal histological damage was scored in duodenal sections. In control and treated mice of both sexes, urinary excretion of iohexol peaked at 4 h. From W2 to W4/W5, urinary iohexol excretion increased in treated mice of both sexes, consistent with development of duodenitis in this model. Positive correlations were observed between the urinary excretion of iohexol in W4/W5 and the histological severity of duodenitis in treated male mice. We conclude that a 6 h cumulative urine sample appears sufficient to evaluate small IP to iohexol in this mouse model, improving animal welfare by reducing cage periods

Two-Week Aflibercept or Erlotinib Administration Does Not Induce Changes in Intestinal Morphology in Male Sprague-Dawley Rats But Aflibercept Affects Serum and Urine Metabolic Profiles

Gastrointestinal toxicity is a frequently observed adverse event during cancer treatment with traditional chemotherapeutics. Currently, traditional chemotherapeutics are often combined with targeted biologic agents. These biologics, however, possess a distinct toxicity profile, and they may also exacerbate the adverse effects of traditional chemotherapeutics. In this study, we aimed to characterize the gastrointestinal and metabolic changes after a 2-week treatment period with aflibercept, an antiangiogenic VEGFR decoy, and with erlotinib, a tyrosine-kinase inhibitor. Male rats were treated either with aflibercept or erlotinib for 2 weeks. During the 2-week treatment period, the animals in the aflibercept group received twosubcutaneous doses of 25 mg/kg aflibercept. The erlotinib group got 10 mg/kg of erlotinib by oral gavage every other day. The control groups were treated similarly but received either saline injections or oral gavage of water. Intestinal toxicity was assessed by measuring intestinal permeability and by histological analyses of intestinal tissues. Metabolic changes were measured with H-1 nuclear magnetic resonance in serum and urine. Neither aflibercept nor erlotinib induced changes in intestinal permeability or intestinal tissue morphology. However, aflibercept treatment resulted in stunted body weight gain and altered choline, amino acid, and lipid metabolism. Two-week treatment with aflibercept or erlotinib alone does not induce observable changes in gastrointestinal morphology and function. However, observed aflibercept-treatment related metabolic changes suggest alterations in intestinal microbiota, nutrient intake, and adipose tissue function. The metabolic changes are also interesting in respect to the systemic effects of aflibercept and their possible associations with adverse events caused by aflibercept administration.Peer reviewe

Influence of the intestinal microbiota on disease susceptibility in kittens with experimentally-induced carriage of atypical enteropathogenic Escherichia coli

Typical enteropathogenic E. coli (tEPEC) carries the highest hazard of death in children with diarrhea and atypical EPEC (aEPEC) was recently identified as significantly associated with diarrheal mortality in kittens. In both children and kittens there is a significant association between aEPEC burden and diarrheal disease, however the infection can be found in individuals with and without diarrhea. It remains unclear to what extent, under what conditions, or by what mechanisms aEPEC serves as a primary pathogen in individuals with diarrhea. It seems likely that a combination of host and bacterial factors enable aEPEC to cause disease in some individuals and not in others. The purpose of this study was to determine the impact of aEPEC on intestinal function and diarrhea in kittens following experimentally-induced carriage and the influence of a disrupted intestinal microbiota on disease susceptibility. Results of this study identify aEPEC as a potential pathogen in kittens. In the absence of disruption to the intestinal microbiota, kittens are resistant to clinical signs of aEPEC carriage but demonstrate significant occult changes in intestinal absorption and permeability. Antibiotic-induced disruption of the intestinal microbiota prior to infection increases subsequent intestinal water loss as determined by % fecal wet weight. Enrichment of the intestinal microbiota with a commensal member of the feline mucosa-associated microbiota, Enterococcus hirae, ameliorated the effects of aEPEC experimental infection on intestinal function and water loss. These observations begin to unravel the mechanisms by which aEPEC infection may be able to exploit susceptible hosts.Peer reviewe