Consensus hologram QSAR modeling for the prediction of human intestinal absorption

Consistent in silico models for ADME properties are useful tools in early drug discovery. Here, we report the hologram QSAR modeling of human intestinal absorption using a dataset of 638 compounds with experimental data associated. The final validated models are consistent and robust for the consensus prediction of this important pharmacokinetic property and are suitable for virtual screening applications. (C) 2012 Elsevier Ltd. All rights reserved.

Acute heat stress impairs performance parameters and induces mild intestinal enteritis in broiler chickens: Role of acute hypothalamic-pituitary-adrenal axis activation

Studies on the environmental consequences of stress are relevant for economic and animal welfare reasons. We recently reported that long-term heat stressors (31 +/- 1 degrees C and 36 +/- 1 degrees C for 10 h/d) applied to broiler chickens (Gallus gallus domesticus) from d 35 to 42 of life increased serum corticosterone concentrations, decreased performance variables and the macrophage oxidative burst, and produced mild, multifocal acute enteritis. Being cognizant of the relevance of acute heat stress on tropical and subtropical poultry production, we designed the current experiment to analyze, from a neuroimmune perspective, the effects of an acute heat stress (31 +/- 1 degrees C for 10 h on d 35 of life) on serum corticosterone, performance variables, intestinal histology, and peritoneal macrophage activity in chickens. We demonstrated that the acute heat stress increased serum corticosterone concentrations and mortality and decreased food intake, BW gain, and feed conversion (P < 0.05). We did not find changes in the relative weights of the spleen, thymus, and bursa of Fabricius (P > 0.05). Increases in the basal and the Staphylococcus aureus-induced macrophage oxidative bursts and a decrease in the percentage of macrophages performing phagocytosis were also observed. Finally, mild, multifocal acute enteritis, characterized by the increased presence of lymphocytes and plasmocytes within the lamina propria of the jejunum, was also observed. We found that the stress-induced hypothalamic-pituitary-adrenal axis activation was responsible for the negative effects observed on chicken performance and immune function as well as for the changes in the intestinal mucosa. The data presented here corroborate with those presented in other studies in the field of neuroimmunomodulation and open new avenues for the improvement of broiler chicken welfare and production performance.

Obstructive acute abdomen due to intestinal intussusception in adolescent

Introduction: Intestinal intussusception is a rare disease out of childhood. It is represented by an invagination of a bowel into the lumen of the adjacent segment. Case Report: This article reports a case of 14 year-old patient presenting intestinal obstruction caused by an intussusception at the level of the terminal ileum. A surgical resection of the invaginated segment was done and the histopathological study disclosed no evidence of malignancy. Discussion: In children, it is usually idiopathic, but among adolescents and adults it is often related to anatomic lesions, some of them neoplastic with high risk of malignancy. Preoperative diagnosis of intestinal intussusception is difficult due to its nonspecific and subacute symptoms. Computed tomography and ultrassonography can confirm the intussusception through characteristic images. Conclusion: Intestinal intussusception in adolescents is a rare and often misdiagnosed disease, deserving special attention from surgeons and general doctors.

Expression of tlr4, md2 and cd14 in equine blood leukocytes during endotoxin infusion and in intestinal tissues from healthy horses

The expression of tlr4, md2 and cd14 was studied in equine blood leukocytes and in intestinal samples using real time PCR. The stability of three commonly used reference genes, glyceraldehyde-3P-dehydrogenase (GAPDH), hypoxantine ribosyltransferase (HPRT) and succinate dehydrogenase complex subunit A (SDHA), was evaluated using qbase(PLUS). The equine peripheral blood mononuclear cells (eqPBMC) examined were either stimulated in vitro with Phorbol 12-myristate 13-acetate (PMA) and ionomycin or with the CpG oligodeoxynuclotide 2216 (CpG-ODN 2216) or obtained from horses before, during and after infusion of endotoxin. Intestinal tissue from healthy horses was sampled at ileum, right dorsal colon and rectum. Ranking of the three reference genes used for normalisation identified the combination HPRT/SDHA as most suitable both when determined ex vivo in leukocytes obtained from experimentally induced endotoxaemia and in eqPBMC activated in vitro while HPRT/GAPDH were most appropriate for the intestinal samples. The relative amounts of mRNA for TLR4 and MD-2 increased threefold during in vitro activation of the cells with CpG-ODN 2216 but was decreased in cultures stimulated with PMA/ionomycin. A transient elevation in the transcription of tlr4 and md2 was also evident for equine blood leukocytes following endotoxaemia. The levels of mRNA for CD14 on the other hard remained unaffected both during the induction of endotoxaemia and in the in vitro stimulated PBMCs. A low steady expression of TLR4, MD-2 and CD14 mRNA was demonstrated for the intestinal samples with no variation between the intestinal segments analysed. Thus, the foundation for real time PCR based levels of analysis of mRNA for all three components in the equine LPS receptor complex in different intestinal segments was set, making it possible to carry out future expression studies on clinical material. (C) 2012 Elsevier B.V. All rights reserved.

Intestinal Lymph-Borne Factors Induce Lung Release of Inflammatory Mediators and Expression of Adhesion Molecules After an Intestinal Ischemic Insult

Background. Intestinal ischemia and reperfusion (I/R) is a documented cause of acute lung injury (ALI) and systemic inflammation. We previously reported that obstruction of thoracic lymphatic flow during intestinal I/R blunts pulmonary neutrophil recruitment and microvascular injury and decreases the systemic levels of tumor necrosis factor. Here, we consider the existence of a gut-lung axis promoting the induction of systemic inflammation, whereby drained intestinal lymph stimulates lung expression of adhesion molecules and matrix components and generation of inflammatory mediators. Material and Methods. Upon administration of anesthesia, male Wistar rats were subjected to occlusion of the superior mesenteric artery for 45 min, followed by 2 h of intestinal reperfusion (I/R); groups of rats were subjected to I/R with or without thoracic lymphatic duct ligation immediately before the procedure. The non-manipulated rats were used to investigate basal parameters. Results. Obstruction of thoracic lymphatic flow before intestinal I/R decreased the ability of cultured lung tissue explants to release IL-1 beta, IL-10, and VEGF. In contrast, lymphatic obstruction normalized the elevated lung expression of PECAM-1 caused by intestinal I/R. On the other hand, lung E-selectin expression was significantly reduced, whereas fibronectin expression and collagen synthesis were not affected. Lymph levels of LTB4 and TXB2 were found to be significantly increased. Conclusions. These data suggest that lymph factors drained from the intestine during ischemic trauma stimulate the lung to generate inflammatory mediators and alter the expression of adhesion molecules. Disturbances in lung homeostasis mediated by lymph might contribute to the spread of inflammatory processes, thereby accounting for the systemic inflammation induced by intestinal I/R. (C) 2012 Elsevier Inc. All rights reserved.

Involvement of nitric oxide on the pathogenesis of irinotecan-induced intestinal mucositis: role of cytokines on inducible nitric oxide synthase activation

Purpose Intestinal mucositis and the closely associated diarrhea are common costly side effects of irinotecan. Cytokine modulators, such as thalidomide and pentoxifylline, are found capable of attenuating intestinal mucositis progression. Nitric oxide (NO) seems to be a key mediator of the antineoplastic drug toxicity. The aim of this study was to investigate the role of NO on the pathogenesis of intestinal mucositis, as well as the participation of cytokines upon inducible nitric oxide synthase (iNOS) expression in irinotecan-induced intestinal mucositis. Methods iNOS-knockout (iNOS(-/-)) and C57BL/6 (WT, wild type) animals (n = 5-6) were given either saline or irinotecan (60 mg/kg i.p for 4 days), with or without pretreatment with aminoguanidine (50 mg/kg s.c.), thalidomide (60 mg/kg s.c), infliximab (5 mg/kg i.v.), or pentoxifylline (1.7 mg/kg s.c). On day 5, diarrhea was assessed, and following euthanasia, proximal intestinal samples were obtained for myeloperoxidase (MPO) and iNOS activity, morphometric analysis, western blot and immunohistochemistry to iNOS, cytokine dosage, and for in vitro evaluation of gut contractility. Results Irinotecan induced severe diarrhea and intestinal smooth muscle over-contractility, accompanied with histopathological changes. Additionally, increased MPO and iNOS activity and iNOS immunoexpression were found in WT animals treated with irinotecan. The rise in MPO, smooth muscle over-contractility, and diarrhea were abrogated in aminoguanidine-treated and iNOS(-/-) mice. Moreover, through western blot, we verified that infliximab and pentoxifylline significantly inhibited irinotecan-induced iNOS expression. In addition, cytokine concentration was found only partially decreased in irinotecan-treated iNOS(-/-) mice when compared with wild-type animals that were given irinotecan. Conclusions This study suggests a role of nitric oxide in the pathogenesis of irinotecan-induced intestinal mucositis and also provides evidence for the participation of cytokines on iNOS induction.

Heat stress impairs performance and induces intestinal inflammation in broiler chickens infected with Salmonella Enteritidis

Stressful situations reduce the welfare, production indices and immune status of chickens. Salmonella spp. are a major zoonotic pathogens that annually cause over 1 billion infections worldwide. We therefore designed the current experiment to analyse the effects of 31 +/- 1 degrees C heat stress (HS) (from 35 to 41 days) on performance parameters, Salmonella invasion and small intestine integrity in broiler chickens infected with Salmonella Enteritidis. We observed that HS decreased body weight gain and feed intake. However, feed conversion was only increased when HS was combined with Salmonella Enteritidis infection. In addition, we observed an increase in serum corticosterone levels in all of the birds that were subjected to HS, showing a hypothalamus-pituitary-adrenal axis activation. Furthermore, mild acute multifocal lymphoplasmacytic enteritis, characterized by foci of heterophil infiltration in the duodenum, jejunum and ileum, was observed in the HS group. In contrast, similar but more evident enteritis was noted in the heat-stressed and Salmonella-infected group. In this group, moderate enteritis was observed in all parts of the small intestine. Lastly, we observed an increase in Salmonella counts in the spleens of the stressed and Salmonella-infected chickens. The combination of HS and Salmonella Enteritidis infection may therefore disrupt the intestinal barrier, which would allow pathogenic bacteria to migrate through the intestinal mucosa to the spleen and generate an inflammatory infiltrate in the gut, decreasing performance parameters.

Annexin-A1 peptide down-regulates the leukocyte recruitment and up-regulates interleukin-10 release into lung after intestinal ischemia-reperfusion in mice

Abstract Background Intestinal ischemia/reperfusion (IR) injury is a serious and triggering event in the development of remote organ dysfunction, from which the lung is the main target. This condition is characterized by intense neutrophil recruitment, increased microvascular permeability. Intestinal IR is also responsible for induction of adult respiratory distress syndrome, the most serious and life-threatening form of acute lung injury. The purpose of this study was to investigate the effect of annexin-A1 protein as an endogenous regulator of the organ remote injury induced by intestinal ischemia/reperfusion. Male C57bl/6 mice were subjected to intestinal ischemia, induced by 45 min occlusion of the superior mesenteric artery, followed by reperfusion. Results The intestinal ischemia/reperfusion evoked a high intensity lung inflammation as indicated by the number of neutrophils as compared to control group. Treatment with annexin-A1 peptidomimetic Ac2-26, reduced the number of neutrophils in the lung tissue and increased its number in the blood vessels, which suggests a regulatory effect of the peptide Ac2-26 in the neutrophil migration. Moreover, the peptide Ac2-26 treatment was associated with higher levels of plasma IL-10. Conclusion Our data suggest that the annexin-A1 peptidomimetic Ac2-26 treatment has a regulatory and protective effect in the intestinal ischemia/reperfusion by attenuation of the leukocyte migration to the lung and induction of the anti-inflammatory cytokine IL-10 release into the plasma. The anti-inflammatory action of annexin-A1 and its peptidomimetic described here may serve as a basis for future therapeutic approach in mitigating inflammatory processes due to intestinal ischemia/reperfusion.

Avaliação do número de células caliciformes nas criptas da mucosa colônica com e sem trânsito intestinal

OBJETIVO: Medir a espessura das criptas e quantificar o número de células caliciformes comparando a mucosa cólica com e sem trânsito intestinal, relacionando-as ao tempo de exclusão. MÉTODOS: Sessenta ratos Wistar, foram distribuídos em três grupos com 20 animais segundo a operação final para a retirada dos cólons, realizadas em seis, 12 ou 18 semanas. Em cada grupo, 15 animais foram submetidos à derivação do trânsito por colostomia proximal no cólon esquerdo e fístula mucosa distal e cinco apenas à laparotomia (controle). Os cólons com e sem trânsito fecal foram removidos, processados, submetidos a cortes histológicos corados pela hematoxilina-eosina. A altura das criptas colônicas e o número de células caliciformes foram mensurados por morfometria computadorizada. Foram utilizados os testes t de Student e Kruskal-Wallis para comparação e análise de variância, estabelecendo-se nível de significância de 5% (p<0,05). RESULTADOS: A altura das criptas diminui nos segmentos sem trânsito fecal (p=0,0001), reduzindo entre seis e 12 semanas de exclusão (p=0,0003), estabilizando-se após este período. O número de células caliciformes nas criptas é menor nos segmentos sem trânsito após 12 e 18 semanas (p=0,0001), porém aumenta com o decorrer do tempo de exclusão (p=0,04) CONCLUSÃO: A exclusão do trânsito intestinal diminui a espessura das criptas colônicas e o número de células caliciformes nos segmentos sem trânsito. Existe aumento do número de células caliciformes com o decorrer do tempo de exclusão.

Experiencing sexuality after intestinal stoma

OBJECTIVE: Identify the Social Representations (SR) of ostomized people in terms of sexuality after the stoma. METHODS: An exploratory, descriptive, qualitative study using the Social Representation Theory with 15 ostomized people (8 females), mean age of 57.9 years, between August and September 2005. Data obtained from transcribed interviews were submitted to content analysis, resulting in the thematic unit "Giving new meaning to sexuality" and subthemes. RESULTS: The study demonstrated that the intestinal stoma interferes in the sexuality experience, showing that the meanings attributed to this experience are based on individual life stories, quality of personal relationships established in practice and perception of sexuality, despite the stoma. CONCLUSIONS: The Social Representations, in terms of experiencing sexuality after the stoma, are based on meanings attributed to the body, associated with daily life and present in the social imaginary. It is influenced by other factors, such as physiological changes resulting from the surgery and the fact of having or not a partner. Care taken during sexual practices provide greater security and comfort in moments of intimacy, resembling the closest to what ostomized people experienced before the stoma. The self-irrigation technique associated or not with the use of artificial occluder, has been attested by its users as a positive element that makes a difference in sexual practice after the stoma. The support to ostomized people should be comprehensive, not limited to technical care and disease, which are important, but not sufficient. The interdisciplinary health team should consider all aspects of the person, seeking a real meeting between subjects.

Elaboração de manual sobre fibras alimentares e constipação intestinal

Objetivo: elaborar um manual com alimentos fonte de fibras para ser usado na composição da dieta líquida homogênea dos pacientes em pós-operatório no HRAC, de todas as idades, para reduzir ou prevenir a constipação intestinal. Métodos: o manual contém temática que esclarece sobre a importância das fibras alimentares, classificação, fontes, quantidades de uso, interação com outros nutrientes, forma de preparo, solubilidade, funções e problemas causados pelo excesso de ingestão. Consta também de uma lista de alimentos com quantidades de fibras presentes por 100gramas de cada alimento. Tais dados foram retirados da Tabela Brasileira de composição de Alimentos da UNICAMP e da Tabela Brasileira de Composição de Alimentos da USP. O manual foi elaborado pelas alunas do programa de Aprimoramento Profissional Fundap e será distribuído gratuitamente para todos os pacientes em pós-operatórios submetidos à dieta líquida homogênea. Além disto, o manual será disponibilizado nos sites www.centrinho.usp.br/manual e www.redeprofis.com.br. para consulta e cópias gratuitas. A arte e as ilustrações do manual foram feitas por aluno do Curso de Publicidade e Propaganda da USC. Resultados: O uso das fibras será orientado de forma preventiva para os pacientes que não apresentam constipação intestinal e de forma corretiva para os já constipados. Conclusões: A constipação intestinal é um problema de saúde pública no Brasil, principalmente entre as mulheres e tem seu quadro agravado quando estes indivíduos são submetidos a dietas líquidas e homogêneas, aonde os alimentos são liquidificados e coados e os resíduos (fibras) desprezados. Sendo assim, a composição desta dieta tem que ser enriquecida com fibras alimentares para prevenir ou corrigir a constipação intestinal.

Suppressive effect of low-level laser therapy on tracheal hyperresponsiveness and lung inflammation in rat subjected to intestinal ischemia and reperfusion

Intestinal ischemia and reperfusion (i-I/R) is an insult associated with acute respiratory distress syndrome (ARDS). It is not known if pro- and anti-inflammatory mediators in ARDS induced by i-I/R can be controlled by low-level laser therapy (LLLT). This study was designed to evaluate the effect of LLLT on tracheal cholinergic reactivity dysfunction and the release of inflammatory mediators from the lung after i-I/R. Anesthetized rats were subjected to superior mesenteric artery occlusion (45 min) and killed after clamp release and preestablished periods of intestinal reperfusion (30 min, 2 or 4 h). The LLLT (660 nm, 7.5 J/cm(2)) was carried out by irradiating the rats on the skin over the right upper bronchus for 15 and 30 min after initiating reperfusion and then euthanizing them 30 min, 2, or 4 h later. Lung edema was measured by the Evans blue extravasation technique, and pulmonary neutrophils were determined by myeloperoxidase (MPO) activity. Pulmonary tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), intercellular adhesion molecule-1 (ICAM-1), and isoform of NO synthase (iNOS) mRNA expression were analyzed by real-time PCR. TNF-α, IL-10, and iNOS proteins in the lung were measured by the enzyme-linked immunoassay technique. LLLT (660 nm, 7.5 J/cm(2)) restored the tracheal hyperresponsiveness and hyporesponsiveness in all the periods after intestinal reperfusion. Although LLLT reduced edema and MPO activity, it did not do so in all the postreperfusion periods. It was also observed with the ICAM-1 expression. In addition to reducing both TNF-α and iNOS, LLLT increased IL-10 in the lungs of animals subjected to i-I/R. The results indicate that LLLT can control the lung's inflammatory response and the airway reactivity dysfunction by simultaneously reducing both TNF-α and iNOS.

Annexin-A1 peptide down-regulates the leukocyte recruitment and up-regulates interleukin-10 release into lung after intestinal ischemia-reperfusion in mice

BACKGROUND: Intestinal ischemia/reperfusion (IR) injury is a serious and triggering event in the development of remote organ dysfunction, from which the lung is the main target. This condition is characterized by intense neutrophil recruitment, increased microvascular permeability. Intestinal IR is also responsible for induction of adult respiratory distress syndrome, the most serious and life-threatening form of acute lung injury. The purpose of this study was to investigate the effect of annexin-A1 protein as an endogenous regulator of the organ remote injury induced by intestinal ischemia/reperfusion. Male C57bl/6 mice were subjected to intestinal ischemia, induced by 45 min occlusion of the superior mesenteric artery, followed by reperfusion. RESULTS: The intestinal ischemia/reperfusion evoked a high intensity lung inflammation as indicated by the number of neutrophils as compared to control group. Treatment with annexin-A1 peptidomimetic Ac2-26, reduced the number of neutrophils in the lung tissue and increased its number in the blood vessels, which suggests a regulatory effect of the peptide Ac2-26 in the neutrophil migration. Moreover, the peptide Ac2-26 treatment was associated with higher levels of plasma IL-10. CONCLUSION: Our data suggest that the annexin-A1 peptidomimetic Ac2-26 treatment has a regulatory and protective effect in the intestinal ischemia/reperfusion by attenuation of the leukocyte migration to the lung and induction of the anti-inflammatory cytokine IL-10 release into the plasma. The anti-inflammatory action of annexin-A1 and its peptidomimetic described here may serve as a basis for future therapeutic approach in mitigating inflammatory processes due to intestinal