Lactobacillus delbrueckii UFV-H2b20 increases IFN-γ production and CD39+CD73+ Treg cell numbers in lungs, and protects mice against experimental allergic asthma.

Asthma is a disorder characterized by airflow obstruction, inflammation, declining airway function, bronchial hyperresponsiveness and tissue remodelling. Probiotics are defined as "live microorganisms that, when administered in adequate amounts, confer a health benefit on the host". The use of probiotics is becoming increasingly studied and recent evidence has suggested that it may provide therapeutic benefits in asthma and other diseases. Lactobacillus delbrueckii UFV-H2b20 fulfils all the requirements to be classified as probiotic. Previous studies have already shown the ability of L. delbrueckii UFV-H2b20 to stimulate the immune system. Our objective was to evaluate the protective effects of L. delbrueckii UFV-H2b20 in experimental allergic asthma. We used a murine model of ovalbumin-induced allergic airway inflammation to mimic allergic asthma. Oral treatment with L. delbrueckii UFV-H2b20 improves respiratory parameters and inhibits the inflammatory response in the lungs by decreasing the numbers of inflammatory monocytes, eosinophils and alveolar macrophages, as well as IgE levels. Treatment increased the IFN-γ/IL-4 cytokine ratio. Levels of IL-10 in the lungs were also increased in treated animals. Our results also showed that the probiotic administration increases the number of CD39+CD73+ T regulatory lymphocytes in the lung, suggesting a role for purinergic signals in the regulation of inflammation promoted by the treatment. Understanding the mechanisms of modulation of the immune system by probiotics could allow the development of probiotic preparations that are safe and have a direct action. Our results suggest that oral administration of L. delbrueckii UFV-H2b20 could be helpful to treat chronic inflammatory airway diseases, such as asthma.

Evaluation of the immunomodulatory activity of thalidomide on tumor-associated macrophages in the 4T1 murine metastatic breast cancer model / [Avaliação do efeito imunomodulador da talidomida em macrófagos associados a tumores no modelo murino de câncer de mama metastático 4T1]

The present work evaluated the immunomodulatory effect of thalidomide (Thal) at different doses on tumor-associated macrophages (TAMs) using a mouse model of human breast cancer. Mice were inoculated with 4T1 cells in the left flank and treated with Thal once a day at concentrations of 50, 100, and 150mg/kg body weight from the 5th day until the 28th day of tumor inoculation. The tumors were sized, proliferation index and TAMs count were evaluated in primary tumors and metastatic lungs. In addition, the metastasis rate was evaluated in the lungs. Thal at 150mg/kg significantly decreased tumor growth, proliferation index, and TAMs infiltration in primary tumors. Conversely, a higher number of TAMs and lower proliferation index were observed in metastatic lungs in mice treated with 150mg/kg of Thal. Furthermore, Thal at 150mg/kg significantly decreased the metastatic nodules in the lungs. Our findings demonstrated that Thal treatment considerably decreased the primary tumor and lung metastasis in mice associated with different TAM infiltration effects in these sites.(AU)

No presente trabalho, foi avaliado o efeito imunomodulador de diferentes doses de talidomida em macrófagos associados ao tumor (TAMs), em um modelo murino de câncer de mama. Camundongos foram inoculados com células 4T1, na região do flanco esquerdo, e tratados com talidomida, uma vez ao dia, nas doses de 50, 100 e 150mg/k, por massa corporal, do quinto dia ao 28º dia de inoculação tumoral. Os tumores foram medidos, o índice de proliferação celular e a contagem de TAMs foram avaliados nos tumores primários e nos pulmões com metástases. Além disso, a taxa de metástases pulmonares também foi avaliada. A talidomida na dose de 150mg/kg diminuiu significativamente o crescimento tumoral, o índice de proliferação celular e a infiltração de TAMs nos tumores primários. Por outro lado, maior número de TAMs e menor índice de proliferação celular foram observados nos pulmões metastáticos, em camundongos tratados com 150mg/kg de talidomida. Ademais, a talidomida na dose de 150mg/kg diminuiu significativamente os nódulos metastáticos nos pulmões. Os resultados demonstraram que o tratamento com talidomida diminuiu o crescimento tumoral e as metástases pulmonares em camundongos, associado com diferentes efeitos na infiltração de TAMs nesses locais.(AU)

Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2 non-competitive allosteric inhibitor.

BACKGROUND AND PURPOSE: DF 2156A is a new dual inhibitor of IL-8 receptors CXCR1 and CXCR2 with an optimal pharmacokinetic profile. We characterized its binding mode, molecular mechanism of action and selectivity, and evaluated its therapeutic potential. EXPERIMENTAL APPROACH: The binding mode, molecular mechanism of action and selectivity were investigated using chemotaxis of L1.2 transfectants and human leucocytes, in addition to radioligand and [(35) S]-GTPγS binding approaches. The therapeutic potential of DF 2156A was evaluated in acute (liver ischaemia and reperfusion) and chronic (sponge-induced angiogenesis) experimental models of inflammation. KEY RESULTS: A network of polar interactions stabilized by a direct ionic bond between DF 2156A and Lys(99) on CXCR1 and the non-conserved residue Asp(293) on CXCR2 are the key determinants of DF 2156A binding. DF 2156A acted as a non-competitive allosteric inhibitor blocking the signal transduction leading to chemotaxis without altering the binding affinity of natural ligands. DF 2156A effectively and selectively inhibited CXCR1/CXCR2-mediated chemotaxis of L1.2 transfectants and leucocytes. In a murine model of sponge-induced angiogenesis, DF 2156A reduced leucocyte influx, TNF-α production and neovessel formation. In vitro, DF 2156A prevented proliferation, migration and capillary-like organization of HUVECs in response to human IL-8. In a rat model of liver ischaemia and reperfusion (I/R) injury, DF 2156A decreased PMN and monocyte-macrophage infiltration and associated hepatocellular injury. CONCLUSION AND IMPLICATIONS: DF 2156A is a non-competitive allosteric inhibitor of both IL-8 receptors CXCR1 and CXCR2. It prevented experimental angiogenesis and hepatic I/R injury in vivo and, therefore, has therapeutic potential for acute and chronic inflammatory diseases.

Functional dissimilarity of melanomacrophage centres in the liver and spleen from females of the teleost fish Prochilodus argenteus.

Melanomacrophage centres (MMCs) are formed by macrophage aggregates containing pigments such as hemosiderin, melanin and lipofuscin. MMCs are found in animals such as reptiles, amphibians and, mainly, fishes, in organs such as the kidney, spleen, thymus and liver. In teleost fish, several functions have been attributed to MMCs, including the capture and storage of cations, the phagocytosis of cellular debris and immunological reactions. As the use of MMCs has been suggested as a tool for the assessment of environmental impacts, our aim has been to describe the various metabolic processes performed by MMCs in diverse organs (liver and spleen) by using the teleost Prochilodus argenteus as an animal model. MMCs from the liver and spleen were assessed by histochemistry, transmission electron microscopy, scanning electron microscopy, X-ray microanalysis techniques and biochemical assay for N-acetylglucosaminidase activity. The data showed metabolic differences in MMCs between the liver and spleen of P. argenteus in their morphometric characteristics and biochemical and elemental composition. The implications of these findings are discussed, focusing on their role in organ metabolism.

Early infection with Leishmania major restrains pathogenic response to Leishmania amazonensis and parasite growth.

Experimental models of infection with Leishmania spp. have provided knowledge of several immunological events involved in the resistance mechanism used by the host to restrain parasite growth. It is well accepted that concomitant immunity exists, and there is some evidence that it would play a major role in long-lasting acquired resistance to infection. In this paper, the resistance to Leishmania amazonensis infection in C57BL/6 mice infected with Leishmania major was investigated. C57BL/6 mice, which spontaneously heal lesions caused by infection with L. major, were infected with L. amazonensis at different times before and after L. major. We demonstrated that C57BL/6 mice previously infected with L. major restrain pathogenic responses induced by L. amazonensis infection and decrease parasite burdens by one order of magnitude. Co-infected mice showed production of IFN-gamma in lesions similar to mice infected solely with L. major, but higher TNF-alpha and nitric oxide synthase (iNOS) mRNA expression was observed. Surprisingly, the restrained pathogenic response was not related to IL-10 production, as evidenced by lower levels of both mRNA, protein expression in lesions from co-infected mice and in co-infections in IL-10(-/-) mice. Examination of the inflammatory infiltrate at the site of infection showed a reduced number of monocytes and lymphocytes in L. amazonensis lesions. Additionally, differential production of the CCL3/MIP-1 alpha and CCL5/RANTES was observed. We suggest that the control of lesion progression caused by L. amazonensis in C57BL/6 mice pre-infected with L. major is related to the induction of a down-regulatory environment at the site of infection with L. amazonensis.

Development of marine water quality criteria for the USA.

The US Environmental Protection Agency has developed guidelines for deriving numerical national water quality criteria for the protection of aquatic organisms and their uses. These guidelines provide the method for deriving water quality criteria, including minimum data base requirements, data evaluation procedures, and calculations. The guidelines have been in place for a long time, and states have used them to derive water quality standards for their water bodies. More recent efforts have been directed towards the development of technical guidance based on the concept that bioassessment and biocriteria programs for estuaries and near coastal waters are interrelated and are critical components of comprehensive water resource protection and management. This is a holistic approach to protection and management, integrating biological assessments into traditional chemical and physical evaluations and augmenting the established water quality criteria. The method for deriving water quality criteria and the approach for biocriteria development for marine systems are described.

The management of septal perforations.

Twenty-five patients with septal perforations were seen between July 1, 1983, and June 30, 1989. There were 16 males and 9 females, who ranged in age from 21 to 72 years, with the median age of 41.7 years. The majority of the perforations were traumatic in origin, with 19 cases seen following septal surgery, and were between 1.5 and 2.5 cm (20), with a range of 0.5 to 4 cm. All were located at the posterior border of the quadrilateral cartilage at the vomer-ethmoid junction. All but 3 patients underwent surgical repair, and successful closure was achieved in all but 3. However, only 1 patient remained symptomatic after surgery. The surgical technique employed includes an external rhinoplasty approach, septal and intranasal mucosal flaps, and an autograft of mastoid periosteum or temporalis fascia.

Treatment of nasal surgery complications.

There are numerous articles on how to prevent and manage the untoward aesthetic and functional results of nasal surgery. However, little has been written on the disabling or life-threatening complications of nasal surgery. Recent series have reported the incidence of these complications to be between 5% and 18%. Severe complications from nasal surgery can be divided into the following four categories: hemorrhagic, infectious, traumatic, and miscellaneous. Postoperative hemorrhage is the most commonly seen problem. However, there are numerous case reports of toxic shock syndrome associated with nasal surgery and even of intracranial complications. In this article, we provide an overview of these complications and their treatment.

External rhinoplasties: indications for use.

The technique, indications and role of external rhinoplasty in nasal surgery are presented. The technique has been utilised in 563 patients with a minimum follow-up of 18 months. The external approach has been especially helpful in the severely twisted nose, secondary rhinoplasty, augmentation rhinoplasty, congenital deformities of the nose, closure of septal perforations and in the teaching and learning of rhinoplasty. In this series there were no reported complications attributable to the external approach.

Vascular smooth muscle cell proliferation and its therapeutic modulation in hypertension.

The increased growth potential of vascular smooth muscle cells (VSMCs) represents one of the crucial anomalies responsible for the development of essential hypertension, diabetic macroangiopathy, and atherosclerosis. The exaggerated response to growth factors of VSMC from spontaneously hypertensive rats (SHRs) persists in culture when compared with normotensive Wistar-Kyoto control rats, indicating an intrinsic defect in the hypertension-producing mechanism. This greater proliferation is characterized by two intermediate phenotypes: (1) accelerated entry into the S phase of the cell cycle, which results from hyperresponsiveness to epidermal growth factor and platelet-derived growth factor, and (2) abnormal contact inhibition. The enhanced expression of transforming growth factor beta 1 (TGF-beta 1) messenger ribonucleic acid in SHRs precedes this altered contact inhibition, and only VSMCs from SHRs respond to exogenously added TGF-beta 1 at a high cell density, which suggests that abnormal TGF-beta 1 autoregulation may be implicated in the second phenotype. Platelets contain major growth factors for VSMC. Platelet extracts from hypertensive and diabetic patients present augmented growth-promoting activity on VSMCs, which is most evident when both diseases occur simultaneously. Growth-promoting activity may be further influenced by antihypertensive therapy. This growth-promoting activity is increased by hydrochlorothiazide but not by indapamide, atenolol, or captopril in diabetic hypertensive and nondiabetic hypertensive patients. In conclusion, VSMCs in hypertension manifest an intrinsic growth defect that is modulated by extrinsic platelet growth factors and antihypertensive drugs.

External rhinoplasty technique.

External rhinoplasty is a valuable tool in the surgical armamentarium of all nasal surgeons. It does not change the dynamics of the operation but offers a new method of exposure. The purpose of this paper is to present our experience with the external rhinoplasty technique in 601 patients, and review the results and complications of this approach to nasal surgery. Two patient reports are presented to demonstrate use of the technique in nasal surgery.