Highlights in Endocytosis of Nanostructured Systems.

The focus of this review is the cellular internalisation mechanism of nanostructured systems (NSs) and their endosomal escape for targeted drug delivery. Endocytosis is a cellular process of internalisation of different molecules and foreign microorganisms. It is currently being studied for drug delivery through nanostructured systems. The most commonly studied routes of cellular uptake are phagocytosis, macro-pinocytosis, clathrinmediated endocytosis, caveolin-mediated endocytosis, and clathrin and caveolinindependent endocytosis. The mechanism utilised by NSs for cellular entry depends on factors such as cell type and its physicochemical properties. Currently, with the development of drugs-loaded onto NSs, it has been possible to increase the therapeutic index against few diseases. The NSs can deliver the active drug at locations that conventional drugs cannot, thereby minimising unwanted side effects. On cellular entry of NSs, there is a possibility of an endosomal escape of the contents into the cytoplasm, a mechanism that can be exploited so that NSs can migrate intra-cellularly and deliver the drug to the target of interest. Designing endolysosomal escape strategy is not an easy task, but it is critical for the optimal pharmacological action on the target tissue. The cellular uptake of drugs is a very important factor in therapy. Although NSs have emerged as effective drug delivery vehicle for treatment of diseases, it is crucial to understand the mechanism of NSs endocytosis.

Paracoccidioides-host Interaction: An Overview on Recent Advances in the Paracoccidioidomycosis.

Paracoccidioides brasiliensis and P. lutzii are etiologic agents of paracoccidioidomycosis (PCM), an important endemic mycosis in Latin America. During its evolution, these fungi have developed characteristics and mechanisms that allow their growth in adverse conditions within their host through which they efficiently cause disease. This process is multi-factorial and involves host-pathogen interactions (adaptation, adhesion, and invasion), as well as fungal virulence and host immune response. In this review, we demonstrated the glycoproteins and polysaccharides network, which composes the cell wall of Paracoccidioides spp. These are important for the change of conidia or mycelial (26°C) to parasitic yeast (37°C). The morphological switch, a mechanism for the pathogen to adapt and thrive inside the host, is obligatory for the establishment of the infection and seems to be related to pathogenicity. For these fungi, one of the most important steps during the interaction with the host is the adhesion. Cell surface proteins called adhesins, responsible for the first contact with host cells, contribute to host colonization and invasion by mediating this process. These fungi also present the capacity to form biofilm and through which they may evade the host's immune system. During infection, Paracoccidioides spp. can interact with different host cell types and has the ability to modulate the host's adaptive and/or innate immune response. In addition, it participates and interferes in the coagulation system and phenomena like cytoskeletal rearrangement and apoptosis. In recent years, Paracoccidioides spp. have had their endemic areas expanding in correlation with the expansion of agriculture. In response, several studies were developed to understand the infection using in vitro and in vivo systems, including alternative non-mammal models. Moreover, new advances were made in treating these infections using both well-established and new antifungal agents. These included natural and/or derivate synthetic substances as well as vaccines, peptides, and anti-adhesins sera. Because of all the advances in the PCM study, this review has the objective to summarize all of the recent discoveries on Paracoccidioides-host interaction, with particular emphasis on fungi surface proteins (molecules that play a fundamental role in the adhesion and/or dissemination of the fungi to host-cells), as well as advances in the treatment of PCM with new and well-established antifungal agents and approaches.

Elimination diet in cow's milk allergy: risk for impaired growth in young children.

OBJECTIVE: The objective of this study was to evaluate the nutritional impact of therapeutic elimination diets and to identify risk factors predisposing infants with food allergy to poor growth. STUDY DESIGN: We studied 100 children (mean age 7 months) with atopic dermatitis and challenge-proven cow's milk allergy and evaluated their growth during the symptomatic period before diagnosis and during the therapeutic elimination diet. RESULTS: Clinical control of symptoms was achieved in all patients. The mean length SD score and weight-for-length index of patients decreased compared with those in healthy age-matched children, p < 0.0001 and p = 0.03, respectively. Low serum albumin was present in 6% of the patients, 24% had an abnormal urea concentration, and 8% had a low serum phospholipid docosahexaenoic acid. The delay in growth was more pronounced in a subgroup of patients with early onset than in those with later of symptoms (F = 6.665, p < 0.0001). The duration of breast-feeding correlated positively with the sum of n-3 polyunsaturated fatty acids (r = 0.39, p = 0.001) and with the relative amount of docosahexaenoic acid (r = 0.36, p = 0.002). CONCLUSION: A delicate balance exists between the benefits and the risks of elimination diets.

Local immune response in patients with cow milk allergy: follow-up of patients retaining allergy or becoming tolerant.

To assist in identifying factors that determine the clinical outcome of cow milk allergy, we subjected to rechallenge 37 patients with a history of cow milk allergy, mean (+/- SD) age 27.6 +/- 7.1 months, after a follow-up of 13.5 +/- 5.1 months with a milk-free diet. A solid-phase enzyme-linked immunoassay was used to assess the total number of immunoglobulin-secreting and specific antibody-secreting cells among peripheral blood lymphocytes primed during provocation by milk antigens, giving indirect evidence of local immune response in the gut. Patients with persistent cow milk allergy (n = 13) had milder reactions at rechallenge than they had shown at the time of diagnosis. Numbers of immunoglobulin-secreting cells in these patients increased significantly from a geometric mean (95% confidence interval) in the IgA class of 1570 (1009, 2445) to 2984 (1941, 4583) IgA-secreting cells/10(6) cells, in the IgG class of 1445 (1067, 1959) to 2740 (1698, 4425) IgG-secreting cells/10(6) cells, and in the IgM class of 842 (534, 1325) to 2235 (1429, 3495) IgM-secreting cells/10(6) cells. By contrast, in patients (n = 24) who had acquired cow milk tolerance, the number of immunoglobulin-secreting cells did not increase during provocation. The total number of IgA-secreting cells before rechallenge was significantly higher than it had been before the initial challenge. The patients who acquired cow milk tolerance also had specific antibody-secreting cells of IgA isotype before the second challenge. These results indicate that in cow milk allergy the ability to mount a local immune response against cow milk antigens, particularly in the IgA class, is related to the suppression of clinical sensitivity.