Cytokines produced by susceptible and resistant mice in the course of Paracoccidioides brasiliensis infection

Paracoccidioidomycosis (PCM) is the most prevalent deep mycosis in Latin America and presents a wide spectrum of clinical manifestations. We established a genetically controlled murine model of PCM, where A/Sn mice develop an infection which mimics the benign disease (immune responses which favor cellular immunity) and B10.A animals present the progressive disseminated form of PCM (preferential activation of B cells and impairment of cellular immune responses). To understand the immunoregulatory phenomena associated with resistance and susceptibility in experimental PCM, A/Sn and B10.A mice were studied regarding antigen-elicited secretion of monokines (TNF-a and TGF-ß) and type-1 (IL-2 and IFN-g) and type-2 (IL-4,5,10) cytokines. Total lymph node cells from resistant mice infected ip with P. brasiliensis produced early and sustained levels of IFN-g and IL-2; type-2 cytokines (IL-4 and IL-5) started to appear 8 weeks after infection. In contrast, susceptible mice produced low levels of IFN-g concomitant with significant levels of IL-5 and IL-10 early in the infection. In the chronic phase of the disease, susceptible animals presented a transitory secretion of IL-2, and IL-4. In the pulmonary infection IL-4, IL-5 and IL-10 were preferentially detected in the lung cells washings of susceptible animals. After in vitro challenge with fungal antigens, normal peritoneal macrophages from B10.A mice secreted high levels of TGF-ß and low levels of TNF-a. In contrast, macrophages from A/Sn animals released high levels of TNF-a associated with a small production of TGF-ß. The in vivo depletion of IFN-g not only abrogated the resistance of A/Sn mice but also diminished the relative resistance of B10.A animals. The in vivo depletion of IL-4 did not alter the disease outcome, whereas administration of rIL-12 significantly enhanced resistance in susceptible animals. Taken together, these results suggest that an early secretion of high levels of TNF-a and IFN-g followed by a sustained secretion of IL-2 and IFN-g plays a dominant role in the resistance mechanisms to P. brasiliensis infection. In contrast, an early and ephemeral secretion of low levels of TNF-a and IFN-g associated with production of IL-5, IL-10 and TGF-ß characterizes the progressive disease of susceptible animals.

The immunomodulator glatiramer acetate influences spinal motoneuron plasticity during the course of multiple sclerosis in an animal model

The immunomodulador glatiramer acetate (GA) has been shown to significantly reduce the severity of symptoms during the course of multiple sclerosis and in its animal model - experimental autoimmune encephalomyelitis (EAE). Since GA may influence the response of non-neuronal cells in the spinal cord, it is possible that, to some extent, this drug affects the synaptic changes induced during the exacerbation of EAE. In the present study, we investigated whether GA has a positive influence on the loss of inputs to the motoneurons during the course of EAE in rats. Lewis rats were subjected to EAE associated with GA or placebo treatment. The animals were sacrificed after 15 days of treatment and the spinal cords processed for immunohistochemical analysis and transmission electron microscopy. A correlation between the synaptic changes and glial activation was obtained by performing labeling of synaptophysin and glial fibrillary acidic protein using immunohistochemical analysis. Ultrastructural analysis of the terminals apposed to alpha motoneurons was also performed by electron transmission microscopy. Interestingly, although the GA treatment preserved synaptophysin labeling, it did not significantly reduce the glial reaction, indicating that inflammatory activity was still present. Also, ultrastructural analysis showed that GA treatment significantly prevented retraction of both F and S type terminals compared to placebo. The present results indicate that the immunomodulator GA has an influence on the stability of nerve terminals in the spinal cord, which in turn may contribute to its neuroprotective effects during the course of multiple sclerosis.

Some Incidents and Circumstances Written by William F. Haile in the Course of his Life, 1859

William Frederick Haile was born in Putney, Windham County, Vermont on November 4th, 1791. He was raised in Fairfield, Herkimer County, New York. At the age of 21 he entered the United States Army. He served in the War of 1812 as a lieutenant in the 11th United States Infantry. He was severely wounded in the Battle of Lundy’s Lane [not mentioned in this memoir]. After the war he settled in Plattsburgh, New York and became a lawyer. He was a judge from April 1837 to March of 1843. He was also the fifth collector of customs for the District of Champlain. He died on October 1861 at the age of 69. This document was written for the children of William Frederick Haile in January of 1859 [as noted on p.23]. The memoir ends in July of 1814 before the Battle of Lundy’s Lane. Haile’s memoir is laced with names of military personnel and he expresses his opinions freely.

Travels and adventures in México : in the course of fourneys of upueard of 2500 miles, performed on foot...

UANL

Critical-Level Population Principles and the Repugnant Conclusion

Critical-level generalized-utilitarian population principles with positive critical levels pro-vide an ethically attractive way of avoiding the repugnant conclusion. We discuss the axiomatic foundations of critical-level generalized utilitarianism and investigate its rela-tionship to the sadistic and strong sadistic conclusions. A positive critical level avoids the repugnant conclusion. We demonstrate that, although no critical-level generalized-utilitarian principle can avoid both the repugnant and strong sadistic conclusions, princi-ples that avoid both have significant defects.

Postpartum GAD is a risk factor for postpartum MDD: the course and longitudinal relationships of postpartum GAD and MDD

Background The objective was to examine the course and longitudinal associations of generalized anxiety disorder (GAD) and major depressive disorder (MDD) in mothers over the postpartum 2 years. Method Using a prospective naturalistic design, 296 mothers recruited from a large community pool were assessed for GAD and MDD at 3, 6, 10, 14, and 24 months postpartum. Structured clinical interviews were used for diagnoses, and symptoms were assessed using self-report questionnaires. Logistic regression analyses were used to examine diagnostic stability and longitudinal relations, and latent variable modeling was employed to examine change in symptoms. Results MDD without co-occurring GAD, GAD without co-occurring MDD, and co-occurring GAD and MDD, displayed significant stability during the postpartum period. Whereas MDD did not predict subsequent GAD, GAD predicted subsequent MDD (in the form of GAD + MDD). Those with GAD + MDD at 3 months postpartum were significantly less likely to be diagnosis free during the follow-up period than those in other diagnostic categories. At the symptom level, symptoms of GAD were more trait-like than those of depression. Conclusions Postpartum GAD and MDD are relatively stable conditions, and GAD is a risk factor for MDD but not vice versa. Given the tendency of MDD and GAD to be persistent, especially when comorbid, and the increased risk for MDD in mothers with GAD, as well as the potential negative effects of cumulative exposure to maternal depression and anxiety on child development, the present findings clearly highlight the need for screening and treatment of GAD in addition to MDD during the postpartum period.

Incorporation of different and changing client interests in the course of a project

There is a widespread assumption that clients’ expectations should be accommodated during a building project. However, there may be conflicting expectations within a client organization and these may change over time in the course of a project. Actor-Network Theory (ANT) is used to study the incorporation of client expectations into the on-going development of a building project. To illustrate this, negotiations over a particular decision, namely the location of a building on one university campus was analysed. Negotiations went through a number of stages, involving a master plan architect, members of the public, campus maps and the Vice Chancellor. An ANT analysis helped to trace diverse actors' interests in a series of discussions and how these interests conflict with each other as one option was chosen over another. The analysis revealed new client interests in each negotiation process. Also, the prioritisation of client interests changed over time. The documentation of diverse and dynamic client interests especially contributes to the understanding of how some client interests fail to be incorporated in decision-making processes

Tracing client interests in the course of a project: why are some client interests incorporated whereas others are not?

Many construction professionals and policy-makers would agree that client expectations should be accommodated during a building project. However, this aspiration is not easy to deal with as there may be conflicting interests within a client organization and these may change over time in the course of a project. This research asks why some client interests, and not others, are incorporated into the development of a building project. Actor-Network Theory (ANT) is used to study a single building project on a University campus. The building project is analysed as a number of discussions and negotiations, in which actors persuade each other to choose one solution over another. The analysis traces dynamic client engagement in decision-making processes as available options became increasingly constrained. However, this relative loss of control was countered by clients who continued the control over the timing of participants' involvement, and thus the way to impose their interests even at the later stage of the project.