T cell reactions of Eimeria bovis primary- and challenge-infected calves

Eimeria bovis infections commonly have clinical impact only on young animals, as homologous reinfections generally are under immunological control. So far, the nature of the immune responses delivering protection to calves has not been investigated. In this study we therefore analysed local and peripheral proliferative T cell activities of primary- and challenge-infected calves and investigated the occurrence of T cell phenotypes in the peripheral blood and in mucosal gut segments isolated either by bioptic means or by necropsies. We show that lymphocytes of E. bovis-infected calves exhibit effective, transient antigen-specific proliferative responses in the course of prepatency of primary infection but fail to react after homologous reinfection suggesting early abrogation of parasite development. Whilst in primary infection an expansion of peripheral CD4⁺ T cells was observed, reinfection had no effect on the proportions of CD4⁺, CD8⁺ subsets or γδTCR⁺ T cells. In contrast, both E. bovis primary and challenge infections had an impact on local tissue T cell distribution. Primary infection was characterised by a CD4⁺ T cell infiltration early in prepatency in ileum and later in colon mucosa, whereas CD8⁺ T cells were only found accumulating in the latter gut segment. Challenge infection led to infiltration of both CD4⁺ and CD8⁺ T cells in small intestine and large intestine segments indicating protective functions of both cell types. In contrast, infiltration of ileum and colon mucosa with γδTCR⁺ T cells was restricted to primary infection.     

Eimeria bovis: An update on parasite–host cell interactions

Apicomplexan parasites are obligate intracellular protozoans and are well recognized modulators of the host cell machinery on varying levels such as host cell metabolism, MHC expression, cell cycle, or apoptosis in order to guarantee their intracellular development and survival. One of the most thoroughly examined apicomplexan pathogens demonstrating a potent manipulative capacity with respect to various host cell functions is Toxoplasma gondii, a protozoon exhibiting rapid intracellular development with small meronts in any nucleated cell, almost irrespective of the cell type or host origin. In contrast, Eimeria bovis merogony I is host- and cell type-restricted and occurs exclusively in bovine endothelial host cells. Furthermore, as a peculiarity, intracellular E. bovis meront I development is a long-lasting process (up to 3 weeks), leading to the formation of huge macromeronts of up to 300 μm in size, containing up to 120,000 merozoites I as offspring. In consequence, the necessity for intense host cell modulation to support this particular development appears even more pressing than in other apicomplexan parasite cases. Here we review the data currently available on E. bovis–host cell interactions, indicating the intriguing capacity of this protozoan to exploit and utilize its host cell for its own benefit.     

Evaluation of tolerability and efficacy of imatinib mesylate in elderly patients with chronic phase CML: ELDERGLI study

Imatinib mesylate (IM) is the treatment of choice in patients with newly diagnosed chronic myeloid leukemia (CML), irrespectively of their age. Nevertheless, information regarding tolerability and responses in advanced-age patients, a subgroup in which co-morbidities and other factors may influence outcome, is scarce, since they were excluded from most clinical trials. In this observational study (ELDERGLI), information regarding demographics, concomitant medication, physical examination, performance status, hemogram, biochemistry, hematologic, cytogenetic and molecular responses, time to progression, adverse events (AE) and severe adverse events (SAE) were prospectively recorded in a series of 36 elderly patients with CML, with a median age of 76.6 years. Most patients had cardiovascular co-morbidities, especially hypertension. Regarding IM toxicity, around one third of patients required treatment interruptions because of adverse events, especially hematologic toxicity (66% of cases that needed dose interruptions). When analyzing non hematologic adverse events, the most frequent ones were superficial edemas and GI symptoms. Of note, 9 of patients experienced an infection episode during the follow-up, and 4 were diagnosed during the study period of another type of cancer. Finally, cardiovascular events were reported in 7 patients, most of them with prior cardiovascular risk factors. Regarding responses, after 12 months of imatinib therapy, the rate of complete hematologic response (CHR), complete cytogenetic response (CCyR) and major molecular response (MMolR) were 89%, 72% and 55% respectively. In summary, IM display, in advanced-age patients with chronic phase CML, an efficacy and safety profile comparable to younger patients.     

A Ser/Thr cluster within the C-terminal domain of the rat prostaglandin receptor EP3alpha is essential for agonist-induced phosphorylation, desensitization and internalization

Two isoforms of the rat prostaglandin E(2) receptor, rEP3alpha-R and rEP3beta-R, differ only in their C-terminal domain. To analyze the function of the rEP3-R C-terminal domain in agonist induced desensitization, a cluster of Ser/Thr residues in the C-terminal domain of the rEP3alpha-R was mutated to Ala and both isoforms and the receptor mutant (rEP3alpha-ST341-349A-R) were stably expressed in HEK293 cells. All rEP3-R receptors showed a similar ligand-binding profile. They were functionally coupled to Gi and reduced forskolin-induced cAMP-formation. Repeated exposure of cells expressing the rEP3alpha-R isoform to PGE(2) reduced the agonist induced inhibition of forskolin-stimulated cAMP-formation by 50% and led to internalization of the receptor to intracellular endocytotic vesicles. By contrast, Gi-response as well as plasma membrane localization of the rEP3beta-R and the rEP3alpha-ST341-349A-R were not affected by prior agonist-stimulation. Agonist-stimulation of HEK293-rEP3alpha-R cells induced a time- and dose-dependent phosphorylation of the receptor most likely by G protein-coupled receptor kinases and not by protein kinase A or protein kinase C. By contrast, upon agonist-stimulation the rEP3beta-R was not phosphorylated and the rEP3alpha-ST341-349A-R was phosphorylated only weakly. These results led to the hypothesis that agonist-induced desensitization of the rEP3alpha-R isoform is mediated most likely by a GRK-dependent phosphorylation of Ser/Thr residues 341-349. Phosphorylation then initiates uncoupling of the receptor from Gi protein and receptor internalization.     

Mapping the key issues shaping the landscape of global public health

Abstract A survey of global health experts attending an invited meeting provided a means to map key issues perceived to be shaping emerging global public health agendas. Eighty-five participants proposed three major issues likely to have the most significant impact on the field of global health in the coming years. Six raters grouped the resultant items, with multi-dimensional scaling (MDS) analysis producing a composite two-dimensional map depicting the overall patterning of items. Thematic clusters were incorporated within four major domains: changing health and prevention needs (15% of items), globalisation and global health governance (33% of items), transforming health systems (30% of items) and innovations in science and technology (7% of items). The remaining 15% of items addressed forms of environmental change. The distribution of items across domains was not significantly influenced by the current professional role of participants, their current location in the 'global north' or 'global south' or their region of focus (although the latter approached threshold significance). The constraints on interpretation imposed by the biases influencing participation in the survey are noted. However, the exercise suggests the potential for coherently defining shared agendas for diverse stakeholders to address emerging priorities. The closer integration of environmental concerns with other global public issues is clearly warranted.     

CoCanCPG. Coordination of cancer clinical practice in Europe

All European countries are facing common challenges for delivering appropriate, evidence-based care to patients with cancer. Despite tangible improvements in diagnosis and treatment, marked differences in cancer survival exist throughout Europe. The reliable translation of new research evidence into consistent patient-oriented strategies is a key endeavour to overcome inequalities in healthcare. Clinical-practice guidelines are important tools for improving quality of care by informing professionals and patients about the most appropriate clinical practice. Guideline programmes in different countries use similar strategies to achieve similar goals. This results in unnecessary duplication of effort and inefficient use of resources. While different initiatives at the international level have attempted to improve the quality of guidelines, less investment has been made to overcome existing fragmentation and duplication of effort in cancer guideline development and research. To provide added value to existing initiatives and foster equitable access to evidence-based cancer care in Europe, CoCanCPG will establish cooperation between cancer guideline programmes. CoCanCPG is an ERA-Net coordinated by the French National Cancer Institute with 17 partners from 11 countries. The CoCanCPG partners will achieve their goal through an ambitious, stepwise approach with a long-term perspective, involving: 1. implementing a common framework for sharing knowledge and skills; 2. developing shared activities for guideline development; 3. assembling a critical mass for pertinent research into guideline methods; 4. implementing an appropriate framework for cooperation. Successful development of joint activities involves learning how to adopt common quality standards and how to share responsibilities, while taking into account the cultural and organisational diversity of the participating organisations. Languages barriers and different organisational settings add a level of complexity to setting up transnational collaboration. Through its activities, CoCanCPG will make an important contribution towards better access to evidence-based cancer practices and thus contribute to reducing inequalities and improving care for patients with cancer across Europe.     

Blastocystosis and other intestinal protozoan infections in human riverside communities of the Valdivia River basin, Chile]

Between March and October 1987, the prevalence of infection by Blastocystis hominis and other intestinal protozoan, their relationship with the age and sex of the hosts, and the percentage of infected persons in family groups were determined in riverside communities of Valdivia River Basin, Chile. One or more intestinal protozoan species were determined in 72.5% of the examined persons. The prevalence was greater for B. hominis (61.8%). The prevalences of B. hominis, Endolimax nana and Entamoeba coli were greater in relation to the age of the host. The sex of the host and prevalence of infections by B. hominis and other species of intestinal protozoans did not show association. Prevalence of B. hominis was greater in persons from houses with no sanitary faeces disposal. Over 60% of the members of family groups showed infection by B. hominis in 53.1% of the groups compared to 2.4%-21.8% of infections by other protozoan species. Faecal samples of 45 pigs revealed 22.2% of infection by Blastocystis.     

Genotype-phenotype correlation for pulmonary function in cystic fibrosis

Background: Since the CFTR gene was cloned, more than 1000 mutations have been identified. To date, a clear relationship has not been established between genotype and the progression of lung damage. A study was undertaken of the relationship between genotype, progression of lung disease, and survival in adult patients with cystic fibrosis (CF). Methods: A prospective cohort of adult patients with CF and two CFTR mutations followed up in an adult cystic fibrosis unit was analysed. Patients were classified according to functional effects of classes of CFTR mutations and were grouped based on the CFTR molecular position on the epithelial cell surface (I–II/I–II, I–II/III–V). Spirometric values, progression of lung disease, probability of survival, and clinical characteristics were analysed between groups. Results: Seventy four patients were included in the study. Patients with genotype I–II/I–II had significantly lower current spirometric values (p<0.001), greater loss of pulmonary function (p<0.04), a higher proportion of end-stage lung disease (p<0.001), a higher risk of suffering from moderate to severe lung disease (odds ratio 7.12 (95% CI 1.3 to 40.5)) and a lower probability of survival than patients with genotype I–II/III, I–II/IV and I–II/V (p<0.001). Conclusions: The presence of class I or II mutations on both chromosomes is associated with worse respiratory disease and a lower probability of survival.