Effects of tropism and virulence of Leishmania parasites on cytokine production by infected human monocytes

The nature of early interactions between Leishmania and macrophages which determine the outcome of infection can be related directly to parasite biological properties. Here we compared the capacity of L. major (Lm) strains, reported to be high (LmHV) and low virulent and (LmLV) in the mouse model and L. infantum (Li) strains, dermotropic (LiD) and viscerotropic (LiV), to infect and modulate cytokine production in human peripheral blood derived monocytes. Monocytes were infected with metacyclic promastigotes for 24, 48 and 72 h. Parasite burden was significantly higher in Lm‐ than in Li‐infected monocytes. LmHV and LiD induced a significantly higher parasite burden than LmLV and LiV respectively. Cytokine production was evaluated in monocytes infected for 24 h. Contrary to interleukin (IL)‐12p70, monocyte chemotactic protein‐1 and transforming growth factor‐β production was increased significantly in infected monocytes with no differences between strains. Lm isolates induced significantly higher quantities of tumour necrosis factor (TNF)‐α than Li isolates. Low levels of IL‐10 were induced by all Leishmania strains and, interestingly, co‐stimulation with lipopolysaccharide (LPS) was accompanied by a dramatic increase in IL‐10 production by infected monocytes. In conclusion, Lm isolates displaying different levels of virulence in mice exhibited significant differences in parasite burden but similar abilities to modulate cytokine production in human monocytes. Li strains showed weaker infectivity and TNF‐α inducing‐capacity compared with Lm strains. The dramatic increase of IL‐10 production in infected monocytes co‐stimulated by LPS may play a role in disease progression considering the presence of LPS during bacterial superinfections observed during human leishmaniasis.     

Tid1 functions as a tumour suppressor in head and neck squamous cell carcinoma

Human tumourous imaginal disc (Tid1), a human homologue of the Drosophila tumour suppressor protein Tid56, is involved in multiple intracellular signalling pathways such as apoptosis, cell proliferation, and cell survival. Here, we investigated the anti‐tumourigenic activity of Tid1 in head and neck squamous cell carcinoma (HNSCC) in vitro and in vivo. Firstly, the clinical association between Tid1 expression and progression of HNSCC was explored. It was found that expression of Tid1 was negatively associated with tumour status, recurrence, and survival prognosis using immunohistochemical analysis of primary HNSCC patient tumour tissue. Secondly, ectopic expression of Tid1 in HNSCC cells was shown to significantly inhibit cell proliferation, migration, invasion, anchorage‐independent growth, and xenotransplantation tumourigenicity. Thirdly, we showed that overexpression of Tid1 attenuated EGFR activity and blocked the activation of AKT in HNSCC cells, which are known to be involved in the regulation of survival in HNSCC cells. On the other hand, ectopic expression of constitutively active AKT greatly reduced apoptosis induced by Tid1 overexpression. Together, these findings suggest that Tid1 functions as a tumour suppressor in HNSCC tumourigenesis. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

The association between degenerative hip joint pathology and size of the gluteus maximus and tensor fascia lata muscles

The aim of this study was to obtain, using Magnetic Resonance Imaging (MRI), muscle volume measurements for the gluteus maximus (upper: UGM and lower: LGM portions) and tensor fascia lata (TFL) muscles in both healthy subjects (n = 12) and those with unilateral osteoarthritis (OA) of the hip (mild: n = 6, and advanced: n = 6). While control group subjects were symmetrical between sides for the muscles measured, subjects with hip joint pathology showed asymmetry in GM muscle volume dependent on stage of pathology. The LGM demonstrated atrophy around the affected hip in subjects with advanced pathology (p < 0.05), however asymmetry of the UGM (p < 0.01) could be attributed largely to hypertrophy on the unaffected side, based on between group comparisons of muscle volume. TFL showed no significant asymmetry, or difference compared to the normal control group. This study highlights the functional separation of UGM and LGM, and the similarities of the UGM and TFL, both superficial abductors appearing to maintain their size around the affected hip. Further research is required to determine the specific changes occurring in the deeper abductor muscles. This information may assist in the development of more targeted and effective exercise programmes in the management of OA of the hip.     

The impact of chemokine receptor CX3CR1 deficiency during respiratory infections with Mycobacterium tuberculosis or Francisella tularensis

Recruitment of immune cells to infection sites is a critical component of the host response to pathogens. This process is facilitated partly through interactions of chemokines with cognate receptors. Here, we examine the importance of fractalkine (CX3CL1) receptor, CX3CR1, which regulates function and trafficking of macrophages and dendritic cells, in the host''s ability to control respiratory infections with Mycobacterium tuberculosis or Francisella tularensis. Following low-dose aerosol challenge with M. tuberculosis, CX3CR1^−/− mice were no more susceptible to infection than wild-type C57BL/6 mice as measured by organ burden and survival time. Similarly, following inhalation of F. tularensis, CX3CR1^−/− mice displayed similar organ burdens to wild-type mice. CX3CR1^−/− mice had increased recruitment of monocytes and neutrophils in the lung; however, this did not result in increased abundance of infected monocytes or neutrophils. We conclude that CX3CR1-deficiency affects immune-cell recruitment; however, loss of CX3CR1 alone does not render the host more susceptible to M. tuberculosis or F. tularensis.     

Are People with Intellectual Disabilities Represented in European Public Health Surveys?

Background Evidence suggests that people with intellectual disabilities experience secondary health conditions and report inequities in health status and access to health systems. Reliable information is essential to identify health disparities. A review of health interview and health examination surveys conducted in 17 European countries was undertaken to determine whether people with intellectual disabilities were represented. Method Using the online HIS HES database, 123 health surveys were scrutinized to determine whether they contained questions relevant to the Pomona 18 indicator set, and whether data could be extracted specifically on behalf of respondents with intellectual disabilities. Results Findings reveal that while items relating to 16 of the Pomona 18 health indicators were found in 123 of the surveys scrutinized, only nine surveys were identified as having potential to extract data on respondents with intellectual disabilities. Conclusion These findings have implications for those charged with the collection of comparable information about population health.     

Is the early cyclosporine A level predictive of the outcome of immunosuppressive therapy in severe aplastic anemia?

Immunosuppressive therapy (IST) has provided an alternative treatment option for cure of aplastic anemia patients who cannot receive bone marrow transplantation. Although there have been many recent studies on the efficacy of antithymoglobulin (ATG) combined with cyclosporine A (CsA), there is no data on the correlation between the variability of CsA levels and the response to IST. Therefore, we retrospectively assessed the factors associated with IST efficacy in patients with acquired severe aplastic anemia (SAA). Sixty‐six patients were treated with ATG combined with CsA for 6 months. In the response group, the CsA levels were increased rapidly to more than 200 ng/mL within the first 2 wk after starting the IST. However, the non‐response group had a pattern of slower increase of the CsA levels. The CsA levels, during the first and second week of treatment with IST, were significantly different in the responders and non‐responders. The factors predictive of response to IST and survival were analyzed. The univariate analysis showed that a younger age at the initiation of IST, a high absolute neutrophil count prior to starting IST, a short interval between the diagnosis and initiation of IST, and high CsA levels during the first and second week of IST treatment were positively associated with the response rate and overall survival. The multivariate analysis showed that these four factors were independent factors associated with a longer patient survival. A high response rate was associated with a short interval between diagnosis and initiation of IST as well as high CsA levels during the first and second week of IST. Therefore, early intensification of CsA levels might improve patient outcome.