Models of Parkinson's disease.

Parkinson's disease (PD) is a heterogenous disease likely to be caused by more than one specific aetiological factor. In rare familial cases of PD with similar clinical features to the idiopathic form of the disease, the underlying genetic cause has been identified. These PD-associated genes have been manipulated to create animal and cell culture models of the disease that have helped to further our understanding of the pathogenesis of PD, particularly concerning causes of the selective loss of dopaminergic neurons at the molecular level. In addition, these models will aid the future development of rational therapeutic strategies. This study briefly reviews toxin-induced models and the genetics of PD. It focuses on recently developed animal models of PD, as well as in vitro approaches to model the disease.     

Dissecting the complexity of the memory T cell response

Memory immune responses are classically attributed to the reactivation of long-lived, antigen-specific T lymphocytes that persist in a quiescent state. Determining mechanisms for the generation of memory T cells and dissecting the functional nature of the memory T cell pool has been encumbered by an inability to distinguish recently activated effector T cells from memory T cells. We have established new activation and biochemical criteria that distinguish effector and memory T cells and have applied these criteria to follow memory generation from activated cells in vivo. We found that the resultant memory T cell pool is heterogeneous and consists of effector-like and resting memory-like subsets that differ in expression of the homing receptor, CD62L. We discuss these findings in the context of memory T cell heterogeneity identified in human and mouse systems. These results suggest that more than one type of previously activated T cell can mediate recall or memory immune responses and that elucidating the fundamental phenotypic and functional features of memory T cell subsets is therefore critical to deciphering the complex nature of the memory immune response.     

Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of thefirst phase I clinical trial

BACKGROUND: DC derived-exosomes are nanomeric vesicles harboring functional MHC/peptide complexes capable of promoting T cell immune responses and tumor rejection. Here we report the feasability and safety of the first Phase I clinical trial using autologous exosomes pulsed with MAGE 3 peptides for the immunization of stage III/IV melanoma patients. Secondary endpoints were the monitoring of T cell responses and the clinical outcome. PATIENTS AND METHODS: Exosomes were purified from day 7 autologous monocyte derived-DC cultures. Fifteen patients fullfilling the inclusion criteria (stage IIIB and IV, HLA-A1+, or -B35+ and HLA-DPO4+ leukocyte phenotype, tumor expressing MAGE3 antigen) were enrolled from 2000 to 2002 and received four exosome vaccinations. Two dose levels of either MHC class II molecules (0.13 versus 0.40 x 1014 molecules) or peptides (10 versus 100 mug/ml) were tested. Evaluations were performed before and 2 weeks after immunization. A continuation treatment was performed in 4 cases of non progression. RESULTS: The GMP process allowed to harvest about 5 x 1014 exosomal MHC class II molecules allowing inclusion of all 15 patients. There was no grade II toxicity and the maximal tolerated dose was not achieved. One patient exhibited a partial response according to the RECIST criteria. This HLA-B35+/A2+ patient vaccinated with A1/B35 defined CTL epitopes developed halo of depigmentation around naevi, a MART1-specific HLA-A2 restricted T cell response in the tumor bed associated with progressive loss of HLA-A2 and HLA-BC molecules on tumor cells during therapy with exosomes. In addition, one minor, two stable and one mixed responses were observed in skin and lymph node sites. MAGE3 specific CD4+ and CD8+ T cell responses could not be detected in peripheral blood. CONCLUSION: The first exosome Phase I trial highlighted the feasibility of large scale exosome production and the safety of exosome administration.     

Whole blood real-time quantitative PCR for cytomegalovirus infection follow-up in transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) remains a major opportunistic agent among transplant recipients. While detection of CMV pp65-lower matrix protein (pp65Ag) is still widely used for monitoring CMV infection, real-time PCR assays have been recently developed for routine quantitation of CMV DNA. However, correlations are lacking between results of pp65Ag and quantitative PCR assays and there is no consensus yet as to the more appropriate blood compartment (whole blood (WB), leukocytes, plasma) to be tested with PCR assays. OBJECTIVES: The aims of the study were to determine, in a population of transplant recipients: (i) the correlation between pp65Ag and CMV quantitative real-time PCR in our setting and (ii) the utility of plasma CMV DNA quantitation in comparison to WB quantitation. METHODS: In 170 blood samples (from 61 solid organ or bone marrow transplant recipients) with pp65Ag results, CMV quantitation was performed in WB and plasma using an in-house real-time quantitative PCR. RESULTS: Real-time PCR and pp65Ag results in WB were correlated: thresholds of 10 and 50(+) cells/200,000 cells were equivalent to 3.3 log(10)copies/mL (2,000 copies/mL) and 3.8 log(10)copies/mL (6,300 copies/mL), respectively. When WB viral load was >or=3.6 log(10)copies/mL, the risk to have a negative plasma CMV DNA result was 相似文献   

Effect of 940 nm laser diode irradiation prior to bonding procedure on postoperative sensitivity following class II composite restorations: a split-mouth randomized clinical trial

The aim of this study was to evaluate the effect of 940 nm laser diode on class II composite cavities prior to bonding and restoration process on the postoperative sensitivity (POS). Thirty patients with two bilateral premolars with mesio or disto-occlusal carious lesions were evaluated. In each patient, the teeth were randomly divided into the control and laser groups. After cavity preparation and isolation and before the bonding process, the laser group was subjected to 940 nm irradiation (Epic 10, Biolase, USA) by 400 μ tip continuously at 100 mW with 398 J/cm² energy density of tip, which was applied for 5 s at a distance of 2 mm on the axial wall of the cavity. In the control group, irradiation was performed by using the aiming beam. Access cavity was then restored with a composite resin. Cold sensitivity was measured using a cold spray application on the middle third of teeth buccal surface at baseline (before the intervention), 1, 14, and 30 days after the restoration by visual analog scale (VAS) criteria. The mean Friedman and Wilcoxon signed-rank tests were used for data analysis. It was shown that in both laser and control groups, the VAS was significantly decreased at all times compared to the baseline (p ≤ 0.05). There was no statistically significant difference between the mean VAS of two groups at baseline and first day (p ≤ 0.05), but at 14 and 30 days after the intervention, it was significantly lower in the laser group (p ≤ 0.05). The results of this study demonstrated that the cavity pretreatment with laser diode (940 nm) effectively reduces the postoperative sensitivity in class II composite restorations.

     

Regulation of Th17 cells by P. UF1 against systemic Listeria monocytogenes infection

Regulation of Th17 and Th1 cell responses against intracellular pathogens, including Listeria monocytogenes (L. m), is critical to limit inflammation-induced tissue damage. We recently demonstrated the ability of P. UF1 bacterium derived from the intestinal bacterial commensals of preterm infants fed human breast milk to significantly mitigate pathogen-induced inflammation limiting colonic tissue damage. Here we further elucidated the potential of P. UF1 to also regulate innate and T cells, particularly Th17 and Th1 cells, against systemic L. m infection. Data demonstrate that P. UF1 not only robustly regulated protective Th17 and Th1 cells, but also sustained regulatory T cells (Treg cells) resulting in accelerated L. m clearance. Together, regulation of pathogenic inflammation by a novel probiotic bacterium such as P. UF1 may illuminate a new strategy to specifically control Th17-Th1 cells via IL-10⁺ Treg cells to limit systemic tissue damage induced by intracellular pathogens, including L. m.