Inhaled allergen-driven CD1c up-regulation and enhanced antigen uptake by activated human respiratory-tract dendritic cells in atopic asthma

Background Dendritic cells (DC) mediate inflammation in rodent models of allergic airway disease, but the role played by human respiratory‐tract DC (hRTDC) in atopic asthma remains poorly defined. Recent data suggest that CD1 antigen presentation by hRTDC may contribute to asthma pathogenesis. Objective To investigate the influence of hRTDC on the balance between atopy and allergic asthma in human subjects and to determine whether CD1 expression by hRTDC is modulated during asthmatic inflammation. Methods Sputum cells were induced from steroid‐naïve, allergen‐challenged and allergen‐naïve subjects (atopic asthmatics, atopic non‐asthmatics and non‐atopic controls). hRTDC were identified using monoclonal antibody labelling and analysis by flow cytometry. Results hRTDC stained HLA‐DR⁺ (negative for markers of other cell lineages) were predominantly myeloid and comprised ∼0.5% of viable sputum cells. Sputum cells were potent stimulators of allogeneic CD4⁺ naïve T cells and enrichment/depletion experiments correlated stimulatory potency with DC numbers. Sputum contained cells that exhibited typical dendritic morphology when analysed by electron microscopy. Myeloid hRTDC were endocytically active, but uptake of FITC‐dextran was enhanced in cells from asthmatics (P<0.001). Despite their increased endocytic capacity, asthmatic myeloid hRTDC appeared mature and expressed increased levels of maturation markers (P<0.05–P<0.001), CD1c, CD1d and langerin (P<0.05). CD1c expression by asthmatic myeloid hRTDC was enhanced upon in vivo allergen challenge (three to ninefold within 24 h; P<0.05). CD11c⁻CD123^high hRTDC were only detected in asthmatic sputum and were increased in number following allergen challenge. Conclusion Despite limited cell numbers, it proved possible to analyse human RTDC in induced sputum, providing evidence that increased antigen uptake and enhanced CD1 presentation by activated hRTDC may contribute to allergic airway disease. CD1 presentation by hRTDC in atopic asthma may therefore constitute a novel target for future intervention strategies.     

Mouse chromosome 9 quantitative trait loci for soft tissue regeneration: Congenic analysis and fine mapping

Development of gene therapies for wound healing will depend on the identification of the genes involved in wound healing and tissue regeneration. Previous quantitative trait loci (QTL) studies in mice using the ear punch model have shown that major QTL exist on chromosome (Chr) 9 for soft tissue regeneration. In this study, we have developed a congenic line that contains the Chr 9 QTL chromosomal region from super healer MRL/MpJ in the genomic background of poor-healing SJL/J. The phenotypic effect of this QTL was confirmed in male mice, where the congenic line has shown significant healing improvement over SJL. Fine mapping of the Chr 9 QTL region with 23 markers at an average distance of 4.2 Mb using a total of 1,564 MRL/MpJ x SJL/J F(2) mice revealed the presence of at least three QTL peaks, implying that three separate loci may contribute to the phenotypic effect of this QTL. Based on the 2-LOD intervals, the total QTL region was confined to a combined length of no more than 28.2 Mb. Application of a Bayesian shrinkage estimation indicated that a major locus was located in a region of just 1.3 Mb.     

Mycobacterium tuberculosis and Mycobacterium avium inhibit IFN- gamma -induced gene expression by TLR2-dependent and independent pathways.

Mycobacteria-infected macrophages are poor responders to interferon-gamma (IFN-gamma), resulting in decreased expression of IFN-gamma-induced genes. In the present study, we examined the inhibition of IFN-gamma-induced gene expression by Mycobacterium tuberculosis and four different Mycobacterium avium strains in mouse RAW264.7 macrophages. Gamma-irradiated M. tuberculosis inhibited mRNA expression of a panel of six different IFN- gamma-induced genes. All four of the M. avium strains completely inhibited IFN-gamma-induced expression of MHC class II Aalpha and Ebeta mRNA. However, the Mac101 strain, which is serovar 1, inhibited IFN-gamma induction of IFN regulatory factor-1 (IRF-1) and guanylate-binding protein-1 (GBP-1) mRNA to a greater extent than the other M. avium strains, which are serovar 2. In this study, we also show that mycobacteria inhibit gene expression by both toll-like receptor 2 (TLR2)-dependent and independent pathways. The inhibition of IFN-gamma-induced gene expression by M. avium was reduced but not completely blocked in macrophages from TLR2(/) mice. IFN-gamma-induced gene expression was also inhibited by mycobacteria in RAW264.7 cells expressing dominantnegative TLR2 or myeloid differentiation factor 88 (MyD88), further indicating the existence of a pathway independent of TLR2 and MyD88. These data suggest that mycobacteria inhibit IFN-gamma-induced gene expression by multiple pathways involving both TLR2 and non-TLR receptors.     

An in vivo investigation into bond failure rates with a new self-etching primer system.

Self-etching primers have recently been introduced to simplify the orthodontic bonding process. The aim of this study was to compare the effectiveness of such a product with conventional 2-stage etching and priming with 37% o-phosphoric acid and a conventional unfilled primer. Twenty consecutive patients having orthodontic bonds placed were selected to participate in this cross-mouth control study. Diagonally opposite quadrants were randomly allocated to either the self-etching primer group or the conventional etching and priming group. A total of 364 teeth were bonded with a light-cured diacrylate adhesive; bond failures were then monitored over 6 months. There were 20 bond failures (10.99%) in the self-etching primer group and 9 bond failures (4.95%) in the conventional etch and priming group over this period. The results were analyzed with the McNemar test and 95% confidence interval. The difference between the failure proportions was -0.06 with an associated 95% confidence interval of -0.121 to 0.001. This study produced weak evidence to suggest that bond failures with a self-etching primer will be higher than those with conventional etching and priming. This increased likelihood of bond failure must be weighed against the time advantage of the self-etching primer when used at the initial bonding appointment.     

Mapping brain size and cortical gray matter changes in elderly depression.

BACKGROUND: In elderly depression, volumetric brain imaging findings suggest abnormalities of the frontal lobe, particularly the orbitofrontal cortex, and the hippocampus. No studies to date have mapped cortical abnormalities over the entire brain surface in major depression. Here, we conducted detailed spatial analyses of brain size and gray matter within the cortical mantle in elderly patients with major depression. METHODS: High-resolution, three-dimensional, structural magnetic resonance imaging data and cortical pattern matching methods were used in 24 depressed elderly patients and 19 group-matched controls to measure local brain size and proportions of gray matter at thousands of homologous cortical surface locations. RESULTS: Prominent brain size reductions were observed in the depressed subjects in the orbitofrontal cortex bilaterally. Cortical gray matter measurements revealed significant gray matter increases in the orbitofrontal cortex, adjacent to focal trend level significant decreases of gray matter in the same region. Depressed patients also exhibited significant gray matter increases in parietal cortices, as well as the left temporal cortex. CONCLUSIONS: Complex cortical changes may contribute to the brain size reduction of the orbitofrontal cortex and to the gray matter abnormalities detected in orbitofrontal cortex and temporoparietal cortices, thereby providing a potentially new window into the pathophysiology of elderly depression.     

Corticomotoneuronal dysfunction in ALS patients with different SOD1 mutations.

OBJECTIVE: To examine corticomotoneuronal function in amyotrophic lateral sclerosis (ALS) patients carrying superoxide dismutase 1 (SOD1) mutations using peristimulus time histograms (PSTH). METHODS: Six I113T, 3 A4V, one G41D and one G114A patient were studied along with 21 healthy control subjects. Analyses included comparison with previously reported data from 8 D90A homozygous and 12 sporadic ALS (SALS) patients examined by the authors using identical methodology. RESULTS: Cortical threshold was significantly reduced in A4V patients (41.3%) compared to I113T (58%), SALS (57%) and D90A (71%) patients, as well as healthy controls (49.7%). Estimated excitatory postsynaptic potentials (EPSPs) were significantly larger in A4V patients (4.39 mV) compared to healthy controls (2.95 mV), I113T (2.71 mV) and SALS (2.39 mV) patients. Clinical features and PSTH parameters in I113T were similar to SALS, however, PSTH primary peaks (PP) were significantly more dispersed, 9.5 ms compared to 4ms in SALS. PSTHs from single G41D and G114A patients were unremarkable, apart from large EPSP amplitudes in the G114A patient. CONCLUSIONS: ALS patients with A4V and I113T SOD1 mutations have distinctive corticomotoneuronal changes that are different from those in D90A homozygous and SALS patients. SIGNIFICANCE: PSTH studies should be considered for future in vivo studies of SOD1 pathophysiology in ALS.     

Combining treatment for written and spoken naming.

Individuals with left-hemisphere damage often have concomitant impairment of spoken and written language. Whereas some treatment studies have shown that reading paired with spoken naming can benefit both language modalities, little systematic research has been directed toward the treatment of spelling combined with spoken naming. The purpose of this study was to examine the therapeutic effect of pairing a lexical spelling treatment referred to as Copy and Recall Treatment (CART) with verbal repetition of target words. This approach (CART + Repetition) was compared with treatment using verbal repetition without the inclusion of orthographic training (Repetition Only). Two individuals with moderate aphasia and severe impairment of spelling participated in the study using a multiple baseline design across stimulus sets and treatment conditions. Both participants improved spelling of targeted words as well as spoken naming of those items, but improvement in spoken naming was marked for one individual in the CART + Repetition condition, while the other participant made smaller gains in spoken than written naming irrespective of treatment condition. Consideration of the participant profiles suggested that CART + Repetition provides greater benefit when there is some residual phonological ability and the treatment serves to stimulate links between orthography and phonology.