Age and gender differences in disabling foot pain using different definitions of the manchester foot pain and disability index

Extent: 9p.Background: The Manchester Foot Pain and Disability Index (MFPDI) has been used to determine the prevalence of disabling foot pain in several studies, however there is some debate as to which case definition is most appropriate. The objective of this study was to explore age and gender differences in the proportion of people with disabling foot pain using three different case definitions of the MFPDI and for each individual MFPDI item. Methods: A random sample of 223 participants aged 27 to 90 years (88 males and 135 females) from the North West Adelaide Health Study, who reported having pain, aching or stiffness in either of their feet on most days in the last month, completed the MFPDI by telephone interview. The proportion of people with disabling foot pain was determined using three definitions: (i) Definition A-at least one of the 17 items documented on at least some days in the last month; (ii) Definition B-at least one of the 17 items documented on most/every day(s) in the last month, and; (iii) Definition C-at least one of the ten functional limitation items documented on most/every day(s) in the last month. Cross-tabulations and chi-squared statistics were used to explore differences in responses to the MFPDI items according to age and gender. Results: The proportion of people with disabling foot pain according to each definition was as follows: Definition A (100%), Definition B (95.1%) and Definition C (77.6%). Definition C was most sensitive to age and gender differences. Exploration of individual MFPDI items indicated that age significantly affected both the pain intensity and functional limitation items, with younger people more likely to report their foot pain being worse in the morning, and older people more likely to report functional limitations. Although gender did not influence responses to the personal appearance items, women were more likely report functional limitations than men. Conclusions: Definition C of the MFPDI is more sensitive to age and gender differences in the proportion of people with disabling foot pain, and would therefore seem to be the most appropriate case definition to use in epidemiological studies involving a broad age range of participants.Hylton B Menz, Tiffany K Gill, Anne W Taylor and Catherine L Hil

Poor immunogenicity of a self/tumor antigen derives from peptide–MHC-I instability and is independent of tolerance

Understanding the mechanisms underlying the poor immunogenicity of human self/tumor antigens is challenging because of experimental limitations in humans. Here, we developed a human-mouse chimeric model that allows us to investigate the roles of the frequency and self-reactivity of antigen-specific T cells in determination of the immunogenicity of an epitope (amino acids 209–217) derived from a human melanoma antigen, gp100. In these transgenic mice, CD8(+) T cells express the variable regions of a human T cell receptor (hTCR) specific for an HLA-A*0201–restricted gp100(209–217). Immunization of hTCR-transgenic mice with gp100(209–217) peptide elicited minimal T cell responses, even in mice in which the epitope was knocked out. Conversely, a modified epitope, gp100(209–217(2M)), was significantly more immunogenic. Both biological and physical assays revealed a fast rate of dissociation of the native peptide from the HLA-A*0201 molecule and a considerably slower rate of dissociation of the modified peptide. In vivo, the time allowed for dissociation of peptide-MHC complexes on APCs prior to their exposure to T cells significantly affected the induction of immune responses. These findings indicate that the poor immunogenicity of some self/tumor antigens is due to the instability of the peptide-MHC complex rather than to the continual deletion or tolerization of self-reactive T cells

T-cell receptor-optimized peptide skewing of the T-cell repertoire can enhance antigen targeting

Altered peptide antigens that enhance T-cell immunogenicity have been used to improve peptide-based vaccination for a range of diseases. Although this strategy can prime T-cell responses of greater magnitude, the efficacy of constituent T-cell clonotypes within the primed population can be poor. To overcome this limitation, we isolated a CD8⁺ T-cell clone (MEL5) with an enhanced ability to recognize the HLA A*0201-Melan A₂₇₋₃₅ (HLA A*0201-AAGIGILTV) antigen expressed on the surface of malignant melanoma cells. We used combinatorial peptide library screening to design an optimal peptide sequence that enhanced functional activation of the MEL5 clone, but not other CD8⁺ T-cell clones that recognized HLA A*0201-AAGIGILTV poorly. Structural analysis revealed the potential for new contacts between the MEL5 T-cell receptor and the optimized peptide. Furthermore, the optimized peptide was able to prime CD8+ T-cell populations in peripheral blood mononuclear cell isolates from multiple HLA A*0201⁺ individuals that were capable of efficient HLA A*0201⁺ melanoma cell destruction. This proof-of-concept study demonstrates that it is possible to design altered peptide antigens for the selection of superior T-cell clonotypes with enhanced antigen recognition properties

Maternal Epistemological Perspectives and Variations in Mental State Talk

Purpose: This study examined how complexity of maternal epistemological beliefs predicted mothers\u27 and children’s talk about the mind. Method: Twenty-eight mothers of 5- to 10-year-olds completed a measure of receptive vocabulary, and mothers and children participated in a storytelling task specifically designed to elicit talk about the mind. Their use of mental state terms to encode pragmatic functions and mothers\u27 epistemologies were assessed and compared. Results: Maternal mental state talk and amount of talk increased with epistemological complexity. With the number of utterances held constant, mothers with simple, dualistic perspectives of knowledge used mental states more often to direct interaction; mothers with more complex epistemologies used mental states more often to encourage child reflection. Mothers with the less complex perspective underperformed on the receptive vocabulary measure in comparison to others. Children’s amount of talk and use of a variety of mental state terms also increased with maternal epistemological complexity. The amount of talk and mental state terms produced by mothers and children frequently persisted after the effects of maternal receptive vocabulary were removed. Conclusions: Maternal epistemologies predict several qualities of mothers\u27 and children’s mental state talk that may contribute to children’s developing theory of mind