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The virtues and limits of taping in clinical learning are considered. Enamored of technology, we may at times use it unwisely. Appropriate client selection, teaching to develop good clinical memory, the need to differentiate verbalized assent from true consent, and related issues are examined and illustrated.
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Cognitive event-related potentials (ERPs) were measured during a timbre discrimination task from three subject groups varying in musical experience. The P3 component of the ERP was recorded from musicians with absolute pitch, musicians without absolute pitch, and nonmusicians during a task comprising timbres of varying difficulty. The three-timbre series, all of which consisted of the same pitch, were (1) string instruments in the same family (cello and viola), (2) flutes made of different materials (silver and wood), and (3) instruments of slightly different size (B-flat versus F tubas). The amplitude and latency of the P3 component varied systematically as a function of musical experience and type of timbre discrimination. The difficult timbre task resulted in mean P3 amplitudes which were larger for musicians relative to nonmusicians, however P3 amplitudes were similar for the two additional timbre series. The mean P3 latencies for musicians were shorter when compared to nonmusicians across all three series. In comparison, the AP subjects displayed the shortest mean P3 latencies, but had smaller P3 amplitudes relative to both musicians and nonmusicians. The implications of these findings suggest that perceptual tasks involving one of the fundamental building blocks of music, namely timbre, does elicit differential brain activity from memory or information processing systems from subjects with varying degrees of musical training.
Modalities that induce specific differentiation to T cell memory in immune responses are important for vaccine design, but there is a paucity of well characterized molecular pathways useful to target for this purpose. We have shown previously that pentoxifylline (PF), a phosphodiesterase (PDE) inhibitor in common clinical use, enhances the commitment of in vitro allo-primed human T cells to secondary responsiveness, a characteristic crucial for memory T cells, which are key determinants of the longevity of the immune response. We now show that this effect can also be mediated by activation of adenylate cyclase (AC) and involves PDE4, but not PDE3 or PDE7. PF-mediated enhancement of T-cell priming is inhibited by blocking AC, is specifically signaled via cAMP-dependent protein kinase A (PKA) isoform I, and is probably independent of both nuclear factor-kappaB and the mitogen-activated protein kinase cascade. Furthermore, known pharmacological inhibitors of AC or PKA by themselves cannot block T-cell priming in the absence of PF or rolipram (Rm), and enhancement of priming requires the presence of PF only relatively late during a 4-day priming in vitro (at 48-96 h), suggesting that pharmacological extension of cAMP-mediated signaling can bring about an event critical for T cell commitment to memory. Furthermore, PF and Rm prevent induction of caspase activation and apoptosis in anti-CD3-activated human T cells. Together, our data suggest that PKA-I-mediated signals triggered by prolonging the half-life of cAMP induced during T-cell priming increase survival of activated T cells and enhance memory T cell commitment.
The requisite molecular interactions for CD8 T cell memory were determined by comparison of monoclonal naïve and memory CD8(+) T cells bearing the T cell receptor (TCR) for the HY antigen. Naïve T cells required only the right major histocompatibility complex (MHC) class I-restricting molecule to survive; to expand, they also needed antigen. In contrast, for survival, memory cells did not require the restricting MHC allele, but needed only a nonspecific class I; for expansion the correct class I, but not antigen, was required. Thus, maintenance of CD8 T cell memory still required TCR-MHC class I interactions, but memory T cells may have a lower functional activation threshold that facilitates secondary responses.
Global anterograde amnesia is described in three patients with brain injuries that occurred in one case at birth, in another by age 4, and in the third at age 9. Magnetic resonance techniques revealed bilateral hippocampal pathology in all three cases. Remarkably, despite their pronounced amnesia for the episodes of everyday life, all three patients attended mainstream schools and attained levels of speech and language competence, literacy, and factual knowledge that are within the low average to average range. The findings provide support for the view that the episodic and semantic components of cognitive memory are partly dissociable, with only the episodic component being fully dependent on the hippocampus.
BACKGROUND: The adipocyte derived hormone, leptin, has cytokine like function and may mediate the effects of starvation on immunity. Mice with congenital leptin deficiency (ob/ob) have small hypocellular thymuses and impaired cellular immunity. In humans leptin influences the differentiation of naïve and memory cells in vitro, and genetic leptin deficiency has been associated with an ill defined susceptibility to infection. AIMS: To describe the in vivo relation of leptin and immune function in children. METHODS: Fasting plasma leptin concentrations, immune function (T and B cell mediated vaccine responses and delayed type hypersensitivity), and mucosal function (dual sugar permeability test and salivary sIgA concentrations) were measured in a cohort of 472 moderately undernourished rural Gambian children. RESULTS: Leptin concentrations correlated with body fat assessed by mid upper arm circumference or BMI for age Z scores, and were very low compared to well nourished European norms (males 1.8 v 11.1 ng/ml; females 2.4 v 13.8 ng/ml). No detectable relations were found between leptin concentrations and any of the measures of immune or mucosal function. CONCLUSIONS: The data confirm that leptin acts as a peripheral signal of energy restriction, but do not support an association between fasting plasma leptin levels and immune function in children of this age.
UNLABELLED: The impact of efferocytosis-related genes (ERGs) on the diagnosis of colorectal cancer (CRC) remains unclear. In this study, efferocytosis-associated biomarkers for the diagnosis of CRC were identified by integrating data from transcriptome sequencing and public databases. Finally, the expression of biomarkers was validated by real-time quantitative polymerase chain reaction (RT-qPCR). Our study may provide a reference for CRC diagnosis. BACKGROUND: It has been shown that some efferocytosis related genes (ERGs) are associated with the development of cancer. However, it is still uncertain how ERGs may influence the diagnosis of colorectal cancer (CRC). METHODS: In our study, the CRC cohorts were gained from transcriptome sequencing and the gene expression omnibus (GEO) database (GSE71187). Efferocytosis related biomarkers with diagnostic utility for CRC were identified through combining differentially expressed analysis, machine learning algorithms, and receiver operating characteristic (ROC) analysis. Then, infiltration abundance of immune cells between CRC and control was evaluated. The regulatory networks (including mRNA-miRNA-lncRNA and miRNA/transcription factors (TF)-mRNA networks) were created. Finally, the expression of biomarkers was validated via real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: There were 3 biomarkers (ELMO3, P2RY12, and PDK4) related diagnosis for CRC patients gained. ELMO3 was highly expressed in CRC group, while P2RY12 and PDK4 was lowly expressed. Besides, the infiltrating abundance of 3 immune cells between CRC and control groups was significantly differential, namely activated CD4 memory T cells, macrophages M0, and resting mast cells. We then constructed a mRNA-miRNA-lncRNA network containing 3 mRNAs, 33 miRNAs, and 22 lncRNAs, and a miRNA/TF-mRNA network including 3 mRNAs, 33 miRNAs, and 7 TFs. Additionally, RT-qPCR results revealed that the expression trends of all biomarkers were consistent with the transcriptome sequencing data and GSE71187. CONCLUSION: Taken together, this study provides three efferocytosis related biomarkers (ELMO3, P2RY12, and PDK4) for diagnosis of CRC, providing a scientific reference for further studies of CRC.
Despite the important role immunoglobulin G (IgG)-secreting plasma cells play in memory immune responses, the differentiation and homeostasis of these cells are not completely understood. Here, we studied the differentiation of human IgG-secreting cells ex vivo and in vitro, identifying these cells by the cellular affinity matrix technology. Several subpopulations of IgG-secreting cells were identified among the cells isolated from tonsils and bone marrow, particularly differing in the expression levels of CD9, CD19, and CD38. CD38 low IgG-secreting cells were present exclusively in the tonsils. A major fraction of these cells appeared to be early plasma cell precursors, as upon activation of B cells in vitro, IgG secretion preceded up-regulation of CD38, and on tonsillar sections, IgG-containing, CD38 low cells with a plasmacytoid phenotype were found in follicles, where plasma cell differentiation starts. A unitary phenotype of migratory peripheral blood IgG-secreting cells suggests that all bone marrow plasma cell populations share a common precursor cell. These data are compatible with a multistep model for plasma cell differentiation and imply that a common CD38 low IgG-secreting precursor gives rise to a diverse plasma cell compartment.
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Mycosis fungoides and the Sézary Syndrome are characterized by clonal accumulation of well differentiated T-helper memory cells in the skin and, in the case of the Sézary Syndrome, also in the blood and lymph nodes. Well known immunological abnormalities in patients with MF and SS include reduced delayed type hypersensitivity, decreased proliferation upon stimulation with mitogens of the peripheral blood mononuclear cells, elevated IgE or IgA serum levels and eosinophilia. These abnormalities can be explained by the predominance of T-helper 2 cytokines. Clonal T-lymphocytes purified from the peripheral blood of SS patients transcribe mainly IL-10 and IL-5. They can be CD7 positive or negative. These clonal T cells express the accessory factor-1 (AF-1) or Interferon gamma receptor beta-chain that is essential for Interferon gamma signalling. These results imply perspectives for new therapeutical approaches, such as IL-12 or chimeric fusion proteins.
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CD4(+)CD25(+) regulatory T (Treg) cells naturally occur in mice and humans, and similar Treg cells can be induced in vivo and in vitro. However, the molecular mechanisms that mediate the generation of these Treg cell populations remain unknown. We previously described anti-4C8 mAbs that inhibit the postadhesive transendothelial migration of T cells through human endothelial cell monolayers. We demonstrate in this work that Treg cells are induced by costimulation of CD4(+) T cells with anti-CD3 plus anti-4C8. The costimulation induced full activation of CD4(+) T cells with high levels of IL-2 production and cellular expansion that were comparable to those obtained on costimulation by CD28. However, upon restimulation, 4C8-costimulated cells produced high levels of IL-10 but no IL-2 or IL-4, and maintained high expression levels of CD25 and intracellular CD152, as compared to CD28-costimulated cells. The former cells showed hyporesponsiveness to anti-CD3 stimulation and suppressed the activation of bystander T cells depending on cell contact but not IL-10 or TGF-beta. The suppressor cells developed from CD4(+)CD25(-)CD45RO(+) cells. The results suggest that 4C8 costimulation induces the generation of Treg cells that share phenotypic and functional features with CD4(+)CD25(+) T cells, and that CD25(-) memory T cells may differentiate into certain Treg cell subsets in the periphery.
Despite the superior efficacy of high-dose influenza vaccines, over one-third of older adults fail to respond. Yet, the mechanisms underlying this impaired vaccine responsiveness remain poorly understood. Here, we performed longitudinal profiling of older adults (n=60) receiving high-dose influenza vaccination to identify immune programs associated with vaccine responsiveness. Strong responders exhibited a primed baseline immune state characterized by elevated plasma cytokines and chemokines, followed by enhanced IFN-γ responses and coordinated transcriptional and epigenetic activation of cDC2 cells at day 1. By day 7, CD4+ T-cell trajectories diverged: strong responders preferentially expanded influenza-specific activated cTfh1 (CXCR5 + CXCR3 + ICOS + CD38 +) and influenza-specific Th10 (CXCR5 - CXCR3 + PD1 + IL10 +) cells, whereas weak responders expanded regulatory cTfr (CXCR5 + FOXP3 +) cells. Th10 expansion correlated with plasmablast and antibody responses and was independently validated in a larger influenza vaccination cohort, including younger adults. Functionally, Th10 cells promoted memory B-cell differentiation into plasmablasts and production of influenza-specific IgGs. TCR analyses revealed minimal clonal overlap between Th10 and cTfh1 cells. Together, these findings identify divergent helper and regulatory CD4+ T cell programs associated with vaccine responsiveness and establish Th10 cells as a previously unrecognized component of vaccine-induced humoral immunity.
B cells are required for both the expression of lupus nephritis and spontaneous T cell activation/memory cell accumulation in MRL-Faslpr mice (MRL/lpr). Autoimmunity in the MRL/lpr strain is the result of Fas-deficiency and multiple background genes; however, the precise roles of background genes vs Fas-deficiency have not been fully defined. Fas-deficiency (i.e., the lpr defect) is required in B cells for optimal autoantibody expression, raising the possibility that the central role for B cells in MRL/lpr mice may not extend to MRL/+ mice and, thus, to lupus models that do not depend on Fas-deficiency ("polygenic lupus"). To address this issue, B cell-deficient, Fas-intact MRL/+ mice (JHd-MRL/) were created; and disease was evaluated in aged animals (>9 mo). The JHd-MRL/+ animals did not develop nephritis or vasculitis at a time when the B cell-intact littermates had severe disease. In addition, while activated/memory CD4+ and CD8+ T cells accumulated in B cell-intact mice, such accumulation was substantially inhibited in the absence of B cells. This effect appeared to be restricted to the MRL strain because it was not seen in B cell-deficient BALB/c mice (JHd-BALB) of similar ages. The results indicate that B cells are essential in promoting systemic autoimmunity in a Fas-independent model. Therefore, B cells have an important role in pathogenesis, generalizable to lupus models that depend on multiple genes even when Fas expression is intact. The results provide further rationale for B cell suppression as therapy for systemic lupus erythematosus.
INTRODUCTION AND OBJECTIVES: During the last 15 years several diagnostic categories have appeared to describe a group of adults with cognitive impairment compared to their age-matched standardized norms but without dementia. In this work, the main studies relating to these categories are reviewed and compared in order to establish if they define similar or different aged populations. DEVELOPMENT: Differences in prevalence or in prognostic values among studies are probably due to the selection of diagnostic categories or the differences in the application of inclusion/exclusion criteria. Genetic and neuroimaging data have contributed to reinforce the validity of the proposed classifications to identify the age related cognitive decline. CONCLUSIONS: The criteria used seems to be very important in the inclusion of subjects closer to normal aging or to dementia. In this respect further longitudinal studies and a consensus from previous described categories are need to reliably identify aged population with lower cognitive function compared to their age norms but different from patients in the initial stages of dementia.
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