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Bias and heteroscedastic memory error in self-reported health behavior: an investigation using covariance structure analysis.

BACKGROUND: Frequent use of self-reports for investigating recent and past behavior in medical research requires statistical techniques capable of analyzing complex sources of bias associated with this methodology. In particular, although decreasing accuracy of recalling more distant past events is commonplace, the bias due to differential in memory errors resulting from it has rarely been modeled statistically. METHODS: Covariance structure analysis was used to estimate the recall error of self-reported number of sexual partners for past periods of varying duration and its implication for the bias. RESULTS: Results indicated increasing levels of inaccuracy for reports about more distant past. Considerable positive bias was found for a small fraction of respondents who reported ten or more partners in the last year, last two years and last five years. This is consistent with the effect of heteroscedastic random error where the majority of partners had been acquired in the more distant past and therefore were recalled less accurately than the partners acquired more recently to the time of interviewing. CONCLUSIONS: Memory errors of this type depend on the salience of the events recalled and are likely to be present in many areas of health research based on self-reported behavior.

Adult↗

Germinal center B cells rescued from apoptosis by CD40 ligation or attachment to follicular dendritic cells, but not by engagement of surface immunoglobulin or adhesion receptors, become resistant to CD95-induced apoptosis.

Germinal centers (GC) constitute a specialized microenvironment essential for the formation of memory B cells, B cell affinity maturation and isotype switching. Within the GC, the B cells closely interact with follicular dendritic cells (FDC) and T cells, which both provide stimuli to the B cells that prevent their entry into apoptosis and promote their differentiation into memory cells or plasma cells. Cross-linking of B cell immunoglobulin (Ig) receptors by antigen, stimulation of the integrin adhesion molecules LFA-1 and VLA-4 on the B cell through interaction with their counter receptors ICAM-1 and VCAM-1 on the FDC and cross-linking of CD40 on the B cells through interaction with the CD40 ligand (CD40L) on T cells have been shown to prevent entry into apoptosis of GC B cells. Triggering of CD95, on the other hand, has been shown to induce apoptosis. We therefore investigated the interaction between adhesion-mediated signals, Ig, CD40, and CD95. The spontaneous apoptosis of GC B cells was not further increased by adding anti-CD95. However, CD95 stimulation did result in apoptosis of GC B cells in the presence of anti-Ig or adhesion-mediated rescue signals, which indicates that CD95 expressed on GC B cells is functionally active. In contrast, anti-CD95 was unable to induce apoptosis in cells rescued via CD40 stimulation, suggesting an important role for CD40L expressed on GC T cells in apoptosis regulation. We also studied apoptosis of B cells adhering to FDC, and found that B cells that interact with FDC were also rescued from CD95-induced apoptosis. A human CD40.Fc mu fusion protein that blocks CD40 ligation failed to inhibit this effect. Our studies therefore indicate that neither CD40, Ig receptors, nor adhesion receptors mediate rescue from apoptosis by FDC.

Apoptosis↗

Articulatory rehearsal in verbal working memory: a possible neurocognitive endophenotype that differentiates between schizophrenia and schizoaffective disorder.

Recent fMRI studies have identified brain systems underlying different components of working memory in healthy individuals. The aim of this study was to compare the functional integrity of these neural networks in terms of behavioural performance in patients with schizophrenia, schizoaffective disorder and healthy controls. In order to detect specific working memory deficits based on dysfunctions of underlying brain circuits we used the same verbal and visuospatial Sternberg item-recognition tasks as in previous neuroimaging studies. Clinical and performance data from matched groups consisting of 14 subjects each were statistically analyzed. Schizophrenic patients exhibited pronounced impairments of both verbal and visuospatial working memory, whereas verbal working memory performance was preserved in schizoaffective patients. The findings provide first evidence that dysfunction of a brain system subserving articulatory rehearsal could represent a biological marker which differentiates between schizophrenia and schizoaffective disorder.

Adult↗

Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections.

The viruses HIV-1, Epstein-Barr virus (EBV), cytomegalovirus (CMV) and hepatitis C virus (HCV) are characterized by the establishment of lifelong infection in the human host, where their replication is thought to be tightly controlled by virus-specific CD8+ T cells. Here we present detailed studies of the differentiation phenotype of these cells, which can be separated into three distinct subsets based on expression of the costimulatory receptors CD28 and CD27. Whereas CD8+ T cells specific for HIV, EBV and HCV exhibit similar characteristics during primary infection, there are significant enrichments at different stages of cellular differentiation in the chronic phase of persistent infection according to the viral specificity, which suggests that distinct memory T-cell populations are established in different virus infections. These findings challenge the current definitions of memory and effector subsets in humans, and suggest that ascribing effector and memory functions to subsets with different differentiation phenotypes is no longer appropriate.

Adolescent↗

Functionally distinct CD8+ memory T cell subsets in persistent EBV infection are differentiated by migratory receptor expression.

Human memory T lymphocytes have recently been re-defined as central or effector memory cells (Sallusto, F., Lenig, D., Forster, R., Lipp, M. and Lanzavecchia, A., Nature 1999. 401: 708-712). Effector memory cells (T(em)) are targeted to the peripheral tissues and show rapid effector function in response to antigenic stimulation. Central memory (T(cm)) cells are targeted to the lymph nodes and cannot be immediately activated. In this report HLA-A2-Epstein-Barr virus (EBV) peptide tetramers have been used to characterize the EBV-specific CD8+ T cell subsets in persistent EBV infection. In short-term activation studies two populations of tetramer-positive T cells were identified. One group resembled T(em) cells in that they rapidly produced IFN-gamma and lacked the lymph node homing receptor, CD62L, the second was similar to T(cm) cells since they were CD62L+ but could not be immediately induced to express IFN-gamma.

Antigens, CD↗

Short-term memory processes in delayed visual differentiation in rhesus macaques after bilateral removal of field 7 of the parietal cortex.

Monkeys (Macaca mulatta) with preliminary removal of field 7 of the lower parietal cortex and previously trained to differentiate images differing in shape, color, size, orientation, and spatial relationships were used to study the processes involved in short-term storage of different types of information required for a delayed (by 0-8 sec) visual differentiation task and the effects on these processes of the antioxidant Oxymetacil. Significant differences were found in comparison with intact animals. Removal of field 7 sharply worsened short-term storage processes during visual differentiation of different types of images, including those differing in terms of properties such as color, geometrical shape, and the spatial relationships between image elements. There were significant reductions in the level of correct responses for all delay periods with significant increases in the motor reaction time, indicating a sharp reduction in the duration of short-term information storage, which suggests that the monkeys' short-term memory mechanisms were disrupted. Oxymetacil had a correcting effect only in relation to stimuli differing in terms of color and shape, but had no effect at all on the short-term storage of spatial information. It is suggested that these data suggest that field 7 has at least two functions. These are, firstly, a role in processes underlying the evaluation, differentiation, and storage of spatial information depending on visual-vestibular interactions, and secondly, a role in the mechanisms underlying the attention system, which is disrupted by removal of field 7 and restored by treatment with the antioxidant when there is no need to differentiate spatial information, a process which depends on assessment of the body image and egocentric orientation based on visual-vestibular interactions.

Animals↗

Regulation of the CD8+ T cell responses against Plasmodium liver stages in mice.

CD8+ T cells induced by immunization with Plasmodium sporozoites play a major role in protective immunity against parasite infection, inhibiting the development of liver stages. The activation of these T cells is initiated just a few hours after exposure to parasites and progresses rapidly through a tightly regulated program. Effector functions in CD8+ T are detectable as early as 24 h after immunization and this event is followed 24-48 h later by an accelerated expansion of the CD8+ T cell numbers which reaches a peak 4-5 days after priming. Concomitantly with the development of anti-parasite activity, CD8+ T cells acquire a self-regulatory role limiting the magnitude of the CD8+ T cell response. Once activated, CD8+ T cells strongly inhibit the priming of additional naive CD8+ T cells by competing for antigen presenting cells. On days 6-8 after immunization, a sudden contraction of this T cell response occurs due to programmed cell death of 70-80% of the activated cells. After this contraction phase, 15-20 days after priming, activated cells establish memory populations. The development and maintenance of these memory populations strictly depends on the presence of CD4+ T cells and IL-4, and probably also IL-7, IL-15 and IL-2. These cytokines, some of which are produced by CD4+ T cells, provide signals to prevents apoptosis and also induce the differentiation of memory sub-populations, most of which acquire definitive phenotypes 20-30 days after immunization.

Animals↗

False memories are hard to inhibit: differential effects of directed forgetting on accurate and false recall in the DRM procedure.

Directed forgetting research shows that people can inhibit the retrieval of words that they were previously instructed to forget. The present research applied the directed forgetting procedure to the Deese/Roediger and McDermott (DRM) recall task to determine if directed forgetting instructions have similar or different effects on accurate and false memory. After studying lists of semantically related words, some participants were told to forget those lists, whereas other participants were not. All participants were then shown additional lists to remember. Following study, all participants were asked to free recall as many of the studied words as possible, including those they were previously instructed to forget. Directed forgetting instructions inhibited the accurate recall of studied words, but not the false recall of nonstudied critical words, whether measured by a within-participant or between-participants design. Contrary to an implicit activation hypothesis, false memories survived instructions to forget. These findings were reviewed in terms of fuzzy trace theory and the activation/monitoring approach to false memory.

Adolescent↗

Models of CD8+ responses: 1. What is the antigen-independent proliferation program.

Recent experimental results show that even brief stimulation with antigen can cause antigen-specific CD8 T-cells to undergo sustained proliferation followed by differentiation into memory cells. These results show that the dynamics of these immune responses are not governed by constant monitoring of antigen levels, but rather that following stimulation immune cells commit to a "program". At present relatively little is known about the program which governs CD8 cell proliferation and differentiation. For example, we do not know whether the program is completely specified by the initial encounter of a T cell with antigen, or whether it subsequently can be modified by the amount of antigen present. Nor do we know whether the entire program for T cell proliferation and differentiation resides within the T cell itself, or whether some component(s) of the program are determined by cells or molecules external to the CD8 cell. In this paper we construct simple mathematical models which incorporate antigen-independent proliferation and differentiation of CD8 cells during acute infections. We use these models to determine what characteristics the program must have in order to be consistent with the existing data on the dynamics of CD8 responses, and in particular to answer the questions posed above. Our results suggest that the program is not completely defined by the initial encounter of T cell with antigen but may be augmented by exposure to antigen in a brief window shortly after infection; furthermore, parts of the program may reside external to the T-cells. Finally we examine some of the consequences of the "program" for pathogen-host coevolution.

Animals↗

Overexpression of interleukin (IL)-7 leads to IL-15-independent generation of memory phenotype CD8+ T cells.

Transgenic (TG) mice expressing a high copy number of interleukin (IL)-7 cDNA under the control of the major histocomaptability complex (MHC) class II promoter display a 10-20-fold increase in total T cell numbers. Here, we show that the increase in T cell numbers in IL-7 TG mice is most apparent at the level of memory phenotype CD44hi CD122hi CD8+ cells. Based on studies with T cell receptor (TCR) TG mice crossed to IL-7 TG mice, increased levels of IL-7 may provide costimulation for TCR recognition of self-MHC ligands and thus cause naive CD8+ cells to proliferate and differentiate into memory phenotype cells. In addition, a marked increase in CD44hi CD122hi CD8+ cells was found in IL-7 TG IL-15(-) mice. Since these cell are rare in normal IL-15(-) mice, the dependency of memory phenotype CD8+ cells on IL-15 can be overcome by overexpression of IL-7.

Animals↗

Histogenesis of CD5-positive and CD5-negative B-cell neoplasms on the aspect of somatic mutation of immunoglobulin heavy chain gene variable region.

The immunoglobulin heavy chain (IgH) gene of B-cells dramatically alters twice in their differentiation to memory or plasma cells; VDJ recombination at B-cell precursor and somatic hypermutation, class switch recombination and receptor revision at germinal center (GC) B-cells. Among them, somatic hypermutation of the IgH gene variable region (VH gene) is a powerful tool for detection of B cell differentiation. B-cells and B-cell neoplasms have been divided into following; 1) pre-GC B-cells and neoplasms with a germline VH gene and 2) GC and post-GC B-cells and neoplasms with a somatically mutated VH gene. In this article, we review normal B-cell differentiation and histogenesis of various types of B-cell neoplasms on the aspect of somatic mutation of the rearranged VH gene. In particular, differences between CD5+ and CD5- B-cell neoplasms, using our own data of over 100 cases with B-cell neoplasms, are discussed. Although CD5+ B-cells are included in pre-GC B-cells for the reason of germline VH gene in most of CD5+ B-cells, an about 5% of CD5+ B-cells show somatically mutated VH gene. The rearranged VH gene of CD5+ B-cell neoplasms shows heterogeneity, whereas CD5- B-cell neoplasms possess somatically mutated VH gene with a mean of 8 approximately 12%. Both CD5+ B-cell chronic lymphocytic leukemia and CD5+ diffuse large B-cell lymphoma display that about half of cases show a germline or low frequency of somatic mutation and the others possess somatically mutated VH gene. CD5+ mantle cell lymphoma constitutes most cases with germline and a small number of cases with mutated VH gene. Therefore, CD5- B-cells & CD5- B-cell neoplasms are distinct from CD5+ B-cells and CD5+ B-cell neoplasms in somatic mutation of VH gene. It suggests that each of CD5- and CD5+ B-cells independently has its own differentiation.

B-Lymphocytes↗

Decreased dependence of myelin basic protein-reactive T cells on CD28-mediated costimulation in multiple sclerosis patients. A marker of activated/memory T cells.

Although multiple sclerosis (MS) patients and healthy individuals have similar frequencies of myelin basic protein (MBP)-specific T cells, the activation state of these cells has not been well characterized. Therefore, we investigated the dependence of MBP-reactive T cells on CD28-mediated costimulation in MS patients, healthy controls, and stroke patients. MBP-reactive T cells from healthy controls and stroke patients failed to proliferate efficiently when costimulation was blocked using anti-CD28, consistent with a naive T cell response. In contrast, MBP-specific T cell proliferation was not inhibited, or was only partially inhibited when CD28-mediated costimulation was blocked in MS patients. Blockade of CD28 failed to inhibit tetanus toxoid-specific T cell proliferation in both the controls and MS patients, demonstrating that memory cells are not dependent on CD28-mediated costimulation. Limiting dilution analysis indicated that the frequency of MBP-reactive T cells was significantly decreased in healthy controls compared with MS patients when CD28-mediated costimulation was blocked. These data suggest that MBP-reactive T cells are more likely to have been activated in vivo and/or differentiated into memory T cells in MS patients compared with controls, indicating that these cells may be participating in the pathogenesis of MS.

Abatacept↗

A case of reactive plasmacytosis mimicking multiple myeloma in a patient with primary Sjogren's syndrome.

Primary Sjogren's syndrome (pSS) is a chronic autoimmune disease with well-documented association of lymphoid malignancies during the progress of the disease. Although several types of malignancy and pseudomalignancy have been reported in pSS, low-grade non-Hodgkin's lymphomas are the most frequently observed. Reactive plasmacytosis mimicking myeloma is a very rare condition in association with pSS. We describe a 72-yr-old woman with pSS who presented with hypergammaglobulinemia, and extensive bone marrow and lymph node plasmacytosis, which mimicked multiple myeloma. In this patient, there was an abnormal differentiation of memory B cells to plasma cells in the peripheral blood suggesting underlying pathogenetic mechanism for this condition.

Aged↗

fMRI evidence of compensatory mechanisms in older adults at genetic risk for Alzheimer disease.

OBJECTIVE: To determine whether APOE genotype influences brain response and whether nonverbal stimuli generate findings comparable with those of previous studies that used verbal stimuli. The relationship between APOE genotype and blood oxygenation level dependent (BOLD) brain response was examined during a picture-encoding task in nondemented older adults. METHODS: Twenty nondemented participants with normal episodic memory function were divided into two groups based on the presence (n = 10) or absence (n = 10) of the APOE epsilon4 allele. Picture learning was completed during functional MRI in a blocked design alternating between experimental (novel pictures) and control (repeated picture) conditions. RESULTS: Nondemented older adults with an APOE epsilon4 allele showed greater magnitude and extent of BOLD brain response during learning of new pictures relative to their matched epsilon3 counterparts. Different patterns and directions of association between hippocampal activity and learning and memory performance were also demonstrated. CONCLUSIONS: The results suggest that brain response differences are not due to poorer general memory abilities, differential atrophy, or brain response during control conditions, but instead appear to be directly influenced by APOE genotype. Results are consistent with a compensatory hypothesis wherein older adults at genetic risk for Alzheimer disease by virtue of the APOE epsilon4 allele appear to require additional cognitive effort to achieve comparable performance levels on tests of episodic memory encoding.

Adaptation, Psychological↗

Improvement-related functional plasticity following pitch memory training.

Functional activation patterns of an auditory working memory task were examined prior to and after 5 days of training (1 h/day). A control group with no training was scanned twice at the same intervals to assess test-retest effects. Based on behavioral improvement scores, the training group (n = 14) was divided into "Strong-Learners (SL)" and "Weak-Learners (WL)". No significant functional or structural brain differences were seen between the SL and WL groups prior to training. Imaging contrasts comparing post- with pre-training sessions showed a significant signal increase in the left Heschl's gyrus (HG) as well as in the left posterior superior temporal and supramarginal gyrus for the SL group, while the WL group showed significant signal increases in the left HG and anterior insular cortex as well as in a lingual-orbitofrontal-parahippocampal network. The test-retest analysis in the control group revealed only minimal signal increases in a right dorsolateral prefrontal region. A random effects analysis comparing the SL group with the WL group using the post- and pre-training contrast images showed increased activation only in the left supramarginal gyrus but not in HG. The importance of HG in pitch discrimination has been established in previous studies. The pitch memory component differentiated our task from a straight pitch discrimination task. It is most likely that the activation of the SMG reflects its importance in the short-term storage of auditory material, and it was this activation that best differentiated between subjects' levels of performance.

Adult↗

GAD65-reactive T cells are activated in patients with autoimmune type 1a diabetes.

Insulin-dependent type 1 diabetes is an autoimmune disease mediated by T lymphocytes recognizing pancreatic islet cell antigens. Glutamic acid decarboxylase 65 (GAD65) appears to be an important autoantigen in the disease. However, T cells from both patients with type 1 diabetes and healthy subjects vigorously proliferate in response to GAD65 stimulation ex vivo, leading us to postulate that the critical event in the onset of human diabetes is the activation of autoreactive T cells. Thus, we investigated whether GAD65-reactive T cells in patients with diabetes functioned as previously activated memory T cells, no longer requiring a second, costimulatory signal for clonal expansion. We found that in patients with new-onset type 1 diabetes, GAD65-reactive T cells were strikingly less dependent on CD28 and B7-1 costimulation to enter into cell cycle and proliferate than were equivalent cells derived from healthy controls. We hypothesize that these autoreactive T cells have been activated in vivo and have differentiated into memory cells, suggesting a pathogenic role in type 1 diabetes. In addition, we observed different effects with selective blockade of either B7-1 or B7-2 molecules; B7-1 appears to deliver a negative signal by engaging CTLA-4, while B7-2 engagement of CD28 upregulates T cell proliferation and cytokine secretion.

Abatacept↗

Selection and function of CD4+ T lymphocytes in transgenic mice expressing mutant MHC class II molecules deficient in their interaction with CD4.

Interactions of the T cell coreceptors, CD4 and CD8, with MHC molecules participate in regulating thymocyte development and T lymphocyte activation and differentiation to memory T cells. However, the exact roles of these interactions in normal T cell development and function remain unclear. CD4 interacts with class II MHC7 molecules via several noncontiguous regions in both the class II MHC alpha- and beta-chains. We have introduced a double mutation that disrupts interaction with CD4 into the I-A(beta)k gene and used this construct to generate transgenic mice expressing only mutant class II MHC. Although CD4+ thymocytes matured to the single-positive stage in these mice, their frequency was reduced by threefold compared with that of wild-type transgenics. Positive selection of CD4+ T cells in the mutant transgenic mice may have been mediated by TCRs with a higher than usual affinity for class II MHC/Ag complexes. In A(beta)k mutant transgenics, peripheral CD4+ lymphocytes promoted B cell differentiation to plasma cells. These CD4+ T cells also secreted IFN-gamma in response to various stimuli (e.g., protein Ag, bacterial superantigen, and alloantigen), but were deficient in IL-2 secretion. Interactions between CD4 and class II MHC molecules appeared to regulate lymphokine production, with a strong bias toward IFN-gamma and against IL-2 in the absence of these interactions. Our results have implications for the manipulation of T cell-dependent immune responses.

Amino Acid Substitution↗