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Evaluation of general behavior, memory, learning performance, and brain sexual differentiation in F1 offspring males of rats treated with flutamide during late gestation.

Flutamide is a drug with antiandrogen effects that are mediated through androgen receptors (ARs). In this study, flutamide was subcutaneously administered to female rats (3, 10 or 30 mg/kg/day) on gestation Days 16-21 to evaluate effects on memory and learning performance in F1 offspring. Brain sexual differentiation was also evaluated by measuring the volume of the sexual dimorphic nucleus of the preoptic area (SDN-POA) and analyzing levels of androgen receptor (AR) mRNA expression in the prostate, hypothalamus and hippocampus. In F1 offspring exposed in utero to flutamide, evaluation of motor activity, learning performance and spatial perception showed that flutamide tended to exert a dose-dependent increase on the motor activity in F1 males, but no significant differences were identified in the other measurements. Prominent changes in development of the SDN-POA were apparent in males after maturation. Doses of > or =3 mg/kg/day resulted in significantly decreased length and volume of the SDN-POA compared to controls. These differences tended to become more marked at higher doses. Volumes of the SDN-POA did not differ significantly between F1 males and females exposed to flutamide at 30 mg/kg/day. AR mRNA was assayed using the dot-blotting method in F1 animals. In flutamide dose groups, AR mRNA expression tended to be increased in the prostate gland and decreased in the hippocampus. These results might suggest that exposure to flutamide in utero might affect controlling AR expression on a hormonal signal transduction system mediated by testosterone. However, these changes were not clearly correlated to learning performance in male offspring other than motor activity.

Androgen Antagonists↗

Differential effects of chronic stress on memory processes in the tree shrew.

Unpredictable and uncontrollable stressful events have been shown to affect cognitive processes. Interestingly, only hippocampus-mediated memory processes are thought to be sensitive to the effects of chronic stress. In contrast, the hippocampus-independent memory processes have been shown to be resistant to chronic stressful experiences. A central feature of the stress response is the activation of the hypothalamus-pituitary-adrenocortical (HPA)-axis, resulting in increased plasma levels of glucocorticoids, and several studies suggested that the performance of hippocampus-mediated memory processes might be directly modulated by these adrenal steroids. We investigated the impact of chronic psychosocial stress on hippocampus-mediated and hippocampus-independent memory processes in male tree shrews. By using a modified holeboard we followed memory performance during 23 weeks of alternating stress-free and stressful conditions. This schedule was designed to mimic a more realistic situation with stress-free conditions being sequentially interrupted by challenging events. The results indicate that chronic stress differentially affects hippocampus-mediated and hippocampus-independent memory processes in tree shrews. While hippocampus-independent memory processes remained unimpaired throughout the study, hippocampus-mediated memory was persistently impaired, not only during stress periods but also during recovery periods. This persistent impairment seems not to be exclusively triggered by glucocorticoids because urinary free cortisol concentration returned to normal during recovery periods. The present study is the first to evaluate the consequences of sequential stress exposure on memory performance in animals. Apparently, the mechanisms modulating cognitive processes are far from being understood and need a very systematic analysis in animal models with a high face and predictive validity to human stress-related memory disorders.

Aggression↗

Selective effects of triazolam on memory for emotional, relative to neutral, stimuli: differential effects on gist versus detail.

Benzodiazepines are known to reduce learning and memory performance, presumably through their facilitation of GABAergic neurotransmission, but the effects of these drugs specifically on memory for emotional material has not been addressed in humans. The effects of a benzodiazepine (triazolam, 0.25 mg) on nonincidental memory for emotional stimuli were assessed in 20 healthy volunteers (10 female). Triazolam reduced the normally facilitative effect of emotion on memory. The drug specifically affected memory for the gist of stimuli while leaving detail memory relatively unaffected. This pattern of performance is similar to that seen in patients with amygdala damage. Results suggest an effect of GABAergic neurotransmission at the level of the amygdala on memory modulation.

Adult↗

Differential TCR signaling and the generation of memory T cells.

There are currently two models for the generation of memory T cells: 1) memory T cells arise directly from activated effector T cells that have reverted to the resting state via an unknown mechanism; and 2) memory T cells are generated directly from naive T cells, bypassing an effector stage. I discuss here how recent results on the activation and signaling requirements of naive vs memory CD4 T cells favor the second model and how differential signaling of naive T cells may direct their developmental outcome.

Animals↗

Differentiating location- and distance-based processes in memory for time: an ERP study.

Memory for the time of events may benefit from reconstructive, location-based, and distance-based processes, but these processes are difficult to dissociate with behavioral methods. Neuropsychological research has emphasized the contribution of prefrontal brain mechanisms to memory for time but has not clearly differentiated location- from distance-based processing. The present experiment recorded event-related brain potentials (ERPs) while subjects completed two different temporal memory tests, designed to emphasize either location- or distance-based processing. The subjects' reports of location-based versus distance-based strategies and the reaction time pattern validated our experimental manipulation. Late (800-1,800 msec) frontal ERP effects were related to location-based processing. The results provide support for a two-process theory of memory for time and suggest that frontal memory mechanisms are specifically related to reconstructive, location-based processing.

Distance Perception↗

Different neurons in different regions of human temporal lobe distinguish correct from incorrect identification or memory.

Changes in the frequency of neural activity differentiating correct from incorrect responses were identified in extracellular recordings from 113 neurons at 62 sites in temporal lobe of 26 patients undergoing awake neurosurgery, during identification and recent explicit memory for object names, text or auditory words. Activity significantly differentiating correct from incorrect performance was identified in 22 neurons at 16 sites in 12 patients. Different neurons in different regions differentiated identification or memory performance. The 13 neurons differentiating identification performance were overrepresented in medial-basal recordings, the 9 neurons differentiating memory performance in superior temporal gyrus. All memory changes occurred during encoding. For both identification and memory there was separation of neurons showing differentiation early during perception and processing from those showing differentiation late, when output should occur, perhaps reflecting response monitoring. Early differentiating neurons were located more superior-laterally within the different regions related to accuracy of identification or memory.

Adolescent↗

Generation of plasma cells from peripheral blood memory B cells: synergistic effect of interleukin-10 and CD27/CD70 interaction.

B cells can differentiate into the antibody-secreting cells, plasma cells, whereas the crucial signals that positively control the entry into the pathway to plasma cells have been unclear. Triggering via CD27 by CD27 ligand (CD70) on purified peripheral blood B cells yielded an increase in the number of plasma cells in the presence of interleukin-10 (IL-10). Differentiation into plasma cells by a combination of IL-10 and CD70 transfectants occurred in CD27+ B cells but not in CD27- B cells. Moreover, addition of IL-2 to the IL-10 and CD70-transfect activation system greatly induced differentiation into plasma cells. In the presence of only IL-2, IL-4, or IL-6, CD70 transfectants did not promote differentiation into plasma cells. On the other hand, CD40 signaling increased the expansion of a B-cell pool from peripheral blood B cells primarily activated by IL-2, IL-10, and anti-CD40 monoclonal antibody (MoAb). Finally, CD27 signaling also rescued B cells from IL-10-mediated apoptosis. These data demonstrate that CD27 ligand (CD70) is a key molecule to prevent the IL-10-mediated promotion of apoptosis and to direct the differentiation of CD27+ memory B cells toward plasma cells in cooperation with IL-10.

Adult↗

Committed to memory: lineage choices for activated T cells.

The mechanisms for the generation of memory T cells and their delineation into heterogeneous subsets remain unknown. The linear model for memory T-cell generation from differentiated effector cells has been favored, although there is evidence that memory T cells can emerge directly from naive T cells undergoing homeostatic expansion and from activated T cells lacking effector functions. Here, we discuss the evidence from diverse studies of memory generation that support a new 'intersecting pathway' model for memory T-cell generation in which antigen-driven effector differentiation and homeostasis-driven memory differentiation follow distinct but analogous pathways. Antigen withdrawal during effector differentiation enables intersection with the memory pathway through a pre-memory intermediate, and memory heterogeneity is influenced by homeostasis, migration and persistence in vivo.

Animals↗

Cutting edge: HIV-1 Tat protein differentially modulates the B cell response of naive, memory, and germinal center B cells.

Critical steps of B cell differentiation occur within lymphoid organs that are also major sites of HIV-1 replication. Because Tat can be released by infected cells, we investigated whether extracellular HIV-1 Tat modulates cell proliferation of B cells at critical stages of their differentiation. Here we show that extracellular Tat inhibited the proliferation of B cell receptor-triggered naive and memory B cells by >80% but had no effect on their CD40 mAb and IL-4-mediated proliferation. In striking contrast, Tat doubled the germinal center B cell proliferation induced by CD40 mAb and IL-4. These effects were dose dependent and required the addition of Tat at the initiation of the culture, suggesting that Tat acts on early stages of cell cycle progression. By its effects on B cell subsets, Tat might directly affect the normal B cell differentiation process in HIV-positive patients and favor the occurrence of AIDS-associated B cell lymphomas.

Adjuvants, Immunologic↗

Free recirculation of memory B cells versus antigen-dependent differentiation to antibody-forming cells.

This study investigated whether or not the localization of persisting Ag influenced the localization of memory B and/or of Ab-forming cells (AFC). As a model Ag, we used vesicular stomatitis virus, which does not measurably replicate extraneuronally in adult mice after peripheral infection. Our results show that memory B cells and AFC are induced at the site where Ag is present; induced memory B cells then recirculate throughout the lymphoid system independently of Ag localization. In contrast, AFC are induced only at the sites of Ag persistence. These triggered Ab producing cells do not recirculate through the lymphoid tissue but migrate to the bone marrow.

Animals↗

Toll-dependent control mechanisms of CD4 T cell activation.

Toll-like receptors (TLRs) detect microbial infection and play an essential role in the induction of innate and adaptive immune responses. The mechanisms of TLR-mediated control of adaptive immunity are not yet fully understood. Induction of dendritic cell (DC) maturation is essential for activation of naive T cells. Here, we demonstrate that TLR-induced DC maturation and migration to the lymph nodes, in the absence of TLR-induced inflammatory cytokines, are not sufficient for T cell activation in vivo. We show that transient depletion of regulatory T (Tr) cells recovers the primary CD4 T cells response in MyD88-deficient mice, demonstrating that a major mechanism of TLR-mediated activation of T cell responses is the blocking of suppression by regulatory T cells. In addition we show that a TLR-induced signal(s) is required for memory CD4 T cell differentiation, but not for activation of memory T cells.

Adaptor Proteins, Signal Transducing↗

Evidence for differential expression of CD45 isoforms by precursors for memory-dependent and independent cytotoxic responses: human CD8 memory CTLp selectively express CD45RO (UCHL1).

On the basis of differential CD45 expression, human T cells can be separated into approximately reciprocal populations. The mAb UCHL1 detects a 180 kd molecular mass isoform, CD45R0. The CD45RA cluster of mAbs reacts with CD45 isoforms of 205 and 220 kd molecular mass. These reagents subdivide both CD4 and CD8 T cell populations. CD4 T cells that proliferate in response to memory-dependent (recall) antigens have been shown to selectively express CD45R0. We extend these observations to a model for cytotoxic responses that allows the functional analysis of CD8 T cells with differential CD45 expression. Precursors for allo-specific CTL responses are readily detectable in CD45R0 as well as CD45RA populations. In contrast, we find memory CTLp greatly enriched among CD45R0 cells. In combination with earlier work, these results suggest that differential expression of CD45 isoforms is associated with memory formation for different classes of immune responses in both major T cell lineages.

Antigens, Differentiation↗

Two related forms of memory in the crab Chasmagnathus are differentially affected by NMDA receptor antagonists.

A visual danger stimulus (VDS) elicits an escape response in the crab Chasmagnathus that declines after a few iterative presentations. Long-lasting retention of such decrement, termed context-signal memory (CSM), is mediated by an association between danger stimulus and environmental cues, cycloheximide sensitive, correlated with PKA activity and NFkappa-B activation, positively modulated by angiotensins, and selectively regulated by a muscarinic-cholinergic mechanism. The present research was aimed at studying the possible involvement of NMDA-like receptors in CSM, given the role attributed to these receptors in vertebrate memory and their occurrence in invertebrates including crustaceans. Vertebrate antagonists (+/-)-2-amino-5-phosphonopentanoic acid (AP5) and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) were used. Memory retention impairment was shown with MK-801 10(-3) M (1 microg/g) injected immediately before training or after training, or delayed 1 or 4 h, but not 6 h, posttraining. An AP5 10(-3) M dose (0.6 microg/g) impairs retention when given before but not after training. Neither antagonist produced retrieval deficit. A memory process similar to CSM but nonassociative in nature and induced by massed training (termed signal memory, SM), proved entirely insensitive to AP5 or MK-801, confirming the view that distinct mechanisms subserve these different types of memory in the crab.

Animals↗

CD8+ T-cell memory: only the good ones last.

Generating long-lasting, protective CD8(+) T-cell memory via vaccination is critical for combating infectious diseases. Advances in the past year have provided many new insights into how memory CD8(+) T cells are generated. It is now recognized that CD8(+) T cells differentiate from 'effector memory' cells into 'central memory' cells, which are stably maintained and confer superior protective immunity. Furthermore, CD4(+) T-cell help plays an important role in guiding the differentiation of CD8(+) T cells into long-lasting, functional memory. These findings have important implications for developing vaccine strategies that induce high-quality CD8(+) T-cell memory, not just high quantity.

Animals↗

Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation.

The interleukin-21 (IL-21)-IL-21-receptor system was discovered in 2000. It was immediately of great interest because of the homology of IL-21 to IL-2, IL-4 and IL-15, and of the IL-21-receptor subunit IL-21R to the beta-subunit of the IL-2 receptor, and because the IL-21 receptor also contains the common cytokine-receptor gamma-chain, the protein that is mutated in X-linked severe combined immunodeficiency. As we discuss, IL-21 has pleiotropic actions, from augmenting the proliferation of T cells and driving the differentiation of B cells into memory cells and terminally differentiated plasma cells to augmenting the activity of natural killer cells. Moreover, it has antitumour activity and might have a role in the development of autoimmunity, so these findings have implications for the treatment of cancer and autoimmune diseases.

Animals↗

IL-10 interrupts memory B cell expansion in the germinal center by inducing differentiation into plasma cells.

Germinal center (GC) B cells undergo proliferation, somatic hypermutation and isotype switching in the course of differentiation into plasma cells to produce high-affinity antibodies. To understand the molecular mechanism regulating the expansion of memory B cells and the termination of expansion by differentiation into plasma cells, we investigated the effect of interleukin-2 (IL-2), IL-4, IL-10 and CD40 ligand (CD40L) on the differentiation of GC B cells in the defined culture system containing a follicular dendritic cell (FDC)-like cell line. IL-2, IL-4 and CD40L are required for the optimum proliferation and differentiation of GC B cells. When IL-10 was added to this culture condition, CD20+ CD38+ GC B cells sequentially differentiated into CD20+ CD38- memory B cells and then CD20- CD38+ plasma cells. In the absence of IL-10, the resulting CD20+ CD38- memory B cells continued to proliferate and retained its phenotype. The proliferation of memory B cells was interrupted by addition of IL-10 which induced the differentiation into plasma cells. The expression of CD80 and CD86 was up-regulated in the memory B cells, compared to naive B cells and plasma cells. The identity of memory B cells generated in vitro from GC B cells was further substantiated since memory B cells generated in vivo displayed the identical pattern of proliferation and differentiation under the same culture condition. These results highlight the potent role of GCT helper cells in the expansion and differentiation of memory B cells by regulating different cytokine production.

ADP-ribosyl Cyclase↗

Locally invasive, well-differentiated thyroid cancer. 22 years' experience at Memorial Sloan-Kettering Cancer Center.

Our experience with 32 cases of locally invasive well-differentiated thyroid carcinoma suggests the following: (1) Thyroidectomy may be limited to the area of gross tumor involvement with little risk of recurrence in the normal opposite lobe. (2) Elective neck dissection should be considered in patients with locally invasive tumors since the incidence of nodal metastases is high. As observed in this study, occult metastases were present in five of six patients dissected electively, and nodal metastases developed later in four of eight patients observed. (3) Surgical procedures for the primary tumor should remove all gross disease. This is possible with conservative operations in most patients; the only deaths from uncontrolled local disease occurred in two patients in whom gross disease was left at the first procedure. Most deaths were caused by distant metastases, and the 5, 10 and 15 year survival rates were 86, 64 and 64 percent, respectively.

Adenocarcinoma↗