Developing adaptive control: Age-related differences in task choices and awareness of proactive and reactive control demands.

Developmental changes in executive function are often explained in terms of core cognitive processes and associated neural substrates. For example, younger children tend to engage control reactively in the moment as needed, whereas older children increasingly engage control proactively, in anticipation of needing it. Such developments may reflect increasing capacities for active maintenance dependent upon dorsolateral prefrontal cortex. However, younger children will engage proactive control when reactive control is made more difficult, suggesting that developmental changes may also reflect decisions about whether to engage control, and how. We tested awareness of temporal control demands and associated task choices in 5-year-olds and 10-year-olds and adults using a demand selection task. Participants chose between one task that enabled proactive control and another task that enabled reactive control. Adults reported awareness of these different control demands and preferentially played the proactive task option. Ten-year-olds reported awareness of control demands but selected task options at chance. Five-year-olds showed neither awareness nor task preference, but a subsample who exhibited awareness of control demands preferentially played the reactive task option, mirroring their typical control mode. Thus, developmental improvements in executive function may in part reflect better awareness of cognitive demands and adaptive behavior, which may in turn reflect changes in dorsal anterior cingulate in signaling task demands to lateral prefrontal cortex.

Laparoscopic inguinal hernioplasty after robot-assisted laparoscopic radical prostatectomy.

PURPOSE: To evaluate the efficacy and safety of laparoscopic transabdominal preperitoneal (TAPP) inguinal hernia repair in patients who have undergone robot-assisted laparoscopic radical prostatectomy (RALP). METHODS: From July 2014 to December 2016, TAPP inguinal hernia repair was conducted in 40 consecutive patients who had previously undergone RALP. Their data were retrospectively analyzed as an uncontrolled case series. RESULTS: The mean operation time in patients who had previously undergone RALP was 99.5 ± 38.0 min. The intraoperative blood loss volume was small, and the duration of hospitalization was 2.0 ± 0.5 days. No intraoperative complications or major postoperative complications occurred. During the average 11.2-month follow-up period, no patients who had previously undergone prostatectomy developed recurrence. CONCLUSIONS: Laparoscopic TAPP inguinal hernia repair after RALP was safe and effective. TAPP inguinal hernia repair may be a valuable alternative to open hernioplasty.

Rapid inhibitory effect of tacrolimus on T cell migration by suppressing CD29-related functions.

OBJECTIVE: To clarify the direct effect of Tacrolimus (FK506) on T cell function in relation to CD29. METHODS: Human T cell line H9 and phytohemagglutinin (PHA)-activated T cells were incubated with or without Tacrolimus. The cells underwent cell migration assay by using fibronectin-coated trans-wells, and at the same time the degree of adherence by cultured cells to fibronectin-coated plastic wells was measured. For H9 cells, intracellular filamentous actin formation and the cell surface expression of CD3, CD11a, CD25, CD26, CD44, CD29 were measured by using flow cytometry. Intracellular tyrosin-phosphorylation induced by fibronectin by CD29 stimulation in H9 cells was analyzed by immunoblotting. RESULTS: The ability of H9 cells and PHA-activated T cells incubated with Tacrolimus for 2 hours (hrs) to migrate and to adhere to fibronectin was significantly suppressed. However, the inhibiton was transient, because the ability of cells incubated with Tacrolimus for 24 hrs to migrate was not affected despite the suppression of cell replication. Tacrolimus showed slight but significant reduction of cell surface expression of CD29 within 4 hrs, but CD3, CD11a, CD25, CD26 and CD44 were not affected. Tacrolimus rapidly inhibited intracellular filamentous actin formation; the maximum inhibition was within 2 hrs and the effect was not observed at 6 hrs. Intracellular tyrosin-phosphorylation induced by CD29 stimulation was also inhibited by, Tacrolimus in H9 cells. CONCLUSION: Tacrolimus appeared to have transient early phase inhibitory effects on CD29-related function that may be associated with T cell migration.

Ebastine inhibits T cell migration, production of Th2-type cytokines and proinflammatory cytokines.

BACKGROUND: Cytokine imbalance and cellular migration to inflammatory sites are critical components of allergic diseases. Redirecting cytokine imbalance and inhibiting cell migration therefore represent important therapeutic strategies for the treatment of these disorders. OBJECTIVES: To study the in vitro effect of ebastine, a novel non-sedating H1 receptor antagonist, on cytokine secretion and migration of activated T cells, as well as production of pro-inflammatory cytokines by macrophages. METHODS: Peripheral T cells obtained from healthy volunteers were cultured in wells coated with the combination of anti-CD3 monoclonal antibody (mAb) and anti-CD26 mAb, anti-CD3 mAb and anti-CD28 mAb, or anti-CD3 mAb with PMA, in the presence or absence of ebastine. T cell proliferation and the production of cytokines were measured by [3H]thymidine incorporation assay and ELISA, respectively. In addition, transendothelial migration of T cells and production of pro-inflammatory cytokines by macrophages were examined. RESULTS: Ebastine inhibited T cell proliferation and the production of IL-4, IL-5, IL-6, and TNF-alpha by T cells under each co-stimulatory condition tested, whereas it exhibited no effect on the production of IL-2 or IFN-gamma. In addition, T cell migration and the production of such pro-inflammatory cytokines as TNF-alpha and IL-6 by macrophages were inhibited by ebastine. CONCLUSIONS: These results indicate that ebastine has a specific inhibitory effect on Th2-type cytokine production. Moreover, ebastine inhibited T cell migration and pro-inflammatory cytokine production by T cells and macrophages, suggesting that ebastine might be useful for the treatment of T cell-mediated allergic inflammatory disorders, including asthma, atopic dermatitis, and Th2-type autoimmune diseases.

Soluble CD26/dipeptidyl peptidase IV induces T cell proliferation through CD86 up-regulation on APCs.

CD26 is a T cell costimulatory molecule with dipeptidyl peptidase IV enzyme activity in its extracellular region. We have previously reported that the addition of soluble CD26 (sCD26) resulted in enhanced proliferation of peripheral blood T lymphocytes induced by the recall Ag, tetanus toxoid (TT). However, the mechanism involved in this immune enhancement has not yet been elucidated. In this paper, we demonstrate that the enhancing effect of sCD26 on TT-induced T cell proliferation occurred in the early stages of immune response. The cells directly affected by exogenously added sCD26 are the CD14-positive monocytes in the peripheral blood. Mannose-6 phosphate interfered with the uptake of sCD26 into monocytes, suggesting that mannose-6 phosphate/insulin-like growth factor II receptor plays a role in the transportation of sCD26 into monocytes. When sCD26 was added after Ag presentation had taken place, enhancement in TT-induced T cell proliferation was not observed. In addition, enhancement of TT-mediated T cell proliferation by sCD26 does not result from trimming of the MHC-bound peptide on the surface of monocytes. Importantly, we also showed that exogenously added sCD26 up-regulated the expression of the costimulatory molecule CD86 on monocytes through its dipeptidyl peptidase IV activity, and that this increased expression of CD86 was observed at both protein and mRNA level. Therefore, our findings suggest that sCD26 enhances T cell immune response to recall Ag via its direct effect on APCs.

Intraosseous ganglion in the first metacarpal bone.

Intraosseous ganglia occur most frequently in the long bones of the lower limbs, particularly in the medial malleolus of the tibia. They usually appear as radiographically well circumscribed juxta-articular cystic lesions, containing myxoid fibrous tissue histologically. Intraosseous ganglia in the hand are very rare. Most reported cases have involved the carpal bones, in particular the lunate and scaphoid. To our knowledge, the present case is the third report of an intraosseous ganglion appearing in the first metacarpal bone; it arose in a patient who had been on dialysis for 25 years, mimicking amyloidosis of bone.

All together now: when dissociations between knowledge and action disappear.

Why do people sometimes seem to know things but fail to act appropriately on the basis of this knowledge? Such dissociations between knowledge and action often occur in infants and children, and in adults following brain damage. These dissociations have supported inferences about the organization of cognitive processes (e.g., separable knowledge and action systems) and their development (e.g., knowledge systems develop before action systems). The current study tested the basis for knowledge-action dissociations in a card-sorting task in which children typically correctly answer questions about sorting rules while sorting cards incorrectly. When questions and sorting measures were more closely equated for the amount of conflict that needed to be resolved for a correct response, children showed no systematic dissociation between knowledge and action. The results challenge standard interpretations of knowledge-action dissociations and support an alternative account based on graded knowledge representations.

Graded representations in behavioral dissociations.

Why do people sometimes seem to know things when they are tested in one way, while seeming unaware of this information when tested in a different way? Such task-dependent behaviors, or dissociations, often occur in infants and children, and in adults following brain damage. To explain these dissociations, researchers have posited separable knowledge systems that are differentially tapped by various tasks, develop at different rates and can be selectively impaired. There is an alternative account in which knowledge is viewed as graded in nature. Certain tasks tap weaker representations, while other tasks require stronger representations, leading to dissociations in behavior. The graded representations approach addresses dissociations observed in perception, attention, memory, executive functioning and language, and has implications for the organization, development and impairment of our cognitive systems.

Visual representation in the wild: how rhesus monkeys parse objects.

Visual object representation was studied in free-ranging rhesus monkeys. To facilitate comparison with humans, and to provide a new tool for neurophysiologists, we used a looking time procedure originally developed for studies of human infants. Monkeys' looking times were measured to displays with one or two distinct objects, separated or together, stationary or moving. Results indicate that rhesus monkeys used featural information to parse the displays into distinct objects, and they found events in which distinct objects moved together more novel or unnatural than events in which distinct objects moved separately. These findings show both commonalities and contrasts with those obtained from human infants. We discuss their implications for the development and neural mechanisms of higher-level vision.

Chemically modified ribozyme to V gene inhibits anti-DNA production and the formation of immune deposits caused by lupus lymphocytes.

A variety of autoantibodies is responsible for the tissue injury in autoimmune diseases. We have demonstrated that the human anti-DNA Ab O-81, of which Ids are commonly detected in renal glomeruli of active lupus nephritis, uses the V3-7 gene. We tried to develop a new therapy for lupus nephritis by using chemically modified ribozymes to specifically inhibit the expression of the mRNA of Ig V gene. The transfection of hammerhead ribozyme or the addition of chemically modified ribozyme against the flanking region of V3-7 caused a potent and selective inhibition of anti-DNA production in V3-7-using B cell clones, but not in irrelevant V gene-using clones in vitro. Chemically modified ribozyme was long-acting and resistant to RNase, and nonspecific cytotoxicity of the ribozyme was negligible. To know the efficacy of the ribozyme in vivo, we used a model of immune complex nephritis in SCID mice in which 5 x 10(6) PBLs from patients with active lupus nephritis (lupus PBL) were transferred twice. The injection of lupus PBL in combination with chemically modified ribozyme to increase resistance to RNase significantly reduced anti-DNA Ab levels in blood and decreased levels of urinary protein in the immune deposit models. Immunofluorescence study also revealed a marked decrease in IgG deposits at renal glomeruli in the ribozyme-treated group. These results indicate an efficacy of chemically modified ribozyme therapy for autoantibody-mediated immune diseases.

Novel in vitro effects of bucillamine: inhibitory effects on proinflammatory cytokine production and transendothelial migration of T cells.

OBJECTIVE: To investigate the novel antiinflammatory mechanism of a disease-modifying antirheumatic drug, bucillamine, on activated T cells, specifically its effect on T cell proliferation, cytokine production, and migration of T cells. METHODS: T cells were cultured in wells coated with anti-CD3 monoclonal antibodies (mAb) plus anti-CD26 mAb or anti-CD3 plus anti-CD28 mAb, with or without bucillamine. Proliferative responses and the production of interleukin-2 (IL-2), interferon-gamma (IFNgamma), tumor necrosis factor alpha (TNFalpha), IL-6, IL-4, and IL-5 were measured under these costimulatory conditions. Phytohemagglutinin (PHA)-activated T cells were cultured on human umbilical vein endothelial cell-coated transwells in the presence or absence of bucillamine, and T cells migrating through the endothelial cell layer were counted. Immunofluorescence analysis was also performed to analyze the effect of bucillamine on the surface expression of adhesion molecules on T cells. RESULTS: Bucillamine (64 microM) significantly inhibited T cell proliferation and the production of IL-2, IFNgamma, TNFalpha, and IL-6, whereas it had no inhibitory effects on the production of IL-4 and IL-5 in the cultures with anti-CD3 plus anti-CD26 mAb. In contrast, bucillamine had no effects on T cell proliferation or any cytokine production in the cultures with anti-CD3 plus anti-CD28 mAb. Furthermore, the same concentration of bucillamine inhibited transendothelial migration of PHA-activated T cells, and reduced the expression level of CD44 on T cells. CONCLUSION: This study demonstrated the novel effects of bucillamine in vitro, showing inhibition of type 1 T helper-type cytokine production and proinflammatory cytokine production induced by certain costimulatory conditions, and inhibition of transendothelial migration of T cells. The inhibition of T cell migration appeared to be mediated partly through the reduced expression of CD44, an adhesion molecule on the T cell surface.

Internalization of CD26 by mannose 6-phosphate/insulin-like growth factor II receptor contributes to T cell activation.

CD26 is a T cell activation antigen known to bind adenosine deaminase and have dipeptidyl peptidase IV activity. Cross-linking of CD26 and CD3 with immobilized mAbs can deliver a costimulatory signal that contributes to T cell activation. Our earlier studies revealed that cross-linking of CD26 induces its internalization, the phosphorylation of a number of proteins involved in the signaling pathway, and subsequent T cell proliferation. Although these findings suggest the importance of internalization in the function of CD26, CD26 has only 6 aa residues in its cytoplasmic region with no known motif for endocytosis. In the present study, we have identified the mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGFIIR) as a binding protein for CD26 and that mannose 6-phosphate (M6P) residues in the carbohydrate moiety of CD26 are critical for this binding. Activation of peripheral blood T cells results in the mannose 6 phosphorylation of CD26. In addition, the cross-linking of CD26 with an anti-CD26 antibody induces not only capping and internalization of CD26 but also colocalization of CD26 with M6P/IGFIIR. Finally, both internalization of CD26 and the T cell proliferative response induced by CD26-mediated costimulation were inhibited by the addition of M6P, but not by glucose 6-phosphate or mannose 1-phosphate. These results indicate that internalization of CD26 after cross-linking is mediated in part by M6P/IGFIIR and that the interaction between mannose 6-phosphorylated CD26 and M6P/IGFIIR may play an important role in CD26-mediated T cell costimulatory signaling.

[A case of far advanced breast cancer with distant metastases which had mostly disappeared after chemoendocrine therapy].

We report a case of far advanced breast cancer showing an excellent response to chemo-endocrine therapy. A 40-year-old female with a huge ulcerated tumor on her left anterior chest visited our hospital. Distant metastases were found in the lymph nodes, liver and bone. Therefore, endocrine therapy (toremifene and medroxyprogesterone acetate) and chemotherapy (cyclophosphamide, Therarubicin and 5-fluorouracil) were started as a combination treatment. As a result, the main tumor and metastatic lesion were remarkably reduced, and extended mastectomy with resection of right axillary lymph nodes was performed. Histologically, cancer cells in the primary lesion mostly disappeared, and only one lymph node in the left axillary lesion showed metastasis. No recurrence was found for 16 months after the surgical treatment. The combined therapy in the present case was extremely effective.

Detection of complement-fixing antiphospholipid antibodies in association with thrombosis.

Antiphospholipid antibody (aPL) is a hallmark of antiphospholipid syndrome (APS), characterized by thrombosis and recurrent fetal loss. We developed a novel ELISA system to detect complement-fixing ability of anticardiolipin antibody (aCL), and evaluated its clinical usefulness through studying the prevalence of the antibodies in rheumatic diseases, especially in association with thrombosis and recurrent abortion. Among 189 patients with rheumatic diseases, the complement-fixing aCL was positive in 26 (83.9%) of 31 patients with APS and 2 (1.3%) of 158 with other disease categories, whereas it was not positive among 52 normal subjects. Twenty-seven of 28 patients (96.4%), who were positive for complement-fixing aCL, had the episodes or history of thrombosis and/or recurrent abortion, at the time we studied. The remaining one in this group developed APS manifesting pulmonary infarction and occlusion of mesenteric artery 6 months after the evaluation. The sensitivity and specificity of this assay system were 75.0% and 99.3%, respectively, in relation with thrombotic episodes. On the other hand, the IgG aCL were positive in 28 (77.8%) of 36 cases with recent thrombotic episodes and 24 (15.7%) of 153 cases with no recent thrombotic episodes. The sensitivity and specificity of IgG aCL assay system were 77.8% and 84.3%, respectively, in relation with thrombotic episodes. These results indicate that complement-fixing aCL may specifically occur in association with the episodes of thrombosis and/or recurrent abortion in patients with APS compared to IgG-aCL. The method for detecting the complement-fixing aCL is simple, and it provides the useful diagnostic marker for thrombotic manifestations associated with APS.

Role of GABAA and GABAC receptors in the biphasic GABA responses in neurons of the rat major pelvic ganglia.

The role of gamma-aminobutyric acid-A (GABAA) and GABAC receptors in the GABA-induced biphasic response in neurons of the rat major pelvic ganglia (MPG) were examined in vitro. Application of GABA (100 microM) to MPG neurons produced a biphasic response, an initial depolarization (GABAd) followed by a hyperpolarization (GABAh). The input resistance of the MPG neurons was decreased during the GABAd, whereas it was increased during the GABAh. The GABAd could be further separated into the early component (early GABAd) with a duration of 27 +/- 5 s (mean +/- SE; n = 11) and the late component (late GABAd) with a duration of 109 +/- 11 s (n = 11). The duration of the GABAh was 516 +/- 64 s (n = 11). The effects of GABA (5-500 microM) in producing the depolarization and the hyperpolarization were concentration-dependent. GABA (5-30 microM) induced only late depolarizations. The early component of the depolarization appeared when the concentration of GABA was >50 microM. Muscimol produced only early depolarizing responses. Baclofen (100 microM) had no effect on the membrane potential and input resistance of MPG neurons. Bicuculline (60 microM) blocked the early GABAd but not the late GABAd and the GABAh. Application of picrotoxin (100 microM) with bicuculline (60 microM) blocked both the late GABAd and the GABAh. CGP55845A (3 microM), a selective GABAB receptor antagonist, did not affect the GABA-induced responses. cis-4-Aminocrotonic acid (CACA, 1 mM) and trans-4-aminocrotonic acid (TACA, 1 mM), selective GABAC receptor agonists, produced late biphasic responses in the MPG neurons. The duration of the CACA responses was almost the same as those of the late GABAd and GABAh obtained in the presence of bicuculline. Imidazole-4-acetic acid (I4AA, 100 microM), a GABAC receptor antagonist, depressed the late GABAd and the GABAh but not the early GABAd. I4AA (100 microM) and picrotoxin (100 microM) also suppressed the biphasic response to CACA. The early GABAd and the late GABAd were reversed in polarity at -32 +/- 3 mV (n = 7) and -38 +/- 2 mV (n = 4), respectively, in the Krebs solution. The reversal potential of the GABAh was -34 +/- 2 mV (n = 4) in the Krebs solution. The reversal potentials of the late GABAd and the GABAh shifted to -20 +/- 3 mV (n = 5) and -22 +/- 3 mV (n = 5), respectively, in 85 mM Cl- solution. These results indicate that the late GABA(d) and the GABAh are mediated predominantly by bicuculline-insensitive, picrotoxin-sensitive GABA receptors, GABAC (or GABAAOr) receptors, in neurons of the rat MPG.

Specific inhibition of TH2-type cytokine production from human peripheral T cells by terfenadine in vitro.

BACKGROUND: Cytokine imbalance is thought to be one of the causes for allergic diseases. The effect of anti-allergic drugs on cytokine production from T cells should be examined in a convenient way. OBJECTIVES: To study the in vitro effect of terfenadine, a prototype non-sedating H1 receptor antagonist, on cytokine production from activated T cells. METHODS: T cells were cultured in the presence of terfenadine on anti-CD3 mAb and anti-CD26 mAb-coated wells, anti-CD3 mAb and anti-CD28 mAb-coated wells, and anti-CD3 mAb wells with PMA. T-cell proliferation, along with the concentrations of interleukin (IL) -2, interferon (IFN) -gamma, IL-4, and IL-5 were measured. RESULTS: Terfenadine inhibited T-cell proliferation and IL-4 and IL-5 production under each costimulatory condition tested, whereas it had no effect on IL-2 and IFN-gamma production. CONCLUSIONS: These results indicate that terfenadine has a specific inhibitory effect on TH2-type cytokine production induced by several ways of costimulatory activation.

Decreased dipeptidyl peptidase IV enzyme activity of plasma soluble CD26 and its inverse correlation with HIV-1 RNA in HIV-1 infected individuals.

Human plasma contains soluble CD26/dipeptidyl peptidase IV (sCD26/DPPIV) although its physiological significance remains unclear. To determine whether the plasma sCD26 levels have clinical relevance in HIV-1 infected individuals, the concentration and DPPIV enzyme activity of plasma sCD26 were measured. While there is no significant difference between the plasma levels of sCD26 in 90 HIV-1 infected individuals and in 79 uninfected controls, specific DPPIV enzyme activity of sCD26 was significantly decreased HIV-1 infected individuals (P < 0.0001). Specific DPPIV enzyme activity was correlated with the levels of CD4+ T cells (r = 0.247; P < 0.02), CD8+ T cells (r = 0.236; P < 0.03), and adenosine deaminase (r = 0.227; P < 0.05) and had an inverse correlation with HIV-1 RNA (Spearman's r = 0.474; P = 0.0012). Furthermore, recombinant sCD26 enhanced the in vitro PPD-induced response of lymphocytes from HIV-1 infected individuals with decreased specific DPPIV enzyme activity. These results suggest that the specific DPPIV enzyme activity of plasma sCD26 may contribute to the immunopathogenesis of HIV infection.

CD26/dipeptidyl peptidase IV differentially regulates the chemotaxis of T cells and monocytes toward RANTES: possible mechanism for the switch from innate to acquired immune response.

CD26, a 110 kDa cell surface glycoprotein, exhibits dipeptidyl peptidase IV (DPPIV; EC 3.4.14.5) enzyme activity and plays an important role in T cell co-stimulation. In the present study, the function of CD26/DPPIV in transendothelial migration was examined using beta-chemokines as chemoattractants. When soluble recombinant CD26 (sCD26/DPPIV+) was added to the transendothelial chemotaxis system, chemotactic migration of T cells toward RANTES was significantly enhanced. Addition of sCD26 to 50 ng/ml of RANTES enhanced the migratory response by a factor of two compared to RANTES alone, whereas mutant soluble CD26 (mCD26), lacking the DPPIV enzyme activity, had no enhancing effect on RANTES-induced T cell migration. In the process of analyzing the mechanisms of the enhancement of T cell migration by sCD26, we showed that RANTES was cleaved by sCD26 under physiologic conditions at the precise site characteristic of its enzyme specificity. However, synthesized RANTES which lacks two N-terminal amino acids showed a chemotactic activity equivalent to full-length RANTES on T cells. Furthermore, addition of sCD26 showed enhancement of T cell migration induced by both forms of RANTES. In contrast to T cells, the truncated RANTES is inactive in chemotaxis of purified monocytes and supplement of sCD26 but not mCD26 reduced the migratory response of monocytes to RANTES. These results suggest that CD26/DPPIV differentially regulate the chemotactic response of T cells and monocytes to RANTES.