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Learning motion discrimination with suppressed and un-suppressed MT.

Perceptual learning of motion direction discrimination is generally thought to rely on the middle temporal area of the brain (MT/V5). A recent study investigating learning of motion discrimination when MT was psychophysically suppressed found that learning was possible with suppressed MT, but only when the task was sufficiently easy [Lu, H., Qian, N., Liu, Z. (2004). Learning motion discrimination with suppressed MT. Vision Research 44, 1817-1825]. We investigated whether this effect was indeed due to MT suppression or whether it could be explained by task difficulty alone. By comparing learning of motion discrimination when MT was suppressed vs. un-suppressed, at different task difficulties, we found that task difficulty alone could not explain the effects. At the highest difficulty, learning was not possible with suppressed MT, confirming [Lu, H., Qian, N., Liu, Z. (2004). Learning motion discrimination with suppressed MT. Vision Research 44, 1817-1825]. In comparison, learning was possible with un-suppressed MT at the same difficulty level. At the intermediate task difficulty, there was a clear learning disadvantage when MT was suppressed. Only for the easiest level of difficulty, did learning become equally possible for both suppressed and un-suppressed conditions. These findings suggest that MT plays an important role in learning to discriminate relatively fine differences in motion direction.

Discrimination, Psychological↗

Burst suppression or isoelectric encephalogram for cerebral protection: evidence from metabolic suppression studies.

Metabolic suppression may have a role in cerebral protection. It is often assumed that the cerebral metabolic and protective effects of qualitative burst suppression are similar to those of the isoelectric encephalogram (EEG). We have examined the effect of different degrees of EEG suppression on blood flow and oxygen difference during general anaesthesia. We studied 11 patients undergoing general anaesthesia for resection of acoustic neuromas. The study was performed after surgery with propofol and remifentanil anaesthesia. Transcranial Doppler ultrasonography and jugular bulb venous saturations were measured at values of EEG suppression: 0%, 50% and 100% (isoelectric EEG). Data from nine patients were suitable for analysis. There were no significant differences in mean arterial pressure, heart rate or PaCO2 during EEG activity, 50% burst suppression ratio or isoelectric EEG. There was a significant decrease in middle cerebral artery flow velocity (vmca) with increasing EEG suppression (0% suppression, mean 38 (SEM 4) cm s-1; 50% suppression, 29 (3) cm s-1; and 100% suppression, 24 (2) cm s-1; P < 0.05). Jugular bulb venous saturations did not change consistently with the change in EEG activity, indicating intact flow-metabolism coupling. We conclude that the degree of EEG suppression had a significant effect on blood flow. If flow-metabolism coupling is maintained, the assumption that cerebral metabolism during 50% EEG burst suppression is equivalent to isoelectric EEG may not be justified. If cerebral protection is related to brain metabolism, then an isoelectric EEG may give more cerebral protection than 50% burst suppression.

Anesthesia, General↗

Macrophage-mediated suppression. I. Evidence for participation of both hdyrogen peroxide and prostaglandins in suppression of murine lymphocyte proliferation.

Macrophage-mediated suppression of Con A induced proliferation of murine splenic lymphocytes was studied in vitro. Either Corynebacterium parvrum-induced peritoneal exudate cells (PEC) or thioglycollate-induced PEC could totally suppress lymphocyte proliferation at a PEC:lymphocyte ratio of 2:10, whereas a ratio of 1 to 1.5: 10 caused a partial (60 to 68%) suppression. Exogenous PGE1 and PGE2 at concentrations of 10(-8) to 10(-6) M could not totally suppress lymphocyte proliferation. Conversely, indomethacin reversed the partial suppression by macrophages but only partially protected the totally suppressed lymphocyte cultures. Macrophage-mediated cytotoxicity and cytostasis have been proposed to be mediated by hydrogen peroxide. Therefore, hydrogen peroxide was investigated as a possible additional cause for macrophage-mediated suppression, by testing the anti-inhibitory effects of catalase. Partially suppressed cultures were effectively protected from suppression by catalase. In totally suppressed cultures, catalase alone was only minimally effective, but a synergistic effect of catalase and indomethacin was obtained, which provided complete protection from maximal macrophage-mediated suppression. Catalase presumably contributes to the reversal of macrophage suppressive effects both by reducing the direct toxic effect of H2O2 and by preventing the H2O2 from generating additional prostaglandins.

Animals↗

Recall of specific suppression: co-dominance of suppression after primary or secondary antigen stimulation.

Mouse spleen cells primed in vivo with beta-galactosidase (GZ), and cultured in vitro with trinitrophenyl beta-galactosidase (TNP-GZ), make a very poor anti-TNP response compared to cultures of normal spleen cells. The lack of response is caused by active suppression as indicated by cell mixture experiments. At 2-months following priming, while the helper effect predominates, suppression can be recalled by rechallenge of the mice with GZ. Both primary suppression (after a single injection) and secondary suppression (after two injections) reduce the response of normal or carrier-primed helper cells at equivalent cell ratios in mixture experiments. Both kinds of suppression are carrier specific, slectively suppress high avidity antibody production, and require cell division to suppress the response of normal cells. The only difference between primary and secondary suppression is that primary suppression is obliterated in cultures which are not challenged with antigen until 24 hr after cultures are established. Secondary suppression is still observed when cultures receive TNP-GZ at 24 hr. Suppression appears to be an early component of both primary and secondary responses. The regulatory function of such suppression may be the delay of antibody secretion.

Animals↗

Suppression of the allogeneic response by human IL-10: a critical role for suppression of a synergy between IL-2 and TNF-alpha.

The effect of IL-10 on T-cell activation by alloantigens in primary mixed lymphocyte reaction (MLR) was examined. IL-10 strongly suppressed proliferation and cytokine synthesis observed in this reaction. To determine the cytokine synthesis inhibition that was critical for the IL-10 induced suppression of proliferation in MLR, the effect of exogenous cytokines (IL-1 alpha, IL-1 beta, IL-2, IL-4, IL-6, IFN-gamma, or TNF-alpha) on this suppression was examined. None of these cytokines, when used at high concentration, was able to completely restore proliferation in the MLR to the levels observed in the absence of IL-10. However, IL-2 and TNF-alpha, when added alone at high concentration, could partially overcome the IL-10 induced suppression of proliferation in MLR. Moreover, when a combination of IL-2 and TNF-alpha was added at suboptimal doses to IL-10-suppressed MLR, complete restoration of the proliferative response was obtained. The ability of IL-10 to suppress proliferation in MLR was dependent on the type of cells used as stimulators. Thus, IL-10 suppressed proliferation in MLR when allogeneic normal peripheral blood mononuclear cells (PBMC), highly purified monocytes or B cells, were used, but not when B-cell lines were used as stimulators. Investigation of the effect of IL-10 on cytokine synthesis revealed that when B-cell lines were used as stimulators of MLR, IL-10 suppressed IFN-gamma and IL-2 synthesis but was unable to suppress TNF-alpha production. In contrast, CSA, which inhibited proliferation in MLR induced by B-cell lines, also inhibited TNF-alpha. IL-2 and IFN-gamma synthesis. Together these data suggest that the suppression of MLR by IL-10 requires the effective inhibition of both IL-2 and TNF-alpha production to suppress a synergy between these two cytokines.

Antibodies, Monoclonal↗

Suppression of human monocyte tumour necrosis factor-alpha release by glucocorticoid therapy: relationship to systemic monocytopaenia and cortisol suppression.

AIMS: Glucocorticoids suppress the release of tumour necrosis factor-alpha (TNF-alpha) by macrophages in vitro and cause monocytopaenia in vivo. These actions may contribute to anti-inflammatory and immunosuppressant effects. We therefore examined relationships between prednisolone concentration, suppression of monocyte TNF-alpha release, monocytopaenia and suppression of total cortisol concentration in healthy volunteers treated with a single dose (1.5 mg kg-1) of the glucocorticoid, prednisolone. METHODS: Monocyte numbers, total cortisol concentration and prednisolone concentration were measured in blood samples collected over 48 h after the dose. Plasma from these samples was also tested for its capacity to suppress lipopolysaccharide-induced TNF-alpha release from monocytes in autologous whole blood cultures. RESULTS: At 4 h after the dose, monocyte numbers in peripheral blood had fallen to a mean of 18% of the pre-dose level whilst plasma total cortisol had fallen to 9% of the pre-dose concentration. Monocyte numbers recovered in concordance with elimination of prednisolone and there was a significant relative monocytosis at 24 h. The recovery of plasma cortisol was delayed in comparison, with cortisol remaining significantly suppressed at 24 h. Plasma samples taken at 2 h after the dose (corresponding to peak plasma prednisolone concentration) suppressed the lipopolysaccharide-stimulated production of TNF-alpha by autologous blood monocytes to 27% of pre-dose control. Plasma collected at intervals over the 48 h from dosing also suppressed monocyte TNF-alpha release in relation to the prednisolone concentration therein. Suppression was largely reversed by the glucocorticoid antagonist, mifepristone. A similar relationship between prednisolone concentration and TNF-alpha suppression was observed when prednisolone was added to blood samples collected from the volunteers when they were drug-free. CONCLUSIONS: Blood concentration of prednisolone achieved after a dose of 1.5 mg kg-1 are sufficient to suppress monocyte TNF-alpha release and cause a biphasic change in peripheral blood monocyte numbers. Suppression of TNF-alpha is principally a direct glucocorticoid effect, rather than a consequence of other prednisolone-induced changes to blood composition.

Administration, Oral↗

Active suppression of immunoglobulin allotype synthesis. 3. Identification of T cells as responsible for suppression by cells from spleen, thymus, lymph node, and bone marrow.

Thymus-derived cells (T cells) that actively suppress production of IgG2a immunoglobulins carrying the Ig-1b allotype have been found in adult (SJL x BALB/c)F(1) mice exposed to anti-Ig-1b early in life. The suppression is specific for Ig-1b. The allelic product, Ig-1a, is unaffected. Spleen, lymph node, bone marrow, or thymus cells from suppressed mice suppress production of Ig-1b by syngeneic spleen cells from normal F(1) mice. When a mixture of suppressed and normal cells is transferred into lethally irradiated BALB/c mice, there is a short burst of Ig-1b production after which Ig-1b levels in the recipient fall rapidly below detectability. Pretreatment of the cells from the suppressed mice with antiserum specific for T cells (anti-Thy-1b) plus complement before mixture destroys the suppressing activity. Similar results with suppressor cells were obtained in vitro using Mishell-Dutton cultures. Mixture of spleen cells from suppressed animals with sheep erythrocyte (SRBC)-primed syngeneic normal spleen before culture suppresses Ig-1b plaque-forming cell (PFC) formation while leaving Ig-1a PFC unaffected. Treatment of the suppressed spleen with anti-Thy-1b before transfer removes the suppressing activity.

Animals↗

Endometrial volume and thickness measurements predict pituitary suppression and non-suppression during IVF.

BACKGROUND: The aim of this prospective study was to evaluate the usefulness of three-dimensional (3D) ultrasound measurement of endometrial volume and thickness as a predictor of pituitary suppression and non-suppression following GnRH agonist administration for IVF. METHODS: A total of 144 women undergoing 164 IVF cycles had transvaginal ultrasound measurement of their endometrial volume and thickness following 8-14 days of buserelin acetate administration. Serum estradiol concentrations were measured on the same day. Receiver operating characteristic (ROC) curve analysis was used for statistics. A ROC curve was produced for each of four estradiol thresholds commonly used by clinics to diagnose pituitary suppression (100, 150, 200, 250 pmol/l). From each curve, endometrial volume and thickness thresholds that best predicted pituitary suppression and, separately, non-suppression were selected and the associated sensitivity, specificity, positive and negative predictive values were reported. RESULTS: The area under the curve (AUC) was consistently higher (better test) for 3D volume than thickness estimation for all four estradiol thresholds, although it was only significantly different when a threshold of 200 pmol/l was used. The AUC increased towards 1.0 (perfect test) for both volume and thickness measurement as the selected estradiol threshold increased. Very different volume and thickness thresholds were optimal depending on whether the aim of the test was to predict pituitary suppression or non-suppression. CONCLUSIONS: 3D endometrial volume estimation provides a new tool, alongside endometrial thickness measurement, to diagnose pituitary suppression and non-suppression during IVF. Different endometrial thresholds must be selected depending upon whether the priority is to identify pituitary suppressed, or arguably more importantly, non-suppressed cycles.

Adult↗

Suppression of in vitro cell-mediated lympholysis generation by alloactivated lymphocytes. Examination of radioresistant suppressive activity.

We investigated the radioresistant (1000 rads) suppression of CML generation mediated by alloactivated murine splenocytes. Suppressive cells were generated in MLCs by stimulation of (A X 6R)F1 splenocytes with irradiated C57BL/10 splenocytes. Suppressive cells could lyse targets bearing H-2b alloantigens, but would not lyse parental B10.T(6R) or B10.A targets. Suppressive activity was detected by including the alloactivated (A X 6R)F1 cells in B10.T(6R) anti-B10.A(1R) MLCs. Relative to the suppressive (A X 6R)F1 cells, the B10.A(1R) lymphocytes display both parental and suppressor-inducing alloantigens. In the absence of a suppressive population, B10.A(1R) stimulators cause B10.T(6R) splenocytes to generate cytolytic activity specific for both H-2Db (suppressor-inducing) and H-2Kk (suppressor-borne) target determinants. The irradiated, alloactivated (A X 6R)F1 cells decrease the H-2Db-specific CML generated in this system, thus mediating apparent antigen-specific suppression. However, cytolytic activity concomitantly generated in the same culture against the unrelated H-2Kk target determinants is similarly reduced by the (A X 6R)F1 cells. Thus, radioresistant suppression by alloactivated splenocytes is not necessarily antigen-specific. The irradiated (A X 6R)F1 cells would not suppress the generation of H-2Kk-specific CTL in B10.T(6R) anti-B10.A MLCs. Hence, the irradiated (A X 6R)F1 cells can impede CML generation against third-party alloantigens if, and only if, those alloantigens are coexpressed with suppressor-inducing alloantigens on the stimulator cells in suppressed MLCs. Similar results were also obtained using a different histoincompatible lymphocyte combination. Since the pattern of suppressor specificity and the pattern of CTL specificity were identical and concomitant under these experimental conditions, these data are consistent with the hypothesis that radioresistant suppression by alloactivated lymphocytes can reflect coincidental in vitro cytolytic T cell function in vitro.

Animals↗

Causal linkage between insulin suppression of lipolysis and suppression of liver glucose output in dogs.

Suppression of hepatic glucose output (HGO) has been shown to be primarily mediated by peripheral rather than portal insulin concentrations; however, the mechanism by which peripheral insulin suppresses HGO has not yet been determined. Previous findings by our group indicated a strong correlation between free fatty acids (FFA) and HGO, suggesting that insulin suppression of HGO is mediated via suppression of lipolysis. To directly test the hypothesis that insulin suppression of HGO is causally linked to the suppression of adipose tissue lipolysis, we performed euglycemic-hyperinsulinemic glucose clamps in conscious dogs (n = 8) in which FFA were either allowed to fall or were prevented from falling with Liposyn plus heparin infusion (LI; 0.5 ml/min 20% Liposyn plus 25 U/min heparin with a 250 U prime). Endogenous insulin and glucagon were suppressed with somatostatin (1 microgram/min/kg), and insulin was infused at a rate of either 0.125 or 0.5 mU/min/kg. Two additional experiments were performed at the 0.5 mU/min/kg insulin dose: a double Liposyn infusion (2 x LI; 1.0 ml/min 20% Liposyn, heparin as above), and a glycerol infusion (19 mg/min). With the 0.125 mU/min/kg insulin infusion, FFA fell 40% and HGO fell 33%; preventing the fall in FFA with LI entirely prevented this decline in HGO. With 0.5 mU/min/kg insulin infusion, FFA levels fell 64% while HGO declined 62%. Preventing the fall in FFA at this higher insulin dose largely prevented the fall in HGO; however, steady state HGO still declined by 18%. Doubling the LI infusion did not further affect HGO, suggesting that the effect of FFA on HGO is saturable. Elevating plasma glycerol levels did not alter insulin's ability to suppress HGO. These data directly support the concept that insulin suppression of HGO is not direct, but rather is mediated via insulin suppression of adipose tissue lipolysis. Thus, resistance to insulin control of hepatic glucose production in obesity and/or non-insulin-dependent diabetes mellitus may reflect resistance of the adipocyte to insulin suppression of lipolysis.

Animals↗

Carbofuran suppresses T-cell-mediated immune responses by the suppression of T-cell responsiveness, the differential inhibition of cytokine production, and NO production in macrophages.

The effects of carbofuran (2,3-dihydro-2,2-dimethyl-7-benzo-furanol N-methylcarbamate) on the functions of T cells in splenocytes and peritoneal macrophages were examined in view of T-cell-mediated immune response (CMIR) in male C57BL/6 mice. Intraperitoneal administration of carbofuran (0.075, 0.15 and 0.3 mg/kg body weight) resulted in significant suppression of delayed type hypersensitivity (DTH), indicating that it caused the suppression of CMIR. Carbofuran decreased Concanavalin A (Con A)- and alloantigen-induced proliferation, and interleukin (IL)-2 production of splenocytes. In vitro addition of rIL-2 could not completely restore the suppressed T-cell proliferation, and IL-2-induced proliferation of Con A-activated splenocytes was also suppressed, which implied that carbofuran caused defects in IL-2 production and responsiveness of splenocytes to IL-2, leading to the suppression of T-cell proliferation. Con A-induced production of interferon-gamma (IFN-gamma) was significantly suppressed by carbofuran, while that of IL-4 was not affected. The production of transforming growth factor-beta from splenocytes was also significantly inhibited by carbofuran. Judging from these results, carbofuran might directly suppress the cytokine production in T helper 1 (Th1) cells. In addition, IFN-gamma-induced production of nitric oxide (NO) in macrophages was also inhibited by carbofuran, which might be one of the important mechanisms of carbofuran-induced CMIR suppression in mice. Collectively, the present study suggests that carbofuran might suppress CMIR through the suppression of T-cell responsiveness, IFN-gamma production in Th1 cells, and NO generation in macrophages.

Animals↗

Active suppression of immunoglobulin allotype synthesis. I. Chronic suppression after perinatal exposure to maternal antibody to paternal allotype in (SJL x BALB-c)F 1 mice.

Long-term (chronic) allotype suppression, previously reported only in rabbits, is shown here to occur in at least one strain combination of mice as well. Close to 50% of the offspring of SJL (Ig(b)) males mated to BALB/c (Ig(a)) females immunized against the paternal allotype were found to be suppressed for Ig-1b (gammaG(2a)) at 6 months of age. These mice are called "chronically" suppressed. The percentage of offspring in this strain combination suppressed for the paternal allotype at 8 wk of age is the same as that seen in an earlier strain combination tested, [(C57 x BALB/c)F(1)], in which all mice recover from suppression by 10-12 wk. After 8 wk, two distinct patterns of long-term (chronic) suppression emerge in (SJL x BALB/c)F(1) mice: a small number of these mice never produce detectable amounts of Ig-1b throughout their lives, while the majority produce detectable Ig-1b sporadically, sometimes over a period of several weeks, the level of which eventually falls below detectability. Attempts to "cure" suppression by destroying the existent lymphoid population and forcing endogenous repopulation in chronically suppressed animals were unsuccessful. Furthermore, attempts to restore Ig-1b production by injection of cells from syngeneic Ig(a)/Ig(b) donors into irradiated, chronically suppressed recipients were also unsuccessful, although the same cell inocula, when injected into irradiated BALB/c (Ig(a)/Ig(a)) mice produced high levels of gamma globulin carrying the allotype. These results suggest that long-term allotype suppression resulting from perinatal exposure of offspring to specific anti-allotype antibody (anti-Ig-1b), is not due merely to an absence of Ig-1b-producing cells or their progenitors, but appears to be an active process, which dominates physiologically over normal production.

Animals↗

Properties of the antigen-specific suppressive T-cell factor in the regulation of antibody response of the mouse. III. Dual gene control of the T-cell-mediated suppression of the antibody response.

The antigen-specific suppressive T-cell factor of mice, which had previously been shown to be an I region gene product, could effectively suppress the in vitro secondary antibody response of spleen cells from syngeneic or H-2 compatible mouse strains but not that of H-2 incompatible strains. The identities among genes in the left side half (K, I-A, and I-B) of the H-2 complex between the donor and recipient strains were found to be both necessary and sufficient for the induction of suppression. This suggests that the acceptor site for the suppressive T-cell factor is also determined by the gene present in the left side half of the H-2 complex. The cell type which expresses the acceptor site was found to be a subset of T cell. In general, the suppressive T-cell factor obtained from F1 mice could suppress the responses of both parental strains, and the parental factors could suppress the response of F1 mice. The results indicate that both suppressor and acceptor molecules are codominantly expressed on F1 T cells. There were found two types of defects in the expression of suppressor and acceptor molecules among mouse strains: A/J mice could not produce the suppressive T-cell factor despite that they could accept the factor produced by other H-2 compatible mouse strains. In contrast, all the B10 congeneic lines could produce the T-cell factor, but could not accept the factor produced by syngeneic and H-2 compatible non-B10 congeneic lines. The F1 hybrid of A/J and B10. A could both produce and accept the T-cell factor, and thus the expressions of suppressor and acceptor molecules were found to be dominant traits. These results indicate that the antigen-specific T-cell-mediated suppression is regulated by at least two genes both present in the H-2 complex, and that the complementation of these two genes is required for the induction of suppression.

Animals↗

Intravenous immunoglobulins suppress immunoglobulin productions by suppressing Ca(2+)-dependent signal transduction through Fc gamma receptors in B lymphocytes.

A high dose intravenous immunoglobulin (IVIG) therapy is used in the treatment of a wide range of autoimmune disorders. However, the mechanisms of the action of IVIGs remain poorly understood. To analyse the mechanisms of effects of IVIGs on immunoglobulin (Ig) production of B cells, the effects of IVIGs on B lymphoblastoid cell lines transformed by Epstein-Barr virus (LCLs) were investigated. The productions of IgG or IgM of LCLs were dose-dependently suppressed by polyethylene glycol (PEG)-treated IVIG or pH 4-treated IVIG though the productions were not or only slightly suppressed by pepsin-treated IVIG. The suppression by IVIGs was blocked by anti-human IgG Fc or anti-Fc gamma RII. C mu gene expression and mu s C terminal gene expression of LCLs were suppressed by PEG-treated IVIG, whereas neither C mu gene expression nor mu s C terminal gene expression of LCLs were suppressed by pepsin-treated IVIG. Although the increase in intracellular calcium concentration in LCLs was not suppressed by pepsin-treated IVIG, the increase was suppressed by PEG-treated IVIG. This suppressing effect of PEG-treated IVIG on intracellular calcium concentration of LCLs was blocked by anti-human IgG Fc or anti- Fc gamma RII. Our results suggest that IVIGs suppressed the Ca(2+)-dependent signal transduction through Fc gamma R on B-cell membrane, consequently, the transcription of C mu mRNA, especially secreted mu mRNA was suppressed in the B cells.

B-Lymphocytes↗

Suppression of immune response to Listeria monocytogenes: mechanism(s) of immune complex suppression.

We have investigated possible mechanisms underlying immune complex suppression of resistance to Listeria monocytogenes. Inhibition of resistance was found when immune complexes were formed in vivo in immune mice or in nonimmune mice adoptively transferred with specific antibody. Suppression was also found when nonimmune mice were injected with immune complexes preformed in vitro. We investigated the role of complement by decomplementing mice with cobra venom factor purified by high-pressure liquid chromatography. Complete depletion of serum C3 did not eliminate immune complex suppression of resistance to L. monocytogenes, suggesting that complement activation is not required for immune complex suppression. Infection-induced changes in the surface phenotype and functional properties of macrophages from normal and immune complex-suppressed mice were also investigated. Macrophage expression of both H-2K and Ia molecules increased during the response of normal mice to L. monocytogenes. However, these changes were not found in immune complex-suppressed mice. In contrast, membrane interleukin 1 expression was increased in macrophages from suppressed mice compared with macrophages from normal mice. Macrophages from L. monocytogenes-infected normal and immune complex-suppressed mice expressed cytotoxicity against tumor cells in vitro. We conclude that immune complexes do not inhibit resistance to L. monocytogenes by activation of complement or decreasing macrophage cytotoxic activity. Rather, defects in Ia expression by macrophages from suppressed mice might be one component responsible for immune complex suppression of resistance to L. monocytogenes.

Animals↗

Suppression of visually and memory-guided saccades induced by electrical stimulation of the monkey frontal eye field. I. Suppression of ipsilateral saccades.

When a saccade occurs to an interesting object, visual fixation holds its image on the fovea and suppresses saccades to other objects. Electrical stimulation of the frontal eye field (FEF) has been reported to elicit saccades, and recently also to suppress saccades. This study was performed to characterize properties of the suppression of visually guided (Vsacs) and memory-guided saccades (Msacs) induced by electrical stimulation of the FEF in trained monkeys. For any given stimulation site, we determined the threshold for electrically evoked saccades (Esacs) at < or =50 microA and then examined suppressive effects of stimulation at the same site on Vsacs and Msacs. FEF stimulation suppressed the initiation of both Vsacs and Msacs during and about 50 ms after stimulation at stimulus intensities lower than those for eliciting Esacs, but did not affect the vector of these saccades. Suppression occurred for ipsiversive but not contraversive saccades, and more strongly for saccades with larger amplitudes and those with initial eye positions shifted more in the saccadic direction. The most effective stimulation timing for suppression was about 50 ms before saccade onset, which suggests that suppression occurred in the efferent pathway for generating Vsacs at the premotor rather than the motoneuronal level, most probably in the superior colliculus and/or the paramedian pontine reticular formation. Suppression sites of ipsilateral saccades were distributed over the classical FEF where saccade-related movement neurons were observed. The results suggest that the FEF may play roles in not only generating contraversive saccades but also maintaining visual fixation by suppressing ipsiversive saccades.

Animals↗

The protein kinase Cbeta-selective inhibitor, Enzastaurin (LY317615.HCl), suppresses signaling through the AKT pathway, induces apoptosis, and suppresses growth of human colon cancer and glioblastoma xenografts.

Activation of protein kinase Cbeta (PKCbeta) has been repeatedly implicated in tumor-induced angiogenesis. The PKCbeta-selective inhibitor, Enzastaurin (LY317615.HCl), suppresses angiogenesis and was advanced for clinical development based upon this antiangiogenic activity. Activation of PKCbeta has now also been implicated in tumor cell proliferation, apoptosis, and tumor invasiveness. Herein, we show that Enzastaurin has a direct effect on human tumor cells, inducing apoptosis and suppressing the proliferation of cultured tumor cells. Enzastaurin treatment also suppresses the phosphorylation of GSK3betaser9, ribosomal protein S6(S240/244), and AKT(Thr308). Oral dosing with Enzastaurin to yield plasma concentrations similar to those achieved in clinical trials significantly suppresses the growth of human glioblastoma and colon carcinoma xenografts. As in cultured tumor cells, Enzastaurin treatment suppresses the phosphorylation of GSK3beta in these xenograft tumor tissues. Enzastaurin treatment also suppresses GSK3beta phosphorylation to a similar extent in peripheral blood mononuclear cells (PBMCs) from these treated mice. These data show that Enzastaurin has a direct antitumor effect and that Enzastaurin treatment suppresses GSK3beta phosphorylation in both tumor tissue and in PBMCs, suggesting that GSK3beta phosphorylation may serve as a reliable pharmacodynamic marker for Enzastaurin activity. With previously published reports, these data support the notion that Enzastaurin suppresses tumor growth through multiple mechanisms: direct suppression of tumor cell proliferation and the induction of tumor cell death coupled to the indirect effect of suppressing tumor-induced angiogenesis.

Animals↗

Consequences of stereotype suppression and internal suppression motivation: a self-regulation approach.

The present research studied the effects of suppression of stereotypes on subsequent stereotyping. Moreover, the moderating influence of motivation to suppress stereotypes was examined. The first three experiments showed that suppression of stereotypes leads to the experience of engaging in self-control (Study 1), to depleted regulatory resources as indicated by worse performance on an unrelated subsequent task that involves self-regulation (Study 2), and to hyperaccessibility of the suppressed thoughts (Study 3). However, these effects were moderated by internal suppression motivation: Increased self-control, depleted regulatory resources, and hyperaccessibility of suppressed thoughts only occur for people with low internal suppression motivation. Furthermore, in line with the argument that depletion of regulatory resources after suppression also should result in increased stereotyping in general, it was found that suppression of a specific stereotype leads to an increased use of stereotypes in general, but only for people with low internal suppression motivation (Study 4).

Adult↗