Reduction of Antral and Duodenal Gastrin Activity by electrical Vagal Stimulation1

The effect of electrical vegal stimulation on the antral and duodenal gastrin activity was determined in anesthetized cats. Vagal stimulation for 1 hr at 5, 10 and 20 imp/sec reduced the antral gastrin activity to about 75, 50 and 35 per cent, respectively. Corresponding figures for figures for 2 hrs stimulation was 45, 30 and 25 percent of the activity in unstimulated cats, thus showing a further reduction. Stimulation for 4 hrs did not produce any further reduction. Vagal stimulation for 2 hrs with all 3 frequencies reduced the gastrin activity in the mucosa of the proximal duodenum to unmeasurable levels.     

An Examination of Error-Related Brain Activity and Its Modulation by Error Value in Young Children

The error-related negativity (ERN) is an event-related brain potential observed in adults when errors are committed, and which appears to be sensitive to error value. Recent work suggests that the ERN can also be elicited in relatively young children using simple tasks and that ERN amplitude might be sensitive to error value. The current study employed a Go No-Go paradigm in which 5–7-year-old children (N = 18) earned low or high points for correct responses. Results indicated that errors were associated with an ERN; however, the size was not reliably moderated by error value.     

Inhibition of Baroreflex Vagal Bradycardia by Selective Stimulation of Arterial Chemoreceptors in Rats

We reported recently that hypoxia inhibits baroreflex vagal bradycardia (BVB) in rats and that this inhibition persists following chemoreceptor denervation. However, since it is possible that hypoxia also affects the central processing of chemoreceptive input, the existence of chemoreceptor-mediated inhibition of BVB cannot be ruled out. Therefore, we have studied whether selective chemoreceptor activation affects BVB in normoxic conditions. In pentobarbital-urethane-anaesthetized, succinylcholine-immobilized, artificially ventilated rats, BVB was provoked by electrical stimulation of the aortic depressor nerve. Arterial chemoreceptors were selectively activated by intracarotid injection of a minute amount of sodium cyanide. Cyanide injection consistently increased blood pressure while changing heart rate variably. BVB was inhibited in a dose-dependent manner. This inhibition, as well as changes in blood pressure and heart rate, was abolished following transection of the carotid sinus nerve (CSN) ipsilateral to the injection. Spinal cord transection at the C2 level did not affect the inhibition. On the other hand, intracarotid cyanide had no effect on bradycardia elicited by electrical stimulation of a peripheral cut end of the cervical vagus nerve. We conclude that chemoreceptor activation definitely inhibits BVB and that this inhibition is mediated by the CSN, and predominantly occurs in the central nervous system. The possibility is suggested that severe hypoxia suppresses not only BVB but also the chemoreceptor-mediated inhibition of BVB, both via the direct, central action.     

Modulation of Nitric Oxide Synthase Activity by Ibuprofen

Inhibition of NO synthesis represents a new therapeutical approach in the treatment of inflammation. Clinical use of NOS inhibitors will necessitate the design of drugs selective for iNOS, because inhibition of constitutive endothelial NOS may cause adverse cardiovascular side effects. This study examines the effect of ibuprofen and its stereoeisomeric components on the activation of iNOS and cNOS as well as on the NO production by human umbilical vein endothelial cells. At therapeutic concentrations Ibuprofen activated iNOS and inhibited cNOS. In endothelial cell culture experiments activation of NO production was seen especially at supratherapeutic ibuprofen concentrations. Both stereoisomeric components of ibuprofen showed comparable effects. This drug can therefore not be used for the selective inhibition of iNOS.     

Modulation of the Immune Response by Plasma Protease Inhibitors

In two different cytolytic assays, dose-dependent inhibition of antibody-dependent cell-mediated cytotoxicity and natural killing by alpha 2-macroglobulin (alpha 2m) and its subunits was observed. Alpha 2m subunits were approximately four times more inhibitory in both assays than the native alpha 2m molecule on a molar basis. Analysis of trypsin protein esterase activity demonstrated that alpha 2 subunits were four times more active than the parent molecule.     

Modulation of the Immune Response by Plasma Protease Inhibitors

The two major protease inhibitors in human serum, alpha₁-antitrypsin (_α1AT) and alpha₂-macroglobulin (_α2m), were analysed for their effects on antibody-dependent cell-mediated cytotoxocity (ADCC) and natural killing (NK). The results indicate that both _α1AT and _α2m decrease ADCC and NK in a dose-responsive pattern.     

Inhibition of T-Cell Activity by Cyclosporin A

Cyclosporin A (CyA) inhibits early events in the T-ccll response. It strongly suppresses the activation of naive T cells by IL1 or IL2 and alloantigen. CyA exerts a selective effect on activ ated T cells, It inhibits the ability of these cells to release IL2 in response to antigen or mitogen restimulation, at concentrations that have no effect on the ability of these same cell populations to respond to IL2 by proliferation. The specific effects of CyA are not limited to T cells, however, and this drug will inhibit IL1 production by lipopolysaccharide W-stimulated PU5-IR cells.     

Activity Inhibition of Cytolytic Lymphocytes by Omeprazole

This study examined the in vitro effect of omeprazole (OM) on various types of murine cytocidal lymphocytes. The results show that OM caused a strong inhibition of basal natural killer (NK) activity in spleen cells (SC) from untreated CD2F1 mice; in peritoneal exudate cells and SC activated in vivo by injection of maleic anhydride divinyl ether 1,2-copolymer (MVE-2) or inactivated Candida albicans (CA); in lymphokine-activated killer (LAK) activity generated in vitro from splenocytes cultured with rhIL-2 and in allo-specific cytotoxic lymphocyte-mediated lysis generated in vitro. A significant inhibition of cytotoxic activity of all types of effector cells after 30 min incubation was already induced by OM at 1 × 10^?3 m concentration, after 1 h incubation at 5 × 10^?4 m and after 4 h incubation at 1 × 10^?4 m OM. Complete inhibition of lytic activity was obtained after 4 h incubation of effector cells with 1 × 10^?3 m OM. No inhibitory effect was observed at 5 × 10^?5 m OM concentration. Indomethacin did not abrogate the OM inhibitory effect on NK/LAK activity, suggesting that prostaglandins are not involved in the process leading to suppression of cytocidal activity. When effector cells were incubated with OM in presence of rhIL-2 (500 U/ml), the cytokine failed to antagonize the inhibitory effect of the drug. On the contrary, if OM pretreated cells were incubated with rhIL-2 for a further 18 h after drug removal, this cytokine was able to restore NK activity, but only when NK inhibition was incomplete. These results demonstrate for the first time that in vitro OM causes a rapid, strong effect on various types of cytotoxic lymphocytes ranging from cytotoxicity inhibition to irreversible cell damage.     

Interleukin 1 Activity Produced by Human Rheumatoid and Normal Dendritic Cells

Dendritic cells (DC) from the synovial inflammatory tissue and peripheral blood of patients with rheumatoid arthritis and from the peripheral blood of normal blood donors were compared with the autologous monocytes for their capacity to produce and release interleukin 1 (IL-1). Synovial DC often spontaneously released higher amounts of IL-1 activity than unstimulated and lipopolysaccharide-stimulated peripheral blood DC and monocytes. The IL-1 production by both DC and monocytes increased after stimulation with bacterial lipopolysaccharide. In contrast with synovial DC the peripheral blood DC from both patients with rheumatoid arthritis and normal controls released less IL-1 activity than peripheral blood monocytes did. Inhibition with an antiserum to IL-1 revealed that IL-1 production is important for the accessory activity of the peripheral blood DC. Thus human DC from inflammatory sites and peripheral blood produce IL-1 activity.     

Advances in the Modulation of Cutaneous Wound Healing and Scarring

Cutaneous wounds inevitably heal with scars, which can be disfiguring and compromise function. In general, the greater the insult, the worse the scarring, although genetic make up, regional variations and age can influence the final result. Excessive scarring manifests as hypertrophic and keloid scars. At the other end of the spectrum are poorly healing chronic wounds, such as foot ulcers in diabetic patients and pressure sores. Current therapies to minimize scarring and accelerate wound healing rely on the optimization of systemic conditions, early wound coverage and closure of lacerations, and surgical incisions with minimal trauma to the surrounding skin. The possible benefits of topical therapies have also been assessed. Further major improvements in wound healing and scarring require an understanding of the molecular basis of this process. Promising strategies for modulating healing include the local administration of platelet derived growth factor (PDGF)-BB to accelerate the healing of chronic ulcers, and increasing the relative ratio of transforming growth factor (TGF)beta-3 to TGFbeta-1 and TGFbeta-2 in order to minimize scarring.     

Reflex Inhibition of Sympathetic Nerve Activity by Phenoxybenzamine

The effects on baroreceptor and sympathetic nerve activity of the a-adrenergic blocking agent phenoxybemamirie have been investigated in 13 anesthetized rabbits. Nerve activities were recorded at various blood pressure levels, obtained by stepwise changes of blood volume. With phenoxybenzamine, aortic nerve activity at 80 and 90 mm Hg exceeded control values by 66 and 62 %. At the same pressures, renal nerve activity was reduced by 30 and 55 %. Although blood pressure started to fall shortly after injecting the drug, about 20 min elapsed before development of maximum effects on the nerves. When studied during stepwise changes of blood pressure after a similar period of hypotension—but without the drug-sympathetic nerve activity had increased. Phenoxybenzamine had accordingly effected a suppression of sympathetic activity, suggesting that the hypotensive response to phenoxybenzamine is aided by increased reflex inhibition of sympathetic nerve activity.     

The Temporal Dynamics of Response Inhibition and their Modulation by Cognitive Control

Behavioral adjustments require interactions between distinct modes of cognitive control and response inhibition. Hypothetically, fast and global inhibition is exerted in the reactive control mode, whereas proactive control enables the preparation of inhibitory pathways in advance while relying on the slower selective inhibitory system. We compared the temporal progression of inhibition in the reactive and proactive control modes using simultaneous electroencephalography (EEG) and electromyography (EMG) recordings. A selective stop signal task was used where go stimuli required bimanual responses, but only one hand’s response had to be suppressed in stop trials. Reactive and proactive conditions were incorporated by non-informative and informative cues, respectively. In 47% of successful stop trials, subthreshold EMG activity was detected that was interrupted as early as 150 ms after stop stimulus presentation, indicating that inhibition occurs much earlier than previously thought. Inhibition latencies were similar across the reactive and proactive control modes. The EMG of the responding hand in successful selective stop trials indicated a global suppression of ongoing motor actions in the reactive condition, and less inhibitory interference on the ongoing actions in the proactive condition. Group-level second order blind separation (SOBI) was applied to the EEG to dissociate temporally overlapping event-related potentials. The components capturing the N1 and N2 were larger in the reactive than the proactive condition. P3 activity was distributed across four components, three of which were augmented in the proactive condition. Thus, although EEG indices were modulated by the control mode, the inhibition latency remained unaffected.     

Modulation of Leukocyte Phagocytic and Oxidative Burst Responses by Human Seminal Plasma

The typical absence of immune responses to spermatozoa in the female reproductive tract at the time of insemination, despite the presence of a marked leukocytic infiltrate into the cervical mucus is intriguing. It may be that localised immunoregulatory mechanisms exist and this study used whole blood flow cytometry to determine the effects of human seminal plasma on neutrophil and monocyte function. Seminal plasma inhibited the proportion of neutrophils and monocytes phagocytosing E.coli, and the intensity of neutrophil phagocytosis, but enhanced the magnitude of the phagocytic response of those monocytes that escaped inhibition relative to PBS treated controls. Oxidative burst responses to E.coli were also inhibited and this effect was mediated by low molecular weight species, as dialysis totally abrogated the inhibitory activity. Seminal plasma had no effect on the neutrophil burst response to fMLP when compared to the controls, however there was a significant difference between the responses of undialysed and dialysed seminal plasma treated samples. Undialysed seminal plasma significantly inhibited the proportion of monocytes undergoing the burst response to fMLP and there were significant differences between the proportion of cells responding and their intensity in undialysed and dialysed seminal plasma treated samples. In summary, this study reports differential modification of neutrophil and monocyte function by human seminal plasma. The residual capacity of these cells to undergo phagocytosis and generate oxidative burst responses suggests that localised innate immune function remains intact and is possibly enhanced in the female reproductive tract at the time of insemination. Other mechanisms must protect inseminated sperm at this time.     

Modulation of Leukocyte Phagocytic and Oxidative Burst Responses by Human Seminal Plasma

The typical absence of immune responses to spermatozoa in the female reproductive tract at the time of insemination, despite the presence of a marked leukocytic infiltrate into the cervical mucus is intriguing. It may be that localised immunoregulatory mechanisms exist and this study used whole blood flow cytometry to determine the effects of human seminal plasma on neutrophil and monocyte function. Seminal plasma inhibited the proportion of neutrophils and monocytes phagocytosing E.coli, and the intensity of neutrophil phagocytosis, but enhanced the magnitude of the phagocytic response of those monocytes that escaped inhibition relative to PBS treated controls. Oxidative burst responses to E.coli were also inhibited and this effect was mediated by low molecular weight species, as dialysis totally abrogated the inhibitory activity. Seminal plasma had no effect on the neutrophil burst response to fMLP when compared to the controls, however there was a significant difference between the responses of undialysed and dialysed seminal plasma treated samples. Undialysed seminal plasma significantly inhibited the proportion of monocytes undergoing the burst response to fMLP and there were significant differences between the proportion of cells responding and their intensity in undialysed and dialysed seminal plasma treated samples. In summary, this study reports differential modification of neutrophil and monocyte function by human seminal plasma. The residual capacity of these cells to undergo phagocytosis and generate oxidative burst responses suggests that localised innate immune function remains intact and is possibly enhanced in the female reproductive tract at the time of insemination. Other mechanisms must protect inseminated sperm at this time.