Nizatidine improves clinical symptoms and gastric emptying in patients with functional dyspepsia accompanied by impaired gastric emptying.

BACKGROUND/AIMS: In this crossover study, we investigated whether nizatidine, a H(2)-receptor antagonist, can alleviate clinical symptoms and gastric emptying in patients with Rome III-based functional dyspepsia (FD) with or without impaired gastric emptying. METHODS: We enrolled 30 patients presenting with FD symptoms (epigastric pain syndrome, n = 6; postprandial distress syndrome, n = 24). Rome III-based FD patients were treated with nizatidine (300 mg/day) or placebo for 4 weeks in a crossover trial. Gastric motility was mainly evaluated with the T(max) value using the (13)C-acetate breath test. Meal-related symptoms were defined as postprandial fullness and early satiation. Gastroesophageal symptom was defined as a burning feeling rising from the stomach or lower chest up toward the neck. Acylated- and desacylated ghrelin levels were evaluated by the ELISA method. Clinical symptoms, gastric emptying and ghrelin levels were evaluated at three different points during the study (pretreatment, after 4 weeks former treatment and after 4 weeks later treatment). The primary end point of this study was to determine whether nizatidine would improve clinical symptoms and gastric emptying in FD patients with or without impaired gastric emptying via affecting ghrelin levels. RESULTS: Meal-related symptoms of the patients treated with nizatidine improved significantly (21/30; 70%) compared to those treated with placebo (3/30; 10%). In addition, nizatidine treatment also significantly improved gastroesophageal symptoms (16/30; 53%) compared to those treated with placebo (0/30; 0%). Nizatidine treatment in patients with FD accompanied by impaired gastric emptying significantly improved clinical symptoms and T(max) value as a marker of gastric emptying (10/11, 91%; 9/11, 82%) compared to placebo therapy, respectively. There were no significant differences in ghrelin levels between nizatidine treatment and placebo therapy. CONCLUSION: Nizatidine administration significantly improved both gastric emptying and clinical symptoms in FD patients with impaired gastric emptying.

The vergence eye movements induced by radial optic flow: some fundamental properties of the underlying local-motion detectors.

Radial optic flow applied to large random dot patterns is known to elicit horizontal vergence eye movements at short latency, expansion causing convergence and contraction causing divergence: the Radial Flow Vergence Response (RFVR). We elicited RFVRs in human subjects by applying radial motion to concentric circular patterns whose radial luminance modulation was that of a square wave lacking the fundamental: the missing fundamental (mf) stimulus. The radial motion consisted of successive 1/4-wavelength steps, so that the overall pattern and the 4n+1 harmonics (where n=integer) underwent radial expansion (or contraction), whereas the 4n-1 harmonics--including the strongest Fourier component (the 3rd harmonic)--underwent the opposite radial motion. Radial motion commenced only after the subject had fixated the center of the pattern. The initial RFVRs were always in the direction of the 3rd harmonic, e.g., expansion of the mf pattern causing divergence. Thus, the earliest RFVRs were strongly dependent on the motion of the major Fourier component, consistent with early spatio-temporal filtering prior to motion detection, as in the well-known energy model of motion analysis. If the radial mf stimulus was reduced to just two competing harmonics--the 3rd and 5th--the initial RFVRs showed a nonlinear dependence on their relative contrasts: when the two harmonics differed in contrast by more than about an octave then the one with the higher contrast completely dominated the RFVRs and the one with lower contrast lost its influence: winner-take-all. We suggest that these nonlinear interactions result from mutual inhibition between the mechanisms sensing the motion of the different competing harmonics. If single radial-flow steps were used, a brief inter-stimulus interval resulted in reversed RFVRs, consistent with the idea that the motion detectors mediating these responses receive a visual input whose temporal impulse response function is strongly biphasic. Lastly, all of these characteristics of the RFVR, which we attribute to the early cortical processing of visual motion, are known to be shared by the Ocular Following Response (OFR)--a conjugate tracking (version) response elicited at short-latency by linear motion-and even the quantitative details are generally very similar. Thus, although the RFVR and OFR respond to very different patterns of global motion-radial vs. linear-they have very similar local spatiotemporal properties as though mediated by the same low-level, local-motion detectors, which we suggest are in the striate cortex.

Human ocular following initiated by competing image motions: evidence for a winner-take-all mechanism.

The initial ocular following responses (OFRs) elicited by 1/4-wavelength steps applied to the missing fundamental (mf) stimulus are in the backward direction and largely determined by the principal Fourier component, the 3rd harmonic [Sheliga, B. M., Chen, K. J., FitzGibbon, E. J., & Miles, F. A. (2005). Initial ocular following in humans: A response to first-order motion energy. Vision Research, 45, 3307-3321]. When the contrast of the 3rd harmonic was selectively reduced below that of the next most prominent harmonic-the 5th, which moves in the opposite (forward) direction-then the OFR reversed direction and the 3rd harmonic effectively lost all of its influence as the OFR was now largely determined by the 5th harmonic. Restricting the stimulus to just two sine waves (of equal efficacy when of equal contrast and presented singly) with the spatial frequencies of the 3rd and 5th harmonics of the mf stimulus indicated that the critical factor was the ratio of their two contrasts: when of similar contrast both were effective (vector sum/averaging), but when the contrast of one was <1/2 that of the other then the one with the lower contrast became ineffective (winner-take-all). This nonlinear dependence on the contrast ratio was attributed to mutual inhibition and was well described by a weighted-average model with just two free parameters. Further experiments with broadband and dual-grating stimuli indicated that nonlinear interactions occur not only in the neural processing of stimuli moving in opposite directions but also of stimuli that share the same direction and differ only in their spatial frequency and speed. Clearly, broad-band and dual-grating stimuli can uncover significant nonlinearities in visual information processing that are not evident with single sine-wave stimuli.

Improvement of meal-related symptoms and epigastric pain in patients with functional dyspepsia treated with acotiamide was associated with acylated ghrelin levels in Japan.

BACKGROUND: The aim of this study is to clarify whether acotiamide and rabeprazole combination therapy can improve clinical symptoms, gastric emptying, and satisfaction with treatment in functional dyspepsia (FD) patients more effectively than acotiamide or rabeprazole monotherapy alone. We also aimed to determine whether acotiamide affects these changes via its effect on gastric emptying and appetite-related hormones such as ghrelin. METHODS: We used Rome III criteria to evaluate upper abdominal symptoms and anxiety by the State-Trait Anxiety Inventory (STAI). Gastric motility was evaluated by the (13) C-acetate breath test. Eighty-one FD patients were treated with acotiamide (300 mg/day) (n = 35), acotiamide (300 mg/day) and rabeprazole (10 mg/day) (n = 28), or rabeprazole (10 mg/day) (n = 18) for a period of 4 weeks and followed after 4 weeks of no treatment. Adenocorticotropic hormone (ACTH), cortisol, leptin and ghrelin levels were measured in all FD patients. KEY RESULTS: Acotiamide and rabeprazole combination therapy significantly improved postprandial distress syndrome (PDS)-like symptoms (p = 0.018, p = 0.04 and p = 0.041, respectively) and epigastric pain (p = 0.024) as wells as STAI-state scores (p = 0.04) compared to rabeprazole monotherapy. Both acotiamide monotherapy, and acotiamide taken in combination with rabeprazole, significantly (p = 0.001 and p = 0.02, respectively) improved satisfaction with treatment, compared to rabeprazole monotherapy. Acotiamide and rabeprazole combination therapy had no significant effect on ACTH and cortisol levels in FD patients. Of interest, acotiamide monotherapy, and acotiamide and rabeprazole combination therapy, significantly (p < 0.0001 and p = 0.018, respectively) increased acylated ghrelin/total ghrelin ratios and significantly (p = 0.04) improved impaired gastric emptying compared to rabeprazole monotherapy. CONCLUSIONS & INFERENCES: Further studies are warranted to clarify how acotiamide treatment improves clinical symptoms in FD patients.

Effects of eye position on saccades evoked by stimulation of the monkey superior colliculus.

Effects of different initial eye positions on saccades evoked by electrical stimulation of the superior colliculus (SC) were investigated in alert monkeys with the head restrained. The dependence of saccade vector on initial eye position was studied quantitatively by multiple regression analysis. Following stimulation at 240 of 367 sites in the SC, saccade vector was influenced by initial eye position. The magnitude of eye position effects on horizontal saccade component was similar to that for vertical component. These effects were mostly found with stimulation in the caudal SC. Results suggest that eye position signals may control excitability of neurones in the SC.

Neuronal activity in the frontal eye field of the monkey is modulated while attention is focused on to a stimulus in the peripheral visual field, irrespective of eye movement.

We tested the hypothesis that the frontal eye field (FEF) is involved in attention to the peripheral visual field (PVF). Neuronal activity was recorded in the FEF of two monkeys while they were performing three oculomotor tasks. In the visual attention task (VAT), the monkeys released a lever when a test stimulus (TS) presented in the PVF dimmed while they were looking at a central fixation point (FP). In the visual saccade task (VST), the monkeys exhibited saccadic eye movements when the FP was extinguished. In the visual fixation task (VFT), the monkeys released the lever when the FP dimmed. Overall, the activities of 80 FEF neurons were examined. The responses to visual stimuli of 41 of these neurons (51%) were modulated during the VAT. Twenty-five neurons showed pre-saccadic activity. Of these, 13 neurons (52%) exhibited activity modulation during the VAT. Eighteen neurons showed no pre-saccadic activity. Of these, 10 neurons (56%) exhibited activity modulation during the VAT. These results suggest that the FEF is involved in selecting the visual stimuli relevant to performing a task irrespective of eye movements.

Short-latency vergence eye movements elicited by looming step in monkeys.

The looming associated with forward and backward motion of the observer has been shown to elicit vergence eye movements with short-latency (approximately 80 ms) in human subjects. We studied the vergence eye movements elicited by looming in three monkeys (Macaca fuscata). The animals faced a large tangent screen onto which a random dot pattern was back-projected. The movements of both eyes were recorded with an electromagnetic induction technique. Fifty milliseconds after a centering saccade, this first pattern was replaced with a new one that showed the same image viewed from a slightly different distance. This looming step (two-frame movie) included both radial optic flow and a size change. As expected from the optical geometry, centrifugal flow coupled with enlargement (signaling forward motion) increased the vergence angle, whereas the converse combination decreased the vergence angle. In both cases, the optimal step-change in apparent viewing distance was 2%. The latency of these vergence responses was very short and similar to those induced when disparity steps are applied to such large patterns (approximately 60 ms). We suggest that these two systems act in synergy to help maintain binocular alignment during forward and backward motion of the observer.

Effects of smooth pursuit eye movement on ocular responses to sudden background motion in humans.

We studied the effects of horizontal smooth pursuit on the ocular tracking responses to brief perturbations of a textured background in humans. When the subject was fixating a stationary spot, a brief perturbation (60 degrees/s, 40 ms) of the background in any one of four directions (right, left, up, down) elicited a small tracking response. When the subject was pursuing a target moving against the stationary background, the same background perturbation elicited a larger response when in the same direction as the pursuit, but a smaller response when its direction was opposite to the pursuit; the response to vertical background perturbations was also enhanced during pursuit. When the subject was pursuing while the target and background were moving together, the same background perturbations elicited the larger responses regardless of their direction. These results indicate that the sensitivity to background motion is increased during smooth pursuit. However, when pursuit is executed against a stationary background--the usual situation in everyday life--the system is selectively insensitive to the reafferent visual input associated with pursuit, thereby reducing the potentially adverse effect of the background on pursuit performance.

Regulation of decidualization in human endometrial stromal cells through exchange protein directly activated by cyclic AMP (Epac).

INTRODUCTION: Human endometrial stromal cells (ESCs) undergo differentiation during the decidualization process. Decidualization is characterized by their enhanced production of IGF binding protein-1 (IGFBP-1), prolactin (PRL), and the forkhead transcriptional factor FOXO1, and transformation into more rounded cells, during the secretory phase of the menstrual cycle and subsequent pregnancy. Protein kinase A (PKA)-mediated cAMP signaling is crucial for this process. The present study was undertaken to examine the involvement of a mediator of cAMP signaling, exchange protein directly activated by cAMP (Epac), in decidualization of cultured ESCs. RESULTS: Treatment of ESCs with the Epac-selective cAMP analog 8-CPT-2-OMe-cAMP (CPT) had no effect on IGFBP-1, PRL, and FOXO1 mRNA expression. However, CPT potentiated IGFBP-1 and PRL expression stimulated by the PKA-selective cAMP analog N(6)-Phe-cAMP (Phe) and activated Rap1, a downstream regulator of Epac signaling. Knock-down of Epac1, Epac2, or Rap1 significantly inhibited the Phe- or Phe/CPT-induced increase in IGFBP-1 and PRL expression, as well as Rap1 activation. Furthermore, CPT enhanced IGFBP-1 and PRL expression and the morphological differentiation induced by ovarian steroids, whereas Epac1, Epac2, or Rap1 knock-down suppressed these events. CONCLUSION: These data provide evidence for the involvement of the Epac/Rap1 signaling pathway in cAMP-mediated decidualization of human ESCs.

G-protein ß3 subunit 825CC genotype is associated with postprandial distress syndrome with impaired gastric emptying and with the feeling of hunger in Japanese.

BACKGROUND: G-protein dysfunction related alteration of intracellular signal transduction might be linked to various abnormalities of functional gastrointestinal (GI) disorders. Serotonin (5-hydroxytryptamine; 5-HT) as well as G-protein is also key signaling molecule sensorimotor functions in the GI tract. Thus, this study aims to evaluate the correlation between gastric emptying and GNß3 and 5-HTs polymorphisms in functional dyspepsia (FD) as defined by Rome III classification. METHODS: Seventy-four patients presenting with typical symptoms of FD (epigastric pain syndrome: EPS, n=24; postprandial distress syndrome: PDS, n = 51) and sixty-four healthy volunteers were enrolled. Gastric motility was evaluated with the T(max) value using the (13) C-acetate breath test. We used Rome III criteria to evaluate upper abdominal symptoms and SRQ-D scores to determine depression status. GNß3-C825T, 5-HT(1A) -C1019G, 5-HT(2A) -G1438A, 5-HT(3A) -C42T, and 5-HT(4A) -G353+6A polymorphisms were analyzed in DNA from blood samples of enrolled subjects. Genotyping was performed by polymerase chain reaction. KEY RESULTS: There was a significant relationship (P=0.045) between GNß3 825CC genotype and PDS patients without gastro-esophageal reflux symptoms with impaired gastric emptying. In Japanese, GNß3 825CC genotype in FD patients was significantly associated (P=0.0485) with the feeling of hunger compared with GNß3 825CT and TT genotypes. CONCLUSIONS & INFERENCES: Our results suggest that the GNß3 825CC genotype is significantly associated with PDS patients without gastro-esophageal reflux with impairments of gastric emptying and also with the feeling of hunger in patients with FD. Further studies are needed to clarify whether the GNß3 825CC genotype is linked to disturbances of gastric emptying via altered signal transduction responses.

Initiation of smooth pursuit in humans. Dependence on target saliency.

We examined the influence of target saliency on the initiation of smooth pursuit. The eye movements of five human subjects were recorded with the scleral search-coil technique. A video-projection system was used to create a pursuit target, consisting of a cluster of 14 red or green dots (0.5 degrees squares) extending randomly over a 3 degrees x3 degrees region, and a surrounding background, consisting of stationary, random dots of the same size and density extending over an area 70 degrees x 40 degrees. When the dots in the background and the target were of the same color, the target was indistinguishable from the background until it started to move. On the other hand, when the colors were different, the target was salient, even when stationary. We measured the changes in eye position over the 70-ms interval starting 70 ms after the onset of target motion (initial tracking response). When the target moved toward the fovea (centripetal motion), the initial tracking responses developed earlier when the dots in the target and background were of different color than when the two sets of dots were of the same color. However, in order to see this effect of target salience, it was critical that the colors be different before the onset of motion, but not afterwards. When the target moved away from the fovea (centrifugal motion), the initial tracking responses were independent of whether the colors of the target and the background were the same or different. Our data indicate that the initiation of tracking responses is very sensitive to the saliency of the target before the onset of target motion when that motion is toward the fovea.