Diagnostic Yield of Chilaiditi's Sign in Advanced-Phase Late-Onset Pompe Disease.

PURPOSE: Chilaiditi's sign (CS), hepatodiaphragmatic interposition of the intestine, was caused by morphological abnormalities such as diaphragmatic atrophy, intestinal dilation, and liver atrophy. The sign is potentially important due to associations with clinically recurrent abdominal pain or even colonic volvulus. Late-onset Pompe disease (LOPD) could have the high prevalence of CS because of widened hepatodiaphragmatic space, following diaphragmatic atrophy, and the abnormal dilation of intestine caused by glycogen accumulation in smooth muscle of intestine. Our aim was to investigate the prevalence of CS in LOPD, and to identify the risk factors of CS in LOPD patients. METHODS: Medical records of genetically confirmed patients of Pompe disease at the National Center Hospital, National Center of Neurology and Psychiatry were retrospectively reviewed. We evaluated CS using chest X-ray (CXR) and abdominal CT and assessed the prevalence of CS in LOPD patients. We also divided the patients into two groups, CS and non-CS group, and evaluated the factor associated with CS compared to clinical variables between groups. RESULTS: Three of seven (43%) were detected in CS. CS group (P5-7) and non-CS group (P1-4) were obtained. In comparison of clinical variables, the severity of atrophy in right diaphragms was significantly higher in CS than non-CS groups (p = 0.029). Also, the frequency of abnormal position of right diaphragm and liver, and abnormally dilated bowel was seen in all of CS patients, but none of non-CS patient (p = 0.029, each). CONCLUSION: In LOPD patients, the prevalence of CS was much higher of 43%, compared to healthy groups, or even in similarly respiratory muscle impaired neuromuscular diseases. The anatomically abnormal position of diaphragm and liver, atrophy and fat infiltration of diaphragms, and abnormally dilated bowel were significantly associated with CS in LOPD. We should pay more attention to CXR or abdominal CT as follow up in LOPD patients.

Pathologic and Neuropathologic Study of a Case of COVID-19.

A 68-year-old woman with a history of schizophrenia developed coronavirus disease (COVID)-19 and was transferred to our hospital. Despite treatment, she died of respiratory failure 16 days after the onset. At the time of autopsy, polymerase chain reaction (PCR) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA using swabs from the nasopharynx and the lung was positive; however, the cerebrospinal fluid was negative. An autopsy showed diffuse alveolar damage and recent multiple cerebral infarcts. Acute splenitis was observed with thrombi adhering to the vascular endothelium in areas of severe neutrophilic infiltration. Immunohistochemistry using an antibody against the SARS-CoV-2 nucleocapsid showed immunoreactivity along the hyaline membrane of the lung; however, the antibody showed no immunoreactivity in the medulla, the thalamus, the frontal lobe, and the pituitary. Future pathologic studies should clarify the mechanisms involved in a variety of clinical and pathological changes related to COVID-19.

Hybrid Cognitive Behavioral Therapy With Interoceptive Exposure for Irritable Bowel Syndrome: A Feasibility Study.

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder, which severely impairs the quality of life of patients. Treatment of refractory IBS patients is needed, but it is not yet widely available. Therefore, we previously developed a Japanese version of cognitive behavioral therapy with interoceptive exposure (CBT-IE) involving 10 face-to-face sessions to treat refractory IBS patients. To disseminate this treatment of IBS in places where therapists are limited, we further developed a hybrid CBT-IE program with complementary video materials that include psychoeducation and homework instructions so that patients can prepare for face-to-face sessions in advance at home and the session time can be shortened, thereby reducing the burden on both patient and therapist. In this study, we conducted a trial to evaluate the feasibility, efficacy, and safety of the hybrid CBT-IE program for Japanese IBS patients. The study was a single-arm, open-label pilot clinical trial. A total of 16 IBS patients were included in the study and 14 patients completed the intervention, which consisted of 10 weekly individual hybrid CBT-IE sessions. We performed an intention to treat analysis. The primary outcome measure for the efficacy of the intervention was a decrease in the severity of IBS symptoms. The feasibility and safety of the intervention were examined by the dropout rate and recording of adverse events, respectively. The dropout rate of the hybrid CBT-IE was comparable to that of our previous CBT-IE with only face-to-face sessions and no adverse events were recorded. The severity of IBS symptoms within-group was significantly decreased from the baseline to mid-treatment [Hedges' g = -0.98 (-1.54, -0.41)], post-treatment [Hedges' g = -1.48 (-2.09, -0.88)], 3-month follow-up [Hedges' g = -1.78 (-2.41, -1.14)], and 6-month follow-up [Hedges' g = -1.76 (-2.39, -1.13)]. Our results suggest that the hybrid CBT-IE is effective and could be conducted safely. To confirm the effectiveness of the hybrid CBT-IE, it is necessary to conduct a multicenter, parallel-design randomized control trial. Clinical Trial Registration: [https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000041376], identifier [UMIN000036327].

Urocortin 1: A putative excitatory neurotransmitter in the enteric nervous system.

BACKGROUND: Urocortin 1 (Ucn1), a stress-related peptide, is a member of the corticotropin-releasing factor (CRF) family and acts as a CRF1 receptor agonist. Ucn1 and CRF1 receptor immunoreactivity are present in the enteric nervous system (ENS), and Ucn1 elicits contraction of colonic muscle strips. Considering these findings, we have hypothesized that Ucn1 acts as an excitatory neurotransmitter in the ENS. The present study was conducted to determine whether exogenously applied Ucn1 causes contractions, whether it participates in neurally mediated contraction, and whether it is released from the ENS of the rat colon. METHODS: Isometric tension of the rat colonic muscle strips (middle to distal colon) in a longitudinal direction was measured. The effects of Ucn1 on phasic contractions were examined in the absence and presence of antalarmin (CRF1 receptor antagonist), tetrodotoxin (TTX), and atropine. The effects of antalarmin on electrical field stimulation (EFS)-induced contractions were examined in the absence and presence of atropine. Ucn1 peptide in the bath solution was measured after EFS using an EIA kit. KEY RESULTS: Ucn1 caused a significant and dose-dependent increase in phasic contractions. These effects were completely inhibited by antalarmin, TTX, and atropine. EFS-induced contractions were inhibited by antalarmin. Atropine markedly reduced EFS-induced contractions, and antalarmin did not decrease these contractions further. EFS elicited a significant increase in the concentration of Ucn1 in the bath solution, and this increase was completely inhibited by TTX. CONCLUSIONS AND INFERENCES: These results suggest that Ucn1 acts as an excitatory neurotransmitter in the ENS enhancing the cholinergic neurotransmission.

Riluzole-induced interstitial lung disease is a rare and potentially life-threatening adverse event successfully treated with high-dose steroid therapy: Case reports and review of the literature.

Riluzole (RZ)-induced interstitial lung disease (RZ-ILD) is a rare and potentially life-threatening adverse event in amyotrophic lateral sclerosis (ALS) patients, which is rarely reported. Therefore, the optimal treatment for RZ-ILD is unclear. We describe herein three Japanese cases of ALS complicated with RZ-ILD, of which two were successfully treated with high-dose steroid therapy. In our all ALS cases with RZ-ILD, the duration of RZ exposure until RZ-ILD onset was within 2 months. All three cases showed respiratory symptoms, dorsal predominant ground-glass opacities by imaging analysis, and abnormal laboratory findings associated with interstitial lung diseases, such as Krebs von den Lungen-6 and surfactant protein-D. Intravenous high-dose steroid therapy together with the discontinuation of RZ in two cases with respiratory symptoms markedly ameliorated their symptoms and abnormal findings of RZ-ILD. One case showed mild respiratory symptoms compared with the others and recovered after the withdrawal of RZ only. According to previous case reports and our cases, RZ-ILD may develop 2 months after initiating RZ and exacerbate respiratory symptoms rapidly in ALS patients with severe respiratory muscle involvement or complicating aspiration pneumonia. Transient high-dose steroid therapy in addition to discontinuation of RZ might be a good therapeutic option for RZ-ILD.

Dual role of mosapride citrate hydrate on the gastric emptying evaluated by the breath test in conscious rats.

Mosapride citrate hydrate (mosapride) has been known to act as a 5-HT4 agonist and to enhance gastric emptying. However, its mode of action, such as time course and dosage effect, on gastric emptying has not been clarified. This study aimed to clarify these points by the breath test using [1-(13)C]acetic acid in conscious rats. Mosapride significantly and dose-dependently enhanced the gastric emptying increased Cmax and AUC120 min at doses between 0.1 and 3 mg/kg. Pre-treatment with GR113808 (5-HT4 antagonist) significantly attenuated the enhancement of gastric emptying by mosapride. On the contrary, at a dose of 30 mg/kg, mosapride significantly inhibited the gastric emptying. The major metabolite (M1: 5-HT3 receptor antagonist) significantly inhibited gastric emptying at doses of 19.2 and 64.1 mg/kg (equimolar to 30 and 100 mg/kg of mosapride, respectively), suggesting that the inhibitory effect by mosapride may be caused at least in part by the 5-HT3 receptor antagonistic effect of M1. These findings show that mosapride has dual role on the gastric emptying and may support the usefulness of mosapride for the therapy of postprandial distress syndrome such as early satiation and postprandial fullness.

Electroacupuncture improves imbalance of autonomic function under restraint stress in conscious rats.

Acupuncture may modulate the imbalance of the autonomic nervous system. It is well known that restraint stress delays gastric emptying via inhibiting parasympathetic activity and/or stimulating sympathetic activity in rats. We have previously shown that electroacupuncture (EA) improves delayed gastric emptying induced by restraint stress in rats. To investigate whether the beneficial effect of EA on delayed gastric emptying is associated with its modulatory effects on autonomic nervous activity, we utilized spectral analysis of heart rate variability (HRV). In rats, the power in the low frequency (LF; 0.04-1.0 Hz) and high frequency (HF; 1.0-3 Hz) band of HRV represent sympathetic and parasympathetic activities, respectively. Electrocardiography (ECG)-electrodes were implanted on the subcutaneous tissues of the back. One week after the surgery, ECG was recorded before, during and after the restraint stress loading in a conscious state. EA (10 Hz) was applied at bilateral acupuncture points [ST-36 (lower leg) or BL-21 (back)] during restraint stress loading. In response to restraint stress, heart rate and LF component were increased, suggesting the increased activity of sympathetic tone. EA at ST-36 significantly reduced the elevated heart rate and LF, compared to that of control group. EA at ST-36 also significantly increased HF component after finishing the stress loading. In contrast, EA at BL-21 had no significant effect on the heart rate, LF and HF. It is suggested that EA at ST-36 stimulates parasympathetic activity and inhibits sympathetic activity under the restraint stress in rats.

Effects of ghrelin on interdigestive contractions of the rat gastrointestinal tract.

Ghrelin causes interdigestive contractions of the stomach in rats. However, it remains unknown whether ghrelin causes interdigestive contractions in the small intestine. Four strain gauge transducers were implanted on the antrum, duodenum, proximal and distal jejunum. After an overnight fast, gastrointestinal (GI) contractions were recorded in freely moving conscious rats. Spontaneous phase III-like contractions were observed at every 13-16 min in rat GI tract. The fasted motor patterns were replaced by the fed motor pattern immediately after food intake. Two minutes after finishing the spontaneous phase III-like contractions in the antrum, acyl ghrelin (0.8, 2.4 and 8.0 microg/kg per min) was continuously infused for 30 min. Three-five minutes after the starting ghrelin infusion, augmented phase III-like contractions were observed at the antrum, duodenum, and jejunum. Ghrelin infusion (0.8, 2.4 and 8.0 microg/kg per min) significantly increased motility index of phase III-like contractions at the antrum and jejunum in a dose dependent manner, compared to that of saline injection. Thus, it is likely that exogenously administered ghrelin causes phase III-like contraction at the antrum, which migrates to the duodenum and jejunum. The possible role of 5-HT, in addition to ghrelin, in mediating intestinal migrating motor complex (MMC), is discussed.

Endogenous ghrelin and 5-HT regulate interdigestive gastrointestinal contractions in conscious rats.

Endogenous ghrelin causes interdigestive contractions of the stomach in rats. In contrast, previous studies showed that 5-HT(3) and 5-HT(4) receptors were involved in regulating intestinal interdigestive contractions. We studied the possible role of endogenous ghrelin and 5-HT regulating interdigestive gastrointestinal (GI) contractions in rats. Four strain gauge transducers were implanted on the antrum, duodenum, and proximal and distal jejunum. After an overnight fast, GI contractions were recorded in freely moving conscious rats and ghrelin receptor antagonists [(d-lys3)GHRP6; 1 micromol/kg], 5-HT(3) antagonists (Ondansetron; 0.5 mg/kg) and 5-HT(4) antagonists (GR 125,487; 1 mg/kg) were administered (bolus iv). To evaluate the relationship between the luminal concentrations of 5-HT and phase III-like contractions of the duodenum, duodenal juice was collected via the intraduodenal catheter. 5-HT content of the duodenal juice was measured by HPLC. (d-lys3)GHRP6 significantly attenuated the occurrence and amplitude of phase III-like contractions of the antrum, but not the duodenum and jejunum. 5-HT(4) antagonists significantly reduced spontaneous phase III-like contractions of the jejunum, without affecting those of the antrum and duodenum. In contrast, 5-HT(3) antagonists did not affect phase III-like contractions in GI tract. Luminal concentration of 5-HT at the phase III-like contraction (36.0 +/- 13.3 ng/ml, n = 9) was significantly higher than that at the phase I-like contractions of the duodenum (4.9 +/- 1.6 ng/ml, n = 9, P < 0.05). It is suggested that released ghrelin from the gastric mucosa mediates gastric phase III-like contractions, whereas 5-HT released from enterochromaffin cells of the duodenal mucosa mediates intestinal phase III-like contractions via 5-HT(4) receptors.

Does ghrelin explain accelerated gastric emptying in the early stages of diabetes mellitus?

During the early stages of diabetes, gastric emptying is often accelerated, rather than delayed. The mechanism of accelerated gastric emptying in diabetes has not been fully studied. A recent study showed that plasma ghrelin levels were elevated in diabetes. As postprandial antropyloric coordination plays an important role in mediating solid gastric emptying, we hypothesize that the elevated plasma ghrelin levels increase postprandial antropyloric coordination to accelerate emptying in the early stages of diabetes. To test this hypothesis, rats were made diabetic by streptozotocin (STZ; 50 mg/kg) injection, and, 2 wk later, pre- and postprandial plasma ghrelin levels, antropyloric coordination, and solid gastric emptying were determined. In control rats, plasma ghrelin levels were immediately reduced after feeding. In contrast, plasma ghrelin levels remained within the fasted levels in STZ rats after feeding. In STZ rats, gastric emptying was significantly accelerated (77.4 +/- 3.2%, n = 6), compared with that of control rats (58.8 +/- 2.5%, n = 6, P < 0.05). Treatments with anti-ghrelin antibodies attenuated accelerated gastric emptying in STZ rats (50.1 +/- 3.5%, n = 6, P < 0.05), while having little effect in vehicle control rats. The incidence of postprandial antropyloric coordination was significantly increased in STZ rats, compared with that of control rats (P < 0.05). Treatments with anti-ghrelin antibodies suppressed this enhanced antropyloric coordination in STZ rats. Our study suggests that elevated endogenous ghrelin enhances antropyloric coordination, which accelerates gastric emptying in the early stages of diabetes.

Fixed feeding potentiates interdigestive gastric motor activity in rats: importance of eating habits for maintaining interdigestive MMC.

Endogenous ghrelin regulates the occurrence of interdigestive gastric phase III-like contractions in rats. However, the fasted motor pattern is not as regular and potent in humans and dogs. We hypothesize that eating habits play an important role in maintaining a regular interdigestive gastric contractions. We studied the effect of fixed-feeding regimen on interdigestive gastric contractions and plasma acyl ghrelin levels. The fixed-fed rats were trained to the assigned meal feeding regimen, once daily at 12:00 PM to 4:00 PM for 14 days. Free-fed rats were maintained with free access to food. As ghrelin regulates gastric emptying as well, solid gastric emptying was also studied in fixed-fed rats and free-fed rats. In free-fed rats, two of six rats did not show interdigestive gastric phase III-like contractions. In contrast, phase III-like contractions were observed in all rats 14 days after starting the fixed-feeding regimen. The maximal amplitude of phase III-like contractions significantly increased from 8.4 +/- 0.6 to 16.3 +/- 1.8 g (n = 6, P < 0.05) 14 days after the start of the fixed feeding. Fasted and postprandial plasma ghrelin levels were significantly increased after 14 days of fixed feeding. Solid gastric emptying was significantly accelerated in fixed-fed rats (72.1 +/- 4.2%) compared with that of free-fed rats (58.7 +/- 2.7%, n = 6, P < 0.05). Our present findings suggest that fixed feeding increases plasma ghrelin levels, potent interdigestive contractions, and acceleration of gastric emptying.

Effects of electroacupuncture on gastric motility and heart rate variability in conscious rats.

To clarify the mechanism of site-specific effects of acupuncture on gastric motor function, we studied the simultaneous recording of gastric motility and electrocardiogram (ECG) for heart rate variability (HRV) analysis in conscious rats. Gastric motility and ECG were recorded before, during and after electroacupuncture (EA) at ST-36 (hind limb) or ST-25 (abdomen). EA at ST-36 significantly increased gastric motility and decreased the ratio of low frequency (LF)/high frequency (HF) of the HRV analysis. In contrast, EA at ST-25 significantly inhibited gastric motility and increased LF/HF ratio. There was a significant correlation observed between the changes of gastric motility and LF/HF ratio in response to EA. It is suggested that the stimulatory effect of EA at ST-36 on gastric motility is associated with its stimulatory effect on vagal activity. The inhibitory effect of EA at ST-25 on gastric motility is associated with its stimulatory effect on the sympathetic nerve activity.

Ghrelin accelerates gastric emptying via early manifestation of antro-pyloric coordination in conscious rats.

Ghrelin is known to enhance gastric motility and accelerate gastric emptying of liquid and solid food in rats. As solid gastric emptying is regulated by the coordinated motor pattern between the antrum and pylorus (antro-pyloric coordination), we studied the correlation between solid gastric emptying and antro-pyloric coordination in response to ghrelin. Rats were given 1.5 g of solid food after a 24-h fasting. Immediately after the ingestion, ghrelin (0.4-8.0 microg/kg) or saline was administered by intraperitoneal (i.p.) injection. Ninety minutes after the feeding, rats were euthanized and gastric content was removed to calculate gastric emptying. To evaluate the antro-pyloric coordination, strain gauge transducers were sutured on the antrum and pylorus. The incidence of postprandial antro-pyloric coordination was compared between ghrelin-and saline-injected rats. In saline-injected rats, gastric emptying was 58.3+/-3.7% (n=6). Ghrelin (4.0-8.0 microg/kg), accelerated gastric emptying. Maximum effect was obtained by ghrelin (4.0 microg/kg), which significantly accelerated gastric emptying to 77.4+/-3.7% (n=6, p<0.05). The number of antro-pyloric coordination 20-40 min after feeding was significantly increased in ghrelin-injected rats, compared to that of saline-injected rats (n=4, p<0.05). It is suggested that enhanced antro-pyloric coordination play an important role in accelerated solid gastric emptying induced by ghrelin.

Urocortin I is present in the enteric nervous system and exerts an excitatory effect via cholinergic and serotonergic pathways in the rat colon.

Corticotropin-releasing factor (CRF) and urocortin I (UcnI) have been shown to accelerate colonic transit after central nervous system (CNS) or peripheral administration, but the mechanism of their peripheral effect on colonic motor function has not been fully investigated. Furthermore, the localization of UcnI in the enteric nervous system (ENS) of the colon is unknown. We investigated the effect of CRF and UcnI on colonic motor function and examined the localization of CRF, UcnI, CRF receptors, choline acetyltransferase (ChAT), and 5-HT. Isometric tension of rat colonic muscle strips was measured. The effect of CRF, UcnI on phasic contractions, and electrical field stimulation (EFS)-induced off-contractions were examined. The effects of UcnI on both types of contraction were also studied in the presence of antalarmin, astressin2-B, tetrodotoxin (TTX), atropine, and 5-HT antagonists. The localizations of CRF, UcnI, CRF receptors, ChAT, and 5-HT in the colon were investigated by immunohistochemistry. CRF and UcnI increased both contractions dose dependently. UcnI exerted a more potent effect than CRF. Antalarmin, TTX, atropine, and 5-HT antagonists abolished the contractile effects of UcnI. CRF and UcnI were observed in the neuronal cells of the myenteric plexus. UcnI and ChAT, as well as UcnI and 5-HT, were colocalized in some of the neuronal cells of the myenteric plexus. This study demonstrated that CRF and UcnI act on the ENS and increase colonic contractility by enhancing cholinergic and serotonergic neurotransmission. These peptides are present in myenteric neurons. CRF and, perhaps, to a greater extent, UcnI appear to act as neuromodulators in the ENS of the rat colon.

Luminally released serotonin stimulates colonic motility and accelerates colonic transit in rats.

Enterochromaffin (EC) cells of the epithelial cells release 5-HT into the lumen, as well as basolateral border. However, the physiological role of released 5-HT into the lumen is poorly understood. Concentrations of 5-HT in the colonic mucosa, colonic lumen, and feces were measured by HPLC in rats. To investigate whether intraluminal 5-HT accelerates colonic transit, 5-HT and (51)Cr were administered into the lumen of the proximal colon, and colonic transit was measured. To investigate whether 5-HT is released into the lumen, we used an ex vivo model of isolated vascularly and luminally perfused rat proximal colon. To investigate whether luminal 5-HT is involved in regulating stress-induced colonic motility, the distal colonic motility was recorded under the stress loading, and a 5-HT(3) receptor antagonist (ondansetron, 10(-6) M, 0.5 ml) was administered intraluminally of the distal colon. Tissue content of 5-HT in the proximal colon (15.2 +/- 4.3 ng/mg wet tissue) was significantly higher than that in the distal colon (3.3 +/- 0.7 ng/mg wet tissue), while fecal content and luminal concentration of 5-HT was almost the same between the proximal and distal colon. Luminal administration of 5-HT (10(-6)-10(-5) M) significantly accelerated colonic transit. Elevation of intraluminal pressure by 10 cmH(2)O significantly increased the luminal concentration of 5-HT but not the vascular concentration of 5-HT. Stress-induced stimulation of the distal colonic motility was significantly attenuated by the luminal administration of ondansetron. These results suggest that luminally released 5-HT from EC cells plays an important role in regulating colonic motility in rats.