Integrative effects of transcutaneous auricular vagus nerve stimulation on esophageal motility and pharyngeal symptoms via vagal mechanisms in patients with laryngopharyngeal reflux disease.

Background and aim: Laryngopharyngeal reflux disease (LPRD) is primarily characterized by discomfort in the pharynx and has limited treatment options. This research aimed to assess the efficacy of transcutaneous auricular vagus nerve stimulation (tVNS) in patients with LPRD and delve into the potential underlying mechanisms. Methods: A total of 44 participants, diagnosed with LPRD were divided into two groups randomly. Twice-daily stimulation was delivered for 2 weeks for patients in experimental group, with stimulation ranging from 1.0 mA to 1.5 mA (n = 22), while the control group underwent sham tVNS (n = 22) with the same stimulation parameters and different anatomical location. The severity of symptoms and levels of anxiety and depression were monitored using questionnaires. High-resolution esophageal manometry data were collected, and the patients' autonomic function was assessed through heart rate variability analysis. Results: There was a positive correlation between reflux symptom index (RSI) scores and low frequency/high frequency (LF/HF) ratio (r = 0.619; p < 0.001), Hamilton anxiety scale (HAMA) scores (r = 0.623; p < 0.001), and Hamilton depression scale (HAMD) scores (r = 0.593; p < 0.001). Compared to the pre-tVNS phase, RSI (p < 0.001), HAMA (p < 0.001), and HAMD (p < 0.001) scores were significantly reduced after 2 weeks of treatment. Additionally, the resting pressure of the upper esophageal sphincter (UESP; p < 0.05) and lower esophageal sphincter (LESP; p < 0.05) showed significant enhancement. Notably, tVNS led to an increase in root mean square of successive differences (RMSSD; p < 0.05) and high frequency (HF; p < 0.05) within heart rate variability compared to the pre-treatment baseline. Compared to the control group, RSI (p < 0.001), HAMA (p < 0.001), and HAMD (p < 0.001) scores in tVNS group were significantly lower at the end of treatment. Similarly, the resting pressure of UESP (p < 0.05) and LESP (p < 0.05) in tVNS group were significantly higher than that of control group. Notably, RMSSD (p < 0.05) and HF (p < 0.05) in tVNS group were significantly higher than that of control group. Conclusion: This study demonstrated that tVNS as a therapeutic approach is effective in alleviating LPRD symptoms. Furthermore, it suggests that improvements in esophageal motility could be associated with vagus nerve-dependent mechanisms.

Ameliorating effects of transcutaneous auricular vagus nerve stimulation on a mouse model of constipation-predominant irritable bowel syndrome.

Limited treatment options have been shown to alter the natural course of constipation-predominant irritable bowel syndrome (IBS-C). Therefore, safer and more effective approaches are urgently needed. We investigated the effects of transcutaneous auricular vagus nerve stimulation (taVNS) in a mouse model of IBS-C. In the current study, C57BL/6 mice were randomly divided into normal control, IBS-C model control, sham-electrostimulation (sham-ES), taVNS, and drug treatment groups. The effects of taVNS on fecal pellet number, fecal water content, and gastrointestinal transit were evaluated in IBS-C model mice. We assessed the effect of taVNS on visceral hypersensitivity using the colorectal distention test. 16S rRNA sequencing was used to analyze the fecal microbiota of the experimental groups. First, we found that taVNS increased fecal pellet number, fecal water content, and gastrointestinal transit in IBS-C model mice compared with the sham-ES group. Second, taVNS significantly decreased the abdominal withdrawal reflex (AWR) score compared with the sham-ES group, thus relieving visceral hyperalgesia. Third, the gut microbiota outcomes showed that taVNS restored Lactobacillus abundance while increasing Bifidobacterium probiotic abundance at the genus level. Notably, taVNS increased the number of c-kit-positive interstitial cells of Cajal (ICC) in the myenteric plexus region in IBS-C mice compared with the sham-ES group. Therefore, our study indicated that taVNS effectively ameliorated IBS-C in the gut microbiota and ICC.

Colorectal motility patterns and psychiatric traits in functional constipation and constipation-predominant irritable bowel syndrome: A study from China.

BACKGROUND: Functional constipation (FC) and constipation-predominant irritable bowel syndrome (IBS-C) represent a spectrum of constipation disorders. However, the majority of previous clinical investigations have focused on Western populations, with limited data originating from China. AIM: To determine and compare the colorectal motility and psychiatric features of FC and IBS-C in an Eastern Chinese population. METHODS: Consecutive chronic constipation patients referred to our motility clinic from December 2019 to February 2023 were enrolled. FC and IBS-C diagnoses were established using ROME IV criteria, and patients underwent high-resolution anorectal manometry (ARM) and a colonic transmit test using the Sitz marker study. Constipation-related symptoms were obtained through questionnaires. Anxiety and depression were assessed by the Hamilton anxiety rating scale and the Hamilton Depression Rating Scale-21. The clinical characteristics and colorectal motility patterns of FC and IBS-C patients were compared. RESULTS: No significant differences in sex, age or abdominal discomfort symptoms were observed between IBS-C and FC patients (all P > 0.05). The proportion of IBS-C patients with delayed colonic transit was higher than that of patients with FC (36.63% vs 15.91%, P < 0.05), while rectosigmoid accumulation of radiopaque markers was more common in the FC group than in the IBS-C group (50% vs 26.73%, P < 0.05). Diverse proportions of these dyssynergic patterns were noted within both the FC and IBS-C groups by ARM. IBS-C patients were found to have a higher prevalence of depression than FC patients (66.30% vs 42.42%, P < 0.05). The scores for feelings of guilt, suicide, psychomotor agitation, diurnal variation, obsessive/compulsive disorder, hopelessness, self-abasedment and gastrointestinal symptoms were significantly higher in IBS-C patients than that in FC patients (P < 0.05). For IBS-C (χ2 = 5.438, P < 0.05) but not FC, patients with normal colon transit time were significantly more likely to have anxiety than those with slow colon transit time. For IBS-C patients but not FC patients, the threshold of first constant sensation, desire to defecate and sustained urgency were all weakly correlated with the degree of anxiety (r = 0.414, r = 0.404, and r = 0.418, respectively, P < 0.05). The proportion of patients with a low threshold of desire to defecate among IBS-C patients with depression was lower than that in those without depression (69.6% vs 41.9%, χ2 = 4.054, P < 0.05). CONCLUSION: Our findings highlight both overlapping and distinctive patterns of colon transit, dyssynergic patterns, anorectal sensation, psychological distress, and associations of psychiatric and colorectal motility characteristics in FC and IBS-C patients in an Eastern Chinese population, providing valuable insights into the pathophysiological underpinnings of these disorders.

Intestinal Ultrasound Combined with Blood Inflammatory Markers Is a More Efficient Tool in Evaluating Severity of Crohn's Disease: A Pilot Study.

Background and Aims: Intestinal ultrasound (IUS) is considered a nonirradiating, noninvasive, well-tolerated, and valuable tool for objectively assessing Crohn's disease (CD) activity. However, there is no widely accepted intestinal ultrasound scoring system. This study is aimed at evaluating the efficacy of IUS key parameters, the International Bowel Ultrasound Activity Score (IBUS-SAS), and IBUS-SAS combined with blood inflammatory markers in assessing CD activity. Methods: 40 CD patients were reviewed in this retrospective study and were divided into the moderate-severe group (n = 25) and nonmoderate-severe group (n = 15) based on a simplified endoscopic score of Crohn's disease (SES-CD). Double-balloon enteroscopy/colonoscopy were reviewed by three gastroenterologists. A transabdominal ultrasound was performed by two ultrasound specialists. Blood inflammatory markers were measured from morning samples. Results: In evaluating moderate to severe CD patients, (1) IBUS-SAS had a good predictive effect with an area-under-the-curve (AUC) of 0.855 (P < 0.001); (2) IUS key parameters (including BWT, CDS, BWS, and I-fat) yielded good predictive effects with AUC of 0.811, 0.731, 0.724, and 0.747, respectively (P < 0.001); (3) blood inflammatory markers (including ESR, CRP, PLR, MLR, and NLR) also had good predictive effects with AUC of 0.771, 0.837, 0.728, 0.743, and 0.775, respectively (P < 0.001); (4) IBUS-SAS combined with ESR and CRP exerted the best predictive effect with the highest AUC of 0.912 (95% CI: 0.823-1.000), and the sensitivity and specificity were 88.0% and 80.0%, respectively (P < 0.001). Conclusion: IBUS-SAS combined with ESR and CRP is a more efficient tool than IBUS-SAS alone or inflammatory markers alone in evaluating CD patients with moderate to severe disease activity.

Gut Microbiome and Metabonomic Profile Predict Early Remission to Anti-Integrin Therapy in Patients with Moderate to Severe Ulcerative Colitis.

Patients with ulcerative colitis (UC) have low response rates to anti-integrin medications, necessitating the identification of noninvasive biomarkers for predicting remission to anti-integrin therapy. In this study, patients with moderate to severe UC commencing anti-integrin therapy (n = 29), inactive to mild UC patients (n = 13), and healthy controls (n = 11) were selected. Besides clinical evaluation, fecal samples were collected at baseline and week 14 from moderate to severe UC patients. The clinical remission was defined based on the Mayo score. Fecal samples were assessed with 16S rRNA gene sequencing, liquid chromatography-tandem mass spectrometry, and gas chromatography-mass spectrometry (GC-MS). We identified that Verrucomicrobiota was significantly more abundant in the remission group (P < 0.001) than that of nonremission group at phylum level for patients commencing vedolizumab. GC-MS analysis revealed that the concentrations of butyric acid (P = 0.024) and isobutyric acid (P = 0.042) were significantly higher in the remission group compared to the nonremission group at baseline. Finally, the combination of Verrucomicrobiota, butyric acid, and isobutyric acid improved the diagnosis of early remission to anti-integrin therapy (area under the concentration-time curve = 0.961). We identified significantly higher phylum level diversity of Verrucomicrobiota in remission than the nonremission groups at baseline. Notably, the combination of gut microbiome and metabonomic profiles improved the diagnosis of early remission to anti-integrin therapy. IMPORTANCE It is reported that patients with ulcerative colitis (UC) have low response rates to anti-integrin medications in the latest VARSITY study. Therefore, our primary goals were to discover differences in the gut microbiome and metabonomics patterns between early remission and nonremission patients and to explore the diagnostic value in predicting clinical remission to anti-integrin therapy accurately. In this study, we found that Verrucomicrobiota was significantly more abundant in the remission group (P < 0.001) than that of nonremission group at phylum level for patients commencing vedolizumab. Gas chromatography-mass spectrometry analysis revealed that the concentrations of butyric acid (P = 0.024) and isobutyric acid (P = 0.042) were significantly higher in the remission group compared with the nonremission group at baseline. Notably, the combination of Verrucomicrobiota, butyric acid, and isobutyric acid improved the diagnosis of early remission to anti-integrin therapy (area under the concentration-time curve = 0.961).

Slow, deep breathing intervention improved symptoms and altered rectal sensitivity in patients with constipation-predominant irritable bowel syndrome.

Background and aim: Limited treatment options have been shown to alter the natural course of irritable bowel syndrome (IBS). Slow, deep breathing (SDB) is a common pain self-management intervention. This pilot study aimed to explore the impact of SDB on measures of autonomic and anorectal functions as well as patient-reported symptoms in constipation-predominant IBS (IBS-C). Methods: Eighty-five IBS-C patients were enrolled in this study and randomly assigned to the experimental group (Group A, n = 42) and the control group (Group B, n = 43). SDB was conducted at six breathing cycles per minute with an inhalation for 4 s and exhalation for 6 s at a ratio of 2:3 and repeated for 30 min during the intervention. All subjects underwent high-resolution anorectal manometry (HRAM) and completed the standardized IBS symptom severity system (IBS-SSS) questionnaire. Meanwhile, changes in stool consistency, weekly frequency of complete spontaneous bowel movements (CSBMs), and weekly frequency of spontaneous bowel movements (SBMs) were recorded. All IBS-C patients received electrocardiogram (ECG) recordings for heart rate variability (HRV) analysis at baseline, weeks 3, 6. Results: At baseline, no differences were found between Groups A and B. The IBS-SSS score and its five sub-scores of Group B patients were significantly higher at week 6 than those of Group A patients (all p < 0.001). Furthermore, compared with Group B patients, Group A patients had a significantly higher threshold volume for the first sensation (p < 0.001), desire to defecate (p = 0.017), and maximum tolerable volume (p = 0.018) at week 6 of the SDB treatment. We also noted significant improvements in stool consistency (p = 0.002), weekly SBM frequencies (p < 0.001), and weekly CSBM frequencies (p = 0.018) of Group A patients at week 6 when compared with Group B patients. Finally, the corrected high frequency (HF) of Group A patients was significantly higher than the HF of Group B patients at week 3 (p < 0.001) and at week 6 (p < 0.001). Likewise, patients in Group A had a significantly higher root mean square of the successive differences (RMSSD) than that of patients in Group B at week 3 (p < 0.001) and at week 6 (p < 0.001). Conclusion: We found that a 6-week SDB intervention improved symptoms and altered rectal sensation in IBS-C patients. Moreover, SDB enhanced vagal activity. These findings suggest that the effect of SDB on IBS-C may be due to mechanisms involving autonomic responses.

Sleep Deficiency Is Associated With Exacerbation of Symptoms and Impairment of Anorectal and Autonomic Functions in Patients With Functional Constipation.

Objective: Sleep deficiency (SD) is commonly seen in patients with functional constipation (FC). Our aim was to determine whether the presence of SD would influence symptoms, anorectal motility, sensation, and autonomic function in FC patients. Materials and Methods: A total of 85 FC patients with SD and 193 FC patients without SD underwent high-resolution anorectal manometry. SD was assessed by using the Pittsburgh Sleep Quality Index (PSQI) score. Participants were required to fill in the entire questionnaires, including Patients' Constipation-symptoms, State-Trait Anxiety Inventory, and Hamilton Depression Scale. Autonomic dysfunction was studied by recording the heart rate variability. Multiple logistic regression was performed to explore the potential risk factors for anorectal function. Results: Functional constipation patients with SD had a higher total score of constipation symptom (P < 0.001), in comparison with those without SD. FC patients with SD demonstrated significantly lower threshold volume for first sensation (P < 0.001) and urge (P < 0.001), as compared to those without SD. The PSQI score positively correlated with constipation symptom total score (P < 0.001), and negatively correlated with threshold volume for first sensation (P < 0.001) and urge (P < 0.001). FC patients with SD had a reduced vagal activity (P = 0.016) and a higher sympathetic activity as compared to those without SD (P = 0.003). Multivariate logistic regression revealed that SD, anxiety and depression were independent risk factors for anorectal function, with SD exhibiting the highest degree of association with first sensation (OR: 4.235). Conclusion: Sleep deficiency is associated with worse constipation related symptoms, altered anorectal function and perception, and impaired autonomic function in FC patients.

Placebo Response Rates in Acupuncture Therapy Trials for Functional Dyspepsia: A Systematic Review and Meta-Analysis.

BACKGROUND: Functional dyspepsia (FD) is a functional digestive disease with limited management selection. Previous studies revealed that acupuncture therapy is effective for FD. However, because sham controls were not implemented in most clinical trials following acupuncture therapy, it is difficult to differentiate overall treatment responses from placebo. This study aims to quantify placebo responses in clinical trials in which FD patients received sham manual acupuncture (MA) and sham electroacupuncture (EA). MATERIALS AND METHODS: Randomized controlled trials of MA and EA for FD patients were searched in PubMed, Web of Science, Cochrane Library, and Embase databases, as well as 4 Chinese language databases from inception to January 2021. RevMan 5.20 software was used for pooled analysis of symptom scores and quality of life. The symptom scores were combined using standard mean difference (SMD) or weighted mean difference (WMD) with a 95% confidence interval (CI). The quality of included studies was tested using modified Jadad scale and Standards for Reporting Interventions in Controlled Trials of Acupuncture (STRICTA) checklist. Egger's test, Begg's test, and sensitivity analyses were conducted using Stata 11.0 statistical software. The protocol of this study is registered in PROSPERO as CRD42021233858. RESULTS: After screening, the current systematic review included 13 randomized controlled trials, of which 8 studies were used in the meta-analysis. Regarding subjective outcomes, the combined effect of sham MA on FD symptoms was [SMD=-0.42, 95% CI (-0.72, -0.12); P=0.005], whereas sham EA treatment was [SMD=-0.54, 95% CI (-0.81, -0.27); P<0.001]. The combined effect on FD quality of life of post-sham MA group was [SMD=-0.32, 95% CI (-0.52, -0.12); P=0.002]. With regard to objective outcomes, the combined effect of sham EA on dominant frequency was [WMD=-0.11, 95% CI (-0.30, -0.08); P=0.24], while the combined effect of sham EA on dominant power was [WMD=-3.35, 95% CI (-8.04, 1.35); P=0.16]. CONCLUSIONS: Sham MA and sham EA remarkably improve symptoms and quality of life scores of FD without influencing objective outcomes, highlighting the significance of sham controls in acupuncture therapy clinical trials.

Subjective Changes of Taste and Smell in Conjunction With Anxiety and Depression Are Associated With Symptoms in Globus Patients Without Evidence of Pathologic Acid Reflux.

BACKGROUND/AIM: Patients suffering from globus often report decreased enjoyment when eating as well as a psychological abnormality. Some patients exhibit taste and smell changes (TSCs) when compared with the period before the diagnosis. The main aim of this study was to explore if TSCs and psychological abnormality are present in patients with globus, whether they are associated with the severity of throat symptoms, and the potential risk factors for globus. PATIENTS AND METHODS: A total of 116 included patients who met the Rome IV diagnostic criteria for globus had been performed 24-hour pH monitoring, and the results shown no evidence of pathologic acid reflux. Meanwhile, 125 healthy controls were enrolled in this prospective study. All subjects completed several questionnaires including the Taste and Smell Survey, the Glasgow Edinburgh Throat Scale, the Hamilton Anxiety Scale (HAMA), and the Hamilton Depression Scale (HAMD). Multiple logistic regression was performed to explore the potential risk factors for globus. The study protocol was registered on the Chinese Clinical Trial Registry (No. ChiCTR-2100044972). RESULTS: First, globus patients without evidence of pathologic acid reflux exhibited a 58.62% and 31.03% change in taste and smell, respectively, while their levels of anxiety and depression were 51.72% and 44.83%, respectively. Second, there was a significant difference in the taste score (Z=-4.954, P<0.001) and smell score (Z=-4.552, P<0.001) between globus group patients and healthy controls. Similarly, globus group patients had a higher HAMA score (9.52±2.437 vs. 3.12±1.059, t=6.867, P<0.001) and HAMD score (9.79±2.931 vs. 3.16±1.650, t=6.416, P<0.001) when compared with the healthy controls. Third, in globus group patients, the Glasgow Edinburgh Throat Scale was significantly correlated with the taste score (Spearman ρ=0.782; P<0.001), smell score (Spearman ρ=0.582; P=0.001), HAMA (Spearman ρ=0.676; P<0.001), and HAMD (Spearman ρ=0.672; P<0.001). In addition, the taste score was significantly correlated with HAMA (Spearman ρ=0.532; P=0.004) and HAMD (Spearman ρ=0.681; P<0.001), while the smell score was significantly correlated with HAMD (Spearman ρ=0.392; P=0.035). Finally, multivariate logistic regression revealed that TSCs, anxiety, and depression were significant independent risk factors for globus, with depression exhibiting the highest degree of association (odds ratio: 3.244). CONCLUSIONS: TSCs and psychological comorbidities are prominent in globus patients without evidence of pathologic acid reflux. The obtained results indicated that there is a strong relationship between TSCs, psychological comorbidities, and globus. Therefore, awareness of this high prevalence of TSCs and psychological disorder may help to better understand the severity of throat symptoms.

Digital Rectal Examination Is a Valuable Bedside Tool for Detecting Dyssynergic Defecation: A Diagnostic Study and a Meta-Analysis.

Background: Accurate dyssynergic defecation (DD) diagnosis depends on anorectal physiological tests that are not widely available. Aim: The purpose of this study is to evaluate the diagnostic yield of digital rectal examination (DRE) compared with anorectal physiological tests in diagnosing DD in patients with constipation. Methods: A total of 218 chronic constipation patients who fulfilled the Rome IV diagnostic criteria for functional constipation (FC) and underwent a standardized DRE and high-resolution anorectal manometry (HRAM) test were enrolled in this study. The diagnostic accuracy of DRE compared with HRAM was evaluated, and the agreement between DRE and HRAM was calculated. Furthermore, a comprehensive literature search on PubMed, Web of Science, Cochrane Library, and Embase database was conducted to further elucidate the pooled diagnostic accuracy of DRE in DD patients. Results: A total of 101 patients (46.33%) had a DD pattern using HRAM, while 117 patients (53.67%) were diagnosed without DD. The sensitivity of DRE in diagnosing dyssynergia was 71.3%, and the specificity was 76.1%. There was a moderate agreement between DRE and HRAM for diagnosing DD (κ-coefficient = 0.474, P < 0.001). Meanwhile, six studies (including our study) comprising 964 constipated patients were included in our meta-analysis. The outcomes demonstrated that the AUC was 0.85 (95% CI 0.82-0.88) with 77% summary sensitivity (95% CI 65-86) and 80% summary specificity (95% CI 71-86) to diagnose DD. Conclusions: DRE could be a valuable tool for screening DD. Our study revealed acceptable sensitivity and specificity of DRE in detecting dyssynergia compared with the physiological tests. Meanwhile, our study highlights that DRE remains an important tool in clinical practice.

Subjective Taste and Smell Changes in Conjunction with Anxiety and Depression Are Associated with Symptoms in Patients with Functional Constipation and Irritable Bowel Syndrome.

BACKGROUND: Patients with functional constipation (FC) and irritable bowel syndrome (IBS) often report psychological abnormalities and decreased eating enjoyment. Several patients also complain of changes in the sense of smell and taste, but these are often disregarded clinically. AIMS: Therefore, there is a need to determine whether taste/smell disturbances and psychological abnormalities are present in patients with FC or IBS and whether these are related to the severity of lower gastrointestinal symptoms. METHODS: A total of 337 subjects were recruited, including FC (n = 115), IBS (n = 126), and healthy controls (n = 96). All participants completed questionnaires evaluating taste and smell (taste and smell survey (TSS)), Lower Gastrointestinal Symptoms Rating Scale (LGSRS), Hamilton anxiety scale (HAMA), and Hamilton depression scale (HAMD). TSS recorded information on the nature of taste and smell changes (TSCs) and the impact of these changes on the quality of life. LGSRS was used to assess the severity of lower gastrointestinal symptoms; HAMA and HAMD scales were used to reflect the psychosocial state. This study protocol was registered on the Chinese Clinical Trial Registry (No. ChiCTR-2100044643). RESULTS: Firstly, we found that taste and smell scores were higher in patients with IBS than in healthy controls. Secondly, for FC and IBS patients, LGSRS was significantly correlated with the taste score (Spearman's rho = 0.832, P < 0.001). LGSRS was also significantly correlated with HAMA (Spearman's rho = 0.357, P = 0.017) and HAMD (Spearman's rho = 0.377, P = 0.012). In addition, the taste score was significantly correlated with HAMD (Spearman's rho = 0.479, P = 0.001), while the smell score was also significantly correlated with HAMD (Spearman's rho = 0.325, P = 0.031). Thirdly, 60.87% and 71.43% of patients complained of taste abnormality, while 65.22% and 71.43% had smell abnormality in the FC and IBS groups, respectively. Meanwhile, 47.83% and 47.62% of patients suffered from anxiety, while 43.48% and 57.14% suffered from depression in the FC and IBS groups, respectively. Finally, we found significant differences in the taste, smell, HAMD, and LGSRS scores between the female and male IBS groups (P < 0.050). CONCLUSIONS: TSCs and psychological disorders are prominent in FC and IBS patients. Taste abnormalities, as well as anxiety and depression, are significantly correlated with LGSRS. Awareness of this high prevalence of taste/smell abnormalities and the psychological changes among patients with FC and IBS may help better predict and understand the severity of symptoms.

Ameliorating Effects of Transcutaneous Electrical Acustimulation at Neiguan (PC6) and Zusanli (ST36) Acupoints Combined with Adaptive Biofeedback Training on Functional Outlet Obstruction Constipation.

BACKGROUND: Stimulant laxatives are still considered the most common treatment for functional outlet obstruction constipation (FOOC). However, the effectiveness of laxatives is unsatisfactory, and the long-term use of laxatives may cause certain adverse events. With this in mind, it is, however, paramount that novel complementary treatment(s) and/or other forms of alternative medicine are adequately investigated. AIMS: The study aims to explore the effects and potential mechanism(s) of transcutaneous electrical acustimulation (TEA) combined with adaptive biofeedback training (ABT) on FOOC. METHODS: A total of forty-five patients with FOOC were recruited and were randomly assigned to receive either Macrogol 4000 Powder (MAC, 10 g bid) (group A, n = 15) only, ABT + MAC + Sham-TEA (group B, n = 15), or TEA + ABT + MAC (group C, n = 15) in a six-week study. Individual patients' constipation-symptoms (PAC-SYM) and constipation-quality of life (PAC-QOL) were both assessed and scored. Serum acetylcholine (Ach) and nitric oxide (NO) were measured from drawn blood samples while individual patients' heart rate variability (HRV) was calculated at baseline and after each corresponding therapy. Anorectal manometry and balloon expulsion test were both performed before and after treatment. RESULTS: Firstly, participants in group C had significantly lower scores of PAC-SYM, PAC-QOL, and a decreased anal defecating pressure (ADP) as compared to participants in group B (all p < 0.050). These results, however, suggest the TEAs effect. Secondly, the low-frequency band (LF)/(LF + HF) ratio in groups B and C were decreased as compared to group A (p=0.037, p=0.010, respectively) regarding HRV. On the other hand, the high-frequency band (HF)/(LF + HF) ratio in groups B and C showed an opposite outcome. Finally, the serum Ach in groups B and C was significantly higher as compared to group A (p=0.023, p=0.012, respectively). Of significant importance, the serum NO in groups B and C were notably low as compared to group A (p=0.001, p < 0.001, respectively). CONCLUSIONS: TEA, combined with ABT, effectively improves constipation symptoms as well as QOL in FOOC patients. It is, however, achieved by decreasing ADP, which mechanisms are mediated via the autonomic and enteric mechanisms.

Predictive Value of Fissured Tongue in Functional Dyspepsia Combined with Depression.

Anxiety and depression are common in functional dyspepsia (FD) patients. Although fissured tongue (FT) is often observed in FD, its clinical value in such patients is rarely reported. We analyzed clinical data of FD patients with FT with the aim of elucidating the clinical value of FT in FD. This study suggests FD patients with different types of FT with the course of disease and the 9-item Patient Health Questionnaire (PHQ9) showed a significant difference. The PHQ9, course of disease, and self-rated dyspepsia symptoms (SRDS) correlated positively with the types of FT by the Spearman rank analysis. Epigastric pain, bloating, nausea, and SRDS showed a significant difference between FT-FD and nonfissured tongue- (NFT-) FD as well as between FD patients with and without symptoms of depression. Many FD patients also have FT, which may be associated with depressive symptoms. The longer the course of disease, the more serious the fissured tongue; thus, it may provide a predictive value for the diagnosis of depressive symptoms in FD patients.

A role for the non-receptor tyrosine kinase ACK1 in TNF-alpha-mediated apoptosis and proliferation in human intestinal epithelial caco-2 cells.

The roles of tumor necrosis factor alpha (TNF-alpha) and its mediators in cellular processes related to intestinal diseases remain elusive. In this study, we aimed to determine the biological role of activated Cdc42-associated kinase 1 (ACK1) in TNF-alpha-mediated apoptosis and proliferation in Caco-2 cells. ACK1 expression was knocked down using ACK1-specific siRNAs, and ACK1 activity was disrupted using a small molecule ACK1 inhibitor. The Terminal deoxynucleotidyl transferase biotin-dUTP Nick End Labeling (TUNEL) and the BrdU incorporation assays were used to measure apoptosis and cell proliferation, respectively. ACK1-specific siRNA and the pharmacological ACK1 inhibitor significantly abrogated the TNF-alpha-mediated anti-apoptotic effects and proliferation of Caco-2 cells. Interestingly, TNF-alpha activated ACK1 at tyrosine 284 (Tyr284), and the ErbB family of proteins was implicated in ACK1 activation in Caco-2 cells. ACK1-Tyr284 was required for protein kinase B (AKT) activation, and ACK1 signaling was mediated through recruiting and phosphorylating the down-stream adaptor protein AKT, which likely promoted cell proliferation in response to TNF-alpha. Moreover, ACK1 activated AKT and Src enhanced nuclear factor-кB (NF-кB) activity, suggesting a correlation between NF-кB signaling and TNF-alpha-mediated apoptosis in Caco-2 cells. Our results demonstrate that ACK1 plays an important role in modulating TNF-alpha-induced aberrant cell proliferation and apoptosis, mediated in part by ACK1 activation. ACK1 and its down-stream effectors may hold promise as therapeutic targets in the prevention and treatment of gastrointestinal cancers, in particular, those induced by chronic intestinal inflammation.

Involvement of Activated Cdc42 Kinase1 in Colitis and Colorectal Neoplasms.

BACKGROUND Activated Cdc42 kinase1 (ACK1) is a non-receptor tyrosine kinase which is critical for cell survival, proliferation, and migration. Genomic amplification of ACK1 has been reported in multiple human cancers. We aimed to investigate ACK1 protein expression in colorectal mucosa with inflammation and neoplasm, and to evaluate its correlation with disease activity and severity. MATERIAL AND METHODS A total of 250 individuals who underwent total colonoscopy were collected randomly from January 2007 to May 2013 in Nanfang Hospital, Guangzhou, China. Colorectal mucosal biopsy specimens were obtained by endoscopy from 78 patients with ulcerative colitis (UC), 22 with Crohn's disease (CD), 20 with infectious colitis, 26 with non-IBD and noninfectious colitis, 16 with sporadic adenomas, 4 with dysplasia-associated lesions or masses, 10 with sporadic colorectal cancer (CRC), 4 with UC-related CRC, 10 with hyperplastic polyps, and 60 without colonic abnormalities. ACK1 protein levels were determined immunohistochemically. The correlations of ACK1 expression with disease activity and severity were also evaluated. RESULTS Significantly increased ACK1 expression was observed in epithelial cells of colorectal mucosa with inflammation and dysplasia compared to controls (P<0.05). ACK1 expression correlated with clinical activity in IBD (χ²=4.57, P=0.033 for UC; χ²=5.68, P=0.017 for CD), as well as grade of dysplasia in preneoplastic lesions (P<0.05). No significant differences in ACK1 expression were found between UC and CD, or between IBD and non-IBD conditions (P>0.05). CONCLUSIONS ACK1 protein is increased extensively in colitis and colorectal dysplasia. ACK1 overexpression may play a role in colorectal inflammation and neoplasms.

[Annexin A2 expression in intestinal mucosa of patients with inflammatory bowel disease and its clinical implications].

OBJECTIVE: To explore the role of annexin A2 (ANXA2) expression in the intestinal mucosa in the pathogenesis of inflammatory bowel disease (IBD). METHODS: Intestinal or colonic mucosal biopsy samples were obtained from 54 patients with ulcerative colitis (UC), 37 with Crohn's disease (CD), and 15 healthy control subjects. Immunohistochemistry was employed to examine the expression of ANXA2 in the intestinal mucosa, and mRNA expression of ANXA2 was detected using real-time PCR. RESULTS: Immunohistochemistry showed a ANXA2 positivity rate of 83.3% (45/54) in patients with UC, 27.0% (10/37) in patients with CD, and 53.3% (8/15) in the control subjects. ANXA2 expression in the intestinal or colonic mucosa was significantly up-regulated in patients with UC compared with the patients with CD and healthy control subjects, but was significantly lower in patients with CD than in the healthy controls (P<0.05). The expression levels of ANXA2 were strongly associated with the severity of clinical manifestations and the histopathological grades of UC (P<0.05). Compared with the healthy controls and patients with CD, patients with UC showed a significantly increased ANXA2 mRNA expression level in the inflamed mucosa of UC (P<0.05). CONCLUSION: ANXA2 can serve as a marker for differential diagnosis of IBD, and its up-regulated expression is closely related to the pathogenesis of UC.

Anti-Saccharomyces cerevisiae antibodies associate with phenotypes and higher risk for surgery in Crohn's disease: a meta-analysis.

BACKGROUND: Recent studies suggested that anti-Saccharomyces cerevisiae antibody (ASCA) status was associated with diagnostic findings, stratified classification phenotypes, disease activity and clinical course of Crohn's disease (CD). However, the relationship between ASCA status and phenotypes of CD remains controversial in these studies. AIMS: The purpose of this study was to evaluate whether ASCA status is associated with the phenotypes and the risk of surgery in diverse populations in CD. METHODS: We conducted a meta-analysis of studies assessing the association of ASCA status with phenotypes and risk of surgery in CD. Three independent reviewers undertook data extraction. We pooled odds ratios separately for the cohort and case-control studies. RESULTS: We identified ten cohort studies (n = 2,365) and 14 case-control studies (n = 1,887) that investigated the association of ASCA status with phenotypes and risk of surgery in CD. The meta-analysis of the cohort studies showed significant association between the ASCA-positive status and higher risk of early-onset age (OR 2.25, 95 % CI 1.41-3.57, P < 0.001), ileal involvement disease (1.70, 1.05-2.77, P = 0.03), complicated disease behavior (2.09, 1.71-2.57, P < 0.001), perianal disease (1.49, 1.14-1.94, P = 0.004), and risk for surgery (1.61, 1.29-2.01, P < 0.001). Meta-analysis of the case-control studies also showed a significantly higher risk in ileal involvement disease (1.77, 1.25-2.49, P = 0.001), complicated disease behavior (2.13, 1.70-2.68, P < 0.001), perianal disease (1.96, 1.38-2.78, P < 0.001), and risk for surgery (1.71, 1.17-2.49, P = 0.005), except for the early-onset age (1.16, 0.80-1.69, P = 0.44). CONCLUSIONS: This meta-analysis indicated that positive ASCA status is a risk factor for early-onset age, ileal involvement, complicated behavior, perianal disease and requirement for surgery in CD.

Confirmation of three inflammatory bowel disease susceptibility loci in a Chinese cohort.

PURPOSE: Recent genome-wide association studies have identified a number of inflammatory bowel diseases (IBD) susceptibility loci in White populations. The aim of our study was to evaluate whether these susceptibility loci also existed in a Chinese Han IBD population. METHODS: Peripheral blood DNA samples from groups of patients with Crohn's disease (CD) (n = 48), ulcerative colitis (UC) (n = 49), and healthy controls (n = 50) were genotyped for eight genes. Then, an extended analysis of the relationship between genotype and phenotype was performed. RESULTS: NOD2-P268S (P = 0.025) was found to contribute susceptibility to CD in the Chinese population. IL23R-rs11805303 was detected to confer a strong protective effect against UC (P = 0.010), whereas PTPN2-rs2542151 was significantly associated with an increased risk of UC (P = 0.001). Further phenotype-genotype analysis revealed that P268S was associated with early age of onset (P = 0.028), ileal disease (P = 0.003), and enteric cavity narrowing (P = 0.007). CONCLUSIONS: The study indicates that IL23R-rs11805303 and PTPN2-rs2542151 might contribute to the development of UC and NOD2-P268S might be involved in the etiology of CD in the Chinese Han population.