Modulation of intracortical circuits in primary motor cortex during automatic action tendencies.

Humans display automatic action tendencies toward emotional stimuli, showing faster automatic behavior (i.e., approaching a positive stimulus and avoiding a negative stimulus) than regulated behavior (i.e., avoiding a positive stimulus and approaching a negative stimulus). Previous studies have shown that the primary motor cortex is involved in the processing of automatic actions, with higher motor evoked potential amplitudes during automatic behavior elicited by single-pulse transcranial magnetic stimulation. However, it is unknown how intracortical circuits are involved with automatic action tendencies. Here, we measured short-interval intracortical inhibition and intracortical facilitation within the primary motor cortex by using paired-pulse transcranial magnetic stimulation protocols during a manikin task, which has been widely used to explore approaching and avoiding behavior. Results showed that intracortical facilitation was stronger during automatic behavior than during regulated behavior. Moreover, there was a significant negative correlation between reaction times and intracortical facilitation effect during automatic behavior: individuals with short reaction times had stronger faciliatory activity, as shown by higher intracortical facilitation. By contrast, no significant difference was found for short-interval intracortical inhibition between automatic behavior and regulated behavior. The results indicated that the intracortical facilitation circuit, mediated by excitatory glutamatergic neurons, in the primary motor cortex, plays an important role in mediating automatic action tendencies. This finding further supports the link between emotional perception and the action system.

The serotonin receptor 3E variant is a risk factor for female IBS-D.

Irritable bowel syndrome (IBS) is a gut-brain disorder of multifactorial origin. Evidence of disturbed serotonergic function in IBS accumulated for the 5-HT3 receptor family. 5-HT3Rs are encoded by HTR3 genes and control GI function, and peristalsis and secretion, in particular. Moreover, 5-HT3R antagonists are beneficial in the treatment of diarrhea predominant IBS (IBS-D). We previously reported on functionally relevant SNPs in HTR3A c.-42C > T (rs1062613), HTR3C p.N163K (rs6766410), and HTR3E c.*76G > A (rs56109847 = rs62625044) being associated with IBS-D, and the HTR3B variant p.Y129S (rs1176744) was also described within the context of IBS. We performed a multi-center study to validate previous results and provide further evidence for the relevance of HTR3 genes in IBS pathogenesis. Therefore, genotype data of 2682 IBS patients and 9650 controls from 14 cohorts (Chile, Germany (2), Greece, Ireland, Spain, Sweden (2), the UK (3), and the USA (3)) were taken into account. Subsequent meta-analysis confirmed HTR3E c.*76G > A (rs56109847 = rs62625044) to be associated with female IBS-D (OR = 1.58; 95% CI (1.18, 2.12)). Complementary expression studies of four GI regions (jejunum, ileum, colon, sigmoid colon) of 66 IBS patients and 42 controls revealed only HTR3E to be robustly expressed. On top, HTR3E transcript levels were significantly reduced in the sigma of IBS patients (p = 0.0187); more specifically, in those diagnosed with IBS-D (p = 0.0145). In conclusion, meta-analysis confirmed rs56109847 = rs62625044 as a risk factor for female IBS-D. Expression analysis revealed reduced HTR3E levels in the sigmoid colon of IBS-D patients, which underlines the relevance of HTR3E in the pathogenesis of IBS-D.

Serotonin type 3 receptor subunit gene polymorphisms associated with psychosomatic symptoms in irritable bowel syndrome: A multicenter retrospective study.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) of the serotonin type 3 receptor subunit (HTR3) genes have been associated with psychosomatic symptoms, but it is not clear whether these associations exist in irritable bowel syndrome (IBS). AIM: To assess the association of HTR3 polymorphisms with depressive, anxiety, and somatization symptoms in individuals with IBS. METHODS: In this retrospective study, 623 participants with IBS were recruited from five specialty centers in Germany, Sweden, the United States, the United Kingdom, and Ireland. Depressive, anxiety, and somatization symptoms and sociodemographic characteristics were collected. Four functional SNPs - HTR3A c.-42C>T, HTR3B c.386A>C, HTR3C c.489C>A, and HTR3E c.*76G>A - were genotyped and analyzed using the dominant and recessive models. We also performed separate analyses for sex and IBS subtypes. SNP scores were calculated as the number of minor alleles of the SNPs above. The impact of HTR3C c.489C>A was tested by radioligand-binding and calcium influx assays. RESULTS: Depressive and anxiety symptoms significantly worsened with increasing numbers of minor HTR3C c.489C>A alleles in the dominant model (F depressive = 7.475, P depressive = 0.006; F anxiety = 6.535, P anxiety = 0.011). A higher SNP score (range 0-6) was linked to a worsened depressive symptoms score (F = 7.710, P-linear trend = 0.006) in IBS. The potential relevance of the HTR3C SNP was corroborated, showing changes in the expression level of 5-HT3AC variant receptors. CONCLUSION: We have provided the first evidence that HTR3C c.489C>A is involved in depressive and anxiety symptoms in individuals with IBS. The SNP score indicated that an increasing number of minor alleles is linked to the worsening of depressive symptoms in IBS.

Effect of size and crystalline phase of TiO2 nanotubes on cell behaviors: A high throughput study using gradient TiO2 nanotubes.

The research of TiO2 nanotubes (TNTs) in the field of biomedicine has been increasingly active. However, given the diversity of the nanoscale dimension and controversial reports, our understanding of the structure-property relationships of TNTs is not yet complete. In this paper, gradient TNTs with a wide diameter range of 20-350 nm were achieved by bipolar electrochemistry and utilized for a thorough high-throughput study of the effect of nanotube dimension and crystalline phase on protein adsorption and cell behaviors. Results indicated that protein adsorption escalated with nanotube dimension whereas cell proliferation and differentiation are preferred on small diameter (<70 nm) nanotubes. Large diameter anatase nanotubes had higher adsorption of serum proteins than as-prepared ones. But only as-prepared small diameter nanotubes presented slightly higher cell proliferation than corresponding annealed nanotubes whereas there was no discernible difference between as-prepared and annealed nanotubes on cell differentiation for the entire gradient. Those findings replenish previous research about how cell responses to TNTs with a wide diameter range and provide scientific guidance for the optimal design of biomedical materials.

Stressful Life Events Moderate the Relationship Between Changes in Symptom Severity and Health-related Quality of Life in Patients With Irritable Bowel Syndrome.

OBJECTIVES: The relationship between changes in symptom severity and health-related quality of life (HRQOL), which may be impacted by stressful life events, in irritable bowel syndrome (IBS), is unclear. Therefore, we investigated the relationship between changes in symptom severity and HRQOL and examined the moderating role of stressful life events in patients with IBS. METHODS: This study is part of a cohort follow-up study on psychological factors in patients with IBS in tertiary care, and it included 158 patients. In addition to symptom severity and HRQOL, stressful life events were assessed by the Social Readjustment Rating Scale (SRRS). The relationship between symptom severity and HRQOL and the moderating role of stressful life events (in the 12 mo before the follow-up assessment) were analyzed. RESULTS: The majority of participants had moderate levels of stressful life events (41.8%), followed by those who had mild levels (39.2%) and severe levels (19.0%) of stressful life events. Symptom severity could predict HRQOL, and the relationship between symptom severity and HRQOL was affected by the level of stressful life events. Compared with mild levels of stressful life events, a severe level of stressful life events significantly affected the relationship between changes in symptom severity and HRQOL (Z=-3.048, P<0.01). A similar result was found when comparing moderate and severe levels of stressful life events (Z=-1.810, P<0.10). CONCLUSIONS: The study demonstrated that symptom severity predicted HRQOL during the progression of IBS and that stressful life events moderated the impact of symptom severity on HRQOL. The more stressful life events an IBS patient experiences, the less predictable the relationship is between changes in symptom severity and HRQOL.

High Rates of Non-Response Across Treatment Attempts in Chronic Irritable Bowel Syndrome: Results From a Follow-Up Study in Tertiary Care.

Objective: Despite a wealth of treatment options for irritable bowel syndrome (IBS), data on the subjective experience of treatments in ongoing clinical practice are sparse. This follow-up study assessed the individual usage of treatment modalities by IBS patients over time and investigated the patients' subjective experience of therapeutic impact. Methods: The study was conducted at the Specialty Clinic for Functional Gastrointestinal Disorders of the Heidelberg University Hospital. All patients who fulfilled the Rome III criteria for IBS and treated in our outpatient clinic between January 2012 and December 2016 were invited to the assessment. The primary outcome variables were individual usage of treatment modalities and the Patient Global Impression of Change (PGIC) with treatments. Results: Three hundred and sixty-six patients fulfilled the Rome III criteria for IBS and thus were eligible for this study. Two hundred and seven patients dropped out from the study. The study could include 159 patients (43.7 ± 17.1 years; 71.1% female). The mean time since the first visit to the clinic was 2.8 ± 1.3 years (median 3.0 years). The mean time of symptom duration was 14.1 ± 11.1 years (median 10 years). The average number of treatment attempts was 12, ranging from 2 to 39). With respect to the subjective experience of therapeutic impact, there were no significant differences in the PGIC scores among different treatments (p = 0.183). The rates of non-response rates (minimally improved, no change, or minimally worse) ranged from 63.0% to 83.9%. The PGIC score was correlated negatively with the mean number of treatment attempts (r = -0.316, p < 0.01). The mean number of treatment attempts was correlated negatively with quality of life (r = -0.262, p < 0.01). Conclusion: A multidisciplinary treatment approach of IBS is characterized by high rates of non-response and a high number of frustrating treatment attempts. The connection between the various treatment attempts and the frustrating subjective experience of therapeutic impact puts a substantial burden on IBS patients.

Rational Design of Silver Gradient for Studying Size Effect of Silver Nanoparticles on Contact Killing.

The cellular mechanism underlying bacteria responses to silver nanoparticles (AgNPs) has not been fully elucidated. Especially, it is difficult to distinguish the contact killing from release killing as Ag+ releases from AgNPs. In this paper, AgNPs gradient was designed for evaluating the size effect of AgNPs on contact killing. A size gradient of AgNPs (5-45 nm) was achieved on TiO2 nanotubes (TNTs) by rational design of bipolar electrochemical reaction, including applied voltage, electrolyte concentration, and sample size. High-throughput investigation of cellular responses showed that the smallest AgNPs were the most efficient in suppressing bacteria whereas the largest AgNPs were more favorable for MC3T3-E1 cell adhesion and proliferation. As Ag+ concentration was the same for the entire gradient, the difference in cellular responses was dominated by the contact effect (rather than difference in released Ag+) which was tuned by AgNPs size. This method offers new prospect for efficient evaluation of the contact effect of nanoparticles, such as Ag, Au, and Cu.

Is body mass index associated with symptom severity and health-related quality of life in irritable bowel syndrome? A cross-sectional study.

OBJECTIVE: The aim of this study was to describe the body mass index (BMI) distribution in patients with irritable bowel syndrome (IBS) based on the Rome III criteria and to evaluate the association of BMI with symptom severity and quality of life (QOL). METHODS: A cross-sectional study was carried out in patients visiting our outpatient functional gastrointestinal disorders specialty clinic. IBS diagnosis was made based on Rome III criteria. IBS symptom severity was investigated using the IBS severity score system. QOL was assessed using the Short Form 36 Health Survey, which consists of physical health and mental health. RESULTS: 366 patients (252 women) who fulfilled Rome III criteria and provided complete BMI data (23.90±5.22 kg/m2) were included. Overall, 59.0% of patients with IBS were in the normal weight range, 30.3% were overweight or obese, and 10.7% were underweight. Both physical and mental health decreased significantly with the severity of symptoms (all p<0.01), while controlling for several covariates (age, gender, family status, education status and IBS subtypes). Obesity and symptom severity (ß=-0.177,△R2=0.037, p<0.01; ß=-0.387,△R2=0.147, p<0.01) were significant negative factors that influencing physical health. Symptom severity (ß=-0.301,△R2=0.084, p<0.01) was significant negative factor that influencing mental health. However, BMI didn't account for additional variance in mental health (p>0.05). CONCLUSION: Being overweight is a common phenomenon in patients with IBS regardless of IBS subtype. The association between QOL and symptom severity followed a negative dose-response pattern. Patients with higher BMI, especially obese patients, were more frequently in poor physical health. However, this kind of relationship was not found in BMI and mental health.

Telomere length and telomere repeating factors: Cellular markers for post-traumatic stress disorder-like model.

OBJECTIVE: The aim of the present study was to explore the telomere length of peripheral blood leukocytes from a rat model of post-traumatic stress disorder (PTSD), as well as the expression level of telomere-binding protein in the hippocampal CA1 region. METHODS: The PTSD model was established with 42 adult male Wistar rats. The relative telomere length of the leukocytes was measured by real-time fluorescence quantitative polymerase chain reaction, and the expression levels of telomere repeating factor 1 (TRF1) and telomere repeating factor 2 (TRF2) in the hippocampal CA1 region of the PTSD rat model were determined by immunofluorescence technology. The covariance analysis of repeated measurements by the mixed model approach was used for the telomere length analysis. The comparison of averaged data among groups was performed using least significant difference and analysis of variance. The Student's t test or the Mann-Whitney U test was used for intragroup comparison. The association study among groups was conducted using the Spearman test. RESULTS: The shortening speed of telomere length significantly accelerated in rats after Single Prolonged Stress (SPS) stimulation (P<0.05). The expression levels of TRF1 and TRF2 increased with the progress of PTSD, and the expression peak was shown in day 14, which was significantly different from the control group (P<0.05). CONCLUSION: The shortening speed of the telomere length of peripheral blood leukocytes accelerated in PTSD rats, and the expression levels of TRF1 and TRF2 increased in hippocampus, both of which were closely associated with the pathological progress of the PTSD-like model and unfavorable prognosis.