BACKGROUND/AIMS: Patients with irritable bowel syndrome (IBS) often report poor sleep quality. Whether poor sleep is associated with tryptophan (Trp) metabolites is unknown. We compared serum Trp metabolites in women with IBS and healthy controls (HCs) using targeted liquid chromatography mass spectrometry (LC-MS)-based profiling. In IBS only, we explored whether Trp metabolites are associated with IBS symptoms and subjective and objective sleep indices, serum cortisol, plasma adrenocorticotropic hormone (ACTH), and cortisol/ACTH levels. METHODS: Blood samples were obtained every 80 minutes in 21 HCs and 38 IBS subjects following an anticipation-of-public-speaking stressor during a sleep laboratory protocol. Subjects completed symptom diaries for 28 days. Adjacent values of metabolites were averaged to represent 4 time-periods: awake, early sleep, mid-sleep, and mid-to-late sleep. Thirteen of 20 targeted Trp metabolites were identified. RESULTS: Ten of 13 Trp metabolites decreased across the night, while nicotinamide increased in both groups. A MANOVA omnibus test performed after principal component analysis showed a significant difference in these 13 principal component (P = 0.014) between groups. Compared to HCs, nicotinamide levels were higher and indole-3-lactic acid levels lower in the IBS group. Melatonin and indole-3-acetic acid levels were associated with several subjective/objective sleep measures; decreased stool consistency/frequency and abdominal pain were positively associated with melatonin and serotonin in the IBS group. The kynurenine and kynurenic acid were associated with ACTH (positively) and cortisol/ACTH (negatively). CONCLUSIONS: Nighttime Trp metabolites may provide clues to poor sleep and stress with IBS. Further study of the mechanism of metabolite action is warranted.
Abdominal Pain ; Adrenocorticotropic Hormone ; Chromatography, Liquid ; Female ; Humans ; Hydrocortisone ; Irritable Bowel Syndrome ; Kynurenic Acid ; Kynurenine ; Mass Spectrometry ; Melatonin ; Niacinamide ; Plasma ; Principal Component Analysis ; Serotonin ; Tryptophan

BACKGROUND/AIMS: Irritable bowel syndrome (IBS) is a multifaceted disorder that afflicts millions of individuals worldwide. IBS is currently diagnosed based on the presence/duration of symptoms and systematic exclusion of other conditions. A more direct manner to identify IBS is needed to reduce healthcare costs and the time required for accurate diagnosis. The overarching objective of this work is to identify gene expression-based biological signatures and biomarkers of IBS. METHODS: Gene transcripts from 24 tissue biopsy samples were hybridized to microarrays for gene expression profiling. A combination of multiple statistical analyses was utilized to narrow the raw microarray data to the top 200 differentially expressed genes between IBS versus control subjects. In addition, quantitative polymerase chain reaction was employed for validation of the DNA microarray data. Gene ontology/pathway enrichment analysis was performed to investigate gene expression patterns in biochemical pathways. Finally, since vitamin D has been shown to modulate serotonin production in some models, the relationship between serum vitamin D and IBS was investigated via 25-hydroxyvitamin D (25[OH]D) chemiluminescence immunoassay. RESULTS: A total of 858 genetic features were identified with differential expression levels between IBS and asymptomatic populations. Gene ontology enrichment analysis revealed the serotonergic pathway as most prevalent among the differentially expressed genes. Further analysis via real-time polymerase chain reaction suggested that IBS patient-derived RNA exhibited lower levels of tryptophan hydroxylase-1 expression, the enzyme that catalyzes the rate-limiting step in serotonin biosynthesis. Finally, mean values for 25(OH)D were lower in IBS patients relative to non-IBS controls. CONCLUSIONS: Values for serum 25(OH)D concentrations exhibited a trend towards lower vitamin D levels within the IBS cohort. In addition, the expression of select IBS genetic biomarkers, including tryptophan hydroxylase 1, was modulated by vitamin D. Strikingly, the direction of gene regulation elicited by vitamin D in colonic cells is “opposite” to the gene expression profile observed in IBS patients, suggesting that vitamin D may help “reverse” the pathological direction of biomarker gene expression in IBS. Thus, our results intimate that IBS pathogenesis and pathophysiology may involve dysregulated serotonin production and/or vitamin D insufficiency.
Biomarkers ; Biopsy ; Cohort Studies ; Colon ; Diagnosis ; Gene Expression Profiling ; Gene Expression ; Gene Ontology ; Health Care Costs ; Humans ; Immunoassay ; Irritable Bowel Syndrome ; Luminescence ; Oligonucleotide Array Sequence Analysis ; Polymerase Chain Reaction ; Real-Time Polymerase Chain Reaction ; RNA ; Serotonin ; Transcriptome ; Tryptophan ; Tryptophan Hydroxylase ; Vitamin D ; Vitamins

BACKGROUND/AIMS: MicroRNAs (miRNAs) were reported to be responsible for intestinal permeability in diarrhea-predominant irritable bowel syndrome (IBS-D) rats in our previous study. However, whether and how miRNAs regulate visceral hypersensitivity in IBS-D remains largely unknown. METHODS: We established the IBS-D rat model and evaluated it using the nociceptive visceral hypersensitivity test, myeloperoxidase activity assay, restraint stress-induced defecation, and electromyographic (EMG) activity. The distal colon was subjected to miRNA microarray analysis followed by isolation and culture of colonic epithelial cells (CECs). Bioinformatic analysis and further experiments, including dual luciferase assays, quantitative real-time polymerase chain reaction, western blot, and enzyme-linked immunosorbent assay, were used to detect the expression of miRNAs and how it regulates visceral hypersensitivity in IBS-D rats. RESULTS: The IBS-D rat model was successfully established. A total of 24 miRNAs were differentially expressed in the distal colon of IBS-D rats; 9 were upregulated and 15 were downregulated. Among them, the most significant upregulation was miR-200a, accompanied by downregulation of cannabinoid receptor 1 (CNR1) and serotonin transporter (SERT). MiR-200a mimic markedly inhibited the expression of CNR1/SERT. Bioinformatic analysis and luciferase assay confirmed that CNR1/SERT are direct targets of miR-200a. Rescue experiments that overexpressed CNR1/SERT significantly abolished the inhibitory effect of miR-200a on the IBS-D rats CECs. CONCLUSIONS: This study suggests that miR-200a could induce visceral hyperalgesia by targeting the downregulation of CNR1 and SERT, aggravating or leading to the development and progression of IBS-D. MiR-200a may be a regulator of visceral hypersensitivity, which provides potential targets for the treatment of IBS-D.
Animals ; Blotting, Western ; Colon ; Computational Biology ; Defecation ; Diarrhea ; Down-Regulation ; Enzyme-Linked Immunosorbent Assay ; Epithelial Cells ; Hyperalgesia ; Hypersensitivity ; Irritable Bowel Syndrome ; Luciferases ; Microarray Analysis ; MicroRNAs ; Models, Animal ; Permeability ; Peroxidase ; Rats ; Real-Time Polymerase Chain Reaction ; Receptors, Cannabinoid ; Serotonin Plasma Membrane Transport Proteins ; Serotonin ; Up-Regulation

STUDY DESIGN: Retrospective case-control study. PURPOSE: The purpose of this study was to examine the effect of antidepressants on blood loss and transfusion requirements in spinal surgery patients. OVERVIEW OF LITERATURE: Several studies have shown an increase in perioperative bleeding in orthopedic surgery patients on antidepressant drug therapy, yet no study has examined the impact of these agents on spinal surgery patients. METHODS: Charts of patients who underwent single-level spinal fusion (posterior lumbar interbody fusion with posterior instrumentation) performed by five fellowship-trained surgeons at a tertiary spine center between 2008 and 2013, were retrospectively reviewed. Exclusion criteria included select medical comorbidities, select drug therapy, and Amercian Society of Anesthesiologists Physical Status Classification score of greater than 2. Serotonergic antidepressants were examined in multivariate analysis to assess their predictive value on estimated blood loss and risk of transfusion. RESULTS: A total of 235 patients, of which 52% were female, were included. Allogeneic blood was transfused in 7% of patients. The average estimated blood loss was 682±463 mL. Selective serotonin reuptake inhibitors were taken by 10% of all patients. Multivariable regression analysis showed that intake of selective serotonin reuptake inhibitors was a significant predictor for blood loss (average increase of 34%, p=0.015) and for the need of allogeneic blood transfusion (odds ratio, 4.550; p=0.029). CONCLUSIONS: There was a statistically significant association between selective serotonin reuptake inhibitors and both increased blood loss and risk of allogeneic red blood cell transfusion. Surgeons and perioperative providers should take these findings into account when assessing patients' preoperative risk for blood loss and transfusion.
Antidepressive Agents* ; Blood Transfusion ; Case-Control Studies ; Classification ; Comorbidity ; Drug Therapy ; Erythrocyte Transfusion ; Female ; Hemorrhage ; Humans ; Multivariate Analysis ; Orthopedics ; Retrospective Studies ; Serotonin Uptake Inhibitors ; Spinal Fusion ; Spine ; Spondylosis ; Surgeons

PURPOSE: The purpose of this study was to assess the potential benefit of a 5-hydroxytryptamine receptor antagonist, sarpogrelate-based triple antiplatelet therapy (TAPT) in comparison with dual antiplatelet therapy (DAPT) in patients undergoing primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI). MATERIALS AND METHODS: 119 patients of STEMI were retrospectively assessed. All patients received aspirin and clopidogrel per standard of care. Among them, 53 patients received an additional loading dose of sarpogrelate and a maintenance dose for 6 months post-PCI (TAPT group), while others did not (DAPT group). RESULTS: The rates of complete ST-segment resolution at 30 minutes post-PCI and post-procedural thrombolysis in myocardial infarction flow were not significantly different between the two groups (52.8% vs. 48.5%, p=0.200; 92.5% vs. 89.4%, p=0.080). In addition, no significant differences were observed between the two groups with regard to 30-day and 12-month clinical outcomes (cardiac death, myocardial infarction, stent thrombosis, target vessel revascularization, and severe bleeding). Meanwhile, improvement in left ventricular (LV) systolic function was observed in the TAPT group [ΔLV ejection fraction (LVEF)=17.1±9.4%, p<0.001; Δglobal longitudinal strain (GLS)=−9.4±4.2% , p<0.001] at 6 months, whereas it was not in the DAPT group (ΔLVEF= 8.8±6.5%, p=0.090; ΔGLS=−4.6±3.4%, p=0.106). In multivariate analyses, TAPT was an independent predictor for LV functional recovery (odds ratio, 2.61; 95% confidence interval, 1.16–5.87; p=0.003). CONCLUSION: Sarpogrelate-based TAPT improved LV systolic function at 6 months in STEMI patients undergoing primary PCI.
Aspirin ; Humans ; Multivariate Analysis ; Myocardial Infarction* ; Percutaneous Coronary Intervention ; Retrospective Studies* ; Serotonin ; Standard of Care ; Stents ; Thrombosis ; Ventricular Function, Left

OBJECTIVES: To identify recent prescription patterns, as well as the demographic and clinical correlates of antidepressants (ADs) usage in schizophrenic patients. METHODS: A total of 297 patients diagnosed with schizophrenia enrolled at Seoul National Hospital in 2013. Brief Psychiatric Rating Scale (BPRS) was used to evaluate current psychiatric symptoms. Bivariate comparisons were used to assess the usage of concomitant psychotropics, demographic and clinical characteristics of ADs users compared with non-users. Multivariate analysis of covariance was performed consecutively. RESULTS: The rate of ADs usage was 26.3% and the most commonly used ADs were selective serotonin reuptake inhibitors. ADs users more often took benzodiazepine than ADs non-users (p=0.005), whereas there were no significant demographic and other clinical difference between the two groups. Regarding BPRS, somatic concern (p=0.022), anxiety (p=0.001) and depressive mood (p=0.009) scores were higher, and excitement (p=0.006) and hostility (p=0.04) scores were lower among ADs users compared to non-users, although there was no significant difference in the other scores of BPRS between the two groups. Moreover, among 5 components of BPRS, scores of affective symptoms (p < 0.001) were significantly higher, and scores of activation symptoms (p=0.014) were significantly lower in ADs users compared to non-users. CONCLUSION: This study suggests that the usage of ADs could be related to affective symptoms regardless of positive and negative symptoms of schizophrenia. Further studies are required in order to confirm the clinical correlates of ADs usage and the interactions between affective symptoms and psychotic symptoms.
Affective Symptoms ; Antidepressive Agents* ; Anxiety ; Benzodiazepines ; Brief Psychiatric Rating Scale ; Hostility ; Humans ; Multivariate Analysis ; Prescriptions* ; Schizophrenia* ; Seoul ; Serotonin Uptake Inhibitors

There is growing evidence of poor health-related quality of life (HRQOL) in patients with panic disorder (PD). However, little is known about the factors affecting HRQOL in patients with PD. The authors examined whether 5-HTTLPR tri-allelic approach and Cathechol-O-methyltransferase (COMT) Val(158)Met polymorphism can predict HRQOL in patients with PD controlling for sociodemographic factors and disorder-related symptom levels. The sample consisted of 179 patients with PD consecutively recruited from an outpatient clinic and age- and gender ratio-matched 110 healthy controls. The SF-36 was used to assess multiple domains of HRQOL. Hierarchical multiple regression analysis was performed to determine the independent effect of the 5-HTTLPR and COMT Val(158)Met on the SF-36 in panic patients. Patients with PD showed lowered HRQOL in all sub-domains of the SF-36 compared to healthy controls. The 5-HTTLPR independently and additively accounted for 2.2% of variation (6.7% of inherited variance) of perceived general health and the COMT Val(158)Met independently and additively accounted for 1.5% of variation (5.0% of inherited variance) of role limitation due to emotional problems in patient group. The present study suggests that specific genetic polymorphisms are associated with certain domains of HRQOL and provides a new insight on exploring the factors that predict HRQOL in patients with PD.
Adult ; Age Factors ; Alleles ; Case-Control Studies ; Catechol O-Methyltransferase/*genetics ; Female ; Genotype ; Humans ; Male ; Middle Aged ; Panic Disorder/genetics/*pathology ; Polymorphism, Single Nucleotide ; *Quality of Life ; Regression Analysis ; Serotonin Plasma Membrane Transport Proteins/*genetics ; Sex Factors

OBJECTIVETo compare the effects of electroacupuncture (EA) and moxibustion therapies on patients with diarrhea-predominant irritable bowel syndrome (D-IBS).

METHODSA total of 60 D-IBS patients were randomly allocated to the EA group (30 cases) and moxibustion group (30 cases). Before and after treatment, the gastrointestinal symptoms and psychological symptoms were scored by Visual Analogue Scale, Bristol Stool Form Scale, Hamilton Anxiety Rating Scale (HAMA), and Hamilton Depression Rating Scale (HAMD); the expressions of 5-hydroxytryptamine (5-HT), 5-HT3 receptor (5-HT3R), and 5-HT4 receptor (5-HT4R) in the sigmoid mucosal tissue were measured by immunohistochemical staining. Additionally, the effects on the functional brain areas of the anterior cingulate cortex (ACC), insular cortex (IC) and prefrontal cortex (PFC) were observed by functional magnetic resonance imaging.

RESULTSCompared with before treatment, both EA and moxibustion groups reported significant improvements in abdominal pain and abdominal bloating after treatment (P<0.01 or P<0.05). The moxibustion group reported greater improvements in defecation emergency, defecation frequency, and stool feature than the EA group (P<0.01). Both HAMA and HAMD scores were significantly decreased in the moxibustion group than in the EA group (P<0.01). Both groups demonstrated significantly reduced expressions of 5-HT, 5-HT3R and 5-HT4R in the colonic mucosa after treatment (P<0.01), with a greater reduction of 5-HT in the moxibustion group (P<0.05). Finally, decreased activated voxel values were observed in the left IC, right IC and PFC brain regions of patients in the moxibustion group under stimulation with 150 mL colorectal distension after treatment (P<0.05 or P<0.01), while in the EA group only PFC area demonstrated a reduction (P<0.05).

CONCLUSIONMoxibustion can significantly improve the symptoms of D-IBS, suggesting that moxibustion may be a more effective therapy than EA for D-IBS patients.

Adult ; Anxiety ; Brain ; physiology ; Cerebral Cortex ; physiopathology ; Colon, Sigmoid ; chemistry ; Depression ; Diarrhea ; physiopathology ; Electroacupuncture ; Gastrointestinal Tract ; physiology ; Gyrus Cinguli ; physiopathology ; Humans ; Immunohistochemistry ; Intestinal Mucosa ; chemistry ; Irritable Bowel Syndrome ; physiopathology ; psychology ; therapy ; Magnetic Resonance Imaging ; Moxibustion ; Pain Measurement ; Prefrontal Cortex ; physiopathology ; Receptors, Serotonin, 5-HT3 ; analysis ; Serotonin ; analysis

Migraine is one of the common and frequently encountered diseases. The study proves that 5-hydroxytryptamine (5-HT) receptor, plays an important role in the occurrence of migraine. Rat striatum was used for preparation of the cell membrane stationary phase (CMSP) in our experiments. The cell membrane chromatography (CMC)-offline-HPLC system was applied to specifically recognize the components from the drug pair of Chuanxiong Rhizoma and Angelicae Dahuricae Radix, which interact with the receptors on CMSP. The dissociation equilibrium constant (KD) was measured in a rat striatum/CMC system, performed by continuously pumping sumatriptan, a 5-HT1D agonist, ranging from 2.42 x 10(-8) to 4.84 x 10(-7) mol · L(-1) through a CMC column, and the capacity factors (k') were recorded. The KD value obtained from the model was (4.59 ± 0.33) x 10(-6) mol · L(-1) for imperatorin, and the rat model of migraine induced by nitroglycerin was applied to validate the pharmacological effects of the drug pair. The results indicated that the CMC method could be a quick and efficient way for characterizing the drug-receptor interactions in vitro.
Angelica ; chemistry ; Animals ; Cell Membrane ; chemistry ; Chromatography, High Pressure Liquid ; methods ; Drug Evaluation, Preclinical ; methods ; Drugs, Chinese Herbal ; chemistry ; Male ; Migraine Disorders ; drug therapy ; Rats ; Rats, Sprague-Dawley ; Receptor, Serotonin, 5-HT1D ; chemistry ; Serotonin Receptor Agonists ; analysis

The efficacy of Chinese herbal formula in treating depression has been proved in many studies. In this study, six different Kaixin San formulas were compared to investigate their effects on central monoamine neurotransmitters of chronic stress rats and against depression based on their different components in plasma, in order to discuss the efficacy-comparability relationship and the possible efficacy mechanism. The classic isolation method and the chronic unpredictable mild stress (CUMS) depression model were combined to investigate the changes in contents in hippocampus and monoamine neurotransmitters (NE, DA, 5-HT) and the components of some formulas in plasma with HPLC and UPLC-Q-TOF-MSE methods. As a result, Dingzhi Xiaowan recorded in Essential Recipes for Emergent Use Worth A Thousand significantly increased the behavioral scores, NE and 5-HT contents in hippocampus and NE, DA and 5-HT contents in cortex, with the best anti-depressant effect. Dingzhi Xiaowan recorded in Complete Records of Ancient and Modern Medical Works showed a notable increase in sucrose preference and open field score in model rats, NE content in hippocampus and NE, DA and 5-HT contents in cortex, with a certain anti anti-depressant effect. Kaixin San recorded in Ishinpo showed remarkable rise in weight of model rats. NE content in hippocampus and DA content in cortex. Puxin Decoction recorded in A Supplement to Recipes Worth A Thousand Gold showed 5-HT content in hippocampus and DA content in cortex. Kaixin San recorded in Yimenfang only showed DA content in cortex. Kaixin Wan recorded in Essential Recipes for Emergent Use Worth A Thousand did not mention the antidepressant effect. According to the results, the formulas' different anti-depressant effects may be related to the different plasma components.
Animals ; Behavior, Animal ; drug effects ; Biogenic Monoamines ; analysis ; Brain Chemistry ; drug effects ; Chronic Disease ; Drugs, Chinese Herbal ; pharmacology ; Male ; Medicine, Chinese Traditional ; Neurotransmitter Agents ; analysis ; Norepinephrine ; analysis ; Rats ; Rats, Sprague-Dawley ; Serotonin ; analysis ; Stress, Psychological ; metabolism