[Analysis of clinical features and prognosis in patients with primary Sjögren's syndrome and autoimmune liver disease].

OBJECTIVE: To analyze the clinical features and prognosis in patients with primary Sjögren's syndrome (pSS) and autoimmune liver diseases (ALD). METHODS: A retrospective analysis of clinical manifestation and prognosis was performed in patients with ALD or without ALD during the three years (February 2014 to December 2017). RESULTS: Totally, 203 patients with pSS were included in this study, 68 patients had ALD (31 patients with autoimmune hepatitis, 37 patients with primary biliary cholangitis), while 135 patients did not have ALD. There were no differences between the two groups regarding age, gender, clinical manifestations, such as dry mouth, dry eyes, pain, fatigue, lymphadenopathy, glandular swelling, cutaneous involvement, lung involvement, and renal involvement, and the incidence rate of other autoimmune diseases, such as autoimmune thyroid disease, rheumatoid arthritis, and vasculitis. There were also no differences in the titer of antinuclear antibody (ANA), the positive rates of anti-Sjögren's syndrome A antibody (SSA), SSA52, and anti-Sjögren's syndrome B antibody (SSB), and at the levels of erythrocyte sedimentation rate and C-reactive protein between the two groups. Most importantly, the pSS patients with ALD had a shorter disease course, a higher positive rate of anti-mitochondrial M2 antibody (AMA-M2) and anti-centromere antibody, a higher level of IgG and IgM, a lower level of complement 3, and a decreased number of blood cells. They also had a higher level of liver related serum index, such as alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase and total bilirubin, direct bilirubin, indirect bilirubin, a higher incidence rate of liver cirrhosis, an increased death incident (the mortality was 13.24% in the pSS patients with ALD, while 2.96% in the controls, P=0.013), and a worse prognosis. Binary Logistic regression analysis revealed that liver cirrhosis, the EULAR Sjögren's syndrome disease activity index (ESSDAI) scores and the level of total bilirubin were the prognostic factors of mortality in the pSS patients with ALD. The survival curve was estimated by the Kaplan-Meier method. It demonstrated that the pSS patients with ALD had a lower survival rate when compared with the controls. CONCLUSION: The patients with both pSS and ALD will suffer from a more severe disease and a higher death incident. We should pay more attention to these patients and provide a better symptomatic treatment for them during clinical practice.

Altered oesophageal mechanosensitivity of secondary peristalsis as a pathophysiological marker in patients with globus sensation.

OBJECTIVE: Secondary peristalsis is important for clearance of retained food bolus and refluxate from the oesophagus. We aimed to investigate whether patients with globus sensation have altered physiological characteristics of secondary peristalsis. DESIGN: Prospective case-controlled study SETTING: Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan. PARTICIPANTS: Seventeen globus patients and 18 healthy controls. MAIN OUTCOME MEASURES: After a baseline recording of primary peristalsis, secondary peristalsis was stimulated with slow and rapid mid-oesophageal injections of air. Distension thresholds and peristaltic activities of secondary peristalsis were analysed and compared between the patients and healthy controls. RESULTS: The threshold volume for generating secondary peristalsis during slow air distension did not differ between the patient and control groups (P = .55). The threshold volume for generating secondary peristalsis during rapid air distension was significantly greater in patients with globus than healthy controls (7.0 ± 0.9 vs 5.0 ± 0.3 mL, P = .04). Secondary peristalsis was triggered less frequently in globus patients as compared with healthy control after rapid air distension (40% [30%-65%] vs 60% [60%-83%], P = .001). There was no difference in any of peristaltic parameters for primary and secondary peristalsis between the groups. CONCLUSIONS: Our work identifies functional defects of oesophageal secondary peristalsis in patients with globus sensation and such defects are characterised with defective triggering of secondary peristalsis during rapid air distension. Whether current findings have therapeutic implication in the management of patients with globus sensation warrants further investigation.

Esophageal solid bolus transit: studies using combined multichannel intraluminal impedance and manometry in healthy volunteers.

The purpose of this study is to apply combined multichannel intraluminal impedance and esophageal manometry (MII-EM) to test esophageal function during solid swallowing in a normal healthy population. We determined whether combined MII-EM with solid bolus is more sensitive than that with viscous bolus in the detection of motility abnormality. Eighteen healthy volunteers (11 men and 7 women; mean age 22 years, range 20-26 years) underwent combined MII-EM with a catheter containing four impedance-measuring segments and five solid-state pressure transducers. Each subject received 10 viscous and 10 solid materials. Tracings were analyzed manually for bolus presence time, total bolus transit time, contraction amplitude, duration, and onset velocity. Three hundred and sixty swallows including viscous and solid materials were analyzed. Contraction amplitude for the viscous swallows was higher at 20 cm above the lower esophageal sphincter (LES) (P= 0.049) but lower at 15 cm above the LES (P < 0.001). Duration of contractions for the solid swallows was longer at 15 cm (P= 0.002) and 10 cm above the LES (P= 0.011) compared with viscous swallows. The total bolus transit time for solid was significantly shorter than that for viscous boluses (6.8 vs. 7.7 seconds, P < 0.001). Bolus presence time appeared to be similar between viscous and solid boluses (except in the proximal esophagus). The percentage of swallows with ineffective peristalsis by manometry, as well as those with incomplete bolus transit by impedance, did not differ between viscous and solid swallows. The proportion of manometrically ineffective solid swallows with incomplete bolus transit was greater than that of viscous swallows (62.1% vs. 34.8%, P= 0.05). Application of solid boluses may potentially enhance diagnostic capability of esophageal function testing. Solid boluses can be regarded as a valuable complement to viscous boluses in the detection of esophageal motility abnormalities when applied with combined MII-EM.

Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family.

Holt-Oram syndrome is a developmental disorder affecting the heart and upper limb, the gene for which was mapped to chromosome 12 two years ago. We have now identified a gene for this disorder (HOS1). The gene (TBX5) is a member of the Brachyury (T) family corresponding to the mouse Tbx5 gene. We have identified six mutations, three in HOS families and three in sporadic HOS cases. Each of the mutations introduces a premature stop codon in the TBX5 gene product. Tissue in situ hybridization studies on human embryos from days 26 to 52 of gestation reveal expression of TBX5 in heart and limb, consistent with a role in human embryonic development.

Effects of hip muscle activation on the stiffness and energy absorption of the trochanteric soft tissue during impact in sideways falls.

The trochanteric soft tissue attenuates impact force or absorbs impact energy during a fall on the hip (thereby helps to reduce a risk of hip fracture). While the benefits should be affected by contractions of muscles spanning the hip joint, no information is available to date. We examined how the stiffness (force attenuation capacity) and energy absorption of the trochanteric soft tissue were affected by hip muscle activation during a fall. Thirteen healthy young individuals (5 males, 8 females) participated in the pelvis release experiment. Falling trials were acquired with three muscle contraction conditions: 0-20% ("relaxed"), 20-50% ("moderate"), and 60-100% ("maximal") of the maximal voluntary isometric contraction of the gluteus medius muscle. During trials, we measured real-time force and deformation behaviour of the trochanteric soft tissue. Outcome variables included the stiffness and energy absorption of the soft tissue. The stiffness and energy absorption ranged from 56.1 to 446.9 kN/m, and from 0.15 to 2.26 J, respectively. The stiffness value increased with muscle contraction, and 59% greater in "maximal" than "relaxed" condition (232.2 (SD = 121.4) versus 146.1 (SD = 49.9)). However, energy absorption decreased with muscle contraction, and 58.9% greater in "relaxed" than "maximal" condition (0.89 (SD = 0.63) versus 0.56 (SD = 0.41)). Our results provide insights on biomechanics of the trochanteric soft tissue ("natural" padding device) during impact stage of a fall, suggesting that soft tissues' protective benefits are largely affected by the level of muscle contraction.

Disease progression in non-erosive reflux disease (NERD): impact of initial esophageal acid exposure.

We investigated the 5-year clinical course in a cohort of patients with typical reflux symptoms and negative endoscopy. Prospective follow-up was conducted in patients with non-erosive reflux disease (NERD) for at least 5 years after initial evaluation with esophageal pH monitoring and upper gastrointestinal endoscopy. Within the last year of follow-up, reflux symptoms occurred in 27 of the 30 patients (90%). Twenty-five of twenty-seven symptomatic patients (93%) were on acid suppression therapy. The majority of our patients (70%) remained unchanged regarding their endoscopic status over 5 years. Progression to erosive esophagitis occurred in four patients with Los Angeles (LA) A (13%), three patients with LA B (10%), and two patients with LA C (7%). The presence of pathological acid exposure did not alter the presence of reflux symptoms over 5 years. Disease progression to erosive esophagitis occurred more frequently in patients with pathological acid exposure than those without pathological acid exposure (P= 0.025). Most NERD patients have symptoms and require acid suppression therapy 5 years after their initial diagnosis. Initial pathological acid exposure does not influence the use of acid suppression; however, it does influence the progression of NERD within 5 years of follow-up.

Genetic association between functional haplotype of collagen type III alpha 1 and chronic hepatitis B and cirrhosis in Koreans.

Collagen type III alpha 1 (COL3A1) is one of the extracelluar matrix (ECM) proteins. The expression of COL3A1 is closely related to chronic liver diseases. In this study, we investigated whether single nucleotide polymorphisms (SNPs) of COL3A1 confer genetic susceptibility to patients with hepatitis B virus-infected liver diseases including chronic hepatitis B (CH), liver cirrhosis (CIR), and hepatocellular carcinoma (HCC). A total of 399 Korean (KOR) people, 111 patients with CH, 95 patients with CIR, 86 patients with HCC, and 107 spontaneously recovery, were genotyped for 16 SNPs of the COL3A1 gene. The 'A' allele of rs3106796 was highly associated with the CH [odds ratio (OR) = 1.62, P = 0.01], CIR (OR = 1.67, P = 0.01), and HCC (OR = 1.59, P = 0.03). There were six polymorphic SNPs that could be divided into two linkage disequilibrium (LD) blocks. The haplotype pattern of the KOR control seems to be similar to the patterns displayed in the Japanese, Chinese, and Caucasian populations sampled in the International HapMap project. Haplotype 3 (A-G-A) of the LD block 2 was significantly associated with CH (OR = 2.23, P = 0.02), CIR (OR = 2.24, P = 0.03), and HCC (OR = 2.27, P = 0.03). Moreover, diplotype analysis showed that they had increased relative risk for CH and CIR in the two diplotypes, dt3 (A-G-A/G-G-A; OR = 4.05, P = 0.01) and dt6 (A-A-A/A-G-A; OR = 7.42, P = 0.01 and OR = 5.84, P = 0.05) against dt1 (G-G-A/G-G-A), the most common diplotype in both KOR groups. In vitro reporter gene assays showed that the constructs containing the 'G' allele of rs3106796 appear to exert lower transcriptional activity of COL3A1 than the 'A' allele, depending on the promoter types.

Utility of esophageal impedance in identifying dysmotility in patients with erosive esophagitis.

SUMMARY: This study was intended to assess the utility of combined multiple intraluminal impedance and esophageal manometry (MII-EM) in evaluating reflux patients and in identifying those with esophageal dysmotility. Thirteen controls and 20 patients with gastroesophageal reflux disease (GERD) underwent combined MII-EM with a catheter containing four impedance-measuring segments and four solid-state pressure transducers. Each subject received 10 liquid and 10 viscous boluses to be swallowed. Distal esophageal contraction amplitude was significantly lower in GERD patients than in controls for viscous swallows (58.3 +/- 7.3 mmHg versus 82.4 +/- 4.1 mmHg, P = 0.005). Total bolus transit time was significantly slower in GERD patients than in controls for liquid swallows (P = 0.035). The percentages of complete bolus transit were significantly lower in GERD patients compared with controls (all P = 0.005). Half of GERD patients with normal EM still had abnormal bolus transit while three-quarters of those with abnormal EM had abnormal bolus transit. MII helps identify bolus transit abnormalities not detected by conventional manometry. Combined MII-EM is clinically useful for detecting esophageal dysmotility in patients with erosive esophagitis.

Physiological augmentation of esophageal distension pressure and peristalsis during conditions of increased esophageal emptying resistance.

BACKGROUND: Abdominal compression has been implemented as a provocative maneuver in high-resolution impedance manometry (HRIM) to "challenge" normal esophageal physiology with the aim of revealing abnormal motor patterns which may explain symptoms. In this study, we measured the effects of abdominal compression on esophageal functioning utilizing novel pressure-impedance parameters and attempted to identify differences between healthy controls and globus patients. METHODS: Twenty-two healthy volunteers (aged 23-32 years, 41% female) and 22 globus patients (aged 23-72 years, 68% female) were evaluated with HRIM using a 3.2-mm water perfused manometric and impedance catheter. All participants received 10 × 5 mL liquid swallows; healthy controls also received 10 × 5 mL liquid swallows with abdominal compression created using an inflatable cuff. All swallows were analyzed to assess esophageal pressure topography (EPT) and pressure-flow metrics, indicative of distension pressure, flow timing and bolus clearance were derived. KEY RESULTS: The effect of abdominal compression was shown as a greater contractile vigor of the distal esophagus by EPT and higher distension pressure based on pressure-flow metrics. Age and body mass index also increased contractile vigor and distension pressure. Globus patients were similar to controls. CONCLUSIONS AND INTERFERENCES: Intrabolus pressure and contractile vigor are indicative of the physiological modulation of bolus transport mechanisms. Provocative testing by abdominal compression induces changes in these esophageal bolus dynamics.

Effect of complex decongestive therapy on edema and the quality of life in breast cancer patients with unilateral leymphedema.

There is increasing interest in the health-related quality of life (QOL) of patients with chronic lymphedema. The aim of this study was to ascertain whether complex decongestive therapy (CDT) for upper limb lymphedema results in long-term changes in lymphedema and QOL, and to determine whether the treatment-induced change in the percentage excess volume (PCEV) is correlated with any changes in QOL. Fifty-three patients who had lymphedema were treated with CDT. PCEV and QOL were recorded before and 1 month after CDT, and at a 6-month follow-up visit. PCEV was significantly (p<0.05) decreased at 1 month, but significantly (p<0.05) increased at 6 months compared to 1 month [but still significantly reduced (p<0.05) from baseline]. The QOL scores at 1 and 6 months were significantly higher than the score at baseline, indicating an improvement in the QOL. Significant changes were evident in the single domains of physical functioning, role-physical, mental health, and general health. The change in PCEV was associated with a change in physical functioning, vitality, bodily pain, and general health at 1 and 6 months (p<0.05). This study suggests that QOL significantly improved with upper limb lymphedema during the maintenance phase, which was necessarily correlated with the reduction in limb volume.

Evidence for up-regulation of purinergic receptor genes associating with TRPV1 receptors and neurotrophic factors in the inflamed human esophagus.

Purinergic receptors are implicated in nociceptive signaling in small primary afferents via activation of adenosine triphosphate (ATP). ATP appears to mediate HCl-induced transient receptor potential vanilloid receptor 1 (TRPV1) activation in esophageal mucosa. Up-regulation of TRPV1 expression in gastroesophageal reflux disease (GERD) is associated with increased nerve growth factor (NGF) and glial derived neurotrophic factor (GDNF). This study aims to genetically determine the expression of purinergic receptors in severe inflamed human esophagus. Distal esophageal biopsies from the subjects with erosive GERD, asymptomatic patients (AP) and healthy ones were examined. Using real-time qPCR for detecting purinergic receptors (P2X2, P2X3, P2X7, P2Y1, P2Y2, P2Y4, P2Y6 and P2Y12), TRPV1, TRPV4, NGF, and GDNF was done in this study. Both P2X3 and P2X7 mRNA expressions in GERD patients significantly increased than those in healthy controls (P < 0.001) and AP (P < 0.001), but P2X2, P2Y1, P2Y2, P2Y4, P2Y6, P2Y12 or P2Y12 had no difference within the control, AP or GERD subjects. The well correlated expression in P2X3 gene with TRPV1 (r = 0.46, P = 0.002), NGF (r = 0.54, P = 0.0002), and GDNF (r = 0.64, P = 0.0001) was found. The P2X7 gene expressions also well correlated with TRPV1 (r = 0.47, P = 0.002), NGF (r = 0.32, P = 0.037), and GDNF (r = 0.42, P = 0.005). These results suggest that chronic esophagitis increases mRNA expressions of P2X3 and P2X7 receptors accompanied by up-regulation of TRPV1 and neurotrophic factors (NGF and GDNF). These genetical alterations in esophageal mucosa might mediate sensitization of inflamed human esophagus.

Influence of repeated infusion of capsaicin-contained red pepper sauce on esophageal secondary peristalsis in humans.

BACKGROUND: The transient receptor potential vanilloid 1 has been implicated as a target mediator for heartburn perception and modulation of esophageal secondary peristalsis. Our aim was to determine the effect of repeated esophageal infusion of capsaicin-contained red pepper sauce on heartburn perception and secondary peristalsis in healthy adults. METHODS: Secondary peristalsis was performed with mid-esophageal injections of air in 15 healthy adults. Two separate protocols including esophageal infusion with saline and capsaicin-contained red pepper sauce and 2 consecutive sessions of capsaicin-contained red pepper sauce were randomly performed. KEY RESULTS: After repeated infusion of capsaicin-contained red pepper sauce, the threshold volume to activate secondary peristalsis was significantly increased during slow (p < 0.001) and rapid air injections (p = 0.004). Acute infusion of capsaicin-contained red pepper sauce enhanced heartburn perception (p < 0.001), but the intensity of heartburn perception was significantly reduced after repeated capsaicin-contained red pepper sauce infusion (p = 0.007). Acute infusion of capsaicin-contained red pepper sauce significantly increased pressure wave amplitudes of distal esophagus during slow (p = 0.003) and rapid air injections (p = 0.01), but repeated infusion of capsaicin-contained red pepper sauce significantly decreased pressure wave amplitude of distal esophagus during slow (p = 0.0005) and rapid air injections (p = 0.003). CONCLUSIONS & INFERENCES: Repeated esophageal infusion of capsaicin appears to attenuate heartburn perception and inhibit distension-induced secondary peristalsis in healthy adults. These results suggest capsaicin-sensitive afferents in modulating sensorimotor function of secondary peristalsis in human esophagus.

Control of esophageal distension-induced secondary peristalsis by the GABA(B) agonist baclofen in humans.

BACKGROUND: Secondary peristalsis is important for the clearance of retained food bolus or refluxate from the esophagus. The effects of the gamma aminobutyric acid receptor type B (GABA(B) ) agonist on secondary peristalsis remain unclear in humans. We aimed to investigate the effect of a GABA(B) agonist baclofen on esophageal secondary peristalsis. METHODS: After a baseline recording of esophageal motility, secondary peristalsis was generated by slow and rapid mid-esophageal injections of air in 15 healthy subjects. Two separate sessions with 40mg oral baclofen or placebo were randomly performed to test their effects on secondary peristalsis. KEY RESULTS: Baclofen increased the threshold volume for triggering secondary peristalsis during slow air distension (P=0.003) and rapid air distension (P=0.002). Baclofen reduced the rate of secondary peristalsis by rapid air distension from 90% to 30% (P=0.0002). Baclofen increased basal lower esophageal sphincter pressure (P=0.03). Baclofen did not affect any of peristaltic parameters during primary or secondary peristalsis. CONCLUSIONS & INFERENCES: This study provides an evidence for inhibitory modulation of esophageal secondary peristalsis by the GABA(B) agonist baclofen. Activation of secondary peristalsis is probably modulated by GABA(B) receptors; however, baclofen does not lead to any motility change in secondary peristalsis.

Integration of apoptosis and metabolism.

Apoptotic resistance is a hallmark of human cancers. Recent advances have contributed to our understanding of the molecular mechanisms that intimately integrate cell metabolism and apoptosis. Coordinated activation of the proapoptotic Bcl-2 family and the caspase family during apoptosis often leads to permeabilization of the mitochondrial outer membrane and release of multiple enzymes that normally function in regulating energy production and metabolism. The roles of these metabolic enzymes in promoting caspase activation demonstrate a primordial need to couple apoptotic cell death and metabolic catastrophe during cellular destruction. The Bcl-2 family also directly interacts with the multiple metabolic regulators to protect or promote mitochondrial damage during apoptosis. However, the integration of metabolism and apoptosis is not simply limited to the maintenance of mitochondrial integrity. A recent study demonstrates that the NatA complex, a protein N-α-acetyltransferase complex, is required for DNA damage-mediated apoptosis and suggests that regulation of protein acetylation might provide an important mechanism for regulating apoptotic sensitivity. Since acetyl-CoA (coenzyme A) is a key cofactor for the NatA complex, protein acetylation is subject to the availability of acetyl-CoA and, thus, under metabolic regulation. The revelation that protein N-α-acetylation is regulated by Bcl-xL, a major antiapoptotic mitochondrial protein, demonstrates a mechanism by which metabolism can regulate the activation of multiple key apoptotic factors simultaneously.

Effects of mosapride on esophageal secondary peristalsis in humans.

BACKGROUND: Secondary peristalsis is important for the clearance of refluxate or retained food bolus from the esophagus. Mosapride is a prokinetic agent that enhances GI motility by stimulating 5-hydroxytrypatamine(4) (5-HT(4) ) receptors, but its effects on secondary peristalsis are yet unclear in humans. We aimed to investigate the effect of a 5-HT(4) agonist mosapride on esophageal distension-induced secondary peristalsis in normal subjects. METHODS: After a baseline recording esophageal motility, secondary peristalsis was generated by slow and rapid mid-esophageal injections of air in 15 healthy subjects. Two separate sessions with 40mg oral mosapride or placebo were randomly performed to test their effects on esophageal secondary peristalsis. KEY RESULTS: Mosapride decreased the threshold volume for triggering secondary peristalsis during rapid air distension (4.5±0.3 vs 5.3±0.4mL; P=0.04) but not slow air distension (14.3±1.2 vs 13.3±1.3mL; P=0.41). Secondary peristalsis was triggered more frequently in response to rapid air distension after application of mosapride [100% (90-100%) vs 90% (80-100%); P=0.02]. Mosapride significantly increased pressure wave amplitudes of secondary peristalsis during slow (135.4±13.8 vs 105.0±12.9mmHg; P=0.001) and rapid air distensions (124.0±11.6 vs 95.9±14.0mmHg; P=0.002). CONCLUSIONS & INFERENCES: Mosapride enhances sensitivity to distension-induced secondary peristalsis and facilitates secondary peristaltic contractility. These data provide an evidence for modulation of esophageal secondary peristalsis by the 5-HT(4) agonist mosapride, as well support for its clinical utility.

Effects of lidocaine on esophageal secondary peristalsis in humans.

BACKGROUND: Secondary peristalsis is important for the clearance of retained food bolus or refluxate from the esophagus. Lidocaine has been used to evaluate the role of mucosa-mediating pathways of esophageal reflexes in animal model, but its effects on esophageal secondary peristalsis are yet unclear in humans. We aimed to investigate whether esophageal secondary peristalsis can be affected by intraluminal infusion of lidocaine into the esophagus. METHODS: After a baseline recording esophageal motility, secondary peristalsis was generated by slow and rapid mid-esophageal injections of air in 13 healthy subjects. Two separate sessions with saline and lidocaine were randomly performed to test their effects on esophageal secondary peristalsis by mid-esophageal air distension. KEY RESULTS: Secondary peristalsis can be induced by slow or rapid air infusion. Secondary peristalsis was triggered less frequently in response to rapid air distension after lidocaine infusion (P = 0.001). After lidocaine infusion, the threshold volume to generate secondary peristalsis was significantly increased during rapid (P = 0.001), but not slow air infusions (P = NS). Infusion of lidocaine or saline did not affect pressure wave amplitude or duration during rapid and slow air infusions (P = NS). CONCLUSIONS & INFERENCES: We have demonstrated selectively inhibitory effect of lidocaine on the triggering of esophageal secondary peristalsis during acute gaseous esophageal distension. The data suggest that part of the activation of secondary peristalsis is probably mediated by lidocaine-sensitive mechanoreceptors; however, the infusion of lidocaine does not lead to any motility change in secondary peristalsis induced by either slow or rapid air infusions.

Effects of capsaicin-containing red pepper sauce suspension on esophageal secondary peristalsis in humans.

BACKGROUND: Capsaicin-sensitive afferents have been implicated in the modulation of gastrointestinal sensorimotor functions. Secondary peristalsis is important for the clearance of retained refluxate or material from the esophagus. The aim of this study was to evaluate the effects of capsaicin-containing red pepper sauce suspension on esophageal secondary peristalsis in healthy adults. METHODS: After a baseline recording of esophageal motility, secondary peristalsis was generated by slow and rapid mid-esophageal injections of air in 10 healthy subjects. Two separate sessions with saline and capsaicin-containing red pepper sauce were randomly performed to test their effects on esophageal secondary peristalsis. KEY RESULTS: Infusion of capsaicin significantly increased pressure wave amplitude during rapid (P = 0.002) and slow air infusions (P = 0.01). After capsaicin, the threshold volume to generate secondary peristalsis was significantly decreased during rapid (P < 0.05) and slow air infusions (P = 0.02). Infusion of saline did not affect any parameters of secondary peristalsis during rapid or slow air infusion. The administration of capsaicin was accompanied by the occurrence of heartburn in all subjects. CONCLUSIONS & INFERENCES: The acute administration of capsaicin-containing red pepper sauce suspension enhances sensitivity to distension-induced secondary peristalsis and facilitates secondary peristaltic contractility. These data suggest the involvement of capsaicin-sensitive afferents in the modulation of esophageal distension-induced secondary peristalsis in humans.

The reactive tumor microenvironment: MUC1 signaling directly reprograms transcription of CTGF.

The MUC1 cytoplasmic tail (MUC1.CT) conducts signals from spatial and extracellular cues (growth factor and cytokine stimulation) to evoke a reprogramming of the cellular transcriptional profile. Specific phosphorylated forms of the MUC1.CT achieve this function by differentially associating with transcription factors and redirecting their transcriptional regulatory capabilities at specific gene regulatory elements. The specificity of interaction between MUC1.CT and several transcription factors is dictated by the phosphorylation pattern of the 18 potential phosphorylation motifs within the MUC1.CT. To better appreciate the scope of differential gene expression triggered by MUC1.CT activation, we performed microarray gene expression analysis and chromatin immunoprecipitation (ChIP)-chip promoter analysis and identified the genome-wide transcriptional targets of MUC1.CT signaling in pancreatic cancer. On a global scale, MUC1.CT preferentially targets genes related to invasion, angiogenesis and metastasis, suggesting that MUC1.CT signaling contributes to establishing a reactive tumor microenvironment during tumor progression to metastatic disease. We examined in detail the molecular mechanisms of MUC1.CT signaling that induces the expression of connective tissue growth factor (CTGF/CCN2), a potent mediator of ECM remodeling and angiogenesis. We demonstrate a robust induction of CTGF synthesis and secretion in response to serum factors that is enabled only when MUC1 is highly expressed. We demonstrate the requirement of phosphorylation at distinct tyrosine motifs within the MUC1.CT for MUC1-induced CTGF expression and demonstrate a phosphorylation-specific localization of MUC1.CT to the CTGF promoter. We found that MUC1 reorganizes transcription factor occupancy of genomic regions upstream of the CTGF gene, directing ß-catenin and mutant p53 to CTGF gene regulatory elements to promote CTGF expression and destabilizing the interaction at these regions of the transcriptional repressor, c-Jun. With this example we illustrate the capacity of MUC1.CT to mediate transcription factor activity in a context-dependent manner to achieve wide spread and robust changes in gene expression and facilitate creation of the reactive tumor microenvironment.

Evidence for neurotrophic factors associating with TRPV1 gene expression in the inflamed human esophagus.

BACKGROUND: Transient receptor potential vanilloid-1 (TRPV1) receptor has been implicated in the mechanism of acid induced inflammation in gastro-esophageal reflux disease (GERD). It has been demonstrated that the increase in nerve growth factor (NGF) and glial derived neurotrophic factor (GDNF) was associated with the increased expression of TRPV1. We aimed to determine whether expression of TRPV1 was increased in severe inflamed human esophagus, and to test the hypothesis whether the expression of TRPV1 was mediated by neurotrophic factors such as NGF and GDNF. METHODS: We compared biopsies taken from the distal esophagus of 15 patients with erosive GERD, 16 asymptomatic patients (AP), and 10 healthy controls. We assessed the biopsies with reverse transcription polymerase chain reaction (RT-PCR) and real-time quantitative polymerase chain reaction (qPCR) for TRPV1, NGF, and GDNF. Immunohistochemical analysis of TRPV1 protein expression was also determined. KEY RESULTS: Transient receptor potential vanilloid-1 mRNA level and its protein expression were significantly greater in patients with erosive esophagitis than AP (P < 0.001) and healthy controls (P < 0.001). Nerve growth factor and GDNF gene levels in the esophageal mucosa were also significantly increased in patients with erosive esophagitis compared with AP and healthy controls (all P < 0.001). Transient receptor potential vanilloid-1 mRNA correlated well with NGF (r = 0.61, P < 0.001) and GDNF (r = 0.58, P < 0.001). CONCLUSIONS & INFERENCES: These results support the association of NGF and GDNF in the up-regulation of TRPV1 receptors in patients with erosive esophagitis.