Relationship between Helicobacter pylori Eradication and Barrett's Esophagus Elongation.

INTRODUCTION: Helicobacter pylori eradication therapy may worsen gastroesophageal reflux disease that is a significant risk factor for Barrett's esophagus. However, the relationship between eradication therapy and Barrett's esophagus remains controversial. This study evaluated the impact of Helicobacter pylori eradication on the lengthening of Barrett's esophagus. MATERIALS AND METHODS: We conducted a retrospective analysis of consecutive patients who successfully underwent Helicobacter pylori eradication between 2004 and 2017. Endoscopic images obtained before and after eradication therapy were compared for Barrett's esophagus length according to the Prague C&M criteria and the presence of reflux esophagitis based on the Los Angeles classification. RESULTS: A total of 340 patients were analyzed (mean age: 66.9 ± 12.9 years) for a median follow-up of 55 months (interquartile range: 29.8-89.3). At the initial endoscopic assessment, 187 patients (55%) had a hiatal hernia, and all patients had gastric atrophy (C-0 to I: 2%, C-II to III: 47%, O-I to III: 51%). Reflux esophagitis was detected in 7 patients (2%) before eradication and in 21 patients (6%) afterward, which was a significant increase (p = 0.007). Barrett's esophagus was identified in 69 patients (20%) before eradication, with a median length of C0M1. Elongation after treatment was observed in only 2 patients (0.6%). We observed no significant increase in either the prevalence (p = 0.85) or the median length (p = 0.5) of Barrett's esophagus. CONCLUSIONS: Only 0.6% of patients exhibited Barrett's esophagus lengthening after Helicobacter pylori eradication therapy, suggesting no significant impact of the treatment on the development or elongation of Barrett's esophagus.

Association between endoscopic evidence of bile reflux and Barrett's esophagus: A large-scale case-control study.

BACKGROUND: Although bile reflux plays an important role in the development of Barrett's esophagus, the relationship between endoscopic findings of bile reflux and Barrett's esophagus remains unclear. OBJECTIVE: This study evaluated whether endoscopic evidence of bile reflux was associated with the presence of Barrett's esophagus. METHODS: A retrospective analysis of a prospectively maintained database comprising consecutive patients who underwent screening esophagogastroduodenoscopy was conducted. Endoscopic evidence of bile reflux was defined as the presence of bile-stained fluid in the gastric fundus. We performed multivariate analysis to identify predictive factors that differed significantly between patients with and without Barrett's esophagus. RESULTS: Of 4021 patients, 922 (23%) had Barrett's esophagus, and 1000 (25%) showed endoscopic findings of bile reflux. Multivariate analysis revealed endoscopic evidence of bile reflux as the strongest independent factor associated with the presence of Barrett's esophagus (odds ratio [OR] 5.65, 95% confidence interval [CI] 4.71-6.76) in relation to the presence of hiatal hernia (OR 3.30, 95% CI 2.70-4.04) and male gender (OR 1.54, 95% CI 1.24-1.91). CONCLUSIONS: Endoscopic evidence of bile reflux was independently associated with the presence of Barrett's esophagus. This finding might help identify patients at future risk of Barrett's esophagus who could benefit from increased endoscopy surveillance.

Pyogenic liver abscess associated with Klebsiella oxytoca: Mimicking invasive liver abscess syndrome.

A pyogenic liver abscess (PLA) is a space-occupying lesion in the liver that is associated with significant morbidity and mortality. We herein present the case of a Japanese 76-year-old man who visited our hospital with fever and back pain lasting 3 weeks after endoscopic treatment for common bile duct stones. He was accompanied by poorly controlled diabetes mellitus (DM) with an HbA1c of 9.7 %. Laboratory tests disclosed elevated C-reactive protein level (22.1 mg/dL) and white cell count (11,910/µL). Abdominal computed tomography (CT) revealed hypodense lesions in the right liver lobe, with abdominal ultrasonography showing an echogenicity-mixed hypoechoic lesion. Percutaneous needle aspiration of a liver lesion was performed under suspicion of a PLA. Subsequent enhanced CT and magnetic resonance imaging confirmed the hepatic lesions in the right lobe as well as a septic pulmonary embolism, right hepatic vein thrombosis, spondylodiscitis, and a retroperitoneal abscess. Gram staining of the abscess drainage revealed gram-negative bacteria. The above findings indicated invasive liver abscess syndrome (ILAS) caused by Klebsiella pneumoniae. However, further examination of blood, urine, and abscess drainage cultures revealed positivity for Klebsiella oxytoca. This case illustrates that K. oxytoca may cause ILAS-like symptoms. Screening for systemic metastatic infection should be considered in patients with PLA due to K. oxytoca in whom therapeutic intervention has been delayed, especially in patients with poorly controlled DM.

Histopathologically defined intestinal metaplasia in lesser curvature of corpus prior to Helicobacter pylori eradication is a risk factor for gastric cancer development.

BACKGROUND AND AIM: Helicobacter pylori eradication has been shown to reduce the risk of gastric cancer (GC), with the number of eradication therapy cases on the rise. However, GC can still occur after successful treatment, and the histological differences prior to eradication in patients with and without GC are unclear. This study investigated the pre-treatment histological risk factors for GC development following eradication therapy. METHODS: We retrospectively enrolled consecutive adult patients diagnosed as having H. pylori infection between April 2004 and December 2018. Atrophy and intestinal metaplasia (IM) were histologically assessed according to the updated Sydney System. The operative link on gastritis assessment and the operative link on gastric intestinal metaplasia (OLGIM) were evaluated as well. RESULTS: Of the 247 patients analyzed in this study, 11 (4.5%) experienced GC after eradication therapy. Histological IM scores in the GC group were significantly higher at all gastric biopsy sites (p < .05), and the proportion of OLGIM III/IV stage was significantly greater in GC patients (81.8% vs. 31.8%, p < .01). For GC prediction, the area under the receiver operating characteristic curve for IM score at the lesser curvature of the corpus was the highest among all biopsy sites and not inferior to OLGIM results. CONCLUSIONS: Patients with histological IM prior to H. pylori eradication, especially at the lesser curvature of the corpus, may be at elevated risk for GC development after eradication therapy and require close surveillance.

Clinicopathological features of nodular gastritis in three classes of age.

BACKGROUND: Nodular gastritis is most often one of the manifestations of Helicobacter pylori (H. pylori) infection, which is a risk factor for gastric cancer. This study aimed to determine if the histological characteristics of nodular gastritis differed across classes of age. METHODS: We conducted a retrospective analysis of consecutive patients who had undergone esophagogastroduodenoscopy with multiple mucosal biopsies of the stomach between 2003 and 2019 for evaluation of updated Sydney System scores. We analyzed and compared the histological characteristics of pediatric (≤15 years old), young (16-29 years old), and older (≥30 years old) patients. RESULTS: Of the 1321 patients enrolled, 1027 patients (78%) had H. pylori infection, with 214 patients (21%) of them displaying nodular gastritis. Among nodular gastritis patients, mononuclear cell infiltration Sydney System scores in the gastric body were significantly higher in the older group than in the pediatric (p < .001) and young (p < .001) groups. Similar results were seen for neutrophil infiltration scores in the gastric body. To clarify the characteristics of older nodular gastritis, we investigated 1056 older patients (66 with nodular gastritis, 754 with atrophic gastritis, and 236 H. pylori-negative). The scores for mononuclear and neutrophil cell infiltration in the gastric body were significantly higher in nodular gastritis patients than in atrophic gastritis patients (both p < .001) and patients negative for H. pylori (both p < .001). CONCLUSIONS: The inflammatory changes in the gastric body in older nodular gastritis patients were more severe as compared with those in pediatric and young nodular gastritis patients in addition to older atrophic gastritis patients.

Increased center of pressure trajectory of the finger during precision grip task in stroke patients.

The aim of this study was to assess the spatial stability of stroke patients while holding a freely movable object. Twenty-two acute stroke patients with mild hand impairment performed a grip and lift task using the thumb and index finger. The displacement of the center of pressure (COP) trajectory, the grip force (GF) and several clinical parameters were monitored. Although the GF was not different between paretic and nonparetic hands, the COP trajectory of the paretic index finger was increased. Moreover, the COP trajectories of the thumb and index finger in hemorrhagic patients were longer than those in ischemic patients. These discrepancies between kinetic parameters suggest that different aspects of grip force control may be considered in patients with mild stroke.

Relationship between the amount of bitter substances adsorbed onto lipid/polymer membrane and the electric response of taste sensors.

The bitterness of bitter substances can be measured by the change in the membrane electric potential caused by adsorption (CPA) using a taste sensor (electronic tongue). In this study, we examined the relationship between the CPA value due to an acidic bitter substance and the amount of the bitter substance adsorbed onto lipid/polymer membranes, which contain different lipid contents, used in the taste sensor. We used iso-α-acid which is an acidic bitter substance found in several foods and beverages. The amount of adsorbed iso-α-acid, which was determined by spectroscopy, showed a maximum at the lipid concentration 0.1 wt % of the membrane, and the same phenomenon was observed for the CPA value. At the higher lipid concentration, however, the amount adsorbed decreased and then remained constant, while the CPA value decreased monotonically to zero. This constant adsorption amount was observed when the membrane potential in the reference solution did not change with increasing lipid concentration. The decrease in CPA value in spite of the constant adsorption amount is caused by a decrease in the sensitivity of the membrane as the surface charge density increases. The reason why the peaks appeared in both the CPA value and adsorption amount is based on the contradictory adsorption properties of iso-α-acid. The increasing charged lipid concentration of the membrane causes an increasing electrostatic attractive interaction between iso-α-acid and the membrane, but simultaneously causes a decreasing hydrophobic interaction that results in decreasing adsorption of iso-α-acid, which also has hydrophobic properties, onto the membrane. Estimates of the amount of adsorption suggest that iso-α-acid molecules are adsorbed onto both the surface and interior of the membrane.

Persistent BDNF exon I-IX mRNA expression following the withdrawal of neuronal activity in neurons.

It is still unclear whether an active state of transcription once established in chromatin persists in neurons. Here, we focused on BDNF exon I-IX mRNA expression because of its marked induction upon the treatment of rat cortical neurons with trichostatin A, suggesting strong repression of the expression through histone deacetylase activity. Acetylation of histones H3 and H4 in promoter-I of the BDNF gene (BDNF-PI) was induced by membrane depolarization time- and dose-dependently, corresponding with the increase in mRNA expression. Following withdrawal of the depolarization, the mRNA level remained elevated for at least 6h, the persistence of which depended upon the strength of depolarization, whereas the BDNF exon IV-IX expression did not. The acetylation of histones was also maintained with BDNF-PI. Thus, BDNF exon I-IX mRNA expression remained increased after depolarization was withdrawn, suggesting that once activated, the BDNF-PI transcription persists due to chromatin remodeling.

Remote control of activity-dependent BDNF gene promoter-I transcription mediated by REST/NRSF.

To know the role of repressor element-1 (RE-1)-silencing transcription factor (REST) in activity-dependent gene transcription in neurons, we investigated whether the Ca2+ signal-induced transcription of brain-derived neurotrophic factor promoter-I (BDNF-PI) is repressed by RE-1 located in exon II from far downstream of BDNF promoter-II (BDNF-PII). By constructing plasmids in which the location between BDNF-PI, -PII, and -RE-1 is maintained, we found, by conducting promoter assays with cortical neurons, that the promoter activity was constitutively repressed through the actions of BDNF-RE-1 but activated by Ca2+ signals evoked via membrane depolarization, which was due to BDNF-PI but not to BDNF-PII. The over-expression of REST reduced the level of transcriptional activation through the N- and C-terminals, suggesting the recruitment of a histone deacetylase. On over-expression of REST, an increased depolarization did not allow the activation. Thus, REST remotely represses activity-dependent gene transcription, the level of which controls the magnitude of the repression.

Valproic acid induces up- or down-regulation of gene expression responsible for the neuronal excitation and inhibition in rat cortical neurons through its epigenetic actions.

Valproic acid (VPA), a drug used to treat epilepsy and bipolar mood disorder, inhibits histone deacetylase (HDAC), which is associated with the epigenetic regulation of gene expression. Using a microarray, we comprehensively examined which genes are affected by stimulating cultured rat cortical neurons with VPA, and found that the VPA-treatment markedly altered gene expression (up-regulated; 726 genes, down-regulated; 577 genes). The mRNA expression for brain-derived neurotrophic factor (BDNF) and the alpha4 subunit of the GABA(A) receptor (GABA(A)Ralpha4), known to be involved in epileptogenesis, was up-regulated, with the increase in BDNF exon I-IX mRNA expression being remarkable, whereas that for GABA(A)Rgamma2, GAD65 and 67, and the K(+)/Cl(-) co-transporter KCC2, which are responsible for the development of GABAergic inhibitory neurons, was down-regulated. The number of GAD67-positive neurons decreased upon VPA-treatment. Similar changes of up- and down-regulation were obtained by trichostatin A. VPA did not affect the intracellular Ca(2+) concentration and the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), suggesting its direct action on HDAC. The acetylation of histones H3 and H4 was increased in the promoters of up-regulated but not down-regulated genes. Thus, VPA may disrupt a balance between excitatory and inhibitory neuronal activities through its epigenetic effect.

Regulation of neurotrophin-3 gene transcription by Sp3 and Sp4 in neurons.

Neurotrophin-3 (NT-3), a neurotrophin member, plays crucial roles in neuronal development, function and plasticity. Previous studies have demonstrated that NT-3 gene transcription is driven by alternative promoters A and B, located upstream of exons 1A (EIA) and 1B (EIB), respectively. However, the transcription factors and DNA elements that drive NT-3 gene transcription remain to be identified. Here, we analysed the promoter region of the NT-3 gene and found that an NT-3 transcript containing EIB is predominantly expressed in cortical neurons which preferentially utilize promoter B, and two tandemly repeated GC-boxes, located between -100 and -60 base pairs within promoter B, are required for the transcription. Electrophoretic mobility shift and chromatin immunoprecipitation assays revealed that both specificity protein (Sp)3 and Sp4 were able to bind to the Sp1 binding sequences within the GC boxes. Expression of dominant-negative Sp3 and Sp4 small interfering RNA in cortical neurons reduced the activity of the NT-3 gene promoter. Over-expression of Sp1 family members, especially Sp4, resulted in an increase of the NT-3 gene promoter. These findings indicate that the NT-3 gene is a target gene for Sp4 that is abundantly expressed in the brain.

Deltamethrin, a pyrethroid insecticide, is a potent inducer for the activity-dependent gene expression of brain-derived neurotrophic factor in neurons.

The mRNA expression of brain-derived neurotrophic factor (BDNF) is controlled in an activity-dependent manner through Ca(2+) influx into neurons. Pyrethroids are widely used insecticides of low acute toxicity in mammals, but their effects on sodium channels are known to lead to hyperexcitation in neuronal cells of insects. In this study, we found that deltamethrin, a type II pyrethroid insecticide, was highly effective in inducing BDNF expression in culture and in the rat brain. Addition of deltamethrin to rat cortical cells in culture markedly increased the expression of BDNF exon III-V mRNA and protein, dependent upon the neuronal activity accompanying the influx of Ca(2+) into neurons and the Ca(2+) influx-dependent phosphorylation of extracellular signal-regulated kinases 1/2. The elevated expression was maintained for at least 48 h, even after deltamethrin was withdrawn from the culture medium. Comparison of the effects of selected pyrethroids on the expression revealed that type II but not type I pyrethroids effectively induced BDNF mRNA expression. In addition, administration of deltamethrin to rats increased the level of BDNF protein in the cerebral cortex and hippocampus. These results indicate that deltamethrin is a potent inducer of BDNF expression in neurons and that it may induce neuronal hyperexcitation if it reaches the brain.

Interference with activity-dependent transcriptional activation of BDNF gene depending upon the expanded polyglutamines in neurons.

Expanded polyglutamines (polyQ) have been demonstrated to impair the CREB-dependent transcription in established cell lines. Since activity-dependent transcription in neurons, which plays an important role in forming neuronal plasticity, is largely controlled by CREB, it is important to study whether polyQ interferes with the activity-dependent transcriptional activation of genes in neurons. In cultured rat cortical neurons, over-expression of truncated dentatorubral-pallidoluysian atrophy proteins containing expanded polyQ, which form aggregation bodies in nucleus, reduced the calcium (Ca(2+)) signal-mediated transcriptional activation of brain-derived neurotrophic factor, c-fos, and pituitary adenylate cyclase-activating polypeptide gene promoters in a dose-dependent manner. The interference with the transcriptional activation was dependent upon the presence of polyQ, the strength of which was increased as the length of polyQ stretches was expanded. Thus, polyQ interferes with the activity-dependent transcription in a polyQ-length-dependent manner, which may correspond to the severity of polyglutamine diseases.