Similar Effect of Vonoprazan and Oral Proton Pump Inhibitors for Preventing Rebleeding in Cases of Upper Gastrointestinal Bleeding.

Objective The use of a proton pump inhibitor (PPI) reduces rebleeding and mortality in patients with upper gastrointestinal bleeding (UGIB). Vonoprazan is a novel oral agent with strong and sustained acid-inhibitory activity. We clarified the effect of vonoprazan compared with oral PPIs in such patients. Methods We analyzed the Diagnosis Procedure Combination database. The primary outcome was rebleeding, and secondary outcomes were in-hospital mortality and in-hospital mortality after rebleeding. Propensity score matching was performed to balance the comparison groups, and logistic regression analyses were used to compare the outcomes between vonoprazan and oral PPIs. Patients Patients on vonoprazan or oral PPIs who underwent endoscopic hemostasis for UGIB between 2014 and 2019 were included. Results We enrolled 78,964 patients, of whom 27,101 and 51,863 were prescribed vonoprazan and a PPI, respectively. After propensity score matching, the rebleeding rate of vonoprazan did not significantly differ from that of oral PPIs [6.4% vs. 6.1%; odds ratio (OR), 1.05; 95% confidence interval (CI), 0.98-1.13]; similarly, the in-hospital mortality rate (1.4% vs. 1.5%; OR, 0.91; 95% CI, 0.79-1.05) and in-hospital mortality after rebleeding (0.3% vs. 0.2%; OR, 1.09; 95% CI, 0.78-1.54) also did not significantly differ between the groups. The acquired findings were robust across dose-restricted analyses and several sensitivity analyses. Conclusion Rebleeding and in-hospital mortality risks in patients on vonoprazan were similar to those in patients on oral PPIs. Considering the higher cost of vonoprazan, oral PPIs might be an optimal oral agent as an acid-suppressive therapy in such patients.

Endoscopic Grading of Gastric Intestinal Metaplasia Using Magnifying and Nonmagnifying Narrow-Band Imaging Endoscopy.

Several endoscopic findings obtained by magnifying image-enhanced endoscopy (IEE) are reportedly correlated with gastric intestinal metaplasia (IM); however, the differences between magnifying and nonmagnifying IEE for the diagnosis of gastric IM remain unknown. This study included 100 consecutive patients who underwent narrow-band imaging endoscopy. Four areas of the stomach were evaluated using nonmagnifying and magnifying IEE. Light-blue crest (LBC), white opaque substance (WOS), and endoscopic grading of the gastric IM (EGGIM) were assessed. The concordance rates between nonmagnifying and magnifying IEE were 80.5% for LBC and 93.3% for WOS. The strength of agreement between each observation technique showed good reproducibility, with a kappa value of 0.69 and 0.83 for LBC and WOS, respectively. The individual EGGIM score indicated a good correlation between nonmagnifying and magnifying IEE (concordance rate, 75%; kappa value, 0.67). The prevalence of a high EGGIM score in patients with and without gastric cancer (GC) showed a significant difference both with nonmagnifying IEE (odds ratio (OR), 3.3; 95% confidence interval (CI), 1.2-9.0), and magnifying IEE (OR, 3.1; 95% CI, 1.1-8.9). Nonmagnifying IEE has the potential to stratify the individual risk of GC, similar to magnifying IEE, warranting further investigation with histological assessment.

Laparoscopic and endoscopic cooperative surgery for intra-mucosal gastric carcinoma adjacent to the ulcer scars.

BACKGROUND: Laparoscopic and endoscopic cooperative surgery (LECS) was performed for the local resection of gastrointestinal stromal tumors (GIST). LECS enables less resection of the lesion area and preserves function. Furthermore, LECS can be safely performed and independent of tumor location. However, LECS is not usually used for cases involving gastric carcinoma because it may seed tumor cells into the peritoneal cavity when the gastric wall is perforated. Here, we report seven cases of LECS for intra-mucosal gastric carcinoma, which were difficult to carry out by endoscopic submucosal dissection (ESD) because of ulcer scars. METHODS: We performed LECS (classical LECS and inverted LECS) in seven cases of intra-mucosal gastric carcinoma. All cases had ulcer scars beside the tumor. LECS was chosen because ESD was thought to be difficult because of the ulcer scars. We only selected cases in which the patients did not prefer gastrectomy and endoscopic examination was indicative of intra-mucosal gastric carcinoma. RESULTS: In all cases, LECS was performed without severe complications including postoperative stenosis. Histopathology findings proved that the tumors were intra-mucosal carcinoma and had been resected completely. Furthermore, there were ulcer scars (Ul IIIs-IVs) beside the tumor. Currently, dissemination and recurrence have not been apparent. CONCLUSIONS: LECS for intra-mucosal gastric carcinoma is an efficient procedure, but strict observation is necessary because of the possibility of peritoneal dissemination. Results suggest that LECS is likely to be effective for cases involving intra-mucosal gastric carcinoma that are difficult to treat by ESD due to ulcer scars.

Chemical structure of posttranslational modification with a farnesyl group on tryptophan.

Bacillus subtilis and related bacilli produce a posttranslationally modified oligopeptide, the ComX pheromone, that stimulates natural genetic competence controlled by quorum sensing. The ComX(RO-C-2) pheromone from strain RO-C-2 must be modified with a farnesyl group on the Trp residue, but the precise structure is not known. Here we report the precise nature of posttranslational farnesylation of ComX(RO-C-2) pheromone on the Trp residue, resulting in the formation of a tricyclic structure. The ComX(168) pheromone, produced by the standard laboratory strain used in the study of B. subtilis, is also posttranslationally farnesylated according to phylogenetic resemblance.

Successful efavirenz dose reduction in HIV type 1-infected individuals with cytochrome P450 2B6 *6 and *26.

BACKGROUND: Efavirenz (EFV) is metabolized primarily by cytochrome P450 2B6 (CYP2B6), and high plasma concentrations of the drug are associated with a G-->T polymorphism at position 516 (516G-->T) of CYP2B6 and frequent central nervous system (CNS)-related side effects. Here, we tested the feasibility of genotype-based dose reduction of EFV. METHODS: CYP2B6 genotypes were determined in 456 human immunodeficiency virus type 1 (HIV-1)-infected patients who were receiving EFV treatment or were scheduled to receive EFV-containing treatment. EFV dose was reduced in CYP2B6 516G-->T carriers who had high plasma EFV concentrations while receiving the standard dosage (600 mg). EFV-naive homozygous CYP2B6 516G-->T carriers were treated with low-dose EFV. In both groups, the dose was further reduced when plasma EFV concentration remained high. RESULTS: CYP2B6 516G-->T was identified in the *6 allele (found in 17.9% of our subjects) and a novel allele, *26 (found in 1.3% of our patients). All EFV-treated CYP2B6 *6/*6 and *6/*26 carriers had extremely high plasma EFV concentrations (>6000 ng/mL) while receiving the standard dosage. EFV dose was reduced to 400 mg for 11 patients and to 200 mg for 7 patients with persistently suppressed HIV-1 loads. EFV-containing treatment was initiated at 400 mg in 4 CYP2B6 *6/*6 carriers and one *6/*26 carrier. Two of them still had a high plasma EFV concentration while receiving that dose, and the dose was further reduced to 200 mg, with successful HIV-1 suppression. CNS-related symptoms improved with dose reduction in 10 of the 14 patients, although some had not been aware of the symptoms at initial dosage. CONCLUSIONS: Genotype-based EFV dose reduction is feasible in CYP2B6 *6/*6 and *6/*26 carriers, which can reduce EFV-associated CNS symptoms.

Acid labile ComX pheromone from Bacillus mojavensis RO-H-1.

Bacillus mojavensis strain RO-H-1 produces a posttranslationally modified hexapeptide, the ComX(RO-H-1) pheromone, that stimulates natural genetic competence controlled by quorum sensing. LC/ESI-MS analysis of partially purification of the ComX(RO-H-1) pheromone suggested a precise modification in its tryptophan residue. The corresponding ComX(RO-H-1) pheromone prepared by solid-phase synthesis was identical to the natural pheromone, and showed significant biological activity. These results indicated that the posttranslational modification of the ComX(RO-H-1) pheromone was geranylation on the tryptophan residue, resulting in the formation of a tricyclic structure. The ComX(RO-H-1) pheromone was immediately dehydrated by acid because of its extreme acid lability.

Structure-activity relationship studies on quorum sensing ComX(RO-E-2) pheromone.

The ComX pheromone is a posttranslationally modified oligopeptide that stimulates natural genetic competence in Bacillus subtilis. Various ComX(RO-E-2) analogs were synthesized and their biological activities were studied to investigate structure-activity relationships. These results showed that the minimal active unit was the tripeptide, [3-5]ComX(RO-E-2), and all residues except the modified tryptophan residue were replaceable by alanine without total loss of activity.

Non-contact Breath Motion Monitor ing System in Full Automation.

It is said that sleep apnea syndrome is one of the main causes of airplane, train and car accidents. We have developed a non-contact breathing measurement system which diagnoses not only sleep apnea syndrome but also other sleep disorders. This system calculates the amount of the volume change and makes the movement of the outside of the body by the breath motion visible. If the patient is breathing abnormally, we are able to recognize the appearance of abnormality at a glance and know the amount of the volume change in that location. To verify the amount of the volume change, we compare the amount of ventilation measured with a spirometer to the amount of volume change measured with this system. As a result, there is a high correlation in the amount of the volume change and the amount of ventilation in any sleeping position.

Structure of the Bacillus subtilis quorum-sensing peptide pheromone ComX.

The ComX pheromone is an extracellular signaling molecule that stimulates natural competence in response to crowding in the gram-positive bacterium Bacillus subtilis. The pheromone is formed by isoprenylation of an inactive precursor peptide, but its precise structure is not known. Here we report the structure of the ComX pheromone, showing that addition of a geranyl group to a tryptophan residue results in the formation of an unusual ring structure.

Towards structural determination of the ComX pheromone: synthetic studies on peptides containing geranyltryptophan.

Bacteria produce and respond to signal molecules depending on their cell density. This process is called "quorum sensing". The ComX pheromone, controlled by quorum sensing, activates natural genetic competence in Bacillus subtilis. ComX is an oligopeptide with a posttranslational modification. It has been suggested that ComX pheromone is modified with an isoprenoid at its tryptophan residue, but the complete chemical structure is unknown. We first determined the molecular formula of ComX(RO-E-2), a competence factor for B. subtilis strain RO-E-2. Then we synthesized putative pheromones with 1-, 2-, 4-, 5-, 6-, or 7-geranyl substituted tryptophan residues. The regio- and stereo-selective synthesis of the geranyl tryptophans was successful, and we prepared the six peptides with modified tryptophan residues. These peptides had the same molecular formula and showed similar hydrophobicity to the natural ComX(RO-E-2) in LC-MS analysis. But, none of them showed the same retention time as the natural pheromone and none exhibited its biological activity. These results suggest that the isoprenoid modification pattern of the tryptophan residue is more complex than postulated.

[A case of coronary artery spasm during epidural anesthesia with continuous infusion of propofol].

A 50-year-old male patient was scheduled for left partial pulmonary resection and biopsy. The patient had neither complication nor history of ischemic heart disease. After arriving in the operation room, an epidural catheter was inserted into the epidural space at the T 4-5 intervertebral space. Anesthesia was induced with intravenous propofol 100 mg, fentanyl 100 microgram and vecuronium 6 mg and then a double lumen endotracheal tube was inserted. Anesthesia was maintained with O2 and air (FIO2 0.3-1.0), continuous infusion of propofol, intermittent intravenous administration of fentanyl and epidural injection of 1% lidocaine. Forty-five minutes after the start of operation, ECG showed an elevation of ST segment and soon it passed into ventricular tachycardia and ventricular fibrillation. The patient was treated with cardiopulmonary resuscitation. Fifteen minutes later, ECG returned to sinus rhythm but the elevation of ST segment remained. We considered that these cardiac events were due to coronary spasm, and started continuous infusion of nitroglycerin and nicorandil. One hour later, ST segment returned to normal. The possible inducing factors in this case were altered balance between sympathetic and parasympathetic nervous activity caused by infusion of propofol and epidural block, and alpha-stimulation caused by ephedrine.

Involvement of spinal tyrosine kinase in inflammatory and N-methyl-D-aspartate-induced hyperalgesia in rats.

Phosphorylation of a subunit of N-methyl-D-aspartate (NMDA) receptor by protein tyrosine kinase (PTK) Src or Trk is known to enhance its channel activity. We examined whether a spinally administered selective PTK inhibitor, lavendustin A, which has high affinity for Src and Trk tyrosine kinases, could influence the development and maintenance of inflammatory hyperalgesia or NMDA-induced hyperalgesia. Inflammation was induced by injection of a mixture of carrageenan and kaolin into the tail base of rats. In another group of rats, hyperalgesia was induced by intrathecal administration of NMDA. Intrathecal administration of lavendustin A (1.0 microg) or NMDA receptor antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptane-5,10-iminemaleate, MK-801 (3.0 microg) before injection of a mixture of carrageenan and kaolin or after the development of inflammation inhibited carrageenan-kaolin-induced mechanical hyperalgesia. Intrathecal injection of 1.0 microg NMDA produced thermal and mechanical hyperalgesia. Co-administration of 1.0 microg lavendustin A with NMDA significantly reduced the duration of spontaneous pain behaviour and inhibited NMDA-induced hyperalgesia. Lavendustin A itself did not cause any sedation, motor impairment or analgesia. Our results suggest that inhibition of PTK could be therapeutically effective as an analgesic in some NMDA receptor-mediated hyperalgesic states.

[Assessment of peripheral blood perfusion during open heart surgery with sublingual PCO2 measured by ISFET-PCO2 sensor].

Sublingual tissue PCO2 (PSLCO2) was continuously monitored with an ISFET-based PCO2 sensor during and after the open-heart surgery under cardiopulmonary bypass (CPB) in order to study the effect of CPB on the peripheral blood perfusion. In addition, PSLCO2 monitoring was carried out in several cases of off-pump CABG. In the cases of open-heart surgery with CPB, PSLCO2 increased from 35.0 +/- 5.6 mmHg at the induction of anesthesia to the maximum value of 55.7 +/- 6.0 mmHg during CPB. After declamping of the aorta, PSLCO2 decreased gradually to 49.0 +/- 4.0 mm Hg 6 hr after the admission to ICU. The value of arterial lactate as another index of peripheral blood perfusion also increased gradually after the start of CPB, reaching to the maximum value of 8.8 +/- 1.1 mmol.l-1 just after being admitted into ICU. In the case of off-pump CABG, PSLCO2 and arterial lactate showed a slight increase during the later part of the surgery, but the change was not so significant as in the case of open-heart surgery under CPB. Through this study, typical changing pattern of PSLCO2 during the open-heart surgery was recognized. The change of PSLCO2 always preceded that of arterial lactate. We also experienced one case in which early stage of hypoperfusion was detected through the monitoring of PSLCO2. These results suggest clinical advantages of PSLCO2 monitoring.