Frontline Science: Conversion of neutrophils into atypical Ly6G+ SiglecF+ immune cells with neurosupportive potential in olfactory neuroepithelium.

Neutrophils are generally considered as short-lived, homogenous, and terminally differentiated phagocytes that play crucial roles in conquering infection, although they occasionally cause severe collateral tissue damage or chronic inflammation. Recent reports have indicated that neutrophils also play a protective role in inflammation resolution and tissue repair. However, how terminally differentiated neutrophils have diverse functions remains unclear. Here, we show that neutrophils undergo conversion into Ly6G+ SiglecF+ double-positive cells expressing neurosupportive genes in the olfactory neuroepithelium (OE) under an inflammatory state. Through comprehensive flow cytometric analysis of murine nose, we identified Ly6G+ SiglecF+ double-positive cells that reside only in the OE under steady-state conditions. Double-positive cells were neutrophil-derived cells and increased by more than 10-fold during inflammation or tissue injury. We found that neutrophils infiltrate into the nose to express proinflammatory genes in the acute phase of inflammatory state, and they gradually change their surface markers and gene expression, expressing some neurogenesis-related genes in addition to inflammation related genes in the later phase. As the OE is known to have exceptionally high regeneration capacity as a nervous system, these findings suggest that neutrophils have the potential to contribute neurogenesis after conversion in peripheral nervous tissues, providing a challenge on a classic view of neutrophils as terminally differentiated leukocytes.

Pathophysiology of Potassium-competitive Acid Blocker-refractory Gastroesophageal Reflux and the Potential of Potassium-competitive Acid Blocker Test.

BACKGROUND/AIMS: Potassium-competitive acid blockers are expected to be the next generation of drugs for the treatment of diseases caused by gastric acid. In 2015, vonoprazan fumarate, a novel potassium-competitive acid blocker, was approved by the Japanese health insurance system. Since its approval, patients refractory to vonoprazan can be encountered in clinical settings. We designed this study to clarify the pathophysiology of gastroesophageal reflux disease refractory to vonoprazan. METHODS: In this retrospective study, we involved patients who had refractory symptoms after administration of standard-dose proton pump inhibitors or vonoprazan and underwent diagnostic testing with esophageal high-resolution manometry and 24-hour multichannel intraluminal impedance and pH monitoring while using proton pump inhibitors or vonoprazan. Patients were diagnosed based on the Rome IV criteria for functional gastrointestinal disorders and diagnostic test results. RESULTS: Twenty-seven patients were analyzed during this study. Gastric pH ≥ 4 was sustained for a longer period of time, and the esophageal acid exposure time and number of acid reflux events were shorter in the vonoprazan group than in the proton pump inhibitor group. The percentage of patients diagnosed with acidic gastroesophageal reflux disease in the vonoprazan group was lower than that in the proton pump inhibitor group. CONCLUSIONS: Intra-gastric pH and acid reflux were strongly suppressed by 20-mg vonoprazan. When patients with gastroesophageal reflux disease present symptoms after administration of 20-mg vonoprazan, the possibility of pathophysiologies other than acid reflux should be considered.

Burden of impaired sleep quality on work productivity in functional dyspepsia.

BACKGROUND: Impaired sleep quality is common, and can reduce work productivity in patients with functional dyspepsia (FD). OBJECTIVE: The objective of this article is to evaluate whether there is a direct association between the presence of FD and the severity of impaired sleep quality, and to calculate the economic loss due to the decreased work productivity associated with sleep quality. METHODS: In Study 1, using a web-based survey completed by workers with and without FD, we evaluated impaired sleep quality, work and daily productivity, and the severity of reflux and bowel symptoms. In Study 2, the association between the presence of FD and the severity of impaired sleep quality was validated in a hospital-based cohort. RESULTS: In both Study 1 and 2, although impaired sleep quality was more frequent in participants with FD than in those without FD, the independent association between the presence of FD and the severity of impaired sleep quality was not observed after adjustment for the severity of reflux and bowel symptoms. FD participants with impaired sleep quality reported additional economic loss of 53,500 Japanese yen/month. CONCLUSION: Although the association between impaired sleep quality and FD was indirect, concomitant impaired sleep quality could worsen economic loss.

Gender Difference of Gastric Emptying in Healthy Volunteers and Patients with Functional Dyspepsia.

BACKGROUND AND AIM: Delayed gastric emptying is one of the reasons why functional dyspepsia (FD) occurs. The 13C-acetate breath test is widely used to evaluate gastric emptying. Nevertheless, the standard value of 13C-acetate breath test has not taken into account the gender difference of gastric emptying among healthy individuals. The main aim of this study was to readjust the standard value of 13C-acetate breath test in the light of gender differences. In addition, we clarified the prevalence and clinical characteristics of delayed gastric emptying in patients with FD using the modified standard values of 13C-acetate breath test. METHODS: Fifty-two healthy individuals and 126 patients with patients with FD were enrolled. Gastric emptying was evaluated by the 13C-acetate breath test. The cut-off points of Tmax for the diagnosis of delayed gastric emptying were determined on the basis of results from healthy individuals making a distinction of genders. Gastroesophageal reflux symptoms, dyspeptic symptoms, scores of anxiety and depression, age, body mass index (BMI), smoking and alcohol consumption were compared between the delayed gastric emptying group and the non-delayed gastric emptying group. RESULTS: Since gastric emptying was delayed in healthy women compared with that in healthy men (Tmax, 53.6 ± 19.3 vs. 42.7 ± 16.9 min, p = 0.04), we set the cut-off points of Tmax at 60 min in men and at 75 min in women. In patients with FD, the prevalence of delayed gastric emptying was not different between men and women with the modified standard values of 13C-acetate breath test. (31.0 vs. 27.4%, p = 0.68). BMI was lower in the delayed gastric emptying group than in the non-delayed group among the male patients. Reflux symptoms were more severe in delayed gastric emptying group than in the non-delayed group among the female patients. CONCLUSION: The standard values of 13C-acetate breath test should be modified bearing the gender difference in mind. It provides us more appropriate information to understand the mechanisms of FD.

Purulent pericarditis in a dog administered immune-suppressing drugs.

A 5-year-old castrated mongrel dog was brought to our hospital with anorexia and vomiting. Laboratory testing revealed immune-mediated hemolytic anemia (IMHA), and so treatment was initiated with multiple immune-suppressing drugs, achieving partial remission from IMHA. However, cardiac tamponade due to purulent pericarditis was identified as a secondary disease. Culture of pericardial fluid yielded numerous Candida albicans and multidrug-resistant Acinetobacter sp. Pericardiocentesis was performed, and the condition of the dog improved. However, the dog died the next day.

Comparison of the effects of candesartan cilexetil and enalapril maleate on right ventricular myocardial remodeling in dogs with experimentally induced pulmonary stenosis.

OBJECTIVE: To compare the effects of candesartan cilexetil and enalapril maleate on right ventricular myocardial remodeling in dogs with experimentally induced pulmonary stenosis. ANIMALS: 24 Beagles. PROCEDURES: 18 dogs underwent pulmonary arterial banding (PAB) to induce right ventricular pressure overload, and 6 healthy dogs underwent sham operations (thoracotomy only [sham-operated group]). Dogs that underwent PAB were allocated to receive 1 of 3 treatments (6 dogs/group): candesartan (1 mg/kg, PO, q 24 h [PABC group]), enalapril (0.5 mg/kg, PO, q 24 h [PABE group]), or no treatment (PABNT group). Administration of treatments was commenced the day prior to surgery; control dogs received no cardiac medications. Sixty days after surgery, right ventricular wall thickness was assessed echocardiographically and plasma renin activity, angiotensin-converting enzyme activity, and angiotensin I and II concentrations were assessed; all dogs were euthanatized, and collagenous fiber area, cardiomyocyte diameter, and tissue angiotensin-converting enzyme and chymase-like activities in the right ventricle were evaluated. RESULTS: After 60 days of treatment, right ventricular wall thickness, cardiomyocyte diameter, and collagenous fiber area in the PABNT and PABE groups were significantly increased, compared with values in the PABC and sham-operated groups. Chymase-like activity was markedly greater in the PABE group than in other groups. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that treatment with candesartan but not enalapril effectively prevented myocardial remodeling in dogs with experimentally induced subacute right ventricular pressure overload.

Increased chymase-like activity in a dog with congenital pulmonic stenosis.

OBJECTIVES: This study was intended to compare the tissue chymase-like activity and angiotensin converting enzyme (ACE) activity in the right and left ventricles of a dog with congenital pulmonic stenosis (PS), with normal dogs, and to discuss the potential clinical implications of these findings. ANIMALS, MATERIALS AND METHODS: Study subjects included a one-year-old Beagle dog with spontaneous PS and six clinically normal Beagles. Chymase-like and ACE activities were determined in all hearts by high pressure liquid chromatography. RESULTS: In the PS dog right ventricular (RV) chymase-like activity (49.79 nmol/min/g tissue) and left ventricular (LV) chymase-like activity (36.85 nmol/min/g tissue) were elevated vs normal Beagle dogs (mean+/-standard deviation, RV: 20.17+/-5.24 nmol/min/g, LV: 19.03+/-3.27 nmol/min/g). CONCLUSIONS: Activation of the tissue RAA system was detected in a dog with congenital PS. This interesting finding should be pursued with further studies to validate this result, and to explore whether pharmacological blockade of chymase, or the angiotensin II receptor, represents a useful strategy to prevent myocardial remodeling in this condition.

Inhibition of fatty acid beta-oxidation attenuates the reinforcing effects and palatability to fat.

OBJECTIVE: We investigated the effects of the energy signal on the reinforcing effects and palatability to fat in mice. METHODS: To examine the effects of postingestive energy signal, mice were injected with 400 micromol/kg body mass of mercaptoacetate, a beta-oxidation blocker or with saline (control group). Reinforcing effects and palatability response were examined with the conditioned place preference and one-bottle tests, respectively. RESULTS: In conditioned place preference tests, the mercaptoacetate group exhibited reinforcing effects when offered a 40% sucrose solution, which is not metabolized by the beta-oxidation pathway, but not when offered 100% corn oil. The control group exhibited reinforcing effects when offered the sucrose solution and when offered corn oil. In one-bottle tests, the control group exhibited palatability to corn oil, but the mercaptoacetate group did not. Consumption of sucrose solution was identical for both groups. CONCLUSIONS: These results suggest that postingestive energy signal influences the reinforcing effects and palatability of fat.

Time course sequences of angiotensin converting enzyme and chymase-like activities during development of right ventricular hypertrophy induced by pulmonary artery constriction in dogs.

ACE and chymase play crucial roles in the establishment of pressure overload-induced cardiac hypertrophy. In the present study, time sequences of ACE and chymase-like activities, and their correlation with hypertrophic changes including free wall thickness and cardiac fibrosis, were elucidated in dogs with constant pressure overload to the right ventricle. Pulmonary artery banding (PAB) was applied so that the diameter of the main pulmonary artery was reduced to 60% of the original size, right ventricular pressure was elevated by about 70%, and pulmonary artery flow was increased by about three times of that in sham operation groups. These increases remained unchanged 15, 60, and 180 days after PAB, suggesting that constant right ventricular pressure overload was obtained, at least during this period. The diameter of the right ventricular myocyte was slightly increased and the percentage of fractional shortening was decreased 15 days after PAB. Right ventricular wall thickness and interstitial collagenous fiber were, however, not different from those of sham-operated dogs, suggesting that this period is a period of adaptation to the overload. Sixty days after PAB, the diameter of the right ventricular myocyte was further increased, and right ventricular wall thickness and interstitial collagenous fiber were also increased. These changes were almost identical even 180 days after PAB. Thus, stable hypertrophy was elicited from 60 through 180 days after PAB. ACE activity was facilitated at the adaptation period to the overload (15 days after PAB), but chymase activity was not facilitated at this period. On the other hand, both ACE and chymase-like activities were unchanged in the earlier phase (60 days after PAB) of stable hypertrophy, but facilitated in the latter phase (180 days after PAB). These findings suggest the pathophysiologic roles of these enzymes may be different over the time course of pressure overload-induced hypertrophy.

Transcatheter closure of congenital ventricular septal defects in 3 dogs with a detachable coil.

The purpose of this study was to evaluate the feasibility, safety, and efficacy of transcatheter closure in dogs with a congenital perimembranous ventricular septal defect (VSD) by using a detachable coil. No dogs showed any symptoms, and results of chest X-rays and ECGs were normal. The diameters of VSD ranged from 2 to 4 mm on echocardiogram. The defect was 2-2.5 mm from the aortic valve. A detachable coil (size 5 mm with 5 loops) designed for patent ductus arteriosus was delivered via the transarterial route. The device was successfully employed in all dogs. A minimal residual shunt was observed in all dogs even though Qp/Qs decreased. Hemolysis and a rate-dependent right-bundle branch block were observed in 1 dog, but there was no clinical significance. No major complication was noted. Pathologic examination after 1 year revealed that the coils were covered with tissue without significant damage to the His-Purkinje conduction system. In conclusion, transcatheter closure of a small perimembranous VSD with a detachable coil can be achieved without major complications or significant pathologic damage at the lesion site.

Integration of orosensory and postingestive stimuli for the control of excessive fat intake in mice.

OBJECTIVES: Long-term preferences for, and reinforcement effects of, undigested fat substitutes were investigated by means of a two-bottle choice test and the conditioned place preference (CPP) test. METHODS: We tested intact corn oil and sorbitol fatty acid esters, which have been developed as non-digestible fat substitutes with low energy (1.5 kcal/g). RESULTS: Palatability of the sorbitol fatty acid esters was similar to corn oil over 30 min in the short-term two-bottle choice test in mice. However, mice did not continue to eat the fat substitute in the long-term two-bottle choice test, which included postprandial feedback effects. Moreover, sorbitol fatty acid ester did not act as a reinforcer in the CPP test. Mice with 0.1 mL of corn oil placed into their stomachs just before conditioning showed reinforcing effects on taking sorbitol fatty acid ester in the CPP test. However, intragastric administration of corn oil alone without stimulation of the oral cavity did not show any such reinforcing effects against corn oil. CONCLUSIONS: These results suggest that the postingestible effects of corn oil are involved in long-term preference and reinforcing effects.