A Case of Amyand's Hernia With Abscess Managed by Two-Stage Surgery: Elective Hernia Mesh Repair Following Emergency Laparoscopic Appendectomy.

An 82-year-old man presented to our emergency department with a bulge in the right groin and worsening pain that had been present for one week. An abdominal computed tomography scan revealed fluid collection within a right inguinal hernia and a thickened appendix within the hernia sac. The patient underwent an emergency laparoscopic appendectomy under a diagnosis of Amyand's hernia with peri-appendicular abscess. During surgery, the incarcerated appendix was pulled back into the abdominal cavity from the hernia sac, and the perforated appendix was resected. For drainage of the abscess, a drain tube was laparoscopically placed into the hernia sac through the internal inguinal ring. Considering the risk of mesh infection and wound infection, the patient underwent appendectomy alone but not hernia repair at this time. Two months later, Lichtenstein repair using mesh was performed as a second-stage procedure. For Amyand's hernia with abscess, this type of two-stage strategy may avoid the surgical site infection, and the use of mesh in a second procedure would minimize the possibility of hernia recurrence, unlike previously reported cases treated by concomitant appendectomy and hernia repair.

Relationship Between Fluoroquinolone Resistance and Mutations in the Quinolone Resistance-Determining Region in Corynebacterium macginleyi.

Purpose: The purpose of this study was to investigate the bacterial composition in the conjunctiva and to determine the relationship between fluoroquinolone resistance and mutations in the quinolone resistance-determining region (QRDR) in Corynebacterium macginleyi (C. macginleyi). Methods: Bacteria isolated from conjunctival swabs of patients awaiting ophthalmic surgery or patients with presumed keratoconjunctivitis were included in this study. For C. macginleyi isolates from 49 samples, the minimum inhibitory concentrations (MICs) of second- to fourth-generation fluoroquinolones were determined by broth microdilution. Additionally, we determined the sequence of the QRDR in the gyrA gene of C. macginleyi-positive isolates by direct sequencing and investigated the relationship between the QRDR mutation and the MICs of fluoroquinolones for C. macginleyi. Results: Among 423 eyes of 296 preoperative patients who underwent conjunctival culture testing, 105 eyes of 89 patients were culture-positive, and among 148 eyes of 147 patients with keratoconjunctivitis, 55 eyes of 54 patients were culture-positive. C. macginleyi accounted for the largest proportion of cultured organisms (34.8%). C. macginleyi-positive isolates were found in 45 eyes of 37 preoperative patients and in 4 eyes of 4 patients with keratoconjunctivitis. Direct sequencing revealed that 91.8% of C. macginleyi-positive isolates had amino acid mutations in the QRDR and 95.5% of mutations were found at Ser-87 and Asp-91. Isolates harboring double mutations at Ser-87 and Asp-91 were resistant to second- to fourth-generation fluoroquinolones. One isolate with double mutations at Ser-87 and Ala-88 but no mutation in Asp-91 showed intermediate susceptibility to moxifloxacin, a fourth-generation fluoroquinolone. Conclusions: C. macginleyi isolated from conjunctiva harboring QRDR amino acid mutations were resistant to second- to fourth-generation fluoroquinolones.

Far-Ultraviolet Light at 222 nm Affects Membrane Integrity in Monolayered DLD1 Colon Cancer Cells.

222 nm far-ultraviolet (F-UV) light has a bactericidal effect similar to deep-ultraviolet (D-UV) light of about a 260 nm wavelength. The cytotoxic effect of 222 nm F-UV has not been fully investigated. DLD-1 cells were cultured in a monolayer and irradiated with 222 nm F-UV or 254 nm D-UV. The cytotoxicity of the two different wavelengths of UV light was compared. Changes in cell morphology after F-UV irradiation were observed by time-lapse imaging. Differences in the staining images of DNA-binding agents Syto9 and propidium iodide (PI) and the amount of cyclobutane pyrimidine dimer (CPD) were examined after UV irradiation. F-UV was cytotoxic to the monolayer culture of DLD-1 cells in a radiant energy-dependent manner. When radiant energy was set to 30 mJ/cm2, F-UV and D-UV showed comparable cytotoxicity. DLD-1 cells began to expand immediately after 222 nm F-UV light irradiation, and many cells incorporated PI; in contrast, PI uptake was at a low level after D-UV irradiation. The amount of CPD, an indicator of DNA damage, was higher in cells irradiated with D-UV than in cells irradiated with F-UV. This study proved that D-UV induced apoptosis from DNA damage, whereas F-UV affected membrane integrity in monolayer cells.

Endogenous activation of peroxisome proliferator-activated receptor-α in proximal tubule cells in counteracting phosphate toxicity.

Increased dietary phosphate consumption intensifies renal phosphate burden. Several mechanisms for phosphate-induced renal tubulointerstitial fibrosis have been reported. Considering the dual nature of phosphate as both a potential renal toxin and an essential nutrient for the body, kidneys may possess inherent protective mechanisms against phosphate overload, rather than succumbing solely to injury. However, there is limited understanding of such mechanisms. To identify these mechanisms, we conducted single-cell RNA sequencing (scRNA-seq) analysis of the kidneys of control and dietary phosphate-loaded (Phos) mice at a time point when the Phos group had not yet developed tubulointerstitial fibrosis. scRNA-seq analysis identified the highest number of differentially expressed genes in the clusters belonging to proximal tubular epithelial cells (PTECs). Based on these differentially expressed genes, in silico analyses suggested that the Phos group activated peroxisome proliferator-activated receptor-α (PPAR-α) and fatty acid ß-oxidation (FAO) in the PTECs. This activation was further substantiated through various experiments, including the use of an FAO activity visualization probe. Compared with wild-type mice, Ppara knockout mice exhibited exacerbated tubulointerstitial fibrosis in response to phosphate overload. Experiments conducted with cultured PTECs demonstrated that activation of the PPAR-α/FAO pathway leads to improved cellular viability under high-phosphate conditions. The Phos group mice showed a decreased serum concentration of free fatty acids, which are endogenous PPAR-α agonists. Instead, experiments using cultured PTECs revealed that phosphate directly activates the PPAR-α/FAO pathway. These findings indicate that noncanonical metabolic reprogramming via endogenous activation of the PPAR-α/FAO pathway in PTECs is essential to counteract phosphate toxicity.NEW & NOTEWORTHY This study revealed the activation of peroxisome proliferator-activated receptor-α and fatty acid ß-oxidation in proximal tubular epithelial cells as an endogenous mechanism to protect the kidney from phosphate toxicity. These findings highlight noncanonical metabolic reprogramming as a potential target for suppressing phosphate toxicity in the kidneys.

Postoperative long­term outcomes of acute normovolemic hemodilution in pancreatic cancer: A propensity score matching analysis.

Acute normovolemic hemodilution (ANH) is a useful intraoperative blood conservation technique. However, the impact on long-term outcomes in pancreatic ductal adenocarcinoma (PDAC) remains unclear. The present study investigated the impact of ANH on long-term outcomes in patients with PDAC undergoing radical surgery. Data from 155 resectable PDAC cases were collected. Patients were categorized according to whether or not they had received intraoperative allogeneic blood transfusion (ABT) or ANH. Postoperative complications, recurrence-free survival (RFS) and disease-specific survival (DSS), before and after propensity score matching (PSM), were compared among patients who did and did not receive ANH. A total of 44 patients (28.4%) were included in the ANH group and 30 patients (19.4%) were included in the ABT group; 81 (52.3%) patients, comprising the standard management (STD) group, received neither ANH nor ABT. The ABT group had the worst prognosis among them. Before PSM, ANH was significantly associated with decreased RFS (P=0.043) and DSS (P=0.029) compared with the STD group before applying Bonferroni correction; however, no significant difference was observed after applying Bonferroni correction. Cox regression analysis identified ANH as an independent prognostic factor for RFS [relative risk (RR), 1.696; P=0.019] and DSS (RR, 1.876; P=0.009). After PSM, the ANH group exhibited less favorable RFS [median survival time (MST), 12.1 vs. 18.1 months; P=0.097] and DSS (MST, 32.1 vs. 50.5 months; P=0.097) compared with the STD group; however, these differences were not statistically significant. In conclusion, while ANH was not as harmful as ABT, it exhibited potentially more negative effects on long-term postoperative outcomes in PDAC than STD.

Clinical Features of 544 Patients With Ruptured Aortic Aneurysm　- A Report From the Tokyo Acute Aortic Super Network Database.

BACKGROUND: Epidemiological data on ruptured aortic aneurysms from large-scale studies are scarce. The aims of this study were to: clarify the clinical course of ruptured aortic aneurysms; identify aneurysm site-specific therapies and outcomes; and determine the clinical course of patients receiving conservative therapy. METHODS AND RESULTS: Using the Tokyo Acute Aortic Super Network database, we retrospectively analyzed 544 patients (mean [±SD] age 78±10 years; 70% male) with ruptured non-dissecting aortic aneurysms (AAs) after excluding those with impending rupture. Patient characteristics, status on admission, therapeutic strategy, and outcomes were evaluated. Shock or pulselessness on admission were observed in 45% of all patients. Conservative therapy, endovascular therapy (EVT), and open surgery (OS) accounted for 32%, 23%, and 42% of cases, respectively, with corresponding mortality rates of 93%, 30%, and 29%. The overall in-hospital mortality rate was 50%. The prevalence of pulselessness was highest (48%) in the ruptured ascending AA group, and in-hospital mortality was the highest (70%) in the ruptured thoracoabdominal AA group. Multivariable logistic regression analysis indicated in-hospital mortality was positively associated with pulselessness (odds ratio [OR] 10.12; 95% confidence interval [CI] 4.09-25.07), and negatively associated with invasive therapy (EVT and OS; OR 0.11; 95% CI 0.06-0.20). CONCLUSIONS: The outcomes of ruptured AAs remain poor; emergency invasive therapy is essential to save lives, although it remains challenging to reduce the risk of death.

Efficacy and Safety of Warfarin for the Treatment of Venous Thromboembolism　- A Multicenter Prospective Observational Cohort Study in Japan (AKAFUJI Study).

BACKGROUND: A large-scale prospective study of the efficacy and safety of warfarin for the treatment of venous thromboembolism (VTE) has not been conducted in Japan. Therefore, we conducted a real-world prospective multicenter observational cohort study (AKAFUJI Study; UMIN000014132) to investigate the efficacy and safety of warfarin for VTE.Methods and Results: Between May 2014 and March 2017, 352 patients (mean [±SD] age 67.7±14.8 years; 57% female) with acute symptomatic/asymptomatic VTE were enrolled; 284 were treated with warfarin. The cumulative incidence of recurrent symptomatic VTE was higher in patients without warfarin than in those treated with warfarin (8.7 vs. 2.2 per 100 person-years, respectively; P=0.018). The cumulative incidence of bleeding complications was not significantly different between the 2 groups. The mean prothrombin time-international normalized ratio (PT-INR) during warfarin on-treatment was <1.5 in 180 patients, 1.5-2.5 in 97 patients, and >2.5 in 6 patients. The incidence of bleeding complications was significantly higher in patients with PT-INR >2.5, whereas the incidence of recurrent VTE was not significantly different between the 3 PT-INR groups. The cumulative incidence of recurrent VTE and bleeding complications did not differ significantly among those in whom VTE was provoked by a transient risk factor, was unprovoked, or was associated with cancer. CONCLUSIONS: Warfarin therapy with an appropriate PT-INR according to Japanese guidelines is effective without increasing bleeding complications, regardless of patient characteristics.

A new insight into superacute care for type A acute aortic dissection in the Tokyo Acute Aortic Super Network.

OBJECTIVE: To determine the status of type A acute aortic dissection using the Tokyo Acute Aortic Super Network. METHODS: Data of 6283 patients with acute aortic dissection between 2015 and 2019 were collected. Data of 3303 patients with type A acute aortic dissection were extracted for analysis. RESULTS: Overall, 51.0% of patients were nondirect admissions. On arrival, 23.1% of patients were in shock, 10.0% in cardiopulmonary arrest, and 11.8% in deep coma or coma. Overall, 9.8% of patients were assessed as untreatable. Of 2979 treatable patients, 18.3% underwent medical treatment, whereas 80.7% underwent surgery (open [78.8%], endovascular [1.9%], and peripheral [1.1%] repair). The early mortality rate was 20.5%, including untreatable cases. Among treatable patients, in-hospital mortality rates were 8.6% for open repair, 10.7% for endovascular repair, and 25.3% for medical treatment. Advanced age, preoperative comorbidities, classical dissection, and medical treatment were risk factors for in-hospital mortality. Nondirect admission did not cause increased deaths. The mortality rates were high during the superacute phase following symptom onset. CONCLUSIONS: This study demonstrated current practices in the emergency care of type A acute aortic dissection via the Tokyo Acute Aortic Super Network system, specifically a high rate of untreatable or inoperable cases and favorable outcomes in patients undergoing surgical treatment. High mortality rates were observed during the super acute phase after symptom onset or hospital arrival.

Outcomes of type A acute aortic dissection with cardiopulmonary arrest: Tokyo Acute Aortic Super-network Registry.

OBJECTIVES: Preventing loss of life in patients with type A acute aortic dissection (AAD) who present with cardiopulmonary arrest (CPA) can be extremely difficult. Thus, we investigated the early outcomes in these patients. METHODS: Patients with type A AAD who were transported to hospitals belonging to the Tokyo Acute Aortic Super-network between January 2015 and December 2019 were considered for this study. We assessed the early mortality of these patients presenting with CPA and also investigated the differences in outcomes between patients with out-of-hospital and in-hospital CPA. RESULTS: A total of 3307 patients with type A AAD were transported, 434 (13.1%) of whom presented with CPA. The overall mortality of patients presenting with CPA was 88.2% (383/434), of which 94.5% (240/254) experienced out-of-hospital CPA and 79.4% (143/180) experienced in-hospital CPA (P < 0.001). Multivariable analysis revealed that aortic surgery [odds ratio (OR), 0.022; 95% confidence interval (CI), 0.008-0.060; P < 0.001] and patient age over 80 years (OR, 2.946; 95% CI, 1.012-8.572; P = 0.047) were related with mortality in patients with type A AAD and CPA. Between in-hospital and out-of-hospital CPA, the proportions of DeBakey type 1 (OR, 2.32; 95% CI, 1.065-5.054; P = 0.034), cerebral malperfusion (OR, 0.188; 95% CI, 0.056-0.629; P = 0.007), aortic surgery (OR, 0.111; 95% CI, 0.045-0.271; P = 0.001), age (OR, 0.969; 95% CI, 0.940-0.998; P = 0.039) and the time from symptom onset to hospital admission (OR, 1.122; 95% CI, 1.025-1.228; P = 0.012) were significantly different. CONCLUSIONS: Patients with type A AAD presenting with CPA exhibited extremely high rates of death. Patient outcomes following in-hospital CPA tended to be better than those following out-of-hospital CPA; however, this difference was not significantly different. To prevent deaths, aortic surgery, when possible, should be considered in patients with type A AAD who sustained CPA.

[A Case of Long-Term Survival of Breast Cancer with Extra-Regional Lymph Node Metastases].

We present the case of a 65-year-old woman who presented with nipple retraction of her left breast. The patient has a family history of breast cancer. She was diagnosed with bilateral breast cancer with left axillary, cervical, and mediastinal lymph node metastasis(right breast cancer, cT1cN0M0, cStage Ⅰ, Luminal A-like, left breast cancer, cT2N3bM1[LYM], Stage Ⅳ, triple negative type). She was recommended chemotherapy due to her inoperable advanced-stage breast cancer. After 6 courses of administration of AC chemotherapy(doxorubicin and cyclophosphamide)and 5 courses of tri-weekly docetaxel chemotherapy, shrinkage of the primary lesion and disappearance of each swollen lymph node were observed via computed tomography. Surgery was performed 11 weeks post-chemotherapy. Residual lesions, less than 10 mm in size in both the left and right breast masses, were observed. No lymph node metastasis was observed. Four years later, no signs of recurrence have been noted.

Angioscopic findings 1 year after percutaneous coronary intervention for chronic total occlusion.

BACKGROUND: Chronic total occlusion (CTO) is a high-risk factor for stent thrombosis, but little is known about the difference in neointimal healing between CTO and non-CTO lesions regarding implanted stents. We investigated factors affecting neointimal healing after stent implantation for CTO and non-CTO lesions using angioscopy. METHODS: We retrospectively evaluated 106 stents in 85 consecutive patients between March 2016 and July 2020. Their average age was 68 ±â€¯11 years, and participants (73 male and 12 female) underwent follow-up angiography and angioscopy 1 year after percutaneous coronary intervention (PCI). The stents (n = 106) were divided into three groups according to the lesion status at the previous PCI: CTO (n = 17), acute coronary syndrome (ACS) (n = 35), and stable coronary artery disease without CTO or non-CTO (n = 54). RESULTS: The neointimal stent coverage grade was significantly lower in the CTO and ACS groups than in the non-CTO group (0.4 ±â€¯0.5, 0.9 ±â€¯0.8, and 1.4 ±â€¯0.8, respectively, p < 0.001). Thrombi were significantly more frequent in CTO and ACS than in non-CTO (71 %, 51 %, and 15 %, respectively, p < 0.001). The yellow grade in CTO was comparable to that in ACS but significantly higher in CTO than in non-CTO (CTO vs. ACS vs. non-CTO 1.5 ±â€¯0.7, 1.4 ±â€¯0.6, and 0.9 ±â€¯0.7, respectively, p = 0.007). CONCLUSIONS: Delayed healing occurs in stents implanted for CTO lesions. Longer dual-antithrombotic therapy may be beneficial.

Sex Differences in DeBakey Type I/II Acute Aortic Dissection Outcomes: The Tokyo Acute Aortic Super-network.

Background: Sex differences in the clinical presentation and outcomes of DeBakey type I/II (Stanford type A) acute aortic dissection (AAD) remain unclear. Objectives: The authors aimed to determine the impact of sex on the clinical presentation and in-hospital outcomes of surgically or medically treated patients with type I/II AAD. Methods: We studied 3,089 patients with type I/II AAD enrolled in multicenter Japanese registry between 2013 and 2018. The patients were divided into 2 treatment groups: surgical and medical. Multivariable logistic regression was used to examine the association between sex and in-hospital mortality. Results: In the entire cohort, women were older and more likely to have hyperlipidemia, previous stroke, altered consciousness, and shock/hypotension at presentation than men. Women had higher proportions of intramural hematomas and type II dissections than men. In the surgical group (n = 2,543), men had higher rates of preoperative end-organ malperfusion (P = 0.003) and in-hospital mortality (P = 0.002) than women. Multivariable analysis revealed that male sex was associated with higher in-hospital mortality after surgery (OR: 1.71; 95% CI: 1.24-2.35; P < 0.001). In the medical group (n = 546), women were older and had higher rates of cardiac tamponade (P = 0.004) and in-hospital mortality (P = 0.039) than men; no significant association between sex and in-hospital mortality was found after multivariable adjustment (OR: 0.95; 95% CI: 0.56-1.59; P = 0.832). Conclusions: Male sex was associated with higher in-hospital mortality for type I/II AAD in the surgical group but not in the medical group. Further research is needed to understand the mechanisms responsible for worse surgical outcomes in men.

[Treatment Strategy for Stage â £ Rectal Cancer Considering Local Treatment Outcomes].

We investigated 36 patients with Stage Ⅳ rectal cancer who underwent primary resection in our department between November 2015 and June 2020. Tumor localization was upper in 20 cases and lower in 16 cases. Six patients had the cT4b stage at initial diagnosis, and lateral lymph node metastases were detected in 6 cases. Preoperative treatment consisted of doublet chemotherapy in 20 cases, in combination with bevacizumab in 17 cases. Surgery for distant metastases was performed in 21 patients, and the final results were curative(Cur B)in 20 patients and palliative(Cur C)in 16 patients. Perioperative mortality was observed only in Cur C patients(5.6%). The local R1 resection rates in Cur B and Cur C patients were 10.0% and 18.8%, respectively, and the corresponding local RM≤1 mm rates were 55.0% and 43.8%. Additionally, the local recurrence rates were 25.0% and 0%, and the 3-year OS rates were 80.9% and 25.5%, respectively, in Cur B and Cur C patients. In Cur B, the local RM≤1 mm rates in the preoperative and non-preoperative treatment groups were 38.5% and 85.7%, respectively, and the corresponding local R1 resection rates were 7.7% and 14.3%. Additionally, the 3-year local recurrence-free survival rates were 68.2% and 66.7% and the 3-year OS rates were 82.1% and 80.0%, respectively, in the preoperative and non-preoperative treatment groups. We determined that preoperative chemotherapy alone is not sufficient for the local treatment of Stage Ⅳ rectal cancer, and concomitant preoperative radiotherapy should be considered. The prognosis of patients with Cur C is poor, and surgery-related deaths have been observed, which can be a problem for the palliative resection strategy.

Dantrolene reduces platelet-derived growth factor (PDGF)-induced vascular smooth muscle cell proliferation and neointimal formation following vascular injury in mice.

Dantrolene is a ryanodine receptor blocker that is used clinically for treatment of malignant hyperthermia. This study was conducted using murine aortic vascular smooth muscle cells (MOVAS) and a mouse arterial injury model to investigate the inhibitory effect of dantrolene on smooth muscle cell proliferation and migration. We investigated whether dantrolene suppressed platelet-derived growth factor (PDGF)-induced vascular smooth muscle cell proliferation and migration in vitro. The effect of dantrolene on smooth muscle phenotype was evaluated using immunostaining. In addition, smooth muscle cell proliferation and phenotype switching were tested by applying dantrolene around blood vessels using a mouse arterial injury model. Dantrolene inhibited PDGF-induced cell proliferation and migration of MOVAS. Dantrolene also inhibited the switch from contractile to synthetic phenotype both in vitro and in vivo. Dantrolene is effective at inhibiting vascular smooth muscle cell proliferation, migration, and neointimal formation following arterial injury in mice.

Sex-Related Differences in Clinical Features and In-Hospital Outcomes of Type B Acute Aortic Dissection: A Registry Study.

Background The association between female sex and poor outcomes following surgery for type A acute aortic dissection has been reported; however, sex-related differences in clinical features and in-hospital outcomes of type B acute aortic dissection, including classic aortic dissection and intramural hematoma, remain to be elucidated. Methods and Results We studied 2372 patients with type B acute aortic dissection who were enrolled in the Tokyo Acute Aortic Super-Network Registry. There were fewer and older women than men (median age [interquartile range]: 76 years [66-84 years], n=695 versus 68 years [57-77 years], n=1677; P<0.001). Women presented to the aortic centers later than men. Women had a higher proportion of intramural hematoma (63.7% versus 53.7%, P<0.001), were medically managed more frequently (90.9% versus 86.3%, P=0.002), and had less end-organ malperfusion (2.4% versus 5.7%, P<0.001) and higher in-hospital mortality (5.3% versus 2.7%, P=0.002) than men. In multivariable analysis, age (per year, odds ratio [OR], 1.06 [95% CI, 1.03-1.08]; P<0.001), hyperlipidemia (OR, 2.09 [95% CI, 1.13-3.88]; P=0.019), painlessness (OR, 2.59 [95% CI, 1.14-5.89]; P=0.023), shock/hypotension (OR, 2.93 [95% CI, 1.21-7.11]; P=0.017), non-intramural hematoma (OR, 2.31 [95% CI, 1.32-4.05]; P=0.004), aortic rupture (OR, 26.6 [95% CI, 14.1-50.0]; P<0.001), and end-organ malperfusion (OR, 4.61 [95% CI, 2.11-10.1]; P<0.001) were associated with higher in-hospital mortality, but was not female sex (OR, 1.67 [95% CI, 0.96-2.91]; P=0.072). Conclusions Women affected with type B acute aortic dissection were older and had more intramural hematoma, a lower incidence of end-organ malperfusion, and higher in-hospital mortality than men. However, female sex was not associated with in-hospital mortality after multivariable adjustment.

Cholinergic anti-inflammatory pathway ameliorates murine experimental Th2-type colitis by suppressing the migration of plasmacytoid dendritic cells.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease. Several studies have demonstrated that α7 nicotinic acetylcholine receptors (α7nAChRs) exert anti-inflammatory effects on immune cells and nicotine suppress UC onset and relapse. Plasmacytoid dendritic cells (pDCs) reportedly accumulate in the colon of UC patients. Therefore, we investigated the pathophysiological roles of α7nAChRs on pDCs in the pathology of UC using oxazolone (OXZ)-induced Th2-type colitis with BALB/c mice. 2-deoxy-D-glucose, a central vagal stimulant suppressed OXZ colitis, and nicotine also ameliorated OXZ colitis with suppressing Th2 cytokines, which was reversed by α7nAChR antagonist methyllycaconitine. Additionally, α7nAChRs were expressed on pDCs, which were located very close to cholinergic nerve fibers in the colon of OXZ mice. Furthermore, nicotine suppressed CCL21-induced bone marrow-derived pDC migration due to Rac 1 inactivation, which was reversed by methyllycaconitine, a JAK2 inhibitor AG490 or caspase-3 inhibitor AZ-10417808. CCL21 was mainly expressed in the isolated lymphoid follicles (ILFs) of the colon during OXZ colitis. The therapeutic effect of cholinergic pathway on OXZ colitis probably through α7nAChRs on pDCs were attributed to the suppression of pDC migration toward the ILFs. Therefore, the activation of α7nAChRs has innovative therapeutic potential for the treatment of UC.

Pathophysiological Roles of Neuro-Immune Interactions between Enteric Neurons and Mucosal Mast Cells in the Gut of Food Allergy Mice.

Recently, the involvement of the nervous system in the pathology of allergic diseases has attracted increasing interest. However, the precise pathophysiological role of enteric neurons in food allergies has not been elucidated. We report the presence of functional high-affinity IgE receptors (FcεRIs) in enteric neurons. FcεRI immunoreactivities were observed in approximately 70% of cholinergic myenteric neurons from choline acetyltransferase-eGFP mice. Furthermore, stimulation by IgE-antigen elevated intracellular Ca2+ concentration in isolated myenteric neurons from normal mice, suggesting that FcεRIs are capable of activating myenteric neurons. Additionally, the morphological investigation revealed that the majority of mucosal mast cells were in close proximity to enteric nerve fibers in the colonic mucosa of food allergy mice. Next, using a newly developed coculture system of isolated myenteric neurons and mucosal-type bone-marrow-derived mast cells (mBMMCs) with a calcium imaging system, we demonstrated that the stimulation of isolated myenteric neurons by veratridine caused the activation of mBMMCs, which was suppressed by the adenosine A3 receptor antagonist MRE 3008F20. Moreover, the expression of the adenosine A3 receptor gene was detected in mBMMCs. Therefore, in conclusion, it is suggested that, through interaction with mucosal mast cells, IgE-antigen-activated myenteric neurons play a pathological role in further exacerbating the pathology of food allergy.

Empagliflozin confers reno-protection in acute myocardial infarction and type 2 diabetes mellitus.

AIMS: Although the reno-protective effects of sodium-glucose cotransporter 2 inhibitors are known in patients with heart failure or type 2 diabetes mellitus (T2DM), this effect has not been confirmed in patients with acute myocardial infarction (AMI). METHODS AND RESULTS: The prospective, multicentre, randomized, double-blind, placebo-controlled EMBODY trial investigated patients with AMI and T2DM in Japan. The eligible patients included adults aged 20 years or older, diagnosed with AMI and T2DM, and who could be discharged within 2-12 weeks after the onset of AMI. One hundred and five patients were randomized (1:1) to receive once daily 10 mg empagliflozin or placebo within 2 weeks of AMI onset. In this sub-analysis, we investigated the time course of renal functional parameters such as serum creatinine levels and estimated glomerular filtration rate (eGFR) from baseline to Weeks 4, 12, and 24. Ninety-six patients (64 ± 11 years, 78 male) were included in the full analysis (n = 46 and 50 in the empagliflozin and placebo groups, respectively). We used serum creatinine and eGFR as indicators of renal function. In the placebo group, eGFR decreased from 66.14 mL/min/1.73 m2 at baseline to 62.77 mL/min/1.73 m2 by Week 24 (P = 0.023) but remained unchanged in the empagliflozin group (from 64.60 to 64.36 mL/min/1.73 m2 , P = 0.843). In the latter group, uric acid improved from 5.8 mg/dL at baseline to 4.9 mg/dL at Week 24 (P < 0.001). In the earlier analysis of 56 patients with eGFR ≥ 60 mL/min/1.73 m2 , the eGFR decreased and the serum creatinine increased from baseline to 24 weeks in the placebo group, significantly different to the empagliflozin group (-6.61 vs. +0.22 mL/min/1.73 m2 , P = 0.008 and +0.063 vs. -0.001 mg/dL, P = 0.030, respectively). The changes in serum creatinine and eGFR from baseline to Week 24 were significantly correlated with those in uric acid in the placebo group (r = 0.664, P < 0.001 and r = -0.675, P < 0.001, respectively) but not in the empagliflozin group. CONCLUSIONS: Empagliflozin prevented the kidney functional decline in patients with AMI and T2DM, especially those with baseline eGFR ≥ 60 mL/min/1.73 m2 . Early administration of sodium-glucose cotransporter 2 inhibitors in these patients is considered desirable for renal protection.