Long-Term Culture Captures Injury-Repair Cycles of Colonic Stem Cells.

The colonic epithelium can undergo multiple rounds of damage and repair, often in response to excessive inflammation. The responsive stem cell that mediates this process is unclear, in part because of a lack of in vitro models that recapitulate key epithelial changes that occur in vivo during damage and repair. Here, we identify a Hopx+ colitis-associated regenerative stem cell (CARSC) population that functionally contributes to mucosal repair in mouse models of colitis. Hopx+ CARSCs, enriched for fetal-like markers, transiently arose from hypertrophic crypts known to facilitate regeneration. Importantly, we established a long-term, self-organizing two-dimensional (2D) epithelial monolayer system to model the regenerative properties and responses of Hopx+ CARSCs. This system can reenact the "homeostasis-injury-regeneration" cycles of epithelial alterations that occur in vivo. Using this system, we found that hypoxia and endoplasmic reticulum stress, insults commonly present in inflammatory bowel diseases, mediated the cyclic switch of cellular status in this process.

Repression of the aryl-hydrocarbon receptor prevents oxidative stress and ferroptosis of intestinal intraepithelial lymphocytes.

The aryl-hydrocarbon receptor (AHR) is a ligand-activated transcription factor that buoys intestinal immune responses. AHR induces its own negative regulator, the AHR repressor (AHRR). Here, we show that AHRR is vital to sustaining intestinal intraepithelial lymphocytes (IELs). AHRR deficiency reduced IEL representation in a cell-intrinsic fashion. Single-cell RNA sequencing revealed an oxidative stress profile in Ahrr-/- IELs. AHRR deficiency unleashed AHR-induced expression of CYP1A1, a monooxygenase that generates reactive oxygen species, increasing redox imbalance, lipid peroxidation, and ferroptosis in Ahrr-/- IELs. Dietary supplementation with selenium or vitamin E to restore redox homeostasis rescued Ahrr-/- IELs. Loss of IELs in Ahrr-/- mice caused susceptibility to Clostridium difficile infection and dextran sodium-sulfate-induced colitis. Inflamed tissue of inflammatory bowel disease patients showed reduced Ahrr expression that may contribute to disease. We conclude that AHR signaling must be tightly regulated to prevent oxidative stress and ferroptosis of IELs and to preserve intestinal immune responses.

Single-carrier 220-Gbit/s sub-THz wireless transmission over 214†m using a photonics-based system.

We have demonstrated, for the first time to our knowledge, a single-carrier 220-Gbit/s wireless link over 214-m distance within hard-decision forward error correction (HD-FEC) limit using a 300-GHz-band photonics-based system incorporated with on-line digital signal processing (DSP). The approach to obtaining these results was to optimize the transmission system by using a low-noised two-tone laser system to the transmitter and receiver and to apply the unique Fresnel region of the antenna to achieve longer distances. These research results are expected to serve as a low-cost and basic communication system technology for promising backhaul wireless communications in the sixth-generation era.

Mesothelium-Derived Factors Shape GATA6-Positive Large Cavity Macrophages.

The local microenvironment shapes macrophage differentiation in each tissue. We hypothesized that in the peritoneum, local factors in addition to retinoic acid can support GATA6-driven differentiation and function of peritoneal large cavity macrophages (LCMs). We found that soluble proteins produced by mesothelial cells lining the peritoneal cavity maintained GATA6 expression in cultured LCMs. Analysis of global gene expression of isolated mesothelial cells highlighted mesothelin (Msln) and its binding partner mucin 16 (Muc16) as candidate secreted ligands that potentially regulate GATA6 expression in peritoneal LCMs. Mice deficient for either of these molecules showed diminished GATA6 expression in peritoneal and pleural LCMs that was most prominent in aged mice. The more robust phenotype in older mice suggested that monocyte-derived macrophages were the target of Msln and Muc16. Cell transfer and bone marrow chimera experiments supported this hypothesis. We found that lethally irradiated Msln-/- and Muc16-/- mice reconstituted with wild-type bone marrow had lower levels of GATA6 expression in peritoneal and pleural LCMs. Similarly, during the resolution of zymosan-induced inflammation, repopulated peritoneal LCMs lacking expression of Msln or Muc16 expressed diminished GATA6. These data support a role for mesothelial cell-produced Msln and Muc16 in local macrophage differentiation within large cavity spaces such as the peritoneum. The effect appears to be most prominent on monocyte-derived macrophages that enter into this location as the host ages and also in response to infection.

Antimicrobial therapy and outcome of methicillin-resistant Staphylococcus aureus endocarditis: A retrospective multicenter study in Japan.

BACKGROUND: MRSA (methicillin-resistant Staphylococcus aureus)-infective endocarditis (IE) is associated with high morbidity and mortality. This study aimed to assess data from patients with MRSA-IE across multiple facilities in Japan, with a specific focus on antimicrobial therapy and prognosis. METHODS: This retrospective study enrolled patients with a confirmed diagnosis of IE attributed to MRSA, spanning the period from January 2015 to April 2019. RESULTS: Sixty-four patients from 19 centers were included, with a median age of 67 years. The overall mortality rate was 28.1% at 30 days, with an in-hospital mortality of 45.3%. The most frequently chosen initial anti-MRSA agents were glycopeptide in 67.2% of cases. Daptomycin and linezolid were selected as initial therapy in 23.4% and 17.2% of cases, respectively. Approximately 40% of all patients underwent medication changes due to difficulty in controlling infection or drug-related side effects. Significant prognostic factors by multivariable analysis were DIC for 30-day mortality and surgical treatment for 30-day and in-hospital mortality. For vancomycin as initial monotherapy, there was a trend toward a worse prognosis for 30-day and in-hospital mortality (OR, 6.29; 95%CI, 1.00-39.65; p = 0.050, OR, 3.61; 95%CI, 0.93-14.00; p = 0.064). Regarding the choice of initial antibiotic therapy, statistical analysis did not show significant differences in prognosis. CONCLUSION: Glycopeptide and daptomycin were the preferred antibiotics for the initial therapy of MRSA-IE. Antimicrobial regimens were changed for various reasons. Prognosis was not significantly affected by choice of antibiotic therapy (glycopeptide, daptomycin, linezolid), but further studies are needed to determine which antimicrobials are optimal as first-line agents.

Clinical characteristics and analysis of prognostic factors in methicillin-resistant Staphylococcus aureus endocarditis: A retrospective multicenter study in Japan.

BACKGROUND: Infective endocarditis (IE) caused by MRSA (methicillin-resistant Staphylococcus aureus) is associated with a high mortality rate. This study aimed to elucidate the characteristics of patients with MRSA-IE in Japan and identify the factors associated with prognosis. METHODS: This retrospective study included patients with a confirmed diagnosis of IE caused by MRSA, between January 2015 and April 2019. RESULTS: A total of 65 patients from 19 centers were included, with a mean age of 67 years and 26 % were female. Fifty percent of the patients with IE were had nosocomial infections and 25 % had prosthetic valve involvement. The most common comorbidities were hemodialysis (20 %) and diabetes (20 %). Congestive heart failure was present in 86 % of patients (NYHA class I, II: 48 %; III, IV: 38 %). The 30-day and in-hospital mortality rates were 29 % and 46 %, respectively. Multi-organ failure was the primary cause of death, accounting for 43 % of all causes of death. Prognostic factors for in-hospital mortality were age, disseminated intravascular coagulation, daptomycin and/or linezolid as initial antibiotic therapy, and surgery. Surgical treatment was associated with a lower mortality rate (odds ratio [OR], 0.026; 95 % confidence interval [CI], 0.002-0.382; p = 0.008 for 30-day mortality and OR, 0.130; 95 % CI; 0.029-0.584; p = 0.008 for in-hospital mortality). CONCLUSION: Mortality due to MRSA-IE remains high. Surgical treatment is a significant prognostic predictor of MRSA-IE.

Behçet's Disease with Extremely High Levels of Urinary ß2-Microglobulin after Non-Steroidal Anti-Inflammatory Drug Treatment.

Behçet's disease is an inflammatory disease which manifests itself as various symptoms, such as uveitis, oral and genital aphthae, erythema nodosa, gastro-intestinal ulcerations and encephalopathy. Among the manifestations, renal dysfunction is reported in some percentage of the patients with this disorder. We experienced a middle-aged male with Behçet's disease who showed an extremely high level of urinary ß2-microglulin, which is one of the markers of renal dysfunction, despite normal serum creatinine levels. The patient was on non-steroidal anti-inflammatory drug (NSAID) therapy for 7 weeks, and this could have affected his renal dysfunction. The present report suggests that renal injury should not be underestimated in patients with Behçet's disease, especially in patients using NSAIDs.

Current knowledge among Japanese experienced general dentists regarding prevention of infective endocarditis.

Infective endocarditis (IE), a life-threatening condition predominantly occurring in patients with underlying heart disease, is mainly caused by bacteremia induced by invasive dental treatment. However, the amount of related information shared between cardiologists and dentists appears to be inadequate. In the present study, a survey regarding prevention of IE, composed of 13 major questions, 2 of which also allowed free comments, was sent to approximately 3000 dentists belonging to a prefectural dental association in Japan. Of the 13.6% who returned the forms, more than 80% were general dentists with more than 20 years of experience. Approximately, 55% of the responders reported that they had opportunities to prescribe antibiotics prior to performing treatments with risk of IE, though noted difficulties with designation of which patients with heart disease were at risk. Most of the dentists considered that oral surgery procedures have a high risk for IE, whereas less invasive procedures were considered to be not associated with the disease. Approximately, 35% selected oral amoxicillin, with a dose of 2.0 g (20%) or 500 mg (27%) prescribed for adults, and 50 mg (10%) or 30 mg (12%) per kg of body weight for children. However, the timing of the antibiotics administration varied. The present results reveal current knowledge regarding prevention of IE among general dentists in Japan, and should be valuable for construction of a protocol to establish consensus between dentists and cardiologists.

Improvement in Exercise Capacity by Exercise Training Associated With Favorable Clinical Outcomes in Advanced Heart Failure With High B-Type Natriuretic Peptide Level.

BACKGROUND: The efficacy of exercise training (ET) programs and its relationship with long-term clinical outcomes in advanced heart failure (HF) patients with high levels of B-type natriuretic peptide (BNP) remain uncertain.Methods and Results:We studied 340 consecutive HF patients with ejection fraction (EF) <45% who completed a 3-month ET program. Patients with BNP ≥200 pg/mL (High-BNP, n=170) had more advanced HF characteristics, including lower EF (25.0±8.6% vs. 28.1±8.0%, P=0.0008), than those with BNP <200 pg/mL. In the High-BNP patients, peak oxygen uptake (V̇O2) was significantly increased by 8.3±16.2% during the ET program, and changes in peak V̇O2inversely correlated with changes in BNP (R=-0.453, P<0.0001) and changes in ventilatory efficiency (V̇E/V̇CO2slope) (R=-0.439, P<0.0001). During a median follow-up of 46 months, patients in the upper tertile of changes in peak V̇O2(≥13.0%), compared with those in the lower tertile (<1.0%), had lower rates of the composite of all-cause death or HF hospitalization (37.9% vs. 54.4%, P=0.036) and all-cause death (8.6% vs. 24.6%, P=0.056). In the multivariate analysis, change in peak V̇O2was a significant independent predictor of the composite outcome and all-cause death. CONCLUSIONS: Even among advanced HF patients with high BNP level, an ET program significantly improved exercise capacity, and a greater improvement in exercise capacity was associated with greater decreases in BNP level and V̇E/V̇CO2slope and more favorable long-term clinical outcomes.

Effect of Mitral Valve Surgery in Patients With Dilated Cardiomyopathy and Severe Functional Mitral Regurgitation.

BACKGROUND: Surgical treatment of functional mitral regurgitation (FMR) improves ventricular remodeling in patients with dilated cardiomyopathy (DCM). However, it is unclear whether surgical treatment improves long-term outcomes. We investigated the effects of mitral valve (MV) surgery in patients with DCM and FMR.Methods and Results:Of 525 patients with DCM hospitalized due to heart failure between January 1996 and September 2014, 70 who had severe FMR despite receiving optimal medical therapy were enrolled in the study. Of these patients, 16 underwent surgery for FMR (surgery group; repair=14, replacement=2); the remaining 54 who refused or decided not to undergo surgery were classified as the medication group. There were no differences in age, sex, medication, or echocardiographic parameters between the 2 groups (P>0.05). During the mean follow-up period of 53.6±43.6 months, the occurrence of clinical outcomes (i.e., all-cause death or left ventricular assist device implantation) was 54.3%; the occurrence of clinical outcomes was lower in the surgery group (P=0.008, log-rank test). Multivariate Cox regression analysis using clinical data revealed that MV surgery (hazard ratio [HR] 0.257, 95% confidence interval [CI] 0.103-0.640; P=0.004) and diabetes mellitus (HR 2.924, 95% CI 1.243-6.876; P=0.014) were independent predictors of clinical outcomes after adjusting for age and sex. CONCLUSIONS: Surgery for severe FMR provides better long-term outcomes in patients with DCM.

Prognostic Impact of Functional Mitral Regurgitation in Patients Admitted With Acute Decompensated Heart Failure.

BACKGROUND: Functional mitral regurgitation (FMR) is a common complication of heart failure (HF) and worsens in acute decompensation. It is unclear whether FMR on admission or discharge determines the outcome. This study aimed to elucidate the prognostic significance of FMR on admission or discharge in patients admitted with acute decompensated HF. METHODS AND RESULTS: From 2006 to 2009, 349 patients admitted with acute decompensated HF were enrolled. They were followed with the composite endpoint of all-cause death and hospitalization for HF; 74 (21%) died and 113 (32%) developed the composite endpoint during 2.1±1.3 years. Moderate/severe FMR at discharge was associated with the composite endpoint (P=0.001), whereas that on admission was not. Multivariate Cox proportional hazard analysis showed that moderate/severe FMR (hazard ratio [95% confidence interval] =1.70 [1.03-2.73] P=0.04), logBNP, and NYHA class III/IV at discharge were independent determinants of the outcome. Moderate/severe FMR at discharge with BNP ≥200 pg/ml was prognostic, but BNP <200 pg/ml was no longer prognostic. CONCLUSIONS: Residual moderate/severe FMR after medical therapy for acute decompensated HF was associated with poor outcome, suggesting a potential target for further treatment of HF.

Prognostic significance of late gadolinium enhancement quantification in cardiac magnetic resonance imaging of hypertrophic cardiomyopathy with systolic dysfunction.

Hypertrophic cardiomyopathy (HCM) with systolic dysfunction carries a poor prognosis. Although late gadolinium enhancement (LGE) on cardiac magnetic resonance is associated with adverse cardiac events in HCM and is inversely related to left ventricular ejection fraction (LVEF), it is unknown whether LGE or LVEF more accurately predicts adverse cardiac events in HCM with systolic dysfunction. We retrospectively assessed the extent of LGE with a threshold of 6 standard deviations in 46 consecutive HCM patients with systolic dysfunction defined as LVEF <50 % (average 35 ± 12 %) who underwent cardiac magnetic resonance (35 males, mean age 59 ± 14 years). They were followed up over 1755 ± 594 days. The composite adverse cardiac events end point included cardiovascular death, lethal arrhythmia, cardioembolic stroke, and unplanned heart failure hospitalization. LGE was detected in all patients, and the mean extent was 30 ± 15 %. Twenty-nine patients developed adverse cardiac events. Multivariate Cox proportional hazard analysis revealed the extent of LGE as a good independent predictor of adverse cardiac events. Risk increased with the extent of LGE (hazard ratio = 1.62/10 % increase in LGE, 95 % confidence interval = 1.23-2.15, p < 0.001). LVEF was inversely related to the extent of LGE (r = -0.44; p = 0.002) and was also an independent predictor of adverse cardiac events. Risk decreased with LVEF (hazard ratio = 0.68/10 % increase in LVEF, 95 % confidence interval = 0.51-0.91, p = 0.010). The Akaike information criterion evaluating the fit of a model demonstrated that the extent of LGE was a better independent predictor of MACE than LVEF (Akaike information criterion = 172.20 and 178.09, respectively).The extent of LGE was a good independent predictor of adverse cardiac events and reflected mortality and morbidity more precisely than LVEF in HCM with systolic dysfunction.

The predictability of renin-angiotensin-aldosterone system factors for clinical outcome in patients with acute decompensated heart failure.

Although counter-regulation between B-type natriuretic peptide (BNP) levels and renin-angiotensin-aldosterone system (RAAS) activation in heart failure (HF) has been suggested, whether the regulation is preserved in acute decompensated heart failure (ADHF) patients remains unclear. This study aimed to determine: (1) the relationship between RAAS activation and clinical outcomes in ADHF patients, and (2) the relationships between plasma BNP levels and degrees of activation in RAAS factors. This study included ADHF patients (n = 103, NYHA3-4, plasma BNP > 200 pg/ml). We studied the predictability of RAAS factors for cardiovascular events and the relationships between plasma BNP levels and the degrees of activation in RAAS factors, which were evaluated by plasma renin activity (PRA) and aldosterone concentration (PAC). PRA was a strong predictor of cardiovascular (CV) events over 1 year, even after accounting for plasma BNP levels (hazard ratio (HR): 1.04, CI [1.02-1.06], p < 0.01) and medication such as RAAS blockers (HR: 1.03, CI [1.01-1.05], p < 0.01), whereas PAC was borderline-significant (univariate analysis, p = 0.06). Cut-off value of PRA (5.3 ng/ml/h) was determined by AUC curve. Of the enrolled patients, higher PRA was found in 40 % of them. Although no correlation between the plasma BNP levels and PRA was found (p = 0.36), after adjusting for hemodynamic parameters, eGFR and medication, a correlation was found between them (p = 0.01). Elevated RAAS factors were found in a substantial number of ADHF patients with high plasma BNP levels in the association with hemodynamic state, which predicts poor clinical outcomes. The measurements of RAAS factors help to stratify ADHF patients at risk for further CV events.

Impact of left ventricular diastolic dysfunction on outcome of catheter ablation for atrial fibrillation in patients with hypertrophic cardiomyopathy.

BACKGROUND: The relationship between outcome of radiofrequency catheter ablation (RFCA) for atrial fibrillation (AF) and the severity of left ventricular (LV) diastolic dysfunction in patients with hypertrophic cardiomyopathy (HCM) remains unknown. METHODS AND RESULTS: Twenty-two HCM patients (12 female, aged 65 ± 11 years) with paroxysmal (n=5; 23%) or persistent (n=17; 77%) AF were enrolled. LV diastolic function was evaluated according to the ratio of the mitral inflow early filling velocity to the velocity of the early medial mitral annular ascent (E/e') measured on pulsed wave and tissue Doppler assessments in all patients. Pulmonary vein isolation was performed in all patients. A second procedure was performed in 3 patients. During a follow-up of 21 ± 12 months, sinus rhythm was maintained in 13 of 22 patients (59%). E/e' was significantly higher in the patients with AF recurrence than in those without (18 ± 7 vs. 11 ± 3; P<0.01). On Kaplan-Meier analysis the prevalence of AF recurrence was significantly higher in patients with E/e' ≥ 15 (n=6) than in those with E/e' <15 (n=16; P<0.01). On multivariate Cox regression analysis the only significant and independent predictor for AF recurrence was E/e' (hazard ratio, 1.16; 95% confidence interval: 1.01-1.37, P=0.03). CONCLUSIONS: LV diastolic dysfunction evaluated using E/e' was associated with difficulty of rhythm control after RFCA in patients with HCM and AF.

Late aneurysm formation of Valsalva sinus after aortic valve replacement due to Takayasu's arteritis.

Takayasu's arteritis (TA) is an inflammatory disease of unknown etiology involving the aorta and its branches, and also causes aortic regurgitation (AR). One of the most serious but rare complications after aortic valve replacement (AVR) in TA is aneurysm formation of the sinus of Valsalva. A 64-year-old woman had undergone AVR with a prosthetic valve for AR due to TA 4 years earlier and had received an implanted permanent pacemaker for complete atrioventricular block (AVB) 2 years later. Aortography 4 years postoperatively demonstrated aneurysm formation (47 mm in diameter) at the sinus of Valsalva although preoperative aortography showed severe AR without dilatation of the sinus of Valsalva. We recommended reoperation for the aneurysm but the patient refused. The perioperative histopathological examination revealed extensive destruction of the medial elastic fibers. Both the fragility of the sinus of Valsalva and the residual inflammation could have caused the patient's aneurysm formation. Moreover, extension of TA into the ventricular septum or mechanical compression of the aneurysm against the conduction system might have caused her progressive AVB. Close and lifelong follow-up for patients with TA regarding development of aneurysm after surgical treatment is indispensable when fragility of the aortic root had been confirmed.

Pathophysiological impact of serum fibroblast growth factor 23 in patients with nonischemic cardiac disease and early chronic kidney disease.

Although the important role of fibroblast growth factor (FGF)23 on cardiac remodeling has been suggested in advanced chronic kidney disease (CKD), little is known about serum (s)FGF23 levels in patients with heart failure (HF) due to nonischemic cardiac disease (NICD) and early CKD. The present study aimed to investigate sFGF23 levels in NICD patients and identify the responsible factors for the elevation of sFGF23 levels. We prospectively measured sFGF23 levels in consecutive hospitalized NICD patients with early CKD (estimated glomerular filtration rate ≥ 40 ml·min(-1)·1.73 m(-2)) and analyzed the data of both echocardiography and right heart catheterization. Of the 156 NICD patients (estimated glomerular filtration rate range: 41-128 ml·min(-1)·1.73 m(-2)), the most severe HF symptom (New York Heart Association class III-IV, 53% vs. 33%, P = 0.015) was found in the above median sFGF23 (39.1 pg/ml) group compared with the below median sFGF23 group. sFGF23 levels were higher in patients with HF hospitalization history compared with those without HF [median: 46.8 (interquartile range: 38.8-62.7) vs. 34.7 (interquartile range: 29.6-42.4) pg/ml, P < 0.0001]. In the multivariate analysis, HF hospitalization was independently related to elevated sFGF23 levels (P = 0.022). Both systolic dysfunction and high plasma aldosterone concentration were identified as predictors of high sFGF23 levels (P < 0.05). Among the neurohormonal parameters, elevated sFGF23 levels were the only factor to predict a declining left ventricular ejection fraction (P = 0.001). These findings suggest that the progression of HF per se contributes to the elevation of sFGF23 levels even in the early stages of CKD, which leads to further myocardial dysfunction, potentially creating a vicious cycle.

Impact of cardiac rehabilitation on renal function in patients with and without chronic kidney disease after acute myocardial infarction.

BACKGROUND: Although there is a general fear that exercise training might deteriorate renal function in chronic kidney disease (CKD) patients, the effect of cardiac rehabilitation (CR) on renal function in acute myocardial infarction (AMI) patients with CKD remains unknown. We sought to determine whether CR is associated with amelioration or deterioration of renal function in such patients. METHODS AND RESULTS: We enrolled 528 AMI patients who participated in a 3-month CR program. Clinical data before and after CR were compared according to participation in CR and comorbidities. In patients without CKD (estimated glomerular filtration rate [eGFR] ≥60ml·min(-1)·1.73m(-2), n=348), peak oxygen uptake (VO2) and B-type natriuretic peptide (BNP) improved without a change in eGFR. In contrast, in patients with CKD (eGFR <60ml·min(-1)·1.73m(-2), n=180), eGFR improved (48±12 to 53±15ml·min(-1)·1.73m(-2), P<0.001), together with improvements in peak VO2 and BNP. When patients with CKD were divided into non-active (≤1time/week, n=70) and active participants (≥1.1time/week, n=110) according to attendance in CR, active participants showed an improvement in eGFR (50±10 to 53±13ml·min(-1)·1.73m(-2), P<0.001), whereas eGFR did not change in non-active participants. Similar results were obtained in each subgroup of patients with hypertension, dyslipidemia, or diabetes mellitus. CONCLUSIONS: In AMI patients with CKD, active participation in CR was associated with improved peak VO2, BNP, and eGFR.