Effectiveness of intraoperative endoscopic evaluation in aortic valve repair with valve-sparing aortic root replacement: a comparison of short- and mid-term results.

OBJECTIVES: Valve-sparing aortic root replacement requires expertise to predict repair results and prevent secondary aortic clamping for valve repair or replacement secondary to aortic valve insufficiency. Thus, intraoperative evaluation of the aortic valve using diastolic pressure at the aortic root may be helpful. The goal of this retrospective study was to compare the early and mid-term results of aortic valve repair with those of valve-sparing aortic root replacement using intraoperative endoscopic evaluation. METHODS: We included 158 patients who underwent aortic valve repair with valve-sparing aortic root replacement at our hospital between December 2003 and January 2022. The patients were divided into a non-endoscopic evaluation group (group NE, n = 97; mean age 55 years) and an endoscopic evaluation group (group E, n = 61; mean age 51 years). RESULTS: The incidence of a second aortic clamping for aortic valve insufficiency was significantly greater in group NE (17.5%) than in group E (1.6%; P = 0.002). The presence of none or trivial aortic valve insufficiency on transthoracic echocardiography at discharge in group E (87.6%) was significantly lower than in group NE (98.4%; P = 0.017). No significant difference in the cumulative incidence of recurrence of moderate AI (P = 0.47), hospitalization for heart failure (P = 0.84) and reoperation (P = 0.25) between groups NE and E. CONCLUSIONS: Intraoperative endoscopic evaluation during aortic valve repair with valve-sparing aortic root replacement correlated with a lower incidence of second aortic clamping because of aortic valve insufficiency and effective aortic valve insufficiency control.

IL6 suppresses vaccine responses in neonates by enhancing IL2 activity on T follicular helper cells.

The inability of neonates to develop CD4+FoxP3-CXCR5hiPD-1hi T follicular helper (TFH) cells contributes to their weak vaccine responses. In previous studies, we measured diminished IgG responses when IL-6 was co-injected with a pneumococcal conjugate vaccine (PCV) in neonatal mice. This is in sharp contrast to adults, where IL-6 improves vaccine responses by downregulating the expression of IL-2Rß on TFH cells and protecting them from the inhibitory effect of IL-2. In this study, we found that splenic IL-6 levels rapidly increased in both adult and neonatal mice following immunization, but the increase in neonatal mice was significantly more than that of adult mice. Moreover, immunized neonatal TFH cells expressed significantly more IL-2 as well as its receptors, IL-2Rα and IL-2Rß, than the adult cells. Remarkably, IL-6 co-injection with PCV vaccine further increased the production of IL-2 and the expression of its receptors by neonatal TFH cells, whereas excess IL-6 had totally opposite effect in immunized adult mice. Underscoring the role of IL-6 in activating the IL-2 mediated suppression of vaccine responses, immunization of IL-6 knock-out neonates led to improved antibody responses accompanied by expanded TFH cells as well as lower levels of IL-2 and IL-2 receptors on TFH cells. Moreover, CpG containing PCV improved TFH response in neonates by suppressing the expression of IL-2 receptors on TFH cells and inhibiting IL-2 activity. These findings unveil age-specific differences in IL-6 mediated vaccine responses and highlight the need to consider age-related immunobiological attributes in designing vaccines.

B cell receptor-induced IL-10 production from neonatal mouse CD19+CD43- cells depends on STAT5-mediated IL-6 secretion.

Newborns are unable to reach the adult-level humoral immune response partly due to the potent immunoregulatory role of IL-10. Increased IL-10 production by neonatal B cells has been attributed to the larger population of IL-10-producting CD43+ B-1 cells in neonates. Here, we show that neonatal mouse CD43- non-B-1 cells also produce substantial amounts of IL-10 following B cell antigen receptor (BCR) activation. In neonatal mouse CD43- non-B-1 cells, BCR engagement activated STAT5 under the control of phosphorylated forms of signaling molecules Syk, Btk, PKC, FAK, and Rac1. Neonatal STAT5 activation led to IL-6 production, which in turn was responsible for IL-10 production in an autocrine/paracrine fashion through the activation of STAT3. In addition to the increased IL-6 production in response to BCR stimulation, elevated expression of IL-6Rα expression in neonatal B cells rendered them highly susceptible to IL-6-mediated STAT3 phosphorylation and IL-10 production. Finally, IL-10 secreted from neonatal mouse CD43- non-B-1 cells was sufficient to inhibit TNF-α secretion by macrophages. Our results unveil a distinct mechanism of IL-6-dependent IL-10 production in BCR-stimulated neonatal CD19+CD43- B cells.

Single-stage repair of the right aortic arch with Kommerell diverticulum through the right thoracotomy with SIRC approach.

Kommerell diverticulum (KD) is a congenital vascular disease associated with dilatation at an aberrant subclavian artery's origin. The surgical repair should be considered for the symptomatic patients due to the adjacent organ's compression by the aneurysmal change of KD. An appropriate approach should be selected for the open repair to suit the anatomical type of disease. We reported a 50-year-old female diagnosed with KD undergoing the single-stage open repair through the right thoracotomy with the straight skin incision with rib cross.

A case of aggressive aortic prosthetic valve endocarditis aggressive caused by Staphylococcus lugdunensis.

BACKGROUND: Staphylococcus lugdunensis is a coagulase-negative Staphylococcus species, which are weak pathogenic bacteria generally. However, the acute and severe pathogenicity of Staphylococcus lugdunensis infective endocarditis may be due to the rapid growth of large vegetation and consequent valve destruction. CASE PRESENTATION: The patient was an 81-year-old male who visited our hospital with chief complaints of low back pain and high fever. Four years before this visit, he had undergone aortic valve replacement for aortic regurgitation. He was found to be hypotensive. Although there is no heart murmur on auscultation and echocardiography revealed negative findings with aortic valve, a blood test showed increases in the white blood cell count and C-reactive protein concentration. On the next day, Gram-positive cocci were detected in a blood culture and echocardiography detected a large vegetation on the prosthetic valve with increased flow velocity. Therefore, he underwent redo aortic valve replacement emergently. Staphylococcus lugdunensis was identified in blood samples and vegetation culture. Consequently, the patient was treated with antibiotics for 5 weeks after the operation and discharged home. CONCLUSIONS: We experienced rapidly progressive prosthetic valve endocarditis caused by Staphylococcus lugdunensis. Hence, Staphylococcus lugdunensis infective endocarditis requires aggressive treatment, and the pathogenicity of this coagulase-negative Staphylococcus with high drug susceptibility should not be underestimated.

[Valve-sparing Root Reimplantation for Stanford Type A Acute Aortic Dissection Combined with Aortic Root Dilation and Bicuspid Aortic Valve;Report of a Case].

A 45-year-old male developed Stanford type A acute aortic dissection combined with aortic root dilation and congenital bicuspid aortic valve (BAV). He had a Sieveres type 0 BAV, lateral subtype with right and left cusps. Valve-sparing root reimplantation was performed with decalcification of the cusps. Transthoracic echocardiography(TTE) at discharge revealed no aortic regurgitation, and peak velocity of BAV was 2.15 m/second, mean pressure gradient was 9.6 mmHg and aortic valve area was 2.15 cm2. TTE after 6 months revealed only slight elevation of the peak velocity to 2.78 m/second. To perform successful reimplantation in the case of BAV, anatomic orientation of the cusps should be approximately at 180° and the tissue of the cusps should either be normal or have only minor abnormalities. Valve-sparing root reimplantation for BAV needs a careful follow-up for progression of the aortic valve dysfunction.

Criticality of plasma membrane lipids reflects activation state of macrophage cells.

Signalling is of particular importance in immune cells, and upstream in the signalling pathway many membrane receptors are functional only as complexes, co-locating with particular lipid species. Work over the last 15 years has shown that plasma membrane lipid composition is close to a critical point of phase separation, with evidence that cells adapt their composition in ways that alter the proximity to this thermodynamic point. Macrophage cells are a key component of the innate immune system, are responsive to infections and regulate the local state of inflammation. We investigate changes in the plasma membrane's proximity to the critical point as a response to stimulation by various pro- and anti-inflammatory agents. Pro-inflammatory (interferon γ, Kdo 2-Lipid A, lipopolysaccharide) perturbations induce an increase in the transition temperature of giant plasma membrane vesicles; anti-inflammatory interleukin 4 has the opposite effect. These changes recapitulate complex plasma membrane composition changes, and are consistent with lipid criticality playing a master regulatory role: being closer to critical conditions increases membrane protein activity.

Activation of Toll-like receptors nucleates assembly of the MyDDosome signaling hub.

Infection and tissue damage induces assembly of supramolecular organizing centres (SMOCs)), such as the Toll-like receptor (TLR) MyDDosome, to co-ordinate inflammatory signaling. SMOC assembly is thought to drive digital all-or-none responses, yet TLR activation by diverse microbes induces anything from mild to severe inflammation. Using single-molecule imaging of TLR4-MyDDosome signaling in living macrophages, we find that MyDDosomes assemble within minutes of TLR4 stimulation. TLR4/MD2 activation leads only to formation of TLR4/MD2 heterotetramers, but not oligomers, suggesting a stoichiometric mismatch between activated receptors and MyDDosomes. The strength of TLR4 signalling depends not only on the number and size of MyDDosomes formed but also how quickly these structures assemble. Activated TLR4, therefore, acts transiently nucleating assembly of MyDDosomes, a process that is uncoupled from receptor activation. These data explain how the oncogenic mutation of MyD88 (L265P) assembles MyDDosomes in the absence of receptor activation to cause constitutive activation of pro-survival NF-κB signalling.

IL-6 Impairs Vaccine Responses in Neonatal Mice.

The inability of infants to mount proper follicular helper T (TFH) cell response renders this age group susceptible to infectious diseases. Initial instruction of T cells by antigen presenting cells and subsequent differentiation into TFH cells are controlled by T cell receptor signal strength, co-stimulatory molecules and cytokines such as IL-6 and IL-21. In immunized adults, IL-6 promotes TFH development by increasing the expression of CXCR5 and the TFH master transcription factor, B cell lymphoma 6. Underscoring the importance of IL-6 in TFH generation, we found improved antibody responses accompanied by increased TFH cells and decreased follicular regulatory helper T (TFR) cells, a Foxp3 expressing inhibitory CD4+ T cell occupying the germinal center (GC), when a tetanus toxoid conjugated pneumococcal polysaccharide type 14 vaccine was injected in adult mice together with IL-6. Paradoxically, in neonates IL-6 containing PPS14-TT vaccine suppressed the already impaired TFH development and antibody responses in addition to increasing TFR cell population. Supporting the diminished TFH development, we detected lower frequency of phospho-STAT-3+ TFH in immunized neonatal T cells after IL-6 stimulation than adult cells. Moreover, IL-6 induced more phospho-STAT-3+ TFR in neonatal cells than adult cells. We also measured lower expression of IL-6R on TFH cells and higher expression on TFR cells in neonatal cells than adult cells, a possible explanation for the difference in IL-6 induced signaling in different age groups. Supporting the flow cytometry findings, microscopic examination revealed the localization of Treg cells in the splenic interfollicular niches of immunized adult mice compared to splenic follicles in neonatal mice. In addition to the limitations in the formation of IL-21 producing TFH cells, neonatal mice GC B cells also expressed lower levels of IL-21R in comparison to the adult mice cells. These findings point to diminished IL-6 activity on neonatal TFH cells as an underlying mechanism of the increased TFR: TFH ratio in immunized neonatal mice.

[Valve Replacement for Infective Endocarditis of Pulmonary Valve;Report of a Case].

Generally, infective endocarditis is found at the left side of the heart. The right side infective endocaritis accounts for only 5~10% of all cases of infective endocarditis. The right side infective endocarditis occurs especially among drug users employing intravenous injection. A typical site of infection is the tricupid valve, and isolated pulmonary valve involvement is rare. It is assumed that its rarity is due to the low pressure gradients within the right heart, the low prevalence of valve disease, and the lower oxygen content of the venous blood. We describe a case of isolated pulmonary valve endocarditis requiring valve replacement. Antibiotic therapy was conducted for 4 weeks before surgery and 2 weeks after surgery. Clinical course was favorable and the patent was discharged home 18 days after surgery.

The Role of BAFF System Molecules in Host Response to Pathogens.

The two ligands B cell-activating factor of the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) and the three receptors BAFF receptor (BAFF-R), transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI), and B cell maturation antigen (BCMA) are members of the "BAFF system molecules." BAFF system molecules are primarily involved in B cell homeostasis. The relevance of BAFF system molecules in host responses to microbial assaults has been investigated in clinical studies and in mice deficient for each of these molecules. Many microbial products modulate the expression of these molecules. Data from clinical studies suggest a correlation between increased expression levels of BAFF system molecules and elevated B cell responses. Depending on the pathogen, heightened B cell responses may strengthen the host response or promote susceptibility. Whereas pathogen-mediated increases in the expression levels of the ligands and/or the receptors appear to promote microbial clearance, certain pathogens have evolved to ablate B cell responses by suppressing the expression of TACI and/or BAFF-R on B cells. Other than its well-established role in B cell responses, the TACI-mediated activation of macrophages is also implicated in resistance to intracellular pathogens. An improved understanding of the role that BAFF system molecules play in infection may assist in devising novel strategies for vaccine development.

Coronary artery bypass surgery is superior to second generation drug-eluting stents in three-vessel coronary artery disease: a propensity score matched analysis.

OBJECTIVES: Compared with percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG) appears to be a promising revascularization strategy for multivessel coronary disease. Trials comparing these treatments have not used second-generation drug-eluting stents (2nd DES). We conducted a retrospective evaluation of both treatments using a propensity score-matched analysis (PSMA). METHODS: A total of 537 patients with three-vessel with/without left-main-trunk coronary artery disease underwent CABG (n = 239) or primary PCI using 2nd DES (298) at a single institution. PSMA resulted in 168 matched pairs. For both treatments, Kaplan-Meier analysis and Cox regression were used to compare all-cause mortality, cardiac death, myocardial infarction (MI), stroke rates and target-vessel revascularization (TVR). RESULTS: The CABG group included sicker patients with renal dysfunction, peripheral vascular disease, low ejection fraction and current smokers than those in the PCI group. After PSMA, both groups were well matched in all parameters. Mean follow-up (months) was 32 in CABG and 35 in PCI. In the unmatched patient population, there was no difference in the incidence of all-cause death, cardiac death, MI, or stroke but the incidence of TVR was significantly higher in the PCI group [hazard ratio (HR) 4.63; 95% confidence interval (95% CI) 2.43-8.82; P < 0.001] and, after PSMA, the incidence of all-cause death (HR 2.71; 95% CI 1.14-6.46; P = 0.019) and TVR (HR 9.0; 95% CI 2.73-29.67; P < 0.001) was significantly higher in the PCI group than in the CABG group. CONCLUSIONS: In patients with three-vessel coronary artery disease, CABG is associated with better survival and less revascularization than PCI using 2nd DES at mid-term results.

Positive Regulation of Interleukin-1ß Bioactivity by Physiological ROS-Mediated Cysteine S-Glutathionylation.

Reactive oxygen species (ROS)-induced cysteine S-glutathionylation is an important posttranslational modification (PTM) that controls a wide range of intracellular protein activities. However, whether physiological ROS can modulate the function of extracellular components via S-glutathionylation is unknown. Using a screening approach, we identified ROS-mediated cysteine S-glutathionylation on several extracellular cytokines. Glutathionylation of the highly conserved Cys-188 in IL-1ß positively regulates its bioactivity by preventing its ROS-induced irreversible oxidation, including sulfinic acid and sulfonic acid formation. We show this mechanism protects IL-1ß from deactivation by ROS in an in vivo system of irradiation-induced bone marrow (BM) injury. Glutaredoxin 1 (Grx1), an enzyme that catalyzes deglutathionylation, was present and active in the extracellular space in serum and the BM, physiologically regulating IL-1ß glutathionylation and bioactivity. Collectively, we identify cysteine S-glutathionylation as a cytokine regulatory mechanism that could be a therapeutic target in the treatment of various infectious and inflammatory diseases.

Lipopolysaccharide-induced NF-κB nuclear translocation is primarily dependent on MyD88, but TNFα expression requires TRIF and MyD88.

TLR4 signalling through the MyD88 and TRIF-dependent pathways initiates translocation of the transcription factor NF-κB into the nucleus. In cell population studies using mathematical modeling and functional analyses, Cheng et al. suggested that LPS-driven activation of MyD88, in the absence of TRIF, impairs NF-κB translocation. We tested the model proposed by Cheng et al. using real-time single cell analysis in macrophages expressing EGFP-tagged p65 and a TNFα promoter-driven mCherry. Following LPS stimulation, cells lacking TRIF show a pattern of NF-κB dynamics that is unaltered from wild-type cells, but activation of the TNFα promoter is impaired. In macrophages lacking MyD88, there is minimal NF-κB translocation to the nucleus in response to LPS stimulation, and there is no activation of the TNFα promoter. These findings confirm that signalling through MyD88 is the primary driver for LPS-dependent NF-κB translocation to the nucleus. The pattern of NF-κB dynamics in TRIF-deficient cells does not, however, directly reflect the kinetics of TNFα promoter activation, supporting the concept that TRIF-dependent signalling plays an important role in the transcription of this cytokine.

G-CSF maintains controlled neutrophil mobilization during acute inflammation by negatively regulating CXCR2 signaling.

Cytokine-induced neutrophil mobilization from the bone marrow to circulation is a critical event in acute inflammation, but how it is accurately controlled remains poorly understood. In this study, we report that CXCR2 ligands are responsible for rapid neutrophil mobilization during early-stage acute inflammation. Nevertheless, although serum CXCR2 ligand concentrations increased during inflammation, neutrophil mobilization slowed after an initial acute fast phase, suggesting a suppression of neutrophil response to CXCR2 ligands after the acute phase. We demonstrate that granulocyte colony-stimulating factor (G-CSF), usually considered a prototypical neutrophil-mobilizing cytokine, was expressed later in the acute inflammatory response and unexpectedly impeded CXCR2-induced neutrophil mobilization by negatively regulating CXCR2-mediated intracellular signaling. Blocking G-CSF in vivo paradoxically elevated peripheral blood neutrophil counts in mice injected intraperitoneally with Escherichia coli and sequestered large numbers of neutrophils in the lungs, leading to sterile pulmonary inflammation. In a lipopolysaccharide-induced acute lung injury model, the homeostatic imbalance caused by G-CSF blockade enhanced neutrophil accumulation, edema, and inflammation in the lungs and ultimately led to significant lung damage. Thus, physiologically produced G-CSF not only acts as a neutrophil mobilizer at the relatively late stage of acute inflammation, but also prevents exaggerated neutrophil mobilization and the associated inflammation-induced tissue damage during early-phase infection and inflammation.

[Quadricuspid Aortic Valve Repair].

A 58-year-old man presented with severe aortic regurgitation(AR) with quadricuspid valve. Intraoperatively, the small accessory cusp was separated from non-coronary cusp( NCC). The NCC and small accessory cusp were sutured to obtain 1 competent cusp, aiming at an effective height of 8 mm. His AR was trivial at the postoperative 7th day.

The second best arterial graft to the left coronary system in off-pump bypass surgery: a propensity analysis of the radial artery with a proximal anastomosis to the ascending aorta versus the right internal thoracic artery.

OBJECTIVE: The second best arterial graft to the left coronary artery (LCA) system between the radial artery (RA) and the right internal thoracic artery (RITA) has been unknown. Moreover, a composite RA may be inferior to direct aorta-RA bypass grafting. The aim of the present study is to compare clinical outcomes between the RA anastomosed to the aorta and the RITA as a second arterial graft to the LCA. METHODS: A total of 805 patients received off-pump coronary arterial bypass grafting between 2000 and 2013. Of these patients, 232 received the bilateral internal thoracic arteries (BITA) and 152 received left internal thoracic arteries (LITA) + RA anastomosed to the aorta, following the inclusion criteria. Patients (1) received at least two arterial grafts in the LCA, (2) did not have renal insufficiency, and (3) did not receive composite RA grafts. A propensity score-matched analysis was performed, resulting in 118 matched pairs. RESULTS: There was no difference in operative mortality and stroke rate between the matched groups; however, the mean operation time was significantly shorter in the LITA + RA and the incidence of mediastinitis was lower in the LITA + RA (BITA: 2.5 %, LITA + RA: 0 %, p < 0.01). Kaplan-Meier cumulative mortality and freedom from cardiac events were similar. The long-term patency rates of the RITA and the RA were similar at 5 years (RITA: 78 %, RA: 84 %, p = 0.55). CONCLUSIONS: The RA anastomosed to the aorta appears to have good long-term outcomes, similar to the RITA as the second arterial graft. Furthermore, the choice of RA avoids sternal complications and shortens the operation time compared to the use of BITA.

De novo chemoattractants form supramolecular hydrogels for immunomodulating neutrophils in vivo.

Most immunomodulatory materials (e.g., vaccine adjuvants such as alum) modulate adaptive immunity, and yet little effort has focused on developing materials to regulate innate immunity, which get mentioned only when inflammation affects the biocompatibility of biomaterials. Traditionally considered as short-lived effector cells from innate immunity primarily for the clearance of invading microorganisms without specificity, neutrophils exhibit a key role in launching and shaping the immune response. Here we show that the incorporation of unnatural amino acids into a well-known chemoattractant-N-formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLF)-offers a facile approach to create a de novo, multifunctional chemoattractant that self-assembles to form supramolecular nanofibrils and hydrogels. This de novo chemoattractant not only exhibits preserved cross-species chemoattractant activity to human and murine neutrophils, but also effectively resists proteolysis. Thus, its hydrogel, in vivo, releases the chemoattractant and attracts neutrophils to the desired location in a sustainable manner. As a novel and general approach to generate a new class of biomaterials for modulating innate immunity, this work offers a prolonged acute inflammation model for developing various new applications.

Heparan Sulfate Regrowth Profiles Under Laminar Shear Flow Following Enzymatic Degradation.

The local hemodynamic shear stress waveforms present in an artery dictate the endothelial cell phenotype. The observed decrease of the apical glycocalyx layer on the endothelium in atheroprone regions of the circulation suggests that the glycocalyx may have a central role in determining atherosclerotic plaque formation. However, the kinetics for the cells' ability to adapt its glycocalyx to the environment have not been quantitatively resolved. Here we report that the heparan sulfate component of the glycocalyx of HUVECs increases by 1.4-fold following the onset of high shear stress, compared to static cultured cells, with a time constant of 19 h. Cell morphology experiments show that 12 h are required for the cells to elongate, but only after 36 h have the cells reached maximal alignment to the flow vector. Our findings demonstrate that following enzymatic degradation, heparan sulfate is restored to the cell surface within 12 h under flow whereas the time required is 20 h under static conditions. We also propose a model describing the contribution of endocytosis and exocytosis to apical heparan sulfate expression. The change in HS regrowth kinetics from static to high-shear EC phenotype implies a differential in the rate of endocytic and exocytic membrane turnover.