Radiation in an emergency situation: attempting to respect the patient's beliefs as reported by a minor.

BACKGROUND: Each individual's unique health-related beliefs can greatly impact the patient-clinician relationship. When there is a conflict between the patient's preferences and recommended medical care, it can create a serious ethical dilemma, especially in an emergency setting, and dramatically alter this important relationship. CASE PRESENTATION: A 56-year-old man, who remained comatose after out-of-hospital cardiac arrest, was rushed to our hospital. The patient was scheduled for emergency coronary angiography when his adolescent daughter reported that she and her father held sincere beliefs against radiation exposure. We were concerned that she did not fully understand the potential consequences if her father did not receive the recommended treatment. A physician provided her with in depth information regarding the risks and benefits of the treatment. While we did not want to disregard her statement, we opted to save the patient's life due to concerns about the validity of her report. CONCLUSIONS: Variations in beliefs regarding medical care force clinicians to incorporate patient beliefs into medical practice. However, an emergency may require a completely different approach. When faced with a patient in a life-threatening condition and unconscious, we should take action to prioritize saving their life, unless we are highly certain about the validity of their advance directives.

Diverse Localization Patterns of an R-Type Lectin in Marine Annelids.

Lectins facilitate cell-cell contact and are critical in many cellular processes. Studying lectins may help us understand the mechanisms underlying tissue regeneration. We investigated the localization of an R-type lectin in a marine annelid (Perinereis sp.) with remarkable tissue regeneration abilities. Perinereis nuntia lectin (PnL), a galactose-binding lectin with repeating Gln-X-Trp motifs, is derived from the ricin B-chain. An antiserum was raised against PnL to specifically detect a 32-kDa lectin in the crude extracts from homogenized lugworms. The antiserum detected PnL in the epidermis, setae, oblique muscle, acicula, nerve cord, and nephridium of the annelid. Some of these tissues and organs also produced Galactose (Gal) or N-acetylgalactosamine (GalNAc), which was detected by fluorescent-labeled plant lectin. These results indicated that the PnL was produced in the tissues originating from the endoderm, mesoderm, and ectoderm. Besides, the localizing pattern of PnL partially merged with the binding pattern of a fluorescent-labeled mushroom lectin that binds to Gal and GalNAc. It suggested that PnL co-localized with galactose-containing glycans in Annelid tissue; this might be the reason PnL needed to be extracted with haptenic sugar, such as d-galactose, in the buffer. Furthermore, we found that a fluorescein isothiocyanate-labeled Gal/GalNAc-binding mushroom lectin binding pattern in the annelid tissue overlapped with the localizing pattern of PnL. These findings suggest that lectin functions by interacting with Gal-containing glycoconjugates in the tissues.

Hemodynamic comparison of CoreValve and SAPIEN-XT TAVI valves in Japanese patients.

Transcatheter aortic valve implantation (TAVI) is a viable treatment option for high-risk patients with severe aortic stenosis. In Japan, TAVI can be performed using first-generation self-expandable Medtronic CoreValve or balloon-expandable Edwards SAPIEN-XT from 2012. Since the durability and hemodynamic outcomes after transcatheter heart valve (THV) implantation in Japanese patients have not been clearly elucidated, we assessed serial changes in post-TAVI THV performances over a-3-year period by transthoracic echocardiography (TTE). From January 2012 to September 2014, among 83 patients with severe aortic stenosis, 26 underwent TAVI with CoreValve and 57 underwent TAVI with SAPIEN-XT. We assessed the serial changes in first post-implant (FPI) and 3-year post procedure THV hemodynamics by TTE. Valve performance was evaluated by serial assessment of aortic valve mean pressure gradient (PG) and aortic valve area (AVA) assessments. Three-year clinical outcomes were compared between the patients with CoreValve and those with SAPIEN-XT. Seventeen patients with CoreValve and 34 patients with SAPIEN-XT had FPI and 3-year TTEs. The AVA decreased significantly from FPI to 3-year follow-up among patients with SAPIEN-XT, but not among patients with CoreValve. The mean aortic PG decreased significantly from FPI to the 3-year follow-up point among patients with CoreValve; however, it was not significantly different from those with SAPIEN-XT. The absolute change in mean PG from FPI to the 3-year follow-up point decreased significantly among those with CoreValve compared to those with SAPIEN-XT. Clinical outcomes after TAVI were similar for both devices at 3-years after TAVI. In this study, long-term clinical outcomes for CoreValve and SAPIEN XT were similar. The 3-year THV performance of both devices was maintained after TAVI. Serial change in mean aortic PGs for CoreValve decreases significantly from FPI to the 3-year follow-up point compared to that for SAPIEN-XT.

Guidelines for the use of cerebral oximetry by near-infrared spectroscopy in cardiovascular anesthesia: a report by the cerebrospinal Division of the Academic Committee of the Japanese Society of Cardiovascular Anesthesiologists (JSCVA).

Cerebral Oximetry by Near-infrared Spectroscopy (NIRS) has been used in cardiovascular anesthesia, but there was no guideline of regional cerebral oxygen saturation measured by cerebral oximetry by NIRS. This guideline provides recommendations applicable to patients at a risk of developing cerebral ischemia in cardiovascular surgery. Guidelines are intended to define practices meeting the needs of patients in most, but not all, circumstances, and should not replace clinical judgment. The Japanese Society of Cardiovascular Anesthesiologists (JSCVA) Task Force on Guidelines make an effort to ensure that the guideline writing committee contains broad views in using cerebral oximetry. Adherence to recommendations could be enhanced by shared decision making between healthcare providers and patients. This guideline was focused on cerebral oximetry of pediatric and adult cardiovascular disease. We hope this guideline would play an important role in using cerebral oximetry by measured NIRS.

Catfish rhamnose-binding lectin induces G0/1 cell cycle arrest in Burkitt's lymphoma cells via membrane surface Gb3.

Silurus asotus egg lectin (SAL), an α-galactoside-binding protein isolated from the eggs of catfish, is a member of the rhamnose-binding lectin family that binds to Gb3 glycan (Galα1-4Galß1-4Glc). We have previously demonstrated that SAL reduces the proliferation of Gb3-expressing Burkitt's lymphoma Raji cells and confirm here that it does not reduce their viability, indicating that unlike other lectins, it is not cytotoxic. The aim of this study was to determine the signal transduction mechanism(s) underlying this novel SAL/Gb3 binding-mediated effect profile. SAL/Gb3 interaction arrested the cell cycle through increasing the G0/1 phase population of Raji cells. SAL suppressed the transcription of cell cycle-related factors such as c-MYC, cyclin D3, and cyclin-dependent protein kinase (CDK)-4. Conversely, the CDK inhibitors p21 and p27 were elevated by treatment with SAL. In particular, the production of p27 in response to SAL treatment increased steadily, whereas p21 production was maximal at 12 h and lower at 24 h. Activation of Ras-MEK-ERK pathway led to an increase in expression of p21. Notably, treatment of Raji cells with anti-Gb3 mAb alone did not produce the above effects. Taken together, our findings suggest that Gb3 on the Raji cell surface interacts with SAL to trigger sequential GDP-Ras phosphorylation, Ras-MEK-ERK pathway activation, p21 production, and cell cycle arrest at the G0/1 phase.

cDNA and Gene Structure of MytiLec-1, A Bacteriostatic R-Type Lectin from the Mediterranean Mussel (Mytilus galloprovincialis).

MytiLec is an α-d-galactose-binding lectin with a unique primary structure isolated from the Mediterranean mussel (Mytilus galloprovincialis). The lectin adopts a ß-trefoil fold that is also found in the B-sub-unit of ricin and other ricin-type (R-type) lectins. We are introducing MytiLec(-1) and its two variants (MytiLec-2 and -3), which both possess an additional pore-forming aerolysin-like domain, as members of a novel multi-genic "mytilectin family" in bivalve mollusks. Based on the full length mRNA sequence (911 bps), it was possible to elucidate the coding sequence of MytiLec-1, which displays an extended open reading frame (ORF) at the 5' end of the sequence, confirmed both at the mRNA and at the genomic DNA sequence level. While this extension could potentially produce a polypeptide significantly longer than previously reported, this has not been confirmed yet at the protein level. MytiLec-1 was revealed to be encoded by a gene consisting of two exons and a single intron. The first exon comprised the 5'UTR and the initial ATG codon and it was possible to detect a putative promoter region immediately ahead of the transcription start site in the MytiLec-1 genomic locus. The remaining part of the MytiLec-1 coding sequence (including the three sub-domains, the 3'UTR and the poly-A signal) was included in the second exon. The bacteriostatic activity of MytiLec-1 was determined by the agglutination of both Gram-positive and Gram-negative bacteria, which was reversed by the co-presence of α-galactoside. Altogether, these data support the classification of MytiLec-1 as a member of the novel mytilectin family and suggest that this lectin may play an important role as a pattern recognition receptor in the innate immunity of mussels.

Effect of transcatheter aortic valve implantation on intraoperative left ventricular end-diastolic pressure.

Transcatheter aortic valve implantation (TAVI) for patients with aortic stenosis is a less invasive alternative to surgical aortic valve replacement. Despite this, careful anesthetic management, especially strict control of blood pressure and fluid management, is necessary. During TAVI, normalization of left ventricular afterload due to aortic balloon valvuloplasty and prosthetic valve deployment is expected to result in rapid improvement of systolic function and consequent improvement in diastolic function. However, the early effect of TAVI on left ventricular diastolic function is less clear. We hypothesized that TAVI induces a rapid decrease in left ventricular end-diastolic pressure (LVEDP) after valve deployment. This retrospective observational study included 71 patients who had undergone TAVI using the transfemoral approach with a balloon-expandable valve under general anesthesia. Intraoperative LVEDP was measured using an intracardiac catheter. The severity of residual aortic regurgitation (AR) was assessed using the Sellers criteria. The mean (SD) LVEDP was 17.8 (5.3) mmHg just before TAVI and increased significantly to 27.3 (8.2) mmHg immediately after prosthetic valve deployment (p < 0.0001). The change in LVEDP was 8.7 (8.6) mmHg in patients with low residual AR (Sellers ≤1) and 11.0 (7.1) mmHg in those with high residual AR (Sellers ≥2); however, this difference was not significant. No correlation was found between the LVEDP change and intraoperative fluid balance. In conclusion, LVEDP increased significantly in the early period after valve deployment during TAVI, regardless of residual AR severity. It was suggested that the tolerability of fluid load could be reduced at that time.

MytiLec, a Mussel R-Type Lectin, Interacts with Surface Glycan Gb3 on Burkitt's Lymphoma Cells to Trigger Apoptosis through Multiple Pathways.

MytiLec; a novel lectin isolated from the Mediterranean mussel (Mytilus galloprovincialis); shows strong binding affinity to globotriose (Gb3: Galα1-4Galß1-4Glc). MytiLec revealed ß-trefoil folding as also found in the ricin B-subunit type (R-type) lectin family, although the amino acid sequences were quite different. Classification of R-type lectin family members therefore needs to be based on conformation as well as on primary structure. MytiLec specifically killed Burkitt's lymphoma Ramos cells, which express Gb3. Fluorescein-labeling assay revealed that MytiLec was incorporated inside the cells. MytiLec treatment of Ramos cells resulted in activation of both classical MAPK/ extracellular signal-regulated kinase and extracellular signal-regulated kinase (MEK-ERK) and stress-activated (p38 kinase and JNK) Mitogen-activated protein kinases (MAPK) pathways. In the cells, MytiLec treatment triggered expression of tumor necrosis factor (TNF)-α (a ligand of death receptor-dependent apoptosis) and activation of mitochondria-controlling caspase-9 (initiator caspase) and caspase-3 (activator caspase). Experiments using the specific MEK inhibitor U0126 showed that MytiLec-induced phosphorylation of the MEK-ERK pathway up-regulated expression of the cyclin-dependent kinase inhibitor p21, leading to cell cycle arrest and TNF-α production. Activation of caspase-3 by MytiLec appeared to be regulated by multiple different pathways. Our findings, taken together, indicate that the novel R-type lectin MytiLec initiates programmed cell death of Burkitt's lymphoma cells through multiple pathways (MAPK cascade, death receptor signaling; caspase activation) based on interaction of the lectin with Gb3-containing glycosphingolipid-enriched microdomains on the cell surface.

Role of intraoperative transesophageal echocardiography in detecting masked mitral regurgitation during left atrial myxoma surgery.

Myxomas are the most common type of cardiac tumor. Mobile or large left atrial (LA) myxomas frequently cause functional mitral stenosis, and can lead to mitral regurgitation (MR). Difficulties have been associated with detecting masked MR jets and evaluating the severity of MR during LA myxoma surgery due to the presence of a prolapsing tumor and changes in blood flow. We herein presented a case of LA myxoma with significant MR diagnosed on intraoperative transesophageal echocardiography (TEE) prior to cardiopulmonary bypass. Repeated careful observations on TEE led to a confident diagnosis of MR and the selection of an additional appropriate procedure. This case study highlighted the importance of intraoperative TEE in supporting clinical decision-making for optimal mitral valve procedures during LA myxoma surgery.

A galactose-binding lectin isolated from Aplysia kurodai (sea hare) eggs inhibits streptolysin-induced hemolysis.

A specific galactose-binding lectin was shown to inhibit the hemolytic effect of streptolysin O (SLO), an exotoxin produced by Streptococcus pyogenes. Commercially available lectins that recognize N-acetyllactosamine (ECA), T-antigen (PNA), and Tn-antigen (ABA) agglutinated rabbit erythrocytes, but had no effect on SLO-induced hemolysis. In contrast, SLO-induced hemolysis was inhibited by AKL, a lectin purified from sea hare (Aplysia kurodai) eggs that recognizes α-galactoside oligosaccharides. This inhibitory effect was blocked by the co-presence of d-galactose, which binds to AKL. A possible explanation for these findings is that cholesterol-enriched microdomains containing glycosphingolipids in the erythrocyte membrane become occupied by tightly stacked lectin molecules, blocking the interaction between cholesterol and SLO that would otherwise result in penetration of the membrane. Growth of S. pyogenes was inhibited by lectins from a marine invertebrate (AKL) and a mushroom (ABA), but was promoted by a plant lectin (ECA). Both these inhibitory and promoting effects were blocked by co-presence of galactose in the culture medium. Our findings demonstrate the importance of glycans and lectins in regulating mechanisms of toxicity, creation of pores in the target cell membrane, and bacterial growth.

Binding profiles and cytokine-inducing effects of fish rhamnose-binding lectins on Burkitt's lymphoma Raji cells.

Rhamnose-binding lectin (RBL) is one of the animal lectin categories which take part in the innate immune responses of fish. Osmerus lanceolatus lectin (OLL) from shishamo smelt eggs is an RBL composed of two tandem-repeated domains, both of which are considered to be a carbohydrate-recognition domain. SAL, catfish (Silurus asotus) egg RBL composed of three domains, binds to Burkitt's lymphoma Raji cells through globotriaosylceramide (Gb3) carbohydrate chain and to reduce cell size and growth by altering membrane composition without causing cell death. In this experiment, we tried to compare the binding effects of these two RBLs on Raji cells. Flow cytometric and fluorescence microscopic analyses revealed that OLL also directly bound to and shrunk Raji cells with ten times less reactivity than SAL but reduced cell growth with decreasing cell viability. Anti-Gb3 antibody completely blocked the binding of SAL to Raji cells but not that of OLL. In addition, the direct bindings of OLL and SAL to Raji cells were comparably inhibited by melibiose, but lactose was more effective inhibitor for the binding of OLL than that of SAL. These results suggest that OLL has slightly different cell-binding property compared with SAL and binds not only to Gb3 but also to the other carbohydrate receptor-bearing ß-galactoside chains. The quantitative RT-PCR analysis revealed that SAL induced the expression of TNF-α but not of IFN-γ, IL-1ß, and IL-10. Thus, SAL-induced cytostatic effect on Raji cells might be partially caused by TNF-α-mediated signaling pathway.

A lectin from the mussel Mytilus galloprovincialis has a highly novel primary structure and induces glycan-mediated cytotoxicity of globotriaosylceramide-expressing lymphoma cells.

A novel lectin structure was found for a 17-kDa α-D-galactose-binding lectin (termed "MytiLec") isolated from the Mediterranean mussel, Mytilus galloprovincialis. The complete primary structure of the lectin was determined by Edman degradation and mass spectrometric analysis. MytiLec was found to consist of 149 amino acids with a total molecular mass of 16,812.59 Da by Fourier transform-ion cyclotron resonance mass spectrometry, in good agreement with the calculated value of 16,823.22 Da. MytiLec had an N terminus of acetylthreonine and a primary structure that was highly novel in comparison with those of all known lectins in the structure database. The polypeptide structure consisted of three tandem-repeat domains of ∼50 amino acids each having 45-52% homology with each other. Frontal affinity chromatography technology indicated that MytiLec bound specifically to globotriose (Gb3; Galα1-4Galß1-4Glc), the epitope of globotriaosylceramide. MytiLec showed a dose-dependent cytotoxic effect on human Burkitt lymphoma Raji cells (which have high surface expression of Gb3) but had no such effect on erythroleukemia K562 cells (which do not express Gb3). The cytotoxic effect of MytiLec was specifically blocked by the co-presence of an α-galactoside. MytiLec treatment of Raji cells caused increased binding of anti-annexin V antibody and incorporation of propidium iodide, which are indicators of cell membrane inversion and perforation. MytiLec is the first reported lectin having a primary structure with the highly novel triple tandem-repeat domain and showing transduction of apoptotic signaling against Burkitt lymphoma cells by interaction with a glycosphingolipid-enriched microdomain containing Gb3.

[Safe induction of anesthesia in 3 patients with severe tracheal stenosis caused by thyroid cancer].

Anesthetic induction in a patient with a giant thyroid cancer is challenging for anesthetists. Tracheostomy under local anesthesia is usually impossible in these cases because the tumor mass occupies the anterior mediastinum and interferes with the approach to the trachea. The tumor may further cause tracheal stenosis and laryngeal malformation, leading to airway complications including difficult ventilation, difficult intubation, airway hemorrhage or swelling, and suffocation in the patient. Extracorporeal membrane oxygenation (ECMO) or high-frequency jet ventilation (HFJV) is reported to be a useful tool for safe induction in these patients; however, each of them alone would leave a possibility of inadequate oxygenation. We successfully managed anesthesia using both ECMO and HFJV in 3 patients with imminent danger of airway obstruction due to an extra-large thyroid cancer. A combination of ECMO and HFJV may be a useful tool for safe induction of anesthesia in patients with severe tracheal stenosis.

[Septic shock after total knee arthroplasty in a patient with Waldenström macroglobulinemia].

A 58-year-old man with Waldenström macroglobulinemia (WM) was scheduled for total knee arthroplasty for left proximal-end tibial fracture. Before surgery, he took dexamethasone 2 mg orally, and his preoperative IgM level was 2,388 mg x dl(-1). The intraoperative course was favorable. Two days after surgery, he could move to a wheelchair. But, four days after surgery, he fell into septic shock with disseminated intravascular coagulation. Furthermore, cardiac arrest ocurred twice and he finally died. Autopsy revealed the large volume of turbid ascites and petechia of the digestive tract mucosa and the endocardium. However, the infection focus could be not identified. Four days after surgery, the blood culture showed extended-spectrum beta-lactamase-producing Escherichia coli. In patients with WM, abnormalities in immunoglobulins may frequently lead to infection. Decreased cellular immunity by surgical stress, may lead to severe infection. Perioperative management, such as evaluation of the indications for surgery, appropriate administration of prophylactic antibiotics, and proper selection of anesthetic must be considered.

Adult Scurvy Presenting with Painful Purpura on the Legs.

Prolonged vitamin C deficiency can result in numerous metabolic abnormalities like impaired tissue repair and defective collagen synthesis. This case report describes a middle-age Japanese man presenting painful purpura on his lower limbs, severe anemia, and altered consciousness. The patient had been eating a selective diet lacking in vegetables and fruits since childhood. A serum analysis demonstrated a low level of vitamin C. The patient was treated with vitamin supplementation and psychological intervention. Scurvy is an under-considered illness with a favorable prognosis if diagnosed early while it is still sporadically encountered in some patients with malabsorption or malnutrition even in modern times.

Undiagnosed tracheomalacia accompanied with accidental expiratory central airway collapse after tracheal intubation.

BACKGROUND: A patient with undiagnosed tracheomalacia undergoing surgery experienced accidental expiratory central airway collapse after tracheal intubation. Here, we aimed to diagnose tracheomalacia from the preoperative data. CASE PRESENTATION: A 73-year-old man, scheduled for abdominal surgery, had a clinical history of chronic obstructive pulmonary disease. Preoperative chest computed tomography revealed a lateral narrowing of the tracheal shape. After tracheal intubation, we could not manually ventilate the inflated lung. Emergent bronchoscopy findings, including severe expiratory tracheal collapse, indicated a diagnosis of tracheomalacia. We could fully ventilate the patient by moving the endotracheal tube near the tracheal carina and finally changing it to a double-lumen tube. Airway collapse did not occur under spontaneous breathing. CONCLUSION: Accidental expiratory central airway collapse could occur in patients with undiagnosed tracheomalacia during surgery. A diagnosis of tracheomalacia should be presumed from a deformed trachea on preoperative imaging and history of chronic obstructive pulmonary disease.

[Postoperative pulmonary thromboembolism in a patient with essential thrombocythemia].

A 75-year-old woman with thrombocythemia underwent distal gastrectomy. Preoperative platelet count was 103 x 10(4) x mm(-1). General anesthesia was given and heparin 20 units x kg(-1) was administered intravenously for prevention of deep vein thrombosis. Operation was finished uneventfully. On the next day, she complained chest pain and was diagnosed as pulmonary thromboembolism. Later, she was diagnosed as essential thrombocythemia.

A GM1b/asialo-GM1 oligosaccharide-binding R-type lectin from purplish bifurcate mussels Mytilisepta virgata and its effect on MAP kinases.

A 15-kDa lectin, termed SeviL, was isolated from Mytilisepta virgata (purplish bifurcate mussel). SeviL forms a noncovalent dimer that binds strongly to ganglio-series GM1b oligosaccharide (Neu5Acɑ2-3Galß1-3GalNAcß1-4Galß1-4Glc) and its precursor, asialo-GM1 (Galß1-3GalNAcß1-4Galß1-4Glc). SeviL also interacts weakly with the glycan moiety of SSEA-4 hexaose (Neu5Acα2-3Galß1-3GalNAcß1-3Galα1-4Galß1-4Glc). A partial protein sequence of the lectin was determined by mass spectrometry, and the complete sequence was identified from transcriptomic analysis. SeviL, consisting of 129 amino acids, was classified as an R(icin B)-type lectin, based on the presence of the QxW motif characteristic of this fold. SeviL mRNA is highly expressed in gills and, in particular, mantle rim tissues. Orthologue sequences were identified in other species of the family Mytilidae, including Mytilus galloprovincialis, from which lectin MytiLec-1 was isolated and characterized in our previous studies. Thus, mytilid species contain lectins belonging to at least two distinct families (R-type lectins and mytilectins) that have a common ß-trefoil fold structure but differing glycan-binding specificities. SeviL displayed notable cytotoxic (apoptotic) effects against various cultured cell lines (human breast, ovarian, and colonic cancer; dog kidney) that possess asialo-GM1 oligosaccharide at the cell surface. This cytotoxic effect was inhibited by the presence of anti-asialo-GM1 oligosaccharide antibodies. With HeLa ovarian cancer cells, SeviL showed dose- and time-dependent activation of kinase MKK3/6, p38 MAPK, and caspase-3/9. The transduction pathways activated by SeviL via the glycosphingolipid oligosaccharide were triggered apoptosis. DATABASE: Nucleotide sequence data have been deposited in the GenBank database under accession numbers MK434191, MK434192, MK434193, MK434194, MK434195, MK434196, MK434197, MK434198, MK434199, MK434200, and MK434201.

[Assessment of cardiac function by TEE].

Transesophageal echocardiography (TEE) is a useful tool for assessment of cardiac function in patients undergoing cardiac surgery or in patients undergoing non-cardiac surgery who have cardiovascular complications. Left ventricular (LV) function is composed of systolic function, diastolic function, preload and afterload. To assess systolic and diastolic function several methods are used, and we must use them based on the property of each parameter. Both systolic and diastolic functions are load dependent. To assess the systolic function, ejection fraction (EF) is commonly used. Transmitral flow (TMF) and pulmonary vein flow patterns are commonly used to assess the diastolic function. Newer techniques including mitral annular velocity and color M-mode TMF propagation velocity (Vp) may be less sensitive to changes in loading conditions. LV dP/dt is not affected by preload, and myocardial performance index (Tei index) can be used to assess both systolic and diastolic functions. Tei index is also useful to assess right ventricular function. The recently developed real time 3-dimensional system provides accurate and objective information, such as LV volumetry, wall motion, dyssyncrony and valvular pathology.