Idiopathic pulmonary fibrosis-specific Bayesian network integrating extracellular vesicle proteome and clinical information.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by severe lung fibrosis and a poor prognosis. Although the biomolecules related to IPF have been extensively studied, molecular mechanisms of the pathogenesis and their association with serum biomarkers and clinical findings have not been fully elucidated. We constructed a Bayesian network using multimodal data consisting of a proteome dataset from serum extracellular vesicles, laboratory examinations, and clinical findings from 206 patients with IPF and 36 controls. Differential protein expression analysis was also performed by edgeR and incorporated into the constructed network. We have successfully visualized the relationship between biomolecules and clinical findings with this approach. The IPF-specific network included modules associated with TGF-ß signaling (TGFB1 and LRC32), fibrosis-related (A2MG and PZP), myofibroblast and inflammation (LRP1 and ITIH4), complement-related (SAA1 and SAA2), as well as serum markers, and clinical symptoms (KL-6, SP-D and fine crackles). Notably, it identified SAA2 associated with lymphocyte counts and PSPB connected with the serum markers KL-6 and SP-D, along with fine crackles as clinical manifestations. These results contribute to the elucidation of the pathogenesis of IPF and potential therapeutic targets.

Latent inter-organ mechanism of idiopathic pulmonary fibrosis unveiled by a generative computational approach.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease characterized by complex lung pathogenesis affecting approximately three million people worldwide. While the molecular and cellular details of the IPF mechanism is emerging, our current understanding is centered around the lung itself. On the other hand, many human diseases are the products of complex multi-organ interactions. Hence, we postulate that a dysfunctional crosstalk of the lung with other organs plays a causative role in the onset, progression and/or complications of IPF. In this study, we employed a generative computational approach to identify such inter-organ mechanism of IPF. This approach found unexpected molecular relatedness of IPF to neoplasm, diabetes, Alzheimer's disease, obesity, atherosclerosis, and arteriosclerosis. Furthermore, as a potential mechanism underlying this relatedness, we uncovered a putative molecular crosstalk system across the lung and the liver. In this inter-organ system, a secreted protein, kininogen 1, from hepatocytes in the liver interacts with its receptor, bradykinin receptor B1 in the lung. This ligand-receptor interaction across the liver and the lung leads to the activation of calmodulin pathways in the lung, leading to the activation of interleukin 6 and phosphoenolpyruvate carboxykinase 1 pathway across these organs. Importantly, we retrospectively identified several pre-clinical and clinical evidence supporting this inter-organ mechanism of IPF. In conclusion, such feedforward and feedback loop system across the lung and the liver provides a unique opportunity for the development of the treatment and/or diagnosis of IPF. Furthermore, the result illustrates a generative computational framework for machine-mediated synthesis of mechanisms that facilitates and complements the traditional experimental approaches in biomedical sciences.

Prophylactic Effect of Amiodarone Infusion on Reperfusion Ventricular Fibrillation After Release of Aortic Cross-Clamp in Patients with Left Ventricular Hypertrophy Undergoing Aortic Valve Replacement: ARandomized Controlled Trial.

OBJECTIVE: To investigate whether prophylactic amiodarone infusion prevents ventricular fibrillation after aortic cross-clamp release and attenuates cytokine production in patients with left ventricular hypertrophy undergoing cardiac surgery. DESIGN: Prospective, randomized controlled trial. SETTING: A public hospital. PARTICIPANTS: The study comprised 68 patients undergoing aortic valve replacement for severe aortic stenosis. INTERVENTIONS: Patients were randomly assigned to receive a 150mg bolus then 30mg/h continuous infusion of amiodarone (amiodarone group) or a 1 mg/kg bolus then 1 mg/kg/h continuous infusion of lidocaine (lidocaine group). The primary outcome was the ventricular fibrillation incidence rate after aortic cross-clamp release. Secondary outcomes included perioperative serum interleukin-6 and tumor necrosis factor-alpha levels. MEASUREMENTS AND MAIN RESULTS: The ventricular fibrillation incidence rate was significantly lower in the amiodarone than in the lidocaine group (20.6% v 50%, relative risk 0.41; 95% confidence interval [CI] 0.20-0.86; p = 0.021). Interleukin-6 levels 1hour after aortic cross-clamp release and at intensive care unit admission were significantly lower in the amiodarone than in the lidocaine group (geometric mean [95% CI] 117.4pg/mL [87.1-158.4] v 339.5pg/mL [210.6-547.2]; p < 0.01 and 211.1pg/mL [162.8-73.6] v 434.1pg/mL [293.7-641.5]; p < 0.01, respectively). Tumor necrosis factor-alpha levels 1hour after aortic cross-clamp release were significantly lower in the amiodarone than in the lidocaine group (geometric mean [95% CI] 1.624pg/mL [1.359-1.940] v 2.283pg/mL [1.910-2.731]; p = 0.02). CONCLUSIONS: Amiodarone prevented reperfusion ventricular fibrillation in patients with left ventricular hypertrophy undergoing aortic valve replacement to a greater extent than did lidocaine. Furthermore, amiodarone inhibited postoperative interleukin-6 and tumor necrosis factor-alpha production.

Association of Preoperative Right and Left Ventricular Diastolic Dysfunction With Postoperative Atrial Fibrillation in Patients Undergoing Lung Surgery: A Prospective Observational Study.

OBJECTIVES: To clarify the relationship between right and left ventricular (RV and LV) diastolic function and postoperative atrial fibrillation (POAF). The early effects of major lung surgery on cardiac function in the intraoperative period during lung surgery were evaluated, using transesophageal echocardiography. DESIGN: Single-center prospective observational study. SETTING: A public hospital. PARTICIPANTS: Patients undergoing elective lobectomy with lymph node dissection for lung cancer (n = 116). INTERVENTIONS: Transesophageal echocardiography examination was performed under general anesthesia before skin incision (preoperative) and after chest closure (postoperative). According to measured echocardiographic variables, ventricular systolic and diastolic functions were classified at each time point. MEASUREMENTS AND MAIN RESULTS: Of the 116 patients, 24 (20.7%) experienced POAF. Preoperative RV and LV diastolic dysfunction were more common in patients with POAF than in those without POAF (58.3 v 28.3%, p = 0.008; 54.2 v 19.6%, p = 0.001, respectively). Among patients without preoperative diastolic dysfunction, a small number developed RV and LV diastolic dysfunction immediately after surgery (9.2% and 16.5%, respectively) and these distributions were comparable between patients with POAF and those without POAF. RV systolic dysfunction was observed in 6.5% of patients immediately after surgery and was not related to the occurrence of POAF. Multivariate analysis revealed older age, chronic obstructive pulmonary disease (COPD), and preoperative biventricular diastolic dysfunction as risk factors for POAF. CONCLUSIONS: Preoperative biventricular diastolic dysfunction, as well as older age and COPD, are associated with POAF in patients undergoing lobectomy. Major lung surgery has minimal early effects on postoperative systolic and diastolic functions.

[Successful management of sigmoidectomy with sildenafil citrate in a patient with acute exacerbation of chronic thromboembolic pulmonary hypertension].

An 84-year-old woman with pulmonary hypertension (PH) secondary to chronic pulmonary thromboembolism suffered from continuous warfarin dependent bleeding from sigmoid colon cancer. Sigmoidectomy was scheduled to control continuous bleeding. Six hours after discontinuation of anticoagulant therapy for elective sigmoidectomy, the patient showed hypoxia, pulmonary thromboembolism and pulmonary hypertension with right ventricular systolic pressure (RVSP) of 81 mmHg. The operation was postponed and heparin was infused. Since two-day heparinization therapy did not improve PH, oral administration of sildenafil citrate 60 mg daily was initiated. Seven days after initiation of sildenafil administration, RVSP decreased to 49 mmHg without improvement of hypoxia. Sigmoidectomy was performed under general anesthesia. The patient showed severe hypotension managed with noradrenaline and dopamine infusion during and after surgery, resulting from interaction between sildenafil and vasodilators. The patient was discharged 36 days after the operation without complications.

Phosphoenolpyruvic acid, an intermediary metabolite of glycolysis, as a potential cytoprotectant and anti-oxidant in HeLa cells.

This study examined the cytoprotective and anti-oxidative properties of phosphoenolpyruvic acid (PEP), a glycolysis metabolite with a high-energy phosphate group. PEP (0.1-10 mM) significantly attenuated the decrease in cell viability induced by hydrogen peroxide (H(2)O(2)) in HeLa cells in a dose-dependent manner. PEP also inhibited the decrease in calcein-acetomethoxy-stained cells and the increase in propidium iodide-stained cells that were induced by H(2)O(2). The H(2)O(2)-stimulated increase in intracellular reactive oxygen species was significantly reduced by PEP. PEP also demonstrated scavenging potential against hydroxyl radicals, as assessed by the electron paramagnetic resonance method. In addition, PEP demonstrated scavenging potential against the 1,1-diphenyl-2-picrylhydrazyl radical, a representative artificial radical, although the potential is very weak. PEP (10 mM) slightly inhibited the decrease in cellular ATP content induced by H(2)O(2), but did not show any effects at low doses (0.1, 1 mM). PEP (0.1-10 mM) also attenuated the cell injury but not the decrease in intracellular ATP content, induced by 2-deoxy-D-glucose, a glycolysis inhibitor. These results indicate that PEP exerts cytoprotective effects and has anti-oxidative potential, although the precise cytoprotective mechanisms are not fully elucidated. We suggest that PEP is a functional carbohydrate metabolite with cytoprotective and anti-oxidative activity, and is potentially useful as a therapeutic agent against diseases that involve the oxidative stress.

Association between cerebrovascular carbon dioxide reactivity and postoperative short-term and long-term cognitive dysfunction in patients with diabetes mellitus.

PURPOSE: Our intent was to identify whether cerebrovascular CO(2) reactivity in diabetic patients is a risk factor for postoperative cognitive dysfunction after coronary artery bypass graft (CABG) surgery. METHODS: One hundred twenty-four diabetic patients undergoing elective CABG were studied and analyzed. Diabetic patients were divided into three groups: normal CO(2) reactivity group (above 5%/mmHg), medium CO(2) reactivity group (between 5 and 3%/mmHg), or impaired CO(2) reactivity group (below 3%/mmHg). After the induction of anesthesia and before the start of surgery, cerebrovascular CO(2) reactivity was measured for all patients. Hemodynamic parameters (arterial and jugular venous blood gas values) were measured during cardiopulmonary bypass. All patients underwent a battery of neurological and neuropsychological tests the day before surgery, 7 days after surgery, and 6 months after surgery. RESULTS: At 7 days, the rate of cognitive dysfunction in the impaired CO(2) group was higher than in the other three groups (normal, 30%; medium, 25%; impaired, 57%; *P < 0.01 compared with the other groups). In contrast, at 6 months postoperatively, no significant difference in the rate of cognitive dysfunction was found among the three groups. Age, hypertension, CO(2) reactivity, the duration for which jugular venous oxygen saturation (SjvO(2)) was less than 50%, ascending aorta atherosclerosis, diabetic retinopathy, and insulin therapy were independent predictors of short-term cognitive dysfunction in diabetic patients, and HbA1c, diabetic retinopathy, and insulin therapy were independent predictors of long-term cognitive dysfunction in diabetic patients. CONCLUSIONS: We found that impaired cerebrovascular CO(2) reactivity was associated with postoperative short-term cognitive dysfunction in diabetic patients.

Preoperative depression is a risk factor for postoperative short-term and long-term cognitive dysfunction in patients with diabetes mellitus.

PURPOSE: To identify whether the presence of preoperative depression in patients with diabetes mellitus is a risk factor for postoperative cognitive dysfunction after coronary artery bypass graft (CABG) surgery. METHODS: Data from 90 patients with diabetes mellitus undergoing elective CABG were analyzed. Hemodynamic data (arterial and jugular venous blood gas values) were measured during cardiopulmonary bypass. Preoperatively, all patients were given the 21-item Beck depression inventory to identify the presence of depression. In addition, all patients underwent a battery of neurological and neuropsychological tests the day before surgery, 7 days after surgery, and 6 months after surgery. RESULTS: The rate of cognitive dysfunction was 50% at 7 days and 23% at 6 months after surgery. Age, hypertension, presence of depression, duration of SjvO(2) ≤ 50%, ascending aorta atherosclerosis, diabetic retinopathy, and insulin therapy were independent predictors of short-term cognitive dysfunction, whereas HbA1c, diabetic retinopathy, insulin therapy, and presence of depression were independent predictors of long-term cognitive dysfunction. CONCLUSIONS: We found that the presence of depression preoperatively is associated with short-term and long-term postoperative cognitive dysfunction in patients with diabetes mellitus.

Regurgitant leak from the area between the stent post and the sewing ring of a stented bovine pericardial valve implanted in the aortic valve position.

Biologic valves can sometimes have a small closure or leakage backflow jet originating from the central coaptation point. This is physiologic regurgitation that usually only requires monitoring, and not treatment.Another non-central transvalvular leakage is occasionally seen in both porcine and pericardial valves and originates from the base of the stent post. Typically, it spontaneously decreases or even disappears by the end of the surgery, after administration of protamine. This leak, however, needs to be distinguished from abnormal paravalvular leakages, especially if the regurgitation is relatively large, as this may require an extra cardio-pulmonary bypass (CPB) run.In our case with stented bovine pericardial valves, detailed transesophageal echocardiography (TEE) examination immediately after CPB showed oblique and turbulent flow, which originated from the base of the stent post and flowed toward the anterior mitral leaflet. An extra CPB run, assessment of the cause of the leakage, and restoration if necessary, might have been required if the leakage did not improve or was exacerbated, because contact of the anterior mitral valve leaflet by the oblique flow is associated with the risks of infective endocarditis and hemolysis. Detailed TEE examination accurately delineated the site of the leak, which was subsequently found to originate from the site between the anterior stent post and the sewing ring. The leakage in this case was classified as non-paravalvular, non-central leakage within the sewing ring. Accurate diagnosis of the leakage by intra-operative TEE led to the decision to administer protamine and to adopt a wait-and-watch approach.

Differential effects of hyperventilation on cerebral blood flow velocity after tourniquet deflation during sevoflurane, isoflurane, or propofol anesthesia.

The purpose of this study was to compare the degree of increase in middle cerebral artery (MCA) blood flow velocity after tourniquet deflation when modulating hyperventilation during orthopedic surgery under sevoflurane, isoflurane, or propofol anesthesia. Twenty-four patients undergoing elective orthopedic surgery were randomly divided into sevoflurane, isoflurane, and propofol groups. Anesthesia was maintained with sevoflurane, isoflurane, or propofol administration with 33% oxygen and 67% nitrous oxide at anesthetic drug concentrations adequate to maintain bispectral values between 45 and 50. A 2.0-MHz transcranial Doppler probe was attached to the patient's head at the temporal window, and mean blood flow velocity in the MCA (V (mca)) was continuously measured. The extremity was exsanguinated with an Esmarch bandage, and the pneumatic tourniquet was inflated to a pressure of 450 mmHg. Arterial blood pressure, heart rate, V (mca) and arterial blood gases were measured every minute for 10 min after release of the tourniquet in all three groups. Immediately after tourniquet release, the patients' respiratory rates were increased to tightly maintain end-tidal carbon dioxide (PetCO(2)) at 35 mmHg. No change in partial pressure of carbon dioxide in arterial blood (PaCO(2)) was observed pre- and posttourniquet deflation in any of the three groups. Increase in V (mca) in the isoflurane group was greater than that in the other two groups after tourniquet deflation. In addition, during the study period, no difference in V (mca) after tourniquet deflation was observed between the propofol and sevoflurane groups. Hyperventilation could prevent an increase in V (mca) in the propofol and sevoflurane groups after tourniquet deflation. However, hyperventilation could not prevent an increase in V (mca) in the isoflurane group.

Volatile anesthetics inhibit calcitonin gene-related peptide receptor-mediated responses in pithed rats and human neuroblastoma cells.

Calcitonin gene-related peptide (CGRP) has a potent vasodilatory effect that is mediated by specific receptors predominantly coupled to the activation of adenylate cyclase. The effects of volatile anesthetics on CGRP-induced vasodilation are unclear. We studied the effects of sevoflurane and isoflurane on CGRP-induced vasodilation in pithed rats and CGRP receptor-mediated responses in SK-N-MC cells, which are used as a model system to study the CGRP receptor and its downstream pathways. Male Wistar rats were pithed by inserting a stainless steel rod into the spinal cord. Mean arterial pressure (MAP) and cardiac output were maintained at approximately 100 mmHg and 50 ml.min(-1), respectively, with continuous infusion of noradrenaline. After 30 min of inhalation of anesthetics, CGRP (0.1, 0.3, 1.0, and 3.0 microg/kg) was administered intravenously. In SK-N-MC cells, CGRP-, forskolin-, or cholera toxin-induced cAMP production was measured with or without anesthetics using radioimmunoassays. CGRP receptor binding density and affinity for the agonist were determined with (2-[125I]iodohystidyl10) CGRP with or without the anesthetics. Sevoflurane (4%) and isoflurane (2%) significantly inhibited the decrease in MAP and systemic vascular resistance. Furthermore, both anesthetics significantly inhibited CGRP- but not forskolin-induced cAMP production. Sevoflurane (4%) and isoflurane (4%) significantly inhibited cholera toxin-induced cAMP production. Both anesthetics did not affect ligand binding. These data suggest that sevoflurane and isoflurane inhibit CGRP-induced vasodilation at the site between the CGRP receptor and adenylate cyclase activation. The inhibitory site of volatile anesthetics on the CGRP receptor-mediated response involves Gs protein.

Calibration of force-field dependency in free energy landscapes of peptide conformations by quantum chemical calculations.

The free energy landscapes of peptide conformations were calibrated by ab initio quantum chemical calculations, after the enhanced conformational diversity search using the multicanonical molecular dynamics simulations. Three different potentials of mean force for an isolated dipeptide were individually obtained by the multicanonical molecular dynamics simulations using the conventional force fields, AMBER parm94, AMBER parm96, and CHARMm22. Each potential of mean force was then calibrated based upon the umbrella sampling algorithm from the adiabatic energy map that was calculated separately by the ab initio molecular orbital method, and all of the calibrated potentials of mean force coincided well. The calibration method was also applied to the simulations of a peptide dimer in explicit water models, and it was shown that the calibrated free energy landscapes did not depend on the force field used in the classical simulations, as far as the conformational space was sampled well. The current calibration method fuses the classical free energy calculation with the quantum chemical calculation, and it should generally make simulations for biomolecular systems much more reliable when combining with enhanced conformational sampling.