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A 76-year-old woman presented with dyspnea. Computed tomography showed massive pericardial effusion, so percutaneous catheter drainage was performed. The usual causes of exudate were ruled out, and no diagnosis was reached. Thoracoscopic pericardial fenestration was performed for the purpose of pericardial biopsy and to create a passage allowing longer-term drainage. We observed the pericardial cavity after removing effusion, and incidentally revealed a tumor measuring 2 cm in diameter located between the left atrial appendage and left pulmonary artery. Surgical resection of the tumor attached to the left atrial appendage was performed. The pathological diagnosis was hemangioma.

Permanent pacemaker (PPM) implantation is required in 5% to 10% of patients following transcatheter aortic valve implantation (TAVI). However, there are limited data on the impact of PPM implantation on the incidence of pericardial effusion, cardiac tamponade, and outcomes after TAVI. We identified all hospitalizations in patients ≥18 years of age who underwent TAVI in the years 2016 to 2017 in the Nationwide Readmission Database. The endpoints of the study were pericardial effusion, cardiac tamponade, and percutaneous or surgical drainage of the pericardial cavity in patients that required PPM implantation after TAVI. Multivariable logistic regression determined associations of PPM implantation, pericardial effusion, and tamponade with patient outcomes. A total of 54,317 unweighted hospitalizations for TAVI were identified, of which 5,639 (10.4%) required PPM. The risk of pericardial effusion was significantly greater in patients who required PPM (2.4% vs 1.6%, adjusted odds ratio (aOR) 1.39 (1.15 to 1.70), p

To explore the diagnostic value of deep learning convolutional neural network (CNN)-based computed tomography (CT) scan in tumor disease images, clinical factors related to serous effusion were analyzed. The relevant case data of 224 patients with serosal effusion caused by malignant tumor treated in X Hospital from October 1 to February 2017 were selected, so did the positron emission tomography (PET) image data based on deep learning CNN. Then, the causes and diagnosis of PET effusion in each group were analyzed, and multi-factor analysis was performed on the effusion in the pleural cavity, abdominal cavity, pericardial cavity, and no effusion group. It was found through PET scan under deep learning CNN algorithm that the location of the effusion was related to the primary lesions. The malignant pleural effusion (72 cases) and pericardial effusion (19 cases) both occurred mostly in lung cancer, and the second was the digestive system tumor. The malignant peritoneal effusion concurrent lesions mainly occurred in the digestive system (18 cases of gastric cancer, 4 cases of colon cancer, 2 cases of rectal cancer, and 1 case of small intestine cancer). Malignant multiple serous cavity effusion (57 cases) mostly occurred in lung cancer (30 cases). From the analysis of clinical indicators of pulmonary infection, the infection rates of pericardial cavity (89.13%), abdominal cavity (82.3%), and thoracic cavity (83.78%) were higher in the group with effusion than in the group without effusion (65.23%), and there was a statistical difference (*P

The pericardial cavity, sinuses, and recesses are frequently depicted on Computed Tomography (CT) and Magnetic Resonance (MR).We here review the normal human pericardial structures as provided by MR imaging of young, healthy subject and CT scans acquired after iatrogenic coronary dissection. We compared such radiological information with cadaveric axial and sagittal sections of the human body provided by the Visible Human Server (VHS), Ecole Polytechnique Federale de Lousanne (EPFL), Switzerland.

Hydropneumopericardium is defined as the presence of air and water in the pericardial cavity. Several causes have been postulated which can lead to hydropneumopericardium including trauma, infections secondary to gas-producing bacilli, fistula formation, positive pressure ventilation or even spontaneously without an underlying cause in healthy adults and rarely after pericardiocentesis. We report an uncommon instance of hydropneumopericardium after pericardiocentesis in a 35-year-old man, which developed due to a leaky drainage system. It was immediately drained through the subxiphoid approach under echocardiographic guidance, and the patient was relieved. Hydropneumopericardium is an uncommon but easily diagnosable and avoidable complication of pericardiocentesis. It should be suspected whenever the patient develops increasing dyspnoea following a temporary relief by pericardiocentesis.

A 46-year-old male presented with breathlessness for a few months. He had been operated twice for liver hydatid cysts and once for right pulmonary hydatid cysts at other hospitals. Now he was found to have one hydatid cyst in the upper lobe of the left lung and multiple hydatid cysts adjoining left heart border. On computed tomography (CT) scan chest and echocardiography, it was difficult to ascertain whether these cysts were pulmonary or intrapericardial. Left ventricular ejection fraction (LVEF) was 25%. Enzyme-linked immunosorbent assay (ELISA) was positive for hydatid. Left posterolateral thoracotomy revealed dead hydatid cyst in upper lobe of the lung that was removed. Infected mother hydatid cyst was encountered inside pericardial sac. Scores of daughter hydatid cysts, varying in size from 1 to 30 mm, were scooped out intact from the pericardial cavity. There was significant improvement in cardiac activity, once the tamponade effect of hydatid cyst was removed. Pericardium was about 1 cm thick with lot of purulent and necrotic slough. To prevent future constrictive pericarditis, subtotal pericardiectomy was done. Intrapericardial hydatid cyst should be kept in mind whenever it obscures the heart border and patient has features of cardiac tamponade. Early surgical intervention may be required in these cases.

Dyspnea is an ailment which is relatively frequently reported by cancer patients, and it can be difficult to determine the cause of the symptom at home hospice. Thanks to the application of mobile ultrasound scanner, the physician can often determine the cause of dyspnea during a home visit, which makes it unnecessary to carry out diagnostic procedures at the hospital. The article presents two cases of female patients in whom the application of at-home ultrasound proved to be useful in determining the cause of dyspnea. The first patient was diagnosed with pericardial tamponade at home — pericardial cavity puncture was performed at the hospital — while in the case of the second patient, pneumonia was both diagnosed and monitored at home with the use of ultrasonography.

Postpericardiotomy syndrome (PCTS) develops after cardiosurgical operations as part of the non-specific systemic inflammatory responses syndrome of the body (SIRS) and manifests signs of general intoxication and symptoms of involvement in the autoimmune inflammatory process of pulmonary pleurae and/or pericardial layer to form efflux in the pleural and/or pericardial cavities. PCTS is not a rare pathological condition and often accompanies heart surgeries, especially those which are carried out under cardiopulmonary bypass. However, it can occur in the guise of lung and pleura diseases, cardiac decompensation and other complications of cardiological diseases and cardiosurgical interventions. In the light of the specificity of the therapy of this syndrome, its correct and timely diagnosis is intended to alleviate the already unsatisfactory condition of the patient who has undergone heart surgery and his postoperative prognosis. Although this pathology was described in the middle of the last century, its methods of treatment are still under discussion, in particular the effectiveness of glucocorticosteroids and colchicine is compared and the use of the latter for the prevention of PCTS is considered. This paper presents the case history of PCTS tolerant to hormone therapy and managed with colchicine.

A 71-year-old woman with cardiac sarcoidosis underwent an implantable cardioverter-defibrillator implantation in the left precordium to prevent fatal arrhythmias. Two weeks later, she presented with dyspnea. Chest X-ray revealed right pneumothorax due to the active atrial lead perforation. Subsequently, air was detected surrounding the heart. Although it was difficult to differentiate pneumopericardium from pneumomediastinum, postural conversion computed tomography (CT) in the supine and prone positions documented air migration in the pericardial cavity and diagnosed pneumopericardium. This rare case of pneumopericardium combined with pneumothorax contralateral to the venous access site highlights the utility of postural conversion CT for diagnosis of pneumopericardium.

Introduction and importance: Hypothyroidism is an endocrine disorder with multiorgan involvement and various complications. One of the significant but less often seen complications is pericardial effusion. Since it can progress to life-threatening conditions like cardiac tamponade and hemodynamic instability, early diagnosis, and management of the pericardial effusion in hypothyroidism is a must. Case presentation We present a case of a 35-year-old male who presented with bilateral lower limb swelling, facial puffiness, cold intolerance, fatigue, and hoarseness of voice for one week. Laboratory investigation showed high thyroid-stimulating hormone (TSH), low triiodothyronine (T3), and raised serum anti-thyroid peroxidase (anti-TPO). The lipid profile demonstrated hypertriglyceridemia. Ultrasonography of the neck revealed normal thyroid size with decreased echo texture and increased vascularity. An electrocardiogram showed low voltage complexes with sinus bradycardia. 2D echocardiography revealed minimal pericardial effusion with normal ventricular function. The patient was managed with thyroxine therapy which gradually resolved his symptoms and pericardial effusion. Clinical discussion Pericardial effusion in hypothyroidism is due to the increased capillary permeability and albumin distribution volume and reduced lymph drainage in the pericardial cavity. Its presence in mild cases of hypothyroidism is uncommon although it can be seen in severe, long-standing hypothyroidism. Pericardial effusion in hypothyroidism, though rare, can present in mild cases and if overlooked can be fatal due to conditions like cardiac tamponade. Conclusion With early cardiac assessment and adequate thyroid replacement therapy, pericardial effusion in hypothyroidism can be reversible at an early stage. So, pericardial effusion which can be overlooked in mild cases of hypothyroidism needs to be identified and managed early., Highlights • Hypothyroidism is an endocrine disorder with multiorgan involvement. • Pericardial effusion is a notable complication of hypothyroidism, occurring due to the increased capillary permeability and albumin distribution volume and reduced lymph drainage in the pericardial cavity. • The incidence of pericardial effusion is higher in severe, long-standing hypothyroidism whereas it’s uncommon in early stages and mild form of hypothyroidism. • If presents earlier, with early cardiac assessment and adequate treatment, pericardial effusion can be reversible at an early stage.

A 19-year-old woman in septic shock with recent computed tomography findings of a loculated hepatic abscess was transferred to an intensive care unit where she went into asystolic cardiac arrest. After resuscitation, surgical exploration revealed a purulent pericardial effusion with tamponade and a liver abscess. Microbiological analyses from both sites were negative. Shortly after surgical exploration, she developed multiorgan failure and died. At autopsy, pus was observed both within the pericardial cavity and around the left lobe of the liver. Green "sulfur granules" suggestive of infection with Actinomyces spp. were able to be extruded from the liver during the postmortem examination and cultures returned positive for Actinomyces israelii. This case is a rare example of primary hepatic actinomycosis infection that resulted in the death of a young woman. Nonspecific clinical manifestations may delay diagnosis; however, the finding of "sulfur granules" in areas of abscess formation at autopsy should be taken as an indication of possible underlying Actinomyces infection.

The pericardial sac is made of two layers: the visceral and parietal pericardium. Located between these two layers, the pericardial cavity is found. It contains around 15 to 50 mL of a liquid secreted by mesothelial cells. Pericardial effusion is described as the accumulation of liquid within the pericardial cavity, exceeding the previous mentioned quantity. It has multiple causes, such as malignancy, infectious origins, inflammation, and others, such as hypothyroidism. One of the multiple clinical manifestations associated with hypothyroidism is pericardial effusion. It is related to the severity and duration of the disease, being more frequent in congenital hypothyroidism or cases of a long history of hypothyroidism, as well as clinical hypothyroidism. It can present a clinical challenge mainly due to the discordance between the total volume of the effusion and the clinical symptoms shown by the patient. The main objective of this work is to present a case of a forty-two-year-old male with hypothyroidism-associated pericardial effusion which resolved satisfactorily with hormone replacement therapy.

In the article presented the results of the treatment of pericardial effusion in a patient with sigmoid colon cancer. The pathological process in the pericardial cavity was asymptomatic and was discovered as an accidental find during a preoperative examination before surgery on the abdominal organs. The importance of timely diagnosis of such a serious and rare complication is shown. The presence of pericardial effusion in a patient with colorectal cancer changed the treatment tactics and forced to shift the focus of surgical interventions. This helped to reduce the risk of major surgical intervention on the abdominal organs and a favorable outcome for the patient.

Percutaneous transluminal balloon angioplasty (PTA) is the main treatment option for Budd–Chiari syndrome (BCS) with inferior vena cava (IVC) obstruction. However, IVC rupture caused by PTA has never been reported. Between August 2004 and December 2016, a consecutive cohort of 617 BCS patients with obstructed IVC who underwent PTA with or without stent placement were reviewed retrospectively to identify IVC rupture. Pre- and post-procedural imaging data, clinical and procedural technical data were analyzed. Of the 617 BCS patients, five patients had IVC rupture caused by PTA (0.81%). Four of these patients had retroperitoneal, intra-hepatic IVC rupture without extravasation into abdominal cavity which was successfully managed conservatively. One patient had supra-hepatic IVC rupture into the pericardial cavity which was surgically treated. IVC rupture is a rare complication of PTA treatment of BCS and most commonly located at the intra-hepatic IVC caused by oversized balloons which does not require additional treatment.

Background Second heart field cells and neural crest cells have been reported to participate in the morphogenesis of the pharyngeal arch arteries (PAAs); however, how the PAAs grow out and are separated from the aortic sac into left and right sections is unknown. Results An Isl-1 positive pharyngeal mesenchyme protrusion in the aortic sac ventrally extends and fuses with the aortic sac wall to form a midsagittal septum that divides the aortic sac. The aortic sac division separates the left and right PAAs to form independent arteries. The midsagittal septum dividing the aortic sac has a different expression pattern from the aortic-pulmonary (AP) septum in which Isl-1 positive cells are absent. At 11 days post-conception (dpc) in a mouse embryo, the Isl-1 positive mesenchyme protrusion appears as a heart-shaped structure, in which subpopulations with Isl-1+ Tbx3+ and Isl-1+ Nkx2.5+ cells are included. Conclusions The aortic sac is a dynamic structure that is continuously divided during the migration from the pharyngeal mesenchyme to the pericardial cavity. The separation of the aortic sac is not complete until the AP septum divides the aortic sac into the ascending aorta and pulmonary trunk. Moreover, the midsagittal septum and the AP septum are distinct structures.

Highlights • Minimally invasive cardiac surgery is limited in small children. • Femoral cannulation has high risks in children with body weight, Objective To evaluate the effectiveness and safety of right anterolateral mini-thoracotomy without inferior vena cava (IVC) cannulation for closing atrial septal defect (ASD) in small children. Methods From February 2016 to August 2017, 10 patients (the mean age was 18.5 ± 10.1 months and the mean weight was 8.3 ± 2.1 kg) underwent ASD closure via right anterolateral mini-thoracotomy. The superior vena cava cannula was placed through the right internal jugular vein. A 3–4 cm incision was made on the right chest. The pleural and pericardial cavities were filled with CO2 and the heart was beating during the surgery. Blood returned from IVC was drained by a right heart sucker. All ASDs were closed using artificial patch, continuous suture. Mean follow-up was 18 months (range, 15–22 months). Results No post-operative complications or deaths occurred. Mean operation time and mean cardiopulmonary bypass time were 140.5 ± 27.8 min and 50.3 ± 16.5 min, respectively. These patients were extubated within the first 6 h. The intensive care unit stay time and the post-operative hospital stay time were 19.6 ± 2.6 h and 7.1 ± 1.2 days, respectively. Follow-up transthoracic echocardiography showed no residual shunts or lung atelectasis. Conclusions The right anterolateral mini-thoracotomy without IVC cannulation is feasible for repairing ASD in small children. This technique is effective and safe and can be used as a therapeutic option for ASD.

Among complications of malignant neoplasms of the heart, tumor exudative pericarditis requires emergency surgical measures with the development of chronic tamponade. At the frst stage, puncture drainage of the pericardial cavity is advisable. In case of a common tumor process and the impossibility of radical surgical treatment by the second stage, it is advisable to perform video assisted thoracoscopic pericardial fenestration with biopsy and pleurodesis, if necessary. This tactic improves the quality of life in patients and complies with modern standards of treatment of this disease.

A 44‑year‑old male patient was referred to our department with unremarkable physical examination and laboratory data due to a mass which was incidentally found in the right atrial during a routine examination.Transthoracic and transesophageal echocardiography revealed a 46×30 mm, well-delimited, non-mobile mass in the superior portion of the right atrium. Besides the intracardiac mass, another low density was detected in adjacent pericardial cavity at cardiac computed tomography ;he extracardiac mass appeared to be caused by invasive growth from the intracardiac mass.An operation was performed through right anterolateral minithoracotomy with the patient under hypothermic cardiopulmonary bypass. During operation, it was found that the surface of the right atrium was covered by an adipose mass (30×40 mm; Fig. 2A). Intracardiac mass also showed yellow adipose tissue (40×50 mm; Fig. 2B). Both parts of the mass infiltrated the myocardium. The mass was resected completely; and right atrium was reconstructed by using bovine pericardium pad. After the operation, the pathology confirmed the both intracardiac and extracardiac tissues as lipoma; transthoracic echocardiogram showed the atrial mass was removed completely and the left ventricular ejection fraction was normal . The patient’s postoperative course was uneventful and he was discharged home after 7 days.

Cardiac patches are an effective way to deliver therapeutics to the heart. However, such procedures are normally invasive and difficult to perform. Here, we develop and test a method to utilize the pericardial cavity as a natural “mold” for in situ cardiac patch formation after intrapericardial injection of therapeutics in biocompatible hydrogels. In rodent models of myocardial infarction, we demonstrate that intrapericardial injection is an effective and safe method to deliver hydrogels containing induced pluripotent stem cells-derived cardiac progenitor cells or mesenchymal stem cells-derived exosomes. After injection, the hydrogels form a cardiac patch-like structure in the pericardial cavity, mitigating immune response and increasing the cardiac retention of the therapeutics. With robust cardiovascular repair and stimulation of epicardium-derived cells, the delivered therapeutics mitigate cardiac remodeling and improve cardiac functions post myocardial infarction. Furthermore, we demonstrate the feasibility of minimally-invasive intrapericardial injection in a clinically-relevant porcine model. Collectively, our study establishes intrapericardial injection as a safe and effective method to deliver therapeutic-bearing hydrogels to the heart for cardiac repair., Current routes to deliver therapeutics to the heart are normally invasive or difficult to perform. Here the authors develop intrapericardial injection as an efficient, easy-to-perform and minimally invasive method to deliver therapeutics for cardiac repair.

Pericardial diverticulum is a focal herniation of the pericardium. It is differentiated from a pericardial cyst by the presence of communication with the pericardial cavity. Radiological differentiation between the diverticulum and cyst via computed tomography is difficult unless changes in size are identified with different body positions in additional scans. Herein we describe a case of pericardial diverticulum that was successfully diagnosed via the detection of internal pericardial flow in black blood-prepared T2 half-Fourier acquisition single-shot turbo spin-echo magnetic resonance imaging. Detection of a flow void in the pericardial sac may be a definitive magnetic resonance imaging finding in the diagnosis of pericardial diverticulum.

ObjectiveThe aim of the present study is to isolate and analyze the characterization of pericardial fluid cells (PFCs) from rat and provides a morphological basis for the basic research and clinical application of PFCs.MethodsAfter aseptic thoracotomy was performed, normal saline was injected into the pericardial cavity of 50 adult Sprague–Dawley rats. The mixture of diluted pericardial fluid was extracted, centrifuged, and cultured. The cell morphology of different generations in the pericardial fluid was observed on an inverted microscope. The expression levels of CD44, CD29, CD90, and pan-hematopoietic marker CD45 were analyzed via flow cytometry. The third-generation cells were used for osteogenic, adipogenic, and cardiac differentiation.ResultsPFCs were successfully isolated and subcultured. PFCs were predominantly circular in shape after 24 h of culture. Following subculture for 3 days, the cells demonstrated a spindle shape. The rat pericardial fluid contains cell populations with uniform morphology, good growth state, and strong proliferation ability. Flow cytometry results showed that CD29 (100%) and CD90 (99.3%) were positively expressed, whereas CD45 (0.30%) and CD44 (0.48%) were negatively expressed. The PFCs could differentiate into osteoblasts and adipocytes after being induced. Cardiac differentiation was also confirmed by cardiac troponin T (cTnT) and α-sarcomeric actin (α-SA) staining.ConclusionThis study revealed that a subpopulation of cells was isolated from pericardial fluid, which exhibited progenitor cell features and multiple differentiation potency. PFCs could serve as an alternative cell source for myocardial tissue repair, engineering, and reconstruction.

Annals of thoracic and cardiovascular surgery 28(2), 146-153 (2021). doi:10.5761/atcs.oa.21-00102, Published by Medical Tribune, Tokyo

© 2021-IOS Press. All rights reserved.BACKGROUND: The heart is surrounded by a membrane called pericardium or pericardial cavity. OBJECTIVE: In this study, we investigated the pericardial fluid (PF) for coating polycaprolactone (PCL) scaffolds. PFS, which is a PF component, was used for the coating material. In addition to using PFS for surface coating, MED and fetal bovine serum (FBS) were also used for comparison. METHODS: Pericardial fluid cells (PFSc) isolated from PF were cultured on coated PCL scaffolds for 1, 3, and 5 days. Cell viability was determined using 3-(4, 5-di-methylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. RESULTS: The MTT assay results showed that the viability of cells on PCL scaffold coated with PFS increased over time (P < 0.005), and cell viability was significantly different between PCL scaffolds coated with PFS and non-coated PCL scaffolds. However, cell viability was significantly higher in the PCL scaffolds coated with PFS than non-coated and coated with FBS, MED, and PCL scaffolds. Scanning electron microscopy (SEM) microscopy images and MTT assay indicated that PFSc are attached, proliferated, and spread on PCL scaffolds, especially on PCL scaffolds coated with PFS. CONCLUSIONS: These results suggest that PFS is a biocompatible material for surface modification of PCL scaffolds, which can be used as a suitable material for tissue engineering applications.

Fissureless lobectomy of the lung is an operative technique in which hilar vessels and bronchus are divided before the interlobar fissure is separated. When hilar vessels and bronchus cannot be exposed because of tumor progression, this procedure cannot be used. As an alternative, we propose here trans-pericardial fissureless left upper lobectomy, in which the left upper bronchus is exposed by dividing the posterior wall of the pericardium after the left upper pulmonary vein is divided in the pericardial cavity. This technique enables us to perform fissureless left upper lobectomy even when hilar vessels cannot be accessed outside the pericardium.

We present the postmortem computed tomography and autopsy findings of a 60-year-old man who developed milk of calcium pericardial effusion and died of constrictive epicarditis. He experienced out-of-hospital cardiopulmonary arrest, and spontaneous circulation returned at the hospital. However, 7 h after recovery, the patient died. He had a swollen neck, had been experiencing coughing from 4 to 5 days earlier, and had no significant medical or surgical history. On computed tomography (CT), highly dense pericardial fluid (CT value: 130–150 Hounsfield units) and multiple calcifications along the epicardium and pericardium were visualized. The epicardium and pericardium were thick, hard, rough, and widely calcified with mild adhesions on autopsy. The pericardial cavity contained a pale, reddish brown, turbid, and highly viscous liquid. Bacteriological tests of pericardial fluid cultures revealed the presence of group G β-hemolytic streptococci. Hence, we diagnosed the patient’s cause of death as heart failure due to constrictive epicarditis. We believe that this case of milk of calcium pericardial effusion is the first case confirmed with postmortem CT and autopsy findings.

Objective Pregnancy-associated plasma protein-A (PAPP-A) has been suggested as a proatherogenic enzyme by its ability to locally increase insulin-like growth factor (IGF) activity through proteolytic cleavage of IGF binding protein-4 (IGFBP-4). Recently, stanniocalcin-2 (STC2) was discovered as an inhibitor of PAPP-A. This study aimed to investigate IGFBP-4, PAPP-A, and STC2 as local regulators of IGF bioactivity in the cardiac microenvironment by comparing levels in the pericardial fluid with those in the circulation of patients with cardiovascular disease. Methods Plasma and pericardial fluid were obtained from 39 patients undergoing elective cardiothoracic surgery, hereof 15 patients with type 2 diabetes. Concentrations of IGF-I, intact and fragmented IGFBP-4, PAPP-A, and STC2 were determined by immunoassays and IGF bioactivity by a cell-based assay. Results In pericardial fluid, the concentrations of total IGF-I, intact IGFBP-4, and STC2 were 72 ± 10%, 91 ± 5%, and 40 ± 24% lower than in plasma, while PAPP-A was 15 times more concentrated. The levels of the 2 IGFBP-4 fragments generated by PAPP-A and reflecting PAPP-A activity were elevated by more than 25%. IGF bioactivity was 62 ± 81% higher in the pericardial fluid than plasma. Moreover, pericardial fluid levels of both IGFBP-4 fragments correlated with the concentration of PAPP-A and with the bioactivity of IGF. All protein levels were similar in pericardial fluid from nondiabetic and diabetic subjects. Conclusions PAPP-A increases IGF bioactivity by cleavage of IGFBP-4 in the pericardial cavity of cardiovascular disease patients. This study provides evidence for a distinct local activity of the IGF system, which may promote cardiac dysfunction and coronary atherosclerosis.