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We present autopsy findings of a 22-year-old man who developed chest pain 5 days after the first dose of the BNT162b2 mRNA vaccine and died 7 hours later. Histological examination of the heart revealed isolated atrial myocarditis, with neutrophil and histiocyte predominance. Immunohistochemical C4d staining revealed scattered single-cell necrosis of myocytes which was not accompanied by inflammatory infiltrates. Extensive contraction band necrosis was observed in the atria and ventricles. There was no evidence of microthrombosis or infection in the heart and other organs. The primary cause of death was determined to be myocarditis, causally-associated with the BNT162b2 vaccine., Graphical Abstract

Background Although ganglionated plexi (GPs) are important in the pathogenesis of arrhythmia, their patterns of atrial innervation have remained unclear. We investigated patterns of GP innervation to cardiac atria and the neuroanatomical interconnections among GPs in an animal model. Methods Atrial innervation by GPs was evaluated in 10 mongrel dogs using a retrograde neuronal tracer (cholera toxin subunit B [CTB] conjugated with fluorescent dyes). In Experiment 1, CTB was injected into the atria. In Experiment 2, CTB was injected into the major GP, including the anterior right GP (ARGP), inferior right GP (IRGP), superior left GP (SLGP), and ligament of Marshall (LOM). After 7 days, the GPs were examined for the presence of tracer-positive neurons. Results GPs in either right or left-side were innervating to both the same and opposite sides of the atrium. In quantitative analysis, right-sided GPs, especially ARGP, showed numerical predominance in atrial innervation. Based on the proportion of CTB-labeled ganglion in each GP, atrial innervation by GPs showed a tendency of laterality. In Experiment 2, CTB that was injected to a particular GP widely distributed in different GP. ARGP projected the largest number of innervating neurons to the IRGP, SLGP and LOM. Conclusion This study demonstrated that GPs project axons widely to both the same and opposite sides of atria. ARGP played a dominant role in atrial innervation. Furthermore, there were numerous neuroanatomical interconnections among GPs. These findings about neuronal innervation and interconnections of GPs could offer useful information for understanding intrinsic cardiac nervous system neuroanatomy.

This study attempted to calculate and investigate the incidence of hospitalized acute myocardial infarction (AMI) and stroke in Korea. Using the National Health Insurance claim data, we investigated patients whose main diagnostic codes included AMI or stroke during 2006 to 2010. As a result, we found out that the number of AMI hospitalized patients had decreased since 2006 and amounted to 15,893 in 2010; and that the number of those with stroke had decreased since 2006 and amounted to 73,501 in 2010. The age-standardized incidence rate of hospitalized AMI, after adjustment for readmission, was 41.6 cases per 100,000-population in 2006, and had decreased to 29.4 cases in 2010 (for trend P < 0.001). In the case of stroke was estimated at 172.8 cases per 100,000-population in 2006, and had decreased to 135.1 cases in 2010 (for trend P < 0.001). In conclusion, the age-standardized incidence rates of both hospitalized AMI and stroke in Korea had decreased continuously during 2006 to 2010. We consider this decreasing trend due to the active use of pharmaceuticals, early vascular intervention, and the national cardio-cerebrovascular disease care project as the primary and secondary prevention efforts.

Glioblastoma (GBM) can be classified into molecular subgroups, on the basis of biomarker expression. Here, we classified our cohort of 163 adult GBMs into molecular subgroups according to the expression of proteins encoded by genes of alpha thalassemia/mental retardation syndrome X-linked (ATRX), isocitrate dehydrogenase (IDH) and TP53. We focused on the survival rate of molecular subgroups, depending on each and various combination of these biomarkers. ATRX, IDH1 and p53 protein expression were evaluated immunohistochemically and Kaplan-Meier analysis were carried out in each group. A total of 15.3% of enrolled GBMs demonstrated loss of ATRX expression (ATRX-), 10.4% expressed an aberrant IDH1 R132H protein (IDH1+), and 48.4% exhibited p53 overexpression (p53+). Survival differences were statistically significant when single protein expression or different combinations of expression of these proteins were analyzed. In conclusion, in the case of single protein expression, the patients with each IDH1+, or ATRX-, or p53- GBMs showed better survival than patients with counterparts protein expressed GBMs. In the case of double protein pairs, the patients with ATRX-/p53-, ATRX-/IDH1+, and IDH1+/p53- GBMs revealed better survival than the patients with GBMs with the remained pairs. In the case of triple protein combinations, the patients with ATRX-/p53-/IDH+ showed statistically significant survival gain than the patients with remained combination of proteins-expression status. Therefore, these three biomarkers, individually and as a combination, can stratify GBMs into prognostically relevant subgroups and have strong prognostic values in adult GBMs.

Researchers have an ethical responsibility to report the results of research involving human subjects. Dissemination of results ensures that patient care is based on good science and that the field of medicine advances based on complete and accurate knowledge. However, current evidence suggests that publication is often neglected or substantially delayed, especially in the case of negative and inconclusive results. Researchers, editors and reviewers should value all high-quality research regardless of the conclusiveness of the results and ensure that all research involving human subjects is registered in a publicly accessible database.

To determine the ventricular looping pattern in relation to cardiac laterality, we studied rat embryos treated with retinoic acid (RA). A total of 243 Wistar rat embryos from an in vivo treated group (a single dose of 20-40 mg/kg all-trans RA administered to pregnant rats on day 6.5 to 9.5) and 29 control embryos were examined on day 13 of gestation. Twenty-nine embryos from the in-vitro treated group (treated by all-trans RA at 2 x 10(-7) M for 6 hr on day 9.0 or 9.5 during the entire embryo culture for 72 hr) and seven control embryos were examined on day 12 of gestation. Abnormalities in cardiac laterality and ventricular looping were found in the in-vivo groups treated on day 8.5 and 8.75 and in the in-vitro group on day 9.0. Among 25 animals with abnormal laterality, right isomerism was the most common feature (22 cases), while the type of ventricular looping varied. Cases with normal laterality had a low incidence of abnormal looping (1.4%). In rat embryos treated with all-trans RA, normal cardiac looping was expected when cardiac laterality was normal. But in cases with abnormal laterality, the type of abnormal ventricular looping was unexpected.

Pituitary adenoma (PA) is a common benign neuroendocrine tumor; however, the incidence and proportion of hormone-producing PAs in Korean patients remain unknown. Authors analyzed 506 surgically resected and pathologically proven pituitary lesions of the Seoul National University Hospital from 2006 to 2011. The lesions were categorized as: PAs (n = 422, 83.4%), Rathke's cleft cysts (RCCs) (n = 54, 10.6%), inflammatory lesions (n = 8, 1.6%), meningiomas (n = 4), craniopharyngiomas (n = 4), granular cell tumors (n = 1), metastatic renal cell carcinomas (n = 2), germinomas (n = 1), ependymomas (n = 1), and unsatisfactory specimens (n = 9, 1.8%). PAs were slightly more prevalent in women (M: F = 1:1.17) with a mean age of 48.8 yr (9-80 yr). Immunohistochemical analysis revealed that prolactin-producing PAs (16.6%) and growth hormone-producing adenomas (9.2%) were the most common functional PAs. Plurihormonal PAs and nonfunctioning (null cell) adenomas were found in 14.9% and 42.4% of patients with PAs, respectively. The recurrence rate of PAs was 11.1%, but nearly 0% for the remaining benign lesions such as RCCs. 25.4% of patients with PAs were treated by gamma-knife after surgery due to residual tumors or regrowth of residual tumor. In conclusion, the pituitary lesions and the proportions of hormone-producing PAs in Korean patients are similar to those of previous reports except nonfunctioning (null cell) PAs, which are unusually frequent. Graphical Abstract

Castleman's disease represents an atypical lymphoproliferative disorder, infrequently associated with various immunologic abnormalities or subsequent development of malignancy such as Kaposi sarcoma, malignant lymphoma and plasmacytoma. Its clinicopathologic features depend on various etiologic factors such as Kaposi sarcoma herpesvirus (KSHV), oversecretion of IL-6, adhesion molecule and follicular dendritic cell dysplasia, etc. To investigate the relationship of Castleman's disease (CD) and the above factors, we reviewed 22 cases of CD. Four cases of KSHV positive CD were detected, all multicentric, plasma cell type, and these cases displayed prominent vascular proliferation, characteristic 'Kaposi-like lesion'. IL-6 and CD54 positive mononuclear cells were scattered in interfollicular areas of KSHV positive cases. Follicular dendritic cell hyperplasia, vascular proliferation, expression of IL-6 and CD54 did not show any significant difference between solitary vs multicentric type, and plasma cell type vs hyaline vascular type. Our study suggests that KSHV positive CD reveals unique pathologic features, and the probable relationship of KSHV and IL-6 and CD54 is discussed.

Morphologic features and pathogenesis of arterial changes occurring in Buerger's disease (thromboangiitis obliterans) are still controversial. This study describes histopathologic features of medium sized arteries from patients with Buerger's disease, particularly of the internal elastic lamina in relation to the immunologic mechanism of the injury. Seventeen segments of occluded arteries (femoral or popliteal arteries) from 17 patients with Buerger's disease were analyzed by histopathological and immunohistochemical methods. The most characteristic features were total luminal obliteration, together with a varying degree of recanalization and deposition of hemosiderin pigments. Detailed analysis, however, showed marked undulation and multiplication of the internal elastic lamina (100%) associated with basophilic degeneration and delicate linear calcification (47%). Lymphocytic infiltration along the internal elastic lamina was seen in 71% and was associated with localized edema. Lymphocytes along the lamina were consistently positive for T cell marker. Mild to moderate fibrosis was present at the media in 24%. Adventitial changes included mild, nonspecific and irregular fibrosis seen in 53%. Immunologic injury to the internal elastic lamina associated with T-lymphocytic infiltration might be the initial morphogenetic mechanism of the thrombotic occlusion and organization of medium-sized arteries in Buerger's disease.

In this study of the inhibitory effects of angiopeptin and aspirin on the development of accelerated graft atherosclerosis (AGAS), 22 B10.BR mice received intra-abdominal heterotopic heart transplants from B10.A mice, without immunosuppression. Group 1 (n = 5) received no pharmacological intervention, Group 2 (n = 6) was treated with angiopeptin, Group 3 (n = 5) with aspirin, and Group 4 (n = 6) with both. There was no significant difference in the incidence of AGAS among these groups. The magnitude of intimal lesion development showed less narrowing of large vessels (> 100 microns in diameter) in groups 2 and 4--i.e. the groups received angiopeptin (Group 1 = 46.9 +/- 9.3%, Group 2 = 28.5 +/- 9.2%, Group 3 = 44.1 +/- 10.9%, Group 4 = 24.2 +/- 5.9%; p < 0.01). Comparison of the fraction of tropomyosin-positive staining cells in the intima revealed a lesser degree of staining in Group 2 (p < 0.01). No intervention was effective in preventing smooth muscle cell proliferation in the media or inflammatory cell infiltration in the adventitia. In conclusion, our data suggest that angiopeptin is effective in the direct inhibition of intimal smooth muscle cell proliferation in relatively large vessels, whereas aspirin exhibits no inhibitory role in the progression of AGAS. Angiopeptin appears to be a potential therapeutic agent for inhibiting the progression of postoperative AGAS in clinical heart transplantation.

Atelectasis can impair arterial oxygenation and decrease lung compliance. However, the effects of atelectasis on endotoxemic lungs during ventilation have not been well studied. We hypothesized that ventilation at low volumes below functional residual capacity (FRC) would accentuate lung injury in lipopolysaccharide (LPS)-pretreated rats. LPS-pretreated rats were ventilated with room air at 85 breaths/min for 2 hr at a tidal volume of 10 mL/kg with or without thoracotomy. Positive end-expiratory pressure (PEEP) was applied to restore FRC in the thoracotomy group. While LPS or thoracotomy alone did not cause significant injury, the combination of endotoxemia and thoracotomy caused significant hypoxemia and hypercapnia. The injury was observed along with a marked accumulation of inflammatory cells in the interstitium of the lungs, predominantly comprising neutrophils and mononuclear cells. Immunohistochemistry showed increased inducible nitric oxide synthase (iNOS) expression in mononuclear cells accumulated in the interstitium in the injury group. Pretreatment with PEEP or an iNOS inhibitor (1400 W) attenuated hypoxemia, hypercapnia, and the accumulation of inflammatory cells in the lung. In conclusion, the data suggest that atelectasis induced by thoracotomy causes lung injury during mechanical ventilation in endotoxemic rats through iNOS expression.

The heart transplantation-associated accelerated graft arteriosclerosis (AGAS) is one of the major causes of cardiac allograft failure. We investigated the early time-course of expresssion patterns of cytokines, transcription factor, and its inhibitor in the intraabdominally transplanted mice hearts that differed only in the D locus of class I histocompatibility antigen. The allograft hearts were harvested at 1-3, 5, 7, 14, 28, and 42 days after the transplantation, and the expressions of NF-kappaB/I-kappaB and cytokines (TNF-alpha, INF-gamma) were examined in these specimens. The expressions of TNF-alpha and INF-gamma were observed on day 1, peaking on day 5 and 7, respectively. Activated NF-kappaB (p65) expression was present on the cytoplasm and perinuclear area in the endothelial cells of coronary arteries on day 1. The peak of translocation of NF-B from cytoplasm to nucleus appeared on day 5 in the endothelial cells, myocytes, and leukocytes within the vessels, and remained elevated until day 42. The I-kappaB expression gradually increased from day 1 until day 5, but a remarkable decrease was detected on day 7. Our data suggest that the increased expressions of NF-kappaB/I-kappaB and cytokines (TNF-alpha, INF-gamma) play an important role in inducing immune responses in the donor allograft heart and hence the blockage of the expressions might be mandatory to avoid a potential graft failure.

To investigate the pathogenesis of accelerated graft atherosclerosis after cardiac transplantation, a genetically well-defined and reproducible animal model is required. We performed heterotopic intraabdominal heart transplantation between the two inbred strains of mice. Forty hearts from B10.A mice were transplanted into B10.BR mice. Recipients were sacrificed at 1, 3, 5, 7, 14, 28, and 42 days after implantation. The specimens from both donor and recipient were examined with fluorescent immunohistochemistry and the serial histopathologic changes were evaluated. In the donor hearts, ICAM-1 and VCAM-1 expressions were minimal at day 1 and they gradually increased, reaching their peaks on day 5 or 7 and remained unchanged by day 42. However, there were very little expressions in the recipients' hearts. Mean percent areas of intima in the donor coronaries revealed progressive increase by day 42. However, those in the recipients occupied consistently less than 5% of the lumen. In conclusion, we demonstrated that a heterotopic murine heart transplantation model was a useful tool to produce transplantation coronary artery disease and that adhesion molecules on the cardiac allografts were activated very early and remained elevated at all time-points, nonetheless the arterial lesion was detected after day 28 and its progression was accelerated thereafter.

To establish the early morphogenetic mechanism in retinoid induced cardiac lesions, we investigated the morphology of the heart in cultured rat embryos treated with retinoic acid (RA) at 9.0 and 9.5 days post coitum (d.p.c). Wistar rat embryos were treated with RA (2 x 10(-7) M) for 6 hours from the embryonic day equivalent of 9.0 or 9.5 d.p.c. After further culture in an RA free medium for 2.5 days, embryos were fixed and examined with a stereomicroscope and a scanning electron microscope. Sixty three embryos were treated at 9.0 d.p.c., 14 embryos were treated at 9.5 d.p.c. and 30 embryos were used as control. Abnormal ventricular looping was seen in 31 embryos (49.2%) from the group treated at 9.0 d.p.c., and isomerism of right appendages occurred in 15 (23.8%). Embryos treated with RA at 9.5 d.p.c. showed a low incidence of abnormal ventricular looping (14.3%). We could summarize those abnormal looping as three variants of each looping. The mildest form was hypoplasia of the right ventricle observed in 20 cases. Both the right and left ventricles in the second variant were shifted far to the left or right (10 cases). The third variant was a heart with generalized hypoplasia of both ventricles (3 cases). The incidence of branchial arch anomalies was higher at 9.5 d.p.c. than at 9.0 d.p.c. (71.4% and 30.2%, respectively). Abnormalities in the ventricular looping and the atrial laterality at 9.0 d.p.c. suggest that RA induces derangement in the development of laterality, while at 9.5 d.p.c., the abnormality of the migration of neural crest cells is the principal mechanism.

We studied the biological effect of a magnetic field on murine brain and kidney. Magnetic field we used was generated by Magno-DR apparatus (Hanil Co., Korea) which produced a high density unipolar square pulsating magnetic field, about 0.3 approximately 0.5 Tesla at 7 Hertz. Animals were placed in the chamber of the machine for various times from 4 hours to 24 hours. Histological sections of brain and kidney were made after perfusion fixation with paraformaldehyde. The light microscopic examination showed eosinophilic change of cytoplasm and positive immunohistochemical reaction to amyloid precursor protein in the neurons of the cerebral cortex. However, the thalamus and brain stem were less affected. The changes in the brain was seen in the mouse exposed more than 12 hours. The renal tubular epithelium showed degenerated tubules scattered in cortical area but little change was noted in glomeruli in the cortex and collecting tubules in the medulla. Immunohistochemistry of the kidney showed weakly positive reaction for the amyloid precursor protein in the distal tubular epithelium after 4 hours of exposure. These data suggest that strong pulsating magnetic fields could induce deleterious effect on the murine brain tissue and renal cortical tubules.

The evaluation of prognostic factors in infants with critical stenosis of the aortic valve and intact ventricular septum is often misleading due to a complex interaction among lesions in the mitral and aortic valves, and the left ventricular myocardium. The clinical parameters on the left ventricular function, such as ejection fraction and left ventricular end-diastolic volume, are of particular interest as their effects on survival are very controversial. We performed a clinicopathologic analysis of two autopsied cases of this disease. Besides the morphological hallmarks of the aortic and mitral valves, these two cases showed two extreme types of pathology in the left ventricular myocardium, which might have significant impacts on the clinical evaluation of the left ventricular function. Case 1 showed endocardial fibroelastosis associated with abnormal intertrabecular spaces (so-called spongy myocardium), obscuring accurate estimation of the left ventricular end-diastolic volume. Case 2 showed ischemic necrosis of the apical part of the left ventricular myocardium. This infarct was associated with acute and chronic subendocardial ischemia and mild endocardial fibroelastosis. Aggravation of the left ventricular failure could be caused by the recent ischemic insult. The evaluation of the left ventricular function, therefore, should include the evaluation of the morphologic status of the myocardium as regards to whether there is ischemia, endocardial fibroelastosis or hypertrophied trabeculae in addition to stenotic lesions in the aortic and mitral valves.

Ten cases of post-inflammatory aneurysm of the thoracic aorta were studied morphologically using aortic wall and aortic valve tissue resected during the surgical repair of the lesions. Four cases of aortic aneurysm in Behcet's disease showed massive perivascular infiltration of the lymphocytes and plasma cells in adventitia and vasa vasorum. Fibrous obliteration of the vasa vasorum was seen, and neutrophilic infiltration was also associated in two cases with recurrent prosthetic valve failure. Three cases of aortic aneurysm associated with Takayasu's arteritis showed similar histologic features, but giant cells and histiocytic reactions were additional findings. Plasma cell infiltration was more pronounced compared to the Behcet's aortitis. One case of luetic aortitis showed a non-specific chronic inflammatory reaction with florid endothelial cell proliferation. One case of ankylosing spondylitis showed fibrous thickening at the periannular portion of the aortic valve cusps, but this finding was also seen in an aortic valve of a patient with Behcet's disease. One case without any disease association showed similar features of chronic inflammation with granuloma formation. The findings suggest that they have similar histologic features indistinguishable in terms of the clinical disease association, but a granulomatous reaction could be expected in Takayasu's arteritis.

Conjoined twins show varying degree of conjoining in either facing or side-by-side fashion. Cephalothoracopagus janiceps is a prototype of facing anomaly in which the two bodies demonstrated a cross symmetry to the midline, that is axial symmetry. Interfacial and intersternal lines crossed at a right angle and no abnormality of situs was associated. Dicephalus dipus dibrachius is a case of side-by-side union, in which the bodies facing nearly the same direction were symmetrical to the middle sagittal plane. Abnormal situs of one was always associated. Other types of conjoined twins as thoracopagus lie between the two extremes of facing and side-by-side union. The three dimensional architectures of the organs in each type would be explained using cross sectional figures of skull, thorax and pelvis. Although the facing twins share the internal organs without fusion, the organs in the side-by-side component are fused with modification of the situs. We postulate sixteen pairs of situs and four manners of division for the explanation of the midline organs and the presence of a dominant co-twin. The splenic locations in a given cardiopulmonary situs are evaluated for the appraisal and applicability of these hypotheses.

A statistical analysis was made on 19,140 primary malignant tumors histopathologically diagnosed at Seoul National University Hospital during 9 year period from 1978 to 1986. The study was performed to understand the recent trend of the relative frequency of the primary malignant tumors among Koreans and to compare it with the previous studies using same hospital materials, twice presented in 1968 and 1978, respectively. Sex distribution of the cases was 10,025 (52.38%) males and 9,115 (47.62%) females. Among males the frequency rank was stomach (33.88%), lung and bronchus (8.73%), leukemia (7.02%), liver (4.79%) and oral cavity (4.70%). And among females it was uterine cervix (24.48%), stomach (20.45%), thyroid (7.87%), breast (6.48%) and leukemia (4.78%). The relative frequency of malignant tumors in this study was generally similar to the previous data published in 1978 at this department, except for the fact that stomach and lung cancers were more commonly seen in both sexes during this study period than the previous periods of years.