Age-associated proteomic alterations in human aortic media.

AIM: Human vascular senescence, which mainly occurs in media, is not completely understood. Here, we used proteomic approaches to investigate age-associated changes in human aortic media with the goal of understanding the molecular mechanisms underlying vascular senescence. METHOD: Cryopreserved autopsy samples of aortic media from older-aged (aged 70-100 years, n = 25), middle-aged (aged 49-68 years, n = 24), and young (aged 21-39 years, n = 12) subjects were collected. We used two proteomic techniques, two-dimensional differential gel electrophoresis and isobaric tags for relative and absolute quantitation, and we subjected differentially-expressed proteins among age groups to immunohistochemical analyses. RESULTS: Proteomic analyses showed that the expression of lactadherin, which produces medin, was elevated in aortic media of older-aged individuals. Immunohistochemical and Congo red staining showed that lactadherin and apolipoprotein E were deposited, and that amyloidosis was enhanced in older-aged aortic media. Furthermore, the markers of oxidative damage (8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal) were significantly elevated in aortic media of middle-aged or older-aged individuals. The immunohistochemical expression of anti-oxidant proteins (thioredoxin and extracellular superoxide dismutase) was also high in middle-aged and older-aged groups. Oxidative damage might induce the disruption of smooth muscle cells, resulting in the decrement of α-actin, a highly-expressed protein in smooth muscle cells, and matrix remodeling, in which several proteins associated with extracellular matrix were altered with aging. CONCLUSIONS: Proteomic approaches showed that the elevated expression of lactadherin might contribute to amyloid deposition, enhancement of oxidative stress, induction of antioxidant proteins and matrix remodeling in older-aged aortic media. Geriatr Gerontol Int 2019; 19: 1054-1062.

Acute Liver Failure Associated with Influenza A Virus Infection: an Autopsy Case Report.

An 84-year-old man with chronic renal failure, anemia, and diabetes was admitted for hemodialysis initiation. His vital signs were stable until the eighteenth hospital day, before acquiring an influenza A virus infection. Three days later, he died of septic shock with severe liver impairment. His leukocyte count, prothrombin time (PT-INR), and liver enzyme levels such as aspartate transaminase and alanine aminotransferase, were significantly increased. Hypercytokinemia was also observed. Autopsy revealed bilateral diffuse pneumonia with neutrophil infiltration. The liver showed extensive centrilobular hepatocyte necrosis. Immunohistochemistry for influenza A nucleoprotein revealed positivity in the ciliated columnar epithelium of the bronchi and negativity in the trachea, lungs, and liver. Hypoxic hepatitis is characterized by an abrupt and massive increase in aminotransferase levels (＞ 20 times upper normal limit) due to anoxic centrilobular hepatocyte necrosis. The occurrence of hypoxic hepatitis requires a pre-existing, chronic condition, such as anemia, causing reduced oxygen supply to the liver, followed by an acute decrease in hepatic oxygen supply, such as septic shock. Therefore, this report suggests that hypoxic hepatitis can be an important causative factor for acute liver failure associated with influenza virus infection.

Right ventricular free wall dissection as a rupture tract in left ventricular rupture during acute myocardial infarction.

Three rare cases of cardiac rupture with right ventricular wall dissection during acute myocardial infarction (AMI) were reported. The cases comprised 2% among our 148 previously reported postinfarction cardiac ruptures with sudden death. The dissections occurred in hearts with biventricular inferior wall AMI and developed between the superficial layers and the deeper layers of inferior wall of the right ventricle. All had an endocardial tear at the basal septum where it meets the inferior free wall of the left ventricle, and had an epicardial tear on the middle inferior wall of the right ventricle. Based on the evidence of the ages of the thrombi of the rupture tracts, delayed epicardial rupture was found besides that soon after the right ventricular dissection.

Coronary atherosclerotic lesions in patients with a ruptured abdominal aortic aneurysm.

In this study, the coronary findings in 185 autopsy cases with a ruptured abdominal aortic aneurysm (AAA) from the Tokyo Medical Examiner's Office were examined and compared with those in 1,056 patients undergoing AAA repair at the University of Tokyo Hospital or Sakakibara Heart Institute (Tokyo, Japan). The number of cases with any significant coronary stenosis was significantly greater in the autopsy cases with a ruptured AAA than in the patients undergoing emergency repair of a ruptured AAA, suggesting that the low prevalence of CAD observed in patients undergoing emergency repair of a ruptured AAA was due to the survival bias before reaching hospital. In addition, we also found that significant coronary left main trunk stenosis was more frequent in CAD cases with a ruptured AAA than in those with an unruptured AAA, findings that suggest novel clinical implications. Large-scale prospective studies are warranted to confirm our findings and to clarify the pathophysiological relationship between coronary atherosclerosis and AAA status.

Significant association between hypolipoproteinemia(a) and lifetime risk of cancer: an autopsy study from a community-based Geriatric Hospital.

BACKGROUND: Our recent study showed that a low lipoproteinemia(a) [Lp(a)] level was a risk factor for cancer and all-cause deaths. The purpose of this study was to verify the role of the Lp(a) level on cancer among consecutive autopsy cases. METHODS: The subjects consisted of 1354 cases (775 men and 579 women). The average age at death was 79.9 years. Hypolipoproteinemia(a) was defined as an Lp(a) level of below 80 mg/L. Overall, 62.3% of the subjects had suffered from at least one to a maximum of five malignancies throughout their lives. The most frequent type of malignancy was gastric cancer, followed by leukemia, lung cancer, and colon cancer. RESULTS: The cancer-bearing status decreased linearly according to the Lp(a) level in both men and women (P=0.01 and P<0.001, respectively). The median Lp(a) level was significantly lower among the cases with hepato-biliary-pancreatic cancers or hematopoietic malignancy, but was higher among cases with lung cancer, especially lung adenocarcinoma. Hypolipoproteinemia(a) was a significant risk factor for any origins of cancer, with an odds ratio of 1.94 (95% CI, 1.45-2.60; P<0.001). It was also a risk factor for hepato-biliary cancers and leukemia, but it was a protective factor for lung cancer. CONCLUSIONS: Our findings suggested hypolipoproteinemia(a) would be a significant risk factor for cancer except lung cancer. This study complements our previous study showing that hypolipoproteinemia(a) would increase the lifetime risk of cancer other than lung cancer.

Histopathological and immunohistochemical findings of 20 autopsy cases with 2009 H1N1 virus infection.

Twenty autopsy cases with 2009 pandemic influenza A (2009 H1N1) virus infection, performed between August 2009 and February 2010, were histopathologically analyzed. Hematoxylin-eosin staining, immunohistochemistry for type A influenza nucleoprotein antigen, and real-time reverse transcription-PCR assay for viral RNA were performed on formalin-fixed and paraffin-embedded specimens. In addition, the D222G amino acid substitution in influenza virus hemagglutinin, which binds to specific cell receptors, was analyzed in formalin-fixed and paraffin-embedded trachea and lung sections by direct sequencing of PCR-amplified products. There were several histopathological patterns in the lung according to the most remarkable findings in each case: acute diffuse alveolar damage (DAD) with a hyaline membrane (four cases), organized DAD (one case), acute massive intra-alveolar edema with variable degrees of hemorrhage (three cases), neutrophilic bronchopneumonia (five cases) and tracheobronchitis with limited histopathological changes in alveoli (four cases). In two cases, the main findings were due to preexisting disease. Influenza virus antigen was only detected in the respiratory tract in 10 cases by immunohistochemistry. The antigen was detected in type II pneumocytes (three cases) in the epithelial cells of the trachea, bronchi and glands (six cases), and in the epithelial cells in both of the above (one case). The four cases with acute DAD presented with antigen-positive type II pneumocytes. In one case, the D222G substitution was detected in the lung as a major sequence, although 222D was prominent in the trachea, suggesting that selection of the viral clones occurred in the respiratory tract. In five cases, the pathogenesis of 2009 H1N1 was confirmed to be viral infection in pneumocytes, which caused severe alveolar damage and fatal viral pneumonia. Further studies on both host and viral factors in autopsy or biopsy materials will be essential to elucidate the other pathogenic factors involved in influenza virus infection.

Autopsy and genetic diagnosis of 21-hydroxylase deficiency with bilateral testicular tumors in a case under no medication for over one year.

The autopsy findings of an adult patient with 21-hydroxylase deficiency are presented. Genetic analysis of the 21-hydroxylase gene (CYP21A2) was performed for accurate diagnosis of congenital adrenal hyperplasia (CAH), and bilateral testicular tumors were characterized. We report a 29-year-old Japanese man who was diagnosed with CAH (21-hydroxylase deficiency) in infancy and had continued steroid therapy until the age of 28. However, for more than one year, he had not been treated for CAH and was found dead. In the medico-legal autopsy findings, both adrenal glands were enlarged, and hypertrophy of adrenal cortices and bilateral testicular tumors positive for melan-A were observed. Genomic DNA was prepared from cervical lymph nodes collected during autopsy, and CYP21A2 was PCR amplified and sequenced directly using newly designed primers. From the morphological findings, the bilateral testicular tumors were considered to be adrenogenital syndrome (TTAGS). Through the whole sequence of CYP21A2, the intron 2 splice mutation (656)A to (656)G was found. TTAGS were thought to be adrenal rests enlarged by ACTH stimulus. From the autopsy findings and the result of genetic analysis, he was diagnosed with the salt-wasting form of 21-hydroxylase deficiency and his cause of death was presumed to be heart failure based on abnormal electrolytes.

Age is a major pathobiological determinant of aortic dilatation: a large autopsy study of community deaths.

AIM: Aortic dilatation is a well-known phenomenon in the elderly. We therefore aimed to study the pathobiological determinants of aortic dilatation. METHODS: Retrospective chart review. The subjects were 833 consecutive autopsy cases (616 men and 217 women) of community deaths. The age at death ranged from 20 to 94 years, with an average of 59.2 years. We measured the internal circumference of the aortic root, arch, descending portion, abdominal portion, and bifurcation in unfixed opened aorta at the time of autopsy. RESULTS: The simple correlation between age and aortic circumference was strongest for the descending portion, followed by the arch, abdominal portion, root, and bifurcation. The simple correlation coefficient reached 0.836 for the descending portion (p < 0.001). The circumference of the descending portion increased significantly as the severity of aortic atherosclerosis increased (p for trend < 0.001). Multiple regression analysis showed that age, sex, and body height were significantly correlated with the aortic circumference at all five measurement sites, while severe atherosclerosis was correlated with the aortic circumference at the root, and descending and abdominal portions. Six contributing factors (age, sex, body height, smoking history, hypertension, and severe atherosclerosis) explained 68.5% of the variance in circumference in the descending portion; age explained 57.5%; sex 8.4%; body height 1%; and severe atherosclerosis 0.8%. CONCLUSION: The contribution of atherosclerosis to aortic dilation was very weak, representing less than one seventieth of the contribution of age. The aortic circumference, especially in the descending portion, serves as an excellent age-related marker.

Pathological evaluation of coronary lesions in cases of cardiac rupture during acute myocardial infarction: an autopsy study of 148 out-of-hospital sudden death cases.

We pathologically evaluated coronary artery lesions of left ventricular ruptures during acute myocardial infarctions (148 sudden out-of-hospital death cases; 93 men and 55 women; age range 42-94 years; mean age 68.9 years; 143 atherosclerotic and 5 non-atherosclerotic lesions). Among the 143 hearts with atherosclerotic coronary lesions, three-vessel disease was most frequent, and plaque rupture or erosion and occlusive thrombus were identified in most cases. Ages of the main component of the occlusive thrombus in the culprit coronary artery corresponded histopathologically to those of myocardial infarction. One of the most outstanding features in this pathological study is that acute thrombus in the culprit coronary artery was identified morphologically in most of the cases with advanced myocardial infarction (3 or more days). On the other hand, in cases of fresh myocardial infarction, a preceding mural non-occlusive organizing thrombus was observed mostly underneath the main component of the thrombus. It is suggested that, in most cases, cardiac rupture during acute myocardial infarction occurs at the time of a new ischemic event caused by a new thrombotic coronary lesion.

Elderly patients with minimal common carotid atherosclerosis not infrequently have severe coronary atherosclerosis and myocardial infarction.

BACKGROUND: The presence of discordances between common carotid and coronary atherosclerosis in the same individual has not been previously reported. METHODS AND RESULTS: The subjects of the present study were 1,518 consecutive autopsy cases at a general geriatric hospital. All were aged 60 years or older (821 men, 697 women) with an average age of 80 years. The atherosclerotic index of the common carotid artery (CC-AI) and coronary stenotic index (CSI) were semi-quantitatively evaluated. The simple correlation coefficient between the CC-AI and CSI was 0.456 (p<0.0001). Among 689 cases with minimal common carotid atherosclerosis (CC-AI < or =2), 74 (11%) had severe coronary atherosclerosis (CSI > or =12), 68 (10%) had coronary heart disease, and 80 (12%) had pathologically-verified myocardial infarction (MI). Among those with minimal common carotid atherosclerosis, the serum total cholesterol level, diabetes mellitus, and history of smoking were significantly higher or more frequent in cases with a CSI > or =12 than in the patients with a CSI <12. CONCLUSIONS: A considerable proportion of cases with minimal common carotid atherosclerosis had severe coronary atherosclerosis and MI. This discordance can potentially lead to an underestimation of coronary risks if normal common carotid morphology is obtained by ultrasound.

Endocardial tears and rupture tracts of left ventricular ruptures during acute myocardial infarction: an autopsy study of 50 out-of-hospital sudden death cases.

We pathologically evaluated endocardial tears and rupture tracts of left ventricular ruptures during acute myocardial infarctions (50 sudden out-of-hospital death cases; 28 men and 22 women; age range 42-88 years; mean age 68.4 years). Endocardial tears were frequently seen at or near the base of the papillary muscles (54%) or in the area where the septum meets the free wall (42%). The endocardial tear was longer in the adjacent septum (mean 2.1+/-1.0cm) than at the papillary muscle base (mean 1.0+/-0.8cm). Accessory tears were observed near the main endocardial tear in about half of the cases (44%). The rupture tract was located well within the infarcted area in 88% and at the border of the infarcted and normal myocardium in 12%. Mature fresh thrombus was found on most main endocardial tears. In most rupture tracts, the thrombus was more mature in the subendocardial than in the subepicardial zone. Morphologically, this study confirmed that most cardiac ruptures start with an endocardial tear at or near the base of the papillary muscles or in the area where the septum meets the free wall, and rapidly progress independent of the histopathologic age of the infarction.

Standard organ weights among elderly Japanese who died in hospital, including 50 centenarians.

The present study was conducted to determine standard organ weights among the elderly, because little has been reported on this subject. To analyze the human aging process in terms of organ weights, age-associated changes and correlations among organ weights and the contributions of age and nutrition to organ weights were also examined. The subjects included 1615 consecutive autopsy cases of patients aged 60-99 years who died between 1995 and 2003, and cases of 50 centenarians who died between 1973 and 2005. The weights of nine organs were measured before formalin fixation. If affected by serious diseases, such as cancer, the organs were excluded from the study. Values beyond 99% of the bilateral measurement limits were also excluded. In this manner the standard organ weights were obtained. The organ weights decreased significantly according to age in all organs except for the heart in men and the lungs in both genders. Undernutrition strongly contributed to organ weight except for the hypophysis, and was especially apparent in the heart and liver. In conclusion, the standard organ weights of elderly patients who died while hospitalized were determined. Undernutrition contributed significantly to a reduction in organ weights.

Sustained progression and loss of the gender-related difference in atherosclerosis in the very old: a pathological study of 1074 consecutive autopsy cases.

INTRODUCTION: Epidemiological surveys show decrease or reversal of male predominance in cardiovascular mortality in the very old, but the actual condition of atherosclerosis in the very old is largely unknown. The objective of this paper is to reveal whether the atherosclerosis continues to progress, or the gender-related difference exists in the very old. METHODS: The subjects were 1074 consecutive autopsy cases of in-hospital death. The male:female ratio was 1.1:1 and the average age was 80 years. Macroscopic evaluation was performed on the degree of atherosclerosis in 10 arteries including the intracranial arteries, carotid artery, aorta, coronary artery, and femoral artery. RESULTS: The severity of atherosclerosis differed greatly among arteries. The age-related increase of the atherosclerotic degree was evident, even after 80 years of age. The atherosclerosis was more severe in males than in females in their 60s, but this male predominance decreased with ageing and finally disappeared in their 90s. CONCLUSION: The sustained progression of atherosclerosis and loss of the gender-related difference probably account for the increase of cardiovascular mortality in very old females. They also suggest that the prevention of the atherosclerotic progression is still important in the seventh and eighth decade of life.

[Possible influence of psychotropic drugs detected in blood when determining the cause of death in medicolegal autopsy cases in the Tokyo Medical Examiner's Office].

We reviewed the records of 118 medicolegal autopsy cases, in which psychotropic drugs were detected in blood, in the Tokyo Medical Examiner's Office in 1997, to explore how the drug levels were considered in determining the cause of death. Names and doses of the drugs were clear in 70 of 118 cases, and in most cases of the 70 cases, multiple drugs (up to 13 drugs) were prescribed to a person. It was also evident that 75 of the 118 cases had demonstrated psychosis for several months to 38 years prior to death. No information concerning prescriptions or history of psychosis could be obtained in the other cases. The causes of death in these 118 cases were as follows: deaths from specific diseases, 30 cases (25.4%); deaths from extrinsic factors excluding drug intoxication, 22 cases (18.6%); suicide related to drug intoxication, 31 cases (26.3%); deaths from extrinsic factors related to drug intoxication suggestive of suicide, but not confirmed, 19 cases (16.1%); non-suicide, including probable drug intoxication, 13 cases (11.0%); and deaths from malignant syndrome, 3 cases (2.5%). There were cases diagnosed as death from specific diseases based on morphological findings, though drug concentrations in blood were at a toxic or even lethal level. In some cases, drug intoxication was suspected, but drug levels in their blood were at a therapeutic level and there were no identifiable morphological changes directly associated with deaths, resulting in a cause of death other than drug intoxication being indicated. Thus, drug levels detected in the cadaver's blood are not always useful for determining the cause of death. This might be due to poor information on interactions between drugs (including alcohol), pathological changes or genetic variability of drug metabolism and excretion, and so on. Thus, further studies of these aspects are needed in order to make information on drugs detected in the cadaver more useful for determination of cause of death.

Adenomatoid tumor of the adrenal gland: case report with immunohistochemical study.

Adrenal adenomatoid tumor (AT) is a recently recognized disease with marked male predominance. Herein is presented a case of adrenal AT incidentally found in a 30-year-old man and results of immunohistochemical examination of the tumor. The left adrenal gland, weighing 17 g, contained a mass measuring 3 x 2.5 x 2.5 cm in the cortical tissue. Cut surface showed a relatively well-circumscribed firm tumor with a white solid appearance. Histologically, the tumor had the typical appearance of AT described in the genital tract. Immunohistochemically, the tumor cells were positive for calretinin, D2-40, WT1, mesothelial cell antigen, CA125, thrombomodulin, vimentin and cytokeratins (stained by AE1 + AE3, OV-TL 12/30, CAM5.2 and MNF116), and negative for endothelial markers (CD31, CD34 and factor VIII-related antigen) and CD56. CD56-positive adrenocortical cells were diffusely scattered in the tumor, especially in its periphery. Immunohistochemistry of estrogen, progesterone and androgen receptors was negative. These findings confirm mesothelial origin of the tumor and suggest that this tumor has little relation to sex hormone despite male predominance.

Aortic pulse wave velocity and the degree of atherosclerosis in the elderly: a pathological study based on 304 autopsy cases.

INTRODUCTION: Studies examining the correlation between aortic pulse wave velocity (PWV) and atherosclerosis have reported conflicting results. The present paper verifies this correlation by conducting autopsy examination of elderly subjects. METHODS: A total of 3456 PWV examinations had been performed on 1538 elderly people, as a part of routine physical check-up. During long-term follow-up, many of these subjects died, and autopsy study could be conducted on 304 of these subjects. The average age at death of the subjects was 83 years and the male: female ratio was 6:5. The pathological atherosclerotic index (PAI) was defined as the average pathological degree of atherosclerosis in eight large arteries, including aorta. RESULTS: Significant positive correlations were observed between the age and PWV (gamma=0.273, P<0.001), and between the systolic blood pressure and PWV (gamma=0.478, P<0.001). There was a significantly positive correlation between the aortic atherosclerotic degree and mean PWV (rho=0.239, P<0.005), and between the PAI and mean PWV (gamma=0.323, P<0.001). The partial regression coefficient between the PAI and mean PWV was 0.209, after adjusting for the mean systolic blood pressure and age at death. CONCLUSION: The present study proved a weak correlation between the PWV and the pathologically verified degree of the aortic and systemic atherosclerosis.

Acute coronary syndrome as a cause of sudden death in patients with old myocardial infarction: a pathological analysis.

Old myocardial infarction (OMI) is one of the most important pathological manifestations in sudden cardiac death. Fatal arrhythmia arising from a fibrotic scar has been determined as the cause of death in most cases with old myocardial infarction. However, the significance of acute plaque disruption/thrombosis of the coronary arteries in those patients has not been investigated. We examined a series of 33 hearts from individuals with OMI who died suddenly during the period from 1998 to 2001. Detailed coronary pathological findings on these hearts indicated fresh or recent rupture of the coronary plaque with thrombosis in 18 cases (55%). As a result of comprehensive analysis, the sudden deaths were explained by acute coronary syndrome in 18 cases (55%), fatal arrhythmia in eight (24%), cardiac pump failure in five (14%), and other causes in two (6%) cases. Our findings revealed that a new coronary plaque rupture independent of the old infarct was a major cause of sudden cardiac death with OMI.