Utility of patch testing for patients with drug eruption.

BACKGROUND: Patch testing is less dangerous than oral provocation testing for identification of the causative drug for patients with drug eruption; however, its usefulness for such identification is controversial. AIM: To clarify the rates of positive patch testing for patients with drug eruption, classified by causative drugs and clinical features. METHODS: We analysed results during the period 1990-2010 for 444 patients (151 men, 293 women; mean ± SD age 49.9 ± 18.6 years) who were tested for drug eruption. In the patient group, there were 309 people (69.1%) with maculopapular eruption and 31 (6.9%) with severe drug eruption. The test materials were applied to the back and left for 2 days under occlusion, then results were assessed by the International Contact Dermatitis Research Group (ICDRG) scoring system 3 days after application. Reactions of + to +++ were regarded as positive. RESULTS: Of the 444 patients, 100 (22.4%) had a positive patch test result to a suspected drug. Positive rates were 23.6% and 20.0% for maculopapular eruption and fixed drug eruption, respectively. The class of materials to which most patients reacted positively was contrast medium (n = 53; 41.1%), followed by drugs acting on the central nervous system (n = 18; 28.6%). In the latter group, 16 of the 18 patients were positive to antiepileptics. CONCLUSIONS: Positive rates depend on the causative drug rather than the clinical features of the drug eruption. Patch testing is useful when contrast medium or antiepileptics are suspected to be the causative drugs. However, standardization of patch test materials and method of reading is needed, as well as guidelines regarding when testing should be performed. Although patch testing for drug eruption has significant potential, it requires further validation.

Molecular structure and transcriptional regulation of the gene for the platelet-derived growth factor alpha receptor in cultured vascular smooth muscle cells.

PDGF has been shown to contribute to hypertrophy in vascular smooth muscle cells (VSMC). PDGF-AA differentially promotes protein synthesis in VSMC from spontaneously hypertensive rats (SHR) but not in those from Wistar-Kyoto rats (WKY). This observation has led us to postulate a role for PDGF alpha receptor (PDGFR-alpha) in the hypertensive hypertrophy of blood vessels. Western and Northern blot analyses demonstrated a high and specific expression of the PDGFR-alpha protein and mRNA in SHR cells but not in WKY cells. To clarify the mechanism of the differential expression of the PDGFR-alpha gene, we isolated the promoter region of the gene. Studies on the promoter functions indicated that this promoter is active in SHR cells but not in WKY cells. The regulatory domain responsible for this difference was narrowed to the sequence between -246 and -139, which enhanced the promoter activity of SHR fivefold over the basal activity. DNase I footprinting and gel-shift assay indicated that this sequence specifically interact with nuclear proteins from VSMC through the binding site for CCAAT/enhancer-binding proteins, and members of the C/enhancer-binding protein family play a significant role in the strain-specific transcription of the PDGFR-alpha gene.

Targeted overexpression of CCAAT/enhancer-binding protein-delta evokes enhanced gene transcription of platelet-derived growth factor alpha-receptor in vascular smooth muscle cells.

Platelet-derived growth factor (PDGF) is thought to play a significant role in various models of vascular remodeling, particularly in the early process of vascular diseases. Its action is mediated by its specific receptor, the PDGF receptor. The PDGF alpha-receptor (PDGFalphaR) plays an important role in the growth and proliferation of vascular smooth muscle cells (VSMCs), and its gene expression is thought to be regulated by several potential transcriptional nuclear factors. However, the detailed mechanisms of tissue-specific transactivation of the PDGFalphaR gene in VSMCs remain to be clarified. We have previously demonstrated that the rat PDGFalphaR gene contains an enhancer core sequence for CCAAT/enhancer-binding proteins (C/EBPs) in its promoter region, and we have also suggested that C/EBP-delta is the principal factor involved in the induction of tissue-specific transcriptional activity of the PDGFalphaR gene in VSMCs. To explore the definitive roles of C/EBP-delta protein on PDGFalphaR gene transcription in VSMCs, we developed C/EBP-delta transgenic rats by using a chimeric fusion gene of the mouse smooth muscle alpha-actin promoter and an entire coding region of rat C/EBP-delta cDNA. This report describes the first successful targeted overexpression of C/EBP-delta capable of inducing PDGFalphaR gene transcription and modifying cell proliferative activity to PDGFs. Targeted overexpression of C/EBP-delta evokes high levels of PDGFalphaR gene expression, susceptibility to VSMC growth, and proliferation of VSMCs to PDGFs. The results obtained reveal evidence of a new role and new functional significance of C/EBP-delta on VSMC growth via the PDGFalphaR during the process of vascular remodeling and atherosclerosis.

Platelet-derived growth factor induces apoptosis in vascular smooth muscle cells: roles of the Bcl-2 family.

Apoptosis (programmed cell death) is observed in vascular smooth muscle cells (VSMC) in atherosclerotic lesions and stenotic lesions after injury, and modulates the cellularity of these lesions. It is recognized that cell growth and apoptosis are two linked processes. Platelet-derived growth factor (PDGF) induces VSMC proliferation and migration in vitro. We studied the effect of PDGF on apoptosis in VSMC. Cultured rat VSMC were treated with PDGF-AA or PDGF-BB. PDGF-BB induced cell death in cultured VSMC in a time- and dose-dependent manner, but PDGF-AA did not. Gel electrophoresis of genomic DNA and in situ DNA labeling confirmed that the cell death induced by PDGF-BB is apoptosis. PDGF-BB treatment reduced bcl-2 mRNA and bcl-xl mRNA expression, in contrast, induced bcl-xs mRNA expression, linked with the induction of apoptosis in cultured VSMC.

Novel cis element for tissue-specific transcription of rat platelet-derived growth factor beta-receptor gene.

Platelet-derived growth factor (PDGF) and its receptors are widely expressed in several tissues in the stage of cellular growth and development. In adulthood, PDGF beta-receptor (PDGFbetaR) is mainly detected in pathological conditions such as atherosclerotic lesions and injured vascular wall. The purpose of the present study was to elucidate the underlying mechanism of PDGFbetaR gene expression under pathological conditions in vascular smooth muscle cells (VSMC) and to identify the important cis elements responsible for tissue-specific gene transcription. Gel mobility shift assay and supershift assay indicated that the CCAAT motif located at -67 (C67) was mainly interacted with NF-YC, and this element drove the basal promoter activity of the gene as a putative promoter. On the other hand, another important sequence essential for the basal transcription was found at a 30-bp region (R30) spanning -150 to -121. To test whether R30 actually regulates the tissue-specific transcription of PDGFbetaR gene, electromobility shift pattern was compared between VSMC and hepatoma cell line (HTC). We obtained the result that DNA-protein complex seen only in nuclear extracts from HTC suppressed the promoter activity in HTC in a tissue-specific manner. Furthermore, cis element decoy transfection experiments for C67 and R30 also revealed that both elements were functionally important in mRNA expression of PDGFbetaR in VSMC. From these results, we concluded that the basal activity of PDGFbetaR gene expression was transactivated by the interaction or coordination of both C67 and R30, and the latter one mainly controlled the tissue-specific gene expression in VSMC.

Postprandial hypotension is associated with asymptomatic cerebrovascular damage in essential hypertensive patients.

offelucidate the relationship between postprandial hypotension (PPH) and asymptomatic cerebrovascular damage, we evaluated changes in blood pressure after a meal by 24-hour blood pressure monitoring in 70 hospitalized essential hypertensive patients aged >/=50 years. They received a diet containing standard nutritional ingredients with 120 mmol (7 g) NaCl and were free from medication for at least 1 week. PPH was defined as the mean reduction of systolic blood pressure during 2 hours after a meal. Patients were divided into three groups according to mean values of PPH after 3 meals: PPH-1 (n=16, 5 mm Hg/=10 mm Hg), and normal (n=36, PPH<5 mm Hg). As asymptomatic cerebrovascular damage, lacunae and leukoaraiosis were evaluated by magnetic resonance imaging. PPH did not correlate with daytime or nighttime blood pressure or the nondipper phenomenon; however, PPH was significantly related to asymptomatic cerebrovascular damage. The prevalence of lacunae in the normal, PPH-1, and PPH-2 groups was 44%, 69%, and 83%, respectively (chi2=8.22, P<0.05). The number of lacunae in the normal, PPH-1, and PPH-2 groups was 1.0+/-1.3, 1.3+/-1.2, and 1. 9+/-1.4, respectively (F[2,67]=3.2, P<0.05). The prevalence of advanced leukoaraiosis in the normal, PPH-1, and PPH-2 groups was 44%, 50%, and 83%, respectively (chi2=7.63, P<0.05). Severity score of leukoaraiosis in the normal, PPH-1, and PPH-2 groups was 1.5+/-0. 7, 1.7+/-0.8, and 2.1+/-0.7, respectively (F[2,67]=4.3, P<0.05). These findings indicate that elderly hypertensive patients with marked PPH should be considered to have advanced cerebrovascular damage even in the absence of abnormal neurological findings.

ES-8891, an orally active inhibitor of human renin.

A newly synthesized orally active renin inhibitor, N-morpholinoacetyl-(1-naphthyl)-L-alanyl-(4-thiazolyl)-L-alanyl (3S,4S)-4-amino-3-hydroxy-5-cyclohexylpentanoyl-n-hexylamide (ES-8891), was found to be a highly potent competitive inhibitor of human renin with an inhibition constant of 1.1 nM. This inhibitor was also active against monkey renin, although there was less inhibition of renin in pig, rabbit, and rat. ES-8891 did not inhibit cathepsin D, pepsin, trypsin, chymotrypsin, angiotensin converting enzyme, and urinary kallikrein at a concentration of 10(-5) M. A single oral administration of ES-8891 (10 or 30 mg/kg) to conscious, sodium-depleted marmosets caused a dose-related decrease in plasma renin activity and blood pressure. ES-8891 (30 mg/kg) produced an 80% inhibition of plasma renin activity, which lasted for more than 6 hours. Kidney renin messenger RNA was not significantly changed 6 hours after oral administration of ES-8891 (30 mg/kg). A single oral administration of 240 mg ES-8891 to healthy human volunteers (n = 6) produced a significant inhibition of plasma renin activity (75% inhibition at 0.5 and 1 hour, 50% inhibition at 2 hours) with a good correlation of plasma levels of ES-8891. There were no significant changes in blood pressure or heart rate, and no adverse effects were observed. These results suggest that ES-8891 is an orally active human renin inhibitor that may be clinically useful.

cDNA cloning and mRNA expression of calponin and SM22 in rat aorta smooth muscle cells.

We cloned and sequenced cDNAs encoding calponin (Calp) and SM22 (smooth muscle-specific 22-kDa protein) from rat aorta (RaA) smooth muscle (Smu) cells. The 1504-bp calp cDNA contains a single open reading frame (ORF) which encodes 297 amino acids (aa) (M(r) 33,342). The 1186-bp SM22 cDNA contains a single ORF which encodes 201 aa (M(r) 22,601). There were 43% identical aa in a 181-aa overlap between RaA Calp and SM22. Especially for the C-terminal region of SM22 and for the first repeat motif of Calp, 70% identity was observed. Northern blot analysis revealed that the calp and SM22 mRNAs were expressed in RaA Smu, but not in rat cardiac and skeletal muscles. SM22 mRNA was much more abundant than calp mRNA in RaA (3- to 4-fold). The expression levels of the calp and SM22 mRNAs in RaA showed a significant increase for 5 to 15 week old rats (1.5- to 3-fold) with vascular development and blood pressure elevation. No significant differences were observed in the expression of the RaA calp and SM22 mRNAs between normotensive (Wistar Kyoto) and spontaneously hypertensive rats (SHR).

Kidney renin gene expression in spontaneously hypertensive rats.

We studied the expression of kidney renin gene in hypertensive animals by measuring the kidney renin messenger (m) RNA. The kidney renin mRNA was quantified by densitometric Northern blot analysis using a 32P-labelled rat renin genomic DNA fragment as a hybridization probe. Spontaneously hypertensive rats (SHR) and control Wistar-Kyoto rats (WKY) were treated with a low-sodium diet plus furosemide, captopril or propranolol for a week. Plasma renin activity (PRA) in SHR and WKY was increased similarly by sodium depletion and by treatment with captopril. PRA in both strains was not decreased significantly by treatment with propranolol. Both sodium depletion and captopril treatment caused significant increases in the kidney renin mRNA in SHR and WKY. However, the increases in the kidney renin mRNA of SHR were greater than those in the corresponding WKY (SHR, 10.0- and 22.1-fold increases; WKY, 6.2- and 7.8-fold increases, respectively). Propranolol had no effect on the kidney renin gene expression in either WKY or SHR. These results indicate that SHR show an enhanced expression of the renin gene in the kidney compared with WKY in response to stimuli that increase renin release.

The effect of the renin inhibitor ES-1005 on the expression of the kidney renin gene in sodium-depleted marmosets.

The effect of the renin inhibitor ES-1005 or captopril on the expression of the kidney renin gene was investigated in sodium-depleted marmosets. We measured the level of kidney renin messenger RNA (mRNA) after continuous administration of ES-1005 (48 mg/kg per day) or captopril (2 mg/kg per day) intraperitoneally, via an osmotic mini-pump, for one week. The level of kidney renin mRNA was measured by densitometric Northern blot analysis using an alpha-32P-labelled human renin cDNA fragment as the hybridization probe. Captopril treatment markedly increased plasma renin activity and the level of kidney renin mRNA by 4.7-fold and 6.3-fold, respectively. ES-1005 treatment completely inhibited plasma renin activity and significantly decreased the level of kidney renin mRNA (46% of the normal control P less than 0.01). However, plasma immunoreactive renin concentration was significantly increased by the treatment with ES-1005 (P less than 0.05). These results suggest that the treatment with the renin inhibitor ES-1005 for one week has a paradoxical effect on kidney renin gene expression and renin release from the kidney in sodium-depleted marmosets.

Molecular structure and function of rat platelet-derived growth factor beta-receptor gene promoter.

OBJECTIVE: To understand the regulatory mechanism of platelet-derived growth factor beta-receptor gene expression. METHODS: A 1.7 kb genomic fragment was obtained from a rat genomic library. After we had determined an entire sequence of this fragment, transcription start sites were determined both by primer extension analysis and by riboprobe mapping. We performed a functional promoter assay by using a dual-luciferase reporter system. Progressive 5'-deletions of the fragment and site-directed mutagenesis for the CCAAT motif located at -67 or -94 were used for the assay, and their promoter activities in vascular smooth muscle cells were assessed. Gel-mobility shift analysis was also performed for the CCAAT motif at -67. Effects of the upstream sequence spanning -310 through -120 on heterologous gene promoters were also investigated. RESULTS: Multiple transcription start sites were observed in the 5'-flanking region, and the 1.7 kb sequence was actually active as a functional promoter in vascular smooth muscle cells. Two important sequences responsible for the basal transcriptional activity were identified by the functional promoter assay. One was the CCAAT motif at -67 which acts as a promoter itself, and the other was the upstream region spanning -310 through -210 which positively regulates the basal promoter activity. CONCLUSION: The basal promoter activity of the rat platelet-derived growth factor beta-receptor gene is mainly regulated by the interaction or coordination of two sequences, the CCAAT motif and the upstream control element.

Postprandial hypotension: evaluation by ambulatory blood pressure monitoring.

To elucidate whether postprandial hypotension (PPH) is associated with any diurnal change of blood pressure, ambulatory blood pressure monitoring was performed on 121 hospitalized essential hypertensive patients who received standardized meals. Postprandial change in blood pressure was defined as the difference between mean systolic blood pressure (SBP) 1 h before and 2 h after each meal. The postprandial decline of SBP showed age-dependent augmentation. The degree of PPH was significantly related to the level of preprandial blood pressure for each meal. Patients were divided into the following three groups according to the mean PPH of three meals: Normal group (n = 79); mean postprandial decline of SBP <5 mm Hg, PPH-1 group (n = 24); 5 mm Hg ' mean PPH < 10 mm Hg, and PPH-2 group (n = 18); PPH 2 > or = 10 mm Hg. There was no difference in 24-h, nighttime, or daytime blood pressure among the three groups. The prevalence of dipper and nondipper patients was not different among the three groups. However, patients in PPH-2 showed significantly greater daytime and 24-h blood pressure variability. Furthermore, there was a significant positive relationship between the morning surge of SBP and PPH after breakfast (r = 0.36, P < .001). These findings indicate that PPH increases blood pressure variability independently of nocturnal change in blood pressure.

Asymptomatic cerebrovascular damages in essential hypertension in the elderly.

To investigate the underlying mechanisms of asymptomatic cerebrovascular damage, the diurnal change in blood pressure was evaluated in hypertensive patients with silent cerebral infarction (SCI). Sixty elderly hypertensive patients (age > or = 60 years) were matched with 40 middle-aged patients (age < or = 59 years) for sex and left ventricular mass index (LVMi). Lacunar lesions were evaluated by magnetic resonance imaging as SCI. The presence and the severity of SCI increased with age. In the middle-aged group, the presence of SCI was significantly related to 24-h blood pressure and LVMi evaluated by echocardiography. In elderly patients, the presence of SCI had no relationship with 24-h blood pressure or LVMi. The lowest level of nocturnal diastolic blood pressure showed a J-shaped relationship with the incidence of SCI in the elderly patients. These findings indicate that the hemodynamic characteristics underlying the development of SCI differ between middle-aged and elderly hypertensive patients. A different approach to the treatment of hypertension in the elderly appears necessary.

Autonomic nervous function in essential hypertension in the elderly. Evaluation by power spectral analysis of heart rate variability.

Autonomic nervous function in elderly essential hypertensive patients was investigated by power spectral analysis of heart rate variability. Fifty-seven essential hypertensive patients participated in this study. They were divided into two groups: the middle-aged group (age < or = 59 years, n = 30) and the elderly group (age > or = 60 years, n = 27). All examinations were performed during hospitalization. Power spectral analysis of R-R interval was performed from Holter electrocardiogram every 10 min by the maximum entropy method to obtain the low frequency band (LFB; 0.04 to 0.15 Hz), which is an index of both sympathetic and parasympathetic nervous activity. Twenty-four-hour blood pressure measurement was performed by the cuffoscillometric method to evaluate the nocturnal decrease in blood pressure. Nondipper patients were defined as those whose nocturnal decrease in systolic blood pressure was < 10% of daytime blood pressure. Both LFB and HFB were significantly lower in elderly hypertensive patients than in middle-aged patients (P < .001 and P < .05, respectively). Elderly nondipper patients had further reduced power spectral densities throughout the day. Both LFB and HFB showed a negative correlation with age. However, the age-related decline of power densities was more prominent in dipper patients and was not statistically significant in nondipper patients. These findings indicate that the nondipper phenomenon is superimposed on age-related attenuation of autonomic nervous function in essential hypertension.

The unique 5-flanking region of the human basic calponin gene.

Calponin has been implicated in the regulation of smooth muscle contraction. Basic calponin, one of the calponin isoforms, is expressed exclusively in smooth muscle cell (SMC)-rich tissues, and is considered to be a phenotypic marker of differentiated SMC. To define the molecular mechanism of SMC-specific gene transcription in humans, we isolated and characterized the 5'-flanking region of this gene. Sequence analysis revealed that several putative cis-acting elements were clustered within a 500-bp sequence upstream of the transcription start site. However, the 1.9-kb promoter region obtained herein lacked a completely matched consensus sequence of the CArG box that is commonly identified in the promoter region of other SMC-specific genes. A luciferase assay demonstrated that the 1.9-kb promoter region was sufficient to drive a basal transcriptional activity not only in human vascular smooth muscle cells (VSMC) but also in HeLa cells. In particular, the sequence between positions -1,906 and -867 had a significantly higher transcriptional activity in VSMC than in HeLa cells. In contrast, the promoter activity was drastically decreased between positions -327 and -257 in both types of cells. These results indicate that the sequence spanning from position -327 to -257 contains an essential domain involved in the basal transcriptional activity of the human basic calponin gene, and that the distal region of the 1.9-kb 5'-flanking sequence presented herein may play a pivotal role in the phenotypic modulation of VSMC.

Troglitazone induces apoptosis via the p53 and Gadd45 pathway in vascular smooth muscle cells.

Thiazolidinediones, activators of peroxisome proliferator-activated receptor (PPAR)gamma, have been reported to induce apoptosis in many types of cells. In the present study, we investigated the effects of thiazolidinediones, troglitazone, and pioglitazone on the cell growth of vascular smooth muscle cells, and identified a specific effect of troglitazone in addition to PPARgamma activation. Subconfluent rat culture vascular smooth muscle cells were treated with or without PPARgamma activators, troglitazone (1-30 microM), or pioglitazone (1-30 microM) for 72 h. After treatment, cell viability was significantly reduced by troglitazone in concentrations of 5-30 microM but not by pioglitazone. Vascular smooth muscle cells appeared to float and shrink 48 h after treatment with 20 microM of troglitazone. In situ DNA labeling showed that the nuclei of these cells were positively stained, and genomic DNA extracted from the cells showed nucleosomal laddering. Messenger RNA expression levels of c-myc, p21, bax, bcl-2, and bcl-x were not changed by the treatment with troglitazone. In contrast, along with the induction of vascular smooth muscle cell apoptosis, both the mRNA and protein expression levels of p53 and Gadd45 markedly increased in response to troglitazone. These results strongly suggest that troglitazone can induce vascular smooth muscle cell apoptosis and that this effect is caused primarily by activation of the p53 and Gadd45 pathway but not by PPARgamma activation.

Restriction fragment length polymorphisms of the human renin gene: association study with a family history of essential hypertension.

The aim of this study was to elucidate whether human renin gene restriction fragment length polymorphism (RFLP) is associated with essential hypertension. We sampled randomly 45 inpatients at our hospital and divided them into two groups according to a family history of essential hypertension, FH(-) and FH(+) groups. The FH(+) group was further divided into two subgroups based on the level of BP, FH(+) x HT(-) and FH(+) x HT(+) groups. The frequencies of renin gene RFLP patterns were compared among three groups: FH(-), FH(+) x HT(-) and FH(+) x HT(-). Among 18 restriction endonucleases tested, renin gene RFLPs were detected by three restriction endonucleases, Mbo I, Bg I and Hind III, digestion. There was a significant difference in the distribution of renin gene Mbo I genotypes among the three groups (chi 2 = 13.284, P < 0.01). The distribution of Mbo I genotypes in the FH(-) group was different from FH(+) x HT(-) group (chi 2 = 5.990, P < 0.05) and FH(+) x HT(+) group (chi = 9.210, P < 0.01), but there was no significant difference between the FH(+) x HT(-) and FH(+) x HT(+) groups. The distribution of renin gene Bgl I and Hind III genotypes were similar in the three groups, FH(-), FH(+) x HT(-) and FH(+) x HT(+). These results indicate that human renin gene Mbo I RFLP is significantly associated with a family history of essential hypertension.

Primer extension analysis to map transcription start sites of vascular genes.

The principle of the technique presented in this chapter is illustrated in Fig. 1. As with S1 mapping or riboprobe mapping, this technique can be used to determine precisely the start site of transcription of a mRNA sequence (1-3). Since this technique is relatively easier than other techniques, it is readily used for the primary determination of the transcription start site of a target gene. A radiolabeled probe derived entirely from within the gene is hybridized to mRNA complementary to the probe and extended using reverse transcriptase (RT). The cloned probe is normally derived from a region near the 5' end (cap site) of the gene and the extension reaction terminates at the extreme 5' end of the mRNA. Since only a small fragment of DNA probe is required as a primer, synthetic oligonucleotides are now almost exclusively used (although it is possible to use double-stranded DNA fragments or single-stranded primers generated by restriction enzyme digestion and gel electro-phoresis) (4). Fig. 1. The principle of primer extension analysis using a 5' end-labeled probe. The diagram illustrates how the 5' terminus of a poly(A)(+) mRNA might be determined using a 5' end-labeled single-stranded DNA probe (or synthetic oligonucleotide). Usually the probe would be a fragment derived from a cloned copy of the gene by cleavage with appropriate restriction enzymes or an oligonucleotide synthesized from the known cDNA sequence. The schematic representation of the autoradiogram demonstrates the results expected from a typical experimentLane 1, untreated probe; lanes 2 and 3, probe incubated under annealing conditions in the absence or presence of mRNA complementary to the probe, respectively, and then incubated with RT in the presence of unlabeled four deoxynucleoside trisphosfates (dNTPs). Only when complementary mRNA is present to form a hybrid with the primer, a primer extension product is synthesized as shown in lane 3.

Giant unruptured aneurysm of the thoracic aorta--a case report.

An asymptomatic 88-year-old woman underwent a screening medical examination. The chest x-ray film showed a large mediastinal mass with calcification. Both chest computed tomography and nuclear magnetic resonance imaging revealed an unruptured aortic aneurysm, predominantly affecting the ascending aorta and the proximal part of the aortic arch. Its maximum diameter was 10.5 cm. An ascending aortic aneurysm more than 10 cm in diameter is very rare. She died of acute pulmonary embolism unrelated to the aneurysm, and autopsy indicated that the etiology of the aneurysm was atherosclerotic degeneration. Retrospectively, the natural progression of the aneurysm was able to be followed on a series of chest x-ray films obtained over 18 years.