Distinguishing adrenal adenomas from non-adenomas on dynamic enhanced CT: a comparison of 5 and 10 min delays after intravenous contrast medium injection.

AIM: To evaluate the usefulness of several parameters of 5 min compared to 10 min delayed contrast-enhanced CT in distinguishing adenomas from non-adenomas. MATERIALS AND METHODS: The study population consisted of 94 patients (52 men and 42 women; mean age 62 years) with 103 adrenal lesions (75 adenomas and 28 non-adenomas). In each patient, unenhanced CT was followed by early, 5 and 10 min enhanced CT. Diagnostic parameters included delayed enhanced attenuation at 5 and 10 min, washout attenuation (WO) at 5 and 10 min, absolute percentage washout (APW) at 5 and 10 min, and relative percentage washout (RPW) at 5 and 10 min. The accuracy of each parameter for diagnosing adenomas from non-adenomas was calculated using receiver operating characteristic (ROC) analysis. RESULTS: Upon comparison between 5 and 10 min delayed contrast-enhanced CT for differentiating total adenomas or lipid-poor adenomas from non-adenomas, there was no significant difference in the area under the binomial ROC curve (Az) values of delayed enhanced attenuation (total adenomas versus non-adenomas, p = 0.164; lipid-poor adenomas versus non-adenomas, p = 0.178), WO (total adenomas versus non-adenomas, p = 0.216; lipid-poor adenomas versus non-adenomas, p = 0.230), APW (total adenomas versus non-adenomas, p = 0.401; lipid-poor adenomas versus non-adenomas, p = 0.870), or RPW (total adenomas versus non-adenomas, p = 0.160; lipid-poor adenomas versus non-adenomas, p = 0.780). CONCLUSION: Five minute contrast-enhanced CT was as useful as 10 min contrast-enhanced CT for differentiation of adrenal adenomas from non-adenomas.

Nizatidine improves clinical symptoms and gastric emptying in patients with functional dyspepsia accompanied by impaired gastric emptying.

BACKGROUND/AIMS: In this crossover study, we investigated whether nizatidine, a H(2)-receptor antagonist, can alleviate clinical symptoms and gastric emptying in patients with Rome III-based functional dyspepsia (FD) with or without impaired gastric emptying. METHODS: We enrolled 30 patients presenting with FD symptoms (epigastric pain syndrome, n = 6; postprandial distress syndrome, n = 24). Rome III-based FD patients were treated with nizatidine (300 mg/day) or placebo for 4 weeks in a crossover trial. Gastric motility was mainly evaluated with the T(max) value using the (13)C-acetate breath test. Meal-related symptoms were defined as postprandial fullness and early satiation. Gastroesophageal symptom was defined as a burning feeling rising from the stomach or lower chest up toward the neck. Acylated- and desacylated ghrelin levels were evaluated by the ELISA method. Clinical symptoms, gastric emptying and ghrelin levels were evaluated at three different points during the study (pretreatment, after 4 weeks former treatment and after 4 weeks later treatment). The primary end point of this study was to determine whether nizatidine would improve clinical symptoms and gastric emptying in FD patients with or without impaired gastric emptying via affecting ghrelin levels. RESULTS: Meal-related symptoms of the patients treated with nizatidine improved significantly (21/30; 70%) compared to those treated with placebo (3/30; 10%). In addition, nizatidine treatment also significantly improved gastroesophageal symptoms (16/30; 53%) compared to those treated with placebo (0/30; 0%). Nizatidine treatment in patients with FD accompanied by impaired gastric emptying significantly improved clinical symptoms and T(max) value as a marker of gastric emptying (10/11, 91%; 9/11, 82%) compared to placebo therapy, respectively. There were no significant differences in ghrelin levels between nizatidine treatment and placebo therapy. CONCLUSION: Nizatidine administration significantly improved both gastric emptying and clinical symptoms in FD patients with impaired gastric emptying.

G-protein ß3 subunit 825CC genotype is associated with postprandial distress syndrome with impaired gastric emptying and with the feeling of hunger in Japanese.

BACKGROUND: G-protein dysfunction related alteration of intracellular signal transduction might be linked to various abnormalities of functional gastrointestinal (GI) disorders. Serotonin (5-hydroxytryptamine; 5-HT) as well as G-protein is also key signaling molecule sensorimotor functions in the GI tract. Thus, this study aims to evaluate the correlation between gastric emptying and GNß3 and 5-HTs polymorphisms in functional dyspepsia (FD) as defined by Rome III classification. METHODS: Seventy-four patients presenting with typical symptoms of FD (epigastric pain syndrome: EPS, n=24; postprandial distress syndrome: PDS, n = 51) and sixty-four healthy volunteers were enrolled. Gastric motility was evaluated with the T(max) value using the (13) C-acetate breath test. We used Rome III criteria to evaluate upper abdominal symptoms and SRQ-D scores to determine depression status. GNß3-C825T, 5-HT(1A) -C1019G, 5-HT(2A) -G1438A, 5-HT(3A) -C42T, and 5-HT(4A) -G353+6A polymorphisms were analyzed in DNA from blood samples of enrolled subjects. Genotyping was performed by polymerase chain reaction. KEY RESULTS: There was a significant relationship (P=0.045) between GNß3 825CC genotype and PDS patients without gastro-esophageal reflux symptoms with impaired gastric emptying. In Japanese, GNß3 825CC genotype in FD patients was significantly associated (P=0.0485) with the feeling of hunger compared with GNß3 825CT and TT genotypes. CONCLUSIONS & INFERENCES: Our results suggest that the GNß3 825CC genotype is significantly associated with PDS patients without gastro-esophageal reflux with impairments of gastric emptying and also with the feeling of hunger in patients with FD. Further studies are needed to clarify whether the GNß3 825CC genotype is linked to disturbances of gastric emptying via altered signal transduction responses.

Nonunity permeability in metamaterial-based GaInAsP/InP multimode interferometers.

We demonstrated an InP-based optical multimode interferometer (MMI) combined with metamaterials consisting of minute split-ring resonators (SRRs) arrayed on the MMI. The MMI could operate at an optical fiber communication wavelength of 1.5 µm. Magnetic resonance occurred between the SRR metamaterial and light at 1.5 µm, and the relative permeability of the metamaterial increased to 2.4 around this wavelength. This result shows that it is possible to use new materials with nonunity permeability to construct semiconductor-based photonic devices.

Duodenogastric reflux induced by endoscopic submucosal dissection.

BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) may cause excessive duodenogastric reflux (DGR) in a similar manner to distal gastrectomy, particularly after antral resections. We aimed to examine the occurrence of DGR after ESD. PATIENTS AND METHODS: Patients with gastric neoplasm for whom ESD was indicated were categorized according to lesion site: the antral group (lower [L] stomach, n = 46) and the nonantral group (upper or middle [U or M] stomach, n = 49). Endoscopy was performed before ESD, the day after ESD, and 3 months after ESD, and the fasting bile acid concentration (BAC) in the gastric juice was analyzed. RESULTS: BAC values showed significant interaction between time point and group, although this association differed in the antral and nonantral groups. BACs on the day after ESD were higher in the antral group than in the nonantral group, but not the pre-ESD and 3 months post-ESD levels. In the antral group only, fasting BACs increased significantly the day after ESD and decreased to baseline levels 3 months post-ESD. There was also a correlation between BAC and lesion location in the antral subgroups, with significantly higher BACs found the day after ESD in patients with lesser curvature lesions. CONCLUSIONS: ESD of lesions in the antral lesser curvature may lead to a transient early increase in DGR. However, ESD does not result in long-term DGR, a factor that is known to increase the risk of carcinogenesis following gastrectomy.

Genetic changes in pT2 and pT3 prostate cancer detected by comparative genomic hybridization.

Prostate-specific antigen (PSA) screening has led to a remarkable increase in prostate cancer cases undergoing operative therapy. Over half of patients with locally advanced cancer (>or=pT3) develop rising PSA levels (biochemical failure) within 10 years. It is very difficult to predict which patients will progress rapidly to advanced disease following biochemical failure (BF). Therefore, a more useful prognostic factor is needed to suggest the most appropriate therapies for each patient. To determine chromosomal aberrations, we examined 30 patients with stage pT2 or pT3 primary prostate adenocarcinomas and no metastases (pN0M0) by comparative genomic hybridization (CGH). Laser capture microdissection (LCM) was used to gather cancer cells from frozen prostate specimens. Common chromosomal alterations included losses on 2q23-24, 4q26-28, 6q14-22, 8p12-22 and 13q21-31, as well as gains on 1p32-36, 6p21 and 17q21-22. Losses at 8p12-22 and 13q21-31 were observed more frequently in pT3 than pT2 tumors (P<0.05 and P<0.01, respectively). Losses at 8p12-22 were more frequent in tumors with BF (P<0.05), and those at 13q12-21 were more frequent in tumors with Gleason score (GS) 7 or more than lower GS (P<0.05). These findings suggest that losses of 8p12-22 and 13q21-31 are important determinants of prostate cancer progression.

Chemopreventive effect of celecoxib in gastric cancer.

COX (cyclooxygenase) is one of the key enzymes involved in the synthesis of a variety of prostaglandins (PGs), some of which have been strongly linked to inflammation. One of its two well-known isoforms, COX-2, is an inducible enzyme whose induction and expression is dynamically regulated by growth factors, mitogens, and tumor promoters. Several animal and clinical studies have reported the chemopreventive effect of celecoxib, a selective COX-2 inhibitor; and in particular, a few studies have shown that celecoxib prevents the development of gastric cancer. Administration of celecoxib also showed increases in cardiovascular risk and disruption of renal physiology. Therefore, studies hoping to clarify how selective COX-2 inhibitors modulate gastric cancer must keep in mind that coxibs have also been linked to serious cardiovascular events and disruption of renal physiology.

Genomic copy-number aberrations related to lymph-node metastasis of colon cancer.

Lymph-node metastasis is an important indicator in the diagnosis of colon cancer. In order to determine the genes involved in metastasis, genomic copy-number aberrations in the primary tumours and lymph-node metastases were analysed in 12 patients using comparative genomic hybridization. This method detects genomic copy-number changes at the chromosomal level and the identification of the regions of aberration on any chromosome. Copy-number gains at 6p12 and losses at 8p12 were observed in a greater number of the primary tumours than in the metastases. These aberrations appear to be involved in lymph-node metastasis of colon cancer, and may allow measurement of the risk of lymph-node metastasis from a given colon cancer.

Safety, tolerability, and pharmacokinetics of TAS-108 in normal healthy post-menopausal female subjects: a phase I study on single oral dose.

OBJECTIVES: The present study was conducted to evaluate the safety, tolerability, and pharmacokinetics of TAS-108 after ascending single oral doses and to analyse preliminarily the effect of food on the pharmacokinetics of TAS-108 in normal healthy post-menopausal female subjects. METHODS: Twelve healthy subjects participated in an open-label, ascending single-dose, alternating group, safety, tolerance, and pharmacokinetic study of TAS-108 administered orally to two groups of the subjects, one given alternating doses of 10, 40, 120 mg (group A) and the other of 20, 80, 160 mg (group B), in the fasting state. In addition, six subjects (group A) were administered an additional dose at 120 mg TAS-108 after food consumption. Plasma and urine samples for measurement of TAS-108 were analysed by validated analytical procedures using a liquid chromatographic method with tandem mass spectrometric detection (LC/MS/MS). RESULTS: There was no dose-dependent increase in any adverse events (AEs), and there were no serious AEs or deaths. TAS-108 was readily absorbed following oral administration of the 80-, 120- and 160-mg doses. Plasma TAS-108 levels steadily declined, generally in a mono-exponential manner, with overall mean t(1/2) values ranging from 3.04 to 4.43 h in the fasting groups. Administration of TAS-108 after a high-fat meal markedly increased the bioavailability of the drug. The mean C(max) and AUC(0--t) values increased after a high-fat breakfast by 182 and 191% compared with the fasting value respectively. CONCLUSIONS: In this escalating dose study of TAS-108, the drug was well tolerated by the participants. The maximum and systemic exposure to TAS-108 tended to increase with increasing dose and its bioavailability markedly increased after high-fat food intake.

Significance of the transcription factor KLF5 in cardiovascular remodeling.

Structural remodeling of the heart and blood vessels is an important pathologic process in the development of many cardiovascular diseases. However, transcriptional regulation of altered gene expression during cardiovascular remodeling is not well understood. We previously isolated KLF5/basic transcription element-binding (BTEB)2, a Krüppel-like factor, as a transcription factor that binds the promoter of the embryonic smooth muscle myosin heavy chain gene (SMemb). KLF5 activates many genes inducible during cardiovascular remodeling, such as platelet-derived growth factor (PDGF)-A/B, Egr-1, plasminogen activator inhibitor-1 (PAI-1), inducible nitric oxide synthase (iNOS), and vascular endothelial growth factor (VEGF) receptors. KLF5 is abundantly expressed in embryonic smooth muscles and is down-regulated with vascular development, but reinduced in proliferative neointimal smooth muscles in response to vascular injury. In KLF5 gene-targeted mice, homozygotes die at an early embryonic stage whereas heterozygotes are apparently normal. However, in response to external stress, arteries of heterozygotes exhibit diminished levels of smooth muscle and adventitial cell activation. Furthermore, angiotensin II-induced cardiac hypertrophy and fibrosis are attenuated in heterozygotes. KLF5 activities are regulated by many transcriptional regulators and nuclear receptors, such as retinoic acid receptor-alpha (RAR alpha), NF-kappaB, PPAR gamma, p300, and SET. Interestingly, RAR alpha agonist suppresses KLF5 and cardiovascular remodeling, whereas RAR alpha antagonist activates KLF5 and induces angiogenesis. These results indicate that KLF5 is an essential transcription factor in cardiovascular remodeling and a potential therapeutic target for cardiovascular disease.

Implantation of a pleurovenous shunt for massive chylothorax in a patient with yellow nail syndrome.

Yellow nail syndrome is a type of lymphatic dysplasia syndrome characterised by the triad of yellow nails, lymphoedema, and pleural effusions. The case history is presented of a 70 year old patient with yellow nail syndrome who complained of dyspnoea caused by massive chylothorax. The patient underwent insertion of a pleuroperitoneal shunt which resulted in abdominal distension and deterioration of leg oedema. The pleuroperitoneal shunt was replaced by a pleurovenous shunt on the right side which led to an improvement in the bilateral pleural effusions, abdominal distension, and leg oedema. A pleurovenous shunt may be an alternative rescue therapy for yellow nail syndrome.

Renal damage and salt-dependent hypertension in aged transgenic mice overexpressing endothelin-1.

The recent development of endothelin-1 (ET-1) antagonists and their potential use in the treatment of human disease raises questions as to the role of ET-1 in the pathophysiology of such cardiovascular ailments as hypertension, heart failure, renal failure and atherosclerosis. It is still unclear, for example, whether activation of an endogenous ET-1 system is itself the primary cause of any of these ailments. In that context, the phenotypic manifestations of chronic ET-1 overproduction may provide clues about the tissues and systems affected by ET-1. We therefore established two lines of transgenic mice overexpressing the ET-1 gene under the direction of its own promoter. These mice exhibited low body weight, diminished fur density and two- to fourfold increases in the ET-1 levels measured in plasma, heart, kidney and aorta. There were no apparent histological abnormalities in the visceral organs of young (8 weeks old) transgenic mice, nor was their blood pressure elevated. In aged (12 months old) transgenic mice, however, renal manifestations, including prominent interstitial fibrosis, renal cysts, glomerulosclerosis and narrowing of arterioles, were detected. These pathological changes were accompanied by decreased creatinine clearance, elevated urinary protein excretion and salt-dependent hypertension. It thus appears that mild, chronic overproduction of ET-1 does not primarily cause hypertension but triggers damaging changes in the kidney which lead to the susceptibility to salt-induced hypertension.

Elevated sympathetic nervous activity in mice deficient in alphaCGRP.

alpha-Calcitonin gene-related peptide (alphaCGRP) is a pleiotropic neuropeptide implicated in a variety of physiological processes. To better understand the biological functions of alphaCGRP, we developed an alphaCGRP-null mouse model using a gene targeting approach. Recordings of mean arterial pressure (MAP) and heart rate (HR) showed that basal MAP and HR were significantly higher in both anesthetized and conscious, unrestrained alphaCGRP-null mice than in corresponding wild-type mice. The elevated MAP in alphaCGRP-null mice was shown to be the result of elevated peripheral vascular resistance by alpha-adrenergic blockade with prazosin and by transthoracic echocardiogram, which revealed no significant differences between alphaCGRP-null and wild-type mice in the stroke volume, fractional shortening, and ejection fraction. Moreover, evaluation of autonomic nervous activity by measuring HR after pretreatment of atropine and/or atenolol and by analyzing arterial baroreceptor reflexes showed sympathetic nervous activity to be significantly elevated in alphaCGRP-null mice; elevated levels of urinary catecholamine metabolites and decreased HR variability in mutant mice were also consistent with that finding. These findings suggest that alphaCGRP contributes to the regulation of cardiovascular function through inhibitory modulation of sympathetic nervous activity.

Thin-section CT features of intrapulmonary lymph nodes.

PURPOSE: The objective of this study was to evaluate CT findings of pathologically proven intrapulmonary lymph nodes (IPLNs) and discuss the utility of thin-section CT and contrast-enhanced CT. METHOD: CT findings of 18 nodules in 14 patients with pathologically proven IPLNs were reviewed. CT scanning of the whole lung was performed contiguously with slice thickness of 10 mm. In addition, a helical scan with slice thickness of 2 mm was performed in nine patients, focusing on the nodule. Contrast-enhanced helical CT was performed in four patients, and the utility of thin section CT and contrast-enhanced CT was investigated. RESULTS: One patient had three nodules, 2 patients had two nodules, and the remaining 11 patients had a solitary nodule. All nodules were located below the level of the carina and within 15 mm of the pleura. In one case, conventional CT revealed the nodule 20 mm away from the pleura; however, the nodule attached to the major fissure was clearly revealed on thin-section CT. The size of the nodules was < or =15 mm, and the shape was round (n = 8), oval (n = 9), or lobulated (n = 1) with sharp border. One nodule demonstrated a spiculated border due to a surrounding pulmonary fibrosis on conventional CT; however, thin-section CT showed precisely a sharp border. The lobulated shape of one case histopathologically reflected a hilus of lymph node. On contrast-enhanced helical CT, all four nodules were enhanced and the degree enhancement was 36-85 HU (median 66.6 HU). CONCLUSION: In current times, IPLNs are not uncommon lesions. We should consider IPLN in the differential diagnosis of solitary or multiple pulmonary nodules in the peripheral field and below the level of the carina. Thin-section CT showed precisely the border or relation between IPLNs and the surrounding structure. It was difficult to distinguish between IPLNs and malignant nodules from the degree of enhancement on contrast-enhanced CT. On thin-section and contrast-enhanced CT, the findings of IPLNs are not necessarily specific. Therefore, strict observation on CT is necessary; in certain cases that are increasing in size, video-assisted thoracic surgery should be considered because of their location.

Vascular abnormalities and elevated blood pressure in mice lacking adrenomedullin gene.

BACKGROUND: Adrenomedullin (AM) is a vasodilating peptide involved in the regulation of circulatory homeostasis and in the pathophysiology of certain cardiovascular diseases. Levels of AM are markedly increased in the fetoplacental circulation during pregnancy, although its function there remains unknown. To clarify the physiological functions of AM, we chose a gene-targeting strategy in mice. METHODS AND RESULTS: Targeted null mutation of the AM gene is lethal in utero: the mortality rate among AM(-/-) embryos was >80% at E13.5. The most apparent abnormality in surviving AM(-/-) embryos at E13.5 to E14.0 was severe hemorrhage, readily observable under the skin and in visceral organs. Hemorrhage was not detectable at E12.5 to E13.0, although the yolk sac lacked well-developed vessels. Electron microscopic examination showed endothelial cells to be partially detached from the basement structure at E12.5 in vitelline vessels and hepatic capillaries, which allowed efflux of protoerythrocytes through the disrupted barrier. The basement membrane was not clearly recognizable in the aorta and cervical artery, and the endothelial cells stood out from the wall of the lumen, only partially adhering to the basement structure. AM(+/-) mice survived to adulthood but exhibited elevated blood pressures with diminished nitric oxide production. CONCLUSIONS: AM is indispensable for the vascular morphogenesis during embryonic development and for postnatal regulation of blood pressure by stimulating nitric oxide production.

Vascular smooth muscle cell-directed overexpression of heme oxygenase-1 elevates blood pressure through attenuation of nitric oxide-induced vasodilation in mice.

To elucidate pathophysiological roles of heme oxygenase (HO)-1 in regulation of vascular tone in vivo, we have developed and characterized transgenic (Tg) mice that overexpress HO-1 site specifically in vascular smooth muscle cells (VSMCs). The Tg mice were generated by use of human HO-1 cDNA under the control of SM22-alpha promoter. The HO-1 gene overexpression was demonstrated by Northern blot analysis and coincided with increases in the protein expression in VSMCs and total HO activities. Tg mice exhibited a significant increase in arterial pressure at various ages and displayed impaired nitrovasodilatory responses in isolated aortic segments versus nontransgenic littermates while enhancing their nitric oxide (NO) production. The pressure of Tg mice was unchanged by systemic administration of either N(omega)-nitro-L-arginine or SNP. Furthermore, the isolated aorta in these mice exhibited lesser extents of NO-elicited cGMP elevation via soluble guanylate cyclase (sGC), while exhibiting no notable downregulation of sGC expression. Such impairment of the NO-elicited cGMP increase was restored significantly by tin protoporphyrin IX, an HO inhibitor. On the other hand, 3-(5'-hydroxymethyl-2' furyl)-1-benzyl-indazol (YC-1), an NO-independent activator of sGC, increased cGMP and relaxed aortas from Tg mice to levels comparable with those from nontransgenic mice, which indicates that contents of functionally intact sGC are unlikely to differ between the two systems. These findings suggest that site-specific overexpression of HO-1 in VSMCs suppresses vasodilatory response to NO and thereby leads to an elevation of arterial pressure.

Effects of 5-fluorouracil on the drug-metabolizing enzymes of the small intestine and the consequent drug interaction with nifedipine in rats.

5-Fluorouracil (5-FU) is a widely used antineoplastic agent. 5-FU therapy often causes gastrointestinal toxicity, which is suppressed by concomitant administration of potassium oxonate (Oxo). Here, we investigated the effect of 5-FU on the small-intestinal drug-metabolizing enzymes, which play important roles in the first-pass metabolism of drugs, in rats, by enzyme measurements and immunoblot analyses. During repeated administration of a combination of 1-(2-tetrahydrofuryl)-5-fluorouracil, an oral 5-FU-derivative drug, and 5-chloro-2,4-dihydroxypyridine (FCD), an inhibitor of 5-FU degradation, the activities of 7-ethoxyresorufin-O-deethylase, testosterone 6beta-hydroxylase, 4-methylumbelliferone UDP-glucuronyltransferase, and 1-chloro-2,4-dinitrobenzene glutathione S-transferase decreased significantly on day 4, and the activity of NADPH-cytochrome P450 (CYP) reductase decreased significantly on day 7. These effects were found to be attributable to a reduction in the enzyme protein contents in the small-intestinal mucosa. The enzymatic alterations significantly increased the plasma concentrations of orally administered nifedipine, which was prevented by concomitant administration of Oxo with FCD. However, consecutive administration of FCD for 4 days did not cause any alterations in the activity of the hepatic CYP isozyme-supported testosterone hydroxylase. These results suggest that continuous exposure to 5-FU leads to a decrease in the activities of drug-metabolizing enzymes in the intestinal mucosa by decreasing their enzyme protein contents, and increases the plasma concentrations of orally administered nifedipine, and that the sensitivity of these enzymes to the drug is greater than that of the enzymes of the liver. These effects were prevented by concomitant administration of Oxo.

Thymoma. Analysis of prognostic factors.

OBJECTIVE: We evaluated the prognostic factors for thymoma that remain controversial. METHODS: We studied 72 consecutive patients treated for thymoma during the period between 1966 and 1997. Recurrence-free interval rates and overall survival rates calculated by the Kaplan-Meier method were compared using log-rank test by the Masaoka stage, extent of surgical resection, histology, or associated disease(s). Multivariate analysis was performed using Cox's proportional hazards model. RESULTS: Thirty-two thymomas were at Masaoka stage I, 9 at stage II, 15 at stage III, and 16 were at stage IV. There were 56 complete resections, 7 incomplete resections (2 at stage III and 5 at stage IV), and 9 biopsies (1 at stage III and 8 at stage IV). Forty-one thymomas were cortical, 16 medullary, and 15 were mixed form. Association of myasthenia gravis was found in 20 patients, and pure red cell aplasia in 7. After an average follow-up period of 103 months, the recurrence-free 5-, 10-, 15-year interval rate was 89%, 80%, 80%, respectively, and overall 5-, 10-, 15-year survival rate was 86%, 71%, 59%, respectively. Factors influencing the recurrence-free interval and overall survival included the Masaoka stage, extent of surgical resection, and association with pure red cell aplasia. Multivariate analysis revealed stage IV tumor and association with pure red cell aplasia as risk factors for recurrence. Pure red cell aplasia indicated poor prognosis for overall survival. CONCLUSIONS: Masaoka stage, extent of surgical resection, and association with pure red cell aplasia were prognostic factors for thymoma. Multidisciplinary treatment for stage IV tumors and better control of pure red cell aplasia, if associated, should be investigated.

Diet-induced hyperhomocysteinemia exacerbates neointima formation in rat carotid arteries after balloon injury.

BACKGROUND: Increasing evidence indicates that elevated plasma homocysteine levels are associated with an increased risk of atherosclerosis and endothelial dysfunction, although little specific information on the mechanisms responsible for the atherogenic effects of homocysteine or on the in vivo contribution made by hyperhomocysteinemia to atherosclerosis is currently available. Because homocysteine is known to exert a direct inhibitory effect on endothelial cell growth in vitro, we hypothesized that this effect contributes to the progression of atherosclerotic lesions initiated by endothelial damage caused by mechanical injury. METHODS AND RESULTS: We prepared diet-induced hyperhomocysteinemic rats in which neointima formation after balloon injury to the common carotid artery was assessed. Moderate hyperhomocysteinemia (plasma homocysteine levels 3- to 4-fold higher than control) significantly exacerbated neointima formation. Oral administration of folate, which had a homocysteine-lowering effect, diminished neointima formation induced by moderate hyperhomocysteinemia. Furthermore, the attenuation of reendothelialization was shown in diet-induced hyperhomocysteinemic rats with Evans blue staining. CONCLUSIONS: Diet-induced hyperhomocysteinemia, even mild to moderate, exacerbates neointima formation after denuding injury, making hyperhomocysteinemia a likely risk factor for postangioplasty restenosis. It may be mediated through an inhibitory effect of homocysteine on reendothelialization. Homocysteine lowering with folate supplementation can effectively ameliorate the detrimental effects of moderate hyperhomocysteinemia. Clinical trials would seem to be warranted.