Intrahepatic cholangiocarcinoma and portal hypertension developing in a patient with multicystic biliary microhamartomas.

INTRODUCTION: We report a case of intrahepatic cholangiocarcinoma and portal hypertension developing in a liver with biliary microhamartomas (von Meyenburg's complex). CASE REPORT: The patient was a 55-year-old man who had a past medical history of diffuse multiple liver abscesses. During follow-up examination, a hypovascular nodule measuring 2.1 cm in diameter was incidentally found in segment 8 of the liver. Surgical resection was performed based on a suspected diagnosis of hepatocellular carcinoma. A gastrofiberscopy examination detected characteristic findings of portal hypertensive gastropathy. During the laparotomy, multiple tiny cystic lesions were observed in a diffuse pattern across the liver surface. The liver parenchyma was slightly fibrotic and haemorrhagic. A histopathological examination revealed intrahepatic cholangiocarcinoma with vascular invasions in von Meyenburg's complex. Multiple biliary adenomas were also observed among the biliary microhamartomas adjacent to the main tumour, suggesting that the malignant transformation of the biliary adenomas might have been responsible for the development of the intrahepatic cholangiocarcinoma. The histopathologic examination also revealed sinusoidal dilation and abnormal spacing of the portal tracts and central veins as evidence of portal hypertension.

A prospective, randomized, double-blind, controlled trial on the efficacy of carbon dioxide insufflation in gastric endoscopic submucosal dissection.

BACKGROUND AND STUDY AIMS: Carbon dioxide (CO2) insufflation is expected to be safe and effective in endoscopic submucosal dissection (ESD) as well as in other endoscopic procedures. The present study aimed to clarify the usefulness and safety of CO2 insufflation in gastric ESD. PATIENTS AND METHODS: A total of 102 consecutive patients were randomly assigned to CO2 insufflation (CO2 group, n = 54) or air insufflation (Air group, n = 48). Abdominal pain and distension were chronologically recorded on a 100-mm visual analog scale (VAS). The volume of residual gas in the digestive tract was measured by computed tomography performed immediately after ESD. RESULTS: Abdominal pain on a 100-mm VAS in the CO2 vs. Air group was 4 vs. 3 immediately after ESD, 4 vs. 4 one hour after the procedure, 3 vs. 3 three hours after the procedure, and 1 vs. 4 the next morning, showing no difference between the groups. In addition, there was no difference in abdominal distension on the 100-mm VAS over the time course of the study. The volume of residual gas in the digestive tract in the CO2 group was significantly smaller than that in the Air group (643 mL vs. 1037 mL, P < 0.001). The dose of sedative drugs did not differ between the groups. Neither the incidences of complications nor clinical courses differed between the groups. CONCLUSIONS: Compared with air insufflation, CO2 insufflation during gastric ESD significantly reduced the volume of residual gas in the digestive tract but not the VAS score of abdominal pain and distension.

Results of chemoradiotherapy for stage I esophageal cancer in medically inoperable patients compared with results in operable patients.

The purpose of the present study was to evaluate long-term results of chemoradiotherapy for clinical T1b-2N0M0 esophageal cancer and to compare outcomes for operable and inoperable patients. Patients with stage I esophageal cancer (Union for International Cancer Control [UICC] 2009), excluding patients with cT1a esophageal cancer, were studied. All patients had histologically proven squamous cell carcinoma. Operable patients received cisplatin and 5-fluorouracil with concurrent radiotherapy of 60 Gy including a 2-week break. Inoperable patients received nedaplatin and 5-fluorouracil with concurrent radiotherapy of 60-70 Gy without a pause. End-points were overall survival rate (OS), cause-specific survival rate (CSS), progression-free survival rate (PFS), and locoregional control rate (LC). Thirty-seven operable patients and 30 medically inoperable patients were enrolled. There was a significant difference in only age between the operable group and inoperable group (P = 0.04). The median observation period was 67.9 months. In all patients, 5-year OS, CSS, PFS, and LC were 77.9%, 91.5%, 66.9%, and 80.8%, respectively. Comparison of the operable group and inoperable group showed that there was a significant difference in OS (5-year, 85.5% vs. 68.7%, P = 0.04), but there was no difference in CSS, PFS, or LC. Grade 3 or more late toxicity according to Common Terminology Criteria for Adverse Events v 3.0 was found in seven patients. Even in medically inoperable patients with stage I esophageal cancer, LC of more than 80% can be achieved with chemoradiotherapy. However, OS in medically inoperable patients is significantly worse than that in operable patients.

A pilot study to assess mediastinal emphysema after esophageal endoscopic submucosal dissection with carbon dioxide insufflation.

BACKGROUND AND AIMS: Mediastinal emphysema sometimes develops following esophageal endoscopic submucosal dissection (ESD) without perforation because the esophagus has no serosa. Carbon dioxide (CO2) insufflation during esophageal ESD may reduce the incidence of mediastinal emphysema. The aim of the present study was to compare the incidence and severity of post-ESD mediastinal emphysema in patients receiving CO2 insufflation vs. standard air insufflation during esophageal ESD. PATIENTS AND METHODS: A total of 27 patients who had undergone esophageal ESD with insufflation of CO2 between July 2009 and March 2010 were enrolled in this study (CO2 group). Another 105 patients who had undergone esophageal ESD with air insufflation between March 2004 and May 2009 were included as historical controls (air group). Multi-detector row computed tomography (MDCT) was carried out immediately after ESD. A conventional chest radiograph was taken the next day. Mediastinal emphysema findings on MDCT and radiography were compared between the groups. RESULTS: Mediastinal emphysema detected by chest radiography was 0 % in the CO2 group vs. 6.6 % in the air group (n.s.). Mediastinal emphysema on MDCT was significantly less frequent in the CO2 group compared with the air group (30 % vs. 63 %; P = 0.002). The severity of mediastinal emphysema also tended to be lower in the CO2 group. CONCLUSIONS: Whereas mediastinal emphysema detected by radiography is not so common, MDCT immediately after ESD revealed a certain prevalence of post-ESD mediastinal emphysema. Insufflation of CO2 rather than air during esophageal ESD significantly reduced postprocedural mediastinal emphysema. CO2 can be considered as insufflating gas for esophageal ESD.

The neuroprotective effects of cyclooxygenase-2 inhibition in a mouse model of aneurysmal subarachnoid hemorrhage.

The CNS inflammatory reaction occurring after aneurysmal subarachnoid hemorrhage (SAH) involves the upregulation of numerous cytokines and prostaglandins. Cyclooxygenase (COX) inhibition is a well-established pharmacological anti-inflammatory agent. Previous studies have shown marked increases in COX-2 expression in neurons, astrocytes, microglia, and endothelial cells following brain injury. COX-2 inhibition has been shown to be beneficial following various types of brain injury. This experiment investigates the role of COX-2 activity in early brain injury following SAH. CD-1 mice were subjected to an endovascular perforation model of SAH or SHAM surgery. Following experimental SAH animals were treated with the specific COX-2 inhibitor, NS398, in dosages of either 10 or 30 mg/kg. Neurological performance and brain edema were evaluated 24 and 72 h after SAH. NS398 at 30 mg/kg significantly reduced SAH-induced neurological deterioration. NS 398 at 30 mg/kg resulted in a trend toward the reduction of SAH-induced cerebral edema. Treatment had no effect on mortality. This experiment provides preliminary evidence that COX-2 inhibition is an effective pharmacological intervention for the prevention of brain edema and the preservation of neurological function following SAH.

Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis.

Congenital lipoid adrenal hyperplasia is an autosomal recessive disorder that is characterized by impaired synthesis of all adrenal and gonadal steroid hormones. In three unrelated individuals with this disorder, steroidogenic acute regulatory protein, which enhances the mitochondrial conversion of cholesterol into pregnenolone, was mutated and nonfunctional, providing genetic evidence that this protein is indispensable normal adrenal and gonadal steroidogenesis.

Role of statins in cerebral vasospasm.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, commonly known as statins, are widely used clinically for their lipid lowering properties. Recent evidence shows that statins are also effective in ameliorating cerebral vasospasm, which occurs as sequelae of subarachnoid haemorrhage. This review focuses on the pleiotropic effects of statins, and the putative mechanisms involved in statin mediated attenuation of cerebral vasospasm.

Magnetic resonance imaging in the canine double-haemorrhage subarachnoid haemorrhage model.

In this study, we investigated T2 weighted imaging (T2WI) and T2 values of the cortex, thalamus and cerebrospinal fluid (CSF) of the ventricles in the canine double-haemorrhage subarachnoid haemorrhage (DHSAH) model. T2 values in the cortex increased compared to prescan values from 123.07 +/- 18.72 msec on day 2 to 89.43 +/- 1.98 msec on day 7 (p < 0.05). A trend toward a temporal increase in T2 values was observed in the thalamus, but did not reach significance. The T2 values of the ventricular CSF increased by 102.2% on day 2 and 159.6% on day 7 compared to prescan values. These changes reached significance (p < 0.05) on day 7. Additionally, the ventricular size increased over the study period. Our data suggest that we can use this model to investigate acute brain injury and normal pressure hydrocephalus (NPH) after SAH.

[Clinical analysis of bronchoplastic surgery for lung cancer after 2000].

We investigated surgical complications and prognosis of bronchoplasty and bronchoplasty with pulmonary angioplasty (broncho-angioplasty) for lung cancer. Between October 2000 and October 2007, 37 bronchoplastic procedures were done in 572 patients who underwent lung resections for lung cancer. Eleven (29.7%) bronchoplasties were done with pulmonary angioplasty. There was no operative mortality and 1 hospital mortality (2.7%) causing by myocardial infarction. Six of 11 postoperative complications were bronchial complications and 2 additional lung resections were needed. The 5-year survival for all patients was 55.2% and for bronchoplasty was 57.8%. Though the 5-year survival of broncho-angioplasty was not able to calculate at present, the 3-year survival of which was 72.9%. There was no death of patients with adenocarcinoma after introduction of pre-operative assessment by FDG-PET for lymph node metastasis. These data suggest that bronchoplasty and broncho-angioplasty are safe operative procedures and could provide acceptable intermediate survivals with modern multimodality diagnostic and therapeutic tools.

Spontaneous puberty in 46,XX subjects with congenital lipoid adrenal hyperplasia. Ovarian steroidogenesis is spared to some extent despite inactivating mutations in the steroidogenic acute regulatory protein (StAR) gene.

Congenital lipoid adrenal hyperplasia (lipoid CAH) is the most severe form of CAH in which the synthesis of all gonadal and adrenal cortical steroids is markedly impaired. We report here the clinical, endocrinological, and molecular analyses of two unrelated Japanese kindreds of 46,XX subjects affected with lipoid CAH who manifested spontaneous puberty. Phenotypic female infants with 46,XX karyotypes were diagnosed with lipoid CAH as newborns based on a clinical history of failure to thrive, hyperpigmentation, hyponatremia, hyperkalemia, and low basal values of serum cortisol and urinary 17-hydroxycorticosteroid and 17-ketosteroid. These patients responded to treatment with glucocorticoid and 9alpha-fludrocortisone. Spontaneous thelarche occurred in association with increased serum estradiol levels at the age of 10 and 11 yr, respectively. Pubic hair developed at the age of 12 yr 11 mo in one subject and menarche was at the age of 12 yr in both cases. Both subjects reported periodic menstrual bleeding and subsequently developed polycystic ovaries. To investigate the molecular basis of the steroidogenic lesion in these patients, the StAR gene was characterized by PCR and direct DNA sequence analyses. DNA sequence analysis revealed that one patient is homozygous for the Gln 258 Stop mutation in exon 7 and that the other patient is a compound heterozygote with the Gln 258 Stop mutation and a single A deletion at codon 238 in the other allele causing a frame-shift, which renders the StAR protein nonfunctional. These findings demonstrate that ovarian steroidogenesis can be spared to some extent through puberty when the StAR gene product is inactive. This is in marked contrast to the early onset of severe defects in testicular and adrenocortical steroidogenesis which are characteristics of this disease.

The use of patient-controlled epidural fentanyl in elderly patients.

We studied whether delivering postoperative analgesia, using a patient-controlled epidural analgesia (PCEA) device was effective and safe in elderly patients. We enrolled 40 patients aged > 65 years (elderly group) and 40 patients aged 20-64 years (young group) scheduled for elective major abdominal surgery. PCEA infusion was started following completion of surgery. Mean (SD) fentanyl consumption (10.7 (3.7) compared with 10.5 (2.7) microg.kg(-1), p = 0.76) and number of times patients pressed the bolus switch (32 (36) compared with 44 (38), p = 0.16) during the first 24 h postoperatively were similar in the two groups. Pain scores, which were similar in both groups at rest, were significantly lower in the elderly on coughing (at 24 h, p < 0.05). In addition, average pain scores were similar at the time of PCEA bolus demands in the two groups. Elderly and young adult patients therefore required similar amounts of patient-controlled epidural fentanyl to produce satisfactory pain relief.

Both N-terminal and C-terminal regions of steroid sulfatase are important for enzyme activity.

Steroid sulfatase (STS) is localized in the endoplasmic reticulum and catalyzes desulfation of 3beta-hydroxysteroid sulfates. X-linked ichthyosis (XLI) is an inherited skin disorder caused by deficiency of STS enzyme activity. We previously reported a case in which XLI with a one-base change in the STS gene and variation in amino acid Q560P developed. In this study, we performed molecular analysis to determine the importance of terminal regions of STS and the effect of mutant STS on STS enzyme activity. To examine the effect of terminal truncated STS on the enzyme activity, N- and C-terminal truncated STS expression vectors were transfected into COS-1 cells. The activity of truncated STS lacking the N-terminal regions declined, and the activity of C-terminal-truncated STS declined with extension of the truncated C-terminal region. Although the results of pulse-chase experiments showed that a one-base mutant STS (Q560P) and C-terminal-truncated STS (deltaC2 (1-559)) had no effects on protein synthesis and degradation, the mutant STS and C-terminal-truncated STS have dominant negative effect on STS enzyme activity when the STS mutant or truncated STS protein and a wild-type STS protein coexist in cells. Results of coprecipitation of the truncated STS with an STS-FLAG fusion protein showed that STS formed a dimer conformation in cells. In this study, we have shown that both the N-terminal region and C-terminal region are important for STS enzyme activity. The C-terminal mutant has a dominant negative effect on wild-type STS.

Phenotypes and genotypes in epilepsy with febrile seizures plus.

In the last several years, mutations of sodium channel genes, SCN1A, SCN2A, and SCN1B, and GABA(A) receptor gene, GABRG2 were identified as causes of some febrile seizures related epilepsies. In 19 unrelated Japanese families whose probands had febrile seizures plus or epilepsy following febrile seizures plus, we identified 2 missense mutations of SCN1A to be responsible for the seizure phenotypes in two FS+ families and another mutation of SCN2A in one family. The combined frequency of SCN1A, SCN2A, SCN1B, SCN2B, and GABRG2 mutations in Japanese patients with FS+ was 15.8%. One family, which had R188W mutation in SCN2A, showed digenic inheritance, and another modifier gene was thought to take part in the seizure phenotype. The phenotypes of probands were FS+ in 5, FS+ and partial epilepsy in 10, FS+ and generalized epilepsy in 3, and FS+ and unclassified epilepsy in 1. We proposed the term epilepsy with febrile seizures plus (EFS+), because autosomal-dominant inheritance in EFS+ might be rare, and most of EFS+ display a complex pattern of inheritance, even when it appears to be an autosomal-dominant inheritance. There is a possibility of simultaneous involvement of multiple genes for seizure phenotypes.

Development of a recombinant yeast assay to detect ah-receptor ligands.

Endocrine systems of humans and animals are disturbed by dioxin-like compounds, which are ligands of the aryl hydrocarbon receptor (AhR). It is important to determine the accumulation of dioxin-like compounds in the environment for maintenance of human health. In this study, we developed a new method for screening ligands of the AhR using a yeast hybrid system. Reporter genes constructed by the insertion of dioxin response elements were integrated into HIS and lacZ yeast genomes. Then yeast was transformed with GAL4-activated domain-fused AhR and aryl hydrocarbon receptor nuclear translocator expression constructs. At 10(-4) M of beta-naphthoflavone, which is an AhR ligand, the absorbance of optical density at 600 nm (OD 600) and beta-galactosidase activity was significantly increased. beta-galactosidase activity was increased when the concentration of 3-methylcholanthrene (MC) was increased. ATP concentration increased as concentration of MC increased up to 10(-10) M but decreased at higher concentrations. The concentration of ATP in the cell suspensions increased linearly with OD 600, used as an index of cell density (r(2) = 0.8366, F = 209.9, p < 0.0001, n = 44). The established yeast assay could possibly be used in the future to detect dioxin-like compounds in environmental samples.

Tumor-associated mucin-type glycoprotein (CA54/61) defined by two monoclonal antibodies (MA54 and MA61) in ovarian cancers.

Two monoclonal antibodies, MA54 and MA61, were established by immunizing with culture medium supernatants of a lung adenocarcinoma cell line, and a double-determinant sandwich enzyme immunoassay system was developed by using these two monoclonal antibodies. The antigen recognized by this assay (CA54/61) was found to be often high in the sera of several cancers. The antigen recognized by MA54 (CA54) or MA61 (CA61) proved to be carbohydrate chain on a high molecular weight mucin-type glycoprotein, and CA54 has NeuAc alpha 2-6galactose in the terminal residue. CA54/61 was frequently found in the sera of ovarian cancer patients, the positive rate being 67, 64, 40, and 78% in serous, mucinous, endometrioid, and mesonephroid cancers, respectively, when the cut off value was set at mean + 4 SD. Since the positive rate of CA125, which is now the most widely used for the diagnosis of ovarian cancers, is rather low (approximately less than 50%) in mucinous cystoadenocarcinoma, CA54/61 will be of clinical value. In addition, CA61 was detected immunohistochemically in the fetal red blood cells with nuclei, indicating its oncodevelopmental character in nature.

A diffusion model for the coordination of DNA replication in Schizosaccharomyces pombe.

The locations of proteins and epigenetic marks on the chromosomal DNA sequence are believed to demarcate the eukaryotic genome into distinct structural and functional domains that contribute to gene regulation and genome organization. However, how these proteins and epigenetic marks are organized in three dimensions remains unknown. Recent advances in proximity-ligation methodologies and high resolution microscopy have begun to expand our understanding of these spatial relationships. Here we use polymer models to examine the spatial organization of epigenetic marks, euchromatin and heterochromatin, and origins of replication within the Schizosaccharomyces pombe genome. These models incorporate data from microscopy and proximity-ligation experiments that inform on the positions of certain elements and contacts within and between chromosomes. Our results show a striking degree of compartmentalization of epigenetic and genomic features and lead to the proposal of a diffusion based mechanism, centred on the spindle pole body, for the coordination of DNA replication in S. pombe.

Mitochondrial release of cytochrome c corresponds to the selective vulnerability of hippocampal CA1 neurons in rats after transient global cerebral ischemia.

Release of cytochrome c from mitochondria to the cytosol is a critical step in apoptotic cell death after focal cerebral ischemia. The relationship among cytochrome c release, selective vulnerability, and delayed death of hippocampal CA1 neurons after transient global ischemia was examined. Global ischemia was induced by 10 min of bilateral common carotid artery occlusion and hypotension in rats. Cytosolic expression of cytochrome c was evaluated by immunohistochemistry and Western blotting. Apoptosis after global ischemia was also characterized by terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end-labeling (TUNEL) staining and DNA gel electrophoresis. Immunohistochemistry showed cytosolic cytochrome c-positive cells exclusively in the CA1 subregion of the hippocampus as early as 2 hr after ischemia. Double fluorescent immunostaining confirmed that CA1 neurons and a small number of astrocytes expressed cytochrome c. Western blot analysis revealed a band (15 kDa) of cytochrome c in the cytosolic fraction and a corresponding decrease in the mitochondrial fraction. A significant number of TUNEL-positive cells appeared only in the CA1 pyramidal cell layer of the hippocampus, and DNA gel electrophoresis showed a significant amount of DNA fragmentation 3-5 d after ischemia. Our data provide the first evidence that cytochrome c was released to the cytosol from mitochondria in CA1 neurons after global ischemia and that the release preceded DNA fragmentation. These findings suggest cytochrome c involvement in the delayed death of hippocampal CA1 neurons in rats after transient global ischemia.

The cytosolic antioxidant copper/zinc-superoxide dismutase prevents the early release of mitochondrial cytochrome c in ischemic brain after transient focal cerebral ischemia in mice.

Release of mitochondrial cytochrome c into the cytosol is a critical step in apoptosis. We have reported that early release of cytochrome c in vivo occurs after permanent focal cerebral ischemia (FCI) and is mediated by the mitochondrial antioxidant manganese superoxide dismutase (SOD). However, the role of reactive oxygen species produced after ischemia-reperfusion in the mitochondrial apoptosis process is still unknown, although overexpression of copper/zinc-SOD (SOD1), a cytosolic isoenzyme, protects against ischemia-reperfusion. We now hypothesize that the overexpression of SOD1 also prevents apoptosis after FCI. To address this issue, we examined the subcellular distribution of the cytochrome c protein in both wild-type mice and in SOD1 transgenic (Tg) mice after transient FCI. Cytosolic cytochrome c was detected as early as 2 hr after reperfusion, and correspondingly, mitochondrial cytochrome c was significantly reduced after FCI. Cytosolic cytochrome c was significantly lower in the SOD1 Tg mice compared with wild types 2 (p < 0.0001) and 4 (p < 0.05) hr after FCI. Apaf-1, which interacts with cytochrome c and activates caspases, was constitutively expressed in both groups of animals, with no alteration after FCI. Double staining with cytochrome c immunohistochemistry and terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end labeling showed a spatial relationship between cytosolic cytochrome c expression and DNA fragmentation. A significant amount of DNA laddering was detected 24 hr after ischemia and was reduced in SOD1 Tg mice. These data suggest that SOD1 blocks cytosolic release of cytochrome c and could thereby reduce apoptosis after transient FCI.

Molecular cloning and structural analysis of human sterol C5 desaturase.

Sterol C5 desaturase (SC5D) converts lathosterol to 7-dehydrocholesterol in cholesterol biosynthesis. In this study, we investigated the genome structure of SC5D and transcription of the human SC5D gene to try to elucidate the mechanism by which cholesterol synthesis is regulated. The SC5D gene had a structural gene from a single copy from genome DNA that contained five exons and four introns. The human SC5D was found to be located in chromosome 11q24.2-24.3 by fluorescence in situ hybridization mapping. Human SC5D mRNA transcripts, of which the major transcript was a 2 kb and the minor transcripts were 8 kb and 1.4 kb mRNA transcripts, were detected in almost all of the tissues examined. The human SC5D gene contained a GC box instead of a TATA box upstream of the transcript start sites. Human SC5D transcription started from several transcription start sites, and the first start site was located 31 bp upstream of the translation start site (ATG). The expression level of SC5D mRNA extracted from human liver carcinoma cells decreased as the amount of cholesterol added to the culture medium was increased. Inhibition of SC5D transcription was ascribed to the suppression of promoter activity of SC5D.

Angiotensin-converting enzyme inhibition attenuates hypofibrinolysis and reduces cardiac perivascular fibrosis in genetically obese diabetic mice.

BACKGROUND: Obesity and insulin resistance are associated with accelerated macrovascular and microvascular coronary disease, cardiomyopathic phenomena, and increased concentrations and activity in blood of plasminogen activator inhibitor type 1 (PAI-1), the primary physiological inhibitor of fibrinolysis. METHODS AND RESULTS: To determine whether hypofibrinolysis in blood and tissues and its potential sequelae could be attenuated pharmacologically, we studied genetically modified obese mice. By 10 weeks of age, obese mice exhibited increases in left ventricular weight and glucose and immunoreactive insulin in blood. PAI-1 activity in blood measured spectrophotometrically was significantly elevated as well. The difference compared with values in lean controls widened by 20 weeks of age. Perivascular fibrosis in coronary arterioles and small coronary arteries was evident in obese mice 10 and 20 weeks of age, paralleling increases in PAI-1 and tissue factor expression evident by immunohistochemical image analysis, in situ hybridization, and reverse transcription-polymerase chain reaction. Inhibition of ACE activity initiated in obese mice 10 weeks of age and continued for 20 weeks arrested the increase in PAI-1 activity in blood and in cardiac PAI-1 and tissue factor mRNA as well as coronary perivascular fibrosis. CONCLUSIONS: Thus, inhibition of proteo(fibrino)lysis and augmented tissue factor expression in the heart precede and may contribute to the coronary perivascular fibrosis seen with obesity and insulin resistance. Furthermore, inhibition of ACE activity can attenuate all 3 phenomena.