Nobuhiro Akuzawa

Hypoxia Induces Transcription of the Plasminogen Activator Inhibitor-1 Gene Through Genistein-Sensitive Tyrosine Kinase Pathways in Vascular Endothelial Cells

A decline in oxygen concentration perturbs endothelial function, which promotes local thrombosis. In this study, we determined whether hypoxia in the range of that observed in pathophysiological hypoxic states stimulates plasminogen activator inhibitor-1 (PAI-1) production in bovine aortic endothelial cells. PAI-1 production, measured by ELISA, was increased by 4.7-fold (P<0.05 versus normoxic control, n=4) at 12 hours after hypoxic stimulation. Northern blot analysis showed the progressive time-dependent increase in the steady-state level of PAI-1 mRNA expression by hypoxia, which reached a 7.5-fold increase (P<0.05 versus control, n=4) at 12 hours. Deferoxamine, which has been known to bind heme protein and to reproduce the hypoxic response, induced PAI-1 production at both the mRNA and protein levels. The half-life of PAI-1 mRNA, as determined by a standard decay assay, was not affected by hypoxia, suggesting that induction of PAI-1 mRNA was regulated mainly at the transcriptional level. Transient transfection assays of the human PAI-1 promoter-luciferase construct indicates that a hypoxia-responsive region lies between -414 and -107 relative to the transcription start site, where no putative hypoxia response element is found. The hypoxia-mediated increase in PAI-1 mRNA levels was attenuated by the tyrosine kinase inhibitors genistein (50 micromol/L) and herbimycin A (1 micromol/L), whereas PD98059 (50 micromol/L, MEK1 inhibitor), SB203580 (10 micromol/L, p38 mitogen-activated protein kinase inhibitor), and calphostin C (1 micromol/L, protein kinase C inhibitor) had no effect on the induction of PAI-1 expression by hypoxia and deferoxamine. Genistein but not daidzein blocked the production of hypoxia- and deferoxamine-induced PAI-1 protein. Thus, we conclude that hypoxia stimulates PAI-1 gene transcription and protein production through a signaling pathway involving genistein-sensitive tyrosine kinases in vascular endothelial cells.

Antihypertensive agents prevent nephrosclerosis and left ventricular hypertrophy induced in rats by prolonged inhibition of nitric oxide synthesis.

We investigated the ability of the angiotensin converting enzyme (ACE) inhibitor imidapril hydrochloride, and of the calcium channel blocker amlodipine besilate, to prevent nephrosclerosis and left ventricular hypertrophy (LVH) in rats with hypertension induced by chronic inhibition of nitric oxide (NO). Male Wistar rats were given distilled water (control), NG-nitro-L-arginine methyl ester (L-NAME) 500 mg/L, L-NAME plus imidapril 10 mg/L or 100 mg/L, or L-NAME plus amlodipine 50 mg/L or 100 mg/L in the drinking water (n = 10-12). We then collected 24-h urine samples at 2, 4, and 6 weeks, obtained blood samples at 6 weeks, and histologically examined the kidney and heart. L-NAME markedly reduced the levels of NO metabolites in serum and urine while increasing the tail-cuff blood pressure, the urinary albumin level (1.90 +/- 0.65 v 0.05 +/- 0.02 mg/day/100 g in control), and the area of the left ventricular wall (83.3 +/- 3.0 v 69.8 +/- 1.8 mm2 in control). Nephrosclerosis and myocardial interstitial fibrosis were documented histologically. The plasma renin activity was significantly higher in rats treated with L-NAME than in the control rats. The concomitant administration of imidapril (10 mg/L) with L-NAME completely normalized the tail-cuff pressure, the LVH (70.8 +/- 1.8 mm2), the albuminuria (0.05 +/- 0.01 mg/day/100 g), and the histologic changes. Amlodipine (50 mg/L) also ameliorated the L-NAME-induced effects, but to a lesser extent. Thus, the chronic inhibition of NO synthesis in rats produced nephrosclerosis and LVH that were effectively prevented by giving imidapril at a dose lower than that of amlodipine. We conclude that ACE inhibitors can prevent nephrosclerosis and LVH even in the presence of a reduction in NO production, implying that in rats the inhibition of the renin-angiotensin system is more effective than the blockade of calcium channels in preventing hypertensive tissue injury.

Myocarditis, hepatitis, and pancreatitis in a patient with coxsackievirus A4 infection: a case report

Viral myocarditis presents with various symptoms, including fatal arrhythmia and cardiogenic shock, and may develop chronic myocarditis and dilated cardiomyopathy in some patients. We report here a case of viral myocarditis with liver dysfunction and pancreatitis. A 63-year-old man was admitted to our hospital with dyspnea. The initial investigation showed pulmonary congestion, complete atrioventricular block, left ventricular dysfunction, elevated serum troponin I, and elevated liver enzyme levels. He developed pancreatitis five days after admission. Further investigation revealed a high antibody titer against coxsackievirus A4. The patient’s left ventricular dysfunction, pancreatitis, and liver dysfunction had resolved by day 14, but his troponin I levels remained high, and an endomyocardial biopsy showed T-lymphocyte infiltration of the myocardium, confirming acute myocarditis. The patient underwent radical low anterior resection five weeks after admission for advanced rectal cancer found incidentally. His serum troponin I and plasma brain natriuretic peptide levels normalized six months after admission. He has now been followed-up for two years, and his left ventricular ejection fraction is stable.This is the first report of an adult with myocarditis and pancreatitis attributed to coxsackievirus A4. Combined myocarditis and pancreatitis arising from coxsackievirus infection is rare. This patient’s clinical course suggests that changes in his immune response associated with his rectal cancer contributed to the amelioration of his viral myocarditis.

Two Patients with Ruptured Posterior Inferior Pancreaticoduodenal Artery Aneurysms Associated with Compression of the Celiac Axis by the Median Arcuate Ligament

Patients with compression of the celiac axis by the median arcuate ligament may develop aneurysms in the pancreaticoduodenal arcades. We experienced two cases of ruptured pancreaticoduodenal artery aneurysm associated with this condition. Both patients presented with abdominal pain and shock, and abdominal contrast-enhanced computed tomography showed retroperitoneal hematoma and compression of the celiac axis by the median arcuate ligament. Both patients were successfully treated by coil embolization. Patients with celiac axis compression or stenosis may develop recurrent aneurysms unless revascularization of the celiac axis is performed. Long-term follow-up is required because aneurysms may develop after 10 years or longer.

Reciprocal expression of vascular endothelial growth factor and nitric oxide synthase by coronary arterial wall cells during chronic inhibition of nitric oxide synthesis in rats

Chronic inhibition of nitric oxide (NO) synthesis by oral administration of NG-nitro-L-arginine methyl ester (L-NAME) causes hypertension and produces arteriosclerosis in rats. Balloon injury induces upregulation of vascular endothelial growth factor (VEGF) in medial smooth muscle cells of the rat arterial wall, and NO secreted by a restored endothelium acts as the negative feedback mechanism that downregulates VEGF expression to basal levels. In this study, we tested the hypothesis that a reciprocal relation between VEGF and NO would be established in a rat model of chronic NO blockade. Male Wister rats received plain drinking water (n = 10) or L-NAME (0.5 mg/ml) in the drinking water (n = 11) for 6 weeks. After 6 weeks, the wall-to-lumen ratios and perivascular fibrosis in the coronary arteries were greater in the L-NAME group than in the control group. NO synthase-positive cells in the intima were abundantly observed in the control group, whereas no such cells were seen in the L-NAME group. In contrast, the number of VEGF-positive smooth muscle cells in the media was greater in the L-NAME group than in the control group. These findings strongly suggest a reciprocal relation between VEGF and NO even in a rat model of chronic NO blockade.

Multiple liver abscesses and bacteremia caused by Streptococcus constellatus infection: a case report

The Streptococcus milleri group (SMG) comprises commensal mucosal bacteria. Pyogenic liver abscesses due to hematogenous SMG infection are rare but can be observed even in healthy patients. In such cases, physicians should consider the existence of primary lesions that allow penetration of the SMG.

Three Cases of Spontaneous Isolated Dissection of the Superior Mesenteric Artery

BACKGROUND Spontaneous isolated superior mesenteric artery dissection is a rare disease that may cause bowel ischemia or aneurysm rupture and subsequent death. Thus, the establishment of a correct diagnosis in the early stage is quite important. OBJECTIVE To describe the presentation of 3 patients diagnosed with spontaneous isolated supramesenteric artery dissection and briefly summarize the diagnostic procedure, treatment, and clinical course. CASE REPORTS We experienced three cases of isolated mesenteric artery dissection in the past 5 years. A definitive diagnosis was obtained by abdominal spiral computed tomography in two cases and angiography in one case. All patients were provided anticoagulation therapy. CONCLUSION One patient died of bowel ischemia, 2 were discharged within 21 days without complications, and one was able to discontinue anticoagulation therapy 12 months after discharge. The remaining patient has continued warfarin, making it difficult to determine the end point of anticoagulation.

Spontaneous isolated dissection of the superior mesenteric artery and aneurysm formation resulting from segmental arterial mediolysis: a case report

BackgroundSpontaneous isolated dissection of the superior mesenteric artery (SMA) can lead to bowel ischemia, aneurysm rupture, or even death. Studies have suggested that mechanical or hemodynamic stress on the vascular wall of the SMA may be a contributor, but its pathogenesis is unclear.Case presentationA 57-year-old Japanese man with a history of untreated hypertension and hyperuricemia was admitted to our hospital with the sudden onset of severe epigastric pain. Laboratory findings showed elevated white blood cell count and C-reactive protein, and contrast-enhanced computed tomography (CT) of the abdomen demonstrated arterial dissection with luminal stenosis and aneurysm formation at the distal portion of the SMA after the branching of the jejunal artery, and intravenous nicardipine was administered. The patient’s epigastric pain resolved spontaneously but recurred on day 6 of his hospital stay. Contrast-enhanced abdominal CT revealed an enlarged aneurysm with wall thinning. Because of the risk of aneurysm rupture, the decision was made to perform aneurysmectomy and bowel resection on day 6. Histologic examinations revealed two separate dissecting lesions: one latent and the other resulting in aneurysm formation. Both lesions showed characteristics of segmental arterial mediolysis (SAM) with lack of arterial media, absence of internal and external elastic laminae and intimal proliferation.ConclusionsHistologic findings in the present case suggest that mechanical or hemodynamic stress on the vascular wall and SAM-related vascular vulnerability may concomitantly contribute to the onset of isolated SMA dissection.

Acute suppurative thyroiditis caused by Streptococcus agalactiae infection: a case report

Acute suppurative thyroiditis is a serious disease; therefore, its diagnosis in the acute phase is important. Fine needle aspiration biopsy of the thyroid gland plays a pivotal role in the diagnosis of acute suppurative thyroiditis. Appropriate culture technique and optimal imaging modalities are also important for its diagnosis.

Pneumatosis intestinalis with a benign clinical course: a report of two cases

BackgroundPneumatosis intestinalis (PI) is a rare condition characterized by the presence of gas within the gastrointestinal tract wall. Most cases of PI have a benign clinical course, although some have serious outcomes. Mechanical stress on or bacterial infection of the gastrointestinal tract wall may be responsible for the onset of PI, but the detailed mechanism of PI pathogenesis is still unclear. Here, we describe two Japanese patients presenting with benign PI.Case presentationCase 1, a 37-year-old previously healthy male patient, had a 1-week history of abdominal pain, and case 2, a 78-year-old female diabetic patient, had a 2-week history of voglibose treatment and abdominal pain. Intramural gas was mainly distributed in the colon in case 1 and in the small intestine in case 2. Interestingly, neither patient showed obvious inflammatory signs upon admission and recovered spontaneously with conservative treatment, including fasting and fluid infusion without antibiotics. Voglibose treatment was terminated in case 2. Recent studies have shown the presence of nonpathogenic bacteria, such as Clostridium spp., in PI lesions, which usually play an important role in modulating the tolerance of the gastrointestinal immune responses. The benign clinical course and spontaneous resolution of PI in these patients, without specific treatment, suggests that nonpathogenic indigenous bacteria in the gastrointestinal tract participate in the pathogenesis of PI.ConclusionIn patients with benign PI, the absence of an inflammatory response and the spontaneous resolution of the disease without specific treatment suggest the participation of nonpathogenic indigenous bacteria of the gastrointestinal tract.