Paradoxical mineralocorticoid receptor activation and left ventricular diastolic dysfunction under high oxidative stress conditions

BACKGROUND: Salt status plays a pivotal role in angiotensin-II-induced organ damage by regulating reactive oxygen species status, and it is reported that reactive oxygen species activate mineralocorticoid receptors. METHOD: To clarify the role of reactive oxygen species-related mineralocorticoid receptor activation in angiotensin-II-induced cardiac dysfunction, we examined the effect of the following: salt status; an MR antagonist, eplerenone; and an antioxidant, tempol in angiotensin-II-loaded Sprague-Dawley rats. RESULTS: Angiotensin-II/salt-loading elevated blood pressure, and neither eplerenone nor tempol antagonized the rise in blood pressure significantly. Left ventricular diastolic function was monitored by measuring peak velocity of a mitral early inflow (E), the ratio of mitral early inflow to atrial contraction related flow (E/A), deceleration time of mitral early inflow and -dP/dt, the time constant (T), and filling pressure (left ventricular end-diastolic pressure) by echocardiography or cardiac catheterization. Despite the suppressed serum aldosterone, left ventricular diastolic function was deteriorated with angiotensin II/high salt, but not affected by angiotensin II/low salt. However, angiotensin-II/salt-induced cardiac dysfunction was restored by eplerenone and tempol. Nicotinamide adenine dinucleotide phosphateoxidase-derived superoxide formation was greater in the hearts of the angiotensin II/high-salt rats than of the angiotensin II/low-salt rats. The expression of the Na(+) -H(+) exchanger isoform 1, a target of mineralocorticoid receptor activation, was significantly increased in the angiotensin II/high-salt group. Both tempol and eplerenone inhibited the angiotensin-II/salt-induced upregulation of Na(+) -H(+) exchanger isoform 1. CONCLUSION: These findings demonstrate that mineralocorticoid receptor activation by oxidative stress can cause left ventricular diastolic dysfunction in a rat model of mild hypertension.     

An esophageal cancer case unresectable due to tuberculous fibrosing mediastinitis: report of a case

We present a case of esophageal carcinoma in which esophagectomy was not possible because of tuberculous fibrosing mediastinitis. A 77-year-old man was diagnosed with carcinoma of the thoracic esophagus and admitted to our hospital. Chest radiography on admission revealed no abnormality except pleural thickening of the pulmonary apices, suggesting a history of subclinical infection of tuberculous pleurisy. The patient underwent surgery with a curative intent. Thoracotomy revealed that the mediastinum had been replaced with dense fibrous tissues and was widely encased with laminar calcification. Esophagectomy was not performed because it was considered impossible to do so safely. Although diagnosis of fibrous mediastinitis was not made preoperatively, review of the preoperative computed tomographic scans revealed proliferation of mediastinal soft tissues that were associated with patchy and laminar calcifications. Tuberculous fibrosing mediastinitis is an uncommon but clinically important disease for physicians who are involved in the diagnosis and treatment of esophageal cancer.     

Effect of the calcium antagonist,diltiazem, on beta-agonist-induced reduction of beta-adrenergic responsiveness in the guinea pig lung

This study was designed to clarify the mechanism of tolerance that occurs during prolonged administration of a beta-agonist in relation to membrane phospholipid degradation and to elucidate the effect of diltiazem, a calcium antagonist. Guinea pigs were divided into 3 groups: (1) control—physiological saline (0.5 ml) was injected once a day for 7 successive days; (2) metaproterenol (Mp)—Mp was injected intraperitoneally (10 mg/kg/day) for 7 successive days; (3) Mp + diltiazem—diltiazem was injected intraperitoneally (20 mg/kg/day) 30 min before Mp injection for 7 successive days. The number of beta-adrenoceptors and the 10⁻⁵ M (−)-isoproterenol-stimulated adenylate cyclase activity were significantly decreased in the metaproterenol group. Diltiazem reduced these decreases. Phospholipase activity was increased and phosphatidylcholine and phosphatidylethanolamine levels were decreased in the metaproterenol group. Diltiazem also reduced these changes. These results suggest that the degradation of membrane phospholipids by phospholipase may be involved in a decrease in beta-adrenergic response caused by successive administration of metaproterenol. Diltiazem protects membrane phospholipids from phospholipase attack, which in turn maintains beta-adrenergic responsiveness. Part of this study was presented at the Annual Meeting of the American Thoracic Society, May 12, 1987, New Orleans, Louisiana     

Malignant Transformation of the Mouse Anorectal Epithelium Induced by an Inoculated Human Cancer Cell Line

Four kinds of human cancer cell lines and one mouse cancer cell line were inoculated into the subepithelial area of the anorectum of female nude mice. Among the cell lines, two cell lines (KATO III and Lu 135) showed the potential enforcement of atypical changes in the adjacent mouse anorectal epithelium. Moreover, the submucosal invasion of the malignant transformed cells of the mouse epithelium was demonstrated in specimens obtained from three KATO III-inoculated mice. This exciting and novel phenomenon clearly demonstrates the need to change the present general concept of a single-cell origin of cancer tissue. This valuable and novel discovery may change the basis of oncology research while also providing new ideas for projects to investigate the mechanisms of carcinogenesis from several aspects such as molecular biology, cell biology, and pathology. Moreover, the novel experimental design itself is also extremely useful as a simple model for investigating the mechanisms of oncogenesis.     

Unique surface structures of community-associated methicillin-resistant Staphylococcus aureus ST8/SCCmecIVl

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) threatens human health. A local CA-MRSA with ST8/SCCmecIVl (CA-MRSA/J) has emerged in Japan, being associated with progression from bullous impetigo to potentially fatal invasive infection. We found that CA-MRSA/J has unique bacterial surface structures, spikes, spikes with a cap, and long spikes, reflecting clinical origins.     

Microbiome composition comparison in oral and atherosclerotic plaque from patients with and without periodontitis

Odontology - There is no conclusive evidence regarding a causal relationship between periodontitis and atherosclerosis. In this study, we examined the microbiome in the oral cavity and atheromatous...     

Characteristic features of folate-deficient neurological diseases in the elderly

Background:  Folic acid (folate) deficiency causes neurological disorders in aged people, the characteristic features of which were examined.
Methods:  Serum folate levels were determined in 343 neurological patients by chemiluminescence. We found 36 folate-deficient patients (10.5%) who were divided into elderly ≥ 65 years old (12 cases) and younger group, < 65 years old (24 cases), and were administered folate (15 mg/day) for 60 days.
Results:   Serum folate levels were not different between the elderly and younger group, while folate levels were lower in elderly females than elderly males. Neuropathy was more frequent in elderly male than elderly female patients. Elderly neurological patients with neuropathy more readily responded to folate supplementation than those without neuropathy. Folate-deficient patients with dementia were older than those without dementia, although nine younger patients had dementia and four of nine cases showed frontal dementia. Anemia or female sex was more frequent and neuropathy was less frequent among elderly patients with central nervous system involvement. Serum folate levels were lower in elderly anemic than nonanemic patients. Tube feeding was more frequent in elderly folate-deficient neurological patients than in younger ones. Folate therapy was less effective in elderly patients with dementia, although three cases improved. Elderly folate-deficient patients treated with tube feeding did not respond to the folate supplement.
Conclusion:   Folate deficiency was not rare among aged neurological patients, and its features were different from younger patients. Since folate-deficient neuroencephalopathies are responsive to folate supplementation in the elderly, the examination of elderly patients' serum folate level is valuable.     

Cloning and expression of rat 25-hydroxyvitamin D3-1α-hydroxylase cDNA

A full-length cDNA for the rat kidney mitochondrial cytochrome P450 mixed function oxidase, 25-hydroxyvitamin D₃-1α-hydroxylase (P4501α), was cloned from a vitamin D-deficient rat kidney cDNA library and subcloned into the mammalian expression vector pcDNA 3.1(+). When P4501α cDNA was transfected into COS-7 transformed monkey kidney cells, they expressed 25-hydroxyvitamin D₃-1α-hydroxylase activity. The sequence analysis showed that P4501α was of 2,469 bp long and contained an ORF encoding 501 amino acids. The deduced amino acid sequence showed a 53% similarity and 44% identity to the vitamin D₃-25-hydroxylase (CYP27), whereas it has 42.6% similarity and 34% identity with the 25-hydroxyvitamin D₃-24-hydroxylase (CYP24). Thus, it composes a new subfamily of the CYP27 family. Further, it is more closely related to the CYP27 than to the CYP24. The expression of P4501α mRNA was greatly increased in the kidney of vitamin D-deficient rats. In rats with the enhanced renal production of 1α,25-dihydroxyvitamin D₃ (rats fed a low Ca diet), P4501α mRNA was greatly increased in the renal proximal convoluted tubules.     

Functional giant parathyroid cyst with high concentration of CA19-9 in cystic fluid

A 63-year-old man was admitted to our hospital for the evaluation of hypercalcemia and anterior neck mass. Laboratory findings revealed hypercalcemia, hypophosphatemia, and hypercalciuria, as well as elevated serum levels of parathyroid hormone (PTH) and alkaline phosphatase. Computerized tomography and magnetic resonance images showed that the mass contained a cystic area. Parathyroid scintigraphy using either 99mTc-sestamibi alone or 201Tl-chloride in conjunction with 99mTc-pertechnetate for thyroid image subtraction showed uptake of the radioactivity into the cyst wall, suggesting that the mass originated from the parathyroid. Fine needle aspiration biopsy revealed that the cyst fluid was serous and bloody with extremely high concentrations of both PTH and CA19-9. The patient was diagnosed as primary hyperparathyroidism caused by parathyroid cyst and cervical exploration was performed. The cyst was dissected away along with the right lobe of the thyroid gland. After tumor removal, serum calcium and PTH levels were normalized. Histological study showed that the tumor possessed malignant potential with capsular invasion as well as moderate cellular atypia with trabecular pattern in arrangement. Parathyroid cells in the wall of the cystic tumor were immunostained positively for CA19-9, suggesting that CA19-9 in the cyst fluid was produced from the cells.