Effect of the angiotensin II receptor antagonist losartan on uric acid and oxypurine metabolism in healthy subjects

OBJECTIVE: The acute effects of the angiotensin II receptor antagonist losartan on uric acid and oxypurine metabolism were evaluated. METHODS: Losartan (50 mg) was administered orally to 6 healthy males. Blood and urine samples for uric acid and oxypurine were collected before and up to 6 hours after losartan administration. The same examinations were performed later using enalapril (5 mg). RESULTS: Losartan decreased the serum uric acid concentration (from 5.9 +/- 0.9 to 5.2 +/- 1.0 mg/dl) and increased its fractional clearance, which reached a maximum after 2 hours, while enalapril did not. Losartan also induced an increase in the plasma concentration of hypoxanthine, peaking in the fourth hour, and a decrease in its urinary clearance, while the plasma xanthine concentration and its urinary clearance were unchanged. The extent of uric acid excretion was much greater than that of the oxypurines. CONCLUSIONS: Losartan, which has a high affinity for the urate/anion exchanger, has a transient uricosuric effect. Our data indicate that losartan induces a significant decrease in the urinary excretion of hypoxanthine without changes in xanthine.     

Accumulation of T-cells with selected T-cell receptors in the brains of Japanese encephalitis virus-infected mice

Japanese encephalitis is a severe central nervous system (CNS) disease with a high case fatality rate in humans. We characterized T-cells infiltrating the brain after infection with Japanese encephalitis virus (JEV) in a mouse model and determined the clonality of the infiltrating T-cells by analyzing the sequences of complementary determining region 3 (CDR3) of the T-cell receptor. C3H/He mice died after intraperitoneal infection with the JaTH160 strain of JEV, demonstrating CNS degeneration and prominent T-cell infiltration. The percentages of T-cells bearing the VA5-1, VA17-1, VA19-1, VB2-1, VB8-3 and VB13-1 subfamilies were significantly increased following infiltration of the brains in infected mice. Additionally, CDR3 size spectratyping revealed the oligoclonality in T-cells bearing VA11-1 and VA18-1. CDR3 amino acid sequences were then determined for the VA5-1, VA11-1, VA18-1, VB8-3 and VB13-1 subfamilies. There were high levels of identity and similarity in amino acid sequences of CDR3 in these T-cells. Quantitative real-time PCR analysis also revealed that CD8, interferon-gamma and tumor necrosis factor-alpha were highly expressed in the infected mouse brain. These results indicate that T-cells with high clonality and similarity infiltrate the JEV-infected mouse brain, and that these T-cells are mainly CD8-positive and have the Th1/Tc1 phenotype.     

Improvement of Splenomegaly and Pancytopenia by Enzyme Replacement Therapy Against Type 1 Gaucher Disease: A Report of Sibling Cases

Gaucher disease is a genetic lipid storage disease and represents a potentially serious health problem. It arises from a deficiency of glucocerebrosidase activity with secondary accumulation of large quantities of glucocerebroside. Symptoms are usually multisystemic, often debilitating or disabling, and sometimes disfiguring, and they can lead to death. We report objective clinical response's to repeated infusion of human placental and recombinant glucocerebrosidase in 2 patients with type 1 Gaucher disease and increased hemoglobin levels and platelet counts. Splenic volume decreased during the period of enzyme administration. Enzyme replacement therapy has improved the treatment of type 1 Gaucher disease by safely and effectively arresting, decreasing, or normalizing many of its major signs and symptoms. Consideration by physicians must be given to Gaucher disease, and appropriate treatments must be given when confronted with cryptogenic pancytopenia or hepatosplenomegaly.     

Progressive systemic sclerosis associated with primary small cell carcinoma of the stomach

A 64-year-old man with a 5-year history of progressive systemic sclerosis (PSS) was hospitalized because of melena. Radiological and endoscopic examinations showed an ulcerative lesion with sharply demarcated and raised margins in the fornix of the stomach. Tumor markers—serum carcinoembryonic antigen (CEA, 11.3 ng/ml) and neuron-specific enolase (NSE, 38.9 ng/ml) were elevated. Histological examination of endoscopic biopsy specimens (and of necropsy specimens) showed proliferation of atypical small round cells. Immunohistological examination of these cells showed they were positive for epithelial membranous antigen (EMA), and neuron-specific enolase (NSE), but negative for UCHL1, leukocyte common antigen (LCA), anti-leukocyte B-cell (MB1), and antileukocyte T-cell (MT1) antigens. Based on these histological and immunohistological tests, a definite diagnosis of small cell carcinoma of the stomach with PSS was established. Our case is a rare combination of PSS and gastric small cell carcinoma. We also reviewed the literature for the association between PSS and gastric cancer in Japanese patients.     

Pathological findings of bronchiectases caused by Mycobacterium avium intracellulare complex

It has been argued whether bronchiectasis is truly caused by MAC infection or just a predisposed condition in which MAC colonizes. Our present study was designed to evaluate the pathological findings of bronchiectases caused by Mycobacterium avium intracellulare complex (MAC) lung infection and to demonstrate MAC in the lesion of bronchiectases. A retrospective study was performed in nine cases with positive cultures for MAC in whom lung resections were performed. A determination of whether or not MAC caused pulmonary disease was made using the 1997 criteria required by the American Thoracic Society. In addition, MAC were cultured from all nine lung specimens. Pathological findings of bronchiectases were evaluated in these nine patients. Destruction of bronchial cartilage and smooth muscles layer, obstruction of airway by granulomas, and ulceration of bronchial mucosa were frequently observed. Our present study demonstrates that destruction of fundamental bronchial structure due to extensive granuloma formation throughout the airways was likely the main cause of bronchiectases in MAC infection.     

Whole-body periodic acceleration enhances brachial endothelial function.

BACKGROUND: Periodic acceleration in the direction of the spinal axis through repetitive movement increases the shear stress on the vascular endothelium. In the present study it was assessed whether whole-body periodic acceleration with a new device would enhance endothelial function in sedentary adult volunteers. METHODS AND RESULTS: Twenty-six sedentary subjects (44+/-3 years) were randomly assigned to remain sedentary or perform exercise training for 4 weeks, followed by crossover. Periodic acceleration was applied with a horizontal motion platform at 2-3 Hz and approximately +/-2.2 m/s2 for 45 min. Increases in the brachial artery diameter were examined at rest, during reactive hyperemia (flow-mediated dilatation: %FMD) and after sublingual administration of 0.3 mg nitroglycerin (%NTG) using high-resolution ultrasound. All subjects completed the study with no adverse side-effects. There were no significant changes in the resting heart rate or arterial pressure, body weight, or lipid profiles during the study. Although %FMD did not change during the non-training period with periodic acceleration, it significantly increased from 7.3+/-0.4% at baseline to 8.4+/-0.4% after the training period (p<0.05), while %NTG remained unchanged. CONCLUSIONS: Whole-body periodic acceleration with a horizontal motion platform improved vascular endothelial function in sedentary adults. This device might offer an alternative to active exercise for patients whose medical condition limits physical activity.     

C-type natriuretic peptide, a novel antifibrotic and antihypertrophic agent, prevents cardiac remodeling after myocardial infarction

OBJECTIVES: We assessed the hypothesis that in vivo administration of C-type natriuretic peptide (CNP) might attenuate cardiac remodeling after myocardial infarction (MI) through its antifibrotic and antihypertrophic action. BACKGROUND: Recently, we have shown that CNP has more potent antifibrotic and antihypertrophic effects than atrial natriuretic peptide (ANP) in cultured cardiac fibroblasts and cardiomyocytes. METHODS: Experimental MI was induced by coronary ligation in male Sprague-Dawley rats; CNP at 0.1 mug/kg/min (n = 34) or vehicle (n = 35) was intravenously infused by osmotic mini-pump starting four days after MI. Sham-operated rats (n = 34) served as controls. After two weeks of infusion, the effects of CNP on cardiac remodeling were evaluated by echocardiograpic, hemodynamic, histopathologic, and gene analysis. RESULTS: C-type natriuretic peptide markedly attenuated the left ventricular (LV) enlargement caused by MI (LV end-diastolic dimension, sham: 6.7 +/- 0.1 mm; MI+vehicle; 8.3 +/- 0.1 mm; MI+CNP: 7.7 +/- 0.1 mm, p < 0.01) without affecting arterial pressure. Moreover, there was a substantial decrease in LV end-diastolic pressure, and increases in dP/dt(max), dP/dt(min), and cardiac output in CNP-treated MI rats compared with vehicle-treated MI rats. Importantly, CNP infusion markedly attenuated an increase in morphometrical collagen volume fraction in the noninfarct region (sham: 3.1 +/- 0.2%; MI+vehicle: 5.7 +/- 0.5%; MI+CNP: 3.9 +/- 0.3%, p < 0.01). In addition, CNP significantly reduced an increase in cross-sectional area of the cardiomyocytes. These effects of CNP were accompanied by suppression of MI-induced increases in collagen I, collagen III, ANP, and beta-myosin heavy chain messenger ribonucleic acid levels in the noninfarct region. CONCLUSIONS: These data suggest that CNP may be useful as a novel antiremodeling agent.     

Effects of prolactin and growth hormone on proliferation and survival of cultured trout leucocytes

The in vitro effects of prolactin (PRL) and growth hormone (GH) on the proliferation and survival of leucocytes isolated from the blood of the rainbow trout (Oncorhynchus mykiss) were examined, with special reference to the immunosuppression by cortisol. Both PRL and GH induced a mitogenic effect in trout leucocytes. Contrary, the frequencies of annexin V-positive apoptotic cells and propidium iodide-positive dead cells were decreased by the administration of PRL, but were uninfluenced by GH. Administration of cortisol suppressed the mitotic activity and induced cell death of leucocytes. PRL inhibited the decrease in mitosis and the increase in cell death due to cortisol. GH significantly assisted recovery of cortisol-suppressed mitosis but did not influence the survival of leucocytes. These results suggest that PRL and GH are involved in the maintenance of specific immune functions in fish through a prevention of immunosuppression by cortisol.