Effect of Antihypertensive Drugs on Uric Acid Metabolism in Patients with Hypertension: Cross-Sectional Cohort Study.

Background: Hypertension is a common complication in patients with gout and/or hyperuricemia. Besides, hyperuricemia is a risk factor of gout as well as ischemic heart disease in hypertensive patients. Moreover, the risk of gout is modified by antihypertensive drugs. However, it remains unclear how antihypertensive agents affect uric acid metabolism. Purpose: In the present study, we investigated the uric acid metabolism in treated hypertensive patients to find out whether any of them would influence serum levels of uric acid. Patients and methods: 751 hypertensive patients (313 men and 438 women) under antihypertensive treatment were selected. Blood pressure (BP), serum uric acid (SUA) and serum creatinine (Scr) were measured and evaluated statistically. Results: In patients treated with diuretics, beta-blockers and/or alpha-1 blockers SUA levels were significantly higher than in patients who were not taking these drugs. Besides, the estimated glomerular filtration rate (eGFR) in patients treated with diuretics, beta-blockers and/or alpha-1 blockers was negatively correlated with SUA level. There were gender differences in the effects of beta-blockers and alpha-1 blockers. Multiple regression analysis indicated that both diuretics and beta-blockers significantly contributed to hyperuricemia in patients with medication for hypertension. Conclusion: Diuretics, beta-blockers and alpha-1 blockers reduced glomerular filtration rate and raised SUA levels. Calcium channel blockers, ACE inhibitors and angiotensin receptor blockers, including losartan, did not increase SUA levels.

Relaxation dynamics of photoexcited excitons in rubrene single crystals using femtosecond absorption spectroscopy.

The relaxation dynamics of an exciton in rubrene was investigated by femtosecond absorption spectroscopy. Exciton relaxation to a self-trapped state occurs via the coherent oscillation with 78 cm(-1) due to a coupled mode of molecular deformations with phenyl-side-group motions and molecular displacements. From the temperature dependence of the decay time of excitons, the energy necessary for an exciton to escape from a self-trapped state is evaluated to be ~35 meV (~400 K). As a result, a self-trapped exciton is stable at low temperatures. At room temperature, excitons can escape from a self-trapped state and, subsequently, they are dissociated to charged species. The exciton dissociation mechanism is discussed on the basis of the results.

Postoperative pain status after intraoperative systemic dexmedetomidine and epidural neostigmine in patients undergoing lower abdominal surgery.

BACKGROUND AND OBJECTIVES: To determine whether intraoperative systemic dexmedetomidine improves postoperative pain and interacts with epidural neostigmine to produce analgesic effects. METHODS: Sixty patients undergoing gynaecological surgery were randomly divided into four groups to receive epidural neostigmine and/or systemic dexmedetomidine: control (Group C), epidural neostigmine (Group N), systemic dexmedetomidine (Group D) and co-administered neostigmine and dexmedetomidine (Group ND). Epidural neostigmine (0.3 mg) was administered with 10 mL of 0.75% ropivacaine before the induction of general anaesthesia. Systemic dexmedetomidine (loading dose of 1 mug kg-1 over 10 min followed by 0.4 mug kg-1 h-1) was infused after the induction of general anaesthesia and continued until the end of surgery. The pain status of patients was assessed using the visual analogue scale at 2, 4, 6, 24 and 72 h postoperatively. RESULTS: Intraoperative systemic dexmedetomidine alone did not reduce postoperative pain scores. However, co-administered neostigmine and dexmedetomidine significantly decreased scores at 24 and 72 h (Group C: 3.0 [1.0-5.8] and 2.0 [0.3-3.0]; Group N: 1.5 [0.3-3.4] and 0 [0-1.3]; Group D: 3.5 [0-5.0] and 0 [0-1.4]; and Group ND: 0 [0-1.0]* and 0 [0-0]; median [interquartile range] *P = 0.0031, P = 0.0045 compared with Group C). CONCLUSIONS: The intraoperative systemic infusion of dexmedetomidine alone at doses causing sedation does not result in postoperative analgesic effects. However, the co-administration of systemic dexmedetomidine and epidural neostigmine at higher doses may be a useful method to improve postoperative pain although side-effects have to be evaluated.

[Surgical treatment for infectious tricuspid valve endocarditis with ventricular septal defect; report of a case].

We report a case of tricuspid valve endocarditis with a ventricular septal defect (VSD). A 54-year-old female who had a history of dental therapy admitted to our hospital with a fever of unknown origin. Echocardiography showed vegetation attached to the tricuspid valve and small VSD. The direct closure of VSD and tricuspid valve replacement was performed. The patient's postoperative course was uneventful.

Evaluation of the flow characteristics of an internal thoracic artery graft after coronary artery bypass grafting by intercostal Duplex scanning ultrasonography.

AIM: We previously reported intercostal duplex scanning ultrasonography to be a reliable technique for the evaluation of the internal thoracic artery (ITA). The purpose of this study was to determine the flow characteristics of the ITA graft using this technique. METHODS: We evaluated the flow characteristics of 69 ITA grafts who underwent coronary artery bypass grafting by this technique. The internal diameter, mean systolic and diastolic velocity, total flow volume and diastolic fraction were all thus obtained. RESULTS: One occluded graft was found during the follow-up. The mean systolic velocity significantly decreased after the operation (P=0.0001) and the mean diastolic velocity significantly increased both just after the operation (P=0.0002) and 1 year later (P=0.0283). The average diameter of the ITA graft after the operation (1.70+/-0.39), at 1 year (1.73+/-0.29) and at 2 years thereafter (1.66+/-0.27 mm) all significantly decreased in comparison to the preoperative value (2.30+/-0.35 mm) (P=0.0001). The average total flow volume after the operation (35.8+/-22.2), and at 1 year (29.4+/-16.5) and 2 years thereafter (23.4+/-12.7), respectively, were significantly decreased in comparison to the preoperative value (59.4+/-28.6 mL/min) (P=0.0001). However, the average diastolic fraction which was 25.1+/-10.5% before the operation significantly increased after the operation (54.5+/-12.0, 53.2+/-11.2 at 1 year and 50.4+/-9.3 at 2 years) (P=0.0001). CONCLUSION: This technique is thus considered to be a useful noninvasive for the postoperative follow-up of the graft function. A significant increase in the diastolic fraction is thought to be important for maintaining long term graft patency.

Epigenetic abnormalities in cutaneous squamous cell carcinomas: frequent inactivation of the RB1/p16 and p53 pathways.

BACKGROUND: Aberrant methylation of CpG islands in the promoter regions of cancer-related genes has been demonstrated in many human tumours. However, the methylation profile of these regions in cutaneous squamous cell carcinomas (SCCs) has not been well studied. OBJECTIVES: To examine epigenetic abnormalities of a wide range of cancer-related genes in SCCs. METHODS: We investigated the methylation status of 11 candidate cancer-related genes (CDH1, p16(INK4a), p14(ARF), DAPK1, MGMT, RB1, RASSF1, p15(INK4b), PTEN, PRDM2 and p53) in 20 cases of SCC by methylation-specific polymerase chain reaction, and comparatively examined the protein production of E-cadherin (CDH1), p16, RB1, p14, BMI1 and cyclin A by immunohistochemical analysis. RESULTS: The frequency of cancer-related gene methylation in SCCs was: CDH1 (95%), p16 (20%), p14 (15%), DAPK1 (15%), MGMT (15%), RB1 (5%), RASSF1 (5%), p15 (0%), PTEN (0%), PRDM2 (0%) and p53 (0%). Almost all cases with hypermethylation of CDH1, p16, RB1 and p14 showed no obvious production of each protein, suggesting that promoter hypermethylation of these genes contributes to the loss of protein production. The results of methylation analysis, in combination with the results of our previous mutation analysis of CDKN2A locus and p53, revealed that 70% of SCCs have alterations in the RB1/p16 or p53 pathway. CONCLUSIONS: Our findings indicate that the promoter hypermethylation of cancer-related genes, especially CDH1, is frequently shown in SCCs, and dysregulation of the RB1/p16 and/or p53 pathway through either genetic or epigenetic mechanisms, except for epigenetic abnormalities of p53 itself, should contribute to the carcinogenesis of SCCs.

Evaluation of an internal thoracic artery as a coronary artery bypass graft by intercostal duplex scanning ultrasonography.

OBJECTIVES: Although angiography is often used to determine whether the internal thoracic artery is appropriate as a coronary bypass graft, but use of duplex scanning ultrasonography for this purpose is not yet widespread. METHODS: The internal diameter and flow of the internal thoracic artery were measured using intercostal duplex scanning in 100 patients during April 1995. The ultrasonographic device (sonos 2000, Hewlett Packard) used had a linear probe delivering a frequency of 7.5 MHz. Bilateral internal thoracic arteries and their blood flow were imaged clearly in all subjects. Diameter was compared by angiography and duplex scanning ultrasonography in 20 patients. RESULTS: The average internal diameter of internal thoracic artery was 2.19 +/- 0.46 mm (right) or 2.13 +/- 0.32 mm (left) in men and 2.05 +/- 0.44 mm (right) or 2.09 +/- 0.42 mm (left) in women. The gender difference was statistically significant (p = 0.05). The maximum systolic blood flow velocity through the internal thoracic artery was 0.85 +/- 0.34 m/s (right) or 0.84 +/- 0.36 m/s (left) in men and 0.87 +/- 0.28 m/s (right) or 0.82 +/- 0.28 m/s (left) in women. The average internal thoracic arterial blood flow (F) was 54.6 +/- 29.0 ml/min (right) or 50.9 +/- 28.8 ml/min (left) in men and 56.8 +/- 38.2 ml/min (right) or 58.2 +/- 33.4 ml/min (left) in women. Duplex scanning ultrasonography using an intercostal approach enables easy imaging of bilateral internal thoracic arteries and visualizes entire internal thoracic artery structure by simply changing the probe position. CONCLUSION: Intercostal duplex scanning ultrasonography is thus recommended for reliable evaluation of the internal diameter and blood flow of the internal thoracic artery.

Chronic extrinsic denervation after small bowel transplantation in rat jejunum: Effects and adaptation in nitrergic and non-nitrergic neuromuscular inhibitory mechanisms.

BACKGROUND: Extrinsic denervation of the transplanted small bowel could play a substantial role in motor dysfunction of the transplanted gut. We attempted to determine the effect of chronic extrinsic denervation on intestinal contractility. METHODS: Jejunal longitudinal muscle strips were obtained from rats 1 week and 8 weeks after (1) syngeneic small bowel transplantation, (2) ischemia/reperfusion, or (3) gut transection/reanastomosis. Nonoperated rats (naive controls) and sham-operated rats (sham controls), 1 week after celiotomy/gut manipulation, served as controls. We evaluated the effects of exogenous nitric oxide, increasing doses of cholinergic and adrenergic agonists, and electrical field stimulation (EFS) in the presence or absence of N(G)-monomethyl-l-arginine, methylene blue, tetraethylammonium, or tetrodotoxin. RESULTS: Spontaneous contractile activity (_chi +/- SEM), when compared with the naive controls (11.3 +/- 2.0 g.5 min/mg), was increased in all 4 groups at 1 week (15.9 +/- 10 to 19.4 +/- 2 g.5 min/mg; P < or =.03 each) but not at 8 weeks postoperatively. The inhibition of contractile activity by nitric oxide was increased in small bowel transplantation in naive controls at 8 weeks to 80% +/- 10% versus 50% +/- 7% (P <.02). EFS induced an inhibition of contractile activity that was tetraethylammonium- and tetrodotoxin-sensitive but N(G)-monomethyl-l-arginine- and methylene blue-insensitive; the maximal EFS-induced inhibition was increased at 1 week and 8 weeks but only in the small bowel transplantation groups to 103% +/- 5% and 95% +/- 7%, respectively, versus 72% +/- 8% in naive controls (P

Progression of prostate cancer: diagnostic and prognostic utility of prostate-specific antigen, alpha2-macroglobulin, and their complexes.

We previously reported cases of advanced prostate cancer (PCa) in which serum alpha2-macroglobulin (alpha2M) levels were markedly decreased to less than approximately 50 mg/dl whereas serum prostate-specific antigen (PSA) levels were remarkably increased. These cases were not complicated with disseminated intravascular coagulation (DIC). In this study, we measured serum PSA and alpha2M in 108 patients with either benign prostatic hyperplasia (BPH) or PCa to elucidate the relationship between PSA, i.e. the serum protease derived from the prostatic tissue, and alpha2M, i.e. the protease inhibitor that was the most abundantly contained in serum. alpha2M was determined by ELISA, total PSA and PSA-alpha1-antichymotrypsin (PSA-ACT) by EIA, and free-PSA by RIA in 44 patients with untreated BPH and 64 patients with untreated PCa. The ready association of alpha2M and PSA was assessed using Western blotting to identify complexes of the two. Levels of total serum PSA correlated positively with those of PSA-ACT in PCa (r = 0.99, p < 0.001), and both levels increased with advancing stage of disease. In contrast, the serum-free PSA/total PSA ratio (free/total PSA) and alpha2M levels decreased as the disease progressed. However, only the free/total PSA ratio attained significant difference for localized cancer in stage T1,2 versus BPH (p < 0.05). In stage M1b PCa, in which serum PSA levels were very high, there was a negative correlation between the total PSA and alpha2M values (r = -0.57, p < 0.05). In addition, serum alpha2M levels tended to decrease with progression of PCa. Serum total PSA levels correlated tightly with serum PSA-ACT levels. It is suggested that PSA is usually complexed with ACT in the serum. Free/total PSA was useful for differential diagnosis between early cancer and BPH. Levels of serum alpha2M of less than 50 mg/dl in PCa patients may indicate a possibility of bone metastases.

Levels of alpha 2 macroglobulin can predict bone metastases in prostate cancer.

BACKGROUND: In prostate cancer, we previously reported that a marked decrease of serum alpha 2 macroglobulin (alpha 2M) to less than approximately 50 mg/dl was associated with the presence of bone metastases. In order to investigate the relationship between bone metastases and alpha 2M, we assessed these two parameters in 128 patients with prostatic diseases. MATERIALS AND METHODS: 66 patients with untreated benign prostatic hypertrophy and 62 with untreated prostate cancer were included in the study. Measurement of alpha 2M concentration was performed by Laser-Nephelometry, prostate-specific antigen (PSA) by EIA. RESULTS: The serum alpha 2M levels in prostate cancer with bone metastases showed a significantly lower level compared with the group without bone metastases (p < 0.01). Cases with serum alpha 2M levels of less than 50 mg/dl all had bone metastases. Serum alpha 2M levels were inversely related to PSA levels in stage M1b disease. CONCLUSIONS: Measurement of serum alpha 2M levels may be useful for the diagnosis and follow up of bone metastases in prostate cancer.

Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence.

The p16INK4a cyclin-dependent kinase inhibitor is implicated in replicative senescence, the state of permanent growth arrest provoked by cumulative cell divisions or as a response to constitutive Ras-Raf-MEK signalling in somatic cells. Some contribution to senescence presumably underlies the importance of p16INK4a as a tumour suppressor but the mechanisms regulating its expression in these different contexts remain unknown. Here we demonstrate a role for the Ets1 and Ets2 transcription factors based on their ability to activate the p16INK4a promoter through an ETS-binding site and their patterns of expression during the lifespan of human diploid fibroblasts. The induction of p16INK4a by Ets2, which is abundant in young human diploid fibroblasts, is potentiated by signalling through the Ras-Raf-MEK kinase cascade and inhibited by a direct interaction with the helix-loop-helix protein Id1 (ref. 11). In senescent cells, where the Ets2 levels and MEK signalling decline, the marked increase in p16INK4a expression is consistent with the reciprocal reduction of Id1 and accumulation of Ets1.

Involvement of the Oct-1 regulatory element of the gadd45 promoter in the p53-independent response to ultraviolet irradiation.

The gadd45 gene, a growth arrest and DNA damage (gadd)-induced gene, is transcriptionally activated by UV irradiation through two distinct pathways. One requires the sequence-specific binding of the p53 tumor suppressor protein to a responsive element within the third intron of the gadd45 gene, and the other is p53-independent activation of the gadd45 promoter region, although the UV-response element that mediates this has yet to be defined. To investigate the sequences involved in induction of gadd45 by UV irradiation in a p53-independent pathway, we performed mutation analyses of the human gadd45 promoter fused to the luciferase reporter gene in cell lines in which p53 was inactivated. We found that the UV-responsive element was involved in the Oct-1 binding site at -99 bp relative to the transcription start site. Electrophoretic mobility shift assays showed that Oct-1, a transcription factor, bound this element on the gadd45 gene, although the intensity and mobility pattern of the retarded bands were not altered by UV irradiation. These results suggest that the Oct-1 regulatory element might be one of the essential elements involved in the activation of the gadd45 promoter by UV irradiation in a p53-independent pathway.

Selective down-regulation of high-affinity IgE receptor (FcepsilonRI) alpha-chain messenger RNA among transcriptome in cord blood-derived versus adult peripheral blood-derived cultured human mast cells.

Substantial numbers of human mast cells (MCs) were generated from umbilical cord blood (CB) and from adult peripheral blood (PB). A single CB progenitor produced 15 436 MCs, whereas a single PB progenitor produced 807 MCs on average. However, PB-derived MCs were far more active than CB-derived MCs in terms of high-affinity IgE receptor (FcepsilonRI)-mediated reactions. One million sensitized PB-derived MCs released 3.6 microg histamine, 215 pg IL-5, and 14 ng granulocyte macrophage-colony-stimulating factor (GM-CSF), whereas 10(6) sensitized CB-derived MCs released only 0.8 microg histamine, 31 pg IL-5, and 0.58 ng GM-CSF on anti-IgE challenge. However, ionophore A23 187 released similar levels of histamine from the 2 MC types. PB-derived MCs highly expressed surface FcepsilonRI alpha chain, and CB-derived MCs almost lacked it in the absence of IgE. PB-derived MCs expressed approximately 5 times higher levels of messenger RNA (mRNA) for FcepsilonRI alpha chain than CB-derived MCs, but mRNAs for beta and gamma chains of the receptors were equally expressed. Among the approximately 5600 kinds of full-length human genes examined by using the high-density oligonucleotide probe-array system, FcepsilonRIalpha was ranked the fifth most increased transcript in PB-derived MCs. The 4 other increased transcripts were unrelated to MC function. These results suggest that IgE-mediated reactions may be restricted during early infancy through the selective inhibition of FcepsilonRIalpha transcription, which is probably committed at progenitor stages and is, at least in part, cytokine-insensitive.

Heat labile ribonuclease HI from a psychrotrophic bacterium: gene cloning, characterization and site-directed mutagenesis.

The rnhA gene encoding RNase HI from a psychrotrophic bacterium, Shewanella sp. SIB1, was cloned, sequenced and overexpressed in an rnh mutant strain of Escherichia coli. SIB1 RNase HI is composed of 157 amino acid residues and shows 63% amino acid sequence identity to E.coli RNase HI. Upon induction, the recombinant protein accumulated in the cells in an insoluble form. This protein was solubilized and purified in the presence of 7 M urea and refolded by removing urea. Determination of the enzymatic activity using M13 DNA-RNA hybrid as a substrate revealed that the enzymatic properties of SIB1 RNase HI, such as divalent cation requirement, pH optimum and cleavage mode of a substrate, are similar to those of E.coli RNase HI. However, SIB1 RNase HI was much less stable than E.coli RNase HI and the temperature (T(1/2)) at which the enzyme loses half of its activity upon incubation for 10 min was approximately 25 degrees C for SIB1 RNase HI and approximately 60 degrees C for E.coli RNase HI. The optimum temperature for the SIB1 RNase HI activity was also shifted downward by 20 degrees C compared with that of E.coli RNase HI. Nevertheless, SIB1 RNase HI was less active than E.coli RNase HI even at low temperatures. The specific activity determined at 10 degrees C was 0.29 units/mg for SIB1 RNase HI and 1.3 units/mg for E.coli RNase HI. Site-directed mutagenesis studies suggest that the amino acid substitution in the middle of the alphaI-helix (Pro52 for SIB1 RNase HI and Ala52 for E.coli RNase HI) partly accounts for the difference in the stability and activity between SIB1 and E.coli RNases HI.

Mediators for fat-induced ileal brake are different between stomach and proximal small intestine in conscious dogs.

Our aim was to determine the mechanisms by which intraileal fat alters proximal gastrointestinal motility--the ileal brake. Five mongrel dogs with ileal Thiry-Vella fistulas were equipped with strain gauge force transducers on the upper gut to measure contractile activity. Ileal infusions of 115 mmol/L oleic acid and triglyceride were studied in dogs with extrinsically innervated and extrinsically denervated Thiry-Vella loops. Plasma concentrations of peptide YY and total glucagon-like immunoactivity were measured. Oleic acid but not triglyceride inhibited postprandial contractions in the gastric antrum in dogs with innervated and denervated Thiry-Vella loops. Postprandial duodenal and jejunal motility was inhibited by oleic acid regardless of extrinsic denervation to the loops (P <0.05), but triglyceride inhibited small intestinal motility only in dogs with innervated Thiry-Vella loops. Intraileal oleic acid but not triglyceride increased plasma concentrations of peptide YY and total glucagon-like immunoactivity in dogs with innervated and denervated Thiry-Vella loops. Intraileal oleic acid inhibits gastric and small intestinal motility possibly via increased plasma concentrations of peptide YY and enteroglucagon. Intact extrinsic innervation is necessary for intraileal triglyceride to inhibit small intestinal motility.

Chronic diversion of bile to the urinary bladder induces pancreatic growth in dogs.

The aim of this study was to elucidate the mechanism of chronic biliary diversion and its effect on pancreatic growth. In the first part of the study, nine mongrel dogs underwent diversion of bile from the gastrointestinal tract by ligating the common bile duct and interposing a segment of jejunum between the gallbladder and the urinary bladder (cholecystojejunocystostomy [CJC]). Despite the loss of 7% of their body weight at 12 weeks after bilioenteric diversion, CJC dogs had significantly greater pancreatic wet weight than control dogs (51.2 +/- 2.2 g vs. 37.1 +/- 2.2 g). In the second part of the study, six other dogs underwent CJC. Twelve weeks later, bilioenteric continuity was restored by creating a cholecystojejunoduodenostomy (CJD). The dogs were given butter (3 g/kg) by mouth (prior to surgery, 12 weeks after CJC, and 4 weeks after CJD). Pancreatic excisional biopsy specimens were obtained at each operation and at autopsy. CJC induced more pancreatic RNA per milligram of weight (743 +/- 52, CJC; 579 +/- 44, prior to surgery, P <0.05 vs. CJC; 520 +/- 26 microg/100 mg tissue, CJD, P <0.01 vs. CJC), but not more DNA, and significantly higher basal plasma cholecystokinin levels and butter-stimulated cholecystokinin responses when compared with values prior to surgery or following CJD. We conclude that chronic biliary diversion induces pancreatic growth associated with hypersecretion of cholecystokinin in dogs.

An experience of a case with perforation of an aneurysm in the anterior mitral cusp developing after aortic valve replacement.

Mitral valve aneurysm is a rare disease and in Japan, cases of perforation which is considered to be mainly caused by infectious endocarditis is usually only encountered through case reports. We experienced a case who received aortic valve replacement and mitral valve annuloplasty for combined valvular heart disease of aortic insufficiency and mitral insufficiency followed by mitral valve replacement for severe mitral valve regurgitation subsequent to perforation of the anterior mitral cusp, leading to recovery.