The importance of NAMPT/NAD/SIRT1 in the systemic regulation of metabolism and ageing.

Ageing is associated with a variety of pathophysiological changes, including development of insulin resistance, progressive decline in ß-cell function and chronic inflammation, all of which affect metabolic homeostasis in response to nutritional and environmental stimuli. SIRT1, the mammalian nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylase, and nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting NAD biosynthetic enzyme, together comprise a novel systemic regulatory network, named the 'NAD World', that orchestrates physiological responses to internal and external perturbations and maintains the robustness of the physiological system in mammals. In the past decade, an accumulating body of evidence has demonstrated that SIRT1 and NAMPT, two essential components in the NAD World, play a critical role in regulating insulin sensitivity and insulin secretion throughout the body. In this article, we will summarize the physiological significance of SIRT1 and NAMPT-mediated NAD biosynthesis in metabolic regulation and discuss the ideas of functional hierarchy and frailty in determining the robustness of the system. We will also discuss the potential of key NAD intermediates as effective nutriceuticals for the prevention and the treatment of age-associated metabolic complications, such as type 2 diabetes.

Repeated recurrence of gastric mucosal lesions in rats after a single treatment with compound 48/80, a mast cell degranulator.

We examined the recurrence of gastric mucosal lesions in rats after a single treatment with compound 48/80 (C48/80), a mast cell degranulator. During the period of 0.5 h to 24 h after treatment with C 48/80 (0.75 mg/kg, i.p.), an apparent recurrence of gastric mucosal lesions was found 18 and 24 h after the lesion formation, progression, and recovery occurred during the period of 12 h. Gastric mucosal blood flow showed the maximum reduction at 0.5, 16, and 22 h after treatment followed by the maximum recovery of the decrease at 12, 20, and 24 h, respectively. Gastric mucosal myeloperoxide and xanthine oxidase activities and lipid peroxide content showed the maximum increase at 3, 18, and 24 h after treatment. Gastric mucosal superoxide dismutase activity unchanged after treatment and gastric mucosal catalase activity decreased only at 24 h. Gastric mucosal Se-glutathione peroxidase activity and vitamin E, ascorbic acid, and hexosamine contents showed their maximum decrease at 3, 18, and 24 h after treatment. Gastric mucosal non-protein SH content showed the maximum decrease at 0.5, 16, and 22 h after treatment. Serum histamine and serotonin concentrations increased rapidly after treatment but the increases in serum histamine and serotonin concentrations diminished completely until 12 and 14 h, respectively. These results indicate that lesions recur repeatedly accompanied with an ischemia-reperfusion-like change in blood flow, inflammation, and disruption of antioxidant defense systems in the gastric mucosa of rats in no relation to released histamine and serotonin after a single C48/80 treatment.

Microarray analysis of a reversible model and an irreversible model of anti-Thy-1 nephritis.

A single intravenous injection of anti-Thy-1 monoclonal antibody (mAb) 1-22-3 is known to cause reversible mesangial proliferative glomerulonephritis. However, mAb 1-22-3 injection followed by unilateral nephrectomy leads to progressive glomerulosclerosis and tubulointerstitial change with an irreversible course. To identify genes that play an important role in the irreversible progression of renal injury, we used microarray technology to identify differences in gene expression between these models. Rats were intravenously injected with mAb 1-22-3 1 week after unilateral nephrectomy (irreversible model) or a sham operation (reversible model), and rats were killed on days 4, 7, 14, 42, and 56 after the injection. complementary DNA probes prepared from kidney messenger RNAs were hybridized with oligonucleotide microarrays containing 4854 rat genes. The microarray identified 189 differentially expressed genes, having at least a two-fold difference in expression level between the two models, and they were classified into five clusters. One of the clusters consisted of genes whose expression was markedly upregulated in the irreversible model. This cluster included the genes encoding osteopontin, kidney injury molecule-1, and thymosin beta10. Increased expression of thymosin beta10 was localized mainly in macrophages in the fibrotic interstitium, and upregulation of thymosin beta10 expression was also observed in a unilateral ureteral obstruction model. The microarray analysis yielded information on the molecular mechanisms responsible for the difference in disease progression between the reversible and irreversible model of anti-Thy-1 nephritis. Thymosin beta10 may play an important role in the progression of kidney disease.

Multiple actions of halothane on contractile response to noradrenaline in isolated mesenteric resistance arteries.

Halothane, a volatile anaesthetic, produces systemic hypotension and significantly alters organ blood flow. Isometric force was recorded in isolated rat small mesenteric arteries to investigate its action on contractile response to noradrenaline, the sympathetic neurotransmitter. Halothane (1-5%) enhanced contractile response to noradrenaline in the endothelium-intact arteries, but had little influence in the endothelium-denuded arteries. However, halothane consistently inhibited the noradrenaline response in the endothelium-denuded arteries pretreated with ryanodine (10 microM). The enhancement of the contractile response to noradrenaline in the endothelium-intact arteries was unaffected by treatment with N(G)-nitro L-arginine, tetraethylammonium, apamin, charybdotoxin, indomethacin, diclofenac, nordihydroguaiaretic acid, BQ-123, BQ-788, losartan, ketanserin, or superoxide dismutase. Halothane prolonged vasorelaxation after washout of noradrenaline in the endothelium-denuded arteries. Both ryanodine and vanadate (0.1-0.3 mM), a putative inhibitor of the plasma membrane Ca2+-ATPase, also prolonged the vasorelaxation. Halothane still prolonged the vasorelaxation in the ryanodine-treated arteries, but not in the vanadate-treated arteries. Halothane decreased the pD2 value for the pCa-force relation in the beta-escin-permeabilised, endothelium-denuded arteries. Halothane appears to influence contractile response to noradrenaline through multiple actions including endothelium-dependent enhancing, endothelium-independent enhancing, and endothelium-independent inhibitory actions. Nitric oxide, endothelium-derived hyperpolarising factor, cyclooxygenase products, lipoxygenase products, endothelin-1, angiotensin-II, serotonin, and superoxide anions are not involved in the endothelium-dependent enhancement. The endothelium-independent enhancement is presumably due to its ability to stimulate Ca2+ release from the ryanodine-sensitive intracellular stores, while the endothelium-independent inhibition is due, at least in part, to depressed Ca2+-activation of contractile proteins. Halothane may inhibit the plasma membrane Ca2+-ATPase of vascular smooth muscle cells.

Reliability of fingertip skin-surface temperature and its related thermal measures as indices of peripheral perfusion in the clinical setting of the operating theatre.

During the perioperative period, evaluation of digital blood flow would be useful in early detection of decreased circulating volume, thermoregulatory responses or anaphylactoid reactions, and assessment of the effects of vasoactive agents. This study was designed to assess the reliability of fingertip temperature, core-fingertip temperature gradients and fingertip-forearm temperature gradients as indices of fingertip blood flow in the clinical setting of the operating theatre. In 22 adult patients undergoing abdominal surgery with general anaesthesia, fingertip skin-surface temperature, forearm skin-surface temperature, and nasopharyngeal temperature were measured every five minutes during the surgery. Fingertip skin-surface blood flow was simultaneously estimated using laser Doppler flowmetry. These measurements were made in the same upper limb with an IV catheter (+ IV group, n=11) or without an IV catheter (-IV group, n=11). Fingertip blood flow, transformed to a logarithmic scale, significantly correlated with any of the three thermal measures in both the groups. Their rank order as an index of fingertip blood flow in the -IV group was forearm-fingertip temperature gradient (r=-0.86) > fingertip temperature (r=0.83) > nasopharyngeal-fingertip temperature gradient (r=-0.82), while that in the +IV group was nasopharyngeal-fingertip temperature gradient (r=-0.77) > fingertip temperature (r=0.71) > forearm-fingertip temperature gradient (r=-0.66). The relation of fingertip blood flow to each thermal measure in the -IV/group was stronger (P<0.05) than that in the +IV group. In the clinical setting of the operating theatre, using the upper limb without IV catheters, fingertip skin-surface temperature, nasopharyngeal-fingertip temperature gradients, and forearm-fingertip temperature gradients are almost equally reliable measures of fingertip skin-surface blood flow.

Intraoperative changes in arterial oxygenation during volume-controlled mechanical ventilation in modestly obese patients undergoing laparotomies with general anesthesia.

BACKGROUND: In obese patients, arterial oxygenation can be greatly impaired during general anesthesia. Both avoidance of denitrogenation and application of positive end-expiratory pressure (PEEP) during mechanical ventilation may be effective in preventing such impairment of arterial oxygenation. METHODS: We studied 28 obese/overweight and seven non-obese (BMI < 25 kg x m-2) patients who underwent laparotomies with general anesthesia (i.e. isoflurane with or without nitrous oxide). During anesthesia, their lungs were mechanically ventilated at a rate of 10 breaths x min-1 with a constant flow, inspiratory-to-expiratory ratio 1 : 2, and tidal volume approximately 10 ml x kg-1. The obese/overweight patients were allocated to four different groups in terms of denitrogenation and application of PEEP (7 cm H2O) during the ventilation (n = 7 each). In the non-obese patients, their denitrogenated lungs were ventilated without application of PEEP. Arterial gas analyses were performed before induction of anesthesia, and 30, 90, 150 and 210 min after tracheal intubation. The ratio of PaO2 to FiO2 was calculated as an index of arterial oxygenation. RESULTS: No significant changes in the PaO2/FiO2 ratio were observed throughout the study in the non-obese patients and in the obese/overweight patients whose non-denitrogenated lungs were ventilated with PEEP. In the obese/overweight patients whose lungs were ventilated after denitrogenation or without application of PEEP, significant decreases in the PaO2/FiO2 ratio were observed 30 and 90 min after tracheal intubation. CONCLUSIONS: In obese or overweight patients under general anesthesia, it may be advisable to avoid denitrogenation and apply PEEP during mechanical ventilation in order to minimize the impairment of arterial oxygenation.

Chemical structure of a novel aminophospholipid from Hydrogenobacter thermophilus strain TK-6.

The phospholipid composition of Hydrogenobacter thermophilus strain TK-6, an obligately chemolithoautotrophic, extremely thermophilic hydrogen bacterium, was analyzed. Two of four phospholipids detected from the strain were assumed to be phosphatidylinositol and phosphatidylglycerol. An aminophospholipid named PX, whose content among the phospholipids was 65%, was found to have a novel chemical structure by analysis of the dilyso form with nuclear magnetic resonance and fast atom bombardment-mass spectrometry (FAB-MS) and by analysis of the intact PX with FAB-MS as 1,2-diacyl-3-O-(phospho-2'-O-(1'-amino)-2',3',4',5'-pentanetetrol)-sn-glycerol. Structurally similar phospholipids have been identified in Methanospirillum hungatei, Methanolacinia paynteri, and Methanogenium cariaci, which all belong to the Archaea.

Domestic violence and women's mental health in Japan.

There are positive changes in both the social and legal understanding of domestic violence in Japan. However, the scope of the problem has not been investigated in depth and described in the Japanese nursing literature. This descriptive study of a random sample of 177 women investigated domestic violence and the relationship between domestic violence and the mental health of the victims. Sixty-seven per cent of the female respondents reported having experiences of physical, psychological and/or sexual abuse. Forty-seven per cent of the abused women achieved statistically significant General Health Questionnaire scores that indicated clinical depression or anxiety. The findings of this study will enable Japanese nurses to better assess and intervene on behalf of their patients. In addition, avenues for further nursing research are suggested.

EUS-guided one-step drainage of pancreatic pseudocysts: experience in 3 patients.

BACKGROUND: EUS-guided drainage has been recognized as a nonsurgical treatment for pancreatic pseudocysts. Bleeding at the puncture site is a known complication of this procedure. This is a report of the use of new equipment for one-step drainage without the use of an electrosurgical needle. METHODS: EUS-guided cystoenterostomy was performed in 3 patients. The mean size of the pseudocysts was 8 cm (head = 1, body = 2). A needle and drainage tube were inserted in a one-step procedure into the cyst through the accessory channel of an echoendoscope under EUS. The drainage tube was released immediately after insertion. OBSERVATIONS: All 3 patients were treated successfully without complication. A drainage tube was inserted through the duodenal bulb (n = l) and the body of the stomach (n = 2). The drain was removed after 1 month in all patients. Two of the 3 drains were obstructed by sludge. One pseudocyst recurrence was observed at a mean follow-up of 3.6 months (range 2-6 months). CONCLUSIONS: The EUS-guided one-step system is simple to use and suitable for drainage of pancreatic pseudocysts. It appears to minimize the risk of hemorrhage.

Long-term persistence of cellular immunity to Oka vaccine virus induced by pernasal co-administration with Escherichia coli enterotoxin in mice.

A mutant of Escherichia coli enterotoxin induced cellular immunity to a live varicella vaccine (the Oka strain) as a mucosal adjuvant in mice. The persistence of this cellular immunity was investigated. A commercially available live Oka vaccine virus and toxin were administered once simultaneously via the nasal route, in mice. Ten or 12 months later, a delayed-type hypersensitivity to the vaccine virus was detected by footpad test, but an antibody neutralizing the varicella-zoster virus was not. When spleen cells from mice immunized with the vaccine and toxin were re-stimulated by live vaccine in vitro, their thymidine uptake and IL-2 production were higher than those from mice immunized with the vaccine alone, but lower than those of spleen cells prepared from mice 2 months after nasal administration. Production of IL-4 in these cells, however, was not induced by re-stimulation in vitro. These results suggest that although humoral immunity for Oka vaccine virus is only weakly induced by one co-administration of the vaccine and toxin, cellular immunity is induced and maintained over 1 year, though it declines with age. The nasal administration of the vaccine and toxin might be effective for maintaining cellular immunity to the varicella-zoster virus long term.

Preventive effect of ebselen on acute gastric mucosal lesion development in rats treated with compound 48/80.

The preventive effect of ebselen, a seleno-organic compound, which is known to possess glutathione peroxidase-like activity and antioxidative and anti-inflammatory properties, on the development of acute gastric mucosal lesions was examined in rats with a single injection of compound 48/80 (0.75 mg/kg, i.p.), a mast cell degranulator. Pre-administration of ebselen (p.o.) at a dose of 50 or 100 mg/kg, but not 10 mg/kg, prevented gastric mucosal lesion development at 3 h, but not gastric mucosal lesion formation at 0.5 h, after compound 48/80 injection, although any dose of pre-administered ebselen did not affect decreased gastric mucosal blood flow and increased serum serotonin and histamine concentrations found at 0.5 and 3 h after compound 48/80 injection. A decrease in Se-glutathione peroxidase activity and increases in the activities of myeloperoxidase, an index of tissue neutrophil infiltration, and xanthine oxidase and the concentration of thiobarbituric acid reactive substances, an index of lipid peroxidation, were found in gastric mucosal tissues at 0.5 h after compound 48/80 injection and these changes were further enhanced at 3 h. Pre-administration of ebselen (p.o.) at a dose of 50 or 100 mg/kg, but not 10 mg/kg, attenuated all these changes found at 3 h after compound 48/80 injection. These preventive effects of ebselen occurred in a dose-dependent manner. The present results indicate that pre-administered ebselen prevents the development of compound 48/80-induced acute gastric mucosal lesions in rats, and suggest that this preventive effect of ebselen could be due to its glutathione peroxidase-like activity and antioxidative and anti-inflammatory properties.

Teprenone promotes the healing of acetic acid-induced chronic gastric ulcers in rats by inhibiting neutrophil infiltration and lipid peroxidation in ulcerated gastric tissues.

Teprenone, an anti-ulcer drug, has been reported to promote the healing of acetic acid-induced chronic gastric ulcers in rats by stimulating gastric mucus synthesis and secretion. Recently, it has been implicated that neutrophil infiltration and lipid peroxidation in ulcerated gastric tissues have an inhibitory effect on the healing of acetic acid-induced chronic gastric ulcers in rats. Therefore, we attempted to clarify whether teprenone exerts a healing-promoting effect on acetic acid-induced chronic gastric ulcers through its inhibitory effect on neutrophil infiltration and lipid peroxidation in ulcerated gastric tissues. In rats with chronic gastric ulcers made by applying acetic acid to the stomach, gastric ulcer healing started later than 3 days after the acetic acid application. Gastric mucosal myeloperoxidase (MPO) activity, an index of tissue neutrophil infiltration, and lipid peroxide content were higher in the ulcerated region than in the intact region on the 8th, 15th, and 22nd day after the acetic acid application. Gastric mucosal non-protein SH content was lower in the ulcerated region than in the intact region on the 8th, 15th, and 22nd day after the acetic acid application, and gastric mucosal adherent mucus content was lower in the ulcerated region than in the intact region on the 8th and 15th day. Daily oral administration of teprenone (100 mg kg(-1)x 2) for 7 or 14 days, starting on the 8th day after the application of acetic acid to the stomach, enhanced the reduction of the ulcer area with attenuation of all these biochemical changes found in the ulcerated region. The teprenone administration caused a decrease in MPO activity and an increase in adherent mucus content in the gastric mucosa of the intact region. These results suggest that the healing-promoting effect of teprenone on acetic acid-induced chronic gastric ulcers in rats could be due not only to stimulation of gastric mucus secretion but also to inhibition of neutrophil infiltration and enhanced lipid peroxidation in the ulcerated gastric tissue.

[Long-term outcome after extracorporeal shock wave lithotripsy for gallstones].

We retrospectively reviewed 289 cases followed for a long time after extracorporeal shock wave lithotripy (ESWL) for gallstones. Follow-up periods ranged from 0.5 years to 9.2 years, with a median of 4.1 years. The complete resolution rate was 45.6%. A solitary gallstone, non-calcified gallstones on CT, and Tsuchiya's sonographic type Ia and Ib gallstones were found to be statistically significant variable for resolution of the disease. With a maximum follow-up period of 9 years, the cumulative recurrence rate was 30.7%. Among the 156 patients whose gallstones did not resolve, 70 were symptomatic and the other 86 were asymptomatic. Thirty-eight of the symptomatic patients (54.3%) became symptom-free, while 23 asymptomatic patients (29.1%) became symptomatic. The cumulative rate of occurrence of colic attacks and/or acute cholecystitis was significantly higher in the cases with lithotripsy fragments 4 mm or more in size than in the cases wih fragments 3 mm or less in size (51.8% vs. 16.7%; p < 0.05). ESWL was followed by surgery in 23.1% because symptoms developed or became aggravated after ESWL in 58.3% of them. Gallbladder cancer was discovered in one case. Patients undergoing ESWL should be followed by focusing on postoperative recurrence, symptoms, and gallbladder cancer.

Volume measurement using tissue characterization of three-dimensional endoscopic ultrasonographic images.

BACKGROUND AND STUDY AIMS: Although it is time-consuming to measure the volume of lesions using three-dimensional endoscopic ultrasonography (3D-EUS), the technique is suitable for tissue characterization, as it allows images of multiple areas to be obtained simultaneously in uniform conditions. The present study tested automatic volume measurement using tissue characterization based on 3D-EUS. MATERIALS AND METHODS: Nine polygonal sections of resected spleen (volume 0.66 +/- 0.19 cm3) were immersed in water, and 40 radial 3D-EUS images were obtained. For tissue characterization, the methods of co-occurrence matrix and gray-level difference and discriminant analysis were used. Each spleen section was also measured using 3D-EUS. The volume of tissue identified as spleen using tissue characterization and the volume calculated on the basis of the 3D-EUS images were both compared with the actual volume measured beforehand. Measurements using tissue characterization and 3D-EUS were carried out for every third image. In three clinical cases of cancer the volume of the lesion was measured using tissue characterization and 3D-EUS. RESULTS: The mean volume of the nine splenic sections estimated using tissue characterization was 1.2 +/- 0.41 cm3 (mean +/- SD), while the mean volume estimated with 3D-EUS imaging was 1.1 +/- 0.30 cm3 (mean +/- SD). The volumes measured using tissue characterization were on average 13% larger than those obtained with 3D-EUS. Linear regression analysis showed a high degree of correlation between the two sets of measurements (r=0.97, P<0.00005), and also showed a high correlation between the volumes obtained using tissue characterization and the actual volume (r=0.93, P<0.0005). However, the volumes calculated using 3D-EUS images were larger than the actual volume (61% on average), and the volumes estimated using tissue characterization were also greater than the actual volume. The overestimation reflected the fact that measurement was only carried out in every third 3D-EUS image. In the clinical cases, the mean value for "true" tumor tissue as determined on EUS imaging represented 73% of the volume interpreted as cancer using tissue characterization. CONCLUSIONS: There was a good correlation between the volume measured with 3D-EUS and the volume obtained using tissue characterization. The tissue characterization volumes were only relatively slightly larger than the volumes measured using 3D-EUS, suggesting that there may be some promise for this application of tissue characterization.

[Evaluation of chemotherapy for gastric cancer by endoscopic ultrasonography].

We judged the efficacy of chemotherapy using endoscopic ultrasonography (EUS) in 26 cases of gastric cancer. Treatment efficacy was evaluated according to the General Rules for the Gastric Cancer Study, based on the reduction of the largest cross-sectional area of the tumor. A reduction of over 50% was rated as U-PR and a reduction of -25-50% was rated as U-NC. Our findings showed U-PR in 11 cases and U-NC in 15 cases. Three cases initially considered to be NC according to the rules were judged to be U-PR based on EUS findings. Marked therapeutic efficacy in these 3 cases was demonstrated clinically and this was confirmed by EUS findings. Generalized Wilcoxon test showed a significant difference in the cumulative survival rate between U-PR and U-NC cases (p < 0.05). EUS provides an objective means of evaluating the efficacy of chemotherapy in gastric cancer patients, including those with lesions that cannot be evaluated by the General Rules for the Gastric Cancer Study.

Purification and characterization of membrane-bound hydrogenase from Hydrogenobacter thermophilus strain TK-6, an obligately autotrophic, thermophilic, hydrogen-oxidizing bacterium.

A membrane-bound hydrogenase was purified to electrophoretic homogeneity from the cells of Hydrogenobacter thermophilus strain TK-6, an obligately autotrophic, thermophilic, hydrogen-oxidizing bacterium. Solubilization and purification were done aerobically in the presence of Triton X-100. Three chromatography steps were done for purification; Butyl-Sepharose, Mono-Q, and Superose 6, in this order. Purification was completed with 6.73% yield of total activity and with 21.4-fold increase of specific activity when compared with the values for the membrane fraction. The purified hydrogenase was shown to be a tetramer with alpha2beta2 structure, with a molecular mass of 60,000 Da for the large subunit and 38,000 Da for the small subunit. The purified hydrogenase directly reduced methionaquinone with an apparent Km of around 300 microM and with a turnover number around 2900 (min(-1)). Metal analysis and EPR properties of the hydrogenase have shown that the enzyme is one of the [NiFe]-hydrogenases. Also, optimum pH and temperature for reaction, thermal stability, and electron acceptor specificity were reported. Finally, a model is presented for energy and central metabolism of H. thermophilus strain TK-6.