Clinical significance of serum glutathione reductase in various clinical conditions, especially in liver diseases.

Serum glutathione reductase activity was measured in various conditions including acute hepatitis, chronic hepatitis, liver cirrhosis, malignant neoplastic diseases, and obstructive jaundice. A statistically significant elevation of the enzyme activity was found in all of these clinical conditions above normal value, especially in patients with acute hepatitis, some liver cancer, and malignant biliary obstruction. Comparison with other liver function tests showed the existence of statistically significant correlations of serum glutathione reductase with SGOT, SGPT and alkaline phosphatase in acute hepatitis, and with alkaline phosphatase in cirrhosis. In parenchymatous liver disease, serial determination was found to be important. High values in obstructive jaundice suggest the malignant obstruction.     

One‐pot radiosynthesis of [13N]urea and [13N]carbamate using no‐carrier‐added [13N]NH3

The aim of this study was to develop a practical labeling method of [¹³N]ligands using no‐carrier‐added [¹³N]NH₃ with high specific activity. [¹³N]urea analogues [¹³N]1a and [¹³N]2a or [¹³N]carbamate [¹³N]3a were synthesized by reacting isocyanate 5a, carbamoyl chloride 6a or chloroformate 7a with [¹³N]NH₃. The precursors 5a–7a were prepared by treating amines 8a and 9a and alcohol 10a with triphosgene in situ. These reaction mixtures were not purified and were used directly for [¹³N]ammonolysis, respectively. Using the one‐pot method, we synthesized [¹³N]carbamazepine ([¹³N]4), a putative positron emission tomography ligand for brain imaging. Copyright © 2009 John Wiley & Sons, Ltd.     

Drug-resistant bacteria isolated from pharyngeal swab cultures and urine in acutely or chronically febrile elderly nursing home inmates

AIM: Patients in nursing homes are becoming more and more elderly and also prone to infectious diseases. It is important to select proper antimicrobial agents in treating such patients because of the increase in drug-resistant bacteria in recent years. METHODS: Pathogenic aerobic bacteria were isolated from cultures of the pharyngeal swab obtained from patients with acute febrile episodes and those with chronic febrile conditions with a repetition of fever or continuing low-grade fever. Isolation of pathogens was also carried out in patients with a urinary tract infection that was resistant to treatment. Isolated bacteria were tested for sensitivity to commonly used antimicrobial agents. RESULTS: Pathogenic bacteria were isolated from 33% of the patients with acute febrile episodes, while they were isolated from 75% of the patients with chronic febrile conditions. The number of major pathogenic bacteria from 85 isolates were methicillin-resistant staphylococcus aureus (MRSA) 13, methicillin-sensitive staphylococcus aureus (MSSA) 6, Streptococcus pneumoniae 8, beta-hemolytic streptococcus 5, Klebsiella pneumoniae 10, and Enterobacter cloacae 6. Only two isolates of Streptococcus pneumoniae were penicillin-sensitive (PSSP), while the others were penicillin-resistant (PRSP) (1) or penicillin-insensitive (PISP) (5). Among these 8 isolates, 5 were resistant to levofloxacin (LVFX). Escherichia coli was isolated from the pharyngeal swab of 2 patients, one of the 2 isolates being resistant to LVFX. Escherichia coli was isolated from 5 patients with urinary tract infection and 5 of the 6 isolates were resistant to LVFX; with one of them being extended spectrum beta-lactamases (ESBL). CONCLUSION: The frequency of isolation of antimicrobial-resistant pathogens was extremely high among elderly patients in our nursing home compared to values reported from a nation-wide survey recently carried out in Japan. In particular, attention should be focused on the resistance of bacteria to fluoroquinolones.     

Radiosynthesis of 13N‐labeled thalidomide using no‐carrier‐added [13N]NH3

Recent studies revealed that thalidomide (1) has unique and broad pharmacological effects on multi‐targets although the application of 1 in therapy is still controversial. In this study, we synthesized nitrogen‐13‐labeled thalidomide ([¹³N]1) as a potential positron emission tomography (PET) probe using no‐carrier‐added [¹³N]NH₃ as a labeling agent. By use of an automated system, [¹³N]1 was prepared by reacting N‐phthaloylglutamic anhydride (2) with [¹³N]NH₃, following by cyclization with carbonyldiimidazole in a radiochemical yield of 56±12% (based on [¹¹N]NH₃, corrected for decay) and specific activity of 49±24 GBq/µmol at the end of synthesis (EOS). At EOS, 570–780 MBq (n=7) of [¹³N]1 was obtained at a beam current of 15 µA after 15 min proton bombardment with a synthesis time of 14 min from the end of bombardment. Using a small animal PET scanner, preliminary biodistribution of [¹³N]1 in mice was examined. Copyright © 2010 John Wiley & Sons, Ltd.     

N-(5-Fluoro-2-phenoxyphenyl)-N-(2-[(131)I]iodo-5-me thoxybenzyl)acetamide: a potent iodinated radioligand for the peripheral-type benzodiazepine receptor in brain

To image the peripheral-type benzodiazepine receptor (PBR) in vivo, we previously developed two positron emission tomography (PET) ligands, N-(2-[11C],5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide ([11C]1a) and its [18F]fluoroethyl analogue ([18F]1b), for the investigation of PBR in the living human brain. This time, using 1a as a leading compound, we designed two novel iodinated analogues, N-(5-fluoro-2-phenoxyphenyl)-N-(2-iodo-5-methoxybenzyl)acetamide (3a) and N-(2,5-dimethoxybenzyl)-N-(5-iodo-2-phenoxyphenyl)acetamide (3b) for the PBR imaging. Ligands 3 were synthesized by the iodination of tributystannyl precursors 10. Radiolabeling for 3 with 131I was carried out by the reaction of 10 with [131I]NaI using H2O2 as an oxidizing agent. In vitro competition experiments determined that 3a exhibited both high affinity and selectivity for PBR (IC50: 7.8 nM) vs CBR (>1 microM). Biodistribution study in mice determined that [131I]3a had a high radioactivity level (1.69% dose/g) in the brain, and its distribution pattern in the brain was consistent with the known distribution of PBR in rodents. Ex vivo autoradiography of the rat brain gave visual evidence that [131I]3a was a potent and specific radioligand for PBR.     

Correction of hyperphosphatemia suppresses cardiac remodeling in uremic rats

Background

Hyperphosphatemia is associated with cardiovascular disease in patients with chronic kidney disease. To examine the effects of correction of hyperphosphatemia, we investigated the association between phosphate metabolism and cardiac remodeling in uremic rats.

Methods

Four groups were studied for 8 weeks: (1) control (sham), (2) 5/6 nephrectomized (Nx) rats fed a normal phosphate regular diet (Nx + NP), (3) Nx rats fed a high phosphate (1.2 %) diet (Nx + HP), and (4) Nx rats fed a high phosphate diet containing 2 % lanthanum carbonate (Nx + HP + La). The relationship between phosphate metabolism and cardiac remodeling was analyzed.

Results

Nx + HP rats showed a significant increase in serum phosphate and PTH compared with Nx + NP rats, while Nx + HP + La rats showed slight decreases in these levels. Both Nx + HP and Nx + HP + La rats showed a significant increase in fibroblast growth factor-23 (FGF23) compared with Nx + NP rats. Urinary phosphate excretion showed a similar trend to that of FGF23. Nx + HP rats showed a significant increase in LV weight and matrix deposition compared with Nx + NP rats, and this increase was also significantly suppressed in Nx + HP + La rats. Serum phosphate levels and PTH were significantly correlated with LV weight and matrix deposition, but FGF23 levels did not show the correlation. FGF23 had a high correlation with urinary phosphate excretion.

Conclusions

These results suggest that correction of hyperphosphatemia by lanthanum carbonate could suppress cardiac remodeling independently of changes in FGF23.     

Correlation Between Splenectomy and Portal Vein Complications in Living Donor Liver Transplantation

Objectives

In adults undergoing living donor liver transplantation (LDLT), the transplanted livers are partial grafts, and the portal venous pressure is higher than that observed with whole liver grafts. In patients undergoing LDLT concomitant with splenomegaly, portal venous flow is often diverted to collateral vessels, leading to a high risk of portal vein thrombosis. In such cases, occlusion of the collateral veins is important; however, complete occlusion of all collaterals without blocking the blood flow through the splenic artery causes portal hypertension and liver failure. We aimed to examine the effect of performing a splenectomy concomitant with LDLT to reduce portal vein complications.

In vivo imaging and quantitative analysis of TSPO in rat peripheral tissues using small-animal PET with [18F]FEDAC

IntroductionThe translocator protein (18 kDa) (TSPO) is widely expressed in peripheral tissues, including the heart, lung, and kidney. Our laboratory developed N-benzyl-N-methyl-2-[7,8-dihydro-7-(2-[¹⁸F]fluoroethyl)-8-oxo-2-phenyl-9H-purin-9-yl]acetamide ([¹⁸F]FEDAC) as a TSPO positron emission tomography (PET) ligand. Here, using small-animal PET with [¹⁸F]FEDAC, we performed TSPO imaging and quantitative analysis of TSPO binding in rat peripheral tissues.MethodsThe in vivo distribution and kinetics of [¹⁸F]FEDAC were measured in rat peripheral tissues (heart, lung and kidney). Using the in vivo pseudo-equilibrium method, TSPO binding parameters [TSPO density (B_max), dissociation constant (K_D)] and receptor occupancy were estimated in these peripheral tissues.Results[¹⁸F]FEDAC was highly distributed in the lung, heart and kidney, and these TSPO-enriched tissues could be clearly visualized. The kinetics of this radioligand in these tissues was rapid, which is suitable for the determination of in vivo TSPO binding parameters and receptor occupancy. The B_max value of TSPO in the heart, lung, and kidney was 393, 141, and 158 pmol/ml, respectively. The K_D value of the radioligand in the heart, lung, and kidney was 119, 36 and 123 nM, respectively. By pretreatment with 5 mg/kg Ro 5-4864 (a TSPO ligand), about 90% of binding sites for TSPO in the heart and lung were occupied. In the kidney, the binding sites were completely occupied by 5 mg/kg Ro 5-4864.Conclusions[¹⁸F]FEDAC is a suitable PET ligand for TSPO imaging and quantitative analysis of TSPO binding in rat peripheral tissues. The utilization of [¹⁸F]FEDAC-PET and the pseudo-equilibrium method can contribute to the study of the TSPO function and evaluate the in vivo binding parameters and receptor occupancy of TSPO therapeutic compounds.     

The Enhancing Effect of Tumour Necrosis Factor-α on Oxidative Stress in Endotoxemia

Abstract: The enhancing effect of tumour necrosis factor-α (TNF-α) on oxidative stress with or without a sublethal dose of endotoxin was examined. The mortality of mice treated with recombinant human TNF-α (1X10⁴ units/mouse, intravenously) and endotoxin (0.01-1 mg/kg, intraperitoneally) was dependent on the dose of endotoxin. The liver lipid peroxide level, superoxide anion generation and serum lactate dehydrogenase activity, especially serum lactate dehydrogenase-5 isozyme leakage, in mice 2-4 hr after administration of recombinant human TNF to endotoxin-pretreated mice (0.5 mg/kg, intraperitoneally) were markedly higher than in those without endotoxin, whereas the administration of recombinant human TNF significantly decreased the non-protein sulfhydryl level, superoxide dismutase and glutathione peroxide activities in the liver of endotoxin-injected mice compared with those in mice treated with recombinant human TNF or endotoxin alone. Furthermore, findings clearly demonstrated that J774A.1 cells stimulated with recombinant human TNF (1X10⁴ units/ml) can effectively produce nitric oxide in the presence of endotoxin, and the production was dependent on the dose of endotoxin (0.01-10 μg/ml). The level of lipid peroxide in mice 4 hr after administration of recombinant human TNF and lead acetate (50 mg/kg, intravenously) was markedly higher than that in the mice treated with recombinant human TNF alone. By contrast, injection of polymyxin-B (20 mg/kg, intraperitoneally, an anti-endotoxin drug) markedly decreased the lipid peroxide level in the liver of the mice treated with recombinant human TNF and lead acetate. These findings suggest that the oxidative stress caused by TNF occurs as a enhancing effect of endotoxion or by bacterial translocation from the intestinal gut under reduction of reticuloendothelial system function in various disease states, and that the effect of TNF may cause a marked increase of toxicity of oxidative stress by endotoxin.     

Extracorporeal shock wave lithotripsy for ureteral stones and cystine stones]

We report our experience with extracorporeal shock wave lithotripsy (ESWL) in the treatment of ureteral and cystine stones, which are known to be difficult to treat by this method. First, in order to determine the effectiveness of the ureteral catheter in the destruction of ureteral stones, we compared the clinical results of 121 patients treated without the catheter and 141 patients inserted with the catheter. There was no significant difference in the success rate between the two groups regardless of stone size, which indicates that the use of the ureteral catheter had no effect on the outcome of treatment. We then studied the clinical results of impacted ureteral stones which are especially difficult to destroy. Excretory urography was performed to non-invasively diagnose these stones, and those without visualization in the ureter below the stone were diagnosed as impacted stones and treated by ESWL without the ureteral catheter. Among the stones with a diameter of 1 to 2 cm, the success rate was significantly lower in impacted stones compared to non-impacted stone. These findings suggest that ESWL treatment without the ureteral catheter may be effective for ureteral stones with a diameter of less than 1 cm and non-impacted stones with a diameter of 1 to 2 cm, while combination therapy with other methods such as TUL may be better for other stones. We also performed ESWL on 6 patients with renal stones and 2 patients with ureteral stones which were cystine stones. Renal stones required an average 4.1 treatment with an average of 1,875 shocks per treatment, and ureteral stones required 1.5 treatment with an average of 1,833 shocks.(ABSTRACT TRUNCATED AT 250 WORDS)