11C-AC-5216: a novel PET ligand for peripheral benzodiazepine receptors in the primate brain.

Developing a PET ligand for imaging of the peripheral benzodiazepine receptor (PBR; Translocator Protein [18 kDa] TSPO) is of great importance for studying its role in glial cells in the injured brain and in neurodegenerative disorders, such as Alzheimer's disease. The aim of this study was to synthesize and evaluate N-benzyl-N-ethyl-2-(7-(11)C-methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl)acetamide ((11)C-AC-5216) as a PET ligand for imaging PBR in the primate brain. METHODS: AC-5216 and its desmethyl precursor (compound 1) were synthesized starting from commercially available compounds. The radiosynthesis of (11)C-AC-5216 was performed through the reaction of compound 1 with (11)C-CH(3)I in the presence of NaH. The in vivo brain regional distribution was determined in mice (dissection) and a monkey (PET). RESULTS: (11)C-AC-5216 (800-1,230 MBq; n = 25) was obtained with a radiochemical purity of 98% and a specific activity of 85-130 GBq/mumol at the end of synthesis. After injection of (11)C-AC-5216 into mice, a high accumulation of radioactivity was found in the lungs, heart, adrenal glands, and other PBR-rich organs. In the mouse brain, high radioactivity was observed in the olfactory bulb and cerebellum. Radioactivity in these regions was inhibited by nonradioactive AC-5216 or PK11195 but was not decreased by central benzodiazepine receptor-selective flumazenil and Ro15-4513. A PET study of the monkey brain determined that (11)C-AC-5216 had a relatively high uptake in the occipital cortex, a rich PBR-dense area in the primate brain. Pretreatment with nonradioactive AC-5216 and PK11195 reduced the radioactivity of (11)C-AC-5216 in the occipital cortex significantly, suggesting its high specific binding with PBR in the brain. Metabolite analysis demonstrated that (11)C-AC-5216 was stable in vivo in the mouse brain, although it was metabolized in the plasma of mice and the monkey. CONCLUSION: (11)C-AC-5216 is a promising PET ligand for imaging PBR in rodent and primate brains.     

Palliative treatment of bone metastases in hormone-refractory prostate cancer: effects of pamidronate on the carboxyterminal telopeptide of type-I collagen level in patients with increasing prostate-specific antigen levels

PURPOSE: Bisphosphonates have been reported to be effective in reducing bone pain and skeletal-related events associated with bone metastases in hormone-refractory prostate cancer (HRPC). However, whether bone resorption is reduced primarily by these particular drugs is difficult to evaluate because patients with HRPC are usually treated with secondary or tertiary hormonal manipulations including second-line antiandrogens, high-dose diethylstilbestrol, or low-dose dexamethasone therapies, some of which may also be effective. Thus, we assessed changes in the level of the carboxyterminal telopeptide of type-I collagen (ICTP), a bone resorption marker, before and after pamidronate administration in HRPC patients with increasing prostate-specific antigen (PSA) levels. PATIENTS AND METHODS: Twenty-one HRPC patients with bone metastases and increasing PSA levels were intravenously treated with pamidronate at a dose of 30 mg either every 2 or every 4 weeks. Pamidronate administration was started immediately after confirmation of three consecutive increases in the PSA level. RESULTS: In 14 patients (67%), the ICTP levels decreased after the administration of pamidronate, despite increasing PSA levels. In 7 of these cases, the ICTP levels were lower than those recorded for 6 months or longer before the start of pamidronate administration. The characteristics of the responders were compared with those of the non-responders. CONCLUSION: In 67% of the HRPC patients with increasing PSA levels, pamidronate reduced the accelerated turnover of bone metabolism caused by metastases of prostate cancer.     

Treatment of respiratory and urinary tract infections in elderly inmates at a nursing home by selective antimicrobial agents based on the sensitivity of the isolated bacteria

OBJECTIVES: Elderly patients living in nursing homes can easily find themselves unable to carry out their daily activities, once they become ill, even with infectious diseases of a slight to mild degree, and rapid treatment is required to cure them of their malaise. However, treatment is often difficult due to the presence of drug-resistant bacteria. This study was designed to evaluate the efficacy of the selective use of antimicrobial agents based on a sensitivity test of isolated bacteria. METHODS: Possible pathogenic bacteria were isolated from cultures of pharyngeal swabs or urine obtained from patients with chronic febrile conditions or urinary tract infections, resistant to antimicrobial treatment. The efficacy of the treatment was evaluated based on release from febrile conditions and improvement of activities of daily living (ADL) accompanied by the disappearance of possible pathogenic bacteria following the use of selective antimicrobial agents. RESULTS: The outcome of 14 cases with sustaining febrile conditions and 3 cases with urinary tract infections was reviewed. Most of them showed a good response to treatment with remarkable improvement in ADL. In some cases, patients were switched from one antimicrobial agent to another each time new pathogenic bacteria were detected in the culture. A combination of rifampicin and sulfamethoxazole/trimethoprim (RFP/ST) was found to be the most convenient and effective treatment in patients with MRSA or drug-resistant Streptococcus pneumoniae. Levofloxacin (LVFX)-resistant Escherichia coli were detected together with MRSA in our 3 patients with urinary tract infections, corresponding to the frequent use of LVFX in our community. CONCLUSIONS: Identification of possible pathogenic bacteria and the use of proper antibiotic agents based on a sensitivity test are very effective in the treatment of elderly patients with chronic febrile conditions arising from the presence of drug-resistant bacteria. Careful use of fluoroquinolones is required in patients in whom MRSA is or had once been detected. This is beneficial not only for the elderly patients themselves but is also useful in preventing the spread of drug-resistant bacteria.     

How to introduce radioactive chlorine into a benzene ring using [*Cl]Cl(-)?

The aim of this study was how to introduce radioactive chlorine (*Cl) isotope into a benzene ring to afford *Cl-labeled chlorobenzene ([*Cl]1). Using tributylphenylstannyl compound (2) as a starting material, we determined two routes for introducing *Cl into the benzene ring: reaction of [*Cl]Cl(-) with 2 in the presence of chloramine-T and nucleophilic reaction of [*Cl]Cl(-) with diphenyliodonium tosylate (3). The two routes provide suitable tools to prepare [*Cl]1 without electron-abstracting group in the benzene ring.     

Correlations of asthma mortality with traffic-related factors: use of catalytic converters and radial tires

OBJECTIVE:: The objective of this study was to test the hypotheses that the post-1970 rise in asthma mortality in industrialized nations was related to introduction of catalytic converters and/or radial tires. METHODS:: Annual asthma mortality data were plotted on linear coordinates for fraction of automobile fleet with converters or radial tires in Canada, Germany, Japan, and the United States. RESULTS:: Catalytic converter association could not account for asthma mortality that rose in Germany before general adoption of the technology there. Radial tire use was, however, linearly correlated with asthma mortality in all four countries. CONCLUSION:: Rising exposure to materials related to radial tire use may account for a substantial fraction of increased asthma mortality risk since approximately 1970.     

Living-Donor Kidney Transplantation With Laparoscopic Nephrectomy From a Donor With Horseshoe Kidney: A Case Report

BackgroundIn living-donor kidney transplantation, laparoscopic nephrectomy from a donor has become widespread. However, more careful treatment is required for nephrectomy from a donor with horseshoe kidney. This report presents an interesting surgical case of laparoscopic nephrectomy from a donor with horseshoe kidney.Case presentationA woman aged 53 years was a donor candidate for living-donor kidney transplantation for her husband. She had no medical history and had no problems on preoperative examination, but contrast-enhanced computed tomography revealed that she had horseshoe kidney. As the isthmus was thin and the contrast effect was poor, the isthmus was considered to have poor kidney parenchyma and consisted almost exclusively of fibrous tissue. Therefore, laparoscopic nephrectomy was performed for the donor. On the basis of the 99m Tc-dimercaptosuccinic acid renal scintigraphy results, the right kidney was collected. A laparoscopic nephrectomy with a retroperitoneal approach was performed using GelPort access platforms in a right abdominal incision with an accessory port. We firmly expanded the isthmus and then dissected it just above the aorta using a linear stapling device. Subsequently, we sutured a renal artery and vein with linear stapling devices. The recipient's surgery was also performed without any problems, and the postoperative course of both donor and recipient was good.ConclusionsWe suggest that even if the donor has horseshoe kidney, laparoscopic donor nephrectomy should be actively considered depending on the thickness of the isthmus of the horseshoe kidney.     

Induction of cellular senescence in a telomerase negative human immortal fibroblast cell line,LCS-AF.1-3, by human chromosome 6

In immortal cells (LCS-AF.1-3) which originated from cultured skin fibroblasts from a patient with Li-Fraumeni syndrome, a specific deletion has been identified on chromosome 6. To examine the relationship between this deletion and the loss of function in aging genes, we performed microcell mediated chromosome transfer (MMCT) of normal human chromosome 6 into LCS-AF.1-3 cells and analyzed their characteristics. Transferred human chromosome 6 induced morphological changes in the cells and cellular senescence with growth suppression. In a revertant clone that had escaped from induced senescence, a specific deletion was found at D6S309 in the transferred chromosome 6. High molecular weight telomeric sequences were lost in a clone that had been induced to senescence by introduction of human chromosome 6. On the other hand, human chromosome 7 induces senescence in immortal cells by suppressing the alternative lengthening of telomere (ALT) mechanism. We also performed MMCT of chromosome 7 and discuss the effect of chromosome transfer by comparing the two chromosomes. LCS-AF.1-3 cells containing a transferred chromosome 7 showed no changes in immortality. These results suggest that genes which are new candidates for aging and which suppress the ALT mechanism are located in the region D6S309 in human chromosome 6.     

Role of renin-angiotensin system and nuclear factor-kappaB in the obstructed kidney of rats with unilateral ureteral obstruction

The present study was conducted to elucidate the role of oxidative stress and nuclear factor-kappaB (NF-kappaB) in the beneficial effects of angiotensin receptor blockade on obstructive nephropathy. Unilateral ureteral occlusion in rats elicited tubulo-interstitial fibrosis with concomitant macrophage infiltration and increased expression of monocyte chemoattractant protein-1. These changes were accompanied by an induction of renal cortical lipid peroxidation and activation of NF-kappaB. Both an AT(1) antagonist, candesartan, and a NF-kappaB inhibitor, pyrrolidine dithiocarbamate, markedly attenuated these changes and to a similar extent. These results suggest that the beneficial effects of angiotensin blockade are mediated by the inhibition of oxidative stress and subsequent NF-kappaB activation in obstructive nephropathy.     

Evaluation of 4'-[methyl-14C]thiothymidine for in vivo DNA synthesis imaging.

We evaluated 4'-[methyl-11C]thiothymidine ([methyl-11C]S-dThd) to obtain a thymidine analog that might prove simpler to use for imaging DNA synthesis and that might follow the same biochemistry as its surrogate. METHODS: [Methyl-14C]S-dThd was synthesized by rapid methylation of 5-trimethylstannyl-4'-thio-2'-deoxyuridine via a palladium-mediated Stille coupling reaction with 14C-methyl iodide. Degradation of [methyl-14C]S-dThd, when incubated in human blood, was analyzed by high-performance liquid chromatography (HPLC). The in vivo potential of [methyl-14C]S-dThd was evaluated by studying its distribution in EMT-6 mammary carcinoma-bearing mice. 2-Fluoro-2'-deoxycytidine, a potent inhibitor of DNA synthesis, was used to modulate cell proliferation. Tissue extraction was also performed to investigate the incorporation of [methyl-14C]S-dThd into DNA. RESULTS: [Methyl-14C]S-dThd was obtained in a 31%-41% radiochemical yield (calculated from 14C-methyl iodide) at 130 degrees C, 5-min reaction in N,N-dimethylformamide followed by semipreparative HPLC purification. The radiochemical purity of [methyl-14C]S-dThd was >99% and the specific activity was 2.04 GBq/mmol (according to the specific activity of 14C-methyl iodide). [2-14C]Thymidine, when incubated with human blood, demonstrated rapid degradation. In contrast, [methyl-14C]S-dThd was stable with <3% degradation at 60 min. An in vivo distribution study showed the accumulation of radioactivity in proliferating tissues (spleen, thymus, duodenum, and tumor). On the other hand, the radioactivity of nonproliferating tissues (lung, liver, kidney, and muscle) was rapidly cleared in parallel with the clearance of blood radioactivity. The tumor uptake of [methyl-14C]S-dThd was high (8.8 percentage injected dose per gram at 60 min) and selective (tumor-to-blood ratio, 12.2 at 60 min). 2-Fluoro-2'-deoxycytidine pretreatment significantly reduced the tumor uptake of [methyl-14C]S-dThd. Relative blood flow as measured by the uptake of 4-[N-methyl-14C]iodoantipyrine was similar between the treated and untreated groups. Tissue extraction studies showed that most of the total tissue radioactivity of rapidly proliferating tissues was recovered in the DNA fraction at 60 min after [methyl-14C]S-dThd injection. CONCLUSION: The labeling procedure is rapid and suitable for 11C labeling. Positron-labeled 4'-thiothymidine should be useful for imaging DNA synthesis by PET.