Comparison of99mTc-tetrofosmin uptakes on planar images with those in excised rats organs with those in excised rats organs

The radioactivity in the organs adjacent to the heart causes interference with the quantitative assessment of myocardial uptake of tracer on scintigraphy. In order to investigate how much the functions of these organs affect myocardial uptake seen in imaging, we compared the myocardial uptake measured by means of a gamma camera with the actual activity in the excised organs. Methods: Thirty-three rats were imaged at 5, 10, 15, 30, 45, 60, 90 and 120 min after the administration of 99mTc-tetrofosmin, and % injected dose per pixel (%ID/pixel) for each organ was assessed on planar images (PI measurement). Percent injected dose per gram of tissue (%ID/g) in the heart as well as lungs, liver, gastrointestines and blood was measured by means of a well scintillation counter (WC measurement). Comparison between PI and WC measurements was performed with % uptake, the PI-to-WC ratio and heart-to-organ ratios. Results: Our WC measurement showed an increase in cardiac uptake until 30 min (1.67 +/- 0.31%) postinjection and subsequent gradual decrease, whereas PI measurement showed maximum activity of 1.81 +/- 0.52% at 15 min postinjection. There was a prominent difference between the two measurements, particularly at 10 min, with a PI/WC ratio of about 1.6 times. Our WC measurement showed maximum pulmonary uptake at 15 min (0.87 +/- 0.31%) and a gradual decrease over 15 min, whereas PI measurement showed maximum uptake at 10 min (1.14 +/- 0.38%). There was hardly any variation in activity observed later than at 10 min. Our WC measurement showed hardly any variance in hepatic activity from 5 min (0.77 +/- 0.19%) to 30 min (0.69 +/- 0.27%) with a subsequent gradual decrease. The percent uptake in PI measurement was generally greater than that in WC measurement, and high values were found at 10 min and 15 min with PI/WC ratios of about 3.3 times and 2.3 times, respectively. Conclusion: Percent uptakes in PI measurement were greater than those in WC measurement. The difference between the two measurements was prominent in the early phases. The cardiac uptake in PI measurement was significantly greater than that in WC measurement at 10 min. It was considered that this discrepancy between the two measurements was caused by the Compton scatter from the organs adjacent to the heart.     

Striatal dopamine turnover during treadmill running in the rat: Relation to the speed of running

HATTORI, S., M. NAOI AND H. NISHINO. Striatal dopamine turnover during treadmill running in the rat: Relation to the speed of running. BRAIN RES BULL 35(1) 41–49, 1994.—To evaluate the physiological action of Striatal dopamine (DA) in exercise, rats were trained to run on a straight treadmill. Extracellular DA and its metabolites, dihydroxyphenylacetic acid (DO-PAC), and homovanillic acid (HVA) were measured by in vivo microdialysis, and striatal tissue tyrosine hydroxylase (TH) activity and monoamine oxidase (MAO) activity were measured using high performance liquid chromatography (HPLC) and spectrophotometer. DA turnover was increased by running, and the increase in DOPAC and HVA was closely related to the speed of running, while the increase in DA had no relationship to the speed. The threshold for the increase in DA, DOPAC, and HVA was between 300 and 660 cm/min. Striatal tissue TH activity was elevated up to 135% of basal values after the rats were trained for 7 days to run at 1800 cm/min. Just after running for 20 min, there was a further increase to 180%. These values became 150% and 90% of basal values at 2 h and 6 h, showing a similar time course as DA detected by microdialysis. MAO-B activity increased up to 160% of basal values after 7 days training but decreased to 130% and 110% just after and 2 h after running, then increased to 145% 6 h after running. MAO-A showed a similar variation as MAO-B. These data suggest that both the synthesis and metabolism of DA have a close relationship with physical exercise and might contribute to adjusting extracellular DA levels within an adequate range in response to exercise intensity.     

A potent apoptosis-inducing activity of a sesquiterpene lactone, arucanolide, in HL60 cells: a crucial role of apoptosis-inducing factor

Six main sesquiterpene lactones (germacranolides) from Calea urticifolia were evaluated for in vitro cytotoxicity against human tumor cell lines HL60 and SW480 cells. Among them, arucanolide and parthenolide displayed marked cytotoxicity against both cell lines. Arucanolide exhibited a low IC(50) in HL60 cells. The cytotoxic activity of arucanolide was observed at lower concentrations compared to that of parthenolide, which has been reported to be a typical and simple germacranolide. The activity was found to be mainly due to apoptosis that was assessed by morphological findings, DNA ladder formation (24 - 36 h), and flow cytometric analysis in HL60 cells. Western blotting and an apoptosis inhibition assay using caspase inhibitors did not demonstrate the activation of any caspases tested. However, the mitochondrial membrane potential of HL60 cells was lost after 24-h treatment with arucanolide, and concurrently apoptosis-inducing factor (AIF) released from mitochondria was detected by Western blot analysis. The inactivation of nuclear factor-kappaB, which has been commonly shown in parthenolide-induced apoptosis, did not occur in arucanolide-induced apoptosis. Taken together, the findings presented here indicate that arucanolide induced marked apoptosis in HL60 cells mainly by dissipating mitochondrial membrane potential, which would trigger AIF-induced apoptosis.     

Rasagiline: neurodegeneration, neuroprotection, and mitochondrial permeability transition

Mitochondria are involved directly in cell survival and death. The assumption has been made that drugs that protect mitochondrial viability and prevent apoptotic cascade-induced mitochondrial permeability transition pore (MPTp) opening will be cytoprotective. Rasagiline (N-propargyl-1R-aminoindan) is a novel, highly potent irreversible monoamine oxidase (MAO) B inhibitor anti-Parkinson drug. Unlike selegiline, it is not derived from amphetamine, and is not metabolized to neurotoxic L-methamphetamine derivative. In addition, it does not have sympathomimetic activity. Rasagiline is effective as monotherapy or adjunct to levodopa for patients with early and late Parkinson's disease (PD) and adverse events do not occur with greater frequency in subjects receiving rasagiline than in those on placebo. Phase III controlled studies indicate that it might have a disease-modifying effect in PD that may be related to its neuroprotective activity. Its S isomer, TVP1022, is more than 1,000 times less potent as an MAO inhibitor. Both drugs, however, have neuroprotective activity in neuronal cell cultures in response to various neurotoxins, and in vivo in response to global ischemia, neurotrauma, head injury, anoxia, etc., indicating that MAO inhibition is not a prerequisite for neuroprotection. Their neuroprotective effect has been demonstrated to be associated directly with the propargylamine moiety, which protects mitochondrial viability and MTPp by activating Bcl-2 and protein kinase C (PKC) and by downregulating the proapoptotic FAS and Bax protein families. Rasagiline and its derivatives also process amyloid precursor protein (APP) to the neuroprotective, neurotrophic, soluble APP alpha (sAPPalpha) by PKC- and MAP kinase-dependent activation of alpha-secretase. The identification of the propargylamine moiety as the neuroprotective component of rasagiline has led us to development of novel bifunctional anti-Alzheimer drugs (ladostigil) possessing cholinesterase and brain-selective MAO inhibitory activity and a similar neuroprotective mechanism of action.     

Novel MYOC gene mutation, Phe369Leu, in Japanese patients with primary open-angle glaucoma detected by denaturing high-performance liquid chromatography

PURPOSE: To screen for mutations in the MYOC gene in Japanese patients with primary open-angle glaucoma (POAG) using denaturing high-performance liquid chromatography (DHPLC). PATIENTS AND METHODS: Blood samples were collected from 171 patients with POAG and 100 controls from seven institutions in Japan. For high-throughput analysis, seven exonic regions were amplified by polymerase chain reaction using DNA pooled from three patients; each DNA pool was then analyzed chromatographically. For analysis of a small number of samples, 7 exonic regions were amplified separately but simultaneously with annealing at 58 degrees C in each patient and then chromatographed, using 7 wells of the same 96-well plate per sample. When chromatographic patterns were abnormal by either method, the PCR products of the individual samples were sequenced. RESULTS: Four glaucoma-causing mutations were identified in five POAG patients (2.9%). One missense mutation, Phe369Leu, is new; and three others, Ile360Asn, Ala363Thr, and Thr448Pro, have been reported in Japanese patients. Phe369Leu was associated with adult onset POAG. CONCLUSIONS: Mutations in the MYOC gene were demonstrated chromatographically in 2.9% of our Japanese POAG patients. The use of pooled DNAs with DHPLC analysis is a time- and labor-saving technique. All mutations detected appear to be specific to Japanese patients.     

A report of two cases--two patients of the extremely advanced hepatocellular carcinoma have responded completely for a long time after a combination therapy consisting of arterial chemotherapy and injection of interferon-alpha

The prognosis of advanced hepatocellular carcinoma (HCC) is extremely poor. Patient 1 was a 43-year-old male with major portal tumor thrombi. He received combination therapy consisting of continuous arterial infusion (MTX 30 mg/m2, day 1, CDDP/5-FU 6 mg/m2: 250 mg/m2, day 1-14) and subcutaneous injection of IFN-alpha (500 x 10(4) U, 3 times a week, 4 weeks). Patient 2 was a 66-year-old male with major hepatic venous tumor thrombi. He received combination therapy consisting of continuous arterial infusion (5-FU 6 mg/m2: 250 mg/m2, day 1-14) and subcutaneous injection of IFN-alpha (500 x 10(4) U, 3 times a week, 4 weeks). Decrease in tumor was observed in both patients markers and marked regression of tumor was observed in both patients. They are still in complete response. This combination therapy is an effective strategy for advanced HCC.     

TS-1 and lentinan combination immunochemotherapy for advanced or recurrent gastric cancer: a preliminary report

The immunocompetence and nutritional state of patients with advanced or recurrent gastric cancer is low, making it important to conduct chemotherapy while at the same time improving or maintaining their immunocompetence and nutritional state. To reduce the side effects but not the antitumor effect of TS-1, a 2-week regime of TS-1, and 1-week drug-free interval, in combination with the immunotherapeutic agent lentinan (LNT) was started in 5 patients with advanced or recurrent gastric cancer. Toxicity, efficacy, immunocompetence and nutritional state were investigated preliminarily to examine whether or not usefulness of lentinan could be evaluated. The IAP tended to decrease. TS-1 and lentinan combination immunochemotherapy was able to be carried out safely in patients with advanced recurrent gastric cancer. In order to examine the usefulness of combined LNT, it is thought to be necessary to perform a randomized trial using toxicity and not only efficacy but QOL and immunological and nutritional parameters as indicators.     

A new regimen for S-1 therapy aiming at adverse reaction mitigation and prolonged medication by introducing a 1-week drug-free interval after each 2-week dosing session: efficacy and feasibility in clinical practice

Background

The response rate of advanced or recurrent gastric cancer to S-1 (TS-1^®) is 46.5%, which is higher than the response rate of this type of cancer to any other anticancer agent. However, the incidence of adverse reactions to this drug has also been reported to be as high as 83.2%. According to a postmarketing survey, adverse reactions to this drug begin to appear 2–3 weeks after the start of drug administration. With these findings in mind, we recently devised a new dosing regimen for the drug, by which the drug is administered for 2-week periods separated by 1-week drug-free intervals (the 2-week regimen). The aim of this retrospective study was to evaluate the efficacy and feasibility of the 2-week regimen in comparison with a 4-week dosing regimen with a 2-week interval between sessions (the 4-week regimen) as the historical control.

Methods

The subjects were 27 patients with advanced or recurrent gastric cancer who received S-1 therapy at our center between September 1999 and November 2001. Of these patients, 14 who received the 4-week regimen before January 2001 served as historical controls, and the results in these patients were compared with those of the remaining 13 patients, who received the 2-week regimen after February 2001. Patient backgrounds, adverse reactions, compliance, and efficacy were investigated retrospectively.

Results

The incidence of adverse reactions tended to be lower in the 2-week-regimen group (77%) than in the 4-week-regimen group (93%). The percentage of patients who received the drug for 6 months in complete compliance with the dosing schedule, as calculated by the Kaplan-Meier method, was 85% in the 2-week-regimen group and 40% in the 4-week-regimen group. The response rate to the drug was 23% in the 2-week-regimen group and 21% in the 4-week-regimen group.

Conclusion

These results suggest that this 2-week regimen may mitigate adverse reactions and prolong the medication period.

     

An inhibitor of mitochondrial complex I, rotenone, inactivates proteasome by oxidative modification and induces aggregation of oxidized proteins in SH-SY5Y cells

In Parkinson's disease, characteristic pathological features are the cell death of nigrostriatal dopamine neurons and the formation of Lewy bodies composed of oxidized proteins. Mitochondrial dysfunction and aggregation of abnormal proteins have been proposed to cause the pathological changes. However, the relation between these two factors remains to be clarified. In this study, the effects of mitochondrial dysfunction on the oxidative modification and accumulation of proteins were analyzed using an inhibitor of mitochondrial complex I, rotenone, and antibodies against acrolein- and dityrosine-modified proteins. Under conditions inducing mainly apoptosis in neuroblastoma SH-SY5Y cells, rotenone markedly increased oxidized proteins, especially those modified with acrolein, even though the increase in intracellular reactive oxygen and nitrogen species was only transient and was not so marked. In addition, the activity of the proteasome system degrading oxidized proteins was reduced profoundly after treatment with rotenone. The 20S beta subunit of proteasome was modified with acrolein, to which other acrolein-modified proteins were found to bind, as shown by coprecipitation with the antibody against 20S beta subunit. These results suggest that mitochondrial dysfunction, especially decreased activity of complex I, may reduce proteasome activity through oxidative modification of proteasome itself and aggregation with other oxidized proteins. This mechanism might account for the accumulation of modified protein and, at least partially, for cell death of the dopamine neurons in Parkinson's disease.     

Low Phase Angle Is Correlated With Worse General Condition in Patients with Advanced Cancer

Objectives: Phase angle (PA) is a poor prognostic factor in patients with advanced cancer. This study aimed to identify possible correlations between PA and symptoms, quality of life, fluid retention, and laboratory data in cancer patients in palliative care settings.

Methods: Individuals who visited the outpatient clinic or were admitted to the palliative care unit were eligible. Patients with a performance status of 4 and/or those unable to complete questionnaires were excluded. PA was evaluated using a bioanalyzer device. The correlation coefficient between PA and the variables of interest was analyzed.

Results: A total of 102 patients were analyzed. PA was weakly correlated with age (ρ = ?0.22), performance status (ρ = ?0.30), functional well-being (ρ?=?0.20), anorexia/cachexia subscale (ρ?=?0.22), and Functional Assessment of Anorexia/Cachexia Therapy trial outcome index (ρ?=?0.26). PA was also correlated with fluid retention (ρ = ?0.34) and albumin (ρ?=?0.32), C-reactive protein (ρ = ?0.31), and hemoglobin (ρ?=?0.41) levels. Sub-analysis stratified according to sex revealed that males demonstrated the same results; however, female sex demonstrated a correlation between PA and social well-being (ρ = ?0.43).

Conclusions: PA was correlated with physical condition, but not with psychological well-being.