Visualization of stroke with clinical MR imagers in rats: a feasibility study

This experiment was conducted in compliance with the guidelines of the International Committee on Thrombosis and Hemostasis and the current institutional regulations for use and care of laboratory animals. The purpose of the present study was to report the feasibility of using clinical magnetic resonance (MR) imaging devices for depiction of stroke in a rat model. Twenty-four rats with photochemically induced thrombosis of the middle cerebral artery were examined at superacute (1 hour, n = 24), acute (12 hours, n = 12), and subacute (24 hours, n = 12) phases with 1.5-T MR imaging weighted for T1, T2, diffusion, and gadopentetate dimeglumine-enhanced perfusion. With reasonable signal-to-noise ratio and imaging times, ischemic lesions were well distinguished on MR images as validated qualitatively and quantitatively with postmortem standard-of-reference techniques, including volume-rendered computed tomography, microangiography, and histochemistry. In the superacute phase, the perfusion defect at perfusion-weighted MR imaging was well matched with microangiographic and pathologic findings (P > .05). There was no difference in lesion size at perfusion-weighted MR imaging between superacute and subacute phases (P > .05). Performance of certain stroke-related research in rats is feasible with clinical MR imagers.     

Terminal telomere repeats are actually short in telomerase-negative immortal human cells

Telomerase-negative immortal human cells maintained telomere length by a mechanism called alternative lengthening of telomeres (ALT mechanism). These cells (ALT cells) have two prominent characteristics of long telomere repeats at each chromosome end revealed by Southern blotting (terminal restriction fragments: TRF) and the presence extrachromosomal telomere repeat (ECTR) DNA. We report here that the TRF length of ALT cells revealed by the conventional unidirectional (UD) current or pulse-field (PF) current electrophoresis appeared to be over estimated. The TRF length determined by the pulse inverse-field (PIF) current electrophoresis (2-9 kbp depending upon cell lines) was much smaller than that (ca. 23 kbp) by UD or PF current electrophoresis. These results were in consistent with very weak telomere staining in situ at chromosome ends in ALT cells. When a mixture of HinfI-digested genomic DNA of human diploid fibroblasts and synthetic telomere repeat DNA with similar size of ECTR DNA was electrophoresed using a UD current, the apparent TRF size shifted to larger molecular weight, while the size shift did not occur by PIF current electrophoresis. These results together with other data indicate that the unusually long TRF of ALT cells determined by using conventional electrophoresis is an artifact produced by a complex formed by short TRF and short ECTR DNA.     

New method for detecting misrouted retinofugal fibers in humans with albinism by magnetoencephalography

In humans with albinism, a large percentage of the ganglion cell axons from the temporal retina decussate abnormally in the chiasm and synapse in the contralateral LGN. The aim of this study was to determine whether the misrouting of the optic fibers can be detected by magnetoencephalography (MEG). Visually evoked magnetic fields (VEFs) were recorded from three patients with albinism. After monocular stimulation, the isofield contour maps of the VEFs showed a single current dipole pattern over the contralateral hemisphere in patients with albinism. These results clearly illustrated the reduced uncrossed retinofugal pathway of patients with albinism.     

Topical administration of iganidipine, a new water-soluble Ca2+ antagonist, increases ipsilateral optic nerve head circulation in rabbits and cynomolgus monkeys

PURPOSE: To evaluate the effects of topically administered iganidipine hydrochloride, a novel water-soluble Ca2+- channel blocker, on optic nerve head (ONH) circulation in Dutch rabbits and cynomolgus monkeys. METHODS: ONH tissue blood velocity (NBONH) was determined using the laser speckle method. In rabbits, NBONH was measured for 90 minutes before and after a single iganidipine administration, or before and after twice-daily ad- ministrations for 21 days (0.03%). In monkeys, NBONH was measured before and after twice-daily administrations of iganidipine for 7 days (0.03 or 0.1%). RESULTS: Iganidipine (0.03% solution) significantly increased NBONH by 8 to 10% in treated eyes after a single administration (p < 0.05) or by 18 to 35% after 7-, 14-, or 21-day twice-daily administration in rabbits (p < 0.05). In monkeys, 0.03% and 0.1% iganidipine significantly increased NBONH in treated eyes by 20 and 41% after 7-day (p < 0.05) twice-daily administration, respectively. CONCLUSION: Topical iganidipine significantly increased ONH blood velocity in treated eyes.     

New diarylheptanoids from the rhizomes of Dioscorea spongiosa and their antiosteoporotic activity

Bioassay-guided fractionation of the water extract of the rhizomes of Dioscorea spongiosa led to the isolation and identification of new diarylheptanoids, diospongins A - C, together with three known lignans. Their structures, including absolute stereochemistry, were determined by analyses of NMR data, chemical conversions and CD spectrum. The isolated compounds, except for diospongin A, exerted potent inhibitory activities on bone resorption induced by parathyroid hormone in a bone organ culture system.     

Tissue-specific regulation of 4E-BP1 and S6K1 phosphorylation by alpha-ketoisocaproate

The indispensable branched-chain amino acid leucine acts as a key regulator of mRNA translation by modulating the phosphorylation of proteins that represent important control points in translation initiation, including the translational repressor, eukaryotic initiation factor (eIF) 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase (S6K1). In the current study, we compared the effects of L- and D-enantiomers of leucine on the phosphorylation of 4E-BP1 and S6K1. We also assessed whether leucine itself or its metabolite, alpha-ketoisocaproate (alpha-KIC), mediates the effects of leucine. Food-deprived (18 h) rats were orally administered 135 mg/100 g body weight L-leucine, D-leucine or alpha-KIC and were sacrificed after 1 h. L-Leucine administration had an obvious stimulatory effect on the phosphorylation of 4E-BP1 and S6K1 in both skeletal muscle and liver while D-leucine was much less effective, indicating that the effect of leucine is stereospecific. Oral administration of alpha-KIC mimicked the stimulatory effect of L-leucine in skeletal muscle. In contrast to skeletal muscle, provision of alpha-KIC was significantly less effective than L-leucine in the liver. The results showing that the efficacy of L-leucine and alpha-KIC in stimulating phosphorylation of S6K1 and 4E-BP1 is equivalent in skeletal muscle, may be explained by the conversion of alpha-KIC to L-leucine.     

Richter's syndrome presenting as a nasal lymphoma

Richter's syndrome (RS) is a high-grade large cell lymphoma arising in patients with B-cell chronic lymphocytic leukemia (CLL). The prognosis of RS is very poor and the development of RS is a serious complication of CLL. We present a case of a patient with a 4-year history of B-cell CLL who developed diffuse large B-cell nasal lymphoma. The patient exhibited good response to chemotherapy and irradiation and achieved complete remission. Five months later, the patient suffered leptomeningeal involvement and has been treated with repeated intrathecal chemotherapy. Leukemic cells of the patient expressed CD13. CD13+ CLLs have been reported to have an unfavorable prognosis and this case may support the view.     

Antitumor effect of MCC-465, pegylated liposomal doxorubicin tagged with newly developed monoclonal antibody GAH, in colorectal cancer xenografts

MCC-465 is an immunoliposome-encapsulated doxorubicin. The liposome is tagged with polyethylene glycol and the F(ab')2 of a monoclonal antibody named GAH, a human antibody obtained by the hybridoma technique. The epitope recognized by GAH is not well characterized, but human gastric, colorectal, and mammary cancer cells were GAH-positive, while the normal counterparts were GAH-negative. Pegylated liposome doxorubicin (PLD) and MCC-465 did not show significant antitumor activity against GAH-negative Caco-2 xenografts. On the other hand, MCC-465 exhibited significantly superior antitumor effects against GAH-positive WiDr-Tc and SW837 xenografts, compared with PLD. Immunohistochemistry with GAH revealed that 94% (100 of 106) of surgical specimens of colorectal cancer were GAH-positive. These results warrant a phase I clinical trial of MCC-465 for patients with metastatic colorectal cancer.     

Local hyperthermia combined with external irradiation for regional recurrent breast carcinoma

Backgrounds The purpose of this study was to evaluate the therapeutic effects of hyperthermia in combination with radiotherapy for locoregional recurrence of breast cancer, and to assess the factors related to subsequent local tumor control.Methods Between March 1981 and February 2001, 85 lesions in 73 patients were treated with local hyperthermia combined with external irradiation. Of 75 evaluable lesions, 41 were previously irradiated. Mean radiation dose to the previously unirradiated area was 59.5 ± 6.8Gy (range, 40–70Gy), while a total dose of 43.0 ± 12.4Gy (range, 12–74.4Gy) was administered to previously irradiated tumors. Hyperthermia was administered once or twice per week. The average number of hyperthermia sessions was 4.5 (2–9).Results Complete responses (CRs) were achieved in 56% (23/41) of previously irradiated and 47% (16/34) of unirradiated tumors. There was no significant difference in the CR rate between the two groups. Compared with the response of bulky/nodular tumors, diffuse/multiple small nodular tumors showed a higher CR rate at 4 weeks after treatment. However, at 6 months after treatment, they showed a significantly lower local control rate.Conclusions The present findings suggested a significant benefit of local hyperthermia combined with radiotherapy in the treatment of locally recurrent breast cancer, especially for previously irradiated recurrence, by reducing the total irradiation dose. Diffuse/multiple small nodular tumors respond earlier than bulky/large nodular tumors; however, they tend to recur within the treatment field.