Current human T‐cell lymphotropic virus type 1 mother‐to‐child transmission prevention status in Kagoshima

The aim of this study was to assess the current human T‐cell lymphotropic virus type 1 (HTLV‐I) mother‐to‐child transmission (MTCT) prevention system in Kagoshima Prefecture. We investigated the rate of carrier pregnant women from obstetrics facilities in Kagoshima by mail in 2012 and compared our results with previous study results. We interviewed carrier pregnant women about their choices for infant nutrition, and we interviewed midwives about the follow‐up system. In 2012, 8719 screening tests were performed, covering 58.1% of all pregnant women in Kagoshima; the rate of carrier pregnant women was 1.3%. Of 59 carriers, 39 chose short‐term breast‐feeding. The HTLV‐I carrier rate among pregnant women in Kagoshima has declined. The current HTLV‐I MTCT prevention system in Kagoshima is effective, but not sufficient. To bring the nutrition methods to completion, various types of support are needed. Further studies will elucidate many unsolved problems concerning MTCT.     

Antitumor effects of tyropeptin‐boronic acid derivatives: New proteasome inhibitors

The proteasome degrades numerous regulatory proteins that are critical for tumor growth. Thus, proteasome inhibitors are promising antitumor agents. New proteasome inhibitors, such as tyropeptins and tyropeptin‐boronic acid derivatives, have a potent inhibitory activity. Here we report the antitumor effects of two new tyropeptin‐boronic acid derivatives, AS‐06 and AS‐29. AS‐06 and AS‐29 significantly suppress the degradation of the proteasome‐sensitive fluorescent proteins in HEK293PS cells, and induce the accumulation of ubiquitinated proteins in human multiple myeloma cells. We show that these derivatives also suppress the degradation of the NF‐κB inhibitor IκB‐α and the nuclear translocation of NF‐κB p65 in multiple myeloma cells, resulting in the inhibition of NF‐κB activation. Furthermore, we demonstrate that AS‐06 and AS‐29 induce apoptosis through the caspase‐8 and caspase‐9 cascades. In a xenograft mouse model, i.v. administration of tyropeptin‐boronic acid derivatives inhibits proteasome in tumors and clearly suppresses tumor growth in mice bearing human multiple myeloma. Our results indicate that tyropeptin‐boronic acid derivatives could be lead therapeutic agents against human multiple myeloma.     

New recommendations for vancomycin dosage for patients with MRSA pneumonia with various degrees of renal function impairment

New recommendations for vancomycin (VCM) dosages and dosing intervals for MRSA-infected pneumonia patients with various degrees of renal function impairment were established based on Japanese population pharmacokinetic parameters proposed by Yasuhara et al. in 1998. Based on individual creatinine clearance (CLcr), we proposed the optimum VCM dosages and dosing intervals so that the peak level of VCM (level at 1 h after the end of infusion) is maintained in the range of 25–40 µg/ml and the trough level is kept under 15 µg/ml. The recommended doses and intervals of VCM were as follows: 20 mg/kg every 12 h for CLcr of 80–100 ml/min, 18 mg/kg every 12 h for CLcr of 70 ml/min, 25 mg/kg every 24 h for CLcr of 50–60 ml/min, 22 mg/kg every 36 h for CLcr of 40 ml/min, and 18 mg/kg every 48 h for CLcr of 30 ml/min. Using the recorded pharmacokinetic parameters of VCM from eight patients with pneumonia who were admitted to Aoyama Second Hospital between November 1997 and January 2002, these recommendations were used in computer simulations for the eight patients, and the usefulness of these recommendations was confirmed.     

Evaluation of action mechanisms of toxic chemicals using JFCR39, a panel of human cancer cell lines

We previously established a panel of human cancer cell lines, JFCR39, coupled to an anticancer drug activity database; this panel is comparable with the NCI60 panel developed by the National Cancer Institute. The JFCR39 system can be used to predict the molecular targets or evaluate the action mechanisms of the test compounds by comparing their cell growth inhibition profiles (i.e., fingerprints) with those of the standard anticancer drugs using the COMPARE program. In this study, we used this drug activity database-coupled JFCR39 system to evaluate the action mechanisms of various chemical compounds, including toxic chemicals, agricultural chemicals, drugs, and synthetic intermediates. Fingerprints of 130 chemicals were determined and stored in the database. Sixty-nine of 130 chemicals ( approximately 60%) satisfied our criteria for the further analysis and were classified by cluster analysis of the fingerprints of these chemicals and several standard anticancer drugs into the following three clusters: 1) anticancer drugs, 2) chemicals that shared similar action mechanisms (for example, ouabain and digoxin), and 3) chemicals whose action mechanisms were unknown. These results suggested that chemicals belonging to a cluster (i.e., a cluster of toxic chemicals, a cluster of anticancer drugs, etc.) shared similar action mechanism. In summary, the JFCR39 system can classify chemicals based on their fingerprints, even when their action mechanisms are unknown, and it is highly probable that the chemicals within a cluster share common action mechanisms.     

Specific biological functions of vacuolar-type H(+)-ATPase and lysosomal cysteine proteinase,cathepsin K,in osteoclasts

We report the effects of specific and potent inhibitors of vacular-type H(+)-ATPase and lysosomal cysteine proteinases, cathepsins, on the ultrastructure, expression of these enzymes, and resorptive functions of cultured osteoclasts. Osteoclasts were formed by co-culture of marrow cells and calvarial primary osteoblasts of ddY mice. Formed osteoclasts were cultured on dentine slices for 6-48 hr with either an H(+)-ATPase inhibitor, bafilomycin A1, or a cysteine proteinase inhibitor, E-64. In control cultures with no additive, osteoclasts were structurally characterized by the development of ruffled borders and clear zones, and formed many resorption lacunae on dentine slices. Both H(+)-ATPase and cathepsin K were strongly expressed in the ruffled borders of these osteoclasts. In bafilomycin A1-treated cultures, osteoclasts lacked ruffled borders, and resorption lacuna formation was markedly diminished. This effect of bafilomycin A1 on osteoclast structure was reversible by removal of the compound. Bafilomycin A1 treatment altered the subcellular localization and decreased the expression of H(+)-ATPase molecules. H(+)-ATPase expression was observed throughout the cytoplasm, but not along the plasma membranes facing dentine slices. On the other hand, E-64 treatment did not affect the ultrastructure of osteoclasts and the expression of enzyme molecules. Although E-64 showed no effect on demineralization of dentine slices, it dose-dependently reduced resorption lacuna formation. Our results suggest that 1) bafilomycin A1 dose-dependently inhibits resorption lacuna formation via inhibition of ruffled border formation, 2) H(+)-ATPase expression is closely associated with the cytoskeleton of osteoclasts, and 3) E-64 treatment decreases the depth of resorption lacunae, by inhibition of secreted cathepsin K activity, but does not impair ruffled border formation and the associated expression of H(+)-ATPase and cathepsin K in osteoclasts.     

Identification of candidate predictive markers of anticancer drug sensitivity using a panel of human cancer cell lines

We previously investigated the correlations between the expression of 9216 genes and various chemosensitivities in a panel of 39 human cancer cell lines¹⁾ and found that the expression levels of AKR1B1 and CTSH were correlated with sensitivity and resistance to multiple drugs, respectively. To validate these correlations, we investigated the expression of these two genes and the chemosensitivities in 12 additional gastric cancer cell lines. The expression of AKR1B1 in the additional cell lines exhibited significant correlations with sensitivities to 8 of the 23 drugs examined, while that of CTSH displayed a significant negative correlation with only one (MS-247) of the 27 drugs examined. Their expressions were weakly correlated with sensitivity and resistance, respectively, to the remainder of the drugs. Moreover, when the 12 cell lines were divided into high-expressing and low-expressing groups, a comparison of these groups using Mann-Whitney's U test revealed that high expression levels of AKR1B1 and CTSH were related to sensitivity to 21 of the drugs and resistance to 8 of the drugs, respectively. The present results suggest that AKR1B1 and CTSH may be good markers for prediction of sensitivity to certain drugs and that our panel of 39 cell lines has the potential to identify candidate predictive marker genes.     

Spermatogenesis in Snell dwarf, little and congenitally hypothyroid mice

The status of spermatogenesis in Snell dwarf, little and congenitally hypothyroid mice was studied. In all of these mice with a hormone deficiency the seminiferous tubules were smaller in size and contained fewer spermatogonia, spermatocytes, spermatids and spermatozoa than did those of normal control mice. There was no substantial difference in the Johnsen score between the hormone-deficient mice and normal control mice, but the former had underdeveloped seminiferous tubules with a corresponding paucity of germ cells, which may be partly responsible for the infertility of these mice. In the present study, growth hormone and thyroxine were administered separately to growth hormone-deficient and thyroxine-deficient mice, respectively. Such replacement therapy brought about an increase in cell counts of the seminiferous tubules and in sperm counts in both groups.     

Mesenchymal dysplasia of the placenta

A severe case of placental mesenchymal dysplasia occurred in association with intrauterine fetal death (IUFD). The gravida-1, para-1 mother was a 26-year-old Japanese. The first pregnancy was unremarkable and a healthy female infant was delivered. The present pregnancy had been uneventful until 34 weeks of gestation when IUFD was detected. The 1516-g (mean +/- SD, 2050 +/- 387 g) stillborn infant had no external abnormalities and the karyotype was 46,XX. The placenta was markedly enlarged (1050 g; mean +/- SD, 452 +/- 202 g), and approximately 80% was occupied by extraordinary enlarged villous structures with a myxoid appearance. Histologically, the dysplastic villi had myxoid stroma and a decreased number of, occasionally obliterated, fetal vessels. There was no abnormal trophoblastic proliferation. Large-sized fetal vessels in the chorionic plate frequently contained organized thrombi. This is the first case of placental mesenchymal dysplasia, which possibly lead to the IUFD.     

Comparison of muscle strength between hemodialysis patients and non-dialysis patients with chronic kidney disease

[Purpose] Muscle weakness in patients with chronic kidney disease is associated with several disease-related factors, and this study aimed to examine whether hemodialysis is one of risk factors for muscle weakness in patients with chronic kidney disease. [Participants and Methods] We conducted a cross-sectional study with 74 non-dialysis and 84 hemodialysis patients. Muscle strength evaluations were performed by measuring isometric knee extensor muscle strength and grip strength. Each evaluation item was compared between the hemodialysis and non-dialysis groups, and multiple regression analysis was performed to determine the factors associated with muscle strength. In addition, the correlation between lower-extremity muscle strength and grip strength was examined in each group. [Results] Isometric knee extensor muscle strength was significantly lower in the hemodialysis group than in the non-dialysis group. Grip strength was also significantly lower in the hemodialysis group than in the non-dialysis group. Hemodialysis was determined to be an independent risk factor associated with lower limb muscle strength as well as grip strength. The positive correlation between isometric knee extensor muscle strength and grip strength was almost the same in the groups. [Conclusion] Hemodialysis treatment was an independent risk factor for muscle weakness. Regular monitoring of grip strength may facilitate better management with physical therapy in hemodialysis patients.