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An intravenous (IV) formulation of edaravone has been shown to slow the rate of physical functional decline in amyotrophic lateral sclerosis (ALS). An oral suspension formulation of edaravone was recently approved by the United States Food and Drug Administration for use in patients with ALS. This study assessed the safety and tolerability of oral edaravone.This global, open-label, phase 3 study evaluated the long-term safety and tolerability of oral edaravone in adults with ALS who had a baseline forced vital capacity ≥70% of predicted and disease duration ≤3 y. The primary safety analysis was assessed at weeks 24 and 48. Patients received a 105-mg dose of oral edaravone in treatment cycles replicating the dosing of IV edaravone.The study enrolled 185 patients (64.3% male; mean age, 59.9 y; mean disease duration, 1.56 y). The most common treatment-emergent adverse events (TEAEs) at week 48 were fall (22.2%), muscular weakness (21.1%) and constipation (17.8%). Serious TEAEs were reported by 25.9% of patients; the most common were worsening ALS symptoms, dysphagia, dyspnea, and respiratory failure. Twelve TEAEs leading to death were reported. Forty-six (24.9%) patients reported TEAEs that were considered related to study drug; the most common were fatigue, dizziness, headache, and constipation. Sixteen (8.6%) patients discontinued study drug due to TEAEs. No serious TEAEs were related to study drug.This study indicated that oral edaravone was well tolerated during 48 wk of treatment, with no new safety concerns identified.

A limb symmetry index (LSI) of ≥90% for the quadriceps is recommended for return to sports activity after anterior cruciate ligament reconstruction (ACLR). However, there is no information on differences in muscle fatigability between patients with LSI of90% and ≥90%. The aim of this study was to assess the difference in quadriceps muscle fatigability on the involved side between post-ACLR patients with LSI of90% and ≥90%. We hypothesized that there were differences between the two groups in muscle fatigability on the involved side reflecting difference in muscle fiber composition in the vastus medialis (VM) muscle.The study subjects were 18 adult men who had undergone ACLR followed by rehabilitation therapy. LSI was90% in 10 and ≥90% in 8 adult men. Surface electromyography (EMG) of the VM muscle was recorded during sustained quadriceps muscle isometric contraction. The median frequency (MF) was computed from the raw EMG signal using fast Fourier transform spectrum analysis. The MF slope was also calculated.There were no differences in anthropometric characteristics, time since ACLR, anterior tibial translation and peak torque of knee extension on the involved side between the two groups. However, MF slope was significantly lower in the LSI ≥ 90% group than the90% group.Our results demonstrated fatigue-resistant vastus medialis in post-ACLR patients with LSI ≥90% compared to those with LSI90%. The finding adds support to the use of ≥90% as the cutoff value for LSI for return of post-ACLR patients to sports activity.

Flecainide, an anti-arrhythmic drug, undergoes renal excretion through active renal tubular secretion in addition to passive glomerular filtration. The contribution of renal uptake and efflux transporters in active renal tubular secretion of flecainide remains unclear except that flecainide is a substrate of human multidrug resistance protein 1 (MDR1). To elucidate renal efflux and uptake transporters involved with active renal tubular secretion of flecainide, we conducted in vitro interaction studies of flecainide using organic cation transporter 2 (OCT2), multidrug and toxin extrusion (MATE) 1, and MATE2-K. Uptake transporter inhibition assays using hOCT2-Chinese hamster ovary (CHO), hMATE1-CHO, and hMATE2-K-Madin Darby canine kidney strain II (MDCKII) cells revealed that flecainide (2.5 µM) inhibited hMATE1-mediated transport by 40% with an IC50 value of 6.7 µM; however, it showed no or weak inhibitory effects on hOCT2- and hMATE2-K-mediated transport. For investigating flecainide as a substrate of hMATE1, the accumulation of flecainide in hMATE1-CHO was compared with that in control cells. Uptake transporter substrate assay revealed that flecainide (1 µM) showed 1.11-fold accumulation though the hMATE1-related active transport was significantly decreased in the presence of quinidine (42.0 ± 23.9 vs. 11.8 ± 4.1 pmol/mg in transfected cells; p < 0.05). These results suggest that flecainide is a weak substrate of hMATE1, which is involved in the renal tubular secretion of cationic drugs, and hMATE1 may be less important in the pharmacokinetic drug-drug interaction for renal excretion of flecainide. However, in vivo drug-drug interaction studies of flecainide with substrates of hMATE1 may be needed because flecainide has the potential to inhibit hMATE1.

Typically, sulfate-reducing bioreactors used to treat acid mine drainage (AMD) undergo an initial incubation period of a few weeks to acclimatize sulfate-reducing bacteria (SRB), although necessity of this preincubation has rarely been evaluated. To reduce time and economic cost, we developed an SRB acclimatization method using the continuous flow of AMD into bioreactors fed with rice bran, and compared with the conventional acclimatization method. We found that the SRB sufficiently acclimatized without the preincubation phase. Furthermore, we examined the performance and SRB communities in bioreactors operated for >200 days under seven different conditions, in which the amount of rice bran added and hydraulic retention times (HRTs) were varied. A comparison of the various bioreactor conditions revealed that the lowest rice bran amount (50 g) and the shortest HRT (6 h) caused a deterioration in reactor performance after day 144 and 229, respectively. In both cases, relatively aerobic environments developed due to the lack of organic matter seemed to inhibit sulfate reduction. Of the conditions tested, operation of the bioreactors with 200 g of rice bran and an HRT of 12.5 h was the most effective in treating AMD, showing a sulfate reduction rate of 20.7–77.9% during days 54–242. Data and materials availability All data needed to evaluate the conclusions of this study are presented in the paper and/or the appendix.

Patients with advanced unresectable hilar cholangiocarcinoma have poor prognosis, and the survival is usually short. Herein, we report a 9-year survival case of unresectable hilar cholangiocarcinoma treated with chemoradiotherapy. A 64-year-old male patient presented with hilar cholangiocarcinoma. The tumor was located in the right hepatic duct, and it extended from the bifurcation of the anterior and posterior branches to the periphery. In the left side, the tumor extended from the umbilical portion to B2 and B3. However, there was no distant metastasis. The patient was then diagnosed with locally advanced, unresectable hilar cholangiocarcinoma and was treated with chemoradiotherapy. He received a total dose of 60 Gy in 30 daily fractions via intensity-modulated radiation therapy. In addition, he received gemcitabine chemotherapy for 5 years. There has been neither re-elevation of carbohydrate antigen 19-9 levels nor tumor relapse for 5 years during chemotherapy. Therefore, gemcitabine treatment was discontinued. However, the patient experienced tumor relapse 3 years after the last chemotherapy. Hence, chemotherapy with gemcitabine and cisplatin was initiated. At present, 1 year has passed after treatment for recurrence, and the patient has survived for 9 years since the initial treatment. Herein, we report a rare case of long-term survival with chemoradiotherapy in locally advanced unresectable hilar cholangiocarcinoma.

Sulfate-reducing bioreactors, also called biochemical reactors, represent a promising option for passive treatment of mining-influenced water (MIW) based on similar technology to aerobic/anaerobic-constructed wetlands and vertical-flow wetlands. MIW from each mine site has a variety of site-specific properties related to its treatment; therefore, design factors, including the organic substrates and inorganic materials packed into the bioreactor, must be tested and evaluated before installation of full-scale sulfate-reducing bioreactors. Several full-scale sulfate-reducing bioreactors operating at mine sites provide examples, but holistic understanding of the complex treatment processes occurring inside the bioreactors is lacking. With the recent introduction of high-throughput DNA sequencing technologies, microbial processes within bioreactors may be clarified based on the relationships between operational parameters and key microorganisms identified using high-resolution microbiome data. In this review, the test design procedures and precedents of full-scale bioreactor application for MIW treatment are briefly summarized, and recent knowledge on the sulfate-reducing microbial communities of field-based bioreactors from fine-scale monitoring is presented.Key points• Sulfate-reducing bioreactors are promising for treatment of mining-influenced water.• Various design factors should be tested for application of full-scale bioreactors.• Introduction of several full-scale passive bioreactor systems at mine sites.• Desulfosporosinus spp. can be one of the key bacteria within field-based bioreactors.

Sulfate-reducing passive bioreactor is an option for treating acid mine drainage (AMD) for a long period of time without maintenance. A 35-L packed-bed sulfate-reducing bioreactor containing rice bran was continuously operated for over 800 days, however, reactor performance became progressively worsened after day 871, resulting in the effluent zinc concentration increasing above the national effluent standard. Both microbial communities and chemical parameters along the height of the bioreactor were analyzed by using Illumina sequencing of 16S rRNA genes and analytical instruments, respectively, in order to compare the data before and after day 871. During the monitoring period (day 800 to day 884), the total organic carbon concentration remained low (5.3–8.1 mg L–1), indicating that the substrates for sulfate-reducing bacteria (SRB) in the bioreactor were nearly depleted. On day 872, oxidation-reduction potential (ORP) values increased, especially in the upper portion of the bioreactor, resulting in dominance of aerobic Alishewanella- and Mitsuaria-related microorganisms. In the lower portion of the bioreactor, relative abundance of SRB decreased significantly on day 872, whereas the candidate phylum OP11 bacteria increased. These results suggested that low organic concentration, high ORP, and low AMD temperature conditions after day 871 decreased the relative abundance of SRB in the bioreactor, leading to the deterioration of the reactor performance.

The etiology of amyotrophic lateral sclerosis (ALS) is unknown. Oxidative stress may be one of the major mechanisms involved. In vitro and in vivo data of edaravone suggest that it may possess broad free radical scavenging activity and protect neurons, glia, and vascular endothelial cells against oxidative stress. During the 1980s and 1990s, edaravone was developed for the treatment of acute ischemic stroke. In 2001, a clinical program in ALS was initiated and five clinical studies were conducted in Japan. Phase III studies were designed to rapidly evaluate (within a 24-week double-blind study window) functional changes using the Revised ALS Functional Rating Scale (ALSFRS-R) as a primary endpoint. The study populations were selected according to these considerations and were further refined as the studies proceeded. Although the first phase III study did not meet its primary endpoint, post-hoc analyses showed an apparent effect of edaravone, when additional patient inclusion criteria defined by ALSFRS-R score, pulmonary function, certainty of ALS diagnosis, and duration of disease were applied. This population was hypothesized not only to have retained broad functionality and normal respiratory function at study baseline but also to be likely to show measurable disease progression over 24 weeks. A second confirmatory phase III study applying these refinements in patient selection was prospectively designed and successfully documented a statistically significant difference between the edaravone and placebo groups in the ALSFRS-R primary endpoint. This paper describes and reviews data pertinent to the potential mechanism of action of edaravone, and reviews the development history of edaravone for the treatment of ALS.

The development of compact and cost-effective passive treatment systems is of critical importance for acid mine drainage (AMD) remediation in Japan. The purpose of this study was to construct an AMD treatment system comprising a sulfate-reducing bioreactor using rice bran as a carbon source for sulfate-reducing bacteria (SRB) and to demonstrate its stable operation for at least a year in terms of continuous sulfate reduction and metal removal. Our 35 L bioreactor comprised a packed inoculum layer of a mixture of rice husks, limestone, and field soil, which was covered with rice bran. During operation, the AMD input flow rate was adjusted to 11.7 mL/min (hydraulic retention time, HRT; 50 h). Throughout the year, physicochemical analyses of system input and output AMD samples revealed that both pH and oxidation–reduction potential values were consistent with the process of sulfate reduction by SRB, although this reduction was observed to be stronger in summer than in winter. Efficient metal removal was observed, with concentrations at the outlet port of

The role of L-type amino-acid transporter 1 (LAT1), an oncofetal protein, in tumor progression is not well known, although it is important for the survival and proliferation of cancer cells. LAT1 expression was immunohistochemically analyzed and compared in sporadic (conventional) colorectal tumors and ulcerative colitis (UC)-associated neoplasia development and progression. LAT1 expression showed a significant stepwise increase in the order: conventional low-grade tubular adenoma, high-grade tubular adenoma, and invasive adenocarcinoma. Similarly, the same increasing trend in LAT1 expression was found in UC-associated low-grade dysplasia, high-grade dysplasia, and adenocarcinoma, whereas expression was significantly lower compared with that in an adenoma-adenocarcinoma series. LAT1 expression was predominant in the upper half of mucosal lesions in low-grade adenoma. This localized difference in LAT1 expression between the upper and lower halves of mucosal lesions disappeared in conventional high-grade adenoma and adenocarcinoma. LAT1 expression in the colorectal mucosa was significantly increased in the order: nontumor mucosa, quiescent phase of UC, and active phase of UC. Considering the histological pattern of Ki-67 labeling, LAT1 expression appeared partly related to cell proliferation, but this was not significant. In relation to the prognosis of patients with sporadic phase IV colorectal adenocarcinoma, this was significantly poorer in the group with high LAT1 expression compared with that with low LAT1 expression. This suggests LAT1 expression may be used as a companion biomarker for anti-cancer therapy targeting the LAT1 molecule in colorectal cancers.

Five types of sulfate-reducing passive bioreactors with rice bran as substrate were operated at three different mine sites under various operating conditions to investigate and compare the dominant sulfate-reducing bacteria (SRBs) involved in acid mine drainage (AMD) treatment. In all bioreactors, AMD was properly treated under the national effluent standard of Japan when 16 samples in total were taken from different depths of the bioreactors at different sampling times. Analysis of the microbiomes in the five bioreactors by Illumina sequencing showed that Desulfosporosinus spp. were dominant SRBs in all bioreactors (the relative abundances were ~ 26.0% of the total population) regardless of reactor configurations, sizes, and operating conditions. This genus is known to comprise spore-forming, acid-tolerant, and oxygen-resistant SRBs with versatile metabolic capabilities. Microbial populations of AMD water and soil samples (as inocula) from the respective mine sites were also analyzed to investigate the origin of the genus Desulfosporosinus. Desulfosporosinus spp. were detectable in most AMD water samples, even at low relative abundances (0.0025 to 0.0069% of total AMD population), suggesting that the genus Desulfosporosinus is present within the AMD water that flows into the bioreactor. These data strongly imply that the passive treatment system is a versatile and widely applicable process for AMD treatment.

The objective of the present multicenter randomized study was to compare weekly teriparatide with alendronate in their inhibition of vertebral collapse, effects on delayed union, pain relief, and improvement of quality of life (QOL) in women with new osteoporotic vertebral fractures within 1 week after onset of the fracture. Patients were randomly allocated to the teriparatide and alendronate groups. Vertebral collapse, low back pain assessed by a visual analog scale, and QOL assessed by EuroQol 5 dimension at weeks 1, 2, 4, 8, and 12 after the start of the treatment were compared between the groups. Lumbar bone mineral density (BMD) at baseline and week 12 and the rate of delayed union at week 12 were also compared. Each group consisted of 48 subjects. Vertebral collapse progressed over time in both groups, with no significant difference between the groups. Pain on rising up from lying position, turning over in bed, and resting in the lying position improved over time in both groups, with no significant difference between the groups. There were no significant differences in increase in BMD and delayed union. QOL in the teriparatide group showed significant improvement in comparison with that in the alendronate group at week 12. The weekly formulation of teriparatide showed comparable inhibition of vertebral collapse, increase in BMD, promotion of bone union, and improvement of pain and significant improvement of QOL at week 12 in comparison with alendronate in patients with a new osteoporotic vertebral fracture within 1 week after onset of the fracture. The weekly formulation of teriparatide may have improved components of QOL other than pain at week 12.

Background The erector spinae is more resistant to fatigue in adult women than men. However, no study has reported the sex differences in back muscle fatigue in children. Objective The aim of this study was to evaluate the fatigability of erector spinae in prepubertal children and adults, in both males and females. Methods Fourteen prepubertal boys, 13 prepubertal girls, 14 adult men, and 13 adult women performed the Sorensen back isometric endurance test until exhaustion. The results of electromyographic (EMG) power spectral analysis of erector spinae were compared between both age groups and sexes. Results The slopes of EMG power spectral median and mean power frequency were significantly higher in males than in females, in both age groups. Furthermore, the slopes were significantly lower in prepubertal children than in adults, in both males and females. Conclusions Our results showed major differences in the fatigue threshold of the erector spinae between boys and girls and children and adults. The muscle fatigued faster in prepubertal boys and adult men than in prepubertal girls and adult women. In both sexes, a lower slope of EMG power spectrum parameters of the erector spinae was noted during endurance test in prepubertal children compared to adults.

We analyzed the functional properties of five single nucleotide polymorphisms (SNPs) in organic cation transporter OCT3 gene (SLC22A3) resulting in the amino acid changes with a transient expression system. Three SNPs (A116S, T400I, and A439V) exhibited reduced uptake of both [ 3H]histamine and [3H]MPP+, although their protein expressions were detected in the plasma membrane of transfected cells. This study suggests that the OCT3 variants will contribute to interindividual variations leading to the differences in cationic drug disposition as well as certain disease processes such as hypertension, allergic diseases, and neuropsychiatric diseases by the clearance of endogenous organic cations such as biogenic amines. Keywords:: organic cation transporter, single nucleotide polymorphism, histamine

Although IGF-I has been identified as an important growth factor for the skeleton, the role of IGF-I on embryonic bone development remains unknown. Here we show that, in IGF-I-deficient (IGF-I−/−) mice, skeletal malformations, including short-limbed dwarfism, were evident at days post coitus (dpc) 14.5 to 18.5, accompanied by delays of mineralization in the spinal column, sternum, and fore paws. Reduced chondrocyte proliferation and increased chondrocyte apoptosis were identified in both the spinal ossification center and the growth plate of long bones. Abnormal chondrocyte differentiation and delayed initiation of mineralization was characterized by small size and fewer numbers of type X collagen expressing hypertrophic chondrocytes and lower osteocalcin expression. The Indian hedgehog-PTHrP feedback loop was altered; expression of Indian hedgehog was reduced in IGF-I−/− mice in long bones and in the spine, whereas expression of PTHrP was increased. Our results indicate that IGF-I plays an important role in skeletal development by promoting chondrocyte proliferation and maturation while inhibiting apoptosis to form bones of appropriate size and strength.

The proton-coupled peptide transporter PEPT2 ( SLC15A2 ) mediates the high-affinity low-capacity transport of small peptides as well as various oral peptide-like drugs in the kidney. In contrast to its well-characterized transport properties, there is less information available on its regulatory mechanism, although the interaction of PEPT2 to the PDZ (PSD-95, DglA, and ZO-1)-domain protein PDZK1 has been preliminarily reported. To examine whether PDZK1 is a physiological partner of PEPT2 in kidneys, we started from a yeast two-hybrid screen of a human kidney cDNA library with the C-terminus of PEPT2 (PEPT2 C-terminus (PEPT2-CT)) as bait. We could identify PDZK1 as one of the positive clones. This interaction requires the PDZ motif of PEPT2-CT detected by a yeast two-hybrid assay, in vitro binding assay and co-immunoprecipitation. The binding affinities of second and third PDZ domains of PDZK1 to PEPT2-CT were measured by surface plasmon resonance. Co-immunoprecipitation using human kidney membrane fraction and localization of PEPT2 in renal apical proximal tubules revealed the physiological meaning of this interaction in kidneys. Furthermore, we clarified the mechanism of enhanced glycylsarcosine (Gly-Sar) transport activity in PEPT2-expressing HEK293 cells after the PDZK1 coexpression. This augmentation was accompanied by a significant increase in the V max of Gly-Sar transport via PEPT2 and it was also associated with the increased surface expression level of PEPT2. These results indicate that the PEPT2–PDZK1 interaction thus plays a physiologically important role in both oligopeptide handling as well as peptide-like drug transport in the human kidney.

We propose a new CAM architecture for the large-scale integration and low-power operation of a network router application. This CAM reduces entry count by an average of 52%, using a newly developed one-hot-spot block code. This code eliminates redundancy in a memory cell and improves the efficiency of IP address compression. To implement the proposed code, a hierarchical match-line structure and an on-chip entry compression/extraction scheme are introduced. With this architecture, a search-depth control scheme deactivates unnecessary search lines and reduces power consumption by 45%. Using a DRAM cell, our new content addressable memory (CAM) can achieve 1.5 million entries in 0.13-/spl mu/m technology, which is six times more than a conventional static ternary CAM.

We analyzed the effect of unloading by tail suspension on the anabolic action of intermittent PTH in the tibia of growing mice. Unloading alleviated the PTH-induced increase of bone formation and accelerated bone resorption, consequently reducing bone mass. Reduction of the PTH-induced anabolic actions on bone was associated with unloading, which was apparently related to suppression of c-fos mRNA expression in bone marrow. Introduction: The effects of intermittent parathyroid hormone (PTH) administration on unloading bone have not been well elucidated at the cellular and molecular levels. We tested the effects of PTH on unloaded tibias of tail-suspended mice. Materials and Methods: Eighty male C57BL/6J mice, 8 weeks of age, were divided into four groups with loading or unloading and administration of PTH (40 μg/kg body weight) or vehicle five times per week. Mice were killed at 8 or 15 days, and both tibias were obtained. Bone histomorphometry of the trabecular bone in the proximal tibia, development of osteogenic cells, and mRNA expression of osteogenic molecules in bone marrow cells were assessed. Results and Conclusions: At 15 days of unloading, bone volume decreased in PTH-treated mice. The increase in the bone formation rate by PTH was depressed, and the osteoclast surface was thoroughly increased. The increase in alkaline phosphatase-positive colony-forming units-fibroblastic (CFU-f) colonies induced by PTH was maintained and that of TRACP+ multinucleated cells enhanced. The PTH-induced increase in c-fos mRNA was depressed, but the increases in Osterix and RANKL mRNA were maintained. Unloading promoted the PTH-associated osteoclastogenesis and seemed to delay the progression of osteogenic differentiation in association with reduction of the PTH-dependent increase of c-fos mRNA in bone marrow cells.

Skeletal unloading results in an inhibition of bone formation associated with a decrease in osteoblast number, impaired mineralization of bone, and altered proliferation and differentiation of osteoprogenitor cells. Although such changes are likely to be mediated by multiple factors, resistance to the growth-promoting action of insulin-like growth factor I (IGF-I) has been hypothesized to play an important role. To determine whether skeletal unloading induces resistance to IGF-I on bone formation, we examined the response of unloaded (hindlimb elevation) and normally loaded tibia and femur to IGF-I administration. To eliminate the variable of endogenous growth hormone production and secretion during exogenous IGF-I administration, we used growth hormone-deficient dwarf rats (dw-4). The rats were given IGF-I (2.5 mg/kg/day) or vehicle during 7 and 14 days of unloading or normal loading. This significantly increased the serum level of IGF-I in both the normally loaded and unloaded rats. Unloading did not affect the serum level of IGF-I in the vehicle-treated rats. IGF-I markedly increased periosteal bone formation at the tibiofibular junction of normally loaded rats. Unloading decreased bone formation in the vehicle-treated rats, and blocked the ability of IGF-I to increase bone formation. On the other hand, IGF-I increased periosteal bone formation at the midpoint of the humerus (normally loaded in this model) in both hindlimb-elevated and normally loaded rats. IGF-I significantly increased osteogenic colony number, total ALP activity, and total mineralization in bone marrow osteoprogenitor (BMOp) cells of normally loaded rats. Unloading reduced these parameters in the vehicle-treated rats, and blocked the stimulation by IGF-I. Furthermore, IGF-I administration (10 ng/ml) in vitro significantly increased cell proliferation of the BMOp cells isolated from normally loaded bone, but not that of cells from unloaded bone. These results indicate that skeletal unloading induces resistance to IGF-I on bone formation.

In general, an unstructured grid technique has a good flexibility for a complex geometry, and already its usefulness has been demonstrated for full aircraft computations. In the case of three-dimensional, high Reynolds number viscous flow calculations, however, the very fine and stretched grids are required to resolve accurately thin boundary layers developed along the body surface, and so we often have some difficulties in high quality grid generation. A hybrid unstructured grid technique is incorporated into CASPER, a CFD-based design system developed at TRDI-JDA. In this paper, transonic and high Reynolds number flows around an ONERA Model M5 configuration are computed using the CASPER. To validate the present code, with respect to pressure distributions, longitudinal forces and moment coefficients, and transition lines, the present computed results are quantitatively compared with the other computed results and wind-tunnel testing data. Furthermore, some approaches are discussed for reliable drag prediction using CFD method.

To test the hypothesis that the effect of trabecular microarchitecture on bone strength varies with the duration of estrogen loss, we evaluated the relationship between three-dimensional (3D) parameters for trabecular microarchitecture and bone minerals with the compressive load of the lumbar vertebra in rats. Female Sprague-Dawley rats (n = 190) were divided into 19 groups. Ten rats were killed at day 0. Half of the remaining rats underwent bilateral ovariectomy (ovx), and the others were subjected to sham surgery. Ten rats from each group were killed at 3, 7, 11, 14, 28, 42, 56, 70, and 84 days postsurgery. Urinary deoxypyridinoline and serum osteocalcin increased significantly in the ovx group from days 28 and 11, respectively, compared with the sham group. Bone mineral content (BMC) and bone mineral density (BMD) of the fifth lumbar body diminished from days 42 and 84, respectively, compared with the sham group. In ovx rats, trabecular bone volume (BV/TV), measured using 3D images of microcomputed tomography, diminished from day 28 compared with both baseline control and sham. The trabecular bone pattern factor (TBPf) and structure model index (SMI) increased from day 28 in the ovx group compared with both baseline control and sham. Ultimate compression loads diminished at day 28 compared with baseline control and decreased progressively thereafter. Neither of these parameters changed in the sham group during the same period. Within 4 weeks post-ovx, TBPf, SMI, and BV/TV correlated with load (p < 0.01). BMC and BMD correlated with load from 6 weeks post-ovx (p < 0.01). Stepwise regression analysis showed that TBPf was the most significant determinant of load within 4 weeks post-ovx (coefficient of determination [R(2)] = 0.669; p < 0.01). SMI correlated with TBPf (R(2) = 0.968; p < 0.01). Moreover, R(2) for ultimate load indicated higher values of 0.975 with TBPf and SMI. However, BMC was the most significant determinant of load from 6 weeks post-ovx (R(2) = 0.511; p < 0.01), as it was in the sham group. These data suggest that changes in trabecular bone contour with increased bone turnover are critical for reducing lumbar bone strength during the early post-ovx period in rats.

ddY mice, 6 weeks of age, were neurectomized (Nx) in the right hindlimbs and sham-operated (Sham) in the left limbs for evaluation of the effects of intermittent injections of human parathyroid hormone (hPTH) on trabecular bone turnover and bone marrow cell development in unloaded and loaded limbs. Mice were given subcutaneous injections of hPTH(1-34) five times a week at a dose of 0 (vehicle), 4 (low dose), or 40 (high dose) microg/kg of body weight for 2, 4, or 6 weeks. Histomorphometric analyses of the trabecular bone of the proximal tibiae revealed that high-dose hPTH injections preserved the trabecular bone volume of the Nx limbs, which was reduced after neurectomy, at the same level as that of the contralateral Sham limbs. The mineral apposition rate in the Nx limbs was elevated to values above even that of the Sham limbs by high-dose hPTH injections. The bone formation rate reduced by neurectomy was maintained at the Sham level by low- and high-dose hPTH injections. The neurectomy-induced increase in osteoclast number was suppressed by high-dose hPTH injections. In the bone marrow cells, the numbers of nonadherent and adherent cells per tibia obtained from the Nx and Sham limbs did not change. The hPTH injections decreased the numbers of nonadherent cells and increased those of adherent cells in both the Nx and the Sham limbs, but the effects were less marked in the Nx than in the Sham limbs even at high-dose injections. The formation of osteogenic nodules in the marrow cultures obtained from the Nx limbs was decreased after surgery and was maintained at the level of the Sham limbs by high-dose hPTH injections. The number of osteoclast-like multinucleated cells was reduced in the Sham limbs by high-dose hPTH injections. The value was increased at 2 weeks after neurectomy, but it was maintained at the Sham level by high-dose hPTH injections through the experimental period. The numbers of colony forming units-fibroblastic, which were reduced by neurectomy, and those of colony forming units for granulocytes and macrophages were not altered by hPTH injections. These results demonstrate that intermittent high-dose hPTH administration in the Nx limbs as well as in the contralateral Sham limbs has similar anabolic effects, stimulating osteoblast cell lineage and suppressing osteoclast cell lineage. The anabolic effects at 4 microg were reduced, but the effects at 40 microg seemed to be less affected by unloading due to sciatic neurectomy.

Here we demonstrate the presence of the A'-RNA conformation using the single crystal structure of a tridecamer: r(UGAGCUUCGGCUC). The average A'-RNA conformation deduced from X-ray fiber diffraction data had only been available previously, but now the presence of the A'-RNA conformation has been found in a single crystal structure for the first time. Statistical analysis showed that the A'-RNA conformation is distinguishable from the A-RNA conformation in a plot of the major groove width against the base pair inclination angle. The major groove of the A'-RNA conformation is wide enough to accommodate a protein or peptide while that of the A-RNA conformation is too narrow to do so. The presence of the A'-RNA conformation is significant for protein-RNA interaction.

A precise on-chip voltage generator for gigascale DRAM's with a negative word-line scheme is described. It combines a charge-pump regulator and a series-pass regulator, and it also includes a positive and negative offset voltage generator that uses a bandgap generator with a differential amplifier. The proposed circuit was experimentally evaluated with a test device fabricated using a 0.3-/spl mu/m process. The simulation results show that the series-pass regulator suppresses the noise on a word-line low voltage (negative) to below 30 mV for the word-line transient and V/sub BB/ bouncing. A dc-voltage error of less than 6% without trimming is confirmed for the positive and negative offset voltage generator through the test device. These results show that the described scheme can be used in future low-voltage gigascale DRAM's.

A charge-share modified (CSM) precharge-level architecture for selective subdataline activation designed to simultaneously achieve high-speed and low-power ferroelectric nonvolatile memories is described. In this architecture, to read the data of only one memory cell destructively, the precharge level of the selected subdataline is modified by charge-sharing between the subdataline and main dataline. This architecture enables high-speed read operations, because the operations of modifying the precharge level and reading the data of memory cells are achieved simultaneously. Three circuit technologies are used in the CSM architecture to increase the operating margin: self-timing precharge circuits which solve the polarization disturbance problem without adding extra signal lines or timing margins, a boosted precharge level technique which increases the signal voltage of the nonvolatile data, and shared dummy cell circuits which improve the precision of the reference voltage over that of a conventional voltage generator. These techniques and circuits are evaluated for a simulated 16-Mb ferroelectric memory. They reduce the access time by 20 ns to 51 ns compared with the conventional architecture, while reducing the memory array current to less than 1% that of the all-subdataline activation technology.

A distributed-column-control architecture is proposed to reduce the burst-mode cycle time of large-capacity DRAMs. It features independent operation of the I/O block and subarrays, eliminating the wiring delay in the internal buses from the longest pipeline stage. The timing difference between the I/O block and the subarrays is compensated for by event-driven circuits. This architecture also eliminates the timing margin between the activation of column selection lines, reducing the cycle time by 25%. To evaluate this architecture, an experimental synchronously operating 1-Gb DRAM was designed and fabricated using a 0.16-/spl mu/m CMOS process. It operates with a 22O-MHz clock and a 1.5-V power supply.

The proposed ringing-canceling output buffer transmits a superimposed two-step pulse that almost completely cancels the ringing in the received waveform. Simulation showed that this circuit increases the noise margin by a factor of 2.6 compared to using a conventional circuit in a bus interface at a data rate of 200 MHz. A test circuit was designed and fabricated to experimentally verify the fundamental ringing-canceling effect. Compared with other approaches to reducing ringing, the ringing-canceling output buffer provides a bigger improvement in the noise margin with a smaller signal-delay. This output buffer is promising for improving the data transfer rate of the memory bus.

Background context Previous studies reported that the erector spinae muscle is more resistant to fatigue in healthy adult women than in men. However, no study has reported changes in back muscle fatigue with aging in healthy men and women. Purpose The aim of this study was to evaluate age-related changes in muscle fatigue of erector spinae muscle in men and women. Study design/setting This cross-sectional study was conducted in a laboratory. Patient sample Fifty-three healthy subjects (11 elderly men, 11 elderly women, 17 young men, and 14 young women) without low back pain history. Outcome measures The median frequency (MF) and mean power frequency (MPF) during trunk holding test were derived from the raw electromyographic (EMG) signal using Fast Fourier Transform spectrum analysis program. The rates of changes in MF and MPF were calculated. Methods Subjects performed the unsupported trunk holding test until exhaustion. The results of power spectral analysis of the EMG activity of the left erector spinae muscle were compared in both age groups and sexes. Results The endurance time in young men was significantly shorter than in young women. The slopes of MF and MPF in young men were significantly higher than in young women. There were no significant differences in MF and MPF slopes of elderly men and elderly women. Furthermore, the MF and MPF slopes were significantly lower in elderly men than young men but similar in the two women groups. Conclusions Age-related changes in the slopes of MF and MPF of erector spinae muscle occur in healthy men but not in healthy women.

Two subthreshold-current reduction circuit schemes are described to suppress the increase in current in multi-gigabit DRAM's. One is a hierarchical power-line scheme for iterative circuits. In this scheme, a group of circuits is divided into blocks; only the selected block is supplied with power, while the subthreshold current to the many nonselected blocks is reduced. This scheme minimizes the number of circuits carrying the large subthreshold current. Applications of this scheme to word drivers, decoders and sense-amplifier driving circuits are shown. The other scheme is a switched-power-supply inverter with a level holder for random combinational logic circuits. In the active mode of the chip, the operating period of the inverter is distinguished from the inactive period. The inverter is supplied with power only in the operating period, while in the inactive period the subthreshold current is shut off and the output level is kept by the flip-flop level holder. This scheme shortens the period in which the large subthreshold current flows. Both schemes are evaluated for a conceptually-designed 16-Gb DRAM. They reduce its active current by ten-fold from the conventional 1.2 A to 116 mA. >