The efficacy of add-on tacrolimus for minor flare in patients with systemic lupus erythematosus: a retrospective study.

OBJECTIVE: We have assessed the effectiveness of tacrolimus for minor flares in systemic lupus erythematosus (SLE) patients. METHODS: The medical records of 313 patients were retrospectively reviewed over a period of seven years, from 2006 to 2013. We enrolled patients with minor flare treated with add-on tacrolimus, without glucocorticoid (GC) intensification (tacrolimus group). Minor flare was defined as a ≥ 1-point increase in a total score between 3 and 11 in the SLE Disease Activity Index (SLEDAI). We enrolled as controls patients who were administered increased doses of GC for minor flare (GC group). All patients were followed for one year. The primary outcome measure was the proportion of responders. RESULTS: There were 14 eligible patients in the tacrolimus group and 20 eligible patients in the GC group. The mean SLEDAI at flare tended to be higher in the tacrolimus group than in the GC group (7.5 vs. 6.2, p = 0.085). A mean dose of 1.6 mg tacrolimus/day was administered for flare, while the mean GC dose was 13.7 mg/day in the GC group. The proportion of responders was 86% (12/14) in the tacrolimus group and 75% (15/20) in the GC group (p = 0.67). The mean dose of GC at 12 months was higher in the GC group than in the tacrolimus group (9.7 mg/day vs. 7.1 mg/day, p < 0.05). Only one patient discontinued tacrolimus because of fatigue after three months. CONCLUSION: Adding tacrolimus without increasing the GC dose may provide an effective treatment option for minor flares in patients with SLE.

Neural depolarization triggers Mg2+ influx in rat hippocampal neurons.

Homeostasis of magnesium ion (Mg(2+)) plays key roles in healthy neuronal functions, and deficiency of Mg(2+) is involved in various neuronal diseases. In neurons, we have reported that excitotoxicity induced by excitatory neurotransmitter glutamate increases intracellular Mg(2+) concentration ([Mg(2+)]i). However, it has not been revealed whether neuronal activity under physiological condition modulates [Mg(2+)]i. The aim of this study is to explore the direct relationship between neural activity and [Mg(2+)]i dynamics. In rat primary-dissociated hippocampal neurons, the [Mg(2+)]i and [Ca(2+)]i dynamics were simultaneously visualized with a highly selective fluorescent Mg(2+) probe, KMG-104, and a fluorescent Ca(2+) probe, Fura Red, respectively. [Mg(2+)]i increase concomitant with neural activity by direct current stimulation was observed in neurons plated on an indium-tin oxide (ITO) glass electrode, which enables fluorescent imaging during neural stimulation. The neural activity-dependent [Mg(2+)]i increase was also detected in neurons whose excitability was enhanced by the treatment of a voltage-gated K(+) channel blocker, tetraethylammonium (TEA) at the timings of spontaneous Ca(2+) increase. Furthermore, the [Mg(2+)]i increase was abolished in Mg(2+)-free extracellular medium, indicating [Mg(2+)]i increase is due to Mg(2+) influx induced by neural activity. The direct neuronal depolarization by veratridine, a Na(+) channel opener, induced [Mg(2+)]i increase, and this [Mg(2+)]i increase was suppressed by the pretreatment of a non-specific Mg(2+) channel inhibitor, 2-aminoethoxydiphenyl borate (2-APB). Overall, activity-dependent [Mg(2+)]i increase results from Mg(2+) influx through 2-APB-sensitive channels in rat hippocampal neurons.

Effects of heat exposure in the absence of hyperthermia on power output during repeated cycling sprints.

The aim of this study was to investigate the effects of heat exposure in the absence of hyperthermia on power output during repeated cycling sprints. Seven males performed four 10-s cycling sprints interspersed by 30 s of active recovery on a cycle ergometer in hot-dry and thermoneutral environments. Changes in rectal temperature were similar under the two ambient conditions. The mean 2-s power output over the 1st-4th sprints was significantly lower under the hot-dry condition than under the thermoneutral condition. The amplitude of the electromyogram was lower under the hot-dry condition than under the thermoneutral condition during the early phase (0-3 s) of each cycling sprint. No significant difference was observed for blood lactate concentration between the two ambient conditions. Power output at the onset of a cycling sprint during repeated cycling sprints is decreased due to heat exposure in the absence of hyperthermia.

Oscillation in O2 uptake in impulse exercise.

The purpose of the present study was to examine 1) whether O(2) uptake (VO(2)) oscillates during light exercise and 2) whether the oscillation is enhanced after impulse exercise. After resting for 1 min on a bicycle seat, subjects performed 5-min pre-exercise with 25 watts work load, 10-s impulse exercise with 200 watts work load and 15-min post exercise with 25 watts work load at 80 rpm. VO(2) during pre-exercise significantly increased during impulse exercise and suddenly decreased and re-increased until 23 s after impulse exercise. In the cross correlation between heart rate (HR) and VO(2) after impulse exercise, VO(2) strongly correlated to HR with a time delay of -4 s. Peak of power spectral density (PSD) in HR appeared at 0.0039 Hz and peak of PSD in VO(2) appeared at 0.019 Hz. The peak of the cross power spectrum between VO(2) and HR appeared at 0.0078 Hz. The results suggested that there is an oscillation in O(2) uptake during light exercise that is associated with the oscillation in O(2) consumption in active muscle. The oscillation is enhanced not only by change in O(2) consumption but also by O(2) content transported from active muscle to the lungs.

Effect of work intensity on time delay in mediation of ventilation by arterial carbon dioxide during recovery from impulse exercise.

Time delay in the mediation of ventilation (V(.)E) by arterial CO(2) pressure (PaCO(2)) was studied during recovery from short impulse-like exercises with different work loads of recovery. Subjects performed two tests including 10-s impulse like exercise with work load of 200 watts and 15-min recovery with 25 watts in test one and 50 watts in test two. V(.)E, end tidal CO(2) pressure (PETCO(2)) and heart rate (HR) were measured continuously during rest, warming up, exercise and recovery. PaCO(2) was estimated from PETCO(2) and tidal volume (V(T)). Results showed that predicted arterial CO(2) pressure (PaCO(2 pre)) increased during recovery in both tests. In both tests, V(.)E increased and peaked at the end of exercise. V(.)E decreased in the first few seconds of recovery but started to increase again. The highest correlation coefficient between PaCO(2 pre) and V(.)E was obtained in the time delay of 7 s (r=0.854) in test one and in time delays of 6 s (r=0.451) and 31 s (r=0.567) in test two. HR was significantly higher in test two than in test one. These results indicate that PaCO(2 pre) drives V(.)E with a time delay and that higher work intensity induces a shorter time delay.

Oscillation of oxygenation in skeletal muscle at rest and in light exercise.

The aim of the present study was to compare the frequency of oxygenation determined in the vastus lateralis by near-infrared spectroscopy (NIRS) in light exercise with that at rest. A subject rested in a recumbent position for 5 min and changed body position to a sitting position on a cycle ergometer for 9 min. Then exercise with low intensity (work rate of 60% of maximal oxygen uptake) was carried out for 30 min. Total hemoglobin and myoglobin (THb/Mb) suddenly decreased after the start of exercise and gradually increased for 6 min. Oxygenated hemoglobin and myoglobin (Hb/MbO2) suddenly decreased and returned to a steady-state after the start of exercise. The difference between Hb/MbO2 and THb/Mb showed a sudden decrease and then a steady-state. This difference was analyzed by fast Fourier transform. The peak frequencies of the power spectrum density (PSD) were 0.0169 ± 0.0076 Hz at rest and 0.0117 ± 0.0042 Hz in exercise. The peak frequency of PSD was significantly decreased in exercise. In exercise, the range of frequencies was expanded. It is concluded that there are oscillations at rest as well as in exercise and that the frequency of peak PSD becomes lower in exercise than at rest.

Relationship between ventilation and predicted arterial CO2 pressure during recovery from an impulse-like exercise without metabolic acidosis.

We investigated ventilation (V(.)E) control factors during recovery from light impulse-like exercise (100 watts) with a duration of 20 s. Blood ions and gases were measured at rest and during recovery. V(.)E, end tidal CO(2) pressure (PETCO(2)) and respiratory exchange ratio (RER) were measured continuously during rest, exercise and recovery periods. Arterial CO(2) pressure (PaCO(2) (pre) was estimated from PETCO(2) and tidal volume (V(T)). RER at 20 s of exercise and until 50 s during recovery was significantly lower than RER at rest. Despite no change in arterialized blood pH level, PaCO(2) (pre) was significantly higher in the last 10 s of exercise and until 70 s during recovery than the resting value. V(.)E increased during exercise and then decreased during recovery; however, it was elevated and was significantly higher than the resting value until 155 s (p<0.05). There was a significant relationship between V(.)E and PaCO(2) (pre) during the first 70 s of recovery in each subject. The results suggest that PaCO(2) drives V(.)E during the first 70 s of recovery after light impulse-like exercise. Elevated V(.)E in the interval from 70 s until 155 s during recovery might be due to neural factors.

Comparison of oscillation of oxygenation in skeletal muscle between early and late phases in prolonged exercise.

The aim of the present study was to compare the oscillations of oxygenation in skeletal muscle between early and late phases in prolonged exercise. During prolonged exercise at 60 % of peak oxygen uptake (V(.)o(2)) for 60 min and at rest, oxygenated hemoglobin/myoglobin (Hb/MbO(2)) and total Hb/Mb (THb/Mb) were determined by near-infrared spectroscopy in the vastus lateralis. Power spectra density (PSD) for the difference between Hb/MbO(2) and THb/Mb (-HHb/MbO(2): deoxygenation) was obtained by fast Fourier transform at rest, in the early phase (1-6 min) and in the late phase (55-60 min) in exercise. Peak PSD in the early phase was significantly higher than that at rest. There were at least three peaks of PSD in exercise. The highest peak was a band around 0.01 Hz, the next peak was a band around 0.04 Hz, and the lowest peak was a band around 0.06 Hz. PSD in the early phase was not significantly different from that in the late phase in exercise. Heart rate (HR) showed a continuous significant increase from 3 min in exercise until the end of exercise. Skin blood flow (SBF) around the early phase was significantly lower than that around the late phase. It was concluded that oscillation of oxygenation in the muscle oxygen system in the early phase is not different from that in the late phase in prolonged exercise despite cardiovascular drift.

Effects of deception for intensity on surface electromyogram (SEMG) activity and blood lactate concentration during intermittent cycling followed by exhaustive cycling.

The purpose of the present study was to determine the effects of deception for exercise intensity on surface electromyogram (SEMG) activity and blood lactate concentration during intermittent cycling exercise (ICE) tests. Sixteen healthy male were randomly assigned to two groups who completed two ICE [three 4-min cycling at 80% peak power output (PPO) with 3-min passive recovery periods followed by exhaustive cycling] tests (ICE-1 and ICE-2). The experimental group (ICED) was deceived of the actual cycling intensity, while the control group (ICEC) was informed of the actual protocol in ICE-2. In ICE-1, both groups were informed of the actual protocol. In ICE-2, root mean square (RMS) calculated from SEMG during submaximal cycling was significantly higher in the ICEC than in the ICED and blood lactate concentration ([La-]) was significantly higher in the ICEC than in the ICED. In particular, the difference in RMS between the groups was also observed during the first 4-min cycling, in which there was no difference in [La-] between the groups. These results suggest that the CNS modulates skeletal muscle recruitment due to the prior deception for exercise intensity.

Effect of arterial carbon dioxide on ventilation during recovery from impulse exercises of various intensities.

To determine that whether arterial carbon dioxide (PaCO2) affects ventilation (VE) during recovery from impulse-like exercises of various intensities, subjects performed four impulse-like tests with different workloads. Each test consisted of a 20-sec impulse-like exercise at 80 rpm and 60-min recovery. Blood samples were collected at rest and during recovery to measure blood ions and gases. VE was measured continuously during rest, exercise and recovery periods. A significant curvilinear relationship was observed between VE and pH during recovery from the 300- and 400-watt tests in all subjects. VE was elevated during recovery from the 100-watt test despite no change in any of the humoral factors. Arterialized carbon dioxide (PaCO2) kinetics showed fluctuation, being increased at 1 min and decreased at 5 min during recovery, and this fluctuation was more enhanced with increase in exercise intensity. There was a significant relationship between VE and PaCO2 during recovery from the 300- and 400-watt tests in all subjects. The results of the present study demonstrate that pH and neural factors drive VE during recovery from impulse-like exercise and that fluctuation in PaCO2 controls VE as a feedback loop and this feedback function is more enhanced as the work intensity increases.

Effects of humoral factors on ventilation kinetics during recovery after impulse-like exercise.

To clarify the ventilatory kinetics during recovery after impulse-like exercise, subjects performed one impulse-like exercise test (one-impulse) and a five-times repeated impulse-like exercises test (five-impulse). Duration and intensity of the impulse-like exercise were 20 sec and 400 watts (80 rpm), respectively. Although blood pH during recovery (until 10 min) was significantly lower in the five-impulse test than in the one-impulse test, ventilation (.VE) in the two tests was similar except during the first 30 sec of recovery, in which it was higher in the five-impulse test. In one-impulse, blood CO2 pressure (PCO2) was significantly increased at 1 min during recovery and then returned to the pre-exercise level at 5 min during recovery. In the five-impulse test, PCO2 at 1 min during recovery was similar to the pre-exercise level, and then it decreased to a level lower than the pre-exercise level at 5 min during recovery. Accordingly, PCO2 during recovery (until 30 min) was significantly lower in the five-impulse than in one-impulse test..VE and pH during recovery showed a curvilinear relationship, and at the same pH, ventilation was higher in the one-impulse test. These results suggest that ventilatory kinetics during recovery after impulse-like exercise is attributed partly to pH, but the stimulatory effect of lower pH is diminished by the inhibitory effect of lower PCO2.

SU-E-T-196: Commissioning for Volumetric Modulated Radiation Therapy on Varian Clinac 21EX.

PURPOSE: Recently the volumetric arc therapy (VMAT) technology such as RapidArc is widely distributed in Japan. These technologies are normally provided by the high spec linear accelerator such as Trilogy, Novalis Tx, Synergy, et al. The specific DICOM-file is generally used for commissioning of these technologies. On the other hand, we had to apply RapidArc into historic linear accelerator. This title expresses an experience how we performed the commissioning of RapidArc with the old linear accelerator. METHODS: Two Varian's linear accelerators "Clinac 21EX" equipped with Millenium multi-leaf collimator and a Varian's treatment planning system "Eclipse ver.8.9" were used for this study. The commissioning for RapidArc was performed in energy 4,6,10,15 MV (Max-DR: 250, 600, 400, 600 MU/min). Commissioning procedure composed two categories: the general machine QA for DMLC-IMRT procedure and the specific RapidArc QA procedure. In RapidArc QA procedure, we modified DICOM-file to apply into the potential spec of Clinac 21EX optimally. The specific MLC-motion sequence and the gantry rotation speed were created by the dedicated programs (Shaper and DicomEdit, Varian) for RapidArc QA procedure. Each tolerance value was defied by the data from daily/monthly QA and the paper by Ling et al. RESULTS: As the results of the general machine QA procedure, the variance of radiation output during static/dynamic gantry rotation was less than 1%. The deference of fence tests during static/dynamic gantry rotation and RapidArc were less than 1 mm in each. However, the results of the RapidArc QA were worse than the latest machine (especially variable gantry speed) and it was careful to define tolerance level. CONCLUSION: The procedure of commissioning for RapidArc on historic linear accelerator was proposed. Several minor revisions for DICOM-file should be required for suitable commissioning and it may ensure the tolerance limit for gantry/MLC-leaf motion speeds.

Co[V2]o4: a spinel approaching the itinerant electron limit.

Studies of the structure, magnetization, and resistivity under pressure on stoichiometric normal spinel Co[V(2)]O(4) single crystals show (i) absence of a structural distortion, (ii) abnormal magnetic critical exponents, and (iii) metallic conductivity induced by pressures at low temperatures. All these results prove that Co[V(2)]O(4) sits on the edge of the itinerant-electron limit. Compared with similar measurements on Fe[V(2)]O(4) and other A[V(2)]O(4) studies, it is shown that a critical V-V separation for a localized-itinerant electronic phase transition exists.

Effects of mechanical stimulation by a powered toothbrush on the healing of periodontal tissue in a rat model of periodontal disease.

BACKGROUND AND OBJECTIVE: Elimination of pathogens is the main aim of periodontal treatment; however, modulation of the host immune response should also be considered. This study aimed to evaluate the effects of mechanical stimulation on periodontal healing in rats. MATERIAL AND METHODS: Before starting the experiment, lipopolysaccharide and proteases were applied once a day, for 4 wk, to both maxillary first molars of 30 rats to induce periodontal disease, and the application was stopped at the end of the 4-wk period. The experiment started immediately following this pretreatment. In the experiment, the left palatal gingiva was stimulated once daily using a powered toothbrush and the right gingiva served as a control (no mechanical stimulation). Pathological changes, and proliferation and cell death in periodontal tissues, were evaluated histometrically and immunohistochemically at baseline (0 wk), and at 1 and 3 wk of stimulation. RESULTS: The control showed a reduction of polymorphonuclear leukocyte infiltration in connective tissue and an increase in the numbers of gingival and periodontal ligament fibroblasts. Mechanical stimulation reduced polymorphonuclear leukocyte infiltration and the area of destroyed collagen in connective tissue, and increased the number of gingival fibroblasts; however, it had no effect on alveolar bone and root resorption or on the number of periodontal ligament fibroblasts. CONCLUSION: Mechanical stimulation accelerated the healing of gingival inflammation by reducing the infiltration of polymorphonuclear leukocytes and enhancing fibroblast proliferation and collagen synthesis.

Relation of dietary preference to bite force and occlusal contact area in Japanese children.

The purpose of this study was to examine the relationship of dietary preference to bite force and occlusal contact area in Japanese elementary school children. A total of 348 children, aged 7-12 years, from two public elementary schools located in Okayama Prefecture, Japan, participated in the study. Clinical examination included decayed, missing and filled teeth (dmft and DMFT), and total numbers of deciduous and permanent teeth. Bite force and occlusal contact area were measured using a pressure-detecting sheet. Dietary preference was assessed using a questionnaire in which the answers were given in like/dislike form. Mann-Whitney U-test and multiple logistic regression analysis were applied to analyse the data. In multiple logistic regression analysis after adjustment for age, gender and total number of teeth present, children who liked cabbage and celery showed significantly higher bite force (P = 0.05 and P < 0.01, respectively) than those who disliked these. Children who liked cabbage and celery also showed higher occlusal contact area (P < 0.05 and P < 0.01, respectively) than those who disliked these. The Japanese elementary school children who liked hard foods such as cabbage and celery showed higher bite force and higher occlusal contact area than those who disliked these foods. A positive attitude towards harder food items might contribute to healthy development of the masticatory apparatus.

Identification of expressed genes characterizing long-term survival in malignant glioma patients.

Better understanding of the underlying biology of malignant gliomas is critical for the development of early detection strategies and new therapeutics. This study aimed to define genes associated with survival. We investigated whether genes coupled with a class prediction model could be used to define subgroups of high-grade gliomas in a more objective manner than standard pathology. RNAs from 29 malignant gliomas were analysed using Agilent microarrays. We identified 21 genes whose expression was most strongly and consistently related to patient survival based on univariate proportional hazards models. In six out of 10 genes, changes in gene expression were validated by quantitative real-time PCR. After adjusting for clinical covariates based on a multivariate analysis, we finally obtained a statistical significance level for DDR1 (discoidin domain receptor family, member 1), DYRK3 (dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 3) and KSP37 (Ksp37 protein). In independent samples, it was confirmed that DDR1 protein expression was also correlated to the prognosis of glioma patients detected by immunohistochemical staining. Furthermore, we analysed the efficacy of the short interfering RNA (siRNA)-mediated inhibition of DDR1 mRNA synthesis in glioma cell lines. Cell proliferation and invasion were significantly suppressed by siRNA against DDR1. Thus, DDR1 can be a novel molecular target of therapy as well as an important predictive marker for survival in patients with glioma. Our method was effective at classifying high-grade gliomas objectively, and provided a more accurate predictor of prognosis than histological grading.

Proteases augment the effects of lipopolysaccharide in rat gingiva.

OBJECTIVES: Lipopolysaccharide (LPS) and proteases have been implicated as important factors in the initiation and progression of human periodontal diseases. A single application of LPS or proteases is insufficient to induce periodontal pocket formation or periodontitis. The aim of the present study was to assess the combined effect of lipopolysaccharide and proteases on rat periodontal tissues, and create a periodontal disease model. MATERIALS AND METHODS: Forty male Wistar rats were divided into four groups: combination group (treated with both LPS and proteases solutions); LPS group; proteases group; and control. Each solution was introduced daily into the palatal gingival sulcus of maxillary molars for 8 weeks. The tissues were evaluated histometrically and immunohistochemically. RESULTS: In the LPS group, elongation of rete ridge, apical migration of junctional epithelium (JE), increased numbers of B cells in connective tissue, and resorption of alveolar bone were observed. In the proteases group, the increase in the number of infiltrating polymorphonuclear leukocytes and blood vessels in the connective tissue was greater than that of the LPS group. CONCLUSIONS: The effects of LPS on periodontal tissues differed from those of proteases. The addition of proteases augmented and increased the effects of LPS, which were apical migration, intraepithelial cleavage of JE, and increased B cell density. The lesions in the combination group resembled established lesions of human periodontitis, with the exception of the low density of plasma cells.

Vaccination of recurrent glioma patients with tumour lysate-pulsed dendritic cells elicits immune responses: results of a clinical phase I/II trial.

In this Phase I/II trial, the patient's peripheral blood dendritic cells were pulsed with an autologous tumour lysate of the glioma. Seven patients with glioblastoma and three patients with anaplastic glioma, ranging in age from 20 to 69 years, participated in this study. The mean numbers of vaccinations of tumour lysate-pulsed dendritic cells were 3.7 times intradermally close to a cervical lymph node, and 3.2 times intratumorally via an Ommaya reservoir. The percentage of CD56-positive cells in the peripheral blood lymphocytes increased after immunisation. There were two minor responses and four no-change cases evaluated by radiological findings. Dendritic cell vaccination elicited T-cell-mediated antitumour activity, as evaluated by the ELISPOT assay after vaccination in two of five tested patients. Three patients showed delayed-type hypersensitivity reactivity to the autologous tumour lysate, two of these had a minor clinical response, and two had an increased ELISPOT result. Intratumoral CD4+ and CD8+ T-cell infiltration was detected in two patients who underwent reoperation after vaccination. This study demonstrated the safety and antitumour effects of autologous tumour lysate-pulsed dendritic cell therapy for patients with malignant glioma.

Status of NAT screening for HCV, HIV and HBV: experience in Japan.

The first nationwide nucleic acid amplification testing (NAT) for hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus type 1 (HIV-1) of voluntarily donated blood after serological pre-screening and before release of cellular components and plasma for fractionation was implemented by the Japanese Red Cross Blood Transfusion Services. The NAT screening assay using multiplex reagent is time-saving, cost effective, and labour-saving procedure for all blood and blood products including short-shelf life platelets. During the 50-mini-pool NAT screening of serologically negative donations (February 1, 2001-April 30, 2001), we were able to screen out 112 HBV-positive, 25 HCV-positive, and 4 HIV-1 positive units from blood and blood components.

Induction of therapeutic antitumor antiangiogenesis by intratumoral injection of genetically engineered endostatin-producing Semliki Forest virus.

Antiangiogenic therapy using Semliki Forest virus (SFV) carrying Endostatin gene for malignant brain tumor was investigated to improve the therapeutic efficacy. The efficiency of SFV-mediated gene delivery was first evaluated for B 16 cells and compared with the efficiency in cells of endothelial origin (HMVECs). HMVECs are more susceptible to SFV infection than B 16 cells. For the in vivo treatment model, phosphate-buffered saline, SFV-LacZ, retrovirus vector GCsap-Endostatin, and SFV-Endostatin were injected to mice bearing B 16 brain tumors. A very significant inhibition of tumor growth was observed in the group that had been treated with SFV-Endostatin. A marked reduction of intratumoral vascularization was seen in the tumor sections from the SFV-Endostatin group compared with tumor sections from the SFV-LacZ or GCsap-Endostatin groups. Moreover, at day 7 after intravenous administration of SFV-Endostatin, the serum level of endostatin was augmented more than 3-fold compared to that after intravenous administration of GCsap-Endostatin. The results indicated that treatment with SFV-Endostatin inhibited the angiogenesis with established tumors. Gene therapy with Endostatin delivered via SFV may be a candidate for the development of new therapy for brain tumors.