Motion-Induced Transition of Positronium through a Static Periodic Magnetic Field in the Sub-THz Region.

Atoms moving in a static periodic field experience a time-dependent oscillating field in their own rest frame. By tuning the frequency, an atomic transition can be induced. So far, this type of transition has been demonstrated in the EUV region or at higher frequencies by crystalline fields and in the microwave region by artificial fields. Here, we present the observation of the transition of positronium (Ps) in the sub-THz region by using an energy-tunable Ps beam with a multilayered magnetic grating. This grating produces a microsized periodic field, whose amplitude corresponds to a huge energy flux of ∼100 MW cm^{-2}, resulting in the efficient magnetic dipole transition.

Effects of the time-of-day (morning vs. afternoon) of implementing a combined physical and cognitive exercise program on cognitive functions and mood of older adults: A randomized controlled study.

This study examined the effects of the time of conducting a combined physical and cognitive exercise program on cognitive functions and the mood of older adults. We randomly assigned 17 participants (8 men, 9 women, age 73,24±3,75) to the morning group (AM Group), 18 (8 men, 10 women, age 73,11±4,84) to the afternoon group (PM Group), and they completed a 12-week, dual-task exercise program in the morning or the afternoon, respectively. Moreover, the waiting-list control group consisted of 12 participants (6 men, 6 women, age 73,25±5,93). The cognitive functions and the mood of the participants were assessed before and after the program by using the Neurobehavioral Cognitive Status Examination, and the short version of the Profile of Mood States, respectively. As a result, the exercise program conducted in the afternoon had broader effects on cognitive functions (increased Repetition and Memory) than in the morning (increased Repetition), or the waiting-list control group (increased Judgment). Moreover, the program in the afternoon tended to reduce Anger-Hostility, and Fatigue. In conclusion, conducting the exercise program in the afternoon might be more effective for improving cognitive functions and the mood of older adults than in the morning. However, there was heterogeneity between the groups despite the randomization. Therefore, we suggest conducting a more rigorously controlled study using a larger sample to validate these findings.

Genetic analysis of adult leukoencephalopathy patients using a custom-designed gene panel.

Leukoencephalopathies encompass all clinical syndromes that predominantly affect brain white matter. Genetic diagnosis informs clinical management of these patients, but a large part of the genetic contribution to adult leukoencephalopathy remains unresolved. To examine this genetic contribution, we analyzed genomic DNA from 60 Japanese patients with adult leukoencephalopathy of unknown cause by next generation sequencing using a custom-designed gene panel. We selected 55 leukoencephalopathy-related genes for the gene panel. We identified pathogenic mutations in 8 of the 60 adult leukoencephalopathy patients (13.3%): NOTCH3 mutations were detected in 5 patients, and EIF2B2, CSF1R, and POLR3A mutations were found independently in 1 patient each. These results indicate that cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3 mutations is the most frequent adult leukoencephalopathy in our cohort. Moreover, brain imaging analysis indicates that CADASIL patients who do not present typical phenotypes may be underdiagnosed if not examined genetically.

First Findings in the Route of the Maize Bushy Stunt Phytoplasma Within Its Vector Dalbulus maidis (Hemiptera: Cicadellidae).

In the pathosystem of Dalbulus madis (DeLong & Wolcott) (Hemiptera: Cicadellidae), a vector of maize bushy stunt phytoplasma (MBSP), the interactions occurring during the passage, invasion, and multiplication of the phytoplasma inside the vector body have been generalized from other pathosystems, with a poor understanding of the specific interactions. With the aim to understand MBSP movement and potential specific interactions with its vector, D. maidis adults were dissected to obtain the intestine and salivary gland of both infected (acquisition access period=4 d; latent period=23 d) and noninfected individuals. The organs were processed for visualization with transmission electronic microscopy. Images of phytoplasma cells were observed in the alimentary canal, epithelium of the mesenteron, hemocele, and salivary gland of the vector, and were confirmed through observation of similar cells in maize roots with advanced disease symptoms. The study of the MBSP movement within its vector shows novel findings between the synergy of the MBSP phytoplasma and D. maidis.

Effect of hypoxia on UDP-glucuronosyl transferase mRNA expression in human hepatocarcinoma functional liver celL4 cell line.

Although hypoxic conditions have been reported to affect the expression levels of various enzymes like cytochrome P450, the effect of hypoxia for UDP-glucuronosyl transferase (UGT) expression has been unclear. We evaluated the mRNA expression of UGTs (UGT1A1·1A6·1A9·2B7) in a functional liver cell-4 (FLC-4) cell line by three-dimensional culture under hypoxic conditions (37 °C, 1% O2, 5% CO2) fo 7 days. The mRNA expression of UGT1A1·1A6·1A9·2B7 decreased significantly after 3 days and that of UGT1A1·1A6·1A9 decreased significantly after 7 days. Hypoxic conditions affect the expression levels of UGT enzymes, thus the adjustment of dosage and interval should be considered in drug therapy that metabolized by UGT.

The combination of strong expression of ZNF143 and high MIB-1 labelling index independently predicts shorter disease-specific survival in lung adenocarcinoma.

BACKGROUND: The transcription factor, zinc finger protein 143 (ZNF143), positively regulates many cell-cycle-related genes. The ZNF143 would show high expression of multiple solid tumours related closely to cancer cell growth, similar to the widely accepted Ki67 (MIB-1) protein, but the underlying mechanisms for ZNF143 remain unclear. We investigated the association of ZNF143 expression with clinicopathological features and prognoses of patients with lung adenocarcinoma. METHODS: Expressions of ZNF143 and MIB-1 were immunohistochemically analysed in 183 paraffin-embedded tumour samples of patients with lung adenocarcinoma. The ZNF143 expression was considered to be strong when >30% of the cancer cells demonstrated positive staining. RESULTS: Strong ZNF143+ expression showed a significantly close relationship to pathologically moderate to poor differentiation and highly invasive characteristics. The ZNF143 positivity potentially induced cell growth of lung adenocarcinoma, correlated significantly with high MIB-1 labelling index (⩾10%). Univariate and multivariate analyses demonstrated that both strong ZNF143+ and the high MIB-1 index group have only and significantly worse survival rates. CONCLUSIONS: The combination of strong ZNF143 expression and high MIB-1 index potentially predicts high proliferating activity and poor prognosis in patients with lung adenocarcinoma, and may offer a therapeutic target against ZNF143.

Overexpression of PFTK1 predicts resistance to chemotherapy in patients with oesophageal squamous cell carcinoma.

BACKGROUND: Recently, PFTK1 was identified as a member of the cyclin-dependent kinase family; however, its expression and clinical significance in oesophageal squamous cell carcinoma (ESCC) have not been evaluated. METHODS: PFTK1 expression was initially examined by expression microarray in 77 ESCC patients. Using independent samples of 223 patients, PFTK1 expression was evaluated immunohistochemically to assess the relationship between expression and various clinicopathological parameters. The association between PFTK1 and the response to chemotherapy was also investigated in pretreatment samples of 85 patients who received chemotherapy as first treatment. RESULTS: Significant upregulation of PFTK1 expression was noted in ESCC compared with normal epithelium. PFTK1 expression was positive in 51.6% (115 out of 223) of the tumours, but did not correlate with any clinicopathological parameter. The 5-year overall survival rate was poorer in patients positive for PFTK1 (43.6%) than those with negative expression (66.2%, P<0.001). Uni- and multivariate analyses identified PFTK1 as an independent marker of prognosis (RR=2.428, 95% CI=1.615-3.711, P<0.001). Out of 85 biopsy samples, 40 (47.1%) tumours showed PFTK1-positive expression, and the response rate to chemotherapy was significantly lower than PFTK1-negative tumours (27.9% vs 72.1%, P<0.001). CONCLUSION: PFTK1 is not only useful as a prognostic marker, but also as a predictor of the response to chemotherapy.

Thymidylate synthase (TS) gene expression in primary lung cancer patients: a large-scale study in Japanese population.

BACKGROUND: Previous small-sized studies showed lower thymidylate synthase (TS) expression in adenocarcinoma of the lung, which may explain higher antitumor activity of TS-inhibiting agents such as pemetrexed. PATIENTS AND METHODS: To quantitatively measure TS gene expression in a large-scale Japanese population (n = 2621) with primary lung cancer, laser-captured microdissected sections were cut from primary tumors, surrounding normal lung tissues and involved nodes. RESULTS: TS gene expression level in primary tumor was significantly higher than that in normal lung tissue (mean TS/ß-actin, 3.4 and 1.0, respectively; P < 0.01), and TS gene expression level was further higher in involved node (mean TS/ß-actin, 7.7; P < 0.01). Analyses of TS gene expression levels in primary tumor according to histologic cell type revealed that small-cell carcinoma showed highest TS expression (mean TS/ß-actin, 13.8) and that squamous cell carcinoma showed higher TS expression as compared with adenocarcinoma (mean TS/ß-actin, 4.3 and 2.3, respectively; P < 0.01); TS gene expression was significantly increased along with a decrease in the grade of tumor cell differentiation. There was no significant difference in TS gene expression according to any other patient characteristics including tumor progression. CONCLUSION: Lower TS expression in adenocarcinoma of the lung was confirmed in a large-scale study.

The endoscopic diagnosis of nonerosive reflux disease using flexible spectral imaging color enhancement image: a feasibility trial.

Nonerosive reflux disease (NERD) is classified into grade M (minimal change, endoscopically; erythema without sharp demarcation, whitish turbidity, and/or invisibility of vessels due to these findings) and grade N (normal) in the modified Los Angeles classification system in Japan. However, the classification of grades M and N NERD is not included in the original Los Angeles system because interobserver agreement for the conventional endoscopic diagnosis of grades M or N NERD is poor. Flexible spectral imaging color enhancement (FICE) is a virtual chromoendoscopy technique that enhances mucosal and vascular visibility. The aim of this study is to evaluate whether the endoscopic diagnosis of grades M or N NERD using FICE images is feasible. Between April 2006 and May 2008, 26 NERD patients and 31 controls were enrolled in the present study. First, an experienced endoscopist assessed the color pattern of minimal change in FICE images using conventional endoscopic images and FICE images side-by-side and comparing the proportion of minimal change between the two groups. Second, three blinded endoscopists assessed the presence or absence of minimal change in both groups using conventional endoscopic images and FICE images separately. Intraobserver variability was compared using McNemar's test, and interobserver agreement was described using the kappa value. Minimal changes, such as erythema and whitish turbidity, which were detected using conventional endoscopic images, showed up as navy blue and pink-white, respectively, in color using FICE images in the present FICE mode. The NERD group had a higher proportion of minimal change, compared with the control group (77% and 48%, respectively) (P= 0.033). In all three readers, the detection rates of minimal change using FICE images were greater than those using conventional endoscopic images (P= 0.025, <0.0001, and 0.034 for readers A, B, and C, respectively). The kappa values for all pairs of three readers using FICE images were between 0.683 and 0.812, while those using conventional endoscopic images were between 0.364 and 0.624. Thus, the endoscopic diagnosis of grades M or N NERD using FICE images is feasible and may improve interobserver agreement.

Prognostic significance of lymphovascular invasion for patients with stage I non-small cell lung cancer.

AIMS: This study retrospectively investigated the clinical significance of lymphovascular invasion (LVI) following a complete resection for stage I non-small cell lung cancer (NSCLC). METHODS: A total of 226 patients who underwent a complete resection for pathological stage I NSCLC were examined. RESULTS: Lymphatic invasion was pathologically diagnosed as ly0 in 156 patients, ly1 in 65, and ly2 in 5 patients. The pathological vascular invasion was diagnosed as v0 in 178 patients, v1 in 35, v2 in 10, and v3 in 3 patients. The 5-year survival rate after surgery of the patients with and without lymphatic invasion was 76.8 and 90.6%, respectively. There was a significantly more unfavorable prognosis in patients with lymphatic invasion (p = 0.042). The 5-year survival rate of the patients with vascular invasion was also significantly more unfavorable (67.8%) than that of patients without vascular invasion (90.4%; p = 0.004). LVI was found to significantly correlate with tumor size and the presence of pleural invasion. CONCLUSION: The LVI of NSCLC is a significant prognostic factor in patients with stage I tumors. In future clinical trials, it is necessary to evaluate the efficacy of adjuvant therapy for the selection of patients according to this criterion.

Uracil-tegafur and tamoxifen vs cyclophosphamide, methotrexate, fluorouracil, and tamoxifen in post-operative adjuvant therapy for stage I, II, or IIIA lymph node-positive breast cancer: a comparative study.

BACKGROUND: It has been reported that treatment with uracil-tegafur (UFT) has shown significantly better survival and relapse-free survival (RFS) than surgery alone. Therefore, we compared UFT with a combination therapy of cyclophosphamide, methotrexate, and fluorouracil (CMF) in patients who had undergone curative surgery for axillary lymph node-positive breast cancer. METHODS: A total of 377 node-positive patients with stage I, II, or IIIA disease were registered from September 1996 through July 2000 and were randomly assigned to either 6 cycles of CMF or 2 years of UFT. In both arms, tamoxifen (TAM) was concurrently administered for 2 years. The primary end point in this study was the non-inferiority of UFT to CMF. RESULTS: No statistically significant difference between the two groups was observed with regard to the 5-year RFS rate (72.2% in the UFT and 76.3% in the CMF). Adverse event profiles differed between the two groups, with a significantly lower incidence of leukopenia and anaemia in the UFT group, as well as anorexia, nausea/vomiting, stomatitis, and alopecia, which have implications for quality of life. CONCLUSION: UFT administered in combination with TAM holds promise in the treatment of lymph node-positive early breast cancer. On stratified analysis, the recurrence rate in the UFT group was found to be better in oestrogen receptor (ER)-positive patients. Tegafur-based treatment should be evaluated by a prospective randomised trial conducted in ER-positive patients.

Calcium/calmodulin-dependent protein kinase II (CaMKII) regulates tumour necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis of fibroblast-like synovial cells (FLS) by phosphorylation of Akt.

OBJECTIVE: We tried to determine whether calcium/calmodulin-dependent protein kinase II (CaMKII) regulates tumour necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis of fibroblast-like synovial cells (FLS). METHODS: CaMKII expression in FLS was studied by both western blotting and real time reverse transcription polymerase chain reaction (RT-PCR). TRAIL-mediated apoptosis of FLS was quantified by disruption of mitochondrial transmembrane potential (DeltaPsim), Leu-Glu-His-Asp (IETD) ase activity and DNA degradation. Involvement of CaMKII and other kinases, including extracellular signal-regulated kinase (ERK), p38, c-Jun N-terminal kinase (JNK) and Akt during TRAIL-mediated apoptosis of FLS was estimated by the use of specific each kinase chemical inhibitor. RESULTS: Predominant expression of delta and gamma isoform of CaMKII, especially delta isoform, was determined in cultured FLS. TRAIL rapidly induced apoptosis of FLS as well as the phosphorylation of extracellular signal-regulated kinase (ERK), p38, c-Jun N-terminal kinase (JNK) and Akt. Chemical kinase inhibitor toward CaMKII and Akt significantly augmented TRAIL-mediated apoptosis of FLS whereas those toward ERK, p38 and JNK did not. Notably, CaMKII chemical inhibitor abrogated TRAIL-induced phosphorylation of Akt. Elevation of Leu-Glu-His-Asp (IETD) ase activity was associated with the apoptotic phenomena, which was almost suppressed by IETD competitive peptides. CONCLUSION: Our results suggest a first observation that CaMKII regulates TRAIL-mediated apoptosis of FLS through Akt, standing an upstream of caspase-8-dependent cascades. Furthermore, CaMKII is suggested to be a new therapeutic target molecule of rheumatoid arthritis (RA).

A high-quality and energy-tunable positronium beam system employing a trap-based positron beam.

We constructed a new apparatus, built upon a trap-based slow positron beam, for the production of a collimated, energy-tunable positronium beam under ultra-high vacuum conditions employing the photodetachment of positronium negative ions. A slow positron generator consisting of a 22Na radioisotope (20 mCi) combined with a buffer-gas positron trap is employed to generate high-quality, nano-second positron bursts with a repetition rate of 1 Hz-1 kHz. The positron bursts are focused onto an efficient positron-to-positronium negative ion converter, a Na-coated W thin film in a transmission geometry, using a magnetic lens system. The ions emitted from the opposite surface of the film are electrostatically accelerated to a given energy and photodetached by a pulsed infrared laser to form a mono-energetic positronium beam with kinetic energies of 0.2 keV-3.3 keV. The achieved detection rate of Ps atoms is 23 cps at the energy of 3.3 keV with a signal-to-background ratio as high as 300. The energy spread of the beam was evaluated by comparing the result of the time-of-flight measurements and particle-tracking simulations. With the use of a collimator of 1 mm diameter, a coherent beam with an angular divergence of less than 0.3° is obtained. The obtained Ps beam, having a much higher quality than those reported hitherto, will open up a new field of experimental investigations, such as Ps interacting with a variety of materials and fundamental studies on Ps spectroscopy.

Mitotic centromere-associated kinesin is a novel marker for prognosis and lymph node metastasis in colorectal cancer.

Mitotic centromere-associated kinesin (MCAK) is a microtubule depolymerase that is essential for proper kinetochore-microtubule attachment during spindle formation. Overexpression of MCAK has been correlated with aggressive forms of carcinoma, resulting in poor prognosis of colorectal cancer. The purpose of this study was to quantify MCAK expression in malignant and benign colorectal tissues and to determine if MCAK expression levels correlate with clinicopathologic factors and prognosis in colorectal cancer patients. Paired colorectal tissue samples from tumours and the corresponding normal tissues were obtained from 120 patients with colorectal cancer who underwent surgical resection. The real-time reverse transcriptase-PCR and immunohistochemistry were used to analyse mRNA and protein expression status with respect to various clinicopathological factors. MCAK expression was higher in colorectal cancer tissue (P<0.01) than in corresponding normal tissue, and this elevated expression level was markedly associated with factors such as lymph node metastasis (P=0.0023), venous invasion (P=0.019), peritoneal dissemination (P=0.021) and Dukes' classification (P=0.0023). Patients with high MCAK mRNA expression also showed a far poorer survival rate than those with low MCAK mRNA expression (P<0.01). Elevated MCAK expression was an independent predictor of overall survival and lymph node metastasis. These data suggest that MCAK expression may serve as a good marker of prognosis and lymph node metastasis in colorectal cancer.

Neuropathic pain correlates with myelinated fibre loss and cytokine profile in POEMS syndrome.

OBJECTIVE: To reveal characteristic clinicopathological correlates of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS) syndrome. METHODS: The clinical features of 22 patients with POEMS syndrome were investigated and correlated with the histopathological features of sural nerves and serum cytokine profiles. RESULTS: More than half of the patients complained of pain in the lower extremities, which is closely related to hyperalgesia. Assessment of the total nerve fibre population using complete transverse sural nerve cross-sections, excluding the marked enlargement of endoneurial areas due to intrafascicular oedema, showed that myelinated fibres, especially small myelinated fibres, were reduced, whereas unmyelinated fibres were preserved. Uncompacted myelin lamellae and segmental demyelination were seen more frequently in the small, rather than the large, myelinated fibres. The presence of hyperalgesia was electrophysiologically associated with a reduction of sensory nerve action potentials in the sural nerve (p<0.05) and histopathologically associated with myelinated fibre loss (p<0.01). Serum levels of proinflammatory cytokines (interleukin-1beta, interleukin-6 and tumour necrosis factor-alpha), but not their soluble receptors, were significantly elevated in patients with hyperalgesia (p<0.05-0.01). CONCLUSIONS: Hyperalgesia seen in patients with POEMS syndrome is closely related with a reduction in the myelinated, but not unmyelinated, fibre population. Elevation of proinflammatory cytokines is also correlated with hyperalgesia. The painful symptoms in POEMS syndrome may be generated by well-preserved unmyelinated C-fibres due to the lack of inhibitory myelinated A-fibres, along with cytokine sensitisation.

Prevalence and incidence rates of chronic inflammatory demyelinating polyneuropathy in the Japanese population.

OBJECTIVE AND METHODS: To characterise the epidemiological features of chronic inflammatory demyelinating polyneuropathy (CIDP) in the Japanese population, this study performed a nationwide assessment of the prevalence and incidence rates in Japan. RESULTS: The prevalence rate per 100 000 was 1.61 in the total population; 2.01 in males and 1.23 in females. The age dependent prevalence rates were 0.23 in juveniles (<15 years old), 1.50 in young adults (15-55 years) and 2.31 in elderly adults (>55 years). The sex and age dependent prevalence rates were 0.22 in males and 0.24 in females in juveniles, 1.81 in males and 1.19 in females in young adults, and 3.12 in males and 1.64 in females in elderly adults. The annual incidence rate per 100 000 was 0.48 in the total population, 0.58 in males and 0.38 in females. The age dependent incidence rate was 0.06 in juveniles, 0.40 in young adults and 0.73 in elderly adults. The sex and age dependent incidence rate was 0.05 in males and 0.08 in females in juveniles, 0.50 in males and 0.30 in females in young adults, and 0.93 in males and 0.58 in females in elderly adults. Both the prevalence and incidence rates were very similar throughout the eight geographical areas studied, from the northern to the southern parts of Japan. CONCLUSIONS: The prevalence and incidence rates were similar to those reported in the Caucasian population. The pathogenic background is suggested to be common throughout the different races and geographic areas, while gender and age effects should be taken into account in the pathogenesis of CIDP.

Cognitive impairment in spinocerebellar ataxia type 6.

OBJECTIVE: The aim of this study was to evaluate cognitive impairment in patients with spinocerebellar ataxia type 6 (SCA6) and to verify the role of cerebellar involvement in intellectual abilities. METHODS: Cognitive function was examined in 18 patients with genetically confirmed SCA6 and in 21 age and education matched controls using a test battery for attention, verbal and visuospatial memory, as well as executive function. RESULTS: Verbal fluency and immediate visual memory task were markedly impaired in SCA6 compared with the control group (p = 0.007, 0.004 and 0.014, respectively). The results of the Rule Shift Cards Test was reduced in patients with SCA6, but the reduction was not significant. These cognitive dysfunctions did not correlated with CAG repeat length, age at onset, ataxic motor dysfunctional scale or depression. CONCLUSIONS: Our results demonstrate that specific cognitive deficits occur in patients with SCA6, independent of ataxic motor dysfunction. These deficits may reflect disruption of cortico-cerebellar circuits.

Prefrontal hypoperfusion and cognitive dysfunction correlates in spinocerebellar ataxia type 6.

OBJECTIVE: The aim of this study is to evaluate the correlation between brain perfusion and cognitive dysfunction in spinocerebellar ataxia type 6 (SCA6) patients. METHODS: Thirteen genetically confirmed SCA6 patients and 21 age- and education-matched control subjects were subjected to single photon emission computed tomography (SPECT) and neuropsychological tests. Brain perfusion was examined with SPECT analysis, while general cognition, verbal and visual memory, attention, visuospatial ability, language, executive function, depression, and anxiety were examined with the neuropsychological tests. RESULTS: SCA6 patients showed prefrontal hypoperfusion, and impairments of visual memory, verbal fluency, and executive function compared to control subjects. These neuropsychological impairments in SCA6 patients were significantly correlated with a decrease in prefrontal perfusion. This relation was not correlated to other factors, such as age, education and severity of cerebellar ataxia, which are possible relevant factors associated with cognitive performance. CONCLUSIONS: SCA6 patients have mild cognitive impairment, and correlating prefrontal hypoperfusion. These results indicate cognitive impairment in SCA6 patients resulting from prefrontal hypoperfusion.