Identification of Lepidapedon oregonense as the current world's deepest trematode.

The deepest recorded depth for trematodes currently stands at approximately 6200 m. This depth record was achieved solely through sequence datasets of Lepidapedon sp. obtained from a gastropod. Given that trematodes of this genus typically use fish as definitive hosts, the origin of the trematode sequence was thought to be larval stages. However, the specific species remained unclear owing to the absence of reported adult-stage sequences. In the present study, we definitively identified the deepest trematode as Lepidapedon oregonense by comparing 28S ribosomal DNA sequences from adult worms from the macrourid fish Coelorinchus gilberti with data from the gastropod in the previous study.

Programmed death-1 ligands and tumor infiltrating T lymphocytes in primary and lymph node metastasis of esophageal cancer patients.

Neoadjuvant chemotherapy (NAC) is administered to many patients with esophageal squamous cell carcinoma (ESCC) prior to surgery, but it is also true that some of these patients demonstrated no response to the therapy following surgery. In addition, the prognosis of advanced case such as ESCC patients with lymph node metastasis has remained relatively low. Programmed death ligand-1 (PD-L1) in conjunction with tumor-infiltrating lymphocytes (TILs) has been studied as a potential mechanism of "immune escape" in several human malignancies. Therefore, in this study, we studied PD-L1 status in carcinoma cells and forkhead box protein 3 (FOXP3) and CD8 status among TILs in the residual tumors of primary and metastatic sites following NAC. We also studied the association of these factors with the clinicopathological findings in 44 patients with ESCC harboring lymph node metastasis. There was discordance in the pathological response to chemotherapy between the primary tumor and lymph node metastasis, and histologically identified resistance to NAC in lymph node metastases tended to be correlated with an adverse clinical outcome (P = 0.0765) than resistance in the primary tumor. Both univariate and multivariate analyses for disease-specific survival (DSS) revealed that the PD-L1 status of carcinoma cells in metastatic lymph nodes and a higher FOXP3/CD8 ratio in the primary tumor were both significantly correlated with an eventual adverse clinical outcome of the patients (P = 0.0178, P = 0.0463, respectively). These results all indicated that the PD-L1 status of carcinoma cells in metastatic lymph nodes and the FOXP3/CD8 ratio in primary tumors could predict eventual clinical outcomes in ESCC patients with NAC.

Anharmonicity in a double hydrogen transfer reaction studied in a single porphycene molecule on a Cu(110) surface.

Anharmonicity plays a crucial role in hydrogen transfer reactions in hydrogen-bonding systems, which leads to a peculiar spectral line shape of the hydrogen stretching mode as well as highly complex intra/intermolecular vibrational energy relaxation. Single-molecule study with a well-defined model is necessary to elucidate a fundamental mechanism. Recent low-temperature scanning tunnelling microscopy (STM) experiments revealed that the cis↔cis tautomerization in a single porphycene molecule on Cu(110) at 5 K can be induced by vibrational excitation via an inelastic electron tunnelling process and the N-H(D) stretching mode couples with the tautomerization coordinate [Kumagai et al. Phys. Rev. Lett. 2013, 111, 246101]. Here we discuss a pronounced anharmonicity of the N-H stretching mode observed in the STM action spectra and the conductance spectra. Density functional theory calculations find a strong intermode coupling of the N-H stretching with an in-plane bending mode within porphycene on Cu(110).

Residual carcinoma cells after chemoradiotherapy for esophageal squamous cell carcinoma patients: striving toward appropriate judgment of biopsy.

In esophageal squamous cell carcinoma (ESCC) patients who are treated with chemoradiotherapy (CRT), identification of the presence or absence of residual or recurrent carcinoma is usually pivotal in their clinical management. In addition, the extent of carcinoma invasion into the esophageal wall could determine the clinical outcome of these patients following CRT. Therefore, in this study, we evaluated the response to CRT both macroscopically and histologically in a consecutive series of 42 ESCC patients receiving neoadjuvant chemoradiotherapy following curative esophageal resection at Tohoku University Hospital between August 2011 and December 2012. The histological grading of tumor regression was as follows: grade 3, markedly effective (no viable residual tumor cells); grade 2, moderately effective (residual tumor cells in less than one-third of the tumor); grade 1, slightly effective (1b, residual tumor cells in one-third to two-thirds of the tumor; 1a, residual tumor cells in more than two-thirds of the tumor); and grade 0, ineffective. In this study, we selected grade 2 and 1b cases because they might show a complete response with definitive CRT. We evaluated the presence of any residual in situ lesions and tumor depth in detail. The grading of tumor regression in primary sites was as follows: grade 3 (7 cases), grade 2 (16 cases), grade 1b (13 cases), and grade 1a (6 cases). The concordance rate between macroscopic and histopathological evaluation on the depth of the tumor was 40% (17/42). Among 29 cases (grade 2 and grade 1b), intraepithelial lesions were not detected in 17 cases, and tumor nests were not detected in the lamina propria mucosae in 9 cases. The results of this study highlight the difficulties of detecting residual carcinoma cells using conventional endoscopic biopsy in patients who have received CRT. Therefore, when residual cancer is clinically suspected in patients who have received CRT, the biopsy specimen should be obtained from the deep layer of the esophagus whenever possible. Additionally, close follow-up is required using positron emission tomography/computed tomography, endoscopy, and other radiological evaluations.

Spectroscopic and microscopic investigations of tautomerization in porphycenes: condensed phases, supersonic jets, and single molecule studies.

We describe various experimental approaches that have been used to obtain a detailed understanding of double hydrogen transfer in porphycene, a model system for intramolecular hydrogen bonding and tautomerism. The emerging picture is that of a multidimensional tautomerization coordinate, with several vibrational modes acting as reaction-promoters or inhibitors through anharmonic intermode coupling. Tunnelling processes, coherent in the case of isolated molecules and incoherent in condensed phases, are found to play a major role even at elevated temperatures. Single-molecule spectroscopy studies reveal large fluctuations in hydrogen transfer rates observed over time for the same chromophore. Scanning probe microscopy is employed to directly observe the structure and tautomerization dynamics of single molecules adsorbed on metal surfaces and demonstrates how the interactions of the molecules with atoms of the supporting surface affect their static and dynamic properties: different tautomeric forms are stabilized for molecules depending on the surface structure and the reaction mechanism can also change, from a concerted to a stepwise transfer. The scanning probe microscopy studies prove that tautomerization in single molecules can be induced by different stimuli: heat, electron attachment, light, and force exerted by the microscope's tip. Possible applications utilizing tautomerism are discussed in combination with molecular architectures on surfaces, which could pave the way for the development of single-molecule electronics.

Direct Observation of Photoinduced Tautomerization in Single Molecules at a Metal Surface.

Molecular switches are of fundamental importance in nature, and light is an important stimulus to selectively drive the switching process. However, the local dynamics of a conformational change in these molecules remain far from being completely understood at the single-molecule level. Here, we report the direct observation of photoinduced tautomerization in single porphycene molecules on a Cu(111) surface by using a combination of low-temperature scanning tunneling microscopy and laser excitation in the near-infrared to ultraviolet regime. It is found that the thermodynamically stable trans configuration of porphycene can be converted to the metastable cis configuration in a unidirectional fashion by photoirradiation. The wavelength dependence of the tautomerization cross section exhibits a steep increase around 2 eV and demonstrates that excitation of the Cu d-band electrons and the resulting hot carriers play a dominant role in the photochemical process. Additionally, a pronounced isotope effect in the cross section (∼100) is observed when the transferred hydrogen atoms are substituted with deuterium, indicating a significant contribution of zero-point energy in the reaction. Combined with the study of inelastic tunneling electron-induced tautomerization with the STM, we propose that tautomerization occurs via excitation of molecular vibrations after photoexcitation. Interestingly, the observed cross section of ∼10(-19) cm(2) in the visible-ultraviolet region is much higher than that of previously studied molecular switches on a metal surface, for example, azobenzene derivatives (10(-23)-10(-22) cm(2)). Furthermore, we examined a local environmental impact on the photoinduced tautomerization by varying molecular density on the surface and find substantial changes in the cross section and quenching of the process due to the intermolecular interaction at high density.

Novel double step approach for optical sensing via microsphere WGM resonance.

The use of resonant whispering gallery modes (WGMs) for sensing exhibits various drawbacks and critical points related to the microsphere and tapered optical fiber fabrication tolerance. The uncertainty on the fiber taper and microsphere geometry or the gap between the microsphere and the fiber taper can complicate or limit the actual use of these devices for sensing, requiring peculiar calibration of the WGM based sensing set-up. An alternative double-step approach is proposed in this paper. In particular, the geometrical parameters of the set-up are recovered preliminarily and then the rare earth parameters are recovered via simple transmittance/gain measurements. The method is based on a refined electromagnetic model of the device suitably integrated with a particle swarm optimization (PSO) approach. The percent errors made on the up-conversion coefficients Cup and C3 are extremely low, being 0.75%, 0.05%, respectively. The procedure is very robust. It can be applied more in general, allowing the sensing of other physical parameters via simple transmittance measurements instead of wavelength shift ones, in both microsphere and microbubble based set-up.

Device for simultaneous positron emission tomography, laser speckle imaging and RGB reflectometry: validation and application to cortical spreading depression and brain ischemia in rats.

Brain function critically relies on the supply with energy substrates (oxygen and glucose) via blood flow. Alterations in energy demand as during neuronal activation induce dynamic changes in substrate fluxes and blood flow. To study the complex system that regulates cerebral metabolism requires the combination of methods for the simultaneous assessment of multiple parameters. We developed a multimodal imaging device to combine positron emission tomography (PET) with laser speckle imaging (LSI) and RGB reflectometry (RGBR). Depending on the radiotracer, PET provides 3-dimensional quantitative information of specific molecular processes, while LSI and RGBR measure cerebral blood flow (CBF) and hemoglobin oxygenation at high temporal and spatial resolution. We first tested the functional capability of each modality within our system and showed that interference between the modalities is negligible. We then cross-calibrated the system by simultaneously measuring absolute CBF using (15)O-H2O PET (CBF(PET)) and the inverse correlation time (ICT), the LSI surrogate for CBF. ICT and CBF(PET) correlated in multiple measurements in individuals as well as across different animals (R(2)=0.87, n=44 measurements) indicating that ICT can be used for absolute quantitative assessment of CBF. To demonstrate the potential of the combined system, we applied it to cortical spreading depression (CSD), a wave of transient cellular depolarization that served here as a model system for neurovascular and neurometabolic coupling. We analyzed time courses of hemoglobin oxygenation and CBF alterations coupled to CSD, and simultaneously measured regional uptake of (18)F-2-fluoro-2-deoxy-D-glucose ((18)F-FDG) used as a radiotracer for regional glucose metabolism, in response to a single CSD and to a cluster of CSD waves. With this unique combination, we characterized the changes in cerebral metabolic rate of oxygen (CMRO2) in real-time and showed a correlation between (18)F-FDG uptake and the number of CSD waves that passed the local tissue. Finally, we examined CSD spontaneously occurring during focal ischemia also referred to as peri-infarct depolarization (PID). In the vicinity of the ischemic territory, we observed PIDs that were characterized by reduced CMRO2 and increased oxygen extraction fraction (OEF), indicating a limitation of oxygen supply. Simultaneously measured PET showed an increased (18)F-FDG uptake in these regions. Our combined system proved to be a novel tool for the simultaneous study of dynamic spatiotemporal alterations of cortical blood flow, oxygen metabolism and glucose consumption under normal and pathologic conditions.

Contamination, distribution and pathogenicity of Toxocara canis and T. cati eggs from sandpits in Tokyo, Japan.

The contamination, distribution and pathogenicity of Toxocara canis and T. cati eggs in sandpits in the Tokyo metropolitan area, Japan, are described. A total of 34 sandpits were examined, 14 of which were contaminated with T. cati eggs, as assessed by the floatation method and polymerase chain reaction (PCR) analysis. Two naturally contaminated sandpits were investigated to determine the vertical and horizontal distribution of eggs, and an inverse relationship between the sand depth and number of eggs was observed. To examine the pathogenicity of the eggs, three ICR mice were inoculated with 300 eggs, which were recovered from sandpits. The mice exhibited eosinophilia in the peripheral blood and IgG antibody production in the sera after 3 weeks of infection. Most migrating larvae were recovered from carcasses, although three were found in the brains of two infected mice. These three larvae were determined to be T. canis by PCR, revealing that not only T. cati, but also T. canis eggs could be found in sandpits and, further, that eggs recovered from sandpits have the ability to invade a paratenic host.

H-atom relay reactions in real space.

Hydrogen bonds are the path through which protons and hydrogen atoms can be transferred between molecules. The relay mechanism, in which H-atom transfer occurs in a sequential fashion along hydrogen bonds, plays an essential role in many functional compounds. Here we use the scanning tunnelling microscope to construct and operate a test-bed for real-space observation of H-atom relay reactions at a single-molecule level. We demonstrate that the transfer of H-atoms along hydrogen-bonded chains assembled on a Cu(110) surface is controllable and reversible, and is triggered by excitation of molecular vibrations induced by inelastic tunnelling electrons. The experimental findings are rationalized by ab initio calculations for adsorption geometry, active vibrational modes and reaction pathway, to reach a detailed microscopic picture of the elementary processes.

A change of osteocalcin (OC) and tartrate resistant acid phosphatase 5b (TRACP-5b) with the menstrual cycle.

Bone metabolism markers associated with 4 menstrual cycle phases were evaluated in 14 healthy young females without menstrual disorder. Menstrual cycle phases were confirmed with basal body temperature for 3 months, luteinizing hormone kits, and sexual hormone concentrations of serum. The bone metabolism markers used were osteocalcin (OC), which was measured by immunoradiometric assay (IRMA), and tartrate resistant acid phosphatase 5b (TRACP-5b), which was measured by enzyme immunometric assay (EIA). The highest values of OC and TRACP-5b were observed in the ovulation phase, and TRACP-5b increased significantly when compared with levels in the menstrual phase (p<0.05). Furthermore, the changes in sex-hormone secretion involved in OC and TRACP-5b showed specific patterns during the menstrual cycle. In other words, TRACP-5b levels are influenced by sex hormones produced during the menstrual period and are based on the bone-formation status. Therefore, it is presumed that the TRACP-5b levels during ovulation play a central role in bone formation and bone metabolism.

Final overall survival analysis from the phase III J-ALEX study of alectinib versus crizotinib in ALK inhibitor-naïve Japanese patients with ALK-positive non-small-cell lung cancer.

BACKGROUND: Mature progression-free survival (PFS) data from the phase III J-ALEX study showed superiority for alectinib versus crizotinib [hazard ratio (HR) 0.37, 95% confidence interval (CI) 0.26-0.52; median PFS 34.1 versus 10.2 months, respectively] in advanced ALK (anaplastic lymphoma kinase)-positive non-small-cell lung cancer (NSCLC). Overall survival (OS) data were immature (HR 0.80, 99.8799% CI 0.35-1.82) at the time of data cut-off (30 June 2018). We report final OS data after ≥5 years of follow-up. PATIENTS AND METHODS: ALK inhibitor naive Japanese patients who were chemotherapy naive or had received one prior chemotherapy regimen were enrolled. Patients were randomized to receive alectinib 300 mg (n = 103) or crizotinib 250 mg (n = 104) twice daily until progressive disease, unacceptable toxicity, death, or withdrawal. The primary endpoint was independent review facility-assessed PFS, with OS (not fully powered) as a secondary endpoint. RESULTS: Median duration of OS follow-up was 68.6 months with alectinib and 68.0 months with crizotinib. Treatment with alectinib did not prolong OS relative to crizotinib (HR 1.03, 95.0405% CI 0.67-1.58; P = 0.9105). Five-year OS rates were 60.9% (95% CI 51.4-70.3) with alectinib and 64.1% (95% CI 54.9-73.4) with crizotinib. In total, 91.3% (n = 95/104) of crizotinib-treated patients and 46.6% (n = 48/103) of alectinib-treated patients received at least one subsequent anticancer therapy. After study drug discontinuation, 78.8% of patients in the crizotinib arm switched to alectinib, while 10.7% of patients in the alectinib arm switched to crizotinib as a first subsequent anticancer therapy. Patients randomized to crizotinib tended to switch treatment earlier than those randomized to alectinib. CONCLUSION: Final OS analysis from J-ALEX did not show superiority of alectinib to crizotinib; this result was most likely confounded by treatment crossover. Alectinib remains a standard of care for the treatment of patients with advanced ALK-positive NSCLC.

Water clusters on Cu(110): chain versus cyclic structures.

Water clusters are assembled and imaged on Cu(110) by using a scanning tunneling microscope. Water molecules are arranged along the Cu row to form "ferroelectric" zigzag chains of trimer to hexamer. The trimer prefers the chain form to a cyclic one in spite of the reduced number of hydrogen bonds, highlighting the crucial role of the water-substrate interaction in the clustering of adsorbed water molecules. On the other hand, the cyclic form with maximal hydrogen bonds becomes more favorable for the tetramer, indicating the crossover from chain to cyclic configurations as the constituent number increases.

A direct numerical simulation method for complex modulus of particle dispersions.

We report an extension of the smoothed profile method (SPM) (Y. Nakayama, K. Kim, and R. Yamamoto, Eur. Phys. J. E 26, 361 (2008)), a direct numerical simulation method for calculating the complex modulus of the dispersion of particles, in which we introduce a temporally oscillatory external force into the system. The validity of the method was examined by evaluating the storage G'(ω) and loss G"(ω) moduli of a system composed of identical spherical particles dispersed in an incompressible Newtonian host fluid at volume fractions of Φ = 0 , 0.41, 0.46, and 0.51. The moduli were evaluated at several frequencies of shear flow; the shear flow used here has a zigzag profile, as is consistent with the usual periodic boundary conditions. The simulation results were compared with several experiments for colloidal dispersions of spherical particles.

Early detection of Niemann-pick disease type C with cataplexy and orexin levels: continuous observation with and without Miglustat.

STUDY OBJECTIVES: Niemann-Pick type C (NPC) is an autosomal recessive and congenital neurological disorder characterized by the accumulation of cholesterol and glycosphingolipids. Symptoms include hepatosplenomegaly, vertical supranuclear saccadic palsy, ataxia, dystonia, and dementia. Some cases frequently display narcolepsy-like symptoms, including cataplexy which was reported in 26% of all NPC patients and was more often recorded among late-infantile onset (50%) and juvenile onset (38%) patients. In this current study, we examined CSF orexin levels in the 10 patients of NPC with and without cataplexy, which supports previous findings. METHODS: Ten patients with NPC were included in the study (5 males and 5 females). NPC diagnosis was biochemically confirmed in all 10 patients, from which 8 patients with NPC1 gene were identified. We compared CSF orexin levels among NPC, narcoleptic and idiopathic hypersomnia patients. RESULTS: Six NPC patients with cataplexy had low or intermediate orexin levels. In 4 cases without cataplexy, their orexin levels were normal. In 5 cases with Miglustat treatment, their symptoms stabilized or improved. For cases without Miglustat treatment, their conditions worsened generally. The CSF orexin levels of NPC patients were significantly higher than those of patients with narcolepsy-cataplexy and lower than those of patients with idiopathic hypersomnia, which was considered as the control group with normal CSF orexin levels. DISCUSSION: Our study indicates that orexin level measurements can be an early alert of potential NPC. Low or intermediate orexin levels could further decrease due to reduction in the neuronal function in the orexin system, accelerating the patients' NPC pathophysiology. However with Miglustat treatment, the orexin levels stabilized or improved, along with other general symptoms. Although the circuitry is unclear, this supports that orexin system is indeed involved in narcolepsy-cataplexy in NPC patients. CONCLUSION: The NPC patients with cataplexy had low or intermediate orexin levels. In the cases without cataplexy, their orexin levels were normal. Our study suggests that orexin measurements can serve as an early alert for potential NPC; furthermore, they could be a marker of therapy monitoring during a treatment.

Factors associated with possession of accurate knowledge regarding occupational health management among operations leaders of radiation decontamination workers in Fukushima, Japan: a cross-sectional study.

OBJECTIVES: An operations leader (OL) takes an important role in occupational health management for radiation decontamination workers in Japan, and candidates for the position must participate in a training session to acquire the necessary knowledge as required by law. However, it has not been clarified whether the candidates for the OL position actually possess accurate knowledge regarding occupational health management for such work after the training session. We, therefore, aimed at examining the current occupational health management knowledge among the candidates and investigating factors related to the knowledge, with hypothesis that possession of accurate knowledge is associated with prior experience of having worked in radiation decontamination. DESIGN: A cross-sectional study. SETTING: The training sessions held by Fukushima Prefecture Labor Standard Associations in Fukushima, Japan, in 2017. PARTICIPANTS: Eighty male candidates participated in the training sessions. OUTCOME: The number/proportion of correct answers to the questions regarding occupational health management, such as those on working environment management, control of operations and health management. RESULTS: The proportion of those who possessed accurate knowledge regarding working environment management, control of operations and health management was 68.8%, 55.0% and 51.2%, respectively. Experience of radiation decontamination work was associated with the possession of inaccurate knowledge regarding working environment management (OR 0.140 (95% CI 0.042 to 0.464)), and the uncertainty of future radiation decontamination work schedules in difficult-to-return zones was associated with the possession of accurate knowledge regarding health management (OR 4.344 (95% CI 1.509 to 12.50)). CONCLUSIONS: Previous experience in radiation decontamination work may hinder the ability to acquire accurate information regarding working environment management among candidates for an OL position. To promote adequate occupational health management for radiation decontamination workers, it is required to establish an effective instructional method for the OL candidate training sessions with consideration of previous relevant experience.

Knowledge, attitudes and behaviour regarding the infant oral health visit: are dentists in Ireland aware of the recommendation for a first visit to the dentist by age 1 year?

AIM: To assess the knowledge, attitudes and behaviour of dentists nationwide in Ireland regarding the infant oral health visit, and also to elucidate whether dentists were aware of the recommendation for a first dental visit by age 1 year and of what care should be provided at this visit. METHODS: A validated 10-item questionnaire was distributed to a representative sample of non-paediatric dentists (non-PDs) and paediatric dentists (PDs) practicing in Ireland. The questionnaire focused on respondents' demographics in addition to their knowledge, attitudes and behaviour regarding the infant dental visit. RESULTS: Seventy-three percent of non-PDs reported seeing patients aged 0-36 months. Compared to all PD respondents, 58% of non-PDs believed that the first dental visit should occur by age 1 year. Furthermore, non-PDs provided the same care as PDs at the infant dental visit, with the exception of evaluating for fluoride needs and placing fluoride varnish. The main barrier to early oral healthcare was reported to be parents not requesting dental appointments for their infants. CONCLUSIONS: There remains a need to increase the proportion of non-PDs in Ireland seeing infants by their first birthday. It is recommended that Irish undergraduate and continuing education courses incorporate clinical training regarding the infant oral health visit and emphasise fluoride needs evaluation and fluoride varnish application. Additionally, a nationwide health promotion initiative is indicated to inform parents of the importance of a dental visit by age 1 year.

Microanalysis of an antimicrobial peptide, beta-defensin-2, in the stratum corneum from patients with atopic dermatitis.

BACKGROUND: Antimicrobial peptides, such as defensin and cathelicidin, have recently been reported to play important roles in host defence and in cutaneous innate immunity. Although beta-defensin-2 has been reported to be downregulated in the skin of patients with atopic dermatitis (AD), little is known about its role in the colonization of Staphylococcus aureus in the stratum corneum of patients with AD. A precise evaluation of these peptides in the stratum corneum as an antimicrobial barrier against S. aureus colonization has not yet been performed. OBJECTIVES: To compare beta-defensin-2 levels in the skin of patients with AD and healthy controls. METHODS: We developed a microanalytical technique to measure beta-defensin-2 in the stratum corneum using a combination of immunoprecipitation and Western blotting. RESULTS: beta-Defensin-2 in the stratum corneum was significantly higher in AD lesional skin compared with healthy control skin. The beta-defensin-2 content in AD lesional skin also increased in proportion to the severity of the disease. Counting bacterial colonies revealed higher populations of S. aureus on lesional and nonlesional skin surfaces of patients with AD compared with healthy controls. Comparison of S. aureus colony numbers and beta-defensin-2 levels demonstrated a positive correlation (r = 0.342, P = 0.004, n = 67) between both factors. CONCLUSIONS: Collectively, these findings suggest that beta-defensin-2 is induced in response to bacteria, injury or inflammatory stimuli and is not associated with vulnerability to S. aureus colonization in the skin of patients with AD.