Safety and feasibility of minimally invasive esophagectomy for elderly esophageal cancer patients.

The number of elderly patients with esophageal cancer has increased in recent years. The use of thoracoscopic esophagectomy has also increased, and its minimal invasiveness is believed to contribute to postoperative outcomes. However, the short- and long-term outcomes in elderly patients remain unclear. This study aimed to elucidate the safety and feasibility of minimally invasive esophagectomy in elderly patients. This retrospective study included 207 patients who underwent radical thoracoscopic esophagectomy for thoracic esophageal squamous cell carcinoma at Kobe University Hospital between 2005 and 2014. Patients were divided into non-elderly (<75 years) and elderly (≥75 years) groups. A propensity score matching analysis was performed for sex and clinical T and N stage, with a total of 29 matched pairs. General preoperative data, surgical procedures, intraoperative data, postoperative complications, in-hospital death, cancer-specific survival, and overall survival were compared between groups. The elderly group was characterized by lower preoperative serum albumin levels and higher American Society of Anesthesiologists grade. Intraoperative data and postoperative complications did not differ between the groups. The in-hospital death rate was 4% in the elderly group, which did not significantly differ from the non-elderly group. Cancer-specific survival was similar between the two groups. Although overall survival tended to be poor in the elderly group, it was not significantly worse than that of the non-elderly group. In conclusion, the short- and long-term outcomes of minimally invasive esophagectomy in elderly versus non-elderly patients were acceptable. Minimally invasive esophagectomy is a safe and feasible modality for elderly patients with appropriate indications.

Switching of band inversion and topological surface states by charge density wave.

Topologically nontrivial materials host protected edge states associated with the bulk band inversion through the bulk-edge correspondence. Manipulating such edge states is highly desired for developing new functions and devices practically using their dissipation-less nature and spin-momentum locking. Here we introduce a transition-metal dichalcogenide VTe2, that hosts a charge density wave (CDW) coupled with the band inversion involving V3d and Te5p orbitals. Spin- and angle-resolved photoemission spectroscopy with first-principles calculations reveal the huge anisotropic modification of the bulk electronic structure by the CDW formation, accompanying the selective disappearance of Dirac-type spin-polarized topological surface states that exist in the normal state. Thorough three dimensional investigation of bulk states indicates that the corresponding band inversion at the Brillouin zone boundary dissolves upon the CDW formation, by transforming into anomalous flat bands. Our finding provides a new insight to the topological manipulation of matters by utilizing CDWs' flexible characters to external stimuli.

Refining Markov state models for conformational dynamics using ensemble-averaged data and time-series trajectories.

A data-driven modeling scheme is proposed for conformational dynamics of biomolecules based on molecular dynamics (MD) simulations and experimental measurements. In this scheme, an initial Markov State Model (MSM) is constructed from MD simulation trajectories, and then, the MSM parameters are refined using experimental measurements through machine learning techniques. The second step can reduce the bias of MD simulation results due to inaccurate force-field parameters. Either time-series trajectories or ensemble-averaged data are available as a training data set in the scheme. Using a coarse-grained model of a dye-labeled polyproline-20, we compare the performance of machine learning estimations from the two types of training data sets. Machine learning from time-series data could provide the equilibrium populations of conformational states as well as their transition probabilities. It estimates hidden conformational states in more robust ways compared to that from ensemble-averaged data although there are limitations in estimating the transition probabilities between minor states. We discuss how to use the machine learning scheme for various experimental measurements including single-molecule time-series trajectories.

Photoexcitation dynamics of p-nitroaniline and N,N-dimethyl-p-nitroaniline in 1-alkyl-3-methylimidazolium-cation based ionic liquids with different alkyl-chain lengths.

Photoexcitation dynamics of p-nitroaniline (pNA) and N,N-dimethyl-p-nitroaniline (DMpNA) in 1-alkyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide ([Cnmim][NTf2]) with different alkyl chain lengths (from C2 to C12) was investigated using transient absorption spectroscopy. The internal conversion rate from the excited state to the ground state was estimated from bleach recovery around the ground state absorption centre, and the successive vibrational cooling rate in the ground state was estimated from the decay of the hot band observed at the red-edge of ground state absorption. The internal conversion rate slightly decreased with an increase in the alkyl-chain length of the cation, while the dependence of DMpNA was more significant than that of pNA. The extent of change was correlated with the change of the reaction free energy and solvent reorganization energy estimated from the absorption spectrum assuming that the internal conversion process is modelled by a back-electron-transfer process. The vibrational cooling rate estimated from the decay of hot-band absorption slightly decreased with an increase in the alkyl-chain length of the cation for both solutes. The hot-band decay of pNA was about 1.5-times faster than that of DMpNA, irrespective of the alkyl-chain length.

Protective effect of hypotaurine against oxidative stress-induced cytotoxicity in rat placental trophoblasts.

INTRODUCTION: Hypotaurine is a precursor of taurine and an antioxidant, and is concentrated in fetal plasma compared to maternal plasma. Hypotaurine is significantly decreased in fetal plasma of ezrin (Vil2) knock-out mice, and fetuses show intrauterine growth retardation. The aim of this study was to characterize the mechanism through which cellular hypotaurine level is maintained in placental trophoblasts, and the effect of hypotaurine on oxidative stress induced by hydrogen peroxide (H2O2). METHODS: Hypotaurine transfer from extracellular fluid and antioxidant effect of hypotaurine were analyzed in rat placental trophoblast TR-TBT 18d-1 cells. RESULTS: We found that hypotaurine is concentrated into rat placental trophoblast TR-TBT 18d-1 cells, and the level of hypotaurine was markedly reduced by culture in medium supplemented with dialyzed fetal bovine serum (FBS) instead of normal FBS. The hypotaurine level recovered almost completely when hypotaurine was added to the culture medium, indicating that intracellular hypotaurine is predominantly supplied by transport across the plasma membrane from extracellular fluid rather than by biosynthesis. Hypotaurine showed a cytoprotective effect against H2O2-induced oxidative damage in TR-TBT 18d-1 cells. Hypotaurine treatment of TR-TBT 18d-1 cells increased antioxidant capacity against hydroxyl radical and peroxyl radical. The concentration of intracellular hydroxyl radical induced by H2O2 in TR-TBT 18d-1 cells was significantly reduced by hypotaurine treatment. DISCUSSION: These results indicate that intracellular hypotaurine is mainly supplied to placental trophoblasts by transfer from extracellular fluid across the plasma membrane, and may play a role in cell protection by scavenging reactive oxygen species.

Inflammatory bone loss in experimental periodontitis induced by Aggregatibacter actinomycetemcomitans in interleukin-1 receptor antagonist knockout mice.

The interleukin-1 receptor antagonist (IL-1Ra) binds to IL-1 receptors and inhibits IL-1 activity. However, it is not clear whether IL-1Ra plays a protective role in periodontal disease. This study was undertaken to compare experimental periodontitis induced by Aggregatibacter actinomycetemcomitans in IL-1Ra knockout (KO) mice and wild-type (WT) mice. Computed tomography (CT) analysis and hematoxylin-and-eosin (H&E) and tartrate-resistant acid phosphatase (TRAP) staining were performed. In addition, osteoblasts were isolated; the mRNA expression of relevant genes was assessed by real-time quantitative PCR (qPCR); and calcification was detected by Alizarin Red staining. Infected IL-1Ra KO mice exhibited elevated (P, <0.05) levels of antibody against A. actinomycetemcomitans, bone loss in furcation areas, and alveolar fenestrations. Moreover, protein for tumor necrosis factor alpha (TNF-α) and IL-6, mRNA for macrophage colony-stimulating factor (M-CSF), and receptor activator of NF-κB ligand (RANKL) in IL-1Ra KO mouse osteoblasts stimulated with A. actinomycetemcomitans were increased (P, <0.05) compared to in WT mice. Alkaline phosphatase (ALP), bone sialoprotein (BSP), osteocalcin (OCN)/bone gla protein (BGP), and runt-related gene 2 (Runx2) mRNA levels were decreased (P, <0.05). IL-1α mRNA expression was increased, and calcification was not observed, in IL-1 Ra KO mouse osteoblasts. In brief, IL-1Ra deficiency promoted the expression of inflammatory cytokines beyond IL-1 and altered the expression of genes involved in bone resorption in A. actinomycetemcomitans-infected osteoblasts. Alterations consistent with rapid bone loss in infected IL-Ra KO mice were also observed for genes expressed in bone formation and calcification. In short, these data suggest that IL-1Ra may serve as a potential therapeutic drug for periodontal disease.

Follicular dendritic cell-secreted protein is decreased in experimental periodontitis concurrently with the increase of interleukin-17 expression and the Rankl/Opg mRNA ratio.

BACKGROUND AND OBJECTIVE: T-helper type 17 (Th17) cells produce interleukin-17 (IL-17) and help to protect against inflammation and infection in periodontal disease. Furthermore, while follicular dendritic cell-secreted protein (FDC-SP) may be involved in the inflammation of periodontal tissue, the biological role of FDP-SP in periodontal disease is still unknown. The purpose of the present study was to clarify the expression of IL-17 and FDC-SP in experimental periodontitis in rats. MATERIAL AND METHODS: Seven-week-old male Wistar rats were divided into baseline control, sham and test groups. Experimental periodontitis was induced by placing a ligature in the mesiopalatal area, and untreated rats served as a baseline control group. Morphological changes in alveolar bone were investigated 7, 14 and 28 d after treatment. Expression of the Rankl, osteoprotegerin (Opg) and Il17 genes was analyzed 5 and 7 d after the induction of experimental periodontitis. RESULTS: Alveolar bone resorption progressed in the test group for 7 d, but not thereafter. At 5 d after the induction of periodontitis, the Rankl/Opg mRNA ratio and the expression of IL-17 in the test group were significantly increased compared with the respective values in the baseline control group; however, there were no significant differences between the test and control groups at 7 d. The expression of FDC-SP was significantly decreased in the test group compared with the baseline control group at 5 and 7 d after the induction of periodontitis, and this value had returned to normal levels at 14 and 28 d. CONCLUSION: These results suggest that both IL-17 and FDC-SP could be involved in the inflammatory response, and FDC-SP in the junctional epithelium might play an important role in the Th17 cell-related immune response.

Severe hyponatremia caused by syndrome of inappropriate secretion of antidiuretic hormone developed as initial manifestation of human herpesvirus-6-associated acute limbic encephalitis after unrelated bone marrow transplantation.

Severe hyponatremia is a critical electrolyte abnormality in allogeneic stem cell transplantation (allo-SCT) recipients and >50% of cases of severe hyponatremia are caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Here, we present a patient with rapidly progressive severe hyponatremia as an initial sign and symptom of human herpesvirus-6-associated post-transplantation acute limbic encephalitis (HHV-6 PALE) after allo-SCT. A 45-year-old woman with acute lymphoblastic leukemia received unrelated bone marrow transplantation from a one locus-mismatched donor at the DR locus. On day 21, she developed a generalized seizure and loss of consciousness with severe hyponatremia, elevated serum antidiuretic hormone (ADH), and decreased serum osmolality. A high titer of HHV-6 DNA was detected in cerebrospinal fluid. Treatment with foscarnet sodium and hypertonic saline was started with improvement of neurological condition within several days. Although an elevated serum ADH, low serum osmolality, and high urinary osmolality persisted for 2 months, she had no other recurrent symptoms of encephalitis. Our experience suggests that hyponatremia accompanied by SIADH should be recognized as a prodromal or concomitant manifestation of HHV-6 PALE, and close monitoring of serum sodium levels in high-risk patients for HHV-6 PALE is necessary for immediate diagnosis and treatment initiation.

Gene expression analysis of rheumatoid arthritis synovial lining regions by cDNA microarray combined with laser microdissection: up-regulation of inflammation-associated STAT1, IRF1, CXCL9, CXCL10, and CCL5.

OBJECTIVES: The main histological change in rheumatoid arthritis (RA) is the villous proliferation of synovial lining cells, an important source of cytokines and chemokines, which are associated with inflammation. The aim of this study was to evaluate gene expression in the microdissected synovial lining cells of RA patients, using those of osteoarthritis (OA) patients as the control. METHODS: Samples were obtained during total joint replacement from 11 RA and five OA patients. Total RNA from the synovial lining cells was derived from selected specimens by laser microdissection (LMD) for subsequent cDNA microarray analysis. In addition, the expression of significant genes was confirmed immunohistochemically. RESULTS: The 14 519 genes detected by cDNA microarray were used to compare gene expression levels in synovial lining cells from RA with those from OA patients. Cluster analysis indicated that RA cells, including low- and high-expression subgroups, and OA cells were stored in two main clusters. The molecular activity of RA was statistically consistent with its clinical and histological activity. Expression levels of signal transducer and activator of transcription 1 (STAT1), interferon regulatory factor 1 (IRF1), and the chemokines CXCL9, CXCL10, and CCL5 were statistically significantly higher in the synovium of RA than in that of OA. Immunohistochemically, the lining synovium of RA, but not that of OA, clearly expressed STAT1, IRF1, and chemokines, as was seen in microarray analysis combined with LMD. CONCLUSIONS: Our findings indicate an important role for lining synovial cells in the inflammatory and proliferative processes of RA. Further understanding of the local signalling in structural components is important in rheumatology.

Imaging features contributing to the diagnosis of ameloblastomas and keratocystic odontogenic tumours: logistic regression analysis.

OBJECTIVE: The aim of this study was to clarify the characteristic imaging features that can be used to differentiate ameloblastomas from keratocystic odontogenic tumours and to examine the significant imaging features contributing to a correct diagnosis. METHODS: 60 observers (39 specialists in oral and maxillofacial radiology and 21 non-specialists) examined CT and/or panoramic images of 10 ameloblastomas and 10 keratocystic odontogenic tumours shown on a webpage and made diagnoses. Their correct answer ratios were then calculated. The imaging features of the tumours were evaluated and expressed as binary numbers or quantitative values. The imaging features that contributed to a correct diagnosis were elucidated using logistic regression analysis. RESULTS: The mean correct answer ratio was 61.3% ± 17.2% for the diagnosis of ameloblastomas and keratocystic odontogenic tumours. CT images produced higher correct answer ratios for diagnosis of keratocystic odontogenic tumours by specialists. The significantly different imaging features between ameloblastomas and keratocystic odontogenic tumours were the degree of bone expansion and the presence of high-density areas. The significant imaging features contributing to a correct imaging diagnosis were the number of locules, the presence of high-density areas and the inclusion of impacted teeth. CONCLUSION: The presence of high-density areas is the most useful feature in the differential diagnosis of ameloblastomas and keratocystic odontogenic tumours based on comparison of the imaging features of both tumours and examination of the diagnostic contributions of these features.

N-acetyl cysteine protects TMJ chondrocytes from oxidative stress.

Temporomandibular joint (TMJ) inflammation is closely associated with oxidative stress. This study tested the potential of N-acetyl cysteine (NAC), an anti-oxidant amino-acid derivative, in alleviating oxidative stress-related damage in TMJ chondrocytes. The inflammatory condition was simulated by the addition of hydrogen peroxide (H2O2) to TMJ-derived chondrocyte cultures. Exposure to H2O2 decreased the cell population by half within 2 days as a result of induced apoptosis and reduced proliferation. Gene expression of aggrecan and collagen II, as well as glycosaminoglycan production, were reduced by more than 70%. These compromised chondrocyte viability and function were fully restored by the addition of NAC to the cultures. NAC reduced the H2O2-elevated intracellular reactive oxygen species to the normal level and increased cellular glutathione reserves. These results indicate that NAC restores oxidative stress-induced cell death and severe functional impairment in TMJ chondrocytes, and warrant in vivo testing to explore its therapeutic potential as an anti-inflammatory agent.

Lung diseases directly associated with rheumatoid arthritis and their relationship to outcome.

The outcome and cause of death of each lung disease directly associated with rheumatoid arthritis (RA-LD) have been poorly investigated. A retrospective study was conducted of 144 patients with RA-LD, in whom the median follow-up period after the initial visit for a respiratory examination was 4.5 yrs. A total of 57 patients were identified with usual interstitial pneumonia (UIP), 31 with bronchiectasis, 16 with nonspecific interstitial pneumonia (NSIP), 11 with bronchiolitis, five with organising pneumonia (OP), five with diffuse alveolar damage (DAD) and 19 with combined disease. The 5-yr survival rates were 36.6% in the UIP group, 87.1% in the bronchiectasis group, 93.8% in the NSIP group, 88.9% in the bronchiolitis group, 60.0% in the OP group and 20.0% in the DAD group. Survival of patients with DAD was worse than that of patients with UIP. Overall, survival of patients with UIP was worse than that of patients with bronchiectasis, NSIP or bronchiolitis. Of the 144 patients, 71 (49.3%) died, of whom 58 (81.7%) died due to respiratory lesions. Of patients with RA-LD, patients with DAD experienced the highest mortality, and the survival of patients with UIP was worse than that of patients with NSIP.

Distribution of optokinetic sensitivity across the retina of mice in relation to eye orientation.

We examined the effects of stimulus size and location on the mouse optokinetic response (OKR). To this end, we recorded initial OKRs elicited by a brief presentation of horizontally moving grating patterns of different vertical widths and locations in the visual field. Large-field stimuli generated large sustained OKRs, whereas visual stimuli of narrower vertical widths elicited weaker sustained responses at the later period (400-500 ms after the onset of stimulus motion). However, even stimuli of only 5 degrees vertical width elicited detectable transient responses at the initial open-loop period (100-200 ms after the onset of stimulus motion). Presenting 5 degrees -width stimuli at different vertical locations (-10 degrees to +35 degrees relative to the horizon) revealed the spatial distribution of optokinetic sensitivity across the retina. The most sensitive part of the visual field was located at +25 degrees . In addition, we examined the vertical orientation of the eye under our stereotaxic set-up. We observed the optic disc using a hand-held fundus camera and determined the ocular orientation. All eye orientations were distributed in the range of +20-30 degrees relative to the horizon (25.2+/-2.5 degrees ). Thus, the direction of the most sensitive visual field matched the angle of eye orientation. These findings indicate that the spatial distribution of visual field sensitivity to optokinetic stimuli coincides with the distribution of retinal ganglion cell density.

The effect of Lactobacillus helveticus fermented milk on sleep and health perception in elderly subjects.

OBJECTIVE: To study the effect of Lactobacillus helveticus fermented milk on sleep and health perception in elderly healthy subjects. SUBJECTS: The study included 29 healthy elderly subjects aged 60-81 years. METHODS: Prospective, randomized, double-blind and placebo-controlled, with a crossover design. The study included two intervention periods of 3 weeks each, separated by a 3-week washout period. Subjects took 100 g of fermented milk drink or a placebo drink (artificially acidified milk) daily in the first supplementary period and the other drink in the second supplementary period. For each period, we measured sleep quality by means of actigraphy and a sleep questionnaire, and assessed the quality of life (QOL) by SF-36 health survey. RESULTS: There was a significant improvement in sleep efficiency (P=0.03) and number of wakening episodes (P=0.007) in actigraph data after intake of fermented milk, whereas no significant changes were observed for the placebo. Fermented milk did not improve the SF-36 scores significantly from the baseline period. In the GH domain (general health perception) of the SF-36, however, there was marginal improvement as compared to the baseline period. Although the difference between fermented milk and placebo was not statistically significant for any of the sleep or QOL parameters, fermented milk produced slightly greater mean values for many parameters. CONCLUSION: This short-term (3-week) intervention study indicates that Lactobacillus helveticus fermented milk may have a more favorable effect on improving sleep in healthy elderly people as compared with placebo.

Anti-tumor activity of murine peritoneal macrophages induced by porcine skin gelatin.

AIM: To study the induction of anti-tumor activity of murine peritoneal macrophages in vitro by porcine skin gelatin. METHODS: Anti-tumor activity of the macrophages was evaluated with tritium thymidine uptake by target tumor cells. ELISA was used to measure amounts of cytokines secreted in culture medium. RESULTS: The ability of the gelatin to induce anti-tumor activity of the macrophages was stronger than that of lipopolysaccharide of E. coli. Combination of the lipopolysaccharide and interferon-gamma synergistically stimulated the macrophages but that of the gelatin and interferon-gamma additionally did. The culture supernatant of the macrophages incubated with the gelatin also showed higher anti-tumor activity than that with the lipopolysaccharide though the lipopolysaccharide was more excellent than the gelatin in stimulating secretion of anti-tumor cytokines (IL-1, IL-6, TNF-alpha, IFN-gamma) by the macrophages. Anti-TNF-alpha antibody partially suppressed the anti-tumor activity of the culture supernatant of the macrophages incubated with the lipopolysaccharide but not with the gelatin. The gelatin induced anti-tumor activity of the macrophages of C3H/HeJ as well as C3H/HeN mice whereas the lipopolysaccharide did only in C3H/HeN mice. The macrophages stimulated in vitro by the gelatin exerted anti-tumor activity in vivo. Moreover, the gelatin stimulated peritoneal exudates cells in vivo when subcutaneously administered with them. CONCLUSIONS: Porcine skin gelatin induces anti-tumor activity of macrophages in mice and its magnitude is greater than that of lipopolysaccharide of E. coli. Its mechanism is different from that of the lipopolysaccharide but not fully clarified.

The initial disparity vergence elicited with single and dual grating stimuli in monkeys: evidence for disparity energy sensing and nonlinear interactions.

We recorded the initial vertical vergence eye movements elicited in monkeys at short latency ( approximately 70 ms) when the two eyes see one-dimensional (1D) horizontal grating patterns that are identical except for a phase difference (disparity) of one-quarter wavelength. With gratings composed of single sine waves, responses were always compensatory, showing Gaussian dependence on log spatial frequency (on average: peak = 0.75 cycles/deg; SD = 0.74; r(2) = 0.980) and monotonic dependence on log contrast with a gradual saturation well described by the Naka-Rushton equation (on average: n = 0.89; C(50) = 4.1%; r(2) = 0.978). With gratings composed of two sine waves whose spatial frequencies were in the ratio 3:5 and whose disparities were of opposite sign (the 3f5f stimulus), responses were determined by the disparities and contrasts of the two sine-wave components rather than the disparity of the features, consistent with early spatial filtering of the monocular inputs before their binocular combination and mediation by detectors sensitive to disparity energy. In addition, responses to the 3f5f stimulus showed a nonlinear dependence on the relative contrasts of the two sine waves. Thus on average, when the contrast of one sine wave was 2.3 times greater than that of the other, the one with the lower contrast was largely ineffective as though suppressed, and responses were determined almost entirely by the sine wave of higher contrast: Winner-Take-All. These findings are very similar to those published previously on the vertical vergence responses of humans, indicating that the monkey provides a good animal model for studying these disparity vergence responses.