Feeding catheter gastrostomy with the round ligament of the liver prevents mechanical bowel obstruction after esophagectomy.

Jejunostomy, which requires the fixation of the jejunum to the abdominal wall, is commonly used as an enteral feeding access after esophagectomy. However, this procedure sometimes causes severe complications, such as mechanical bowel obstruction. In 2009, we developed a modified approach to insert an enteral feeding tube through the reconstructed gastric tube using the round ligament of the liver. The aim of this study is to investigate the usefulness of this approach as compared to the approach through jejunostomy. Between January 2005 and March 2015, 420 patients with thoracic esophageal cancer underwent esophagectomy via thoracotomy and laparotomy. Of these, 214 underwent feeding jejunostomy (FJ group) and 206 patients underwent feeding via gastric tube with round ligament of the liver (FG group). Catheter-related complications, other postoperative complications, and mortality were compared between the two groups. The incidence of catheter site infection during catheterization in the FG group was significantly lower (n = 1/206, 0.5%) compared to the FJ group (n = 11/214, 5.1%) (P < 0.01). The postoperative bowel obstruction did not occur in the FG group, while it occurred in eight patients (3.7%) in the FJ group (P < 0.01). The incidences of other catheter-related and postoperative complications were similar between the two groups. Feeding catheter gastrostomy with the round ligament of the liver can be a useful enteral feeding access after esophagectomy, because the incidence rate of severe catheter-related complications, such as surgical site infection and mechanical obstruction tend to be lower with this technique compare to jejunostomy.

IL-1ß-induced matrix metalloproteinase-3 regulates cell proliferation in rat dental pulp cells.

OBJECTIVE: We previously reported that matrix metalloproteinase-3(MMP-3) accelerates wound healing following dental pulp injury. In this study, we tested the hypothesis that induction of MMP-3 activity by interleukin-1ß would promote proliferation and apoptosis of dental pulp cells. MATERIALS AND METHODS: Dental pulp cells were isolated from rat incisors and subjected to interleukin-1ß. Matrix metalloproteinase-3 mRNA and protein expression were assessed using reverse transcription-polymerase chain reaction and Western blotting, respectively. Matrix metalloproteinase-3 activity was measured using fluorescence. Dental pulp cell proliferation and apoptosis were determined using enzyme-linked immunosorbent assays (ELISA) for BrdU and DNA fragmentation, respectively. siRNA was used to reduce MMP-3 transcripts in these cells. RESULTS: Treatment with interleukin-1ß increased MMP-3 mRNA and protein levels as well as its activity in dental pulp cells. Cell proliferation was also markedly increased, with no changes in apoptosis observed. Treatment with siRNA against MMP-3 potently suppressed this interleukin-1ß-induced increase in MMP-3 expression and activity, and also suppressed cell proliferation but unexpectedly increased apoptosis in these cells (P < 0.05). This siRNA-mediated increase in apoptosis could be reversed with exogenous MMP-3 stimulation (P < 0.05). CONCLUSIONS: Interleukin-1ß induces MMP-3-regulated cell proliferation and suppresses apoptosis in dental pulp cells.

Mouse ES cells have a potential to differentiate into odontoblast-like cells using hanging drop method.

OBJECTIVES: We examined whether mouse embryonic stem (ES) cells can differentiate into odontoblast-like cells without epithelial-mesenchymal interaction. MATERIALS AND METHODS: Cells were cultured by the 'hanging drop' method using a collagen type-I scaffold (CS) combined with bone morphogenetic protein (BMP)-4 (CS/BMP-4). Expression of odontoblast-related mRNA and protein, and cell proliferation were performed by reverse transcription-polymerase chain reaction (RT-PCR), immunofluorescence staining and WST-1 assay, respectively. RESULTS: Cells potently expressed odontoblast-related cell marker mRNAs following induction of odontoblastic differentiation. Dentin sialophosphoprotein, a marker of mature odontoblasts, was strongly expressed in differentiated ES cells. The cells also acquired an odontoblast-like functional phenotype, as evidenced by the appearance of alkaline phosphatase activity and calcification. The cell-surface expression of α2, α6, αV and αVß3 integrin proteins was rapidly upregulated in differentiated cells. Finally, anti-α2 integrin antibody suppressed the expression of odontoblastic markers in cells grown using this culture system, suggesting that α2 integrin expression in ES cells triggers their differentiation into odontoblast-like cells. CONCLUSIONS: Mouse ES cells cultured by the 'hanging drop' method are able to differentiate into cells with odontoblast-specific physiological functions and cell-surface integrin protein expression.

Cytokines induce MMP-3-regulated proliferation of embryonic stem cell-derived odontoblast-like cells.

OBJECTIVES: Matrix metalloproteinase (MMP)-3 expression increases after pulpectomy and accelerates angiogenesis in rat dental pulp by an uncharacterised mechanism. Odontoblasts, a major component of dental pulp, could represent a therapeutic target. We investigated whether MMP-3 activity is induced by cytokines and/or is associated with cell proliferation and apoptosis in embryonic stem cell-derived odontoblast-like cells. MATERIALS AND METHODS: We used reverse transcriptase polymerase chain reaction, western blotting, an MMP-3 activity assay, a BrdU-cell proliferation enzyme-linked immunosorbent assay and DNA fragmentation analysis to evaluate siRNA-mediated downregulation of MMP-3 expression and activity, and any changes in the proliferative and apoptotic responses associated with this reduced expression. RESULTS: Pro-inflammatory cytokines (interleukin-1ß, tumour necrosis factor-α and interferon-γ, at relatively low concentrations) induced MMP-3 mRNA and protein expression, and increased MMP-3 activity and cell proliferation, but not apoptosis. MMP-3 silencing produced a potent and significant suppression of cytokine-induced MMP-3 expression and activity, decreased cell proliferation and increased apoptosis. These effects were rescued by application of exogenous MMP-3. CONCLUSIONS: Our results suggest that pro-inflammatory cytokines induce MMP-3-regulated cell proliferation and anti-apoptosis effects in odontoblast-like cells derived from embryonic stem cells, in addition to their well-documented destructive role in inflammation.

High-density lipoprotein cholesterol is positively associated with hypertension in apparently healthy Japanese men and women.

Among five components of metabolic syndrome, high-density lipoprotein (HDL) cholesterol is unique because it is not significantly associated with blood pressure. This study looks at cross-sectional relationships between HDL cholesterol and hypertension using medical check-up data from 1803 apparently healthy Japanese men aged 49.9 +/- 9.0 years, and 1150 Japanese women aged 49.5 +/- 9.0 years. Pearson's correlation coefficients between systolic blood pressure (SBP)/diastolic blood pressure (DBP) and HDL cholesterol were -0.01 (ns)/-0.01 (ns) in men and -0.04 (ns)/-0.01 (ns) in women. The standardised partial regression coefficient of HDL cholesterol for SBP/DBP (mmHg) controlling for age, body mass index (BMI), fasting plasma glucose (FPG), triglycerides, high-sensitivity C-reactive protein (hs-CRP) and low-density lipoprotein (LDL) cholesterol were 0.15 (P < 0.0001)/0.15 (P < 0.0001) in men and 0.10 (P < 0.0001)/0.12 (P < 0.0001) in women. The odds ratio (OR; 95% confidence interval [CI]) of a 1 mg/dL increment of HDL cholesterol for hypertension controlling for age, BMI, FPG, triglycerides, hs-CRP, LDL cholesterol, metabolic syndrome, diabetes, exercise status, drinking status, and smoking status was 1.03 (1.02-1.04; P < 0.001) in men and 1.03 (1.01-1.05; P = 0.002) in women. Thus, HDL cholesterol was independently positively associated with hypertension in apparently healthy Japanese men and women.

Comparative pharmacokinetics of RAD001 (everolimus) in normal and tumor-bearing rodents.

PURPOSE: Comparative pharmacokinetic (PK) analysis of the mTOR inhibitor RAD001 (everolimus) in rats and mice. METHODS: Blood cell partitioning, plasma protein binding and PK parameters of RAD001 in blood and tissues (including brain) of both mice and rats were determined. PK modeling predicted plasma/blood and tumor levels from a variety of regimens and these were compared with the known human PK profile. DCE-MRI was used to compare tumor vascularity between mice and rats. Estimation of IC50 values in vitro and ED50 values in vivo were used to provide an indication of anti-tumor activity. RESULTS: The PK properties of RAD001 differed between mice and rats, including erythrocyte partitioning, plasma protein binding, plasma/blood t(1/2), oral bioavailability, volume of distribution, tissue/tumor penetration and elimination. Modeling of tumor and blood/plasma PK suggested that in mice, multiple daily administrations result in a 2-fold increase in tumor levels of RAD001 at steady state, whereas in rats, a 7.9-fold increase would occur. Weekly high-dose regimens were predicted not to facilitate tumor accumulation in either species. Total tumor levels of RAD001 were four- to eight-fold greater in rats than in mice. Rat tumors had a >2-fold greater plasma content and permeability compared to mouse tumors, which could contribute to differences in tumor drug uptake. Maximal antitumor effects (T/C of 0.04-0.35) were observed in both species after daily administration with similar C(max) and AUC values of unbound (free) RAD001. These free levels of RAD001 are exceeded in serum from cancer patients receiving clinically beneficial daily regimens. In rodents, brain penetration of RAD001 was poor, but was dose-dependent and showed over-proportional uptake in rats with a longer t(1/2) compared to the systemic circulation. CONCLUSIONS: The PK of RAD001 differed between mice and rats, with rats having a PK profile closer to that of humans. High intermittent doses of RAD001 may be more appropriate for treatment of brain tumors.

Deactivation of anti-cancer drug letrozole to a carbinol metabolite by polymorphic cytochrome P450 2A6 in human liver microsomes.

Cytochromes P450 (P450) involved in letrozole metabolism were investigated. Among 13 recombinant P450 forms examined, only P450 2A6 and 3A4 showed activities in transforming letrozole to its carbinol metabolite with small K(m) and high Vmax values yielding apparent Vmax/K(m) values of 0.48 and 0.24 nl min(-1) nmol(-1) P450, respectively. The metabolic activities of individual human liver microsomes showed a significant correlation with coumarin 7-hydroxylase activities (P450 2A6 marker) at a letrozole concentration of 0.5 microM, while a good correlation was also seen with testosterone 6beta-hydroxylase activities (P450 3A4 marker) at 5 microM substrate concentration with different inhibition by 8-methoxypsolaren. Significantly low carbinol-forming activities were seen in human liver microsomes from individuals possessing CYP2A6*4/*4 (whole CYP2A6 gene deletion) at a letrozole concentration of 0.5 microM. A Vmax/K(m) value measured for CYP2A6.7 (amino acid substitution type) in human liver microsomes, in the presence of anti-P450 3A4 antibodies, was approximately seven-fold smaller than that for CYP2A6.1 (wild-type). These results demonstrate that P450 2A6 and 3A4 catalyse the conversion of letrozole to its carbinol metabolite in vitro at low and high concentrations of letrozole. Polymorphic variation of CYP2A6 is considered to be relevant to inter-subject variation in therapeutic exposure of letrozole.

Continuous and discontinuous phase transitions and partial synchronization in stochastic three-state oscillators.

We investigate both continuous (second-order) and discontinuous (first-order) transitions to macroscopic synchronization within a single class of discrete, stochastic (globally) phase-coupled oscillators. We provide analytical and numerical evidence that the continuity of the transition depends on the coupling coefficients and, in some nonuniform populations, on the degree of quenched disorder. Hence, in a relatively simple setting this class of models exhibits the qualitative behaviors characteristic of a variety of considerably more complicated models. In addition, we study the microscopic basis of synchronization above threshold and detail the counterintuitive subtleties relating measurements of time-averaged frequencies and mean-field oscillations. Most notably, we observe a state of suprathreshold partial synchronization in which time-averaged frequency measurements from individual oscillators do not correspond to the frequency of macroscopic oscillations observed in the population.

Fluctuation theorem for entropy production during effusion of an ideal gas with momentum transfer.

We derive an exact expression for entropy production during effusion of an ideal gas driven by momentum transfer in addition to energy and particle flux. Following the treatment in Cleuren [Phys. Rev. E 74, 021117 (2006)], we construct a master equation formulation of the process and explicitly verify the thermodynamic fluctuation theorem, thereby directly exhibiting its extended applicability to particle flows and hence to hydrodynamic systems.

Effects of disorder on synchronization of discrete phase-coupled oscillators.

We study synchronization in populations of phase-coupled stochastic three-state oscillators characterized by a distribution of transition rates. We present results on an exactly solvable dimer as well as a systematic characterization of globally connected arrays of N types of oscillators (N=2,3,4) by exploring the linear stability of the nonsynchronous fixed point. We also provide results for globally coupled arrays where the transition rate of each unit is drawn from a uniform distribution of finite width. Even in the presence of transition rate disorder, numerical and analytical results point to a single phase transition to macroscopic synchrony at a critical value of the coupling strength. Numerical simulations make possible further characterization of the synchronized arrays.

Dissipation: the phase-space perspective.

We show, through a refinement of the work theorem, that the average dissipation, upon perturbing a Hamiltonian system arbitrarily far out of equilibrium in a transition between two canonical equilibrium states, is exactly given by =W-DeltaF=kTD(rho||rho[over ])=kT, where rho and rho[over ] are the phase-space density of the system measured at the same intermediate but otherwise arbitrary point in time, for the forward and backward process. D(rho||rho[over ]) is the relative entropy of rho versus rho[over ]. This result also implies general inequalities, which are significantly more accurate than the second law and include, as a special case, the celebrated Landauer principle on the dissipation involved in irreversible computations.

Ethnic sensitivity study of fingolimod in white and Asian subjects.

OBJECTIVE: The authors compared the pharmacokinetics and pharmacological effects of the immunomodulator fingolimod in healthy white and Asian subjects for potential ethnic differences. METHODS: White and Asian (Japanese) healthy subjects were demographically matched for sex, age and weight. Subjects received single 1.25 mg doses of fingolimod (6 ethnic pairs), 2.5 mg (7 pairs), 5 mg (6 pairs) or 5 mg/day for 7 days (6 pairs). The pharmacokinetics of fingolimod, major metabolites, peripheral blood lymphocyte counts and heart rate were characterized over 1 month after single-dose and 2 months after multiple-dose administration. RESULTS: There were no clinically relevant differences in the fingolimod dose Cmax or dose AUC relationships between Asian subjects (slopes 0.84 and 1.05) versus white subjects (slopes 1.13 and 1.26) after single-dose administration. During multiple-dose administration, there were no clinically relevant interethnic differences in fingolimod accumulation ratios (6.6 +/- 0.4 for whites, 7.0 +/- 0.7 for Asians), area under the concentration-time curve (390 +/- 73 versus 382 +/- 106 ng x h/ml), or elimination half-life (7.4 +/- 0.8 versus 7.9 +/- 2.0 days). The acute decrease in lymphocyte counts after single- and multiple-dose fingolimod were similar in the two ethnic groups. The lymphocyte recovery rate to baseline after a 5 mg single dose and 5 mg/day multiple dose was reduced by 36 and 15% in Asian subjects compared with white subjects. The transient, acute decrease in heart rate after the first dose of fingolimod and the subsequent return to baseline was similar in the two ethnic groups. CONCLUSION: There were no marked differences between healthy white and Asian subjects in fingolimod single-dose and multiple-dose pharmacokinetics, lymphocyte trafficking and heart rate responses.

Fluctuation theorem for the effusion of an ideal gas.

The probability distribution of the entropy production for the effusion of an ideal gas between two compartments is calculated explicitly. The fluctuation theorem is verified. The analytic results are in good agreement with numerical data from hard disk molecular dynamics simulations.

Critical behavior and synchronization of discrete stochastic phase-coupled oscillators.

Synchronization of stochastic phase-coupled oscillators is known to occur but difficult to characterize because sufficiently complete analytic work is not yet within our reach, and thorough numerical description usually defies all resources. We present a discrete model that is sufficiently simple to be characterized in meaningful detail. In the mean-field limit, the model exhibits a supercritical Hopf bifurcation and global oscillatory behavior as coupling crosses a critical value. When coupling between units is strictly local, the model undergoes a continuous phase transition that we characterize numerically using finite-size scaling analysis. In particular, we explicitly rule out multistability and show that the onset of global synchrony is marked by signatures of the XY universality class. Our numerical results cover dimensions d=2, 3, 4, and 5 and lead to the appropriate XY classical exponents beta and nu, a lower critical dimension dlc=2, and an upper critical dimension duc=4.

Brownian refrigerator.

Onsager symmetry implies that a Brownian motor, driven by a temperature gradient, will also perform a refrigerator function upon loading. We analytically calculate the corresponding heat flow for an exactly solvable microscopic model and compare it with molecular dynamics simulations.

Universality of synchrony: critical behavior in a discrete model of stochastic phase-coupled oscillators.

We present the simplest discrete model to date that leads to synchronization of stochastic phase-coupled oscillators. In the mean field limit, the model exhibits a Hopf bifurcation and global oscillatory behavior as coupling crosses a critical value. When coupling between units is strictly local, the model undergoes a continuous phase transition which we characterize numerically using finite-size scaling analysis. In particular, the onset of global synchrony is marked by signatures of the XY universality class, including the appropriate classical exponents beta and nu, a lower critical dimension d(lc) = 2, and an upper critical dimension d(uc) = 4.

Fluctuation and dissipation of work in a Joule experiment.

We elucidate the connection between various fluctuation theorems by a microcanonical version of the Crooks relation. We derive the microscopically exact expression for the work distribution in an idealized Joule experiment, namely, for a convex object moving at constant speed through an ideal gas. Analytic results are compared with molecular dynamics simulations of a hard disk gas.

Microscopic analysis of a thermal brownian motor.

We study a genuine Brownian motor by hard disk molecular dynamics and calculate analytically its properties, including its drift speed and thermal conductivity, from microscopic theory.

Macroscopic limit cycle via pure noise-induced phase transitions.

Bistability generated via a pure noise-induced phase transition is reexamined from the view of bifurcations in macroscopic cumulant dynamics. It allows an analytical study of the phase diagram in more general cases than previous methods. In addition, using this approach we investigate spatially extended systems with two degrees of freedom per site. For this system, the analytic solution of the stationary Fokker-Planck equation is not available and a standard mean field approach cannot be used to find noise-induced phase transitions. A different approach based on cumulant dynamics predicts a noise-induced phase transition through a Hopf bifurcation leading to a macroscopic limit cycle motion, which is confirmed by numerical simulation.

Drift by dichotomous Markov noise.

We derive explicit results for the asymptotic probability density and drift velocity in systems driven by dichotomous Markov noise, including the situation in which the asymptotic dynamics crosses unstable fixed points. The results are illustrated on the problem of the rocking ratchet.