HIF-2α Inhibits Ameloblast Differentiation via Hey2 in Tooth Development.

Enamel is the highly mineralized outer layer of teeth; the cells responsible for enamel formation are ameloblasts. Local hypoxia and hypoxia inducible factor (HIF) in embryonic tissues are important to promote normal organogenesis. However, hypoxic state in tooth germs and the roles of HIF in ameloblast differentiation have not been understood. The aim of this study is to clarify the role of HIF in ameloblast differentiation during tooth germ development. We found that tooth germs were under hypoxia and HIF-1α and HIF-2α were expressed in tooth germs in embryonic mice. Then, we used HIF inhibitors to evaluate the function of HIF during tooth germ development. The HIF-2α inhibitor significantly decreased the size of tooth germs in organ culture, while the HIF-1α inhibitor did not apparently affect the size of tooth germs. The HIF-2α inhibitor enhanced the expression of amelogenin, a marker of ameloblast differentiation, in the tooth germs in organ culture and rat dental epithelial SF2 cells. Moreover, we found that the HIF-2α inhibitor-stimulating amelogenin expression was regulated by hes-related family basic helix-loop-helix transcription factor with YRPW motif 2(Hey2) in SF2 cells. These findings suggest that the HIF-2α-Hey2 axis plays an important role in ameloblast differentiation during tooth germ development.

Impact of near-infrared fluorescence imaging with indocyanine green on structural sequelae of anastomotic leakage after laparoscopic intersphincteric resection of malignant rectal tumors.

BACKGROUND: Recent studies have indicated the potential benefit of intraoperative near-infrared fluorescence imaging (NIR-FI) with indocyanine green in reducing early anastomotic leakage in colorectal surgery. Nonetheless, whether NIR-FI is effective in reducing structural sequelae of anastomotic leakage (SSAL) remains unclear. The aim of the present study was to investigate the impact of NIR-FI on SSAL after laparoscopic intersphincteric resection (ISR) of malignant rectal tumors. METHODS: This study was a retrospective single-center cohort study. A total of 293 consecutive patients who underwent elective laparoscopic ISR from May 2010 to August 2017 were included. Patients were divided into 2 groups; those who underwent elective laparoscopic ISR with lymphadenectomy for malignant rectal tumors using NIR-F (NIR-FI group) and those who underwent elective laparoscopic ISR with lymphadenectomy for malignant rectal tumors without using NIR-FI (control group). Thirty were excluded from the analyses (13 died, 7 had pelvic recurrence, and 10 were lost to follow-up). The primary endpoint was the rate of SSAL within 2 years after the primary resection, whereas the secondary endpoint was the rate of natural defecation via the anus at 2 years after the primary resection. Using various statistical analyses, such as propensity score matching, the rate of SSAL was compared between groups. RESULTS: A total of 263 patients were analyzed [177 males and 86 females, median age 61 (27-84) years]. Prior to propensity score matching (n = 263), NIR-FI was performed in 70 patients (26.6%) The rates of SSAL were 1.4% (1/70) in the NIR-FI group and 10.4% (20/193) in the control group (p = 0.02). After propensity score matching (n = 163), the rates of SSAL were 1.5% (1/66) in the NIR-FI group and 11.7% (12/103) in the control group (p = 0.02). Propensity score analyses, as well as simple regression analyses, revealed that NIR-FI was associated with a significantly lower risk of SSAL (OR 0.10-0.13; p = 0.03-0.05). CONCLUSIONS: NIR-FI is useful in reducing the rate of SSAL after laparoscopic ISR.

Impact of prompt intervention in response to positive blood culture results during weekends by collaboration between infectious disease specialists and microbiology laboratory staff.

The purpose of this investigation was to elucidate the impact of prompt intervention for patients whose blood culture results became positive during weekends, as this is not standard care in some countries. A retrospective cohort study was conducted in a tertiary referral hospital. From June 2015, results of positive blood cultures became available during weekends. If infectious disease specialists identified cases of bacteremia on suboptimal antimicrobial coverage, they contacted the primary team for modification of antibiotic treatment. We reviewed patients whose blood culture results became positive during weekends, comparing the pre-intervention (September 2014 to May 2015) and post-intervention (June 2015 to February 2016) periods. In total, 1081 (post-intervention 568 [52.5%]) bacteremia episodes were included (median patient age [interquartile range, IQR]: 72 [60-82] years; men: 625 [57.8%]). During the post-intervention period, 187 (32.9%) bacteremia episodes were detected during weekends. Infectious disease specialists evaluated the positive blood culture results 1, 2, and ≥3 days prior in 77 (13.6%), 88 (15.5%), and 22 (3.9%) cases, respectively. Although the 7- and 30-day mortality did not significantly improve after the intervention, the length of hospital stay (LOS) in the hospital-acquired bacteremia group was significantly reduced during the post-intervention period after controlling for confounders (post- vs. pre-intervention: median days [IQR]: 37 [19-63] vs. 46.5 [24.8-86.3], p = 0.030). Blood culture results became positive during weekends in one-third of bacteremia cases. The LOS was shortened after the intervention in the hospital-acquired bacteremia group. This could be an important antimicrobial stewardship target.

Unique characteristics of community-onset healthcare- associated bloodstream infections: a multi-centre prospective surveillance study of bloodstream infections in Japan.

BACKGROUND: Analysis of bloodstream infections (BSIs) is valuable for their diagnosis, treatment and prevention. However, limited data are available in Japan. AIM: To investigate the characteristics of patients with bacteraemia in Japan. METHODS: This study was conducted in five hospitals from October 2012 to September 2013. Clinical, demographic, microbiological and outcome data for all blood-culture-positive cases were analysed. FINDINGS: In total, 3206 cases of BSI were analysed: 551 community-onset healthcare-associated (CHA)-BSIs, 1891 hospital-acquired (HA)-BSIs and 764 community-acquired (CA)-BSIs. The seven- and 30-day mortality rates were higher in patients with CHA- and HA-BSIs than in patients with CA-BSIs. The odds ratios (ORs) for seven-day mortality were 2.56 [95% confidence interval (CI) 1.48-4.41] and 2.63 (95% CI 1.64-4.19) for CHA- and HA-BSIs, respectively. The ORs for 30-day mortality were 2.41 (95% CI 1.63-3.57) and 3.31 (95% CI 2.39-4.59) for CHA- and HA-BSIs, respectively. There were 499 cases (15.2%) of central-line-associated BSI and 163 cases (5.0%) of peripheral-line-associated BSI. Major pathogens included coagulase-negative staphylococci (N = 736, 23.0%), Escherichia coli (N = 581, 18.1%), Staphylococcus aureus (N = 294, 9.2%) and Klebsiella pneumoniae (N = 263, 8.2%). E. coli exhibited a higher 30-day mortality rate among patients with HA-BSIs (22.3%) compared with patients with CHA-BSIs (12.3%) and CA-BSIs (3.4%). K. pneumoniae exhibited higher 30-day mortality rates in patients with HA-BSIs (22.0%) and CHA-BSIs (22.7%) compared with patients with CA-BSIs (7.8%). CONCLUSION: CHA- and HA-BSIs had higher mortality rates than CA-BSIs. The prognoses of E. coli- and K. pneumonia-related BSIs differed according to the category of bacteraemia.

Salmonella enterica serotype Paratyphi A carrying CTX-M-15 type extended-spectrum beta-lactamase isolated from a Japanese traveller returning from India, Japan, July 2013.

Emerging drug resistance in Salmonella Typhi and S. Paratyphi is a substantial public health concern. We report what appears to be the first case and isolation of multidrug resistant S. Paratyphi A carrying CTXM-15-type extended-spectrum beta-lactamase from a Japanese traveller returning from India.

Serum microRNA expression profile: miR-1246 as a novel diagnostic and prognostic biomarker for oesophageal squamous cell carcinoma.

BACKGROUND: Recent studies have demonstrated that microRNAs (miRNAs) are stably detectable in blood and can serve as useful biomarkers for cancer. METHODS: We performed an miRNA array using serum samples obtained from oesophageal squamous cell carcinoma (ESCC) patients or healthy controls. MiR-1246 was the most markedly elevated in ESCC patients. Therefore, miR-1246 was selected as a candidate for further analysis. The serum miR-1246 level in 46 healthy controls and 101 ESCC patients was evaluated and compared among various clinicopathological characteristics. MiR-1246 expressions in tissue, exosomal, and cellular samples were also examined. RESULTS: Serum miR-1246 alone yielded an receiver-operating characteristic curve area of 0.754, with 71.3% sensitivity and 73.9% specificity for distinguishing ESCC patients from healthy controls. Serum miR-1246 was significantly correlated with the TNM stage and showed to be the strongest independent risk factor for poor survival (HR, 4.032; P=0.017). Unlike the tendency shown in previous reports, miR-1246 was not upregulated in ESCC tissue samples. Furthermore, exosomal miR-1246 did not reflect the abundance in the cell of origin. CONCLUSION: These data support our contention that serum miR-1246 has strong potential as a novel diagnostic and prognostic biomarker in ESCC, and its releasing mechanism is selective and independent of tissue miRNA abundance.

Anomalous metallic state in the vicinity of metal to valence-bond solid insulator transition in LiVS2.

We investigate LiVS2 and LiVSe2 with a triangular lattice as itinerant analogues of LiVO2 known for the formation of a valence-bond solid (VBS) state out of an S=1 frustrated magnet. LiVS2, which is located at the border between a metal and a correlated insulator, shows a first order transition from a paramagnetic metal to a VBS insulator at Tc approximately 305 K upon cooling. The presence of a VBS state in the close vicinity of insulator-metal transition may suggest the importance of itinerancy in the formation of a VBS state. We argue that the high temperature metallic phase of LiVS2 has a pseudogap, likely originating from the VBS fluctuation. LiVSe2 was found to be a paramagnetic metal down to 2 K.

Emergence of a diffusive metal state with no magnetic order near the Mott transition in frustrated pyrochlore-type molybdates.

The electron-correlation driven metal-insulator (Mott) transition in pyrocholore-type R2Mo2O7(R being rare-earth-metal ions) is accompanied by the change of the magnetic state from ferromagnetic to spin glass due to the competing double-exchange and superexchange interactions on the frustrated lattice. By application of high pressures on the compounds with Mott criticality, however, a new unique paramagnetic metal phase is observed to show up with nearly temperature-independent high resistivity close to the Ioffe-Regel limit. A possible non-Fermi-liquid character of this anomalously diffuse metallic state is argued in terms of the extended double-exchange model with the magnetically frustrated local S=1/2 spins.

Multicritical end point of the first-order ferromagnetic transition in colossal magnetoresistive manganites.

We have studied the bandwidth-temperature-magnetic-field phase diagram of RE0.55Sr0.45MnO3 colossal magnetoresistance manganites with ferromagnetic metal (FM) ground state. The bandwidth was controlled both via chemical substitution and hydrostatic pressure with a focus on the vicinity of the critical pressure p;{*} where the character of the zero-field FM transition changes from first to second order. Below p;{*} the first-order FM transition extends up to a critical magnetic field. It approaches zero on the larger bandwidth side where the surface of the first-order FM phase boundary is terminated by a multicritical end point. The change in the character of the transition and the decrease of the colossal magnetoresistance effect is attributed to the reduced charge-order and orbital-order fluctuations.

Manometer extension for high pressure measurement: nuclear quadrupole resonance study of Cu2O with a modified Bridgman anvil cell up to 10 GPa.

We report (63)Cu nuclear quadrupole resonance (NQR) measurement of Cu(2)O under pressure up to about 10 GPa at low temperatures. Because the lattice parameter of Cu(2)O changes with increasing pressure, the electric field gradient at the Cu site also changes correspondingly with pressure. This enables us to use the Cu(2)O as an in situ manometer for high pressure nuclear magnetic resonance/NQR up to about 9 GPa.

Enhancement of superconductivity and evidence of structural instability in intercalated graphite CaC6 under high pressure.

We measured the temperature dependent resistivity, varrho(T), of the intercalated graphite superconductor CaC6 as a function of pressure up to 16 GPa. We found a large linear increase of critical temperature, Tc, from the ambient pressure value 11.5 K up to 15.1 K, the largest value for intercalated graphite, at 7.5 GPa. At approximately 8 GPa, a jump of varrho and a sudden drop of Tc down to approximately 5 K indicates the occurrence of a phase transition. Our data analysis suggests that a pressure-induced phonon softening related to an in-plane Ca phonon mode is responsible for the Tc increase and that higher pressures greater, similar8 GPa lead to a structural transition into a new phase with a low Tc less, similar3 K.

Mott-Anderson transition controlled by a magnetic field in pyrochlore molybdate.

The pyrochlore molybdate Gd2MO2O7 locates near the phase boundary between the ferromagnetic-metallic and the spin-glass insulating state. This metal-insulator transition is governed on a large energy scale by the electron-correlation effect, while the geometrical frustration causes the random potential. The magnetic field can tune the randomness of the potential and control, under a suitable pressure, the continuous Mott-Anderson transition precisely. The critical exponent (mu = 1.04 +/- 0.1) of the Mott-Anderson transition has been determined for this ferromagnetic orbital-degenerate electron system.

Anomalous pressure dependence of the superconducting transition temperature of beta-pyrochlore AOs2O6 oxides.

High-pressure effects on the superconducting transitions of beta-pyrochlore oxide superconductors AOs(2)O(6) (A = Cs,Rb,K) are studied by measuring resistivity under high pressures up to 10 GPa. The superconducting transition temperature T(c) first increases with increasing pressure in every compound and then exhibits a broad maximum at 7.6 K (6 GPa), 8.2 K (2 GPa), and 10 K (0.6 GPa) for A = Cs, Rb, and K, respectively. Finally, the superconductivity is suppressed completely at a critical pressure near 7 GPa and 6 GPa for A = Rb and K and probably above 10 GPa for A = Cs. Characteristic changes in the coefficient A of the T(2) term in resistivity and residual resistivity are observed, both of which are synchronized with the corresponding change in T(c).

Galanin-immunoreactive nerve fibers in the periodontal ligament during experimental tooth movement.

Neuropeptides have been suggested to play a role in pain transmission during orthodontic tooth movement. We examined this hypothesis by examining the effect of orthodontic tooth movement on the expression of galanin (GAL)-immunoreactive (ir) nerve fibers in the periodontal ligament (PDL) of one mesial root (MR) and two distal roots (DRs) of the rat maxillary first molar. In control rats, GAL-ir fibers were very rare in the PDL. One day after the insertion of the elastic band, the number of GAL-ir fibers increased, becoming most numerous at 3 days. From 5 to 28 days, GAL-ir fibers tended to decrease. Electron microscopic observation showed that all of the GAL-ir fibers were unmyelinated. These findings suggest that GAL-containing nerve fibers in the PDL may play an important role in the response of the tissue to experimental tooth movement.

Competition of static stripe and superconducting phases in La(1.48)Nd(0.4)Sr(0.12)CuO(4) controlled by pressure.

We have investigated the pressure effect on T(c) and the Hall coefficient in the static stripe-ordered phase of La(1.48)Nd(0.4)Sr(0.12)CuO(4) crystal under hydrostatic pressure. We found a dramatic change of the Hall coefficient and an abrupt increase of T(c) at low pressure of about 0.1 GPa. The results are indicative of a transition from one- to two-dimensional charge transport, associated with the suppression of low-temperature-tetragonal (LTT) phase. From the uniaxial pressure measurements it turns out that the observed critical change is induced primarily due to the in-plane compression of the CuO(2) planes which would make the pinning potential of the LTT lattice distortions weaker.

Tumor-specific responses in lymph nodes draining murine sarcomas are concentrated in cells expressing P-selectin binding sites.

Tumor-draining lymph node (TDLN) cells develop substantial antitumor activity after activation on immobilized alphaCD3 and culture in low-dose IL-2. This study found that the minor subset of TDLN T cells expressing binding sites for the adhesion receptor P-selectin (Plig(high) T cells) produced T lymphoblasts with the most tumor-specific IFN-gamma synthesis in vitro and antitumor activity following adoptive transfer in vivo. The Plig(high) T cells constituted <25% of the cells with the phenotype of recently activated cells including high levels of CD69, CD44, or CD25, and low levels of CD62L. The cultured Plig(high) TDLN were 10- to 20-fold more active against established pulmonary micrometastases than cultured unfractionated TDLN, and >30-fold more active than cultured TDLN cells depleted of the Plig(high) fraction before expansion (Plig(low) cells). Tumor-specific IFN-gamma synthesis in vitro paralleled the antitumor activities of the cultured fractions in vivo, implying that increased Tc1 and Th1 effector functions contributed to the tumor suppression. Neither nonspecific interaction with the P-selectin chimera used for sorting nor endogenous costimulatory activity in the Plig(high) fraction accounted for the marked increase in antitumor activities after culture. The cultured Plig(high) fraction contained a variety of potential effector cells; however, the CD8 and CD4 subsets of alphabeta T cells accounted for 95-97% of its antitumor activity. The authors propose that P-selectin sorting increased antitumor activities by concentrating Tc1 and Th1 pre-effector/effector cells before culture.

Antitumor reactivity of lymph node cells primed in vivo with dendritic cell-based vaccines.

Tumor lysate-pulsed dendritic cells were used to generate nodal effector T cells in the murine MCA 205 tumor model. Dendritic cells were derived from bone marrow and cultured in granulocyte-macrophage colony-stimulating factor/interleukin 4 before pulsation with tumor lysate. Multiple subcutaneous administrations of tumor lysate-pulsed dendritic cells (TP-DCs) resulted in an approximately eightfold hypertrophy of the vaccine draining nodes, with an increased influx of dendritic (CD11c+/CD80+) cells and B (B220+) cells. The vaccine-primed lymph node (VPLN) cells were secondarily activated with anti-CD3/interleukin 2 and exhibited specific interferon-gamma release to tumor antigen. The adoptive transfer of TP-DC VPLN cells resulted in regression of established 3-day pulmonary metastases. The antitumor reactivity of TP-DC VPLN cells was comparable to anti-CD3/interleukin 2 activated tumor-draining lymph node cells. However, the admixture of keyhole limpet hemocyanin (KLH) with tumor lysate during pulsation of dendritic cells significantly enhanced the induction of tumor-reactive VPLN cells. Tumor lysate-pulsed dendritic cells can be used as a strategy to generate effector T cells for adoptive immunotherapy.