Maximum flexion and lateral rollback revealed better patient satisfaction after total knee arthroplasty.

INTRODUCTION: Patient satisfaction is an important outcome of total knee arthroplasty (TKA). However, we cannot predict how and why patients are satisfied or dissatisfied with TKA. The hypothesis of this study was that patient-reported outcomes (PROs) correlate with in vivo kinematics after TKA. MATERIALS AND METHODS: One hundred knees were analyzed after TKA. The in vivo kinematics of deep knee bending motion were estimated from single-plane fluoroscopy using a two-to-three-dimensional registration technique. Active knee flexion, femoral rotation and rollback were evaluated. The PROs were obtained after surgery using the 2011 Knee Society Scoring System (KSS), and their relationship with in vivo kinematics was determined. RESULTS: The average minimum and maximum flexion were -2.4 ± 7.3° and 113.2 ± 13.6°, respectively. The average femoral rotation was 7.4 ± 3.4°, and the average medial and lateral rollback were 2.4 ± 4.8 mm and 7.2 ± 5.6 mm, respectively. The multiple regression analysis revealed that the maximum flexion angle significantly contributed to symptoms and satisfaction. In addition, lateral rollback was also a significant factor affecting patient satisfaction. Lateral rollback and lateral Anterior-Posterior (AP) position at maximum flexion were correlated with the maximum flexion angle, whereas femoral rotation did not correlate with flexion angles. CONCLUSIONS: Maximum flexion and lateral rollback are important for better patient satisfaction after TKA. To obtain the maximum flexion angle, it was necessary to perform the normal kinematic pattern with a large amount of lateral rollback.

Picosecond-Scale Ultrafast Many-Body Dynamics in an Ultracold Rydberg-Excited Atomic Mott Insulator.

We report the observation and control of ultrafast many-body dynamics of electrons in ultracold Rydberg-excited atoms, spatially ordered in a three-dimensional Mott insulator (MI) with unity filling in an optical lattice. By mapping out the time-domain Ramsey interferometry in the picosecond timescale, we can deduce entanglement growth indicating the emergence of many-body correlations via dipolar forces. We analyze our observations with different theoretical approaches and find that the semiclassical model breaks down, thus indicating that quantum fluctuations play a decisive role in the observed dynamics. Combining picosecond Rydberg excitation with MI lattice thus provides a platform for simulating nonequilibrium dynamics of strongly correlated systems in synthetic ultracold atomic crystals, such as in a metal-like quantum gas regime.

In vivo three-dimensional kinematics of normal knees during different high-flexion activities.

AIMS: In Asia and the Middle-East, people often flex their knees deeply in order to perform activities of daily living. The purpose of this study was to investigate the 3D kinematics of normal knees during high-flexion activities. Our hypothesis was that the femorotibial rotation, varus-valgus angle, translations, and kinematic pathway of normal knees during high-flexion activities, varied according to activity. MATERIALS AND METHODS: We investigated the in vivo kinematics of eight normal knees in four male volunteers (mean age 41.8 years; 37 to 53) using 2D and 3D registration technique, and modelled the knees with a computer aided design program. Each subject squatted, kneeled, and sat cross-legged. We evaluated the femoral rotation and varus-valgus angle relative to the tibia and anteroposterior translation of the medial and lateral side, using the transepicodylar axis as our femoral reference relative to the perpendicular projection on to the tibial plateau. This method evaluates the femur medially from what has elsewhere been described as the extension facet centre, and differs from the method classically applied. RESULTS: During squatting and kneeling, the knees displayed femoral external rotation. When sitting cross-legged, femurs displayed internal rotation from 10° to 100°. From 100°, femoral external rotation was observed. No significant difference in varus-valgus angle was seen between squatting and kneeling, whereas a varus position was observed from 140° when sitting cross-legged. The measure kinematic pathway using our methodology found during squatting a medial pivoting pattern from 0° to 40° and bicondylar rollback from 40° to 150°. During kneeling, a medial pivot pattern was evident. When sitting cross-legged, a lateral pivot pattern was seen from 0° to 100°, and a medial pivot pattern beyond 100°. CONCLUSION: The kinematics of normal knees during high flexion are variable according to activity. Nevertheless, our study was limited to a small number of male patients using a different technique to report the kinematics than previous publications. Accordingly, caution should be observed in generalizing our findings. Cite this article: Bone Joint J 2018;100-B:50-5.

Evidence for magnetic Weyl fermions in a correlated metal.

Weyl fermions have been observed as three-dimensional, gapless topological excitations in weakly correlated, inversion-symmetry-breaking semimetals. However, their realization in spontaneously time-reversal-symmetry-breaking phases of strongly correlated materials has so far remained hypothetical. Here, we report experimental evidence for magnetic Weyl fermions in Mn3Sn, a non-collinear antiferromagnet that exhibits a large anomalous Hall effect, even at room temperature. Detailed comparison between angle-resolved photoemission spectroscopy (ARPES) measurements and density functional theory (DFT) calculations reveals significant bandwidth renormalization and damping effects due to the strong correlation among Mn 3d electrons. Magnetotransport measurements provide strong evidence for the chiral anomaly of Weyl fermions-namely, the emergence of positive magnetoconductance only in the presence of parallel electric and magnetic fields. Since weak magnetic fields (approximately 10 mT) are adequate to control the distribution of Weyl points and the large fictitious fields (equivalent to approximately a few hundred T) produced by them in momentum space, our discovery lays the foundation for a new field of science and technology involving the magnetic Weyl excitations of strongly correlated electron systems such as Mn3Sn.

Probing the Structure and Function Relationships of Presenilin by Substituted-Cysteine Accessibility Method.

Presenilin is a catalytic subunit of γ-secretase, which hydrolyzes several transmembrane proteins within the lipid bilayer, together with binding cofactors such as nicastrin, Aph-1, and Pen-2. However, the structural basis as well as molecular mechanism of this unusual proteolytic process remains unknown. We have analyzed the structure and function relationships of presenilin using the substituted-cysteine accessibility method (SCAM), which enables identification of the hydrophilic environment by the accessibility of sulfhydryl reagents to cysteine residues introduced at a desired position. In combination with small molecule inhibitors/modulators and cross-linking experiments, we were able to identify certain residues and regions of presenilin that contribute to its intramembrane-cleaving activity. In addition, we revealed the structural dynamics of the transmembrane domains of presenilin during the formation of the complex and its proteolytic process. The SCAM provides new insights into the relationship between the structure and activity of presenilin, and is useful for probing the protein dynamics of the membrane-embedded enzymes.

Slater to Mott Crossover in the Metal to Insulator Transition of Nd_{2}Ir_{2}O_{7}.

We present an angle-resolved photoemission study of the electronic structure of the three-dimensional pyrochlore iridate Nd_{2}Ir_{2}O_{7} through its magnetic metal-insulator transition. Our data reveal that metallic Nd_{2}Ir_{2}O_{7} has a quadratic band, touching the Fermi level at the Γ point, similar to that of Pr_{2}Ir_{2}O_{7}. The Fermi node state is, therefore, a common feature of the metallic phase of the pyrochlore iridates. Upon cooling below the transition temperature, this compound exhibits a gap opening with an energy shift of quasiparticle peaks like a band gap insulator. The quasiparticle peaks are strongly suppressed, however, with further decrease of temperature, and eventually vanish at the lowest temperature, leaving a nondispersive flat band lacking long-lived electrons. We thereby identify a remarkable crossover from Slater to Mott insulators with decreasing temperature. These observations explain the puzzling absence of Weyl points in this material, despite its proximity to the zero temperature metal-insulator transition.

Patient-controlled bolus femoral nerve block after knee arthroplasty: quadriceps recovery, analgesia, local anesthetic consumption.

BACKGROUND: Continuous femoral nerve block (cFNB) induces quadriceps muscle weakness, but patient-controlled femoral nerve block (PCFNB) can provide analgesia with lower consumption of local anesthetics compared to cFNB. We hypothesized that cFNB followed by PCFNB leads to accelerated recovery of quadriceps weakness after total knee arthroplasty compared to cFNB alone. Secondary outcomes were local anesthetic consumption, pain, and mobilization. METHODS: Fifty-six subjects received post-operative cFNB for 24 h and then randomized to receive either cFNB (basal infusion of 6 ml/h using a dummy bolus button; n = 27) or PCFNB (bolus infusion of 3 ml with a lockout time of 30 min and no basal infusion; n = 29) using 0.08% levobupivacaine for the subsequent 24 h in a double-blind manner (registration: UMIN000010105). Quadriceps strength was assessed using a hand-held dynamometer. The percentage change from baseline was compared between groups. RESULTS: Quadriceps strength at 48 h was 47.3 ± 18.3% in the cFNB group and 49.7 ± 15.7% in the PCFNB group (95% confidence interval -7.0-11.9%, P = 0.61). Local anesthetic consumption during the post-operative period was significantly lower in the PCFNB group compared to the cFNB group (102 ± 10.8 ml vs.146 ± 4.6 ml; P < 0.001). No significant differences were found in any of the other outcomes, including pain scores at rest and during knee rehabilitation. CONCLUSION: Continuous femoral nerve block followed by PCFNB does not improve quadriceps strength recovery time compared to cFNB alone after total knee arthroplasty, but similar analgesic effects were demonstrated with reduced levobupivacaine consumption.

Impairment of gastric accommodation induced by water-avoidance stress is mediated by 5-HT2B receptors.

BACKGROUND: Psychological stress has been shown to impair gastric accommodation (GA), but its mechanism has not been elucidated. This study was conducted to clarify the role of 5-HT2B receptors in a guinea pig model of stress-induced impairment of GA. METHODS: Gastric accommodation was evaluated by measuring the intrabag pressure in the proximal stomach after administration of a liquid meal. The guinea pigs were subjected to water-avoidance stress. The role of 5-HT2B receptors in impairment of GA was investigated by administering a 5-HT2B receptor agonist (BW723C86) or antagonist (SB215505), the traditional Japanese medicine rikkunshito (RKT), a muscarinic M3 receptor antagonist (1,1-dimethyl-4-diphenylacetoxypiperidium iodide [4-DAMP]), or a nitric oxide synthase inhibitor (Nω -nitro-L-arginine [L-NNA]). KEY RESULTS: In normal animals, liquid meal-induced GA was inhibited by BW723C86, but was not affected by SB215505. The inhibition of GA by BW723C86 was reversed by co-administration of 4-DAMP. Compared to normal animals, GA in stressed animals was significantly inhibited. SB215505 and RKT significantly suppressed stress-induced impairment of GA. After meal administration, the level of cyclic guanosine monophosphate in gastric fundus tissue increased by approximately twofold in normal animals, but did not change in stressed animals. The inhibition of GA by L-NNA was suppressed by SB215505 or RKT. At a dose that did not affect GA in normal animals, BW723C86 exacerbated the impairment of GA in stressed animals. CONCLUSIONS AND INFERENCES: Stress-induced impairment of GA may be mediated by an increased responsiveness of 5-HT2B receptors, and activation of the 5-HT2B receptor signaling pathway may have an inhibitory effect on nitric oxide function.

Development of dual fluorescent stage specific reporter strain of Toxoplasma gondii to follow tachyzoite and bradyzoite development in vitro and in vivo.

Toxoplasma gondii is a protozoan that infects 30% of humans as intermediate hosts. T Sexual reproduction can occur only within the intestinal tract of felines, however, infection in other mammals and birds is associated with asexual replication and interconversion between the tachyzoite and bradyzoite stages. Bradyzoites are slow growing forms found in tissue cysts in latent infection. Recently, our group described the biological behavior of the EGS strain that forms thick walled cysts spontaneously in tissue culture, constituting a useful tool for examining the developmental biology of T. gondii. To further improve the usefulness of this model, we constructed genetically modified EGS parasites that express fluorescent tags under the control of stage specific promoters. The promoter regions for SAG-1 (tachyzoite specific), BAG-1 and LDH-2 (bradyzoite specific) were amplified by PCR and plasmids were constructed with mCherry (redT) and sfGFP (greenB) sequences, respectively. Strains of parasites were selected using FACS to arrive at single fluorescent and dual fluorescent strains of EGS expressing tags in a stage specific manner. In cell cultures, vacuoles labeled by immunofluorescence assay using anti-CST-1 a marker for T. gondii cyst wall contained parasites that were positive for BAG1-GFP and negative for SAG1-mCherry. Tachyzoites and bradyzoites harvested from the mice expressed stage specific mCherry and GFP proteins, respectively. These new dual fluorescent transgenic EGS strains are a promising tool to elucidate the mechanisms of T. gondii differentiation both in vitro and in vivo.

Eritoran inhibits S100A8-mediated TLR4/MD-2 activation and tumor growth by changing the immune microenvironment.

S100A8/A9 is a major component of the acute phase of inflammation, and appears to regulate cell proliferation, redox regulation and chemotaxis. We previously reported that S100A8/S100A9 are upregulated in the premetastatic lung. However, the detailed mechanisms by which S100A8 contributes to tumor progression have not been elucidated. In this study, we investigated the TLR4/MD-2 dependency by S100A8 on tumor progression. We found that S100A8 (2-89) peptide stimulated cell migration in a manner dependent on TLR4, MD-2 and MyD88. The S100A8 (2-89) peptide also activated p38 and NF-κB in TLR4-dependent manner. The peptide induced the upregulation of both IL-6 and Ccl2 in peritoneal macrophages obtained from wild-type mice, but not TLR4-deficient mice. We then investigated the responsible region of S100A8 for TLR4/MD-2 binding by a binding assay, and found that C-terminal region of S100A8 binds to TLR4/MD-2 complex. To further evaluate the TLR4 dependency on tumor microenvironment, Lewis lung carcinoma-bearing mice were treated with Eritoran, an antagonist of TLR4/MD-2 complex. We found that both tumor volume and pulmonary recruitment of myeloid-derived suppressor cells were reduced with the treatment of Eritoran for five consecutive days. Eritoran reduced the development of tumor vasculature, and increased tumor-infiltration of CD8(+) T-cells. Taken together, S100A8 appears to play a crucial role in the activation of the TLR4/MD-2 pathway and the promotion of a tumor growth-enhancing immune microenvironment.

CD133 and DNA-PK regulate MDR1 via the PI3K- or Akt-NF-κB pathway in multidrug-resistant glioblastoma cells in vitro.

Chemotherapy is an adjuvant treatment for glioblastomas, however, chemotherapy remains palliative because of the development of multidrug resistance (MDR). Following prolonged chemotherapy, MDR protein 1 (MDR1) and CD133 increase in recurrent glioblastomas. CD133 positive (CD133+) glioma cancer stem-like cells (GCSCs) markedly promote drug resistance and exhibit increased DNA damage repair capability; thus they have a key role in determining tumor chemosensitivity. Although CD133, DNA-dependent protein kinase (DNA-PK), and MDR1 are elevated in CD133+ GCSCs, the relationship among these molecules has not been elucidated. In this study, MDR glioblastoma cell lines were created in response to prolonged doxorubicin chemotherapy. CD133, DNA-PK and MDR1 were markedly elevated in these cells. CD133 and DNA-PK may increase MDR1 via the phosphatidylinositol-3-kinase (PI3K)-Akt signal pathway. PI3K downstream targets Akt and nuclear factor (NF)-κB, which interacts with the MDR1 promoter, were also elevated in these cells. Downregulation of CD133 and DNA-PK by small interfering RNA, or inhibition of PI3K or Akt, decreased Akt, NF-κB and MDR1 expression. The results indicate that CD133 and DNA-PK regulate MDR1 through the PI3K- or Akt-NF-κB signal pathway. Consequently, a novel chemotherapeutic regimen targeting CD133 and DNA-PK in combination with traditional protocols may increase chemotherapeutic efficacy and improve prognosis for individuals who present with glioblastoma.

Indomethacin-induced generation of reactive oxygen species leads to epithelial cell injury before the formation of intestinal lesions in mice.

Recently, with the increasing number of elderly patients who continuously take aspirin and/or nonsteroidal anti-inflammatory drugs (NSAIDs), the number of cases of severe hemorrhagic gastrointestinal (GI) bleeding is also on the increase. Gastric acid has been reported to play the most important role in hemorrhagic gastric mucosal injury. However, the pathogenesis of NSAID-derived mucosal injury in the intestine, where there is no acidic environment, remains unknown. We previously reported that NSAID-derived mitochondrial reactive oxygen species (ROS) are directly involved in GI cellular injury in vitro, although an in vivo study has not yet been carried out. In this study, we investigated the relationship between NSAID-derived ROS and intestinal injury formation. For this purpose, intestinal mucosal live imaging in mice was carried out using an ROS-indicating fluorescent probe. Treatment with indomethacin caused macroscopic intestinal injury in mice; however, many dying cells were observed even in areas that macroscopically appeared to have no injury after treatment with indomethacin. A fluorescent probe revealed that mucosal cells in the apparently uninjured areas had a high concentration of ROS. Treatment with rebamipide significantly decreased both the ROS concentration and the number of dying cells: this drug is prescribed clinically for gastric injury patients and has been reported to upregulate the expression of manganese superoxide dismutase. On the basis of these results, we propose that NSAID treatment causes a high cellular concentration of ROS in mucosae, possibly decreasing mucosal organo-protective efficacy. Moreover, intestinal food contents are likely to damage the mucosal structure when it is in such a fragile condition.

IL-22 produced by cancer-associated fibroblasts promotes gastric cancer cell invasion via STAT3 and ERK signaling.

BACKGROUND: Interleukin-22 (IL-22) has been recently highlighted owing to its biological significance in the modulation of tissue responses during inflammation. However, the role of IL-22 in carcinogenesis has remained unclear. Here, we investigated the pathophysiological significance of IL-22 expression in gastric cancer tissues and examined the mechanism by which IL-22 promotes gastric cancer cell invasion. METHODS: Human gastric cancer specimens were analysed by immunohistochemistry for expression of IL-22 and IL-22 receptor 1 (IL-22R1). The effects of IL-22-induced STAT3 and ERK signalling on invasive ability of gastric cancer cells were examined using a small-interfering RNA system and specific inhibitors. AGS cells were co-cultured with cancer-associated fibroblasts (CAFs) from human gastric cancer tissues and assessed by invasion assay. RESULTS: Interleukin-22 and its receptor were expressed in α-smooth muscle actin-positive stromal cells and tumour cells at the invasive front of gastric cancer tissues, respectively. The expression of IL-22 and IL-22R1 was significantly related to lymphatic invasion. Interleukin-22 treatment promoted the invasive ability of gastric cancer cells through STAT3 and ERK activation. The invasive ability of gastric cancer cells was significantly enhanced by co-culture with IL-22-expressing CAFs. CONCLUSIONS: Interleukin-22 produced by CAFs promotes gastric cancer cell invasion via STAT3 and ERK signalling.

Effect of rikkunshito on the expression of substance P and CGRP in dorsal root ganglion neurons and voluntary movement in rats with experimental reflux esophagitis.

BACKGROUND: While there are reports that the herbal medicine rikkunshito (RKT) relieves upper gastrointestinal disease symptoms, the effect of RKT on primary afferent neurons is unknown. METHODS: A model of reflux esophagitis (RE) was implemented using male Wistar rats aged 6-7 weeks. Ten days after surgery, the total area of esophageal mucosal erosion sites was determined. Th8-10 dorsal root ganglia (DRG) were dissected out and the expression of substance P (SP), calcitonin gene-related peptide (CGRP), and phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) was determined in DRG using immunohistochemistry. RKT (0.6%/WV) or omeprazole (OME) (10 mg/kg) was administered for 10 days beginning on the day after surgery. Voluntary movement was measured with an infrared sensor for 22 h each day. KEY RESULTS: RE rats showed esophageal mucosal erosion and significantly increased number of SP/CGRP- and p-ERK1/2-immunoreactive neurons in DRG. Treatment with OME improved the size of erosive lesions in the esophageal mucosa of RE rats, while RKT did not. Treatment with RKT or OME significantly reduced the expression of SP/CGRP and p-ERK1/2 in DRG, and significantly increased voluntary movement in RE rats. CONCLUSIONS & INFERENCES: RKT inhibited the activation of ERK1/2 and decreased the expression of SP and CGRP in DRG of RE rats, which may be associated with the observed amelioration of voluntary movement.

Amyloid beta (A4) precursor protein expression in human periodontitis-affected gingival tissues.

OBJECTIVE: Periodontitis involves periodontal tissue destruction and is associated with chronic inflammation and ageing. Periodontitis has recently been recognised as a risk factor for Alzheimer's disease (AD). We showed upregulation of molecules in the AD pathway including amyloid beta (A4) precursor protein (APP), a key gene in AD, interleukin-1 beta (IL-1ß), and complement component 1 (q subcomponent, A chain) (C1QA) in periodontitis compared to healthy tissues. Here, we quantitatively analysed the expression levels of APP, IL-1ß, and C1QA and determined the localisation of APP in gingival tissues. DESIGN: Fourteen chronic periodontitis patients and 14 healthy participants were enrolled. Six samples of total RNA from two distinct sites of healthy and periodontitis-affected gingival tissues from three randomly selected patients were used for microarray analyses, and significant biological pathways in periodontitis were identified. Differential gene expression of APP, IL-1ß, and C1QA, which belong to the AD pathway, were analysed with quantitative reverse transcription real-time polymerase chain reaction (qRT-PCR) using samples from these 14 chronic periodontitis patients and 14 healthy controls. APP localisation was analysed with immunohistochemistry. RESULTS: APP, IL-1ß, and C1QA mRNA levels were significantly upregulated in periodontitis-affected gingival tissues. APP was mainly localised in macrophages in gingival connective tissues underneath the epithelial layers. CONCLUSIONS: An association between AD and periodontitis was detected with microarray and computer-aided data mining analyses. qRT-PCR identified differential gene expression in periodontitis-affected gingival tissue that may be related to AD pathogenesis. Elevated APP, IL-1ß, and C1QA transcripts and APP-expressing macrophages in periodontitis-affected gingival tissues were observed, suggesting a relationship between periodontitis and AD pathogenesis.

Northernmost record of a whale shark Rhincodon typus from the Sea of Okhotsk.

The whale shark Rhincodon typus is the world's largest fish and it occurs in tropical, subtropical and warm temperate waters. Here, the northernmost record of R. typus is reported, when it was found in the Sea of Okhotsk for the first time. This occurrence can be explained by the unusually high sea surface temperature during the summer of 2012.

ADAM12-cleaved ephrin-A1 contributes to lung metastasis.

Eph receptor tyrosine kinases and their ephrin ligands have been implicated in neuronal development and neovascularization. Overexpression of ephrin-A1 has been implicated in tumor progression and poor prognosis. However, the mechanisms are not clear. Here, we report a role of the Eph/ephrin system in a cell adhesion mechanism. Clustered erythropoietin-producing hepatocellular receptor A1 (EphA1)/ephrin-A1 complexes on the plasma membrane did not undergo endocytosis, and the cell remained adherent to one another. The cell-cell contacts were maintained in an Eph tyrosine kinase activity-independent manner even in the absence of E-cadherin. EphA1 and ephrin-A1 co-localized in pulmonary endothelial cells, and regulated vascular permeability and metastasis in the lungs. We identified ADAM12 (A disintegrin and metalloproteinase 12) as an EphA1-binding partner by yeast two-hybrid screening and found that ADAM12 enhanced ephrin-A1 cleavage in response to transforming growth factor-ß1 in primary tumors. Released soluble ephrin-A1 in the serum deteriorated the EphA1/ephrin-A1-mediated cell adhesion in the lungs in an endocrine manner, causing lung hyperpermeability that facilitated tumor cell entry into the lungs. Depletion of soluble ephrin-A1 by its neutralizing antibody significantly inhibited lung metastasis.

Occurrence of the Chilean devil ray Mobula tarapacana (Elasmobranchii: Batoidea: Myliobatiformes) in the Sea of Okhotsk: first record from cold temperate waters.

The northernmost record for Chilean devil ray Mobula tarapacana, a circumglobal species that occurs in tropical, subtropical and limited warm temperate waters, is described. An adult female was caught incidentally in the Sea of Okhotsk on 17 September 2011. This specimen is the first confirmed occurrence of devil rays Mobula spp. in cold temperate waters.