Structural variation of the 3-acetamido-4,5,6-trihydroxyazepane iminosugar through epimerization and C-alkylation leads to low micromolar HexAB and NagZ inhibitors.

We report the synthesis of seven-membered iminosugars derived from a 3S-acetamido-4R,5R,6S-trihydroxyazepane scaffold and their evaluation as inhibitors of functionally related exo-N-acetylhexosaminidases including human O-GlcNAcase (OGA), human lysosomal ß-hexosaminidase (HexAB), and Escherichia coli NagZ. Capitalizing on the flexibility of azepanes and the active site tolerances of hexosaminidases, we explore the effects of epimerization of stereocenters at C-3, C-5 and C-6 and C-alkylation at the C-2 or C-7 positions. Accordingly, epimerization at C-6 (L-ido) and at C-5 (D-galacto) led to selective HexAB inhibitors whereas introduction of a propyl group at C-7 on the C-3 epimer furnished a potent NagZ inhibitor.

Application and outcomes of a standardized lymphadenectomy in laparoscopic right hemicolectomy requiring ligation of the middle colic artery.

BACKGROUND: Complete mesocolic excision with central vessel ligation may be important for accurate staging and improving the prognosis of right-sided colon cancer. Although the procedure is often performed laparoscopically, approaching the middle colic artery (MCA) is technically demanding, especially when complete ligation of arteries at their roots is desired. We standardized our laparoscopic approach by establishing the dissection boundary along the superior mesenteric artery to achieve D3 lymphadenectomy in the region of the MCA. The aim of the present study was to evaluate, on the basis of perioperative and short-term oncologic outcomes, the feasibility and safety of our technique METHODS: We conducted a retrospective study on consecutive patients with cancer located at the ascending colon and transverse colon who had laparoscopic right hemicolectomy requiring ligation of the MCA. RESULTS: There were 41 patients (22 males, median age 71 years [range 49-86] years). The median operation time was 285 min, and blood loss volume was 40 mL. Conversion to open surgery was required in 1 case. Complications that were Clavien-Dindo grade III or above occurred in 3 patients (7.3%). There was no anastomotic leakage. The median number of lymph nodes harvested was 46. CONCLUSIONS: Our technique was shown to be a safe, feasible, and useful strategy for performance of right hemicolectomy requiring ligation of the MCA in cases of colon cancer. The technique facilitates maximal lymph node dissection. Having obtained favorable outcomes, we look forward to investigation into long-term outcomes.

A Paul trap with sectored ring electrodes for experiments with two-dimensional ion crystals.

We have developed a trapped ion system for producing two-dimensional (2D) ion crystals for applications in scalable quantum computing, quantum simulations, and 2D crystal phase transition and defect studies. The trap is a modification of a Paul trap with its ring electrode flattened and split into eight identical sectors and its two endcap electrodes shaped as truncated hollow cones for laser and imaging optics access. All ten trap electrodes can be independently DC-biased to create various aspect ratio trap geometries. We trap and Doppler cool 2D crystals of up to 30 Ba+ ions and demonstrate the tunability of the trapping potential both in the plane of the crystal and in the transverse direction.

Antarctic petrels 'on the ice rocks': wintering strategy of an Antarctic seabird.

There is a paucity of information on the foraging ecology, especially individual use of sea-ice features and icebergs, over the non-breeding season in many seabird species. Using geolocators and stable isotopes, we defined the movements, distribution and diet of adult Antarctic petrels Thalassoica antarctica from the largest known breeding colony, the inland Svarthamaren, Antarctica. More specifically, we examined how sea-ice concentration and free-drifting icebergs affect the distribution of Antarctic petrels. After breeding, birds moved north to the marginal ice zone (MIZ) in the Weddell sector of the Southern Ocean, following its northward extension during freeze-up in April, and they wintered there in April-August. There, the birds stayed predominantly out of the water (60-80% of the time) suggesting they use icebergs as platforms to stand on and/or to rest. Feather δ15N values encompassed one full trophic level, indicating that birds fed on various proportions of crustaceans and fish/squid, most likely Antarctic krill Euphausia superba and the myctophid fish Electrona antarctica and/or the squid Psychroteuthis glacialis. Birds showed strong affinity for the open waters of the northern boundary of the MIZ, an important iceberg transit area, which offers roosting opportunities and rich prey fields. The strong association of Antarctic petrels with sea-ice cycle and icebergs suggests the species can serve, year-round, as a sentinel of environmental changes for this remote region.

The role of renal biomarkers to predict the need of surgery in congenital urinary tract obstruction in infants.

INTRODUCTION: The diagnosis of renal function impairment and deterioration in congenital urinary tract obstruction (UTO) continues to be extremely challenging. The use of new renal biomarkers in this setting may favor early renal injury detection, allowing for a reliable choice of optimal therapeutic options and the prevention or minimization of definitive renal damage. OBJECTIVE: The aim of the study was to investigate a selection of promising biomarkers of renal injury with the intention of evaluating and comparing their profile with clinically based decisions for surgical intervention of infants with congenital obstructive uropathies. STUDY DESIGN: The first-year profile of renal biomarkers, serum creatinine (sCr), serum and urine cystatin C (CyC), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), transforming growth factor beta-1 (TGF-ß1), retinol-binding protein (RBP), and microalbuminuria (µALB), was analyzed in a cohort of 37 infants with congenital UTO, divided into three subgroups, 14 cases with grade III unilateral hydro(uretero)nephrosis, 13 cases with grade III bilateral hydro(uretero)nephrosis, and 10 cases with low urinary tract obstruction (LUTO), compared with 24 healthy infants matched by gestational age and birth weight. Serum and urine samples were stored at -70 °C and thereafter analyzed by quantitative enzymatic immunoassay. RESULTS: Compared with the control group (Figure), all renal biomarker values were significantly increased in patients (P ≤ 0.02). In the unilateral hydronephrosis and LUTO group, RBP (P ≤ 0.043), NGAL (P ≤ 0.043), KIM-1 (P ≤ 0.03), and TGF-ß1 (P ≤ 0.034) values dropped significantly after surgery. Neutrophil gelatinase-associated lipocalin alone and in combination with urine and serum CyC demonstrated the best performance in determining the need for surgery (area under the curve, 0.801 and 0.881, respectively). Biomarker profile analysis was suggestive of surgical intervention in 55.4% (7/13) of non-operated cases, and most of the biomarker values were above the cutoff levels within at least 3 months before the clinically based surgical decision in 58% (14/24) of all operated patients. DISCUSSION: To the best of the authors' knowledge, this is the first study to present the clinical use of selected group of serum and urinary biomarkers in the setting of UTO to distinguish between patients who would benefit from surgery intervention. The most promising results were obtained using NGAL, RBP, TGF-ß1, and KIM-1, especially in the unilateral hydro(uretero)nephrosis and LUTO subgroups when compared with the control group. CONCLUSIONS: Urine biomarkers, alone and in combination, demonstrated high potential as a non-invasive diagnostic tool for identifying infants who may benefit from earlier surgical intervention.

Micro-computed tomographic evaluation of the shaping ability of four instrumentation systems in curved root canals.

AIM: To compare the shaping ability of four instrumentation systems in curved molar root canals, using computerized microtomography (micro-CT). METHODOLOGY: Forty mesial roots of mandibular molars were submitted first to radiographic examination to determine their curvature and then to a micro-CT scan to analyse other initial morphological characteristics. The specimens were distributed into four experimental groups, according to the endodontic instrumentation system used (n = 10): Group R, Reciproc; Group PTN, ProTaper Next; Group WOG, WaveOne Gold; Group PDL, ProDesign Logic. After root canal instrumentation, the specimens were submitted to a second micro-CT scan, and the pre- and postoperative data were examined to evaluate the following parameters: volume of dentine removed (DR), increase in root canal volume (VI), untouched root canal surface area (UA), volume of accumulated hard tissue debris (AD) and structure model index (SMI). The data observed for these parameters after instrumentation were analysed using generalized linear models. R software was used for the analyses, and the level of significance adopted was 5%. RESULTS: There were no significant differences among the instrumentation systems regarding the DR, VI, UA and AD parameters (P > 0.05). PTN and WOG systems were associated with greater increases in SMI than the PDL system (P < 0.05). CONCLUSIONS: The four systems evaluated were similar regarding the parameters analysed, with the exception of the SMI, with the rate of variation of this parameter being greater after using the PTN and WOG systems than after using the PDL system. These results indicate that the four systems perform similarly in terms of their shaping ability, but that the PTN and WOG systems produced more rounded preparations than the PDL system.

Acupuncture for reducing pruritus induced by intrathecal morphine at elective cesarean delivery: a placebo-controlled, randomized, double-blind trial.

BACKGROUND: Intrathecal morphine is a standard postoperative analgesic administered after cesarean delivery, but frequently causes pruritus. Acupuncture reportedly resolves refractory pruritus in certain patients. The aim of the study was to investigate the effectiveness of acupuncture in preventing pruritus induced by intrathecal morphine. METHODS: Thirty parturients received intrathecal hyperbaric bupivacaine (12 mg), fentanyl (10 µg), and morphine (150 µg) for spinal anesthesia at elective cesarean delivery at term. Patients were randomly divided into the acupuncture group (n=15) and the control group (n=15). In the acupuncture and control groups, certified acupuncturists inserted either indwelling press needles or sham needles, into Hegu (LI4), Neiguan (PC6), Quchi (LI11), and Zhigou (SJ6) on both arms the day before surgery. Needles were removed 48 hours postoperatively. The primary outcome was the incidence of postoperative pruritus. Adverse effects including nausea and vomiting were also investigated. RESULTS: There were no significant differences between the acupuncture group and the control group in the incidence of pruritus (67% vs. 67%, P=1.000, RR 1.0 [95% CI 0.60 to 1.66]) or the requirement for antipruritic therapy (6.7% vs. 20.0%, P=0.283, RR 0.33 [95% CI 0.04 to 2.85]). The incidence of postoperative nausea in the acupuncture group versus control group was 40.0% vs. 13.3%, P=0.099, RR 3.0 [95% CI 0.72 to 12.6]). The postoperative analgesic effect was comparable. CONCLUSION: Preoperatively administered acupuncture using press needles did not decrease intrathecal morphine-induced pruritus or the requirement for treatment.

Spontaneous endometriosis in cynomolgus monkeys as a clinically relevant experimental model.

STUDY QUESTION: Does spontaneous endometriosis in cynomolgus monkeys have the characteristics required of a good experimental model? SUMMARY ANSWER: Spontaneous endometriosis in cynomolgus monkeys exhibited similar clinicopathological characteristics to the human disease and was useful as an experimental model. WHAT IS KNOWN ALREADY: The prevalence of endometriosis in autopsied cynomolgus monkeys (Macaca fascicularis) in a breeding colony was reported to be 28.7% in 1993. The histopathological findings we reported recently showed that components of spontaneous endometriosis were not only endometriotic epithelium and stromal cells (CD10-positive) with hemorrhage and inflammation, but also smooth muscle metaplasia and nerve fibers. STUDY DESIGN, SIZE, DURATION: During routine medical examinations at a research facility from 2008 to 2012, 614 female cynomolgus monkeys of reproductive age (6-25 years) were screened for endometriosis by the presence of regular menstrual bleeding, serum CA125 levels and palpation of the abdomen. In total, 29 monkeys were selected as subjects for the following study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Of the 29 monkeys selected, 15 were diagnosed with endometriosis by laparoscopy and/or open surgery. The monkeys were monitored by observing their general condition, and eight of these were monitored using laparoscopy and MRI. In addition, to investigate appropriate screening parameters and endometriosis-associated biological parameters in monkeys, we retrospectively examined general laboratory parameters that correlate to the menstrual cycle and disease status. MAIN RESULTS AND THE ROLE OF CHANCE: The combination of CA125 serum levels (this was a useful marker for chocolate cysts), palpation of the abdomen, and fecal abnormalities was the most efficient screening method for diagnosing monkeys with endometriosis. Each animal could be diagnosed and assigned a disease stage by laparoscopy. While monitoring the disease stage by laparoscopy and/or MRI, disease status in individual monkeys was mainly stable or was progressive for 2-7 months. The detection rate by screening was low (15/614) but age-specific analysis suggests that screening would be more efficient if a colony for an endometriosis model is maintained with 11-20-year olds. As an endometriosis-associated biological parameter, the decrease in food consumption that coincided with menstruation was selected and correlated well (R2 value = 0.8239) with disease status (according to a modified adhesion revised American Fertility Society score). LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Peritoneal fluid was not analyzed because a smaller amount is produced in cynomolgus monkeys than in baboons. Although clinical endometriosis-associated pain is evaluated in women using a visual analog scale, pain could not be directly evaluated in this non-human primate model. WIDER IMPLICATIONS OF THE FINDINGS: Although cynomolgus monkeys are relatively small (2-5 kg) primates, laparoscopy and MRI make it possible to evaluate spontaneous endometriosis in these monkeys and to monitor its development over time. Spontaneous endometriosis in cynomolgus monkeys is a useful model for evaluating disease progress and drug efficacy because they have similar lesions to those in humans, and conventional laboratory methods and parameters for assessment are well established. STUDY FUNDING/COMPETING INTEREST(S): No external funds were used for this study. A.N.-K., K.T., H.T., A.K. and M.S. are full-time employees of Chugai Pharmaceutical Co., Ltd. R.K. received a consultancy fee from Chugai Pharmaceutical Co., Ltd. and lecture fees from Chugai Pharmaceuticals, Japan Vaccine Co. Ltd., Merck & Co., Mochida Co. Ltd., Roche Diagnostics, and BD, unrelated to the submitted work. S.N., S.O. and T.S. have nothing to declare.

Short-chain fatty acids induce tissue plasminogen activator in airway epithelial cells via GPR41&43.

BACKGROUND: Chronic rhinosinusitis (CRS) is a heterogeneous chronic inflammatory disease generally divided based on the presence or absence of nasal polyps (NPs). One of the features of NPs is excessive fibrin deposition, which is associated with down-regulation of tissue plasminogen activator (t-PA) in NPs. As t-PA is expressed in epithelial cells, and epithelium is readily accessible to topical therapies, identifying compounds that can mediate the induction of t-PA would be a potential new strategy for the treatment of NPs. OBJECTIVE: The objective of this study was to determine whether short-chain fatty acids (SCFAs) can induce t-PA in airway epithelial cells via their known receptors GPR41 and GPR43. METHODS: We performed immunohistochemistry (IHC) to determine whether receptors for SCFAs, known as G protein-coupled receptor 41/free fatty acid receptor 3 (GPR41/FFAR3) and GPR43/FFAR2, are expressed in nasal tissue. Primary normal human bronchial epithelial (NHBE) cells were stimulated with different concentrations of SCFAs to test induction of t-PA, which was analysed by expression of mRNA and protein. Mediation of responses by SCFA receptors was evaluated by specific receptor gene silencing with siRNA. RESULTS: Immunohistochemistry study revealed that airway epithelial cells expressed GPR41 and GPR43. Acetic acid, propionic acid, butyric acid and valeric acid significantly induced t-PA expression from two- to tenfolds. The strongest inducer of t-PA from NHBE cells was propionic acid; cells stimulated with propionic acid released t-PA into the supernatant in its active form. Gene silencing of GPR41 and GPR43 revealed that induction of t-PA by SCFAs was dependent upon both GPR41 and GPR43. CONCLUSIONS AND CLINICAL RELEVANCE: Short-chain fatty acids were shown to induce airway epithelial cell expression of t-PA via GPR41 and GPR43. Topical delivery of potent compounds that activate these receptors may have value by reducing fibrin deposition and shrinking nasal polyp growth.

A spin-orbital-entangled quantum liquid on a honeycomb lattice.

The honeycomb lattice is one of the simplest lattice structures. Electrons and spins on this simple lattice, however, often form exotic phases with non-trivial excitations. Massless Dirac fermions can emerge out of itinerant electrons, as demonstrated experimentally in graphene, and a topological quantum spin liquid with exotic quasiparticles can be realized in spin-1/2 magnets, as proposed theoretically in the Kitaev model. The quantum spin liquid is a long-sought exotic state of matter, in which interacting spins remain quantum-disordered without spontaneous symmetry breaking. The Kitaev model describes one example of a quantum spin liquid, and can be solved exactly by introducing two types of Majorana fermion. Realizing a Kitaev model in the laboratory, however, remains a challenge in materials science. Mott insulators with a honeycomb lattice of spin-orbital-entangled pseudospin-1/2 moments have been proposed, including the 5d-electron systems α-Na2IrO3 (ref. 5) and α-Li2IrO3 (ref. 6) and the 4d-electron system α-RuCl3 (ref. 7). However, these candidates were found to magnetically order rather than form a liquid at sufficiently low temperatures, owing to non-Kitaev interactions. Here we report a quantum-liquid state of pseudospin-1/2 moments in the 5d-electron honeycomb compound H3LiIr2O6. This iridate does not display magnetic ordering down to 0.05 kelvin, despite an interaction energy of about 100 kelvin. We observe signatures of low-energy fermionic excitations that originate from a small number of spin defects in the nuclear-magnetic-resonance relaxation and the specific heat. We therefore conclude that H3LiIr2O6 is a quantum spin liquid. This result opens the door to finding exotic quasiparticles in a strongly spin-orbit-coupled 5d-electron transition-metal oxide.

Rapid nongenomic modulation by neurosteroids of dendritic spines in the hippocampus: Androgen, oestrogen and corticosteroid.

Memories are stored in synapses that consist of axon terminals and dendritic spines. Dendritic spines are postsynaptic structures of synapses and are essential for synaptic plasticity and cognition. Therefore, extensive investigations concerning the functions and structures of spines have been performed. Sex steroids and stress steroids have been shown to modulate hippocampal synapses. Although the rapid modulatory action of sex steroids on synapses has been studied in hippocampal neurones over several decades, the essential molecular mechanisms have not been fully understood. Here, a description of kinase-dependent signalling mechanisms is provided that can explain the rapid nongenomic modulation of dendritic spinogenesis in rat and mouse hippocampal slices by the application of sex steroids, including dihydrotestosterone, testosterone, oestradiol and progesterone. We also indicate the role of synaptic (classic) sex steroid receptors that trigger these rapid synaptic modulations. Moreover, we describe rapid nongenomic spine modulation by applying corticosterone, which is an acute stress model of the hippocampus. The explanations for the results obtained are mainly based on the optical imaging of dendritic spines. Comparisons are also performed with results obtained from other types of imaging, including electron microscopic imaging. Relationships between spine modulation and modulation of cognition are discussed. We recognise that most of rapid effects of exogenously applied oestrogen and androgen were observed in steroid-depleted conditions, including acute slices of the hippocampus, castrated male animals and ovariectomised female animals. Therefore, the previously observed effects can be considered as a type of recovery event, which may be essentially similar to hormone replacement therapy under hormone-decreased conditions. On the other hand, in gonadally intact young animals with high levels of endogenous sex hormones, further supplementation of sex hormones might not be effective, whereas the infusion of blockers for steroid receptors or kinases may be effective, with respect to suppressing sex hormone functions, thus providing useful information regarding molecular mechanisms.

Perfusion MR Imaging Using a 3D Pulsed Continuous Arterial Spin-Labeling Method for Acute Cerebral Infarction Classified as Branch Atheromatous Disease Involving the Lenticulostriate Artery Territory.

BACKGROUND AND PURPOSE: Branch atheromatous disease is a stroke subtype considered a risk factor for early neurologic deterioration. Meanwhile, crossed cerebellar diaschisis is thought to be influenced by the degree and location of supratentorial perfusion abnormalities and is associated with the clinical outcome in the case of an ischemic stroke. In this article, our aim was to clarify the utility of using a whole-brain 3D pulsed continuous arterial spin-labeling method as an imaging biomarker for predicting neurologic severity in branch atheromatous disease. MATERIALS AND METHODS: Twenty-three patients with branch atheromatous disease in the lenticulostriate artery territory were enrolled. All patients underwent MR imaging, including DWI, 3D-TOF-MRA, and 3D-arterial spin-labeling. We measured the asymmetry index of CBF in the affected area (branch atheromatous disease), the asymmetry index of the contralateral cerebellar hemisphere (crossed cerebellar diaschisis), and the DWI infarct volume in the lenticulostriate artery territory. We also compared each parameter with the initial NIHSS score with the Pearson correlation coefficient. RESULTS: Among the 23 patients, we found no correlation between NIHSS score and the asymmetry index of CBF in the affected area (branch atheromatous disease) (r = -0.027, P = .724), whereas the asymmetry index of the contralateral cerebellar hemisphere (crossed cerebellar diaschisis) and DWI infarct volumes were significantly correlated with NIHSS score (r = 0.515, P = .012; r = 0.664, P = .001, respectively). CONCLUSIONS: In patients with branch atheromatous disease, 3D-arterial spin-labeling can detect crossed cerebellar diaschisis, which is correlated with the degree of neurologic severity.

Selective trihydroxylated azepane inhibitors of NagZ, a glycosidase involved in Pseudomonas aeruginosa resistance to ß-lactam antibiotics.

The synthesis of a series of d-gluco-like configured 4,5,6-trihydroxyazepanes bearing a triazole, a sulfonamide or a fluorinated acetamide moiety at C-3 is described. These synthetic derivatives have been tested for their ability to selectively inhibit the muropeptide recycling glucosaminidase NagZ and to thereby increase sensitivity of Pseudomonas aeruginosa to ß-lactams, a pathway with substantial therapeutic potential. While introduction of triazole and sulfamide groups failed to lead to glucosaminidase inhibitors, the NHCOCF3 analog proved to be a selective inhibitor of NagZ over other glucosaminidases including human O-GlcNAcase and lysosomal hexosaminidases HexA and B.

Distribution of ASIC4 transcripts in the adult wild-type mouse brain.

Acid-sensing ion channel 4 (ASIC4) belongs to the ASIC gene family of neuronal proton-gated cation channels, and is the least understood subtype among the members. Previous studies of ASIC4 expression in the mammalian central nervous system have shown that ASIC4 is abundantly expressed in the spinal cord and in various brain regions, such as the cerebral cortex, the hippocampus, and the cerebellum. However, the detailed distribution of ASIC4 transcripts in mammalian brains still remains to be elucidated. In the present study, radioactive in situ hybridization histochemistry with an ASIC4-specific cRNA probe was performed on wild-type mouse brains, followed by X-gal staining experiments with Asic4-lacZ reporter mice Asic4tm1a(KOMP)Mbp. It was found that ASIC4 mRNAs were widely expressed throughout the wild-type brain, but preferentially concentrated in the olfactory bulb, the piriform cortex, the caudate putamen, the preoptic area, the paraventricular nucleus, the medial habenular nucleus, the pretectal area, the lateral geniculate nucleus, the amygdaloid complex, the superior colliculus, the interpeduncular nucleus, and the granule cell layer of the ventral hippocampus, and these results were in agreement with the X-gal-positive reactions observed in the mutant brain. In addition, X-gal staining combined with immunohistochemistry identified intense signals for ASIC4 transcriptional activity in most of the choline acetyltransferase (ChAT)-positive principal neurons located in the basal forebrain cholinergic nuclei. Our data provide useful information to speculate possible roles of ASIC4 in diverse brain functions.

Chronic airway inflammation provides a unique environment for B cell activation and antibody production.

BACKGROUND: B cells play many roles in health and disease. However, little is known about the mechanisms that drive B cell responses in the airways, especially in humans. Chronic rhinosinusitis (CRS) is an inflammatory disease of the upper airways that affects 10% of Europeans and Americans. A subset of CRS patients develop nasal polyps (NPs), which are characterized by type 2 inflammation, eosinophils and group 2 innate lymphoid cells (ILC2s). We have reported that NP contain elevated levels of B cells and antibodies, making NP an ideal system for studying B cells in the airways. OBJECTIVE: We sought to determine the mechanisms that drive B cell activation and antibody production during chronic airway inflammation. METHODS: We analysed B cells from NP or tonsil, or after ILC2 coculture, by flow cytometry. Antibody production from tissue was measured using Luminex assays and the frequency of antibody-secreting cells by ELISpot. Formation of B cell clusters was assessed using immunohistochemistry. Expression of genes associated with B cell activation and class switch recombination was measured by qRT-PCR. RESULTS: NP contained significantly elevated frequencies of plasmablasts, especially those that expressed the extrafollicular marker Epstein-Barr virus-induced protein 2 (EBI2), but significantly fewer germinal centre (GC) B cells compared with tonsil. Antibody production and the frequency of antibody-secreting cells were significantly elevated in NP, and there was evidence for local class switch recombination in NP. Finally, ILC2s directly induced EBI2 expression on B cells in vitro. CONCLUSIONS AND CLINICAL RELEVANCE: Our data suggest there is a unique B cell activation environment within NP that is distinct from classic GC-mediated mechanisms. We show for the first time that ILC2s directly induce EBI2 expression on B cells, indicating that ILC2s may play an important role in B cell responses. B cell-targeted therapies may provide new treatment options for CRSwNP.

Periodontal tissue engineering by nano beta-tricalcium phosphate scaffold and fibroblast growth factor-2 in one-wall infrabony defects of dogs.

BACKGROUND AND OBJECTIVE: Nanoparticle bioceramics are being investigated for biomedical applications. We fabricated a regenerative scaffold comprising type I collagen and beta-tricalcium phosphate (ß-TCP) nanoparticles. Fibroblast growth factor-2 (FGF-2) is a bioeffective signaling molecule that stimulates cell proliferation and wound healing. This study examined the effects, on bioactivity, of a nano-ß-TCP/collagen scaffold loaded with FGF-2, particularly on periodontal tissue wound healing. MATERIAL AND METHODS: Beta-tricalcium phosphate was pulverized into nanosize particles (84 nm) and was then dispersed. A nano-ß-TCP scaffold was prepared by coating the surface of a collagen scaffold with a nanosize ß-TCP dispersion. Scaffolds were characterized using scanning electron microscopy, compressive testing, cell seeding and rat subcutaneous implant testing. Then, nano-ß-TCP scaffold, nano-ß-TCP scaffold loaded with FGF-2 and noncoated collagen scaffold were implanted into a dog one-wall infrabony defect model. Histological observations were made at 10 d and 4 wk postsurgery. RESULTS: Scanning electron microscopy images show that TCP nanoparticles were attached to collagen fibers. The nano-ß-TCP scaffold showed higher compressive strength and cytocompatibility compared with the noncoated collagen scaffold. Rat subcutaneous implant tests showed that the DNA contents of infiltrating cells in the nano-ß-TCP scaffold and the FGF-2-loaded scaffold were approximately 2.8-fold and 3.7-fold greater, respectively, than in the collagen scaffold. Histological samples from the periodontal defect model showed about five-fold greater periodontal tissue repair following implantation of the nano-ß-TCP scaffold loaded with FGF-2 compared with the collagen scaffold. CONCLUSION: The ß-TCP nanoparticle coating strongly improved the collagen scaffold bioactivity. Nano-ß-TCP scaffolds containing FGF-2 are anticipated for use in periodontal tissue engineering.

Structural essentials for ß-N-acetylhexosaminidase inhibition by amides of prolines, pipecolic and azetidine carboxylic acids.

This paper explores the computer modelling aided design and synthesis of ß-N-acetylhexosaminidase inhibitors along with their applicability to human disease treatment through biological evaluation in both an enzymatic and cellular setting. We investigated the importance of individual stereocenters, variations in structure-activity relationships along with factors influencing cell penetration. To achieve these goals we modified nitrogen heterocycles in terms of ring size, side chains present and ring nitrogen derivatization. By reducing the inhibitor interactions with the active site down to the essentials we were able to determine that besides the established 2S,3R trans-relationship, the presence and stereochemistry of the CH2OH side chain is of crucial importance for activity. In terms of cellular penetration, N-butyl side chains favour cellar uptake, while hydroxy- and carboxy-group bearing sidechains on the ring nitrogen retarded cellular penetration. Furthermore we show an early proof of principle study that ß-N-acetylhexosaminidase inhibitors can be applicable to use in a potential anti-invasive anti-cancer strategy.

Characteristics of histologically confirmed endometriosis in cynomolgus monkeys.

STUDY QUESTION: What are the characteristics of spontaneous endometriosis in cynomolgus monkeys? SUMMARY ANSWER: Spontaneous endometriosis in cynomolgus monkeys exhibited similar characteristics to the human disease. WHAT IS KNOWN ALREADY: One previous report described the prevalence and the basic histopathology of spontaneous endometriosis in cynomolgus monkeys. STUDY DESIGN, SIZE, DURATION: Endometriotic lesions that had been histologically confirmed in 8 female cynomolgus monkeys between 5 and 21 years old were subjected to study. PARTICIPANTS/MATERIALS, SETTING, METHODS: The monkeys died of, or were sacrificed because of, sickness consequent on endometriosis. Specimens were evaluated histopathologically with haematoxylin and eosin staining, iron staining and immunohistochemistry (CD10, CD31, α-SMA and PGP9.5), and by observing them under a microscope. MAIN RESULTS AND THE ROLE OF CHANCE: Endometriotic and stromal cells (CD10-positive) with haemorrhage and inflammation were observed. Smooth muscle metaplasia and nerve fibres were also noted in the endometriotic lesions. Endometriotic lesions in lymph nodes were incidentally found. LIMITATIONS AND REASONS FOR CAUTION: Since laparoscopic analysis for monitoring the disease state was not set as a parameter of the current study, time course changes (progression) of the disease were not assessed. WIDER IMPLICATIONS OF THE FINDINGS: Further investigation of spontaneous endometriosis in cynomolgus monkeys may contribute to better understanding of the disease pathobiology. STUDY FUNDING/COMPETING INTERESTS: No external funds were used for this study. A.N.K., S.M., S.H., T.I., O.K., A.K. and M.S. are full-time employees of Chugai Pharmaceutical Co., Ltd. R.K. received lecture fees from Chugai Pharmaceutical Co., Ltd., unrelated to the submitted work. S.N., S. O., L.Y., K.Y. and T.S. have nothing to declare. TRIAL REGISTRATION NUMBER: N/A.

Probiotic Lactobacillus casei strain Shirota relieves stress-associated symptoms by modulating the gut-brain interaction in human and animal models.

BACKGROUND: This study aimed to examine the effects of Lactobacillus casei strain Shirota (LcS) on gut-brain interactions under stressful conditions. METHODS: Three double-blind, placebo-controlled trials were conducted to examine the effects of LcS on psychological and physiological stress responses in healthy medical students under academic examination stress. Subjects received LcS-fermented milk or placebo daily for 8 weeks prior to taking a national standardized examination. Subjective anxiety scores, salivary cortisol levels, and the presence of physical symptoms during the intervention were pooled and analyzed. In the animal study, rats were given feed with or without LcS for 2 weeks, then submitted to water avoidance stress (WAS). Plasma corticosterone concentration and the expression of cFos and corticotropin releasing factor (CRF) in the paraventricular nucleus (PVN) were measured immediately after WAS. In an electrophysiological study, gastric vagal afferent nerve activity was monitored after intragastric administration of LcS to urethane-anesthetized rats. KEY RESULTS: Academic stress-induced increases in salivary cortisol levels and the incidence rate of physical symptoms were significantly suppressed in the LcS group compared with the placebo group. In rats pretreated with LcS, WAS-induced increases in plasma corticosterone were significantly suppressed, and the number of CRF-expressing cells in the PVN was reduced. Intragastric administration of LcS stimulated gastric vagal afferent activity in a dose-dependent manner. CONCLUSIONS & INFERENCES: These findings suggest that LcS may prevent hypersecretion of cortisol and physical symptoms under stressful conditions, possibly through vagal afferent signaling to the brain and reduced stress reactivity in the PVN.