Chitin recognition via chitotriosidase promotes pathologic type-2 helper T cell responses to cryptococcal infection.

Pulmonary mycoses are often associated with type-2 helper T (Th2) cell responses. However, mechanisms of Th2 cell accumulation are multifactorial and incompletely known. To investigate Th2 cell responses to pulmonary fungal infection, we developed a peptide-MHCII tetramer to track antigen-specific CD4+ T cells produced in response to infection with the fungal pathogen Cryptococcus neoformans. We noted massive accruement of pathologic cryptococcal antigen-specific Th2 cells in the lungs following infection that was coordinated by lung-resident CD11b+ IRF4-dependent conventional dendritic cells. Other researchers have demonstrated that this dendritic cell subset is also capable of priming protective Th17 cell responses to another pulmonary fungal infection, Aspergillus fumigatus. Thus, higher order detection of specific features of fungal infection by these dendritic cells must direct Th2 cell lineage commitment. Since chitin-containing parasites commonly elicit Th2 responses, we hypothesized that recognition of fungal chitin is an important determinant of Th2 cell-mediated mycosis. Using C. neoformans mutants or purified chitin, we found that chitin abundance impacted Th2 cell accumulation and disease. Importantly, we determined Th2 cell induction depended on cleavage of chitin via the mammalian chitinase, chitotriosidase, an enzyme that was also prevalent in humans experiencing overt cryptococcosis. The data presented herein offers a new perspective on fungal disease susceptibility, whereby chitin recognition via chitotriosidase leads to the initiation of harmful Th2 cell differentiation by CD11b+ conventional dendritic cells in response to pulmonary fungal infection.

Impact of clinical input variable uncertainties on ten-year atherosclerotic cardiovascular disease risk using new pooled cohort equations.

BACKGROUND: Recently released American College of Cardiology/American Heart Association (ACC/AHA) guideline recommends the Pooled Cohort equations for evaluating atherosclerotic cardiovascular risk of individuals. The impact of the clinical input variable uncertainties on the estimates of ten-year cardiovascular risk based on ACC/AHA guidelines is not known. METHODS: Using a publicly available the National Health and Nutrition Examination Survey dataset (2005-2010), we computed maximum and minimum ten-year cardiovascular risks by assuming clinically relevant variations/uncertainties in input of age (0-1 year) and ±10 % variation in total-cholesterol, high density lipoprotein- cholesterol, and systolic blood pressure and by assuming uniform distribution of the variance of each variable. We analyzed the changes in risk category compared to the actual inputs at 5 % and 7.5 % risk limits as these limits define the thresholds for consideration of drug therapy in the new guidelines. The new-pooled cohort equations for risk estimation were implemented in a custom software package. RESULTS: Based on our input variances, changes in risk category were possible in up to 24 % of the population cohort at both 5 % and 7.5 % risk boundary limits. This trend was consistently noted across all subgroups except in African American males where most of the cohort had ≥7.5 % baseline risk regardless of the variation in the variables. CONCLUSIONS: The uncertainties in the input variables can alter the risk categorization. The impact of these variances on the ten-year risk needs to be incorporated into the patient/clinician discussion and clinical decision making. Incorporating good clinical practices for the measurement of critical clinical variables and robust standardization of laboratory parameters to more stringent reference standards is extremely important for successful implementation of the new guidelines. Furthermore, ability to customize the risk calculator inputs to better represent unique clinical circumstances specific to individual needs would be highly desirable in the future versions of the risk calculator.

Chitinase 3-like-1 regulates both visceral fat accumulation and asthma-like Th2 inflammation.

RATIONALE: Obesity, especially truncal obesity, is a risk factor for asthma incidence, prevalence, and severity. Chitinase 3-like-1 (Chi3l1) is an evolutionarily conserved moiety that plays a critical role in antipathogen and Th2 responses. However, the mechanisms that underlie the association between asthma and obesity and the role(s) of Chi3l1 in fat accumulation have not been defined. OBJECTIVES: To determine whether Chi3l1 is regulated by a high-fat diet (HFD) and simultaneously plays an important role(s) in the pathogenesis of asthma and obesity. METHODS: We evaluated the regulation of Chi3l1 by an HFD and Th2 inflammation. We also used genetically modified mice to define the roles of Chi3l1 in white adipose tissue (WAT) accumulation and Th2 inflammation and blockers of sirtuin 1 (Sirt1) to define its roles in these responses. Finally, the human relevance of these findings was assessed with a case-control study involving obese and lean control subjects and those with asthma. MEASUREMENTS AND MAIN RESULTS: These studies demonstrate that an HFD and aeroallergen challenge augment the expression of WAT and pulmonary Chi3l1. Chi3l1 also played a critical role in WAT accumulation and lung Th2 inflammation. In addition, Chi3l1 inhibited Sirt1 expression, and the deficient visceral fat and Th2 responses in Chi3l1 null mice were reversed by Sirt1 inhibition. Finally, serum and sputum Chi3l1 were positively associated with truncal adiposity, and serum Chi3l1 was associated with persistent asthma and low lung function in obese subjects with asthma. CONCLUSIONS: Chi3l1 is induced by an HFD and Th2 inflammation, and simultaneously contributes to the genesis of obesity and asthma.

Fatty acid binding protein 4 regulates VEGF-induced airway angiogenesis and inflammation in a transgenic mouse model: implications for asthma.

Neovascularization of the airways occurs in several inflammatory lung diseases, including asthma. Vascular endothelial growth factor (VEGF) plays an important role in vascular remodeling in the asthmatic airways. Fatty acid binding protein 4 (FABP4 or aP2) is an intracellular lipid chaperone that is induced by VEGF in endothelial cells. FABP4 exhibits a proangiogenic function in vitro, but whether it plays a role in modulation of angiogenesis in vivo is not known. We hypothesized that FABP4 promotes VEGF-induced airway angiogenesis and investigated this hypothesis with the use of a transgenic mouse model with inducible overexpression of VEGF165 under a CC10 promoter [VEGF-TG (transgenic) mice]. We found a significant increase in FABP4 mRNA levels and density of FABP4-expressing vascular endothelial cells in mouse airways with VEGF overexpression. FABP4(-/-) mouse airways showed a significant decrease in neovessel formation and endothelial cell proliferation in response to VEGF overexpression. These alterations in airway vasculature were accompanied by attenuated expression of proinflammatory mediators. Furthermore, VEGF-TG/FABP4(-/-) mice showed markedly decreased expression of endothelial nitric oxide synthase, a well-known mediator of VEGF-induced responses, compared with VEGF-TG mice. Finally, the density of FABP4-immunoreactive vessels in endobronchial biopsy specimens was significantly higher in patients with asthma than in control subjects. Taken together, these data unravel FABP4 as a potential target of pathologic airway remodeling in asthma.

Left ventricular torsion shear angle volume analysis in patients with hypertension: a global approach for LV diastolic function.

BACKGROUND: Torsion shear angle φ is an important measure of left ventricular (LV) systolic and diastolic functions. Here we provide a novel index utilizing LV normalized torsion shear angle φ ^ volume V ^ loop to assess LV diastolic functional properties. We defined the area within φ ^ V ^ loop as torsion hysteresis area, and hypothesized that it may be an important global parameter of diastolic function. We evaluated the φ ^ changes to increased V ^ during early diastole - d φ ^ / d V ^ as a potential measure of LV suction. METHODS: Sixty resistant hypertension patients (HTN), forty control volunteers were studied using cardiovascular magnetic resonance with tissue tagging. Volumetric and torsional parameters were evaluated. RESULTS: HTN demonstrated concentric remodeling with preserved ejection fraction. HTN had significantly decreased normalized early filling rate, early diastolic mitral annulus velocity and E/A (1.33 ± 1.13 vs. 2.19 ± 1.07, P < 0.0001) vs. control. Torsion hysteresis area was greater (0.11 ± 0.07 vs. 0.079 ± 0.045, P < 0.001) and peak - d φ ^ / d V ^ at early diastole was higher (10.46 ± 8.51 vs. 6.29 ± 3.85, P = 0.002) than control. Torsion hysteresis area was significantly correlated with E/A (r = -0.23, P = 0.025). Thirteen HTN patients had both E/A ratio < 1.12 (Control mean E/A-1SD) and torsion hysteresis area > 0.12 (Control mean torsion hysteresis area + 1SD). CONCLUSIONS: Torsion hysteresis area and peak early diastolic - d φ ^ / d V ^ were significantly increased in hypertensive concentric remodeling. The φ ^ V ^ loop takes into account the active and passive recoil processes of LV diastolic and systolic phases, therefore provides a new global description of LV diastolic function.

Distinct cross talk of IL-17 & TGF-ß with the immature CD11c+ TRAF6(-/-) -null myeloid dendritic cell-derived osteoclast precursor (mDDOCp) may engage signaling toward an alternative pathway of osteoclastogenesis for arthritic bone loss in vivo.

BACKGROUND: Dendritic cells (DCs), though borne heterogeneous, are the most potent antigen-presenting cells, whose critical functions include triggering antigen-specific naïve T-cell responses and fine-tuning the innate versus adaptive immunity at the osteo-immune and/or mucosal mesenchyme interface. We previously reported that immature myeloid-CD11c+ DCs/mDCs may act like osteoclast (OC) precursors (OCp/mDDOCp) capable of developing into functional OCs via an alternative pathway of inflammation-induced osteoclastogenesis; however, what are their contribution and signaling interactions with key osteotropic cytokines (i.e., interleukin-17 [IL-17] and transforming growth factor-ß [TGF-ß]) to bearing such inflammatory bone loss in vivo remain unclear to date. METHODS: Herein, we employed mature adult bone marrow-reconstituted C57BL/6 TRAF6(-/-) -null chimeras without the classical monocyte/macrophage (Mo/Mϕ)-derived OCs to address their potential contribution to OCp/mDDOCp-mediated osteoclastogenesis in the chicken type-II-collagen (CC-II)-induced joint inflammation versus arthritic bone loss and parallel associations with the double-positive CD11c+ TRAP+ TRAF6-null(-/-)  DC-like OCs detected in vivo via the quantitative dual-immunohistochemistry and digital histomorphometry for analyses. RESULTS: The resulting findings revealed the unrecognized novel insight that (i) immature myeloid-CD11c+ TRAF6(-/-) TRAP+ DC-like OCs were involved, co-localized, and strongly associated with joint inflammation and bone loss, independent of the Mo/Mϕ-derived classical OCs, in CC-II-immunized TRAF6(-/-) -null chimeras, and (ii) the osteotropic IL-17 may engage distinct crosstalk with CD11c+ mDCs/mDDOCp before developing the CD11c+ TRAP+ TRAF6(-/-) OCs via a TGF-ß-dependent interaction toward inflammation-induced arthritic bone loss in vivo. CONCLUSION: These results confirm and substantiate the validity of TRAF6(-/-) -null chimeras to address the significance of immature mCD11c+ TRAP+ DC-like OCs/mDDOCp subset for an alternative pathway of arthritic bone loss in vivo. Such CD11c+ mDCs/mDDOCp-associated osteoclastogenesis through the step-wise twist-in-turns osteo-immune cross talks are thereby theme highlighted to depict a summative re-visitation proposed.

Magnetic resonance imaging with 3-dimensional analysis of left ventricular remodeling in isolated mitral regurgitation: implications beyond dimensions.

BACKGROUND: Although surgery is indicated in patients with mitral regurgitation (MR) when left ventricular (LV) end-systolic (LVES) dimension is >40 mm, LV ejection fraction may decrease after mitral valve surgery. We hypothesize that significant LV remodeling before surgery is not reflected by standard echocardiographic parameters measured at the base of the heart. METHODS AND RESULTS: Ninety-four patients (age, 54 ± 11 years; 38% female) with degenerative isolated MR underwent cine magnetic resonance imaging with tissue tagging and 3-dimensional analysis. In 51 control subjects (age, 44 ± 14 years; 53% female), the relation between LVES volume (LVESV) and LVES dimension was quadratic, whereas in 94 MR patients, this relation was cubic, indicating a greater increase in LVESV per LVES dimension among MR patients. Moreover, magnetic resonance imaging LVESV from summated serial short-axis slices was significantly greater than LVESV assessed with the Bullet formula in MR patients, attributed to a more spherical remodeling distal to the tips of the papillary muscles (P<0.001). Thirty-five patients underwent mitral valve repair per current guideline recommendations. LV ejection fraction decreased from 61 ± 7% to 54 ± 8% (P<0.0001) and maximum shortening decreased significantly below normal at 1 year postoperatively (P<0.0001). Despite normalization of LV stroke volume and LV end-diastolic volume/mass ratio, there was a persistent significant increase in distal LVES 3-dimensional radius/wall thickness ratio and LVESV index after surgery. CONCLUSIONS: Despite apparently preserved LVES dimension, MR patients demonstrate significant spherical mid to apical LVES remodeling that contributes to higher LVESV than predicted by standard geometry-based calculations. Decreased LV strain after surgery suggests that a volumetric analysis of LV remodeling and function may be preferred to evaluate disease progression in isolated MR.

A phase I/II study of sepantronium bromide (YM155, survivin suppressor) with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer.

BACKGROUND: This phase I/II study examined the safety and efficacy of Sepantronium Bromide (S), a small-molecule selective survivin suppressant, administered in combination with carboplatin (C) and paclitaxel (P). PATIENTS AND METHODS: Forty-one patients were treated on study. Twenty-two patients received escalating doses of S (3.6-12 mg/m(2)) and 19 with untreated stage IV non-small-cell lung cancer (NSCLC) were treated with the maximum tolerated dose of 10 mg/m(2) in combination with standard doses of C (AUC6) and P (200 mg/m(2)) for six cycles. S was administered as a continuous intravenous infusion (CIVI) over 72 h in 21-day treatment cycles. Study end points included safety and toxic effect, response rate, progression-free and overall survival (PFS and OS), as well as exploratory pharmacodynamic correlates. RESULTS: Treatment with S was well tolerated, and toxic effects were mostly hematological in the phase II study. Two (11%) partial responses were observed with a median PFS of 5.7 months and median OS 16.1 months. Pharmacodynamic analysis did not demonstrate an association with response. CONCLUSION: The combination of S (10 mg/m(2)/day 72-h CIVI) administered with C and P every 3 weeks exhibited a favorable safety profile but failed to demonstrate an improvement in response rate in advanced NSCLC. CLINICAL TRIAL NUMBER: NCT01100931.

Hyperoxia causes angiopoietin 2-mediated acute lung injury and necrotic cell death.

The angiogenic growth factor angiopoietin 2 (Ang2) destabilizes blood vessels, enhances vascular leak and induces vascular regression and endothelial cell apoptosis. We considered that Ang2 might be important in hyperoxic acute lung injury (ALI). Here we have characterized the responses in lungs induced by hyperoxia in wild-type and Ang2-/- mice or those given either recombinant Ang2 or short interfering RNA (siRNA) targeted to Ang2. During hyperoxia Ang2 expression is induced in lung epithelial cells, while hyperoxia-induced oxidant injury, cell death, inflammation, permeability alterations and mortality are ameliorated in Ang2-/- and siRNA-treated mice. Hyperoxia induces and activates the extrinsic and mitochondrial cell death pathways and activates initiator and effector caspases through Ang2-dependent pathways in vivo. Ang2 increases inflammation and cell death during hyperoxia in vivo and stimulates epithelial necrosis in hyperoxia in vitro. Ang2 in plasma and alveolar edema fluid is increased in adults with ALI and pulmonary edema. Tracheal Ang2 is also increased in neonates that develop bronchopulmonary dysplasia. Ang2 is thus a mediator of epithelial necrosis with an important role in hyperoxic ALI and pulmonary edema.

Chinese herbal medicine for atopic eczema.

BACKGROUND: Chinese herbal medicine (CHM) has been increasingly used for atopic eczema. A previous version of this Cochrane review published in 2004 found some evidence of a possible benefit for oral ingestion of CHM for eczema, but the results were inconclusive and the evidence needs to be updated. We have expanded the scope of this review to include an assessment of the topical and oral effects of CHM for eczema. OBJECTIVES: To assess the effects of oral ingestion and topical applications of CHM for the management of eczema in children and adults. SEARCH METHODS: We searched the following databases up to September 2012: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2012, Issue 8), MEDLINE (from 1946), EMBASE (from 1974), AMED (from 1985), LILACS (from 1982), and CINAHL (from 1981). We searched the following from inception: SCOPUS, HERBMED, ProQuest, CQVIP, CNKI, and Wanfang Data. We also searched trials registers, handsearched conference proceedings, checked the reference lists of all included and excluded studies and review articles for further references to relevant trials, and contacted experts in Chinese medicine for unpublished studies. SELECTION CRITERIA: All randomised controlled trials (RCTs) in children and adults with eczema comparing CHM to placebo; no intervention; active controls, including acupuncture; or conventional medicines. DATA COLLECTION AND ANALYSIS: Two authors selected the RCTs, extracted data, and assessed quality independently. We contacted study authors for missing data. We collected adverse events from the included studies. MAIN RESULTS: We included 28 studies, with a total of 2306 participants. We assessed most of the studies at high 'risk of bias', particularly in blinding of participants and personnel, and there was substantial inconsistency between studies, so any positive effect of CHM must be treated with caution. We did not include the four studies from the previous version in this review, because they investigated a CHM product that has been withdrawn from the market since 2004.Four studies (three oral and one topical) compared CHM to placebo. Pooled data from 2 studies showed the total effectiveness rate in the CHM group was higher (by risk ratio (RR) 2.09, 95% confidence interval (CI) 1.32 to 3.32; 2 studies; n = 85), and the itching visual analogue score (VAS) in the CHM group was 1.53 lower (by standardised mean difference (SMD), 95% CI 2.64 to 0.41; 2 Studies; n = 94) than the placebo group, where a lower VAS score indicates reduced itch. One study of 85 participants with moderate to severe eczema who received an oral CHM formula for 12 weeks reported a quality of life (QoL) score 2.5 lower in the CHM group (by difference in means (MD), 95% CI 4.77 to 0.23; 1 study; n = 85) than the placebo group, where a lower score indicates better QoL.  Twenty-two studies and 1 arm from a study with a 4-arm parallel controlled design compared CHM (5 oral, 6 topical, and 12 mixed oral and topical) to conventional medicines. The total effectiveness rate in the CHM groups was superior (RR 1.43, 95% CI 1.27 to 1.61; 21 studies; n = 1868; very low quality evidence), and the itching VAS in the CHM groups was 0.83 lower (SMD, 95% CI 1.43 to 0.22; 7 studies; n = 465) than the comparators.Two studies compared combined oral and topical CHM to the same oral CHM formula alone. The total effectiveness rate in 1 study was not statistically significant (RR 1.13, 95% CI 0.78 to 1.63; 1 study; n = 20). In the other study, the itching VAS in the CHM group was 1.05 lower (MD, 95% CI 1.75 to 0.35; 1 study; n = 23) than the control group.With regard to side-effects, four studies did not give any report of adverse events. The other 24 studies reported minor adverse events, which were reversed soon after stopping CHM. One participant withdrew from one trial because of exacerbation of their condition after using the CHM intervention.Eight studies received government funding. AUTHORS' CONCLUSIONS: We could not find conclusive evidence that CHM taken by mouth or applied topically to the skin could reduce the severity of eczema in children or adults.Well-designed, adequately powered RCTs are needed to evaluate the efficacy and safety of CHM for managing eczema.

Potential contribution of immature myeloid CD11c+dendritic cells-derived osteoclast precursor to inflammation-induced bone loss in the TRAF6-null chimeras in-vivo.

Dendritic cells (DC) are potent antigen-presenting-cells widely distributed at the osteo-immune and/or mucosal-mesenchyme interface, consequentially implicating in certain bone-sparing disorders; i.e., via signaling Receptor-activator-of-nuclear-factor-kappa-B-ligand/RANKL-Receptor-activator-of-nuclear-factor-kB/RANK-Osteoprotegerin/OPG-TRAF6 transducer-complex etc., evidently associated with arthritis, osteoporosis and periodontitis. We have reported that the immature myeloid CD11c+-DC subsets can act as osteoclast precursor (OCp; mDDOCp), thereby developing into osteoclasts (OCs) via an alternative pathway for osteoclastogenesis. Importantly, cytokine TGF-ß remains critical to prime CD11c+-mDDOCp-cells deficient of TRAF6-&-related immune/osteotropic signaling, featuring distinctive TGF-ß-&-IL-17-invoked effectors in the environmental milieu sufficient to driving bona-fide osteoclastogenesis in-vitro. Herein, we sought to explore the potential contribution of immature-mDDOCp/OCp to inflammation-induced bone-loss, where comparable CD11c+TRAP+multinucleated-OC-like/mDDOCp existed, lacking the endogenous TRAF6-associated monocyte/macrophage-derived OCs in type-II-collagen induced joint/paw inflammation of the C56BL/6-TRAF6(-/-)null chimeras (H-2b-halpotype) examined. The results suggest that such TRAF6-null chimeric mice may offer a useful model to assess the specific functions of OCp or mDDOCp as an analog to human conditions in-vivo.

Vascular endothelial growth factor enhances macrophage clearance of apoptotic cells.

Efficient clearance of apoptotic cells from the lung by alveolar macrophages is important for the maintenance of tissue structure and function. Lung tissue from humans with emphysema contains increased numbers of apoptotic cells and decreased levels of vascular endothelial growth factor (VEGF). Mice treated with VEGF receptor inhibitors have increased numbers of apoptotic cells and develop emphysema. We hypothesized that VEGF regulates apoptotic cell clearance by alveolar macrophages (AM) via its interaction with VEGF receptor 1 (VEGF R1). Our data show that the uptake of apoptotic cells by murine AMs and human monocyte-derived macrophages is inhibited by depletion of VEGF and that VEGF activates Rac1. Antibody blockade or pharmacological inhibition of VEGF R1 activity also decreased apoptotic cell uptake ex vivo. Conversely, overexpression of VEGF significantly enhanced apoptotic cell uptake by AMs in vivo. These results indicate that VEGF serves a positive regulatory role via its interaction with VEGF R1 to activate Rac1 and enhance AM apoptotic cell clearance.

Three-dimensional plus time biventricular strain from tagged MR images by phase-unwrapped harmonic phase.

PURPOSE: To validate a method called bi-ventricular strain unwrapped phase (BiSUP) for reconstructing three-dimensional plus time (3D+t) biventricular strain maps from phase-unwrapped harmonic phase (HARP) images derived from tagged cardiac magnetic resonance imaging (MRI). MATERIALS AND METHODS: A set of 30 human subjects were imaged with tagged MRI. In each study, HARP phase was computed and unwrapped in each short-axis and long-axis image. Inconsistencies in unwrapped phase were resolved using branch cuts manually placed with a graphical user interface. The 3D strain maps were computed independently in each imaged time frame through systole and mid diastole in each study. The BiSUP strain and displacements were compared with those estimated by a 3D feature-based (FB) technique and a 2D+t HARP technique. RESULTS: The standard deviation of the difference between strains measured by the FB and the BiSUP methods was less than 4% of the average of the strains from the two methods. The correlation between peak minimum principal strain measured using the BiSUP and HARP techniques was over 83%. CONCLUSION: The BiSUP technique can reconstruct full 3D+t strain maps from tagged MR images through the cardiac cycle in a reasonable amount of time and user interaction compared with other 3D analysis methods.

Evaluation of several adjuvants in avian influenza vaccine to chickens and ducks.

The effects of three different adjuvants, mineral oil, Montanide™ ISA 70M VG, and Montanide™ ISA 206 VG, were evaluated on reverse genetics H5N3 avian influenza virus cell cultured vaccine. The immune results of SPF chickens after challenging with highly pathogenic avian influenza (HPAI) virus demonstrated that mineral oil adjuvant group and 70M adjuvant group provided 100% protection efficiency, but 206 adjuvant group provided only 40%. Statistical analysis indicated that the protection effects of mineral oil adjuvant group and the 70M adjuvant showed no significant difference to each other, but with significant difference to 206 adjuvant group. All three groups could induce high titres of antibody after immunizing SPF ducks, but there was no significant difference among them. The immunization effect of 70M adjuvant group on SPF chickens were the best and showed significant difference compared with optimized 70Mi Montanide™ eight series adjuvants groups. These results suggest that 70M adjuvant could be a novel adjuvant for preparing avian influenza vaccine.

Chitin is a size-dependent regulator of macrophage TNF and IL-10 production.

Chitin is a ubiquitous polysaccharide in fungi, insects, and parasites. We hypothesized that chitin is a size-dependent regulator of innate immunity. To test this hypothesis, we characterized the effects of chitins of different sizes on murine bronchoalveolar or peritoneal macrophages. In these studies, large chitin fragments were inert, while both intermediate-sized chitin (40-70 microm) and small chitin (SC; <40 microm, largely 2-10 microm) stimulated TNF elaboration. In contrast, only SC induced IL-10 elaboration. The effects of intermediate-sized chitin were mediated by pathways that involve TLR2, dectin-1, and NF-kappaB. In contrast, the effects of SC were mediated by TLR2-dependent and -independent, dectin-1-dependent pathways that involved the mannose receptor and spleen tyrosine kinase. Chitin contains size-dependent pathogen-associated molecular patterns that stimulate TLR2, dectin-1, and the mannose receptor, differentially activate NF-kappaB and spleen tyrosine kinase, and stimulate the production of pro- and anti-inflammatory cytokines.

Update and review of the gerodontology prospective for 2020's: Linking the interactions of oral (hypo)-functions to health vs. systemic diseases.

New lines of evidence suggest that the oral-systemic medical links and oral hypo-function are progressively transcending beyond the traditional clinical signs and symptoms of oral diseases. Research into the dysbiotic microbiome, host immune/inflammatory regulations and patho-physiologic changes and subsequent adaptations through the oral-systemic measures under ageism points to pathways leading to mastication deficiency, dysphagia, signature brain activities for (neuro)-cognition circuitries, dementia and certain cancers of the digestive system as well. Therefore, the coming era of oral health-linked systemic disorders will likely reshape the future of diagnostics in oral geriatrics, treatment modalities and professional therapies in clinical disciplines. In parallel to these highlights, a recent international symposium was jointly held by the International Association of Gerontology and Geriatrics (IAGG), Japanese Society of Gerodontology (JSG), the representative of USA and Taiwan Academy of Geriatric Dentistry (TAGD) on Oct 25th, 2019. Herein, specific notes are briefly addressed and updated for a summative prospective from this symposium and the recent literature.

TLR-2 and IL-17A in chitin-induced macrophage activation and acute inflammation.

Chitin is a ubiquitous polysaccharide in fungi, insects, and parasites. To test the hypothesis that chitin is an important immune modulator, we characterized the ability of chitin fragments to regulate murine macrophage cytokine production in vitro and induce acute inflammation in vivo. In this study, we show that chitin is a size-dependent stimulator of macrophage IL-17A production and IL-17AR expression and demonstrate that these responses are TLR-2 and MyD88-dependent. We further demonstrate that IL-17A pathway activation is an essential event in the stimulation of some but not all chitin-stimulated cytokines and that chitin uses a TLR-2, MyD88-, and IL-17A-dependent mechanism(s) to induce acute inflammation. These studies demonstrate that chitin is a size-dependent pathogen-associated molecular pattern that activates TLR-2 and MyD88 in a novel IL-17A/IL-17AR-based innate immunity pathway.

Modeling the effects of constructed wetland on nonpoint source pollution control and reservoir water quality improvement.

This article describes the integrated modeling approach for planning the size and the operation of constructed wetlands for maximizing retention of nonpoint source pollutant loads and reservoir water-quality improvement at a catchment scale. The experimental field-scale wetland systems (four sets, 0.88 ha each) have been in operation since 2002, where water depth was maintained at 30-50 cm and hydraulic loading rate was at 6.3-18.8 cm/day. The wetland system was found to be adequate for treating polluted stream water with stable removal efficiency even during the winter. The integrated modeling system (modified-BASINS) was applied to the Seokmoon estuarine reservoir watershed and calibrated with monitoring data from constructed wetland, stream, and reservoir. The calibrated integrated modeling system estimated that constructing wetlands on 0.5% (about 114 ha) of the watershed area at the mouth of reservoir could reduce 11.61% and 13.49% of total external nitrogen and phosphorus loads, respectively. It also might improve the nitrogen and phosphorus concentration of the reservoir by 9.69% and 16.48%, respectively. The study suggested that about 0.1%-1.0% of the watershed area should be allocated for constructed wetland to meet specified water-quality standards for the estuarine reservoir at the polder area where land use planning is relatively less complicated.

Effectiveness of an innovative prototype subtracted diversity array (SDA) for fingerprinting plant species of medicinal importance.

The accurate identification of medicinal plants is becoming increasingly important due to reported concerns about purity, quality and safety. The previously developed prototype subtracted diversity array (SDA) had been validated for the ability to distinguish clade-level targets in a phylogenetically accurate manner. This study represents the rigorous investigation of the SDA for genotyping capabilities, including the genotyping of plant species not included during the construction of the SDA, as well as to lower classification levels including family and species. The results show that the SDA, in its current form, has the ability to accurately genotype species not included during SDA development to clade level. Additionally, for those species that were included during SDA development, genotyping is successful to the family level, and to the species level with minor exceptions. Twenty polymorphic SDA features were sequenced in a first attempt to characterize the polymorphic DNA between species, which showed that transposon-like sequences may be valuable as polymorphic features to differentiate angiosperm families and species. Future refinements of the SDA to allow more sensitive genotyping are discussed with the overall goal of accurate medicinal plant identification in mind.