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Objectives: \ud To assess the involvement of the CCR6/CCL20 axis in psoriatic arthritis (PsA) and psoriasis (PsO) and to evaluate its potential as a therapeutic target.\ud \ud Methods: \ud First, we quantified CCL20 levels in peripheral blood and synovial fluid of PsA patients and the presence of CCR6+ cells in synovial and tendon tissue. Utilizing an IL-23 minicircle DNA (MC) mouse model exhibiting key features of both PsO and PsA, we investigated CCR6 and CCL20 expression and the preventive and therapeutical effect of CCL20 blockade. Healthy tendon stromal cells were stimulated in vitro with IL-1β to assess the production of CCL20 by qPCR and ELISA. The effect of conditioned media from stimulated tenocytes in inducing T cell migration was interrogated with a transwell system.\ud \ud Results: \ud We observed an upregulation of both CCR6 and CCL20 in the enthesis of IL-23 MC-treated mice, which was confirmed in human biopsies. Specific targeting of the CCR6/CCL20 axis with a CCL20 locked dimer (CCL20LD) blocked entheseal inflammation, leading to profound reductions in clinical and proinflammatory markers in the joints and skin of IL-23 MC-treated mice. The stromal compartment in the tendon was the main source of CCL20 in this model and accordingly, in vitro activated human tendon cells were able to produce this chemokine and to induce CCR6+ T cell migration, the latter of which could be blocked by CCL20LD.\ud \ud Conclusions: \ud Our studies highlight the pathogenic role of CCR6-CCL20 axis in enthesitis and raise the prospect of a novel therapeutic approach for treating patients with PsO and PsA.

PURPOSE To assess the capability of in vivo positron emission tomography (PET) using 18 F-fluorodeoxyglucose (18 F-FDG) to quantify changes in inflammatory activity in response to tofacitinib, a Janus kinase (JAK) inhibitor, over a timeframe of a few hours to few days in a preclinical model of rheumatoid arthritis (RA). METHODS Twenty-four mice with collagen-induced arthritis in the following groups were assessed: Group 1, where the changes in PET measures for the extremity joints were evaluated at the peak and trough plasma drug levels after administration of a single dose of tofacitinib (4 hours apart); Group 2, where joint PET measures were assessed before treatment and after 6 days of administration of a daily dose of tofacitinib; and group 3 (controls), where joint PET measures were derived from the same mice, 6 days apart. RESULTS At about peak plasma levels of the drug after a single tofacitinib administration, there was a reduction in PET measures compared to pretreatment values, suggesting decreased inflammatory activity. These measures were equivalent to those obtained after 6 days of daily dosing by tofacitinib. However, PET measures at trough plasma levels of the drug from tofacitinib administration were significantly higher than those at peak plasma drug levels and equivalent to pretreatment measures. There were insignificant changes in PET measures for the control animals. CONCLUSION 18 F-FDG PET can detect changes in inflammatory activity occurring in response to the JAK inhibitor tofacitinib: (a) during peak and trough plasma drug levels, that is within mere hours of treatment; and (b) over a span of days.

A transition-metal-catalyzed borrowing hydrogen/hydrogen auto-transfer strategy allows the utilization of feedstock alcohols as an alkylating partner, which avoids the formation of stoichiometric salt waste and enables a direct and benign approach for the construction of C-N and C-C bonds. In this study, a nickel-catalyzed α-alkylation of unactivated amides and ester (tert-butyl acetate) is carried out by using primary alcohols under mild conditions. This C-C bond-forming reaction is catalyzed by a new, molecularly defined nickel(II) NNN-pincer complex (0.1-1 mol %) and proceeds through hydrogen auto-transfer, thereby releasing water as the sole byproduct. In addition, N-alkylation of cyclic amides under Ni-catalytic conditions is demonstrated.

Ubergangsmetall-Wasserstofftransferkatalysatoren ermoglichen ausgehend von einfachen Ausgangsmaterialien einen schnellen Zugang zu wichtigen Strukturmotiven, so auch zu Heterocyclen. Ubergangsmetallkatalysierte Wasserstofftransferanellierungen sind umweltvertraglich und in hohem Mase atomokonomisch, da sie Wasser und Wasserstoff als Nebenprodukt freisetzen und erneuerbare Alkohole als Ausgangsmaterialien verwenden. Hier werden neueste Fortschritte auf diesem Gebiet im Hinblick auf Anellierungen von Alkoholen mit verschiedenen nucleophilen Reaktionspartnern vorgestellt, bei denen heterocyclische Geruste gebildet werden.

Chilika Lake, Asia's largest brackish water lagoon, is located in the state of Odisha on the east coast of India. It was designated as a Ramsar site in 1981, being the first Indian wetland of international importance under the Ramsar convention. Siltation of the lake is become a major concern, because it is leading to various geomorphic changes that are affecting the shape and size of the lagoon, which receives a major silt load through the Daya and Bhargovi rivers (both being branches of the Mahanadi river) via the Kathajodi and Kuakhai rivers. The Naraj barrage was constructed at the mouth of the Kathajodi river to regulate its inflow, and also its silt load, into the lagoon. Two observatories are established in the Daya and Bhargovi rivers to determine the quantity of silt entering Chilika Lake through the rivers, with the bed load and suspended (total solids) being measured. Various effects of siltation in the lagoon because of the barrage are analysed in this study, to include the pre- and postconstruction situation. By considering different flood situations in the Mahanadi river, various alternate strategies for operation of the Naraj barrage were studied, with the goal of minimizing the siltation in Chilika Lake. These alternate operation strategies, and their potential effects on the inflow into the lagoon, are analysed and discussed in this report.

Background Scleroma is a rare, chronic, granulomatous infectious disease of the respiratory tract mucosa which begins in the nose and spreads to the respiratory tract and adjoining structures. We report on the extensions and the management of 134 cases of scleroma in the Highlands region of Papua New Guinea. Methods The charts and treatment records of 134 scleroma cases were retrospectively reviewed from 1995 to 2013. The staging, extensions, treatment and results of treatment were reviewed and analysed. Results Of the 134 cases, 72 (53.7%) were females and the age ranged from 6 to 65 years. The disease was confined to the nose and nasopharynx in 71 (53.0%) cases. Extension of the disease from the nose to the Eustachian tube occurred in nine (6.7%) cases and into the middle ear in four (3.0%) cases. Further extensions to the larynx and trachea were seen in 17 (12.7%) cases each and the bronchus in three (2.2%) cases. Primary laryngoscleroma without involvement of the nose and nasopharyngeal stenosis without laryngeal involvement were managed in 11 (8.2%) and nine (6.7%) cases respectively. Others cases treated were ethmoid scleroma with proptosis and scleroma involving the upper lip in one (0.75%) case each. Ninety-nine (74.9%) patients were treated medically while 35 (26.1%) patients required surgery. Cure were achieved in 83 (61.9%) cases treated medically and 26 (19.4%) had successful surgical outcome. Conclusion Scleroma begins in the nose and when not arrested, extends causing obstruction to the airway and cosmetic deformity which requires surgical intervention.

Background: In the conventional technique of transpalatal approach, the palatal mucoperiosteum is incised and widely elevated and hard palate bone is removed in piece meal and discarded. These technique lead to complications, namely, temporary or permanent palatal fistula, palatal scarring leading to palatal disfiguration and velopharyngeal incompetence. In this article we describe a new technique of doing palatotomy to avoid these complications. Methods: A retrospective review of post-operative complications of 20 patients that underwent transpalatal approach by the conventional technique was performed. To avoid the complications encountered in these cases, a new approach was designed when the palatal mucoperiosteum on the pathological side was elevated partially, greater palatine artery was coagulated and palatal osteotomy was performed from the oral side. On the non-pathological side, hard palate was sectioned from the nasal side, thus preserving the ipsilateral palatal mucoperiosteum. The entire mucoperiosteum with attached hard palate was reflected orally as a single block which was pedicled on the greater palatine artery and palatal mucoperiosteum of the non-pathological side, thereby creating palatal osteo-mucoperiosteal flap. The flap was placed back at the end of the procedure. Eight patients were operated by this new technique. Results: All 20 patients operated by the conventional transpalatal approach developed post-operative complications. In the eight patients operated by the new technique, no post-operative complications were encountered after 2 years' follow-up. Conclusions: We found palatal osteo-mucoperiosteal flap an easy and safe way of preserving the hard palate mucoperiosteum and bone with its vasculature resulting in quicker healing and minimal functional impairment.

Objective The effect of nerve growth factor (NGF) and its receptor (NGFR) in inflammatory diseases is a novel research field. The purpose of this study was to investigate the role of NGF/NGFR in human T cell subpopulations and fibroblast-like synovial cells (FLS) and examine its pathophysiologic significance in psoriatic arthritis (PsA) and rheumatoid arthritis (RA). Methods Expression of NGF/NGFR was examined in synovial fluid (SF), FLS, peripheral blood (PB)–derived T cells, and SF-derived T cells from patients with PsA, RA, and osteoarthritis (OA). NGF levels were determined by enzyme-linked immunosorbent assay. NGF-induced T cell/FLS proliferation was examined by MTT assay. Low-affinity (p75)/high-affinity (TrkA) NGFR expression was determined by high-dimensional fluorescence-activated cell sorting. A monochlorobimane assay was used to determine the effect of NGF on T cell survival. Results Levels of NGF were higher in SF samples from PsA and RA patients as compared to SF samples from OA patients. NGF-induced FLS proliferation was more marked in PsA and RA patients. TrkA was up-regulated on activated SF T cells from PsA (mean ± SD 22 ± 6.2%) and RA (8 ± 1.3%) patients, whereas in SF samples from OA patients, TrkA+CD3+ T cells were not detectable. NGF induced the proliferation of PB T cells, induced the phosphorylation of Akt in activated T cells, and consistent with known pAkt activity, inhibited tumor necrosis factor α–induced cell death in these T cells. Conclusion Based on our findings, we propose a model in which NGF secreted by FLS into PsA and RA synovium promotes the survival of activated autoreactive T cells as well as FLS proliferation. Thus, NGF has the potential to sustain the chronic inflammatory cascades of arthritis of autoimmune origin.

Boswellia serrata resin is regarded as a potent anti-inflammatory agent in traditional and herbal medicine in the Indian subcontinent. The compound 3-O-acetyl-11-keto-β-boswellic acid (AKBA) is the most effective boswellic acid and mostly responsible for B. serrata's anti-inflammatory properties. Here, we reexamined the anti-inflammatory potential of a product selectively enriched with 30% AKBA (BE-30, also known as 5-Loxin®) and evaluated its underlying possible molecular mechanism of action. BE-30 was 42.96% more effective than regular Boswellia extract (BE-3) in inhibiting 5-lipoxygenase activity. In lipopolysaccharide (LPS)-induced THP-1 human monocytes, BE-30 showed a strong anti-TNFαactivity (half maximal inhibitory concentration 4.61 ± 0.87 µg/mL), which provides 71.14% (P

Objective: The objective of this is to determine the incidence of otogenic complications of chronic suppurative otitis media (CSOM) and its management. Study Design: The authors conducted a retrospective study. Methods: The study was conducted at the tertiary referral and teaching hospital. An analysis was made about the clinical and operative findings, surgical techniques and approaches, the overall management and recovery of the patients. The data were then compared with the relevant and available literature. Results: Of the 70 cases, 47 (67%) had a single complication, of which eight (11%) had intracranial and 39 (56%) had extracranial complications. Twenty-three (33%) had two or more complications. The commonly encountered intracranial complications were otitic meningitis, lateral sinus thrombosis, and cerebellar abscess, which were seen in 13 (19%), 10 (14%), and 6 (9%) cases, respectively. Among the extracranial complications, mastoid abscess, postauricular fistula, and facial palsy were encountered in 26 (37%), 17 (24%) and 10 (14%) patients, respectively. Surgeries were the main mode of treatment for these conditions. According to severity, we found four different types of the lateral sinus involvement. Three patients with otitic facial palsy failed to regain full facial function despite surgery. A total of nine patients with the diagnosis of otitic meningitis, lateral sinus thrombosis and interhemispheric abscess expired. It constituted the mortality rate of 13% in our study. Conclusion: CSOM complications, despite its reduced incidence, still pose a great challenge in developing countries as the disease present in the advanced stage leading to difficulty in management and consequently higher morbidity and mortality.

The ability of hydrogen-transfer transition-metal catalysts, which enable increasingly rapid access to important structural scaffolds from simple starting materials, has led to a plethora of research efforts on the construction of heterocyclic scaffolds. Transition-metal-catalyzed hydrogen-transfer annulations are environmentally benign and highly atom-economical as they release of water and hydrogen as by-product and utilize renewable feedstock alcohols as starting materials. Recent advances in this field with respect to the annulations of alcohols with various nucleophilic partners, thus leading to the formation of heterocyclic scaffolds, are highlighted herein.

Background An important cellular aberration at sites of psoriatic inflammation is an increase in the number of dermal mast cells. Being multifactorial immune effector cells, it is believed that mast cells play an essential role in perpetuating the inflammatory process of psoriasis. However, factors responsible for the infiltration and accumulation of mast cells in psoriatic lesions are largely unknown. Recent studies have demonstrated that Interleukin-8 (IL-8) exerts strong chemotactic effects on mast cells in vitro. Overexpression of IL-8 has also been reported in psoriatic lesions. In this study, we have found a correlation between the expression of IL-8 and dermal mast cell density in lesional psoriatic skin as compared to nonlesional psoriatic skin. Methods Four-mm punch biopsies were taken from 14 psoriatic patients and eight healthy volunteers. Using immunohistochemical techniques, 8 microm sections of lesional psoriatic, nonlesional psoriatic, and normal control samples were evaluated for dermal mast cell density and the density of IL-8 expressing keratinocytes. Results It was found that dermal mast cell density in lesional psoriatic, nonlesional psoriatic, and normal skin was 105.4 +/- 71.2, 42.3 +/- 30.1, and 47.5 +/- 32.5 mast cells/mm(2), respectively. IL-8+ keratinocyte density in lesional psoriatic, non lesional psoriatic, and normal skin was 171.5 +/- 67.1, 25.4 +/- 14.9 and 20.6 +/- 8.7 IL-8+ Keratinocytes/mm(2), respectively. Conclusions The results of this study suggest that increased levels of IL-8 in the keratinocytes of psoriatic plaques play a contributing role in the migration of mast cells to lesion sites.

The etiology and pathogenesis of psoriasis--one of the most common chronic, inflammatory, hyperproliferative skin disorders of man--have long fascinated dermatologists, pathologists and biologists alike. Here, we have a model disease that offers to study neuroectodermal-mesenchymal interactions in the widest sense possible. Epithelial, endothelial, and hematopoietic cells as well as neurons projecting into the skin apparently all interact with each other to generate the characteristic psoriatic lesion. For decades, the ongoing controversy on the molecular nature, choreography and hierarchy of these complex interactions e.g. between epidermal keratinocytes, T cells, neurotrophils, endothelial cells and sensory nerves has served as a driving force propelling investigative dermatology to ever new horizons. This debate has not only been at the heart of our quest to develop more effective forms of therapy for this socially crippling disease, but it also has profoundly influenced how we view the skin as a whole: the numerous competing theories on the pathogenesis of psoriasis published so far also are reflections on the evolution of mainstream thought in skin biology over the last decades. These days, conventional wisdom infatuated with a T-cell-centered approach to inflammatory skin diseases-- portrays psoriasis as an autoimmune disease, where misguided T lymphocyte activities cause secondary epithelial abnormalities. And yet, as this CONTROVERSIES feature reminds us, some authoritative "pockets of academic resistance" are still quite alive, and interpret psoriasis e.g. as a genetically determined, abnormal epithelial response pattern to infectious and/or physicochemical skin insults. Weighing the corresponding lines of argumentation is not only an intriguing, clinically relevant intellectual exercise, but also serves as a wonderful instrument for questioning our own views of the skin universe and its patterns of deviation from a state of homeostasis.

Psoriasis in childhood is not uncommon. We report data collected from 223 pediatric onset and 484 adult onset psoriasis patients. In the pediatric onset psoriasis patients (POPPs), prevalence of family history was 68.2% compared to 54% in the adult onset psoriasis patients (AOPPs). Also we noticed that exacerbation of psoriasis induced by precipitating factors such as stress (50.4% in POPPs, 42. 7% in AOPPs), pharyngitis (27.9% in POPPs, 12.2% in AOPPs), and trauma (49.6% in POPPs and 38.9% in AOPPs) were more frequent in POPPs. Our data show that the frequency of spontaneous remission in POPPs was 35.3% compared to 24.3% in AOPPs. A disfiguring skin disease in childhood may have profound emotional effects. Childhood psoriasis needs special attention. To achieve a prolonged remission it is essential that children with psoriasis and their parents have an understanding of the exogenous and endogenous factors responsible for the increased morbidity of psoriasis.

Murine mast cells adhere spontaneously to plate-bound vitronectin (VNPB) via alphav-containing integrins, and this adhesive interaction results in an augmented interleukin-3 (IL-3)-dependent mast-cell proliferation. In this report we demonstrate that the activation of murine mast cells through alphav-integrin, as well as through the high affinity immunoglobulin E (IgE) receptor (FcepsilonRI), results in enhanced tyrosine phosphorylation of focal adhesion kinase (FAK), a cytoplasmic protein tyrosine kinase involved in mitogenic and oncogenic signal transduction. While mast cell adhesion to VNPB resulted in enhanced FAK phosphorylation, treatment with soluble vitronectin (VNSOL) failed to do so. Spontaneous mast cell adhesion to entactin (EN) did not induce tyrosine phosphorylation of FAK, demonstrating that not all adhesive interactions lead to the same sequence of biochemical events. Because FAK has intrinsic tyrosine kinase activity, we examined whether activating mast cells via alphav-integrins, or via FcepsilonRI-cross-linking stimulated the in vitro kinase activity of FAK. Both pathways were found independently to activate FAK in mast cells and together appeared additive. Protein kinase C depletion in mast cells and calcium depletion in the medium caused decreased tyrosine phosphorylation of FAK, indicating that optimal tyrosine phosphorylation of FAK is regulated by both pathways. These data are consistent with the conclusion that the tyrosine phosphorylation of FAK represents at least one example of a point of convergence in the intracellular tyrosine phosphorylation cascades induced by alphav integrin-and FcepsilonRI-mediated signal transduction pathways in mast cells.

Background. After vascular extravasation, mononuclear cells (MNC) undergo chemotaxis and adhesion to extracellular matrix proteins, resulting in their differentiation into macrophages. Although endothelial adhesion and chemotaxis are altered in psoriasis, MNC adhesion to extracellular matrix proteins has not been previously studied in the disease. Since MNC adhesion to endothelial cells is abnormally regulated in psoriasis by TGF-beta, we tested they hypothesis that in psoriasis substance P also regulates the adhesion of monocytes to the extracellular matrix protein fibronectin. Methods. Monocytes from 16 normal controls and 11 psoriatic individuals were isolated and purified using a two-step gradient centrifugation procedure. Adhesion to fibronectin was studied by plating monocyte suspensions onto fibronectin-precoated microtiter plates. The number of adherent cells was quantified by measuring their hex-osaminidase activity. Results. Although statistically significant differences in the basal (unstimulated) adhesion or in the substance P-stimulated adhesion between normal control monocytes and those obtained from psoriatic individuals were not observed, a subpopulation of psoriatics was identified who responded to substance P. Furthermore, this in vitro response to substance P was correlated with the clinical status of the subpopulation which was characterized by unstable psoriasis triggered by stressful life events. Conclusions. The results of this study indicate that priming of monocytes by the extracellular matrix protein fibronectin or by elevated levels of substance P are not critical steps in the pathogenesis of stable, chronic psoriasis. Substance P may contribute to the appearance of new lesions in some individuals with unstable psoriasis.

Aluminum borate, 9Al2O3·2B2O3 or Al18B4O33, was synthesized by the reaction of stoichiometric amounts of α-Al2O3 and B2O3. The Al18B4O33 material was formed into a dense ceramic by pressureless sintering with CaO, MgO, or CaAl2B2O7 additives. The material was characterized by low bulk density, moderate coefficient of thermal expansion (3 × 10−6/°C to 5 × 10−6/°C), moderate strength (210 to 324 MPa), and low dielectric constant.

Aluminum borate, 9Al2O3·2B2O3 or Al18B4O33, was synthesized by the reaction of stoichiometric amounts of α-Al2O3 and B2O3. The Al18B4O33 material was formed into a dense ceramic by pressureless sintering with CaO, MgO, or CaAl2B2O7 additives. The material was characterized by low bulk density, moderate coefficient of thermal expansion (3 × 10−6/°C to 5 × 10−6/°C), moderate strength (210 to 324 MPa), and low dielectric constant.

Background. Kaposi's varicelliform eruption (KVE) is characterized by disseminated cutaneous eruptions usually caused by infection with herpes simplex virus (HSV). Kaposi's varicelliform eruption is commonly observed among patients with atopic dermatitis (AD). Why AD patients are prone to HSV infections is still an enigma. Recent findings suggest that an increased number of IL-4-secreting cells can be cloned from lesions of AD. Because IL-4 is a known Th1 cell inhibitor, theoretically, by inhibiting the Th1 cells, it could downregulate the immune response against HSV. In this study, we have evaluated the role of IL-4 on HSV replication. Methods. Peripheral blood mononuclear cells (PBMC) from 10 HSV seronegative and five seropositive healthy individuals were stimulated with PHA, recall antigen (tetanus toxoid), and HSV antigen in combination with IL-4 and anti-IL-4. Supernatants were assessed for interferon (IFN) gamma, IL-4 by enzyme-linked immunosorbent assay (ELISA), and for anti-HSV effect. Anti-HSV effect was assessed by measuring inhibition of the cytopathic effect (CPE) of HSV on a Vero cell line. Results. Both seropositive and seronegative groups showed significant inhibition of IFN-gamma secretion with addition of IL-4 (P < .001, Wilcoxon rank sum test) and this effect could be neutralized by anti-IL-4. There was a direct relationship between the IFN-gamma concentration and the HSV cytopathic effect and an inverse relationship between IL-4 concentration and HSV CPE. Conclusions. This study provides evidence that IL-4 can enhance HSV infection. Therefore, it is conceivable that patients with conditions of increased activity of IL-4, as in ad, would be prone to extensive forms of HSV infection.