The Immunological Basis of Dry Eye Disease and Current Topical Treatment Options.

Homeostasis of the lacrimal functional unit is needed to ensure a well-regulated ocular immune response comprising innate and adaptive phases. When the ocular immune system is excessively stimulated and/or immunoregulatory mechanisms are disrupted, the balance between innate and adaptive phases is dysregulated and chronic ocular surface inflammation can result, leading to chronic dry eye disease (DED). According to the Tear Film and Ocular Surface Society Dry Eye Workshop II definition, DED is a multifactorial disorder of the ocular surface characterized by impairment and loss of tear homeostasis (hyperosmolarity), ocular discomfort or pain, and neurosensory abnormalities. Dysregulated ocular immune responses result in ocular surface damage, which is a further contributing factor to DED pathology. Several therapeutics are available to break the vicious circle of DED and prevent chronic disease and progression, including immunosuppressive agents (steroids) and immunomodulators (cyclosporine and lifitegrast). Given the chronic inflammatory nature of DED, each of these agents is commonly used in clinical practice. In this study, we review the immunopathology of DED and the molecular and cellular actions of current topical DED therapeutics to inform clinical decision making

A Case Study on Agro-based E-Commerce Portal

This paper has investigated the practice of E-Commerce portal named Metrotarkari for marketing vegetables and fruit items in Kathmandu valley. A case study approach underpinned the study so as to identify current issues and practice of E-Commerce portal for vegetable and fruit items thereby adopt appropriate strategies for its sustainability in this sector. The study used explanatory form of analysis on the issues of business model, payment system, distribution system, overall challenges and marketing strategies based on the face to face interview with chief operating officer of Metrotarkari. The result shows that their B2B feature is serving more customers than B2C feature does in daily basis. The cash on delivery has been the preferable option of payment system although they have facility of Paypal, E-Sewa and Sctmoco. The main reason behind the problem in maintaining and delivering quality items is the lack of their own inventory and their dependency on others vendors. Establishing their own cold store or inventory and appending the C2C feature in their existing portal are major suggestions made to provide benefit to farmers and customers thereby sustain in this sector

Quality of analytical performance in inherited metabolic disorders: the role of ERNDIM

Summary: External quality assurance (EQA) schemes are essential for improvement of accuracy, reliability and comparability of results of biochemical genetic tests. ERNDIM (European Research Network for evaluation and improvement of screening, Diagnosis and treatment of Inherited disorders of Metabolism), established in 1994, operates nine EQA schemes for biochemical genetic testing according to international norms and recommendations. These comprise qualitative schemes for amino acids, organic acids, purines and pyrimidines, special assays in serum and urine and white cell cystine, qualitative organic acid and acylcarnitine schemes, as well as diagnostic proficiency testing. The total number of participants has increased from 123 in 1994 to 268 in 2007. Additional activities include participation in the Eurogentest project, a laboratory directory, training, education and development of guidelines. Results from the quantitative amino acid scheme with 170 participants reveal good variation within and between laboratories of below 10% for 10 amino acids; good within-laboratory variation but intermediate inter-laboratory variation of 10-22% for 11 amino acids; and higher variation within and between laboratories for 8 amino acids. Results on samples from 51 inherited metabolic disorders from two of five centres organizing diagnostic proficiency testing indicate overall diagnostic efficiency above 80% and improved performance of individual laboratories. Comparison of results for 10 and 12 compounds in the serum and urine special assay schemes respectively for 2000 and 2007 reveal clear improvement of precision within laboratories and in inter-laboratory variation. There is considerable evidence that performance in biochemical genetic testing has improved since the introduction of ERNDIM scheme

Bladder inflammatory transcriptome in response to tachykinins: Neurokinin 1 receptor-dependent genes and transcription regulatory elements

Background Tachykinins (TK), such as substance P, and their neurokinin receptors which are ubiquitously expressed in the human urinary tract, represent an endogenous system regulating bladder inflammatory, immune responses, and visceral hypersensitivity. Increasing evidence correlates alterations in the TK system with urinary tract diseases such as neurogenic bladders, outflow obstruction, idiopathic detrusor instability, and interstitial cystitis. However, despite promising effects in animal models, there seems to be no published clinical study showing that NK-receptor antagonists are an effective treatment of pain in general or urinary tract disorders, such as detrusor overactivity. In order to search for therapeutic targets that could block the tachykinin system, we set forth to determine the regulatory network downstream of NK1 receptor activation. First, NK1R-dependent transcripts were determined and used to query known databases for their respective transcription regulatory elements (TREs). Methods: An expression analysis was performed using urinary bladders isolated from sensitized wild type (WT) and NK1R-/- mice that were stimulated with saline, LPS, or antigen to provoke inflammation. Based on cDNA array results, NK1R-dependent genes were selected. PAINT software was used to query TRANSFAC database and to retrieve upstream TREs that were confirmed by electrophoretic mobility shift assays. Results: The regulatory network of TREs driving NK1R-dependent genes presented cRel in a central position driving 22% of all genes, followed by AP-1, NF-kappaB, v-Myb, CRE-BP1/c-Jun, USF, Pax-6, Efr-1, Egr-3, and AREB6. A comparison between NK1R-dependent and NK1R-independent genes revealed Nkx-2.5 as a unique discriminator. In the presence of NK1R, Nkx2-5 _01 was significantly correlated with 36 transcripts which included several candidates for mediating bladder development (FGF) and inflammation (PAR-3, IL-1R, IL-6, α-NGF, TSP2). In the absence of NK1R, the matrix Nkx2-5_02 had a predominant participation driving 8 transcripts, which includes those involved in cancer (EYA1, Trail, HSF1, and ELK-1), smooth-to-skeletal muscle trans-differentiation, and Z01, a tight-junction protein, expression. Electrophoretic mobility shift assays confirmed that, in the mouse urinary bladder, activation of NK1R by substance P (SP) induces both NKx-2.5 and NF-kappaB translocations. Conclusion: This is the first report describing a role for Nkx2.5 in the urinary tract. As Nkx2.5 is the unique discriminator of NK1R-modulated inflammation, it can be imagined that in the near future, new based therapies selective for controlling Nkx2.5 activity in the urinary tract may be used in the treatment in a number of bladder disorders

Sequential Deliberation for Social Choice

In large scale collective decision making, social choice is a normative study of how one ought to design a protocol for reaching consensus. However, in instances where the underlying decision space is too large or complex for ordinal voting, standard voting methods of social choice may be impractical. How then can we design a mechanism - preferably decentralized, simple, scalable, and not requiring any special knowledge of the decision space - to reach consensus? We propose sequential deliberation as a natural solution to this problem. In this iterative method, successive pairs of agents bargain over the decision space using the previous decision as a disagreement alternative. We describe the general method and analyze the quality of its outcome when the space of preferences define a median graph. We show that sequential deliberation finds a 1.208- approximation to the optimal social cost on such graphs, coming very close to this value with only a small constant number of agents sampled from the population. We also show lower bounds on simpler classes of mechanisms to justify our design choices. We further show that sequential deliberation is ex-post Pareto efficient and has truthful reporting as an equilibrium of the induced extensive form game. We finally show that for general metric spaces, the second moment of of the distribution of social cost of the outcomes produced by sequential deliberation is also bounded

Information Management within the LHC Hardware Commissioning Project

The core task of the commissioning of the LHC technical systems was the individual test of the 1572 superconducting circuits of the collider, the powering tests. The two objectives of these tests were the validation of the different sub-systems making each superconducting circuit as well as the validation of the superconducting elements of the circuits in their final configuration in the tunnel. A wide set of software applications were developed by the team in charge of coordinating the powering activities (Hardware Commissioning Coordination) in order to manage the amount of information required for the preparation, execution and traceability of the tests. In all the cases special care was taken in order to keep the tools consistent with the LHC quality assurance policy, avoid redundancies between applications, ensure integrity and coherence of the test results and optimise their usability within an accelerator operation environment. This paper describes the main characteristics of these tools; it details their positive impact on the completion on time of the LHC Hardware Commissioning Project and presents usage being envisaged during the coming years of operation of the LHC

The LHC Prototype Full-Cell: Design Study

As a continuation of the experimental program carried-out with String 1, project management decided toward the end of 1995 to construct an LHC prototype Full-Cell, also known as String 2. The present document reports on the outcome of the one-year design effort by the community of specialists contributing to the LHC Prototype Full-Cell: it informs specialists on the boundary areas with other syste ms and conveys to the general public a description of the facility

Optimization of the powering tests of the LHC superconducting circuits

The Large Hadron Collider has (LHC) 1572 superconducting circuits which are distributed along the eight 3.5 km LHC sectors [1]. Time and resources during the commissioning of the LHC technical systems were mostly consumed by the powering tests of each circuit. The tests consisted in carrying out several powering cycles at different current levels for each superconducting circuit. The Hardware Commissioning Coordination was in charge of planning, following up and piloting the execution of the test program. The first powering test campaign was carried out in summer 2007 for sector 7-8 with an expected duration of 12 weeks. The experience gained during these tests was used by the commissioning team for minimising the duration of the following powering campaigns to comply with the stringent LHC project deadlines. Improvements concerned several areas: strategy, procedures, control tools, automatization, and resource allocation led to an average daily test rate increase from 25 to 200 tests per day. This paper describes these improvements and details their impact on the operation during the last months of LHC Hardware Commissioning