Genetics of chemokines & cytokines in non-infectious posterior segment uveitis

Background and Aims: Non-infectious posterior segment uveitis is a potentially blinding disease that usually affects people of working age group. Like other immune mediated diseases, uveitis is a complex polygenic disease. Several cytokines have been identified as important regulators of the immune system during, induction, progression and remission of ocular inflammation in uveitis. The work described in this thesis is based on the hypothesis that polymorphisms in chemokine and cytokine genes can predict clinical outcome in non-infectious uveitis. Methods: Functional polymorphisms in sixteen chemokine and cytokine genes were genotyped and there associations were studied in a cohort of British Caucasians suffering with non-infectious posterior segment uveitis. Results: This study has shown that polymorphisms in IL-18, IL-10 & CCR2 genes can influence the susceptibility to certain phenotypes of non-infectious uveitis. Polymorphisms in many genes particularly, IL-1 , IL-6, CCR5 & IL-18 are found to affect the visual outcome and severity of the disease. Conclusion: The identification of these genetic variants that add susceptibility or resistance to uveitis has provided us further insights into the pathogenesis of uveitis. This work will help us identify patients who are at a greater risk of losing sight with this disease. This, in turn would allow tailored aggressive therapy to be given at presentation when vision is still good with a precise aim to prevent significant amount of blindness

Efficiently Testable Circuits

In this work, we put forward the notion of "efficiently testable circuits" and provide circuit compilers that transform any circuit into an efficiently testable one. Informally, a circuit is testable if one can detect tampering with the circuit by evaluating it on a small number of inputs from some test set. Our technical contribution is a compiler that transforms any circuit C into a testable circuit (C?,??) for which we can detect arbitrary tampering with all wires in C?. The notion of a testable circuit is weaker or incomparable to existing notions of tamper-resilience, which aim to detect or even correct for errors introduced by tampering during every query, but our new notion is interesting in several settings, and we achieve security against much more general tampering classes - like tampering with all wires - with very modest overhead. Concretely, starting from a circuit C of size n and depth d, for any L (think of L as a small constant, say L = 4), we get a testable (C?,??) where C? is of size ? 12n and depth d+log(n)+L? n^{1/L}. The test set ?? is of size 4? 2^L. The number of extra input and output wires (i.e., pins) we need to add for the testing is 3+L and 2^L, respectively

A Systematic Review and Meta-Analysis of Practices Exposing Humans to Avian Influenza Viruses, Their Prevalence, and Rationale

Almost all human infections by avian influenza viruses (AIVs) are transmitted from poultry. A systematic review was conducted to identify practices associated with human infections, their prevalence, and rationale. Observational studies were identified through database searches. Meta-analysis produced combined odds ratio estimates. The prevalence of practices and rationales for their adoptions were reported. Of the 48,217 records initially identified, 65 articles were included. Direct and indirect exposures to poultry were associated with infection for all investigated viral subtypes and settings. For the most frequently reported practices, association with infection seemed stronger in markets than households, for sick and dead than healthy poultry, and for H7N9 than H5N1. Practices were often described in general terms and their frequency and intensity of contact were not provided. The prevalence of practices was highly variable across studies, and no studies comprehensively explored reasons behind the adoption of practices. Combining epidemiological and targeted anthropological studies would increase the spectrum and detail of practices that could be investigated and should aim to provide insights into the rationale(s) for their existence. A better understanding of these rationales may help to design more realistic and acceptable preventive public health measures and messages

Antioxidant rich flavonoids from Oreocnide integrifolia enhance glucose uptake and insulin secretion and protects pancreatic β-cells from streptozotocin insult

<p>Abstract</p> <p>Background</p> <p>Insulin deficiency is the prime basis of all diabetic manifestations and agents that can bring about insulin secretion would be of pivotal significance for cure of diabetes. To test this hypothesis, we carried out bioactivity guided fractionation of <it>Oreocnide integrifolia </it>(Urticaceae); a folklore plant consumed for ameliorating diabetic symptoms using experimental models.</p> <p>Methods</p> <p>We carried out bioassay guided fractionation using RINmF and C2C12 cell line for glucose stimulated insulin secretion (GSIS) and glucose uptake potential of fractions. Further, the bioactive fraction was challenged for its GSIS in cultured mouse islets with basal (4.5 mM) and stimulated (16.7 mM) levels of glucose concentrations. The Flavonoid rich fraction (FRF) was exposed to 2 mM streptozotocin stress and the anti-ROS/RNS potential was evaluated. Additionally, the bioactive fraction was assessed for its antidiabetic and anti-apoptotic property <it>in-vivo </it>using multidose streptozotocin induced diabetes in BALB/c mice.</p> <p>Results</p> <p>The results suggested FRF to be the most active fraction as assessed by GSIS in RINm5F cells and its ability for glucose uptake in C2C12 cells. FRF displayed significant potential in terms of increasing intracellular calcium and cAMP levels even in presence of a phosphodiesterase inhibitor, IBMX in cultured pancreatic islets. FRF depicted a dose-dependent reversal of all the cytotoxic manifestations except peroxynitrite and NO formation when subjected <it>in-vitro </it>along with STZ. Further scrutinization of FRF for its <it>in-vivo </it>antidiabetic property demonstrated improved glycemic indices and decreased pancreatic β-cell apoptosis.</p> <p>Conclusions</p> <p>Overall, the flavonoid mixture has shown to have significant insulin secretogogue, insulinomimetic and cytoprotective effects and can be evaluated for clinical trials as a therapeutant in the management of diabetic manifestations.</p

Perceptions of complementary/alternative medicine use and influence on evidence-based asthma medicine adherence in Malaysian children

Abstract Complementary and alternative medicine (CAM) is widely used especially in Asia including for childhood asthma. The use of CAM could influence adherence to evidence-based (E-B) medicine. We explored the views of carers of Malaysian children with asthma regarding the use of CAM for childhood asthma, and its relationship with self-reported adherence to E-B medicine. We used a screening questionnaire to identify children diagnosed with asthma from seven suburban primary schools in Malaysia. Informed consent was obtained prior to the interviews. We conducted the interviews using a semi-structured topic guide in participants’ preferred language (Malay, Mandarin, or Tamil). All interviews were audio-recorded, transcribed verbatim and coded using Nvivo. Analysis was performed thematically, informed by the Necessity-Concerns Framework. A total of 46 carers (16 Malays, 21 Indians, 9 Chinese) contributed to 12 focus groups and one individual interview. We categorised participants’ as ‘Non-CAM’; ‘CAM’; or ‘combination’ user. Cultural practices and beliefs in the efficacy of CAM resulted in widespread use of CAM. Most carers used CAM as ‘complementary’ to E-B medicine. Concerns about dependence on or side effects of E-B treatment influenced carers’ decisions to rely on CAM as an ‘alternative’, with an important minority of accounts describing potentially harmful CAM-use. Healthcare professionals should discuss beliefs about the necessity for and concerns about use of both E-B medicine and CAM, and provide balanced information about effectiveness and safety. The aim is to improve adherence to regular E-B preventer medication and prevent delays in seeking medical advice and harmful practices associated with CAM

Global Retinoblastoma Presentation and Analysis by National Income Level.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs