Regulation of T Cell Receptor Signaling by Diacylglycerol Kinases and Phosphatidylinositol Transfer Proteins

Signals transduced through the T cell receptor (TCR) lead to T cell differentiation, proliferation, and elaboration of cytokines, all of which are required for optimal immunity. Phosphoinositide (PI) mediated signaling plays a particularly prominent role in this process. TCR signaling is amplified by the activation of phospholipase C γ1 (PLCγ1), which cleaves phosphatidylinositol-4,5-bisphosphate (PIP2) to form the second messengers diacylglycerol (DAG) and inositol triphosphate (IP3). Regulation of PI and products such as DAG are therefore essential for normal TCR signaling. DAG levels are reduced by diacylglycerol kinases (DGKs), which metabolize DAG and diminish DAG-mediated signaling. In T cells, the predominant DGK isoforms expressed are DGKα and DGKζ. Deletion of either isoform enhances DAG-mediated signaling, yet the relative importance of these enzymes is unknown. Here, we describe that DGKζ but not DGKα suppresses natural regulatory T cell development and predominantly controls Ras and AKT signaling. The differential functions of DGKα and DGKζ are not attributable to differences in expression levels or localization to the T cell-APC contact site. However, RasGRP1, a key activator of Ras signaling, associated to a greater extent with DGKζ than DGKα. In addition, DGKζ displayed greater metabolism of DAG to PA after TCR stimulation than DGKα. In silico modeling of TCR-stimulated Ras activation in DGKα- versus DGKζ-deficient T cells suggested that a greater catalytic rate for DGKζ than DGKα could lead to increased suppression of Ras-mediated signals by DGKζ. DGKζ dominant functions over DGKα, therefore, are in part due to DGKζ\u27s greater effective enzymatic activity and association with RasGRP1. Future experiments will establish how DGK isoform function is regulated by TCR signaling. To examine how the DAG precursor PI is regulated, we performed a preliminary analysis of mice with a T cell specific deficiency of phosphatidylinositol transfer protein (PITP) α and β, which regulate PI-mediated signaling in vitro. Our initial in vivo studies suggest that deletion of PITPα and PITPβ at the double positive stage of T cell development results in loss of mature T cells in the thymus and periphery. Further experiments will establish why PITPs are required for normal T cell development

PHARMACEUTICAL ANALYTICAL STUDY OF KAMPAVATARI RASA - AN AYURVEDIC HERBO MINERAL FORMULATION

Kampavatari Rasa (KVR) is a unique Ayurvedic herbo- mineral formulation mentioned in the classics Rasa Raj Sundar in Vata vyadhi and indicated mainly in Kampavata which resembles Parkinson's disease. The line of treatment in Ayurveda is to combat Vata dosha and to sustain neuronutrition by Rasayana remedies, which can be achieved by Kamapavatari Rasa with its properties like Tridosh shamaka and Rasayana. The present study was executed to establish a finger print for this unique formulation which can be used further for drug standardization. Kampavatari rasa is prepared by triturating Tamra bhasma and Rasa Sindura in equal quantity with Katuki swaras (Picrohiza kurroa) for 21 times. Each ingredient was prepared according to the norms of Ayurvedic classical texts. Raw drugs were selected on bases of Grahya lakshana and its percentage. To ensure the proper preparation of Tamra bhasma, standard tests (Bhasma Pariksha), XRD, NPST and SEM were carried and for Rasa sindura NPST test and XRD were employed. After been complied these tests KVR was prepared and subjected for physico chemical analysis and quantitative analysis of Mercury, Sulphur and Copper by ICPAES. The study of Kampavatari Rasa revealed that its Loss on Drying - 3.4%, Total Ash - 48 %, Acid insoluble ash -13%, water soluble ash - 9.5%, Hardness test was 7kg/cm2 and Tablet disintegration test 14/min which are within the normal limits and ICP – AES shows the percentage of Copper 20.51, Sulphur 8.9, and Mercury 20.43. This is the first study to establish the characterization of Kampavatari rasa

An Extensive Volar Forearm Laceration – The Spaghetti Wrist: A Systematic Review

PURPOSE: ‘Spaghetti wrist’ is an extensive laceration that involves multiple structures in the volar wrist, including tendons, nerves and arteries. This injury is frequently encountered in trauma units, but despite its complex nature, management is often handled by junior surgeons. Furthermore, the guidance on how to approach these injuries is limited, with a relatively poor evidence base on management and outcomes. METHODS: In this article, we perform a systematic review of the literature on the management and outcomes of the spaghetti wrist injury. Patient demographics, definitions of spaghetti wrist, mechanism of injury, operative and rehabilitative techniques and surgical outcomes are discussed. RESULTS: Results from this study show significant physical, functional, psychological and financial impacts of spaghetti wrist injuries. Operative technique appears relatively consistent; even though reporting of injuries and outcomes was heterogeneous, no current classification system is in common usage. CONCLUSIONS: An increased focus on the standardisation of assessment, management and rehabilitation and on overcoming the obstacles to care will serve as a guidance to the operative and post-operative management of the spaghetti wrist injury. The use of a single definition and classification system has been proposed to standardise outcome measures and improve inter-observer reliability

Apathy and its response to antipsychotic review and non-pharmacological interventions in people with dementia living in nursing homes : WHELD, A factorial cluster randomised controlled trial

Objectives: Apathy is common, impactful, and difficult to manage in people with dementia. We evaluated the efficacy of non-pharmacological interventions, exercise and social interaction, in combination with antipsychotic review, to reduce apathy in people with dementia living in nursing homes in a cluster randomised controlled trial (RCT). Methods: Well-being and health for people with dementia (WHELD) programme included a 2X2X2 factorial cluster RCT involving people with dementia living in 16 nursing homes in UK. All homes received training in person-centred care, and were randomised to receive antipsychotic review, social interaction, and exercise, either alone or in combinations. Apathy was one of the secondary outcomes of the WHELD trial, and it was measured by the Neuropsychiatric Inventory-nursing home version at baseline and nine months (N=273). We employed multilevel mixed effects linear regression models to assess the impact of the interventions on apathy. Results: Prevalence of apathy was 44.0% (n=120; 95% CI 38.1-49.9%) at baseline. Severity of apathy had significant positive correlations with dementia severity, neuropsychiatric symptoms, depressive symptoms, agitation, and the needs of the people with dementia (p<0.001). Antipsychotic review reduced antipsychotic use, but it significantly increased apathy (β=5.37; SE=0.91; p<0.001). However, antipsychotic review in combination with either social interaction (β=-5.84; SE=1.15; p<0.001) or exercise (β=-7.54; SE=0.93; p<0.001) significantly reduced apathy. Conclusions: Antipsychotic review can play a significant role in improving apathy in people with dementia living in nursing homes, when combined with psychosocial interventions such as social interaction and exercise. Guidance must be adapted to reflect this subtlety in care

Antioxidants and breast cancer risk- a population-based case-control study in Canada

<p>Abstract</p> <p>Background</p> <p>The effect of antioxidants on breast cancer is still controversial. Our objective was to assess the association between antioxidants and breast cancer risk in a large population-based case-control study.</p> <p>Methods</p> <p>The study population included 2,362 cases with pathologically confirmed incident breast cancer (866 premenopausal and 1,496 postmenopausal) and 2,462 controls in Canada. Intakes of antioxidants from diet and from supplementation as well as other potential risk factors for breast cancer were collected by a self-reported questionnaire.</p> <p>Results</p> <p>Compared with subjects with no supplementation, 10 years or longer supplementation of zinc had multivariable-adjusted odds ratios (OR) and 95% confidence intervals (CI) of 0.46 (0.25-0.85) for premenopausal women, while supplementation of 10 years or longer of multiple vitamin, beta-carotene, vitamin C, vitamin E and zinc had multivariable-adjusted ORs (95% CIs) of 0.74 (0.59, 0.92), 0.58 (0.36, 0.95), 0.79 (0.63-0.99), 0.75 (0.58, 0.97), and 0.47 (0.28-0.78), respectively, for postmenopausal women. No significant effect of antioxidants from dietary sources (including beta-carotene, alpha-carotene, lycopene, lutein and zeaxanthin, vitamin C, vitamin E, selenium and zinc) or from supplementation less than 10 years was observed.</p> <p>Conclusions</p> <p>This study suggests that supplementation of zinc in premenopausal women, and supplementation of multiple vitamin, beta-carotene, vitamin C, vitamin E and zinc in postmenopausal women for 10 or more years may protect women from developing breast cancer. However, we were unable to determine the overall effect of total dose or intake from both diet and supplement.</p

Dynamics of Hot QCD Matter -- Current Status and Developments

The discovery and characterization of hot and dense QCD matter, known as Quark Gluon Plasma (QGP), remains the most international collaborative effort and synergy between theorists and experimentalists in modern nuclear physics to date. The experimentalists around the world not only collect an unprecedented amount of data in heavy-ion collisions, at Relativistic Heavy Ion Collider (RHIC), at Brookhaven National Laboratory (BNL) in New York, USA, and the Large Hadron Collider (LHC), at CERN in Geneva, Switzerland but also analyze these data to unravel the mystery of this new phase of matter that filled a few microseconds old universe, just after the Big Bang. In the meantime, advancements in theoretical works and computing capability extend our wisdom about the hot-dense QCD matter and its dynamics through mathematical equations. The exchange of ideas between experimentalists and theoreticians is crucial for the progress of our knowledge. The motivation of this first conference named "HOT QCD Matter 2022" is to bring the community together to have a discourse on this topic. In this article, there are 36 sections discussing various topics in the field of relativistic heavy-ion collisions and related phenomena that cover a snapshot of the current experimental observations and theoretical progress. This article begins with the theoretical overview of relativistic spin-hydrodynamics in the presence of the external magnetic field, followed by the Lattice QCD results on heavy quarks in QGP, and finally, it ends with an overview of experiment results.Comment: Compilation of the contributions (148 pages) as presented in the `Hot QCD Matter 2022 conference', held from May 12 to 14, 2022, jointly organized by IIT Goa & Goa University, Goa, Indi

Burden of injury along the development spectrum : associations between the Socio-demographic Index and disability-adjusted life year estimates from the Global Burden of Disease Study 2017

Background The epidemiological transition of non-communicable diseases replacing infectious diseases as the main contributors to disease burden has been well documented in global health literature. Less focus, however, has been given to the relationship between sociodemographic changes and injury. The aim of this study was to examine the association between disability-adjusted life years (DALYs) from injury for 195 countries and territories at different levels along the development spectrum between 1990 and 2017 based on the Global Burden of Disease (GBD) 2017 estimates. Methods Injury mortality was estimated using the GBD mortality database, corrections for garbage coding and CODEm-the cause of death ensemble modelling tool. Morbidity estimation was based on surveys and inpatient and outpatient data sets for 30 cause-of-injury with 47 nature-of-injury categories each. The Socio-demographic Index (SDI) is a composite indicator that includes lagged income per capita, average educational attainment over age 15 years and total fertility rate. Results For many causes of injury, age-standardised DALY rates declined with increasing SDI, although road injury, interpersonal violence and self-harm did not follow this pattern. Particularly for self-harm opposing patterns were observed in regions with similar SDI levels. For road injuries, this effect was less pronounced. Conclusions The overall global pattern is that of declining injury burden with increasing SDI. However, not all injuries follow this pattern, which suggests multiple underlying mechanisms influencing injury DALYs. There is a need for a detailed understanding of these patterns to help to inform national and global efforts to address injury-related health outcomes across the development spectrum.Peer reviewe

Estimating global injuries morbidity and mortality : methods and data used in the Global Burden of Disease 2017 study

Background While there is a long history of measuring death and disability from injuries, modern research methods must account for the wide spectrum of disability that can occur in an injury, and must provide estimates with sufficient demographic, geographical and temporal detail to be useful for policy makers. The Global Burden of Disease (GBD) 2017 study used methods to provide highly detailed estimates of global injury burden that meet these criteria. Methods In this study, we report and discuss the methods used in GBD 2017 for injury morbidity and mortality burden estimation. In summary, these methods included estimating cause-specific mortality for every cause of injury, and then estimating incidence for every cause of injury. Non-fatal disability for each cause is then calculated based on the probabilities of suffering from different types of bodily injury experienced. Results GBD 2017 produced morbidity and mortality estimates for 38 causes of injury. Estimates were produced in terms of incidence, prevalence, years lived with disability, cause-specific mortality, years of life lost and disability-adjusted life-years for a 28-year period for 22 age groups, 195 countries and both sexes. Conclusions GBD 2017 demonstrated a complex and sophisticated series of analytical steps using the largest known database of morbidity and mortality data on injuries. GBD 2017 results should be used to help inform injury prevention policy making and resource allocation. We also identify important avenues for improving injury burden estimation in the future.Peer reviewe

Adolescent transport and unintentional injuries: a systematic analysis using the Global Burden of Disease Study 2019

Background: Globally, transport and unintentional injuries persist as leading preventable causes of mortality and morbidity for adolescents. We sought to report comprehensive trends in injury-related mortality and morbidity for adolescents aged 10–24 years during the past three decades. Methods: Using the Global Burden of Disease, Injuries, and Risk Factors 2019 Study, we analysed mortality and disability-adjusted life-years (DALYs) attributed to transport and unintentional injuries for adolescents in 204 countries. Burden is reported in absolute numbers and age-standardised rates per 100 000 population by sex, age group (10–14, 15–19, and 20–24 years), and sociodemographic index (SDI) with 95% uncertainty intervals (UIs). We report percentage changes in deaths and DALYs between 1990 and 2019. Findings: In 2019, 369 061 deaths (of which 214 337 [58%] were transport related) and 31·1 million DALYs (of which 16·2 million [52%] were transport related) among adolescents aged 10–24 years were caused by transport and unintentional injuries combined. If compared with other causes, transport and unintentional injuries combined accounted for 25% of deaths and 14% of DALYs in 2019, and showed little improvement from 1990 when such injuries accounted for 26% of adolescent deaths and 17% of adolescent DALYs. Throughout adolescence, transport and unintentional injury fatality rates increased by age group. The unintentional injury burden was higher among males than females for all injury types, except for injuries related to fire, heat, and hot substances, or to adverse effects of medical treatment. From 1990 to 2019, global mortality rates declined by 34·4% (from 17·5 to 11·5 per 100 000) for transport injuries, and by 47·7% (from 15·9 to 8·3 per 100 000) for unintentional injuries. However, in low-SDI nations the absolute number of deaths increased (by 80·5% to 42 774 for transport injuries and by 39·4% to 31 961 for unintentional injuries). In the high-SDI quintile in 2010–19, the rate per 100 000 of transport injury DALYs was reduced by 16·7%, from 838 in 2010 to 699 in 2019. This was a substantially slower pace of reduction compared with the 48·5% reduction between 1990 and 2010, from 1626 per 100 000 in 1990 to 838 per 100 000 in 2010. Between 2010 and 2019, the rate of unintentional injury DALYs per 100 000 also remained largely unchanged in high-SDI countries (555 in 2010 vs 554 in 2019; 0·2% reduction). The number and rate of adolescent deaths and DALYs owing to environmental heat and cold exposure increased for the high-SDI quintile during 2010–19. Interpretation: As other causes of mortality are addressed, inadequate progress in reducing transport and unintentional injury mortality as a proportion of adolescent deaths becomes apparent. The relative shift in the burden of injury from high-SDI countries to low and low–middle-SDI countries necessitates focused action, including global donor, government, and industry investment in injury prevention. The persisting burden of DALYs related to transport and unintentional injuries indicates a need to prioritise innovative measures for the primary prevention of adolescent injury. Funding: Bill &amp; Melinda Gates Foundation

Erratum: Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017

Interpretation: By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning