Regulatory T cells control NK cells in an insulitic lesion by depriving them of IL-2

Regulatory T (T reg) cells control progression to autoimmune diabetes in the BDC2.5/NOD mouse model by reining in natural killer (NK) cells that infiltrate the pancreatic islets, inhibiting both their proliferation and production of diabetogenic interferon-γ. In this study, we have explored the molecular mechanisms underlying this NK–T reg cell axis, following leads from a kinetic exploration of gene expression changes early after punctual perturbation of T reg cells in BDC2.5/NOD mice. Results from gene signature analyses, quantification of STAT5 phosphorylation levels, cytokine neutralization experiments, cytokine supplementation studies, and evaluations of intracellular cytokine levels collectively argue for a scenario in which T reg cells regulate NK cell functions by controlling the bioavailability of limiting amounts of IL-2 in the islets, generated mainly by infiltrating CD4+ T cells. This scenario represents a previously unappreciated intertwining of the innate and adaptive immune systems: CD4+ T cells priming NK cells to provoke a destructive T effector cell response. Our findings highlight the need to consider potential effects on NK cells when designing therapeutic strategies based on manipulation of IL-2 levels or targets

AFTER THE LICENSE APPROVAL: HOW ANALYTICS CAN KEEP YOU IN THE MARKET

Getting a BLA approved for a new vaccine can be a daunting task, but keeping the market supplied after licensure of a successful vaccine can be an even bigger challenge. Analytics can play an important role in keeping product supplied to the marketplace, especially during the critical launch phase The talk will describe the application of analytical comparability to GARDASIL®, Merck’s novel new vaccine to prevent cervical cancer, in order to bridge product produced by a launch facility to that produced by a scale-up facility without the need for a clinical trial. This effort assured a smooth transition of supply and fulfilled marketing needs during the critical catch-up market phase for this product. Analytical tools are also important to sustain the market for older vaccine products which have been licensed for decades. In this case, the issues involved in modernization of the release methods will be discussed. Of particular note will be the special issues for bridging potency assay procedures for legacy products

AFTER THE LICENSE APPROVAL: HOW ANALYTICS CAN KEEP YOU IN THE MARKET

Getting a BLA approved for a new vaccine can be a daunting task, but keeping the market supplied after licensure of a successful vaccine can be an even bigger challenge. Analytics can play an important role in keeping product supplied to the marketplace, especially during the critical launch phase The talk will describe the application of analytical comparability to GARDASIL®, Merck’s novel new vaccine to prevent cervical cancer, in order to bridge product produced by a launch facility to that produced by a scale-up facility without the need for a clinical trial. This effort assured a smooth transition of supply and fulfilled marketing needs during the critical catch-up market phase for this product. Analytical tools are also important to sustain the market for older vaccine products which have been licensed for decades. In this case, the issues involved in modernization of the release methods will be discussed. Of particular note will be the special issues for bridging potency assay procedures for legacy products

Managing Histories of Human Rights Abuses: Democratic Transitions and the Manifestation of Transitional Justice in Post-Dictatorship Spain and Chile.

HonorsInternational StudiesUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/162631/1/alizasit.pd

Reactions to evidence of white privilege by clinical psychologists

White cultural norms harm psychotherapy clients of the global majority. Racial microaggressions committed by White clinical psychologists threaten therapeutic alliance and treatment. Engagement with the advantages of being White is necessary for clinical psychologists to provide ethical therapy, but engagement is limited by defensive reactions to White privilege. This study intended to reveal defensive responses that arise in White clinical psychologists when they read about privilege with the goal of increasing awareness for the betterment of the field. The study hypothesized that White privilege exposure would predict increased colorblind racial attitudes (CBRA), increased racial system justification (RSJ), increased White racial affect (WRA), decreased empathy, increased anxiety, and increased immature defense mechanisms (IDM). Moreover, these relationships would be moderated by multicultural competence (MC). Participants were 196 White American clinical psychologists who completed self-report questionnaires online. Participants were randomly assigned to one of two groups: the control group read a neutral paragraph. The experimental group read a White privilege paragraph. All participants then completed the same measures. White privilege exposure significantly predicted increased anxiety. CBRA, RSJ, WRA, empathy, and IDM were not predicted by exposure, therefore, there were no moderations by MC. Exploratory constructs, mature defense mechanisms and implicit negative affect, were impacted by White privilege exposure, which predicted significantly decreased mature defense mechanisms. The interaction of White privilege exposure and MC significantly predicted decreased implicit negative affect. Possible implications are discussed

Effect on Neonatal Mortality of Newborn Infection Management at Health Posts When Referral Is Not Possible: A Cluster-Randomized Trial in Rural Ethiopia.

BACKGROUND: The World Health Organization recently provided guidelines for outpatient treatment of possible severe bacterial infections (PSBI) in young infants, when referral to hospital is not feasible. This study evaluated newborn infection treatment at the most peripheral level of the health system in rural Ethiopia. METHODS: We performed a cluster-randomized trial in 22 geographical clusters (11 allocated to intervention, 11 to control). In both arms, volunteers and government-employed Health Extension Workers (HEWs) conducted home visits to pregnant and newly delivered mothers; assessed newborns; and counseled caregivers on prevention of newborn illness, danger signs, and care seeking. Volunteers referred sick newborns to health posts for further assessment; HEWs referred newborns with PSBI signs to health centers. In the intervention arm only, between July 2011 and June 2013, HEWs treated newborns with PSBI with intramuscular gentamicin and oral amoxicillin for 7 days at health posts when referral to health centers was not possible or acceptable to caregivers. Intervention communities were informed of treatment availability at health posts to encourage care seeking. Masking was not feasible. The primary outcome was all-cause mortality of newborns 2-27 days after birth, measured by household survey data. Baseline data were collected between June 2008 and May 2009; endline data, between February 2013 and June 2013. We sought to detect a 33% mortality reduction. Analysis was by intention to treat. (ClinicalTrials.gov registry: NCT00743691). RESULTS: Of 1,011 sick newborns presenting at intervention health posts, 576 (57%) were identified by HEWs as having at least 1 PSBI sign; 90% refused referral and were treated at the health post, with at least 79% completing the antibiotic regimen. Estimated treatment coverage at health posts was in the region of 50%. Post-day 1 neonatal mortality declined more in the intervention arm (17.9 deaths per 1,000 live births at baseline vs. 9.4 per 1,000 at endline) than the comparison arm (14.4 per 1,000 vs. 11.2 per 1,000, respectively). After adjusting for baseline mortality and region, the estimated post-day 1 mortality risk ratio was 0.83, but the result was not statistically significant (95% confidence interval, 0.55 to 1.24; P=.33). INTERPRETATION: When referral to higher levels of care is not possible, HEWs can deliver outpatient antibiotic treatment of newborns with PSBI, but estimated treatment coverage in a rural Ethiopian setting was only around 50%. While our data suggest a mortality reduction consistent with that which might be expected at this level of coverage, they do not provide conclusive results

Наноалмазы как идеальные наноносители для циансодежащих цитостатиков

Цианосодержащие цитостатики - новый класс открытых нами лекарств, которые благодаря цианогруппам хорошо закрепляются на наноалмазах, с увеличением активности

Count every newborn; a measurement improvement roadmap for coverage data.

BACKGROUND: The Every Newborn Action Plan (ENAP), launched in 2014, aims to end preventable newborn deaths and stillbirths, with national targets of ≤12 neonatal deaths per 1000 live births and ≤12 stillbirths per 1000 total births by 2030. This requires ambitious improvement of the data on care at birth and of small and sick newborns, particularly to track coverage, quality and equity. METHODS: In a multistage process, a matrix of 70 indicators were assessed by the Every Newborn steering group. Indicators were graded based on their availability and importance to ENAP, resulting in 10 core and 10 additional indicators. A consultation process was undertaken to assess the status of each ENAP core indicator definition, data availability and measurement feasibility. Coverage indicators for the specific ENAP treatment interventions were assigned task teams and given priority as they were identified as requiring the most technical work. Consultations were held throughout. RESULTS: ENAP published 10 core indicators plus 10 additional indicators. Three core impact indicators (neonatal mortality rate, maternal mortality ratio, stillbirth rate) are well defined, with future efforts needed to focus on improving data quantity and quality. Three core indicators on coverage of care for all mothers and newborns (intrapartum/skilled birth attendance, early postnatal care, essential newborn care) have defined contact points, but gaps exist in measuring content and quality of the interventions. Four core (antenatal corticosteroids, neonatal resuscitation, treatment of serious neonatal infections, kangaroo mother care) and one additional coverage indicator for newborns at risk or with complications (chlorhexidine cord cleansing) lack indicator definitions or data, especially for denominators (population in need). To address these gaps, feasible coverage indicator definitions are presented for validity testing. Measurable process indicators to help monitor health service readiness are also presented. A major measurement gap exists to monitor care of small and sick babies, yet signal functions could be tracked similarly to emergency obstetric care. CONCLUSIONS: The ENAP Measurement Improvement Roadmap (2015-2020) outlines tools to be developed (e.g., improved birth and death registration, audit, and minimum perinatal dataset) and actions to test, validate and institutionalise proposed coverage indicators. The roadmap presents a unique opportunity to strengthen routine health information systems, crosslinking these data with civil registration and vital statistics and population-based surveys. Real measurement change requires intentional transfer of leadership to countries with the greatest disease burden and will be achieved by working with centres of excellence and existing networks

Urokinase expression in mononuclear phagocytes: cytokine‐specific modulation by interferon‐γ and tumor necrosis factor‐α

This study delineates the regulatory effects of inflammatory cytokines on mononuclear phagocyte plasminogen activator (PA) activity. The mechanisms by which mononuclear phagocytes modulate PA activity are described. Mononuclear phagocytes regulate net PA activity by the balanced expression of urokinase‐type PA (uPA), in either secreted or membrane‐associated forms, and a specific plasminogen activator inhibitor, PAI‐2. Therefore, understanding how immunomodulators regulate macrophage PA activity requires that the comparative effects of uPA and PAI‐2 be elucidated. We determined how recombinant interferon‐γ (IFN) and tumor necrosis factor‐α (TNF) regulate plasminogen activation in monoblast‐like U937 cells and normal human monocytes. In U937 cells, both IFN and TNF induced concurrent increases in secreted PA and PA inhibitor activities. These effects were accompanied by increased immunoreactive uPA and PAI‐2 in conditioned media (enzyme‐linked immunosorbent assay) and steady‐state levels of cellular uPA and PAI‐2 mRNA (Northern analysis). To determine the relative abilities of IFN and TNF to either promote or inhibit plasmin generation, we directly compared the effects IFN and TNF, using optimal stimulating concentrations. IFN induced PA activity to 180% of the level achieved by TNF. In contrast, IFN elicited only 78% of the PA inhibitor produced by TNF stimulation. These differences in secreted activity can be explained by the shift in balance between uPA and PAI‐2 proteins. Immunoreactive uPA was induced equally by IFN and TNF, but TNF generated higher levels of PAI‐2. The same overall pattern of results was seen in normal human monocytes. IFN and TNF differ greatly in the ability to augment receptor‐bound PA activity in U937 cells, as IFN induced a twofold increase but TNF had no effect. We conclude that IFN and TNF modulate mononuclear phagocyte proteolytic activity through coordinate regulation of secreted and receptor‐bound uPA, balanced against concurrent expression of PAI‐2. These effects are cytokine specific, as IFN is superior to TNF in stimulating expression of both secreted and receptor‐associated PA activities. These properties suggest mechanisms by which mononuclear phagocytes control proteolysis in cytokinerich inflammatory foci.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141202/1/jlb0256.pd