Science.gov

Sample records for reduced death toll

  1. Uncovering the 2010 Haiti earthquake death toll

    NASA Astrophysics Data System (ADS)

    Daniell, J. E.; Khazai, B.; Wenzel, F.

    2013-05-01

    Casualties are estimated for the 12 January 2010 earthquake in Haiti using various reports calibrated by observed building damage states from satellite imagery and reconnaissance reports on the ground. By investigating various damage reports, casualty estimates and burial figures, for a one year period from 12 January 2010 until 12 January 2011, there is also strong evidence that the official government figures of 316 000 total dead and missing, reported to have been caused by the earthquake, are significantly overestimated. The authors have examined damage and casualties report to arrive at their estimation that the median death toll is less than half of this value (±137 000). The authors show through a study of historical earthquake death tolls, that overestimates of earthquake death tolls occur in many cases, and is not unique to Haiti. As death toll is one of the key elements for determining the amount of aid and reconstruction funds that will be mobilized, scientific means to estimate death tolls should be applied. Studies of international aid in recent natural disasters reveal that large distributions of aid which do not match the respective needs may cause oversupply of help, aggravate corruption and social disruption rather than reduce them, and lead to distrust within the donor community.

  2. Mangroves protected villages and reduced death toll during Indian super cyclone.

    PubMed

    Das, Saudamini; Vincent, Jeffrey R

    2009-05-01

    Protection against coastal disasters has been identified as an important service of mangrove ecosystems. Empirical studies on this service have been criticized, however, for using small samples and inadequately controlling for confounding factors. We used data on several hundred villages to test the impact of mangroves on human deaths during a 1999 super cyclone that struck Orissa, India. We found that villages with wider mangroves between them and the coast experienced significantly fewer deaths than ones with narrower or no mangroves. This finding was robust to the inclusion of a wide range of other variables to our statistical model, including controls for the historical extent of mangroves. Although mangroves evidently saved fewer lives than an early warning issued by the government, the retention of remaining mangroves in Orissa is economically justified even without considering the many benefits they provide to human society besides storm-protection services. PMID:19380735

  3. Combined Prediction Model of Death Toll for Road Traffic Accidents Based on Independent and Dependent Variables

    PubMed Central

    Zhong-xiang, Feng; Shi-sheng, Lu; Wei-hua, Zhang; Nan-nan, Zhang

    2014-01-01

    In order to build a combined model which can meet the variation rule of death toll data for road traffic accidents and can reflect the influence of multiple factors on traffic accidents and improve prediction accuracy for accidents, the Verhulst model was built based on the number of death tolls for road traffic accidents in China from 2002 to 2011; and car ownership, population, GDP, highway freight volume, highway passenger transportation volume, and highway mileage were chosen as the factors to build the death toll multivariate linear regression model. Then the two models were combined to be a combined prediction model which has weight coefficient. Shapley value method was applied to calculate the weight coefficient by assessing contributions. Finally, the combined model was used to recalculate the number of death tolls from 2002 to 2011, and the combined model was compared with the Verhulst and multivariate linear regression models. The results showed that the new model could not only characterize the death toll data characteristics but also quantify the degree of influence to the death toll by each influencing factor and had high accuracy as well as strong practicability. PMID:25610454

  4. Differential immunomodulatory activity of tumor cell death induced by cancer therapeutic toll-like receptor ligands.

    PubMed

    Klein, Johanna C; Wild, Clarissa A; Lang, Stephan; Brandau, Sven

    2016-06-01

    Synthetic toll-like receptor (TLR) ligands stimulate defined immune cell subsets and are currently tested as novel immunotherapeutic agents against cancer with, however, varying clinical efficacy. Recent data showed the expression of TLR receptors also on tumor cells. In this study we investigated immunological events associated with the induction of tumor cell death by poly(I:C) and imiquimod. A human head and neck squamous cell carcinoma (HNSCC) cell line was exposed to poly(I:C) and imiquimod, which were delivered exogenously via culture medium or via electroporation. Cell death and cell biological consequences thereof were analyzed. For in vivo analyses, a human xenograft and a syngeneic immunocompetent mouse model were used. Poly(I:C) induced cell death only if delivered by electroporation into the cytosol. Cell death induced by poly(I:C) resulted in cytokine release and activation of monocytes in vitro. Monocytes activated by the supernatant of cancer cells previously exposed to poly(I:C) recruited significantly more Th1 cells than monocytes exposed to control supernatants. If delivered exogenously, imiquimod also induced tumor cell death and some release of interleukin-6, but cell death was not associated with release of Th1 cytokines, interferons, monocyte activation and Th1 recruitment. Interestingly, intratumoral injection of poly(I:C) triggered tumor cell death in tumor-bearing mice and reduced tumor growth independent of TLR signaling on host cells. Imiquimod did not affect tumor size. Our data suggest that common cancer therapeutic RNA compounds can induce functionally diverse types of cell death in tumor cells with implications for the use of TLR ligands in cancer immunotherapy. PMID:27034235

  5. The Boundaries of Genocide: Quantifying the Uncertainty of the Death Toll During the Pol Pot Regime (1975-1979)

    PubMed Central

    Heuveline, Patrick

    2015-01-01

    Estimates of excess deaths under Pol Pot's rule of Cambodia (1975-79) range from under one million to over three million. The more plausible among those, methodologically, still vary from one to two million deaths, but this range of independent point estimates has no particular statistical meaning. Stochastically reconstructing population dynamics in Cambodia from extant historical and demographic data yields interpretable distributions of the death toll and other demographic indicators. The resulting 95-percent simulation interval (1.2 to 2.8 million excess deaths) demonstrates substantial uncertainty with regards to the exact scale of mortality, yet still excludes nearly half of the previous death-toll estimates. The 1.5 to 2.25 million interval contains 69 per cent of the simulations for the actual number of excess death, more than the wider (one to two million) range of previous plausible estimates. The median value of 1.9 million excess deaths represents 21 percent of the population at risk. PMID:26218856

  6. Reducing deaths from pregnancy and childbirth. Asia.

    PubMed

    Pillai, G

    1993-01-01

    99% of all maternal deaths occur in the developing world, and South Asian countries account for most deaths. The causes are obstructed labor, hemorrhage, pregnancy-related hypertension (eclampsia), or unsafe abortion. The United Nation's Children's Fund estimates 340 maternal deaths for every 100,000 live births in India. In Indian rural areas, the maternal mortality rate is between 800 and 900 deaths per 100,000 live births in Bangladesh, 600; in Nepal, 830; and in Bhutan, 1710. IN comparison, the rate in the United States is 8 deaths per 100,000 live births. The technology for reducing maternal mortality has been utilized in most developed countries, as well as in parts of South Asia, in particular in Sri Lanka. The goal of the Safe Motherhood Initiative was to reduce maternal mortality by 50% by the year 2000. The immediate causes of maternal mortality include pregnancy and delivery and the management of complications such as hemorrhage, toxic and bacterial infections (sepsis), eclampsia, and obstructed labor. The poor health, nutrition, and socioeconomic status of women are the underlying causes of maternal death. One study in India found that inadequate medical treatment contributes to 36% to 47% of maternal deaths in hospitals. In India, abortion services are legal and acceptable on social, religious, and political grounds, but services are inaccessible. In Bangladesh, the availability of menstrual regulation is estimated to save 100,000 to 160,000 women from unsafe abortions each year. However, the inaccessibility of this service accounts for 700,000 unsafe abortions and 7000 maternal deaths. Gender bias in the allocation of meager food supplies results in the poor health and nutritional status of women, rendering a woman's pelvis too small, which causes obstructed labor and even death. Socioeconomic status is linked to access the family planning and health services which affect mortality and reproductive health. In Sri Lanka and Kerala, government

  7. Common Therapy for Rheumatoid Arthritis Reduces Risk of Death

    MedlinePlus

    ... Research 2013 April 2013 (historical) Common Therapy for Rheumatoid Arthritis Reduces Risk of Death Taking methotrexate—a commonly ... reduce the risk of death among patients with rheumatoid arthritis (RA), according to recently-published research in the ...

  8. Thinking about Death Reduces Delay Discounting

    PubMed Central

    Kelley, Nicholas J.; Schmeichel, Brandon J.

    2015-01-01

    The current study tested competing predictions regarding the effect of mortality salience on delay discounting. One prediction, based on evolutionary considerations, was that reminders of death increase the value of the present. Another prediction, based in part on construal level theory, was that reminders of death increase the value of the future. One-hundred eighteen participants thought about personal mortality or a control topic and then completed an inter-temporal choice task pitting the chance to gain $50 now against increasingly attractive rewards three months later. Consistent with the hypothesis inspired by construal theory, participants in the mortality salience condition traded $50 now for $66.67 in three months, whereas participants in the dental pain salience condition required $72.84 in three months in lieu of $50 now. Thus, participants in the mortality salience condition discounted future monetary gains less than other participants, suggesting that thoughts of death may increase the subjective value of the future. PMID:26630664

  9. Toll-Like Receptor 4 Reduces Oxidative Injury via Glutathione Activity in Sheep.

    PubMed

    Deng, Shoulong; Yu, Kun; Wu, Qian; Li, Yan; Zhang, Xiaosheng; Zhang, Baolu; Liu, Guoshi; Liu, Yixun; Lian, Zhengxing

    2016-01-01

    Toll-like receptor 4 (TLR4) is an important sensor of Gram-negative bacteria and can trigger activation of the innate immune system. Increased activation of TLR4 can lead to the induction of oxidative stress. Herein, the pathway whereby TLR4 affects antioxidant activity was studied. In TLR4-overexpressing sheep, TLR4 expression was found to be related to the integration copy number when monocytes were challenged with lipopolysaccharide (LPS). Consequently, production of malondialdehyde (MDA) was increased, which could increase the activation of prooxidative stress enzymes. Meanwhile, activation of an antioxidative enzyme, glutathione peroxidase (GSH-Px), was increased. Real-time PCR showed that expression of activating protein-1 (AP-1) and the antioxidative-related genes was increased. By contrast, the expression levels of superoxide dismutase 1 (SOD1) and catalase (CAT) were reduced. In transgenic sheep, glutathione (GSH) levels were dramatically reduced. Furthermore, transgenic sheep were intradermally injected with LPS in each ear. The amounts of inflammatory infiltrates were correlated with the number of TLR4 copies that were integrated in the genome. Additionally, the translation of γ-glutamylcysteine synthetase (γ-GCS) was increased. Our findings indicated that overexpression of TLR4 in sheep could ameliorate oxidative injury through GSH secretion that was induced by LPS stimulation. Furthermore, TLR4 promoted γ-GCS translation through the AP-1 pathway, which was essential for GSH synthesis. PMID:26640618

  10. Toll-Like Receptor 4 Reduces Oxidative Injury via Glutathione Activity in Sheep

    PubMed Central

    Deng, Shoulong; Yu, Kun; Wu, Qian; Li, Yan; Zhang, Xiaosheng; Zhang, Baolu; Liu, Guoshi; Liu, Yixun; Lian, Zhengxing

    2016-01-01

    Toll-like receptor 4 (TLR4) is an important sensor of Gram-negative bacteria and can trigger activation of the innate immune system. Increased activation of TLR4 can lead to the induction of oxidative stress. Herein, the pathway whereby TLR4 affects antioxidant activity was studied. In TLR4-overexpressing sheep, TLR4 expression was found to be related to the integration copy number when monocytes were challenged with lipopolysaccharide (LPS). Consequently, production of malondialdehyde (MDA) was increased, which could increase the activation of prooxidative stress enzymes. Meanwhile, activation of an antioxidative enzyme, glutathione peroxidase (GSH-Px), was increased. Real-time PCR showed that expression of activating protein-1 (AP-1) and the antioxidative-related genes was increased. By contrast, the expression levels of superoxide dismutase 1 (SOD1) and catalase (CAT) were reduced. In transgenic sheep, glutathione (GSH) levels were dramatically reduced. Furthermore, transgenic sheep were intradermally injected with LPS in each ear. The amounts of inflammatory infiltrates were correlated with the number of TLR4 copies that were integrated in the genome. Additionally, the translation of γ-glutamylcysteine synthetase (γ-GCS) was increased. Our findings indicated that overexpression of TLR4 in sheep could ameliorate oxidative injury through GSH secretion that was induced by LPS stimulation. Furthermore, TLR4 promoted γ-GCS translation through the AP-1 pathway, which was essential for GSH synthesis. PMID:26640618

  11. Pleural mesothelioma: forecasts of the death toll in the area of Casale Monferrato, Italy.

    PubMed

    Furlan, Claudia; Mortarino, Cinzia

    2012-12-20

    In the city of Casale Monferrato, the largest Italian factory that produced asbestos-cement goods was active from 1907 to 1985. Consequently, asbestos fibers scattered in the surrounding area and caused an enormous number of cases of pleural mesothelioma. Owing to the very long latency of this disease, many subjects have not exhibited its symptoms yet. The aim of this paper is to model and predict the future evolution of the number of deaths due to this disease among residents in the area around that city. The model used here is based on a cellular automata that is assumed to pass through three steps: exposure, contamination, and diagnosis. In this way, forecasts of the future evolution take into account the environmental conditions that changed over the last century because of different levels of plant activity. The model is fitted to annual diagnosis data from 1954 to 2008. Results show that deaths will not end until 2031 and that in the next two decades, at least 505 more subjects will be diagnosed with this disease. PMID:22829461

  12. The boundaries of genocide: Quantifying the uncertainty of the death toll during the Pol Pot regime in Cambodia (1975-79).

    PubMed

    Heuveline, Patrick

    2015-01-01

    The range of estimates of excess deaths under Pol Pot's rule of Cambodia (1975-79) is too wide to be useful: they range from under 1 to over 3 million, with the more plausible estimates still varying from 1 to 2 million. By stochastically reconstructing population dynamics in Cambodia from extant historical and demographic data, we produced interpretable distributions of the death toll and other demographic indicators. The resulting 95 per cent simulation interval (1.2-2.8 million excess deaths) demonstrates substantial uncertainty over the exact scale of mortality, yet it still excludes nearly half of the previous death-toll estimates. The 1.5-2.25 million interval contains 69 per cent of the simulations for the actual number of excess deaths, more than the wider (1-2 million) range of previous plausible estimates. The median value of 1.9 million excess deaths represents 21 per cent of the population at risk. Supplementary material for this article is available at: http://dx.doi.org/10.1080/00324728.2015.1045546. PMID:26218856

  13. Reducing the Child Death Rate. KIDS COUNT Indicator Brief

    ERIC Educational Resources Information Center

    Shore, Rima; Shore, Barbara

    2009-01-01

    In the 20th century's final decades, advances in the prevention and treatment of infectious diseases sharply reduced the child death rate. Despite this progress, the child death rate in the U.S. remains higher than in many other wealthy nations. The under-five mortality rate in the U.S. is almost three times higher than that of Iceland and Sweden…

  14. Suppression of Ischemia-Induced Hippocampal Pyramidal Neuron Death by Hyaluronan Tetrasaccharide through Inhibition of Toll-Like Receptor 2 Signaling Pathway.

    PubMed

    Sunabori, Takehiko; Koike, Masato; Asari, Akira; Oonuki, Yoji; Uchiyama, Yasuo

    2016-08-01

    Toll-like receptors (TLRs) are one of the main contributors that induce inflammation under tissue injury and infection. Because excessive inflammation can aggravate disease states, it is important to control inflammation at a moderate level. Herein, we show that hyaluronan (HA) oligomer, HA tetrasaccharide (HA4), could suppress the expression of proinflammatory cytokine IL-1β when stimulated with both TLR2- and TLR4-specific agonists in primary hippocampal neurons. To understand the effect of HA4 against ischemic insult, we performed hypoxic-ischemic (H/I) brain injury against neonatal mice. HA4 treatment significantly prevented hippocampal pyramidal cell death even 7 days after H/I injury, compared with the control mice. Although TLR2 and TLR4 are known as receptors for HA and also act as a receptor for inducing inflammation, only TLR2-deficient mice showed tolerance against H/I injury. Moreover, HA4 administration suppressed gliosis by inhibiting the activation of NF-κB, the downstream target of TLR2, which led to the suppression of IL-1β expression. Taken together, our data suggest that the neuroprotective effect of HA4 relies on antagonizing the TLR2/NF-κB pathway to reduce inflammation through suppressing the expression of proinflammatory cytokines after neonatal H/I brain injury. PMID:27301359

  15. Use of toll-like receptor agonists to reduce Salmonella colonization in neonatal swine

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Toll-like receptors (TLR) are members of a highly conserved group of receptors which recognize conserved molecular aspects of microbes. The purpose of these experiments were to ascertain the effects of the administration of the TLR 9 agonist, CpG, on the colonization of neonatal swine with Salmonel...

  16. Monocytes from tuberculosis patients that exhibit cleaved caspase 9 and denaturalized cytochrome c are more susceptible to death mediated by Toll-like receptor 2

    PubMed Central

    Chávez-Galán, Leslie; Sada-Ovalle, Isabel; Baez-Saldaña, Renata; Chávez, Raúl; Lascurain, Ricardo

    2012-01-01

    Experimental models have shown that lipoproteins from Mycobacterium tuberculosis induce apoptosis via Toll-like receptor 2 (TLR2) in the THP-1 cell line and in monocyte-derived macrophages from healthy volunteers. We found an increased percentage of circulating monocytes in patients with tuberculosis (TB) in comparison to healthy controls. Patients with TB showed a higher TLR2 and TLR4 expression density on monocytes, and a higher proportion of TLR2+ monocytes, as well as increased serum tumour necrosis factor-α level. In culture, monocytes from TB patients were more susceptible to death than monocytes from healthy controls. Moreover, death-susceptible monocytes were positive to both TLR2 and TLR4 at the start of culture. Freshly obtained monocytes from TB patients exhibited cleaved caspase 9 and denaturalized cytochrome c. For levels of caspase 8, apoptosis-regulating signal kinase 1, and phospho-p38 mitogen-activated protein kinase there was no difference between samples from TB patients and from healthy controls. The culture filtrate antigen extract from M. tuberculosis H37Rv strain induced the death of monocytes from patient with TB after a 4-hr incubation, which was abrogated by neutralizing antibodies for TLR2 but not TLR4. Similarly, Pam3CSK4, a synthetic agonist triacylated ligand to TLR2, also induced the death of monocytes, although it did not increase levels of cleaved caspase 9. Our findings suggest that monocytes from TB patients are more susceptible to death, probably through mitochondrial damage, and that cell death increases in the presence of mycobacterial antigen by a TLR2-dependent pathway. PMID:22133266

  17. How Can the Science Community Support Reality Based Policies to Reducing the Escalating Toll of Natural Hazards?

    NASA Astrophysics Data System (ADS)

    Thomas, E. A.

    2012-12-01

    Worldwide, the toll of disaster damage caused by foreseeable natural hazards is growing, despite the fact that science is increasingly able to quantify the risk and foresee the likely location of natural events (NCDC 2012; NHC 2010). Those events can cause disastrous consequences if human built infrastructure is not properly designed for both the current state and future events (IBHS, 2012). Our existing approaches are not working at reducing the mounting toll of disasters which follow foreseeable natural events. Rather, even if the climate were not changing, current land use decisions coupled with development, engineering, design, and construction practices are significantly contributing to further increasing an unsustainable toll from disasters (Pielke, Gratz et al. 2007). Safe and proper construction practices developed to reduce flood losses (e.g. Design for Flooding, Watson, Adams et al., 2010) are all too often thought of as a zero sum situation where the community wins and the developer loses. In reality, the United States and the rest of the world often can find win-win solutions based on sound economics, law, ethics, and environmental sustainability that will benefit communities, developers, and natural hazard risk mitigation practitioners. While such solutions are being implemented in a fragmentary manner throughout the United States, communities implementing these solutions are increasingly working together in peer networks, such as the Natural Hazard Mitigation Association (NHMA)'s Resilient Neighbors Network. Examples include the Urban Drainage and Flood Control District that covers the metropolitan Denver area and recent work in Tulsa, Oklahoma. This presentation will set forth the scientific, ethical, and legal basis of higher development standards which, when combined with good negotiations techniques, can significantly decrease the terrible misery from wildfires, tornadoes, floods, and other natural disasters. Communities clearly have the legal

  18. Reduced cerebral ischemia-reperfusion injury in Toll-like receptor 4 deficient mice

    SciTech Connect

    Cao Canxiang; Yang Qingwu . E-mail: yangqwmlys@hotmail.com; Lv Fenglin; Cui Jie; Fu Huabin; Wang Jingzhou

    2007-02-09

    Inflammatory reaction plays an important role in cerebral ischemia-reperfusion injury, however, its mechanism is still unclear. Our study aims to explore the function of Toll-like receptor 4 (TLR4) in the process of cerebral ischemia-reperfusion. We made middle cerebral artery ischemia-reperfusion model in mice with line embolism method. Compared with C3H/OuJ mice, scores of cerebral water content, cerebral infarct size and neurologic impairment in C3H/Hej mice were obviously lower after 6 h ischemia and 24 h reperfusion. Light microscopic and electron microscopic results showed that cerebral ischemia-reperfusion injury in C3H/Hej mice was less serious than that in C3H/OuJ mice. TNF-{alpha} and IL-6 contents in C3H/HeJ mice were obviously lower than that in C3H/OuJ mice with ELISA. The results showed that TLR4 participates in the process of cerebral ischemia-reperfusion injury probably through decrease of inflammatory cytokines. TLR4 may become a new target for prevention of cerebral ischemia-reperfusion injury. Our study suggests that TLR4 is one of the mechanisms of cerebral ischemia-reperfusion injury besides its important role in innate immunity.

  19. Power and death: Mortality salience increases power seeking while feeling powerful reduces death anxiety.

    PubMed

    Belmi, Peter; Pfeffer, Jeffrey

    2016-05-01

    According to Terror Management Theory, people respond to reminders of mortality by seeking psychological security and bolstering their self-esteem. Because previous research suggests that having power can provide individuals a sense of security and self-worth, we hypothesize that mortality salience leads to an increased motivation to acquire power, especially among men. Study 1 found that men (but not women) who wrote about their death reported more interest in acquiring power. Study 2A and Study 2B demonstrated that when primed with reminders of death, men (but not women) reported behaving more dominantly during the subsequent week, while both men and women reported behaving more prosocially during that week. Thus, mortality salience prompts people to respond in ways that help them manage their death anxiety but in ways consistent with normative gender expectations. Furthermore, Studies 3-5 showed that feeling powerful reduces anxiety when mortality is salient. Specifically, we found that when primed to feel more powerful, both men and women experienced less mortality anxiety. (PsycINFO Database Record PMID:26867106

  20. Carbon monoxide down-modulates Toll-like receptor 4/MD2 expression on innate immune cells and reduces endotoxic shock susceptibility

    PubMed Central

    Riquelme, Sebastián A; Bueno, Susan M; Kalergis, Alexis M

    2015-01-01

    Carbon monoxide (CO) has been recently reported as the main anti-inflammatory mediator of the haem-degrading enzyme haem-oxygenase 1 (HO-1). It has been shown that either HO-1 induction or CO treatment reduces the ability of monocytes to respond to inflammatory stimuli, such as lipopolysaccharide (LPS), due to an inhibition of the signalling pathways leading to nuclear factor-κB, mitogen-activated protein kinases and interferon regulatory factor 3 activation. Hence, it has been suggested that CO impairs the stimulation of the Toll-like receptor 4 (TLR4)/myeloid differentiation factor-2 (MD2) complex located on the surface of immune cells. However, whether CO can negatively modulate the surface expression of the TLR4/MD2 complex in immune cells remains unknown. Here we report that either HO-1 induction or treatment with CO decreases the surface expression of TLR4/MD2 in dendritic cells (DC) and neutrophils. In addition, in a septic shock model of mice intraperitoneally injected with lipopolysaccharide (LPS), prophylactic treatment with CO protected animals from hypothermia, weight loss, mobility loss and death. Further, mice pre-treated with CO and challenged with LPS showed reduced recruitment of DC and neutrophils to peripheral blood, suggesting that this gas causes a systemic tolerance to endotoxin challenge. No differences in the amount of innate cells in lymphoid tissues were observed in CO-treated mice. Our results suggest that CO treatment reduces the expression of the TLR4/MD2 complex on the surface of myeloid cells, which renders them resistant to LPS priming in vitro, as well as in vivo in a model of endotoxic shock. PMID:25179131

  1. Vaccination greatly reduces disease, disability, death and inequity worldwide.

    PubMed

    Andre, F E; Booy, R; Bock, H L; Clemens, J; Datta, S K; John, T J; Lee, B W; Lolekha, S; Peltola, H; Ruff, T A; Santosham, M; Schmitt, H J

    2008-02-01

    In low-income countries, infectious diseases still account for a large proportion of deaths, highlighting health inequities largely caused by economic differences. Vaccination can cut health-care costs and reduce these inequities. Disease control, elimination or eradication can save billions of US dollars for communities and countries. Vaccines have lowered the incidence of hepatocellular carcinoma and will control cervical cancer. Travellers can be protected against "exotic" diseases by appropriate vaccination. Vaccines are considered indispensable against bioterrorism. They can combat resistance to antibiotics in some pathogens. Noncommunicable diseases, such as ischaemic heart disease, could also be reduced by influenza vaccination. Immunization programmes have improved the primary care infrastructure in developing countries, lowered mortality in childhood and empowered women to better plan their families, with consequent health, social and economic benefits. Vaccination helps economic growth everywhere, because of lower morbidity and mortality. The annual return on investment in vaccination has been calculated to be between 12% and 18%. Vaccination leads to increased life expectancy. Long healthy lives are now recognized as a prerequisite for wealth, and wealth promotes health. Vaccines are thus efficient tools to reduce disparities in wealth and inequities in health. PMID:18297169

  2. Reducing the Teen Death Rate. KIDS COUNT Indicator Brief

    ERIC Educational Resources Information Center

    Shore, Rima; Shore, Barbara

    2009-01-01

    Life continues to hold considerable risk for adolescents in the United States. In 2006, the teen death rate stood at 64 deaths per 100,000 teens (13,739 teens) (KIDS COUNT Data Center, 2009). Although it has declined by 4 percent since 2000, the rate of teen death in this country remains substantially higher than in many peer nations, based…

  3. The Mortality Toll of Estrogen Avoidance: An Analysis of Excess Deaths Among Hysterectomized Women Aged 50 to 59 Years

    PubMed Central

    Njike, Valentine Y.; Vinante, Valentina; Katz, David L.

    2013-01-01

    Objectives. We examined the effect of estrogen avoidance on mortality rates among hysterectomized women aged 50 to 59 years. Methods. We derived a formula to relate the excess mortality among hysterectomized women aged 50 to 59 years assigned to placebo in the Women’s Health Initiative randomized controlled trial to the entire population of comparable women in the United States, incorporating the decline in estrogen use observed between 2002 and 2011. Results. Over a 10-year span, starting in 2002, a minimum of 18 601 and as many as 91 610 postmenopausal women died prematurely because of the avoidance of estrogen therapy (ET). Conclusions. ET in younger postmenopausal women is associated with a decisive reduction in all-cause mortality, but estrogen use in this population is low and continuing to fall. Our data indicate an associated annual mortality toll in the thousands of women aged 50 to 59 years. Informed discussion between these women and their health care providers about the effects of ET is a matter of considerable urgency. PMID:23865654

  4. Reducing deaths from diarrhoea through oral rehydration therapy.

    PubMed Central

    Victora, C. G.; Bryce, J.; Fontaine, O.; Monasch, R.

    2000-01-01

    In 1980, diarrhoea was the leading cause of child mortality, accounting for 4.6 million deaths annually. Efforts to control diarrhoea over the past decade have been based on multiple, potentially powerful interventions implemented more or less simultaneously. Oral rehydration therapy (ORT) was introduced in 1979 and rapidly became the cornerstone of programmes for the control of diarrhoeal diseases. We report on the strategy for controlling diarrhoea through case management, with special reference to ORT, and on the relationship between its implementation and reduced mortality. Population-based data on the coverage and quality of facility-based use of ORT are scarce, despite its potential importance in reducing mortality, especially for severe cases. ORT use rates during the 1980s are available for only a few countries. An improvement in the availability of data occurred in the mid-1990s. The study of time trends is hampered by the use of several different definitions of ORT. Nevertheless, the data show positive trends in diarrhoea management in most parts of the world. ORT is now given to the majority of children with diarrhoea. The annual number of deaths attributable to diarrhoea among children aged under 5 years fell from the estimated 4.6 million in 1980 to about 1.5 million today. Case studies in Brazil, Egypt, Mexico, and the Philippines confirm increases in the use of ORT which are concomitant with marked falls in mortality. In some countries, possible alternative explanations for the observed decline in mortality have been fairly confidently ruled out. Experience with ORT can provide useful guidance for child survival programmes. With adequate political will and financial support, cost-effective interventions other than that of immunization can be successfully delivered by national programmes. Furthermore, there are important lessons for evaluators. The population-based data needed to establish trends in health service delivery, outcomes and impact are not

  5. Widely Used Type 2 Diabetes Drug May Reduce Cancer Death Risk

    MedlinePlus

    ... Used Type 2 Diabetes Drug May Reduce Cancer Death Risk Older women taking metformin saw a boost ... a risk factor for cancer and cancer-related death, and metformin therapy, compared to other diabetes medications, ...

  6. A Century of Australian Natural Disasters and How to Reduce the Toll from Future Events

    NASA Astrophysics Data System (ADS)

    McAneney, J.

    2014-12-01

    This study reviews Australian experience of natural disasters over the last century and considers how to reduce this nation's vulnerability to such events in the future. In line with global experience, the cost of Australian weather-related natural disasters has been increasing, while loss of life has decreased, with extreme heat events responsible for more fatalities than all other natural perils combined, baring epidemics. However when disaster costs arising from historical events are normalised to current day exposure, no long-term trend emerges. Moreover the frequency of these losses shows no sign of increasing since 1950. In other words, the rising cost of natural disasters can be firmly sheeted home to the fact that there are now more of us living in vulnerable places with more to lose. In view of the above, emergency management and government risk management and strategic planning should focus on plausible large event scenarios, whatever their cause. If we wish to reduce disaster losses, land-use planning has to become risk-informed and building codes need to consider potential economic impacts, rather than just life safety. Insurers can play a role by pricing risk correctly and sending clear signals to homeowners (and governments) to stimulate risk-reducing behaviours. The tools to achieve fine-grained risk assessments are increasingly available. The success of the regulated use of the building code in tropical cyclone-prone regions in Australia and the performance of modern seismic building codes in New Zealand, shows what can be achieved when there is a demonstrated need and political will.

  7. Pneumococal Surface Protein A (PspA) Regulates Programmed Death Ligand 1 Expression on Dendritic Cells in a Toll-Like Receptor 2 and Calcium Dependent Manner

    PubMed Central

    Vashishta, Mohit; Khan, Naeem; Mehto, Subhash; Sehgal, Devinder; Natarajan, Krishnamurthy

    2015-01-01

    Pneumonia leads to high mortality in children under the age of five years worldwide, resulting in close to 20 percent of all deaths in this age group. Therefore, investigations into host-pathogen interactions during Streptococcus pneumoniae infection are key in devising strategies towards the development of better vaccines and drugs. To that end, in this study we investigated the role of S. pneumoniae and its surface antigen Pneumococcal surface protein A (PspA) in modulating the expression of co-stimulatory molecule Programmed Death Ligand 1 (PD-L1) expression on dendritic cells (DCs) and the subsequent effects of increased PD-L1 on key defence responses. Our data indicate that stimulation of DCs with PspA increases the surface expression of PD-L1 in a time and dose dependent manner. Characterization of mechanisms involved in PspA induced expression of PD-L1 indicate the involvement of Toll-Like Receptor 2 (TLR2) and calcium homeostasis. While calcium release from intracellular stores positively regulated PD-L1 expression, calcium influx from external milieu negatively regulated PD-L1 expression. Increase in PD-L1 expression, when costimulated with PspA and through TLR2 was higher than when stimulated with PspA or through TLR2. Further, knockdown of TLR2 and the intermediates in the TLR signaling machinery pointed towards the involvement of a MyD88 dependent pathway in PspA induced PD-L1 expression. Incubation of DCs with S. pneumoniae resulted in the up-regulation of PD-L1 expression, while infection with a strain lacking surface PspA failed to do so. Our data also suggests the role of PspA in ROS generation. These results suggest a novel and specific role for PspA in modulating immune responses against S. pneumoniae by regulating PD-L1 expression. PMID:26214513

  8. RIPK1 and RIPK3 Kinases Promote Cell-Death-Independent Inflammation by Toll-like Receptor 4.

    PubMed

    Najjar, Malek; Saleh, Danish; Zelic, Matija; Nogusa, Shoko; Shah, Saumil; Tai, Albert; Finger, Joshua N; Polykratis, Apostolos; Gough, Peter J; Bertin, John; Whalen, Michael J; Pasparakis, Manolis; Balachandran, Siddharth; Kelliher, Michelle; Poltorak, Alexander; Degterev, Alexei

    2016-07-19

    Macrophages are a crucial component of the innate immune system in sensing pathogens and promoting local and systemic inflammation. RIPK1 and RIPK3 are homologous kinases, previously linked to activation of necroptotic death. In this study, we have described roles for these kinases as master regulators of pro-inflammatory gene expression induced by lipopolysaccharide, independent of their well-documented cell death functions. In primary macrophages, this regulation was elicited in the absence of caspase-8 activity, required the adaptor molecule TRIF, and proceeded in a cell autonomous manner. RIPK1 and RIPK3 kinases promoted sustained activation of Erk, cFos, and NF-κB, which were required for inflammatory changes. Utilizing genetic and pharmacologic tools, we showed that RIPK1 and RIPK3 account for acute inflammatory responses induced by lipopolysaccharide in vivo; notably, this regulation did not require exogenous manipulation of caspases. These findings identified a new pharmacologically accessible pathway that may be relevant to inflammatory pathologies. PMID:27396959

  9. Hydrocortisone Reduces Toll-Like Receptor 4 Expression on Peripheral CD14+ Monocytes in Patients Undergoing Percutanoues Coronary Intervention

    PubMed Central

    Bagheri, Bahador; Sohrabi, Bahram; Movassaghpour, Ali Akbar; Mashayekhi, Simin; Garjani, Afagh; Shokri, Mehriar; Pezeshkian, Masoud; Garjani, Alireza

    2014-01-01

    Bacground: Evidence from several lines of investigations suggests that Toll-like receptor 4 (TLR4) is involved in atherosclerosis as a bridge between innate and acquired immunity. Percutaneous coronary intervention (PCI) can trigger inflammation through activation of human TLR4 (hTLR4) on monocytes. Hydrocortisone as an anti-inflammatory and immuno-suppressant agent has multiple mechanisms of action. In this study, we aimed at assessing the effects of hydrocortisone on monocyte expression and activity of hTLR4 in patients underwent PCI. Methods: Blood samples were taken from a total of 71 patients with chronic stable angina who were scheduled for a PCI, before the intervention. Thirty patients received 100 mg hydrocortisone prior to the procedure. Control group was composed of 41 patients underwent PCI without receiving hydrocortisone. Blood collection was repeated 2 and 4 h after PCI. The expression of hTLR4 on the surface of CD14+ monocytes and the serum levels of TNF-α and IL-1β were measured using flowcytometry and Sandwich ELISA. Results: Compared with controls, hydrocortisone significantly reduced monocyte expression of hTLR4 in test group (P<0.01). In addition, it had a significant effect on reduction of serum concentrations of TNF-α and IL-1β in test group in a time-dependent manner (P<0.01). Conclusion: In this study, hydrocortisone was able to reduce the hTLR4/CD14 positive monocytes and its related pro-inflammatory cytokines, thus it can decrease inflammatory responses following PCI. PMID:24518547

  10. Toll-Like Receptor 4 Deficiency Causes Reduced Exploratory Behavior in Mice Under Approach-Avoidance Conflict.

    PubMed

    Li, Chunlu; Yan, Yixiu; Cheng, Jingjing; Xiao, Gang; Gu, Jueqing; Zhang, Luqi; Yuan, Siyu; Wang, Junlu; Shen, Yi; Zhou, Yu-Dong

    2016-04-01

    Abnormal approach-avoidance behavior has been linked to deficits in the mesolimbic dopamine (DA) system of the brain. Recently, increasing evidence has indicated that toll-like receptor 4 (TLR4), an important pattern-recognition receptor in the innate immune system, can be directly activated by substances of abuse, resulting in an increase of the extracellular DA level in the nucleus accumbens. We thus hypothesized that TLR4-dependent signaling might regulate approach-avoidance behavior. To test this hypothesis, we compared the novelty-seeking and social interaction behaviors of TLR4-deficient (TLR4(-/-)) and wild-type (WT) mice in an approach-avoidance conflict situation in which the positive motivation to explore a novel object or interact with an unfamiliar mouse was counteracted by the negative motivation to hide in exposed, large spaces. We found that TLR4(-/-) mice exhibited reduced novelty-seeking and social interaction in the large open spaces. In less stressful test apparatuses similar in size to the mouse cage, however, TLR4(-/-) mice performed normally in both novelty-seeking and social interaction tests. The reduced exploratory behaviors under approach-avoidance conflict were not due to a high anxiety level or an enhanced fear response in the TLR4(-/-) mice, as these mice showed normal anxiety and fear responses in the open field and passive avoidance tests, respectively. Importantly, the novelty-seeking behavior in the large open field induced a higher level of c-Fos activation in the nucleus accumbens shell (NAcSh) in TLR4(-/-) mice than in WT mice. Partially inactivating the NAcSh via infusion of GABA receptor agonists restored the novelty-seeking behavior of TLR4(-/-) mice. These data suggested that TLR4 is crucial for positive motivational behavior under approach-avoidance conflict. TLR4-dependent activation of neurons in the NAcSh may contribute to this phenomenon. PMID:26898297

  11. Sudden Unexpected Infant Death and Sudden Infant Death Syndrome: Reducing the Risk

    MedlinePlus

    ... organizations offer support: CJ Foundation for SIDS First Candle Sudden Unexplained Death In Childhood Foundation (SUDC) The ... and Caregivers Healthy Children Safe to Sleep First Candle CJ Foundation for SIDS Cribs for Kids Safe ...

  12. Progress in reducing road-related deaths and injuries in Irish children.

    PubMed

    Donnelly, J; Bimpeh, Y; Trace, F; Waters, A; Nicholson, A J

    2012-04-01

    The aim was to study road-related injuries and fatalities in under 15 year olds in two time periods (1996-2000 and 2004-2008 inclusive) to assess whether progress has been made via cross-sectoral efforts to reduce this injury toll in Ireland. For pedestrian and car-related accidents, police assistance is required and at the time a detailed CT 68 form is completed by the attending officer and sent to the Road Safety Authority for analysis. Details re the severity of injury, light and road conditions and safety measures such as seat belt or car restraint use, seat position and helmet use if a cyclist were recorded. Injuries were sub-classified as fatalities, serious (detained in hospital, fractures, severe head injury, severe internal injuries or shock requiring treatment) or minor. All data for the two time periods was entered onto an SPSS database. A concerted national campaign re road safety media campaign allied to random breath testing, penalty points for driving offences, on the spot fines for speeding and far greater police enforcement took place between the two time frames and continues to this day. When looked at as most likely estimates of death ratios the results were found to be statistically significant with an overall p value of < 0.0001 CI [0.39, 0.69]. When broken down into specific age ranges all were significant apart from the 0-3 age range with a p value of 0.69 CI [0.26, 1.1]. The most significant changes were found in the 7-9 years, 10-12 and 13-15 year age ranges with p values of < 0.0001, 0.0002 and 0.0007 respectively. When results were compared between the two cohorts, car occupant fatalities between both groups dropped by 36%. Pedestrian injuries dropped from 1719 to 1232, pedestrian fatalities decreased by almost 50% as did serious pedestrian injuries from 261 down to 129. Cyclist fatalities saw the most significant fall (76%) with a dramatic reduction in cyclist injuries from 25 down to 6 (63%). The 13-15 year old age group had the highest

  13. Colonoscopy Reduces Risk of Death from Colorectal Cancer in High-Risk Patients

    Cancer.gov

    Long-term results from the National Polyp Study confirm that removing precancerous adenomas not only reduces the risk of colorectal cancer but also reduces the number of deaths from the disease by more than half.

  14. Toll-like receptor ligands sensitize B-cell receptor signalling by reducing actin-dependent spatial confinement of the receptor

    PubMed Central

    Freeman, Spencer A.; Jaumouillé, Valentin; Choi, Kate; Hsu, Brian E.; Wong, Harikesh S.; Abraham, Libin; Graves, Marcia L.; Coombs, Daniel; Roskelley, Calvin D.; Das, Raibatak; Grinstein, Sergio; Gold, Michael R.

    2015-01-01

    Integrating signals from multiple receptors allows cells to interpret the physiological context in which a signal is received. Here we describe a mechanism for receptor crosstalk in which receptor-induced increases in actin dynamics lower the threshold for signalling by another receptor. We show that the Toll-like receptor ligands lipopolysaccharide and CpG DNA, which are conserved microbial molecules, enhance signalling by the B-cell antigen receptor (BCR) by activating the actin-severing protein cofilin. Single-particle tracking reveals that increased severing of actin filaments reduces the spatial confinement of the BCR within the plasma membrane and increases BCR mobility. This allows more frequent collisions between BCRs and greater signalling in response to low densities of membrane-bound antigen. These findings implicate actin dynamics as a means of tuning receptor signalling and as a mechanism by which B cells distinguish inert antigens from those that are accompanied by indicators of microbial infection. PMID:25644899

  15. Stable Toll-Like Receptor 10 Knockdown in THP-1 Cells Reduces TLR-Ligand-Induced Proinflammatory Cytokine Expression.

    PubMed

    Le, Hai Van; Kim, Jae Young

    2016-01-01

    Toll-like receptor 10 (TLR10) is the only orphan receptor whose natural ligand and function are unknown among the 10 human TLRs. In this study, to test whether TLR10 recognizes some known TLR ligands, we established a stable TLR10 knockdown human monocytic cell line THP-1 using TLR10 short hairpin RNA lentiviral particle and puromycin selection. Among 60 TLR10 knockdown clones that were derived from each single transduced cell, six clones were randomly selected, and then one of those clones, named E7, was chosen for the functional study. E7 exhibited approximately 50% inhibition of TLR10 mRNA and protein expression. Of all the TLRs, only the expression of TLR10 changed significantly in this cell line. Additionally, phorbol 12-myristate 13-acetate-induced macrophage differentiation of TLR10 knockdown cells was not affected in the knockdown cells. When exposed to TLR ligands, such as synthetic diacylated lipoprotein (FSL-1), lipopolysaccharide (LPS), and flagellin, significant induction of proinflammatory cytokine gene expression including Interleukin-8 (IL-8), Interleukin-1 beta (IL-1β), Tumor necrosis factor-alpha (TNF-α) and Chemokine (C-C Motif) Ligand 20 (CCL20) expression, was found in the control THP-1 cells, whereas the TLR10 knockdown cells exhibited a significant reduction in the expression of IL-8, IL-1β, and CCL20. TNF-α was the only cytokine for which the expression did not decrease in the TLR10 knockdown cells from that measured in the control cells. Analysis of putative binding sites for transcription factors using a binding-site-prediction program revealed that the TNF-α promoter does not have putative binding sites for AP-1 or c-Jun, comprising a major transcription factor along with NF-κB for TLR signaling. Our results suggest that TLR10 is involved in the recognition of FSL-1, LPS, and flagellin and TLR-ligand-induced expression of TNF-α does not depend on TLR10. PMID:27258267

  16. Stable Toll-Like Receptor 10 Knockdown in THP-1 Cells Reduces TLR-Ligand-Induced Proinflammatory Cytokine Expression

    PubMed Central

    Le, Hai Van; Kim, Jae Young

    2016-01-01

    Toll-like receptor 10 (TLR10) is the only orphan receptor whose natural ligand and function are unknown among the 10 human TLRs. In this study, to test whether TLR10 recognizes some known TLR ligands, we established a stable TLR10 knockdown human monocytic cell line THP-1 using TLR10 short hairpin RNA lentiviral particle and puromycin selection. Among 60 TLR10 knockdown clones that were derived from each single transduced cell, six clones were randomly selected, and then one of those clones, named E7, was chosen for the functional study. E7 exhibited approximately 50% inhibition of TLR10 mRNA and protein expression. Of all the TLRs, only the expression of TLR10 changed significantly in this cell line. Additionally, phorbol 12-myristate 13-acetate-induced macrophage differentiation of TLR10 knockdown cells was not affected in the knockdown cells. When exposed to TLR ligands, such as synthetic diacylated lipoprotein (FSL-1), lipopolysaccharide (LPS), and flagellin, significant induction of proinflammatory cytokine gene expression including Interleukin-8 (IL-8), Interleukin-1 beta (IL-1β), Tumor necrosis factor-alpha (TNF-α) and Chemokine (C–C Motif) Ligand 20 (CCL20) expression, was found in the control THP-1 cells, whereas the TLR10 knockdown cells exhibited a significant reduction in the expression of IL-8, IL-1β, and CCL20. TNF-α was the only cytokine for which the expression did not decrease in the TLR10 knockdown cells from that measured in the control cells. Analysis of putative binding sites for transcription factors using a binding-site-prediction program revealed that the TNF-α promoter does not have putative binding sites for AP-1 or c-Jun, comprising a major transcription factor along with NF-κB for TLR signaling. Our results suggest that TLR10 is involved in the recognition of FSL-1, LPS, and flagellin and TLR-ligand-induced expression of TNF-α does not depend on TLR10. PMID:27258267

  17. In ovo delivery of Toll-like receptor 2 ligand, lipoteichoic acid induces pro-inflammatory mediators reducing post-hatch infectious laryngotracheitis virus infection.

    PubMed

    Thapa, S; Nagy, E; Abdul-Careem, M F

    2015-04-15

    Toll-like receptor (TLR) ligands are pathogen associated molecular patterns (PAMPs) recognized by the TLRs resulting in induction of host innate immune responses. One of the PAMPs that binds to TLR2 and cluster of differentiation (CD) 14 is lipotechoic acid (LTA), which activates downstream signals culminating in the release of pro-inflammatory cytokines. In this study, we investigated whether in ovo LTA delivery leads to the induction of antiviral responses against post-hatch infectious laryngotracheitis virus (ILTV) infection. We first delivered the LTA into embryo day (ED)18 eggs via in ovo route so that the compound is available at the respiratory mucosa. Then the LTA treated and control ED18 eggs were allowed to hatch and the hatched chicken was infected with ILTV intratracheally on the day of hatch. We found that in ovo delivered LTA reduces ILTV infection post-hatch. We also found that in ovo delivery of LTA significantly increases mRNA expression of pro-inflammatory mediators in pre-hatch embryo lungs as well as mononuclear cell infiltration, predominantly macrophages, in lung of post-hatch chickens. Altogether, the data suggest that in ovo delivered LTA could be used to reduce ILTV infection in newly hatched chickens. PMID:25764942

  18. Limiting Cumulative HIV Viremia Copy-Years by Early Treatment Reduces Risk of AIDS and Death

    PubMed Central

    Walker, A. Sarah; Suthar, Amitabh B.; Sabin, Caroline; Bucher, Heiner C.; Jarrin, Inma; Moreno, Santiago; Perez-Hoyos, Santiago; Porter, Kholoud; Ford, Deborah

    2016-01-01

    Background: Viremia copy-years (VCY), a time-updated measure of cumulative HIV exposure, predicts AIDS/death; although its utility in deciding when to start combination antiretroviral therapy (cART) remains unclear. We aimed to assess the impact of initiating versus deferring cART on risk of AIDS/death by levels of VCY both independent of and within CD4 cell count strata ≥500 cells per cubic millimeter. Methods: Using Concerted Action on Seroconversion to AIDS and Death in Europe (CASCADE) data, we created a series of nested “trials” corresponding to consecutive months for individuals ≥16 years at seroconversion after 1995 who were cART-naive and AIDS-free. Pooling across all trials, time to AIDS/death by CD4, and VCY strata was compared in those initiating vs. deferring cART using Cox models adjusted for: country, sex, risk group, seroconversion year, age, time since last HIV-RNA, and current CD4, VCY, HIV-RNA, and mean number of previous CD4/HIV-RNA measurements/year. Results: Of 9353 individuals, 5312 (57%) initiated cART and 486 (5%) acquired AIDS/died. Pooling CD4 strata, risk of AIDS/death associated with initiating vs. deferring cART reduced as VCY increased. In patients with high CD4 cell counts, ≥500 cells per cubic millimeter, there was a trend for a greater reduction for those initiating vs. deferring with increasing VCY (P = 0.09), with the largest benefit in the VCY ≥100,000 copy-years/mL group [hazard ratio (95% CI) = 0.41 (0.19 to 0.87)]. Conclusions: For individuals with CD4 ≥500 cells per cubic millimeter, limiting the cumulative HIV burden to <100,000 copy-years/mL through cART may reduce the risk of AIDS/death. PMID:27116045

  19. Induced superficial chondrocyte death reduces catabolic cartilage damage in murine posttraumatic osteoarthritis.

    PubMed

    Zhang, Minjie; Mani, Sriniwasan B; He, Yao; Hall, Amber M; Xu, Lin; Li, Yefu; Zurakowski, David; Jay, Gregory D; Warman, Matthew L

    2016-08-01

    Joints that have degenerated as a result of aging or injury contain dead chondrocytes and damaged cartilage. Some studies have suggested that chondrocyte death precedes cartilage damage, but how the loss of chondrocytes affects cartilage integrity is not clear. In this study, we examined whether chondrocyte death undermines cartilage integrity in aging and injury using a rapid 3D confocal cartilage imaging technique coupled with standard histology. We induced autonomous expression of diphtheria toxin to kill articular surface chondrocytes in mice and determined that chondrocyte death did not lead to cartilage damage. Moreover, cartilage damage after surgical destabilization of the medial meniscus of the knee was increased in mice with intact chondrocytes compared with animals whose chondrocytes had been killed, suggesting that chondrocyte death does not drive cartilage damage in response to injury. These data imply that chondrocyte catabolism, not death, contributes to articular cartilage damage following injury. Therefore, therapies targeted at reducing the catabolic phenotype may protect against degenerative joint disease. PMID:27427985

  20. A minocycline derivative reduces nerve injury-induced allodynia, LPS-induced prostaglandin E2 microglial production and signaling via toll-like receptors 2 and 4

    PubMed Central

    Bastos, Leandro F. S.; Godin, Adriana M.; Zhang, Yingning; Jarussophon, Suwatchai; Ferreira, Bruno C. S.; Machado, Renes R.; Maier, Steven F.; Konishi, Yasuo; de Freitas, Rossimiriam P.; Fiebich, Bernd L.; Watkins, Linda R.; Coelho, Márcio M.; Moraes, Márcio F. D.

    2013-01-01

    Many studies have shown that minocycline, an antibacterial tetracycline, suppresses experimental pain. While minocycline’s positive effects on pain resolution suggest that clinical use of such drugs may prove beneficial, minocycline’s antibiotic actions and divalent cation (Ca2+; Mg2+) chelating effects detract from its potential utility. Thus, we tested the antiallodynic effect induced by a non-antibacterial, non-chelating minocycline derivative in a model of neuropathic pain and performed an initial investigation of its anti-inflammatory effects in vitro. Intraperitoneal minocycline (100 mg/kg) and 12S-hydroxy-1,12-pyrazolinominocycline (PMIN; 23.75, 47.50 or 95.00 mg/kg) reduce the mechanical allodynia induced by chronic constriction injury of mouse sciatic nerve. PMIN reduces the LPS-induced production of PGE2 by primary microglial cell cultures. Human embryonic kidney cells were transfected to express human toll-like receptors 2 and 4, and the signaling via both receptors stimulated with PAM3CSK4 or LPS (respectively) was affected either by minocycline or PMIN. Importantly, these treatments did not affect the cell viability, as assessed by MTT test. Altogether, these results reinforce the evidence that the anti-inflammatory and experimental pain suppressive effects induced by tetracyclines are neither necessarily linked to antibacterial nor to Ca2+ chelating activities. This study supports the evaluation of the potential usefulness of PMIN in the management of neuropathic pain, as its lack of antibacterial and Ca2+ chelating activities might confer greater safety over conventional tetracyclines. PMID:23523650

  1. A minocycline derivative reduces nerve injury-induced allodynia, LPS-induced prostaglandin E2 microglial production and signaling via toll-like receptors 2 and 4.

    PubMed

    Bastos, Leandro F S; Godin, Adriana M; Zhang, Yingning; Jarussophon, Suwatchai; Ferreira, Bruno C S; Machado, Renes R; Maier, Steven F; Konishi, Yasuo; de Freitas, Rossimiriam P; Fiebich, Bernd L; Watkins, Linda R; Coelho, Márcio M; Moraes, Márcio F D

    2013-05-24

    Many studies have shown that minocycline, an antibacterial tetracycline, suppresses experimental pain. While minocycline's positive effects on pain resolution suggest that clinical use of such drugs may prove beneficial, minocycline's antibiotic actions and divalent cation (Ca(2+); Mg(2+)) chelating effects detract from its potential utility. Thus, we tested the antiallodynic effect induced by a non-antibacterial, non-chelating minocycline derivative in a model of neuropathic pain and performed an initial investigation of its anti-inflammatory effects in vitro. Intraperitoneal minocycline (100mg/kg) and 12S-hydroxy-1,12-pyrazolinominocycline (PMIN; 23.75 mg/kg, 47.50mg/kg or 95.00 mg/kg) reduce the mechanical allodynia induced by chronic constriction injury of mouse sciatic nerve. PMIN reduces the LPS-induced production of PGE2 by primary microglial cell cultures. Human embryonic kidney cells were transfected to express human toll-like receptors 2 and 4, and the signaling via both receptors stimulated with PAM3CSK4 or LPS (respectively) was affected either by minocycline or PMIN. Importantly, these treatments did not affect the cell viability, as assessed by MTT test. Altogether, these results reinforce the evidence that the anti-inflammatory and experimental pain suppressive effects induced by tetracyclines are neither necessarily linked to antibacterial nor to Ca(2+) chelating activities. This study supports the evaluation of the potential usefulness of PMIN in the management of neuropathic pain, as its lack of antibacterial and Ca(2+) chelating activities might confer greater safety over conventional tetracyclines. PMID:23523650

  2. Extracellular mtDNA activates NF-κB via toll-like receptor 9 and induces cell death in cardiomyocytes.

    PubMed

    Bliksøen, Marte; Mariero, Lars Henrik; Torp, May Kristin; Baysa, Anton; Ytrehus, Kirsti; Haugen, Fred; Seljeflot, Ingebjørg; Vaage, Jarle; Valen, Guro; Stensløkken, Kåre-Olav

    2016-07-01

    Acute myocardial infarction (AMI) causes sterile inflammation, which exacerbates tissue injury. Elevated levels of circulating mitochondrial DNA (mtDNA) have been associated with AMI. We hypothesized that mtDNA triggers an innate immune response via TLR9 and NF-κB activation, causing cardiomyocyte injury. Murine cardiomyocytes express TLR9 mRNA and protein and were able to internalize fluorescently labeled mouse mtDNA. Incubation of human embryonic kidney cells with serum from AMI patients containing naturally elevated levels of mtDNA induced TLR9-dependent NF-κB activity. This effect was mimicked by isolated mtDNA. mtDNA activated NF-κB in reporter mice both in vivo and in isolated cardiomyocytes. Moreover, incubation of isolated cardiomyocytes with mtDNA induced cell death after 4 and 24 h. Laser confocal microscopy showed that incubation of cardiomyocytes with mtDNA accelerated mitochondrial depolarization induced by reactive oxygen species. In contrast to mtDNA, isolated total DNA did not activate NF-κB nor induce cell death. In conclusion, mtDNA can induce TLR9-dependent NF-κB activation in reporter cells and activate NF-κB in cardiomyocytes. In cardiomyocytes, mtDNA causes mitochondrial dysfunction and death. Endogenous mtDNA in the extracellular space is a danger signal with direct detrimental effects on cardiomyocytes. PMID:27164906

  3. Inhibition of microglial activity alters spinal wide dynamic range neuron discharge and reduces microglial Toll-like receptor 4 expression in neuropathic rats.

    PubMed

    Nazemi, Samad; Manaheji, Homa; Noorbakhsh, Syyed Mohammad; Zaringhalam, Jalal; Sadeghi, Mehdi; Mohammad-Zadeh, Mohammad; Haghparast, Abbas

    2015-07-01

    It is believed that neuropathic pain results from aberrant neuronal discharges although some evidence suggests that the activation of glia cells contributes to pain after an injury to the nervous system. This study aimed to evaluate the role of microglial activation on the hyper-responsiveness of wide dynamic range neurons (WDR) and Toll-like receptor 4 (TLR4) expressions in a chronic constriction injury (CCI) model of neuropathic pain in rats. Adult male Wistar rats (230 ± 30 g) underwent surgery for induction of CCI neuropathy. Six days after surgery, administration of minocycline (10, 20, and 40 mg/kg, i.p.) was initiated and continued until day 14. After administration of the last dose of minocycline or saline, a behavioral test was conducted, then animals were sacrificed and lumbar segments of the spinal cord were collected for Western blot analysis of TLR4 expression. The electrophysiological properties of WDR neurons were investigated by single unit recordings in separate groups. The findings showed that after CCI, in parallel with thermal hyperalgesia, the expression of TLR4 in the spinal cord and the evoked response of the WDR neurons to electrical, mechanical, and thermal stimulation significantly increased. Post-injury administration of minocycline effectively decreased thermal hyperalgesia, TLR4 expression, and hyper-responsiveness of WDR neurons in CCI rats. The results of this study indicate that post-injury, repeated administration of minocycline attenuated neuropathic pain by suppressing microglia activation and reducing WDR neuron hyper-responsiveness. This study confirms that post-injury modulation of microglial activity is a new strategy for treating neuropathic pain. PMID:25933029

  4. Elevated CO2 Reduced Floret Death in Wheat Under Warmer Average Temperatures and Terminal Drought

    PubMed Central

    Dias de Oliveira, Eduardo; Palta, Jairo A.; Bramley, Helen; Stefanova, Katia; Siddique, Kadambot H. M.

    2015-01-01

    Elevated CO2 often increases grain yield in wheat by enhancing grain number per ear, which can result from an increase in the potential number of florets or a reduction in the death of developed florets. The hypotheses that elevated CO2 reduces floret death rather than increases floret development, and that grain size in a genotype with more grains per unit area is limited by the rate of grain filling, were tested in a pair of sister lines contrasting in tillering capacity (restricted- vs. free-tillering). The hypotheses were tested under elevated CO2, combined with +3°C above ambient temperature and terminal drought, using specialized field tunnel houses. Elevated CO2 increased net leaf photosynthetic rates and likely the availability of carbon assimilates, which significantly reduced the rates of floret death and increased the potential number of grains at anthesis in both sister lines by an average of 42%. The restricted-tillering line had faster grain-filling rates than the free-tillering line because the free-tillering line had more grains to fill. Furthermore, grain-filling rates were faster under elevated CO2 and +3°C above ambient. Terminal drought reduced grain yield in both lines by 19%. Elevated CO2 alone increased the potential number of grains, but a trade-off in yield components limited grain yield in the free-tillering line. This emphasizes the need for breeding cultivars with a greater potential number of florets, since this was not affected by the predicted future climate variables. PMID:26635837

  5. Efficacy of side air bags in reducing driver deaths in driver-side collisions.

    PubMed

    Braver, Elisa R; Kyrychenko, Sergey Y

    2004-03-15

    Side air bags, a relatively new technology designed to protect the head and/or torso in side-impact collisions, are becoming increasingly common in automobiles. Their efficacy in preventing US driver deaths among cars struck on the near (driver's) side was examined using data from the Fatality Analysis Reporting System and the General Estimates System. Risk ratios for driver death per nearside collision during 1999-2001 were computed for head/torso and torso-only side air bags in cars from model years 1997-2002, relative to cars without side air bags. Confounding was addressed by adjusting nearside risk ratios for front- and rear-impact mortality, which is unaffected by side air bags. Risk ratios were 0.55 (95% confidence interval: 0.43, 0.71) for head/torso air bags and 0.89 (95% confidence interval: 0.79, 1.01) for torso-only air bags. Risk was reduced when cars with head/torso air bags were struck by cars/minivans (significant) or pickup trucks/sport utility vehicles (nonsignificant). Risk was reduced in two-vehicle collisions and among male drivers and drivers aged 16-64 years. Protective effects associated with torso-only air bags were observed in single-vehicle crashes and among male and 16- to 64-year-old drivers. Head/torso side air bags appear to be very effective in reducing nearside driver deaths, whereas torso-only air bags appear less protective. PMID:15003959

  6. β-Blockers Reduce Breast Cancer Recurrence and Breast Cancer Death: A Meta-Analysis.

    PubMed

    Childers, W Kurtis; Hollenbeak, Christopher S; Cheriyath, Pramil

    2015-12-01

    The normal physiologic stress mechanism, mediated by the sympathetic nervous system, causes a release of the neurotransmitters epinephrine and norepinephrine. Preclinical data have demonstrated an effect on tumor progression and metastasis via the sympathetic nervous system mediated primarily through the β-adrenergic receptor (β-AR) pathway. In vitro data have shown an increase in tumor growth, migration, tumor angiogenesis, and metastatic spread in breast cancer through activation of the β-AR. Retrospective cohort studies on the clinical outcomes of β-blockers in breast cancer outcomes showed no clear consensus. The purpose of this study was to perform a systematic review and meta-analysis of the effect of β-blockers on breast cancer outcomes. A systematic review was performed using the Cochrane library and PubMed. Publications between the dates of January 2010 and December 2013 were identified. Available hazard ratios (HRs) were extracted for breast cancer recurrence, breast cancer death, and all-cause mortality and pooled using a random effects meta-analysis. A total of 7 studies contained results for at least 1 of the outcomes of breast cancer recurrence, breast cancer death, or all-cause mortality in breast cancer patients receiving β-blockers. In the 5 studies that contained results for breast cancer recurrence, there was no statistically significant risk reduction (HR, 0.67; 95% confidence interval [CI], 0.39-1.13). Breast cancer death results were contained in 4 studies, which also suggested a significant reduction in risk (HR, 0.50; 95% CI, 0.32-0.80). Among the 4 studies that reported all-cause mortality, there was no significant effect of β-blockers on risk (HR, 1.02; 95% CI, 0.75-1.37). Results of this systematic review and meta-analysis suggest that the use of β-blockers significantly reduced risk of breast cancer death among women with breast cancer. PMID:26516037

  7. Reduced death rates from cyclones in Bangladesh: what more needs to be done?

    PubMed

    Haque, Ubydul; Hashizume, Masahiro; Kolivras, Korine N; Overgaard, Hans J; Das, Bivash; Yamamoto, Taro

    2012-02-01

    Tropical storms, such as cyclones, hurricanes and typhoons, present major threats to coastal communities. Around two million people worldwide have died and millions have been injured over the past two centuries as a result of tropical storms. Bangladesh is especially vulnerable to tropical cyclones, with around 718 000 deaths from them in the past 50 years. However, cyclone-related mortality in Bangladesh has declined by more than 100-fold over the past 40 years, from 500 000 deaths in 1970 to 4234 in 2007. The main factors responsible for these reduced fatalities and injuries are improved defensive measures, including early warning systems, cyclone shelters, evacuation plans, coastal embankments, reforestation schemes and increased awareness and communication. Although warning systems have been improved, evacuation before a cyclone remains a challenge, with major problems caused by illiteracy, lack of awareness and poor communication. Despite the potential risks of climate change and tropical storms, little empirical knowledge exists on how to develop effective strategies to reduce or mitigate the effects of cyclones. This paper summarizes the most recent data and outlines the strategy adopted in Bangladesh. It offers guidance on how similar strategies can be adopted by other countries vulnerable to tropical storms. Further research is needed to enable countries to limit the risks that cyclones present to public health. PMID:22423166

  8. Reduced death rates from cyclones in Bangladesh: what more needs to be done?

    PubMed Central

    Hashizume, Masahiro; Kolivras, Korine N; Overgaard, Hans J; Das, Bivash; Yamamoto, Taro

    2012-01-01

    Abstract Tropical storms, such as cyclones, hurricanes and typhoons, present major threats to coastal communities. Around two million people worldwide have died and millions have been injured over the past two centuries as a result of tropical storms. Bangladesh is especially vulnerable to tropical cyclones, with around 718 000 deaths from them in the past 50 years. However, cyclone-related mortality in Bangladesh has declined by more than 100-fold over the past 40 years, from 500 000 deaths in 1970 to 4234 in 2007. The main factors responsible for these reduced fatalities and injuries are improved defensive measures, including early warning systems, cyclone shelters, evacuation plans, coastal embankments, reforestation schemes and increased awareness and communication. Although warning systems have been improved, evacuation before a cyclone remains a challenge, with major problems caused by illiteracy, lack of awareness and poor communication. Despite the potential risks of climate change and tropical storms, little empirical knowledge exists on how to develop effective strategies to reduce or mitigate the effects of cyclones. This paper summarizes the most recent data and outlines the strategy adopted in Bangladesh. It offers guidance on how similar strategies can be adopted by other countries vulnerable to tropical storms. Further research is needed to enable countries to limit the risks that cyclones present to public health. PMID:22423166

  9. The costs of a suburban paramedic program in reducing deaths due to cardiac arrest.

    PubMed

    Urban, N; Bergner, L; Eisenberg, M S

    1981-04-01

    The marginal costs per averted death of a suburban paramedic program are estimated to be approximately $42,000, when program costs are attributed entirely to cardiac arrest cases due to underlying heart disease, and indirect costs attributable to episode-related hospitalization are included, It is suggested that at $42,000 per cardiac arrest death averted the program is cost-beneficial by two criteria. First, it compares favorably with an estimate obtained from the literature of the value to the average individual of saving the life of a myocardial infarction patient. Second, the people of King County passed a cost-commensurate Paramedic Program Property Tax Levy in 1979, revealing their willingness to support the program. Results of the study should be generalized in accordance with the facts that in King County 1) the population density averages approximately 1,300 per square mile; 2) a basic emergency medical system ensures a 4-minute average response time to initiation of cardiopulmonary resuscitation; 3) a citizen-training program in cardiopulmonary resuscitation further reduces average time to initiation of basic life support; and 4) the paramedic program is designed to ensure a 10-minute average time to definitive care. PMID:6785539

  10. Improving patient safety to reduce preventable deaths: the case of a California safety net hospital.

    PubMed

    Leach, Linda Searle; Kagawa, Frank; Mayo, Ann; Pugh, Connie

    2012-01-01

    Preventable deaths occur when signs and symptoms of risk and decline are not detected yet are present many hours prior to a deteriorating course. Rapid responses teams (RRTs), also referred to as medical emergency teams (METs) were introduced to improve patient safety by preventing code arrests and death. This research using a case study methodology describes a nurse-led RRT, developed at a large, safety net, teaching hospital in California. Safety-net hospitals are challenged to deliver care and meet the complex needs of vulnerable patient populations. This hospital is a mission driven organization that is focused on the patient and the needs of underserved populations. To respond to the call for reform for patient safety and reduce adverse events, the organization adopted RRTs, early recognition rounds by RRT registered nurses (RNs) and the use of trigger alerts by nursing assistants (NAs) to expand the surveillance and identification of patients most at risk of clinical deterioration. Collaboration with interns and residents (house staff) facilitated their involvement and response to RRT calls. Using quality data from 2005 to 2010, findings from this patient safety innovation address RRT utilization, frequency of non-ICU code arrests, hospital mortality, and post-arrest survival outcomes. PMID:23552203

  11. Teaching Child Care Providers to Reduce the Risk of SIDS (Sudden Infant Death Syndrome)

    ERIC Educational Resources Information Center

    Byington, Teresa; Martin, Sally; Reilly, Jackie; Weigel, Dan

    2011-01-01

    Keeping children safe and healthy is one of the main concerns of parents and child care providers. SIDS (Sudden Infant Death Syndrome) is the leading cause of death in infants 1 month to 12 months of age. Over 2,000 infants die from SIDS every year in the United States, and almost 15% of these deaths occur in child care settings. A targeted…

  12. Management Strategies Aiming to Improve Horse Welfare Reduce Embryonic Death Rates in Mares.

    PubMed

    Malschitzky, E; Pimentel, A M; Garbade, P; Jobim, Mim; Gregory, R M; Mattos, R C

    2015-08-01

    The objective of this retrospective study was to evaluate the effect of management strategies aiming to improve animal well-being on pregnancy and embryonic death (ED) rates. Breeding records of a cohort of 1206 Thoroughbred mares brought to a stallion station facility, to be bred with the stallions housed there, were evaluated during ten breeding seasons. Mares were blocked according to management strategies in two groups: Stress and Relax. Strategies used to improve animal well-being (Relax group) were as follows: stopping the teasing routine, reducing or eliminating stall confinement, reducing the number of mares per group and maintaining herd stability during the breeding season. In barren mares, the pregnancy rate was higher in the Relax group (91.8%) when compared to the observed in Stress group (84.7%). However, no difference in pregnancy rates were observed (Stress = 85.2% vs. Relax = 86.2) in foaling mares. ED rate was higher in barren and foaling mares of the Stress group mares (25.5% and 26.8%, respectively) compared with the Relax group (16.1% and 14.7%, respectively). No significant differences were observed on foal heat pregnancy rate between groups; yet, the embryo loss on foal heat was significant reduced in Relax mares (Relax = 8.7% vs Stress = 24.5%). In conclusion, management strategies aimed to reduce social stress can reduce early pregnancy losses and the average cycles per pregnancy, improving reproductive performance in mares. PMID:25981406

  13. Sigma-1 receptor deficiency reduces MPTP-induced parkinsonism and death of dopaminergic neurons

    PubMed Central

    Hong, J; Sha, S; Zhou, L; Wang, C; Yin, J; Chen, L

    2015-01-01

    Sigma-1 receptor (σ1R) has been reported to be decreased in nigrostriatal motor system of Parkinson's disease patients. Using heterozygous and homozygous σ1R knockout (σ1R+/− and σ1R−/−) mice, we investigated the influence of σ1R deficiency on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-impaired nigrostriatal motor system. The injection of MPTP for 5 weeks in wild-type mice (MPTP-WT mice), but not in σ1R+/− or σ1R−/− mice (MPTP-σ1R+/− or MPTP-σ1R−/− mice), caused motor deficits and ~40% death of dopaminergic neurons in substantia nigra pars compacta with an elevation of N-methyl-d-aspartate receptor (NMDAr) NR2B phosphorylation. The σ1R antagonist NE100 or the NR2B inhibitor Ro25-6981 could alleviate the motor deficits and the death of dopaminergic neurons in MPTP-WT mice. By contrast, MPTP-σ1R+/− mice treated with the σ1R agonist PRE084 or MPTP-σ1R−/− mice treated with the NMDAr agonist NMDA appeared to have similar motor deficits and loss of dopaminergic neurons as MPTP-WT mice. The pharmacological or genetic inactivation of σ1R suppressed the expression of dopamine transporter (DAT) in substantia nigra, which was corrected by NMDA. The activation of σ1R by PRE084 enhanced the DAT expression in WT mice or σ1R+/− mice. By contrast, the level of vesicular monoamine transporter 2 (VMAT2) in σ1R+/− mice or σ1R−/− mice had no difference from WT mice. Interestingly, MPTP-WT mice showed the reduction in the levels of DAT and VMAT2, but MPTP-σ1R−/− mice did not. The inactivation of σ1R by NE100 could prevent the reduction of VMAT2 in MPTP-WT mice. In addition, the activation of microglia cells in substantia nigra was equally enhanced in MPTP-WT mice and MPTP-σ1R−/− mice. The number of activated astrocytes in MPTP-σ1R−/− mice was less than that in MPTP-WT mice. The findings indicate that the σ1R deficiency through suppressing NMDAr function and DAT expression can reduce MPTP-induced death of

  14. Cabergoline, Dopamine D2 Receptor Agonist, Prevents Neuronal Cell Death under Oxidative Stress via Reducing Excitotoxicity

    PubMed Central

    Odaka, Haruki; Numakawa, Tadahiro; Adachi, Naoki; Ooshima, Yoshiko; Nakajima, Shingo; Katanuma, Yusuke; Inoue, Takafumi; Kunugi, Hiroshi

    2014-01-01

    Several lines of evidence demonstrate that oxidative stress is involved in the pathogenesis of neurodegenerative diseases, including Parkinson's disease. Potent antioxidants may therefore be effective in the treatment of such diseases. Cabergoline, a dopamine D2 receptor agonist and antiparkinson drug, has been studied using several cell types including mesencephalic neurons, and is recognized as a potent radical scavenger. Here, we examined whether cabergoline exerts neuroprotective effects against oxidative stress through a receptor-mediated mechanism in cultured cortical neurons. We found that neuronal death induced by H2O2 exposure was inhibited by pretreatment with cabergoline, while this protective effect was eliminated in the presence of a dopamine D2 receptor inhibitor, spiperone. Activation of ERK1/2 by H2O2 was suppressed by cabergoline, and an ERK signaling pathway inhibitor, U0126, similarly protected cortical neurons from cell death. This suggested the ERK signaling pathway has a critical role in cabergoline-mediated neuroprotection. Furthermore, increased extracellular levels of glutamate induced by H2O2, which might contribute to ERK activation, were reduced by cabergoline, while inhibitors for NMDA receptor or L-type Ca2+ channel demonstrated a survival effect against H2O2. Interestingly, we found that cabergoline increased expression levels of glutamate transporters such as EAAC1. Taken together, these results suggest that cabergoline has a protective effect on cortical neurons via a receptor-mediated mechanism including repression of ERK1/2 activation and extracellular glutamate accumulation induced by H2O2. PMID:24914776

  15. Adalimumab Reduces Photoreceptor Cell Death in A Mouse Model of Retinal Degeneration

    PubMed Central

    Martínez-Fernández de la Cámara, Cristina; Hernández-Pinto, Alberto M.; Olivares-González, Lorena; Cuevas-Martín, Carmen; Sánchez-Aragó, María; Hervás, David; Salom, David; Cuezva, José M.; de la Rosa, Enrique J.; Millán, José M; Rodrigo, Regina

    2015-01-01

    Growing evidence suggests that inflammation is involved in the progression of retinitis pigmentosa (RP) both in patients and in animal models. The aim of this study was to investigate the effect of Adalimumab, a monoclonal anti-TNFα antibody, on retinal degeneration in a murine model of human autosomal recessive RP, the rd10 mice at postnatal day (P) 18. In our housing conditions, rd10 retinas were seriously damaged at P18. Adalimumab reduced photoreceptor cell death, as determined by scoring the number of TUNEL-positive cells. In addition, nuclear poly (ADP) ribose (PAR) content, an indirect measure of PAR polymerase (PARP) activity, was also reduced after treatment. The blockade of TNFα ameliorated reactive gliosis, as visualized by decreased GFAP and IBA1 immunolabelling (Müller cell and microglial markers, respectively) and decreased up-regulation of TNFα gene expression. Adalimumab also improved antioxidant response by restoring total antioxidant capacity and superoxide dismutase activity. Finally, we observed that Adalimumab normalized energetic and metabolic pattern in rd10 mouse retinas. Our study suggests that the TNFα blockade could be a successful therapeutic approach to increase photoreceptor survival during the progression of RP. Further studies are needed to characterize its effect along the progression of the disease. PMID:26170250

  16. Reduced photoreceptor death and improved retinal function during retinal degeneration in mice lacking innate immunity adaptor protein MyD88

    PubMed Central

    Syeda, Sarah; Patel, Amit K.; Lee, Tinthu; Hackam, Abigail S.

    2015-01-01

    The injury inflammatory response mediated by the innate immune system is an important contributor to neurodegeneration in the central nervous system (CNS) and retina. A major branch of the innate immune system is regulated by the Toll-like receptors (TLRs), which are receptors for endogenous damage associated molecules released from injured cells as well as pathogen-derived molecules, and interleukin-1 receptors (IL-1R), which are activated by IL-1α, IL-1β and IL-18 cytokines. TLRs and IL-1R are expressed on immune and non-immune cell types and act as first responders to cell damage, which results in tissue repair, or inflammation and apoptosis. Both TLR and IL-1R require the adaptor protein myeloid differentiation primary response gene 88 (MyD88) for signaling. Although inflammation is implicated in neuronal death in the retina, the role of MyD88-dependent TLR and IL-1R signaling in retinal degeneration is unknown. Therefore, the purpose of this study was to investigate the role of MyD88-mediated signaling in neuronal degeneration in the retinal degeneration 1 (rd1) mouse model, which exhibits a phenotype of rapid photoreceptor death and inflammation. To generate rd1 mice lacking the MyD88 gene, rd1 were bred with MyD88 knockout mice (MyD88-/-) for several generations to produce rd1/MyD88+/+ and rd1/MyD88-/- genotypes. Chemokine mRNA expression levels were analyzed by qRT-PCR, and recruitment of activated microglia was quantified by immunodetection of the IBA-1 protein. Retinal outer nuclear layer cell counts were performed to quantify photoreceptor degeneration, and retinal function was assessed using electroretinograms (ERG). Our results revealed that retinal expression of Ccl2, Ccl4, Ccl7 and Cxcl10 was reduced by 2 to 8-fold in rd1/MyD88-/- mice compared with rd1/MyD88+/+ mice (p<0.05), which coincided with attenuated microglial activation, higher numbers of photoreceptors and higher retina responses to photopic and scotopic stimuli. At later ages, rd1/MyD88

  17. Performance-based regulation: enterprise responsibility for reducing death, injury, and disease caused by consumer products.

    PubMed

    Sugarman, Stephen D

    2009-12-01

    This article offers a bold new idea for confronting the staggering level of death, injury, and disease caused by five consumer products: cigarettes, alcohol, guns, junk food, and motor vehicles. Business leaders try to frame these negative outcomes as "collateral damage" that is someone else's problem. That framing not only is morally objectionable but also overlooks the possibility that, with proper prodding, industry could substantially lessen these public health disasters. I seek to reframe the public perception of who is responsible and propose to deploy a promising approach called "performance-based regulation" to combat the problem. Performance-based regulation would impose on manufacturers a legal obligation to reduce the negative social costs of their products. Rather than involving them in litigation or forcing them to operate differently (as "command-and-control" regimes do), performance-based regulation allows the firms to determine how best to decrease bad public health consequences. Like other public health strategies, performance-based regulation focuses on those who are far more likely than individual consumers to achieve real gains. Analogous to a tax on causing harm that exceeds a threshold level, performance-based regulation seeks to harness private initiative in pursuit of the public good. PMID:20018990

  18. Reduced expression of plasma membrane calcium ATPase 2 and collapsin response mediator protein 1 promotes death of spinal cord neurons.

    PubMed

    Kurnellas, M P; Li, H; Jain, M R; Giraud, S N; Nicot, A B; Ratnayake, A; Heary, R F; Elkabes, S

    2010-09-01

    The mechanisms underlying neuronal pathology and death in the spinal cord (SC) during inflammation remain elusive. We previously showed the important role of plasma membrane calcium ATPases (PMCAs) in the survival of SC neurons, in vitro. We also postulated that a decrease in PMCA2 expression could cause neuronal death during experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. The current studies were undertaken to define the specific contribution of PMCA2 to degeneration of SC neurons, the effectors downstream to PMCA2 mediating neuronal death and the triggers that reduce PMCA2 expression. We report that knockdown of PMCA2 in SC neurons decreases collapsin response mediator protein 1 (CRMP1) levels. This is followed by cell death. Silencing of CRMP1 expression also leads to neuronal loss. Kainic acid reduces both PMCA2 and CRMP1 levels and induces neuronal death. Administration of an alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)/kainate receptor antagonist, at onset or peak of EAE, restores the decreased PMCA2 and CRMP1 levels to control values and ameliorates clinical deficits. Thus, our data link the reduction in PMCA2 expression with perturbations in the expression of CRMP1 and the ensuing death of SC neurons. This represents an additional mechanism underlying AMPA/kainate receptor-mediated excitotoxicity with relevance to neurodegeneration in EAE. PMID:20489728

  19. Safety assessment of the conversion of toll plazas to all-electronic toll collection system.

    PubMed

    Abuzwidah, Muamer; Abdel-Aty, Mohamed

    2015-07-01

    Traditional mainline toll plaza (TMTP) is considered the most high-risk location on the toll roads. Conversion from TMTP or hybrid mainline toll plaza (HMTP) to an all-electronic toll collection (AETC) system has demonstrated measured improvement in traffic operations and environmental issues. However, there is a lack of research that quantifies the safety impacts of these new tolling systems. This study evaluated the safety effectiveness of the conversion from TMTP or HMTP to AETC system. An extensive data collection was conducted that included hundred mainline toll plazas located on more than 750 miles of toll roads in Florida. Various observational before-after studies including the empirical Bayes method were applied. The results indicated that the conversion from the TMTP to an AETC system resulted in an average crash reduction of 76, 75, and 68% for total, fatal-and-injury and property damage only (PDO) crashes, respectively; for rear end and lane change related (LCR) crashes the average reductions were 80 and 74%, respectively. The conversion from HMTP to AETC system enhanced traffic safety by reducing crashes by 24, 28 and 20% of total, fatal-and-injury, and PDO crashes respectively; also, for rear end and LCR crashes, the average reductions were 15 and 22%, respectively. Overall, this paper provided an up-to-date safety impact of using different toll collection systems. The results proved that the AETC system significantly improved traffic safety for all crash categories; and changed toll plazas from the highest risk on Expressways to be similar to regular segments. PMID:25909391

  20. Prophylactic Oophorectomy: Reducing the U.S. Death Rate from Epithelial Ovarian Cancer. A Continuing Debate.

    PubMed

    Piver

    1996-01-01

    If instead of the title "Prophylactic Oophorectomy: Reducing the U.S. Death Rate from Epithelial Ovarian Cancer," the title were "Drug X Reducing the U.S. Death Rate from Epithelial Ovarian Cancer," there would be great media and medical attention worldwide to such a report. Correctly so. Regrettably, there probably is no new Drug X in the foreseeable future that will significantly reduce the death rate from ovarian cancer, be it Taxol®, taxotere, topotecan, gemcitabine, or liposomal doxorubicin-although each may result in significant responses and some prolongation of median survival. Epithelial ovarian cancer is a much more complex disease than anyone envisioned, when it was believed that extensive debulking surgery and the newest cytotoxic chemotherapy would radically reduce the death rate from ovarian cancer in the United States. Over 20 years after the first patient was treated with cisplatin for epithelial ovarian cancer, the annual death rate from ovarian cancer continued to increase. Just in the past decade, the number of women in the United States dying from ovarian cancer has increased 18% (Fig. 1) [1]. Although ovarian cancer is estimated to account for 26,700 cases and 14,800 deaths in 1996, it is a low-prevalence disease in comparison with breast cancer, which in 1996 is estimated to account for 185,700 cases and 44,560 deaths. Inexplicably, similar to breast cancer, the lifetime risk for ovarian cancer in the United States continues to increase. The most recent Surveillance, Epidemiology and End Results (SEER) calculations of lifetime risk for ovarian cancer are that 1 in 55 women will develop ovarian cancer over their lifetime, or 1.8%, up from the 1970 figures of 1 in 70, or 1.4% [2]. The 1.8% baseline lifetime risk for the general population is used to estimate the lifetime risk of known ovarian cancer risk factors (Table 1). Even utilizing what are now believed to be two of the most effective cytotoxic drugs against stage III and IV epithelial

  1. Ovarian Cancer Screening Method Fails to Reduce Deaths from the Disease

    Cancer.gov

    New results from the NCI-sponsored PLCO Cancer Screening Trial show that screening for ovarian cancer with transvaginal ultrasound (TVU) and the CA-125 blood test did not result in fewer deaths from the disease compared with usual care.

  2. Reducing death on the road: the effects of minimum safety standards, publicized crash tests, seat belts, and alcohol.

    PubMed Central

    Robertson, L S

    1996-01-01

    OBJECTIVES. Two phases of attempts to improve passenger car crash worthiness have occurred: minimum safety standards and publicized crash tests. This study evaluated these attempts, as well as changes in seat belt and alcohol use, in terms of their effect on occupant death and fatal crash rates. METHODS. Data on passenger car occupant fatalities and total involvement in fatal crashes, for 1975 through 1991, were obtained from the Fatal Accident Reporting System. Rates per mile were calculated through published sources on vehicle use by vehicle age. Regression estimates of effects of regulation, publicized crash tests, seat belt use and alcohol involvement were obtained. RESULTS. Substantial reductions in fatalities occurred in the vehicle model years from the late 1960s through most of the 1970s, when federal standards were applied. Some additional increments in reduced death rates, attributable to additional improved vehicle crashworthiness, occurred during the period of publicized crash tests. Increased seat belt use and reduced alcohol use also contributed significantly to reduced deaths. CONCLUSIONS. Minimum safety standards, crashworthiness improvements, seat belt use laws, and reduced alcohol use each contributed to a large reduction in passenger car occupant deaths. PMID:8561238

  3. Blocking TWEAK-Fn14 interaction inhibits hematopoietic stem cell transplantation-induced intestinal cell death and reduces GVHD.

    PubMed

    Chopra, Martin; Brandl, Andreas; Siegmund, Daniela; Mottok, Anja; Schäfer, Viktoria; Biehl, Marlene; Kraus, Sabrina; Bäuerlein, Carina A; Ritz, Miriam; Mattenheimer, Katharina; Schwinn, Stefanie; Seher, Axel; Grabinger, Thomas; Einsele, Hermann; Rosenwald, Andreas; Brunner, Thomas; Beilhack, Andreas; Wajant, Harald

    2015-07-23

    Inhibition of the tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducible 14 (Fn14) system reduces intestinal cell death and disease development in several models of colitis. In view of the crucial role of TNF and intestinal cell death in graft-versus-host disease (GVHD) and the ability of TWEAK to enhance TNF-induced cell death, we tested here the therapeutic potential of Fn14 blockade on allogeneic hematopoietic cell transplantation (allo-HCT)-induced intestinal GVHD. An Fn14-specific blocking human immunoglobulin G1 antibody variant with compromised antibody-dependent cellular cytotoxicity (ADCC) activity strongly inhibited the severity of murine allo-HCT-induced GVHD. Treatment of the allo-HCT recipients with this monoclonal antibody reduced cell death of gastrointestinal cells but neither affected organ infiltration by donor T cells nor cytokine production. Fn14 blockade also inhibited intestinal cell death in mice challenged with TNF. This suggests that the protective effect of Fn14 blockade in allo-HCT is based on the protection of intestinal cells from TNF-induced apoptosis and not due to immune suppression. Importantly, Fn14 blockade showed no negative effect on graft-versus-leukemia/lymphoma (GVL) activity. Thus, ADCC-defective Fn14-blocking antibodies are not only possible novel GVL effect-sparing therapeutics for the treatment of GVHD but might also be useful for the treatment of other inflammatory bowel diseases where TNF-induced cell death is of relevance. PMID:26012567

  4. Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures.

    PubMed

    Maroso, Mattia; Balosso, Silvia; Ravizza, Teresa; Liu, Jaron; Aronica, Eleonora; Iyer, Anand M; Rossetti, Carlo; Molteni, Monica; Casalgrandi, Maura; Manfredi, Angelo A; Bianchi, Marco E; Vezzani, Annamaria

    2010-04-01

    Brain inflammation is a major factor in epilepsy, but the impact of specific inflammatory mediators on neuronal excitability is incompletely understood. Using models of acute and chronic seizures in C57BL/6 mice, we discovered a proconvulsant pathway involving high-mobility group box-1 (HMGB1) release from neurons and glia and its interaction with Toll-like receptor 4 (TLR4), a key receptor of innate immunity. Antagonists of HMGB1 and TLR4 retard seizure precipitation and decrease acute and chronic seizure recurrence. TLR4-defective C3H/HeJ mice are resistant to kainate-induced seizures. The proconvulsant effects of HMGB1, like those of interleukin-1beta (IL-1beta), are partly mediated by ifenprodil-sensitive N-methyl-d-aspartate (NMDA) receptors. Increased expression of HMGB1 and TLR4 in human epileptogenic tissue, like that observed in the mouse model of chronic seizures, suggests a role for the HMGB1-TLR4 axis in human epilepsy. Thus, HMGB1-TLR4 signaling may contribute to generating and perpetuating seizures in humans and might be targeted to attain anticonvulsant effects in epilepsies that are currently resistant to drugs. PMID:20348922

  5. Ovarian Cancer Screening Method Fails to Reduce Deaths from the Disease | Division of Cancer Prevention

    Cancer.gov

    New results from the NCI-sponsored Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial show that screening for ovarian cancer with transvaginal ultrasound (TVU) and the CA-125 blood test did not result in fewer deaths from the disease compared with usual care. |

  6. Lung cancer deaths from indoor radon and the cost effectiveness and potential of policies to reduce them

    PubMed Central

    Read, Simon; McGale, Paul; Darby, Sarah

    2009-01-01

    Objective To determine the number of deaths from lung cancer related to radon in the home and to explore the cost effectiveness of alternative policies to control indoor radon and their potential to reduce lung cancer mortality. Design Cost effectiveness analysis. Setting United Kingdom. Data sources Epidemiological data on risks from indoor radon and from smoking, vital statistics on deaths from lung cancer, survey information on effectiveness and costs of radon prevention and remediation. Main outcome measures Estimated number of deaths from lung cancer related to indoor radon, lifetime risks of death from lung cancer before and after various potential interventions to control radon, the cost per quality adjusted life year (QALY) gained from different policies for control of radon, and the potential of those policies to reduce lung cancer mortality. Results The mean radon concentration in UK homes is 21 becquerels per cubic metre (Bq/m3). Each year around 1100 deaths from lung cancer (3.3% of all deaths from lung cancer) are related to radon in the home. Over 85% of these arise from radon concentrations below 100 Bq/m3 and most are caused jointly by radon and active smoking. Current policy requiring basic measures to prevent radon in new homes in selected areas is highly cost effective, and such measures would remain cost effective if extended to the entire UK, with a cost per QALY gained of £11 400 ( €12 200; $16 913). Current policy identifying and remediating existing homes with high radon levels is, however, neither cost effective (cost per QALY gained £36 800) nor effective in reducing lung cancer mortality. Conclusions Policies requiring basic preventive measures against radon in all new homes throughout the UK would be cost effective and could complement existing policies to reduce smoking. Policies involving remedial work on existing homes with high radon levels cannot prevent most radon related deaths, as these are caused by moderate exposure

  7. Toll Gate Metrication Project

    ERIC Educational Resources Information Center

    Izzi, John

    1974-01-01

    The project director of the Toll Gate Metrication Project describes the project as the first structured United States public school educational experiment in implementing change toward the adoption of the International System of Units. He believes the change will simplify, rather than complicate, the educational task. (AG)

  8. Toll Bar on Sea

    ERIC Educational Resources Information Center

    Hunter, Dave

    2008-01-01

    In the summer of 2007 the United Kingdom experienced some of the heaviest rainfall since records began. Toll Bar in South Yorkshire featured prominently in media coverage as the village and the homes surrounding it began to flood. Many people lost everything: their homes, their furniture, their possessions. In an effort to come to terms with what…

  9. Mincle suppresses Toll-like receptor 4 activation.

    PubMed

    Greco, Stephanie H; Mahmood, Syed Kashif; Vahle, Anne-Kristin; Ochi, Atsuo; Batel, Jennifer; Deutsch, Michael; Barilla, Rocky; Seifert, Lena; Pachter, H Leon; Daley, Donnele; Torres-Hernandez, Alejandro; Hundeyin, Mautin; Mani, Vishnu R; Miller, George

    2016-07-01

    Regulation of Toll-like receptor responses is critical for limiting tissue injury and autoimmunity in both sepsis and sterile inflammation. We found that Mincle, a C-type lectin receptor, regulates proinflammatory Toll-like receptor 4 signaling. Specifically, Mincle ligation diminishes Toll-like receptor 4-mediated inflammation, whereas Mincle deletion or knockdown results in marked hyperresponsiveness to lipopolysaccharide in vitro, as well as overwhelming lipopolysaccharide-mediated inflammation in vivo. Mechanistically, Mincle deletion does not up-regulate Toll-like receptor 4 expression or reduce interleukin 10 production after Toll-like receptor 4 ligation; however, Mincle deletion decreases production of the p38 mitogen-activated protein kinase-dependent inhibitory intermediate suppressor of cytokine signaling 1, A20, and ABIN3 and increases expression of the Toll-like receptor 4 coreceptor CD14. Blockade of CD14 mitigates the increased sensitivity of Mincle(-/-) leukocytes to Toll-like receptor 4 ligation. Collectively, we describe a major role for Mincle in suppressing Toll-like receptor 4 responses and implicate its importance in nonmycobacterial models of inflammation. PMID:26747838

  10. Deletion of a Malaria Invasion Gene Reduces Death and Anemia, in Model Hosts

    PubMed Central

    Gómez, Noé D.; Safeukui, Innocent; Adelani, Aanuoluwa A.; Tewari, Rita; Reddy, Janardan K.; Rao, Sam; Holder, Anthony; Buffet, Pierre; Mohandas, Narla; Haldar, Kasturi

    2011-01-01

    Malaria parasites induce complex cellular and clinical phenotypes, including anemia, cerebral malaria and death in a wide range of mammalian hosts. Host genes and parasite ‘toxins’ have been implicated in malarial disease, but the contribution of parasite genes remains to be fully defined. Here we assess disease in BALB/c mice and Wistar rats infected by the rodent malaria parasite Plasmodium berghei with a gene knock out for merozoite surface protein (MSP) 7. MSP7 is not essential for infection but in P. falciparum, it enhances erythrocyte invasion by 20%. In vivo, as compared to wild type, the P. berghei Δmsp7 mutant is associated with an abrogation of death and a decrease from 3% to 2% in peak, circulating parasitemia. The Δmsp7 mutant is also associated with less anemia and modest increase in the size of follicles in the spleen. Together these data show that deletion of a single parasite invasion ligand modulates blood stage disease, as measured by death and anemia. This work is the first to assess the contribution of a gene present in all plasmodial species in severe disease. PMID:21980474

  11. Resuscitation and Obstetrical Care to Reduce Intrapartum-Related Neonatal Deaths: A MANDATE Study.

    PubMed

    Kamath-Rayne, Beena D; Griffin, Jennifer B; Moran, Katelin; Jones, Bonnie; Downs, Allan; McClure, Elizabeth M; Goldenberg, Robert L; Rouse, Doris; Jobe, Alan H

    2015-08-01

    To evaluate the impact of neonatal resuscitation and basic obstetric care on intrapartum-related neonatal mortality in low and middle-income countries, using the mathematical model, Maternal and Neonatal Directed Assessment of Technology (MANDATE). Using MANDATE, we evaluated the impact of interventions for intrapartum-related events causing birth asphyxia (basic neonatal resuscitation, advanced neonatal care, increasing facility birth, and emergency obstetric care) when implemented in home, clinic, and hospital settings of sub-Saharan African and India for 2008. Total intrapartum-related neonatal mortality (IRNM) was acute neonatal deaths from intrapartum-related events plus late neonatal deaths from ongoing intrapartum-related injury. Introducing basic neonatal resuscitation in all settings had a large impact on decreasing IRNM. Increasing facility births and scaling up emergency obstetric care in clinics and hospitals also had a large impact on decreasing IRNM. Increasing prevalence and utilization of advanced neonatal care in hospital settings had limited impact on IRNM. The greatest improvement in IRNM was seen with widespread advanced neonatal care and basic neonatal resuscitation, scaled-up emergency obstetric care in clinics and hospitals, and increased facility deliveries, resulting in an estimated decrease in IRNM to 2.0 per 1,000 live births in India and 2.5 per 1,000 live births in sub-Saharan Africa. With more deliveries occurring in clinics and hospitals, the scale-up of obstetric care can have a greater effect than if modeled individually. Use of MANDATE enables health leaders to direct resources towards interventions that could prevent intrapartum-related deaths. A lack of widespread implementation of basic neonatal resuscitation, increased facility births, and emergency obstetric care are missed opportunities to save newborn lives. PMID:25656720

  12. Photobiomodulation reduces photoreceptor death and regulates cytoprotection in early states of P23H retinal dystrophy

    NASA Astrophysics Data System (ADS)

    Kirk, Diana K.; Gopalakrishnan, Sandeep; Schmitt, Heather; Abroe, Betsy; Stoehr, Michele; Dubis, Adam; Carroll, Joseph; Stone, Jonathan; Valter, Krisztina; Eells, Janis

    2013-03-01

    Irradiation by light in the far-red to near-infrared (NIR) region of the spectrum (photobiomodulation, PBM) has been demonstrated to attenuate the severity of neurodegenerative disease in experimental and clinical studies. The purpose of this study was to test the hypothesis that 670 nm PBM would protect against the loss of retinal function and improve photoreceptor survival in a rodent model of retinitis pigmentosa, the P23H transgenic rat. P23H rat pups were treated once per day with a 670 nm LED array (180 sec treatments at 50 mW/cm2; fluence 9 joules/cm2) (Quantum Devices Inc., Barneveld WI) from postnatal day (p) 16-20 or from p10-20. Sham-treated rats were restrained, but not exposed to NIR light. The status of the retina was determined at p22 by assessment of mitochondrial function, oxidative stress and cell death. In a second series of studies, retinal status was assessed at p30 by measuring photoreceptor function by ERG and retinal morphology by Spectral Domain Optical Coherence Tomography (SD-OCT). 670 nm PBM increased retinal mitochondrial cytochrome oxidase activity and upregulated the retina's production of the key mitochondrial antioxidant enzyme, MnSOD. PBM also attenuated photoreceptor cell loss and improved photoreceptor function. PBM protects photoreceptors in the developing P23H retina, by augmenting mitochondrial function and stimulating antioxidant protective pathways. Photobiomodulation may have therapeutic potential, where mitochondrial damage is a step in the death of photoreceptors.

  13. Fetal death and reduced birth rates associated with exposure to lead-contaminated drinking water.

    PubMed

    Edwards, Marc

    2014-01-01

    This ecologic study notes that fetal death rates (FDR) during the Washington DC drinking water "lead crisis" (2000-2004) peaked in 2001 when water lead levels (WLLs) were highest, and were minimized in 2004 after public health interventions were implemented to protect pregnant women. Changes in the DC FDR vs neighboring Baltimore City were correlated to DC WLL (R(2) = 0.72). Birth rates in DC also increased versus Baltimore City and versus the United States in 2004-2006, when consumers were protected from high WLLs. The increased births in DC neighborhoods comparing 2004 versus 2001 was correlated to the incidence of lead pipes (R(2) = 0.60). DC birth rates from 1999 to 2007 correlated with proxies for maternal blood lead including the geometric mean blood lead in DC children (R(2) = 0.68) and the incidence of lead poisoning in children under age 1.3 years (R(2) = 0.64). After public health protections were removed in 2006, DC FDR spiked in 2007-2009 versus 2004-2006 (p < 0.05), in a manner consistent with high WLL health risks to consumers arising from partial lead service line replacements, and DC FDR dropped to historically low levels in 2010-2011 after consumers were protected and the PSLR program was terminated. Re-evaluation of a historic construction-related miscarriage cluster in the USA Today Building (1987-1988), demonstrates that high WLLs from disturbed plumbing were a possible cause. Overall results are consistent with prior research linking increased lead exposure to higher incidence of miscarriages and fetal death, even at blood lead elevations (≈5 μg/dL) once considered relatively low. PMID:24321041

  14. Activation of aryl hydrocarbon receptor reduces carbendazim-induced cell death.

    PubMed

    Wei, Kuo-Liang; Chen, Fei-Yun; Lin, Chih-Yi; Gao, Guan-Lun; Kao, Wen-Ya; Yeh, Chi-Hui; Chen, Chang-Rong; Huang, Hao-Chun; Tsai, Wei-Ren; Jong, Koa-Jen; Li, Wan-Jung; Su, Jyan-Gwo Joseph

    2016-09-01

    Carbendazim inhibits microtubule assembly, thus blocking mitosis and inhibiting cancer cell proliferation. Accordingly, carbendazim is being explored as an anticancer drug. Data show that carbendazim increased mRNA and protein expressions and promoter activity of CYP1A1. In addition, carbendazim activated transcriptional activity of the aryl hydrocarbon response element, and induced nuclear translocation of the aryl hydrocarbon receptor (AhR), a sign the AhR is activated. Carbendazim-induced CYP1A1 expression was blocked by AhR antagonists, and was abolished in AhR signal-deficient cells. Results demonstrated that carbendazim activated the AhR, thereby stimulating CYP1A1 expression. In order to understand whether AhR-induced metabolic enzymes turn carbendazim into less-toxic metabolites, Hoechst 33342 staining to reveal carbendazim-induced nuclear changes and flow cytometry to reveal the subG0/G1 population were applied to monitor carbendazim-induced cell apoptosis. Carbendazim induced less apoptosis in Hepa-1c1c7 cells than in AhR signal-deficient Hepa-1c1c7 mutant cells. Pretreatment with β-NF, an AhR agonist that highly induces CYP1A1 expression, decreased carbendazim-induced cell death. In addition, the lower the level of AhR was, the lower the vitality present in carbendazim-treated cells, including hepatoma cells and their derivatives with AhR RNA interference, also embryonic kidney cells, bladder carcinoma cells, and AhR signal-deficient Hepa-1c1c7 cells. In summary, carbendazim is an AhR agonist. The toxicity of carbendazim was lower in cells with the AhR signal. This report provides clues indicating that carbendazim is more potent at inducing cell death in tissues without than in those with the AhR signal, an important reference for applying carbendazim in cancer chemotherapy. PMID:27286660

  15. Substance P reduces apoptotic cell death possibly by modulating the immune response at the early stage after spinal cord injury.

    PubMed

    Jiang, Mei Hua; Lim, Ji Eun; Chi, Guang Fan; Ahn, Woosung; Zhang, Mingzi; Chung, Eunkyung; Son, Youngsook

    2013-10-23

    Previously, we have reported that substance P (SP) enhanced functional recovery from spinal cord injury (SCI) possibly by the anti-inflammatory modulation associated with the induction of M2-type macrophages at the injured lesion. In this study, we explored the cytokine expression profiles and apoptotic cell death in the lesion site of the SCI after an immediate intravenous injection of SP. SP injection increased the levels of interleukin-4 (IL-4), IL-6, and IL-10 at day 1 after the SCI approximately by 2-, 9-, and 10-folds when compared with the control SCI, respectively. On the basis of double immunofluorescence staining with IL-10 and CD11b, activated macrophages or microglia expressing IL-10 appeared in the margin of the lesion site at day 1 only after the SP injection. This SP-mediated alteration in the lesion microenvironment was shown to be associated with the lower cell death of neuronal cells at day 1 and oligodendrocytes at day 5 by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, which was also accompanied by a decrease in caspase-3 activation. These findings suggest that SP may reduce the inflammation-induced secondary cell death, possibly through immune modulation at an early stage after the SCI. PMID:23995292

  16. Para-Phenylenediamine Induces Apoptotic Death of Melanoma Cells and Reduces Melanoma Tumour Growth in Mice.

    PubMed

    Bhowmick, Debajit; Bhar, Kaushik; Mallick, Sanjaya K; Das, Subhadip; Chatterjee, Nabanita; Sarkar, Tuhin Subhra; Chakrabarti, Rajarshi; Das Saha, Krishna; Siddhanta, Anirban

    2016-01-01

    Melanoma is one of the most aggressive forms of cancer, usually resistant to standard chemotherapeutics. Despite a huge number of clinical trials, any success to find a chemotherapeutic agent that can effectively destroy melanoma is yet to be achieved. Para-phenylenediamine (p-PD) in the hair dyes is reported to purely serve as an external dyeing agent. Very little is known about whether p-PD has any effect on the melanin producing cells. We have demonstrated p-PD mediated apoptotic death of both human and mouse melanoma cells in vitro. Mouse melanoma tumour growth was also arrested by the apoptotic activity of intraperitoneal administration of p-PD with almost no side effects. This apoptosis is shown to occur primarily via loss of mitochondrial membrane potential (MMP), generation of reactive oxygen species (ROS), and caspase 8 activation. p-PD mediated apoptosis was also confirmed by the increase in sub-G0/G1 cell number. Thus, our experimental observation suggests that p-PD can be a potential less expensive candidate to be developed as a chemotherapeutic agent for melanoma. PMID:27293892

  17. Methoxychlor and fenvalerate induce neuronal death by reducing GluR2 expression.

    PubMed

    Umeda, Kanae; Kotake, Yaichiro; Miyara, Masatsugu; Ishida, Keishi; Sanoh, Seigo; Ohta, Shigeru

    2016-04-01

    GluR2, an α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subunit, plays important roles in neuronal survival. We previously showed that exposure of cultured rat cortical neurons to several chemicals decreases GluR2 protein expression, leading to neuronal toxicity. Methoxychlor, the bis-p-methoxy derivative of dichlorodiphenyltrichloroethane, and fenvalerate, a synthetic pyrethroid chemical, have been used commercially as agricultural pesticides in several countries. In this study, we investigated the effects of long-term methoxychlor and fenvalerate exposure on neuronal glutamate receptors. Treatment of cultured rat cortical neurons with 1 or 10 µM methoxychlor and fenvalerate for 9 days selectively decreased GluR2 protein expression; the expression of other AMPA receptor subunits GluR1, GluR3, and GluR4 did not change under the same conditions. Importantly, the decreases in GluR2 protein expression were also observed on the cell surface membrane where AMPA receptors typically function. In addition, both chemicals decreased neuronal viability, which was blocked by pretreatment with 1-naphtylacetylspermine, an antagonist of GluR2-lacking AMPA receptors, and MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist. These results suggest that long-term exposure to methoxychlor and fenvalerate decreases GluR2 protein expression, leading to neuronal death via overactivation of GluR2-lacking AMPA and NMDA receptors. PMID:26961610

  18. Diva Reduces Cell Death in Response to Oxidative Stress and Cytotoxicity

    PubMed Central

    Liu, Nicole Suyun; Du, Xiaoli; Lu, Jia; He, Bei Ping

    2012-01-01

    Diva is a member of the Bcl2 family but its function in apoptosis remains largely unclear because of its specific expression found within limited adult tissues. Previous overexpression studies done on various cell lines yielded conflicting conclusions pertaining to its apoptotic function. Here, we discovered the expression of endogenous Diva in PC12 neuronal-like cell line and rat bone marrow mesenchymal stem cells (BMSCs), leading to their utilisation for the functional study of Diva. Through usage of recombinant Fas ligand, hydrogen peroxide, overexpression and knock down experiments, we discovered that Diva plays a crucial pro-survival role via the mitochondrial death pathway. In addition, immunoprecipitation studies also noted a decrease in Diva’s interaction with Bcl2 and Bax following apoptosis induced by oxidative stress. By overexpressing Diva in BMSCs, we had observed an increase in the cells’ capacity to survive under oxidative stress and microglial toxicity. The result obtained from our study gives us reason to believe that Diva plays an important role in controlling the survival of BMSCs. Through overexpression of Diva, the viability of these BMSCs may be boosted under adverse conditions. PMID:22905226

  19. Para-Phenylenediamine Induces Apoptotic Death of Melanoma Cells and Reduces Melanoma Tumour Growth in Mice

    PubMed Central

    Bhowmick, Debajit; Bhar, Kaushik; Mallick, Sanjaya K.; Das, Subhadip; Chatterjee, Nabanita; Sarkar, Tuhin Subhra; Chakrabarti, Rajarshi; Das Saha, Krishna; Siddhanta, Anirban

    2016-01-01

    Melanoma is one of the most aggressive forms of cancer, usually resistant to standard chemotherapeutics. Despite a huge number of clinical trials, any success to find a chemotherapeutic agent that can effectively destroy melanoma is yet to be achieved. Para-phenylenediamine (p-PD) in the hair dyes is reported to purely serve as an external dyeing agent. Very little is known about whether p-PD has any effect on the melanin producing cells. We have demonstrated p-PD mediated apoptotic death of both human and mouse melanoma cells in vitro. Mouse melanoma tumour growth was also arrested by the apoptotic activity of intraperitoneal administration of p-PD with almost no side effects. This apoptosis is shown to occur primarily via loss of mitochondrial membrane potential (MMP), generation of reactive oxygen species (ROS), and caspase 8 activation. p-PD mediated apoptosis was also confirmed by the increase in sub-G0/G1 cell number. Thus, our experimental observation suggests that p-PD can be a potential less expensive candidate to be developed as a chemotherapeutic agent for melanoma. PMID:27293892

  20. Meeting the community halfway to reduce maternal deaths? Evidence from a community-based maternal death review in Uttar Pradesh, India

    PubMed Central

    Raj, Sunil Saksena; Maine, Deborah; Sahoo, Pratap Kumar; Manthri, Suneedh; Chauhan, Kavita

    2013-01-01

    ABSTRACT Background: Uttar Pradesh (UP) is the most populous state in India with the second highest reported maternal mortality ratio in the country. In an effort to analyze the reasons for maternal deaths and implement appropriate interventions, the Government of India introduced Maternal Death Review guidelines in 2010. Methods: We assessed causes of and factors leading to maternal deaths in Unnao District, UP, through 2 methods. First, we conducted a facility gap assessment in 15 of the 16 block-level and district health facilities to collect information on the performance of the facilities in terms of treating obstetric complications. Second, teams of trained physicians conducted community-based maternal death reviews (verbal autopsies) in a sample of maternal deaths occurring between June 1, 2009, and May 31, 2010. Results: Of the 248 maternal deaths that would be expected in this district in a year, we identified 153 (62%) through community workers and conducted verbal autopsies with families of 57 of them. Verbal autopsies indicated that 23% and 30% of these maternal deaths occurred at home and on the way to a health facility, respectively. Most of the women who died had been taken to at least 2 health facilities. The facility assessment revealed that only the district hospital met the recommended criteria for either basic or comprehensive emergency obstetric and neonatal care. Conclusions: Life-saving treatment of obstetric complications was not offered at the appropriate level of government facilities in a representative district in UP, and an inadequate referral system provided fatal delays. Expensive transportation costs to get pregnant women to a functioning medical facility also contributed to maternal death. The maternal death review, coupled with the facility gap assessment, is a useful tool to address the adequacy of emergency obstetric and neonatal care services to prevent further maternal deaths. PMID:25276519

  1. A High Soy Diet Reduces Programmed Cell Death and Enhances Bcl-xL Expression In Experimental Stroke

    PubMed Central

    Lovekamp-Swan, Tara; Glendenning, Michele; Schreihofer, Derek A.

    2009-01-01

    Soy phytoestrogens have been proposed as an alternative to estrogen replacement therapy and have demonstrated potential neuroprotective effects in the brain. We have shown that a high soy diet significantly reduces infarct size following permanent middle cerebral artery occlusion (MCAO). Here, we tested the hypothesis that a high soy diet would attenuate programmed cell death after stroke. Adult female Sprague-Dawley rats were ovariectomized and fed either an isoflavone-reduced diet (IFP) or a high soy diet (SP) for 2 weeks before undergoing 90 minutes of transient MCAO (tMCAO) followed by 22.5 hr reperfusion. Infarct size, as assessed by TTC staining, was significantly reduced by a high soy diet (p< 0.05). Apoptosis in the ischemic cortex, measured by TUNEL staining, was significantly reduced by the high soy diet. The number of active caspase-3 positive cells and caspase-mediated α-spectrin cleavage was also significantly decreased in the ischemic cortex of SP rats. Furthermore, nuclear translocation of apoptosis-inducing factor (AIF) was significantly reduced in the ischemic cortex of SP rats. Soy significantly increased bcl-xL mRNA and protein expression in the ischemic cortex compared to IFP rats. Immunohistochemistry revealed increased neuronal expression of bcl-2 and bcl-xL in the ischemic cortex of both IFP and SP rats following tMCAO. These results suggest that a high soy diet decreases both caspase-dependent and caspase-independent programmed cell death following tMCAO. Further, a high soy diet enhances expression of the cell survival factor bcl-xL following tMCAO, contributing to the neuroprotective effects of soy in the ischemic cortex. PMID:17706879

  2. Safe Sleep for My Grandbaby: Reduce the Risk of Sudden Infant Death Syndrome (SIDS)

    MedlinePlus

    For more information on sleep position for babies and reducing the risk of SIDS, contact the Back to Sleep campaign at: Mail: 31 Center Drive, 31/2A32, ... http://www.nichd.nih.gov/SIDS Back to Sleep campaign sponsors include: National Institute of Child Health ...

  3. SIRT1 activating compounds reduce oxidative stress and prevent cell death in neuronal cells

    PubMed Central

    Khan, Reas S.; Fonseca-Kelly, Zoe; Callinan, Catherine; Zuo, Ling; Sachdeva, Mira M.; Shindler, Kenneth S.

    2012-01-01

    Activation of SIRT1, an NAD+-dependent deacetylase, prevents retinal ganglion cell (RGC) loss in optic neuritis, an inflammatory demyelinating optic nerve disease. While SIRT1 deacetylates numerous protein targets, downstream mechanisms of SIRT1 activation mediating this neuroprotective effect are unknown. SIRT1 increases mitochondrial function and reduces oxidative stress in muscle and other cells, and oxidative stress occurs in neuronal degeneration. We examined whether SIRT1 activators reduce oxidative stress and promote mitochondrial function in neuronal cells. Oxidative stress, marked by reactive oxygen species (ROS) accumulation, was induced in RGC-5 cells by serum deprivation, or addition of doxorubicin or hydrogen peroxide, and resulted in significant cell loss. SIRT1 activators resveratrol (RSV) and SRTAW04 reduced ROS levels and promoted cell survival in RGC-5 cells as well as primary RGC cultures. Effects were blocked by SIRT1 siRNA. SIRT1 activators also increased expression of succinate dehydrogenase (SDH), a mitochondrial enzyme, and promoted deacetylation of PGC-1α, a co-enzyme involved in mitochondrial function. Results show SIRT1 activators prevent cell loss by reducing oxidative stress and promoting mitochondrial function in a neuronal cell line. Results suggest SIRT1 activators can mediate neuroprotective effects during optic neuritis by these mechanisms, and they have the potential to preserve neurons in other neurodegenerative diseases that involve oxidative stress. PMID:23293585

  4. Annual Screening with Chest X-Ray Does Not Reduce Lung Cancer Deaths

    Cancer.gov

    Annual screening for lung cancer using a standard chest x-ray does not reduce the risk of dying from lung cancer when compared with no annual screening, according to findings from the NCI-led Prostate, Lung, Colorectal, and Ovarian (PLCO) screening trial.

  5. Inverse Susceptibility to Oxidative Death of Lymphocytes Obtained From Alzheimer's Patients and Skin Cancer Survivors: Increased Apoptosis in Alzheimer's and Reduced Necrosis in Cancer

    PubMed Central

    Silva, Monica; Salech, Felipe; Ponce, Daniela P.; Merino, Daniela; Sinning, Mariana; Xiong, Chengjie; Roe, Catherine M.; Quest, Andrew F. G.

    2012-01-01

    A paucity of cancer in individuals with Alzheimer's disease (AD) and low rates of AD in cancer survivors has been reported in epidemiological studies. Deregulation in opposite directions of biological mechanisms, such as susceptibility to cell death, might be shared in the two disorders. We analyzed lymphocytes from AD and skin cancer patients as well as healthy controls and found significantly increased vulnerability of AD lymphocytes to H2O2-induced apoptotic death and higher resistance to death of skin cancer lymphocytes, due to reduced necrosis, as compared with healthy controls by pairwise comparisons adjusted for age and sex. H2O2-induced death in lymphocytes was caspase independent and significantly reduced by PARP-1 inhibition in all three groups. These differences in the susceptibility to cell death observed for lymphocytes from AD and skin cancer patients may be one of the mechanisms that help explain the inverse correlation detected between these diseases in epidemiological studies. PMID:22367434

  6. Alpha-tubulin enhanced renal tubular cell proliferation and tissue repair but reduced cell death and cell-crystal adhesion.

    PubMed

    Manissorn, Juthatip; Khamchun, Supaporn; Vinaiphat, Arada; Thongboonkerd, Visith

    2016-01-01

    Adhesion of calcium oxalate (CaOx) crystals on renal tubular epithelial cells is a critical event for kidney stone disease that triggers many cascades of cellular response. Our previous expression proteomics study identified several altered proteins in MDCK renal tubular cells induced by CaOx crystals. However, functional significance of those changes had not been investigated. The present study thus aimed to define functional roles of such proteome data. Global protein network analysis using STRING software revealed α-tubulin, which was decreased, as one of central nodes of protein-protein interactions. Overexpression of α-tubulin (pcDNA6.2-TUBA1A) was then performed and its efficacy was confirmed. pcDNA6.2-TUBA1A could maintain levels of α-tubulin and its direct interacting partner, vimentin, after crystal exposure. Also, pcDNA6.2-TUBA1A successfully reduced cell death to almost the basal level and increased cell proliferation after crystal exposure. Additionally, tissue repair capacity was improved in pcDNA6.2-TUBA1A cells. Moreover, cell-crystal adhesion was reduced by pcDNA6.2-TUBA1A. Finally, levels of potential crystal receptors (HSP90, HSP70, and α-enolase) on apical membrane were dramatically reduced to basal levels by pcDNA6.2-TUBA1A. These findings implicate that α-tubulin has protective roles in kidney stone disease by preventing cell death and cell-crystal adhesion, but on the other hand, enhancing cell proliferation and tissue repair function. PMID:27363348

  7. Alpha-tubulin enhanced renal tubular cell proliferation and tissue repair but reduced cell death and cell-crystal adhesion

    PubMed Central

    Manissorn, Juthatip; Khamchun, Supaporn; Vinaiphat, Arada; Thongboonkerd, Visith

    2016-01-01

    Adhesion of calcium oxalate (CaOx) crystals on renal tubular epithelial cells is a critical event for kidney stone disease that triggers many cascades of cellular response. Our previous expression proteomics study identified several altered proteins in MDCK renal tubular cells induced by CaOx crystals. However, functional significance of those changes had not been investigated. The present study thus aimed to define functional roles of such proteome data. Global protein network analysis using STRING software revealed α-tubulin, which was decreased, as one of central nodes of protein-protein interactions. Overexpression of α-tubulin (pcDNA6.2-TUBA1A) was then performed and its efficacy was confirmed. pcDNA6.2-TUBA1A could maintain levels of α-tubulin and its direct interacting partner, vimentin, after crystal exposure. Also, pcDNA6.2-TUBA1A successfully reduced cell death to almost the basal level and increased cell proliferation after crystal exposure. Additionally, tissue repair capacity was improved in pcDNA6.2-TUBA1A cells. Moreover, cell-crystal adhesion was reduced by pcDNA6.2-TUBA1A. Finally, levels of potential crystal receptors (HSP90, HSP70, and α-enolase) on apical membrane were dramatically reduced to basal levels by pcDNA6.2-TUBA1A. These findings implicate that α-tubulin has protective roles in kidney stone disease by preventing cell death and cell-crystal adhesion, but on the other hand, enhancing cell proliferation and tissue repair function. PMID:27363348

  8. Electrocardiographic Screening for Prolonged QT Interval to Reduce Sudden Cardiac Death in Psychiatric Patients: A Cost-Effectiveness Analysis

    PubMed Central

    Blondon, Marc; Gex-Fabry, Marianne; Combescure, Christophe; Shah, Dipen; Schwartz, Peter J.; Besson, Marie; Girardin, François R.

    2015-01-01

    Importance Sudden cardiac death is a leading cause of mortality in psychiatric patients. Long QT (LQT) is common in this population and predisposes to Torsades-de-Pointes (TdP) and subsequent mortality. Objective To estimate the cost-effectiveness of electrocardiographic screening to detect LQT in psychiatric inpatients. Design, Setting, and Participants We built a decision analytic model based on a decision tree to evaluate the cost-effectiveness and utility of LQT screening from a health care perspective. LQT proportion parameters were derived from an in-hospital cross-sectional study. We performed experts' elicitation to estimate the risk of TdP, given extent of QT prolongation. A TdP reduction of 65% after LQT detection was based on positive drug dechallenge rate and through adequate treatment and electrolyte adjustments. The base-case model uncertainty was assessed with one-way and probabilistic sensitivity analyses. Finally, the TdP related mortality and TdP avoidance parameters were varied in a two-way sensitivity analysis to assess their effect on the Incremental Cost-Effectiveness Ratio (ICER). Main Outcomes and Measures Costs, Quality Ajusted Life Year (QALY), ICER, and probability of cost effectiveness thresholds ($ 10 000, $25 000, and $50 000 per QALY). Results In the base-case scenario, the numbers of patients needed to screen were 1128 and 2817 to avoid one TdP and one death, respectively. The ICER of systematic ECG screening was $8644 (95%CI, 3144-82 498) per QALY. The probability of cost-effectiveness was 96% at a willingness-to-pay of $50 000 for one QALY. In sensitivity analyses, results were sensitive to the case-fatality of TdP episodes and to the TdP reduction following the diagnosis of LQT. Conclusion and Relevance In psychiatric hospitals, performing systematic ECG screening at admission help reduce the number of sudden cardiac deaths in a cost-effective fashion. PMID:26070071

  9. Early generation of nitric oxide contributes to copper tolerance through reducing oxidative stress and cell death in hulless barley roots.

    PubMed

    Hu, Yanfeng

    2016-09-01

    The objective of this study was to investigate the specific role of nitric oxide (NO) in the early response of hulless barley roots to copper (Cu) stress. We used the fluorescent probe diaminofluorescein-FM diacetate to establish NO localization, and hydrogen peroxide (H2O2)-special labeling and histochemical procedures for the detection of reactive oxygen species (ROS) in the root apex. An early production of NO was observed in Cu-treated root tips of hulless barley, but the detection of NO levels was decreased by supplementation with a NO scavenger, 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO). Application of sodium nitroprusside (a NO donor) relieved Cu-induced root inhibition, ROS accumulation and oxidative damage, while c-PTIO treatment had a synergistic effect with Cu and further enhanced ROS levels and oxidative stress. In addition, the Cu-dependent increase in activities of superoxide dismutase, peroxidase and ascorbate peroxidase were further enhanced by exogenous NO, but application of c-PTIO decreased the activities of catalase and ascorbate peroxidase in Cu-treated roots. Subsequently, cell death was observed in root tips and was identified as a type of programed cell death (PCD) by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. The addition of NO prevented the increase of cell death in root tips, whereas inhibiting NO accumulation further increased the number of cells undergoing PCD. These results revealed that NO production is an early response of hulless barley roots to Cu stress and that NO contributes to Cu tolerance in hulless barley possibly by modulating antioxidant defense, subsequently reducing oxidative stress and PCD in root tips. PMID:27294966

  10. Beacon of Hope? Lessons Learned from Efforts to Reduce Civilian Deaths from Police Shootings in an Australian State.

    PubMed

    Saligari, Jessica; Evans, Richard

    2016-04-01

    In the 1990s, the police service in Victoria, Australia, faced a crisis of community confidence due to a spate of civilian deaths from police shootings. In that decade, twice as many civilians died at the hands of the police in Victoria than in every other Australian state combined. Most of those killed were mentally ill and affected by drugs and alcohol, and were rarely a serious threat except to themselves. The problem was also almost entirely an urban phenomenon. Shootings in rural communities, where mentally ill people were more likely to be personally known to local police, were (and remain) almost unknown. The large number of fatalities was recognised as a serious threat to public confidence, and Victoria Police introduced a ground-breaking training programme, Operation Beacon. Operating procedures and weapons training were fundamentally changed, to focus on de-escalation of conflict and avoiding or minimising police use of force. In the short term, Operation Beacon was successful. Shooting incidents were dramatically reduced. However, during the first decade of the new century, the number of civilians being killed again increased. This article examines Operation Beacon, both as a successful model for reducing civilian deaths at the hand of police and as a cautionary tale for police reform. We argue that the lessons of Operation Beacon have been gradually forgotten and that old habits and attitudes resurfaced. Fatal shootings of mentally ill civilians can be prevented, but if success is to be other than temporary, the Beacon philosophy must be continually reemphasised by police management. PMID:26666251

  11. Toll-like receptors.

    PubMed

    Lien, Egil; Ingalls, Robin R

    2002-01-01

    The ability of a host to sense invasion by pathogenic organisms and to respond appropriately to control infection is paramount to survival. In the case of sepsis and septic shock, however, an exaggerated systemic response may, in fact, contribute to the morbidity and mortality associated with overwhelming infections. The innate immune system has evolved as the first line of defense against invading microorganisms. The Toll-like receptors (TLRs) are a part of this innate immune defense, recognizing conserved patterns on microorganisms. These TLRs and their signaling pathways are represented in such diverse creatures as mammals, fruit flies, and plants. Ten members of the TLR family have been identified in humans, and several of them appear to recognize specific microbial products, including lipopolysaccharide, bacterial lipoproteins, peptidoglycan, and bacterial DNA. Signals initiated by the interaction of TLRs with specific microbial patterns direct the subsequent inflammatory response. Thus, TLR signaling represents a key component of the innate immune response to microbial infection. PMID:11782555

  12. A positional Toll receptor code directs convergent extension in Drosophila

    PubMed Central

    Paré, Adam C.; Vichas, Athea; Fincher, Christopher T.; Mirman, Zachary; Farrell, Dene L.; Mainieri, Avantika; Zallen, Jennifer A.

    2016-01-01

    Summary Elongation of the head-to-tail body axis by convergent extension is a conserved developmental process throughout metazoans. In Drosophila, patterns of transcription factor expression provide spatial cues that induce systematically oriented cell movements and promote tissue elongation. However, the mechanisms by which patterned transcriptional inputs control cell polarity and behavior have long been elusive. We demonstrate that three Toll family receptors, Toll-2, Toll-6, and Toll-8, are expressed in overlapping transverse stripes along the anterior-posterior axis and act in combination to direct planar polarity and polarized cell rearrangements during convergent extension. Simultaneous disruption of all three receptors strongly reduces actomyosin-driven junctional remodeling and axis elongation, and an ectopic stripe of Toll receptor expression is sufficient to induce planar polarized actomyosin contractility. These results demonstrate that tissue-level patterns of Toll receptor expression provide spatial signals that link positional information from the anterior-posterior patterning system to the essential cell behaviors that drive convergent extension. PMID:25363762

  13. Reduced neuronal cell death after experimental brain injury in mice lacking a functional alternative pathway of complement activation

    PubMed Central

    Leinhase, Iris; Holers, V Michael; Thurman, Joshua M; Harhausen, Denise; Schmidt, Oliver I; Pietzcker, Malte; Taha, Mohy E; Rittirsch, Daniel; Huber-Lang, Markus; Smith, Wade R; Ward, Peter A; Stahel, Philip F

    2006-01-01

    Background Neuroprotective strategies for prevention of the neuropathological sequelae of traumatic brain injury (TBI) have largely failed in translation to clinical treatment. Thus, there is a substantial need for further understanding the molecular mechanisms and pathways which lead to secondary neuronal cell death in the injured brain. The intracerebral activation of the complement cascade was shown to mediate inflammation and tissue destruction after TBI. However, the exact pathways of complement activation involved in the induction of posttraumatic neurodegeneration have not yet been assessed. In the present study, we investigated the role of the alternative complement activation pathway in contributing to neuronal cell death, based on a standardized TBI model in mice with targeted deletion of the factor B gene (fB-/-), a "key" component required for activation of the alternative complement pathway. Results After experimental TBI in wild-type (fB+/+) mice, there was a massive time-dependent systemic complement activation, as determined by enhanced C5a serum levels for up to 7 days. In contrast, the extent of systemic complement activation was significantly attenuated in fB-/- mice (P < 0.05,fB-/- vs. fB+/+; t = 4 h, 24 h, and 7 days after TBI). TUNEL histochemistry experiments revealed that posttraumatic neuronal cell death was clearly reduced for up to 7 days in the injured brain hemispheres of fB-/- mice, compared to fB+/+ littermates. Furthermore, a strong upregulation of the anti-apoptotic mediator Bcl-2 and downregulation of the pro-apoptotic Fas receptor was detected in brain homogenates of head-injured fB-/- vs. fB+/+ mice by Western blot analysis. Conclusion The alternative pathway of complement activation appears to play a more crucial role in the pathophysiology of TBI than previously appreciated. This notion is based on the findings of (a) the significant attenuation of overall complement activation in head-injured fB-/- mice, as determined by a

  14. 10. LOOKING SW DOWN UTILITY TUNNEL BENEATH EASTBOUND TOLL BOOTHS, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    10. LOOKING SW DOWN UTILITY TUNNEL BENEATH EASTBOUND TOLL BOOTHS, SHOWING RAILS USED TO TRANSPORT COIN BOXES FROM ORIGINAL TOLL COLLECTION SYSTEM. - Chicago Skyway Toll Bridge, Toll Plaza & Service Building, 8801 South Anthony Avenue, Chicago, Cook County, IL

  15. Comparison of immune response in Pacific white shrimp, Litopenaeus vannamei, after knock down of Toll and IMD gene in vivo.

    PubMed

    Liu, Yongjie; Song, Lei; Sun, Yuhang; Liu, Tao; Hou, Fujun; Liu, Xiaolin

    2016-07-01

    The Toll and immune deficiency (IMD) pathways are essential for inducing immune related genes during invasion of pathogens. In the present study, transcripts of eight pathway-related genes in Litopenaeus vannamei, including Toll, IMD, Pelle, IAP1, TRAF6, ALF, Crustin and Penaeidin3 were analyzed to further understand the potential relationship between Toll and IMD pathway. The high transcription levels of TRAF6, Pelle, Toll, IMD and IAP1 in selected tissues indicates their functional roles in Toll and IMD pathways. The increased mRNA expression of Toll and IMD detected in the early stage might suggest the inducible role of Toll and IMD upon bacterial infection. Moreover, the continuous increase of IMD and the high level of Pelle and TRAF6 in Vibrio anguillarum challenged group indicated that Gram-negative bacterium can activate both the Toll and IMD signaling pathway. Silencing of Toll by a dsRNA-mediated RNAi strongly increased the transcripts of IMD, Pelle, TRAF6, IAP1 and Akirin, knocking down of IMD also markedly increased the transcripts of Toll, Pelle, IAP1 and Akirin. Furthermore, ALF expression was significantly increased in response to V. anguillarum and Micrococcus lysodeikticus challenge, while the transcripts of Crustin and Pen3 in hemocytes were significantly reduced in V. anguillarum group, but rose significantly following M. lysodeikticus infection. In summary, we speculate that Toll and IMD pathway are not independent in shrimp, but linked to defense against bacterial infection. PMID:26855014

  16. JNK Inhibition Reduced Retinal Ganglion Cell Death after Ischemia/Reperfusion In Vivo and after Hypoxia In Vitro.

    PubMed

    Produit-Zengaffinen, Nathalie; Favez, Tatiana; Pournaras, Constantin J; Schorderet, Daniel F

    2016-01-01

    Mitogen-activated protein kinases (MAPKs) are key regulators that have been linked to cell survival and death. Among the main classes of MAPKs, c-jun N-terminal kinase (JNK) has been shown to mediate cell stress responses associated with apoptosis. In Vitro, hypoxia induced a significant increase in 661W cell death that paralleled increased activity of JNK and c-jun. 661W cells cultured in presence of the inhibitor of JNK (D-JNKi) were less sensitive to hypoxia-induced cell death. In vivo, elevation in intraocular pressure (IOP) in the rat promoted cell death that correlated with modulation of JNK activation. In vivo inhibition of JNK activation with D-JNKi resulted in a significant and sustained decrease in apoptosis in the ganglion cell layer, the inner nuclear layer and the photoreceptor layer. These results highlight the protective effect of D-JNKi in ischemia/reperfusion induced cell death of the retina. PMID:26427475

  17. Toll receptors and pathogen resistance.

    PubMed

    Takeda, Kiyoshi; Akira, Shizuo

    2003-03-01

    Toll receptors in insects, mammals and plants are key players that sense the invasion of pathogens. Toll-like receptors (TLRs) in mammals have been established to detect specific components of bacterial and fungal pathogens. Furthermore, recent evidence indicates that TLRs are involved in the recognition of viral invasion. Signalling pathways via TLRs originate from the conserved Toll/IL-1 receptor (TIR) domain. The TIR domain-containing MyD88 acts as a common adaptor that induces inflammatory cytokines; however, there exists a MyD88-independent pathway that induces type I IFNs in TLR4 and TLR3 signalling. Another TIR domain-containing adaptor, TIRAP/Mal has recently been shown to mediate the MyD88-dependent activation in the TLR4 and TLR2 signalling pathway. Thus, individual TLRs may have their own signalling systems that characterize their specific activities. PMID:12614458

  18. Growth Retardation, Reduced Invasiveness, and Impaired Colistin-Mediated Cell Death Associated with Colistin Resistance Development in Acinetobacter baumannii

    PubMed Central

    Poulou, Aggeliki; Dafopoulou, Konstantina; Chabane, Yassine Nait; Kristo, Ioulia; Makris, Demosthenes; Hardouin, Julie; Cosette, Pascal; Tsakris, Athanassios; Dé, Emmanuelle

    2014-01-01

    Two colistin-susceptible/colistin-resistant (Cols/Colr) pairs of Acinetobacter baumannii strains assigned to international clone 2, which is prevalent worldwide, were sequentially recovered from two patients after prolonged colistin administration. Compared with the respective Cols isolates (Ab248 and Ab299, both having a colistin MIC of 0.5 μg/ml), both Colr isolates (Ab249 and Ab347, with colistin MICs of 128 and 32 μg/ml, respectively) significantly overexpressed pmrCAB genes, had single-amino-acid shifts in the PmrB protein, and exhibited significantly slower growth. The Colr isolate Ab347, tested by proteomic analysis in comparison with its Cols counterpart Ab299, underexpressed the proteins CsuA/B and C from the csu operon (which is necessary for biofilm formation). This isolate also underexpressed aconitase B and different enzymes involved in the oxidative stress response (KatE catalase, superoxide dismutase, and alkyl hydroperoxide reductase), suggesting a reduced response to reactive oxygen species (ROS) and, consequently, impaired colistin-mediated cell death through hydroxyl radical production. Cols isolates that were indistinguishable by macrorestriction analysis from Ab299 caused six sequential bloodstream infections, and isolates indistinguishable from Ab248 caused severe soft tissue infection, while Colr isolates indistinguishable from Ab347 and Ab249 were mainly colonizers. In particular, a Cols isolate identical to Ab299 was still invading the bloodstream 90 days after the colonization of this patient by Colr isolates. These observations indicate considerably lower invasiveness of A. baumannii clinical isolates following the development of colistin resistance. PMID:24247145

  19. Growth retardation, reduced invasiveness, and impaired colistin-mediated cell death associated with colistin resistance development in Acinetobacter baumannii.

    PubMed

    Pournaras, Spyros; Poulou, Aggeliki; Dafopoulou, Konstantina; Chabane, Yassine Nait; Kristo, Ioulia; Makris, Demosthenes; Hardouin, Julie; Cosette, Pascal; Tsakris, Athanassios; Dé, Emmanuelle

    2014-01-01

    Two colistin-susceptible/colistin-resistant (Col(s)/Col(r)) pairs of Acinetobacter baumannii strains assigned to international clone 2, which is prevalent worldwide, were sequentially recovered from two patients after prolonged colistin administration. Compared with the respective Col(s) isolates (Ab248 and Ab299, both having a colistin MIC of 0.5 μg/ml), both Col(r) isolates (Ab249 and Ab347, with colistin MICs of 128 and 32 μg/ml, respectively) significantly overexpressed pmrCAB genes, had single-amino-acid shifts in the PmrB protein, and exhibited significantly slower growth. The Col(r) isolate Ab347, tested by proteomic analysis in comparison with its Col(s) counterpart Ab299, underexpressed the proteins CsuA/B and C from the csu operon (which is necessary for biofilm formation). This isolate also underexpressed aconitase B and different enzymes involved in the oxidative stress response (KatE catalase, superoxide dismutase, and alkyl hydroperoxide reductase), suggesting a reduced response to reactive oxygen species (ROS) and, consequently, impaired colistin-mediated cell death through hydroxyl radical production. Col(s) isolates that were indistinguishable by macrorestriction analysis from Ab299 caused six sequential bloodstream infections, and isolates indistinguishable from Ab248 caused severe soft tissue infection, while Col(r) isolates indistinguishable from Ab347 and Ab249 were mainly colonizers. In particular, a Col(s) isolate identical to Ab299 was still invading the bloodstream 90 days after the colonization of this patient by Col(r) isolates. These observations indicate considerably lower invasiveness of A. baumannii clinical isolates following the development of colistin resistance. PMID:24247145

  20. Acute Kidney Outreach to Reduce Deterioration and Death (AKORDD) trial: the protocol for a large pilot study

    PubMed Central

    Abdelaziz, Tarek Samy; Lindenmeyer, Antje; Baharani, Jyoti; Mistry, Hema; Sitch, Alice; Temple, R Mark; Perkins, Gavin; Thomas, Mark

    2016-01-01

    Introduction Acute kidney injury (AKI) contributes to morbidity and mortality, and its care is often suboptimal and/or delayed. The Acute Kidney Outreach to Reduce Deterioration and Death (AKORDD) study is a large pilot testing provision of early specialist advice, to improve outcomes for patients with AKI. Methods and analysis This before and after study will test an Outreach service for adult patients with AKI, identified using the national algorithm. During the 2-month before phase, AKI outcomes (30-day mortality, need for dialysis or AKI stage deterioration) will be observed in the intervention and control hospitals and their respective community areas; no interventions will be delivered. Patients will receive good standard care. During the 5-month after phase, the intervention will be delivered to patients with AKI in the intervention hospital and its area. Patients with AKI in the control hospital and its area will continue to have good standard care only. Patients already on dialysis and at end of life will be excluded. The interventions will be initially delivered via a phone call, with or without a visit to the primary clinician, aiming at rapidly establishing the aetiology, correcting reversible causes and conducting further appropriate investigation. Surviving stage 3 patients will be followed-up in an AKI clinic. We will conduct qualitative research using focus group-based discussions with primary and secondary care clinicians during the early and late phases of the trial. This will help break down potential barriers and improve care delivery. Ethics and dissemination Patients will be contacted about the study allowing them to ‘opt out’. The work of an Outreach team, guided by AKI alerts and delivering timely advice to clinicians, may improve outcomes. If the results suggest that benefits are delivered by an AKI Outreach team, this study will lead to a full cluster randomised trial. Trial registration number NCT02398682: Pre-results. PMID:27543592

  1. Back to Sleep: Reduce the Risk of Sudden Infant Death Syndrome (SIDS) [and] Questions and Answers for Professionals on Infant Sleeping Position and SIDS.

    ERIC Educational Resources Information Center

    Health Resources and Services Administration (DHHS/PHS), Washington, DC. Maternal and Child Health Bureau.

    The "Back to Sleep" public health campaign, which recommends that infants be placed on their backs for sleeping help reduce the risk of Sudden Infant Death Syndrome (SIDS), was initiated in 1994. The campaign was led by the National Institute of Child Health and Human Development, and co-sponsored by the U.S. Public Health Service, the American…

  2. 33 CFR 402.4 - Tolls.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 3 2010-07-01 2010-07-01 false Tolls. 402.4 Section 402.4 Navigation and Navigable Waters SAINT LAWRENCE SEAWAY DEVELOPMENT CORPORATION, DEPARTMENT OF TRANSPORTATION TARIFF OF TOLLS § 402.4 Tolls. (a) Every vessel entering, passing through or leaving the Seaway shall...

  3. A WntD-Dependent Integral Feedback Loop Attenuates Variability in Drosophila Toll Signaling.

    PubMed

    Rahimi, Neta; Averbukh, Inna; Haskel-Ittah, Michal; Degani, Neta; Schejter, Eyal D; Barkai, Naama; Shilo, Ben-Zion

    2016-02-22

    Patterning by morphogen gradients relies on the capacity to generate reproducible distribution profiles. Morphogen spread depends on kinetic parameters, including diffusion and degradation rates, which vary between embryos, raising the question of how variability is controlled. We examined this in the context of Toll-dependent dorsoventral (DV) patterning of the Drosophila embryo. We find that low embryo-to-embryo variability in DV patterning relies on wntD, a Toll-target gene expressed initially at the posterior pole. WntD protein is secreted and disperses in the extracellular milieu, associates with its receptor Frizzled4, and inhibits the Toll pathway by blocking the Toll extracellular domain. Mathematical modeling predicts that WntD accumulates until the Toll gradient narrows to its desired spread, and we support this feedback experimentally. This circuit exemplifies a broadly applicable induction-contraction mechanism, which reduces patterning variability through a restricted morphogen-dependent expression of a secreted diffusible inhibitor. PMID:26906736

  4. Cyanide-induced death of dopaminergic cells is mediated by uncoupling protein-2 up-regulation and reduced Bcl-2 expression

    SciTech Connect

    Zhang, X.; Li, L.; Zhang, L.; Borowitz, J.L.; Isom, G.E.

    2009-07-01

    Cyanide is a potent inhibitor of mitochondrial oxidative metabolism and produces mitochondria-mediated death of dopaminergic neurons and sublethal intoxications that are associated with a Parkinson-like syndrome. Cyanide toxicity is enhanced when mitochondrial uncoupling is stimulated following up-regulation of uncoupling protein-2 (UCP-2). In this study, the role of a pro-survival protein, Bcl-2, in cyanide-mediated cell death was determined in a rat dopaminergic immortalized mesencephalic cell line (N27 cells). Following pharmacological up-regulation of UCP-2 by treatment with Wy14,643, cyanide reduced cellular Bcl-2 expression by increasing proteasomal degradation of the protein. The increased turnover of Bcl-2 was mediated by an increase of oxidative stress following UCP-2 up-regulation. The oxidative stress involved depletion of mitochondrial glutathione (mtGSH) and increased H{sub 2}O{sub 2} generation. Repletion of mtGSH by loading cells with glutathione ethyl ester reduced H{sub 2}O{sub 2} generation and in turn blocked the cyanide-induced decrease of Bcl-2. To determine if UCP-2 mediated the response, RNAi knock down was conducted. The RNAi decreased cyanide-induced depletion of mtGSH, reduced H{sub 2}O{sub 2} accumulation, and inhibited down-regulation of Bcl-2, thus blocking cell death. To confirm the role of Bcl-2 down-regulation in the cell death, it was shown that over-expression of Bcl-2 by cDNA transfection attenuated the enhancement of cyanide toxicity after UCP-2 up-regulation. It was concluded that UCP-2 up-regulation sensitizes cells to cyanide by increasing cellular oxidative stress, leading to an increase of Bcl-2 degradation. Then the reduced Bcl-2 levels sensitize the cells to cyanide-mediated cell death.

  5. Down-regulation of BNIP3 by olomoucine, a CDK inhibitor, reduces LPS- and NO-induced cell death in BV2 microglial cells.

    PubMed

    Tsou, Yu-Chi; Wang, Hsiao-Hsien; Hsieh, Chii-Cheng; Sun, Kuang-Hui; Sun, Guang-Huan; Jhou, Ren-Shiang; Lin, Tz-I; Lu, Shou-Yun; Liu, Huan-Yun; Tang, Shye-Jye

    2016-08-15

    Proinflammatory responses eliciting the microglial production of cytokines and nitric oxide (NO) have been reported to play a crucial role in the acute and chronic pathogenic effects of neurodegeneration. Chemical inhibitors of cyclin-dependent kinases (CDKs) may prevent the progression of neurodegeneration by both limiting cell proliferation and reducing cell death. However, the mechanism underlying the protective effect of CDK inhibitors on microglia remains unexplored. In this study, we found that olomoucine, a CDK inhibitor, alleviated lipopolysaccharide (LPS)-induced BV2 microglial cell death by reducing the generation of NO and inhibiting the gene expression of proinflammatory cytokines. In addition, olomoucine reduced inducible NO synthase promoter activity and alleviated NF-κB- and E2F-mediated transcriptional activation. NO-induced cell death involved mitochondrial disruptions such as cytochrome c release and loss of mitochondrial membrane potential, and pretreatment with olomoucine prior to NO exposure reduced these disruptions. Microarray analysis revealed that olomoucine treatment induced prominent down-regulation of Bcl2/adenovirus E1B 19-kDa-interacting protein 3 (BNIP3), a pro-apoptotic Bcl-2 family protein that is involved in mitochondrial disruption. As BNIP3 knock-down significantly increased the viability of LPS- and NO-treated BV2 cells, we conclude that olomoucine may protect cells by limiting proinflammatory responses, thereby reducing NO generation. Simultaneously, down-regulation of BNIP3 prevents NO stimulation from inducing mitochondrial disruption. PMID:27345388

  6. Pelle Modulates dFoxO-Mediated Cell Death in Drosophila.

    PubMed

    Wu, Chenxi; Chen, Yujun; Wang, Feng; Chen, Changyan; Zhang, Shiping; Li, Chaojie; Li, Wenzhe; Wu, Shian; Xue, Lei

    2015-10-01

    Interleukin-1 receptor-associated kinases (IRAKs) are crucial mediators of the IL-1R/TLR signaling pathways that regulate the immune and inflammation response in mammals. Recent studies also suggest a critical role of IRAKs in tumor development, though the underlying mechanism remains elusive. Pelle is the sole Drosophila IRAK homolog implicated in the conserved Toll pathway that regulates Dorsal/Ventral patterning, innate immune response, muscle development and axon guidance. Here we report a novel function of pll in modulating apoptotic cell death, which is independent of the Toll pathway. We found that loss of pll results in reduced size in wing tissue, which is caused by a reduction in cell number but not cell size. Depletion of pll up-regulates the transcription of pro-apoptotic genes, and triggers caspase activation and cell death. The transcription factor dFoxO is required for loss-of-pll induced cell death. Furthermore, loss of pll activates dFoxO, promotes its translocation from cytoplasm to nucleus, and up-regulates the transcription of its target gene Thor/4E-BP. Finally, Pll physically interacts with dFoxO and phosphorylates dFoxO directly. This study not only identifies a previously unknown physiological function of pll in cell death, but also shed light on the mechanism of IRAKs in cell survival/death during tumorigenesis. PMID:26474173

  7. Pelle Modulates dFoxO-Mediated Cell Death in Drosophila

    PubMed Central

    Chen, Changyan; Zhang, Shiping; Li, Chaojie; Li, Wenzhe; Wu, Shian; Xue, Lei

    2015-01-01

    Interleukin-1 receptor-associated kinases (IRAKs) are crucial mediators of the IL-1R/TLR signaling pathways that regulate the immune and inflammation response in mammals. Recent studies also suggest a critical role of IRAKs in tumor development, though the underlying mechanism remains elusive. Pelle is the sole Drosophila IRAK homolog implicated in the conserved Toll pathway that regulates Dorsal/Ventral patterning, innate immune response, muscle development and axon guidance. Here we report a novel function of pll in modulating apoptotic cell death, which is independent of the Toll pathway. We found that loss of pll results in reduced size in wing tissue, which is caused by a reduction in cell number but not cell size. Depletion of pll up-regulates the transcription of pro-apoptotic genes, and triggers caspase activation and cell death. The transcription factor dFoxO is required for loss-of-pll induced cell death. Furthermore, loss of pll activates dFoxO, promotes its translocation from cytoplasm to nucleus, and up-regulates the transcription of its target gene Thor/4E-BP. Finally, Pll physically interacts with dFoxO and phosphorylates dFoxO directly. This study not only identifies a previously unknown physiological function of pll in cell death, but also shed light on the mechanism of IRAKs in cell survival/death during tumorigenesis. PMID:26474173

  8. Genetically induced adult oligodendrocyte cell death is associated with poor myelin clearance, reduced remyelination, and axonal damage.

    PubMed

    Pohl, Hartmut B F; Porcheri, Cristina; Mueggler, Thomas; Bachmann, Lukas C; Martino, Gianvito; Riethmacher, Dieter; Franklin, Robin J M; Rudin, Markus; Suter, Ueli

    2011-01-19

    Loss of oligodendrocytes is a feature of many demyelinating diseases including multiple sclerosis. Here, we have established and characterized a novel model of genetically induced adult oligodendrocyte death. Specific primary loss of adult oligodendrocytes leads to a well defined and highly reproducible course of disease development that can be followed longitudinally by magnetic resonance imaging. Histological and ultrastructural analyses revealed progressive myelin vacuolation, in parallel to disease development that includes motor deficits, tremor, and ataxia. Myelin damage and clearance were associated with induction of oligodendrocyte precursor cell proliferation, albeit with some regional differences. Remyelination was present in the mildly affected corpus callosum. Consequences of acutely induced cell death of adult oligodendrocytes included secondary axonal damage. Microglia were activated in affected areas but without significant influx of B-cells, T-helper cells, or T-cytotoxic cells. Analysis of the model on a RAG-1 (recombination activating gene-1)-deficient background, lacking functional lymphocytes, did not change the observed disease and pathology compared with immune-competent mice. We conclude that this model provides the opportunity to study the consequences of adult oligodendrocyte death in the absence of primary axonal injury and reactive cells of the adaptive immune system. Our results indicate that if the blood-brain barrier is not disrupted, myelin debris is not removed efficiently, remyelination is impaired, and axonal integrity is compromised, likely as the result of myelin detachment. This model will allow the evaluation of strategies aimed at improving remyelination to foster axon protection. PMID:21248132

  9. Toll-6 and Toll-7 function as neurotrophin receptors in the Drosophila central nervous system

    PubMed Central

    McIlroy, Graham; Foldi, Istvan; Aurikko, Jukka; Wentzell, Jill S.; Lim, Mei Ann; Fenton, Janine C.; Gay, Nicholas J.; Hidalgo, Alicia

    2015-01-01

    Neurotrophin receptors corresponding to vertebrate Trk, p75NTR or Sortilin have not been identified in Drosophila, thus it is unknown how neurotrophism may be implemented in insects. Two Drosophila neurotrophins, DNT1 and DNT2, have nervous system functions, but their receptors are unknown. The Toll receptor superfamily has ancient evolutionary origins and a universal function in innate immunity. Here we show that Toll paralogues unrelated to the mammalian neurotrophin receptors function as neurotrophin receptors in fruit-flies. Toll-6 and Toll-7 are expressed in the central nervous system throughout development, and regulate locomotion, motoraxon targeting and neuronal survival. DNT1 and 2 interact genetically with Toll-6 and 7, bind to Toll-7 and 6 promiscuously, and are distributed in vivo in complementary or overlapping domains. We conclude that in fruit-flies, Tolls are not only involved in development and immunity but also in neurotrophism, revealing an unforeseen relationship between the neurotrophin and Toll protein families. PMID:23892553

  10. Toll-Like Receptors in Chronic Pain

    PubMed Central

    Nicotra, Lauren; Loram, Lisa C; Watkins, Linda R; Hutchinson, Mark R

    2011-01-01

    Proinflammatory central immune signaling contributes significantly to the initiation and maintenance of heightened pain states. Recent discoveries have implicated the innate immune system, pattern recognition Toll-like receptors in triggering these proinflammatory central immune signaling events. These exciting developments have been complemented by the discovery of neuronal expression of Toll-like receptors, suggesting pain pathways can be activated directly by the detection of pathogen associated molecular patterns or danger associated molecular patterns. This review will examine the evidence to date implicating Toll-like receptors and their associated signaling components in heightened pain states. In addition, insights into the impact Toll-like receptors have on priming central immune signaling systems for heightened pain states will be discussed. The influence possible sex differences in Toll-like receptor signaling have for female pain and the recognition of small molecule xenobiotics by Toll-like receptors will also be reviewed. PMID:22001158

  11. Chemical chaperones reduce ionizing radiation-induced endoplasmic reticulum stress and cell death in IEC-6 cells

    SciTech Connect

    Lee, Eun Sang; Lee, Hae-June; Lee, Yoon-Jin; Jeong, Jae-Hoon; Kang, Seongman; Lim, Young-Bin

    2014-07-25

    Highlights: • UPR activation precedes caspase activation in irradiated IEC-6 cells. • Chemical ER stress inducers radiosensitize IEC-6 cells. • siRNAs that targeted ER stress responses ameliorate IR-induced cell death. • Chemical chaperons prevent cell death in irradiated IEC-6 cells. - Abstract: Radiotherapy, which is one of the most effective approaches to the treatment of various cancers, plays an important role in malignant cell eradication in the pelvic area and abdomen. However, it also generates some degree of intestinal injury. Apoptosis in the intestinal epithelium is the primary pathological factor that initiates radiation-induced intestinal injury, but the mechanism by which ionizing radiation (IR) induces apoptosis in the intestinal epithelium is not clearly understood. Recently, IR has been shown to induce endoplasmic reticulum (ER) stress, thereby activating the unfolded protein response (UPR) signaling pathway in intestinal epithelial cells. However, the consequences of the IR-induced activation of the UPR signaling pathway on radiosensitivity in intestinal epithelial cells remain to be determined. In this study, we investigated the role of ER stress responses in IR-induced intestinal epithelial cell death. We show that chemical ER stress inducers, such as tunicamycin or thapsigargin, enhanced IR-induced caspase 3 activation and DNA fragmentation in intestinal epithelial cells. Knockdown of Xbp1 or Atf6 with small interfering RNA inhibited IR-induced caspase 3 activation. Treatment with chemical chaperones prevented ER stress and subsequent apoptosis in IR-exposed intestinal epithelial cells. Our results suggest a pro-apoptotic role of ER stress in IR-exposed intestinal epithelial cells. Furthermore, inhibiting ER stress may be an effective strategy to prevent IR-induced intestinal injury.

  12. Road traffic casualties: understanding the night-time death toll.

    PubMed

    Plainis, S; Murray, I J; Pallikaris, I G

    2006-04-01

    A disproportionate number of fatal injuries occur after dark. The paper presents some statistics of road traffic injuries in a novel way which suggests that low luminance plays a major role in this effect. A sound physiological explanation for this is advanced based on the poor temporal characteristics of rod photoreceptors. It is argued that processing information based on low luminance, low contrast targets is much slower than that for high contrast bright targets. To test the idea, simple visual reaction times were measured under typical low visibility conditions encountered on non-lit roads and were found to be substantially longer than under optimal conditions. It is shown that longer reaction times translate into significantly increased stopping distances. This important point has received insufficient attention in the road safety literature, by the Highways Agency, the police, injury prevention officials, and the UK Highway Code. PMID:16595429

  13. Social group memberships in retirement are associated with reduced risk of premature death: evidence from a longitudinal cohort study

    PubMed Central

    Steffens, Niklas K; Cruwys, Tegan; Haslam, Catherine; Jetten, Jolanda; Haslam, S Alexander

    2016-01-01

    Objectives Retirement constitutes a major life transition that poses significant challenges to health, with many retirees experiencing a precipitous decline in health status following retirement. We examine the extent to which membership in social groups following retirement determines quality of life and mortality. Design The longitudinal impact of the number of social group memberships before and after the transition to retirement was assessed on retirees’ quality of life and risk of death 6 years later. Setting Nationally representative cohort study of older adults living in England. Participants Adults who underwent the transition to retirement (N=424). A matched control group (N=424) of participants who had comparable demographic and health characteristics at baseline but did not undergo the transition to retirement were also examined. Outcome measures Analyses examined participants’ quality of life and mortality during a period of 6 years. Results Retirees who had two group memberships prior to retirement had a 2% risk of death in the first 6 years of retirement if they maintained membership in two groups, a 5% risk if they lost one group and a 12% risk if they lost both groups. Furthermore, for every group membership that participants lost in the year following retirement, their experienced quality of life 6 years later was approximately 10% lower. These relationships are robust when controlling for key sociodemographic variables (age, gender, relationship status and socioeconomic status prior to retirement). A comparison with a matched control group confirmed that these effects were specific to those undergoing the transition to retirement. The effect of social group memberships on mortality was comparable to that of physical exercise. Conclusions Theoretical implications for our understanding of the determinants of retiree quality of life and health, and practical implications for the support of people transitioning from a life of work to

  14. Expression of Interferon Lambda 4 Is Associated with Reduced Proliferation and Increased Cell Death in Human Hepatic Cells

    PubMed Central

    Onabajo, Olusegun O.; Porter-Gill, Patricia; Paquin, Ashley; Rao, Nina; Liu, Luyang; Tang, Wei; Brand, Nathan

    2015-01-01

    Interferon lambda 4 (IFN-λ4) is a novel type-III interferon that can be generated only in individuals carrying a ΔG frame-shift allele of an exonic genetic variant (rs368234815-ΔG/TT). The rs368234815-ΔG allele is strongly associated with decreased clearance of hepatitis C virus (HCV) infection. Here, we further explored the biological function of IFN-λ4 expressed in human hepatic cells—a hepatoma cell line HepG2 and fresh primary human hepatocytes (PHHs). We performed live confocal imaging, cell death and proliferation assays, mRNA expression profiling, protein detection, and antibody blocking assays using transient and inducible stable in vitro systems. Not only did we observe significant intracellular retention of IFN-λ4 but also detected secreted IFN-λ4 in the culture media of expressing cells. Secreted IFN-λ4 induced strong activation of the interferon-stimulated genes (ISGs) in IFN-λ4-expressing and surrounding cells in transwell assays. Specifically, in PHHs, secreted IFN-λ4 induced expression of the CXCL10 transcript and a corresponding pro-inflammatory chemokine, IP-10. In IFN-λ4-expressing HepG2 cells, we also observed decreased proliferation and increased cell death. All IFN-λ4-induced phenotypes—activation of ISGs, decreased proliferation, and increased cell death—could be inhibited by an anti-IFN-λ4-specific antibody. Our study offers new insights into biology of IFN-λ4 and its possible role in HCV clearance. PMID:26134097

  15. Toll-Like Receptors and Prostate Cancer

    PubMed Central

    Zhao, Shu; Zhang, Yifan; Zhang, Qingyuan; Wang, Fen; Zhang, Dekai

    2014-01-01

    Prostate cancer is the second leading cause of cancer-related death in men after lung cancer. Immune responses clearly play a critical role in the tumorigenesis and in the efficacy of radiation therapy and chemotherapy in prostate cancer; however, the underlying molecular mechanisms are still poorly understood. Toll-like receptors (TLRs) are a well-known family of pattern recognition receptors that play a key role in host immune system. Recent studies demonstrate that there are links between TLRs and cancer; however, the function and biological importance of TLRs in prostate cancer seems complex. To elucidate the role of TLRs and innate immunity in prostate cancer might provide us with a better understanding of the molecular mechanisms of this disease. Moreover, utilizing the agonists or antagonists of TLRs might represent a promising new strategy against prostate cancer. In this review, we summarize recent advances on the studies of association between TLR signaling and prostate cancer, TLR polymorphisms and prostate cancer risk, and provide some insights about TLRs as potential targets for prostate cancer immunotherapy. PMID:25101092

  16. Role of climate variability in the heatstroke death rates of Kanto region in Japan.

    PubMed

    Akihiko, Takaya; Morioka, Yushi; Behera, Swadhin K

    2014-01-01

    The death toll by heatstroke in Japan, especially in Kanto region, has sharply increased since 1994 together with large interannual variability. The surface air temperature and humidity observed during boreal summers of 1980-2010 were examined to understand the role of climate in the death toll. The extremely hot days, when the daily maximum temperature exceeds 35 °C, are more strongly associated with the death toll than the conventional Wet Bulb Globe Temperature index. The extremely hot days tend to be associated with El Niño/Southern Oscillation or the Indian Ocean Dipole, suggesting a potential link with tropical climate variability to the heatstroke related deaths. Also, the influence of these climate modes on the death toll has strengthened since 1994 probably related to global warming. It is possible to develop early warning systems based on seasonal climate predictions since recent climate models show excellent predictability skills for those climate modes. PMID:25008122

  17. [Innate immunity, Toll receptor and sepsis].

    PubMed

    Carrillo-Esper, Raúl

    2003-01-01

    The innate immune response is the first line of defense against infection. Toll-like receptors (TLRs) recognize bacterial lipopolysaccharide and other pathogen-associated molecular patterns (PAMPs). Intracellular signals initiated by interaction between Toll receptors and specific PAMPs results in inflammatory response. Sepsis and septic shock are the result of an exaggerated inflammatory systemic response induced by innate immune dysregulation. PMID:14617415

  18. Improvements In US Diet Helped Reduce Disease Burden And Lower Premature Deaths, 1999-2012; Overall Diet Remains Poor.

    PubMed

    Wang, Dong D; Li, Yanping; Chiuve, Stephanie E; Hu, Frank B; Willett, Walter C

    2015-11-01

    Evaluation of time trends in dietary quality and their relation to disease burden provides essential feedback for policy making. We used an index titled the Alternate Healthy Eating Index 2010 to evaluate trends in dietary quality among 33,885 US adults. From 1999 to 2012 the index increased from 39.9 to 48.2 (perfect score = 110). Gaps in performance on the index across socioeconomic groups persisted or widened. Using data relating index scores to health outcomes in two large cohorts, we estimated that the improvements in dietary quality from 1999 to 2012 prevented 1.1 million premature deaths. Also, this improvement in diet quality resulted in 8.6 percent fewer cardiovascular disease cases, 1.3 percent fewer cancer cases, and 12.6 percent fewer type 2 diabetes cases. Although the steady improvement in dietary quality likely accounted for substantial reductions in disease burden from 1999 to 2012, overall dietary quality in the United States remains poor. Policy initiatives are needed to ensure further improvements. PMID:26526250

  19. Inhibition of diacylglycerol kinase α restores restimulation-induced cell death and reduces immunopathology in XLP-1.

    PubMed

    Ruffo, Elisa; Malacarne, Valeria; Larsen, Sasha E; Das, Rupali; Patrussi, Laura; Wülfing, Christoph; Biskup, Christoph; Kapnick, Senta M; Verbist, Katherine; Tedrick, Paige; Schwartzberg, Pamela L; Baldari, Cosima T; Rubio, Ignacio; Nichols, Kim E; Snow, Andrew L; Baldanzi, Gianluca; Graziani, Andrea

    2016-01-13

    X-linked lymphoproliferative disease (XLP-1) is an often-fatal primary immunodeficiency associated with the exuberant expansion of activated CD8(+) T cells after Epstein-Barr virus (EBV) infection. XLP-1 is caused by defects in signaling lymphocytic activation molecule (SLAM)-associated protein (SAP), an adaptor protein that modulates T cell receptor (TCR)-induced signaling. SAP-deficient T cells exhibit impaired TCR restimulation-induced cell death (RICD) and diminished TCR-induced inhibition of diacylglycerol kinase α (DGKα), leading to increased diacylglycerol metabolism and decreased signaling through Ras and PKCθ (protein kinase Cθ). We show that down-regulation of DGKα activity in SAP-deficient T cells restores diacylglycerol signaling at the immune synapse and rescues RICD via induction of the proapoptotic proteins NUR77 and NOR1. Pharmacological inhibition of DGKα prevents the excessive CD8(+) T cell expansion and interferon-γ production that occur in SAP-deficient mice after lymphocytic choriomeningitis virus infection without impairing lytic activity. Collectively, these data highlight DGKα as a viable therapeutic target to reverse the life-threatening EBV-associated immunopathology that occurs in XLP-1 patients. PMID:26764158

  20. Improvements In US Diet Helped Reduce Disease Burden And Lower Premature Deaths, 1999–2012; But Overall Diet Remains Poor

    PubMed Central

    Wang, Dong D.; Li, Yanping; Chiuve, Stephanie E.; Hu, Frank B.; Willett, Walter

    2016-01-01

    Evaluation of time trends in dietary quality and their relation to disease burden provides essential feedback for policy making. We used an index titled the Alternate Healthy Eating Index 2010 to evaluate trends in dietary quality among 33,885 US adults. From 1999 to 2012, the index increased from 39.9 to 48.2 (perfect score = 110). Gaps in performance on the index persisted across socioeconomic groups or widened. Using data relating index scores to health outcomes in two large cohorts, we estimated that the improvements in dietary quality from 1999 to 2012 prevented 1,064,840 premature deaths. Also, this improvement in diet quality resulted in 8.6 percent fewer cardiovascular disease cases, 1.3 percent fewer cancer cases, and 12.6 percent fewer type 2 diabetes cases. Although the steady improvement in dietary quality likely accounted for substantial reductions in disease burden from 1999 to 2012, overall dietary quality in the US remains poor. Policy initiatives are needed to ensure further improvements. PMID:26526250

  1. Does Resuscitation Training Reduce Neonatal Deaths in Low-Resource Communities? A Systematic Review of the Literature.

    PubMed

    Sousa, Sarah; Mielke, John G

    2015-10-01

    Every year, nearly 1 million babies succumb to birth asphyxia (BA) within the Asia-Pacific region. The present study sought to determine whether educational interventions containing some element of resuscitation training would decrease the relative risk (RR) of neonatal mortality attributable to BA in low-resource communities. We systematically reviewed 3 electronic databases and identified 14 relevant reports. For community deliveries, providing traditional birth attendants (TBAs) with neonatal resuscitation training modestly reduced the RR in 3 of 4 studies. For institutional deliveries, training a range of clinical staff clearly reduced the RR within 2 of 8 studies. When resuscitation-specific training was directed to community and institutional health care workers, a slight benefit was observed in 1 of 2 studies. Specific training in neonatal resuscitation appears most effective when provided to TBAs (specifically, those presented with ongoing opportunities to review and update their skills), but this particular intervention alone may not appreciably reduce mortality. PMID:26378066

  2. Local Anaesthetic Infiltration and Indwelling Postoperative Wound Catheters for Patients with Hip Fracture Reduce Death Rates and Length of Stay

    PubMed Central

    Harrison, William D.; Lees, Deborah; A'Court, Jamie; Ankers, Thomas; Harper, Ian; Inman, Dominic; Reed, Mike R.

    2015-01-01

    Background. An analgesic enhanced recovery (ER) protocol for patients with a hip fracture was introduced. It was hypothesised that the ER would reduce pain, length of stay and improve clinical outcomes. The protocol used intraoperative infiltration of levobupivacaine followed by ongoing wound infusions. Methods. Consecutive patients admitted to two hospitals were eligible for the ER protocol. Numerical Reporting Scale pain scores (0–10) were recorded alongside opiate requirements. 434 patients in the ER group (316 full ER, 90 partial ER, and 28 no ER) were compared to a control group (CG) of 100 consecutive patients managed with traditional opiate analgesia. Results. Mean opiate requirement was 49.2 mg (CG) versus 32.5 mg (ER). Pain scores were significantly reduced in the full ER group, p < 0.0001. Direct discharge home and mean acute inpatient stay were significantly reduced (p = 0.0031 and p < 0.0001, resp.). 30-day mortality was 15% (CG) versus 5.5% (ER), p = 0.0024. Conclusions. This analgesic ER protocol for patients with a hip fracture was safe and effective and was associated with reduced inpatient stay and mortality. PMID:26649330

  3. Annual Screening with Chest X-Ray Does Not Reduce Lung Cancer Deaths | Division of Cancer Prevention

    Cancer.gov

    Annual screening for lung cancer using a standard chest x-ray does not reduce the risk of dying from lung cancer when compared with no annual screening, according to findings from the NCI-led Prostate, Lung, Colorectal, and Ovarian (PLCO) screening trial. The results from a median of nearly 12 years of follow-up were published online October 26 in JAMA. |

  4. The role of tobacco control policies in reducing smoking and deaths caused by smoking in an Eastern European nation: results from the Albania SimSmoke simulation model.

    PubMed

    Levy, David T; Ross, Hana; Zaloshnja, Eduard; Shuperka, Roland; Rusta, Meriglena

    2008-12-01

    The Albania SimSmoke simulation model is used to examine the effects of tobacco control policies. The model is used to consider the projected trends in smoking prevalence and associated smoking-attributable deaths in the absence of new policies, and then to examine the effect of new policies that are consistent with the Framework Convention for Tobacco Control (FCTC) on these outcomes. The model shows that significant inroads to reducing smoking prevalence and premature mortality can be achieved through tax increases. Acomprehensive strategy to further reduce smoking rates should include a media campaign complete with programs to publicize and enforce clean air laws, a comprehensive cessation treatment program, strong health warnings, advertising bans, and youth access laws. Besides presenting the benefits of a comprehensive tobacco control strategy, the model helps to identify important information needed for both modeling and policymaking. The effectiveness of future tobacco control policy will require proper surveillance and evaluation schemes for Albania. PMID:19256288

  5. Occupational Noise Exposure among Toll Tellers at Toll Plaza in Malaysia

    NASA Astrophysics Data System (ADS)

    Azmi, Sharifah Nadya Syed; Dawal, Siti Zawiah Md; Ya, Tuan Mohammad Yusoff Shah Tuan; Saidin, Hamidi

    2010-10-01

    Toll tellers working at toll plaza have potential of exposure to high noise from the vehicles especially for the peak level of sound emitted by the heavy vehicles. However, occupational exposures in this workplace have not been adequately characterized and identified. Occupational noise exposure among toll tellers at toll plaza was assessed using Sound Level Meter, Noise Dosimeter and through questionnaire survey. These data were combined to estimate the work shift exposure level and health impacts to the toll tellers by using statistical analysis. Noise Dosimeter microphone was located at the hearing zone of the toll teller which working inside the toll booth and full-period measurements were collected for each work shift. The measurements were taken at 20 toll booths from 6.00 am to 2.00 pm for 5 days. 71 respondents participated in the survey to identify the symptoms of noise induced hearing loss and other health related problems among toll tellers. Results of this study indicated that occupational noise exposure among toll tellers for Mean Continuous Equivalent Level, Leq was 79.2±1.4 dB(A), Mean Maximum Level, Lmax was 107.8±3.6 dB(A) and Mean Peak Level, Lpeak was 136.6±9.9 dB. The Peak Level reported statistically significantly at 140 dB, the level of TLV recommended by ACGIH. The research findings indicated that the primary risk exposure to toll tellers comes from noise that emitted from heavy vehicles. Most of the toll tellers show symptoms of noise induced hearing loss and annoyed by the sources of noise at the toll plaza.

  6. Forecasting toll traffic: energy and other impacts

    SciTech Connect

    Greenbaum, D.W.

    1981-01-01

    This analysis focuses on passenger-car activity and attempts to shed some light on the question that is asked so often these days: what is going to happen to future toll road traffic, particularly as influenced by the energy situation. Three main points are covered: (1) a look at the recent losses in passenger car traffic experienced on most toll facilities; (2) a brief analysis of factors causing these losses together with an attempt at forecasting future passenger-car-traffic trends; and, (3) an observation on conditions that may be influencing long-term traffic trends to an even greater degree than the energy situation. Considering the expected energy situation, passenger-car traffic on toll facilities can be expected to increase but generally at a very modest rate. The costs of operating and maintaining toll facilities will rise at a substantially faster rate than the toll traffic. For many toll road operators, periodic toll increases will be a fact of life. In summary, it appears that forecasting techniques, based on detailed analyses of actual operating results, are still valid in these times of change. In the future, the impacts of fuel shortages or prices, assuming no catastrophic changes, probably will be minimal. Changing life styles and economic considerations, however, should be the principal concerns and these will keep automobile traffic from growing as it once did.

  7. 47 CFR 52.111 - Toll free number assignment.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 3 2012-10-01 2012-10-01 false Toll free number assignment. 52.111 Section 52.111 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES (CONTINUED) NUMBERING Toll Free Numbers § 52.111 Toll free number assignment. Toll free numbers shall be made...

  8. 47 CFR 52.111 - Toll free number assignment.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 3 2014-10-01 2014-10-01 false Toll free number assignment. 52.111 Section 52.111 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES (CONTINUED) NUMBERING Toll Free Numbers § 52.111 Toll free number assignment. Toll free numbers shall be made...

  9. 47 CFR 52.111 - Toll free number assignment.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 3 2010-10-01 2010-10-01 false Toll free number assignment. 52.111 Section 52.111 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES (CONTINUED) NUMBERING Toll Free Numbers § 52.111 Toll free number assignment. Toll free numbers shall be made...

  10. 47 CFR 52.111 - Toll free number assignment.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 3 2013-10-01 2013-10-01 false Toll free number assignment. 52.111 Section 52.111 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES (CONTINUED) NUMBERING Toll Free Numbers § 52.111 Toll free number assignment. Toll free numbers shall be made...

  11. 47 CFR 52.111 - Toll free number assignment.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 3 2011-10-01 2011-10-01 false Toll free number assignment. 52.111 Section 52.111 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES (CONTINUED) NUMBERING Toll Free Numbers § 52.111 Toll free number assignment. Toll free numbers shall be made...

  12. Alcohol resistance in Drosophila is modulated by the Toll innate immune pathway.

    PubMed

    Troutwine, B R; Ghezzi, A; Pietrzykowski, A Z; Atkinson, N S

    2016-04-01

    A growing body of evidence has shown that alcohol alters the activity of the innate immune system and that changes in innate immune system activity can influence alcohol-related behaviors. Here, we show that the Toll innate immune signaling pathway modulates the level of alcohol resistance in Drosophila. In humans, a low level of response to alcohol is correlated with increased risk of developing an alcohol use disorder. The Toll signaling pathway was originally discovered in, and has been extensively studied in Drosophila. The Toll pathway is a major regulator of innate immunity in Drosophila, and mammalian Toll-like receptor signaling has been implicated in alcohol responses. Here, we use Drosophila-specific genetic tools to test eight genes in the Toll signaling pathway for effects on the level of response to ethanol. We show that increasing the activity of the pathway increases ethanol resistance whereas decreasing the pathway activity reduces ethanol resistance. Furthermore, we show that gene products known to be outputs of innate immune signaling are rapidly induced following ethanol exposure. The interaction between the Toll signaling pathway and ethanol is rooted in the natural history of Drosophila melanogaster. PMID:26916032

  13. The role of the African-American physician in reducing traffic-related injury and death among African Americans: consensus report of the National Medical Association.

    PubMed Central

    Daniels, Fernando; Moore, Wayne; Conti, Christopher; Norville Perez, Lucille C.; Gaines, Beverly M.; Hood, Rodney G.; Swain, Ian J. J.; Williams, Rudolph; Burgess, Chaka T.

    2002-01-01

    ISSUE: Traffic-related injuries and fatalities disproportionately affect the African American community. These high rates of traffic-related death and injury among African Americans manifest in multiple areas of traffic safety, including: Failure to use seat belts and child restraints. High incidence of alcohol-impaired driving. Failure to follow child passenger and seat belt safety laws and recommendations. High rates of pedestrian accidents, ofen brought on by impairments of drivers and/or pedestrians. Research indicates that national public information campaigns, with general messages only slightly modified for African American audiences, have not been culturally appropriate or effective in changing traffic safety behavior. In addition, traditional distribution mechanisms for these messages have not effectively reached the target population. Evidence suggests that in the African American community, there is a pervasive lack of knowledge of the devastating impact of traffic-related accidents on the overall health status of the community. This lack of information has resulted in a tragic cycle, in which parents fail to model safe operation of motor vehicles, and generation after generation copy this behavior, increasing the community's vulnerability to serious injuries and untimely deaths. This trend toward improper traffic safety habits among African Americans persists despite federal, state and local laws to enforce and promote sound traffic safety practices. OBJECTIVE: To study the existence of disparities in traffic-related injury and death among African Americans and to determine what kinds of traffic safety messages and campaigns will be effective in encouraging African Americans to respond to safety laws in sufficient numbers to reduce the disproportionately high rate of injury and death. Traffic safety issues were examined to effectively recommend policy, address barriers, best practices, and intervention strategies for the National Medical Association

  14. Oxygen-glucose deprivation of neurons transfected with toll-like receptor 3-siRNA: Determination of an optimal transfection sequence

    PubMed Central

    Cui, Guiyun; Wang, Xiaopeng; Ye, Xinchun; Zu, Jie; Zan, Kun; Hua, Fang

    2013-01-01

    Toll-like receptor 3 protein expression has been shown to be upregulated during cerebral ischemia/reperfusion injury in rats. In this study, rat primary cortical neurons were subjected to oxygen-glucose deprivation to simulate cerebral ischemia/reperfusion injury. Chemically synthesized small interfering RNA (siRNA)-1280, -1724 and -418 specific to toll-like receptor 3 were transfected into oxygen-glucose deprived cortical neurons to suppress the upregulation of toll-like receptor 3 protein expression. Western blotting demonstrated that after transfection with siRNA, toll-like receptor 3 protein expression reduced, especially in the toll-like receptor 3-1724 group. These results suggested that siRNA-1724 is an optimal sequence for inhibiting toll-like receptor 3 expression in cortical neurons following oxygen-glucose deprivation. PMID:25206644

  15. Butanol extract of Ecklonia cava prevents production and aggregation of beta-amyloid, and reduces beta-amyloid mediated neuronal death.

    PubMed

    Kang, Il-Jun; Jeon, Young Eun; Yin, Xing Fu; Nam, Jin-Sik; You, Sang Guan; Hong, Myo Soon; Jang, Bong Geom; Kim, Min-Ju

    2011-09-01

    Beta-amyloid (Aβ) is a major pathogenic peptide for Alzheimer's disease (AD) and is generated by the processing of amyloid precursor protein (APP). The Aβ monomers aggregate into oligomeric and fibrillar forms which have been implicated as the toxic species inducing the neuronal dysfunction. Brown algae Ecklonia cava is known for its anti-oxidant and anti-inflammatory functions. Therefore, we tested the effect of E. cava extract on the production and aggregation of Aβ peptides. The butanol extract of E. cava reduced Aβ secretion from HEK293 cells expressing APP with Swedish mutation and increased soluble APPα and C-terminal fragment-α (CTFα), of which activity was similar to BACE (β-site of APP cleaving enzyme) inhibitors. Furthermore, the extract inhibited Aβ oligomerization, particularly mid-size oligomer formation, confirmed by the ultrastructural morphology. Congo red, thioflavin T assays, and electron microscopy showed that the extract inhibited Aβ fibril formation effectively. Finally, the extract protected primary cortical neurons from various Aβ-induced cell deaths, especially oligomer-induced death. Although further study is needed to test the effectiveness of the extract in vivo, our results demonstrate, for the first time, that the butanol extract of E. cava could be used as an anti-Aβ agent for AD therapeutics. PMID:21693162

  16. Enhancing mitochondrial calcium buffering capacity reduces aggregation of misfolded SOD1 and motor neuron cell death without extending survival in mouse models of inherited amyotrophic lateral sclerosis.

    PubMed

    Parone, Philippe A; Da Cruz, Sandrine; Han, Joo Seok; McAlonis-Downes, Melissa; Vetto, Anne P; Lee, Sandra K; Tseng, Eva; Cleveland, Don W

    2013-03-13

    Mitochondria have been proposed as targets for toxicity in amyotrophic lateral sclerosis (ALS), a progressive, fatal adult-onset neurodegenerative disorder characterized by the selective loss of motor neurons. A decrease in the capacity of spinal cord mitochondria to buffer calcium (Ca(2+)) has been observed in mice expressing ALS-linked mutants of SOD1 that develop motor neuron disease with many of the key pathological hallmarks seen in ALS patients. In mice expressing three different ALS-causing SOD1 mutants, we now test the contribution of the loss of mitochondrial Ca(2+)-buffering capacity to disease mechanism(s) by eliminating ubiquitous expression of cyclophilin D, a critical regulator of Ca(2+)-mediated opening of the mitochondrial permeability transition pore that determines mitochondrial Ca(2+) content. A chronic increase in mitochondrial buffering of Ca(2+) in the absence of cyclophilin D was maintained throughout disease course and was associated with improved mitochondrial ATP synthesis, reduced mitochondrial swelling, and retention of normal morphology. This was accompanied by an attenuation of glial activation, reduction in levels of misfolded SOD1 aggregates in the spinal cord, and a significant suppression of motor neuron death throughout disease. Despite this, muscle denervation, motor axon degeneration, and disease progression and survival were unaffected, thereby eliminating mutant SOD1-mediated loss of mitochondrial Ca(2+) buffering capacity, altered mitochondrial morphology, motor neuron death, and misfolded SOD1 aggregates, as primary contributors to disease mechanism for fatal paralysis in these models of familial ALS. PMID:23486940

  17. Mono-galloyl glucose derivatives are potent poly(ADP-ribose) glycohydrolase (PARG) inhibitors and partially reduce PARP-1-dependent cell death

    PubMed Central

    Formentini, L; Arapistas, P; Pittelli, M; Jacomelli, M; Pitozzi, V; Menichetti, S; Romani, A; Giovannelli, L; Moroni, F; Chiarugi, A

    2008-01-01

    Background and purpose: Maintenance of poly(ADP-ribose) (PAR) polymers at homoeostatic levels by PAR glycohydrolase (PARG) is central in cell functioning and survival. Yet the pharmacological relevance of PARG inhibitors is still debated. Gallotannin, a complex mixture of hydrolysable tannins from oak gall, inhibits PARG but which of its constituents is responsible for the inhibition and whether the pharmacodynamic properties are due to its antioxidant properties, has not yet been established. Experimental approach: A structure–activity relationship study was conducted on different natural and synthetic tannins/galloyl derivatives as potential PARG inhibitors, using a novel in vitro enzymic assay. Cytotoxicity was assayed in cultured HeLa cells. Key results: Mono-galloyl glucose compounds were potent inhibitors of PARG, with activities similar to that of ADP-(hydroxymethyl) pyrrolidinediol, the most potent PARG inhibitor yet identified. When tested on HeLa cells exposed to the PAR polymerase (PARP)-1-activating compound 1-methyl-3-nitro-1-nitrosoguanidine (MNNG), 3-galloyl glucose weakly inhibited PAR degradation. Conversely, the more lipophilic, 3-galloyl-1,2-O-isopropylidene glucose, despite being inactive on the pure enzyme, efficiently prolonged the half-life of the polymers in intact HeLa cells. Also, PARG inhibitors, but not radical scavengers, reduced, in part, cell death caused by MNNG. Conclusions and implications: Taken together, our findings identify mono-galloyl glucose derivatives as potent PARG inhibitors, and emphasize the active function of this enzyme in cell death. PMID:18806807

  18. PUFA-induced cell death is mediated by Yca1p-dependent and -independent pathways, and is reduced by vitamin C in yeast.

    PubMed

    Johansson, Magnus; Chen, Xin; Milanova, Stefina; Santos, Cristiano; Petranovic, Dina

    2016-03-01

    Polyunsaturated fatty acids (PUFA) such as linoleic acid (LA, n-6, C18:2) and γ-linolenic acid (GLA, n-6, C18:3) are essential and must be obtained from the diet. There has been a growing interest in establishing a bio-sustainable production of PUFA in several microorganisms, e.g. in yeast Saccharomyces cerevisiae. However, PUFAs can also be toxic to cells because of their susceptibility to peroxidation. Here we investigated the negative effects of LA and GLA production on S. cerevisiae by characterizing a strain expressing active Δ6 and Δ12 desaturases from the fungus Mucor rouxii. Previously, we showed that the PUFA-producing strain has low viability, down-regulated genes for oxidative stress response, and decreased proteasome activity. Here we show that the PUFA strain accumulates high levels of reactive oxygen species (ROS) and lipid peroxides, and accumulates damaged proteins. The PUFA strain also showed great increase in metacaspase Yca1p activity, suggesting cells could die by caspase-mediated cell death. When treated with antioxidant vitamin C, ROS, lipid peroxidation and protein carbonylation were greatly reduced, and the activity of the metacaspase was significantly decreased too, ultimately doubling the lifespan of the PUFA strain. When deleting YCA1, the caspase-like activity and the oxidative stress decreased and although the lifespan was slightly prolonged, the phenotype could not be fully reversed, pointing that Yca1p was not the main executor of cell death. PMID:26833421

  19. 60 million non-facility births: Who can deliver in community settings to reduce intrapartum-related deaths?

    PubMed Central

    Darmstadt, Gary L.; Lee, Anne CC; Cousens, Simon; Sibley, Lynn; Bhutta, Zulqar A.; Donnay, France; Osrin, Dave; Bang, Abhay; Kumar, Vishwajeet; Wall, Steve N.; Baqui, Abdullah; Lawn, Joy E.

    2012-01-01

    care for the rural poor, help reduce gross inequities in maternal and newborn survival and stillbirth rates, and provide an effective transition to higher coverage for facility births. PMID:19815200

  20. The complement system and toll-like receptors as integrated players in the pathophysiology of atherosclerosis.

    PubMed

    Hovland, Anders; Jonasson, Lena; Garred, Peter; Yndestad, Arne; Aukrust, Pål; Lappegård, Knut T; Espevik, Terje; Mollnes, Tom E

    2015-08-01

    Despite recent medical advances, atherosclerosis is a global burden accounting for numerous deaths and hospital admissions. Immune-mediated inflammation is a major component of the atherosclerotic process, but earlier research focus on adaptive immunity has gradually switched towards the role of innate immunity. The complement system and toll-like receptors (TLRs), and the crosstalk between them, may be of particular interest both with respect to pathogenesis and as therapeutic targets in atherosclerosis. Animal studies indicate that inhibition of C3a and C5a reduces atherosclerosis. In humans modified LDL-cholesterol activate complement and TLRs leading to downstream inflammation, and histopathological studies indicate that the innate immune system is present in atherosclerotic lesions. Moreover, clinical studies have demonstrated that both complement and TLRs are upregulated in atherosclerotic diseases, although interventional trials have this far been disappointing. However, based on recent research showing an intimate interplay between complement and TLRs we propose a model in which combined inhibition of both complement and TLRs may represent a potent anti-inflammatory therapeutic approach to reduce atherosclerosis. PMID:26086357

  1. Effectiveness of Scotland's National Naloxone Programme for reducing opioid‐related deaths: a before (2006–10) versus after (2011–13) comparison

    PubMed Central

    McAuley, Andrew; Perry, Samantha; Hunter, Carole

    2016-01-01

    Abstract Aims To assess the effectiveness for Scotland's National Naloxone Programme (NNP) by comparison between 2006–10 (before) and 2011–13 (after NNP started in January 2011) and to assess cost‐effectiveness. Design This was a pre–post evaluation of a national policy. Cost‐effectiveness was assessed by prescription costs against life‐years gained per opioid‐related death (ORD) averted. Setting Scotland, in community settings and all prisons. Intervention Brief training and standardized naloxone supply became available to individuals at risk of opioid overdose. Measurements ORDs as identified by National Records of Scotland. Look‐back determined the proportion of ORDs who, in the 4 weeks before ORD, had been (i) released from prison (primary outcome) and (ii) released from prison or discharged from hospital (secondary). We report 95% confidence intervals for effectiveness in reducing the primary (and secondary) outcome in 2011–13 versus 2006–10. Prescription costs were assessed against 1 or 10 life‐years gained per averted ORD. Findings In 2006–10, 9.8% of ORDs (193 of 1970) were in people released from prison within 4 weeks of death, whereas only 6.3% of ORDs in 2011–13 followed prison release (76 of 1212, P < 0.001; this represented a difference of 3.5% [95% confidence interval (CI) = 1.6–5.4%)]. This reduction in the proportion of prison release ORDs translates into 42 fewer prison release ORDs (95% CI = 19–65) during 2011–13, when 12 000 naloxone kits were issued at current prescription cost of £225 000. Scotland's secondary outcome reduced from 19.0 to 14.9%, a difference of 4.1% (95% CI = 1.4–6.7%). Conclusions Scotland's National Naloxone Programme, which started in 2011, was associated with a 36% reduction in the proportion of opioid‐related deaths that occurred in the 4 weeks following release from prison. PMID:26642424

  2. Patient barriers to implantable cardioverter defibrillator implantation for the primary prevention of sudden cardiac death in patients with heart failure and reduced ejection fraction

    PubMed Central

    Chan, Laura Lihua; Lim, Choon Pin; Aung, Soe Tin; Quetua, Paul; Ho, Kah Leng; Chong, Daniel; Teo, Wee Siong; Sim, David; Ching, Chi Keong

    2016-01-01

    INTRODUCTION Device therapy is efficacious in preventing sudden cardiac death (SCD) in patients with reduced ejection fraction. However, few who need the device eventually opt to undergo implantation and even fewer reconsider their decisions after deliberation. This is due to many factors, including unresolved patient barriers. This study identified the factors that influenced patients’ decision to decline implantable cardioverter defibrillator (ICD) implantation, and those that influenced patients who initially declined an implant to reconsider having one. METHODS A single-centre survey was conducted among 240 patients who had heart failure with reduced ejection fraction and met the ICD implantation criteria, but had declined ICD implantation. RESULTS Participants who refused ICD implantation were mostly male (84%), Chinese (71%), married (72%), currently employed (54%), and had up to primary or secondary education (78%) and monthly income of < SGD 3,000 (51%). Those who were more likely to reconsider their decision were aware that SCD was a consequence of heart failure with reduced ejection fraction, knowledgeable of the preventive role of ICDs, currently employed and aware that their doctor strongly recommended the implant. Based on multivariate analysis, knowledge of the role of ICDs for primary prophylaxis was the most important factor influencing patient decision. CONCLUSION This study identified the demographic and social factors of patients who refused ICD therapy. Knowledge of the role of ICDs in preventing SCD was found to be the strongest marker for reconsidering ICD implantation. Measures to address this information gap may lead to higher rates of ICD implantation. PMID:27075476

  3. Zinc Sensing Receptor Signaling, Mediated by GPR39, Reduces Butyrate-Induced Cell Death in HT29 Colonocytes via Upregulation of Clusterin

    PubMed Central

    Cohen, Limor; Azriel-Tamir, Hagit; Arotsker, Natan; Sekler, Israel; Hershfinkel, Michal

    2012-01-01

    Zinc enhances epithelial proliferation, protects the digestive epithelial layer and has profound antiulcerative and antidiarrheal roles in the colon. Despite the clinical significance of this ion, the mechanisms linking zinc to these cellular processes are poorly understood. We have previously identified an extracellular Zn2+ sensing G-protein coupled receptor (ZnR) that activates Ca2+ signaling in colonocytes, but its molecular identity as well as its effects on colonocytes' survival remained elusive. Here, we show that Zn2+, by activation of the ZnR, protects HT29 colonocytes from butyrate induced cell death. Silencing of the G-protein coupled receptor GPR39 expression abolished ZnR-dependent Ca2+ release and Zn2+-dependent survival of butyrate-treated colonocytes. Importantly, GPR39 also mediated ZnR-dependent upregulation of Na+/H+ exchange activity as this activity was found in native colon tissue but not in tissue obtained from GPR39 knock-out mice. Although ZnR-dependent upregulation of Na+/H+ exchange reduced the cellular acid load induced by butyrate, it did not rescue HT29 cells from butyrate induced cell death. ZnR/GPR39 activation however, increased the expression of the anti-apoptotic protein clusterin in butyrate-treated cells. Furthermore, silencing of clusterin abolished the Zn2+-dependent survival of HT29 cells. Altogether, our results demonstrate that extracellular Zn2+, acting through ZnR, regulates intracellular pH and clusterin expression thereby enhancing survival of HT29 colonocytes. Moreover, we identify GPR39 as the molecular moiety of ZnR in HT29 and native colonocytes. PMID:22545109

  4. Dietary Blueberry Attenuates Whole-Body Insulin Resistance in High Fat-Fed Mice by Reducing Adipocyte Death and Its Inflammatory Sequelae1–3

    PubMed Central

    DeFuria, Jason; Bennett, Grace; Strissel, Katherine J.; Perfield, James W.; Milbury, Paul E.; Greenberg, Andrew S.; Obin, Martin S.

    2009-01-01

    Adipose tissue (AT) inflammation promotes insulin resistance (IR) and other obesity complications. AT inflammation and IR are associated with oxidative stress, adipocyte death, and the scavenging of dead adipocytes by proinflammatory CD11c+ AT macrophages (ATMΦ). We tested the hypothesis that supplementation of an obesitogenic (high-fat) diet with whole blueberry (BB) powder protects against AT inflammation and IR. Male C57Bl/6j mice were maintained for 8 wk on 1 of 3 diets: low-fat (10% of energy) diet (LFD), high-fat (60% of energy) diet (HFD) or the HFD containing 4% (wt:wt) whole BB powder (1:1 Vaccinium ashei and V. corymbosum) (HFD+B). BB supplementation (2.7% of total energy) did not affect HFD-associated alterations in energy intake, metabolic rate, body weight, or adiposity. We observed an emerging pattern of gene expression in AT of HFD mice indicating a shift toward global upregulation of inflammatory genes (tumor necrosis factor-α, interleukin-6, monocyte chemoattractant protein 1, inducible nitric oxide synthase), increased M1-polarized ATMΦ (CD11c+), and increased oxidative stress (reduced glutathione peroxidase 3). This shift was attenuated or nonexistent in HFD+B-fed mice. Furthermore, mice fed the HFD+B were protected from IR and hyperglycemia coincident with reductions in adipocyte death. Salutary effects of BB on adipocyte physiology and ATMΦ gene expression may reflect the ability of BB anthocyanins to alter mitogen-activated protein kinase and nuclear factor-κB stress signaling pathways, which regulate cell fate and inflammatory genes. These results suggest that cytoprotective and antiinflammatory actions of dietary BB can provide metabolic benefits to combat obesity-associated pathology. PMID:19515743

  5. Can a nudge keep you warm? Using nudges to reduce excess winter deaths: insight from the Keeping Warm in Later Life Project (KWILLT)

    PubMed Central

    Allmark, Peter; Tod, Angela M.

    2014-01-01

    Nudges are interventions that aim to change people's behaviour through changing the environment in which they choose rather than appealing to their reasoning. Nudges have been proposed as of possible use in relation to health-related behaviour. However, nudges have been criticized as ethically dubious because they bypass peoples reasoning and (anyway) are of little help in relation to affecting ill-health that results from social determinants, such as poverty. Reducing the rate of excess winter deaths (EWDs) is a public health priority; however, EWD seems clearly to be socially determined such that nudges arguably have little role. This article defends two claims: (i) nudges could have a place in tackling even the heavily socially determined problem of EWD. We draw on evidence from an empirical study, the Keeping Warm in Later Life Project (KWILLT), to argue that in some cases the risk of cold is within the person’s control to some extent such that environmental modifications to influence behaviour such as nudges are possible. (ii) Some uses of behavioural insights in the form of nudges are acceptable, including some in the area of EWD. We suggest a question-based framework by which to judge the ethical acceptability of nudges. PMID:23873728

  6. MiR-335 Regulates Hif-1α to Reduce Cell Death in Both Mouse Cell Line and Rat Ischemic Models

    PubMed Central

    Liu, Fu Jia; Kaur, Prameet; Karolina, Dwi S.; Sepramaniam, Sugunavathi; Armugam, Arunmozhiarasi; Wong, Peter T. H.; Jeyaseelan, Kandiah

    2015-01-01

    Hypoxia inducible factor-1α facilitates cellular adaptation to hypoxic conditions. Hence its tight regulation is crucial in hypoxia related diseases such as cerebral ischemia. Changes in hypoxia inducible factor-1α expression upon cerebral ischemia influence the expression of its downstream genes which eventually determines the extent of cellular damage. MicroRNAs are endogenous regulators of gene expression that have rapidly emerged as promising therapeutic targets in several diseases. In this study, we have identified miR-335 as a direct regulator of hypoxia inducible factor-1α and as a potential therapeutic target in cerebral ischemia. MiR-335 and hypoxia inducible factor-1α mRNA showed an inverse expression profile, both in vivo and in vitro ischemic conditions. Given the biphasic nature of hypoxia inducible factor-1α expression during cerebral ischemia, miR-335 mimic was found to reduce infarct volume in the early time (immediately after middle cerebral artery occlusion) of embolic stroke animal models while the miR-335 inhibitor appears to be beneficial at the late time of stroke (24 hrs after middle cerebral artery occlusion). Modulation of hypoxia inducible factor-1α expression by miR-335 also influenced the expression of crucial genes implicated in neurovascular permeability, cell death and maintenance of the blood brain barrier. These concerted effects, resulting in a reduction in infarct volume bring about a beneficial outcome in ischemic stroke. PMID:26030758

  7. Incidence of sudden cardiac death associated with coronary artery occlusion in dogs with hypertension and left ventricular hypertrophy is reduced by chronic beta-adrenergic blockade.

    PubMed

    Dellsperger, K C; Martins, J B; Clothier, J L; Marcus, M L

    1990-09-01

    Because beta-adrenergic blockade has as one of its many effects altered electrophysiological abnormalities after dogs with left ventricular hypertrophy have been subjected to coronary occlusion, we tested the hypothesis that metoprolol (200-400 mg/day) would reduce mortality rates in dogs with one-kidney, one clip left ventricular hypertrophy while a similar reduction in arterial pressure with enalapril (20-40 mg/day) would not. Dogs with left ventricular hypertrophy were given metoprolol or enalapril for 5-7 days before a 3-hour coronary occlusion. Infarct size and risk area were measured with triphenyltetrazolium chloride stain and barium angiography, respectively. For control (n = 15), left ventricular hypertrophy (n = 17), left ventricular hypertrophy plus metoprolol (n = 12), and left ventricular hypertrophy plus enalapril (n = 15) groups, mean arterial pressure, ratio of infarct size to risk area, and dogs experiencing sudden death were 110 +/- 4, 142 +/- 4, 121 +/- 7, and 120 +/- 3 mm Hg; 44 +/- 5%, 65 +/- 5%, 44 +/- 7%, and 30 +/- 4%; and 27%, 65%, 17%, and 53%, respectively. Thus, the excessive increase in early mortality occurring when dogs with hypertension and left ventricular hypertrophy undergo coronary occlusion is interrupted with beta-blockade, possibly via electrophysiological effects rather than by changes in arterial pressure or infarct size. PMID:1975521

  8. Hydrogen-rich saline reduces cell death through inhibition of DNA oxidative stress and overactivation of poly (ADP-ribose) polymerase-1 in retinal ischemia-reperfusion injury.

    PubMed

    Liu, Hongwei; Hua, Ning; Xie, Keliang; Zhao, Tingting; Yu, Yonghao

    2015-08-01

    Overactivation of poly (ADP-ribose) polymerase 1 (PARP-1), as a result of sustained DNA oxidation in ischemia-reperfusion injury, triggers programmed cell necrosis and apoptosis. The present study was conducted to demonstrate whether hydrogen-rich saline (HRS) has a neuroprotective effect on retinal ischemia reperfusion (RIR) injury through inhibition of PARP-1 activation. RIR was induced by transient elevation of intraocular pressure in rats. HRS (5 ml/kg) was administered peritoneally every day from the beginning of reperfusion in RIR rats until the rats were sacrificed. Retinal damage and cell death was determined using hematoxylin and eosin and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. DNA oxidative stress was evaluated by immunofluorescence staining of 8-hydroxy-2-deoxyguanosine. In addition, the expression of PARP-1 and caspase-3 was investigated by western blot analysis and/or immunohistochemical staining. The results demonstrated that HRS administration improved morphological alterations and reduced apoptosis following RIR injury. Furthermore, the present study found that HRS alleviated DNA oxidation and PARP-1 overactivation in RIR rats. HRS can protect RIR injury by inhibition of PARP-1, which may be involved in DNA oxidative stress and caspase-3-mediated apoptosis. PMID:25954991

  9. Hydrogen-rich saline reduces cell death through inhibition of DNA oxidative stress and overactivation of poly (ADP-ribose) polymerase-1 in retinal ischemia-reperfusion injury

    PubMed Central

    LIU, HONGWEI; HUA, NING; XIE, KELIANG; ZHAO, TINGTING; YU, YONGHAO

    2015-01-01

    Overactivation of poly (ADP-ribose) polymerase 1 (PARP-1), as a result of sustained DNA oxidation in ischemia-reperfusion injury, triggers programmed cell necrosis and apoptosis. The present study was conducted to demonstrate whether hydrogen-rich saline (HRS) has a neuroprotective effect on retinal ischemia reperfusion (RIR) injury through inhibition of PARP-1 activation. RIR was induced by transient elevation of intraocular pressure in rats. HRS (5 ml/kg) was administered peritoneally every day from the beginning of reperfusion in RIR rats until the rats were sacrificed. Retinal damage and cell death was determined using hematoxylin and eosin and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. DNA oxidative stress was evaluated by immunofluorescence staining of 8-hydroxy-2-deoxyguanosine. In addition, the expression of PARP-1 and caspase-3 was investigated by western blot analysis and/or immunohistochemical staining. The results demonstrated that HRS administration improved morphological alterations and reduced apoptosis following RIR injury. Furthermore, the present study found that HRS alleviated DNA oxidation and PARP-1 overactivation in RIR rats. HRS can protect RIR injury by inhibition of PARP-1, which may be involved in DNA oxidative stress and caspase-3-mediated apoptosis. PMID:25954991

  10. Can a nudge keep you warm? Using nudges to reduce excess winter deaths: insight from the Keeping Warm in Later Life Project (KWILLT).

    PubMed

    Allmark, Peter; Tod, Angela M

    2014-03-01

    Nudges are interventions that aim to change people's behaviour through changing the environment in which they choose rather than appealing to their reasoning. Nudges have been proposed as of possible use in relation to health-related behaviour. However, nudges have been criticized as ethically dubious because they bypass peoples reasoning and (anyway) are of little help in relation to affecting ill-health that results from social determinants, such as poverty. Reducing the rate of excess winter deaths (EWDs) is a public health priority; however, EWD seems clearly to be socially determined such that nudges arguably have little role. This article defends two claims: (i) nudges could have a place in tackling even the heavily socially determined problem of EWD. We draw on evidence from an empirical study, the Keeping Warm in Later Life Project (KWILLT), to argue that in some cases the risk of cold is within the person's control to some extent such that environmental modifications to influence behaviour such as nudges are possible. (ii) Some uses of behavioural insights in the form of nudges are acceptable, including some in the area of EWD. We suggest a question-based framework by which to judge the ethical acceptability of nudges. PMID:23873728

  11. A health survey of toll booth workers

    SciTech Connect

    Strauss, P.; Orris, P.; Buckley, L. )

    1992-01-01

    The prevalence of respiratory and other health problems in a cohort of highway toll booth workers was surveyed by mailed questionnaire. In a low proportion of respondents (43.2%), a high prevalence of central nervous system complaints (headaches, irritability, or anxiety, and unusual tiredness), mucous membrane irritation (eye irritation, nasal congestion, and dry throat), and musculoskeletal problems (joint and back pains) was found. We believe these symptoms are reflective of the acute irritant and central nervous system effects of exposure to motor vehicle exhaust. The musculoskeletal complaints are likely the result of bending, reaching, and leaning out of the toll booth. The need for in-depth evaluation of the ventilation systems and the ergonomic and job stressors of work at toll booths is suggested by these results.

  12. Cot Deaths.

    ERIC Educational Resources Information Center

    Tyrrell, Shelagh

    1985-01-01

    Addresses the tragedy of crib deaths, giving particular attention to causes, prevention, and medical research on Sudden Infant Death Syndrome (SIDS). Gives anecdotal accounts of coping strategies used by parents and families of SIDS infants. (DT)

  13. 47 CFR 51.209 - Toll dialing parity.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 3 2012-10-01 2012-10-01 false Toll dialing parity. 51.209 Section 51.209... Obligations of All Local Exchange Carriers § 51.209 Toll dialing parity. (a) A LEC shall implement throughout each state in which it offers telephone exchange service intraLATA and interLATA toll dialing...

  14. 47 CFR 51.209 - Toll dialing parity.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 3 2014-10-01 2014-10-01 false Toll dialing parity. 51.209 Section 51.209... Obligations of All Local Exchange Carriers § 51.209 Toll dialing parity. (a) A LEC shall implement throughout each state in which it offers telephone exchange service intraLATA and interLATA toll dialing...

  15. 47 CFR 51.209 - Toll dialing parity.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 3 2010-10-01 2010-10-01 false Toll dialing parity. 51.209 Section 51.209... Obligations of All Local Exchange Carriers § 51.209 Toll dialing parity. (a) A LEC shall implement throughout each state in which it offers telephone exchange service intraLATA and interLATA toll dialing...

  16. 47 CFR 51.209 - Toll dialing parity.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 3 2013-10-01 2013-10-01 false Toll dialing parity. 51.209 Section 51.209... Obligations of All Local Exchange Carriers § 51.209 Toll dialing parity. (a) A LEC shall implement throughout each state in which it offers telephone exchange service intraLATA and interLATA toll dialing...

  17. 47 CFR 51.209 - Toll dialing parity.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 3 2011-10-01 2011-10-01 false Toll dialing parity. 51.209 Section 51.209... Obligations of All Local Exchange Carriers § 51.209 Toll dialing parity. (a) A LEC shall implement throughout each state in which it offers telephone exchange service intraLATA and interLATA toll dialing...

  18. 40 CFR 52.111 - Toll free number assignment.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 3 2013-07-01 2013-07-01 false Toll free number assignment. 52.111... (CONTINUED) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS Arizona § 52.111 Toll free number assignment. Toll free numbers shall be made available on a first-come, first-served basis unless otherwise...

  19. 40 CFR 52.111 - Toll free number assignment.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 3 2012-07-01 2012-07-01 false Toll free number assignment. 52.111... (CONTINUED) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS Arizona § 52.111 Toll free number assignment. Toll free numbers shall be made available on a first-come, first-served basis unless otherwise...

  20. 40 CFR 52.111 - Toll free number assignment.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 3 2014-07-01 2014-07-01 false Toll free number assignment. 52.111... (CONTINUED) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS Arizona § 52.111 Toll free number assignment. Toll free numbers shall be made available on a first-come, first-served basis unless otherwise...

  1. 40 CFR 52.111 - Toll free number assignment.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 3 2010-07-01 2010-07-01 false Toll free number assignment. 52.111... (CONTINUED) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS Arizona § 52.111 Toll free number assignment. Toll free numbers shall be made available on a first-come, first-served basis unless otherwise...

  2. 40 CFR 52.111 - Toll free number assignment.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 3 2011-07-01 2011-07-01 false Toll free number assignment. 52.111... (CONTINUED) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS Arizona § 52.111 Toll free number assignment. Toll free numbers shall be made available on a first-come, first-served basis unless otherwise...

  3. Understanding Death.

    ERIC Educational Resources Information Center

    Heath, Charles P.

    1986-01-01

    Bibliotherapy can help children prepare for and understand the death of a loved one. An annotated bibliography lists references with age level information on attitudes toward death and deaths of a father, friend, grandparent, mother, pet, and sibling. (Author/CL)

  4. Clean birth and postnatal care practices to reduce neonatal deaths from sepsis and tetanus: a systematic review and Delphi estimation of mortality effect

    PubMed Central

    2011-01-01

    Background Annually over 520,000 newborns die from neonatal sepsis, and 60,000 more from tetanus. Estimates of the effect of clean birth and postnatal care practices are required for evidence-based program planning. Objective To review the evidence for clean birth and postnatal care practices and estimate the effect on neonatal mortality from sepsis and tetanus for the Lives Saved Tool (LiST). Methods We conducted a systematic review of multiple databases. Data were abstracted into standard tables and assessed by GRADE criteria. Where appropriate, meta-analyses were undertaken. For interventions with low quality evidence but a strong GRADE recommendation, a Delphi process was conducted. Results Low quality evidence supports a reduction in all-cause neonatal mortality (19% (95% c.i. 1–34%)), cord infection (30% (95% c.i. 20–39%)) and neonatal tetanus (49% (95% c.i. 35–62%)) with birth attendant handwashing. Very low quality evidence supports a reduction in neonatal tetanus mortality with a clean birth surface (93% (95% c.i. 77-100%)) and no relationship between a clean perineum and tetanus. Low quality evidence supports a reduction of neonatal tetanus with facility birth (68% (95% c.i. 47-88%). No relationship was found between birth place and cord infections or sepsis mortality. For postnatal clean practices, all-cause mortality is reduced with chlorhexidine cord applications in the first 24 hours of life (34% (95% c.i. 5–54%, moderate quality evidence) and antimicrobial cord applications (63% (95% c.i. 41–86%, low quality evidence). One study of postnatal maternal handwashing reported reductions in all-cause mortality (44% (95% c.i. 18–62%)) and cord infection ((24% (95% c.i. 5-40%)). Given the low quality of evidence, a Delphi expert opinion process was undertaken. Thirty experts reached consensus regarding reduction of neonatal sepsis deaths by clean birth practices at home (15% (IQR 10–20)) or in a facility (27% IQR 24–36)), and by clean

  5. Operational benefits of electronic toll collection: Case study

    SciTech Connect

    Al-Deek, H.M.; Mohamed, A.A.; Radwan, A.E.

    1997-11-01

    This paper reports the improvements in traffic operations at the electronic toll collection plazas of the Orlando-Orange County Expressway Authority. Service time, vehicle arrival times, and departure times, as well as vehicle counts were collected before and after the installation of automatic vehicle identification technology known as E-PASS. The findings indicate that, for the dedicated E-PASS lane, the measured capacity has tripled, the service time has decreased by five seconds per vehicle, the average queuing delay has decreased by one minute per vehicle, the maximum queuing delay has decreased by 2.5--3 minutes per vehicle, and the total queuing delay has decreased by 8.5--9.5 vehicle-hours per morning peak hour for that lane. Also, variability in the headway has been reduced significantly in the dedicated E-PASS lane. Capacity, headway, and service times of the mixed (manual/E-PASS or automatic/E-PASS) lanes did not change significantly. However, arrivals have shifted to the dedicated E-PASS lanes, thus reducing delays at the mixed lanes and improving traffic operations for the entire toll plaza.

  6. Exposure to electromagnetic field attenuates oxygen-glucose deprivation-induced microglial cell death by reducing intracellular Ca(2+) and ROS.

    PubMed

    Duong, Cao Nguyen; Kim, Jae Young

    2016-01-01

    Purpose The aim of this research was to demonstrate the protective effects of electromagnetic field (EMF) exposure on the human microglial cell line, HMO6, against ischemic cell death induced by in vitro oxygen-glucose deprivation (OGD). Materials and methods HMO6 cells were cultured for 4 h under OGD with or without exposure to EMF with different combinations of frequencies and intensities (10, 50, or 100 Hz/1 mT and 50 Hz/0.01, 0.1, or 1 mT). Cell survival, intracellular calcium and reactive oxygen species (ROS) levels were measured. Results OGD caused significant HMO6 cell death as well as elevation of intracellular Ca(2+) and ROS levels. Among different combinations of EMF frequencies and intensities, 50 Hz/1 mT EMF was the most potent to attenuate OGD-induced cell death and intracellular Ca(2+) and ROS levels. A significant but less potent protective effect was also found at 10 Hz/1 mT, whereas no protective effect was found at other combinations of EMF. A xanthine oxidase inhibitor reversed OGD-induced ROS production and cell death, while NADPH oxidase and mitochondrial respiration chain complex II inhibitors did not affect cell death. Conclusions 50 Hz/1 mT EMF protects human microglial cells from OGD-induced cell death by interfering with OGD-induced elevation of intracellular Ca(2+) and ROS levels, and xanthine oxidase is one of the main mediators involved in OGD-induced HMO6 cell death. Non-invasive treatment of EMF radiation may be clinically useful to attenuate hypoxic-ischemic brain injury. PMID:26882219

  7. The Excess Winter Deaths Measure

    PubMed Central

    Gasparrini, Antonio

    2016-01-01

    Background: Excess winter deaths, the ratio between average daily deaths in December–March versus other months, is a measure commonly used by public health practitioners and analysts to assess health burdens associated with wintertime weather. We seek to demonstrate that this measure is fundamentally biased and can lead to misleading conclusions about health impacts associated with current and future winter climate. Methods: Time series regression analysis of 779,372 deaths from natural causes in London over 15 years (1 August 1997–31 July 2012),collapsed by day of death and linked to daily temperature values. The outcome measures were the excess winter deaths index, and daily and annual deaths attributable specifically to cold. Results: Most of the excess winter deaths are driven by cold: The excess winter deaths index decreased from 1.19 to 1.07 after excluding deaths attributable to low temperatures. Over 40% of cold-attributable deaths occurred outside of the December–March period, leading to bias in the excess winter deaths measure. Although there was no relationship between winter severity and annual excess winter deaths, there was a clear correlation with annual cold-attributable deaths. Conclusions: Excess winter deaths is not an appropriate indicator of cold-related health impacts, and its use should be discontinued. We advocate alternative measures. The findings we present bring into doubt previous claims that cold-related deaths in the UK will not reduce in future as a result of climate change. PMID:26986872

  8. Hypothermic Machine Perfusion Reduced Inflammatory Reaction by Downregulating the Expression of Matrix Metalloproteinase 9 in a Reperfusion Model of Donation After Cardiac Death.

    PubMed

    Fu, Zhen; Ye, Qifa; Zhang, Yang; Zhong, Zibiao; Xiong, Yan; Wang, Yanfeng; Hu, Long; Wang, Wei; Huang, Wei; Ko, Dicken Shiu-Chung

    2016-06-01

    The exact mechanism by which hypothermic machine perfusion (HMP) improves the graft quality in kidney transplantation of donation after cardiac death (DCD) remains unclear. The aim of this study was to investigate the correlation between the expression of matrix metalloproteinase 9 (MMP-9) and inflammatory reaction in kidney ischemia-reperfusion (I/R) injury injury followed by cold storage (CS) or HMP model of DCD. New Zealand white rabbit kidneys were subjected to 35 min of warm ischemia and 1 h reperfusion, then preserved by either 1 h reperfusion (sham-operated group), 4 h CS or 4 h HMP in vivo. Kidneys were reperfused 24 h followed by further analysis. No treatment was given to rabbits in the normal control group. The expression of MMP-9, nuclear factor-κB (NF-κB), and MMP-2 mRNA were detected by real-time PCR (RT-PCR). MMP-9 was located by immunohistochemistry and immunofluorescence methods. Tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), myeloperoxidase (MPO), superoxide dismutase (SOD), and malondialdehyde (MDA) were measured by kits for each groups. Compared with the CS group, the expression of MMP-9 and NF-κB mRNA were downregulated in HMP group (P < 0.05). In contrast, expression of MMP-2 mRNA had no statistical significance between CS group and HMP group (P > 0.05). In normal control and sham-operated groups, a low level of MMP-9 expression was detected in glomeruli. However, positive signals of MMP-9 were mostly located in the tubulointerstitium and the vascular wall of CS and HMP groups. Expression of TNF-α, IL-6, MDA, and activity of MPO decreased while activity of SOD in the HMP group increased in contrast to the CS group (P < 0.05). In conclusion, inflammatory cytokines mediated MMP-9 expression through NF-κB band to MMP-9 promoter region, resulting in renal injury. Therefore, HMP reduced inflammatory reaction by downregulating the expression of MMP-9, which may be the mechanism of kidney protection in I

  9. Wnt3a mitigates acute lung injury by reducing P2X7 receptor-mediated alveolar epithelial type I cell death

    PubMed Central

    Guo, Y; Mishra, A; Weng, T; Chintagari, N R; Wang, Y; Zhao, C; Huang, C; Liu, L

    2014-01-01

    Acute lung injury (ALI) is characterized by pulmonary endothelial and epithelial cell damage, and loss of the alveolar–capillary barrier. We have previously shown that P2X7 receptor (P2X7R), a cell death receptor, is specifically expressed in alveolar epithelial type I cells (AEC I). In this study, we hypothesized that P2X7R-mediated purinergic signaling and its interaction with Wnt/β-catenin signaling contributes to AEC I death. We examined the effect of P2X7R agonist 2′-3′-O-(4-benzoylbenzoyl)-ATP (BzATP) and Wnt agonist Wnt3a on AEC I death in vitro and in vivo. We also assessed the therapeutic potential of Wnt3a in a clinically relevant ALI model of intratracheal lipopolysaccharide (LPS) exposure in ventilated mice. We found that the activation of P2X7R by BzATP caused the death of AEC I by suppressing Wnt/β-catenin signaling through stimulating glycogen synthase kinase-3β (GSK-3β) and proteasome. On the other hand, the activation of Wnt/β-catenin signaling by Wnt3a, GSK-3β inhibitor, or proteasome inhibitor blocked the P2X7R-mediated cell death. More importantly, Wnt3a attenuated the AEC I damage caused by intratracheal instillation of BzATP in rats or LPS in ventilated mice. Our results suggest that Wnt3a overrides the effect of P2X7R on the Wnt/β-catenin signaling to prevent the AEC I death and restrict the severity of ALI. PMID:24922070

  10. Enhanced antimicrobial peptide-induced activity in the mollusc Toll-2 family through evolution via tandem Toll/interleukin-1 receptor

    PubMed Central

    Cao, Jun; Chen, Yihong; Jin, Min; Ren, Qian

    2016-01-01

    Toll receptors play an important role in the innate immunity of invertebrates. All reported Tolls have only one Toll/interleukin-1 receptor (TIR) domain at the C-terminal. In this study, numerous Tolls with tandem TIRs at the C-terminal were found in molluscs. Such Tolls presented an extra TIR (TIR-1) compared with Toll-I. Thus, Toll-I might be the ancestor of tandem TIRs containing Toll. To test this hypothesis, 83 Toll-I and Toll-2 (most have two TIRs, but others seem to be the evolutionary intermediates) genes from 29 shellfish species were identified. These Tolls were divided into nine groups based on phylogenetic analyses. A strong correlation between phylogeny and motif composition was found. All Toll proteins contained the TIR-2 domain, whereas the TIR-1 domain only existed in some Toll-2 protein, suggesting that TIR-1 domain insertion may play an important role in Toll protein evolution. Further analyses of functional divergence and adaptive evolution showed that some of the critical sites responsible for functional divergence may have been under positive selection. An additional intragenic recombination played an important role in the evolution of the Toll-I and Toll-2 genes. To investigate the functional difference of Toll-I and Toll-2, over expression of Hcu_Toll-I or Hcu_Toll-2-2 in Drosophila S2 cells was performed. Results showed that Hcu_Toll-2-2 had stronger antimicrobial peptide (AMP) activity than Hcu_Toll-I. Therefore, enhanced AMP-induced activity resulted from tandem TIRs in Toll-2s of molluscs during evolution history. PMID:27429771

  11. Enhanced antimicrobial peptide-induced activity in the mollusc Toll-2 family through evolution via tandem Toll/interleukin-1 receptor.

    PubMed

    Cao, Jun; Chen, Yihong; Jin, Min; Ren, Qian

    2016-06-01

    Toll receptors play an important role in the innate immunity of invertebrates. All reported Tolls have only one Toll/interleukin-1 receptor (TIR) domain at the C-terminal. In this study, numerous Tolls with tandem TIRs at the C-terminal were found in molluscs. Such Tolls presented an extra TIR (TIR-1) compared with Toll-I. Thus, Toll-I might be the ancestor of tandem TIRs containing Toll. To test this hypothesis, 83 Toll-I and Toll-2 (most have two TIRs, but others seem to be the evolutionary intermediates) genes from 29 shellfish species were identified. These Tolls were divided into nine groups based on phylogenetic analyses. A strong correlation between phylogeny and motif composition was found. All Toll proteins contained the TIR-2 domain, whereas the TIR-1 domain only existed in some Toll-2 protein, suggesting that TIR-1 domain insertion may play an important role in Toll protein evolution. Further analyses of functional divergence and adaptive evolution showed that some of the critical sites responsible for functional divergence may have been under positive selection. An additional intragenic recombination played an important role in the evolution of the Toll-I and Toll-2 genes. To investigate the functional difference of Toll-I and Toll-2, over expression of Hcu_Toll-I or Hcu_Toll-2-2 in Drosophila S2 cells was performed. Results showed that Hcu_Toll-2-2 had stronger antimicrobial peptide (AMP) activity than Hcu_Toll-I. Therefore, enhanced AMP-induced activity resulted from tandem TIRs in Toll-2s of molluscs during evolution history. PMID:27429771

  12. Practicing death.

    PubMed

    Avny, Ohad; Alon, Aya

    2016-07-01

    This narrative describes the struggle of a primary care physician contending with the challenge of remaining committed to his patient's care despite a sense of burnout in relation to an intense period of patient deaths. The story presents two patient deaths and the physician's reflections on how he handled both cases. PMID:26899633

  13. Dietary blueberry attenuates whole-body insulin resistance in high fat-fed mice by reducing adipocyte death and its inflammatory sequelae

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Adipose tissue (AT) inflammation promotes insulin resistance (IR) and other obesity complications. AT inflammation and IR are associated with oxidative stress, adipocyte death, and the scavenging of dead adipocytes by proinflammatory CD11c+ AT macrophages (ATMF). We tested the hypothesis that supple...

  14. The biology of Toll-like receptors.

    PubMed

    Means, T K; Golenbock, D T; Fenton, M J

    2000-09-01

    In 1997, a human homologue of the Drosophila Toll protein was described, a protein later to be designated Toll-like receptor 4 (TLR4). Since that time, additional human and murine TLR proteins have been identified. Mammalian TLR proteins appear to represent a conserved family of innate immune recognition receptors. These receptors are coupled to a signaling pathway that is conserved in mammals, insects, and plants, resulting in the activation of genes that mediate innate immune defenses. Numerous studies have now identified a wide variety of chemically-diverse bacterial products that serve as putative ligands for TLR proteins. More recent studies have identified the first endogenous protein ligands for TLR proteins. TLR signaling represents a key feature of innate immune response to pathogen invasion. PMID:10817965

  15. 23 CFR 950.5 - Requirement to use electronic toll collection technology.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 23 Highways 1 2011-04-01 2011-04-01 false Requirement to use electronic toll collection technology... technology. (a) Any toll agency operating a toll facility pursuant to authority under a 1604 toll program... agency using electronic toll collection technology must develop and implement reasonable methods...

  16. 23 CFR 950.5 - Requirement to use electronic toll collection technology.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 23 Highways 1 2013-04-01 2013-04-01 false Requirement to use electronic toll collection technology... technology. (a) Any toll agency operating a toll facility pursuant to authority under a 1604 toll program... agency using electronic toll collection technology must develop and implement reasonable methods...

  17. 23 CFR 950.5 - Requirement to use electronic toll collection technology.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 23 Highways 1 2014-04-01 2014-04-01 false Requirement to use electronic toll collection technology... technology. (a) Any toll agency operating a toll facility pursuant to authority under a 1604 toll program... agency using electronic toll collection technology must develop and implement reasonable methods...

  18. 23 CFR 950.5 - Requirement to use electronic toll collection technology.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 23 Highways 1 2012-04-01 2012-04-01 false Requirement to use electronic toll collection technology... technology. (a) Any toll agency operating a toll facility pursuant to authority under a 1604 toll program... agency using electronic toll collection technology must develop and implement reasonable methods...

  19. 23 CFR 950.5 - Requirement to use electronic toll collection technology.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 23 Highways 1 2010-04-01 2010-04-01 false Requirement to use electronic toll collection technology... technology. (a) Any toll agency operating a toll facility pursuant to authority under a 1604 toll program... agency using electronic toll collection technology must develop and implement reasonable methods...

  20. Death duties

    PubMed Central

    Myers, Kathryn A.; Eden, David

    2007-01-01

    PROBLEM BEING ADDRESSED Family physicians are often called upon to pronounce and certify the deaths of patients. Inadequate knowledge of the Coroners Act (in the province of Ontario) and of the correct process of certifying death can make physicians uncomfortable when confronted with these tasks. OBJECTIVE OF PROGRAM To educate family physicians about how to perform the administrative tasks required of them when patients die. PROGRAM DESCRIPTION The program included an educational video, a tutorial outlining the process of death certification, and discussion with a regional coroner about key features of the Coroners Act. In small groups, participants worked through cases of patient deaths in which they were asked to determine whether a coroner needed to be involved, to determine the manner of death, and to complete a mock death certificate for each case. CONCLUSION All participants reported a high level of satisfaction with the workshop and thought the main objective of the program had been achieved. Results of a test given 3 months after the workshop showed substantial improvement in participants’ knowledge of the coroner’s role and of the process of death certification. PMID:17872782

  1. Neonatal Death

    MedlinePlus

    ... story First Candle Centering Corporation The Compassionate Friends Star Legacy Foundation Last reviewed: November, 2015 Neonatal death ... story First Candle Centering Corporation The Compassionate Friends Star Legacy Foundation Last reviewed: November, 2015 Complications & Loss ...

  2. Fructus ligustri lucidi extracts induce human glioma cell death through regulation of Akt/mTOR pathway in vitro and reduce glioma tumor growth in U87MG xenograft mouse model.

    PubMed

    Jeong, Ji Cheon; Kim, Jin Won; Kwon, Chae Hwa; Kim, Thae Hyun; Kim, Yong Keun

    2011-03-01

    The present study was undertaken to examine the effect of Fructus ligustri lucidi (FLL) extracts on glioma cell growth and to determine the underlying mechanism by which FLL extracts exert anticancer properties in human U87MG glioma cells. The FLL extracts resulted in cell death in a dose- and time-dependent manner. Western blot analysis showed that treatment with FLL extracts caused down-regulation of the phosphatidylinositol-3 kinase (PI3K)/Akt pathway. Overexpression of Akt prevented the cell death induced by the FLL extracts. The FLL extracts caused a decrease in the expression of mammalian target of rapamycin (mTOR) and the FLL extract-induced cell death was increased by the mTOR inhibitor rapamycin. The FLL extracts decreased the expression of survivin. Oral administration of FLL extracts in subcutaneous U87MG xenograft models reduced the glioma tumor volume. These findings indicate that the FLL extracts resulted in glioma cell death through regulation of the Akt/mTOR/survivin pathway in vitro and inhibited glioma tumor growth in vivo. These data suggest that the FLL extracts may serve as a potential therapeutic agent for malignant human gliomas. PMID:20737659

  3. Emergency department naloxone distribution: a Rhode Island department of health, recovery community, and emergency department partnership to reduce opioid overdose deaths.

    PubMed

    Samuels, Elizabeth

    2014-10-01

    In response to increasing rates of opioid overdose deaths in Rhode Island (RI), the RI Department of Health, RI emergency physicians, and Anchor Community Recovery Center designed an emergency department (ED) naloxone distribution and peer-recovery coach program for people at risk of opioid overdose. ED patients at risk for overdose are offered a take home naloxone kit, patient education video, and, when available, an Anchor peer recovery coach to provide recovery support and referral to treatment. In August 2014, the program launched at Kent, Miriam, and Rhode Island Hospital Emergency Departments. PMID:25271659

  4. T-cell death following immune activation is mediated by mitochondria-localized SARM.

    PubMed

    Panneerselvam, P; Singh, L P; Selvarajan, V; Chng, W J; Ng, S B; Tan, N S; Ho, B; Chen, J; Ding, J L

    2013-03-01

    Following acute-phase infection, activated T cells are terminated to achieve immune homeostasis, failure of which results in lymphoproliferative and autoimmune diseases. We report that sterile α- and heat armadillo-motif-containing protein (SARM), the most conserved Toll-like receptors adaptor, is proapoptotic during T-cell immune response. SARM expression is significantly reduced in natural killer (NK)/T lymphoma patients compared with healthy individuals, suggesting that decreased SARM supports NK/T-cell proliferation. T cells knocked down of SARM survived and proliferated more significantly compared with wild-type T cells following influenza infection in vivo. During activation of cytotoxic T cells, the SARM level fell before rising, correlating inversely with cell proliferation and subsequent T-cell clearance. SARM knockdown rescued T cells from both activation- and neglect-induced cell deaths. The mitochondria-localized SARM triggers intrinsic apoptosis by generating reactive oxygen species and depolarizing the mitochondrial potential. The proapoptotic function is attributable to the C-terminal sterile alpha motif and Toll/interleukin-1 receptor domains. Mechanistically, SARM mediates intrinsic apoptosis via B cell lymphoma-2 (Bcl-2) family members. SARM suppresses B cell lymphoma-extra large (Bcl-xL) and downregulates extracellular signal-regulated kinase phosphorylation, which are cell survival effectors. Overexpression of Bcl-xL and double knockout of Bcl-2 associated X protein and Bcl-2 homologous antagonist killer substantially reduced SARM-induced apoptosis. Collectively, we have shown how T-cell death following infection is mediated by SARM-induced intrinsic apoptosis, which is crucial for T-cell homeostasis. PMID:23175186

  5. 47 CFR 51.213 - Toll dialing parity implementation plans.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 3 2013-10-01 2013-10-01 false Toll dialing parity implementation plans. 51... parity implementation plans. (a) A LEC must file a plan for providing intraLATA toll dialing parity... dialing parity within a state until the implementation plan has been approved by the appropriate...

  6. 47 CFR 51.213 - Toll dialing parity implementation plans.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 3 2012-10-01 2012-10-01 false Toll dialing parity implementation plans. 51... parity implementation plans. (a) A LEC must file a plan for providing intraLATA toll dialing parity... dialing parity within a state until the implementation plan has been approved by the appropriate...

  7. 47 CFR 51.213 - Toll dialing parity implementation plans.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 3 2014-10-01 2014-10-01 false Toll dialing parity implementation plans. 51... parity implementation plans. (a) A LEC must file a plan for providing intraLATA toll dialing parity... dialing parity within a state until the implementation plan has been approved by the appropriate...

  8. 47 CFR 51.213 - Toll dialing parity implementation plans.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 3 2011-10-01 2011-10-01 false Toll dialing parity implementation plans. 51... parity implementation plans. (a) A LEC must file a plan for providing intraLATA toll dialing parity... dialing parity within a state until the implementation plan has been approved by the appropriate...

  9. 33 CFR 401.26 - Security for tolls.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Section 401.26 Navigation and Navigable Waters SAINT LAWRENCE SEAWAY DEVELOPMENT CORPORATION, DEPARTMENT... applies, security for the payment of tolls in accordance with the “St. Lawrence Seaway Tariff of Tolls” as... sufficient to cover the tolls established in the “St. Lawrence Seaway Tariff of Tolls” for the...

  10. Toll-Like Receptor Gene Expression during Trichinella spiralis Infection

    PubMed Central

    Kim, Sin; Park, Mi Kyung; Yu, Hak Sun

    2015-01-01

    In Trichinella spiralis infection, type 2 helper T (Th2) cell-related and regulatory T (Treg) cell-related immune responses are the most important immune events. In order to clarify which Toll-like receptors (TLRs) are closely associated with these responses, we analyzed the expression of mouse TLR genes in the small intestine and muscle tissue during T. spiralis infection. In addition, the expression of several chemokine- and cytokine-encoding genes, which are related to Th2 and Treg cell mediated immune responses, were analyzed in mouse embryonic fibroblasts (MEFs) isolated from myeloid differentiation factor 88 (MyD88)/TIR-associated proteins (TIRAP) and Toll receptor-associated activator of interferons (TRIF) adapter protein deficient and wild type (WT) mice. The results showed significantly increased TLR4 and TLR9 gene expression in the small intestine after 2 weeks of T. spiralis infection. In the muscle, TLR1, TLR2, TLR5, and TLR9 gene expression significantly increased after 4 weeks of infection. Only the expression of the TLR4 and TLR9 genes was significantly elevated in WT MEF cells after treatment with excretory-secretory (ES) proteins. Gene expression for Th2 chemokine genes were highly enhanced by ES proteins in WT MEF cells, while this elevation was slightly reduced in MyD88/TIRAP-/- MEF cells, and quite substantially decreased in TRIF-/- MEF cells. In contrast, IL-10 and TGF-β expression levels were not elevated in MyD88/TIRAP-/- MEF cells. In conclusion, we suggest that TLR4 and TLR9 might be closely linked to Th2 cell and Treg cell mediated immune responses, although additional data are needed to convincingly prove this observation. PMID:26323841

  11. Toll-Like Receptor Gene Expression during Trichinella spiralis Infection.

    PubMed

    Kim, Sin; Park, Mi Kyung; Yu, Hak Sun

    2015-08-01

    In Trichinella spiralis infection, type 2 helper T (Th2) cell-related and regulatory T (Treg) cell-related immune responses are the most important immune events. In order to clarify which Toll-like receptors (TLRs) are closely associated with these responses, we analyzed the expression of mouse TLR genes in the small intestine and muscle tissue during T. spiralis infection. In addition, the expression of several chemokine- and cytokine-encoding genes, which are related to Th2 and Treg cell mediated immune responses, were analyzed in mouse embryonic fibroblasts (MEFs) isolated from myeloid differentiation factor 88 (MyD88)/TIR-associated proteins (TIRAP) and Toll receptor-associated activator of interferons (TRIF) adapter protein deficient and wild type (WT) mice. The results showed significantly increased TLR4 and TLR9 gene expression in the small intestine after 2 weeks of T. spiralis infection. In the muscle, TLR1, TLR2, TLR5, and TLR9 gene expression significantly increased after 4 weeks of infection. Only the expression of the TLR4 and TLR9 genes was significantly elevated in WT MEF cells after treatment with excretory-secretory (ES) proteins. Gene expression for Th2 chemokine genes were highly enhanced by ES proteins in WT MEF cells, while this elevation was slightly reduced in MyD88/TIRAP(-/-) MEF cells, and quite substantially decreased in TRIF(-/-) MEF cells. In contrast, IL-10 and TGF-β expression levels were not elevated in MyD88/TIRAP(-/-) MEF cells. In conclusion, we suggest that TLR4 and TLR9 might be closely linked to Th2 cell and Treg cell mediated immune responses, although additional data are needed to convincingly prove this observation. PMID:26323841

  12. Conventional and Non-Conventional Drosophila Toll Signaling

    PubMed Central

    Lindsay, Scott A.; Wasserman, Steven A.

    2013-01-01

    The discovery of Toll in Drosophila and of the remarkable conservation in pathway composition and organization catalyzed a transformation in our understanding of innate immune recognition and response. At the center of that picture is a cascade of interactions in which specific microbial cues activate Toll receptors, which then transmit signals driving transcription factor nuclear localization and activity. Experiments gave substance to the vision of pattern recognition receptors, linked phenomena in development, gene regulation, and immunity into a coherent whole, and revealed a rich set of variations for identifying non-self and responding effectively. More recently, research in Drosophila has illuminated the positive and negative regulation of Toll activation, the organization of signaling events at and beneath membranes, the sorting of information flow, and the existence of non-conventional signaling via Toll-related receptors. Here, we provide an overview of the Toll pathway of flies and highlight these ongoing realms of research. PMID:23632253

  13. Toll-like Receptors in Tumor Immunotherapy

    PubMed Central

    Paulos, Chrystal M.; Kaiser, Andrew; Wrzesinski, Claudia; Hinrichs, Christian S.; Cassard, Lydie; Boni, Andrea; Muranski, Pawel; Sanchez-Perez, Luis; Palmer, Douglas C.; Yu, Zhiya; Antony, Paul A.; Gattinoni, Luca; Rosenberg, Steven A.; Restifo, Nicholas P.

    2007-01-01

    Lymphodepletion with chemotherapeutic agents or total body irradiation (TBI) before adoptive transfer of tumor-specific T cells is a critical advancement in the treatment of patients with melanoma. More than 50% of patients that are refractory to other treatments experience an objective or curative response with this approach. Emerging data indicate that the key mechanisms underlying how TBI augments the functions of adoptively transferred T cells include (a) the depletion of regulatory Tcells (Treg) and myeloid-derived suppressor cells that limit the function and proliferation of adoptively transferred cells; (b) the removal of immune cells that act as “sinks” for homeostatic cytokines, whose levels increase after lymphodepletion; and (c) the activation of the innate immune system via Toll-like receptor 4 signaling, which is engaged by microbial lipopolysaccharide that translocated across the radiation-injured gut. Here, we review these mechanisms and focus on the effect of Toll-like receptor agonists in adoptive immunotherapy. We also discuss alternate regimens to chemotherapy or TBI, which might be used to safely treat patients with advanced disease and promote tumor regression. PMID:17875756

  14. 47 CFR 63.65 - Closure of public toll station where another toll station of applicant in the community will...

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 3 2010-10-01 2010-10-01 false Closure of public toll station where another toll station of applicant in the community will continue service. 63.65 Section 63.65 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES (CONTINUED) EXTENSION OF LINES, NEW LINES, AND DISCONTINUANCE,...

  15. The Heart of 25 by 25: Achieving the Goal of Reducing Global and Regional Premature Deaths From Cardiovascular Diseases and Stroke: A Modeling Study From the American Heart Association and World Heart Federation.

    PubMed

    Sacco, Ralph L; Roth, Gregory A; Reddy, K Srinath; Arnett, Donna K; Bonita, Ruth; Gaziano, Thomas A; Heidenreich, Paul A; Huffman, Mark D; Mayosi, Bongani M; Mendis, Shanthi; Murray, Christopher J L; Perel, Pablo; Piñeiro, Daniel J; Smith, Sidney C; Taubert, Kathryn A; Wood, David A; Zhao, Dong; Zoghbi, William A

    2016-06-01

    In 2011, the United Nations set key targets to reach by 2025 to reduce the risk of premature noncommunicable disease death by 25% by 2025. With cardiovascular disease being the largest contributor to global mortality, accounting for nearly half of the 36 million annual noncommunicable disease deaths, achieving the 2025 goal requires that cardiovascular disease and its risk factors be aggressively addressed. The Global Cardiovascular Disease Taskforce, comprising the World Heart Federation, American Heart Association, American College of Cardiology Foundation, European Heart Network, and European Society of Cardiology, with expanded representation from Asia, Africa, and Latin America, along with global cardiovascular disease experts, disseminates information and approaches to reach the United Nations 2025 targets. The writing committee, which reflects Global Cardiovascular Disease Taskforce membership, engaged the Institute for Health Metrics and Evaluation, University of Washington, to develop region-specific estimates of premature cardiovascular mortality in 2025 based on various scenarios. Results show that >5 million premature CVD deaths among men and 2.8 million among women are projected worldwide by 2025, which can be reduced to 3.5 million and 2.2 million, respectively, if risk factor targets for blood pressure, tobacco use, diabetes mellitus, and obesity are achieved. However, global risk factor targets have various effects, depending on region. For most regions, United Nations targets for reducing systolic blood pressure and tobacco use have more substantial effects on future scenarios compared with maintaining current levels of body mass index and fasting plasma glucose. However, preventing increases in body mass index has the largest effect in some high-income countries. An approach achieving reductions in multiple risk factors has the largest impact for almost all regions. Achieving these goals can be accomplished only if countries set priorities

  16. The Heart of 25 by 25: Achieving the Goal of Reducing Global and Regional Premature Deaths From Cardiovascular Diseases and Stroke: A Modeling Study From the American Heart Association and World Heart Federation.

    PubMed

    Sacco, Ralph L; Roth, Gregory A; Reddy, K Srinath; Arnett, Donna K; Bonita, Ruth; Gaziano, Thomas A; Heidenreich, Paul A; Huffman, Mark D; Mayosi, Bongani M; Mendis, Shanthi; Murray, Christopher J L; Perel, Pablo; Piñeiro, Daniel J; Smith, Sidney C; Taubert, Kathryn A; Wood, David A; Zhao, Dong; Zoghbi, William A

    2016-06-01

    In 2011, the United Nations set key targets to reach by 2025 to reduce the risk of premature noncommunicable disease death by 25% by 2025. With cardiovascular disease being the largest contributor to global mortality, accounting for nearly half of the 36 million annual noncommunicable disease deaths, achieving the 2025 goal requires that cardiovascular disease and its risk factors be aggressively addressed. The Global Cardiovascular Disease Taskforce, comprising the World Heart Federation, American Heart Association, American College of Cardiology Foundation, European Heart Network, and European Society of Cardiology, with expanded representation from Asia, Africa, and Latin America, along with global cardiovascular disease experts, disseminates information and approaches to reach the United Nations 2025 targets. The writing committee, which reflects Global Cardiovascular Disease Taskforce membership, engaged the Institute for Health Metrics and Evaluation, University of Washington, to develop region-specific estimates of premature cardiovascular mortality in 2025 based on various scenarios. Results show that >5 million premature CVD deaths among men and 2.8 million among women are projected worldwide by 2025, which can be reduced to 3.5 million and 2.2 million, respectively, if risk factor targets for blood pressure, tobacco use, diabetes mellitus, and obesity are achieved. However, global risk factor targets have various effects, depending on region. For most regions, United Nations targets for reducing systolic blood pressure and tobacco use have more substantial effects on future scenarios compared with maintaining current levels of body mass index and fasting plasma glucose. However, preventing increases in body mass index has the largest effect in some high-income countries. An approach achieving reductions in multiple risk factors has the largest impact for almost all regions. Achieving these goals can be accomplished only if countries set priorities

  17. Phloroglucinols inhibit chemical mediators and xanthine oxidase, and protect cisplatin-induced cell death by reducing reactive oxygen species in normal human urothelial and bladder cancer cells.

    PubMed

    Lin, Kai-Wei; Huang, A-Mei; Tu, Huang-Yao; Weng, Jing-Ru; Hour, Tzyh-Chyuan; Wei, Bai-Luh; Yang, Shyh-Chyun; Wang, Jih-Pyang; Pu, Yeong-Shiau; Lin, Chun-Nan

    2009-10-14

    Phloroglucinols, garcinielliptones HA-HE (1-5), and C (6) were studied in vitro for their inhibitory effects on chemical mediators released from mast cells, neutrophils, and macrophages. Compound 6 revealed significant inhibitory effect on release of lysozyme from rat neutrophils stimulated with formyl-Met-Leu-Phe (fMLP)/cytochalasin B (CB). Compounds 3, 4, and 6 showed significant inhibitory effects on superoxide anion generation in rat neutrophils stimulated with (fMLP)/(CB), while compounds 1 and 5 revealed inhibitory effects on tumor necrosis factor-alpha (TNF-alpha) formation in macrophages stimulated with lipopolysaccharide (LPS). Compounds 1 and 3-6 showed inhibitory effects on xanthine oxidase (XO) and could inhibit the DNA breakage caused by O2(-*). Treatment of NTUB1 with 2 to 60 microM compound 3 and 5 microM cisplatin and SV-HUC1 with 9 to 60 microM 3 and 5 microM cisplatin, respectively, resulted in an increase of viability of cells. These results indicated that compounds 1 and 3-6 showed anti-inflammatory effects and antioxidant activities. Compound 3 mediates through the suppression of XO activity and reduction of reactive oxygen species (ROS), and protection of subsequent cell death. PMID:19754119

  18. Brain death.

    PubMed

    Wijdicks, Eelco F M

    2013-01-01

    The diagnosis of brain death should be based on a simple premise. If every possible confounder has been excluded and all possible treatments have been tried or considered, irreversible loss of brain function is clinically recognized as the absence of brainstem reflexes, verified apnea, loss of vascular tone, invariant heart rate, and, eventually, cardiac standstill. This condition cannot be reversed - not even partly - by medical or surgical intervention, and thus is final. Many countries in the world have introduced laws that acknowledge that a patient can be declared brain-dead by neurologic standards. The U.S. law differs substantially from all other brain death legislation in the world because the U.S. law does not spell out details of the neurologic examination. Evidence-based practice guidelines serve as a standard. In this chapter, I discuss the history of development of the criteria, the current clinical examination, and some of the ethical and legal issues that have emerged. Generally, the concept of brain death has been accepted by all major religions. But patients' families may have different ideas and are mostly influenced by cultural attitudes, traditional customs, and personal beliefs. Suggestions are offered to support these families. PMID:24182378

  19. Death of enterohemorrhagic Escherichia coli O157:H7 in real mayonnaise and reduced-calorie mayonnaise dressing as influenced by initial population and storage temperature.

    PubMed Central

    Hathcox, A K; Beuchat, L R; Doyle, M P

    1995-01-01

    This study was undertaken to determine the survivability of low-density populations (10(0) and 10(2) CFU/g) of enterohemorrhagic Escherichia coli O157:H7 inoculated into real mayonnaise and reduced-calorie mayonnaise dressing and stored at 20 and 30 degrees C, temperatures within the range used for normal commercial mayonnaise distribution and storage. Inactivation patterns at 5 degrees C and inactivation of high-inoculum populations (10(6) CFU/g) were also determined. The pathogen did not grow in either mayonnaise formulation, regardless of the inoculum level or storage temperature. Increases in storage temperature from 5 to 20 degrees C and from 20 to 30 degrees C resulted in dramatic increases in the rate of inactivation. Populations of E. coli O157:H7 in the reduced-calorie and real formulations inoculated with a population of 0.23 to 0.29 log10 CFU/g and held at 30 degrees C were reduced to undetectable levels within 1 and 2 days, respectively; viable cells were not detected after 1 day at 20 degrees C. In mayonnaise containing an initial population of 2.23 log10 CFU/g, viable cells were not detected after 4 days at 30 degrees C or 7 days at 20 degrees C; tolerance was greater in real mayonnaise than in reduced-calorie mayonnaise dressing stored at 5 degrees C. The tolerance of E. coli O157:H7 inoculated at the highest population density (6.23 log 10 CFU/g) was less in reduced-calorie mayonnaise dressing than in real mayonnaise at all storage temperatures. In reduced-calorie mayonnaise dressing and real mayonnaise initially containing 2.23 log10 CFU/g, levels were undetectable after 28 and 58 days at 5 degrees C, respectively.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8534084

  20. Toll-Like Receptors: A Key Marker for Periodontal Disease and Preterm Birth – A Contemporary Review

    PubMed Central

    Mahendra, Jaideep

    2015-01-01

    The receptors of the innate immune system have evolved to recognize pathogenic bacteria in a complex manner. Out of these immune receptors, the pattern recognition receptors (PRRs) such as Toll like receptors have gained importance off late to play a key role in the activation of cascade of inflammatory cytokines in pathogenesis of preterm birth. Preterm birth has become leading cause of neonatal deaths globally. The concept of oral infection influencing the occurrence of preterm delivery has gained importance. Translocation of periodontal pathogens and inflammatory mediators play role in the pathogenesis of preterm labour. The transmembrane toll like receptors of innate immunity have been recently implicated in the association of periodontal infection and preterm labour. The TLRs are considered as a key marker and TLR blockade can be a critical method for treating women who are exposed to periodontal pathogens. This review is aimed at discussing the role of TLR in periodontal disease and its relationship with preterm birth. PMID:26501032

  1. Evaluation of bedtime basics for babies: a national crib distribution program to reduce the risk of sleep-related sudden infant deaths.

    PubMed

    Hauck, Fern R; Tanabe, Kawai O; McMurry, Timothy; Moon, Rachel Y

    2015-06-01

    Rates of sleep-related infant deaths have remained stagnant in recent years. Although most parents are aware of safe sleep recommendations, barriers to adherence, including lack of access to a safe crib, remain. The objective of this study was to describe parental knowledge and practices regarding infant sleep position, bedsharing, pacifier use, and feeding practices before and after receipt of a free crib and safe sleep education. Bedtime Basics for Babies (BBB) enrolled high-risk families in Washington, Indiana, and Washington, DC and provided them with cribs and safe sleep education. Parents completed surveys before ("prenatal" and "postnatal") and 1-3 months after crib receipt ("follow-up"). Descriptive and bivariate analyses were completed. 3,303 prenatal, 1,483 postnatal, and 1,729 follow-up surveys were collected. Parental knowledge of recommended infant sleep position improved from 76% (prenatal) and 77% (postnatal) to 94% after crib receipt (p < 0.001). Intended use of supine positioning increased from 84% (prenatal) and 80% (postnatal) to 87% after the intervention (p < 0.001). Although only 8% of parents intended to bedshare when asked prenatally, 38% of parents receiving the crib after the infant's birth reported that they had bedshared the night before. This decreased to 16% after the intervention. Ninety percent reported that the baby slept in a crib after the intervention, compared with 51% postnatally (p < 0.01). BBB was successful in changing knowledge and practices in the majority of high-risk participants with regards to placing the infant supine in a crib for sleep. Crib distribution and safe sleep education positively influence knowledge and practices about safe sleep. PMID:25331608

  2. Reduced cellular redox status induces 4-hydroxynonenal-mediated caspase 3 activation leading to erythrocyte death during chronic arsenic exposure in rats

    SciTech Connect

    Biswas, Debabrata; Sen, Gargi; Biswas, Tuli

    2010-05-01

    Chronic exposure to arsenic in rats led to gradual accumulation of the toxicant in erythrocytes causing oxidative stress in these cells. 4-Hydroxynonenal (4-HNE), a major aldehyde product of lipid peroxidation, contributed significantly to the cytopathological events observed during oxidative stress in the erythrocytes of exposed rats. 4-HNE triggered death signal cascade that was initiated with the formation of HNE-protein adducts in cytosol. HNE-protein adduct formation resulted in depletion of cytosolic antioxidants followed by increased generation of ROS. Results showed accumulation of hydrogen peroxide (H{sub 2}O{sub 2}) from the early stages of arsenic exposure, while superoxide (O{sub 2}{sup c}entre dot{sup -}) and hydroxyl radical ({sup c}entre dotOH) also contributed to the oxidative stress during longer period of exposure. Suppression of antioxidant system coupled with increased generation of ROS eventually led to activation of caspase 3 during arsenic exposure. Attenuation of HNE-mediated activation of caspase 3 in presence of N-acetylcysteine (NAC) indicated the involvement of GSH in the process. Prevention of HNE-mediated degradation of membrane proteins in presence of Z-DEVD-FMK identified caspase 3 as the principal mediator of HNE-induced cellular damage during arsenic exposure. Degradation of band 3 followed by its aggregation on the red cell surface promoted immunologic recognition of redistributed band 3 by autologous IgG with subsequent attachment of C3b. Finally, the formation of C3b-IgG-band 3 immune complex accelerated the elimination of affected cells from circulation and led to the decline of erythrocyte life span during chronic arsenic toxicity.

  3. Treatment of Elderly Hypertensive Patients with Epithelial Sodium Channel Inhibitors Combined with a Thiazide Diuretic Reduces Coronary Mortality and Sudden Cardiac Death

    PubMed Central

    Hebert, Patricia R.; Coffey, Christopher S.; Byrne, Daniel W.; Scott, Theresa A.; Fagard, Robert H.; Rottman, Jeffrey N.; Murray, Katherine T.; Oates, John A.

    2008-01-01

    Background No reduction in either coronary mortality or sudden cardiac death (SCD) has been demonstrated in overviews of randomized trials of treatment of hypertension with diuretics. Methods An overview was conducted of coronary mortality and SCD in randomized controlled antihypertensive trials in which an epithelial sodium channel (ENaC) inhibitor/ hydrochlorthiazide (HCTZ) combination was used. Secondarily, an analogous overview in which thiazide diuretic was used alone was performed. Randomized trials that used an ENaC inhibitor/ HCTZ combination (or, alternatively, thiazide diuretic alone) were identified from previous meta-analyses, searches of PubMed, search of the Cochrane Clinical Trials database, and review of publications that addressed the consequences of treating hypertension. Trials in which participants were randomized to either an ENaC inhibitor combined with a thiazide diuretic (or to a thiazide diuretic alone) or to control treatment for at least one year and in which coronary mortality was reported were included. Numbers of events in individual trials were abstracted independently by 2 authors. Results Significant reductions in both coronary mortality and SCD were observed in the overview of trials in which elderly patients received an ENaC inhibitor/ HCTZ combination. The odds ratio (OR) for coronary mortality was 0.59 (95% confidence interval [CI] 0.44, 0.78) and for SCD was 0.60 (95% CI 0.38, 0.94). In contrast, an overview of the trials using thiazide diuretics alone showed no significant reductions of either coronary mortality (OR 0.94; 95% CI 0.81, 1.09) or SCD (OR 1.27; 95% CI 0.93, 1.75). Conclusions Use of an ENaC inhibitor combined with HCTZ for treatment of hypertension in the elderly results in favorable effects on coronary mortality and SCD. PMID:19727429

  4. Concentrations of ultrafine particles at a highway toll collection booth and exposure implications for toll collectors.

    PubMed

    Cheng, Yu-Hsiang; Huang, Cheng-Hsiung; Huang, Hsiao-Lin; Tsai, Chuen-Jinn

    2010-12-15

    Research regarding the magnitude of ultrafine particle levels at highway toll stations is limited. This study measured ambient concentrations of ultrafine particles at a highway toll station from October 30 to November 1 and November 5 to November 6, 2008. A scanning mobility particle sizer was used to measure ultrafine particle concentrations at a ticket/cash tollbooth. Levels of hourly average ultrafine particles at the tollbooth were about 3-6 times higher than those in urban backgrounds, indicating that a considerable amount of ultrafine particles are exhausted from passing vehicles. A bi-modal size distribution pattern with a dominant mode at about <6 nm and a minor mode at about 40 nm was observed at the tollbooth. The high amounts of nanoparticles in this study can be attributed to gas-to-particle reactions in fresh fumes emitted directly from vehicles. The influences of traffic volume, wind speed, and relative humidity on ultrafine particle concentrations were also determined. High ambient concentrations of ultrafine particles existed under low wind speed, low relative humidity, and high traffic volume. Although different factors account for high ambient concentrations of ultrafine particles at the tollbooth, measurements indicate that toll collectors who work close to traffic emission sources have a high exposure risk. PMID:21071066

  5. Structure of toll-like receptors.

    PubMed

    Gay, Nicholas J; Gangloff, Monique

    2008-01-01

    The ten human Toll-like receptors are able to respond to an extremely diverse range of microbial products ranging from di- and tri-acylated lipids to nucleic acids. An understanding of the molecular structure adopted by the receptor extracellular, transmembrane, and cytoplasmic domains and the way in which these structures interact with ligands and downstream signaling adapters can explain how recognition and signal transduction are achieved at a molecular level. In this article we discuss how the leucine-rich repeats of the receptor ectodomain have evolved to bind a wide variety of biological molecules. We also discuss how ligand binding induces dimerization of two receptor chains and initiates a series of protein conformational changes that lead to a signaling event in the cytoplasm of the immune system cell. Thus, the signaling process of the TLRs can be viewed as a unidirectional molecular switch. PMID:18071660

  6. Mycobacterial signaling through toll-like receptors

    PubMed Central

    Basu, Joyoti; Shin, Dong-Min; Jo, Eun-Kyeong

    2012-01-01

    Studies over the past decade have helped to decipher molecular networks dependent on Toll-like receptor (TLR) signaling, in mycobacteria-infected macrophages. Stimulation of TLRs by mycobacteria and their antigenic components rapidly induces intracellular signaling cascades involved in the activation of nuclear factor-κB and mitogen-activated protein kinase pathways, which play important roles in orchestrating proinflammatory responses and innate defense through generation of a variety of antimicrobial effector molecules. Recent studies have provided evidence that mycobacterial TLR-signaling cross talks with other intracellular antimicrobial innate pathways, the autophagy process and functional vitamin D receptor (VDR) signaling. In this article we describe recent advances in the recognition, responses, and regulation of mycobacterial signaling through TLRs. PMID:23189273

  7. Toll-Like Receptor Signaling Pathways

    PubMed Central

    Kawasaki, Takumi; Kawai, Taro

    2014-01-01

    Toll-like receptors (TLRs) play crucial roles in the innate immune system by recognizing pathogen-associated molecular patterns derived from various microbes. TLRs signal through the recruitment of specific adaptor molecules, leading to activation of the transcription factors NF-κB and IRFs, which dictate the outcome of innate immune responses. During the past decade, the precise mechanisms underlying TLR signaling have been clarified by various approaches involving genetic, biochemical, structural, cell biological, and bioinformatics studies. TLR signaling appears to be divergent and to play important roles in many aspects of the innate immune responses to given pathogens. In this review, we describe recent progress in our understanding of TLR signaling regulation and its contributions to host defense. PMID:25309543

  8. Enhanced UV-B radiation during pupal stage reduce body mass and fat content, while increasing deformities, mortality and cell death in female adults of solitary bee Osmia bicornis.

    PubMed

    Wasielewski, Oskar; Wojciechowicz, Tatiana; Giejdasz, Karol; Krishnan, Natraj

    2015-08-01

    The effects of enhanced UV-B radiation on the oogenesis and morpho-anatomical characteristics of the European solitary red mason bee Osmia bicornis L. (Hymenoptera: Megachilidae) were tested under laboratory conditions. Cocooned females in the pupal stage were exposed directly to different doses (0, 9.24, 12.32, and 24.64 kJ/m(2) /d) of artificial UV-B. Our experiments revealed that enhanced UV-B radiation can reduce body mass and fat body content, cause deformities and increase mortality. Following UV exposure at all 3 different doses, the body mass of bees was all significantly reduced compared to the control, with the highest UV dose causing the largest reduction. Similarly, following UV-B radiation, in treated groups the fat body index decreased and the fat body index was the lowest in the group receiving the highest dose of UV radiation. Mortality and morphological deformities, between untreated and exposed females varied considerably and increased with the dose of UV-B radiation. Morphological deformities were mainly manifested in the wings and mouthparts, and occurred more frequently with an increased dose of UV. Cell death was quantified by the Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay (DNA fragmentation) during early stages of oogenesis of O. bicornis females. The bees, after UV-B exposure exhibited more germarium cells with fragmented DNA. The TUNEL test indicated that in germarium, low doses of UV-B poorly induced the cell death during early development. However, exposure to moderate UV-B dose increased programmed cell death. In females treated with the highest dose of UV-B the vast majority of germarium cells were TUNEL-positive. PMID:24644123

  9. Activation of the ACE2/Ang-(1-7)/Mas pathway reduces oxygen-glucose deprivation induced tissue swelling, ROS production, and cell death in mouse brain with angiotensin II overproduction

    PubMed Central

    Zheng, Jiaolin; Li, Guangze; Chen, Shuzhen; Chen, Ji; Buck, Joshua; Zhu, Yulan; Xia, Huijing; Lazartigues, Eric; Chen, Yanfang; Olson, James E.

    2014-01-01

    We previously demonstrated that mice which overexpress human renin and angiotensinogen (R+A+) show enhanced cerebral damage in both in vivo and in vitro experimental ischemia models. Angiotensin converting enzyme 2 (ACE2) counteracts the effects of angiotensin (Ang-II) by transforming it into Ang-(1-7), thus reducing the ligand for the AT1 receptor and increasing stimulation of the Mas receptor. Triple transgenic mice, SARA, which specifically overexpress ACE2 in neurons of R+A+ mice were used to study the role of ACE2 in ischemic stroke using oxygen and glucose deprivation (OGD) of brain slices as an in vitro model. We examined tissue swelling, the production of reactive oxygen species (ROS), and cell death in cerebral cortex (CX) and the hippocampal CA1 region during OGD. Expression levels of NADPH oxidase isoforms, Nox2 and Nox4 were measured using western blots. Results show that SARA mice and R+A+ mice treated with the Mas receptor agonist Ang-(1-7) had less swelling, cell death, and ROS production in CX and CA1 areas compared to those in R+A+ animals. Treatment of slices from SARA mice with the Mas antagonist A779 eliminated this protection. Finally, western blots revealed less Nox2 and Nox4 expression in SARA mice compared with R+A+ mice both before and after OGD. We suggest that reduced brain swelling and cell death observed in SARA animals exposed to OGD results from diminished ROS production coupled with lower expression of NADPH oxidases. Thus, the ACE2/Ang-(1-7)/Mas receptor pathway plays a protective role in brain ischemic damage by counteracting the detrimental effects of Ang-II-induced ROS production. PMID:24814023

  10. Activation of the ACE2/Ang-(1-7)/Mas pathway reduces oxygen-glucose deprivation-induced tissue swelling, ROS production, and cell death in mouse brain with angiotensin II overproduction.

    PubMed

    Zheng, J; Li, G; Chen, S; Bihl, J; Buck, J; Zhu, Y; Xia, H; Lazartigues, E; Chen, Y; Olson, J E

    2014-07-25

    We previously demonstrated that mice which overexpress human renin and angiotensinogen (R+A+) show enhanced cerebral damage in both in vivo and in vitro experimental ischemia models. Angiotensin-converting enzyme 2 (ACE2) counteracts the effects of angiotensin (Ang-II) by transforming it into Ang-(1-7), thus reducing the ligand for the AT1 receptor and increasing stimulation of the Mas receptor. Triple transgenic mice, SARA, which specifically overexpress ACE2 in neurons of R+A+ mice were used to study the role of ACE2 in ischemic stroke using oxygen and glucose deprivation (OGD) of brain slices as an in vitro model. We examined tissue swelling, the production of reactive oxygen species (ROS), and cell death in the cerebral cortex (CX) and the hippocampal CA1 region during OGD. Expression levels of NADPH oxidase (Nox) isoforms, Nox2 and Nox4 were measured using western blots. Results show that SARA mice and R+A+ mice treated with the Mas receptor agonist Ang-(1-7) had less swelling, cell death, and ROS production in CX and CA1 areas compared to those in R+A+ animals. Treatment of slices from SARA mice with the Mas antagonist A779 eliminated this protection. Finally, western blots revealed less Nox2 and Nox4 expression in SARA mice compared with R+A+ mice both before and after OGD. We suggest that reduced brain swelling and cell death observed in SARA animals exposed to OGD result from diminished ROS production coupled with lower expression of Nox isoforms. Thus, the ACE2/Ang-(1-7)/Mas receptor pathway plays a protective role in brain ischemic damage by counteracting the detrimental effects of Ang-II-induced ROS production. PMID:24814023

  11. Effect of Chlamydia pneumoniae on Cellular ATP Content in Mouse Macrophages: Role of Toll-Like Receptor 2

    PubMed Central

    Yaraei, Kambiz; Campbell, Lee Ann; Zhu, Xiaodong; Liles, W. Conrad; Kuo, Cho-chou; Rosenfeld, Michael E.

    2005-01-01

    Chlamydiae are obligate intracellular gram-negative bacteria and are dependent on the host cell for ATP. Thus, chlamydial infection may alter the intracellular levels of ATP and affect all energy-dependent processes within the cell. We have shown that both live C. pneumoniae and inactivated C. pneumoniae induce markers of cell death prior to completion of the bacterial growth cycle. As depletion of ATP could account for the observed increase in cell death, the effects of C. pneumoniae on ATP concentrations within mouse macrophages were investigated. Live, heat-killed, and UV-inactivated C. pneumoniae cultures (at multiplicities of infection [MOIs] of 0.01, 0.1, and 1.0) were incubated with mouse bone marrow macrophages isolated from C57BL/6J mice and mice deficient in Toll-like receptors. Treatment of the macrophages with both live and inactivated C. pneumoniae increased the ATP content of the cells. In cells infected with live C. pneumoniae, the increase was inversely proportional to the MOI. In cells treated with inactivated C. pneumoniae, the increase in ATP content was smaller than that induced by infection with live organisms and was proportional to the MOI. The increase in ATP content early in the developmental cycle was independent of the growth of C. pneumoniae, while sustained induction required live organisms. The capacity of C. pneumoniae to increase the ATP content was ablated in macrophages deficient in expression of either Toll-like receptor 2 or the Toll-like receptor accessory protein MyD88. In contrast, no effect was observed in macrophages lacking expression of Toll-like receptor 4. PMID:15972526

  12. Tobacco Control and the Reduction in Smoking-related Premature Deaths in the United States, 1964–2012

    PubMed Central

    Holford, Theodore R.; Meza, Rafael; Warner, Kenneth E.; Meernik, Clare; Jeon, Jihyoun; Moolgavkar, Suresh H.; Levy, David T.

    2014-01-01

    Importance The 50th anniversary of the first Surgeon General’s Report on smoking and health is celebrated in 2014. This seminal document inspired efforts by government s, non-governmental organizations, and the private sector to reduce the toll of cigarette smoking through reduced initiation and increased cessation. Objective To quantify reductions in smoking -related mortality associated with implementation of tobacco control since 1964. Design, Setting and Participants Smoking histories for individual birth cohorts that actually occurred and under likely scenarios had tobacco control never emerged were estimated. National mortality rates and mortality rate ratio estimates from analytical studies of the effect of smoking on mortality yielded death rates by smoking status. Actual smoking -related mortality from 1964–2012 was compared to estimated mortality under no tobacco control that included a likely scenario (primary counterfactual) and upper and lower bounds that would capture plausible alternatives. Exposure National Health Interview Surveys yielded cigarette smoking histories for the US adult population from 1964–2012. Main Outcomes and Measures Number of premature deaths avoided and years of life saved were primary outcomes. Change in life expectancy at age 40 associated with change in cigarette smoking exposure constituted another measure of overall health outcomes. Results From 1964–2012, an estimated 17.6 million deaths were related to smoking, an estimated 8.0 (7.4–8.3, for the lower and upper tobacco control counterfactuals, respectively) million fewer premature smoking-induced deaths than what would have occurred under the alternatives and thus associated with tobacco control (5.3 (4.8–5.5) million males and 2.7 (2.5–2.7) million females). This resulted in an estimated 157 (139–165) million years of life saved, a mean of 19.6 years for each beneficiary, (111 (97–117) million for males, 46 (42–48) million for females). During this

  13. A novel Toll like receptor with two TIR domains (HcToll-2) is involved in regulation of antimicrobial peptide gene expression of Hyriopsis cumingii.

    PubMed

    Ren, Qian; Lan, Jiang-Feng; Zhong, Xue; Song, Xiao-Jun; Ma, Fei; Hui, Kai-Min; Wang, Wen; Yu, Xiao-Qiang; Wang, Jin-Xing

    2014-07-01

    Animal Toll-like receptors (TLRs) are involved in innate immunity. Toll proteins are generally transmembrane proteins. In this study, an atypical Toll-like receptor (HcToll-2) was identified from the triangle-shell pearl mussel Hyriopsis cumingii, which belongs to phylum Mollusca. Unlike the typical Toll like receptors with extracellular leucine-rich repeats (LRRs), transmembrane, and intracellular Toll/interleukin-1 receptor (TIR) domains, HcToll-2 has two homologous TIR domains located at the C-terminal (designated as HcTIR1 and HcTIR2) and lacks a transmembrane domain. Phylogenetic analysis showed that HcTIR1 was clustered with TIR of sea anemone Toll, and HcTIR2 was clustered with TIR of Drosophila Toll. HcToll-2 mRNA could be detected in the hepatopancreas and was upregulated after challenge with Escherichia coli and Staphylococcus aureus. Recombinant HcLRR protein with GST tag could bind to bacteria and also to LPS and PGN. Over-expression of both HcTIR1 and HcTIR2 induced drosomycin genes in Drosophila S2 cells. RNAi analysis showed that HcToll-2 was required for the expression of theromacin, which is a cysteine-rich antimicrobial peptide (AMP) gene. This research is the first report of an atypical Toll-like receptor HcToll-2 involved in antibacterial immunity through induction of AMP expression. PMID:24631579

  14. Toll-Like Receptor 7-Targeted Therapy in Respiratory Disease

    PubMed Central

    Lebold, Katie M.; Jacoby, David B.; Drake, Matthew G.

    2016-01-01

    Summary Allergic asthma and allergic rhinitis are inflammatory diseases of the respiratory tract characterized by an excessive type-2 T helper cell (Th2) immune response. Toll-like receptor 7 (TLR7) is a single-stranded viral RNA receptor expressed in the airway that initiates a Th1 immune response and has garnered interest as a novel therapeutic target for treatment of allergic airway diseases. In animal models, synthetic TLR7 agonists reduce airway hyperreactivity, eosinophilic inflammation, and airway remodeling while decreasing Th2-associated cytokines. Furthermore, activation of TLR7 rapidly relaxes airway smooth muscle via production of nitric oxide. Thus, TLR7 has dual bronchodilator and anti-inflammatory effects. Two TLR7 ligands with promising pharmacologic profiles have entered clinical trials for the treatment of allergic rhinitis. Moreover, TLR7 agonists are potential antiviral therapies against respiratory viruses. TLR7 agonists enhance influenza vaccine efficacy and also reduce viral titers when given during an active airway infection. In this review, we examine the current data supporting TLR7 as a therapeutic target in allergic airway diseases. PMID:27226793

  15. Toll-Like Receptor 7-Targeted Therapy in Respiratory Disease.

    PubMed

    Lebold, Katie M; Jacoby, David B; Drake, Matthew G

    2016-03-01

    Allergic asthma and allergic rhinitis are inflammatory diseases of the respiratory tract characterized by an excessive type-2 T helper cell (Th2) immune response. Toll-like receptor 7 (TLR7) is a single-stranded viral RNA receptor expressed in the airway that initiates a Th1 immune response and has garnered interest as a novel therapeutic target for treatment of allergic airway diseases. In animal models, synthetic TLR7 agonists reduce airway hyperreactivity, eosinophilic inflammation, and airway remodeling while decreasing Th2-associated cytokines. Furthermore, activation of TLR7 rapidly relaxes airway smooth muscle via production of nitric oxide. Thus, TLR7 has dual bronchodilator and anti-inflammatory effects. Two TLR7 ligands with promising pharmacologic profiles have entered clinical trials for the treatment of allergic rhinitis. Moreover, TLR7 agonists are potential antiviral therapies against respiratory viruses. TLR7 agonists enhance influenza vaccine efficacy and also reduce viral titers when given during an active airway infection. In this review, we examine the current data supporting TLR7 as a therapeutic target in allergic airway diseases. PMID:27226793

  16. PTEN Overexpression Cooperates With Lithium to Reduce the Malignancy and to Increase Cell Death by Apoptosis via PI3K/Akt Suppression in Colorectal Cancer Cells.

    PubMed

    de Araujo, Wallace Martins; Robbs, Bruno Kaufmann; Bastos, Lilian G; de Souza, Waldemir F; Vidal, Flávia C B; Viola, João P B; Morgado-Diaz, Jose A

    2016-02-01

    Lithium is a well-established non-competitive inhibitor of glycogen synthase kinase-3β (GSK-3β), a kinase that is involved in several cellular processes related to cancer progression. GSK-3β is regulated upstream by PI3K/Akt, which is negatively modulated by PTEN. The role that lithium plays in cancer is controversial because lithium can activate or inhibit survival signaling pathways depending on the cell type. In this study, we analyzed the mechanisms by which lithium can modulate events related to colorectal cancer (CRC) progression and evaluated the role that survival signaling pathways such as PI3K/Akt and PTEN play in this context. We show that the administration of lithium decreased the proliferative potential of CRC cells in a GSK-3β-independent manner but induced the accumulation of cells in G2/M phase. Furthermore, high doses of lithium increased apoptosis, which was accompanied by decreased proteins levels of Akt and PTEN. Then, cells that were induced to overexpress PTEN were treated with lithium; we observed that low doses of lithium strongly increased apoptosis. Additionally, PTEN overexpression reduced proliferation, but this effect was minor compared with that in cells treated with lithium alone. Furthermore, we demonstrated that PTEN overexpression and lithium treatment separately reduced cell migration, colony formation, and invasion, and these effects were enhanced when lithium treatment and PTEN overexpression were combined. In conclusion, our findings indicate that PTEN overexpression and lithium treatment cooperate to reduce the malignancy of CRC cells and highlight lithium and PTEN as potential candidates for studies to identify new therapeutic approaches for CRC treatment. PMID:26224641

  17. A Role for the Adaptor Proteins TRAM and TRIF in Toll-like Receptor 2 Signaling*

    PubMed Central

    Nilsen, Nadra J.; Vladimer, Gregory I.; Stenvik, Jørgen; Orning, M. Pontus A.; Zeid-Kilani, Maria V.; Bugge, Marit; Bergstroem, Bjarte; Conlon, Joseph; Husebye, Harald; Hise, Amy G.; Fitzgerald, Katherine A.; Espevik, Terje; Lien, Egil

    2015-01-01

    Toll-like receptors (TLRs) are involved in sensing invading microbes by host innate immunity. TLR2 recognizes bacterial lipoproteins/lipopeptides, and lipopolysaccharide activates TLR4. TLR2 and TLR4 signal via the Toll/interleukin-1 receptor adaptors MyD88 and MAL, leading to NF-κB activation. TLR4 also utilizes the adaptors TRAM and TRIF, resulting in activation of interferon regulatory factor (IRF) 3. Here, we report a new role for TRAM and TRIF in TLR2 regulation and signaling. Interestingly, we observed that TLR2-mediated induction of the chemokine Ccl5 was impaired in TRAM or TRIF deficient macrophages. Inhibition of endocytosis reduced Ccl5 release, and the data also suggested that TRAM and TLR2 co-localize in early endosomes, supporting the hypothesis that signaling may occur from an intracellular compartment. Ccl5 release following lipoprotein challenge additionally involved the kinase Tbk-1 and Irf3, as well as MyD88 and Irf1. Induction of Interferon-β and Ccl4 by lipoproteins was also partially impaired in cells lacking TRIF cells. Our results show a novel function of TRAM and TRIF in TLR2-mediated signal transduction, and the findings broaden our understanding of how Toll/interleukin-1 receptor adaptor proteins may participate in signaling downstream from TLR2. PMID:25505250

  18. Artesunate ameliorates severe acute pancreatitis (SAP) in rats by inhibiting expression of pro-inflammatory cytokines and Toll-like receptor 4.

    PubMed

    Cen, Yanyan; Liu, Chao; Li, Xiaoli; Yan, Zifei; Kuang, Mei; Su, Yujie; Pan, Xichun; Qin, Rongxin; Liu, Xin; Zheng, Jiang; Zhou, Hong

    2016-09-01

    Severe acute pancreatitis (SAP) is a severe clinical condition with significant morbidity and mortality. Multiple organs dysfunction (MOD) is the leading cause of SAP-related death. The over-release of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α is the underlying mechanism of MOD; however, there is no effective agent against the inflammation. Herein, artesunate (AS) was found to increase the survival of SAP rats significantly when injected with 3.5% sodium taurocholate into the biliopancreatic duct in a retrograde direction, improving their pancreatic pathology and decreasing serum amylase and pancreatic lipase activities along with substantially reduced pancreatic IL-1β and IL-6 release. In vitro, AS-pretreatment strongly inhibited IL-1β and IL-6 release and their mRNA expressions in the pancreatic acinar cells treated with lipopolysaccharide (LPS) but exerted little effect on TNF-α release. Additionally, AS reduced the mRNA expressions of Toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) p65 as well as their protein expressions in the pancreatic acinar cells. In conclusion, our results demonstrated that AS could significantly protect SAP rats, and this protection was related to the reduction of digestive enzyme activities and pro-inflammatory cytokine expressions via inhibition of TLR4/NF-κB signaling pathway. Therefore, AS may be considered as a potential therapeutic agent against SAP. PMID:27318790

  19. Flint Water Crisis Taking High Toll on Health, Productivity

    MedlinePlus

    ... https://medlineplus.gov/news/fullstory_160307.html Flint Water Crisis Taking High Toll on Health, Productivity Michigan ... 2016 MONDAY, Aug. 8, 2016 (HealthDay News) -- The water crisis in Flint, Mich., has cost $395 million ...

  20. Sleep Apnea May Take Toll on Your Mood, Thinking Skills

    MedlinePlus

    ... nlm.nih.gov/medlineplus/news/fullstory_157515.html Sleep Apnea May Take Toll on Your Mood, Thinking ... 29, 2016 MONDAY, Feb. 29, 2016 (HealthDay News) -- Sleep apnea may have an impact on brain function, ...

  1. Stress May Take Greatest Toll on Younger Women's Hearts

    MedlinePlus

    ... 160597.html Stress May Take Greatest Toll on Younger Women's Hearts: Study Female heart disease patients under ... may be especially hard on the hearts of younger women who have heart disease, new research suggests. ...

  2. CDC Vital Signs: Preventable Deaths from Heart Disease and Stroke

    MedlinePlus

    ... 35 MB] Read the MMWR Science Clips Preventable Deaths from Heart Disease & Stroke Improving care can save ... can reduce death among all ages. Problem Many deaths from heart disease and stroke can be prevented. ...

  3. Amelioration of nicotinamide adenine dinucleotide phosphate-oxidase mediated stress reduces cell death after blast-induced traumatic brain injury.

    PubMed

    Lucke-Wold, Brandon P; Naser, Zachary J; Logsdon, Aric F; Turner, Ryan C; Smith, Kelly E; Robson, Matthew J; Bailes, Julian E; Lee, John M; Rosen, Charles L; Huber, Jason D

    2015-12-01

    A total of 1.7 million traumatic brain injuries (TBIs) occur each year in the United States, but available pharmacologic options for the treatment of acute neurotrauma are limited. Oxidative stress is an important secondary mechanism of injury that can lead to neuronal apoptosis and subsequent behavioral changes. Using a clinically relevant and validated rodent blast model, we investigated how nicotinamide adenine dinucleotide phosphate oxidase (Nox) expression and associated oxidative stress contribute to cellular apoptosis after single and repeat blast injuries. Nox4 forms a complex with p22phox after injury, forming free radicals at neuronal membranes. Using immunohistochemical-staining methods, we found a visible increase in Nox4 after single blast injury in Sprague Dawley rats. Interestingly, Nox4 was also increased in postmortem human samples obtained from athletes diagnosed with chronic traumatic encephalopathy. Nox4 activity correlated with an increase in superoxide formation. Alpha-lipoic acid, an oxidative stress inhibitor, prevented the development of superoxide acutely and increased antiapoptotic markers B-cell lymphoma 2 (t = 3.079, P < 0.05) and heme oxygenase 1 (t = 8.169, P < 0.001) after single blast. Subacutely, alpha-lipoic acid treatment reduced proapoptotic markers Bax (t = 4.483, P < 0.05), caspase 12 (t = 6.157, P < 0.001), and caspase 3 (t = 4.573, P < 0.01) after repetitive blast, and reduced tau hyperphosphorylation indicated by decreased CP-13 and paired helical filament staining. Alpha-lipoic acid ameliorated impulsive-like behavior 7 days after repetitive blast injury (t = 3.573, P < 0.05) compared with blast exposed animals without treatment. TBI can cause debilitating symptoms and psychiatric disorders. Oxidative stress is an ideal target for neuropharmacologic intervention, and alpha-lipoic acid warrants further investigation as a therapeutic for prevention of chronic neurodegeneration. PMID:26414010

  4. The toll of traffic-related fatalities in a metropolitan Italian area through the experience of the Department of Legal Medicine.

    PubMed

    Amadasi, Alberto; Cerutti, Elisa; Spagnoli, Laura; Blandino, Alberto; Rancati, Alessandra; Gallo, Carlotta; Mancini, Elisabetta; Rizzi, Vittorio; Cattaneo, Cristina

    2016-06-01

    Despite the introduction of new traffic laws in Italy, traffic-related deaths are still a huge burden. The study presents data and medico-legal issues behind traffic deaths in Milan between 2001 and 2012 (1506 traffic-related deaths). Data were collected from the database of the Department of Legal Medicine: 79.4% males and 20.6% females (mean age 44.14). The target group concerned traumatic deaths as a consequence of the accident as well as deaths not directly related to an accident. Although 6.1% were non-traumatic deaths (cause of death unconnected to the accident, i.e. because of a heart attack, or when death occurred after survival and cause of death was not related certainly to the accident), multiple skeletal/visceral injuries were the main cause of death (57.9%), occurring in motorcyclists the most (63.7%). Injuries to the skull and brain were the second cause of death (25.9%). Victims were mostly males (79.4%) and drivers (77.6%). Fifty-five per cent were deaths on-scene, while 45% survived. Other variables were also considered: medications, medical history, and drugs/alcohol/smoke. A downward trend in traffic-related fatalities was evident, but the toll is still high. This study should be a glimpse at the actual situation, since it is indicative of a metropolitan area where autopsies are systematically performed. PMID:25563928

  5. 47 CFR 63.504 - Contents of applications to close a public toll station where no other such toll station of the...

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... station where no other such toll station of the applicant in the community will continue service and where... station where no other such toll station of the applicant in the community will continue service and where... community; (g) Name of other carrier or carriers, if any, which will provide toll station service in...

  6. Encountering Death: Structured Activities for Death Awareness.

    ERIC Educational Resources Information Center

    Welch, Ira David; And Others

    This book is intended to be used as a supplement to standard textbooks on death and dying for college students. Chapter 1 "Encountering Death in the Self" builds the foundation for increased self-awareness for the study of death and dying. Chapter 2 "Encountering Death in the Family" provides activities which are appropriate for a wide variety of…

  7. Toll-Like Receptors of Deuterostome Invertebrates

    PubMed Central

    Satake, Honoo; Sekiguchi, Toshio

    2012-01-01

    Defensive systems against pathogens are responsible not only for survival or lifetime of an individual but also for the evolution of a species. Innate immunity is expected to be more important for invertebrates than mammals, given that adaptive immunity has not been acquired in the former. Toll-like receptors (TLRs) have been shown to play a crucial role in host defense of pathogenic microbes in innate immunity of mammals. Recent genome-wide analyses have suggested that TLR or their related genes are conserved in invertebrates. In particular, numerous TLR-related gene candidates were detected in deuterostome invertebrates, including a sea urchin (222 TLR-related gene candidates) and amphioxus (72 TLR-related gene candidates). Molecular phylogenetic analysis verified that most of sea urchin or amphioxus TLR candidates are paralogous, suggesting that these organisms expanded TLR-related genes in a species-specific manner. In contrast, another deuterostome invertebrate, the ascidian Ciona intestinalis, was found to possess only two TLR genes. Moreover, Ciona TLRs, Ci-TLR1 and Ci-TLR2, were shown to possess “hybrid” functionality of mammalian TLRs. Such functionality of Ci-TLRs could not be predicted by sequence comparison with vertebrate TLRs, indicating confounding evolutionary lineages of deuterostome invertebrate TLRs or their candidates. In this review article, we present recent advances in studies of TLRs or their candidates among deuterostome invertebrates, and provide insight into an evolutionary process of TLRs. PMID:22566918

  8. Deviation from major codons in the Toll-like receptor genes is associated with low Toll-like receptor expression

    PubMed Central

    Zhong, Fei; Cao, Weiping; Chan, Edmund; Tay, Puei Nam; Cahya, Florence Feby; Zhang, Haifeng; Lu, Jinhua

    2005-01-01

    Microbial structures activate Toll-like receptors (TLRs) and TLR-mediated cell signalling elicits and regulates host immunity. Most TLRs are poorly expressed but the underlying expression mechanism is not clear. Examination TLR sequences revealed that most human TLR genes deviated from using major human codons. CD14 resembles TLRs in sequence but its gene preferentially uses major codons. Indeed, CD14 expression on monocytes was higher than expression of TLR1 and TLR2. The TLR9 gene is abundant in major codons and it also showed higher expression than TLR1, TLR2 and TLR7 in transfected 293T cells. Change of the 5′-end 302 base pairs of the TLR2 sequence into major human codons markedly increased TLR2 expression, which led to increased TLR2-mediated constitutive nuclear factor-κB activation. Change of the 5′-end 381 base pairs of the CD14 sequence into prevalent TLR codons markedly reduced CD14 expression. These results collectively show that the deviation of TLR sequences from using major codons dictates the low TLR expression and this may protect the host against excessive inflammation and tissue damages. PMID:15606798

  9. Toll Genes Have an Ancestral Role in Axis Elongation.

    PubMed

    Benton, Matthew A; Pechmann, Matthias; Frey, Nadine; Stappert, Dominik; Conrads, Kai H; Chen, Yen-Ta; Stamataki, Evangelia; Pavlopoulos, Anastasios; Roth, Siegfried

    2016-06-20

    One of the key morphogenetic processes used during development is the controlled intercalation of cells between their neighbors. This process has been co-opted into a range of developmental events, and it also underlies an event that occurs in each major group of bilaterians: elongation of the embryo along the anterior-posterior axis [1]. In Drosophila, a novel component of this process was recently discovered by Paré et al., who showed that three Toll genes function together to drive cell intercalation during germband extension [2]. This finding raises the question of whether this role of Toll genes is an evolutionary novelty of flies or a general mechanism of embryonic morphogenesis. Here we show that the Toll gene function in axis elongation is, in fact, widely conserved among arthropods. First, we functionally demonstrate that two Toll genes are required for cell intercalation in the beetle Tribolium castaneum. We then show that these genes belong to a previously undescribed Toll subfamily and that members of this subfamily exhibit striped expression (as seen in Tribolium and previously reported in Drosophila [3-5]) in embryos of six other arthropod species spanning the entire phylum. Last, we show that two of these Toll genes are required for normal morphogenesis during anterior-posterior embryo elongation in the spider Parasteatoda tepidariorum, a member of the most basally branching arthropod lineage. From our findings, we hypothesize that Toll genes had a morphogenetic function in embryo elongation in the last common ancestor of all arthropods, which existed over 550 million years ago. PMID:27212406

  10. Low expression of Toll-like receptors in peripheral blood mononuclear cells of pediatric patients with acute lymphoblastic leukemia.

    PubMed

    Sánchez-Cuaxospa, María; Contreras-Ramos, Alejandra; Pérez-Figueroa, Erandi; Medina-Sansón, Aurora; Jiménez-Hernández, Elva; Torres-Nava, José R; Rojas-Castillo, Emilio; Maldonado-Bernal, Carmen

    2016-08-01

    Cancer is the second most common cause of death among children aged 1-14 years. Leukemia accounts for one-third of all childhood cancers, 78% of which is acute lymphoblastic leukemia (ALL). The development of cancer has been associated with malignant cells that express low levels of immunogenic molecules, which facilitates their escape from the antineoplastic immune response. It is thought that it may be possible to rescue the antineoplastic immune response through the activation of recognition receptors, such as Toll-like receptors (TLRs), which activate the innate immune system. TLRs are type I membrane glycoproteins expressed mainly in immune system cells such as monocytes, neutrophils, macrophages, dendritic cells, T, B and natural killer cells. The aim of the present study was to evaluate the expression of TLR1, TLR3, TLR4, TLR7 and TLR9 in peripheral blood mononuclear cells (PBMCs) in patients with ALL and prior to any treatment. PBMCs were obtained from 50 pediatric patients diagnosed with ALL and from 20 children attending the ophthalmology and orthopedics services. The mean fluorescence intensity was obtained by analysis of immunofluorescence. We found lower expression levels of TLR1, TLR3, TLR4, TLR7 and TLR9 in PBMCs from patients with ALL compared with those from control patients. We also observed that the PBMCs from patients with Pre-B and B ALL had lower TLR4 expression than controls and patients with Pro-B, Pre-B, B and T ALL had lower TLR7 expression than controls. The present study is the first to demonstrate reduced expression of TLRs in PBMCs from pediatric patients with ALL. This finding is of great relevance and may partly explain the reduction in the antineoplastic immune response in patients with ALL. PMID:27277333

  11. Toll like receptor 9 antagonism modulates spinal cord neuronal function and survival: Direct versus astrocyte-mediated mechanisms.

    PubMed

    Acioglu, Cigdem; Mirabelli, Ersilia; Baykal, Ahmet Tarik; Ni, Li; Ratnayake, Ayomi; Heary, Robert F; Elkabes, Stella

    2016-08-01

    Toll like receptors (TLRs) are expressed by cells of the immune system and mediate the host innate immune responses to pathogens. However, increasing evidence indicates that they are important contributors to central nervous system (CNS) function in health and in pathological conditions involving sterile inflammation. In agreement with this idea, we have previously shown that intrathecal administration of a TLR9 antagonist, cytidine-phosphate-guanosine oligodeoxynucleotide 2088 (CpG ODN 2088), ameliorates the outcomes of spinal cord injury (SCI). Although these earlier studies showed a marked effect of CpG ODN 2088 on inflammatory cells, the expression of TLR9 in spinal cord (SC) neurons and astrocytes suggested that the antagonist exerts additional effects through direct actions on these cells. The current study was undertaken to assess the direct effects of CpG ODN 2088 on SC neurons, astrocytes and astrocyte-neuron interactions, in vitro. We report, for the first time, that inhibition of TLR9 in cultured SC neurons alters their function and confers protection against kainic acid (KA)-induced excitotoxic death. Moreover, the TLR9 antagonist attenuated the KA-elicited endoplasmic reticulum (ER) stress response in neurons, in vitro. CpG ODN 2088 also reduced the transcript levels and release of chemokine (C-X-C) motif ligand 1 (CXCL1) and monocyte chemotactic protein 1 (MCP-1) by astrocytes and it diminished interleukin-6 (IL-6) release without affecting transcript levels in vitro. Conditioned medium (CM) of CpG ODN 2088-treated astroglial cultures decreased the viability of SC neurons compared to CM of vehicle-treated astrocytes. However, this toxicity was not observed when astrocytes were co-cultured with neurons. Although CpG ODN 2088 limited the survival-promoting effects of astroglia, it did not reduce neuronal viability compared to controls grown in the absence of astrocytes. We conclude that the TLR9 antagonist acts directly on both SC neurons and astrocytes

  12. Sleep Deprivation and Divergent Toll-like Receptor-4 Activation of Cellular Inflammation in Aging

    PubMed Central

    Carroll, Judith E.; Carrillo, Carmen; Olmstead, Richard; Witarama, Tuff; Breen, Elizabeth C.; Yokomizo, Megumi; Seeman, Teresa E.; Irwin, Michael R.

    2015-01-01

    Objectives: Sleep disturbance and aging are associated with increases in inflammation, as well as increased risk of infectious disease. However, there is limited understanding of the role of sleep loss on age-related differences in immune responses. This study examines the effects of sleep deprivation on toll-like receptor activation of monocytic inflammation in younger compared to older adults. Design, Setting, and Participants: Community-dwelling adults (n = 70) who were categorized as younger (25–39 y old, n = 21) and older (60–84 y old, n = 49) participants, underwent a sleep laboratory-based experimental partial sleep deprivation (PSD) protocol including adaptation, an uninterrupted night of sleep, sleep deprivation (sleep restricted to 03:00–07:00), and recovery. Measurement and Results: Blood samples were obtained each morning to measure toll-like receptor-4 activation of monocyte intracellular production of the inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Partial sleep deprivation induced a significant increase in the production of IL-6 and/or TNF-α that persisted after a night of recovery sleep (F(2,121.2) = 3.8, P < 0.05). Age moderated the effects of sleep loss, such that younger adults had an increase in inflammatory cytokine production that was not present in older adults (F(2,121.2) = 4.0, P < 0.05). Conclusion: Older adults exhibit reduced toll-like receptor 4 stimulated cellular inflammation that, unlike in younger adults, is not activated after a night of partial sleep loss. Whereas sleep loss increases cellular inflammation in younger adults and may contribute to inflammatory disorders, blunted toll-like receptor activation in older adults may increase the risk of infectious disease seen with aging. Citation: Carroll JE, Carrillo C, Olmstead R, Witarama T, Breen EC, Yokomizo M, Seeman TE, Irwin MR. Sleep deprivation and divergent toll-like receptor-4 activation of cellular inflammation in aging. SLEEP

  13. Death and injury from motor vehicle crashes in Colombia.

    PubMed

    Posada, J; Ben-Michael, E; Herman, A; Kahan, E; Richter, E

    2000-02-01

    We report data on the distribution and determinants of road deaths and injuries for all victims in Colombia, with the aim of defining targets and priorities for highway death prevention in that country and other rapidly urbanizing nations. Using information from Colombia's Fund for the Prevention of Road Injury and the national death registry, we studied data on deaths and injuries from 1991 to 1995 for the nation as a whole and for the country's two largest cities, Santa Fe de Bogotá and Medellín. Deaths and injuries are rising in the nation as a whole. Of the deaths, 75% occur in urban areas, and 80% are in males. Pedestrians aged 15-34 are a peak subgroup. Thirty-four percent of deaths are attributable to speeding and/or alcohol consumption. Death tolls are highest at night and on weekends. Specific priority targets for intervention are indicated by the fact that 75% of road deaths in Colombia occur in urban areas and that 80% of all victims are males. PMID:10748658

  14. Molecular cloning and characterization of a Toll receptor gene from Macrobrachium rosenbergii.

    PubMed

    Srisuk, Chutima; Longyant, Siwaporn; Senapin, Saengchan; Sithigorngul, Paisarn; Chaivisuthangkura, Parin

    2014-02-01

    Toll receptors are cell surface molecules acting as pattern recognition receptors (PRRs) that have been implicated in the signaling pathway of innate immune responses. In this study, the full-length cDNA of a Toll receptor gene of Macrobrachium rosenbergii, designated MrToll, was successfully isolated using designed degenerate primers and the rapid amplification of cDNA ends (RACE). The MrToll gene sequence contained an open reading frame (ORF) of 2799 nucleotides encoding a protein of 932 amino acid residues. The protein contained distinct structural motifs of the Toll-like receptor (TLR) family, including an extracellular domain containing 15 leucine-rich repeats (LRRs), a transmembrane segment of 23 amino acids, and a cytoplasmic Toll/interleukin-1R (TIR) domain of 139 residues. Phylogenetic analysis revealed that MrToll and Toll receptor of Marsupenaeus japonicus (MjToll) evolved closely. However, the MrToll ORF demonstrated only 48-49% identity with shrimp Toll1, suggesting that MrToll isolated from a palaemonid shrimp might belong to a novel class of Toll receptors in shrimp. The transcripts of the MrToll gene were constitutively expressed in various tissues, with high levels in hemocytes, the stomach and muscle. A reverse transcriptase PCR assay demonstrated that the expression patterns of MrToll were distinctly modulated after Aeromonas caviae stimulation, with significant enhancement at 3-12 h post-challenge and a decline to basal levels at 24 h post-challenge. In addition, when MrToll-silenced shrimp were challenged with A. caviae, there was a significant increase in mortality and bacterial CFU counts. These results suggest that MrToll might be involved in host innate defense, especially against the pathogen A. caviae. PMID:24398262

  15. Genetic Screen in Drosophila Larvae Links ird1 Function to Toll Signaling in the Fat Body and Hemocyte Motility

    PubMed Central

    Schmid, Martin R.; Anderl, Ines; Vo, Hoa T. M.; Valanne, Susanna; Yang, Hairu; Kronhamn, Jesper; Rämet, Mika; Rusten, Tor Erik

    2016-01-01

    To understand how Toll signaling controls the activation of a cellular immune response in Drosophila blood cells (hemocytes), we carried out a genetic modifier screen, looking for deletions that suppress or enhance the mobilization of sessile hemocytes by the gain-of-function mutation Toll10b (Tl10b). Here we describe the results from chromosome arm 3R, where five regions strongly suppressed this phenotype. We identified the specific genes immune response deficient 1 (ird1), headcase (hdc) and possibly Rab23 as suppressors, and we studied the role of ird1 in more detail. An ird1 null mutant and a mutant that truncates the N-terminal kinase domain of the encoded Ird1 protein affected the Tl10b phenotype, unlike mutations that affect the C-terminal part of the protein. The ird1 null mutant suppressed mobilization of sessile hemocytes, but enhanced other Tl10b hemocyte phenotypes, like the formation of melanotic nodules and the increased number of circulating hemocytes. ird1 mutants also had blood cell phenotypes on their own. They lacked crystal cells and showed aberrant formation of lamellocytes. ird1 mutant plasmatocytes had a reduced ability to spread on an artificial substrate by forming protrusions, which may explain why they did not go into circulation in response to Toll signaling. The effect of the ird1 mutation depended mainly on ird1 expression in hemocytes, but ird1-dependent effects in other tissues may contribute. Specifically, the Toll receptor was translocated from the cell membrane to intracellular vesicles in the fat body of the ird1 mutant, and Toll signaling was activated in that tissue, partially explaining the Tl10b-like phenotype. As ird1 is otherwise known to control vesicular transport, we conclude that the vesicular transport system may be of particular importance during an immune response. PMID:27467079

  16. Genetic Screen in Drosophila Larvae Links ird1 Function to Toll Signaling in the Fat Body and Hemocyte Motility.

    PubMed

    Schmid, Martin R; Anderl, Ines; Vo, Hoa T M; Valanne, Susanna; Yang, Hairu; Kronhamn, Jesper; Rämet, Mika; Rusten, Tor Erik; Hultmark, Dan

    2016-01-01

    To understand how Toll signaling controls the activation of a cellular immune response in Drosophila blood cells (hemocytes), we carried out a genetic modifier screen, looking for deletions that suppress or enhance the mobilization of sessile hemocytes by the gain-of-function mutation Toll10b (Tl10b). Here we describe the results from chromosome arm 3R, where five regions strongly suppressed this phenotype. We identified the specific genes immune response deficient 1 (ird1), headcase (hdc) and possibly Rab23 as suppressors, and we studied the role of ird1 in more detail. An ird1 null mutant and a mutant that truncates the N-terminal kinase domain of the encoded Ird1 protein affected the Tl10b phenotype, unlike mutations that affect the C-terminal part of the protein. The ird1 null mutant suppressed mobilization of sessile hemocytes, but enhanced other Tl10b hemocyte phenotypes, like the formation of melanotic nodules and the increased number of circulating hemocytes. ird1 mutants also had blood cell phenotypes on their own. They lacked crystal cells and showed aberrant formation of lamellocytes. ird1 mutant plasmatocytes had a reduced ability to spread on an artificial substrate by forming protrusions, which may explain why they did not go into circulation in response to Toll signaling. The effect of the ird1 mutation depended mainly on ird1 expression in hemocytes, but ird1-dependent effects in other tissues may contribute. Specifically, the Toll receptor was translocated from the cell membrane to intracellular vesicles in the fat body of the ird1 mutant, and Toll signaling was activated in that tissue, partially explaining the Tl10b-like phenotype. As ird1 is otherwise known to control vesicular transport, we conclude that the vesicular transport system may be of particular importance during an immune response. PMID:27467079

  17. Escherichia coli Nissle 1917-derived factors reduce cell death and late apoptosis and increase transepithelial electrical resistance in a model of 5-fluorouracil-induced intestinal epithelial cell damage

    PubMed Central

    Wang, Hanru; Bastian, Susan EP; Cheah, Ker Y; Lawrence, Andrew; Howarth, Gordon S

    2014-01-01

    We evaluated the capacity for supernatants (SNs) derived from Escherichia coli Nissle 1917 (EcN), cultured under different growth conditions, to prevent 5-fluorouracil (5-FU)-induced intestinal epithelial cell damage. EcN was cultured in: Luria Bertani (LB) broth, tryptone soya broth (TSB), de Man Rogosa Sharpe (MRS) broth, and M17 broth supplemented with 10% (v/v) lactose solution (M17). Intestinal epithelial cells (IEC-6) were treated with the following EcN SNs: LB+, TSB+, MRS+, and M17+ in the presence and absence of 5-FU (1.5 or 5 μM). Cell viability, apoptotic activity and cell monolayer permeability were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry, and transepithelial electrical resistance (TER) assays, respectively. 5-FU significantly reduced cell viability (P < 0.05) at both 24 and 48 h. However, only EcN SN produced from LB and M17 growth media significantly decreased cell death induced by 5-FU (by approximately 10% after 24 and 48 h; and 10% after 24 h, respectively [P < 0.05]). When measured by flow cytometry all EcN SNs in the presence of 5-FU increased the proportion of viable cells (by 3–5% for 24 h, 3–7% for 48 h, P < 0.05) and reduced late-apoptotic cells after 24 and 48 h, compared with 5-FU control. Moreover, all EcN SNs significantly reduced the disruption of IEC-6 cell barrier function induced by 5-FU by 7–10% (P < 0.05), compared with DMEM control. We conclude that EcN derived factors could potentially reduce the severity of intestinal mucositis. PMID:24556751

  18. Escherichia coli Nissle 1917-derived factors reduce cell death and late apoptosis and increase transepithelial electrical resistance in a model of 5-fluorouracil-induced intestinal epithelial cell damage.

    PubMed

    Wang, Hanru; Bastian, Susan E P; Cheah, Ker Y; Lawrence, Andrew; Howarth, Gordon S

    2014-05-01

    We evaluated the capacity for supernatants (SNs) derived from Escherichia coli Nissle 1917 (EcN), cultured under different growth conditions, to prevent 5-fluorouracil (5-FU)-induced intestinal epithelial cell damage. EcN was cultured in: Luria Bertani (LB) broth, tryptone soya broth (TSB), de Man Rogosa Sharpe (MRS) broth, and M17 broth supplemented with 10% (v/v) lactose solution (M17). Intestinal epithelial cells (IEC-6) were treated with the following EcN SNs: LB(+), TSB(+), MRS(+), and M17(+) in the presence and absence of 5-FU (1.5 or 5 μM). Cell viability, apoptotic activity and cell monolayer permeability were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry, and transepithelial electrical resistance (TER) assays, respectively. 5-FU significantly reduced cell viability (P<0.05) at both 24 and 48 h. However, only EcN SN produced from LB and M17 growth media significantly decreased cell death induced by 5-FU (by approximately 10% after 24 and 48 h; and 10% after 24 h, respectively [P<0.05]). When measured by flow cytometry all EcN SNs in the presence of 5-FU increased the proportion of viable cells (by 3-5% for 24 h, 3-7% for 48 h, P<0.05) and reduced late-apoptotic cells after 24 and 48 h, compared with 5-FU control. Moreover, all EcN SNs significantly reduced the disruption of IEC-6 cell barrier function induced by 5-FU by 7-10% (P<0.05), compared with DMEM control. We conclude that EcN derived factors could potentially reduce the severity of intestinal mucositis. PMID:24556751

  19. 25 CFR 170.131 - How can a tribe find out more about designing and operating a toll facility?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... operating a toll facility? Information on designing and operating a toll highway, bridge or tunnel is available from the International Bridge, Tunnel and Turnpike Association. The Association publishes...

  20. 25 CFR 170.131 - How can a tribe find out more about designing and operating a toll facility?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... operating a toll facility? Information on designing and operating a toll highway, bridge or tunnel is available from the International Bridge, Tunnel and Turnpike Association. The Association publishes...

  1. [Hugo Toll - physician, author, and health debater with firm views].

    PubMed

    Nilsson, Peter M

    2004-01-01

    The Swedish physician Hugo Toll (1858-1943) was brought up as the son of a farmer in mid-Sweden. He was a talented young medical student at the University of Uppsala. After finishing his studies Hugo Toll spent some years as a surgeon in the US, working in Minnesota. Before settling down again in Sweden Toll toured many European countries to increase his knowledge in medical matters and public health issues. In his laborous years of work he spent time in Stockholm, running a private practice, and later on as a headmaster at Ersta School of Nursing, outside Stockholm. Through many years Hugo Toll devoted much time and efforts to writing and lecturing on public health, healthy lifestyle matters, and other topics related to medicine. As many other authors of this time, he also included views based on racial biology and the positive health selection of future parents. At this time some Swedish physicians were more or less openly committed to Nazi ideology, such as Ake Berglund, Herman Lundborg and Gösta Häggqvist. Other physicians were never members of any Nazi party, or did not see themselves as believers in any similar ideology. However, in their lectures and writings, a mixture of ideas upon public health were revealed, some of them also related to Nazi ideology. My impression is that Hugo Toll, although an elderly man and almost blind in the 1930's, was one of many Swedish physicians and debaters with ideas that other, more ideologically determined physicians with strong political views could make use of. Therefore, in current times we can learn from the experience of Hugo Toll that physicians with strong beliefs in public health and a healthy lifestyle can provide arguments that others can use in a different context for darker purposes. PMID:16025612

  2. A novel redox-active metalloporphyrin reduces reactive oxygen species and inflammatory markers but does not improve marginal mass engraftment in a murine donation after circulatory death islet transplantation model.

    PubMed

    Bruni, Antonio; Pepper, Andrew R; Gala-Lopez, Boris; Pawlick, Rena; Abualhassan, Nasser; Crapo, James D; Piganelli, Jon D; Shapiro, A M James

    2016-07-01

    Islet transplantation is a highly effective treatment for stabilizing glycemic control for select patients with type-1 diabetes. Despite improvements to clinical transplantation, single-donor transplant success has been hard to achieve routinely, necessitating increasing demands on viable organ availability. Donation after circulatory death (DCD) may be an alternative option to increase organ availability however, these organs tend to be more compromised. The use of metalloporphyrin anti-inflammatory and antioxidant (MnP) compounds previously demonstrated improved in vivo islet function in preclinical islet transplantation. However, the administration of MnP (BMX-001) in a DCD islet isolation and transplantation model has yet to be established. In this study, murine donors were subjected to a 15-min warm ischemic (WI) period prior to isolation and culture with or without MnP. Subsequent to one-hour culture, islets were assessed for in vitro viability and in vivo function. A 15-minute WI period significantly reduced islet yield, regardless of MnP-treatment relative to yields from standard isolation. MnP-treated islets did not improve islet viability compared to DCD islets alone. MnP-treatment did significantly reduce the presence of extracellular reactive oxygen species (ROS) (p < 0 .05). Marginal, syngeneic islets (200 islets) transplanted under the renal capsule exhibited similar in vivo outcomes regardless of WI or MnP-treatment. DCD islet grafts harvested 7 d post-transplant exhibited sustained TNF-α and IL-10, while MnP-treated islet-bearing grafts demonstrated reduced IL-10 levels. Taken together, 15-minute WI in murine islet isolation significantly impairs islet yield. DCD islets do indeed demonstrate in vivo function, though MnP therapy was unable to improve viability and engraftment outcomes. PMID:27220256

  3. Sudden infant death syndrome

    MedlinePlus

    Crib death; SIDS ... However, SIDS is still a major cause of death in infants under 1 year old. Thousands of ... affects boys more often than girls. Most SIDS deaths occur in the winter. The following may increase ...

  4. Death: 'nothing' gives insight.

    PubMed

    Ettema, Eric J

    2013-08-01

    According to a widely accepted belief, we cannot know our own death--death means 'nothing' to us. At first sight, the meaning of 'nothing' just implies the negation or absence of 'something'. Death then simply refers to the negation or absence of life. As a consequence, however, death has no meaning of itself. This leads to an ontological paradox in which death is both acknowledged and denied: death is … nothing. In this article, I investigate whether insight into the ontological paradox of the nothingness of death can contribute to a good end-of-life. By analysing Aquinas', Heidegger's and Derrida's understanding of death as nothingness, I explore how giving meaning to death on different ontological levels connects to, and at the same time provides resistance against, the harsh reality of death. By doing so, I intend to demonstrate that insight into the nothingness of death can count as a framework for a meaningful dealing with death. PMID:23054426

  5. Sudden Infant Death Syndrome

    MedlinePlus

    Sudden infant death syndrome (SIDS) is the sudden, unexplained death of an infant younger than one year old. Some people call SIDS "crib death" because many babies who die of SIDS are found in their ...

  6. Magnesium and sudden death.

    PubMed

    Leary, W P; Reyes, A J

    1983-10-22

    Magnesium deficiency may result from reduced dietary intake of the ion or increased losses in sweat, urine or faeces. Stress potentiates magnesium deficiency, and an increased incidence of sudden death associated with ischaemic heart disease is found in some areas in which soil and drinking water lack magnesium. Furthermore, it has been demonstrated experimentally that reduction of the plasma magnesium level is associated with arterial spasm. Careful studies are required to assess the clinical importance of magnesium and the benefits of magnesium supplementation in man. PMID:6353622

  7. 47 CFR 64.1504 - Restrictions on the use of toll-free numbers.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 3 2014-10-01 2014-10-01 false Restrictions on the use of toll-free numbers... Other Information Services § 64.1504 Restrictions on the use of toll-free numbers. A common carrier... advertised or widely understood to be toll-free, in a manner that would result in: (a) The calling party...

  8. 47 CFR 64.1504 - Restrictions on the use of toll-free numbers.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 3 2012-10-01 2012-10-01 false Restrictions on the use of toll-free numbers... Other Information Services § 64.1504 Restrictions on the use of toll-free numbers. A common carrier... advertised or widely understood to be toll-free, in a manner that would result in: (a) The calling party...

  9. The Toll pathway is required in the epidermis for muscle development in the Drosophila embryo

    NASA Technical Reports Server (NTRS)

    Halfon, M. S.; Keshishian, H.

    1998-01-01

    The Toll signaling pathway functions in several Drosophila processes, including dorsal-ventral pattern formation and the immune response. Here, we demonstrate that this pathway is required in the epidermis for proper muscle development. Previously, we showed that the zygotic Toll protein is necessary for normal muscle development; in the absence of zygotic Toll, close to 50% of hemisegments have muscle patterning defects consisting of missing, duplicated and misinserted muscle fibers (Halfon, M.S., Hashimoto, C., and Keshishian, H., Dev. Biol. 169, 151-167, 1995). We have now also analyzed the requirements for easter, spatzle, tube, and pelle, all of which function in the Toll-mediated dorsal-ventral patterning pathway. We find that spatzle, tube, and pelle, but not easter, are necessary for muscle development. Mutations in these genes give a phenotype identical to that seen in Toll mutants, suggesting that elements of the same pathway used for Toll signaling in dorsal-ventral development are used during muscle development. By expressing the Toll cDNA under the control of distinct Toll enhancer elements in Toll mutant flies, we have examined the spatial requirements for Toll expression during muscle development. Expression of Toll in a subset of epidermal cells that includes the epidermal muscle attachment cells, but not Toll expression in the musculature, is necessary for proper muscle development. Our results suggest that signals received by the epidermis early during muscle development are an important part of the muscle patterning process.

  10. 77 FR 2610 - Open Meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-18

    ... Internal Revenue Service Open Meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee AGENCY... Taxpayer Advocacy Panel Toll-Free Project Committee will be conducted. The Taxpayer Advocacy Panel is... meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee will be held Tuesday, February 7,...

  11. 76 FR 77892 - Open Meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-14

    ... Internal Revenue Service Open Meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee AGENCY... Taxpayer Advocacy Panel Toll-Free Project Committee will be conducted. The Taxpayer Advocacy Panel is... meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee will be held Tuesday, January 03,...

  12. 77 FR 40411 - Open Meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-09

    ... Internal Revenue Service Open Meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee AGENCY... Taxpayer Advocacy Panel Toll-Free Project Committee will be conducted. The Taxpayer Advocacy Panel is... meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee will be held Tuesday, August 7,...

  13. 77 FR 55526 - Open Meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-10

    ... Internal Revenue Service Open Meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee AGENCY... Taxpayer Advocacy Panel Toll-Free Project Committee will be conducted. The Taxpayer Advocacy Panel is... meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee will be held Tuesday, October 2,...

  14. For Whom Does Language Death Toll? Cautionary Notes from the Basque Case

    ERIC Educational Resources Information Center

    Echeverria, Begona

    2010-01-01

    In this article, I show that despite a seemingly inclusive, language-based identity promoted in schools and pedagogical materials, Basque identity and language are embedded with social histories that exclude large swaths of the would-be Basque nation: women and second language learners of Basque. To the extent that these processes continue to…

  15. Microbiota regulates type 1 diabetes through Toll-like receptors

    PubMed Central

    Burrows, Michael P.; Volchkov, Pavel; Kobayashi, Koichi S.; Chervonsky, Alexander V.

    2015-01-01

    Deletion of the innate immune adaptor myeloid differentiation primary response gene 88 (MyD88) in the nonobese diabetic (NOD) mouse model of type 1 diabetes (T1D) results in microbiota-dependent protection from the disease: MyD88-negative mice in germ-free (GF), but not in specific pathogen-free conditions develop the disease. These results could be explained by expansion of particular protective bacteria (“specific lineage hypothesis”) or by dominance of negative (tolerizing) signaling over proinflammatory signaling (“balanced signal hypothesis”) in mutant mice. Here we found that colonization of GF mice with a variety of intestinal bacteria was capable of reducing T1D in MyD88-negative (but not wild-type NOD mice), favoring the balanced signal hypothesis. However, the receptors and signaling pathways involved in prevention or facilitation of the disease remained unknown. The protective signals triggered by the microbiota were revealed by testing NOD mice lacking MyD88 in combination with knockouts of several critical components of innate immune sensing for development of T1D. Only MyD88- and TIR-domain containing adapter inducing IFN β (TRIF) double deficient NOD mice developed the disease. Thus, TRIF signaling (likely downstream of Toll-like receptor 4, TLR4) serves as one of the microbiota-induced tolerizing pathways. At the same time another TLR (TLR2) provided prodiabetic signaling by controlling the microbiota, as reduction in T1D incidence caused by TLR2 deletion was reversed in GF TLR2-negative mice. Our results support the balanced signal hypothesis, in which microbes provide signals that both promote and inhibit autoimmunity by signaling through different receptors, including receptors of the TLR family. PMID:26216961

  16. Radiofrequency Ablation to Prevent Sudden Cardiac Death

    PubMed Central

    Atoui, Moustapha; Gunda, Sampath; Lakkireddy, Dhanunjaya; Mahapatra, Srijoy

    2015-01-01

    Radiofrequency ablation may prevent or treat atrial and ventricular arrhythmias. Since some of these arrhythmias are associated with sudden cardiac death, it has been hypothesized that ablation may prevent sudden death in certain cases. We performed a literature search to better understand under which circumstances ablation may prevent sudden death and found little randomized data demonstrating the long-term effects of ablation. Current literature shows that ablation clearly prevents symptoms of arrhythmia and may reduce the incidence of sudden cardiac death in select patients, although data does not indicate improved mortality. Ongoing clinical trials are needed to better define the role of ablation in preventing sudden cardiac death. PMID:26306130

  17. Drosophila Dicer-2 has an RNA interference–independent function that modulates Toll immune signaling

    PubMed Central

    Wang, Zhaowei; Wu, Di; Liu, Yongxiang; Xia, Xiaoling; Gong, Wanyun; Qiu, Yang; Yang, Jie; Zheng, Ya; Li, Jingjing; Wang, Yu-Feng; Xiang, Ye; Hu, Yuanyang; Zhou, Xi

    2015-01-01

    Dicer-2 is the central player for small interfering RNA biogenesis in the Drosophila RNA interference (RNAi) pathway. Intriguingly, we found that Dicer-2 has an unconventional RNAi-independent function that positively modulates Toll immune signaling, which defends against Gram-positive bacteria, fungi, and some viruses, in both cells and adult flies. The loss of Dicer-2 expression makes fruit flies more susceptible to fungal infection. We further revealed that Dicer-2 posttranscriptionally modulates Toll signaling because Dicer-2 is required for the proper expression of Toll protein but not for Toll protein stability or Toll mRNA transcription. Moreover, Dicer-2 directly binds to the 3′ untranslated region (3′UTR) of Toll mRNA via its PAZ (Piwi/Argonaute/Zwille) domain and is required for protein translation mediated by Toll 3′UTR. The loss of Toll 3′UTR binding activity makes Dicer-2 incapable of promoting Toll signaling. These data indicate that the interaction between Dicer-2 and Toll mRNA plays a pivotal role in Toll immune signaling. In addition, we found that Dicer-2 is also required for the Toll signaling induced by two different RNA viruses in Drosophila cells. Consequently, our findings uncover a novel RNAi-independent function of Dicer-2 in the posttranscriptional regulation of Toll protein expression and signaling, indicate an unexpected intersection of the RNAi pathway and the Toll pathway, and provide new insights into Toll immune signaling, Drosophila Dicer-2, and probably Dicer and Dicer-related proteins in other organisms. PMID:26601278

  18. Drosophila Dicer-2 has an RNA interference-independent function that modulates Toll immune signaling.

    PubMed

    Wang, Zhaowei; Wu, Di; Liu, Yongxiang; Xia, Xiaoling; Gong, Wanyun; Qiu, Yang; Yang, Jie; Zheng, Ya; Li, Jingjing; Wang, Yu-Feng; Xiang, Ye; Hu, Yuanyang; Zhou, Xi

    2015-10-01

    Dicer-2 is the central player for small interfering RNA biogenesis in the Drosophila RNA interference (RNAi) pathway. Intriguingly, we found that Dicer-2 has an unconventional RNAi-independent function that positively modulates Toll immune signaling, which defends against Gram-positive bacteria, fungi, and some viruses, in both cells and adult flies. The loss of Dicer-2 expression makes fruit flies more susceptible to fungal infection. We further revealed that Dicer-2 posttranscriptionally modulates Toll signaling because Dicer-2 is required for the proper expression of Toll protein but not for Toll protein stability or Toll mRNA transcription. Moreover, Dicer-2 directly binds to the 3' untranslated region (3'UTR) of Toll mRNA via its PAZ (Piwi/Argonaute/Zwille) domain and is required for protein translation mediated by Toll 3'UTR. The loss of Toll 3'UTR binding activity makes Dicer-2 incapable of promoting Toll signaling. These data indicate that the interaction between Dicer-2 and Toll mRNA plays a pivotal role in Toll immune signaling. In addition, we found that Dicer-2 is also required for the Toll signaling induced by two different RNA viruses in Drosophila cells. Consequently, our findings uncover a novel RNAi-independent function of Dicer-2 in the posttranscriptional regulation of Toll protein expression and signaling, indicate an unexpected intersection of the RNAi pathway and the Toll pathway, and provide new insights into Toll immune signaling, Drosophila Dicer-2, and probably Dicer and Dicer-related proteins in other organisms. PMID:26601278

  19. The influence of economic incentives linked to road safety indicators on accidents: the case of toll concessions in Spain.

    PubMed

    Rangel, Thais; Vassallo, José Manuel; Herraiz, Israel

    2013-10-01

    The goal of this paper is to evaluate whether the incentives incorporated in toll highway concession contracts in order to encourage private operators to adopt measures to reduce accidents are actually effective at improving safety. To this end, we implemented negative binomial regression models using information about highway characteristics and accident data from toll highway concessions in Spain from 2007 to 2009. Our results show that even though road safety is highly influenced by variables that are not managed by the contractor, such as the annual average daily traffic (AADT), the percentage of heavy vehicles on the highway, number of lanes, number of intersections and average speed; the implementation of these incentives has a positive influence on the reduction of accidents and injuries. Consequently, this measure seems to be an effective way of improving safety performance in road networks. PMID:23954687

  20. 26 CFR 49.4252-2 - Toll telephone service.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... telephone message or conversation. (2) The tax attaches to the total charge made to a hotel or similar subscriber for toll telephone service furnished to the hotel or its guests, but no tax attaches to any charge made by the hotel for service rendered in placing the calls for its guests. (c) Cross reference....

  1. 26 CFR 49.4252-2 - Toll telephone service.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... telephone message or conversation. (2) The tax attaches to the total charge made to a hotel or similar subscriber for toll telephone service furnished to the hotel or its guests, but no tax attaches to any charge made by the hotel for service rendered in placing the calls for its guests. (c) Cross reference....

  2. 26 CFR 49.4252-2 - Toll telephone service.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... telephone message or conversation. (2) The tax attaches to the total charge made to a hotel or similar subscriber for toll telephone service furnished to the hotel or its guests, but no tax attaches to any charge made by the hotel for service rendered in placing the calls for its guests. (c) Cross reference....

  3. 26 CFR 49.4252-2 - Toll telephone service.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... telephone message or conversation. (2) The tax attaches to the total charge made to a hotel or similar subscriber for toll telephone service furnished to the hotel or its guests, but no tax attaches to any charge made by the hotel for service rendered in placing the calls for its guests. (c) Cross reference....

  4. Toll-like receptors in the pathogenesis of inflammatory diseases

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Toll-like receptors (TLRs) are newly established immune receptors which are critical for host defense through the activation of both innate and adaptive immunity. TLRs can recognize molecules with both microbial and non-microbial origins. Emerging evidence now suggests that TLRs are implicated in th...

  5. MAPPING OF TOLL LIKE RECEPTOR (TLR) GENES IN RAINBOW TROUT

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Toll-like receptors (TLRs) are a family of transmembrane proteins that recognize conserved pathogen structures to induce innate immune effector molecules. In vertebrates, TLRs can distinguish among classes of pathogens and serve an important role in orchestrating the appropriate adaptive immune resp...

  6. Toll receptors in lower vertebrates and expanding family

    Technology Transfer Automated Retrieval System (TEKTRAN)

    It has been well established that Toll-like receptors (TLR) are critical actors in the early detection of pathogens. Upon binding of pathogen-associated molecules, they trigger a signaling that activates the immune system and initiates host defense. We undertook the characterization of the TLR in th...

  7. 33 CFR 401.75 - Payment of tolls.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 3 2010-07-01 2010-07-01 false Payment of tolls. 401.75 Section 401.75 Navigation and Navigable Waters SAINT LAWRENCE SEAWAY DEVELOPMENT CORPORATION, DEPARTMENT OF..., established by agreement between Canada and the United States, and known as the St. Lawrence Seaway...

  8. 47 CFR 51.213 - Toll dialing parity implementation plans.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... parity implementation plans. (a) A LEC must file a plan for providing intraLATA toll dialing parity... dialing parity within a state until the implementation plan has been approved by the appropriate state commission or the Commission. (b) A LEC's implementation plan must include: (1) A proposal that explains...

  9. Regulation of migration and invasion by Toll-like receptor-9 signaling network in prostate cancer

    PubMed Central

    Qiu, Jian-Ge; Zhang, Wen-Ji; Mei, Xiao-Long; Shi, Zhi; Di, Jin-Ming

    2015-01-01

    Toll-like receptors (TLRs) play an important role in tumorigenesis and progress of prostate cancer. However, the function and mechanism of Toll-like receptor-9 (TLR9) in prostate cancer is not totally understood. Here, we found that high expression of TLR9 was associated with a higher probability of lymph node metastasis and poor prognosis. Further in vitro functional study verified that silence of TLR9 inhibited migration and invasion of PC-3 cells, indicating expression of TLR9 involving in the migration and invasion of cancer cells. The data of microarray exhibited silence of TLR9 induced 205 genes with larger than 2-fold changes in expression levels, including 164 genes down-regulated and 41 genes up-regulated. Functional Gene Ontology (GO) processes annotation demonstrated that the top three scores of molecular and cellular functions were regulation of programmed cell death, regulation of locomotion and response to calcium ion. TLR9 signaling network analysis of the migration and invasion related genes identified several genes, like matrix metallopeptidase 2 (MMP2), matrix metallopeptidase 9 (MMP9), chemokine receptor 4 (CXCR4) and interleukin 8 (IL8), formed the core interaction network based on their known biological relationships. A few genes, such as odontogenic ameloblast-associated protein (ODAM), claudin 2 (CLDN2), gap junction protein beta 1 (GJB1) and Rho-associated coiled-coil containing protein kinase 1 pseudogene 1 (ROCK1P1), so far have not been found to interact with the other genes. This study provided the foundation to discover the new molecular mechanism in signaling networks of invasion and metastasis in prostate cancer. PMID:26087186

  10. Confidential inquiry into malaria deaths.

    PubMed Central

    Dürrheim, D. N.; Frieremans, S.; Kruger, P.; Mabuza, A.; de Bruyn, J. C.

    1999-01-01

    The results of a confidential inquiry into mortality attributed to malaria in South Africa's Mpumalanga Province are being used to guide the design of strategies for improving the management of cases and reducing the probability of deaths from the disease. PMID:10212518

  11. Targeting the Toll of Drug Abuse: The Translational Potential of Toll-Like Receptor 4.

    PubMed

    Bachtell, Ryan; Hutchinson, Mark R; Wang, Xiaohui; Rice, Kenner C; Maier, Steven F; Watkins, Linda R

    2015-01-01

    There is growing recognition that glial proinflammatory activation importantly contributes to the rewarding and reinforcing effects of a variety of drugs of abuse, including cocaine, methamphetamine, opioids, and alcohol. It has recently been proposed that glia are recognizing, and becoming activated by, such drugs as a CNS immunological response to these agents being xenobiotics; that is, substances foreign to the brain. Activation of glia, primarily microglia, by various drugs of abuse occurs via toll like receptor 4 (TLR4). The detection of such xenobiotics by TLR4 results in the release of glial neuroexcitatory and neurotoxic substances. These glial products of TLR4 activation enhance neuronal excitability within brain reward circuitry, thereby enhancing their rewarding and reinforcing effects. Indeed, selective pharmacological blockade of TLR4 activation, such as with the non-opioid TLR4 antagonist (+)-naltrexone, suppresses a number of indices of drug reward/reinforcement. These include: conditioned place preference, self-administration, drugprimed reinstatement, incubation of craving, and elevations of nucleus accumbens shell dopamine. Notably, TLR4 blockade fails to alter self-administration of food, indicative of a selective effect on drugs of abuse. Genetic disruption of TLR4 signaling recapitulates the effects of pharmacological TLR4 blockade, providing converging lines of evidence of a central importance of TLR4. Taken together, multiple lines of evidence converge to raise TLR4 as a promising therapeutic target for drug abuse. PMID:26022268

  12. Modeling the interactions of bacteria and Toll-like receptor-mediated inflammation in necrotizing enterocolitis

    PubMed Central

    Arciero, Julia; Ermentrout, G. Bard; Siggers, Richard; Afrazi, Amin; Hackam, David; Vodovotz, Yoram; Rubin, Jonathan

    2016-01-01

    Necrotizing enterocolitis (NEC) is a severe disease of the gastrointestinal tract in premature infants, characterized by a disrupted intestinal epithelium and an exaggerated pro-inflammatory response. Since the activation of Toll-like receptor-4 (TLR4) blocks cell migration and proliferation and contributes to an uncontrolled inflammatory response within the intestine, this receptor has been identified as a key contributor to the development of NEC. Toll-like receptor-9 (TLR9) has been shown to sense bacterial genome components (CpG DNA) and to play an anti-inflammatory role in NEC. We present in vitro results demonstrating direct inhibition of TLR4 activation by CpG DNA, and we develop a mathematical model of bacteria–immune interactions within the intestine to investigate how such inhibition of TLR4 signaling might alter inflammation, associated bacterial invasion of tissue, and resulting outcomes. The model predicts that TLR9 can inhibit both the beneficial and detrimental effects of TLR4, and thus a proper balance of action by these two receptors is needed to promote intestinal health. The model results are also used to explore three interventions that could potentially prevent the development of NEC: reducing bacteria in the mucus layer, administering probiotic treatment, and blocking TLR4 activation. While the model shows that these interventions would be successful in most cases, the model is also used to identify situations in which the proposed treatments might be harmful. PMID:23238281

  13. Characteristics of run-off quality and pollution loading from a highway toll-gate.

    PubMed

    Lee, Ju Young

    2012-01-01

    The Ministry of Environment of the Republic of Korea has been seriously considering implementing a TMDL (Total Maximum Daily Load) as a mandatory requirement on watersheds because of the potential water pollution from highway toll-gates. The purpose of this study was to investigate the characteristics of run-off quality and pollution loading during rainfall events at a highway toll-gate. Samples were analysed for run-off quantity and quality parameters such as COD(cr), TSS, total petroleum hydrocarbons, nutrients (TKN, NO3, TP and PO4) and several heavy metals (As, Cu, Cd, Ni, Pb and Zn). Based on a hydrograph and pollutant graph analysis, the pollutant concentration peak occurred in the run-off 10 minutes after the onset of rainfall. The typical first flush effect on the concentration depended on the rainfall intensity and the number of antecedent dry days. The relationships between the run-off and the event mean concentrations of the pollutants (e.g. TSS and COD) were described by general nonlinear equations. For governmental implementation of TMDL policies, the estimation of the cumulative TSS load was 1032 kg/(ha x yr) in 2007, 963.44 kg/(ha x yr) in 2008 and 847.21 kg/(ha x yr) in 2009. This information can lead to improved practical water quality management practices and reduced costs of improving water quality. PMID:22519124

  14. Patents for Toll-like receptor ligands as radiation countermeasures for acute radiation syndrome.

    PubMed

    Singh, Vijay K; Pollard, Harvey B

    2015-01-01

    Acute radiation exposure induces apoptosis of tissues in the hematopoietic, digestive, cutaneous, cardiovascular and nervous systems; extensive apoptosis of these tissues ultimately leads to acute radiation syndrome. A novel strategy for developing radiation countermeasures has been to imitate the genetic mechanisms acquired by radiation-resistant tumors. Two mechanisms that underlie this ability of tumor cells are the p53 and NF-κB pathways. The loss of p53 function results in the inactivation of pro-apoptotic control mechanisms, while constitutive activation of NF-κB results in the up-regulation of anti-apoptotic genes. Various Toll-like receptor ligands are capable of up regulating the NF-κB pathway, which increases radio-resistance and reduces radiation-induced apoptosis in various tissues. Several Toll-like receptor ligands have been patented and are currently under development as radiation countermeasures for acute radiation syndrome. Ongoing studies suggest that a few of these attractive agents are progressing well along the US FDA approval pathway to become radiation countermeasures. PMID:26135043

  15. The Unique Impact of Abolition of Jim Crow Laws on Reducing Inequities in Infant Death Rates and Implications for Choice of Comparison Groups in Analyzing Societal Determinants of Health

    PubMed Central

    Chen, Jarvis T.; Coull, Brent; Waterman, Pamela D.; Beckfield, Jason

    2013-01-01

    Objectives. We explored associations between the abolition of Jim Crow laws (i.e., state laws legalizing racial discrimination overturned by the 1964 US Civil Rights Act) and birth cohort trends in infant death rates. Methods. We analyzed 1959 to 2006 US Black and White infant death rates within and across sets of states (polities) with and without Jim Crow laws. Results. Between 1965 and 1969, a unique convergence of Black infant death rates occurred across polities; in 1960 to 1964, the Black infant death rate was 1.19 times higher (95% confidence interval [CI] = 1.18, 1.20) in the Jim Crow polity than in the non–Jim Crow polity, whereas in 1970 to 1974 the rate ratio shrank to and remained at approximately 1 (with the 95% CI including 1) until 2000, when it rose to 1.10 (95% CI = 1.08, 1.12). No such convergence occurred for Black–White differences in infant death rates or for White infants. Conclusions. Our results suggest that abolition of Jim Crow laws affected US Black infant death rates and that valid analysis of societal determinants of health requires appropriate comparison groups. PMID:24134378

  16. Sudden infant death syndrome.

    PubMed

    Adams, Stephen M; Ward, Chad E; Garcia, Karla L

    2015-06-01

    Sudden infant death syndrome (SIDS) is the sudden unexpected death of a child younger than one year during sleep that cannot be explained after a postmortem evaluation including autopsy, a thorough history, and scene evaluation. The incidence of SIDS has decreased more than 50% in the past 20 years, largely as a result of the Back to Sleep campaign. The most important risk factors relate to the sleep environment. Prone and side sleeping positions are significantly more dangerous than the supine position. Bed sharing with a parent is strongly correlated with an increased risk of SIDS, especially in infants younger than 12 weeks. Apparent life-threatening events are not a risk factor for SIDS. Parents should place infants on their backs to sleep, should not share a bed, and should avoid exposing the infant to tobacco smoke. Other risk-reducing measures include using a firm crib mattress, breastfeeding, keeping vaccinations up to date, avoiding overheating due to overbundling, avoiding soft bedding, and considering the use of a pacifier during sleep once breastfeeding is established. One consequence of the Back to Sleep campaign is a significant increase in the incidence of occipital flattening. Infants who develop a flat spot should be placed with the head facing alternating directions each time he or she is put to bed. Supervised prone positioning while the infant is awake, avoiding excessive use of carriers, and upright positioning while awake are also recommended. PMID:26034855

  17. Sudden infant death syndrome

    PubMed Central

    Hunt, Carl E.; Hauck, Fern R.

    2006-01-01

    Sudden infant death syndrome (SIDS) continues to be the most common cause of postneonatal infant death. SIDS is a complex, multifactorial disorder, the cause of which is still not fully understood. However, much is known now about environmental risk factors, some of which are modifiable. These include maternal and antenatal risk factors such as smoking during pregnancy, as well as infant-related risk factors such as non-supine sleeping position and soft bedding. Emerging evidence also substantiates an expanding number of genetic risk factors. Interactions between environmental and genetic risk factors may be of critical importance in determining an infant's actual risk of SIDS. Although no practical way exists to identify which infants will die of SIDS, nor is there a safe and proven prevention strategy even if identification were feasible, reducing exposure to modifiable risk factors has helped to lower the incidence of SIDS. Current challenges include wider dissemination of guidelines to all people who care for infants, dissemination of guidelines in culturally appropriate ways, and surveillance of SIDS trends and other outcomes associated with implementation of these guidelines. PMID:16785462

  18. High expression of RNA-binding motif protein 3 in esophageal and gastric adenocarcinoma correlates with intestinal metaplasia-associated tumours and independently predicts a reduced risk of recurrence and death

    PubMed Central

    2014-01-01

    Background High nuclear expression of the RNA-binding motif protein 3 (RBM3) has previously been found to correlate with favourable clinicopathological characteristics and a prolonged survival in several cancer forms. Here, we examined the clinicopathological correlates and prognostic significance of RBM3 expression in tumours from a consecutive cohort of upper gastrointestinal adenocarcinoma. Material and methods Immunohistochemical RBM3 expression was analysed in tissue microarrays with primary radiotherapy- and chemotherapy-naive adenocarcinoma of the esophagus, gastroesophageal junction and stomach (n = 173). In addition paired samples of normal squamous epithelium (n = 53), gastric mucosa (n = 117), Barrett’s esophagus/gastric intestinal metaplasia (n = 61) and lymph node metastases (n = 71) were analysed. Kaplan-Meier analysis and Cox proportional hazards modelling was applied to assess the impact of RBM3 expression on overall survival (OS) and recurrence-free survival (RFS). Results RBM3 expression was similar in primary tumours and lymph node metastases, but significantly higher in primary tumours and metastases arising in a background of intestinal metaplasia compared with cases without intestinal metaplasia (p < 0.001). RBM3 expression was significantly reduced in more advanced tumour stages (p = 0.006). Low RBM3 expression was significantly associated with a shorter OS in cases with radically resected (R0) tumours (HR 2.19, 95% CI 1.33-3.61, p = 0.002) and RFS in curatively treated patients with R0 resection/distant metastasis-free disease (HR = 3.21, 95% CI 1.64-6.30, p = 0.001). These associations remained significant in adjusted analysis (HR = 1.95, 95% CI 1.17-3.25, p = 0.010 for OS and HR = 3.02, 95% CI 1.45-6.29, p = 0.003 for RFS). Conclusion High expression of RBM3 may signify a subset of upper gastrointestinal cancers arising in a background of intestinal metaplasia and independently predicts a reduced risk of recurrence

  19. Death by fraternity hazing.

    PubMed

    Boglioli, L R; Taff, M L

    1995-03-01

    Fraternity hazing can cause a variety of injuries and deaths. We recently had the opportunity to investigate a heat-related death that occurred during a college fraternity event. The original death investigation did not consider the circumstances of death, environmental conditions, or the subtle autopsy findings related to heat stroke. This case is intended to alert health care professionals that deaths on college campuses may be related to fraternity hazing and may require in-depth investigations. An analysis of the death and a discussion of heat-related injuries are presented. PMID:7771381

  20. Drug Monitoring Programs Do Curb Overdose Deaths: Study

    MedlinePlus

    ... 159528.html Drug Monitoring Programs Do Curb Overdose Deaths: Study Opioid epidemic demands such measures, researcher says ... News) -- Drug monitoring programs appear to help reduce deaths from prescription painkillers called opioids, a new study ...

  1. Environmental lead exposure to toll booth workers in Hong Kong

    SciTech Connect

    Tan, T.C.; Wong, L.T.L.; Lam, C.W.K.

    1988-01-01

    A survey of workers in the Lion Rock Tunnel toll booths was conducted, as they were regarded as a high risk group in lead exposure due to high density of vehicular traffic. The exposure of the workers to lead was determined by continuous sapling of air around the breathing zone of workers inside the booths. Blood lead concentration of 50 workers showed a mean of 0.65 {mu}mol/L and the mean urine lead concentration was 0.14 {mu}mol/L. Other tests, such as urinary amino-levulinic acid (ALA), erythrocyte zinc protoporphyrin (ZnPP) and hemoglobin concentration (Hb), were also preformed. The blood lead concentrations and other biological parameters of the toll-booth workers were acceptable and may be attributed to the recent legislation to lower the lead content in petrol and to the good preventive measures taken by the management.

  2. Current Views of Toll-Like Receptor Signaling Pathways

    PubMed Central

    Yamamoto, Masahiro; Takeda, Kiyoshi

    2010-01-01

    On microbial invasion, the host immediately evokes innate immune responses. Recent studies have demonstrated that Toll-like receptors (TLRs) play crucial roles in innate responses that lead not only to the clearance of pathogens but also to the efficient establishment of acquired immunity by directly detecting molecules from microbes. In terms of intracellular TLR-mediated signaling pathways, cytoplasmic adaptor molecules containing Toll/IL-1R (TIR) domains play important roles in inflammatory immune responses through the production of proinflammatory cytokines, nitric oxide, and type I interferon, and upregulation of costimulatory molecules. In this paper, we will describe our current understanding of the relationship between TLRs and their ligands derived from pathogens such as viruses, bacteria, fungi, and parasites. Moreover, we will review the historical and current literature to describe the mechanisms behind TLR-mediated activation of innate immune responses. PMID:21197425

  3. Sudden Infant Death Syndrome

    MedlinePlus

    Sudden infant death syndrome (SIDS) is the sudden, unexplained death of an infant younger than one year old. Some people call ... boys, African Americans, and American Indian/Alaska Native infants have a higher risk of SIDS. Although health ...

  4. Toll-deficient Drosophila is susceptible to Pythium insidiosum infection.

    PubMed

    Zanette, Régis A; Santurio, Janio M; Loreto, Érico S; Alves, Sydney H; Kontoyiannis, Dimitrios P

    2013-10-01

    There is a paucity of animal models of pythiosis, a life-threatening disease of humans and animals, the immunopathogenesis of which is poorly understood. A pythiosis model was developed by injecting Toll (Tl)-deficient Drosophila melanogaster flies with Pythium insidiosum zoospores. The infected Tl mutant flies had significantly lower survival rates (73.7%) than did control flies. This study reveals the important role of Tl pathway activation in fly immune response to pythiosis. PMID:23865688

  5. 1. AERIAL VIEW, LOOKING SE. CHICAGO SKYWAY TOLL BRIDGE (HAER ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    1. AERIAL VIEW, LOOKING SE. CHICAGO SKYWAY TOLL BRIDGE (HAER No. IL-145) IS TOWARD RIGHT OF FRAME; PITTSBURGH, FORT WAYNE & CHICAGO RAILWAY BRIDGE IS JUST LEFT OF GRAIN ELEVATOR; PAIR OF LAKE SHORE & MICHIGAN SOUTHERN RAILWAY BRIDGES (HAER No. IL-161) ARE TOWARD LEFT OF FRAME. - Pittsburgh, Fort Wayne & Chicago Railway, Calumet River Bridge, Spanning Calumet River, east of Chicago Skyway (I-90), Chicago, Cook County, IL

  6. Children's Experience with Death.

    ERIC Educational Resources Information Center

    Zeligs, Rose

    Children's concepts of death grow with their age and development The three-year-old begins to notice that living things move and make sounds. The five-year-old thinks that life and death are reversable, but the six-year-old knows that death is final and brings sorrow. Children from eight through ten are interested in the causes of death and what…

  7. The Aedes aegypti Toll Pathway Controls Dengue Virus Infection

    PubMed Central

    Xi, Zhiyong; Ramirez, Jose L.; Dimopoulos, George

    2008-01-01

    Aedes aegypti, the mosquito vector of dengue viruses, utilizes its innate immune system to ward off a variety of pathogens, some of which can cause disease in humans. To date, the features of insects' innate immune defenses against viruses have mainly been studied in the fruit fly Drosophila melanogaster, which appears to utilize different immune pathways against different types of viruses, in addition to an RNA interference–based defense system. We have used the recently released whole-genome sequence of the Ae. aegypti mosquito, in combination with high-throughput gene expression and RNA interference (RNAi)-based reverse genetic analyses, to characterize its response to dengue virus infection in different body compartments. We have further addressed the impact of the mosquito's endogenous microbial flora on virus infection. Our findings indicate a significant role for the Toll pathway in regulating resistance to dengue virus, as indicated by an infection-responsive regulation and functional assessment of several Toll pathway–associated genes. We have also shown that the mosquito's natural microbiota play a role in modulating the dengue virus infection, possibly through basal-level stimulation of the Toll immune pathway. PMID:18604274

  8. Sudden Cardiac Death

    PubMed Central

    Weinberg, Marc

    1978-01-01

    Over the past decade, there has been a significant decrease in the hospital mortality of patients with coronary artery disease. However, sudden cardiac death, which accounts for the majority of deaths from coronary artery disease, hasbeen little affected. This report reviews the pathology, electrophysiology, demographics and clinical presentation of sudden cardiac death. Emergency care and possible preventative measures are examined. PMID:356435

  9. Dreams of Death.

    ERIC Educational Resources Information Center

    Barrett, Deirdre

    1989-01-01

    Examined frequency and characteristics of overt dreams of dying among healthy young adults. Dreams of dying were found to be rare but distinctive content category, representing overwhelmingly pleasant dreams. Over one-half of death dreams involved lengthy afterlife sequence, remainder focused on process of death. Death dreams of these healthy…

  10. Separation, Part I: Death.

    ERIC Educational Resources Information Center

    Jordan, Anne Devereaux

    1997-01-01

    Contends literature is the one place where death still abides, where grief is felt and consolation can be sought. States that young readers can gain a recognition in books that death is natural. Discusses death in folk and fairy tales, in 17th-century didactic children's books and in modern and contemporary literature. Outlines characteristics of…

  11. A serpin mutant links Toll activation to melanization in the host defence of Drosophila

    PubMed Central

    Ligoxygakis, Petros; Pelte, Nadège; Ji, Chuanyi; Leclerc, Vincent; Duvic, Bernard; Belvin, Marcia; Jiang, Haobo; Hoffmann, Jules A.; Reichhart, Jean-Marc

    2002-01-01

    A prominent response during the Drosophila host defence is the induction of proteolytic cascades, some of which lead to localized melanization of pathogen surfaces, while others activate one of the major players in the systemic antimicrobial response, the Toll pathway. Despite the fact that gain-of-function mutations in the Toll receptor gene result in melanization, a clear link between Toll activation and the melanization reaction has not been firmly established. Here, we present evidence for the coordination of hemolymph-borne melanization with activation of the Toll pathway in the Drosophila host defence. The melanization reaction requires Toll pathway activation and depends on the removal of the Drosophila serine protease inhibitor Serpin27A. Flies deficient for this serpin exhibit spontaneous melanization in larvae and adults. Microbial challenge induces its removal from the hemolymph through Toll-dependent transcription of an acute phase immune reaction component. PMID:12456640

  12. Innate Immune Regulation by Toll-Like Receptors in the Brain

    PubMed Central

    Mallard, Carina

    2012-01-01

    The innate immune system plays an important role in cerebral health and disease. In recent years the role of innate immune regulation by toll-like receptors in the brain has been highlighted. In this paper the expression of toll-like receptors and endogenous toll-like receptor ligands in the brain and their role in cerebral ischemia will be discussed. Further, the ability of systemic toll-like receptor ligands to induce cerebral inflammation will be reviewed. Finally, the capacity of toll-like receptors to both increase (sensitization) and decrease (preconditioning/tolerance) the vulnerability of the brain to damage will be disclosed. Studies investigating the role of toll-like receptors in the developing brain will be emphasized. PMID:23097717

  13. Clarifying the discussion on brain death.

    PubMed

    Dagi, F T; Kaufman, R

    2001-10-01

    Definitions of death are based on subjective standards, priorities, and social conventions rather than on objective facts about the state of human physiology. It is the meaning assigned to the facts that determines when someone may be deemed to have died, not the facts themselves. Even though subjective standards for the diagnosis of death show remarkable consistency across communities, they are extrinsic. They are driven, implicitly or explicitly, by ideas about what benefits the community rather than what benefits the individual. The differences that do exist across communities generally reduce to questions about legitimacy and not fact. The questions at the core of the debate about brain death are better framed by asking: "Whom ought we deem to be dead?" rather than: "Who is dead." The rationale for equating brain death with death, therefore, extends well beyond somatic and biological concepts of death. PMID:11588657

  14. Infant death scene investigation.

    PubMed

    Tabor, Pamela D; Ragan, Krista

    2015-01-01

    The sudden unexpected death of an infant is a tragedy to the family, a concern to the community, and an indicator of national health. To accurately determine the cause and manner of the infant's death, a thorough and accurate death scene investigation by properly trained personnel is key. Funding and resources are directed based on autopsy reports, which are only as accurate as the scene investigation. The investigation should include a standardized format, body diagrams, and a photographed or videotaped scene recreation utilizing doll reenactment. Forensic nurses, with their basic nursing knowledge and additional forensic skills and abilities, are optimally suited to conduct infant death scene investigations as well as train others to properly conduct death scene investigations. Currently, 49 states have child death review teams, which is an idea avenue for a forensic nurse to become involved in death scene investigations. PMID:25642921

  15. Dynamic simulation of energy consumption in mixed traffic flow considering highway toll station

    NASA Astrophysics Data System (ADS)

    Qian, Yong-Sheng; Zhang, Xiao-Long; Zeng, Jun-Wei; Shao, Xiao-Ming; Wang, Neng

    2015-01-01

    An improved model of energy consumption including toll station is presented in this paper. Using the model, we study the influences of mixed ratio, the idling energy consumption of vehicle, vehicle peak velocity, dwell time and random deceleration probability on energy consumption of Electronic Toll Collection or Manual Toll Collection mixed traffic flow on single lane under periodic condition. Simulating results indicate that the above five parameters are all increasing functions of total energy consumption, in which the idling energy consumption represents the major amounts with the increase of mixed ratio and occupancy rate. Thus, the existence of toll station has significant effect on the energy consumption of mixed traffic flow.

  16. Incorporation of Phosphonate into Benzonaphthyridine Toll-like Receptor 7 Agonists for Adsorption to Aluminum Hydroxide.

    PubMed

    Cortez, Alex; Li, Yongkai; Miller, Andrew T; Zhang, Xiaoyue; Yue, Kathy; Maginnis, Jillian; Hampton, Janice; Hall, De Shon; Shapiro, Michael; Nayak, Bishnu; D'Oro, Ugo; Li, Chun; Skibinski, David; Mbow, M Lamine; Singh, Manmohan; O'Hagan, Derek T; Cooke, Michael P; Valiante, Nicholas M; Wu, Tom Y-H

    2016-06-23

    Small molecule Toll-like receptor 7 (TLR7) agonists have been used as vaccine adjuvants by enhancing innate immune activation to afford better adaptive response. Localized TLR7 agonists without systemic exposure can afford good adjuvanticity, suggesting peripheral innate activation (non-antigen-specific) is not required for immune priming. To enhance colocalization of antigen and adjuvant, benzonaphthyridine (BZN) TLR7 agonists are chemically modified with phosphonates to allow adsorption onto aluminum hydroxide (alum), a formulation commonly used in vaccines for antigen stabilization and injection site deposition. The adsorption process is facilitated by enhancing aqueous solubility of BZN analogs to avoid physical mixture of two insoluble particulates. These BZN-phosphonates are highly adsorbed onto alum, which significantly reduced systemic exposure and increased local retention post injection. This report demonstrates a novel approach in vaccine adjuvant design using phosphonate modification to afford adsorption of small molecule immune potentiator (SMIP) onto alum, thereby enhancing co-delivery with antigen. PMID:27270029

  17. Nanotechnology Tolls the Bell for Plastic Surgeons

    PubMed Central

    Salehahmadi, Zeinab; Hajiliasgari, Fatemeh

    2013-01-01

    Nanotechnology is an emerging discipline, having power to revolutionarize every scientific field to a very deep level which previously thought to be a science fiction. Having a great potential to beneficially change the way a disease is diagnosed, treated and prevented, nanotechnology practically impacts on state of the art healthcare technologies and plays a crucial role in changing the field of surgery. Surgeons are constantly looking for minimally invasive ways to treat their patients, as recovery is faster when a lesser trauma is inflicted upon a patient, scarring is lessened and there are usually fewer complications in the aftermath of the operation. Through nanotechnology, tiny biosensors could be constructed which could take these factors into account, thus shortening the patient recovery period and saving hospitals money, reducing infection rates within the hospital, reducing the waiting lists for operation and allowing doctors to treat more patients in the same period of time. This review employs a thematic analysis of online series of academic papers focuses on the potentials of nanotechnology in surgery, especially in plastic surgery and addresses the possible future prospects of nanotechnology in this field. PMID:25489508

  18. Nanotechnology tolls the bell for plastic surgeons.

    PubMed

    Salehahmadi, Zeinab; Hajiliasgari, Fatemeh

    2013-06-01

    Nanotechnology is an emerging discipline, having power to revolutionarize every scientific field to a very deep level which previously thought to be a science fiction. Having a great potential to beneficially change the way a disease is diagnosed, treated and prevented, nanotechnology practically impacts on state of the art healthcare technologies and plays a crucial role in changing the field of surgery. Surgeons are constantly looking for minimally invasive ways to treat their patients, as recovery is faster when a lesser trauma is inflicted upon a patient, scarring is lessened and there are usually fewer complications in the aftermath of the operation. Through nanotechnology, tiny biosensors could be constructed which could take these factors into account, thus shortening the patient recovery period and saving hospitals money, reducing infection rates within the hospital, reducing the waiting lists for operation and allowing doctors to treat more patients in the same period of time. This review employs a thematic analysis of online series of academic papers focuses on the potentials of nanotechnology in surgery, especially in plastic surgery and addresses the possible future prospects of nanotechnology in this field. PMID:25489508

  19. Hypoxia preconditioning increases survival and decreases expression of Toll-like receptor 4 in pulmonary artery endothelial cells exposed to lipopolysaccharide.

    PubMed

    Ali, Irshad; Nanchal, Rahul; Husnain, Fouad; Audi, Said; Konduri, G Ganesh; Densmore, John C; Medhora, Meetha; Jacobs, Elizabeth R

    2013-09-01

    Abstract Pulmonary or systemic infections and hypoxemic respiratory failure are among the leading causes of admission to intensive care units, and these conditions frequently exist in sequence or in tandem. Inflammatory responses to infections are reproduced by lipopolysaccharide (LPS) engaging Toll-like receptor 4 (TLR4). Apoptosis is a hallmark of lung injury in sepsis. This study was conducted to determine whether preexposure to LPS or hypoxia modulated the survival of pulmonary artery endothelial cells (PAECs). We also investigated the role TLR4 receptor expression plays in apoptosis due to these conditions. Bovine PAECs were cultured in hypoxic or normoxic environments and treated with LPS. TLR4 antagonist TAK-242 was used to probe the role played by TLR4 receptors in cell survival. Cell apoptosis and survival were measured by caspase 3 activity and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) incorporation. TLR4 expression and tumor necrosis factor α (TNF-α) production were also determined. LPS increased caspase 3 activity in a TAK-242-sensitive manner and decreased MTT incorporation. Apoptosis was decreased in PAECs preconditioned with hypoxia prior to LPS exposure. LPS increased TNF-α production, and hypoxic preconditioning blunted it. Hypoxic preconditioning reduced LPS-induced TLR4 messenger RNA and TLR4 protein. TAK-242 decreased to baseline the LPS-stimulated expression of TLR4 messenger RNA regardless of environmental conditions. In contrast, LPS followed by hypoxia substantially increased apoptosis and cell death. In conclusion, protection from LPS-stimulated PAEC apoptosis by hypoxic preconditioning is attributable in part to reduction in TLR4 expression. If these signaling pathways apply to septic patients, they may account for differing sensitivities of individuals to acute lung injury depending on oxygen tensions in PAECs in vivo. PMID:24618542

  20. Hypoxia preconditioning increases survival and decreases expression of Toll-like receptor 4 in pulmonary artery endothelial cells exposed to lipopolysaccharide

    PubMed Central

    Nanchal, Rahul; Audi, Said; Konduri, G. Ganesh; Medhora, Meetha

    2013-01-01

    Abstract Pulmonary or systemic infections and hypoxemic respiratory failure are among the leading causes of admission to intensive care units, and these conditions frequently exist in sequence or in tandem. Inflammatory responses to infections are reproduced by lipopolysaccharide (LPS) engaging Toll-like receptor 4 (TLR4). Apoptosis is a hallmark of lung injury in sepsis. This study was conducted to determine whether preexposure to LPS or hypoxia modulated the survival of pulmonary artery endothelial cells (PAECs). We also investigated the role TLR4 receptor expression plays in apoptosis due to these conditions. Bovine PAECs were cultured in hypoxic or normoxic environments and treated with LPS. TLR4 antagonist TAK-242 was used to probe the role played by TLR4 receptors in cell survival. Cell apoptosis and survival were measured by caspase 3 activity and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) incorporation. TLR4 expression and tumor necrosis factor α (TNF-α) production were also determined. LPS increased caspase 3 activity in a TAK-242-sensitive manner and decreased MTT incorporation. Apoptosis was decreased in PAECs preconditioned with hypoxia prior to LPS exposure. LPS increased TNF-α production, and hypoxic preconditioning blunted it. Hypoxic preconditioning reduced LPS-induced TLR4 messenger RNA and TLR4 protein. TAK-242 decreased to baseline the LPS-stimulated expression of TLR4 messenger RNA regardless of environmental conditions. In contrast, LPS followed by hypoxia substantially increased apoptosis and cell death. In conclusion, protection from LPS-stimulated PAEC apoptosis by hypoxic preconditioning is attributable in part to reduction in TLR4 expression. If these signaling pathways apply to septic patients, they may account for differing sensitivities of individuals to acute lung injury depending on oxygen tensions in PAECs in vivo. PMID:24618542

  1. [The correlation study between the changes of intestinal mucosa predominant bacteria and Toll-like receptor 2, Toll-like receptor 4 gene expressions in diarrhea-predominant irritable bowel syndrome patients].

    PubMed

    Guo, W T; Liu, P; Dong, L N; Wang, J P

    2016-07-01

    Based on high throughput sequencing and PCR detection technology, this study has found out that intestinal microbial diversity was impaired and the quantities of two main bacteria flora (Bacteroidetes and Clostridium) were significantly reduced in patients with diarrhea-predominant irritable bowel syndrome (D-IBS). Meanwhile mucosal expression of toll-like receptor (TLR) 2 and TLR4 were significantly enhanced, which was inversely correlated with the reduction of Bacteroidetes and Clostridium. Thus, it suggests that D-IBS may be associated with TLR signal transduction triggered by the intestinal dysbacteriosis. PMID:27373290

  2. Laquinimod prevents cuprizone-induced demyelination independent of Toll-like receptor signaling

    PubMed Central

    Menken, Lena; Hayardeny, Liat; Hanisch, Uwe-Karsten; Brück, Wolfgang

    2016-01-01

    Objective: To test whether Toll-like receptor (TLR) signaling plays a key role for reduced nuclear factor B (NF-κB) activation after laquinimod treatment in the model of cuprizone-induced demyelination, oligodendrocyte apoptosis, inflammation, and axonal damage. Methods: Ten-week-old C57BL/6J, TLR4−/−, and MyD88−/− mice received 0.25% cuprizone for 6 weeks and were treated daily with 25 mg/kg laquinimod or vehicle. After 6 weeks of demyelination, extent of demyelination, oligodendrocyte density, microglia infiltration, and axonal damage were analyzed in the corpus callosum. Additionally, we analyzed primary mouse astrocytes from C57BL/6J, TLR4−/−, MyD88−/−, and TRIF−/− mice for alteration in NF-κB signaling. Results: Vehicle-treated controls from C57BL/6J, TLR4−/−, and MyD88−/− mice displayed extensive callosal demyelination as well as microglial activation. In contrast, mice treated with 25 mg/kg laquinimod showed mainly intact callosal myelin. The demyelination score was significantly higher in all untreated mice compared to mice treated with laquinimod. There were significantly fewer APP-positive axonal spheroids, Mac3-positive macrophages/microglia, and less oligodendrocyte apoptosis in the corpus callosum of laquinimod-treated mice in comparison to untreated controls. Stimulated primary mouse astrocytes from laquinimod-treated groups show reduced NF-κB activation compared to vehicle-treated controls. Conclusions: Our results confirm that laquinimod prevents demyelination in the cuprizone mouse model for multiple sclerosis via downregulation of NF-κB activation. This laquinimod effect, however, does not involve upstream Toll-like receptor signaling. PMID:27231712

  3. A critical role of toll-like receptor 2 (TLR2) and its’ in vivo ligands in radio-resistance

    PubMed Central

    Gao, Fu; Zhang, Chaoxiong; Zhou, Chuanfeng; Sun, Weimin; Liu, Xin; Zhang, Pei; Han, Jiaqi; Xian, Linfeng; Bai, Dongchen; Liu, Hu; Cheng, Ying; Li, Bailong; Cui, Jianguo; Cai, Jianming; Liu, Cong

    2015-01-01

    The role of Toll-like receptor-2 (TLR2) in radio-resistance remained largely unknown. TLR2 knockout (TLR2−/−) mice received radiation of 6.5 Gy, and then were studied. We found that radiation resulted in more severe mortality and morbidity rates in TLR2−/− mice. The cause of death in TLR2−/− mice may be severe and persistent bone marrow cell loss. Injection of the TLR2 agonist Pam3CSK4 into wild type (WT) mice induced radio-resistance. Myd88−/− mice were more susceptible to radiation. In conclusion, our data indicate that, similar to TLR4, TLR2 plays a critical role in radio-resistance. PMID:26268450

  4. A critical role of toll-like receptor 2 (TLR2) and its' in vivo ligands in radio-resistance.

    PubMed

    Gao, Fu; Zhang, Chaoxiong; Zhou, Chuanfeng; Sun, Weimin; Liu, Xin; Zhang, Pei; Han, Jiaqi; Xian, Linfeng; Bai, Dongchen; Liu, Hu; Cheng, Ying; Li, Bailong; Cui, Jianguo; Cai, Jianming; Liu, Cong

    2015-01-01

    The role of Toll-like receptor-2 (TLR2) in radio-resistance remained largely unknown. TLR2 knockout (TLR2(-/-)) mice received radiation of 6.5 Gy, and then were studied. We found that radiation resulted in more severe mortality and morbidity rates in TLR2(-/-) mice. The cause of death in TLR2(-/-) mice may be severe and persistent bone marrow cell loss. Injection of the TLR2 agonist Pam3CSK4 into wild type (WT) mice induced radio-resistance. Myd88(-/-) mice were more susceptible to radiation. In conclusion, our data indicate that, similar to TLR4, TLR2 plays a critical role in radio-resistance. PMID:26268450

  5. New Insights into the Pathogenesis and Treatment of Necrotizing Enterocolitis: Toll-like Receptors and Beyond

    PubMed Central

    Afrazi, Amin; Sodhi, Chhinder P.; Richardson, Ward; Neal, Matthew; Good, Misty; Siggers, Richard; Hackam, David J.

    2011-01-01

    Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in the preterm infant. The dismal results of current treatment for NEC highlight the urgent need for greater understanding of the pathogenesis of this disease, and the importance of discovering novel, molecular-specific therapies for it. Current dogma indicates that NEC development reflects an abnormal response by the premature infant to the microbial flora that colonizes the gastrointestinal tract, although the mechanisms that mediate these abnormal bacterial-enterocyte interactions, and the reasons for the particularly increased susceptibility of the premature infant to the development of NEC remain incompletely explained. Recent evidence has shed light on an emerging role for the Toll like receptors (TLR's) of the innate immune system as central players in the pathways that signal in response to enteric bacteria resulting in the development of NEC. We now review recent advances in the field of NEC and identify several exciting potential avenues for novel treatments by focusing on abnormal TLR4 signaling in the premature intestine in the pathogenesis of NEC. In so doing, we seek to offer new hope to the patients and their families that are affected by this devastating disorder. PMID:21135755

  6. Energetics of Endotoxin Recognition in the Toll-Like Receptor 4 Innate Immune Response

    PubMed Central

    Paramo, Teresa; Tomasio, Susana M.; Irvine, Kate L.; Bryant, Clare E.; Bond, Peter J.

    2015-01-01

    Bacterial outer membrane lipopolysaccharide (LPS) potently stimulates the mammalian innate immune system, and can lead to sepsis, the primary cause of death from infections. LPS is sensed by Toll-like receptor 4 (TLR4) in complex with its lipid-binding coreceptor MD-2, but subtle structural variations in LPS can profoundly modulate the response. To better understand the mechanism of LPS-induced stimulation and bacterial evasion, we have calculated the binding affinity to MD-2 of agonistic and antagonistic LPS variants including lipid A, lipid IVa, and synthetic antagonist Eritoran, and provide evidence that the coreceptor is a molecular switch that undergoes ligand-induced conformational changes to appropriately activate or inhibit the receptor complex. The plasticity of the coreceptor binding cavity is shown to be essential for distinguishing between ligands, whilst similar calculations for a model bacterial LPS bilayer reveal the “membrane-like” nature of the protein cavity. The ability to predict the activity of LPS variants should facilitate the rational design of TLR4 therapeutics. PMID:26647780

  7. Toll-Like Receptor 2 and NLRP3 Cooperate To Recognize a Functional Bacterial Amyloid, Curli

    PubMed Central

    Rapsinski, Glenn J.; Wynosky-Dolfi, Meghan A.; Oppong, Gertrude O.; Tursi, Sarah A.; Wilson, R. Paul; Brodsky, Igor E.

    2014-01-01

    Amyloids are proteins with cross-β-sheet structure that contribute to pathology and inflammation in complex human diseases, including Alzheimer's disease, Parkinson's disease, type II diabetes, and secondary amyloidosis. Bacteria also produce amyloids as a component of their extracellular matrix during biofilm formation. Recently, several human amyloids were shown to activate the NLRP3 inflammasome, leading to the activation of caspase 1 and production of interleukin 1β (IL-1β). In this study, we investigated the activation of the NLRP3 inflammasome by bacterial amyloids using curli fibers, produced by Salmonella enterica serovar Typhimurium and Escherichia coli. Here, we show that curli fibers activate the NLRP3 inflammasome, leading to the production of IL-1β via caspase 1 activation. Investigation of the underlying mechanism revealed that activation of Toll-like receptor 2 (TLR2) by curli fibers is critical in the generation of IL-1β. Interestingly, activation of the NLRP3 inflammasome by curli fibers or by amyloid β of Alzheimer's disease does not cause cell death in macrophages. Overall, these data identify a cross talk between TLR2 and NLRP3 in response to the bacterial amyloid curli and generation of IL-1β as a product of this interaction. PMID:25422268

  8. Molecular and Cellular Regulation of Toll-Like Receptor-4 Activity Induced by Lipopolysaccharide Ligands

    PubMed Central

    Liaunardy-Jopeace, Ardiyanto; Gay, Nicholas J.

    2014-01-01

    As well as being the primary signaling receptor for bacterial endotoxin or lipopolysaccharide Toll-like receptor-4 function is modulated by numerous factors not only in the context of microbial pathogenesis but also autoimmune and allergic diseases. TLR4 is subject to multiple levels of endogenous control and regulation from biosynthesis and trafficking to signal transduction and degradation. On the other hand regulation of TLR4 activity breaks down during Gram −ve sepsis leading to systemic damage, multi organ failure, and death. In this article, we review how TLR4 traffics from the early secretory pathway, the cis/trans Golgi to the cell surface and endolysosomal compartments. We will present evidence about how these processes influence signaling and can potentially lead to increased sensitivity to ligand-dependent activation as well as ligand-independent constitutive activation that may contribute to pathogenesis in sepsis. We will also discuss how sustained signaling may be coupled to endocytosis and consider the potential molecular mechanisms of immuno-modulators that modify TLR4 signaling function including the cat allergen FelD1 and endogenous protein ligands such as the extracellular matrix protein tenascin C and calprotectin (MRP8/14). PMID:25339952

  9. Release of Toll-Like Receptor-2-Activating Bacterial Lipoproteins in Shigella flexneri Culture Supernatants

    PubMed Central

    Aliprantis, Antonios O.; Weiss, David S.; Radolf, Justin D.; Zychlinsky, Arturo

    2001-01-01

    Shigella spp. cause dysentery, a severe form of bloody diarrhea. Apoptosis, or programmed cell death, is induced during Shigella infections and has been proposed to be a key event in the pathogenesis of dysentery. Here, we describe a novel cytotoxic activity in the sterile-culture supernatants of Shigella flexneri. An identical activity was identified in purified S. flexneri endotoxin, defined here as a mixture of lipopolysaccharide (LPS) and endotoxin-associated proteins (EP). Separation of endotoxin into EP and LPS revealed the activity to partition exclusively to the EP fraction. Biochemical characterization of S. flexneri EP and culture supernatants, including enzymatic deactivation, reverse-phase high-pressure liquid chromatography analysis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and a Toll-like receptor-2 (TLR2) activation assay, indicates that the cytotoxic component is a mixture of bacterial lipoproteins (BLP). We show that biologically active BLP are liberated into culture supernatants of actively growing S. flexneri. In addition, our data indicate that BLP, and not LPS, are the component of endotoxin of gram-negative organisms responsible for activating TLR2. The activation of apoptosis by BLP shed from S. flexneri is discussed as a novel aspect of the interaction of bacteria with the host. PMID:11553567

  10. The Architecture of the TIR Domain Signalosome in the Toll-like Receptor-4 Signaling Pathway

    PubMed Central

    Guven-Maiorov, Emine; Keskin, Ozlem; Gursoy, Attila; VanWaes, Carter; Chen, Zhong; Tsai, Chung-Jung; Nussinov, Ruth

    2015-01-01

    Activated Toll-like receptors (TLRs) cluster in lipid rafts and induce pro- and anti-tumor responses. The organization of the assembly is critical to the understanding of how these key receptors control major signaling pathways in the cell. Although several models for individual interactions were proposed, the entire TIR-domain signalosome architecture has not been worked out, possibly due to its complexity. We employ a powerful algorithm, crystal structures and experimental data to model the TLR4 and its cluster. The architecture that we obtain with 8 MyD88 molecules provides the structural basis for the MyD88-templated myddosome helical assembly and receptor clustering; it also provides clues to pro- and anti-inflammatory signaling pathways branching at the signalosome level to Mal/MyD88 and TRAM/TRIF pro- and anti-inflammatory pathways. The assembly of MyD88 death domain (DD) with TRAF3 (anti-viral/anti-inflammatory) and TRAF6 (pro-inflammatory) suggest that TRAF3/TRAF6 binding sites on MyD88 DD partially overlap, as do IRAK4 and FADD. Significantly, the organization illuminates mechanisms of oncogenic mutations, demonstrates that almost all TLR4 parallel pathways are competitive and clarifies decisions at pathway branching points. The architectures are compatible with the currently-available experimental data and provide compelling insights into signaling in cancer and inflammation pathways. PMID:26293885

  11. Posttranslational Modification of HOIP Blocks Toll-Like Receptor 4-Mediated Linear-Ubiquitin-Chain Formation

    PubMed Central

    Bowman, James; Rodgers, Mary A.; Shi, Mude; Amatya, Rina; Hostager, Bruce; Iwai, Kazuhiro; Gao, Shou-Jiang

    2015-01-01

    ABSTRACT Linear ubiquitination is an atypical posttranslational modification catalyzed by the linear-ubiquitin-chain assembly complex (LUBAC), containing HOIP, HOIL-1L, and Sharpin. LUBAC facilitates NF-κB activation and inflammation upon receptor stimulation by ligating linear ubiquitin chains to critical signaling molecules. Indeed, linear-ubiquitination-dependent signaling is essential to prevent pyogenic bacterial infections that can lead to death. While linear ubiquitination is essential for intracellular receptor signaling upon microbial infection, this response must be measured and stopped to avoid tissue damage and autoimmunity. While LUBAC is activated upon bacterial stimulation, the mechanisms regulating LUBAC activity in response to bacterial stimuli have remained elusive. We demonstrate that LUBAC activity itself is downregulated through ubiquitination, specifically, ubiquitination of the catalytic subunit HOIP at the carboxyl-terminal lysine 1056. Ubiquitination of Lys1056 dynamically altered HOIP conformation, resulting in the suppression of its catalytic activity. Consequently, HOIP Lys1056-to-Arg mutation led not only to persistent LUBAC activity but also to prolonged NF-κB activation induced by bacterial lipopolysaccharide-mediated Toll-like receptor 4 (TLR4) stimulation, whereas it showed no effect on NF-κB activation induced by CD40 stimulation. This study describes a novel posttranslational regulation of LUBAC-mediated linear ubiquitination that is critical for specifically directing TLR4-mediated NF-κB activation. PMID:26578682

  12. The Architecture of the TIR Domain Signalosome in the Toll-like Receptor-4 Signaling Pathway.

    PubMed

    Guven-Maiorov, Emine; Keskin, Ozlem; Gursoy, Attila; VanWaes, Carter; Chen, Zhong; Tsai, Chung-Jung; Nussinov, Ruth

    2015-01-01

    Activated Toll-like receptors (TLRs) cluster in lipid rafts and induce pro- and anti-tumor responses. The organization of the assembly is critical to the understanding of how these key receptors control major signaling pathways in the cell. Although several models for individual interactions were proposed, the entire TIR-domain signalosome architecture has not been worked out, possibly due to its complexity. We employ a powerful algorithm, crystal structures and experimental data to model the TLR4 and its cluster. The architecture that we obtain with 8 MyD88 molecules provides the structural basis for the MyD88-templated myddosome helical assembly and receptor clustering; it also provides clues to pro- and anti-inflammatory signaling pathways branching at the signalosome level to Mal/MyD88 and TRAM/TRIF pro- and anti-inflammatory pathways. The assembly of MyD88 death domain (DD) with TRAF3 (anti-viral/anti-inflammatory) and TRAF6 (pro-inflammatory) suggest that TRAF3/TRAF6 binding sites on MyD88 DD partially overlap, as do IRAK4 and FADD. Significantly, the organization illuminates mechanisms of oncogenic mutations, demonstrates that almost all TLR4 parallel pathways are competitive and clarifies decisions at pathway branching points. The architectures are compatible with the currently-available experimental data and provide compelling insights into signaling in cancer and inflammation pathways. PMID:26293885

  13. The Effects of Death Education.

    ERIC Educational Resources Information Center

    Freitag, Carl B.; Hassler, Shawn David

    Although fear of death is recorded in the writings of the oldest major religions, the study of death and the fear of death have only occurred for the last few decades. Death education courses have grown in number since the early 1970's. College students participated in an investigation of the effects of death education on death anxiety by…

  14. Incidence of Near-Death Experiences Following Attempted Suicide.

    ERIC Educational Resources Information Center

    Greyson, Bruce

    1986-01-01

    Near-death experiences, profound subjective experiences occurring during a close brush with death and containing transcendental or mystical elements, have been reported to reduce suicidal ideation, despite their "romanticization" of death. Further studies are indicated in regard to the effect of those experiences on subsequent suicidal behavior.…

  15. The Association between Thoughts of Defecation and Thoughts of Death

    ERIC Educational Resources Information Center

    Dunkel, Curtis S.

    2009-01-01

    Three studies were conducted examining the relationship between thoughts of defecation and thoughts of death. In Study 1 and Study 3 it was found that making thoughts of feces salient reduced the accessibility of death thoughts. In Study 2 it was found that making thoughts of death salient decreased the accessibility of feces thoughts. It is…

  16. 25 CFR 170.130 - How can tribes use Federal highway funds for toll and ferry facilities?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... LAND AND WATER INDIAN RESERVATION ROADS PROGRAM Indian Reservation Roads Program Policy and Eligibility Toll, Ferry and Airport Facilities § 170.130 How can tribes use Federal highway funds for toll...

  17. 25 CFR 170.130 - How can tribes use Federal highway funds for toll and ferry facilities?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... LAND AND WATER INDIAN RESERVATION ROADS PROGRAM Indian Reservation Roads Program Policy and Eligibility Toll, Ferry and Airport Facilities § 170.130 How can tribes use Federal highway funds for toll...

  18. TRADITIONAL BIOCHEMICAL ASSAYS FOR STUDYING TOLL-LIKE RECEPTOR 9

    PubMed Central

    Leifer, Cynthia A.; Rose, William A.; Botelho, Fernando

    2015-01-01

    Understanding the mechanistic basis of receptor activation and regulation can offer therapeutic targets for disease treatment. Evidence is emerging for a role of the normally foreign responsive Toll-like receptors (TLRs) in the development of autoimmunity through response to self-patterns. Regulatory mechanisms governing this class of receptors are poorly understood, and failures within this system likely contribute to development of autoimmunity. In this article, we review biochemical assays used to study one of the self-pattern responsive TLRs, TLR9, and suggest that these studies are critical for development of new targets for autoimmune therapies. PMID:23323977

  19. Toll-like Receptor 4 in CNS Pathologies

    PubMed Central

    Buchanan, Madison M.; Hutchinson, Mark; Watkins, Linda R.; Yin, Hang

    2010-01-01

    The responses of the brain to infection, ischemia and trauma share remarkable similarities. These and other conditions of the CNS coordinate an innate immune response marked by activation of microglia, the macrophage-like cells of the nervous system. An important contributor to microglial activation is toll-like receptor 4 (TLR4), a pathogen-associated molecular pattern receptor known to initiate an inflammatory cascade in response to various CNS stimuli. The present review traces new efforts to characterize and control the contribution of TLR4 to inflammatory etiologies of the nervous system. PMID:20402965

  20. Toll-like receptor sensing of human herpesvirus infection

    PubMed Central

    West, John A.; Gregory, Sean M.; Damania, Blossom

    2012-01-01

    Toll-like receptors (TLRs) are evolutionarily conserved pathogen sensors that constitute the first line of defense in the human immune system. Herpesviruses are prevalent throughout the world and cause significant disease in the human population. Sensing of herpesviruses via TLRs has only been documented in the last 10 years and our understanding of the relationship between these sentinels of the immune system and herpesvirus infection has already provided great insight into how the host cell responds to viral infection. This report will summarize the activation and modulation of TLR signaling in the context of human herpesvirus infections. PMID:23061052

  1. Therapeutic potential of Toll-like receptor 9 activation.

    PubMed

    Krieg, Arthur M

    2006-06-01

    In the decade since the discovery that mouse B cells respond to certain unmethylated CpG dinucleotides in bacterial DNA, a specific receptor for these 'CpG motifs' has been identified, Toll-like receptor 9 (TLR9), and a new approach to immunotherapy has moved into the clinic based on the use of synthetic oligodeoxynucleotides (ODN) as TLR9 agonists. This review highlights the current understanding of the mechanism of action of these CpG ODN, and provides an overview of the preclinical data and early human clinical trial results using these drugs to improve vaccines and treat cancer, infectious disease and allergy/asthma. PMID:16763660

  2. The Toll-Dorsal Pathway Is Required for Resistance to Viral Oral Infection in Drosophila

    PubMed Central

    Ferreira, Álvaro Gil; Naylor, Huw; Esteves, Sara Santana; Pais, Inês Silva; Martins, Nelson Eduardo; Teixeira, Luis

    2014-01-01

    Pathogen entry route can have a strong impact on the result of microbial infections in different hosts, including insects. Drosophila melanogaster has been a successful model system to study the immune response to systemic viral infection. Here we investigate the role of the Toll pathway in resistance to oral viral infection in D. melanogaster. We show that several Toll pathway components, including Spätzle, Toll, Pelle and the NF-kB-like transcription factor Dorsal, are required to resist oral infection with Drosophila C virus. Furthermore, in the fat body Dorsal is translocated from the cytoplasm to the nucleus and a Toll pathway target gene reporter is upregulated in response to Drosophila C Virus infection. This pathway also mediates resistance to several other RNA viruses (Cricket paralysis virus, Flock House virus, and Nora virus). Compared with control, viral titres are highly increased in Toll pathway mutants. The role of the Toll pathway in resistance to viruses in D. melanogaster is restricted to oral infection since we do not observe a phenotype associated with systemic infection. We also show that Wolbachia and other Drosophila-associated microbiota do not interact with the Toll pathway-mediated resistance to oral infection. We therefore identify the Toll pathway as a new general inducible pathway that mediates strong resistance to viruses with a route-specific role. These results contribute to a better understanding of viral oral infection resistance in insects, which is particularly relevant in the context of transmission of arboviruses by insect vectors. PMID:25473839

  3. The Toll-dorsal pathway is required for resistance to viral oral infection in Drosophila.

    PubMed

    Ferreira, Álvaro Gil; Naylor, Huw; Esteves, Sara Santana; Pais, Inês Silva; Martins, Nelson Eduardo; Teixeira, Luis

    2014-12-01

    Pathogen entry route can have a strong impact on the result of microbial infections in different hosts, including insects. Drosophila melanogaster has been a successful model system to study the immune response to systemic viral infection. Here we investigate the role of the Toll pathway in resistance to oral viral infection in D. melanogaster. We show that several Toll pathway components, including Spätzle, Toll, Pelle and the NF-kB-like transcription factor Dorsal, are required to resist oral infection with Drosophila C virus. Furthermore, in the fat body Dorsal is translocated from the cytoplasm to the nucleus and a Toll pathway target gene reporter is upregulated in response to Drosophila C Virus infection. This pathway also mediates resistance to several other RNA viruses (Cricket paralysis virus, Flock House virus, and Nora virus). Compared with control, viral titres are highly increased in Toll pathway mutants. The role of the Toll pathway in resistance to viruses in D. melanogaster is restricted to oral infection since we do not observe a phenotype associated with systemic infection. We also show that Wolbachia and other Drosophila-associated microbiota do not interact with the Toll pathway-mediated resistance to oral infection. We therefore identify the Toll pathway as a new general inducible pathway that mediates strong resistance to viruses with a route-specific role. These results contribute to a better understanding of viral oral infection resistance in insects, which is particularly relevant in the context of transmission of arboviruses by insect vectors. PMID:25473839

  4. Programmed necrosis in the Cross Talk of Cell Death and Inflammation

    PubMed Central

    Chan, Francis Ka-Ming; Luz, Nivea Farias; Moriwaki, Kenta

    2015-01-01

    Cell proliferation and cell death are integral elements in maintaining homeostatic balance in metazoans. Disease pathologies ensue when these processes are disturbed. A plethora of evidence indicates that malfunction of cell death can lead to inflammation, autoimmunity or immuno-deficiency. Programmed necrosis or necroptosis is a form of non-apoptotic cell death driven by the receptor interacting protein kinase 3 (RIPK3) and its substrate mixed lineage kinase domain-like (MLKL). RIPK3 partners with its upstream adaptors RIPK1, TRIF or DAI to signal for necroptosis in response to death receptor or toll-like receptor stimulation, pathogen infection, or sterile cell injury. Necroptosis promotes inflammation through leakage of cellular contents from damaged plasma membrane. Intriguingly, many of the signal adaptors of necroptosis have dual functions in innate immune signaling. This unique signature illustrates the cooperative nature of necroptosis and innate inflammatory signaling pathways in managing cell and organismal stresses from pathogen infection and sterile tissue injury. PMID:25493335

  5. Dynamic BMP signaling polarized by Toll patterns the dorsoventral axis in a hemimetabolous insect.

    PubMed

    Sachs, Lena; Chen, Yen-Ta; Drechsler, Axel; Lynch, Jeremy A; Panfilio, Kristen A; Lässig, Michael; Berg, Johannes; Roth, Siegfried

    2015-01-01

    Toll-dependent patterning of the dorsoventral axis in Drosophila represents one of the best understood gene regulatory networks. However, its evolutionary origin has remained elusive. Outside the insects Toll is not known for a patterning function, but rather for a role in pathogen defense. Here, we show that in the milkweed bug Oncopeltus fasciatus, whose lineage split from Drosophila's more than 350 million years ago, Toll is only required to polarize a dynamic BMP signaling network. A theoretical model reveals that this network has self-regulatory properties and that shallow Toll signaling gradients are sufficient to initiate axis formation. Such gradients can account for the experimentally observed twinning of insect embryos upon egg fragmentation and might have evolved from a state of uniform Toll activity associated with protecting insect eggs against pathogens. PMID:25962855

  6. Dynamic BMP signaling polarized by Toll patterns the dorsoventral axis in a hemimetabolous insect

    PubMed Central

    Sachs, Lena; Chen, Yen-Ta; Drechsler, Axel; Lynch, Jeremy A; Panfilio, Kristen A; Lässig, Michael; Berg, Johannes; Roth, Siegfried

    2015-01-01

    Toll-dependent patterning of the dorsoventral axis in Drosophila represents one of the best understood gene regulatory networks. However, its evolutionary origin has remained elusive. Outside the insects Toll is not known for a patterning function, but rather for a role in pathogen defense. Here, we show that in the milkweed bug Oncopeltus fasciatus, whose lineage split from Drosophila's more than 350 million years ago, Toll is only required to polarize a dynamic BMP signaling network. A theoretical model reveals that this network has self-regulatory properties and that shallow Toll signaling gradients are sufficient to initiate axis formation. Such gradients can account for the experimentally observed twinning of insect embryos upon egg fragmentation and might have evolved from a state of uniform Toll activity associated with protecting insect eggs against pathogens. DOI: http://dx.doi.org/10.7554/eLife.05502.001 PMID:25962855

  7. Toll-like receptor signalling and their therapeutic targeting in colorectal cancer.

    PubMed

    Moossavi, Shirin; Rezaei, Nima

    2013-06-01

    Intestinal homeostasis is dependent on the proper host/microbiota interaction via pattern recognition receptors. Toll-like receptors are a specialised group of membrane receptors which detect pathogen-associated conserved structures. They are present in the intestinal tract and are required for intestinal homeostasis. Dysregulation in the Toll-like receptor signalling can conceivably result in a dysregulated immune response which could contribute to major intestinal pathologies including colorectal cancer. Evidence for the role of microbiota and toll-like receptors in colorectal cancer is emerging. In this report the evidence for the contribution of toll-like receptors to the pathogenesis of colorectal cancer; potential mechanisms affecting toll-like receptor signalling; and their therapeutic targeting in colorectal cancer are reviewed. PMID:23602501

  8. Brain Death and Islam

    PubMed Central

    Ziad-Miller, Amna; Elamin, Elamin M.

    2014-01-01

    How one defines death may vary. It is important for clinicians to recognize those aspects of a patient’s religious beliefs that may directly influence medical care and how such practices may interface with local laws governing the determination of death. Debate continues about the validity and certainty of brain death criteria within Islamic traditions. A search of PubMed, Scopus, EMBASE, Web of Science, PsycNet, Sociological Abstracts, DIALOGUE ProQuest, Lexus Nexus, Google, and applicable religious texts was conducted to address the question of whether brain death is accepted as true death among Islamic scholars and clinicians and to discuss how divergent opinions may affect clinical care. The results of the literature review inform this discussion. Brain death has been acknowledged as representing true death by many Muslim scholars and medical organizations, including the Islamic Fiqh Academies of the Organization of the Islamic Conference and the Muslim World League, the Islamic Medical Association of North America, and other faith-based medical organizations as well as legal rulings by multiple Islamic nations. However, consensus in the Muslim world is not unanimous, and a sizable minority accepts death by cardiopulmonary criteria only. PMID:25287999

  9. The Sociology of Death

    ERIC Educational Resources Information Center

    Fulton, Robert

    1977-01-01

    When we start to look at the issues associated with dying and death, we must do so in terms of the broadest parameters imaginable. Presented at the Conference on Death and Dying: Education, Counseling, and Care, December 1-3, 1976, Orlando, Florida. (Author)

  10. Death Acceptance through Ritual

    ERIC Educational Resources Information Center

    Reeves, Nancy C.

    2011-01-01

    This article summarizes the author's original research, which sought to discover the elements necessary for using death-related ritual as a psychotherapeutic technique for grieving people who experience their grief as "stuck," "unending," "maladaptive," and so on. A "death-related ritual" is defined as a ceremony, directly involving at least 1…

  11. Conflicting Thoughts about Death

    ERIC Educational Resources Information Center

    Harris, Paul L.

    2011-01-01

    Most research on children's conception of death has probed their understanding of its biological aspects: its inevitability, irreversibility and terminal impact. Yet many adults subscribe to a religious conception implying that death marks the beginning of a new life. Two recent empirical studies confirm that in the course of development, children…

  12. Reflections on Death Education

    ERIC Educational Resources Information Center

    Riskey, Raymond J.

    1977-01-01

    The author comments on the need to discuss death openly in the classroom, noting that engaging students with the idea of coming to grips with the fact of their own death can prepare them for living, working, and loving more fully. (SH)

  13. Education for Death

    ERIC Educational Resources Information Center

    Puolimatka, Tapio; Solasaari, Ulla

    2006-01-01

    Death is an unavoidable fact of human life, which cannot be totally ignored in education. Children reflect on death and raise questions that deserve serious answers. If an educator completely evades the issue, children will seek other conversation partners. It is possible to find arguments both from secular and religious sources, which alleviate…

  14. Mozart's illnesses and death.

    PubMed Central

    Davies, P J

    1983-01-01

    Throughout his life Mozart suffered frequent attacks of tonsillitis. In 1784 he developed post-streptococcal Schönlein-Henoch syndrome which caused chronic glomerular nephritis and chronic renal failure. His fatal illness was due to Schönlein-Henoch purpura, with death from cerebral haemorrhage and bronchopneumonia. Venesection(s) may have contributed to his death. PMID:6352940

  15. Programmed cell death

    SciTech Connect

    1995-12-31

    The purpose of this conference to provide a multidisciplinary forum for exchange of state-of-the-art information on the role programmed cell death plays in normal development and homeostasis of many organisms. This volume contains abstracts of papers in the following areas: invertebrate development; immunology/neurology; bcl-2 family; biochemistry; programmed cell death in viruses; oncogenesis; vertebrate development; and diseases.

  16. Death Obsession in Palestinians

    ERIC Educational Resources Information Center

    Abdel-Khalek, Ahmed M.; Al-Arja, Nahida S.; Abdalla, Taysir

    2006-01-01

    The authors explored death obsession level and correlates among a sample (N=601) of Palestinians living in the city of Beit Jala, the village of Al-Khader, and the Aida refugee camp in the Bethlehem area. They live in war conditions; the houses of half of them have been demolished. The Death Obsession Scale (DOS) was administered. Its alpha…

  17. SUICIDE ON DEATH ROW.

    PubMed

    Tartaro, Christine; Lester, David

    2015-12-01

    For the period 1976-2011, the suicide rate on death rows in the United States was only weakly (and non-significantly) associated with the marriage, birth, divorce, and unemployment rates in the general population. Possible explanations for why social indicators in the larger society might be associated with the behavior of prisoners on death row were discussed. PMID:26595302

  18. Death Writ Large

    ERIC Educational Resources Information Center

    Kastenbaum, Robert

    2004-01-01

    Mainstream thanatology has devoted its efforts to improving the understanding, care, and social integration of people who are confronted with life-threatening illness or bereavement. This article suggests that it might now be time to expand the scope and mission to include large-scale death and death that occurs through complex and multi-domain…

  19. Near-death experiences.

    PubMed Central

    Blackmore, S J

    1996-01-01

    Reactions to claims of near-death experiences (NDE) range from the popular view that this must be evidence for life after death, to outright rejection of the experiences as, at best, drug induced hallucinations or, at worse, pure invention. Twenty years, and much research, later, it is clear that neither extreme is correct. PMID:8683504

  20. 76 FR 37196 - Open Meeting of the Taxpayer Advocacy Panel Small Business/Self Employed Correspondence Exam Toll...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-24

    ... Correspondence Exam Toll Free Project Committee AGENCY: Internal Revenue Service (IRS), Treasury. ACTION: Notice... Correspondence Exam Toll Free Project Committee will be conducted. The Taxpayer Advocacy Panel is soliciting... Taxpayer Advocacy Panel Small Business/Self Employed Correspondence Exam Toll Free Project Committee...

  1. 76 FR 17996 - Open Meeting of the Taxpayer Advocacy Panel Small Business/Self Employed Correspondence Exam Toll...

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  20. Death in Denmark.

    PubMed Central

    Evans, M

    1990-01-01

    Does it matter that the hearts of 'brainstem dead' patients may persist in beating spontaneously? Hostile reactions, to the Danish inclusion of cardiac criteria in the determination of death, betray reductionist views of human life at the core of 'brainstem' conceptions of death. Such views (whether centred on neurological function or on abstractions concerning 'personhood') supplant the richness of human life and death with the poverty of essentialism: and mask the lethal nature of beating-heart organ retrieval. The affirmation of cardiac criteria for death is not an alternative form of essentialism as some critics suppose, but part of an understanding of human life and death which rejects essentialism altogether. The spontaneously persistent heartbeat does not constitute human life, but most certainly counts for it. PMID:2287015

  1. Toll-like receptors as sensors of pathogens.

    PubMed

    Hallman, M; Rämet, M; Ezekowitz, R A

    2001-09-01

    Initial recognition of microbes, as they enter the body, is based on germ line-encoded pattern recognition receptors that selectively bind to essential components of pathogens. This allows the body to respond immediately to the microbial invasion before the development of active immunity. The signal-transducing receptors that trigger the acute inflammatory cascade have been elusive until very recently. On the basis of their genetic similarity to the Toll signaling pathway in Drosophila, mammalian Toll-like receptors (TLRs) have been identified. By now, nine transmembrane proteins in the TLR family have been described. Mammalian TLR4 is the signal-transducing receptor activated by the bacterial lipopolysaccharide. The activation of TLR4 leads to DNA binding of the transcription factor NF-kappaB, resulting in activation of the inflammatory cascade. Activation of other TLRs is likely to have similar consequences. TLR2 mediates the host response to Gram-positive bacteria and yeast. TLR1 and TLR6 may participate in the activation of macrophages by Gram-positive bacteria, whereas TLR9 appears to respond to a specific sequence of bacterial DNA. The TLRs that control the onset of an acute inflammatory response are critical antecedents for the development of adaptive acquired immunity. Genetic and developmental variation in the expression of microbial pattern recognition receptors may affect the individual's predisposition to infections in childhood and may contribute to susceptibility to severe neonatal inflammatory diseases, allergies, and autoimmune diseases. PMID:11518816

  2. DIFFERENTIAL TOLL-LIKE RECEPTOR ACTIVATION IN LUNG ISCHEMIA REPERFUSION INJURY

    PubMed Central

    Phelan, Patrick; Merry, Heather E.; Hwang, Billanna; Mulligan, Michael S.

    2015-01-01

    Objective The requirement for toll-like receptors in lung ischemia reperfusion injury (LIRI) has been demonstrated but not fully characterized. We have previously reported that toll-like receptor-4 is required by alveolar macrophages but not pulmonary endothelial or epithelial cells for the development of LIRI. Additionally, we have demonstrated differential patterns of mitogen-activated protein kinase activation and cytokine release in these cell types during LIRI. We sought to determine whether the differences in their activation responses related to cell specific toll-like receptor activation requirements. Methods Primary cultures of alveolar macrophages, pulmonary endothelial, and immortalized epithelial cells were pretreated with toll-like receptor-2 or -4 short interference (si)RNA prior to hypoxia and reoxygenation. Cell lysates and media were analyzed for receptor knockdown, mitogen-activated protein kinase activation, and cytokine production. Rats were pretreated with toll-like receptor-2 or -4 siRNA prior to lung ischemia reperfusion and changes in lung vascular permeability were assessed. Results Toll-like receptor-2 knockdown in alveolar macrophages did not affect mitogen-activated protein kinase phosphorylation or cytokine secretion. Conversely, toll-like receptor-2 knockdown in pulmonary endothelial and epithelial cells demonstrated significant reductions in ERK 1/2 activation and cytokine secretion. Toll-like receptor-4, but not toll-like receptor-2, decreased lung permeability index in LIRI. Conclusions Differential toll-like receptor signaling and mitogen-activated protein kinase activation in response to LIRI appear to be cell specific. siRNA provides an outstanding tool for examination of the underlying mechanism. PMID:25911179

  3. Berberine Prevents Intestinal Mucosal Barrier Damage During Early Phase of Sepsis in Rat through the Toll-Like Receptors Signaling Pathway

    PubMed Central

    Li, Guo-xun; Wang, Xi-mo; Jiang, Tao; Gong, Jian-feng; Niu, Ling-ying

    2015-01-01

    Our previous study has shown berberine prevents damage to the intestinal mucosal barrier during early phase of sepsis in rat through mechanisms independent of the NOD-like receptors signaling pathway. In this study, we explored the regulatory effects of berberine on Toll-like receptors during the intestinal mucosal damaging process in rats. Male Sprague-Dawlay (SD) rats were treated with berberine for 5 d before undergoing cecal ligation and puncture (CLP) to induce polymicrobial sepsis. The expression of Toll-like receptor 2 (TLR 2), TLR 4, TLR 9, the activity of nuclear factor-kappa B (NF-κB), the levels of selected cytokines and chemokines, percentage of cell death in intestinal epithelial cells, and mucosal permeability were investigated at 0, 2, 6, 12 and 24 h after CLP. Results showed that the tumor necrosis factor-α (TNF-α ) and interleukin-6 (IL-6) level were significantly lower in berberine-treated rats compared to the control animals. Conversely, the expression level of tight junction proteins, percentage of cell death in intestinal epithelial cells and the mucosal permeability were significantly higher in berberine-treated rats. The mRNA expression of TLR 2, TLR 4, and TLR 9 were significantly affected by berberine treatment. Our results indicate that pretreatment with berberine attenuates tissue injury and protects the intestinal mucosal barrier in early phase of sepsis and this may possibly have been mediated through the TLRs pathway. PMID:25605990

  4. dSarm/Sarm1 is required for activation of an injury-induced axon death pathway.

    PubMed

    Osterloh, Jeannette M; Yang, Jing; Rooney, Timothy M; Fox, A Nicole; Adalbert, Robert; Powell, Eric H; Sheehan, Amy E; Avery, Michelle A; Hackett, Rachel; Logan, Mary A; MacDonald, Jennifer M; Ziegenfuss, Jennifer S; Milde, Stefan; Hou, Ying-Ju; Nathan, Carl; Ding, Aihao; Brown, Robert H; Conforti, Laura; Coleman, Michael; Tessier-Lavigne, Marc; Züchner, Stephan; Freeman, Marc R

    2012-07-27

    Axonal and synaptic degeneration is a hallmark of peripheral neuropathy, brain injury, and neurodegenerative disease. Axonal degeneration has been proposed to be mediated by an active autodestruction program, akin to apoptotic cell death; however, loss-of-function mutations capable of potently blocking axon self-destruction have not been described. Here, we show that loss of the Drosophila Toll receptor adaptor dSarm (sterile α/Armadillo/Toll-Interleukin receptor homology domain protein) cell-autonomously suppresses Wallerian degeneration for weeks after axotomy. Severed mouse Sarm1 null axons exhibit remarkable long-term survival both in vivo and in vitro, indicating that Sarm1 prodegenerative signaling is conserved in mammals. Our results provide direct evidence that axons actively promote their own destruction after injury and identify dSarm/Sarm1 as a member of an ancient axon death signaling pathway. PMID:22678360

  5. [Sudden death in young athletes].

    PubMed

    Gojanovic, B; Feihl, F; Gremion, G; Waeber, B

    2007-02-01

    Sudden cardiac death in a young athlete is a tragic and marking event, even though the media attention it gets is more important than its incidence (1-2/100000 per year). The main etiology is hypertrophic cardiomyopathy, followed by coronary artery anomalies. Sometimes signs of myocarditis are found at autopsy. The pre-participation examination recommandations ask for oriented history and physical examination, routine EKG being controversial. A systematic screening program in Italy has reduced the occurrence of such deaths, which statistics are non-existant in Switzerland. It would be appropriate to implement a standardized pre-participation examination, as well as to make sure that the trainers, teachers and athletes themselves are able to recognize the frequent warning symptoms. PMID:17330410

  6. Acute Treatment With Herbal Extracts Provides Neuroprotective Benefits in In Vitro and In Vivo Stroke Models, Characterized by Reduced Ischemic Cell Death and Maintenance of Motor and Neurological Functions.

    PubMed

    Kaneko, Yuji; Eve, David J; Yu, Seongjin; Shojo, Hideki; Bae, Eunkyung Cate; Park, Dong-Hyuk; Roschek, Bill; Alberte, Randall S; Sanberg, Paul R; Sanberg, Cyndy D; Bickford, Paula C; Borlongan, Cesar V

    2010-01-01

    The present study explored the prophylactic and restorative benefits of cacao and red sage using both in vitro and in vivo models of stroke. For the in vitro study, we initially exposed primary rat cells to the established oxygen-glucose deprivation (OGD) stroke model followed by reperfusion under normoxic conditions, then added different cacao and sage concentrations to the cell culture media. Trypan blue cell viability results revealed specific cacao and sage dosages exerted significant therapeutic effects against OGD-induced cell death compared to cultured cells treated with extract vehicle. We next embarked on testing the therapeutic effects of cacao and sage in an in vivo model of stroke when extract treatment commenced either prior to or after transient middle cerebral artery occlusion (MCAo). Significant reduction in ischemic cell death within the peri-infarct area coupled with better performance in routine motor and neurological tasks were demonstrated by stroke animals that received cacao or sage extracts prior to MCAo compared to those that received the extracts or vehicle after MCAo. In summary, the present results demonstrate that neuroprotective effects were afforded by plant extract treatment, and that the in vitro stroke paradigm approximates in vivo efficacy when considering prophylactic treatment for stroke. PMID:21379315

  7. Calpastatin overexpression reduces oxidative stress-induced mitochondrial impairment and cell death in human neuroblastoma SH-SY5Y cells by decreasing calpain and calcineurin activation, induction of mitochondrial fission and destruction of mitochondrial fusion.

    PubMed

    Tangmansakulchai, Kulvadee; Abubakar, Zuroida; Kitiyanant, Narisorn; Suwanjang, Wilasinee; Leepiyasakulchai, Chaniya; Govitrapong, Piyarat; Chetsawang, Banthit

    2016-09-01

    Calpain is an intracellular Ca(2+)-dependent protease, and the activation of calpain has been implicated in neurodegenerative diseases. Calpain activity can be regulated by calpastatin, an endogenous specific calpain inhibitor. Several lines of evidence have demonstrated a potential role of calpastatin in preventing calpain-mediated pathogenesis. Additionally, several studies have revealed that calpain activation and mitochondrial damage are involved in the cell death process; however, recent evidence has not clearly indicated a neuroprotective mechanism of calpastatin against calpain-dependent mitochondrial impairment in the process of neuronal cell death. Therefore, the purpose of this study was to investigate the potential ability of calpastatin to inhibit calpain activation and mitochondrial impairment in oxidative stress-induced neuron degeneration. Calpastatin was stably overexpressed in human neuroblastoma SH-SY5Y cells. In non-calpastatin overexpressing SH-SY5Y cells, hydrogen peroxide significantly decreased cell viability, superoxide dismutase activity, mitochondrial membrane potential, ATP production and mitochondrial fusion protein (Opa1) levels in the mitochondrial fraction but increased reactive oxygen species formation, calpain and calcineurin activation, mitochondrial fission protein (Fis1 and Drp1) levels in the mitochondrial fraction and apoptotic cells. Nevertheless, these toxic effects were abolished in hydrogen peroxide-treated calpastatin-overexpressing SH-SY5Y cells. The results of the present study demonstrate the potential ability of calpastatin to diminish calpain and calcineurin activation and mitochondrial impairment in neurons that are affected by oxidative damage. PMID:27453331

  8. Firearm Deaths among Children and Youth.

    ERIC Educational Resources Information Center

    O'Donnell, Clifford R.

    1995-01-01

    Examines the long- and short-term policy alternatives in reducing firearm deaths of children. The article advocates the need for multiple steps that include educational efforts such as conflict resolution; safety devices, such as trigger locks; security policies for schools to protect students; and gun access laws to reduce firearm acquisitions by…

  9. Unusual sudden death.

    PubMed Central

    Warren, J. V.

    1985-01-01

    In contrast to usual sudden death seen in the course of coronary artery disease, individuals dying suddenly from other causes form a complex array of situations. In some the causes are readily identifiable. No simple pattern is available to identify the potential candidate, but on review of the many causes some moves by the physician may be helpful. For example, a more complete physical evaluation of young individuals participating in competitive athletics is in order. This is particularly true if the athlete reports an episode of unexplained syncope. This may well be the warning of a propensity towards sudden death under physical and emotional stress. Knowledge of the specific problems in underwater swimming and diving, in high altitude exposure and in various circumstances such as certain weight reduction diets and industrial exposures may lead to control of some types of unusual sudden death. Clearly, more studies are needed to give answers in so called crib death. As the incidence of usual sudden death falls, these unusual forms of sudden death will represent a more important fraction of sudden death in general. PMID:6537674

  10. Molecular characterization and expression analysis of Toll-like receptor 21 cDNA from Paralichthys olivaceus.

    PubMed

    Gao, Hong; Wu, Lian; Sun, Jin-Sheng; Geng, Xu-Yun; Pan, Bao-Ping

    2013-10-01

    Toll-like receptor (TLR) is believed to play crucial role in host defense of pathogenic microbes in innate immune system. In the present study, the full-length cDNA of Paralichthys olivaceus Toll-like receptor 21 (Po-TLR21) was cloned by homology cloning and rapid amplification of cDNA ends (RACE) technique. The Po-TLR21 cDNA sequence was 3687 bp, containing an open reading frame of 2922 bp encoding 973 amino acids. TMHMM and SMART program analysis indicated that protein contained one transmembrane domain, eighteen leucine-rich repeats (LRRs), and one Toll/IL-1 receptor homology domain (TIR). Multiple alignment analysis of the Po-TLR21 protein-coding sequence with other known TLR21 from grouper, pufferfish, zebrafish, cod, catfish, carp and chicken showed the homology of 67%, 63%, 54%, 52%, 51%, 49%, and 39%, respectively. The Po-TLR21 mRNA expression patterns were measured by real-time PCR. The results revealed that TLR21 is widely expressed in various tested healthy tissues, and highly expressed in spleen and gill. In vivo immunostimulation experiments revealed that expression of TLR21 is modulated by Vibrio anguillarum (V. anguillarum), CpG oligodeoxynucleotides (CpG ODN) and poly I:C. Moreover, the inhibitor of homodimerization of myeloid differentiation factor 88 (MyD88) could significantly reduce the up-regulation of TLR21, MyD88, and tumor necrosis factor (TNF) expression in CpG ODN or poly I:C-treated head kidney cells in vitro. These results indicate that TLR21 may be involved in the pathogen recognition in the early innate immune. PMID:23880453

  11. Unnatural sudden infant death

    PubMed Central

    Meadow, R.

    1999-01-01

    AIM—To identify features to help paediatricians differentiate between natural and unnatural infant deaths.
METHOD—Clinical features of 81 children judged by criminal and family courts to have been killed by their parents were studied. Health and social service records, court documents, and records from meetings with parents, relatives, and social workers were studied.
RESULTS—Initially, 42 children had been certified as dying from sudden infant death syndrome (SIDS), and 29 were given another cause of natural death. In 24 families, more than one child died; 58died before the age of 6 months and most died in the afternoon or evening. Seventy per cent had experienced unexplained illnesses; over half were admitted to hospital within the previous month, and 15 had been discharged within 24 hours of death. The mother, father, or both were responsible for death in 43, five, and two families, respectively. Most homes were disadvantaged—no regular income, receiving income support—and mothers smoked. Half the perpetrators had a history of somatising or factitious disorder. Death was usually by smothering and 43% of children had bruises, petechiae, or blood on the face.
CONCLUSIONS—Although certain features are indicative of unnatural infant death, some are also associated with SIDS. Despite the recent reduction in numbers of infants dying suddenly, inadequacies in the assessment of their deaths exist. Until a thorough postmortem examination is combined with evaluation of the history and circumstances of death by an experienced paediatrician, most cases of covert fatal abuse will go undetected. The term SIDS requires revision or abandonment.

 PMID:10325752

  12. Eaten to death

    PubMed Central

    Nelson, Charles; Baehrecke, Eric H.

    2014-01-01

    Macro-autophagy (hereafter referred to as autophagy) delivers cytoplasmic material to the lysosome for degradation, and has been implicated in many cellular processes, including stress, infection, survival, and death. While the regulation and role that autophagy plays in stress, infection, and survival is apparent, the regulation of and role that autophagy has during cell death remains relatively unclear. In this review, we highlight what is known about the role that autophagy can play during physiological cell death, and discuss the implications of better understanding cellular destruction that involves autophagy. PMID:25323556

  13. Children's Death Concepts and Ethnicity.

    ERIC Educational Resources Information Center

    Wass, Hannelore; Towry, Betty J.

    1980-01-01

    Relationships between death concepts of Black and White children and their racial status were examined. Lower-middle-class elementary children completed a four-item questionnaire on death. Most children defined death as the end of living and listed physical causes as the explanation of death. In general, children's death concepts were similar.…

  14. Application potential of toll-like receptors in cancer immunotherapy

    PubMed Central

    Shi, Ming; Chen, Xi; Ye, Kangruo; Yao, Yuanfei; Li, Yu

    2016-01-01

    Abstract Toll-like receptors (TLRs), as the most important pattern recognition receptors in innate immunity, play a pivotal role in inducing immune response through recognition of microbial invaders or specific agonists. Recent studies have suggested that TLRs could serve as important regulators in the development of a variety of cancer. However, increasing evidences have shown that TLRs may display quite opposite outcomes in cancer development. Although several potential therapeutic Toll-like receptor ligands have been found, the mechanism and therapy prospect of TLRs in cancer development has to be further elucidated to accelerate the clinical application. By performing a systematic review of the present findings on TLRs in cancer immunology, we attempted to evaluate the therapeutic potential of TLRs in cancer therapy and elucidate the potential mechanism of cancer progress regulated by TLR signaling and the reported targets on TLRs for clinical application. An electronic databases search was conducted in PubMed, Chinese Scientific Journal Database, and Chinese Biomedical Literature Database from their inception to February 1, 2016. The following keywords were used to search the databases: Toll-like receptors, cancer therapy, therapeutic target, innate immunity. Of 244 studies that were identified, 97 nonrelevant studies were excluded. In total, 147 full-text articles were assessed, and from these, 54 were excluded as they did not provide complete key information. Thus, 93 studies were considered eligible and included in the analysis. According to the data from the included trials, 14 TLR ligands (77.8%) from 82 studies have been demonstrated to display antitumor property in various cancers, whereas 4 ligands (22.2%) from 11 studies promote tumors. Among them, only 3 TLR ligands have been approved for cancer therapy, and 9 ligands were in clinical trials. In addition, the potential mechanism of recently reported targets on TLRs for clinical application was also

  15. Sudden cardiac death.

    PubMed

    Sra, J; Dhala, A; Blanck, Z; Deshpande, S; Cooley, R; Akhtar, M

    1999-08-01

    SCD continues to be an important cause of death and morbidity. Despite expanding insight into the mechanisms causing SCD, the population at high risk is not being effectively identified. Although there is still much to do in the management phase of SCD (predicting the efficacy of various therapies), recent clinical trials have helped define the relative risks and benefits of therapies in preventing SCD. Trials are underway to determine whether treating other patient populations, including asymptomatic patients after MI, will improve survival rate. The approach to reducing mortality rate will always be multifaceted; primary prevention of coronary artery disease and prompt salvage of jeopardized myocardium are 2 important aspects of this approach. In addition to interventions for MI, such as myocardial revascularization when indicated, simple and easily administered therapies that are likely to remain the most effective prophylactic interventions are aspirin, ACE inhibitors, beta-blockers, and cholesterol-lowering agents. However, the MADIT and AVID data clearly demonstrate a role for ICD therapy in a subgroup of patients who have VT/VF and are at risk of cardiac arrest. Even though the absolute magnitude of benefit associated with ICDs is still to be determined, the AVID study and other recent reports provide convincing evidence that patients who have VT/VF fare better with ICDs than with antiarrhythmic drug therapy. For the high-risk population described in this article, in addition to aggressive anti-ischemic and heart failure therapy, ICDs are now a mainstay of life-saving treatment. Still to be surmounted is the challenge of identifying patients who have nonischemic substrates and of providing them with the appropriate therapy. Guided by genetic studies and new insight into the mechanisms of such problems as congenital long QT syndrome, life-saving and life-enhancing therapies may soon be available for the management of SCD. PMID:10459474

  16. Identification and expression analysis of two Toll-like receptor genes from sea cucumber (Apostichopus japonicus).

    PubMed

    Sun, Hongjuan; Zhou, Zunchun; Dong, Ying; Yang, Aifu; Jiang, Bei; Gao, Shan; Chen, Zhong; Guan, Xiaoyan; Wang, Bai; Wang, Xiuli

    2013-01-01

    Toll-like receptors (TLRs) are a family of type I integral membrane glycoproteins which play pivotal roles in innate immunity. In this study, two TLRs named AjTLR3 and AjToll were cloned from sea cucumber (Apostichopus japonicus). The full-length cDNA sequences of AjTLR3 and AjToll are 3484 bp and 4211 bp, with an open reading frame (ORF) of 2679 bp and 2853 bp, encoding 892 and 950 amino acids, respectively. Both AjTLR3 and AjToll are composed of a leucine-rich repeat (LRR) domain, a transmembrane (TM) domain and an intracellular Toll/interleukin-1 receptor (TIR) domain. Evolution analysis revealed that AjTLR3 and AjToll were clustered with the vertebrate-like TLRs (V-TLRs) and the protostome-like TLRs (P-TLRs), respectively. These two genes were widely expressed in all five tested tissues (body wall, coelomocytes, tube feet, intestine and respiratory tree), but showed different expression patterns. The significantly up-regulated expressions of AjTLR3 and AjToll after peptidoglycan (PGN), lipopolysaccharides (LPS), Zymosan A and polyinosinic-polycytidylic acid (PolyI:C) challenges suggested that they were functionally involved in the immune responses to the Cram-positive bacteria, Gram-negative bacteria, fungi and double-stranded RNA (dsRNA) viruses, respectively. PMID:23103635

  17. Death and Grief

    MedlinePlus

    ... for Parents for Kids for Teens Teens Home Body Mind Sexual Health Food & Fitness Diseases & Conditions Infections Q& ... a death or loss. Grief can affect our body, mind, emotions, and spirit. People might notice or show ...

  18. Eighth Amendment & Death Penalty.

    ERIC Educational Resources Information Center

    Shortall, Joseph M.; Merrill, Denise W.

    1987-01-01

    Presents a lesson on capital punishment for juveniles based on three hypothetical cases. The goal of the lesson is to have students understand the complexities of decisions regarding the death penalty for juveniles. (JDH)

  19. Hitler's Death Camps.

    ERIC Educational Resources Information Center

    Wieser, Paul

    1995-01-01

    Presents a high school lesson on Hitler's death camps and the widespread policy of brutality and oppression against European Jews. Includes student objectives, instructional procedures, and a chart listing the value of used clothing taken from the Jews. (CFR)

  20. Brain death and organ donation of children.

    PubMed

    Gündüz, Ramiz Coşkun; Şahin, Şanlıay; Uysal-Yazıcı, Mutlu; Ayar, Ganime; Yakut, Halil İbrahim; Akman, Alkım Öden; Hirfanoğlu, İbrahim Murat; Kalkan, Gökhan

    2014-01-01

    We aimed to define the demographic characteristics, clinical features and outcome of patients with brain death, and to emphasize the importance of organ donation from children. Data for the period from September 2009 to October 2012 were collected retrospectively. Twenty children who were diagnosed as brain death were included. Data including demographics, major cause leading to brain death, duration of brain death evaluation, ancillary tests used to confirm brain death, complications and outcome, duration of hospitalization and organ donation were collected for statistical evaluation. The mean age was 6.2 years, and the male/female ratio 1.85. The major cause leading to brain death was most often traumatic brain injury, seen in 11 patients (55%). The mean duration of brain death evaluation was 6.7 and 1.7 days in Centers I and II respectively. The mean duration of hospitalization was 12.5 days. Electroencephalography (EEG) was used in 18 patients (90%). Complications included hyperglycemia in 13 cases and diabetes incipitus in 7 cases (65% and 35%, respectively). Mean duration of survival was 9.8 days. In Center I, one of the patients' parents gave consent to organ donation, while four parents in Center II agreed to organ donation. The study demonstrated that the duration of brain death evaluation was longer in Center I than in Center II (p<0.05). When both centers were compared, there was no significant difference in regard to obtaining consent for organ donation, survival after diagnosis of brain death and length of stay in the PICU (p>0.05). Early diagnosis of brain death and prompt evaluation of patients by ICU physicians once the diagnosis is taken into consideration will probably yield better organs and reduce costs. Training PICU physicians, nurses and organ donation coordinators, and increasing children's awareness of the need for organ donation via means of public communication may increase families' rate of agreement to organ donation in the future. PMID

  1. Funerals against death

    PubMed Central

    Bailey, Tara; Walter, Tony

    2016-01-01

    While anthropological studies in non-Western societies show how funerals protect the community from the threat of death, sociological studies of British funerals have so far focused on meanings for the private family. The article reports on results from a Mass Observation directive – the first British study to focus specifically on the entire funeral congregation – and shows how attendees experience the contemporary life-centred funeral as a symbolic conquest of death. While the eulogy’s accuracy is important, even more so – at least for some – is its authenticity, namely that the speaker has personal knowledge of the deceased. Whereas Davies analyses the power of professionally delivered ritual words against death, our data reveals how admired is the courage exercised by non-professionals in speaking against death, however faltering their words. Further, the very presence of a congregation whose members have known the deceased in diverse ways embodies a configurational eulogy, which we term relationships against death. We thus argue that funerals symbolically conquer death not only through words delivered by ritual specialists, but also through those who knew the deceased congregating and speaking. PMID:27019605

  2. Classification of cell death

    PubMed Central

    Kroemer, G; Galluzzi, L; Vandenabeele, P; Abrams, J; Alnemri, ES; Baehrecke, EH; Blagosklonny, MV; El-Deiry, WS; Golstein, P; Green, DR; Hengartner, M; Knight, RA; Kumar, S; Lipton, SA; Malorni, W; Nuñez, G; Peter, ME; Tschopp, J; Yuan, J; Piacentini, M; Zhivotovsky, B; Melino, G

    2009-01-01

    Different types of cell death are often defined by morphological criteria, without a clear reference to precise biochemical mechanisms. The Nomenclature Committee on Cell Death (NCCD) proposes unified criteria for the definition of cell death and of its different morphologies, while formulating several caveats against the misuse of words and concepts that slow down progress in the area of cell death research. Authors, reviewers and editors of scientific periodicals are invited to abandon expressions like ‘percentage apoptosis’ and to replace them with more accurate descriptions of the biochemical and cellular parameters that are actually measured. Moreover, at the present stage, it should be accepted that caspase-independent mechanisms can cooperate with (or substitute for) caspases in the execution of lethal signaling pathways and that ‘autophagic cell death’ is a type of cell death occurring together with (but not necessarily by) autophagic vacuolization. This study details the 2009 recommendations of the NCCD on the use of cell death-related terminology including ‘entosis’, ‘mitotic catastrophe’, ‘necrosis’, ‘necroptosis’ and ‘pyroptosis’. PMID:18846107

  3. Deaths: Final Data for 2014.

    PubMed

    Kochanek, Kenneth D; Murphy, Sherry L; Xu, Jiaquan; Tejada-Vera, Betzaida

    2016-06-01

    Objectives-This report presents final 2014 data on U.S. deaths, death rates, life expectancy, infant mortality, and trends, by selected characteristics such as age, sex, Hispanic origin, race, state of residence, and cause of death. PMID:27378572

  4. Toll-like receptors and diabetes complications: recent advances.

    PubMed

    Rosa Ramirez, Sandra; Ravi Krishna Dasu, Mohan

    2012-11-01

    Diabetes mellitus (DM) is a disease with constellation of metabolic aberrations resulting in debilitating complications. The prevalence of DM worldwide was 2.8% (171 million people) in 2000 and estimated to be at 4.4% (366 million people) in 2030. DM is a major risk factor for heart, kidney diseases, and lower limb amputations. Emerging in vitro and in vivo data suggest that systemic inflammation plays a role in the pathogenesis of DM complications via innate immune receptors. Toll-like receptors (TLRs) are key innate immune receptors that mediate the inflammatory responses in DM. There are no reviews that collectively summarize and examine the detrimental role of TLRs in the manifestation of DM complications namely heart disease, nephropathy, neuropathy, and wound healing. Thus, in this review, we will provide summaries of the TLR expression and activation and elucidate their role in propagating inflammation seen in DM complications. PMID:22934553

  5. Toll-like receptors in antiviral innate immunity

    PubMed Central

    Lester, Sandra N.; Li, Kui

    2014-01-01

    Toll-like receptors (TLRs) are fundamental sensor molecules of the host innate immune system, which detect conserved molecular signatures of a wide range of microbial pathogens and initiate innate immune responses via distinct signaling pathways. Various TLRs are implicated in the early interplay of host cells with invading viruses, which regulates viral replication and/or host responses, ultimately impacting on viral pathogenesis. To survive the host innate defense mechanisms, many viruses have developed strategies to evade or counteract signaling through the TLR pathways, creating an advantageous environment for their propagation. Here we review the current knowledge of the roles TLRs play in antiviral innate immune responses, discuss examples of TLR-mediated viral recognition, and describe strategies used by viruses to antagonize the host antiviral innate immune responses. PMID:24316048

  6. Degranulation of Paneth Cells via Toll-Like Receptor 9

    PubMed Central

    Rumio, Cristiano; Besusso, Dario; Palazzo, Marco; Selleri, Silvia; Sfondrini, Lucia; Dubini, Francesco; Ménard, Sylvie; Balsari, Andrea

    2004-01-01

    The release of antimicrobial peptides and growth factors by Paneth cells is thought to play an important role in protecting the small intestine, but the mechanisms involved have remained obscure. Immunohistochemistry and immunofluorescence showed that Paneth cells express Toll-like receptor 9 (TLR9) in the granules. Injection of mice with oligonucleotides containing CpG sequence (CpG-ODNs) led to a down-modulation of TLR9 and a striking decrease in the number of large secretory granules, consistent with degranulation. Moreover CpG-ODN treatment increased resistance to oral challenge with virulent Salmonella typhimurium. Moreover, our findings demonstrate a sentinel role for Paneth cells through TLR9. PMID:15277213

  7. Nucleic acid recognizing Toll-like receptors and autoimmunity.

    PubMed

    von Landenberg, Philipp; Bauer, Stefan

    2007-12-01

    The understanding of autoimmune diseases experienced an impressive boost since the Toll-like receptors (TLRs) have been identified as possible key players in autoimmune pathophysiology. Although these receptors recognize a variety of structures derived from viruses, bacteria, and fungi leading to subsequent initiation of the relevant immune responses, recent data support the idea that TLRs are crucial in the induction and perpetuation of certain autoimmune diseases, especially the systemic lupus erythematosus (SLE). In this review, we will summarize recent data on involvement of TLRs in the development of autoimmune diseases. We will focus on TLRs 7, 8, and 9 that were originally identified as receptors specific for bacterial and viral RNA/DNA, but more recent in vitro and in vivo studies have linked these receptors to the detection of host RNA, DNA, and RNA-associated or DNA-associated proteins in the context of autoimmunity. PMID:18060756

  8. Assembly and localization of Toll-like receptor signalling complexes.

    PubMed

    Gay, Nicholas J; Symmons, Martyn F; Gangloff, Monique; Bryant, Clare E

    2014-08-01

    Signal transduction by the Toll-like receptors (TLRs) is central to host defence against many pathogenic microorganisms and also underlies a large burden of human disease. Thus, the mechanisms and regulation of signalling by TLRs are of considerable interest. In this Review, we discuss the molecular basis for the recognition of pathogen-associated molecular patterns, the nature of the protein complexes that mediate signalling, and the way in which signals are regulated and integrated at the level of allosteric assembly, post-translational modification and subcellular trafficking of the components of the signalling complexes. These fundamental molecular mechanisms determine whether the signalling output leads to a protective immune response or to serious pathologies such as sepsis. A detailed understanding of these processes at the molecular level provides a rational framework for the development of new drugs that can specifically target pathological rather than protective signalling in inflammatory and autoimmune disease. PMID:25060580

  9. Bioinformatic Analysis of Toll-Like Receptor Sequences and Structures.

    PubMed

    Monie, Tom P; Gay, Nicholas J; Gangloff, Monique

    2016-01-01

    Continual advancements in computing power and sophistication, coupled with rapid increases in protein sequence and structural information, have made bioinformatic tools an invaluable resource for the molecular and structural biologist. With the degree of sequence information continuing to expand at an almost exponential rate, it is essential that scientists today have a basic understanding of how to utilise, manipulate and analyse this information for the benefit of their own experiments. In the context of Toll-Interleukin I Receptor domain containing proteins, we describe here a series of the more common and user-friendly bioinformatic tools available as Internet-based resources. These will enable the identification and alignment of protein sequences; the identification of functional motifs; the characterisation of protein secondary structure; the identification of protein structural folds and distantly homologous proteins; and the validation of the structural geometry of modelled protein structures. PMID:26803620

  10. Novel drugs targeting Toll-like receptors for antiviral therapy

    PubMed Central

    Patel, Mira C; Shirey, Kari Ann; Pletneva, Lioubov M; Boukhvalova, Marina S; Garzino-Demo, Alfredo; Vogel, Stefanie N; Blanco, Jorge CG

    2014-01-01

    Toll-like receptors (TLRs) are sentinel receptors of the host innate immune system that recognize conserved ‘pathogen-associated molecular patterns’ of invading microbes, including viruses. The activation of TLRs establishes antiviral innate immune responses and coordinates the development of long-lasting adaptive immunity in order to control viral pathogenesis. However, microbe-induced damage to host tissues may release ‘danger-associated molecular patterns’ that also activate TLRs, leading to an overexuberant inflammatory response and, ultimately, to tissue damage. Thus, TLRs have proven to be promising targets as therapeutics for the treatment of viral infections that result in inflammatory damage or as adjuvants in order to enhance the efficacy of vaccines. Here, we explore recent advances in TLR biology with a focus on novel drugs that target TLRs (agonists and antagonists) for antiviral therapy. PMID:25620999

  11. Dysregulation of Human Toll-like Receptor Function in Aging

    PubMed Central

    Shaw, Albert C.; Panda, Alexander; Joshi, Samit R.; Qian, Feng; Allore, Heather G.; Montgomery, Ruth R.

    2010-01-01

    Studies addressing immunosenescence in the immune system have expanded to focus on the innate as well as the adaptive responses. In particular, aging results in alterations in the function of Toll-like receptors (TLRs), the first described pattern recognition receptor family of the innate immune system. Recent studies have begun to elucidate the consequences of aging on TLR function in human cohorts and add to existing findings performed in animal models. In general, these studies show that human TLR function is impaired in the context of aging, and in addition there is evidence for inappropriate persistence of TLR activation in specific systems. These findings are consistent with an overarching theme of age-associated dysregulation of TLR signaling that likely contributes to the increased morbidity and mortality from infectious diseases found in geriatric patients. PMID:21074638

  12. Unique features of chicken Toll-like receptors.

    PubMed

    Keestra, A Marijke; de Zoete, Marcel R; Bouwman, Lieneke I; Vaezirad, Mahdi M; van Putten, Jos P M

    2013-11-01

    Toll-like receptors (TLRs) are a major class of innate immune pattern recognition receptors that have a key role in immune homeostasis and the defense against infections. The research explosion that followed the discovery of TLRs more than a decade ago has boosted fundamental knowledge on the function of the immune system and the resistance against disease, providing a rational for clinical modulation of the immune response. In addition, the conserved nature of the ancient TLR system throughout the animal kingdom has enabled a comparative biology approach to understand the evolution, structural architecture, and function of TLRs. In the present review we focus on TLR biology in the avian species, and, especially, on the unique functional properties of the chicken TLR repertoire. PMID:23628643

  13. Toll-Like Receptors and Ischemic Brain Injury

    PubMed Central

    Gesuete, Raffaella; Kohama, Steven G.; Stenzel-Poore, Mary

    2014-01-01

    Toll-like receptors (TLRs) are master regulators of innate immunity and play an integral role in the activation of the inflammatory response during infections. In addition, TLRs influence the body’s response to numerous forms of injury. Recent data have shown that TLRs play a modulating role in ischemic brain damage after stroke. Interestingly, their stimulation prior to ischemia induces a tolerant state that is neuroprotective. This phenomenon, referred to as TLR preconditioning, is the result of reprogramming of the TLR response to ischemic injury. This review addresses the role of TLRs in brain ischemia and the activation of endogenous neuroprotective pathways in the setting of preconditioning. We highlight the protective role of the interferon-related response and the potential site of action for TLR preconditioning involving the blood-brain-barrier. Pharmacological modulation of TLR activation to promote protection against stroke is a promising approach for the development of prophylactic and acute therapies targeting ischemic brain injury. PMID:24709682

  14. Toll-Like Receptors in Leishmania Infections: Guardians or Promoters?

    PubMed Central

    Faria, Marilia S.; Reis, Flavia C. G.; Lima, Ana Paula C. A.

    2012-01-01

    Protozoa of the genus Leishmania cause a wide variety of pathologies ranging from self-healing skin lesions to visceral damage, depending on the parasite species. The outcome of infection depends on the quality of the adaptive immune response, which is determined by parasite factors and the host genetic background. Innate responses, resulting in the generation of mediators with anti-leishmanial activity, contribute to parasite control and help the development of efficient adaptive responses. Among those, the potential contribution of members of the Toll-like receptors (TLRs) family in the control of Leishmania infections started to be investigated about a decade ago. Although most studies appoint a protective role for TLRs, there is growing evidence that in some cases, TLRs facilitate infection. This review highlights recent advances in TLR function during Leishmania infections and discusses their potential role in restraining parasite growth versus yielding disease. PMID:22523644

  15. Antiinfective applications of toll-like receptor 9 agonists.

    PubMed

    Krieg, Arthur M

    2007-07-01

    The innate immune system detects pathogens by the presence of highly conserved pathogen-expressed molecules, which trigger host immune defenses. Toll-like receptor (TLR) 9 detects unmethylated CpG dinucleotides in bacterial or viral DNA, and can be stimulated for therapeutic applications with synthetic oligodeoxynucleotides containing immune stimulatory "CpG motifs." TLR9 activation induces both innate and adaptive immunity. The TLR9-induced innate immune activation can be applied in the prevention or treatment of infectious diseases, and the adaptive immune-enhancing effects can be harnessed for improving vaccines. This article highlights the current understanding of the mechanism of action of CpG oligodeoxynucleotides, and provides an overview of the preclinical data and early human clinical trial results, applying these TLR9 agonists in the field of infectious diseases. PMID:17607015

  16. Reprint of: Microglial toll-like receptors and Alzheimer's disease.

    PubMed

    Su, Fan; Bai, Feng; Zhou, Hong; Zhang, Zhijun

    2016-07-01

    Microglial activation represents an important pathological hallmark of Alzheimer's disease (AD), and emerging data highlight the involvement of microglial toll-like receptors (TLRs) in the course of AD. TLRs have been observed to exert both beneficial and detrimental effects on AD-related pathologies, and transgenic animal models have provided direct and credible evidence for an association between TLRs and AD. Moreover, analyses of genetic polymorphisms have suggested interactions between genetic polymorphisms in TLRs and AD risk, further supporting the hypothesis that TLRs are involved in AD. In this review, we summarize the key evidence in this field. Future studies should focus on exploring the mechanisms underlying the potential roles of TLRs in AD. PMID:27255539

  17. Toll-like receptor signaling and regulation of intestinal immunity.

    PubMed

    Kamdar, Karishma; Nguyen, Vivien; DePaolo, R William

    2013-04-01

    The intestine is a complex organ that must maintain tolerance to innocuous food antigens and commensal microbiota while being also able to mount inflammatory responses against invading pathogenic microorganisms. The ability to restrain tolerogenic responses while permitting inflammatory responses requires communication between commensal bacteria, intestinal epithelial cells and immune cells. Disruption or improper signaling between any of these factors may lead to uncontrolled inflammation and the development of inflammatory diseases. Toll-like receptors (TLR) recognize conserved molecular motifs of microorganisms and, not surprisingly, are important for maintaining tolerance to commensal microbiota, as well as inducing inflammation against pathogens. Perturbations in individual TLR signaling can lead to a number of different outcomes and illustrate a system of regulation within the intestine in which each TLR plays a largely non-redundant role in mucosal immunity. This review will discuss recent findings on the roles of individual TLRs and intestinal homeostasis. PMID:23334153

  18. Time-Series Expression of Toll-Like Receptor 4 Signaling in Septic Mice Treated with Mesenchymal Stem Cells.

    PubMed

    Wu, Kang-Hsi; Wu, Han-Ping; Chao, Wan-Ru; Lo, Wei-Yu; Tseng, Pei-Chi; Lee, Chih-Jui; Peng, Ching-Tien; Lee, Maw-Sheng; Chao, Yu-Hua

    2016-06-01

    Sepsis remains an important cause of mortality worldwide, and early deaths resulting from overwhelming inflammation in septic patients have been reported. Vigorous immune reactions are beneficial for bacterial clearance in this circumstance but at the price of self-tissue damage. Mesenchymal stem cells (MSCs) have been found to modulate immune function and attenuate sepsis. As the Toll-like receptor 4 pathway plays an important role in response to infections, here we investigated the mechanisms of MSC-mediated immunomodulation by determining the expression of Toll-like receptor 4 signaling in the liver and by circulating cytokines at 0, 1, 2, 3, and 6 h after cecal ligation and puncture (CLP)-induced sepsis in mice. We found that administration of umbilical cord-derived MSCs (UCMSCs) was beneficial for survival. Six hours after CLP, UCMSC administration decreased the expression of MyD88 mRNA and protein in the liver tissues of the mice, and also the ratio of NFκB phosphorylation (P = 0.041 and 0.005, respectively). Serum levels of TNF-α, MCP-1, IFN-γ, and IL-6 were significantly lower and IL-10 significantly higher 6 h after CLP in the mice receiving UCMSCs compared with those receiving PBS only. Our study provides the first in vivo evidence for the association of the MyD88-NFκB pathway and MSC-mediated immunomodulation during sepsis. The immunomodulatory effect of UCMSCs was noted from 3 to 6 h after injection, and the MyD88-NFκB pathway played an important role in response to the immunomodulatory signals from UCMSCs. PMID:26682950

  19. Podocyte apoptosis is prevented by blocking the Toll-like receptor pathway

    PubMed Central

    Saurus, P; Kuusela, S; Lehtonen, E; Hyvönen, M E; Ristola, M; Fogarty, C L; Tienari, J; Lassenius, M I; Forsblom, C; Lehto, M; Saleem, M A; Groop, P-H; Holthöfer, H; Lehtonen, S

    2015-01-01

    High serum lipopolysaccharide (LPS) activity in normoalbuminuric patients with type 1 diabetes (T1D) predicts the progression of diabetic nephropathy (DN), but the mechanisms behind this remain unclear. We observed that treatment of cultured human podocytes with sera from normoalbuminuric T1D patients with high LPS activity downregulated 3-phosphoinositide-dependent kinase-1 (PDK1), an activator of the Akt cell survival pathway, and induced apoptosis. Knockdown of PDK1 in cultured human podocytes inhibited antiapoptotic Akt pathway, stimulated proapoptotic p38 MAPK pathway, and increased apoptosis demonstrating an antiapoptotic role for PDK1 in podocytes. Interestingly, PDK1 was downregulated in the glomeruli of diabetic rats and patients with type 2 diabetes before the onset of proteinuria, further suggesting that reduced expression of PDK1 associates with podocyte injury and development of DN. Treatment of podocytes in vitro and mice in vivo with LPS reduced PDK1 expression and induced apoptosis, which were prevented by inhibiting the Toll-like receptor (TLR) signaling pathway with the immunomodulatory agent GIT27. Our data show that LPS downregulates the cell survival factor PDK1 and induces podocyte apoptosis, and that blocking the TLR pathway with GIT27 may provide a non-nephrotoxic means to prevent the progression of DN. PMID:25950482

  20. Contribution of Ninjurin1 to Toll-like receptor 4 signaling and systemic inflammation.

    PubMed

    Jennewein, Carla; Sowa, Ralf; Faber, Anne C; Dildey, Madlen; von Knethen, Andreas; Meybohm, Patrick; Scheller, Bertram; Dröse, Stefan; Zacharowski, Kai

    2015-11-01

    Nerve injury-induced protein (Ninjurin [Ninj]) 1 is an adhesion molecule originally identified in Schwann cells after nerve injury, whereas it is also expressed in leukocytes, epithelium, endothelium, and various organs, and is induced under inflammatory conditions. Its contribution to inflammation was so far restricted to the nervous system and exclusively attributed to its role during leukocyte migration. We hypothesized a proinflammatory role for Ninj1 also outside the nervous system. To elucidate its impact during inflammation, we analyzed expression levels and its contribution to inflammation in septic mice and studied its effect on inflammatory signaling in vitro. The effect on inflammation was analyzed by genetic (only in vitro) and pharmacologic repression in septic mice (cecal ligation and puncture) and cell culture, respectively. Repression of Ninj1 by an inhibitory peptide or small interfering RNA attenuated LPS-triggered inflammation in macrophages and endothelial cells by modulating p38 phosphorylation and activator protein-1 activation. Inhibition of Ninj1 in septic mice reduced systemic and pulmonary inflammation as well as organ damage, and ameliorated survival after 24 hours. Ninj1 is elevated under inflammatory conditions and contributes to inflammation not only by mediating leukocyte migration, but also by modulating Toll-like receptor 4-dependent expression of inflammatory mediators. We assume that, owing to both mechanisms, inhibition reduces systemic inflammation and organ damage in septic mice. Our data contribute to a better understanding of the complex inflammatory mechanisms and add a novel therapeutic target for inflammatory conditions such as sepsis. PMID:25860173

  1. The Toll-interleukin-1 receptor member SIGIRR regulates colonic epithelial homeostasis, inflammation, and tumorigenesis.

    PubMed

    Xiao, Hui; Gulen, Muhammet Fatih; Qin, Jinzhong; Yao, Jianhong; Bulek, Katarzyna; Kish, Danielle; Altuntas, Cengiz Zubeyir; Wald, David; Ma, Caixia; Zhou, Hang; Tuohy, Vincent K; Fairchild, Robert L; de la Motte, Carol; Cua, Daniel; Vallance, Bruce A; Li, Xiaoxia

    2007-04-01

    Despite constant contact with the large population of commensal bacteria, the colonic mucosa is normally hyporesponsive to these potentially proinflammatory signals. Here we report that the single immunoglobulin IL-1 receptor-related molecule (SIGIRR), a negative regulator for Toll-IL-1R signaling, plays a critical role in gut homeostasis, intestinal inflammation, and colitis-associated tumorigenesis by maintaining the microbial tolerance of the colonic epithelium. SIGIRR-deficient (Sigirr(-/-)) colonic epithelial cells displayed commensal bacteria-dependent homeostatic defects, as shown by constitutive upregulation of inflammatory genes, increased inflammatory responses to dextran sulfate sodium (DSS) challenge, and increased Azoxymethane (AOM)+DSS-induced colitis-associated tumorigenesis. Gut epithelium-specific expression of the SIGIRR transgene in the SIGIRR-deficient background reduced the cell survival of the SIGIRR-deficient colon epithelium, abrogated the hypersensitivity of the Sigirr(-/-) mice to DSS-induced colitis, and reduced AOM+DSS-induced tumorigenesis. Taken together, our results indicate that epithelium-derived SIGIRR is critical in controlling the homeostasis and innate immune responses of the colon to enteric microflora. PMID:17398123

  2. Myocardial infarct death, the population at risk, and temperature habituation

    NASA Astrophysics Data System (ADS)

    Frost, David B.; Auliciems, Andris

    1993-03-01

    Daily myocardial infarct deaths from Brisbane, 29°28' S, and Montreal, 45°30' N, were used to derive a “pool of susceptible individuals”. Pool size had no effect on the minimum death temperature but large pools increased the value of the acceleration temperature in Brisbane and the maximum death temperature in Montreal. Moderately sized pools in Montreal appeared to produce reduced death rates in cold conditions from both cold avoidance and habituation. A generalized relationship between temperature and myocardial infarct death is postulated.

  3. Brain death declaration

    PubMed Central

    Wahlster, Sarah; Wijdicks, Eelco F.M.; Patel, Pratik V.; Greer, David M.; Hemphill, J. Claude; Carone, Marco

    2015-01-01

    Objective: To assess the practices and perceptions of brain death determination worldwide and analyze the extent and nature of variations among countries. Methods: An electronic survey was distributed globally to physicians with expertise in neurocritical care, neurology, or related disciplines who would encounter patients at risk of brain death. Results: Most countries (n = 91, response rate 76%) reported a legal provision (n = 63, 70%) and an institutional protocol (n = 70, 77%) for brain death. Institutional protocols were less common in lower-income countries (2/9 of low [22%], 9/18 lower-middle [50%], 22/26 upper-middle [85%], and 37/38 high-income countries [97%], p < 0.001). Countries with an organized transplant network were more likely to have a brain death provision compared with countries without one (53/64 [83%] vs 6/25 [24%], p < 0.001). Among institutions with a formalized brain death protocol, marked variability occurred in requisite examination findings (n = 37, 53% of respondents deviated from the American Academy of Neurology criteria), apnea testing, necessity and type of ancillary testing (most commonly required test: EEG [n = 37, 53%]), time to declaration, number and qualifications of physicians present, and criteria in children (distinct pediatric criteria: n = 38, 56%). Conclusions: Substantial differences in perceptions and practices of brain death exist worldwide. The identification of discrepancies, improvement of gaps in medical education, and formalization of protocols in lower-income countries provide first pragmatic steps to reconciling these variations. Whether a harmonized, uniform standard for brain death worldwide can be achieved remains questionable. PMID:25854866

  4. Does superstition help? A study of the role of superstitions and death beliefs on death anxiety amongst Chinese undergraduates in Hong Kong.

    PubMed

    Wong, Shui Hung

    2012-01-01

    Past research has shown that traditional Chinese death beliefs, which mostly consisted of superstitious thoughts, are related to death anxiety. However, other studies have shown that superstitions may help people cope with uncertainty and, therefore, reduce uncertainty-induced anxiety. The role of superstitions, whether related to heightened death anxiety or reduced death anxiety, is unclear. This study attempted to address the knowledge gap by examining the relationships among superstitions and Chinese death beliefs on death anxiety in the Chinese context. One hundred twenty-four undergraduates in Hong Kong completed measures of superstition (R-PBS), death anxiety (MFODS), and Chinese death beliefs scale. Superstition was found to be predictor of death anxiety, as expected. With superstitions highly prevalent in Chinese societies, the study has practical implications in end-of-life care, bereavement support, and death education in the Chinese context. PMID:22852421

  5. Sudden cardiac death in the older athlete.

    PubMed

    Chugh, Sumeet S; Weiss, Joseph B

    2015-02-10

    The overwhelming majority of sports-related sudden deaths occur among those older than 35 years of age. Because increasing numbers of older people are participating in organized endurance and competitive sporting events, the incidence of sports-related sudden death in older adults is expected to rise. Older athletes will approach clinical cardiologists for advice regarding their fitness for participation. It is important to recognize both that strenuous exercise is associated with a transient elevation in risk of sudden cardiac death and that appropriate training substantially reduces this risk. The approach to pre-participation screening for risk of sudden death in the older athlete is a complex issue and at present is largely focused on identifying inducible ischemia due to significant coronary disease. In this brief review, we summarize the current state of knowledge in this area with respect to epidemiology, mechanisms, and approaches to risk stratification, as viewed from the perspective of the consulting clinical cardiologist. PMID:25660928

  6. A coding IRAK2 protein variant compromises Toll-like receptor (TLR) signaling and is associated with colorectal cancer survival.

    PubMed

    Wang, Hui; Flannery, Sinead M; Dickhöfer, Sabine; Huhn, Stefanie; George, Julie; Kubarenko, Andriy V; Lascorz, Jesus; Bevier, Melanie; Willemsen, Joschka; Pichulik, Tica; Schafmayer, Clemens; Binder, Marco; Manoury, Bénédicte; Paludan, Søren R; Alarcon-Riquelme, Marta; Bowie, Andrew G; Försti, Asta; Weber, Alexander N R

    2014-08-15

    Within innate immune signaling pathways, interleukin-1 receptor-associated kinases (IRAKs) fulfill key roles downstream of multiple Toll-like receptors and the interleukin-1 receptor. Although human IRAK4 deficiency was shown to lead to severe immunodeficiency in response to pyogenic bacterial infection during childhood, little is known about the role of human IRAK2. We here identified a non-synonymous IRAK2 variant, rs35060588 (coding R214G), as hypofunctional in terms of NF-κB signaling and Toll-like receptor-mediated cytokine induction. This was due to reduced ubiquitination of TRAF6, a key step in signal transduction. IRAK2 rs35060588 occurs in 3-9% of individuals in different ethnic groups, and our studies suggested a genetic association of rs35060588 with colorectal cancer survival. This for the first time implicates human IRAK2 in a human disease and highlights the R214G IRAK2 variant as a potential novel and broadly applicable biomarker for disease or as a therapeutic intervention point. PMID:24973222

  7. Toll-like receptor 2 of tongue sole Cynoglossus semilaevis: Signaling pathway and involvement in bacterial infection.

    PubMed

    Li, Xue-peng; Sun, Li

    2016-04-01

    Toll-like receptor (TLR) 2 is a member of the TLR family that plays a pivotal role in innate immunity. In mammals, TLR2 is known to recognize specific microbial structures and trigger MyD88-dependent signaling to induce various cytokine responses. In this study, we examined the expression and function of the tongue sole Cynoglossus semilaevis TLR2, CsTLR2. CsTLR2 is composed of 898 amino acid residues and shares 25.6%-27.3% overall sequence identities with known teleost TLR2. CsTLR2 is a transmembrane protein with a toll/interleukin-1 receptor domain and eight leucine-rich repeats. Expression of CsTLR2 occurred in multiple tissues and was upregulated during bacterial infection. Stimulation of the CsTLR2 pathway led to enhanced expression of MyD88-dependent signaling molecules. Recombinant CsTLR2 (rCsTLR2) corresponding to the extracellular region was able to bind to a wide range of bacteria. Under both in vitro and in vivo conditions, rCsTLR2 significantly reduced bacterial infection. These observations add new insights into the signaling and function of teleost TLR2. PMID:26947353

  8. The role of toll-like receptor 9 in chronic stress-induced apoptosis in macrophage.

    PubMed

    Xiang, Yanxiao; Yan, Hui; Zhou, Jun; Zhang, Qi; Hanley, Gregory; Caudle, Yi; LeSage, Gene; Zhang, Xiumei; Yin, Deling

    2015-01-01

    Emerging evidence implied that chronic stress has been exerting detrimental impact on immune system functions in both humans and animals. Toll-like receptors (TLRs) have been shown to play an essential role in modulating immune responses and cell survival. We have recently shown that TLR9 deficiency protects against lymphocyte apoptosis induced by chronic stress. However, the exact role of TLR9 in stress-mediated change of macrophage function remains unclear. The results of the current study showed that when BALB/c mice were treated with restraint stress (12 h daily for 2 days), the number of macrophages recruited to the peritoneal cavity was obviously increased. Results also demonstrated that the sustained effects of stress elevated cytokine IL-1β, TNF-α and IL-10 production yet diminished IFN-γ production from macrophage, which led to apoptotic cell death. However, TLR9 deficiency prevented the chronic stress-mediated accumulation of macrophages. In addition, knocking out TLR9 significantly abolished the chronic stress-induced imbalance of cytokine levels and apoptosis in macrophage. TLR9 deficiency was also found to reverse elevation of plasma IL-1β, IL-10 and IL-17 levels and decrease of plasma IFN-γ level under the condition of chronic stress. These results indicated that TLR9-mediated macrophage responses were required for chronic stress-induced immunosuppression. Further exploration showed that TLR9 deficiency prevented the increment of p38 MAPK phosphorylation and reduction of Akt/Gsk-3β phosphorylation; TLR9 deficiency also attenuated the release of mitochondrial cytochrome c into cytoplasm, caused upregulation of Bcl-2/Bax protein ratio, downregulation of cleavage of caspase-3 and PARP, as well as decreased TUNEL-positive cells in macrophage of stressed mice. Collectively, our studies demonstrated that deficiency of TLR9 maintained macrophage function by modulating macrophage accumulation and attenuating macrophage apoptosis, thus preventing

  9. Evidence of activation of the Toll-like receptor-4 proinflammatory pathway in patients with schizophrenia

    PubMed Central

    García-Bueno, Borja; Gassó, Patricia; MacDowell, Karina S.; Callado, Luis F.; Mas, Sergi; Bernardo, Miguel; Lafuente, Amalia; Meana, J. Javier; Leza, Juan C.

    2016-01-01

    Background Alterations in the innate immune/inflammatory system may underlie the pathophysiology of schizophrenia, but we do not understand the mechanisms involved. The main agents of innate immunity are the Toll-like receptors (TLRs), which detect molecular patterns associated with damage and pathogens. The TLR first reported was TLR4, and it is still the most studied one. Methods We aimed to describe putative modifications to the TLR4 proinflammatory pathway using 2 different strategies in 2 cohorts of patients with schizophrenia and matched controls: 1) quantification of protein and mRNA expression in postmortem prefrontal cortex samples from 30 patients with schizophrenia and 30 controls, and 2) identification of single nucleotide polymorphisms associated with the risk of schizophrenia using whole blood samples from 214 patients with schizophrenia and 216 controls. Results We found evidence of alterations in the expression of the initial elements of the TLR4 signalling pathway (TLR4, Myeloid differentiation primary response gene 88 [MyD88] and nuclear factor-κ B [NF-κB]) in the PFC of patients with schizophrenia. These alterations seem to depend on the presence/absence of antipsychotic treatment at death. Moreover, a polymorphism within the MyD88 gene was significantly associated with schizophrenia risk. Limitations The use of 2 different approaches in 2 different cohorts, the lack of a complementary neuropsychiatric group, the possible confounding effects of antipsychotic treatment and suicide are the main limitations of our study. Conclusion The evidence from this dual approach suggests there is an altered innate immune response in patients with chronic schizophrenia in which the TLR4 proinflammatory pathway could be affected. Improved understanding of the stimuli and mechanisms responsible for this response could lead to improved schizophrenia treatment and better control of the side effects of current antipsychotics. PMID:27070349

  10. Perspectives on Death: An Experiential Course on Death Education.

    ERIC Educational Resources Information Center

    Stefan, Edwin S.

    1978-01-01

    Describes and evaluates a college psychology course on death education (thanatology). Course objectives were to help students become aware of the feelings involved in facing death, encourage discussion on the subject of death, motivate students to change their attitudes about death, and encourage practical planning for funeral arrangements.…

  11. Death Threat and Death Concerns in the College Student.

    ERIC Educational Resources Information Center

    Tobacyk, Jerome; Eckstein, Daniel

    1980-01-01

    Thanatology students reported significantly lesser death threat and significantly greater death concerns. Trait anxiety was found to be a significant predictor of change in death threat in the Thanatology Group, with lesser anxiety associated with greater decline in death threat. (Author)

  12. Poverty Takes Bigger Toll on A Man's Health If He's Black

    MedlinePlus

    ... page: https://medlineplus.gov/news/fullstory_159937.html Poverty Takes Bigger Toll on a Man's Health If ... t surprised by the finding. "The fact that poverty in African Americans can be considered a life- ...

  13. 77 FR 30590 - Open meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee.

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-23

    ...An open meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee will be conducted. The Taxpayer Advocacy Panel is soliciting public comments, ideas and suggestions on improving customer service at the Internal Revenue...

  14. 77 FR 47165 - Open Meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-07

    ...An open meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee will be conducted. The Taxpayer Advocacy Panel is soliciting public comments, ideas, and suggestions on improving customer service at the Internal Revenue...

  15. 77 FR 37102 - Open Meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-06-20

    ...An open meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee will be conducted. The Taxpayer Advocacy Panel is soliciting public comments, ideas and suggestions on improving customer service at the Internal Revenue...

  16. Hour of Exercise a Day May Offset Sitting's Toll on Health

    MedlinePlus

    ... news/fullstory_160102.html Hour of Exercise a Day May Offset Sitting's Toll on Health Study found ... News) -- Just one hour of physical activity a day -- something as simple as a brisk walk or ...

  17. Infant deaths in slings.

    PubMed

    Madre, Chrystèle; Rambaud, Caroline; Avran, David; Michot, Charlotte; Sachs, Philippe; Dauger, Stéphane

    2014-12-01

    Although the incidence of sudden unexpected death in infancy (SUDI) decreased markedly after campaigns to promote supine positioning during sleeping, it has remained unchanged over the last decade. Epidemiological data suggest a role for new causes such as suffocation, asphyxia, and entrapment. Health authorities in several countries have issued warnings about slings used to carry infants. However, few reports of infant deaths in slings have been published in medical journals. Our paediatric intensive care unit has admitted two infants who experienced cardiorespiratory arrest while carried in a sling. Diagnostic investigations including a post-mortem examination established asphyxia as the mechanism of death. In conclusion, baby slings may carry a risk of SUDI, either by compression of the baby into a forward-flexed position or by direct suffocation. European recommendations for the cautious use of baby slings should be disseminated to families and professionals involved in caring for infants, as done recently in Australia, Canada, and the USA. PMID:24343674

  18. The "moment of death".

    PubMed

    Valentine, Christine

    2007-01-01

    The "moment of death," once a dominant concept in preparing for a "good death", has been eclipsed by a focus on the wider concept of the "dying trajectory". However, findings from interviews with 25 bereaved individuals suggest that dying loved ones' final moments may still be experienced as highly significant in their own right. In some accounts the dying individual's final moments did not feature or made little impression, either because the survivor was not present, or there was no obviously definable moment, or because other, usually medical factors, such as whether to resuscitate the person, took precedence. However, in six cases such moments were constructed as profound, special, and memorable occasions. These constructions are explored in relation to achieving a good death, the dying trajectory as a whole, and making sense of the bereavement experience. Their implications for sociological theories of identity and embodiment are also considered. PMID:18214069

  19. [Sexuality and death].

    PubMed

    Sapetti, Adrián

    2006-01-01

    It is intented to show two apparently antithetic poles: Sexuality and Death, in fact interpenetrate themselves, disguising the fear of death, or the desire to die, Eros' world. Different expressions of culture are analyzed, especially the one known as The Profane Time, the time for work, which is characterized by the submission to interdicts (prohibitions) and, on the other hand, the Time for Joy or The Sacred Time, characterized by the transgression of such prohibitions. Its relationship with the interdicts'violations in the sexual as well as in the death arena is analyzed in order to connect the human being's fear in the presence of the unrestraint, the overflow and the abandonment of the time established for work that would imply free sexuality. The latter is connected with some conclusions that could be considered useful in the field of Sexual Therapies, with a certain critical look at the mechanist settlement applied to those treatments. PMID:16645674

  20. [The death of Cleopatra].

    PubMed

    Guillemain, Bernard

    2009-01-01

    The image of a queen bitten by a snake is controversial and the facts, such as the swiftness of her death and her servants, and scientific experiments are in favour of a deadly poisoning. The author reminds that in the ancient texts the snake had sacred virtues and it was a symbolic image to embellish the suicide of the one who was sentenced to death by the Romans. Octaves set up the myth of a fatal bite which became an iconographic image for the cinema. PMID:20503640

  1. [Near death experiences].

    PubMed

    Rubia Vila, Francisco José

    2012-01-01

    Near Death Experiences are those accounted by people who after being clinically dead return to life spontaneously or after reanimation. These experiences have been used traditionally to support the belief in the existence of the soul and of life after death. However, today neuroscience tries to explain these experiences from the scientific point of view, i.e. explaining them based on their brain substrates. Their resemblance to mystic experiences and to altered states of consciousness seems to indicate that they may be produced by hyperactivity of limbic structures caused by anoxia or hypercapnia. PMID:24294729

  2. Toll-like receptor signaling in colorectal cancer: Carcinogenesis to cancer therapy

    PubMed Central

    Li, Ting-Ting; Ogino, Shuji; Qian, Zhi Rong

    2014-01-01

    Toll-like receptors (TLRs) are germ line encoded innate immune sensors that recognize conserved microbial structures and host alarmins, and signal expression of major histocompatibility complex proteins, costimulatory molecules, and inflammatory mediators by macrophages, neutrophils, dendritic cells, and other cell types. These protein receptors are characterized by their ability to respond to invading pathogens promptly by recognizing particular TLR ligands, including flagellin and lipopolysaccharide of bacteria, nucleic acids derived from viruses, and zymosan of fungi. There are 2 major TLR pathways; one is mediated by myeloid differentiation factor 88 (MYD88) adaptor proteins, and the other is independent of MYD88. The MYD88-dependent pathway involves early-phase activation of nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-κB1) and all the TLRs, except TLR3, have been shown to activate this pathway. TLR3 and TLR4 act via MYD88-independent pathways with delayed activation of NF-κB signaling. TLRs play a vital role in activating immune responses. TLRs have been shown to mediate inflammatory responses and maintain epithelial barrier homeostasis, and are highly likely to be involved in the activation of a number of pathways following cancer therapy. Colorectal cancer (CRC) is one of the most common cancers, and accounts for almost half a million deaths annually worldwide. Inflammation is considered a risk factor for many common malignancies including cancers of the colorectum. The key molecules involved in inflammation-driven carcinogenesis include TLRs. As sensors of cell death and tissue remodeling, TLRs may have a universal role in cancer; stimulation of TLRs to activate the innate immune system has been a legitimate therapeutic strategy for some years. TLRs 3/4/7/8/9 are all validated targets for cancer therapy, and a number of companies are developing agonists and vaccine adjuvants. On the other hand, antagonists may favor inhibition

  3. Characterization, expression analysis and localization pattern of toll-like receptor 1 (tlr1) and toll-like receptor 2 (tlr2) genes in grass carp Ctenopharyngodon idella.

    PubMed

    He, L B; Wang, H; Luo, L F; Jiang, S H; Liu, L Y; Li, Y M; Huang, R; Liao, L J; Zhu, Z Y; Wang, Y P

    2016-08-01

    In this study, the toll-like receptor 1 (tlr1) and toll-like receptor 2 (tlr2) genes of grass carp Ctenopharyngodon idella were cloned and characterized. tlr1 and tlr2 were found to be highly expressed in immune system organs such as spleen, middle kidney and heart kidney. The expression level of tlr1 and tlr2 was found to be up-regulated at the later stage of viral challenge process. Moreover, subcellular localization indicated that Tlr1 and Tlr2 shared similar localization pattern and both of them may locate in the plasma membrane of transfected cells. PMID:27221024

  4. The Drosophila Toll pathway controls but does not clear Candida glabrata infections.

    PubMed

    Quintin, Jessica; Asmar, Joelle; Matskevich, Alexey A; Lafarge, Marie-Céline; Ferrandon, Dominique

    2013-03-15

    The pathogenicity of Candida glabrata to patients remains poorly understood for lack of convenient animal models to screen large numbers of mutants for altered virulence. In this study, we explore the minihost model Drosophila melanogaster from the dual perspective of host and pathogen. As in vertebrates, wild-type flies contain C. glabrata systemic infections yet are unable to kill the injected yeasts. As for other fungal infections in Drosophila, the Toll pathway restrains C. glabrata proliferation. Persistent C. glabrata yeasts in wild-type flies do not appear to be able to take shelter in hemocytes from the action of the Toll pathway, the effectors of which remain to be identified. Toll pathway mutant flies succumb to injected C. glabrata. In this immunosuppressed background, cellular defenses provide a residual level of protection. Although both the Gram-negative binding protein 3 pattern recognition receptor and the Persephone protease-dependent detection pathway are required for Toll pathway activation by C. glabrata, only GNBP3, and not psh mutants, are susceptible to the infection. Both Candida albicans and C. glabrata are restrained by the Toll pathway, yet the comparative study of phenoloxidase activation reveals a differential activity of the Toll pathway against these two fungal pathogens. Finally, we establish that the high-osmolarity glycerol pathway and yapsins are required for virulence of C. glabrata in this model. Unexpectedly, yapsins do not appear to be required to counteract the cellular immune response but are needed for the colonization of the wild-type host. PMID:23401590

  5. Toll-Like Receptor 4 Is a Regulator of Monocyte and Electroencephalographic Responses to Sleep Loss

    PubMed Central

    Wisor, Jonathan P.; Clegern, William C.; Schmidt, Michelle A.

    2011-01-01

    Study Objectives: Sleep loss triggers changes in inflammatory signaling pathways in the brain and periphery. The mechanisms that underlie these changes are ill-defined. The Toll-like receptor 4 (TLR4) activates inflammatory signaling cascades in response to endogenous and pathogen-associated ligands known to be elevated in association with sleep loss. TLR4 is therefore a possible mediator of some of the inflammation-related effects of sleep loss. Here we describe the baseline electroencephalographic sleep phenotype and the biochemical and electroencephalographic responses to sleep loss in TLR4-deficient mice. Design, Measurements and Results: TLR4-deficient mice and wild type controls were subjected to electroencephalographic and electromyographic recordings during spontaneous sleep/wake cycles and during and after sleep restriction sessions of 3, 6, and 24-h duration, during which sleep was disrupted by an automated sleep restriction system. Relative to wild type control mice, TLR4-deficient mice exhibited an increase in the duration of the primary daily waking bout occurring at dark onset in a light/dark cycle. The amount of time spent in non-rapid eye movement sleep by TLR4-deficient mice was reduced in proportion to increased wakefulness in the hours immediately after dark onset. Subsequent to sleep restriction, EEG measures of increased sleep drive were attenuated in TLR4-deficient mice relative to wild-type mice. TLR4 was enriched 10-fold in brain cells positive for the cell surface marker CD11b (cells of the monocyte lineage) relative to CD11b-negative cells in wild type mouse brains. To assess whether this population was affected selectively by TLR4 knockout, flow cytometry was used to count F4/80- and CD45-positive cells in the brains of sleep deprived and time of day control mice. While wild-type mice exhibited a significant reduction in the number of CD11b-positive cells in the brain after 24-h sleep restriction, TLR4-deficient mice did not. Conclusion

  6. Sudden Death Syndrome

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Sudden death syndrome (SDS) is an important disease of soybean in North and South America. SDS first occurred in South America in the early 1990s. In the U.S.A., SDS was first detected in AK in 1971. Now SDS occurs in most soybean production areas of the U.S. The SDS pathogen is a soil-borne fungu...

  7. The Death Penalty.

    ERIC Educational Resources Information Center

    Crockett, Mark

    1990-01-01

    Provides a lesson plan on the Eighth Amendment to the U.S. Constitution and the imposition of the death penalty. Focuses on the controversy concerning capital punishment and stimulates critical thinking in an analysis and discussion of eight hypothetical situations. Includes suggestions for readings, videotapes, and writing assignments. (NL)

  8. Death of a Leader.

    ERIC Educational Resources Information Center

    McLaughlin, Thomas E.

    1994-01-01

    When Issaquah (Washington) superintendent, after battling a brain tumor, entered the hospital for the last time, school district had to develop a crisis plan to deal with the possible death of the superintendent. A contingency planning team developed a telephone tree for school officials to keep in close contact with teachers and administrators.…

  9. Digital Language Death

    PubMed Central

    Kornai, András

    2013-01-01

    Of the approximately 7,000 languages spoken today, some 2,500 are generally considered endangered. Here we argue that this consensus figure vastly underestimates the danger of digital language death, in that less than 5% of all languages can still ascend to the digital realm. We present evidence of a massive die-off caused by the digital divide. PMID:24167559

  10. Diagnosis of brain death

    PubMed Central

    Machado, Calixto

    2010-01-01

    Brain death (BD) should be understood as the ultimate clinical expression of a brain catastrophe characterized by a complete and irreversible neurological stoppage, recognized by irreversible coma, absent brainstem reflexes, and apnea. The most common pattern is manifested by an elevation of intracranial pressure to a point beyond the mean arterial pressure, and hence cerebral perfusion pressure falls and, as a result, no net cerebral blood flow is present, in due course leading to permanent cytotoxic injury of the intracranial neuronal tissue. A second mechanism is an intrinsic injury affecting the nervous tissue at a cellular level which, if extensive and unremitting, can also lead to BD. We review here the methodology of diagnosing death, based on finding any of the signs of death. The irreversible loss of cardio-circulatory and respiratory functions can cause death only when ischemia and anoxia are prolonged enough to produce an irreversible destruction of the brain. The sign of such loss of brain functions, that is to say BD diagnosis, is fully reviewed. PMID:21577338

  11. Sudden Infant Death Syndrome.

    ERIC Educational Resources Information Center

    Barnett, Henry L.; And Others

    There is a growing body of evidence that Sudden Infant Death Syndrome (SIDS) victims are not completely normal and healthy, as was once believed. A variety of new information from several disciplines strongly suggests that the infant who dies suddenly and unexpectedly may do so because of subtle developmental, neurologic, cardiorespiratory, and…

  12. Digital language death.

    PubMed

    Kornai, András

    2013-01-01

    Of the approximately 7,000 languages spoken today, some 2,500 are generally considered endangered. Here we argue that this consensus figure vastly underestimates the danger of digital language death, in that less than 5% of all languages can still ascend to the digital realm. We present evidence of a massive die-off caused by the digital divide. PMID:24167559

  13. Targeting Toll-like receptor 2 inhibits growth of head and neck squamous cell carcinoma

    PubMed Central

    Farnebo, Lovisa; Shahangian, Arash; Lee, Yunqin; Shin, June Ho; Scheeren, Ferenc A.; Sunwoo, John B.

    2015-01-01

    Infection-driven inflammation has been proposed to be involved in the tumorigenesis of head and neck squamous cell carcinoma (HNSCC). Oral HNSCC is often colonized with microbes such as gram-positive bacteria and yeast, where ligands derived from their wall components have been shown to specifically bind to Toll-like receptor 2 (TLR2). Although TLR2 has been described to be expressed in oral HNSCC, its function has not been well characterized. Here, we show the expression of TLR2 in both HNSCC cell lines and primary patient-derived HNSCC xenograft tumors. Activation of TLR2 with a yeast-derived ligand of TLR2, zymosan, promoted organoid formation in an ex vivo model of tumor growth, while blockade with anti-TLR2 antibodies inhibited organoid formation. Zymosan also induced phosphorylation of ERK and the p65 subunit of NF-κB, which was inhibited in the presence of anti-TLR2 antibodies, indicating that this receptor is functional in HNSCC and that the signaling through these pathways is intact. TLR2 blockade also inhibited growth of human xenografted tumors in immunodeficient mice. In summary, our data show that TLR2 is a functional receptor expressed in human HNSCC that plays a direct pro-tumorigenic role, and that it can be therapeutically targeted with blocking antibodies to reduce tumor growth. PMID:25846753

  14. The active contribution of Toll-like receptors to allergic airway inflammation.

    PubMed

    Chen, Keqiang; Xiang, Yi; Yao, Xiaohong; Liu, Ying; Gong, Wanghua; Yoshimura, Teizo; Wang, Ji Ming

    2011-10-01

    Epithelia lining the respiratory tract represent a major portal of entry for microorganisms and allergens and are equipped with innate and adaptive immune signaling receptors for host protection. These include Toll-like receptors (TLRs) that recognize microbial components and evoke diverse responses in cells of the respiratory system. TLR stimulation by microorganism-derived molecules activates antigen presenting cells, control T helper (Th) 1, Th2, and Th17 immune cell differentiation, cytokine production by mast cells, and activation of eosinophils. It is clear that TLR are involved in the pathophysiology of allergic airway diseases such as asthma. Dendritic cells (DCs), a kind of antigen presenting cells, which play a key role in the induction of allergic airway inflammation, are privileged targets for pathogen associated molecular patterns (PAMPs). During the allergic responses, engagement of TLRs on DCs determines the Th2 polarization of the T cells. TLR signaling in mast cells increases the release of IL-5, and TLR activation of airway epithelial cells forces the generation of proallergic Th2 type of cytokines. Although these responses aim to protect the host, they may also result in inflammatory tissue damage in the airway. Under certain conditions, stimulation of TLRs, in particular, TLR9, may reduce Th2-dependent allergic inflammation by induction of Th1 responses. Therefore, understanding the complex regulatory roles of TLRs in the pathogenesis of allergic airway inflammation should facilitate the development of preventive and therapeutic measures for asthmatic patients. PMID:21624504

  15. Molecular Regulation of Toll-like Receptors in Asthma and COPD

    PubMed Central

    Zuo, Li; Lucas, Kurt; Fortuna, Christopher A.; Chuang, Chia-Chen; Best, Thomas M.

    2015-01-01

    Asthma and chronic obstructive pulmonary disease (COPD) have both been historically associated with significant morbidity and financial burden. These diseases can be induced by several exogenous factors, such as pathogen-associated molecular patterns (PAMPs) (e.g., allergens and microbes). Endogenous factors, including reactive oxygen species, and damage-associated molecular patterns (DAMPs) recognized by toll-like receptors (TLRs), can also result in airway inflammation. Asthma is characterized by the dominant presence of eosinophils, mast cells, and clusters of differentiation (CD)4+ T cells in the airways, while COPD typically results in the excessive formation of neutrophils, macrophages, and CD8+ T cells in the airways. In both asthma and COPD, in the respiratory tract, TLRs are the primary proteins of interest associated with the innate and adaptive immune responses; hence, multiple treatment options targeting TLRs are being explored in an effort to reduce the severity of the symptoms of these disorders. TLR-mediated pathways for both COPD and asthma have their similarities and differences with regards to cell types and the pro-inflammatory cytotoxins present in the airway. Because of the complex TLR cascade, a variety of treatments have been used to minimize airway hypersensitivity and promote bronchodilation. Although unsuccessful at completely alleviating COPD and severe asthmatic symptoms, new studies are focused on possible targets within the TLR cascade to ameliorate airway inflammation. PMID:26617525

  16. Trichomonas vaginalis infection activates cells through toll-like receptor 4.

    PubMed

    Zariffard, M Reza; Harwani, Sailesh; Novak, Richard M; Graham, Parrie J; Ji, Xin; Spear, Gregory T

    2004-04-01

    While Trichomonas vaginalis infection can cause inflammation and influx of leukocytes into the female genital tract, the molecular pathways important in inducing these effects are not known. This study determined if infection with T. vaginalis activates cells through toll-like receptor 4 (TLR4). Genital tract secretions from infected women stimulated TNF-alpha production by cells with functional TLR4 (350 pg/ml) but significantly less by cells that are unresponsive to TLR4 ligands (44 pg/ml, P = 0.001). Secretions collected after clearance of infection also induced significantly lower responses by cells with functional TLR4 (136 pg/ml, P = 0.008). TNF-alpha responses were not reduced by Polymyxin B and did not correlate with beta(2)-defensin levels, indicating that stimulation of cells was not through lipopolysaccharide or beta(2)-defensin. These studies show that T. vaginalis infection results in the appearance in the genital tract of substance(s) that stimulate cells through TLR4, suggesting a mechanism for the inflammation caused by this infection. PMID:15093558

  17. Adolescent Russian roulette deaths.

    PubMed

    Collins, Kim A

    2010-03-01

    Adolescence, between the ages of 10 and 19 years, is a unique period both physically and emotionally. During this time of life, individuals are known to experiment and engage in risky behavior, sometimes with unforeseen morbidity and mortality. We also see suicide emerge as a manner of death in this age group. The most common method is gunshot wound and sometimes in the form of Russian roulette. Few studies have looked at deaths by Russian roulette, the victims, and scenarios. In particular, no study examines the adolescent victim of Russian roulette. To better understand and classify this entity, adolescent Russian roulette autopsy cases over a 20-year period were examined looking at the victims, scenarios, autopsy findings, cause and manner of death, and the weapons. All victims were males, ages 13 to 19 years, with a Black-to-White ratio of 1:1. No victim had a previous psychiatric history. Toxicology was positive for alcohol and/or marijuana in 50% of the victims. Friends were present when the victim shot himself which occurred in the home the majority of the time. In all but 1 case, premeditation of the game was involved as the victim provided the weapon for the roulette. The cause of death was gunshot wound to the head (6 to the right side, 1 to the mouth, 1 to the forehead), and the manner of death was suicide in 6 cases and accident in 2 cases. A review of the literature discusses the adolescent victim, suicide, and Russian roulette. PMID:20010290

  18. Heme-Mediated Induction of CXCL10 and Depletion of CD34+ Progenitor Cells Is Toll-Like Receptor 4 Dependent

    PubMed Central

    Dickinson-Copeland, Carmen M.; Wilson, Nana O.; Liu, Mingli; Driss, Adel; Salifu, Hassana; Adjei, Andrew A.; Wilson, Michael; Gyan, Ben; Oduro, Daniel; Badu, Kingsley; Botchway, Felix; Anderson, Winston; Bond, Vincent; Bacanamwo, Methode; Singh, Shailesh; Stiles, Jonathan K.

    2015-01-01

    Plasmodium falciparum infection can cause microvascular dysfunction, cerebral encephalopathy and death if untreated. We have previously shown that high concentrations of free heme, and C-X-C motif chemokine 10 (CXCL10) in sera of malaria patients induce apoptosis in microvascular endothelial and neuronal cells contributing to vascular dysfunction, blood-brain barrier (BBB) damage and mortality. Endothelial progenitor cells (EPC) are microvascular endothelial cell precursors partly responsible for repair and regeneration of damaged BBB endothelium. Studies have shown that EPC’s are depleted in severe malaria patients, but the mechanisms mediating this phenomenon are unknown. Toll-like receptors recognize a wide variety of pathogen-associated molecular patterns generated by pathogens such as bacteria and parasites. We tested the hypothesis that EPC depletion during malaria pathogenesis is a function of heme-induced apoptosis mediated by CXCL10 induction and toll-like receptor (TLR) activation. Heme and CXCL10 concentrations in plasma obtained from malaria patients were elevated compared with non-malaria subjects. EPC numbers were significantly decreased in malaria patients (P < 0.02) and TLR4 expression was significantly elevated in vivo. These findings were confirmed in EPC precursors in vitro; where it was determined that heme-induced apoptosis and CXCL10 expression was TLR4-mediated. We conclude that increased serum heme mediates depletion of EPC during malaria pathogenesis. PMID:26555697

  19. Induction of long-term lipopolysaccharide tolerance by an agonistic monoclonal antibody to the toll-like receptor 4/MD-2 complex.

    PubMed

    Ohta, Shoichiro; Bahrun, Uleng; Shimazu, Rintaro; Matsushita, Hidetomo; Fukudome, Kenji; Kimoto, Masao

    2006-10-01

    We have established an agonistic monoclonal antibody, UT12, that induces stimulatory signals comparable to those induced by lipopolysaccharide (LPS) through Toll-like receptor 4 and MD-2. UT12 activated nuclear factor kappaB and induced the production of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) in peritoneal exudative cells. In addition, mice injected with UT12 rapidly fell into endotoxin shock concomitant with the augmentation of serum TNF-alpha and IL-6 levels, followed by death within 12 h. On the other hand, when the mice were pretreated with a sublethal dose of UT12, the mice survived the subsequent lethal LPS challenges, with significant suppression of serum TNF-alpha and IL-6, indicating that UT12 induced tolerance against LPS. This effect of UT12 was maintained for at least 9 days. In contrast, the tolerance induced by LPS continued for less than 3 days. These results illuminate a novel potential therapeutic strategy for endotoxin shock by the use of monoclonal antibodies against the Toll-like receptor 4/MD-2 complex. PMID:17028215

  20. Near-death experiences and the psychology of death.

    PubMed

    Tassell-Matamua, Natasha A

    Little is known about the psychological phenomenology of death. Reported across known history and in all cultures by those who have died or been close to death, NDEs challenge objective-mechanistic models by suggesting the phenomenology of death may involve a variety of complex psychological processes. This article discusses three notable characteristics of the NDE--loss of the fear of death, psychological sequelae, and complex conscious abilities--supporting this claim. The implications these have for advancing societal understandings of death are discussed, and their pragmatic application for professions where death is frequently encountered, such as palliative care, is addressed. PMID:24834668

  1. Tyrosine Phosphorylation in Toll-Like Receptor Signaling

    PubMed Central

    Chattopadhyay, Saurabh; Sen, Ganes C.

    2014-01-01

    There is a wealth of knowledge about how different Ser/Thr protein kinases participate in Toll-like receptor (TLR) signaling. In many cases, we know the identities of the Ser/Thr residues of various components of the TLR-signaling pathways that are phosphorylated, the functional consequences of the phosphorylation and the responsible protein kinases. In contrast, the analysis of Tyr-phosphorylation of TLRs and their signaling proteins is currently incomplete, because several existing analyses are not systematic or they do not rely on robust experimental data. Nevertheless, it is clear that many TLRs require, for signaling, ligand-dependent phosphorylation of specific Tyr residues in their cytoplasmic domains; the list includes TLR2, TLR3, TLR4, TLR5, TLR8 and TLR9. In this article, we discuss the current status of knowledge on the effect of Tyr-phosphorylation of TLRs and their signaling proteins on their biochemical and biological functions, the possible identities of the relevant protein tyrosine kinases (PTKs) and the nature of regulations of PTK-mediated activation of TLR signaling pathways. PMID:25022196

  2. Toll-like receptor signaling in primary immune deficiencies.

    PubMed

    Maglione, Paul J; Simchoni, Noa; Cunningham-Rundles, Charlotte

    2015-11-01

    Toll-like receptors (TLRs) recognize common microbial or host-derived macromolecules and have important roles in early activation of the immune system. Patients with primary immune deficiencies (PIDs) affecting TLR signaling can elucidate the importance of these proteins to the human immune system. Defects in interleukin-1 receptor-associated kinase-4 and myeloid differentiation factor 88 (MyD88) lead to susceptibility to infections with bacteria, while mutations in nuclear factor-κB essential modulator (NEMO) and other downstream mediators generally induce broader susceptibility to bacteria, viruses, and fungi. In contrast, TLR3 signaling defects are specific for susceptibility to herpes simplex virus type 1 encephalitis. Other PIDs induce functional alterations of TLR signaling pathways, such as common variable immunodeficiency in which plasmacytoid dendritic cell defects enhance defective responses of B cells to shared TLR agonists. Dampening of TLR responses is seen for TLRs 2 and 4 in chronic granulomatous disease (CGD) and X-linked agammaglobulinemia (XLA). Enhanced TLR responses, meanwhile, are seen for TLRs 5 and 9 in CGD, TLRs 4, 7/8, and 9 in XLA, TLRs 2 and 4 in hyper IgE syndrome, and for most TLRs in adenosine deaminase deficiency. PMID:25930993

  3. Toll-Like Receptor 4 Deficiency Impairs Motor Coordination

    PubMed Central

    Zhu, Jian-Wei; Li, Yi-Fei; Wang, Zhao-Tao; Jia, Wei-Qiang; Xu, Ru-Xiang

    2016-01-01

    The cerebellum plays an essential role in balance and motor coordination. Purkinje cells (PCs) are the sole output neurons of the cerebellar cortex and are critical for the execution of its functions, including motor coordination. Toll-like receptor (TLR) 4 is involved in the innate immune response and is abundantly expressed in the central nervous system; however, little is known about its role in cerebellum-related motor functions. To address this question, we evaluated motor behavior in TLR4 deficient mice. We found that TLR4−∕− mice showed impaired motor coordination. Morphological analyses revealed that TLR4 deficiency was associated with a reduction in the thickness of the molecular layer of the cerebellum. TLR4 was highly expressed in PCs but not in Bergmann glia or cerebellar granule cells; however, loss of TLR4 decreased the number of PCs. These findings suggest a novel role for TLR4 in cerebellum-related motor coordination through maintenance of the PC population. PMID:26909014

  4. Allergens and Activation of the Toll-Like Receptor Response.

    PubMed

    Monie, Tom P; Bryant, Clare E

    2016-01-01

    Pattern recognition receptors (PRRs) provide a crucial function in the detection of exogenous and endogenous danger signals. The Toll-like receptors (TLRs) were the first family of PRRs to be discovered and have been extensively studied since. Whilst TLRs remain the best characterized family of PRRs there is still much to be learnt about their mode of activation and the mechanisms of signal transduction they employ. Much of our understanding of these processes has been gathered through the use of cell based signaling assays utilizing specific gene-reporters or cytokine secretion based readouts. More recently it has become apparent that the repertoire of ligands recognized by these receptors may be wider than originally assumed and that their activation may be sensitized, or at least modulated by the presence of common household allergens such as the cat dander protein Fel d 1, or the house dust mite allergen Der p 2. In this chapter we provide an overview of the cell culture and stimulation processes required to study TLR signaling in HEK293 based assays and in bone marrow-derived macrophages. PMID:26803639

  5. Liesegang-like patterns of Toll crystals grown in gel

    PubMed Central

    Gangloff, Monique; Moreno, Abel; Gay, Nicholas J.

    2013-01-01

    Generating high-quality crystals remains a bottleneck in biological and materials sciences. Here a counter-diffusion method was used to improve the X-ray diffraction quality of the N-terminal domain of Drosophila melanogaster Toll receptor crystals. It was observed that crystallization occurred with a peculiar pattern along the capillary resembling Liesegang bands; this phenomenon is described at both macroscopic and atomic levels. It was found that bands appeared for native protein as well as for co-crystals of magic triangle (I3C)-bound protein even though they crystallize in different space groups. Crystallization occurred with a linear recurrence independent of the precipitant concentration and a protein-specific spacing coefficient. Bandwidth varied along the capillary, oscillating between large precipitation areas and single crystals. The reported data suggest that repetitive patterns can be generated with biological macromolecules in the presence of sodium malonate as a crystallization agent. A comparison with typical Liesegang patterns and the possible mechanism underlying this phenomenon are discussed. PMID:23596340

  6. Liesegang-like patterns of Toll crystals grown in gel.

    PubMed

    Gangloff, Monique; Moreno, Abel; Gay, Nicholas J

    2013-04-01

    Generating high-quality crystals remains a bottleneck in biological and materials sciences. Here a counter-diffusion method was used to improve the X-ray diffraction quality of the N-terminal domain of Drosophila melanogaster Toll receptor crystals. It was observed that crystallization occurred with a peculiar pattern along the capillary resembling Liesegang bands; this phenomenon is described at both macroscopic and atomic levels. It was found that bands appeared for native protein as well as for co-crystals of magic triangle (I3C)-bound protein even though they crystallize in different space groups. Crystallization occurred with a linear recurrence independent of the precipitant concentration and a protein-specific spacing coefficient. Bandwidth varied along the capillary, oscillating between large precipitation areas and single crystals. The reported data suggest that repetitive patterns can be generated with biological macromolecules in the presence of sodium malonate as a crystallization agent. A comparison with typical Liesegang patterns and the possible mechanism underlying this phenomenon are discussed. PMID:23596340

  7. Toll-like receptors: potential targets for lupus treatment

    PubMed Central

    Wu, Yan-wei; Tang, Wei; Zuo, Jian-ping

    2015-01-01

    Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the loss of tolerance to self-nuclear antigens. Accumulating evidence shows that Toll-like receptors (TLRs), previously proven to be critical for host defense, are implicated in the pathogenesis of autoimmune diseases by recognition of self-molecules. Genome-wide association studies, experimental mouse models and clinical sample studies have provided evidence for the involvement of TLRs, including TLR2/4, TLR5, TLR3 and TLR7/8/9, in SLE pathogenesis. A number of downstream proteins in the TLR signaling cascade (such as MyD88, IRAKs and IFN-α) are identified as potential therapeutic targets for SLE treatment. Numerous antagonists targeting TLR signaling, including oligonucleotides, small molecular inhibitors and antibodies, are currently under preclinical studies or clinical trials for SLE treatment. Moreover, the emerging new manipulation of TLR signaling by microRNA (miRNA) regulation shows promise for the future treatment of SLE. PMID:26592511

  8. Toll-Like Receptor 9 in Breast Cancer

    PubMed Central

    Sandholm, Jouko; Selander, Katri S.

    2014-01-01

    Toll-like receptor 9 (TLR9) is a cellular DNA receptor of the innate immune system. DNA recognition via TLR9 results in an inflammatory reaction, which eventually also activates a Th1-biased adaptive immune attack. In addition to cells of the immune system, TLR9 mRNA and protein are also widely expressed in breast cancer cell lines and in clinical breast cancer specimens. Although synthetic TLR9-ligands induce cancer cell invasion in vitro, the role of TLR9 in cancer pathophysiology has remained unclear. In the studies conducted so far, tumor TLR9 expression has been shown to have prognostic significance only in patients that have triple-negative breast cancer (TNBC). Specifically, high tumor TLR9 expression predicts good prognosis among TNBC patients. Pre-clinical studies suggest that TLR9 expression may affect tumor immunophenotype and contribute to the immunogenic benefit of chemotherapy. In this review, we discuss the possible contribution of tumor TLR9 to the pathogenesis and treatment responses in breast cancer. PMID:25101078

  9. Cathepsins are required for Toll-like receptor 9 responses

    SciTech Connect

    Matsumoto, Fumi; Saitoh, Shin-ichiroh; Fukui, Ryutaroh; Kobayashi, Toshihiko; Tanimura, Natsuko; Konno, Kazunori; Kusumoto, Yutaka; Akashi-Takamura, Sachiko; Miyake, Kensuke

    2008-03-14

    Toll-like receptors (TLR) recognize a variety of microbial products and activate defense responses. Pathogen sensing by TLR2/4 requires accessory molecules, whereas little is known about a molecule required for DNA recognition by TLR9. After endocytosis of microbes, microbial DNA is exposed and recognized by TLR9 in lysosomes. We here show that cathepsins, lysosomal cysteine proteases, are required for TLR9 responses. A cell line Ba/F3 was found to be defective in TLR9 responses despite enforced TLR9 expression. Functional cloning with Ba/F3 identified cathepsin B/L as a molecule required for TLR9 responses. The protease activity was essential for the complementing effect. TLR9 responses were also conferred by cathepsin S or F, but not by cathepsin H. TLR9-dependent B cell proliferation and CD86 upregulation were apparently downregulated by cathepsin B/L inhibitors. Cathepsin B inhibitor downregulated interaction of CpG-B with TLR9 in 293T cells. These results suggest roles for cathepsins in DNA recognition by TLR9.

  10. Subverting Toll-Like Receptor Signaling by Bacterial Pathogens

    PubMed Central

    McGuire, Victoria A.; Arthur, J. Simon C.

    2015-01-01

    Pathogenic bacteria are detected by pattern-recognition receptors (PRRs) expressed on innate immune cells, which activate intracellular signal transduction pathways to elicit an immune response. Toll-like receptors are, perhaps, the most studied of the PRRs and can activate the mitogen-activated protein kinase (MAPK) and Nuclear Factor-κB (NF-κB) pathways. These pathways are critical for mounting an effective immune response. In order to evade detection and promote virulence, many pathogens subvert the host immune response by targeting components of these signal transduction pathways. This mini-review highlights the diverse mechanisms that bacterial pathogens have evolved to manipulate the innate immune response, with a particular focus on those that target MAPK and NF-κB signaling pathways. Understanding the elaborate strategies that pathogens employ to subvert the immune response not only highlights the importance of these proteins in mounting effective immune responses, but may also identify novel approaches for treatment or prevention of infection. PMID:26648936

  11. Toll gates to periodontal host modulation and vaccine therapy

    PubMed Central

    Hajishengallis, George

    2009-01-01

    Summary Toll-like receptors (TLRs) are central mediators of innate antimicrobial and inflammatory responses and play instructive roles in the development of the adaptive immune response. Thus when stimulated by certain agonists, TLRs serve as adjuvant receptors that link innate and adaptive immunity. However, when excessively activated or inadequately controlled during an infection, TLRs may contribute to immunopathology associated with inflammatory diseases, such as periodontitis. Moreover, certain microbial pathogens appear to exploit aspects of TLR signalling in ways that enhance their adaptive fitness. The diverse and important roles played by TLRs suggest that therapeutic manipulation of TLR signalling may have implications in the control of infection, attenuation of inflammation, and the development of vaccine adjuvants for the treatment of periodontitis. Successful application of TLR-based therapeutic modalities in periodontitis would require highly selective and precisely targeted intervention. This would in turn necessitate precise characterization of TLR signalling pathways in response to periodontal pathogens, as well as development of effective and specific agonists or antagonists of TLR function and signalling. This review summarizes the current status of TLR biology as it relates to periodontitis, and evaluates the potential of TLR-based approaches for host-modulation therapy in this oral disease. PMID:19878475

  12. Toll-Like Receptor Pathways in Autoimmune Diseases.

    PubMed

    Chen, Ji-Qing; Szodoray, Peter; Zeher, Margit

    2016-02-01

    Autoimmune diseases are a family of chronic systemic inflammatory disorders, characterized by the dysregulation of the immune system which finally results in the break of tolerance to self-antigen. Several studies suggest that Toll-like receptors (TLRs) play an essential role in the pathogenesis of autoimmune diseases. TLRs belong to the family of pattern recognition receptors (PRRs) that recognize a wide range of pathogen-associated molecular patterns (PAMPs). TLRs are type I transmembrane proteins and located on various cellular membranes. Two main groups have been classified based on their location; the extracelluar group referred to the ones located on the plasma membrane while the intracellular group all located in endosomal compartments responsible for the recognition of nucleic acids. They are released by the host cells and trigger various intracellular pathways which results in the production of proinflammatory cytokines, chemokines, as well as the expression of co-stimulatory molecules to protect against invading microorganisms. In particular, TLR pathway-associated proteins, such as IRAK, TRAF, and SOCS, are often dysregulated in this group of diseases. TLR-associated gene expression profile analysis together with single nucleotide polymorphism (SNP) assessment could be important to explain the pathomechanism driving autoimmune diseases. In this review, we summarize recent findings on TLR pathway regulation in various autoimmune diseases, including Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), systemic sclerosis (SSc), and psoriasis. PMID:25687121

  13. [Negative regulation of Toll-like receptor signalling].

    PubMed

    Antosz, Halina; Choroszyńska, Dorota

    2013-01-01

    The mechanism of innate immunity is based on the pattern recognition receptors (PRR) that recognize molecular patterns associated with pathogens (PAMPs). Among PRR receptors Toll-like receptors (TLR) are distinguished. As a result of contact with pathogens, TLRs activate specific intracellular signaling pathways. It happens through proteins such as adaptor molecules, e.g. MyD88, TIRAP, TRIF, TRAM, and IPS-1, which participate in the cascade activation of kinases (IKK, MAP, RIP-1, TBK-1) as well as transcription factors (NF-κB, AP-1) and regulatory factor (IRF3). The result of this activation is the production of active proinflammatory cytokines, chemokines, interferons and enzymes. The PRR pathways are controlled by extra- and intracellular molecules to prevent overexpression of PRR. They include soluble receptors (sTLR), transmembrane proteins (ST2, SIGIRR, RP105, TRAIL-R) and intracellular inhibitors (SOCS-1, SOCS-3, sMyD88, TOLLIP, IRAK-M, SARM, A20, β-arrestin, CYLD, SHP). These molecules maintain the balance between activation and inhibition and ensure balancing of the beneficial and adverse effects of antigen recognition. PMID:23619234

  14. Selective Toll-Like Receptor Expression in Human Fetal Lung

    PubMed Central

    Petrikin, Joshua E; Gaedigk, Roger; Leeder, J Steven; Truog, William E

    2010-01-01

    Toll-like receptors (TLRs) are critical components of the innate immune system, acting as pattern recognition molecules and triggering an inflammatory response. TLR associated gene products are of interest in modulating inflammatory related pulmonary diseases of the neonate. The ontogeny of TLR related genes in human fetal lung has not been previously described and could elucidate additional functions and identify strategies for attenuating the effects of fetal inflammation. We examined the expression of 84 TLR related genes on 23 human fetal lung samples from three groups with estimated ages of 60 (57-59d), 90 (89-91d), and 130 (117-154d) days. Using a false detection rate algorithm, we identified 32 genes displaying developmental regulation with TLR2 having the greatest up-regulation of TLR genes (9.2 fold increase) and TLR4 unchanged. We confirmed the TLR2 up-regulation by examining an additional 133 fetal lung tissue samples with a fluorogenic polymerase chain reaction assay (TaqMan®) and found an exponential best-fit curve over the time studied. The best-fit curve predicts a 6.1 fold increase from 60d to 130d. We conclude that TLR2 is developmentally expressed from the early pseudoglandular stage of lung development to the canalicular stage. PMID:20581745

  15. Toll-Like Receptor 4 Signaling Pathway Mediates Inhalant Organic Dust-Induced Bone Loss.

    PubMed

    Staab, Elizabeth; Thiele, Geoffrey M; Clarey, Dillon; Wyatt, Todd A; Romberger, Debra J; Wells, Adam D; Dusad, Anand; Wang, Dong; Klassen, Lynell W; Mikuls, Ted R; Duryee, Michael J; Poole, Jill A

    2016-01-01

    Agriculture workers have increased rates of airway and skeletal disease. Inhalant exposure to agricultural organic dust extract (ODE) induces bone deterioration in mice; yet, mechanisms underlying lung-bone crosstalk remain unclear. Because Toll-like receptor 2 (TLR2) and TLR4 are important in mediating the airway consequences of ODE, this study investigated their role in regulating bone responses. First, swine facility ODE stimulated wild-type (WT) bone marrow macrophages to form osteoclasts, and this finding was inhibited in TLR4 knock-out (KO), but not TLR2 KO cells. Next, using an established intranasal inhalation exposure model, WT, TLR2 KO and TLR4 KO mice were treated daily with ODE or saline for 3 weeks. ODE-induced airway neutrophil influx and cytokine/chemokine release were similarly reduced in TLR2 and TLR4 KO animals as compared to WT mice. Utilizing micro-computed tomography (CT), analysis of tibia showed loss of bone mineral density, volume and deterioration of bone micro-architecture and mechanical strength induced by ODE in WT mice were significantly reduced in TLR4 but not TLR2 KO animals. Bone marrow osteoclast precursor cell populations were analyzed by flow cytometry from exposed animals. In WT animals, exposure to inhalant ODE increased osteoclast precursor cell populations as compared to saline, an effect that was reduced in TLR4 but not TLR2 KO mice. These results show that TLR2 and TLR4 pathways mediate ODE-induced airway inflammation, but bone deterioration consequences following inhalant ODE treatment is strongly dependent upon TLR4. Thus, the TLR4 signaling pathway appears critical in regulating the lung-bone inflammatory axis to microbial component-enriched organic dust exposures. PMID:27479208

  16. Toll-Like Receptor 4 Signaling Pathway Mediates Inhalant Organic Dust-Induced Bone Loss

    PubMed Central

    Staab, Elizabeth; Thiele, Geoffrey M.; Clarey, Dillon; Wyatt, Todd A.; Romberger, Debra J.; Wells, Adam D.; Dusad, Anand; Wang, Dong; Klassen, Lynell W.; Mikuls, Ted R.; Duryee, Michael J.; Poole, Jill A.

    2016-01-01

    Agriculture workers have increased rates of airway and skeletal disease. Inhalant exposure to agricultural organic dust extract (ODE) induces bone deterioration in mice; yet, mechanisms underlying lung-bone crosstalk remain unclear. Because Toll-like receptor 2 (TLR2) and TLR4 are important in mediating the airway consequences of ODE, this study investigated their role in regulating bone responses. First, swine facility ODE stimulated wild-type (WT) bone marrow macrophages to form osteoclasts, and this finding was inhibited in TLR4 knock-out (KO), but not TLR2 KO cells. Next, using an established intranasal inhalation exposure model, WT, TLR2 KO and TLR4 KO mice were treated daily with ODE or saline for 3 weeks. ODE-induced airway neutrophil influx and cytokine/chemokine release were similarly reduced in TLR2 and TLR4 KO animals as compared to WT mice. Utilizing micro-computed tomography (CT), analysis of tibia showed loss of bone mineral density, volume and deterioration of bone micro-architecture and mechanical strength induced by ODE in WT mice were significantly reduced in TLR4 but not TLR2 KO animals. Bone marrow osteoclast precursor cell populations were analyzed by flow cytometry from exposed animals. In WT animals, exposure to inhalant ODE increased osteoclast precursor cell populations as compared to saline, an effect that was reduced in TLR4 but not TLR2 KO mice. These results show that TLR2 and TLR4 pathways mediate ODE-induced airway inflammation, but bone deterioration consequences following inhalant ODE treatment is strongly dependent upon TLR4. Thus, the TLR4 signaling pathway appears critical in regulating the lung-bone inflammatory axis to microbial component-enriched organic dust exposures. PMID:27479208

  17. Sudden death of feedlot cattle.

    PubMed

    Glock, R D; DeGroot, B D

    1998-01-01

    Sudden deaths or the sudden death syndrome are perceived as major concerns in cattle feedlots because most of these deaths occur in cattle near market weight. Etiology and preventive measures are poorly defined. The current literature indicates that sudden deaths are associated most commonly with digestive upsets. Death is thought to be the result of interactions between factors including acidosis, bloat, and endotoxemia. Trauma, peracute interstitial pneumonia, and other identifiable events are specifically defined but relatively uncommon. Enterotoxemia is of questionable significance as a cause of sudden deaths. PMID:9464913

  18. Emergency department deaths.

    PubMed

    Webb, G L; McSwain, N E; Webb, W R; Rodriguez, C

    1990-04-01

    This study reviews 186 deaths resulting from trauma in a 2-year period in the Charity Hospital of Louisiana at New Orleans Accident Room in order to evaluate problems in prehospital and hospital resuscitative care. All subjects underwent autopsy, and only six were found to have injuries compatible with survival. Three of these were late arrivals (by transfer or self-imposed delay) and died of protracted hemorrhage. Only three deaths occurring in the Emergency Department itself were found to have been potentially preventable. The important factors in maximizing survival of trauma patients remain rapid transport; immediate, appropriate, rapid evaluation; and quick diagnosis, resuscitation, and definitive therapy. These require a well-trained emergency medical ambulance service delivering patients quickly to a hospital designed to handle trauma patients. One person, preferably a general surgeon with trauma experience, should supervise and monitor the patient continually until the resuscitation phase and all diagnostic tests are completed and definitive therapy is initiated. PMID:2316801

  19. [Death after anal "fisting"].

    PubMed

    Preuss, Johanna; Strehler, Marco; Dettmeyer, Reinhard; Madea, Burkhard

    2008-01-01

    A 45-year-old homeless woman was found dead at her usual sleeping place. Apart from traces of blood on the lower abdomen of the body, the police investigations did not produce any clues pointing to an unnatural death. At autopsy, it was found, however, that death had been caused by extensive disruptions of the intestine. After being confronted with the results, the sexual partner of the victim admitted manual anal penetration, but claimed that this had been done by mutual agreement. The court did not accept that statement and sentenced him to life imprisonment for murder. The frequency of such fatal outcomes of anal penetration, the relationship between the perpetrator and the victim and the special features at the scene are discussed. PMID:18389861

  20. [Karoshi, death by overwork].

    PubMed

    Uehata, Tetsunojo

    2005-07-01

    Karoshi (death by overwork) is one of social medical terms, which used by survivors of victims who attacked with cardiovascular diseases such as stroke, myocardial infarction and sudden cardiac death. In Dec. 2000, Compensation Standard of cardiovascular diseases in Workers' Insurance was changed and admitted the relationship between chronic fatigue and cardiovascular attacks. As a result, compensation numbers of Karoshi attributed to three hundred and more from about 80 cases. The Ministry of Health, Labour and Welfare thinks that most of Karoshi caused by long working hours continuing for several months, especially without payment, so that the Labour Standard Inspector Office requests to decrease overtime work more than 45 hours per month to firm administrators. PMID:16001791

  1. Atypical autoerotic deaths

    SciTech Connect

    Gowitt, G.T.; Hanzlick, R.L. )

    1992-06-01

    So-called typical' autoerotic fatalities are the result of asphyxia due to mechanical compression of the neck, chest, or abdomen, whereas atypical' autoeroticism involves sexual self-stimulation by other means. The authors present five atypical autoerotic fatalities that involved the use of dichlorodifluoromethane, nitrous oxide, isobutyl nitrite, cocaine, or compounds containing 1-1-1-trichloroethane. Mechanisms of death are discussed in each case and the pertinent literature is reviewed.

  2. Motor Vehicle Related Child Deaths: A Plea for Action.

    ERIC Educational Resources Information Center

    Toledo, Jose R.; And Others

    This paper reviews the literature concerning motor related child deaths, emphasizes that automobile related incidents are the major cause of death in children below 14 and over 1 year of age, and provides suggestions about what pediatricians can do to reduce highway fatalities among children. Special attention is given to investigations of the use…

  3. A Death in the Family: Death as a Zen Concept

    ERIC Educational Resources Information Center

    Black, Helen K.; Rubinstein, Robert L.

    2013-01-01

    This study is based on original research that explored family reaction to the death of an elderly husband and father. We interviewed 34 families (a family included a widow and two adult biological children) approximately 6 to 10 months after the death. In one-on-one interviews, we discussed family members' initial reaction to the death, how the…

  4. Death Sentences: A Content Analysis of Children's Death Literature

    ERIC Educational Resources Information Center

    Poling, Devereaux A.; Hupp, Julie M.

    2008-01-01

    A multidimensional concept of death must include biological, sociocultural, and emotional components. Children glean information about death in many ways, one of which is through books. In this study, the authors compared the 3 dimensions of death-related information (irreversibility, inevitability, nonfunctionality) in 24 young children's picture…

  5. A long-awaited merger of the pathways mediating host defence and programmed cell death.

    PubMed

    Blander, J Magarian

    2014-09-01

    Historically, cell death and inflammation have been closely linked, but the necessary divergence of the fields in the past few decades has enriched our molecular understanding of the signalling pathways that mediate various programmes of cell death and multiple types of inflammatory responses. The fields have now come together again demonstrating a surprising level of integration. Intimate interconnections at multiple levels are revealed between the cell death and inflammatory signal transduction pathways that are mobilized in response to the engagement of pattern recognition receptors during microbial infection. Molecules such as receptor-interacting protein kinase 1 (RIPK1), RIPK3, FAS-associated death domain protein (FADD), FLICE-like inhibitory protein (FLIP) and caspase 8 - which are associated with different forms of cell death - are incorporated into compatible and exceedingly dynamic Toll-like receptor, NOD-like receptor and RIG-I-like receptor signalling modules. These signalling modules have a high capacity to switch from inflammation to cell death, or a programmed execution of both, all in an orchestrated battle for host defence and survival. PMID:25145756

  6. Role of mitochondria in apoptotic and necroptotic cell death in the developing brain

    PubMed Central

    Thornton, Claire; Hagberg, Henrik

    2015-01-01

    Hypoxic–ischemic encephalopathy induces secondary brain injury characterized by delayed energy failure. Currently, therapeutic hypothermia is the sole treatment available after severe intrapartum asphyxia in babies and acts to attenuate secondary loss of high energy phosphates improving both short- and long-term outcome. In order to develop the next generation of neuroprotective therapies, we urgently need to understand the underlying molecular mechanisms leading to cell death. Hypoxia–ischemia creates a toxic intracellular environment including accumulation of reactive oxygen/nitrosative species and intracellular calcium after the insult, inducing mitochondrial impairment. More specifically mitochondrial respiration is suppressed and calcium signaling is dysregulated. At a certain threshold, Bax-dependent mitochondrial permeabilization will occur leading to activation of caspase-dependent and apoptosis-inducing factor-dependent apoptotic cell death. In addition, hypoxia–ischemia induces inflammation, which leads to the release of TNF-α, TRAIL, TWEAK, FasL and Toll-like receptor agonists that will activate death receptors on neurons and oligodendroglia. Death receptors trigger apoptotic death via caspase-8 and necroptotic cell death through formation of the necrosome (composed of RIP1, RIP3 and MLKL), both of which converge at the mitochondria. PMID:25661091

  7. Role of mitochondria ROS generation in ethanol-induced NLRP3 inflammasome activation and cell death in astroglial cells

    PubMed Central

    Alfonso-Loeches, Silvia; Ureña-Peralta, Juan R.; Morillo-Bargues, Maria José; Oliver-De La Cruz, Jorge; Guerri, Consuelo

    2014-01-01

    Toll-like receptors (TLRs) and NOD-like receptors (NLRs) are innate immunity sensors that provide an early/effective response to pathogenic or injury conditions. We have reported that ethanol-induced TLR4 activation triggers signaling inflammatory responses in glial cells, causing neuroinflammation and brain damage. However, it is uncertain if ethanol is able to activate NLRs/inflammasome in astroglial cells, which is the mechanism of activation, and whether there is crosstalk between both immune sensors in glial cells. Here we show that chronic ethanol treatment increases the co-localization of caspase-1 with GFAP+ cells, and up-regulates IL-1β and IL-18 in the frontal medial cortex in WT, but not in TLR4 knockout mice. We further show that cultured cortical astrocytes expressed several inflammasomes (NLRP3, AIM2, NLRP1, and IPAF), although NLRP3 mRNA is the predominant form. Ethanol, as ATP and LPS treatments, up-regulates NLRP3 expression, and causes caspase-1 cleavage and the release of IL-1β and IL-18 in astrocytes supernatant. Ethanol-induced NLRP3/caspase-1 activation is mediated by mitochondrial (m) reactive oxygen species (ROS) generation because when using a specific mitochondria ROS scavenger, the mito-TEMPO (500 μM) or NLRP3 blocking peptide (4 μg/ml) or a specific caspase-1 inhibitor, Z-YVAD-FMK (10 μM), abrogates mROS release and reduces the up-regulation of IL-1β and IL-18 induced by ethanol or LPS or ATP. Confocal microscopy studies further confirm that ethanol, ATP or LPS promotes NLRP3/caspase-1 complex recruitment within the mitochondria to promote cell death by caspase-1-mediated pyroptosis, which accounts for ≈73% of total cell death (≈22%) and the remaining (≈25%) die by caspase-3-dependent apoptosis. Suppression of the TLR4 function abrogates most ethanol effects on NLRP3 activation and reduces cell death. These findings suggest that NLRP3 participates, in ethanol-induced neuroinflammation and highlight the NLRP3/TLR4 crosstalk in

  8. Toll of Tobacco in the United States of America

    MedlinePlus

    ... et al., “Estimates of Smoking-Attributable Deaths at Ages 15-54, Motherless or Fatherless Youths, and Resulting Social Security Costs in the United States in 1994,” Preventive Medicine 30(5):353-360, May 2000. Tobacco marketing. U.S. Federal Trade Commission (FTC). Cigarette Report for ...

  9. The novel antiepileptic agent RWJ-333369-A, but not its analog RWJ-333369, reduces regional cerebral edema without affecting neurobehavioral outcome or cell death following experimental traumatic brain injury

    PubMed Central

    Keck, Carrie A.; Thompson, Hilaire J.; Pitkänen, Asla; LeBold, David G.; Morales, Diego M.; Plevy, Jamie B.; Puri, Rishi; Zhao, Boyu; Dichter, Marc; McIntosh, Tracy K.

    2008-01-01

    Purpose To evaluate the therapeutic efficacy of two antiepileptic compounds, RWJ-333369 and RWJ-333369-A in a well-established experimental model of lateral fluid percussion (FP) traumatic brain injury (TBI) in the rat. Methods Anethestized Male Sprague-Dawley rats (n = 227) were subjected to lateral FP brain injury or sham-injury. Animals were randomized to receive treatment with RWJ-333369 (60 mg/kg, p.o.) or its analog RWJ-333369-A (60 mg/kg, p.o.), or vehicle (equal volume) at 15 minutes, 4, 8, and 24 hours post-injury. In Study I, animals were assessed at 48 hours for acute motor and cognitive function and then sacrificed to evaluate regional cerebral edema. In Study II, animals were evaluated post-injury for motor function at 48 hours and weekly thereafter from 1 to 4 weeks. Post-traumatic learning ability was assessed 4 weeks post-injury, followed by evaluation of hemispheric tissue loss. Results In Study I, no improvement in acute memory or motor function was observed following administration of either RWJ-333369 or RWJ-333369-A in brain-injured animals compared to vehicle-treated, brain-injured animals. However, brain-injured animals receiving treatment with RWJ-333369-A had a significant reduction in post-traumatic cerebral edema in both injured and contralateral hippocampus compared to brain-injured, vehicle-treated controls (p < 0.05). In Study II, treatment with either compound did not result in any improvement of neuromotor function, learning ability or change in lesion volume following brain injury. Conclusions These results indicate that the novel antiepileptic compound RWJ-333369-A reduces post-traumatic hippocampal edema without affecting neurobehavioral or histological outcome. It remains unclear whether this small effect on hippocampal edema is related to the ability of this compound to attenuate seizure activity. PMID:17726266

  10. Life, Death, and Second Chances

    MedlinePlus

    ... Home Current Issue Past Issues Special Section Life, Death, and Second Chances Past Issues / Fall 2007 Table ... New Asthma Guidelines: What You Should Know / Life, Death, and Second Chances / Asthma Research: The NIH-NJRC ...

  11. Sudden Infant Death Syndrome (SIDS)

    MedlinePlus

    ... Information Clinical Trials Resources and Publications Sudden Infant Death Syndrome (SIDS): Condition Information Skip sharing on social ... Share this: Page Content SIDS is the sudden death of an infant younger than 1 year of ...

  12. Childhood Deaths from Physical Abuse.

    ERIC Educational Resources Information Center

    Kasim, Mohd. Sham; and Others

    1995-01-01

    This paper describes 30 cases of childhood deaths caused by physical abuse in Kuala Lumpur, Malaysia. Data presented include ethnic origins, age, causes of death, identity of perpetrators, and marital situation of parents. (DB)

  13. Death in Denmark: a reply.

    PubMed Central

    Lamb, D

    1991-01-01

    This reply to Martyn Evans's support for a cardiac-centered concept of death attempts to meet some objections to the brainstem definition of death. Evans's appeal to Wittgenstein's philosophy is also criticised. PMID:1870081

  14. Firearm deaths among children and youth.

    PubMed

    O'Donnell, C R

    1995-09-01

    Nationally, homicide and suicide are the 2nd and 3rd leading causes of death among children and youth under the age of 21. Sixteen to 19-year-olds now have the highest rate of handgun victimization among all age groups. The firearm suicide rate for White males is over 4 times higher than the rate for African American males, whereas the firearm homicide rate is over 9 times higher for African American males. Almost half of all deaths among African American male teenagers now involve firearms. Multiple steps, both short- and long-term, need to be taken to reduce firearm death rates among children and youth. Some of the possible methods to do so are discussed. PMID:7574187

  15. Expression of Toll-Like Receptor 4 Contributes to Corneal Inflammation in Experimental Dry Eye Disease

    PubMed Central

    Lee, Hyun Soo; Hattori, Takaaki; Park, Eun Young; Stevenson, William; Chauhan, Sunil K.; Dana, Reza

    2012-01-01

    Purpose. To investigate the corneal expression of toll-like receptor (TLR) 4 and determine its contribution to the immunopathogenesis of dry eye disease (DED). Methods. Seven to 8-week-old female C57BL/6 mice were housed in a controlled environment chamber and administered scopolamine to induce experimental DED. Mice received intravenous TLR4 inhibitor (Eritoran) to block systemic TLR4-mediated activity. The expression of TLR4 by the corneal epithelium and stroma was evaluated using real-time polymerase chain reaction and flow cytometry. Corneal fluorescein staining (CFS) was performed to evaluate clinical disease severity. The corneal expression of proinflammatory cytokines (IL-1β, IL-6, TNF, and CCL2), corneal infiltration of CD11b+ antigen-presenting cells, and lymph node frequency of mature MHC-IIhi CD11b+ cells were assessed. Results. The epithelial cells of normal corneas expressed TLR4 intracellularly; however, DED significantly increased the cell surface expression of TLR4. Similarly, flow cytometric analysis of stromal cells revealed a significant increase in the expression of TLR4 proteins by DED-induced corneas as compared with normal corneas. DED increased the mRNA expression of TLR4 in corneal stromal cells, but not epithelial cells. TLR4 inhibition decreased the severity of CFS and significantly reduced the mRNA expression of IL-1β, IL-6, and TNF. Furthermore, TLR4 inhibition significantly reduced the corneal infiltration of CD11b+ cells and the lymph node frequency of MHC-IIhi CD11b+ cells. Conclusions. These results suggest that DED increases the corneal expression of TLR4 and that TLR4 participates in the inflammatory response to ocular surface desiccating stress. PMID:22789921

  16. Toll mediated infection response is altered by gravity and spaceflight in Drosophila.

    PubMed

    Taylor, Katherine; Kleinhesselink, Kurt; George, Michael D; Morgan, Rachel; Smallwood, Tangi; Hammonds, Ann S; Fuller, Patrick M; Saelao, Perot; Alley, Jeff; Gibbs, Allen G; Hoshizaki, Deborah K; von Kalm, Laurence; Fuller, Charles A; Beckingham, Kathleen M; Kimbrell, Deborah A

    2014-01-01

    Space travel presents unlimited opportunities for exploration and discovery, but requires better understanding of the biological consequences of long-term exposure to spaceflight. Immune function in particular is relevant for space travel. Human immune responses are weakened in space, with increased vulnerability to opportunistic infections and immune-related conditions. In addition, microorganisms can become more virulent in space, causing further challenges to health. To understand these issues better and to contribute to design of effective countermeasures, we used the Drosophila model of innate immunity to study immune responses in both hypergravity and spaceflight. Focusing on infections mediated through the conserved Toll and Imd signaling pathways, we found that hypergravity improves resistance to Toll-mediated fungal infections except in a known gravitaxis mutant of the yuri gagarin gene. These results led to the first spaceflight project on Drosophila immunity, in which flies that developed to adulthood in microgravity were assessed for immune responses by transcription profiling on return to Earth. Spaceflight alone altered transcription, producing activation of the heat shock stress system. Space flies subsequently infected by fungus failed to activate the Toll pathway. In contrast, bacterial infection produced normal activation of the Imd pathway. We speculate on possible linkage between functional Toll signaling and the heat shock chaperone system. Our major findings are that hypergravity and spaceflight have opposing effects, and that spaceflight produces stress-related transcriptional responses and results in a specific inability to mount a Toll-mediated infection response. PMID:24475130

  17. Toll Mediated Infection Response Is Altered by Gravity and Spaceflight in Drosophila

    PubMed Central

    Taylor, Katherine; Kleinhesselink, Kurt; George, Michael D.; Morgan, Rachel; Smallwood, Tangi; Hammonds, Ann S.; Fuller, Patrick M.; Saelao, Perot; Alley, Jeff; Gibbs, Allen G.; Hoshizaki, Deborah K.; von Kalm, Laurence; Fuller, Charles A.; Beckingham, Kathleen M.; Kimbrell, Deborah A.

    2014-01-01

    Space travel presents unlimited opportunities for exploration and discovery, but requires better understanding of the biological consequences of long-term exposure to spaceflight. Immune function in particular is relevant for space travel. Human immune responses are weakened in space, with increased vulnerability to opportunistic infections and immune-related conditions. In addition, microorganisms can become more virulent in space, causing further challenges to health. To understand these issues better and to contribute to design of effective countermeasures, we used the Drosophila model of innate immunity to study immune responses in both hypergravity and spaceflight. Focusing on infections mediated through the conserved Toll and Imd signaling pathways, we found that hypergravity improves resistance to Toll-mediated fungal infections except in a known gravitaxis mutant of the yuri gagarin gene. These results led to the first spaceflight project on Drosophila immunity, in which flies that developed to adulthood in microgravity were assessed for immune responses by transcription profiling on return to Earth. Spaceflight alone altered transcription, producing activation of the heat shock stress system. Space flies subsequently infected by fungus failed to activate the Toll pathway. In contrast, bacterial infection produced normal activation of the Imd pathway. We speculate on possible linkage between functional Toll signaling and the heat shock chaperone system. Our major findings are that hypergravity and spaceflight have opposing effects, and that spaceflight produces stress-related transcriptional responses and results in a specific inability to mount a Toll-mediated infection response. PMID:24475130

  18. HCV core and NS3 proteins mediate toll like receptor induced innate immune response in corneal epithelium.

    PubMed

    Rajalakshmy, Ayilam Ramachandran; Malathi, Jambulingam; Madhavan, Hajib Naraharirao

    2014-11-01

    Direct association of dry eye syndrome and hepatitis C virus (HCV) infection is a well established fact. In this context, the current study examines the in vitro corneal inflammatory response with respect to HCV core and NS3 antigens. Toll like receptors (TLRs) are pattern recognition receptors which can mediate innate immune response. In the present study, corneal epithelial cells responded to HCV core and NS3 proteins by secreting pro-inflammatory cytokines IL-8, IL-6 and TNF-α via TLR1, TLR2 and TLR6 mediated innate immune response. MyD88/NF-kB signalling was involved in pro-inflammatory cytokine production. Corneal epithelium synthesised nitric oxide (NO) via iNOS during HCV core and NS3 exposure. On later stages of inflammation, cells underwent apoptosis which lead to cell death. SiRNA mediated silencing of TLR1, TLR2 and TLR6 resulted in a significant down regulation of IL-8 and NO. In conclusion, this study indicates that HCV core and NS3 proteins are capable of inducing immune response in corneal epithelium which can potentiate the pathology of HCV associated dry eye condition. Blocking specific TLR response can have therapeutic application in controlling the inflammatory response associated with this dry eye condition. PMID:25280963

  19. On social death: ostracism and the accessibility of death thoughts.

    PubMed

    Steele, Caroline; Kidd, David C; Castano, Emanuele

    2015-01-01

    Being rejected, excluded, or simply ignored is a painful experience. Ostracism researchers have shown its powerful negative consequences (Williams, 2007), and sociologists have referred to such experiences as social death (Bauman, 1992). Is this is just a metaphor or does being ostracized make death more salient in people's minds? An experiment was conducted in which participants experienced ostracism or inclusion using the Cyberball manipulation, and the accessibility of death-related thoughts was measured via a word-stem completion puzzle. Results showed enhanced death-thought accessibility in the ostracism condition, as well as a negative effect of dispositional self-esteem on the accessibility of death-related thoughts. PMID:24592875

  20. Evidence for adaptation of porcine Toll-like receptors.

    PubMed

    Darfour-Oduro, Kwame A; Megens, Hendrik-Jan; Roca, Alfred; Groenen, Martien A M; Schook, Lawrence B

    2016-03-01

    Naturally endemic infectious diseases provide selective pressures for pig populations. Toll-like receptors (TLRs) represent the first line of immune defense against pathogens and are likely to play a crucial adaptive role for pig populations. This study was done to determine whether wild and domestic pig populations representing diverse global environments demonstrate local TLR adaptation. The genomic sequence encoding the ectodomain, responsible for interacting with pathogen ligands of bacterial (TLR1, TLR2 and TLR6) and viral (TLR3, TLR7 and TLR8) receptors, was obtained. Mitochondrial D-loop region sequences were obtained and a phylogenetic analysis using these sequences revealed a clear separation of animals into Asian (n = 27) and European (n = 40) clades. The TLR sequences were then analyzed for population-specific positive selection signatures within wild boars and domesticated pig populations derived from Asian and European clades. Using within-population and between-population tests for positive selection, a TLR2-derived variant 376A (126Thr), estimated to have arisen in 163,000 years ago with a frequency of 83.33% within European wild boars, 98.00% within domestic pig breeds of European origin, 40.00% within Asian wild boars, and 11.36% within Asian domestic pigs, was identified to be under positive selection in pigs of European origin. The variant is located within the N terminal domain of the TLR2 protein 3D crystal structure and could affect ligand binding. This study suggests the TLR2 gene contributing to responses to bacterial pathogens has been crucial in adaptation of pigs to pathogens. PMID:26701185

  1. Stimulation by toll-like receptors inhibits osteoclast differentiation.

    PubMed

    Takami, Masamichi; Kim, Nacksung; Rho, Jaerang; Choi, Yongwon

    2002-08-01

    Osteoclasts, the cells capable of resorbing bone, are derived from hemopoietic precursor cells of monocyte-macrophage lineage. The same precursor cells can also give rise to macrophages and dendritic cells, which are essential for proper immune responses to various pathogens. Immune responses to microbial pathogens are often triggered because various microbial components induce the maturation and activation of immunoregulatory cells such as macrophages or dendritic cells by stimulating Toll-like receptors (TLRs). Since osteoclasts arise from the same precursors as macrophages, we tested whether TLRs play any role during osteoclast differentiation. We showed here that osteoclast precursors prepared from mouse bone marrow cells expressed all known murine TLRs (TLR1-TLR9). Moreover, various TLR ligands (e.g., peptidoglycan, poly(I:C) dsRNA, LPS, and CpG motif of unmethylated DNA, which act as ligands for TLR2, 3, 4, and 9, respectively) induced NF-kappa B activation and up-regulated TNF-alpha production in osteoclast precursor cells. Unexpectedly, however, TLR stimulation of osteoclast precursors by these microbial products strongly inhibited their differentiation into multinucleated, mature osteoclasts induced by TNF-related activation-induced cytokine. Rather, TLR stimulation maintained the phagocytic activity of osteoclast precursors in the presence of osteoclastogenic stimuli M-CSF and TNF-related activation-induced cytokine. Taken together, these results suggest that TLR stimulation of osteoclast precursors inhibits their differentiation into noninflammatory mature osteoclasts during microbial infection. This process favors immune responses and may be critical to prevent pathogenic effects of microbial invasion on bone. PMID:12133979

  2. Toll like receptor polymorphisms in allogeneic hematopoietic cell transplantation

    PubMed Central

    Kornblit, Brian; Enevold, Christian; Wang, Tao; Spellman, Stephen; Haagenson, Mike; Lee, Stephanie J; Müller, Klaus

    2014-01-01

    To assess the impact of the genetic variation in toll-like receptors (TLR) on outcome after allogeneic myeloablative conditioning hematopoietic cell transplantation (HCT) we have investigated 29 single nucleotide polymorphisms (SNP) across 10 TLRs in 816 patients and donors. Only donor genotype of TLR8 rs3764879, which is located on the X chromosome, was significantly associated with outcome at the Bonferroni corrected level P≤0.001. Male hemizygosity and female homozygosity for the minor allele were significantly associated with disease free survival (DFS) (hazard ratio (HR) 1.47 (95% confidence interval (CI) 1.16–1.85); P=0.001). Further analysis stratified by donor sex due to confounding by sex, was suggestive for associations with overall survival (male donor: HR 1.41 (95% CI 1.09–1.83), P=0.010); female donor: (HR 2.78 (95% CI 1.43–5.41), P=0.003), DFS (male donor: HR 1.45 (95% CI 1.12–1.87), P=0.005; female donor: HR 2.34 (95% CI 1.18–4.65), P=0.015) and treatment related mortality (male donor: HR 1.49 (95% CI 1.09–2.04), P=0.012; female donor: HR 3.12 (95% CI 1.44–6.74), P=0.004). In conclusion our findings suggest that the minor allele of TLR8 rs3764879 of the donor is associated with outcome after myeloablative conditioned allogeneic HCT. PMID:25464115

  3. Study of Toll-like receptor gene loci in sarcoidosis

    PubMed Central

    Schürmann, M; Kwiatkowski, R; Albrecht, M; Fischer, A; Hampe, J; Müller-Quernheim, J; Schwinger, E; Schreiber, S

    2008-01-01

    Sarcoidosis is a multi-factorial systemic disease of granulomatous inflammation. Current concepts of the aetiology include interactions of unknown environmental triggers with an inherited susceptibility. Toll-like receptors (TLRs) are main components of innate immunity and therefore TLR genes are candidate susceptibility genes in sarcoidosis. Ten members of the human TLR gene family have been identified and mapped to seven chromosomal segments. The aim of this study was to investigate all known TLR gene loci for genetic linkage with sarcoidosis and to follow positive signals with different methods. We analysed linkage of TLR gene loci to sarcoidosis by use of closely flanking microsatellite markers in 83 families with 180 affected siblings. We found significant linkage between sarcoidosis and markers of the TLR4 gene locus on chromosome 9q (non-parametric linkage score 2·63, P = 0·0043). No linkage was found for the remaining TLR gene loci. We subsequently genotyped 1203 sarcoidosis patients from 997 families, 1084 relatives and 537 control subjects for four single nucleotide polymorphisms of TLR4, including Asp299Gly and Thr399Ile. This genotype data set was studied by case–control comparisons and transmission disequilibrium tests, but showed no significant results. In summary, TLR4 − w ith significant genetic linkage results − appears to be the most promising member of the TLR gene family for further investigation in sarcoidosis. However, our results do not confirm the TLR4 polymorphisms Asp299Gly and Thr399Ile as susceptibility markers. Our results rather point to another as yet unidentified variant within or close to TLR4 that might confer susceptibility to sarcoidosis. PMID:18422738

  4. Toll-like Receptors of the Ascidian Ciona intestinalis

    PubMed Central

    Sasaki, Naoko; Ogasawara, Michio; Sekiguchi, Toshio; Kusumoto, Shoichi; Satake, Honoo

    2009-01-01

    Key transmembrane proteins in the innate immune system, Toll-like receptors (TLRs), have been suggested to occur in the genome of non-mammalian organisms including invertebrates. However, authentic invertebrate TLRs have been neither structurally nor functionally investigated. In this paper, we originally present the structures, localization, ligand recognition, activities, and inflammatory cytokine production of all TLRs of the ascidian Ciona intestinalis, designated as Ci-TLR1 and Ci-TLR2. The amino acid sequence of Ci-TLR1 and Ci-TLR2 were found to possess unique structural organization with moderate sequence similarity to functionally characterized vertebrate TLRs. ci-tlr1 and ci-tlr2 genes were expressed predominantly in the stomach and intestine as well as in hemocytes. Ci-TLR1 and Ci-TLR2 expressed in HEK293 cells, unlike vertebrate TLRs, were localized to both the plasma membrane and endosomes. Intriguingly, both Ci-TLR1 and Ci-TLR2 stimulate NF-κB induction in response to multiple pathogenic ligands such as double-stranded RNA, and bacterial cell wall components that are differentially recognized by respective vertebrate TLRs, revealing that Ci-TLRs recognize broader pathogen-associated molecular patterns than vertebrate TLRs. The Ci-TLR-stimulating pathogenic ligands also induced the expression of Ci-TNFα in the intestine and stomach where Ci-TLRs are expressed. These results provide evidence that the TLR-triggered innate immune systems are essentially conserved in ascidians, and that Ci-TLRs possess “hybrid” biological and immunological functions, compared with vertebrate TLRs. Moreover, it is presumed that chordate TLR ancestors also acquired the Ci-TLR-like multiple cellular localization and pathogen-associated molecular pattern recognition. PMID:19651780

  5. Effects of budesonide on toll-like receptor expression in alveolar macrophages from smokers with and without COPD

    PubMed Central

    Ji, Jie; von Schéele, Ida; Billing, Bo; Dahlén, Barbro; Lantz, Ann-Sofie; Larsson, Kjell; Palmberg, Lena

    2016-01-01

    Introduction Alveolar macrophages (AMs) are equipped with innate immune receptors such as toll-like receptor 2 (TLR2) and toll-like receptor 4 (TLR4). In primary bronchial epithelial cells, exposure of toll-like receptor (TLR) ligands or tumor necrosis factor-alpha (TNF-α) increased TLR2 mRNA expression and reduced interleukin-8 (IL-8) release when coincubated with glucocorticosteroids. The aim of this study was to compare TLR2 and TLR4 expression levels and the effect of a glucocorticosteroid after stimulation with TLR ligands on AMs from smokers with and without COPD compared with the healthy controls. Subjects and methods Bronchoalveolar lavage was performed, and AMs were isolated from smokers with (n=10) and without COPD (n=11) and healthy controls (n=10) and stimulated ex vivo with peptidoglycan (PGN), lipopolysaccharide (LPS), or TNF-α ± budesonide (Bud). Blocking antibodies to TLR2 or TLR4 were added before stimulation with LPS or PGN ± Bud, respectively. The release of proinflammatory cytokine (TNF-α), chemoattractant (CXCL8), and TLR expression was analyzed by enzyme-linked immunosorbent assay and reverse transcription polymerase chain reaction. Results LPS, PGN, and TNF-α induced an increased release of IL-8 and TNF-α in the AMs in all the groups independent of smoking or disease. These responses were inhibited by a glucocorticosteroid (Bud) in all the three groups, except PGN-induced IL-8 secretion in smokers without COPD. Bud increased TLR2 expression in the healthy controls and smokers without COPD. Costimulation of TLR ligands and Bud significantly enhanced TLR2 mRNA expression in both groups of smokers compared with TLR ligands alone. In smokers, costimulation with PGN and Bud significantly increased TLR2 expression when compared with Bud alone. On stimulation with the TLR4 agonist, LPS downregulated TLR4 mRNA expression in all the three groups. Conclusion The combination of glucocorticosteroids with TLR ligands can increase TLR2 expression

  6. Deaths: Leading Causes for 2014.

    PubMed

    Heron, Melonie

    2016-06-01

    Objectives-This report presents final 2014 data on the 10 leading causes of death in the United States by age, sex, race, and Hispanic origin. Leading causes of infant, neonatal, and postneonatal death are also presented. This report supplements "Deaths: Final Data for 2014," the National Center for Health Statistics' annual report of final mortality statistics. PMID:27376998

  7. Death of an Adult Child

    MedlinePlus

    ... iGive.com Purchase Through AmazonSmile Contact Us Donate Death of an Adult Child The death of any child, regardless of cause or age, ... the situations that may have caused their child’s death. Judgmental statements from others indicating that the child ...

  8. Death: Realism in Children's Books.

    ERIC Educational Resources Information Center

    Danielson, Kathy Everts

    In the past, books for children treated death fearfully, morbidly, and didactically, but now children's literature treats death in a more realistic manner and is sensitive to its emotional aspects. Current theories suggest that children perceive death differently at various ages. G. P. Koocher (1973) used J. Piaget's cognitive stages as the basis…

  9. Deaths: Final Data for 1998.

    ERIC Educational Resources Information Center

    Murphy, Sherry L.

    2000-01-01

    This report presents final 1998 data on U.S. deaths and death rates according to demographic and medical characteristics such as age, sex, race, Hispanic origin, marital status, educational attainment, injury at work, state of residence, and cause of death. Trends and patterns in general mortality, life expectancy, and infant and maternal…

  10. Changing Breton Responses to Death.

    ERIC Educational Resources Information Center

    Badone, Ellen

    1988-01-01

    Based on fieldwork conducted in Brittany, France, during 1983 and 1984, discusses changes in Breton responses to death which have accompanied modernization and economic development. Suggests that familiarity with death and acceptance of it are being replaced by the "denial of death" characteristic of contemporary Western culture. Notes parallel…

  11. Teaching about Death to Undergraduates.

    ERIC Educational Resources Information Center

    Pine, Vanderlyn R.; And Others

    Development, implementation, and teaching of a college-level course on dying and death are described. The authors review their own experiences in becoming involved with death education and describe teaching methods, problems, and content of their current course in dying and death at the State University of New York, College at New Paltz. Because…

  12. Almost 19 million childhood injuries result in 11 thousand deaths.

    PubMed

    Waldman, H B

    1996-01-01

    Details are provided from a series of government and private agency reports on the accidents and related deaths of children and the effectiveness of efforts being made to reduce the incidence of these tragedies. In 1992 there were 83,000 accidental deaths and more than 17 million disabling injuries in the United States costing $399 billion. The death rate was down 10 percent from 1991, and also the lowest recorded in recent years. Included in these statistics are 19 million injured children and 11 thousand dead children. The leading cause of death of children less than ten years of age was an unintentional injury. The author presents details on the accidents and related deaths, as well as the effectiveness of efforts to reduce the incidence of these accidents. From the youngest ages to the teen years, a greater number of males than females are injured and die from accident-related causes. The number of accidental deaths of children, ages five to nine years, almost equalled the number of deaths from natural causes. For children ten to fourteen years old, the number of accidental deaths was one third greater than the number from natural causes. Statistics regarding death and injury from motor vehicles, firearms, consumer products, and poison are presented. PMID:8655752

  13. Death after Taking Medicaments

    PubMed Central

    Girdwood, R. H.

    1974-01-01

    A register of reported adverse reactions, recently made available to major hospitals and medical schools gives an indication of prescribing habits under the N.H.S. in England and Wales. An analysis is made here of the chief medicaments allegedly leading to death. Such data are incomplete because of lack of knowledge of the total use of each drug in the United Kingdom and because reporting of adverse reactions is very incomplete. Nevertheless, data about various groups of drugs do draw attention to some hazards and should encourage more widespread reporting of reactions to drugs and other medicaments. PMID:4817164

  14. Anesthetic Complications and Deaths

    PubMed Central

    Pender, John W.

    1968-01-01

    Anesthesiologists should fully inform patients of the possible complications from anesthesia. For rapport with the patient, with whom they usually have no acquaintance until a day or so before an operative procedure, the anesthesiologist should enlist the help of the internist or surgeon who already has established an atmosphere of trust. The extent of morbidity and minor complications from anesthesia has not been adequately recorded. One out of every 1,000 to 2,000 anesthetized patients dies of complications primarily due to or contributed to by anesthesia. Leading causes of death vary from study to study and from year to year. PMID:5652756

  15. Causes of unintentional deaths from carbon monoxide poisonings in California.

    PubMed

    Girman, J R; Chang, Y L; Hayward, S B; Liu, K S

    1998-03-01

    The purpose of this study was to determine the annual number and incidence of unintentional deaths from carbon monoxide (CO) poisonings in California and to identify specific factors that caused or contributed to the deaths. Unintentional CO deaths in California over a ten-year period (1979 to 1988) were identified from the database of the California Master Mortality File and coroners' investigation reports. Factors associated with unintentional CO deaths were determined based on the information from the investigation reports. The annual number of unintentional CO deaths varied from 27 to 58 over the ten years examined, with an average annual death incidence of 1.7 x 10(-6). Death rates were high among males and African-Americans. Alcohol appeared to be a factor in 31% of the cases. The types of combustion sources associated with unintentional CO deaths were: heating or cooking appliances; motor vehicles; charcoal grills and hibachis; small engines; and camping equipment. Factors associated with unintentional CO deaths interact in a complex way. To reduce the rate of unintentional CO deaths effectively, joint efforts involving several prevention methods are suggested. PMID:9549414

  16. Causes of unintentional deaths from carbon monoxide poisonings in California.

    PubMed Central

    Girman, J R; Chang, Y L; Hayward, S B; Liu, K S

    1998-01-01

    The purpose of this study was to determine the annual number and incidence of unintentional deaths from carbon monoxide (CO) poisonings in California and to identify specific factors that caused or contributed to the deaths. Unintentional CO deaths in California over a ten-year period (1979 to 1988) were identified from the database of the California Master Mortality File and coroners' investigation reports. Factors associated with unintentional CO deaths were determined based on the information from the investigation reports. The annual number of unintentional CO deaths varied from 27 to 58 over the ten years examined, with an average annual death incidence of 1.7 x 10(-6). Death rates were high among males and African-Americans. Alcohol appeared to be a factor in 31% of the cases. The types of combustion sources associated with unintentional CO deaths were: heating or cooking appliances; motor vehicles; charcoal grills and hibachis; small engines; and camping equipment. Factors associated with unintentional CO deaths interact in a complex way. To reduce the rate of unintentional CO deaths effectively, joint efforts involving several prevention methods are suggested. PMID:9549414

  17. Happiness and Death Distress: Two Separate Factors

    ERIC Educational Resources Information Center

    Abdel-Khalek, Ahmed M.

    2005-01-01

    The aim of the present study was to explore the relationship between happiness and death distress (death anxiety, death depression, and death obsession) in 275 volunteer Kuwaiti undergraduates. They responded to the Oxford Happiness Inventory, the Death Anxiety Scale, the Arabic Scale of Death Anxiety, the Death Depression Scale-Revised, and the…

  18. Tube Is an IRAK-4 Homolog in a Toll Pathway Adapted for Development and Immunity

    PubMed Central

    Towb, Par; Huaiyu, Sun; Wasserman, Steven A.

    2009-01-01

    Acting through the Pelle and IRAK family of protein kinases, Toll receptors mediate innate immune responses in animals ranging from insects to humans. In flies, the Toll pathway also functions in patterning of the syncytial embryo and requires Tube, a Drosophila-specific adaptor protein lacking a catalytic domain. Here we provide evidence that the Tube, Pelle, and IRAK proteins originated from a common ancestral gene. Following gene duplication, IRAK-4, Tube-like kinases, and Tube diverged from IRAK-1, Pelle, and related kinases. Remarkably, the function of Tube and Pelle in Drosophila embryos can be reconstituted in a chimera modeled on the predicted progenitor gene. In addition, a divergent property of downstream transcription factors was correlated with developmental function. Together, these studies reveal previously unrecognized parallels in Toll signaling in fly and human innate immunity and shed light on the evolution of pathway organization and function. PMID:19498957

  19. Maternal deaths associated with eclampsia in South Africa: Lessons to learn from the confidential enquiries into maternal deaths, 2005 - 2007.

    PubMed

    Moodley, J

    2010-11-01

    Eclampsia is the commonest direct cause of maternal death in South Africa. The latest Saving Mothers Report (2005-2007) indicates that there were 622 maternal deaths due to hypertensive disorders of pregnancy. Of these, 334 (55.3%) were due to eclampsia; of the eclamptic deaths, 50 were over the age of 35 years and 83 were under 20 years old. Avoidable factors involved patient related factors (mainly delay in seeking help), administrative factors (mainly delay in transport) and health personnel issues (mainly due to delay in referring patients). The major causes of death were cerebrovascular accidents and cardiac failure. The majority of deaths due to cardiac failure were due to pulmonary oedema. To reduce deaths from eclampsia, more attention must be given to the detection of pre-eclampsia; the provision of information on the advantages of antenatal care to the population at large and training of health professions in the management of obstetric emergencies. PMID:21081020

  20. Toll Receptors Instruct Axon and Dendrite Targeting and Participate in Synaptic Partner Matching in a Drosophila Olfactory Circuit

    PubMed Central

    Ward, Alex; Hong, Weizhe; Favaloro, Vincenzo; Luo, Liqun

    2015-01-01

    SUMMARY Our understanding of the mechanisms that establish wiring specificity of complex neural circuits is far from complete. During Drosophila olfactory circuit assembly, axons of 50 olfactory receptor neuron (ORN) classes and dendrites of 50 projection neuron (PN) classes precisely target to 50 discrete glomeruli, forming parallel information-processing pathways. Here we show that Toll-6 and Toll-7, members of the Toll receptor family best known for functions in innate immunity and embryonic patterning, cell-autonomously instruct the targeting of specific classes of PN dendrites and ORN axons, respectively. The canonical ligands and downstream partners of Toll receptors in embryonic patterning and innate immunity are not required for the function of Toll-6/Toll-7 in wiring specificity, nor are their cytoplasmic domains. Interestingly, both Toll-6 and Toll-7 participate in synaptic partner matching between ORN axons and PN dendrites. Our investigations reveal that olfactory circuit assembly involves dynamic and long-range interactions between PN dendrites and ORN axons. PMID:25741726