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. Eartkquake Death Tolls

    NASA Astrophysics Data System (ADS)

    Knopoff, Leon; Sornette, Didier

    1995-12-01

    In the risk and insurance literature, the (one-point) distributions of losses in natural disasters have been proposed to be characterized by “fat tail” power laws, i.e. very large destruction may occur with a non-vanishing rate. A naive hypothesis of uncorrelated Poissonian occurrence would suggest that the losses are solely characterized by the properties of the underlying power law distributions, i.e. the longer we wait, the more dramatic will be the largest disaster, which could be as much as a finite fraction of the total population or the total wealth of a country. We find indeed that the numbers Z of deaths in the very largest earthquakes of this century can be described by a power law distribution P(Z)simeq Z^{-(1+δ)} with δ=1.0±0.3, implying an unbounded behavior for the most devastating earthquakes. However, the distribution of the number of deaths per capita in each country in this century has a well-defined maximum value, suggesting that the naive extrapolation of the power law distribution is incorrect and that the understanding of correlations is necessary to ascertain the level of risk from natural disasters. The one-point distributions only provide an upper bound of the expected risk. We propose a speculative model to explain the correlations between deaths in large earthquakes and their countries of occurrence: we suggest that large ancient civilizations that have matured into large present-day populations were the beneficiaries of isolation from marauders due to the relative geographic protection by tectonic processes largely of an orogenic nature.

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

    PubMed

    Das, Saudamini; Vincent, Jeffrey R

    2009-05-05

    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.

  4. Annual Death Toll from Alzheimer's Nearly Doubles in 15 Years

    MedlinePlus

    ... https://medlineplus.gov/news/fullstory_163957.html Annual Death Toll From Alzheimer's Nearly Doubles in 15 Years ... to success in treating other leading causes of death, and partly due to increasing awareness that AD [ ...

  5. Toll pathway modulates TNF-induced JNK-dependent cell death in Drosophila.

    PubMed

    Wu, Chenxi; Chen, Changyan; Dai, Jianli; Zhang, Fan; Chen, Yujun; Li, Wenzhe; Pastor-Pareja, José Carlos; Xue, Lei

    2015-07-01

    Signalling networks that control the life or death of a cell are of central interest in modern biology. While the defined roles of the c-Jun N-terminal kinase (JNK) pathway in regulating cell death have been well-established, additional factors that modulate JNK-mediated cell death have yet to be fully elucidated. To identify novel regulators of JNK-dependent cell death, we performed a dominant-modifier screen in Drosophila and found that the Toll pathway participates in JNK-mediated cell death. Loss of Toll signalling suppresses ectopically and physiologically activated JNK signalling-induced cell death. Our epistasis analysis suggests that the Toll pathway acts as a downstream modulator for JNK-dependent cell death. In addition, gain of JNK signalling results in Toll pathway activation, revealed by stimulated transcription of Drosomycin (Drs) and increased cytoplasm-to-nucleus translocation of Dorsal. Furthermore, the Spätzle (Spz) family ligands for the Toll receptor are transcriptionally upregulated by activated JNK signalling in a non-cell-autonomous manner, providing a molecular mechanism for JNK-induced Toll pathway activation. Finally, gain of Toll signalling exacerbates JNK-mediated cell death and promotes cell death independent of caspases. Thus, we have identified another important function for the evolutionarily conserved Toll pathway, in addition to its well-studied roles in embryonic dorso-ventral patterning and innate immunity.

  6. Toll pathway modulates TNF-induced JNK-dependent cell death in Drosophila

    PubMed Central

    Wu, Chenxi; Chen, Changyan; Dai, Jianli; Zhang, Fan; Chen, Yujun; Li, Wenzhe; Pastor-Pareja, José Carlos; Xue, Lei

    2015-01-01

    Signalling networks that control the life or death of a cell are of central interest in modern biology. While the defined roles of the c-Jun N-terminal kinase (JNK) pathway in regulating cell death have been well-established, additional factors that modulate JNK-mediated cell death have yet to be fully elucidated. To identify novel regulators of JNK-dependent cell death, we performed a dominant-modifier screen in Drosophila and found that the Toll pathway participates in JNK-mediated cell death. Loss of Toll signalling suppresses ectopically and physiologically activated JNK signalling-induced cell death. Our epistasis analysis suggests that the Toll pathway acts as a downstream modulator for JNK-dependent cell death. In addition, gain of JNK signalling results in Toll pathway activation, revealed by stimulated transcription of Drosomycin (Drs) and increased cytoplasm-to-nucleus translocation of Dorsal. Furthermore, the Spätzle (Spz) family ligands for the Toll receptor are transcriptionally upregulated by activated JNK signalling in a non-cell-autonomous manner, providing a molecular mechanism for JNK-induced Toll pathway activation. Finally, gain of Toll signalling exacerbates JNK-mediated cell death and promotes cell death independent of caspases. Thus, we have identified another important function for the evolutionarily conserved Toll pathway, in addition to its well-studied roles in embryonic dorso-ventral patterning and innate immunity. PMID:26202785

  7. A Method for Estimation of Death Tolls in Disastrous Earthquake

    NASA Astrophysics Data System (ADS)

    Pai, C.; Tien, Y.; Teng, T.

    2004-12-01

    Fatality tolls caused by the disastrous earthquake are the one of the most important items among the earthquake damage and losses. If we can precisely estimate the potential tolls and distribution of fatality in individual districts as soon as the earthquake occurrences, it not only make emergency programs and disaster management more effective but also supply critical information to plan and manage the disaster and the allotments of disaster rescue manpower and medicine resources in a timely manner. In this study, we intend to reach the estimation of death tolls caused by the Chi-Chi earthquake in individual districts based on the Attributive Database of Victims, population data, digital maps and Geographic Information Systems. In general, there were involved many factors including the characteristics of ground motions, geological conditions, types and usage habits of buildings, distribution of population and social-economic situations etc., all are related to the damage and losses induced by the disastrous earthquake. The density of seismic stations in Taiwan is the greatest in the world at present. In the meantime, it is easy to get complete seismic data by earthquake rapid-reporting systems from the Central Weather Bureau: mostly within about a minute or less after the earthquake happened. Therefore, it becomes possible to estimate death tolls caused by the earthquake in Taiwan based on the preliminary information. Firstly, we form the arithmetic mean of the three components of the Peak Ground Acceleration (PGA) to give the PGA Index for each individual seismic station, according to the mainshock data of the Chi-Chi earthquake. To supply the distribution of Iso-seismic Intensity Contours in any districts and resolve the problems for which there are no seismic station within partial districts through the PGA Index and geographical coordinates in individual seismic station, the Kriging Interpolation Method and the GIS software, The population density depends on

  8. Combined prediction model of death toll for road traffic accidents based on independent and dependent variables.

    PubMed

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

    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.

  9. Toll-like receptor 2 ligands promote microglial cell death by inducing autophagy.

    PubMed

    Arroyo, Daniela S; Soria, Javier A; Gaviglio, Emilia A; Garcia-Keller, Constanza; Cancela, Liliana M; Rodriguez-Galan, Maria C; Wang, Ji Ming; Iribarren, Pablo

    2013-01-01

    Microglial cells are phagocytes in the central nervous system (CNS) and become activated in pathological conditions, resulting in microgliosis, manifested by increased cell numbers and inflammation in the affected regions. Thus, controlling microgliosis is important to prevent pathological damage to the brain. Here, we evaluated the contribution of Toll-like receptor 2 (TLR2) to microglial survival. We observed that activation of microglial cells with peptidoglycan (PGN) from Staphylococcus aureus and other TLR2 ligands results in cell activation followed by the induction of autophagy and autophagy-dependent cell death. In C57BL/6J mice, intracerebral injection of PGN increased the autophagy of microglial cells and reduced the microglial/macrophage cell number in brain parenchyma. Our results demonstrate a novel role of TLRs in the regulation of microglial cell activation and survival, which are important for the control of microgliosis and associated inflammatory responses in the CNS.

  10. The 2003 Iraq War and avoidable death toll.

    PubMed

    Rawaf, Salman

    2013-10-01

    Salman Rawaf discusses the implications of the most recent estimate of excess deaths associated with the Iraq war and subsequent occupation in the context of the current situation in Iraq. Please see later in the article for the Editors' Summary.

  11. 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

  12. Reduced bioenergetics and toll-like receptor 1 function in human polymorphonuclear leukocytes in aging.

    PubMed

    Qian, Feng; Guo, Xiuyang; Wang, Xiaomei; Yuan, Xiaoling; Chen, Shu; Malawista, Stephen E; Bockenstedt, Linda K; Allore, Heather G; Montgomery, Ruth R

    2014-02-01

    Aging is associated with a progressive decline in immune function (immunosenescence) resulting in an increased susceptibility to viral and bacterial infections. Here we show reduced expression of Toll-like receptor 1 (TLR1) in polymorphonuclear leukocytes (PMN) and an underlying age-dependent deficiency in PMN bioenergetics. In older (>65 years) adults, stimulation through TLR1 led to lower activation of integrins (CD11b and CD18), lower production of the chemokine IL-8, and lower levels of the phosphorylated signaling intermediate p38 MAP kinase than in PMN from younger donors (21-30 years). In addition, loss of CD62L, a marker of PMN activation, was reduced in PMN of older adults stimulated through multiple pathways. Rescue of PMN from apoptosis by stimulation with TLR1 was reduced in PMN from older adults. In seeking an explanation for effects of aging across multiple pathways, we examined PMN energy utilization and found that glucose uptake after stimulation through TLR1 was dramatically lower in PMN of older adults. Our results demonstrate a reduction in TLR1 expression and TLR1-mediated responses in PMN with aging, and reduced efficiency of bioenergetics in PMN. These changes likely contribute to reduced PMN efficiency in aging through multiple aspects of PMN function and suggest potential therapeutic opportunities.

  13. 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

  14. Berberine reduces Toll-like receptor-mediated macrophage migration by suppression of Src enhancement.

    PubMed

    Cheng, Wei-Erh; Ying Chang, Miao; Wei, Jyun-Yan; Chen, Yen-Jen; Maa, Ming-Chei; Leu, Tzeng-Horng

    2015-06-15

    Berberine is an isoquinoline with anti-inflammatory activity. We previously demonstrated that there was a loop of signal amplification between nuclear factor kappa B and Src for macrophage mobility triggered by the engagement of Toll-like receptors (TLRs). The simultaneous suppression of lipopolysaccharide (LPS)-mediated upregulation of inducible nitric oxide synthase, cyclooxygenase 2, and cell mobility in berberine-treated macrophages suggested Src might be a target of berberine. Indeed, th reduced migration, greatly suppressed Src induction in both protein and RNA transcript by berberine were observed in macrophages exposed to LPS, peptidoglycan, polyinosinic-polycytidylic acid, and CpG-oligodeoxynucleotides. In addition to Src induction, berberine also inhibited LPS-mediated Src activation in Src overexpressing macrophages and S-nitroso-N-acetylpenicillamine (a nitric oxide donor) could partly restore it. Moreover, berberine suppressed Src activity in fibronectin-stimulated macrophages and in v-Src transformed cells. These results implied that by effectively reducing Src expression and activity, berberine inhibited TLR-mediated cell motility in macrophages.

  15. 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…

  16. Toll-like receptor agonists induce inflammation and cell death in a model of head and neck squamous cell carcinomas

    PubMed Central

    Rydberg, Camilla; Månsson, Anne; Uddman, Rolf; Riesbeck, Kristian; Cardell, Lars-Olaf

    2009-01-01

    Toll-like receptors (TLRs) are increasingly implicated in the pathogenesis of cancer. The present study describes TLR expression and function in healthy and malignant airway epithelial cells. The squamous cell carcinoma cell line Detroit-562 was compared with the healthy bronchial epithelial cell line NL-20 and primary human nasal epithelial cells (HNECs). TLR2, TLR3 and TLR5 were present in primary head and neck squamous cell carcinomas (HNSCCs). Consistent with this, Detroit-562 expressed TLR2, TLR3 and TLR5, whereas NL-20 expressed mainly TLR3 and HNECs expressed TLR2-5. In Detroit-562, Pam3CSK4, poly(I:C) and flagellin, ligands for TLR2, TLR3 and TLR5, respectively, induced an up-regulation of intercellular adhesion molecule 1 (ICAM-1), an increase in interleukin (IL)-6 and IL-8 secretion and a decrease in cell viability. Additionally, poly(I:C) affected IL-1β production and the migratory behaviour of Detroit-562. NL-20 responded with a slight increase in IL-8 secretion upon poly(I:C) stimulation. Poly(I:C) induced a small increase in IL-1β, IL-6 and IL-8 production in HNECs, while Pam3CSK4 increased viability. The TLR signalling was transcription-dependent, but the pathways involved differed among TLRs as well as cells. In Detroit-562, TLR2 and TLR5 activation was mediated via c-jun N-terminal kinase (JNK)-, p38-, phosphatidylinositol 3-kinase (PI3K)- and nuclear factor (NF)-κB-related pathways, while TLR3 was dependent on NF-κB. In NL-20, TLR3 signalled via p38, and in HNECs, NF-κB, JNK and extracellular signal-regulated kinase (ERK) appeared to be involved. We found that TLR agonists induced a robust response in HNSCCs, characterized by generation of inflammation and cell death. A similar response was not seen in normal epithelial cells. Thus, the TLR system should be considered an important target in future antitumour immunotherapy. PMID:19740321

  17. Science and Public Health Principles Used to Reduce Road Deaths

    PubMed Central

    2014-01-01

    An editorial in a previous issue of this journal falsely claims that the US government’s efforts to reduce road fatalities are not based on science. It says that, as a result, the United States has fallen behind other countries in road death prevention. A large body of research and evaluation informed federal and state safety programs from the outset. Evans’s comparisons of death trends among countries without adjustment for changes in relevant risk factors or specification of the injury reduction policies among the countries tell us nothing about the causes of the declines or the effects of specific ameliorative efforts. PMID:25320900

  18. Science and public health principles used to reduce road deaths.

    PubMed

    Robertson, Leon S

    2014-12-01

    An editorial in a previous issue of this journal falsely claims that the US government's efforts to reduce road fatalities are not based on science. It says that, as a result, the United States has fallen behind other countries in road death prevention. A large body of research and evaluation informed federal and state safety programs from the outset. Evans's comparisons of death trends among countries without adjustment for changes in relevant risk factors or specification of the injury reduction policies among the countries tell us nothing about the causes of the declines or the effects of specific ameliorative efforts.

  19. Toll-like receptor-5 agonist Entolimod broadens the therapeutic window of 5-fluorouracil by reducing its toxicity to normal tissues in mice.

    PubMed

    Kojouharov, Bojidar M; Brackett, Craig M; Veith, Jean M; Johnson, Christopher P; Gitlin, Ilya I; Toshkov, Ilia A; Gleiberman, Anatoli S; Gudkov, Andrei V; Burdelya, Lyudmila G

    2014-02-15

    Myelosuppression and gastrointestinal damage are common side effects of cancer treatment limiting efficacy of DNA-damaging chemotherapeutic drugs. The Toll-like receptor 5 (TLR5) agonist Entolimod has demonstrated efficacy in mitigating damage to hematopoietic and gastrointestinal tissues caused by radiation. Here, using 5-Fluorouracil (5-FU) treated mice as a model of chemotherapy-induced side effects, we demonstrated significant reduction in the severity of 5-FU-induced morbidity and increased survival accompanied by the improved integrity of intestinal tissue and stimulated the restoration of hematopoiesis. Entolimod-stimulated IL-6 production was essential for Entolimod's ability to rescue mice from death caused by doses of 5-FU associated with hematopoietic failure. In contrast, IL-6 induction was not necessary for protection and restoration of drug-damaged gastrointestinal tissue by Entolimod. In a syngeneic mouse CT26 colon adenocarcinoma model, Entolimod reduced the systemic toxicity of 5-FU, but did not reduce its antitumor efficacy indicating that the protective effect of Entolimod was selective for normal, non-tumor, tissues. These results suggest that Entolimod has clinical potential to broaden the therapeutic window of genotoxic anticancer drugs by reducing their associated hematopoietic and gastrointestinal toxicities.

  20. HIV and tuberculosis – science and implementation to turn the tide and reduce deaths

    PubMed Central

    Harries, Anthony D; Lawn, Stephen D; Getahun, Haileyesus; Zachariah, Rony; Havlir, Diane V

    2012-01-01

    Introduction Every year, HIV-associated tuberculosis (TB) deprives 350,000 mainly young people of productive and healthy lives. People die because TB is not diagnosed and treated in those with known HIV infection and HIV infection is not diagnosed in those with TB. Even in those in whom both HIV and TB are diagnosed and treated, this often happens far too late. These deficiencies can be addressed through the application of new scientific evidence and diagnostic tools. Discussion A strategy of starting antiretroviral therapy (ART) early in the course of HIV infection has the potential to considerably reduce both individual and community burden of TB and needs urgent evaluation for efficacy, feasibility and broader social and economic impact. Isoniazid preventive therapy can reduce the risk of TB and, if given strategically in addition to ART, provides synergistic benefit. Intensified TB screening as part of the “Three I's” strategy should be conducted at every clinic, home or community-based attendance using a symptoms-based algorithm, and new diagnostic tools should increasingly be used to confirm or refute TB diagnoses. Until such time when more sensitive and specific TB diagnostic assays are widely available, bolder approaches such as empirical anti-TB treatment need to be considered and evaluated. Patients with suspected or diagnosed TB must be screened for HIV and given cotrimoxazole preventive therapy and ART if HIV-positive. Three large randomized trials provide conclusive evidence that ART initiated within two to four weeks of start of anti-TB treatment saves lives, particularly in those with severe immunosuppression. The key to ensuring that these collaborative activities are delivered is the co-location and integration of TB and HIV services within the health system and the community. Conclusions Progress towards reducing HIV-associated TB deaths can be achieved through attention to simple and deliverable actions on the ground. John Donne, Meditation

  1. 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

  2. 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.

  3. 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…

  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. 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.

  6. Reducing Potentially Excess Deaths from the Five Leading Causes of Death in the Rural United States

    PubMed

    Garcia, Macarena C; Faul, Mark; Massetti, Greta; Thomas, Cheryll C; Hong, Yuling; Bauer, Ursula E; Iademarco, Michael F

    2017-01-13

    In 2014, the all-cause age-adjusted death rate in the United States reached a historic low of 724.6 per 100,000 population (1). However, mortality in rural (nonmetropolitan) areas of the United States has decreased at a much slower pace, resulting in a widening gap between rural mortality rates (830.5) and urban mortality rates (704.3) (1). During 1999–2014, annual age-adjusted death rates for the five leading causes of death in the United States (heart disease, cancer, unintentional injury, chronic lower respiratory disease (CLRD), and stroke) were higher in rural areas than in urban (metropolitan) areas (Figure 1). In most public health regions (Figure 2), the proportion of deaths among persons aged <80 years (U.S. average life expectancy) (2) from the five leading causes that were potentially excess deaths was higher in rural areas compared with urban areas (Figure 3). Several factors probably influence the rural-urban gap in potentially excess deaths from the five leading causes, many of which are associated with sociodemographic differences between rural and urban areas. Residents of rural areas in the United States tend to be older, poorer, and sicker than their urban counterparts (3). A higher proportion of the rural U.S. population reports limited physical activity because of chronic conditions than urban populations (4). Moreover, social circumstances and behaviors have an impact on mortality and potentially contribute to approximately half of the determining causes of potentially excess deaths (5).

  7. 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.

  8. Government introduces action plan to reduce deaths from sepsis.

    PubMed

    Kleebauer, Alistair

    2015-01-20

    Tackling sepsis - the potentially fatal over-reaction of the immune system to infection - must be given the same priority as reducing Clostridium difficile and MRSA infections, the government has said.

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

    MedlinePlus

    ... the National Institute of Child Health and Human Development (NICHD) to learn more about these and other actions. Creating a Safe Sleep Environment Learn more about safe sleep environments and reducing ...

  10. Absence of Toll-IL-1 receptor 8/single immunoglobulin IL-1 receptor-related molecule reduces house dust mite-induced allergic airway inflammation in mice.

    PubMed

    Barry, Jessica; Loh, Zhixuan; Collison, Adam; Mazzone, Stuart; Lalwani, Amit; Zhang, Vivian; Davidson, Sophia; Wybacz, Elisha; Garlanda, Cecilia; Mantovani, Alberto; Mattes, Joerg; Foster, Paul S; Phipps, Simon

    2013-09-01

    Allergic asthma is a chronic inflammatory disease predominately associated with the activation of CD4(+) T helper Type 2 (Th2) cells. Innate pattern recognition receptors are widely acknowledged to shape the adaptive immune response. For example, the activation of airway epithelial Toll-like receptor-4 (TLR4) is necessary for the generation of house dust mite (HDM)-specific Th2 responses and the development of asthma in mice. Here we sought to determine whether the absence of Toll-interleukin-1 receptor (TIR)-8, a negative regulator of TLR4 signaling that is highly expressed in airway epithelial cells, would exacerbate HDM-induced asthma in a murine model. We found that Th2 but not Th1 or Th17 cytokine expression was significantly reduced in the lung and draining lymph nodes in HDM-sensitized/challenged TIR8 gene-deleted mice. Mucus-producing goblet cells, HDM-specific IgG1, and airway hyperreactivity were also significantly reduced in HDM-exposed, TIR8-deficient mice. Consistent with the attenuated Th2 response, eotaxin-2/CCL24 expression and airway and peribronchial eosinophils were significantly reduced in the absence of TIR8. In contrast, IL-17A-responsive chemokines and neutrophil numbers were unaffected. Similar findings were obtained for cockroach allergen. HDM sensitization alone up-regulated the expression of IL-1F5, a putative TIR8 ligand and inducer of IL-4. Of note, innate IL-4, IL-5, IL-13, and IL-33 cytokine expression was reduced during HDM sensitization in the absence of TIR8, as was the recruitment of conventional dendritic cells and basophils to the draining lymph nodes. Our findings suggest that TIR8 enhances the development of HDM-induced innate and adaptive Th2, but not Th1 or Th17 type immunity.

  11. Can the Americans With Disabilities Act Reduce the Death Toll From Police Encounters With Persons With Mental Illness?

    PubMed

    Appelbaum, Paul S

    2015-10-01

    A substantial proportion of people shot by police have mental disorders, and many of these killings appear to have been avoidable. One tool to encourage better police training and more cautious behavior is the Americans with Disabilities Act (ADA). However, police groups oppose application of the ADA to arrests, fearing limits on their discretion, and the U.S. Supreme Court appears to favor that view. When the Court declined a recent opportunity to decide the question, it left open a window of opportunity during which the ADA can be leveraged to improve how police officers deal with persons with mental illness.

  12. 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.

  13. Reduced hepatic injury in Toll-like receptor 4-deficient mice following D-galactosamine/lipopolysaccharide-induced fulminant hepatic failure.

    PubMed

    Ben Ari, Ziv; Avlas, Orna; Pappo, Orit; Zilbermints, Veacheslav; Cheporko, Yelena; Bachmetov, Larissa; Zemel, Romy; Shainberg, Asher; Sharon, Eran; Grief, Franklin; Hochhauser, Edith

    2012-01-01

    Liver transplantation is the only therapy of proven benefit in fulminant hepatic failure (FHF). Lipopolysaccharide (LPS), D-galactosamine (GalN)-induced FHF is a well established model of liver injury in mice. Toll-Like Receptor 4 (TLR4) has been identified as a receptor for LPS. The aim of this study was to investigate the role of TLR4 in FHF induced by D-GalN/LPS administration in mice. Wild type (WT) and TLR4 deficient (TLR4ko) mice were studied in vivo in a fulminant model induced by GalN/LPS. Hepatic TLR4 expression, serum liver enzymes, hepatic and serum TNF-α and interleukin-1β levels were determined. Apoptotic cells were identified by immunohistochemistry for caspase-3. Nuclear factor-kappaβ (NF-κ β) and phosphorylated c-Jun hepatic expression were studied using Western blot analysis. All WT mice died within 24 hours after administration of GalN/LPS while all TLR4ko mice survived. Serum liver enzymes, interleukin-1β, TNF-α level, TLR4 mRNA expression, hepatic injury and hepatocyte apoptosis all significantly decreased in TLR4ko mice compared with WT mice. A significant decrease in hepatic c-Jun and IκB signaling pathway was noted in TLR4ko mice compared with WT mice. In conclusion, following induction of FHF, the inflammatory response and the liver injury in TLR4ko mice was significantly attenuated through decreased hepatic c-Jun and NF-κB expression and thus decreased TNF-α level. Down-regulation of TLR4 expression plays a pivotal role in GalN/LPS induced FHF. These findings might have important implications for the use of the anti TLR4 protein signaling as a potential target for therapeutic intervention in FHF.

  14. Myeloid cell death associated with Toll-like receptor 7/8-mediated inflammatory response. Implication of ASK1, HIF-1 alpha, IL-1 beta and TNF-alpha.

    PubMed

    Nicholas, Sally A; Oniku, Abraham E; Sumbayev, Vadim V

    2010-01-01

    Programmed cell death or apoptosis is an important part of the host innate immune defence, especially against ssRNA viruses (influenza virus, HIV-1, ebola virus, hepatitis C virus and many others). Viral ssRNA is recognised by endosomal Toll-like receptors 7 and 8 (TLR7/8) which induce further stages of immune defence against these pathogens. Some of the immune cells die because of inflammatory stress allowing for the selection of those cells which are resistant to stress-induced apoptosis and which are used in further stages of the host immune response. On the other hand, apoptosis could be used as an instrument to suppress the function of activated inflammatory cells. However, the mechanisms underlying death of the inflammatory cells associated with stress induced by ligands of TLR7/8 remain unclear. In this study we have found that programmed death of human myeloid cells from different cell lines associated with ligand-induced TLR7/8-mediated inflammatory stress depends on activation of apoptosis signal-regulating kinase 1 (ASK1). This enzyme is, however, not required for the production of pro-inflammatory cytokines - TNF-α and IL-1β. We have found that released IL-1β and TNF-α are involved in apoptosis of myeloid cells associated with TLR7/8-mediated inflammatory stress. The pro-apoptotic effect of released TNF-α in this case is much lower compared to that of IL-1β.

  15. Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E.

    PubMed

    Michelsen, Kathrin S; Wong, Michelle H; Shah, Prediman K; Zhang, Wenxuan; Yano, Juliana; Doherty, Terence M; Akira, Shizuo; Rajavashisth, Tripathi B; Arditi, Moshe

    2004-07-20

    Toll-like receptors (TLRs) and the downstream adaptor molecule myeloid differentiation factor 88 (MyD88) play an essential role in the innate immune responses. Here, we demonstrate that genetic deficiency of TLR4 or MyD88 is associated with a significant reduction of aortic plaque areas in atherosclerosis-prone apolipoprotein E-deficient mice, despite persistent hypercholesterolemia, implying an important role for the innate immune system in atherogenesis. Apolipoprotein E-deficient mice that also lacked TLR4 or MyD88 demonstrated reduced aortic atherosclerosis that was associated with reductions in circulating levels of proinflammatory cytokines IL-12 or monocyte chemoattractant protein 1, plaque lipid content, numbers of macrophage, and cyclooxygenase 2 immunoreactivity in their plaques. Endothelial-leukocyte adhesion in response to minimally modified low-density lipoprotein was reduced in aortic endothelial cells derived from MyD88-deficient mice. Taken together, our results suggest an important role for TLR4 and MyD88 signaling in atherosclerosis in a hypercholesterolemic mouse model, providing a pathophysiologic link between innate immunity, inflammation, and atherogenesis.

  16. Both intrinsic and extrinsic apoptotic pathways are involved in Toll-like receptor 4 (TLR4)-induced cell death in monocytic THP-1 cells.

    PubMed

    Liu, Bei; Sun, Ruili; Luo, Hongbo; Liu, Xueting; Jiang, Manli; Yuan, Chuang; Yang, Li; Hu, Jinyue

    2017-02-01

    Our previous study showed that TLR3 induces apoptosis via both death receptors and mitochondial in human endothelial cells. We report here that the activation of TLR4 induced dose- and time-dependent cell death in moncytic THP-1 cells. LPS treatment of THP-1 cells induced the activation of both caspase 8 and 9, suggesting the involvement of intrinsic and extrinsic apoptosis pathways. TNFα was induced by TLR4 activation at both mRNA and protein levels, but its neutralization did not down-regulated TLR4-induced cell death. TLR4 activation also induced the up-regulation of TRAIL and its receptors DR4 and DR5, and the neutralization of TRAIL ameliorated TLR4 induced apoptosis, suggesting the involvement of TRAIL and its receptors DR4 and DR5 in LPS-induced cell death. Meanwhile, LPS treatment down-regulated the expression of FLICE inhibitory protein (FLIP), a suppressor of death receptor-induced cell death. In addition, TLR4 activation down-regulated the anti-apoptotic protein bcl-2, and up-regulated the pro-apoptotic proteins Noxa and Puma, suggesting that mitochondrial apoptotic pathway was also involved in LPS-induced cell death. Furthermore, we found that TAP63α might confer to the activation of intrinsic and extrinsic apoptotic pathways. The treatment of THP-1 cells with LPS induced the translocation of TAP63α from cytoplasm to nucleus. Taken together, our study suggested that both death receptors and mitochondial were involved in TLR4-induced cell death, and TAP63α may be a target for the prevention of LPS-induced cell death.

  17. 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

  18. 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

  19. 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.

  20. 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.

  1. Minimizing fungal disease deaths will allow the UNAIDS target of reducing annual AIDS deaths below 500 000 by 2020 to be realized

    PubMed Central

    2016-01-01

    Deaths from AIDS (1 500 000 in 2013) have been falling more slowly than anticipated with improved access to antiretroviral therapy. Opportunistic infections account for most AIDS-related mortality, with a median age of death in the mid-30s. About 360 000 (24%) of AIDS deaths are attributed to tuberculosis. Fungal infections deaths in AIDS were estimated at more than 700 000 deaths (47%) annually. Rapid diagnostic tools and antifungal agents are available for these diseases and would likely have a major impact in reducing deaths. Scenarios for reduction of avoidable deaths were constructed based on published outcomes of the real-life impact of diagnostics and generic antifungal drugs to 2020. Annual deaths could fall for cryptococcal disease by 70 000, Pneumocystis pneumonia by 162 500, disseminated histoplasmosis by 48 000 and chronic pulmonary aspergillosis by 33 500, with approximately 60% coverage of diagnostics and antifungal agents; a total of >1 000 000 lives saved over 5 years. If factored in with the 90–90–90 campaign rollout and its effect, AIDS deaths could fall to 426 000 annually by 2020, with further reductions possible with increased coverage. Action could and should be taken by donors, national and international public health agencies, NGOs and governments to achieve the UNAIDS mortality reduction target, by scaling up capability to detect and treat fungal disease in AIDS. This article is part of the themed issue ‘Tackling emerging fungal threats to animal health, food security and ecosystem resilience’. PMID:28080991

  2. Minimizing fungal disease deaths will allow the UNAIDS target of reducing annual AIDS deaths below 500 000 by 2020 to be realized.

    PubMed

    Denning, David W

    2016-12-05

    Deaths from AIDS (1 500 000 in 2013) have been falling more slowly than anticipated with improved access to antiretroviral therapy. Opportunistic infections account for most AIDS-related mortality, with a median age of death in the mid-30s. About 360 000 (24%) of AIDS deaths are attributed to tuberculosis. Fungal infections deaths in AIDS were estimated at more than 700 000 deaths (47%) annually. Rapid diagnostic tools and antifungal agents are available for these diseases and would likely have a major impact in reducing deaths. Scenarios for reduction of avoidable deaths were constructed based on published outcomes of the real-life impact of diagnostics and generic antifungal drugs to 2020. Annual deaths could fall for cryptococcal disease by 70 000, Pneumocystis pneumonia by 162 500, disseminated histoplasmosis by 48 000 and chronic pulmonary aspergillosis by 33 500, with approximately 60% coverage of diagnostics and antifungal agents; a total of >1 000 000 lives saved over 5 years. If factored in with the 90-90-90 campaign rollout and its effect, AIDS deaths could fall to 426 000 annually by 2020, with further reductions possible with increased coverage. Action could and should be taken by donors, national and international public health agencies, NGOs and governments to achieve the UNAIDS mortality reduction target, by scaling up capability to detect and treat fungal disease in AIDS.This article is part of the themed issue 'Tackling emerging fungal threats to animal health, food security and ecosystem resilience'.

  3. BDNF injected into the superior colliculus reduces developmental retinal ganglion cell death.

    PubMed

    Ma, Y T; Hsieh, T; Forbes, M E; Johnson, J E; Frost, D O

    1998-03-15

    The role of neurotrophins as survival factors for developing CNS neurons, including retinal ganglion cells (RGCs), is uncertain. Null mutations for brain-derived neurotrophic factor (BDNF) or neurotrophin 4 (NT4), individually or together, are without apparent effect on the number of RGCs that survive beyond the period of normal, developmental RGC death. This contrasts with the BDNF dependence of RGCs in vitro and the effectiveness of BDNF in reducing RGC loss after axotomy. To investigate the effect of target-derived neurotrophins on the survival of developing RGCs, we injected BDNF into the superior colliculus (SC) of neonatal hamsters. At the age when the rate of developmental RGC death is greatest, BDNF produces, 20 hr after injection, a 13-15-fold reduction in the rate of RGC pyknosis compared with the rates in vehicle-injected and untreated hamsters. There is no effect 8 hr after injection. Electrochemiluminescence immunoassay measurements of BDNF protein in the retinae and SC of normal and BDNF-treated hamsters demonstrate that the time course of BDNF transport to RGCs supports a role for target-derived BDNF in promoting RGC survival. The effectiveness of pharmacological doses of BDNF in reducing developmental RGC death may be useful in further studies of the mechanisms of stabilization and elimination of immature central neurons.

  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. Sudden cardiac death in hemodialysis patients: a comprehensive care approach to reduce risk.

    PubMed

    Pun, Patrick H; Middleton, John P

    2012-01-01

    Sudden cardiac death is a major problem in hemodialysis patients, and our understanding of this disease is underdeveloped. The lack of a precise definition tailored for use in the hemodialysis population limits the reliability of epidemiologic reports. Efforts should be directed toward an accurate classification of all deaths that occur in this vulnerable population. The traditional paradigm of disease pathophysiology based on known cardiac risk factors appears to be inadequate to explain the magnitude of sudden cardiac death risk in chronic kidney disease, and numerous unique cofactors and exposures appear to determine risk in this population. Well-designed cohort studies will be needed for a basic understanding of disease pathophysiology and risk factors, and randomized intervention trials will be needed before best management practices can be implemented. This review examines available data to describe the characteristics of the high-risk patient and suggests a comprehensive common sense approach to prevention using existing cardiovascular medications and reducing and monitoring potential dialysis-related arrhythmic triggers. Other unproven cardiovascular therapies such as implantable cardioverter defibrillators should be used on a case-by-case basis, with recognition of the associated hazards that these devices carry among hemodialysis patients.

  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.

  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.

  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. Toll-Booth Purification

    NASA Technical Reports Server (NTRS)

    1977-01-01

    NASA's Technology Application Team at Stanford Research Institute searched available information and suggested a transfer of clean-room technology employing the use of the same laminar flow techniques found in environmental control systems of clean rooms used for contamination-free assembly of precision aerospace equipment. That information, from technology originally developed by NASA and the Energy Research & Development Administration was incorporated in the design of a prototype toll booth purifier. The draft-free design includes a "diffusor", which blows clean air out the toll booth doorway, thus retarding the infiltration of contaminated air. The net effect is a decrease in the toll collector's inhalation of exhaust fumes. The Washington Department of Highways installed the prototype system in a toll booth at the Evergreen Point Bridge near Seattle. After a successful two-year test, the department now has equipped all 10 of the bridge's toll booths with the air purifiers.

  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.

  11. Cabergoline, dopamine D2 receptor agonist, prevents neuronal cell death under oxidative stress via reducing excitotoxicity.

    PubMed

    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.

  12. Moraxella catarrhalis activates murine macrophages through multiple toll like receptors and has reduced clearance in lungs from TLR4 mutant mice.

    PubMed

    Hassan, Ferdaus; Ren, Dabin; Zhang, Wenhong; Merkel, Tod J; Gu, Xin-Xing

    2012-01-01

    Moraxella catarrhalis is a gram negative bacterium and a leading causative agent of otitis media (OM) in children. Several recent reports have provided strong evidence for an association between toll like receptors and OM. It has been found that both Streptococcus pneumoniae and nontypeable Haemophilus influenzae activate host protective immune responses through toll like receptors (TLRs), however, the precise mechanism by which Moraxella catarrhalis initiates the host immune response is currently unknown. In this report, using murine macrophages generated from a series of knock-out mice, we have demonstrated that M. catarrhalis lipooligosaccharide (LOS) and either heat killed or live bacteria are recognized by one or more TLRs. LOS activates the host immune response through a membrane bound CD14-TLR4 complex, while both heat killed and live M.cat require recognition by multiple toll like receptors such as TLR2, TLR4 and TLR9 without the requirement of CD14. We have also shown that M.cat stimuli are capable of triggering the host innate immune response by both MyD88- and TRIF- dependent signaling pathways. We further showed that M.cat induced activation of mitogen activated protein kinase (MAPK) is essential in order to achieve optimal secretion of pro-inflammatory cytokine TNF-α. We finally showed that TLR4 mutant C3H/HeJ mice produce significantly lower levels of pro-inflammatory cytokines TNF-α and IL-6 in vivo, An increased bacterial loads at 12 and 24 hours (P<0.001) in their lungs upon challenge with live M.cat in an aerosol chamber compared to wild-type (WT) control mice. These data suggest that TLRs are crucial for an effective innate immune response induced by M.cat. The results of these studies contribute to an increased understanding of molecular mechanism and possible novel treatment strategies for diseases caused by M.cat by specifically targeting TLRs and their signaling pathways.

  13. Nicotinamide reduces acute cortical neuronal death and edema in the traumatically injured brain.

    PubMed

    Hoane, Michael R; Gilbert, David R; Holland, Michael A; Pierce, Jeremy L

    2006-11-06

    Previous studies have shown that administration of nicotinamide (Vitamin B(3)) in animal models of traumatic brain injury (TBI) and ischemia significantly reduced the size of infarction or injury and improved functional recovery. The present study evaluated the ability of nicotinamide to provide acute neuroprotection and edema reduction following TBI. Groups of rats were assigned to nicotinamide (500mg/kg) or saline (1.0ml/kg) treatment conditions and received contusion injuries or sham surgeries. Drug treatment was administered 15min following injury. Brains were harvested 24h later and either processed for histology or water content. Frozen sections were stained with the degenerating neuron stain (Fluoro-Jade B) (FJ) and cell counts were performed at the site of injury. Additional brains were processed for water content (a measure of injury-induced edema). Results of this study showed that administration of nicotinamide following TBI significantly reduced the number of FJ(+) neurons in the injured cortex compared to saline-treated animals. Examination of the water content of the brains also revealed that administration of nicotinamide significantly attenuated the amount of water compared to saline-treated animals in the injured cortex. These results indicate that nicotinamide administration significantly reduced neuronal death and attenuated cerebral edema following injury. The current findings suggest that nicotinamide significantly modulates acute pathophysiological processes following injury and that this may account for its beneficial effects on recovery of function following injury.

  14. Ways To Reduce the Risk of SIDS and Other Sleep-Related Causes of Infant Death

    MedlinePlus

    ... SIDS and Other Sleep-Related Causes of Infant Death Page Content Research shows that there are several ... SIDS and other sleep-related causes of infant death: The actions listed here and in Safe to ...

  15. 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.

  16. 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…

  17. 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

  18. 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

  19. Reducing Maternal Deaths in Ethiopia: Results of an Intervention Programme in Southwest Ethiopia

    PubMed Central

    Mitiku, Demissew; Zidda, Zillo; Yaya, Yaliso

    2017-01-01

    Background In a large population in Southwest Ethiopia (population 700,000), we carried out a complex set of interventions with the aim of reducing maternal mortality. This study evaluated the effects of several coordinated interventions to help improve effective coverage and reduce maternal deaths. Together with the Ministry of Health in Ethiopia, we designed a project to strengthen the health-care system. A particular emphasis was given to upgrade existing institutions so that they could carry out Basic (BEmOC) and Comprehensive Emergency Obstetric Care (CEmOC). Health institutions were upgraded by training non-clinical physicians and midwives by providing the institutions with essential and basic equipment, and by regular monitoring and supervision by staff competent in emergency obstetric work. Results In this implementation study, the maternal mortality ratio (MMR) was the primary outcome. The study was carried out from 2010 to 2013 in three districts, and we registered 38,312 births. The MMR declined by 64% during the intervention period from 477 to 219 deaths per 100,000 live births (OR 0.46; 95% CI 0.24–0.88). The decline in MMR was higher for the districts with CEmOC, while the mean number of antenatal visits for each woman was 2.6 (Inter Quartile Range 2–4). The percentage of pregnant women who attended four or more antenatal controls increased by 20%, with the number of women who delivered at home declining by 10.5% (P<0.001). Similarly, the number of deliveries at health posts, health centres and hospitals increased, and we observed a decline in the use of traditional birth attendants. Households living near to all-weather roads had lower maternal mortality rates (MMR 220) compared with households without roads (MMR 598; OR 2.72 (95% CI 1.61–4.61)). Conclusions Our results show that it is possible to achieve substantial reductions in maternal mortality rates over a short period of time if the effective coverage of well-known interventions is

  20. Mandatory Provider Review And Pain Clinic Laws Reduce The Amounts Of Opioids Prescribed And Overdose Death Rates.

    PubMed

    Dowell, Deborah; Zhang, Kun; Noonan, Rita K; Hockenberry, Jason M

    2016-10-01

    To address the opioid overdose epidemic in the United States, states have implemented policies to reduce inappropriate opioid prescribing. These policies could affect the coincident heroin overdose epidemic by either driving the substitution of heroin for opioids or reducing simultaneous use of both substances. We used IMS Health's National Prescription Audit and government mortality data to examine the effect of these policies on opioid prescribing and on prescription opioid and heroin overdose death rates in the United States during 2006-13. The analysis revealed that combined implementation of mandated provider review of state-run prescription drug monitoring program data and pain clinic laws reduced opioid amounts prescribed by 8 percent and prescription opioid overdose death rates by 12 percent. We also observed relatively large but statistically insignificant reductions in heroin overdose death rates after implementation of these policies. This combination of policies was effective, but broader approaches to address these coincident epidemics are needed.

  1. Reducing Avoidable Deaths Among Veterans: Directing Private-Sector Surgical Care to High-Performance Hospitals

    PubMed Central

    Weeks, William B.; West, Alan N.; Wallace, Amy E.; Lee, Richard E.; Goodman, David C.; Dimick, Justin B.; Bagian, James P.

    2007-01-01

    Objectives. We quantified older (65 years and older) Veterans Health Administration (VHA) patients’ use of the private sector to obtain 14 surgical procedures and assessed the potential impact of directing that care to high-performance hospitals. Methods. Using a merged VHA–Medicare inpatient database for 2000 and 2001, we determined where older VHA enrollees obtained 6 cardiovascular surgeries and 8 cancer resections and whether private-sector care was obtained in high- or low-performance hospitals (based on historical performance and determined 2 years in advance of the service year). We then modeled the mortality and travel burden effect of directing private-sector care to high-performance hospitals. Results. Older veterans obtained most of their procedures in the private sector, but that care was equally distributed across high- and low-performance hospitals. Directing private-sector care to high-performance hospitals could have led to the avoidance of 376 to 584 deaths, most through improved cardiovascular care outcomes. Using historical mortality to define performance would produce better outcomes with lower travel time. Conclusions. Policy that directs older VHA enrollees’ private-sector care to high-performance hospitals promises to reduce mortality for VHA’s service population and warrants further exploration. PMID:17971543

  2. Uganda study found that death reduced HIV prevalence; did the public take home the wrong message?

    PubMed

    James, John S

    2005-02-25

    Uganda has had a remarkable decline in HIV prevalence, and the question of what caused this decline is controversial. An intensive study of the Rakai region of Uganda from 1994 - 2003 found that much of the decreased prevalence resulted from death of people with HIV. But the incidence of new HIV infections was low throughout this study and did not change greatly, suggesting that the real cause of the success was a large reduction in new infections before the study began. The early data presented at the February 2005 Retroviruses conference also showed increasing use of condoms, and some backsliding on reducing the number of sexual partners. But neither change was big enough to greatly affect the incidence of new infections, at least in the aggregate data across the 50 villages studied. In summary, the big reduction in HIV prevalence occurred because of changes that happened before this study, not those measured within it. Therefore the new information does not contradict reduction in the number of sexual partners as a major cause of Uganda's success.

  3. 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.

  4. Erdosteine protects rat testis tissue from hypoxic injury by reducing apoptotic cell death.

    PubMed

    Guven, A; Ickin, M; Uzun, O; Bakar, C; Balbay, E Gulec; Balbay, O

    2014-02-01

    The purpose of this study was to examine the effects of hypobaric hypoxia on testis morphology and the effects of erdosteine on testis tissue. Caspase-3 and hypoxia-inducible factor 1α expressions were detected by immunohistochemistry. Adult male Wistar rats were placed in a hypobaric hypoxic chamber. Rats in the erdosteine group were exposed to the same conditions and treated orally with erdosteine (20 mg kg(-1) daily) at the same time from the first day of hypoxic exposure for 2 weeks. The normoxia group was evaluated as the control. The hypoxia group showed decreased height of spermatogenic epithelium in some seminiferous tubules, vacuolisation in spermatogenic epithelial cells, deterioration and gaps in the basal membrane and an increase in blood vessels in the interstitial area. The erdosteine group showed amelioration of both epithelial cell vacuolisation and basal membrane deterioration. Numbers of hypoxia-inducible factor 1α-immunostained Sertoli and Leydig cells were significantly higher in the hypoxia group than in the erdosteine group. The number of seminiferous tubules with caspase-3-immunostained germ cells was highest in the hypoxia group and decreased in the erdosteine and normoxia groups respectively. Based on these observations, erdosteine protects testis tissue from hypoxic injury by reducing apoptotic cell death.

  5. Glutathione administration reduces mitochondrial damage and shifts cell death from necrosis to apoptosis in ageing diabetic mice hearts during exercise

    PubMed Central

    Golbidi, S; Botta, A; Gottfred, S; Nusrat, A; Laher, I; Ghosh, S

    2014-01-01

    Background and Purpose The effect of antioxidants on ageing type 2 diabetic (T2D) hearts during exercise is unclear. We hypothesized that GSH therapy during exercise reduces mitochondrial oxidative stress (mOXS) and cell death in ageing db/db mice hearts. Experimental Approach The effect of GSH on cardiac mOXS and cell death was evaluated both in vivo and in vitro. Key Results During exercise, GSH treatment protected db/db hearts from exaggerated mOXS without reducing total cell death. Despite similar cell death, investigations on apoptosis-specific single-stranded DNA breaks and necrosis-specific damage provided the first in vivo evidence of a shift from necrosis to apoptosis, with reduced fibrosis following GSH administration in exercised db/db hearts. Further support for a GSH-regulated ‘switch’ in death phenotypes came from NIH-3T3 fibroblasts and H9c2 cardiomyocytes treated with H2O2, a reactive oxygen species (ROS). Similar to in vivo findings, augmenting GSH by overexpressing glutamyl cysteine ligase (GCLc) protected fibroblasts and cardiomyocytes from necrosis induced by H2O2, but elevated caspase-3 and apoptosis instead. Similar to in vivo findings, where GSH therapy in normoglycaemic mice suppressed endogenous antioxidants and augmented caspase-3 activity, GCLc overexpression during staurosporine-induced death, which was not characterized by ROS, increased GSH efflux and aggravated death in fibroblasts and cardiomyocytes, confirming that oxidative stress is required for GSH-mediated cytoprotection. Conclusions and Implications While GSH treatment is useful for reducing mOXS and attenuating necrosis and fibrosis in ageing T2D hearts during exercise, such antioxidant treatment could be counterproductive in the healthy heart during exercise. PMID:25039894

  6. 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.

  7. Potential Impact of Graphic Health Warnings on Cigarette Packages in Reducing Cigarette Demand and Smoking-Related Deaths in Vietnam.

    PubMed

    Minh, Hoang Van; Chung, Le Hong; Giang, Kim Bao; Duc, Duong Minh; Hinh, Nguyen Duc; Mai, Vu Quynh; Cuong, Nguyen Manh; Manh, Pham Duc; Duc, Ha Anh; Yang, Jui-Chen

    2016-01-01

    Two years after implementation of the graphic health warning intervention in Vietnam, it is very important to evaluate the intervention's potential impact. The objective of this paper was to predict effects of graphic health warnings on cigarette packages, particularly in reducing cigarette demand and smoking-associated deaths in Vietnam. In this study, a discrete choice experiment (DCE) method was used to evaluate the potential impact of graphic tobacco health warnings on smoking demand. To predict the impact of GHWs on reducing premature deaths associated with smoking, we constructed different static models. We adapted the method developed by University of Toronto, Canada and found that GHWs had statistically significant impact on reducing cigarette demand (up to 10.1% through images of lung damage), resulting in an overall decrease of smoking prevalence in Vietnam. We also found that between 428,417- 646,098 premature deaths would be prevented as a result of the GHW intervention. The potential impact of the GHW labels on reducing premature smoking-associated deaths in Vietnam were shown to be stronger among lower socio-economic groups.

  8. Connexin43 mimetic peptide reduces vascular leak and retinal ganglion cell death following retinal ischaemia.

    PubMed

    Danesh-Meyer, Helen V; Kerr, Nathan M; Zhang, Jie; Eady, Elizabeth K; O'Carroll, Simon J; Nicholson, Louise F B; Johnson, Cameron S; Green, Colin R

    2012-02-01

    significantly reduced dye leak at 4 and 24 h. In vitro studies on endothelial cells demonstrate that endothelial cell death following hypoxia can be mediated directly by opening of connexin43 hemichannels in endothelial cells. Blocking connexin43 mediated vascular leakage using a connexin43 mimetic peptide led to increased retinal ganglion cell survival at 7 and 21 days to levels of uninjured retinas. Treatment with scrambled peptide did not result in retinal ganglion cell rescue. Pharmacological targeting of connexin43 gap junction protein by transiently blocking gap junction hemichannels following injury provides new opportunities for treatment of central nervous system ischaemia.

  9. 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…

  10. 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.

  11. 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. |

  12. An Evidence-Based Infant Safe Sleep Program to Reduce Sudden Unexplained Infant Deaths.

    PubMed

    Zachritz, Whitney; Fulmer, Megan; Chaney, Nicole

    2016-11-01

    : Objective: The purpose of this project was to design, implement, and evaluate a safe sleep program for expectant mothers and the families of infants discharged from our hospital's neonatal intensive care unit (NICU). It was prompted by the sleep-related deaths of two infants in the community, both of whom had been discharged from our NICU.

  13. Can addressing death anxiety reduce health care workers' burnout and improve patient care?

    PubMed

    Melo, Carol Gouveia; Oliver, David

    2011-01-01

    Death anxiety may interfere with health care workers' (HCWs) relationships with patients and patients' families and increase HCWs' levels of burnout. This study shows the impact of a six-day course for HCWs that provided training in communication, in offering emotional and spiritual support to patients, and in personal introspection on death anxiety. The HCWs were given questionnaires to evaluate their level of burnout, personal well-being, and death anxiety as well as the quality of their relationships with patients before the course and four months after it. There were 150 study participants, all HCWs involved in caring for dying patients (85 in palliative care units and 65 in other settings). There was a control group of 26 HCWs who cared for the dying in settings other than palliative care units. The results show that the course appeared to lead to a significant reduction in levels of burnout and death anxiety; they also indicated an increase in personal well-being and professional fulfillment, and participants perceived an improvement in the quality of their relationships with patients and patients' families.

  14. 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

  15. A Virtual Out-of-Body Experience Reduces Fear of Death

    PubMed Central

    2017-01-01

    Immersive virtual reality can be used to visually substitute a person’s real body by a life-sized virtual body (VB) that is seen from first person perspective. Using real-time motion capture the VB can be programmed to move synchronously with the real body (visuomotor synchrony), and also virtual objects seen to strike the VB can be felt through corresponding vibrotactile stimulation on the actual body (visuotactile synchrony). This setup typically gives rise to a strong perceptual illusion of ownership over the VB. When the viewpoint is lifted up and out of the VB so that it is seen below this may result in an out-of-body experience (OBE). In a two-factor between-groups experiment with 16 female participants per group we tested how fear of death might be influenced by two different methods for producing an OBE. In an initial embodiment phase where both groups experienced the same multisensory stimuli there was a strong feeling of body ownership. Then the viewpoint was lifted up and behind the VB. In the experimental group once the viewpoint was out of the VB there was no further connection with it (no visuomotor or visuotactile synchrony). In a control condition, although the viewpoint was in the identical place as in the experimental group, visuomotor and visuotactile synchrony continued. While both groups reported high scores on a question about their OBE illusion, the experimental group had a greater feeling of disownership towards the VB below compared to the control group, in line with previous findings. Fear of death in the experimental group was found to be lower than in the control group. This is in line with previous reports that naturally occurring OBEs are often associated with enhanced belief in life after death. PMID:28068368

  16. Toll road crashes of commercial and passenger motor vehicles.

    PubMed

    Braver, Elisa R; Solomon, Mark G; Preusser, David F

    2002-05-01

    Revenue-collection data from toll roads allow for accurate estimates of miles driven by vehicle type and, when combined with crash data, valid estimates of crash involvements per mile driven. Data on vehicle-miles traveled and collisions were obtained from toll road authorities in Florida. Kansas, and New York. In addition, state crash files and published vehicle-miles of travel were obtained for toll roads in Illinois. Indiana, Ohio, and Pennsylvania. Large commercial motor vehicles were significantly underinvolved in single-vehicle crashes on all state toll roads. In five states, commercial motor vehicles were significantly overinvolved in multiple-vehicle crashes relative to passenger vehicles; the exceptions were Kansas, where they had significantly lower multiple-vehicle involvement rates, and Indiana. where there were no significant differences in multiple-vehicle involvements by vehicle type. The risk of commercial motor vehicle involvement in multiple-vehicle crashes resulting in deaths or serious injuries was double that of passenger vehicles in the two states (Ohio and Pennsylvania) that identified serious injuries. Whether crash rates, on toll roads of commercial motor vehicles are higher or lower than those of passenger vehicles appears to depend on the type of crash, specific toll road. and traffic density.

  17. 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.

  18. Using Item Response Theory (IRT) to Reduce Patient Burden When Assessing Desire for Hastened Death.

    PubMed

    Kolva, Elissa; Rosenfeld, Barry; Liu, Ying; Pessin, Hayley; Breitbart, William

    2016-06-09

    Desire for hastened death (DHD) represents a wish to die sooner than might occur by natural disease progression. Efficient and accurate assessment of DHD is vital for clinicians providing care to terminally ill patients. The Schedule of Attitudes Toward Hastened Death (SAHD) is a commonly used self-report measure of DHD. The goal of this study was to use methods grounded in item response theory (IRT) to analyze the psychometric properties of the SAHD and identify an abbreviated version of the scale. Data were drawn from 4 studies of psychological distress at the end of life. Participants were 1,076 patients diagnosed with either advanced cancer or AIDS. The sample was divided into 2 subsamples for scale analysis and development of the shortened form. IRT was used to estimate item parameters. A 6-item version of the SAHD (SAHD-A) was identified through examination of item parameter estimations. The SAHD-A demonstrated adequate convergent validity. Receiver operating characteristic analyses indicated comparable cut scores to identify patients with high levels of DHD. These analyses support the utility of the SAHD-A, which can be more easily integrated into research studies and clinical assessments of DHD. (PsycINFO Database Record

  19. The common pain of surrealism and death: acetaminophen reduces compensatory affirmation following meaning threats.

    PubMed

    Randles, Daniel; Heine, Steven J; Santos, Nathan

    2013-06-01

    The meaning-maintenance model posits that any violation of expectations leads to an affective experience that motivates compensatory affirmation. We explore whether the neural mechanism that responds to meaning threats can be inhibited by acetaminophen, in the same way that acetaminophen inhibits physical pain or the distress caused by social rejection. In two studies, participants received either acetaminophen or a placebo and were provided with either an unsettling experience or a control experience. In Study 1, participants wrote about either their death or a control topic. In Study 2, participants watched either a surrealist film clip or a control film clip. In both studies, participants in the meaning-threat condition who had taken a placebo showed typical compensatory affirmations by becoming more punitive toward lawbreakers, whereas those who had taken acetaminophen, and those in the control conditions, did not.

  20. bcl-2 Overexpression Reduces Apoptotic Photoreceptor Cell Death in Three Different Retinal Degenerations

    NASA Astrophysics Data System (ADS)

    Chen, Jeannie; Flannery, John G.; Lavail, Matthew M.; Steinberg, Roy H.; Xu, Jun; Simon, Melvin I.

    1996-07-01

    Apoptosis of photoreceptors occurs infrequently in adult retina but can be triggered in inherited and environmentally induced retinal degenerations. The protooncogene bcl-2 is known to be a potent regulator of cell survival in neurons. We created lines of transgenic mice overexpressing bcl-2 to test for its ability to increase photoreceptor survival. Bcl-2 increased photoreceptor survival in mice with retinal degeneration caused by a defective opsin or cGMP phosphodiesterase. Overexpression of Bcl-2 in normal photoreceptors also decreased the damaging effects of constant light exposure. Apoptosis was induced in normal photoreceptors by very high levels of bcl-2. We conclude that bcl-2 is an important regulator of photoreceptor cell death in retinal degenerations.

  1. [Being in motion reduces the risk of disease and premature death].

    PubMed

    Henriksson, Jan; Sundberg, Carl Johan

    2015-11-17

    Regular physical activity affects most organs and tissues through a large number of mechanisms which in various ways contribute to improved function and health. Regular physical activity improves quality of life, cognitive functions, mood state and physical capacity, and lowers the risk of many diseases and premature death. Physical activity affects proteins and gene expression through signalling mechanisms, e.g. epigenetic changes. The biological response to physical activity can be markedly different between individuals, to a large degree due to genetic mechanisms. Regular aerobic physical activity (endurance training) improves cardiac function, partly due to an increased stroke volume, and lowers blood pressure due to e.g. improved vasodilation, lower arterial stiffness and increased capillarisation. Regular physical activity helps to maintain muscle mass and function and can improve brain health and function, e.g. executive and memory functions.

  2. 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.

  3. Cathelicidin Antimicrobial Peptides with Reduced Activation of Toll-Like Receptor Signaling Have Potent Bactericidal Activity against Colistin-Resistant Bacteria

    PubMed Central

    Lin, Xiaoyan; Yi, Guanghui; Zhang, Yunliang; Rowe-Magnus, Dean A.; Bush, Karen

    2016-01-01

    ABSTRACT The world is at the precipice of a postantibiotic era in which medical procedures and minor injuries can result in bacterial infections that are no longer effectively treated by antibiotics. Cathelicidins are peptides produced by animals to combat bacterial infections and to regulate innate immune responses. However, cathelicidins are potent activators of the inflammatory response. Cathelicidins with reduced proinflammatory activity and potent bactericidal activity in the low micromolar range against Gram-negative bacteria have been identified. Motifs in cathelicidins that impact bactericidal activity and cytotoxicity to human cells have been elucidated and used to generate peptides that have reduced activation of proinflammatory cytokine production and reduced cytotoxicity to human cells. The resultant peptides have bactericidal activities comparable to that of colistin and can kill colistin-resistant bacteria. PMID:27651360

  4. RAGE on the Toll Road?

    PubMed

    Lin, Li

    2006-10-01

    Mammalian Toll-like receptors (TLRs) are cellular pattern-recognizing receptors (PRRs) that recognize the molecular patterns of pathogens. After engaging the pathogenic patterned ligands, the cytosolic portion of the TLRs in monocytes and macrophages, recruits adaptor proteins, via a receptor-driven signaling cascade, activates the transcription factor NF-kappaB, leading to the expression of proinflammatory cytokines, which trigger inflammation. Such rapid, innate cellular responses serve as the first line of host defense against infection by pathogens, and also stimulate the adaptive immune system to clear the invading microbes. Increasing evidence suggests that TLRs also recognize host-derived ligands, linking this group of PRRs to diseases that may not have an etiology that is associated directly with infections. Advanced glycation end products (AGEs) are nonenzymatically glycated or oxidated proteins, lipids and nucleic acids that are formed in the environment of oxidant stress and hyperglycemia. Binding of AGEs to their receptor RAGE initiates cellular signals that activate NF-kappaB, which results in transcription of proinflammatory factors. RAGE can also interact with other endogenous ligands generated by cell death and tissue injuries. RAGE has been implicated in chronic diseases such as diabetes, atherosclerosis, neurodisorders, cancers, as well as aging. This review discusses the possible role of RAGE as a PRR that may use signaling mechanisms parallel to TLRs', to solicit inflammatory reactions. Thus, in this scenario, RAGE may play a prominent role in the regulation of cellular homeostasis in the context of complex disease progression.

  5. 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

  6. 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.

  7. 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

  8. Reduced Ca2+ entry and suicidal death of erythrocytes in PDK1 hypomorphic mice.

    PubMed

    Föller, Michael; Mahmud, Hasan; Koka, Saisudha; Lang, Florian

    2008-02-01

    The phosphoinositide-dependent kinase PDK1 is a key element in the phosphoinositol-3-kinase signalling pathway, which is involved in the regulation of ion channels, transporters, cell volume and cell survival. Eryptosis, the suicidal death of erythrocytes, is characterized by decrease in cell volume, cell membrane blebbing and phospholipids scrambling with phosphatidylserine exposure at the cell surface. Oxidative stress, osmotic shock or Cl- removal trigger eryptosis by activation of Ca2+-permeable cation channels and subsequent increase in cytosolic Ca2+ activity. To explore the impact of PDK1 for erythrocyte survival, eryptosis was analysed in hypomorphic mice (pdk1hm) expressing only some 25% of PDK1 and in their wild-type littermates (pdk1wt). Cell volume was estimated from forward scatter and phosphatidylserine exposure from annexin-V binding in fluorescence activated cell sorter analysis. Forward scatter was smaller in pdk1hm than in pdk1wt erythrocytes. Oxidative stress (100 microM tert-butylhydroperoxide), osmotic shock (+300 mM sucrose) and Cl- removal (replacement of Cl- with gluconate) all decreased forward scatter and increased the percentage of annexin-V-binding erythrocytes from both pdk1hm and pdk1wt mice. After treatment, the forward scatter was similar in both genotypes, but the percentage of annexin-V binding was significantly smaller in pdk1hm than in pdk1wt erythrocytes. According to Fluo-3 fluorescence, cytosolic Ca2+ activity was significantly smaller in pdk1hm than in pdk1wt erythrocytes. Treatment with Ca2+-ionophore ionomycin (1 microM) was followed by an increase in annexin-V binding to similar levels in pdk1hm and pdk1wt erythrocytes. The experiments reveal that PDK1 deficiency is associated with decreased Ca2+ entry into erythrocytes and thus with blunted eryptotic effects of oxidative stress, osmotic shock and Cl- removal.

  9. Radiation takes its Toll

    PubMed Central

    Ratikan, Josephine A.; Micewicz, Ewa D.; Xie, Michael W.; Schaue, Dörthe

    2015-01-01

    The ability to recognize and respond to universal molecular patterns on invading microorganisms allows our immune system to stay on high alert, sensing danger to our self-integrity. Our own damaged cells and tissues in pathological situations activate similar warning systems as microbes. In this way, the body is able to mount a response that is appropriate to the danger. Toll-like receptors are at the heart of this pattern recognition system that initiates innate pro-oxidant, pro-inflammatory signaling cascades and ultimately bridges recognition of danger to adaptive immunity. The acute inflammatory lesions that are formed segue into resolution of inflammation, repair and healing or, more dysfunctionally, into chronic inflammation, autoimmunity, excessive tissue damage and carcinogenesis. Redox is at the nexus of this decision making process and is the point at which ionizing radiation initially intercepts to trigger similar responses to self-damage. In this review we discuss our current understanding of how radiation-damaged cells interact with Toll-like receptors and how the immune systems interprets these radiation-induced danger signals in the context of whole-body exposures and during local tumor irradiation. PMID:25819030

  10. 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

  11. Metallothionein treatment reduces proinflammatory cytokines IL-6 and TNF-alpha and apoptotic cell death during experimental autoimmune encephalomyelitis (EAE).

    PubMed

    Penkowa, M; Hidalgo, J

    2001-07-01

    Experimental autoimmune encephalomyelitis (EAE) is an animal model for the human autoimmune disease multiple sclerosis (MS). Proinflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) are considered important for induction and pathogenesis of EAE/MS disease, which is characterized by significant inflammation and neuroglial damage. We have recently shown that the exogenous administration of the antioxidant protein zinc-metallothionein-II (Zn-MT-II) significantly decreased the clinical symptoms, mortality, and leukocyte infiltration of the CNS during EAE. However, it is not known how EAE progression is regulated nor how cytokine production and cell death can be reduced. We herewith demonstrate that treatment with Zn-MT-II significantly decreased the CNS expression of IL-6 and TNF-alpha during EAE. Zn-MT-II treatment could also significantly reduce apoptotic cell death of neurons and oligodendrocytes during EAE, as judged by using TUNEL and immunoreactivity for cytochrome c and caspases 1 and 3. In contrast, the number of apoptotic lymphocytes and macrophages was less affected by Zn-MT-II treatment. The Zn-MT-II-induced decrease in proinflammatory cytokines and apoptosis during EAE could contribute to the reported diminution of clinical symptoms and mortality in EAE-immunized rats receiving Zn-MT-II treatment. Our results demonstrate that MT-II reduces the CNS expression of proinflammatory cytokines and the number of apoptotic neurons during EAE in vivo and that MT-II might be a potentially useful factor for treatment of EAE/MS.

  12. Effect of Statin Therapy in Reducing the Risk of Serious Non-AIDS-Defining Events and Nonaccidental Death

    PubMed Central

    Overton, E. T.; Kitch, D.; Benson, C. A.; Hunt, P. W.; Stein, J. H.; Smurzynski, M.; Ribaudo, H. J.; Tebas, P.

    2013-01-01

    Background. Excessive inflammation persists despite antiretroviral treatment. Statins decrease cardiovascular (CV) disease risk by reducing low-density lipoprotein cholesterol and inflammation. We performed an exploratory analysis to evaluate whether statin therapy decreased risk of non-AIDS-defining events and nonaccidental death. Methods. A total of 3601 subjects not on a statin from the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials cohort were included. Outcome was time to first clinical event (CV event, renal or hepatic disease, incident diabetes, thrombotic/embolic event, nontraumatic fracture, non-AIDS-defining malignancy, serious bacterial infection, or nonaccidental death); event categories were also analyzed separately. Inverse probability of treatment and censoring weighted Cox proportional hazard models were used to assess the causal statin effect. Differential statin effects by baseline covariates were evaluated. Results. Over 15 135 person-years (PY) of follow-up, 484 subjects initiated statins; 616 experienced an event (crude event rate, 4.4/100 PY on a statin and 4.1/100 PY not on a statin); the unadjusted hazard ratio (HR) was 1.17 (95% confidence interval [CI], .91–1.50). In a final weighted model, the adjusted HR (AHR) was 0.81 (95% CI, .53– 1.24). Results for other clinical events were similar, except for malignancies (AHR, 0.43 [95% CI, .19–.94]) and bacterial infections (AHR, 1.30 [95% CI, .64–2.65]). No differential statin effects by baseline covariates were detected. Conclusions. Although statin therapy was not associated with a reduction in time to all non-AIDS-defining event or nonaccidental death, it was associated with a statistically significant 57% reduction in non-AIDS-defining malignancies. Confirmatory studies are needed to evaluate statin-associated reduction in risk of cancer and non-AIDS-associated morbidities. PMID:23386631

  13. Davunetide (NAP) protects the retina against early diabetic injury by reducing apoptotic death.

    PubMed

    Scuderi, Soraya; D'Amico, Agata Grazia; Castorina, Alessandro; Federico, Concetta; Marrazzo, Giuseppina; Drago, Filippo; Bucolo, Claudio; D'Agata, Velia

    2014-11-01

    Davunetide (NAP) is an eight amino acid peptide that has been shown to provide potent neuroprotection. In the present study, we investigated the neuroprotective effect of NAP in diabetic retinopathy using an in vivo streptozotocin (STZ)-induced diabetic model. A single intraocular injection of NAP (100 μg/mL) or vehicle was administered 1 week after STZ injection. Three weeks after diabetes induction, we assessed the retinal expression and distribution of apoptosis markers, cleaved caspase-3, and Bcl2, by Western blot and immunofluorescent analysis. Furthermore, we evaluated the activation of mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) and/or phosphatidylinositol-3 kinase/Akt pathways by measuring the protein levels of p-ERK and p-AKT with or without NAP treatment. Results demonstrated that NAP treatment reduced apoptotic event in diabetic retina, and it restored cleaved caspase-3 expression levels in the retina of STZ-injected rats as well as the decreased Bcl2. NAP treatment improved cellular survival through the activation of the MAPK/ERK pathway. Taken together, these findings suggested that NAP might be useful to treat retinal degenerative diseases.

  14. Axin expression reduces staurosporine-induced mitochondria-mediated cell death in HeLa cells.

    PubMed

    Shin, Jee-Hye; Kim, Hyun-wook; Rhyu, Im Joo; Song, Ki-Joon; Kee, Sun-Ho

    2012-10-01

    Cytoplasmic axin expression frequently produces punctuate structures in cells, but the nature of axin puncta has not been fully elucidated. In an effort to analyze cytoplasmic axin puncta, we established HeLa cells expressing axin in a doxycycline-inducible manner (HeLa-Axin). We observed that axin accumulated in an aggregate-like pattern in perinuclear areas and appeared to be associated with mitochondria, Golgi apparatus, and endoplasmic reticulum (ER), but not lysosomes. Further biochemical analysis suggested that some part of the cytoplasmic axin pool was associated with mitochondria. In addition, mitochondrial proteins [i.e., cytochrome oxidase IV (CoxIV) and cytochrome c] were slightly higher in HeLa-Axin cells than in HeLa-EV cells, suggesting altered mitochondrial degradation. HeLa-Axin cells were then treated with staurosporine (STS) to determine if the mitochondria-induced apoptosis pathway was altered. Compared to STS-treated control cells (HeLa-EV), HeLa-Axin cells had less STS-induced cytotoxicity and reduced caspase-3 activation and PARP cleavage. Given that mitochondria outer membrane potential was unchanged, HeLa-Axin cells might be relatively resistant to STS-mediated mitochondrial damage. Mitochondria associated with axin aggregates were resistant to detergent-mediated permeabilization. These results suggest that axin forms aggregate-like structures in association with mitochondria, which render mitochondria resistant to STS-induced membrane damage and cytotoxicity.

  15. Reduced Frequency of a CD14+ CD16+ Monocyte Subset with High Toll-Like Receptor 4 Expression in Cord Blood Compared to Adult Blood Contributes to Lipopolysaccharide Hyporesponsiveness in Newborns

    PubMed Central

    Pedraza-Sánchez, Sigifredo; Hise, Amy G.; Ramachandra, Lakshmi; Arechavaleta-Velasco, Fabian

    2013-01-01

    The human innate immune response to pathogens is not fully effective and mature until well into childhood, as exemplified by various responses to Toll-like receptor (TLR) agonists in newborns compared to adults. To better understand the mechanistic basis for this age-related difference in innate immunity, we compared tumor necrosis factor alpha (TNF-α) production by monocytes from cord blood (CB) and adult blood (AB) in response to LAM (lipoarabinomannan from Mycobacterium tuberculosis, a TLR2 ligand) and LPS (lipopolysaccharide from Escherichia coli, a TLR4 ligand). LPS or LAM-induced TNF-α production was 5 to 18 times higher in AB than in CB monocytes, whereas interleukin-1α (IL-1α) stimulated similar levels of TNF-α in both groups, suggesting that decreased responses to LPS or LAM in CB are unlikely to be due to differences in the MyD88-dependent signaling pathway. This impaired signaling was attributable, in part, to lower functional TLR4 expression, especially on CD14+ CD16+ monocytes, which are the primary cell subset for LPS-induced TNF-α production. Importantly, the frequency of CD14+ CD16+ monocytes in CB was 2.5-fold lower than in AB (P < 0.01). CB from Kenyan newborns sensitized to parasite antigens in utero had more CD14+ CD16+ monocytes (P = 0.02) and produced higher levels of TNF-α in response to LPS (P = 0.004) than CB from unsensitized Kenyan or North American newborns. Thus, a reduced CD14+ CD16+ activated/differentiated monocyte subset and a correspondingly lower level of functional TLR4 on monocytes contributes to the relatively low TNF-α response to LPS observed in immunologically naive newborns compared to the response in adults. PMID:23595503

  16. Lithium carbonate and coenzyme Q10 reduce cell death in a cell model of Machado-Joseph disease

    PubMed Central

    Lopes-Ramos, C.M.; Pereira, T.C.; Dogini, D.B.; Gilioli, R.; Lopes-Cendes, I.

    2016-01-01

    Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by expansion of the polyglutamine domain of the ataxin-3 (ATX3) protein. MJD/SCA3 is the most frequent autosomal dominant ataxia in many countries. The mechanism underlying MJD/SCA3 is thought to be mainly related to protein misfolding and aggregation leading to neuronal dysfunction followed by cell death. Currently, there are no effective treatments for patients with MJD/SCA3. Here, we report on the potential use of lithium carbonate and coenzyme Q10 to reduce cell death caused by the expanded ATX3 in cell culture. Cell viability and apoptosis were evaluated by MTT assay and by flow cytometry after staining with annexin V-FITC/propidium iodide. Treatment with lithium carbonate and coenzyme Q10 led to a significant increase in viability of cells expressing expanded ATX3 (Q84). In addition, we found that the increase in cell viability resulted from a significant reduction in the proportion of apoptotic cells. Furthermore, there was a significant change in the expanded ATX3 monomer/aggregate ratio after lithium carbonate and coenzyme Q10 treatment, with an increase in the monomer fraction and decrease in aggregates. The safety and tolerance of both drugs are well established; thus, our results indicate that lithium carbonate and coenzyme Q10 are good candidates for further in vivo therapeutic trials. PMID:27878228

  17. Lithium carbonate and coenzyme Q10 reduce cell death in a cell model of Machado-Joseph disease.

    PubMed

    Lopes-Ramos, C M; Pereira, T C; Dogini, D B; Gilioli, R; Lopes-Cendes, I

    2016-11-21

    Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by expansion of the polyglutamine domain of the ataxin-3 (ATX3) protein. MJD/SCA3 is the most frequent autosomal dominant ataxia in many countries. The mechanism underlying MJD/SCA3 is thought to be mainly related to protein misfolding and aggregation leading to neuronal dysfunction followed by cell death. Currently, there are no effective treatments for patients with MJD/SCA3. Here, we report on the potential use of lithium carbonate and coenzyme Q10 to reduce cell death caused by the expanded ATX3 in cell culture. Cell viability and apoptosis were evaluated by MTT assay and by flow cytometry after staining with annexin V-FITC/propidium iodide. Treatment with lithium carbonate and coenzyme Q10 led to a significant increase in viability of cells expressing expanded ATX3 (Q84). In addition, we found that the increase in cell viability resulted from a significant reduction in the proportion of apoptotic cells. Furthermore, there was a significant change in the expanded ATX3 monomer/aggregate ratio after lithium carbonate and coenzyme Q10 treatment, with an increase in the monomer fraction and decrease in aggregates. The safety and tolerance of both drugs are well established; thus, our results indicate that lithium carbonate and coenzyme Q10 are good candidates for further in vivo therapeutic trials.

  18. How can we reduce hepatic veno-occlusive disease-related deaths after allogeneic stem cell transplantation?

    PubMed

    Johnson, Douglas B; Savani, Bipin N

    2012-07-01

    Hepatic veno-occlusive disease (VOD) is a common and potentially devastating complication of hematopoietic stem cell transplantation. Confirmative diagnosis of this disorder can prove difficult early post hematopoietic stem cell transplantation, as a broad differential diagnosis exists and no definitive diagnostic test is available. Incidence of VOD has decreased in recent years, with especially dramatic declines in severe and fatal VOD. This improvement is attributed to less toxic and reduced-intensity conditioning regimens, and more appropriate patient selection. When severe VOD does occur, current treatments have been largely ineffective. Prevention remains the primary tool in the clinician's arsenal for managing VOD. Our institution pursues aggressive preventative measures for VOD, including appropriate conditioning regimen selection, avoiding hepatotoxic drugs, early prophylactic use of ursodiol, and aggressive fluid management. With appropriate management steps, we believe the incidence of VOD and related deaths can be further decreased.

  19. 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.

  20. Reduced nicotinamide adenine dinucleotide fluorescence lifetime detected poly(adenosine-5'-diphosphate-ribose) polymerase-1-mediated cell death and therapeutic effect of pyruvate

    NASA Astrophysics Data System (ADS)

    Guo, Han-Wen; Wei, Yau-Huei; Wang, Hsing-Wen

    2011-06-01

    Noninvasive detection of cell death has the potential for definitive diagnosis and monitoring treatment outcomes in real time. Reduced nicotinamide adenine dinucleotide (NADH) fluorescence intensity has long been used as a noninvasive optical probe of metabolic states. NADH fluorescence lifetime has recently been studied for its potential as an alternative optical probe of cellular metabolic states and cell death. In this study, we investigated the potential using NADH fluorescence intensity and/or lifetime to detect poly(adenosine-5'-diphosphate-ribose) polymerase-1 (PARP-1)-mediated cell death in HeLa cells. We also examined if NADH signals respond to treatment by pyruvate. The mechanism of PARP-1-mediated cell death has been well studied that extensive PARP-1 activation leads to cytosolic nicotinamide adenine dinucleotide depletion resulting in glycolytic inhibition, mitochondrial failure, and death. Pyruvate could restore electron transport chain to prevent energy failure and death. Our results show that NADH fluorescence lifetime, not intensity, responded to PARP-1-mediated cell death and the rescue effect of pyruvate. This lifetime change of NADH fluorescence happened before the collapse of mitochondrial membrane potential and mitochondrial uncoupling. Together with our previous findings in staurosporine-induced cell death, we suggest that NADH fluorescence lifetime increase during cell death is mainly due to increased protein-protein interactions but not the intracellular NADH content.

  1. Disseminated cysticercosis: clinical spectrum, Toll-like receptor-4 gene polymorphisms and role of albendazole

    PubMed Central

    Qavi, Abdul; Garg, Ravindra Kumar; Malhotra, Hardeep Singh; Jain, Amita; Kumar, Neeraj; Malhotra, Kiran Preet; Srivastava, Pradeep Kumar; Verma, Rajesh; Sharma, Praveen Kumar

    2016-01-01

    27 patients. Of the 4 deaths recorded, 3 had a heavy parasitic load and died after praziquantel therapy. Toll-like receptor-4 gene polymorphisms are associated with an increased susceptibility to disseminated cysticercosis, in the Indian population. Albendazole treatment seems to reduce the lesion load and improve symptoms. PMID:27684822

  2. Traffic-related air quality assessment for open road tolling highway facility.

    PubMed

    Lin, Jie; Yu, Dan

    2008-09-01

    Open road tolling (ORT) design has been considered as an effective means of smoothing highway traffic and reducing travel delay on toll highways. In this paper it is demonstrated that ORT can also achieve significant air quality benefits over the conventional toll plaza design. The near roadside carbon monoxide (CO) concentration levels can be reduced by up to 37%, and diesel particulate matter (DPM) emissions can decrease by as much as 58%. These large expected air quality benefits have great implications to the regional efforts of reducing mobile source air pollution toward achieving attainment status and healthier living environment.

  3. What you count is what you target: the implications of maternal death classification for tracking progress towards reducing maternal mortality in developing countries

    PubMed Central

    Bell, Jacqueline S; Graham, Wendy J

    2010-01-01

    Abstract The first target of the fifth United Nations Millennium Development Goal is to reduce maternal mortality by 75% between 1990 and 2015. This target is critically off track. Despite difficulties inherent in measuring maternal mortality, interventions aimed at reducing it must be monitored and evaluated to determine the most effective strategies in different contexts. In some contexts, the direct causes of maternal death, such as haemorrhage and sepsis, predominate and can be tackled effectively through providing access to skilled birth attendance and emergency obstetric care. In others, indirect causes of maternal death, such as HIV/AIDS and malaria, make a significant contribution and require alternative interventions. Methods of planning and evaluating maternal health interventions that do not differentiate between direct and indirect maternal deaths may lead to unrealistic expectations of effectiveness or mask progress in tackling specific causes. Furthermore, the need for additional or alternative interventions to tackle the causes of indirect maternal death may not be recognized if all-cause maternal death is used as the sole outcome indicator. This article illustrates the importance of differentiating between direct and indirect maternal deaths by analysing historical data from England and Wales and contemporary data from Ghana, Rwanda and South Africa. The principal aim of the paper is to highlight the need to differentiate deaths in this way when evaluating maternal mortality, particularly when judging progress towards the fifth Millennium Development Goal. It is recommended that the potential effect of maternity services failing to take indirect maternal deaths into account should be modelled. PMID:20428372

  4. Consumer Experiences Calling Toll-Free Corporate Hotlines.

    ERIC Educational Resources Information Center

    Martin, Charles L.; Smart, Denise T.

    1994-01-01

    Finds that dimensions that contribute to caller satisfaction (of toll-free corporate hotlines) included operator characteristics such as knowledge, courtesy, and interest; specific behaviors such as apologizing for a problem, thanking the consumer for calling, and encouraging them to call again; and reducing time placed on "hold." (SR)

  5. 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

  6. 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

  7. 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…

  8. The MOC31PE immunotoxin reduces cell migration and induces gene expression and cell death in ovarian cancer cells

    PubMed Central

    2014-01-01

    Background The standard treatment of ovarian cancer with chemotherapy often leads to drug resistance and relapse of the disease, and the need for development of novel therapy alternatives is obvious. The MOC31PE immunotoxin binds to the cell surface antigen EpCAM, which is expressed by the majority of epithelial cancers including ovarian carcinomas, and we studied the cytotoxic effects of MOC31PE in ovarian cancer cells. Methods Investigation of the effects of MOC31PE treatment on protein synthesis, cell viability, proliferation and gene expression of the ovarian cancer cell lines B76 and HOC7. Results MOC31PE treatment for 24 h caused a dose-dependent reduction of protein synthesis with ID50 values of less than 10 ng/ml, followed by reduced cell viability. In a gene expression array monitoring the expression of 84 key genes in cancer pathways, 13 of the genes were differentially expressed by MOC31PE treatment in comparison to untreated cells. By combining MOC31PE and the immune suppressor cyclosporin A (CsA) the MOC31PE effect on protein synthesis inhibition and cell viability increased tenfold. Cell migration was also reduced, both in the individual MOC31PE and CsA treatment, but even more when combining MOC31PE and CsA. In tumor metastasis PCR arrays, 23 of 84 genes were differentially expressed comparing CsA versus MOC31PE + CsA treatment. Increased expression of the tumor suppressor KISS1 and the nuclear receptor NR4A3 was observed, and the differential candidate gene expression was confirmed in complementary qPCR analyses. For NR4A3 this was not accompanied by increased protein expression. However, a subcellular fractionation assay revealed increased mitochondrial NR4A3 in MOC31PE treated cells, suggesting a role for this protein in MOC31PE-induced apoptotic cell death. Conclusion The present study demonstrates that MOC31PE may become a new targeted therapy for ovarian cancer and that the MOC31PE anti-cancer effect is potentiated by CsA. PMID:24528603

  9. 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.

  10. 17beta-estradiol pretreatment reduces CA1 sector cell death and the spontaneous hyperthermia that follows forebrain ischemia in the gerbil.

    PubMed

    Plahta, W C; Clark, D L; Colbourne, F

    2004-01-01

    Pretreatment with 17beta-estradiol attenuates ischemia-induced hippocampal cornu ammonis 1 (CA1) neuronal death. We assessed whether this is mediated through prevention of hyperthermia that normally follows ischemia in gerbils. Male gerbils were given sustained-released 17beta-estradiol pellets or sham operation. Later, a guide cannula was implanted for brain temperature measurement and some were implanted with core temperature telemetry probes. Gerbils were subjected to either 5 min bilateral carotid artery occlusion or sham procedures 2 weeks after pellet surgery. Brain temperature was normothermic during surgery in all cases. In experiment 1, only core temperature was measured afterward in untreated and estrogen-treated gerbils. In experiment 2, postischemic core temperature was measured in untreated and two estrogen-treated ischemic groups, one of which had their postischemic temperature increased, via infrared lamp, to mimic the untreated group. Habituation was assessed on days 5 and 6. Hyperthermia, like that which occurs spontaneously, was forced on untreated and estrogen-treated ischemic animals in the third experiment, where brain temperature was measured. CA1 cell counts were assessed after a 7-day survival. A fourth experiment measured brain and core temperature simultaneously in normal gerbils during heating with an infrared lamp. Estrogen did not affect core temperature of non-ischemic gerbils whereas spontaneous postischemic hyperthermia was blocked. Estrogen reduced cell death and provided behavioral protection when gerbils regulated their own core temperature, but not when core hyperthermia was enforced. Conversely, estrogen reduced cell death in gerbils that had their brain temperature elevated. Experiment 4 showed that the brain becomes overheated (by approximately 1 degree C) when core temperature is elevated. Accordingly, estrogen likely failed to reduce CA1 injury in experiment 2, when core hyperthermia was enforced, because of overheating the

  11. [Zoledronic acid reduces risk of any new clinical fracture and risk of death after surgical repair of a low-trauma hip fracture].

    PubMed

    Leszczyński, Piotr

    2010-01-01

    The most common treatment option for postmenopausal osteoporosis are the bisphosphonates which inhibit osteoclast function. Bisphosphonates interfere with cellular metabolism and in large clinical trials reduce risk of vertebral and non-vertebral fractures. Zoledronic acid is a potent bisphosphonate also approved for the treatment of postmenopausal osteoporosis. In addition zoledronic acid reduce relative risk of any new clinical fracture after surgical repair of low-trauma hip fracture. Also the reduction in the relative risk of death was observed after repeated once-yearly intravenous infusion. In conclusion, this is another interesting option for the treatment of the patients affected with osteoporosis and previous hip fractures.

  12. 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.

  13. Inhibition of programmed cell death impairs in vitro vascular-like structure formation and reduces in vivo angiogenesis.

    PubMed

    Segura, Inmaculada; Serrano, Antonio; De Buitrago, Gonzalo González; González, Manuel A; Abad, Jose Luis; Clavería, Cristina; Gómez, Lucio; Bernad, Antonio; Martínez-A, Carlos; Riese, Hans H

    2002-06-01

    Tissue remodeling during embryonic development and in the adult organism relies on a subtle balance between cell growth and apoptosis. As angiogenesis involves restructuring of preexisting endothelium, we examined the role of apoptosis in new vessel formation. We show that apoptosis occurs before capillary formation but not after vessels have assembled. Using the human umbilical vein endothelial cell (HUVEC) in vitro Matrigel angiogenesis model, we show that vascular-like structure formation requires apoptotic cell death through activation of a caspase-dependent mechanism and mitochondrial cytochrome c release. Vascular-like structure formation was further blocked by caspase inhibitors such as z-VAD or Ac-DEVD-CHO, using HUVEC and human lung microvascular endothelial cells. Overexpression of anti-apoptotic human Bcl-2 or baculovirus p35 genes in HUVEC altered endothelial cell rearrangement during in vitro angiogenesis, causing impaired vessel-like structure formation. Caspase inhibitors blocked VEGF- or bFGF-induced HUVEC angiogenesis on 2- or 3-D collagen gels, respectively, confirming that apoptosis was not the result of nonspecific cell death after seeding on the matrix. In an in vivo angiogenesis assay, caspase inhibitors blocked VEGF-dependent vascular formation at the alignment step, as demonstrated histologically. This evidence indicates that endothelial cell apoptosis may be relevant for precise vascular tissue rearrangement in in vitro and in vivo angiogenesis.

  14. Road traffic casualties: understanding the night‐time death toll

    PubMed Central

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

    2006-01-01

    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

  15. Deletion Of XIAP reduces the severity of acute pancreatitis via regulation of cell death and nuclear factor-κB activity.

    PubMed

    Liu, Yong; Chen, Xiao-Dong; Yu, Jiang; Chi, Jun-Lin; Long, Fei-Wu; Yang, Hong-Wei; Chen, Ke-Ling; Lv, Zhao-Ying; Zhou, Bin; Peng, Zhi-Hai; Sun, Xiao-Feng; Li, Yuan; Zhou, Zong-Guang

    2017-03-16

    Severe acute pancreatitis (SAP) still remains a clinical challenge, not only for its high mortality but the uncontrolled inflammatory progression from acute pancreatitis (AP) to SAP. Cell death, including apoptosis and necrosis are critical pathology of AP, since the severity of pancreatitis correlates directly with necrosis and inversely with apoptosis Therefore, regulation of cell death from necrosis to apoptosis may have practicably therapeutic value. X-linked inhibitor of apoptosis protein (XIAP) is the best characterized member of the inhibitor of apoptosis proteins (IAP) family, but its function in AP remains unclear. In the present study, we investigated the potential role of XIAP in regulation of cell death and inflammation during acute pancreatitis. The in vivo pancreatitis model was induced by the administration of cerulein with or without lipopolysaccharide (LPS) or by the administration of l-arginine in wild-type or XIAP-deficient mice, and ex vivo model was induced by the administration of cerulein+LPS in AR42J cell line following XIAP inhibition. The severity of acute pancreatitis was determined by serum amylase activity and histological grading. XIAP deletion on cell apoptosis, necrosis and inflammatory response were examined. Caspases activities, nuclear factor-κB (NF-κB) activation and receptor-interacting protein kinase1 (RIP1) degradation were assessed by western blot. Deletion of XIAP resulted in the reduction of amylase activity, decrease of NF-κB activation and less release of TNF-α and IL-6, together with increased caspases activities and RIP1 degradation, leading to enhanced apoptosis and reduced necrosis in pancreatic acinar cells and ameliorated the severity of acute pancreatitis. Our results indicate that deletion of XIAP switches cell death away from necrosis to apoptosis and decreases the inflammatory response, effectively attenuating the severity of AP/SAP. The critical role of XIAP in cell death and inflammation suggests that

  16. Neonatal Death

    MedlinePlus

    ... Home > Complications & Loss > Loss & grief > Neonatal death Neonatal death E-mail to a friend Please fill in ... cope with your baby’s death. What is neonatal death? Neonatal death is when a baby dies in ...

  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.

  18. 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

  19. Novel Toll-like receptor-4 antagonist (+)-naloxone protects mice from inflammation-induced preterm birth

    PubMed Central

    Chin, Peck Yin; Dorian, Camilla L.; Hutchinson, Mark R.; Olson, David M.; Rice, Kenner C.; Moldenhauer, Lachlan M.; Robertson, Sarah A.

    2016-01-01

    Toll-like receptor 4 (TLR4) activation by bacterial infection, or by sterile inflammatory insult is a primary trigger of spontaneous preterm birth. Here we utilize mouse models to investigate the efficacy of a novel small molecule TLR4 antagonist, (+)-naloxone, the non-opioid isomer of the opioid receptor antagonist (−)-naloxone, in infection-associated preterm birth. Treatment with (+)-naloxone prevented preterm delivery and alleviated fetal demise in utero elicited by i.p. LPS administration in late gestation. A similar effect with protection from preterm birth and perinatal death, and partial correction of reduced birth weight and postnatal mortality, was conferred by (+)-naloxone administration after intrauterine administration of heat-killed E. coli. Local induction by E. coli of inflammatory cytokine genes Il1b, Il6, Tnf and Il10 in fetal membranes was suppressed by (+)-naloxone, and cytokine expression in the placenta, and uterine myometrium and decidua, was also attenuated. These data demonstrate that inhibition of TLR4 signaling with the novel TLR4 antagonist (+)-naloxone can suppress the inflammatory cascade of preterm parturition, to prevent preterm birth and perinatal death. Further studies are warranted to investigate the utility of small molecule inhibition of TLR-driven inflammation as a component of strategies for fetal protection and delaying preterm birth in the clinical setting. PMID:27819333

  20. Bone marrow transplantation in hindlimb muscles of motoneuron degenerative mice reduces neuronal death and improves motor function.

    PubMed

    Pastor, Diego; Viso-León, Mari Carmen; Botella-López, Arancha; Jaramillo-Merchan, Jesus; Moraleda, Jose M; Jones, Jonathan; Martínez, Salvador

    2013-06-01

    Bone marrow has proved to be an adequate source of stem cells for the treatment of numerous disorders, including neurodegenerative diseases. Bone marrow can be easily and relatively painlessly extracted from a patient or allogenic donor and then transplanted into the degenerative area. Here, the grafted cells will activate a number of mechanisms in order to protect, repair, and/or regenerate the damaged tissue. These properties make the bone marrow a feasible source for cell therapy. In this work, we transplanted bone marrow cells into a mouse model of motoneuron degeneration, with the particularity of placing the cells in the hindlimb muscles rather than in the spinal cord where neuronal degeneration occurs. To this end, we analyze the possibility for the transplanted cells to increase the survival rate of the spinal cord motoneurons by axonal-guided retrograde neurotrophism. As a result, the mice significantly improved their motor functions. This coincided with an increased number of motoneurons innervating the treated muscle compared with the neurons innervating the non-treated contralateral symmetric muscle. In addition, we detected an increase in glial-derived neurotrophic factor in the spinal cord, a neurotrophic factor known to be involved in the rescue of degenerating motoneurons, exerting a neuroprotective effect. Thus, we have proved that bone marrow injected into the muscles is capable of rescuing these motoneurons from death, which may be a possible therapeutic approach for spinal cord motoneuron degenerative diseases, such as amyotrophic lateral sclerosis.

  1. Association of TrkA and APP Is Promoted by NGF and Reduced by Cell Death-Promoting Agents.

    PubMed

    Canu, Nadia; Pagano, Ilaria; La Rosa, Luca Rosario; Pellegrino, Marsha; Ciotti, Maria Teresa; Mercanti, Delio; Moretti, Fabiola; Sposato, Valentina; Triaca, Viviana; Petrella, Carla; Maruyama, Ichiro N; Levi, Andrea; Calissano, Pietro

    2017-01-01

    The amyloid precursor protein (APP) interacts with the tropomyosin receptor kinase A (TrkA) in normal rat, mouse, and human brain tissue but not in Alzheimer's disease (AD) brain tissue. However, it has not been reported whether the two proteins interact directly, and if so, which domains are involved. Clarifying these points will increase our understanding of the role and regulation of the TrkA/APP interaction in normal brain functioning as well as in AD. Here we addressed these questions using bimolecular fluorescence complementation (BiFC) and the proximity ligation assay (PLA). We demonstrated that exogenously expressed APP and TrkA associate through their juxtamembrane/transmembrane domains, to form a complex that localizes mainly to the plasma membrane, endoplasmic reticulum (ER) and Golgi. Formation of the complex was inhibited by p75NTR, ShcC and Mint-2. Importantly, we demonstrated that the association between endogenous APP and TrkA in primary septal neurons were modified by NGF, or by drugs that either inhibit ER-to-Golgi transport or perturb microtubules and microfilaments. Interestingly, several agents that induce cell death [amyloid β (Aβ)-peptide, staurosporine and rapamycin], albeit via different mechanisms, all caused dissociation of APP/TrkA complexes and increased production of C-terminal fragment (β-CTF) APP fragment. These findings open new perspectives for investigating the interplay between these proteins during neurodegeneration and AD.

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

    PubMed

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

    2014-07-25

    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.

  3. Bone Marrow Transplantation in Hindlimb Muscles of Motoneuron Degenerative Mice Reduces Neuronal Death and Improves Motor Function

    PubMed Central

    Viso-León, Mari Carmen; Botella-López, Arancha; Jaramillo-Merchan, Jesus; Moraleda, Jose M.; Jones, Jonathan; Martínez, Salvador

    2013-01-01

    Bone marrow has proved to be an adequate source of stem cells for the treatment of numerous disorders, including neurodegenerative diseases. Bone marrow can be easily and relatively painlessly extracted from a patient or allogenic donor and then transplanted into the degenerative area. Here, the grafted cells will activate a number of mechanisms in order to protect, repair, and/or regenerate the damaged tissue. These properties make the bone marrow a feasible source for cell therapy. In this work, we transplanted bone marrow cells into a mouse model of motoneuron degeneration, with the particularity of placing the cells in the hindlimb muscles rather than in the spinal cord where neuronal degeneration occurs. To this end, we analyze the possibility for the transplanted cells to increase the survival rate of the spinal cord motoneurons by axonal-guided retrograde neurotrophism. As a result, the mice significantly improved their motor functions. This coincided with an increased number of motoneurons innervating the treated muscle compared with the neurons innervating the non-treated contralateral symmetric muscle. In addition, we detected an increase in glial-derived neurotrophic factor in the spinal cord, a neurotrophic factor known to be involved in the rescue of degenerating motoneurons, exerting a neuroprotective effect. Thus, we have proved that bone marrow injected into the muscles is capable of rescuing these motoneurons from death, which may be a possible therapeutic approach for spinal cord motoneuron degenerative diseases, such as amyotrophic lateral sclerosis. PMID:23282201

  4. Association of TrkA and APP Is Promoted by NGF and Reduced by Cell Death-Promoting Agents

    PubMed Central

    Canu, Nadia; Pagano, Ilaria; La Rosa, Luca Rosario; Pellegrino, Marsha; Ciotti, Maria Teresa; Mercanti, Delio; Moretti, Fabiola; Sposato, Valentina; Triaca, Viviana; Petrella, Carla; Maruyama, Ichiro N.; Levi, Andrea; Calissano, Pietro

    2017-01-01

    The amyloid precursor protein (APP) interacts with the tropomyosin receptor kinase A (TrkA) in normal rat, mouse, and human brain tissue but not in Alzheimer’s disease (AD) brain tissue. However, it has not been reported whether the two proteins interact directly, and if so, which domains are involved. Clarifying these points will increase our understanding of the role and regulation of the TrkA/APP interaction in normal brain functioning as well as in AD. Here we addressed these questions using bimolecular fluorescence complementation (BiFC) and the proximity ligation assay (PLA). We demonstrated that exogenously expressed APP and TrkA associate through their juxtamembrane/transmembrane domains, to form a complex that localizes mainly to the plasma membrane, endoplasmic reticulum (ER) and Golgi. Formation of the complex was inhibited by p75NTR, ShcC and Mint-2. Importantly, we demonstrated that the association between endogenous APP and TrkA in primary septal neurons were modified by NGF, or by drugs that either inhibit ER-to-Golgi transport or perturb microtubules and microfilaments. Interestingly, several agents that induce cell death [amyloid β (Aβ)-peptide, staurosporine and rapamycin], albeit via different mechanisms, all caused dissociation of APP/TrkA complexes and increased production of C-terminal fragment (β-CTF) APP fragment. These findings open new perspectives for investigating the interplay between these proteins during neurodegeneration and AD. PMID:28197073

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

    PubMed Central

    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

    2016-01-01

    X-linked lymphoproliferative disease (XLP-1) is an often-fatal primary immunodeficiency associated with the exuberant expansion of activated CD8+ T cells following Epstein-Barr virus (EBV) infection. XLP-1 is caused by defects in 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 alpha (DGKα), leading to increased diacylglycerol metabolism and decreased signaling through Ras and PKCθ. Here, 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 pro-apoptotic proteins NUR77 and NOR1. Importantly, pharmacological inhibition of DGKα prevents the excessive CD8+ T cell expansion and IFNγ production that occur in Sap-deficient mice following 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

  6. 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.

  7. 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.

  8. 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. |

  9. (+)-Pentazocine Reduces NMDA-Induced Murine Retinal Ganglion Cell Death Through a σR1-Dependent Mechanism

    PubMed Central

    Zhao, Jing; Mysona, Barbara A.; Qureshi, Azam; Kim, Lily; Fields, Taylor; Gonsalvez, Graydon B.; Smith, Sylvia B.; Bollinger, Kathryn E.

    2016-01-01

    Purpose To evaluate, in vivo, the effects of the sigma-1 receptor (σR1) agonist, (+)-pentazocine, on N-methyl-D-aspartate (NMDA)-mediated retinal excitotoxicity. Methods Intravitreal NMDA injections were performed in C57BL/6J mice (wild type [WT]) and σR1−/− (σR1 knockout [KO]) mice. Fellow eyes were injected with phosphate-buffered saline (PBS). An experimental cohort of WT and σR1 KO mice was administered (+)-pentazocine by intraperitoneal injection, and untreated animals served as controls. Retinas derived from mice were flat-mounted and labeled for retinal ganglion cells (RGCs). The number of RGCs was compared between NMDA and PBS-injected eyes for all groups. Apoptosis was assessed using TUNEL assay. Levels of extracellular-signal–regulated kinases (ERK1/2) were analyzed by Western blot. Results N-methyl-D-aspartate induced a significant increase in TUNEL-positive nuclei and a dose-dependent loss of RGCs. Mice deficient in σR1 showed greater RGC loss (≈80%) than WT animals (≈50%). (+)-Pentazocine treatment promoted neuronal survival, and this effect was prevented by deletion of σR1. (+)-Pentazocine treatment resulted in enhanced activation of ERK at the 6-hour time point following NMDA injection. The (+)-pentazocine–induced ERK activation was diminished in σR1 KO mice. Conclusions Targeting σR1 activation prevented RGC death while enhancing activation of the mitogen-activated protein kinase (MAPK), ERK1/2. Sigma-1 receptor is a promising therapeutic target for retinal neurodegenerative diseases. PMID:26868747

  10. 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...

  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. 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...

  13. 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...

  14. 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...

  15. No benefits of statins for sudden cardiac death prevention in patients with heart failure and reduced ejection fraction: A meta-analysis of randomized controlled trials

    PubMed Central

    Le, Hai-Ha; Fall, Mor; Gueyffier, François; Burnand, Bernard

    2017-01-01

    Background and objectives Statins showed mixed results in heart failure (HF) patients. The benefits in major HF outcomes, including all-cause mortality and sudden cardiac death (SCD), have always been discordant across systematic reviews and meta-analyses. We intended to systematically identify and appraise the available evidence that evaluated the effectiveness of statins in clinical outcomes for HF patients. Design Systematic review and meta-analysis Data sources We searched, until April 28, 2016: Medline, Embase, ISI Web of Science and EBM reviews (Cochrane DSR, ACP journal club, DARE, CCTR, CMR, HTA, and NHSEED), checked clinicaltrials.gov for ongoing trials and manually searched references of included studies. Eligibility criteria for selecting studies We identified 24 randomized clinical trials that evaluated the efficacy of statins for HF patients. All randomized clinical trials were assessed for risk of bias and pooled together in a meta-analysis. Pre-specified outcomes were sudden cardiac death, all-cause mortality, and hospitalization for worsening heart failure. Results Statins did not reduce sudden cardiac death (SCD) events in HF patients [relative risk (RR) 0.92, 95% confidence interval (CI) 0.70 to 1.21], all-cause mortality [RR 0.88, 95% CI 0.75 to 1.02] but significantly reduced hospitalization for worsening heart failure (HWHF) although modestly [RR 0.79, 95% CI 0.66 to 0.94]. Nevertheless, estimated predictive intervals were insignificant in SCD, all-cause mortality and HWHF [RR, 0.54 to 1.63, 0.64 to 1.19, and 0.54 to 1.15], respectively. An important finding was the possible presence of publication bias, small-study effects and heterogeneity of the trials conducted in HF patients. Conclusions Statins do not reduce sudden cardiac death, all-cause mortality, but may slightly decrease hospitalization for worsening heart failure in HF patients. The evaluation of the risk of biases suggested moderate quality of the published results. Until new

  16. 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.

  17. Test Procedures for Toll Call Certification Alternatives.

    DTIC Science & Technology

    1987-04-07

    REPORT 4 PERIOD COVERED (U) Test Procedures for Toll CallFia Se86-Ar7 Certification AlternativesFiaSe86-Ar7 6. PERFORMING ORG . REPORT NUMBER 1. AUTHOR(e...toll call sampling is to use the toll call 21 a a C3a En L~a cmaL-a Lna ac C3 a cc u _3 to a- aa aL 4r C14 I Lo a_ V ’ Iara a D r- w U 4 c * a I’ aDUJ

  18. Kaposi's sarcoma-associated herpesvirus microRNAs target IRAK1 and MYD88, two components of the toll-like receptor/interleukin-1R signaling cascade, to reduce inflammatory-cytokine expression.

    PubMed

    Abend, Johanna R; Ramalingam, Dhivya; Kieffer-Kwon, Philippe; Uldrick, Thomas S; Yarchoan, Robert; Ziegelbauer, Joseph M

    2012-11-01

    Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is the causative agent of KS, an important AIDS-associated malignancy. KSHV expresses at least 18 different mature microRNAs (miRNAs). We identified interleukin-1 receptor (IL-1R)-associated kinase 1 (IRAK1) as a potential target of miR-K12-9 (miR-K9) in an array data set examining changes in cellular gene expression levels in the presence of KSHV miRNAs. Using 3'-untranslated region (3'UTR) luciferase reporter assays, we confirmed that miR-K9 and other miRNAs inhibit IRAK1 expression. In addition, IRAK1 expression is downregulated in cells transfected with miR-K9 and during de novo KSHV infection. IRAK1 is an important component of the Toll-like receptor (TLR)/IL-1R signaling cascade. The downregulation of IRAK1 by miR-K9 resulted in the decreased stimulation of NF-κB activity in endothelial cells treated with IL-1α and in B cells treated with a TLR7/8 agonist. Interestingly, miR-K9 had a greater effect on NF-κB activity than did a small interfering RNA (siRNA) targeting IRAK1 despite the more efficient downregulation of IRAK1 expression with the siRNA. We hypothesized that KSHV miRNAs may also be regulating a second component of the TLR/IL-1R signaling cascade, resulting in a stronger phenotype. Reanalysis of the array data set identified myeloid differentiation primary response protein 88 (MYD88) as an additional potential target. 3'UTR luciferase reporter assays and Western blot analysis confirmed the targeting of MYD88 by miR-K5. The presence of miR-K9 and miR-K5 inhibited the production of IL-6 and IL-8 upon the IL-1α stimulation of endothelial cells. These results demonstrate KSHV-encoded miRNAs regulating the TLR/IL-1R signaling cascade at two distinct points and suggest the importance of these pathways during viral infection.

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

    PubMed Central

    Troutwine, Benjamin R.; Ghezzi, Alfredo; Pietrzykowski, Andrzej Z.; Atkinson, Nigel S.

    2016-01-01

    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 (Cui et al., 2014; Vetreno & Crews, 2014). 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 (Schuckit, 1994). 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 while decreasing 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

  20. 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.

  1. Reduced calcium binding protein immunoreactivity induced by electroconvulsive shock indicates neuronal hyperactivity, not neuronal death or deactivation.

    PubMed

    Kim, J-E; Kwak, S-E; Kim, D-S; Won, M H; Kwon, O-S; Choi, S-Y; Kang, T-C

    2006-01-01

    Calcium-binding proteins (CBPs), such as parvalbumin and calbindin D-28k, are useful markers of specific neuronal types in the CNS. In recent studies, expression of CBPs may be indicative of a deactivated neuronal state, particularly epilepsy. However, it is controversial whether altered expression of CBPs in the hippocampus practically indicate neuronal activity. Therefore, the present study was performed to investigate the extent of profiles of expression of CBPs in the rat hippocampus affected by several episodes induced by electroconvulsive shock. In the present study, following electroconvulsive shock expression of CBPs were reduced in the hippocampus in a stimulus-dependent manner, and recovered to the control level at 6 h after electroconvulsive shock. However, paired-pulse responses of the dentate gyrus were transiently impaired by electroconvulsive shock, and immediately normalized to baseline value. In addition, effects of electroconvulsive shock on expression of CBPs and paired-pulse responses were prevented by pretreatment of vigabatrin. These findings suggest that reduced expression of CBPs induced by seizure activity may be indicative of hyperactivity of CBP positive neurons, which is a practical consequence of the abnormal discharge, and that they may play an important role in regulating seizure activity.

  2. Peripheral benzodiazepine receptor ligand PK11195 reduces microglial activation and neuronal death in quinolinic acid-injected rat striatum.

    PubMed

    Ryu, Jae K; Choi, Hyun B; McLarnon, James G

    2005-11-01

    The effects of the peripheral benzodiazepine receptor (PBR) ligand, PK11195, were investigated in the rat striatum following the administration of quinolinic acid (QUIN). Intrastriatal QUIN injection caused an increase of PBR expression in the lesioned striatum as demonstrated by immunohistochemical analysis. Double immunofluorescent staining indicated PBR was primarily expressed in ED1-immunoreactive microglia but not in GFAP-immunoreactive astrocytes or NeuN-immunoreactive neurons. PK11195 treatment significantly reduced the level of microglial activation and the expression of pro-inflammatory cytokines and iNOS in QUIN-injected striatum. Oxidative-mediated striatal QUIN damage, characterized by increased expression of markers for lipid peroxidation (4-HNE) and oxidative DNA damage (8-OHdG), was significantly diminished by PK11195 administration. Furthermore, intrastriatal injection of PK11195 with QUIN significantly reduced striatal lesions induced by the excitatory amino acid and diminished QUIN-mediated caspase-3 activation in striatal neurons. These results suggest that inflammatory responses from activated microglia are damaging to striatal neurons and pharmacological targeting of PBR in microglia may be an effective strategy in protecting neurons in neurological disorders such as Huntington's disease.

  3. Long-term statin use in patients with lung cancer and dyslipidemia reduces the risk of death

    PubMed Central

    Huang, Wen-Yen; Li, Chia-Hsiang; Lin, Cheng-Li; Liang, Ji-An

    2016-01-01

    Background Clinical studies have obtained inconsistent results of statin use on cancer outcomes. This study investigated the association between statin use and lung cancer mortality. Results The use of statin decreased mortality (hazard ratio = 0.91; 95% confidence interval: 0.86–0.96; P < .01). The patients with a high cumulative defined daily dose of statin use before lung cancer diagnosis exhibited a low risk of mortality. Materials and Methods We conducted a population-based case-control study of patients with dyslipidemia. Among them, 6270 had used statins for at least 3 months before lung cancer diagnosis, and 6270 had never used statins. Conclusions We found that statin use can reduce lung cancer mortality. A further prospective study is necessary to confirm these findings. PMID:27283991

  4. Cotton GhMKK5 affects disease resistance, induces HR-like cell death, and reduces the tolerance to salt and drought stress in transgenic Nicotiana benthamiana

    PubMed Central

    Zhang, Liang; Li, Yuzhen; Lu, Wenjing; Meng, Fei; Wu, Chang-ai; Guo, Xingqi

    2012-01-01

    Mitogen-activated protein kinase (MAPK) cascades are involved in various processes from plant growth and development to biotic and abiotic stress responses. MAPK kinases (MAPKKs), which link MAPKs and MAPKK kinases (MAPKKKs), play crucial roles in MAPK cascades to mediate a variety of stress responses in plants. However, few MAPKKs have been functionally characterized in cotton (Gossypium hirsutum). In this study, a novel gene, GhMKK5, from cotton belonging to the group C MAPKKs was isolated and characterized. The expression of GhMKK5 can be induced by pathogen infection, abiotic stresses, and multiple defence-related signal molecules. The overexpression of GhMKK5 in Nicotiana benthamiana enhanced the plants’ resistance to the bacterial pathogen Ralstonia solanacearum by elevating the expression of pathogen resistance (PR) genes, including PR1a, PR2, PR4, PR5, and NPR1, but increased the plants’ sensitivity to the oomycete pathogen Phytophthora parasitica var. nicotianae Tucker. Importantly, GhMKK5-overexpressing plants displayed markedly elevated expression of reactive oxygen species-related and cell death marker genes, such as NtRbohA and NtCDM, and resulted in hypersensitive response (HR)-like cell death characterized by the accumulation of H2O2. Furthermore, it was demonstrated that GhMKK5 overexpression in plants reduced their tolerance to salt and drought stresses, as determined by statistical analysis of seed germination, root length, leaf water loss, and survival rate. Drought obviously accelerated the cell death phenomenon in GhMKK5-overexpressing plants. These results suggest that GhMKK5 may play an important role in pathogen infection and the regulation of the salt and drought stress responses in plants. PMID:22442420

  5. CD147 is increased in HCC cells under starvation and reduces cell death through upregulating p-mTOR in vitro.

    PubMed

    Gou, Xingchun; Tang, Xu; Kong, Derek Kai; He, Xinying; Gao, Xingchun; Guo, Na; Hu, Zhifang; Zhao, Zhaohua; Chen, Yanke

    2016-01-01

    Transarterial chemoembolization (TACE) is the standard of care for treatment of intermediate hepatocellular carcinoma (HCC), however, key molecules involved in HCC cell survival and tumor metastasis post-TACE remain unclear. CD147 is a member of the immunoglobulin superfamily that is overexpressed on the surface of HCC cells and is associated with malignant potential and poor prognosis in HCC patients. In this study, using an Earle's Balanced Salt Solution medium culture model that mimics nutrient deprivation induced by TACE, we investigated the regulation of CD147 expression on HCC cells under starvation conditions and its functional effects on HCC cell death. During early stages of starvation, the expression of CD147 was considerably upregulated in SMMC7721, HepG2 and HCC9204 hepatoma cell lines at the protein levels. Downregulation of CD147 by specific small interfering RNA (siRNA) significantly promoted starvation-induced cell death. In addition, CD147 siRNA-transfected SMMC7721 cells demonstrated significantly increased levels of both apoptosis and autophagy as compared to cells transfected with control siRNA under starvation conditions, whereas no difference was observed between the two treatment groups under normal culture conditions. Furthermore, silencing of CD147 resulted in a remarkable downregulation of phosphorylated mammalian target of rapamycin (p-mTOR) in starved SMMC7721 cells. Finally, the combined treatment of starvation and anti-CD147 monoclonal antibody exhibited a synergistic HCC cell killing effect. Our study suggests that upregulation of CD147 under starvation may reduce hepatoma cell death by modulating both apoptosis and autophagy through mTOR signaling, and that CD147 may be a novel potential molecular target to improve the efficacy of TACE.

  6. Toll-like receptor 7 mediates pruritus.

    PubMed

    Liu, Tong; Xu, Zhen-Zhong; Park, Chul-Kyu; Berta, Temugin; Ji, Ru-Rong

    2010-12-01

    Toll-like receptors are typically expressed in immune cells to regulate innate immunity. We found that functional Toll-like receptor 7 (TLR7) was expressed in C-fiber primary sensory neurons and was important for inducing itch (pruritus), but was not necessary for eliciting mechanical, thermal, inflammatory and neuropathic pain in mice. Our results indicate that TLR7 mediates itching and is a potential therapeutic target for anti-itch treatment in skin disease conditions.

  7. Long-term bioavailability of redox nanoparticles effectively reduces organ dysfunctions and death in whole-body irradiated mice.

    PubMed

    Feliciano, Chitho P; Tsuboi, Koji; Suzuki, Kenshi; Kimura, Hiroyuki; Nagasaki, Yukio

    2017-06-01

    Radioprotective agents have been developed to protect patients against the damaging and lethal effects of ionizing radiation. However, in addition to the intrinsic ability to target reactive oxygen species (ROS), the ability to retain a significant level of bioavailability is desirable in radioprotective agents because that would increase and prolong their radioprotective efficacy and improve its safety. Here, we report the development of a novel nanoparticle-based radioprotective agent with improved bioavailability, which suppressed the adverse effects typically associated with low-molecular-weight (LMW) antioxidants. We developed biocompatible and colloidally stable nanoparticles in which nitroxide radicals that were covalently conjugated (redox nanoparticles, RNP(N)) effectively scavenged radiation-induced ROS with a characteristically prolonged bioavailability and tissue-residence time compared with that of conventional LMW antioxidants. The confinement of the nitroxide radicals in the RNP(N) core prevented its rapid metabolism and excretion out of the body. The nano-sized formulation prevented internalization of RNP(N) in healthy cells, thereby preserving the normal function of the redox reactions in the cell. This improved pharmacological performance dramatically reduced the radiation-induced organ dysfunctions and increased the survival time of the lethally irradiated mice when the nanoparticles were administered 3-24 h before whole-body irradiation.

  8. 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

  9. 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.

  10. 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

  11. 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

  12. 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

  13. Spn1 Regulates the GNBP3-Dependent Toll Signaling Pathway in Drosophila melanogaster▿

    PubMed Central

    Fullaondo, Ane; García-Sánchez, Susana; Sanz-Parra, Arantza; Recio, Emma; Lee, So Young; Gubb, David

    2011-01-01

    The Drosophila genome encodes 29 serpins, most of unknown function. We show here that Spn1 is an active protease inhibitor of the serpin superfamily. Spn1 inhibits trypsin in vitro and regulates the Toll-mediated immune response in vivo. Expression of the Toll-dependent transcripts Drosomycin and IM1 is increased in Spn1 null mutants. Overexpression of Spn1 reduces the induction of Drosomycin upon immune challenge with fungi but not Gram-positive bacteria. Similar reductions in Drosomycin levels are observed in the psh, spz, and grass mutants of the Toll signaling pathway. These results support a role of Spn1 as a repressor of Toll activation upon fungal infection. Epistatic analysis places Spn1 upstream of Spätzle processing enzyme and Grass, in the fungal cell wall-activated side branch of the pathway. Overexpression of the pattern recognition receptor GNBP3 activates the β-1,3-glucan-sensitive side branch of the Toll pathway. The resultant increased Drosomycin level is reduced by concomitant overexpression of Spn1, confirming that Spn1 regulates the fungal cell wall side branch. Spn1 null mutants show altered susceptibility to fungal infection compared to the wild type, demonstrating a requirement for Spn1 in the fine regulation of the immune response. PMID:21576362

  14. End-ischemic machine perfusion reduces bile duct injury in donation after circulatory death rat donor livers independent of the machine perfusion temperature.

    PubMed

    Westerkamp, Andrie C; Mahboub, Paria; Meyer, Sophie L; Hottenrott, Maximilia; Ottens, Petra J; Wiersema-Buist, Janneke; Gouw, Annette S H; Lisman, Ton; Leuvenink, Henri G D; Porte, Robert J

    2015-10-01

    A short period of oxygenated machine perfusion (MP) after static cold storage (SCS) may reduce biliary injury in donation after cardiac death (DCD) donor livers. However, the ideal perfusion temperature for protection of the bile ducts is unknown. In this study, the optimal perfusion temperature for protection of the bile ducts was assessed. DCD rat livers were preserved by SCS for 6 hours. Thereafter, 1 hour of oxygenated MP was performed using either hypothermic machine perfusion, subnormothermic machine perfusion, or with controlled oxygenated rewarming (COR) conditions. Subsequently, graft and bile duct viability were assessed during 2 hours of normothermic ex situ reperfusion. In the MP study groups, lower levels of transaminases, lactate dehydrogenase (LDH), and thiobarbituric acid reactive substances were measured compared to SCS. In parallel, mitochondrial oxygen consumption and adenosine triphosphate (ATP) production were significantly higher in the MP groups. Biomarkers of biliary function, including bile production, biliary bicarbonate concentration, and pH, were significantly higher in the MP groups, whereas biomarkers of biliary epithelial injury (biliary gamma-glutamyltransferase [GGT] and LDH), were significantly lower in MP preserved livers. Histological analysis revealed less injury of large bile duct epithelium in the MP groups compared to SCS. In conclusion, compared to SCS, end-ischemic oxygenated MP of DCD livers provides better preservation of biliary epithelial function and morphology, independent of the temperature at which MP is performed. End-ischemic oxygenated MP could reduce biliary injury after DCD liver transplantation.

  15. 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.

  16. 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

    ... toll station to be retained; (2) Description of service area affected, including approximate population and character of the business of the community; (3) Average number of toll telephone messages...

  17. 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...

  18. 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...

  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, 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...

  1. 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...

  2. 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...

  3. 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...

  4. 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...

  5. 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...

  6. 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...

  7. Voodoo death.

    PubMed

    Lester, David

    2009-01-01

    Scholarly writing on voodoo death is reviewed. Criticisms that voodoo deaths in indigenous societies have never been well documented are refuted with cases medically documented in developed nations. The work of Cannon and Richter on sudden death in animals is reviewed and dismissed as irrelevant for understanding voodoo death. The role of starvation and dehydration is discussed, and it is suggested that the given-up/giving-up hypothesis best fits the phenomenon of voodoo death. Hypotheses for future research are suggested.

  8. Ectoine alters subcellular localization of inclusions and reduces apoptotic cell death induced by the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch.

    PubMed

    Furusho, Kentaro; Yoshizawa, Toshihiro; Shoji, Shinichi

    2005-10-01

    Protein misfolding is considered a key event in the pathogenesis of polyglutamine disease such as Machado-Joseph disease (MJD). Overexpression of chaperone proteins and the application of chemical chaperones are reported to suppress polyglutamine induced cytotoxicity in vitro and in vivo. The effects of compatible solutes, which are osmoprotectants in bacteria and possess the action in stabilizing proteins under stress, have not, to our knowledge, been studied. We explored the protective effects of the compatible solutes ectoine, hydroxyectoine, and betaine on apoptotic cell death produced by the truncated MJD gene product with an expanded polyglutamine tract in cultured neuro2a cells. Ectoine, but not hydroxyectoine or betaine, decreased large cytoplasmic inclusions and increased the frequency of nuclear inclusions. Immunoblot analysis showed that ectoine reduced the total amount of aggregates. Despite the presence of nuclear inclusions, apoptotic features were less frequently observed after ectoine application. Our findings suggest that ectoine, a natural osmoprotectant in bacteria, may function as a novel molecule protecting cells from polyglutamine-induced toxicity.

  9. 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

  10. Toll-like receptor 8: augmentation of innate immunity in platinum resistant ovarian carcinoma

    PubMed Central

    Brueseke, Taylor J; Tewari, Krishnansu S

    2013-01-01

    Ovarian cancer is the most deadly gynecologic cancer, with 15,000 anticipated deaths within the United States alone in 2012, and new treatment strategies are needed. Ovarian cancer tumors are known to host an immunosuppressive microenvironment. This suppression may be reversible via activation of the innate immune response. Toll-like receptor 8 activates innate immunity while simultaneously inhibiting the effects of regulatory T cells within the ovarian cancer tumors. VTX-2337 is a novel small molecule ligand of Toll-like receptor 8 and is currently the subject of a Phase II randomized, double-blind, placebo-controlled trial Gynecologic Oncology Group (GOG)-3003 for patients with recurrent platinum-resistant ovarian cancer. We look forward to the results of this trial as support for the paradigm of process therapy in the treatment of ovarian cancer. PMID:23723721

  11. 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)

  12. 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.

  13. 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

  14. Toll-like Receptor-7 Mediates Pruritus

    PubMed Central

    Liu, Tong; Xu, Zhen-Zhong; Park, Chul-Kyu; Berta, Temugin; Ji, Ru-Rong

    2010-01-01

    Toll-like receptors (TLRs) are typically expressed in immune cells to regulate innate immunity. Here we report that functional TLR7 is expressed in C-fiber primary sensory neurons and important for inducing itch (pruritis) but not necessary for eliciting mechanical, thermal, inflammatory and neuropathic pain in mice. Thus, we have uncovered TLR7 as a novel itch mediator and a potential therapeutic target for anti-itch treatment in skin disease conditions. PMID:21037581

  15. 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...

  16. 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...

  17. 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...

  18. 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...

  19. Inhibition of never in mitosis A (NIMA)-related kinase-4 reduces survivin expression and sensitizes cancer cells to TRAIL-induced cell death

    PubMed Central

    Park, So Jung; Jo, Doo Sin; Jo, Se-Young; Shin, Dong Woon; Shim, Sangmi; Jo, Yoon Kyung; Shin, Ji Hyun; Ha, Ye Jin; Jeong, Seong-Yun; Hwang, Jung Jin; Kim, Young Sam; Suh, Young-Ah; Chang, Jong Wook; Kim, Jin Cheon; Cho, Dong-Hyung

    2016-01-01

    The tumor necrosis factor-related apoptosis inducing ligand (TRAIL) preferentially induces apoptosis in cancer cells. However, many tumors are resistant to TRAIL-induced apoptosis, and resistance mechanisms are not fully understood. To identify novel regulatory molecules of TRAIL resistance, we screened a siRNA library targeting the human kinome, and NEK4 (NIMA-related kinase-4) was identified. Knockdown of NEK4 sensitized TRAIL-resistant cancer cells and in vivo xenografts to cell death. In contrast, over expression of NEK4 suppressed TRAIL-induced cell death in TRAIL-sensitive cancer cells. In addition, loss of NEK4 resulted in decrease of the anti-apoptotic protein survivin, but an increase in apoptotic cell death. Interestingly, NEK4 was highly upregulated in tumor tissues derived from patients with lung cancer and colon cancer. These results suggest that inhibition of NEK4 sensitizes cancer cells to TRAIL-induced apoptosis by regulation of survivin expression. PMID:27602754

  20. 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

  1. Increases in fines and driver licence withdrawal have effectively reduced immediate deaths from trauma on Brazilian roads: first-year report on the new traffic code.

    PubMed

    Poli de Figueiredo, L F; Rasslan, S; Bruscagin, V; Cruz, R; Rocha e Silva, M

    2001-03-01

    Road accidents are a major cause of death in Brazil, with rates increasing steadily for years. Our objective here is to report the impact of the new Brazilian Traffic Code, introduced in 1998. Its main new features include a large increase in fines and a rigid penalty scoring system that leads to driver license withdrawal. Speed limits have actually been raised on many roads, but adherence to the rules has been monitored more closely. We compare the incidence of injured patients and immediate deaths in road accidents and emergency room admissions to a level I trauma centre in downtown São Paulo between January and December 1998 with corresponding data from between January and December 1997. There was an overall 21.3% reduction in the number of accidents and a 24.7% reduction in immediate deaths, saving 5962 lives on Brazilian highways. Tickets issued fell by 49.5% (601977 during 1997 to 304785 during 1998). Motor vehicle accident-related emergency room admissions decreased by 33.2%. We conclude that very costly tickets and threatened driver licences have proved very effective in decreasing immediate deaths from trauma. Further advances in educational programmes associated with road and vehicle safety measures are likely to provide the much needed further reduction in the still high trauma mortality on Brazilian roads and streets.

  2. 23 CFR 950.5 - Requirement to use electronic toll collection technology.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... location and use of such methods do not create unsafe operating conditions on the toll facility. (b) A toll... electronic toll collection technology must develop, implement, and make publicly available privacy...

  3. Invariant death.

    PubMed

    Frank, Steven A

    2016-01-01

    In nematodes, environmental or physiological perturbations alter death's scaling of time. In human cancer, genetic perturbations alter death's curvature of time. Those changes in scale and curvature follow the constraining contours of death's invariant geometry. I show that the constraints arise from a fundamental extension to the theories of randomness, invariance and scale. A generalized Gompertz law follows. The constraints imposed by the invariant Gompertz geometry explain the tendency of perturbations to stretch or bend death's scaling of time. Variability in death rate arises from a combination of constraining universal laws and particular biological processes.

  4. Can plant oncogenes inhibit programmed cell death? The rolB oncogene reduces apoptosis-like symptoms in transformed plant cells.

    PubMed

    Gorpenchenko, Tatiana Y; Aminin, Dmitry L; Vereshchagina, Yuliya V; Shkryl, Yuri N; Veremeichik, Galina N; Tchernoded, Galina K; Bulgakov, Victor P

    2012-09-01

    The rolB oncogene was previously identified as an important player in ROS metabolism in transformed plant cells. Numerous reports indicate a crucial role for animal oncogenes in apoptotic cell death. Whether plant oncogenes such as rolB can induce programmed cell death (PCD) in transformed plant cells is of particular importance. In this investigation, we used a single-cell assay based on confocal microscopy and fluorescent dyes capable of discriminating between apoptotic and necrotic cells. Our results indicate that the expression of rolB in plant cells was sufficient to decrease the proportion of apoptotic cells in steady-state conditions and diminish the rate of apoptotic cells during induced PCD. These data suggest that plant oncogenes, like animal oncogenes, may be involved in the processes mediating PCD.

  5. Severe hypertriglyceridemia, reduced high density lipoprotein, and neonatal death in lipoprotein lipase knockout mice. Mild hypertriglyceridemia with impaired very low density lipoprotein clearance in heterozygotes.

    PubMed Central

    Weinstock, P H; Bisgaier, C L; Aalto-Setälä, K; Radner, H; Ramakrishnan, R; Levak-Frank, S; Essenburg, A D; Zechner, R; Breslow, J L

    1995-01-01

    Lipoprotein lipase (LPL)-deficient mice have been created by gene targeting in embryonic stem cells. At birth, homozygous knockout pups have threefold higher triglycerides and sevenfold higher VLDL cholesterol levels than controls. When permitted to suckle, LPL-deficient mice become pale, then cyanotic, and finally die at approximately 18 h of age. Before death, triglyceride levels are severely elevated (15,087 +/- 3,805 vs 188 +/- 71 mg/dl in controls). Capillaries in tissues of homozygous knockout mice are engorged with chylomicrons. This is especially significant in the lung where marginated chylomicrons prevent red cell contact with the endothelium, a phenomenon which is presumably the cause of cyanosis and death in these mice. Homozygous knockout mice also have diminished adipose tissue stores as well as decreased intracellular fat droplets. By crossbreeding with transgenic mice expressing human LPL driven by a muscle-specific promoter, mouse lines were generated that express LPL exclusively in muscle but not in any other tissue. This tissue-specific LPL expression rescued the LPL knockout mice and normalized their lipoprotein pattern. This supports the contention that hypertriglyceridemia caused the death of these mice and that LPL expression in a single tissue was sufficient for rescue. Heterozygous LPL knockout mice survive to adulthood and have mild hypertriglyceridemia, with 1.5-2-fold elevated triglyceride levels compared with controls in both the fed and fasted states on chow, Western-type, or 10% sucrose diets. In vivo turnover studies revealed that heterozygous knockout mice had impaired VLDL clearance (fractional catabolic rate) but no increase in transport rate. In summary, total LPL deficiency in the mouse prevents triglyceride removal from plasma, causing death in the neonatal period, and expression of LPL in a single tissue alleviates this problem. Furthermore, half-normal levels of LPL cause a decrease in VLDL fractional catabolic rate and mild

  6. Mycobacterium avium MAV2052 protein induces apoptosis in murine macrophage cells through Toll-like receptor 4.

    PubMed

    Lee, Kang-In; Choi, Han-Gyu; Son, Yeo-Jin; Whang, Jake; Kim, Kwangwook; Jeon, Heat Sal; Park, Hye-Soo; Back, Yong Woo; Choi, Seunga; Kim, Seong-Woo; Choi, Chul Hee; Kim, Hwa-Jung

    2016-04-01

    Mycobacterium avium and its sonic extracts induce apoptosis in macrophages. However, little is known about the M. avium components regulating macrophage apoptosis. In this study, using multidimensional fractionation, we identified MAV2052 protein, which induced macrophage apoptosis in M. avium culture filtrates. The recombinant MAV2052 induced macrophage apoptosis in a caspase-dependent manner. The loss of mitochondrial transmembrane potential (ΔΨm), mitochondrial translocation of Bax, and release of cytochrome c from mitochondria were observed in macrophages treated with MAV2052. Further, reactive oxygen species (ROS) production was required for the apoptosis induced by MAV2052. In addition, ROS and mitogen-activated protein kinases were involved in MAV2052-mediated TNF-α and IL-6 production. ROS-mediated activation of apoptosis signal-regulating kinase 1 (ASK1)-JNK pathway was a major signaling pathway for MAV2052-induced apoptosis. Moreover, MAV2052 bound to Toll-like receptor (TLR) 4 molecule and MAV2052-induced ROS production, ΔΨm loss, and apoptosis were all significantly reduced in TLR4(-/-) macrophages. Altogether, our results suggest that MAV2052 induces apoptotic cell death through TLR4 dependent ROS production and JNK pathway in murine macrophages.

  7. A Toll-like receptor in horseshoe crabs.

    PubMed

    Inamori, Kei-ichiro; Ariki, Shigeru; Kawabata, Shun-ichiro

    2004-04-01

    Non-self-recognition of invading microbes relies on the pattern-recognition of pathogen-associated molecular patterns (PAMPs) derived from microbial cell-wall components. Insects and mammals conserve a signaling pathway of the innate immune system through cell-surface receptors called Tolls and Toll-like receptors (TLRs). Bacterial lipopolysaccharides (LPSs) are an important trigger of the horseshoe crab's innate immunity to infectious microorganisms. Horseshoe crabs' granular hemocytes respond specifically to LPS stimulation, inducing the secretion of various defense molecules from the granular hemocytes. Here, we show a cDNA which we named tToll, coding for a TLR identified from hemocytes of the horseshoe crab Tachypleus tridentatus. tToll is most closely related to Drosophila Toll in both domain architecture and overall length. Human TLRs have been suggested to contain numerous PAMP-binding insertions located in the leucine-rich repeats (LRRs) of their ectodomains. However, the LRRs of tToll contained no obvious PAMP-binding insertions. Furthermore, tToll was non-specifically expressed in horseshoe crab tissues. These observations suggest that tToll does not function as an LPS receptor on granular hemocytes.

  8. 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...

  9. 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...

  10. 47 CFR 51.213 - Toll dialing parity implementation plans.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 3 2010-10-01 2010-10-01 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...

  11. 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...

  12. 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...

  13. 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

  14. Inherent low Erk and p38 activity reduce Fas Ligand expression and degranulation in T helper 17 cells leading to activation induced cell death resistance

    PubMed Central

    Peroumal, Doureradjou; Abimannan, Thiruvaimozhi; Tagirasa, Ravichandra; Parida, Jyothi Ranjan; Singh, Santosh Kumar; Padhan, Prasantha; Devadas, Satish

    2016-01-01

    Activation Induced Cell Death of T helper cells is central to maintaining immune homeostasis and a perturbation often manifests in aberrant T helper cells that is associated with immunopathologies. Significant presence of T cells positive for IL-17A (Th17) and dual positive for IFN-γ/IL-17A (Th1/Th17) in both effector (CD45RA+RO+) and memory (CD45RA−RO+) compartments with differential FasL protein in RA peripheral blood suggested their differential TCR AICD sensitivity. Lowered active caspase-3 in Th17 and Th1/Th17 over Th1 cells confirmed their capability to resist AICD and pointed to early upstream events. Differential MAPK activities, FasL protein and downstream caspase-3 activities in murine Th1 and Th17 cells established distinct TCR mediated signaling pathways and suggested low Erk and p38 activity as pivotal for AICD sensitivity. We extrapolated our mouse and human data and report that Fas-FasL is the preferred death pathway for both Th1 and Th17 and that inherently low Erk2 activity protected Th17 cells from TCR AICD. The presence of significantly higher numbers of aberrant T helper cells in RA also suggest an inflammatory cytokine milieu and AICD insensitive T cell link to sustained inflammation. Re sensitization to apoptosis by targeting MAPK activity especially Erk2 in RA might be of therapeutic value. PMID:27486885

  15. 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.

  16. Death foretold.

    PubMed

    Biderman, A; Herman, J

    2000-01-01

    We briefly trace the history of a belief in the possibility that a person in apparent good health may accurately predict his or her own demise. The phenomenon is referred to as death foretold and we present presumed examples of it from the Bible, world literature, medical writings and newspaper reports without pretending to completeness. In two widely quoted scientific papers, death foretold is subsumed under the wider heading of decease due to psychic stress. We speculate on a possible link between the two, taking into consideration the fact that most people who prophesy their end are of an advanced age.

  17. 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.

  18. 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

  19. Toll gates: An emerging therapeutic target

    PubMed Central

    Maheaswari, Rajendran; Sivasankar, Kiruthika; Subbarayan, Sathya

    2014-01-01

    Innate immune system forms the first line of defense against microbial infections, as it exerts an immediate response. Innate immunity works through Toll-like receptors (TLRs) which functions as primary sensors of pathogens. TLR activates multiple signaling cascades leading to the induction of genes responsible for the release of inflammatory cytokines and type I interferon. Thus, they induce antimicrobial responses and also have an instructive role in adaptive immunity. However, TLR-mediated inflammation is said to be responsible for many of the destructive host responses in inflammatory diseases like periodontitis. Hence, therapeutics targeting TLRs are being used to treat disease such as HIV, Hepatitis B, asthma etc. Recently, synthetic TLR agonists are tried as novel vaccine adjuvant in treating periodontal diseases. This paper reviews the scope of TLR-based therapeutics in treating periodontitis. PMID:25624622

  20. 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

    2016-06-07

    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

  1. 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.

  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. 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.

  4. 26 CFR 49.4252-2 - Toll telephone service.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 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....

  5. 26 CFR 49.4252-2 - Toll telephone service.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 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....

  6. 26 CFR 49.4252-2 - Toll telephone service.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 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....

  7. 26 CFR 49.4252-2 - Toll telephone service.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 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....

  8. Delivering Career Information on a Toll-Free Hotline.

    ERIC Educational Resources Information Center

    Snipes, Juanita K.; McDaniels, Carl

    1982-01-01

    Reviews some of the uses of the phone in crisis situations and describes a popular toll-free career information hotline in Virginia. Provides a profile of the mostly adult users along with a user evaluation of the service. (Author)

  9. TSCA Chemical Data Reporting Fact Sheet: Toll Manufacturing

    EPA Pesticide Factsheets

    This fact sheet provides information on existing Chemical Data Reporting (CDR) regulations to persons who are involved in toll manufacturing of chemical substances which may be subject to the CDR rule.

  10. A role for the adaptor proteins TRAM and TRIF in toll-like receptor 2 signaling.

    PubMed

    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

    2015-02-06

    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.

  11. 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.

  12. 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

  13. Impaired toll like receptor-7 and 9 induced immune activation in chronic spinal cord injured patients contributes to immune dysfunction

    PubMed Central

    Gungor, Bilgi; Kahraman, Tamer; Gursel, Mayda; Yilmaz, Bilge

    2017-01-01

    Reduced immune activation or immunosuppression is seen in patients withneurological diseases. Urinary and respiratory infections mainly manifested as septicemia and pneumonia are the most frequent complications following spinal cord injuries and they account for the majority of deaths. The underlying reason of these losses is believed to arise due to impaired immune responses to pathogens. Here, we hypothesized that susceptibility to infections of chronic spinal cord injured (SCI) patients might be due to impairment in recognition of pathogen associated molecular patterns and subsequently declining innate and adaptive immune responses that lead to immune dysfunction. We tested our hypothesis on healthy and chronic SCI patients with a level of injury above T-6. Donor PBMCs were isolated and stimulated with different toll like receptor ligands and T-cell inducers aiming to investigate whether chronic SCI patients display differential immune activation to multiple innate and adaptive immune cell stimulants. We demonstrate that SCI patients' B-cell and plasmacytoid dendritic cells retain their functionality in response to TLR7 and TLR9 ligand stimulation as they secreted similar levels of IL6 and IFNα. The immune dysfunction is not probably due to impaired T-cell function, since neither CD4+ T-cell dependent IFNγ producing cell number nor IL10 producing regulatory T-cells resulted different outcomes in response to PMA-Ionomycin and PHA-LPS stimulation, respectively. We showed that TLR7 dependent IFNγ and IP10 levels and TLR9 mediated APC function reduced substantially in SCI patients compared to healthy subjects. More importantly, IP10 producing monocytes were significantly fewer compared to healthy subjects in response to TLR7 and TLR9 stimulation of SCI PBMCs. When taken together this work implicated that these defects could contribute to persistent complications due to increased susceptibility to infections of chronic SCI patients. PMID:28170444

  14. 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.

  15. Post-irradiation hypoxic incubation of X-irradiated MOLT-4 cells reduces apoptotic cell death by changing the intracellular redox state and modulating SAPK/JNK pathways.

    PubMed

    Hamasu, T; Inanami, O; Tsujitani, M; Yokoyama, K; Takahashi, E; Kashiwakura, I; Kuwabara, M

    2005-05-01

    To elucidate radiobiological effects of hypoxia on X-ray-induced apoptosis, MOLT-4 cells were treated under four set of conditions: (1) both X irradiation and incubation under normoxia, (2) X irradiation under hypoxia and subsequent incubation under normoxia, (3) X irradiation under normoxia and subsequent incubation under hypoxia, and (4) both X irradiation and incubation under hypoxia, and the induction of apoptosis was examined by fluorescence microscopy. About 28-33% apoptosis was observed in cells treated under conditions 1 and 2, but this value was significantly reduced to around 18-20% in cells treated under conditions 3 and 4, suggesting that post-irradiation hypoxic incubation rather than hypoxic irradiation mainly caused the reduction of apoptosis. The activation and expression of apoptosis signal-related molecules SAPK/JNK, Fas and caspase-3 were also suppressed by hypoxic incubation. Effects of hypoxic incubation were canceled when cells were treated under conditions 3 and 4 with an oxygen-mimicking hypoxic cell radiosensitizer, whereas the addition of N-acetyl-L-cysteine again reduced the induction of apoptosis. From these results it was concluded that hypoxia reduced the induction of apoptosis by changing the intracellular redox state, followed by the regulation of apoptotic signals in X-irradiated MOLT-4 cells.

  16. 33 CFR 402.10 - Schedule of tolls.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Column 2 Column 3 1. Subject to item 3, for complete transit of the Seaway, a composite toll, comprising... manifest or other document, as follows: (a) bulk cargo 1.0012 0.6834. (b) general cargo 2.4124 1.0936. (c... of the U.S. portion of tolls for commercial vessels is waived by law (33 U.S.C. 998a(a)). 3...

  17. 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.

  18. Pediatric brain death determination.

    PubMed

    Mathur, Mudit; Ashwal, Stephen

    2015-04-01

    Clinical guidelines for the determination of brain death in children were first published in 1987. These guidelines were revised in 2011 under the auspices of the Society of Critical Care Medicine, the American Academy of Pediatrics, and the Child Neurology Society, and provide the minimum standards that must be satisfied before brain death can be declared in infants and children. After achieving physiologic stability and exclusion of confounders, two examinations including apnea testing separated by an observation period (24 hours for term newborns up to 30 days of age, and 12 hours for infants and children from 31 days up to 18 years) are required to establish brain death. Apnea testing should demonstrate a final arterial PaCO2 20 mm Hg above the baseline and ≥ 60 mm Hg with no respiratory effort during the testing period. Ancillary studies (electroencephalogram and radionuclide cerebral blood flow) are not required to establish brain death and are not a substitute for the neurologic examination. The committee concluded that ancillary studies may be used (1) when components of the examination or apnea testing cannot be completed, (2) if uncertainty about components of the neurologic examination exists, (3) if a medication effect may be present, or (4) to reduce the interexamination observation period. When ancillary studies are used, a second clinical examination and apnea test should still be performed and components that can be completed must remain consistent with brain death.

  19. Amyloid-β reduces the expression of neuronal FAIM-L, thereby shifting the inflammatory response mediated by TNFα from neuronal protection to death

    PubMed Central

    Carriba, P; Jimenez, S; Navarro, V; Moreno-Gonzalez, I; Barneda-Zahonero, B; Moubarak, R S; Lopez-Soriano, J; Gutierrez, A; Vitorica, J; Comella, J X

    2015-01-01

    The brains of patients with Alzheimer's disease (AD) present elevated levels of tumor necrosis factor-α (TNFα), a cytokine that has a dual function in neuronal cells. On one hand, TNFα can activate neuronal apoptosis, and on the other hand, it can protect these cells against amyloid-β (Aβ) toxicity. Given the dual behavior of this molecule, there is some controversy regarding its contribution to the pathogenesis of AD. Here we examined the relevance of the long form of Fas apoptotic inhibitory molecule (FAIM) protein, FAIM-L, in regulating the dual function of TNFα. We detected that FAIM-L was reduced in the hippocampi of patients with AD. We also observed that the entorhinal and hippocampal cortex of a mouse model of AD (PS1M146LxAPP751sl) showed a reduction in this protein before the onset of neurodegeneration. Notably, cultured neurons treated with the cortical soluble fractions of these animals showed a decrease in endogenous FAIM-L, an effect that is mimicked by the treatment with Aβ-derived diffusible ligands (ADDLs). The reduction in the expression of FAIM-L is associated with the progression of the neurodegeneration by changing the inflammatory response mediated by TNFα in neurons. In this sense, we also demonstrate that the protection afforded by TNFα against Aβ toxicity ceases when endogenous FAIM-L is reduced by short hairpin RNA (shRNA) or by treatment with ADDLs. All together, these results support the notion that levels of FAIM-L contribute to determine the protective or deleterious effect of TNFα in neuronal cells. PMID:25675299

  20. Toll receptor response to white spot syndrome virus challenge in giant freshwater prawns (Macrobrachium rosenbergii).

    PubMed

    Feng, Jinling; Zhao, Lingling; Jin, Min; Li, Tingting; Wu, Lei; Chen, Yihong; Ren, Qian

    2016-10-01

    Toll receptors are evolutionary ancient families of pattern recognition receptors with crucial roles in invertebrate innate immune response. In this study, we identified a Toll receptor (MrToll) from giant freshwater prawns (Macrobrachium rosenbergii). The full-length cDNA of MrToll is 4257 bp, which encodes a putative protein of 1367 amino acids. MrToll contains 17 LRR domains, a transmembrane domain, and a TIR domain. Phylogenetic analysis showed that MrToll was grouped with Drosophila Toll7 and other arthropod Tolls. The transcripts of MrToll are mainly distributed in the heart, hepatopancreas, gills, stomach, and intestine. A low level of MrToll expression can be detected in hemocytes and the lymphoid organ. MrToll expression in gills was gradually upregulated to the highest level from 24 h to 48 h during the white spot syndrome virus (WSSV) challenge. The expression levels of the crustin (Cru) genes Cru3 and Cru7 in gills were relatively lower than those of Cru2 and Cru4. The expression levels of Cru3 and Cru7 were inhibited after the RNA interference of MrToll in gills during the WSSV challenge. The anti-lipopolysaccharide factor (ALF) genes ALF2, ALF3, ALF4, and ALF5 were also regulated by MrToll in gills during the virus challenge. These findings suggest that MrToll may contribute to the innate immune defense of M. rosenbergii against WSSV.

  1. 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

    2016-01-01

    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.

  2. Toll-like receptors and cutaneous melanoma

    PubMed Central

    Coati, Ilaria; Miotto, Serena; Zanetti, Irene; Alaibac, Mauro

    2016-01-01

    Innate immune cells recognize highly conserved pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs). Previous studies have demonstrated that PRRs also recognize endogenous molecules, termed damage-associated molecular patterns (DAMPs) that are derived from damaged cells. PRRs include Toll-like receptors (TLRs), scavenger receptors, C-type lectin receptors and nucleotide oligomerization domain-like receptors. To date, 10 TLRs have been identified in humans and each receptor responds to a different ligand. The recognition of PAMPS or DAMPs by TLRs leads to the activation of signaling pathways and cellular responses with subsequent pro-inflammatory cytokine release, phagocytosis and antigen presentation. In the human skin, TLRs are expressed by keratinocytes and melanocytes: The main cells from which skin cancers arise. TLRs 1–6 and 9 are expressed in keratinocytes, while TLRs 2–5, 7, 9 and 10 have been identified in melanocytes. It is hypothesized that TLRs may present a target for melanoma therapies. In this review, the involvement of TLRs in the pathogenesis and treatment of melanoma was discussed. PMID:27900049

  3. Galileo or for whom the bell tolls

    NASA Astrophysics Data System (ADS)

    Legat, K.; Hofmann-Wellenhof, B.

    2000-10-01

    Satellite-based navigation rapidly evolved into an efficient tool extensively used in a wide variety of civilian applications covering numerous modes of transportation, communication, administration, geodesy, agriculture, and many others. The current systems globally available are the US Global Positioning System (GPS) and the conceptually very similar Russian Global Navigation Satellite System (GLONASS). Considering the worldwide applications, GPS clearly predominates over GLONASS. However, GPS and GLONASS are mainly under military control of single nations and, also critical, do not fulfill certain performance requirements of the civil users, especially in terms of safety-critical applications. Thus, augmentations to the current systems and even completely new systems are under investigation. These are usually summarized under the abbreviation Global Navigation Satellite Systems (GNSSs). The various types of GNSS are described where emphasis is put on the future US and European contributions to the second-generation GNSS, i.e., the modernized GPS and the definition of the new European Galileo system. These two systems may be characterized as "compatible competitors"—thus, one might ask for whom the bell tolls.

  4. 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

  5. [Accompany death].

    PubMed

    Salvador Borrell, Montserrat

    2010-11-01

    One of the roles of nursing is to take care of the patients in terminal situation. The time, the experience, the formation, and the personal and professional attitudes that the nurse has will propitiate that taking care of moribund patients might turn into one of the more rewarding human experiences in life. There for, it is indispensable that nurses assume death as a natural and inevitable reality to achieve. The principal aim of the study is to evaluate the competence of confrontation and the autoefficiency of the welfare among nurses who work with adult patients at the end of the life. Descriptive study realized in the units of Oncology, Hametology and Palliative Care of the following centers: La Fe, Clínico, Dr. Peset, H. General, Arnau de Vilanova and Dr. Moliner de Portacoelli in Valencia (Spain). The following instruments were used: the Bugen Scale of confrontation of the Death (1980-1981) and the Robbins Scale of Autoefficiency (1992). Data suggests that major coping gives major autoeffciency and vice versa. The realized study opens numerous questions, specially related with training and the burden of preparation along the whole professional career, in order to achieve competence for coping and autoefficiency.

  6. 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

  7. Invariant death

    PubMed Central

    Frank, Steven A.

    2016-01-01

    In nematodes, environmental or physiological perturbations alter death’s scaling of time. In human cancer, genetic perturbations alter death’s curvature of time. Those changes in scale and curvature follow the constraining contours of death’s invariant geometry. I show that the constraints arise from a fundamental extension to the theories of randomness, invariance and scale. A generalized Gompertz law follows. The constraints imposed by the invariant Gompertz geometry explain the tendency of perturbations to stretch or bend death’s scaling of time. Variability in death rate arises from a combination of constraining universal laws and particular biological processes. PMID:27785361

  8. 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

  9. [The role of maternal care in reducing perinatal and neonatal mortality in developing countries].

    PubMed

    Nicolau, S; Teodoru, G; Popa, I; Nicolescu, S; Feldioreanu, E

    1989-01-01

    -30/1000 live births and the total annual toll reaches 750,000 to 1 million globally mostly because of nonsterile instruments. 90% of tetanus incidence in Romania was eradicated by vaccination. Preventive measures can reduce mortality: education of women on health and hygiene, avoidance of heavy labor during pregnancy, family planning services, aseptic techniques, vaccination against tetanus and other infectious diseases, chemical prophylaxis against malaria, improved obstetrical care, consolidated support system, and community participation.

  10. Fucoidan induces Toll-like receptor 4-regulated reactive oxygen species and promotes endoplasmic reticulum stress-mediated apoptosis in lung cancer

    PubMed Central

    Hsu, Hsien-Yeh; Lin, Tung-Yi; Lu, Mei-Kuang; Leng, Pei-Ju; Tsao, Shu-Ming; Wu, Yu-Chung

    2017-01-01

    Fucoidan, a sulfated polysaccharide extracted from brown algae, exhibits anti-cancer activity. However, the effects and mechanism of fucoidan-induced apoptosis via endoplasmic reticulum (ER) stress is unclear. In this study, we demonstrated that fucoidan prevents tumorigenesis and reduces tumor size in LLC1-xenograft male C57BL/6 mice. Fucoidan induces an ER stress response by activating the PERK-ATF4-CHOP pathway, resulting in apoptotic cell death in vitro and in vivo. Furthermore, ATF4 knockdown abolishes fucoidan-induced CHOP expression and rescues cell viability. Specifically, fucoidan increases intracellular reactive oxygen species (ROS), which increase ATF4 and CHOP in lung cancer cells. Using the ROS scavenger N-acetyl-l-cysteine (NAC), we found that ROS generation is involved in fucoidan-induced ER stress-mediated apoptosis. Moreover, via Toll-like receptor 4 (TLR4) knockdown, we demonstrated that fucoidan-induced ROS and CHOP expression were attenuated. Our study is the first to identify a novel mechanism for the antitumor activity of fucoidan. We showed that fucoidan inhibits tumor viability by activating the TLR4/ROS/ER stress axis and the downstream PERK-ATF4-CHOP pathway, leading to apoptosis and suppression of lung cancer cell progression. Together, these results indicate that fucoidan is a potential preventive and therapeutic agent for lung cancer that acts via activation of ROS-dependent ER stress pathways. PMID:28332554

  11. Fucoidan induces Toll-like receptor 4-regulated reactive oxygen species and promotes endoplasmic reticulum stress-mediated apoptosis in lung cancer.

    PubMed

    Hsu, Hsien-Yeh; Lin, Tung-Yi; Lu, Mei-Kuang; Leng, Pei-Ju; Tsao, Shu-Ming; Wu, Yu-Chung

    2017-03-23

    Fucoidan, a sulfated polysaccharide extracted from brown algae, exhibits anti-cancer activity. However, the effects and mechanism of fucoidan-induced apoptosis via endoplasmic reticulum (ER) stress is unclear. In this study, we demonstrated that fucoidan prevents tumorigenesis and reduces tumor size in LLC1-xenograft male C57BL/6 mice. Fucoidan induces an ER stress response by activating the PERK-ATF4-CHOP pathway, resulting in apoptotic cell death in vitro and in vivo. Furthermore, ATF4 knockdown abolishes fucoidan-induced CHOP expression and rescues cell viability. Specifically, fucoidan increases intracellular reactive oxygen species (ROS), which increase ATF4 and CHOP in lung cancer cells. Using the ROS scavenger N-acetyl-l-cysteine (NAC), we found that ROS generation is involved in fucoidan-induced ER stress-mediated apoptosis. Moreover, via Toll-like receptor 4 (TLR4) knockdown, we demonstrated that fucoidan-induced ROS and CHOP expression were attenuated. Our study is the first to identify a novel mechanism for the antitumor activity of fucoidan. We showed that fucoidan inhibits tumor viability by activating the TLR4/ROS/ER stress axis and the downstream PERK-ATF4-CHOP pathway, leading to apoptosis and suppression of lung cancer cell progression. Together, these results indicate that fucoidan is a potential preventive and therapeutic agent for lung cancer that acts via activation of ROS-dependent ER stress pathways.

  12. 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…

  13. [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.

  14. Toll-like receptor agonists in cancer therapy

    PubMed Central

    Adams, Sylvia

    2010-01-01

    Toll-like receptors (TLRs) are pattern-recognition receptors related to the Drosophila Toll protein. TLR activation alerts the immune system to microbial products and initiates innate and adaptive immune responses. The naturally powerful immunostimulatory property of TLR agonists can be exploited for active immunotherapy against cancer. Antitumor activity has been demonstrated in several cancers, and TLR agonists are now undergoing extensive clinical investigation. This review discusses recent advances in the field and highlights potential opportunities for the clinical development of TLR agonists as single agent immunomodulators, vaccine adjuvants and in combination with conventional cancer therapies. PMID:20563267

  15. Crude Extracts, Flavokawain B and Alpinetin Compounds from the Rhizome of Alpinia mutica Induce Cell Death via UCK2 Enzyme Inhibition and in Turn Reduce 18S rRNA Biosynthesis in HT-29 Cells

    PubMed Central

    Abdullah, Rasedee; Kassim, Nur Kartinee Bt; Rosli, Rozita; Yeap, Swee Keong; Waziri, Peter; Etti, Imaobong Christopher; Bello, Muhammad Bashir

    2017-01-01

    Uridine-cytidine kinase 2 is an enzyme that is overexpressed in abnormal cell growth and its implication is considered a hallmark of cancer. Due to the selective expression of UCK2 in cancer cells, a selective inhibition of this key enzyme necessitates the discovery of its potential inhibitors for cancer chemotherapy. The present study was carried out to demonstrate the potentials of natural phytochemicals from the rhizome of Alpinia mutica to inhibit UCK2 useful for colorectal cancer. Here, we employed the used of in vitro to investigate the effectiveness of natural UCK2 inhibitors to cause HT-29 cell death. Extracts, flavokawain B, and alpinetin compound from the rhizome of Alpinia mutica was used in the study. The study demonstrated that the expression of UCK2 mRNA were substantially reduced in treated HT-29 cells. In addition, downregulation in expression of 18S ribosomal RNA was also observed in all treated HT-29 cells. This was confirmed by fluorescence imaging to measure the level of expression of 18S ribosomal RNA in live cell images. The study suggests the possibility of MDM2 protein was downregulated and its suppression subsequently activates the expression of p53 during inhibition of UCK2 enzyme. The expression of p53 is directly linked to a blockage of cell cycle progression at G0/G1 phase and upregulates Bax, cytochrome c, and caspase 3 while Bcl2 was deregulated. In this respect, apoptosis induction and DNA fragmentation were observed in treated HT-29 cells. Initial results from in vitro studies have shown the ability of the bioactive compounds of flavokawain B and alpinetin to target UCK2 enzyme specifically, inducing cell cycle arrest and subsequently leading to cancer cell death, possibly through interfering the MDM2-p53 signalling pathway. These phenomena have proven that the bioactive compounds could be useful for future therapeutic use in colon cancer. PMID:28103302

  16. Crude Extracts, Flavokawain B and Alpinetin Compounds from the Rhizome of Alpinia mutica Induce Cell Death via UCK2 Enzyme Inhibition and in Turn Reduce 18S rRNA Biosynthesis in HT-29 Cells.

    PubMed

    Malami, Ibrahim; Abdul, Ahmad Bustamam; Abdullah, Rasedee; Kassim, Nur Kartinee Bt; Rosli, Rozita; Yeap, Swee Keong; Waziri, Peter; Etti, Imaobong Christopher; Bello, Muhammad Bashir

    2017-01-01

    Uridine-cytidine kinase 2 is an enzyme that is overexpressed in abnormal cell growth and its implication is considered a hallmark of cancer. Due to the selective expression of UCK2 in cancer cells, a selective inhibition of this key enzyme necessitates the discovery of its potential inhibitors for cancer chemotherapy. The present study was carried out to demonstrate the potentials of natural phytochemicals from the rhizome of Alpinia mutica to inhibit UCK2 useful for colorectal cancer. Here, we employed the used of in vitro to investigate the effectiveness of natural UCK2 inhibitors to cause HT-29 cell death. Extracts, flavokawain B, and alpinetin compound from the rhizome of Alpinia mutica was used in the study. The study demonstrated that the expression of UCK2 mRNA were substantially reduced in treated HT-29 cells. In addition, downregulation in expression of 18S ribosomal RNA was also observed in all treated HT-29 cells. This was confirmed by fluorescence imaging to measure the level of expression of 18S ribosomal RNA in live cell images. The study suggests the possibility of MDM2 protein was downregulated and its suppression subsequently activates the expression of p53 during inhibition of UCK2 enzyme. The expression of p53 is directly linked to a blockage of cell cycle progression at G0/G1 phase and upregulates Bax, cytochrome c, and caspase 3 while Bcl2 was deregulated. In this respect, apoptosis induction and DNA fragmentation were observed in treated HT-29 cells. Initial results from in vitro studies have shown the ability of the bioactive compounds of flavokawain B and alpinetin to target UCK2 enzyme specifically, inducing cell cycle arrest and subsequently leading to cancer cell death, possibly through interfering the MDM2-p53 signalling pathway. These phenomena have proven that the bioactive compounds could be useful for future therapeutic use in colon cancer.

  17. 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.

  18. 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

  19. 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…

  20. 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

  1. Aging and Death Education.

    ERIC Educational Resources Information Center

    Pinder, Margaret M.; Hayslip, Bert, Jr.

    1980-01-01

    The elderly death rate is somewhat higher than the death rate in general. Numbers of schools with gerontological curricula and frequency of death education courses are positively related to elderly death rates. The contention that elderly deaths have less social impact is not supported. (JAC)

  2. 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.

  3. Determination of death: Metaphysical and biomedical discourse.

    PubMed

    Jakušovaitė, Irayda; Luneckaitė, Žydrunė; Peičius, Eimantas; Bagdonaitė, Živilė; Riklikienė, Olga; Stankevičius, Edgaras

    2016-01-01

    The prominence of biomedical criteria relying on brain death reduces the impact of metaphysical, anthropological, psychosocial, cultural, religious, and legal aspects disclosing the real value and essence of human life. The aim of this literature review is to discuss metaphysical and biomedical approaches toward death and their complimentary relationship in the determination of death. A critical appraisal of theoretical and scientific evidence and legal documents supported analytical discourse. In the metaphysical discourse of death, two main questions about what human death is and how to determine the fact of death clearly separate the ontological and epistemological aspects of death. During the 20th century, various understandings of human death distinguished two different approaches toward the human: the human is a subject of activities or a subject of the human being. Extinction of the difference between the entities and the being, emphasized as rational-logical instrumentation, is not sufficient to understand death thoroughly. Biological criteria of death are associated with biological features and irreversible loss of certain cognitive capabilities. Debating on the question "Does a brain death mean death of a human being?" two approaches are considering: the body-centrist and the mind-centrist. By bridging those two alternatives human death appears not only as biomedical, but also as metaphysical phenomenon. It was summarized that a predominance of clinical criteria for determination of death in practice leads to medicalization of death and limits the holistic perspective toward individual's death. Therefore, the balance of metaphysical and biomedical approaches toward death and its determination would decrease the medicalization of the concept of death.

  4. Role of Toll-Like Receptors in Tuberculosis Infection

    PubMed Central

    Biyikli, Oguz Oben; Baysak, Aysegul; Ece, Gulfem; Oz, Adnan Tolga; Ozhan, Mustafa Hikmet; Berdeli, Afig

    2016-01-01

    Background One-third of the world’s population is infected with Mycobacterium tuberculosis. Investigation of Toll-like receptors (TLRs) has revealed new information regarding the immunopathogenesis of this disease. Toll-like receptors can recognize various ligands with a lipoprotein structure in the bacilli. Toll-like receptor 2 and TLR-4 have been identified in association with tuberculosis infection. Objectives The aim of our study was to investigate the relationship between TLR polymorphism and infection progress. Methods Twenty-nine patients with a radiologically, microbiologically, and clinically proven active tuberculosis diagnosis were included in this 25-month study. Toll-like receptor 2 and TLR-4 polymorphisms and allele distributions were compared between these 29 patients and 100 healthy control subjects. Peripheral blood samples were taken from all patients. Genotyping of TLR-2, TLR-4, and macrophage migration inhibitory factor was performed. The extraction step was completed with a Qiagen mini blood purification system kit (Qiagen, Ontario, Canada) using a peripheral blood sample. The genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism. Results In total, 19 of the 29 patients with tuberculosis infection had a TLR-2 polymorphism, and 20 of the 100 healthy subjects had a TLR-2 polymorphism (P < 0.001). The TLR-4 polymorphism and interferon-γ allele distributions were not statistically correlated. Conclusions Toll-like receptor 2 polymorphism is a risk factor for tuberculosis infection. The limiting factor in this study was the lack of investigation of the interferon-γ and tumor necrosis factor-α levels, which are important in the development of infection. Detection of lower levels of these cytokines in bronchoalveolar lavage specimens, especially among patients with TLR-2 defects, will provide new data that may support the results of this study. PMID:27942355

  5. 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.

  6. 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 ...

  7. [Unobserved death of an infant: cot death?].

    PubMed

    van Wouwe, J P; Dandachli, T H; Huber, J

    1999-10-02

    Three children, two girls aged 8 and 12 months and one boy aged 7 weeks, were found dead unexpectedly. Autopsy revealed pneumonia in two children, following which the diagnosis of 'natural, explained death' was made; one child showed no abnormalities and the diagnosis read 'natural, unexplained death' (cot death). Autopsy may currently only be performed with parental permission or, in case of doubt about unnatural cause of death, by order of the public prosecutor. The authors propose routine performance of a protocolled autopsy by GP, pediatrician, pathologist and medical examiner in order to avoid subsequent and possibly incorrect doubt about the cause of death.

  8. Toll Like Receptor 4 Affects the Cerebral Biochemical Changes Induced by MPTP Treatment.

    PubMed

    Conte, Carmela; Roscini, Luca; Sardella, Roccaldo; Mariucci, Giuseppina; Scorzoni, Stefania; Beccari, Tommaso; Corte, Laura

    2017-02-01

    The etiology and pathogenesis of Parkinson's disease (PD) are still unclear. However, multiple lines of evidence suggest a critical role of the toll like receptor 4 (TLR4) in inflammatory response and neuronal death. Neuroinflammation may be associated with the misfolding and aggregation of proteins accompanied by a change in their secondary structure. Recent findings also suggest that biochemical perturbations in cerebral lipid content could contribute to the pathogenesis of central nervous system (CNS) disorders, including PD. Thus, it is of great importance to determine the biochemical changes that occur in PD. In this respect, Fourier Transform Infrared (FTIR) spectroscopy represents a useful tool to detect molecular alterations in biological systems in response to stress stimuli. By relying upon FTIR approach, this study was designed to elucidate the potential role of TLR4 in biochemical changes induced by methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin in a mouse model of PD. The analysis of the FTIR spectra was performed in different brain regions of both wild type (WT) and toll like receptor 4-deficient (TLR4(-/-)) mice. It revealed that each brain region exhibited a characteristic molecular fingerprint at baseline, with no significant differences between genotypes. Conversely, WT and TLR4(-/-) mice showed differential biochemical response to MPTP toxicity, principally related to lipid and protein composition. These differences appeared to be characteristic for each brain area. Furthermore, the present study showed that WT mice resulted more vulnerable than TLR4(-/-) animals to striatal dopamine (DA) depletion following MPTP treatment. These results support the hypothesis of a possible involvement of TLR4 in biochemical changes occurring in neurodegeneration.

  9. Sigma-1 (σ₁) receptor deficiency reduces β-amyloid(25-35)-induced hippocampal neuronal cell death and cognitive deficits through suppressing phosphorylation of the NMDA receptor NR2B.

    PubMed

    Yin, Jun; Sha, Sha; Chen, Tingting; Wang, Conghui; Hong, Juan; Jie, Pinghui; Zhou, Rong; Li, Lin; Sokabe, Masahiro; Chen, Ling

    2015-02-01

    In early Alzheimer's disease (AD) brain, reduction of sigma-1 receptors (σ1R) is detected. In this study, we employed male heterozygous σ1R knockout (σ1R(+/-)) mice showing normal cognitive performance to investigate association of σ1R deficiency with AD risk. Herein we report that a single injection (i.c.v.) of Aβ(25-35) impaired spatial memory with approximately 25% death of pyramidal cells in the hippocampal CA1 region of WT mice (Aβ(25-35)-WT mice), whereas it did not cause such impairments in σ1R(+/-) mice (Aβ(25-35)-σ1R(+/-) mice). Compared with WT mice, Aβ(25-35)-WT mice showed increased levels of NMDA-activated currents (INMDA) and NR2B phosphorylation (phospho-NR2B) in the hippocampal CA1 region at 48 h after Aβ25-35-injection (post-Aβ(25-35)) followed by approximately 40% decline at 72 h post-Aβ(25-35) of their respective control levels, which was inhibited by the σ1R antagonist NE100. In Aβ(25-35)-WT mice, the administration of NR2B inhibitor Ro25-6981 or NE100 on day 1-4 post-Aβ(25-35) attenuated the memory deficits and loss of pyramidal cells. By contrast, Aβ(25-35)-σ1R(+/-) mice showed a slight increase in the INMDA density and the phospho-NR2B at 48 h or 72 h post-Aβ25-35 compared to σ1R(+/-) mice. Treatment with σ1R agonist PRE084 in Aβ(25-35)-σ1R(+/-) mice caused the same changes in the INMDA density and the phospho-NR2B as those in Aβ(25-35)-WT mice. Furthermore, Aβ(25-35)-σ1R(+/-) mice treated with the NMDA receptor agonist NMDA or PRE084 on day 1-4 post-Aβ(25-35) showed a loss of neuronal cells and memory impairment. These results indicate that the σ1R deficiency can reduce Aβ(25-35)-induced neuronal cell death and cognitive deficits through suppressing Aβ(25-35)-enhanced NR2B phosphorylation.

  10. Recognition of lipopeptide patterns by Toll-like receptor 2-Toll-like receptor 6 heterodimer.

    PubMed

    Kang, Jin Young; Nan, Xuehua; Jin, Mi Sun; Youn, Suk-Jun; Ryu, Young Hee; Mah, Shinjee; Han, Seung Hyun; Lee, Hayyoung; Paik, Sang-Gi; Lee, Jie-Oh

    2009-12-18

    Toll-like receptor 2 (TLR2) initiates potent immune responses by recognizing diacylated and triacylated lipopeptides. Its ligand specificity is controlled by whether it heterodimerizes with TLR1 or TLR6. We have determined the crystal structures of TLR2-TLR6-diacylated lipopeptide, TLR2-lipoteichoic acid, and TLR2-PE-DTPA complexes. PE-DTPA, 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N-diethylenetriaminepentaacetic acid, is a synthetic phospholipid derivative. Two major factors contribute to the ligand specificity of TLR2-TLR1 or TLR2-TLR6 heterodimers. First, the lipid channel of TLR6 is blocked by two phenylalanines. Simultaneous mutation of these phenylalanines made TLR2-TLR6 fully responsive not only to diacylated but also to triacylated lipopeptides. Second, the hydrophobic dimerization interface of TLR2-TLR6 is increased by 80%, which compensates for the lack of amide lipid interaction between the lipopeptide and TLR2-TLR6. The structures of the TLR2-lipoteichoic acid and the TLR2-PE-DTPA complexes demonstrate that a precise interaction pattern of the head group is essential for a robust immune response by TLR2 heterodimers.

  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.

  12. Deaths from heart failure: using coarsened exact matching to correct cause-of-death statistics

    PubMed Central

    2010-01-01

    Background Incomplete information on death certificates makes recorded cause-of-death data less useful for public health monitoring and planning. Certifying physicians sometimes list only the mode of death without indicating the underlying disease or diseases that led to the death. Inconsistent cause-of-death assignment among cardiovascular causes of death is of particular concern. This can prevent valid epidemiologic comparisons across countries and over time. Methods We propose that coarsened exact matching be used to infer the underlying causes of death where only the mode of death is known. We focus on the case of heart failure in US, Mexican, and Brazilian death records. Results Redistribution algorithms derived using this method assign the largest proportion of heart failure deaths to ischemic heart disease in all three countries (53%, 26%, and 22% respectively), with larger proportions assigned to hypertensive heart disease and diabetes in Mexico and Brazil (16% and 23% vs. 7% for hypertensive heart disease, and 13% and 9% vs. 6% for diabetes). Reassigning these heart failure deaths increases the US ischemic heart disease mortality rate by 6%. Conclusions The frequency with which physicians list heart failure in the causal chain for various underlying causes of death allows for inference about how physicians use heart failure on the death certificate in different settings. This easy-to-use method has the potential to reduce bias and increase comparability in cause-of-death data, thereby improving the public health utility of death records. PMID:20388206

  13. 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.

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

    PubMed Central

    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. Lifestyle and host defense mechanisms of the dung beetle, Euoniticellus intermedius: the toll signaling pathway.

    PubMed

    Hull, Rodney; Alaouna, Mohamed; Khanyile, Lucky; Byrne, Marcus; Ntwasa, Monde

    2013-01-01

    The dung beetle, Euoniticellus intermedius (Reiche) (Coleoptera: Scarabaeidae) is an important ecological and agricultural agent. Their main activity, the burying of dung, improves quality of the soil and reduces pests that could cause illness in animals. E. intermedius are therefore important for agriculture and for good maintenance of the environment, and are regarded as effective biological control agents for parasites of the gastrointestinal tract in livestock. The ability of E. intermedius to co-exist comfortably with many microorganisms, some of which are important human pathogens, stimulated our interest in its host defense strategies. The aim of this study was to investigate the Toll signaling pathway, which is strongly activated by fungi. Gene expression associated with fungal infection was analyzed by using 2-D gel electrophoresis and mass spectroscopy. Furthermore, the partial adult transcriptome was investigated for the presence of known immune response genes by using high-throughput sequencing and bioinformatics. The results presented here suggest that E. intermedius responds to fungal challenge via the Toll signaling pathway.

  16. Standardization and Interoperability Problems of European Electronic Tolling Service (EETS)

    NASA Astrophysics Data System (ADS)

    Nowacki, Gabriel; Mitraszewska, Izabella; Kamiński, Tomasz; Potapczuk, Włodzimierz; Kallweit, Thomas

    The paper refers to some standardization and interoperability problems of the European Electronic Toll Service (EETS) implementation in European Union. The existing EETS systems in the European Union member states are not interoperable due to many differences among them. European Commission has taken bold steps to address that issue. The first one was the 2004/52/EC Directive on the interoperability in the Community. The second one was the decision to launch Europe's own Galileo system. The third was the EC decision from 6th October 2009, based on Research Charging Interoperability (RCI) and the Common Electronic Fee Collection System for a Road Tolling European Service(CESARE) projects. Furthermore, the Motor Transport Institute researches, concerning the mentioned matters have been presented too.

  17. 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.

  18. Brain Death Determination.

    PubMed

    Spinello, Irene M

    2015-09-01

    In the United States, each year 1% to 2% of deaths are brain deaths. Considerable variation in the practice of determining brain death still remains, despite the publication of practice parameters in 1995 and an evidence-based guideline update in 2010. This review is intended to give bedside clinicians an overview of definition, the causes and pitfalls of misdiagnosing brain death, and a focus on the specifics of the brain death determination process.

  19. 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

  20. 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

  1. 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

  2. Alternate transcription of the Toll-like receptor signaling cascade

    PubMed Central

    Wells, Christine A; Chalk, Alistair M; Forrest, Alistair; Taylor, Darrin; Waddell, Nic; Schroder, Kate; Himes, S Roy; Faulkner, Geoffrey; Lo, Sandra; Kasukawa, Takeya; Kawaji, Hideya; Kai, Chikatoshi; Kawai, Jun; Katayama, Shintaro; Carninci, Piero; Hayashizaki, Yoshihide; Hume, David A; Grimmond, Sean M

    2006-01-01

    Background Alternate splicing of key signaling molecules in the Toll-like receptor (Tlr) cascade has been shown to dramatically alter the signaling capacity of inflammatory cells, but it is not known how common this mechanism is. We provide transcriptional evidence of widespread alternate splicing in the Toll-like receptor signaling pathway, derived from a systematic analysis of the FANTOM3 mouse data set. Functional annotation of variant proteins was assessed in light of inflammatory signaling in mouse primary macrophages, and the expression of each variant transcript was assessed by splicing arrays. Results A total of 256 variant transcripts were identified, including novel variants of Tlr4, Ticam1, Tollip, Rac1, Irak1, 2 and 4, Mapk14/p38, Atf2 and Stat1. The expression of variant transcripts was assessed using custom-designed splicing arrays. We functionally tested the expression of Tlr4 transcripts under a range of cytokine conditions via northern and quantitative real-time polymerase chain reaction. The effects of variant Mapk14/p38 protein expression on macrophage survival were demonstrated. Conclusion Members of the Toll-like receptor signaling pathway are highly alternatively spliced, producing a large number of novel proteins with the potential to functionally alter inflammatory outcomes. These variants are expressed in primary mouse macrophages in response to inflammatory mediators such as interferon-γ and lipopolysaccharide. Our data suggest a surprisingly common role for variant proteins in diversification/repression of inflammatory signaling. PMID:16507160

  3. Study on effect of toll station on the traffic flow on three-line road

    NASA Astrophysics Data System (ADS)

    Wang, Guang-yu; Li, Wen-bo; Feng, Yu-jie

    2013-03-01

    Based on the NaSch Model, a new three-line cellular automata model emphasizing toll station on the high ways is built to discuss the impact of different amount of toll stations on the traffic flow. The models are as follows: Firstly, the process of cars driving is simulated. Secondly, the process of pulling station is simulated. In this part, two Cellular Automata Models are built separately for two cases, three tollbooths in the toll station and four tollbooths. The result shows that when the density of cars is on medium level, comparing with the toll station with three tollbooths, the toll station with four tollbooths can remit the traffic congestion effectively, but when the density of cars is too high or too low, the toll station with three tollbooths can do better.

  4. Whither brain death?

    PubMed

    Bernat, James L

    2014-01-01

    The publicity surrounding the recent McMath and Muñoz cases has rekindled public interest in brain death: the familiar term for human death determination by showing the irreversible cessation of clinical brain functions. The concept of brain death was developed decades ago to permit withdrawal of therapy in hopeless cases and to permit organ donation. It has become widely established medical practice, and laws permit it in all U.S. jurisdictions. Brain death has a biophilosophical justification as a standard for determining human death but remains poorly understood by the public and by health professionals. The current controversies over brain death are largely restricted to the academy, but some practitioners express ambivalence over whether brain death is equivalent to human death. Brain death remains an accepted and sound concept, but more work is necessary to establish its biophilosophical justification and to educate health professionals and the public.

  5. Methods for determining time of death.

    PubMed

    Madea, Burkhard

    2016-12-01

    Medicolegal death time estimation must estimate the time since death reliably. Reliability can only be provided empirically by statistical analysis of errors in field studies. Determining the time since death requires the calculation of measurable data along a time-dependent curve back to the starting point. Various methods are used to estimate the time since death. The current gold standard for death time estimation is a previously established nomogram method based on the two-exponential model of body cooling. Great experimental and practical achievements have been realized using this nomogram method. To reduce the margin of error of the nomogram method, a compound method was developed based on electrical and mechanical excitability of skeletal muscle, pharmacological excitability of the iris, rigor mortis, and postmortem lividity. Further increasing the accuracy of death time estimation involves the development of conditional probability distributions for death time estimation based on the compound method. Although many studies have evaluated chemical methods of death time estimation, such methods play a marginal role in daily forensic practice. However, increased precision of death time estimation has recently been achieved by considering various influencing factors (i.e., preexisting diseases, duration of terminal episode, and ambient temperature). Putrefactive changes may be used for death time estimation in water-immersed bodies. Furthermore, recently developed technologies, such as H magnetic resonance spectroscopy, can be used to quantitatively study decompositional changes. This review addresses the gold standard method of death time estimation in forensic practice and promising technological and scientific developments in the field.

  6. 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.

  7. 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

  8. Racial bias in federal nutrition policy, Part II: Weak guidelines take a disproportionate toll.

    PubMed Central

    Bertron, P.; Barnard, N. D.; Mills, M.

    1999-01-01

    Many diet-related chronic diseases take a disproportionate toll among members of racial minorities. Research shows the prevalence of diabetes, hypertension, cancer, and heart disease is higher among various ethnic groups compared with whites. The Guidelines and the Food Guide Pyramid, however, promote the use of multiple servings of meats and dairy products each day and do not encourage replacing these foods with vegetables, legumes, fruits, and grains. The Dietary Guidelines for Americans encourage a 30% caloric reduction in fat intake and make no provision for further reductions for those who wish to minimize health risks. Abundant evidence has shown that regular exercise combined with diets lower in fat and richer in plant products than is encouraged by the Dietary Guidelines for Americans are associated with reduced risk of these chronic conditions. While ineffective Dietary Guidelines potentially put all Americans at unnecessary risk, this is particularly true for those groups hardest hit by chronic disease. PMID:10333669

  9. Arterial Catheterization and Infection: Toll-like receptors in defense against microorganisms and therapeutic implications

    PubMed Central

    Hambsch, Zakary J.; Kerfeld, Mitchell J.; Kirkpatrick, Daniel R.; McEntire, Dan M.; Reisbig, Mark D.; Youngblood, Charles F.; Agrawal, Devendra K.

    2015-01-01

    Radial artery catheterization has become a preferred route over femoral artery catheterization, in order to monitor the blood pressure of hemodynamically unstable patients or for repeated sampling of arterial blood gases. While the incidence of catheter-related infection is lower in the radial artery than the femoral artery, infection remains a major issue that requires attention. In this review of the literature, we discuss infectious complications of radial artery catheterization, with a focus on various risk factors and establishing the most common causative agents. We also critically review the role of the innate immune system involving Toll-like receptors (TLRs) in host-defense, with the goal of establishing a common pathway used by the innate immune system via TLRs to combat the pathogens that most commonly cause infection in radial artery catheterization. If this pathway can be therapeutically manipulated to preemptively attack pathogenic agents, immunomodulation may be an option in reducing the incidence of infection in this procedure. PMID:26271949

  10. Disruption of IP₃R2-mediated Ca²⁺ signaling pathway in astrocytes ameliorates neuronal death and brain damage while reducing behavioral deficits after focal ischemic stroke.

    PubMed

    Li, Hailong; Xie, Yicheng; Zhang, Nannan; Yu, Yang; Zhang, Qiao; Ding, Shinghua

    2015-12-01

    Inositol trisphosphate receptor (IP3R)-mediated intracellular Ca(2+) increase is the major Ca(2+) signaling pathway in astrocytes in the central nervous system (CNS). Ca(2+) increases in astrocytes have been found to modulate neuronal function through gliotransmitter release. We previously demonstrated that astrocytes exhibit enhanced Ca(2+) signaling in vivo after photothrombosis (PT)-induced ischemia, which is largely due to the activation of G-protein coupled receptors (GPCRs). The aim of this study is to investigate the role of astrocytic IP3R-mediated Ca(2+) signaling in neuronal death, brain damage and behavior outcomes after PT. For this purpose, we conducted experiments using homozygous type 2 IP3R (IP3R2) knockout (KO) mice. Histological and immunostaining studies showed that IP3R2 KO mice were indeed deficient in IP3R2 in astrocytes and exhibited normal brain cytoarchitecture. IP3R2 KO mice also had the same densities of S100β+ astrocytes and NeuN+ neurons in the cortices, and exhibited the same glial fibrillary acidic protein (GFAP) and glial glutamate transporter (GLT-1) levels in the cortices and hippocampi as compared with wild type (WT) mice. Two-photon (2-P) imaging showed that IP3R2 KO mice did not exhibit ATP-induced Ca(2+) waves in vivo in the astrocytic network, which verified the disruption of IP3R-mediated Ca(2+) signaling in astrocytes of these mice. When subject to PT, IP3R2 KO mice had smaller infarction than WT mice in acute and chronic phases of ischemia. IP3R2 KO mice also exhibited less neuronal apoptosis, reactive astrogliosis, and tissue loss than WT mice. Behavioral tests, including cylinder, hanging wire, pole and adhesive tests, showed that IP3R2 KO mice exhibited reduced functional deficits after PT. Collectively, our study demonstrates that disruption of astrocytic Ca(2+) signaling by deleting IP3R2s has beneficial effects on neuronal and brain protection and functional deficits after stroke. These findings reveal a novel non

  11. Death at the Worksite: Helping Grieving Family Members

    MedlinePlus

    ... Understand Your Own Response to Death Understanding your personal response to death can reduce your anxieties and ... and grief. The more you understand your own personal experience, the more you will be able to ...

  12. Are Death Anxiety and Death Depression Distinct Entities?

    ERIC Educational Resources Information Center

    Alvarado, Katherine A.; And Others

    1993-01-01

    Administered Death Anxiety Scale and Death Depression Scale to 200 individuals. Two scales correlated 0.55. Factor analysis of combined 32 items revealed factors: "death anxiety" having highest factor loadings with Death Anxiety Scale, "death depression" having highest factor loadings with Death Depression Scale, "death of…

  13. 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…

  14. Divergent Functions of Toll-like Receptors during Bacterial Lung Infections

    PubMed Central

    Baral, Pankaj; Batra, Sanjay; Zemans, Rachel L.; Downey, Gregory P.

    2014-01-01

    Lower respiratory tract infections caused by bacteria are a major cause of death in humans irrespective of sex, race, or geography. Indeed, accumulated data indicate greater mortality and morbidity due to these infections than cancer, malaria, or HIV infection. Successful recognition of, followed by an appropriate response to, bacterial pathogens in the lungs is crucial for effective pulmonary host defense. Although the early recruitment and activation of neutrophils in the lungs is key in the response against invading microbial pathogens, other sentinels, such as alveolar macrophages, epithelial cells, dendritic cells, and CD4+ T cells, also contribute to the elimination of the bacterial burden. Pattern recognition receptors, such as Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain–like receptors, are important for recognizing and responding to microbes during pulmonary infections. However, bacterial pathogens have acquired crafty evasive strategies to circumvent the pattern recognition receptor response and thus establish infection. Increased understanding of the function of TLRs and evasive mechanisms used by pathogens during pulmonary infection will deepen our knowledge of immunopathogenesis and is crucial for developing effective therapeutic and/or prophylactic measures. This review summarizes current knowledge of the multiple roles of TLRs in bacterial lung infections and highlights the mechanisms used by pathogens to modulate or interfere with TLR signaling in the lungs. PMID:25033332

  15. Toll-like Receptors in the Vascular System: Sensing the Dangers Within

    PubMed Central

    McCarthy, Cameron G.; Webb, R. Clinton

    2016-01-01

    Toll-like receptors (TLRs) are components of the innate immune system that respond to exogenous infectious ligands (pathogen-associated molecular patterns, PAMPs) and endogenous molecules that are released during host tissue injury/death (damage-associated molecular patterns, DAMPs). Interaction of TLRs with their ligands leads to activation of downstream signaling pathways that induce an immune response by producing inflammatory cytokines, type I interferons (IFN), and other inflammatory mediators. TLR activation affects vascular function and remodeling, and these molecular events prime antigen-specific adaptive immune responses. Despite the presence of TLRs in vascular cells, the exact mechanisms whereby TLR signaling affects the function of vascular tissues are largely unknown. Cardiovascular diseases are considered chronic inflammatory conditions, and accumulating data show that TLRs and the innate immune system play a determinant role in the initiation and development of cardiovascular diseases. This evidence unfolds a possibility that targeting TLRs and the innate immune system may be a novel therapeutic goal for these conditions. TLR inhibitors and agonists are already in clinical trials for inflammatory conditions such as asthma, cancer, and autoimmune diseases, but their study in the context of cardiovascular diseases is in its infancy. In this article, we review the current knowledge of TLR signaling in the cardiovascular system with an emphasis on atherosclerosis, hypertension, and cerebrovascular injury. Furthermore, we address the therapeutic potential of TLR as pharmacological targets in cardiovascular disease and consider intriguing research questions for future study. PMID:26721702

  16. NOD2 and Toll-Like Receptors Are Nonredundant Recognition Systems of Mycobacterium tuberculosis

    PubMed Central

    2005-01-01

    Infection with Mycobacterium tuberculosis is one of the leading causes of death worldwide. Recognition of M. tuberculosis by pattern recognition receptors is crucial for activation of both innate and adaptive immune responses. In the present study, we demonstrate that nucleotide-binding oligomerization domain 2 (NOD2) and Toll-like receptors (TLRs) are two nonredundant recognition mechanisms of M. tuberculosis. CHO cell lines transfected with human TLR2 or TLR4 were responsive to M. tuberculosis. TLR2 knock-out mice displayed more than 50% defective cytokine production after stimulation with mycobacteria, whereas TLR4-defective mice also released 30% less cytokines compared to controls. Similarly, HEK293T cells transfected with NOD2 responded to stimulation with M. tuberculosis. The important role of NOD2 for the recognition of M. tuberculosis was demonstrated in mononuclear cells of individuals homozygous for the 3020insC NOD2 mutation, who showed an 80% defective cytokine response after stimulation with M. tuberculosis. Finally, the mycobacterial TLR2 ligand 19-kDa lipoprotein and the NOD2 ligand muramyl dipeptide synergized for the induction of cytokines, and this synergism was lost in cells defective in either TLR2 or NOD2. Together, these results demonstrate that NOD2 and TLR pathways are nonredundant recognition mechanisms of M. tuberculosis that synergize for the induction of proinflammatory cytokines. PMID:16322770

  17. Divergent functions of Toll-like receptors during bacterial lung infections.

    PubMed

    Baral, Pankaj; Batra, Sanjay; Zemans, Rachel L; Downey, Gregory P; Jeyaseelan, Samithamby

    2014-10-01

    Lower respiratory tract infections caused by bacteria are a major cause of death in humans irrespective of sex, race, or geography. Indeed, accumulated data indicate greater mortality and morbidity due to these infections than cancer, malaria, or HIV infection. Successful recognition of, followed by an appropriate response to, bacterial pathogens in the lungs is crucial for effective pulmonary host defense. Although the early recruitment and activation of neutrophils in the lungs is key in the response against invading microbial pathogens, other sentinels, such as alveolar macrophages, epithelial cells, dendritic cells, and CD4(+) T cells, also contribute to the elimination of the bacterial burden. Pattern recognition receptors, such as Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-like receptors, are important for recognizing and responding to microbes during pulmonary infections. However, bacterial pathogens have acquired crafty evasive strategies to circumvent the pattern recognition receptor response and thus establish infection. Increased understanding of the function of TLRs and evasive mechanisms used by pathogens during pulmonary infection will deepen our knowledge of immunopathogenesis and is crucial for developing effective therapeutic and/or prophylactic measures. This review summarizes current knowledge of the multiple roles of TLRs in bacterial lung infections and highlights the mechanisms used by pathogens to modulate or interfere with TLR signaling in the lungs.

  18. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy.

    PubMed

    Apetoh, Lionel; Ghiringhelli, François; Tesniere, Antoine; Obeid, Michel; Ortiz, Carla; Criollo, Alfredo; Mignot, Grégoire; Maiuri, M Chiara; Ullrich, Evelyn; Saulnier, Patrick; Yang, Huan; Amigorena, Sebastian; Ryffel, Bernard; Barrat, Franck J; Saftig, Paul; Levi, Francis; Lidereau, Rosette; Nogues, Catherine; Mira, Jean-Paul; Chompret, Agnès; Joulin, Virginie; Clavel-Chapelon, Françoise; Bourhis, Jean; André, Fabrice; Delaloge, Suzette; Tursz, Thomas; Kroemer, Guido; Zitvogel, Laurence

    2007-09-01

    Conventional cancer treatments rely on radiotherapy and chemotherapy. Such treatments supposedly mediate their effects via the direct elimination of tumor cells. Here we show that the success of some protocols for anticancer therapy depends on innate and adaptive antitumor immune responses. We describe in both mice and humans a previously unrecognized pathway for the activation of tumor antigen-specific T-cell immunity that involves secretion of the high-mobility-group box 1 (HMGB1) alarmin protein by dying tumor cells and the action of HMGB1 on Toll-like receptor 4 (TLR4) expressed by dendritic cells (DCs). During chemotherapy or radiotherapy, DCs require signaling through TLR4 and its adaptor MyD88 for efficient processing and cross-presentation of antigen from dying tumor cells. Patients with breast cancer who carry a TLR4 loss-of-function allele relapse more quickly after radiotherapy and chemotherapy than those carrying the normal TLR4 allele. These results delineate a clinically relevant immunoadjuvant pathway triggered by tumor cell death.

  19. 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

  20. 77 FR 19010 - Zone J Tolling Co., LLC; Supplemental Notice That Initial Market-Based Rate Filing Includes...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-03-29

    ...-000] Zone J Tolling Co., LLC; Supplemental Notice That Initial Market- Based Rate Filing Includes... proceeding of Zone J Tolling Co., LLC's application for market-based rate authority, with an...

  1. 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.

  2. Toll-like Receptor 1 Polymorphisms Affect Innate Immune Responses and Outcomes in Sepsis

    PubMed Central

    Wurfel, Mark M.; Gordon, Anthony C.; Holden, Tarah D.; Radella, Frank; Strout, Jeanna; Kajikawa, Osamu; Ruzinski, John T.; Rona, Gail; Black, R. Anthony; Stratton, Seth; Jarvik, Gail P.; Hajjar, Adeline M.; Nickerson, Deborah A.; Rieder, Mark; Sevransky, Jonathan; Maloney, James P.; Moss, Marc; Martin, Greg; Shanholtz, Carl; Garcia, Joe G. N.; Gao, Li; Brower, Roy; Barnes, Kathleen C.; Walley, Keith R.; Russell, James A.; Martin, Thomas R.

    2008-01-01

    Rationale: Polymorphisms affecting Toll-like receptor (TLR)–mediated responses could predispose to excessive inflammation during an infection and contribute to an increased risk for poor outcomes in patients with sepsis. Objectives: To identify hypermorphic polymorphisms causing elevated TLR-mediated innate immune cytokine and chemokine responses and to test whether these polymorphisms are associated with increased susceptibility to death, organ dysfunction, and infections in patients with sepsis. Methods: We screened single-nucleotide polymorphisms (SNPs) in 43 TLR-related genes to identify variants affecting TLR-mediated inflammatory responses in blood from healthy volunteers ex vivo. The SNP associated most strongly with hypermorphic responses was tested for associations with death, organ dysfunction, and type of infection in two studies: a nested case–control study in a cohort of intensive care unit patients with sepsis, and a case–control study using patients with sepsis, patients with sepsis-related acute lung injury, and healthy control subjects. Measurements and Main Results: The SNP demonstrating the most hypermorphic effect was the G allele of TLR1−7202A/G (rs5743551), which associated with elevated TLR1-mediated cytokine production (P < 2 × 10−20). TLR1−7202G marked a coding SNP that causes higher TLR1-induced NF-κB activation and higher cell surface TLR1 expression. In the cohort of patients with sepsis TLR1−7202G predicted worse organ dysfunction and death (odds ratio, 1.82; 95% confidence interval, 1.07–3.09). In the case-control study TLR1−7202G was associated with sepsis-related acute lung injury (odds ratio, 3.40; 95% confidence interval, 1.59–7.27). TLR1−7202G also associated with a higher prevalence of gram-positive cultures in both clinical studies. Conclusions: Hypermorphic genetic variation in TLR1 is associated with increased susceptibility to organ dysfunction, death, and gram-positive infection in sepsis. PMID

  3. Expression of a Toll Signaling Regulator Serpin in a Mycoinsecticide for Increased Virulence

    PubMed Central

    Yang, Linzhi; Keyhani, Nemat O.; Tang, Guirong; Tian, Chuang; Lu, Ruipeng; Wang, Xin; Pei, Yan

    2014-01-01

    Serpins are ubiquitously distributed serine protease inhibitors that covalently bind to target proteases to exert their activities. Serpins regulate a wide range of activities, particularly those in which protease-mediated cascades are active. The Drosophila melanogaster serpin Spn43Ac negatively controls the Toll pathway that is activated in response to fungal infection. The entomopathogenic fungus Beauveria bassiana offers an environmentally friendly alternative to chemical pesticides for insect control. However, the use of mycoinsecticides remains limited in part due to issues of efficacy (low virulence) and the recalcitrance of the targets (due to strong immune responses). Since Spn43Ac acts to inhibit Toll-mediated activation of defense responses, we explored the feasibility of a new strategy to engineer entomopathogenic fungi with increased virulence by expression of Spn43Ac in the fungus. Compared to the 50% lethal dose (LD50) for the wild-type parent, the LD50 of B. bassiana expressing Spn43Ac (strain Bb::S43Ac-1) was reduced ∼3-fold, and the median lethal time against the greater wax moth (Galleria mellonella) was decreased by ∼24%, with the more rapid proliferation of hyphal bodies being seen in the host hemolymph. In vitro and in vivo assays showed inhibition of phenoloxidase (PO) activation in the presence of Spn43Ac, with Spn43Ac-mediated suppression of activation by chymotrypsin, trypsin, laminarin, and lipopolysaccharide occurring in the following order: chymotrypsin and trypsin > laminarin > lipopolysaccharide. Expression of Spn43Ac had no effect on the activity of the endogenous B. bassiana-derived cuticle-degrading protease (CDEP-1). These results expand our understanding of Spn43Ac function and confirm that suppression of insect immune system defenses represents a feasible approach to engineering entomopathogenic fungi for greater efficacy. PMID:24837378

  4. The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling.

    PubMed

    Carty, Michael; Goodbody, Rory; Schröder, Martina; Stack, Julianne; Moynagh, Paul N; Bowie, Andrew G

    2006-10-01

    Toll-like receptors discriminate between different pathogen-associated molecules and activate signaling cascades that lead to immune responses. The specificity of Toll-like receptor signaling occurs by means of adaptor proteins containing Toll-interleukin 1 receptor (TIR) domains. Activating functions have been assigned to four TIR adaptors: MyD88, Mal, TRIF and TRAM. Here we characterize a fifth TIR adaptor, SARM, as a negative regulator of TRIF-dependent Toll-like receptor signaling. Expression of SARM blocked gene induction 'downstream' of TRIF but not of MyD88. SARM associated with TRIF, and 'knockdown' of endogenous SARM expression by interfering RNA led to enhanced TRIF-dependent cytokine and chemokine induction. Thus, the fifth mammalian TIR adaptor SARM is a negative regulator of Toll-like receptor signaling.

  5. 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

  6. 78 FR 69939 - Open Meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee

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  19. 23 CFR 661.49 - Can IRRBP funds be spent on Interstate, State Highway, and Toll Road IRR bridges?

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    ..., and Toll Road IRR bridges? 661.49 Section 661.49 Highways FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT... Can IRRBP funds be spent on Interstate, State Highway, and Toll Road IRR bridges? Yes. Interstate, State Highway, and Toll Road IRR bridges are eligible for funding as described in § 661.37(b)....

  20. 23 CFR 661.49 - Can IRRBP funds be spent on Interstate, State Highway, and Toll Road IRR bridges?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ..., and Toll Road IRR bridges? 661.49 Section 661.49 Highways FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT... Can IRRBP funds be spent on Interstate, State Highway, and Toll Road IRR bridges? Yes. Interstate, State Highway, and Toll Road IRR bridges are eligible for funding as described in § 661.37(b)....

  1. 25 CFR 170.131 - How can a tribe find out more about designing and operating a toll facility?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 25 Indians 1 2013-04-01 2013-04-01 false How can a tribe find out more about designing and... Eligibility Toll, Ferry and Airport Facilities § 170.131 How can a tribe find out more about designing and operating a toll facility? Information on designing and operating a toll highway, bridge or tunnel...

  2. 25 CFR 170.131 - How can a tribe find out more about designing and operating a toll facility?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 25 Indians 1 2014-04-01 2014-04-01 false How can a tribe find out more about designing and... Eligibility Toll, Ferry and Airport Facilities § 170.131 How can a tribe find out more about designing and operating a toll facility? Information on designing and operating a toll highway, bridge or tunnel...

  3. [The diagnosis of death].

    PubMed

    Echeverría, Carlos; Goic, Alejandro; Lavados, Manuel; Quintana, Carlos; Rojas, Alberto; Serani, Alejandro; Vacarezza, Ricardo

    2004-01-01

    This paper undertakes an analysis of the scientific criteria used in the diagnosis of death and underscores the importance of intellectual rigor in the definition of medical concepts, particularly regarding such a critical issue as the diagnosis of death. Under the cardiorespiratory criterion, death is defined as "the irreversible cessation of the functioning of an organism as a whole", and the tests used to confirm this criterion (negative life-signs) are sensitive and specific. In this case, cadaverous phenomena appear immediately following the diagnosis of death. On the other hand, doubts have arisen concerning the theoretical and the inner consistency of the criterion of brain death, since it does not satisfy the definition of "the irreversible cessation of the functioning of an organism as a whole", nor the requirement of "total and irreversible cessation of all functions of the entire brain, including the brain stem". There is evidence to the effect that the tests used to confirm this criterion are not specific enough. It is clear that brain death marks the beginning of a process that eventually ends in death, though death does not occur at that moment. From an ethical point of view, the conflict arises between the need to provide an unequivocal diagnosis of death and the possibility of saving a life through organ transplantation. The sensitive issue of brain death calls for a more thorough and in-depth discussion among physicians and the community at large.

  4. [Innate immunity: cutaneous expression of Toll-like receptors].

    PubMed

    Musette, Philippe; Auquit Auckbur, Isabelle; Begon, Edouard

    2006-02-01

    Toll receptors were first identified as an essential molecule for embryonic patterning in Drosophila and were subsequently shown to be a key in antibacterial and antifungal immunity in adult flies. Toll receptors have been conserved throughout evolution. In mammals, TLRs have been implicated in both inflammatory responses and innate host defense to pathogens. The 11 different TLRs recognize conserved molecular patterns of microbial pathogens termed pathogen-specific molecular patterns (PAMPs), that permit to confer responsiveness to a wide variety of pathogens. Endogenous ligands are also able to activate TLRs. All adult tissue is capable to express at least one of member of TLR family, but a largest repertoire of TLRs is found in tissues exposed to the external environment. The TLR activation induce the NF-kappaB translocation to the nucleus and cytokine secretion. Since the primary function of skin is to provide an effective barrier against outside agression, it is likely that keratinocytes may play a role in a rapid and efficient host defence system, and the fact that keratinocytes are capable of expressing a wide variety of TLRs is subsequently not surprising.

  5. A good death.

    PubMed

    2011-10-26

    Definitions of a good death often include being at home. Dying at home may be optimal for the patient but could place a significant burden on families and leave them with traumatic memories. Death in hospital should not mean that it is a 'bad death'. How someone dies is more important than where they die and nurses should be taught to provide good end of life care in all settings.

  6. [The extraordinary death].

    PubMed

    Plattner, Thomas; Zollinger, Ulrich

    2008-07-01

    The examination of a deceased person is an important duty for physicians. It comprises the certification of death, the certification of the identity of the deceased, a thorough examination of the body, an estimation of the moment of death and ends with the decision, if death was caused by a certain or possible violent cause in which case it must be reported to the authorities. Problems and pitfalls are discussed on the basis of practical case presentations.

  7. 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…

  8. 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…

  9. 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

  10. 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

  11. 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 Central

    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

  12. Newly identified PcToll4 regulates antimicrobial peptide expression in intestine of red swamp crayfish Procambarus clarkii.

    PubMed

    Huang, Ying; Li, Tingting; Jin, Min; Yin, Shaowu; Hui, Kai-Min; Ren, Qian

    2017-02-14

    Tolls or Toll-like receptors (TLRs) have an essential role in initiating innate immune responses against pathogens. In this study, a novel Toll gene, PcToll4, was first identified from the intestinal transcriptome of the freshwater crayfish, Procambarus clarkii. The PcToll4 cDNA is 4849bp long with a 3036bp open reading frame that encodes a 1011-amino acid protein. PcToll4 contains a signal peptide, 13 LRR domains, 3 LRR TYP domains, 2 LRR CT domains, an LRR NT domain, a transmembrane region, and a TIR domain. Quantitative RT-PCR analysis revealed that PcToll4 mRNA was detected in all tested tissues, and the expression of PcToll4 in the intestine was significantly upregulated after white spot syndrome virus (WSSV) challenge. Overexpression of PcToll4 in Drosophila Schneider 2 (S2) cells activates the antimicrobial peptides (AMPs) of Drosophila, including metchnikowin, drosomycin, attacin A, and shrimp Penaeidin-4. Results of RNA interference by siRNA also showed that PcToll4 regulates the expressions of 5 anti-lipopolysaccharide factors (ALFs) in the intestine of crayfish. Our findings suggest that PcToll4 is important for the innate immune responses of P. clarkii because this gene regulates the expressions of AMPs against WSSV.

  13. 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.

  14. 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…

  15. 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

  16. 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)

  17. Facing Up to Death

    ERIC Educational Resources Information Center

    Ross, Elizabeth Kubler

    1972-01-01

    Doctor urges that Americans accept death as a part of life and suggests ways of helping dying patients and their families face reality calmly, with peace. Dying children and their siblings, as well as children's feelings about relatives' deaths, are also discussed. (PD)

  18. 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…

  19. 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…

  20. 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…

  1. Physician-assisted death.

    PubMed Central

    1995-01-01

    Physician-assisted death includes both euthanasia and assistance in suicide. The CMA urges its members to adhere to the principles of palliative care. It does not support euthanasia and assisted suicide. The following policy summary includes definitions of euthanasia and assisted suicide, background information, basic ethical principles and physician concerns about legalization of physician-assisted death. PMID:7632208

  2. 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…

  3. 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

  4. The Psychology of Death

    ERIC Educational Resources Information Center

    Fields, B. Celestine

    1976-01-01

    Forty-eight black men and women living and/or attending school in the St. Louis and Washington, D.C. areas responded to questionnaires concerning feelings, attitudes, emotions, etc. towards death and dying. It is concluded that blacks see death as a very significant happening; and that although in some areas blacks have become Americanized in…

  5. 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

  6. Death, Children, and Books.

    ERIC Educational Resources Information Center

    Carr, Robin L.

    The books listed in this annotated bibliography are intended to help children understand the reality of death and deal with the mystery and emotions that accompany it. Each entry indicates the genre and reading level of the book and provides a brief description of the attitude toward death that it conveys. The selections include fables, fantasy,…

  7. 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

  8. Toll-like receptors are key players in neurodegeneration.

    PubMed

    Arroyo, Daniela S; Soria, Javier A; Gaviglio, Emilia A; Rodriguez-Galan, Maria C; Iribarren, Pablo

    2011-10-01

    The activation of innate immune response is initiated by engagement of pattern-recognition receptors (PPRs), such as Toll-like receptors (TLRs). These receptors are expressed in peripheral leukocytes and in many cell types in the central nervous system (CNS). The expression of TLRs in CNS was mainly studied in astrocytes and microglial cells. However, new evidence indicates that these receptors may play an important role in neuronal homeostasis. The expression of TLRs in the CNS is variable and can be modulated by multiple factors, including pro-inflammatory molecules, which are elevated in neurodegenerative diseases and can increase the expression of TLRs in CNS cells. Moreover, activation of TLRs induces the release of pro-inflammatory cytokines. Therefore, TLRs have been shown to play a role in several aspects of neurodegenerative diseases. Here we will discuss results reported in the recent literature concerning the participation of TLRs in neurodegenerative diseases.

  9. Toll-like Receptors at the Ocular Surface

    PubMed Central

    Pearlman, Eric; Johnson, Angela; Adhikary, Gautam; Sun, Yan; Chinnery, Holly R.; Fox, Todd; Kester, Mark; Mcmenamin, Paul G.

    2012-01-01

    The Toll-like receptor (TLR) family of pathogen recognition molecules has an important role in recognizing microbial pathogens and microbial breakdown products. Activation of TLRs in the corneal epithelium induces CXC chemokine production and recruitment of neutrophils to the corneal stroma. Although essential for pathogen killing, neutrophils can cause extensive tissue damage, leading to visual impairment and blindness. In this review, we examine the role of TLRs in microbial keratitis and in noninfectious corneal inflammation, most commonly associated with contact lens wear. We present recent findings on TLR signaling pathways in the cornea, including MyD88- and TRIF-dependent responses and discuss the role of resident macrophages and dendritic cells. Finally, we examine the potential for targeting the TLR pathway as a potential therapeutic intervention for microbial keratitis and contact lens-associated corneal inflammation. PMID:18781257

  10. Malaria tolerance – for whom the cell tolls?

    PubMed Central

    Boutlis, Craig S.; Yeo, Tsin W.; Anstey, Nicholas M.

    2009-01-01

    How is it that individuals exposed to intense malaria transmission can tolerate the presence of malaria parasites in their blood at levels that would produce fever in others? In light of evidence discounting a role for nitric oxide or antibodies to plasmodial glycosylphosphatidylinositols in maintaining this tolerant state, refractoriness to toxin-induced Toll-like receptor-mediated signalling has emerged as a likely explanation that links malarial and bacterial endotoxin tolerance. Understanding the mechanisms underlying tolerance and the potential for cross-tolerization has significant implications for understanding the potential for anti-toxic vaccine strategies, as well as interactions between different malaria species and between malaria and other human parasites. PMID:16784889

  11. 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

  12. 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

  13. Toll-like receptors as therapeutic targets for cancer.

    PubMed

    Holldack, Johanna

    2014-04-01

    Stimulation of Toll-like receptors (TLRs) to activate the innate immune system has been a legitimate therapeutic strategy for some years. TLRs 3, 4, 7, 8 and 9 are all validated targets for cancer and a number of companies are developing agonists and vaccine adjuvants. TLR7 in particular has established proof-of-concept as a target in the topical treatment of bladder and skin cancers. However, the development of systemic treatments targeting TLR7 for most other cancers has proved difficult owing to cardiotoxicity or myelosuppression. Tantalisingly, recent animal data have demonstrated that a new class of modified TLR7 agonists can be administered systemically with a good toxicology profile, opening up this target in therapeutic interventions for systemic cancers.

  14. Toll-Like Receptors: Role in Dermatological Disease

    PubMed Central

    Hari, Aswin; Flach, Tracy L.; Shi, Yan; Mydlarski, P. Régine

    2010-01-01

    Toll-like receptors (TLRs) are a class of conserved receptors that recognize pathogen-associated molecular patterns (PAMPs) present in microbes. In humans, at least ten TLRs have been identified, and their recognition targets range from bacterial endotoxins to lipopeptides, DNA, dsRNA, ssRNA, fungal products, and several host factors. Of dermatological interest, these receptors are expressed on several skin cells including keratinocytes, melanocytes, and Langerhans cells. TLRs are essential in identifying microbial products and are known to link the innate and adaptive immune systems. Over the years, there have been significant advances in our understanding of TLRs in skin inflammation, cutaneous malignancies, and defence mechanisms. In this paper, we will describe the association between TLRs and various skin pathologies and discuss proposed TLR therapeutics. PMID:20847936

  15. Life and Death Decision Analysis.

    DTIC Science & Technology

    1979-12-01

    LIFE SMOKING: CANCER, EMPHYSEMA, SHORTENED LIFE BATHING: FALLING, ELECTROCUTION CONTRACEPTION: DEATH , ILLNESS PREGNANCY: DEATH , ILLNESS ABORTION ...economic effect is the one with the highest probability of causing my death . -13- EXPECTED NET SYSTEM DESIGN BENEFIT TO ME DEATH DEATH (r A(excluding death ...0-AO81 424 STANFORD UNIV CALIF DEPT OF ENGtNEERING-ECONOM!C SYSTEMS F/6 12/1 LIFE ANDI DEATH DECISION ANALYSIS.CU) DEC 79 R A HOWARD N0OOIN-79-C-0036

  16. Brain death is not death: a critique of the concept, criterion, and tests of brain death.

    PubMed

    Joffe, Ari R

    2009-01-01

    This paper suggests that there are insurmountable problems for brain death as a criterion of death. The following are argued: (1) brain death does not meet an accepted concept of death, and is not the loss of integration of the organism as a whole; (2) brain death does not meet the criterion of brain death itself; brain death is not the irreversible loss of all critical functions of the entire brain; and (3) brain death may, however rarely, be reversible. I conclude that brain death, while a devastating neurological state with a dismal prognosis, is not death.

  17. [Death experience. Antidote against fear to death].

    PubMed

    Fericgla, Josep M

    2003-12-01

    Fortunately, anthropology has brought to our modern society a higher interest for mankind's cultural dimension and the values which each people employ in order to make sense out of the changes which occur during our lives. It is this cultural dimension which permits men to develop our innate capacities and to become humans. However, in order to achieve this, we need experiences which are codified and interpreted by a values system which each individual has made his/her own. Some of these experiences take place inside cultural mores constructed expressly so that they are useful for one's lifestyle; these are known as rites. A rite, therefore, is an experience which leaves an impression, which implies social and biographical changes, which provides meaning to human beings' universal interests. Nonetheless, since rites usually are organized by diverse religions, it is convenient, as we enter the 21st Century, to speak about Experiences which Activate Structures as means to approach, to come to grasp with, some of the great causes of anxiety in humans: death and insanity. These Experiences which Activate Structures allow us to subjectively experiment, to conquer our fears and to be more conscious of our here and our now. Workshops on the Living Integration of One's Own Death are included in this context as an appropriate forum through which to approach death with knowledge and serenity, inducing changes in our own lifestyle as well and helping us to overcome situations of existential blockage.

  18. 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

  19. A Coding IRAK2 Protein Variant Compromises Toll-like receptor (TLR) Signaling and Is Associated with Colorectal Cancer Survival*

    PubMed Central

    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.

    2014-01-01

    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

  20. 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.

  1. 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

  2. The Role of Toll-Like Receptor 9 in Chronic Stress-Induced Apoptosis in Macrophage

    PubMed Central

    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

  3. 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.…

  4. 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.

  5. 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 ...

  6. 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)

  7. 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)

  8. Preparation for Death

    PubMed Central

    Scott, J. F.

    1981-01-01

    Preparation for death is a physical, psychosocial and spiritual process needing the active participation of both patient and physician. Physicians' denial of death leads to unrelieved symptoms, inappropriate treatment, and poor communication in the care of the terminally ill. This paper discusses strategies to minimize the effect of denial describing a goal-setting approach to terminal care and the use of quality of life indices. Several principles are presented on how to tell bad news to patients. PMID:21289837

  9. Crosstalk between toll-like receptors and hypoxia-dependent pathways in health and disease.

    PubMed

    Crifo, Bianca; Taylor, Cormac T

    2016-02-01

    Toll-like receptors (TLRs) play an important role in shaping the host immune response to infection and inflammation. Tissue hypoxia is a common microenvironmental feature of infected and inflamed tissues. Furthermore, hypoxia significantly impacts the development of immune and inflammatory responses through the regulation of host innate and adaptive immunity. Here, we will discuss current knowledge in relation to the crosstalk that exists between toll-like receptor- and hypoxia-dependent signaling pathways in health and disease.

  10. 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

  11. Dictyostelium cell death

    PubMed Central

    Levraud, Jean-Pierre; Adam, Myriam; Luciani, Marie-Françoise; de Chastellier, Chantal; Blanton, Richard L.; Golstein, Pierre

    2003-01-01

    Cell death in the stalk of Dictyostelium discoideum, a prototypic vacuolar cell death, can be studied in vitro using cells differentiating as a monolayer. To identify early events, we examined potentially dying cells at a time when the classical signs of Dictyostelium cell death, such as heavy vacuolization and membrane lesions, were not yet apparent. We observed that most cells proceeded through a stereotyped series of differentiation stages, including the emergence of “paddle” cells showing high motility and strikingly marked subcellular compartmentalization with actin segregation. Paddle cell emergence and subsequent demise with paddle-to-round cell transition may be critical to the cell death process, as they were contemporary with irreversibility assessed through time-lapse videos and clonogenicity tests. Paddle cell demise was not related to formation of the cellulose shell because cells where the cellulose-synthase gene had been inactivated underwent death indistinguishable from that of parental cells. A major subcellular alteration at the paddle-to-round cell transition was the disappearance of F-actin. The Dictyostelium vacuolar cell death pathway thus does not require cellulose synthesis and includes early actin rearrangements (F-actin segregation, then depolymerization), contemporary with irreversibility, corresponding to the emergence and demise of highly polarized paddle cells. PMID:12654899

  12. 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

  13. Death obsession in Palestinians.

    PubMed

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

    2006-04-01

    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 reliability was .92, denoting high internal consistency. Among women, it yielded 1 factor, (General Death Obsession), whereas among men it yielded 3 factors: Death Rumination, Death Dominance, and Death Idea Repetition. Palestinian men and women attained significantly lower DOS mean scores than participants from 4 Arab countries: Egypt, Kuwait, Syria, and Lebanon in 7 out of 8 comparisons. However, Palestinian women had significantly higher DOS mean score than their Spanish, American and British counterparts, whereas Palestinian men had significantly higher mean DOS score than Spanish peers. The low DOS scores of Palestinians, in proportion to other Arab samples, may reflect their adaptation to strife and violence.

  14. Brain death: the United kingdom perspective.

    PubMed

    Smith, Martin

    2015-04-01

    The United Kingdom (UK) has incorporated a brainstem formulation into its brain death criteria since the first guidelines were published in 1976. A clinical diagnosis incorporating three sequential but interdependent steps is sufficient for the determination of brain death in the UK. There must be no doubt that the patient's comatose condition is due to irreversible brain damage of known etiology, and potentially reversible causes of coma and apnea, such as drug effects, metabolic or endocrine disturbances, or hypothermia, must be excluded. A clinical examination of brainstem reflexes and an apnea test is then undertaken. Confirmatory tests are not required in the UK, but may be useful to reduce any element of uncertainty or minimize the period of observation prior to the diagnosis of brainstem death if the preconditions for clinical testing are not met, or if a comprehensive neurologic examination is not possible. Brainstem death must be diagnosed by two doctors who must be present at each of the two sets of clinical tests that are required to determine death. Although death is not confirmed until the second test has been completed, the legal time of death is when the first test confirms the absence of brainstem reflexes.

  15. 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

  16. [Deaths in hotels].

    PubMed

    Risse, Manfred; Weilbächer, Nadine; Birngruber, Christoph; Verhoff, Marcel A

    2010-01-01

    There are no verified statistics about deaths occurring in hotels, and only a few cases have been described in the literature. A recent case induced us to conduct a systematic search for deaths in hotels in the autopsy reports of the Institute of Legal Medicine in Giessen for the period from 1968 to 2009. This search yielded 22 evaluable cases in which persons had been found dead or had died in hotels. Data evaluated in the study were sex and age of the deceased, reason for the stay in the hotel and cause of death. Among the deaths, 18 were males and 4 females and the average age was 41 and 40 years respectively. 6 of the male guests had died from a natural and 10 from a non-natural cause. In the remaining two cases, the cause of death could not be determined, but as there was no evidence that another party had been involved, the cases were not further investigated. Of the 4 female guests, 3 had died of a natural cause; in one case, the cause of death remained unclear even after morphological and toxicological investigations. Surprisingly, a third of the men were found to be temporarily living in hotels due to social circumstances. This was not true for any of the women. Our retrospective analysis is based on a comparatively small number of deaths in what were mostly hotels in small to medium-sized towns. Interestingly, the gender ratio of 18:4 for deceased men and women was significantly higher than the usual gender ratio of 2:1 found for forensic autopsies. To be able to draw further conclusions, a greater number of cases would have to be analysed, for example by recruiting additional case files from other institutes of legal medicine. This would also open up the option of investigating possible regional variations.

  17. Diversity in the Toll-Like Receptor Genes of the African Penguin (Spheniscus demersus)

    PubMed Central

    Dalton, Desiré Lee; Vermaak, Elaine; Roelofse, Marli; Kotze, Antoinette

    2016-01-01

    The African penguin, Spheniscus demersus, is listed as Endangered by the IUCN Red List of Threatened Species due to the drastic reduction in population numbers over the last 20 years. To date, the only studies on immunogenetic variation in penguins have been conducted on the major histocompatibility complex (MHC) genes. It was shown in humans that up to half of the genetic variability in immune responses to pathogens are located in non-MHC genes. Toll-like receptors (TLRs) are now increasingly being studied in a variety of taxa as a broader approach to determine functional genetic diversity. In this study, we confirm low genetic diversity in the innate immune region of African penguins similar to that observed in New Zealand robin that has undergone several severe population bottlenecks. Single nucleotide polymorphism (SNP) diversity across TLRs varied between ex situ and in situ penguins with the number of non-synonymous alterations in ex situ populations (n = 14) being reduced in comparison to in situ populations (n = 16). Maintaining adaptive diversity is of vital importance in the assurance populations as these animals may potentially be used in the future for re-introductions. Therefore, this study provides essential data on immune gene diversity in penguins and will assist in providing an additional monitoring tool for African penguin in the wild, as well as to monitor diversity in ex situ populations and to ensure that diversity found in the in situ populations are captured in the assurance populations. PMID:27760133

  18. Interplay between Inflammation and Stemness in Cancer Cells: The Role of Toll-Like Receptor Signaling.

    PubMed

    Yeh, Da-Wei; Huang, Li-Rung; Chen, Ya-Wen; Huang, Chi-Ying F; Chuang, Tsung-Hsien

    2016-01-01

    Cancer stem cells (CSCs) are a small population of cancer cells that exhibit stemness. These cells contribute to cancer metastasis, treatment resistance, and relapse following therapy; therefore, they may cause malignancy and reduce the success of cancer treatment. Nuclear factor kappa B- (NF-κB-) mediated inflammatory responses increase stemness in cancer cells, and CSCs constitutively exhibit higher NF-κB activation, which in turn increases their stemness. These opposite effects form a positive feedback loop that further amplifies inflammation and stemness in cancer cells, thereby expanding CSC populations in the tumor. Toll-like receptors (TLRs) activate NF-κB-mediated inflammatory responses when stimulated by carcinogenic microbes and endogenous molecules released from cells killed during cancer treatment. NF-κB activation by extrinsic TLR ligands increases stemness in cancer cells. Moreover, it was recently shown that increased NF-κB activity and inflammatory responses in CSCs may be caused by altered TLR signaling during the enrichment of stemness in cancer cells. Thus, the activation of TLR signaling by extrinsic and intrinsic factors drives a positive interplay between inflammation and stemness in cancer cells.

  19. Effects of age, gender, and immunosuppressive agents on in vivo toll-like receptor pathway responses.

    PubMed

    Khan, Niamat; Summers, Colin W; Helbert, Matthew R; Arkwright, Peter D

    2010-04-01

    Toll-like receptors (TLRs) are important in the initiation of immune responses in both health and disease. How TLR activity alters with age, gender, and also with immunosuppressive agents is still largely unexplored. We studied TLR activity in 49 healthy individuals as well as in 26 patients receiving immunosuppressive drugs. TLR activity did not alter significantly between the ages of 2 and 67 years. However, females had twice the TLR7 ligand-induced interferon-I response of males (OR [95% CI] 2.7 [1.4-5.1]), whereas TLR3 and four activities were not significantly different between the sexes. The T-cell immunosuppressant agents cyclosporine, tacrolimus, and azathioprine, as well as low dose glucocorticosteroids did not significantly alter TLR pathway responses. In contrast, high dose glucocorticosteroids reduced in vivo TLR responses by 70%-90%. We suggest that gender differences in TLR responses may help to explain the female preponderance of some autoimmune disorders. Furthermore, an understanding the effects of immunosuppressive agents on TLR-pathway activity should allow more focused therapy for autoimmune disorders.

  20. 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

  1. Chemotherapy-induced mucositis: the role of the gastrointestinal microbiome and toll-like receptors.

    PubMed

    Thorpe, Daniel W; Stringer, Andrea M; Gibson, Rachel J

    2013-01-01

    Alimentary mucositis is a major clinical problem. Patients with mucositis are at significantly increased risk of infection and are often hospitalized for prolonged periods. More importantly, these patients often have to undergo reductions in their cytotoxic therapy, which may lead to reduced survival. Unfortunately, there are very limited therapeutic options for mucositis and no effective prevention. The human gut microbiome is receiving increased attention as a key player in the pathogenesis of alimentary mucositis with recent literature suggesting that changes in bacteria lead to mucositis. The bacteria which are found throughout the gut are tightly regulated by the toll-like receptor (TLR) family which currently has 13 known members. TLRs play a critical role in gut homeostasis and bacterial regulation. Furthermore, TLRs play a critical role in the regulation of nuclear factor kappa B, a key regulator of alimentary mucositis. However to date, no research has clearly identified a link between TLRs and alimentary mucositis. This critical literature review seeks to correct this.

  2. Interplay between Inflammation and Stemness in Cancer Cells: The Role of Toll-Like Receptor Signaling

    PubMed Central

    Yeh, Da-Wei; Huang, Li-Rung; Chen, Ya-Wen; Huang, Chi-Ying F.

    2016-01-01

    Cancer stem cells (CSCs) are a small population of cancer cells that exhibit stemness. These cells contribute to cancer metastasis, treatment resistance, and relapse following therapy; therefore, they may cause malignancy and reduce the success of cancer treatment. Nuclear factor kappa B- (NF-κB-) mediated inflammatory responses increase stemness in cancer cells, and CSCs constitutively exhibit higher NF-κB activation, which in turn increases their stemness. These opposite effects form a positive feedback loop that further amplifies inflammation and stemness in cancer cells, thereby expanding CSC populations in the tumor. Toll-like receptors (TLRs) activate NF-κB-mediated inflammatory responses when stimulated by carcinogenic microbes and endogenous molecules released from cells killed during cancer treatment. NF-κB activation by extrinsic TLR ligands increases stemness in cancer cells. Moreover, it was recently shown that increased NF-κB activity and inflammatory responses in CSCs may be caused by altered TLR signaling during the enrichment of stemness in cancer cells. Thus, the activation of TLR signaling by extrinsic and intrinsic factors drives a positive interplay between inflammation and stemness in cancer cells. PMID:28116318

  3. Nitric oxide increases susceptibility of toll-like receptor-activated macrophages to spreading Listeria monocytogenes

    PubMed Central

    Cole, Caroline; Thomas, Stacey; Filak, Holly; Henson, Peter M.; Lenz, Laurel L.

    2012-01-01

    SUMMARY Toll-like receptor (TLR) stimulation activates macrophages to resist intracellular pathogens. Yet, the intracellular bacterium Listeria monocytogenes (Lm) causes lethal infections in spite of innate immune cell activation. Lm uses direct cell-cell spread to disseminate within its host. Here, we have shown that TLR-activated macrophages killed cell-free Lm but failed to prevent infection by spreading Lm. Instead, TLR signals increased the efficiency of Lm spread from “donor” to “recipient” macrophages. This enhancement required nitric oxide (NO) production by nitric oxide synthase-2 (NOS2). NO increased Lm escape from secondary vacuoles in recipient cells and delayed maturation of phagosomes containing membrane-like particles that mimic Lm-containing pseudopods. NO also promoted Lm spread during systemic in vivo infection, as inhibition of NOS2 with 1400W reduced spread-dependent Lm burdens in mouse livers. These findings reveal a mechanism by which pathogens capable of cell-cell spread can avoid the consequences of innate immune cell activation by TLR stimuli. PMID:22542147

  4. Diversity in the Toll-Like Receptor Genes of the African Penguin (Spheniscus demersus).

    PubMed

    Dalton, Desiré Lee; Vermaak, Elaine; Roelofse, Marli; Kotze, Antoinette

    2016-01-01

    The African penguin, Spheniscus demersus, is listed as Endangered by the IUCN Red List of Threatened Species due to the drastic reduction in population numbers over the last 20 years. To date, the only studies on immunogenetic variation in penguins have been conducted on the major histocompatibility complex (MHC) genes. It was shown in humans that up to half of the genetic variability in immune responses to pathogens are located in non-MHC genes. Toll-like receptors (TLRs) are now increasingly being studied in a variety of taxa as a broader approach to determine functional genetic diversity. In this study, we confirm low genetic diversity in the innate immune region of African penguins similar to that observed in New Zealand robin that has undergone several severe population bottlenecks. Single nucleotide polymorphism (SNP) diversity across TLRs varied between ex situ and in situ penguins with the number of non-synonymous alterations in ex situ populations (n = 14) being reduced in comparison to in situ populations (n = 16). Maintaining adaptive diversity is of vital importance in the assurance populations as these animals may potentially be used in the future for re-introductions. Therefore, this study provides essential data on immune gene diversity in penguins and will assist in providing an additional monitoring tool for African penguin in the wild, as well as to monitor diversity in ex situ populations and to ensure that diversity found in the in situ populations are captured in the assurance populations.

  5. Thrombomodulin promotes diabetic wound healing by regulating toll-like receptor 4 expression.

    PubMed

    Cheng, Tsung-Lin; Lai, Chao-Han; Chen, Po-Ku; Cho, Chia-Fong; Hsu, Yun-Yan; Wang, Kuan-Chieh; Lin, Wei-Ling; Chang, Bi-Ing; Liu, Shi-Kai; Wu, Yu-Ting; Hsu, Chao-Kai; Shi, Guey-Yueh; Wu, Hua-Lin

    2015-06-01

    Keratinocyte-expressed thrombomodulin (TM) and the released soluble TM (sTM) have been demonstrated to promote wound healing. However, the effects of high glucose on TM expression in keratinocytes and the role of TM in diabetic ulcer remain unclear. In this study, we demonstrated that expressions of TM and Toll-like receptor 4 (TLR4) were both downregulated in high-glucose cultured human keratinocytes and in skin keratinocytes of diabetic patients. In addition, the wound-triggered upregulation of TM and sTM production was abolished in both high-glucose cultured human keratinocytes and streptozotocin-induced diabetic mouse skin. Furthermore, supplementation of recombinant sTM could increase TLR4 expression and promote cutaneous wound healing in both high-glucose cultured human keratinocytes and diabetic mice. However, in Tlr4-deleted mice, which exhibited delayed wound healing, the therapeutic benefit of recombinant sTM was abrogated. Moreover, our results showed that tumor necrosis factor-α (TNF-α) expression in keratinocytes was dose-dependently upregulated by glucose, and TNF-α treatment downregulated the expression of TM and TLR4. Taken together, high-glucose environment reduces the expression of TM and TLR4 in keratinocytes possibly through the action of TNF-α, and recombinant sTM can increase the TLR4 expression and promote wound healing under diabetic condition.

  6. Role of Toll-like receptors in the development of sepsis.

    PubMed

    Tsujimoto, Hironori; Ono, Satoshi; Efron, Philip A; Scumpia, Philip O; Moldawer, Lyle L; Mochizuki, Hidetaka

    2008-03-01

    The outcome of sepsis and septic shock has not significantly improved in recent decades despite the development of numerous drugs and supportive care therapies. To reduce sepsis-related mortality, a better understanding of molecular mechanism(s) associated with the development of sepsis and sepsis-related organ injury is essential. There is increasing evidence that Toll-like receptors (TLRs) play a key role in the mediation of systemic responses to invading pathogens during sepsis. However, the role of TLRs in the development of sepsis and in sepsis-related organ injury remains debatable. In this review, we focus on the biological significance of TLRs during sepsis. Medline was searched for pertinent publications relating to TLRs, with emphasis on their clinical and pathophysiological importance in sepsis. In addition, a summary of the authors' own experimental data from this field was set in the context of current knowledge regarding TLRs. In both animal models and human sepsis, TLRs are highly expressed on monocytes/macrophages, and this TLR expression may not simply be a ligand-specific response in such an environment. The fact that TLR signaling enables TLRs to recognize harmful mediators induced by invading pathogens may be associated with a positive feedback loop for the inflammatory response among different cell populations. This mechanism(s) may contribute to the organ dysfunction and mortality that occurs in sepsis. A better understanding of TLR biology may unveil novel therapeutic approaches for sepsis.

  7. A novel vertebrates Toll-like receptor counterpart regulating the anti-microbial peptides expression in the freshwater crayfish, Procambarus clarkii.

    PubMed

    Wang, Zheng; Chen, Yi-Hong; Dai, Yun-Jia; Tan, Jing-Min; Huang, Ying; Lan, Jiang-Feng; Ren, Qian

    2015-03-01

    Toll-like receptors (TLRs) play an important role in regulation of anti-microbial peptides (AMPs) expression. A novel vertebrates TLR counterpart named PcToll, was firstly identified from the freshwater crayfish, Procambarus clarkii. Phylogenetic analysis showed that PcToll together with Drosophila melanogaster and Anopheles gambiae Toll9 were clustered with human Tolls. PcToll was mainly expressed in hepatopancreas and gills and it also could be detected in hemocytes, heart, stomach and intestine. PcToll was upregulated in hemocytes and gills post 24 h Vibrio anguillarum challenge. In hepatopancreas and intestine, the highest expression level of PcToll could be observed at 12 h V. anguillarum challenge. In hemocytes, PcToll went up post 24 h Staphylococcus aureus challenge and in gills, the expression level of PcToll showed no obvious change from 2 to 24 h S. aureus challenge. In hepatopancreas post 12 h S. aureus challenge, PcToll was upregulated and it showed obvious upregulation post 12 h S. aureus challenge in intestine. RNAi results showed that PcToll was involved in regulation of crustins (Cru1, Cru2), anti-lipopolysaccharide factor 2 (ALF2) and lysozyme 1 (Lys1) expression. Overexpression of PcToll in Drosophila S2 cells could induce Drosophila Attacin (Atta), Metchnikowin (Mtk), Drosomycin (Drs) and shrimp Penaeidin (PEN4) expression. From the results, it could be speculated that PcToll might play important roles in crayfish innate immune defense.

  8. Potentiality, irreversibility, and death.

    PubMed

    Lizza, John P

    2005-02-01

    There has been growing concern about whether individuals who satisfy neurological criteria for death or who become non-heart-beating organ donors are really dead. This concern has focused on the issue of the potential for recovery that these individuals may still have and whether their conditions are irreversible. In this article I examine the concepts of potentiality and irreversibility that have been invoked in the discussions of the definition of death and non-heart-beating organ donation. I initially focus on the recent challenge by D. Alan Shewmon to accepting any neurological criterion of death. I argue that Shewmon relies on a problematic and unrealistic concept of potentiality, and that a better, more realistic concept of potentiality is consistent with accepting a neurological criterion for death. I then turn to an analysis of how the concept of irreversibility has been used in discussion of non-heart-beating organ donation. Similarly, I argue that some participants in this discussion have invoked a problematic and unrealistic concept of irreversibility. I then propose an alternative, more realistic account of irreversibility that explains how "irreversibility" should be understood in the definition and criteria of death.

  9. [Brain death diagnosis].

    PubMed

    Escudero, Dolores

    2009-05-01

    Brain death has been recognized by the scientific community as the person's death, and accepted in the legislation of different countries. Brain death is defined as the irreversible ending of the functions of all the intracranial neurological structure in both the brain and brain stem. This clinical situation appears when intracranial pressure exceeds the patient's systolic blood pressure, leading to brain circulatory arrest. The most frequent are cerebral hemorrhage and cranioencephalic trauma. Clinical diagnostic must be done by doctors with expertise in neurocritical patient treatment. This diagnosis is based on a systematic, complete and extremely rigorous clinical examination that confirms a non-reactive coma, absence of brain stem reflex, and absence of spontaneous breathing. Instrumental tests may be obligatory in some cases, this depending on each country. Electroencephalogram and evoked potentials are the electrophysiological tests used. In patients treated with sedative drugs, cerebral blood flow evaluation tests, such as cerebral angiography, transcranial Doppler or 99Tc-HMPAO scintigraphy, will be used. More than 92% of the transplants performed in Spain are performed with brain death donor organs. Brain death confirmation is a high responsibility act, with medical, ethical and legal significance since it requires removal of all artificial support, or organs extraction for transplant. Extensive knowledge on its diagnostic and correct decision making avoid unnecessary use of resources and improves management of organs for transplant.

  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. Death Depression and Death Anxiety in HIV-Infected Males.

    ERIC Educational Resources Information Center

    Hintze, Julie; And Others

    1993-01-01

    Administered Death Anxiety Scale, Death Depression Scale, Beck Depression Inventory, State-Trait Anxiety Scale, and questionnaire assessing demographic and life-situation variables to 94 human immunodeficiency virus-infected gay men. Higher death anxiety and death depression were most highly correlated with state anxiety, trait anxiety,…

  13. Persephone/Spätzle Pathogen Sensors Mediate the Activation of Toll Receptor Signaling in Response to Endogenous Danger Signals in Apoptosis-deficient Drosophila*

    PubMed Central

    Ming, Ming; Obata, Fumiaki; Kuranaga, Erina; Miura, Masayuki

    2014-01-01

    Apoptosis is an evolutionarily conserved mechanism that removes damaged or unwanted cells, effectively maintaining cellular homeostasis. It has long been suggested that a deficiency in this type of naturally occurring cell death could potentially lead to necrosis, resulting in the release of endogenous immunogenic molecules such as damage-associated molecular patterns (DAMPs) and a noninfectious inflammatory response. However, the details about how danger signals from apoptosis-deficient cells are detected and translated to an immune response are largely unknown. In this study, we found that Drosophila mutants deficient for Dronc, the key initiator caspase required for apoptosis, produced the active form of the endogenous Toll ligand Spätzle (Spz). We speculated that, as a system for sensing potential DAMPs in the hemolymph, the dronc mutants constitutively activate a proteolytic cascade that leads to Spz proteolytic processing. We demonstrated that Toll signaling activation required the action of Persephone, a CLIP domain serine protease that usually reacts to microbial proteolytic activities. Our findings show that the Persephone proteolytic cascade plays a crucial role in mediating DAMP-induced systemic responses in apoptosis-deficient Drosophila mutants. PMID:24492611

  14. Persephone/Spätzle pathogen sensors mediate the activation of Toll receptor signaling in response to endogenous danger signals in apoptosis-deficient Drosophila.

    PubMed

    Ming, Ming; Obata, Fumiaki; Kuranaga, Erina; Miura, Masayuki

    2014-03-14

    Apoptosis is an evolutionarily conserved mechanism that removes damaged or unwanted cells, effectively maintaining cellular homeostasis. It has long been suggested that a deficiency in this type of naturally occurring cell death could potentially lead to necrosis, resulting in the release of endogenous immunogenic molecules such as damage-associated molecular patterns (DAMPs) and a noninfectious inflammatory response. However, the details about how danger signals from apoptosis-deficient cells are detected and translated to an immune response are largely unknown. In this study, we found that Drosophila mutants deficient for Dronc, the key initiator caspase required for apoptosis, produced the active form of the endogenous Toll ligand Spätzle (Spz). We speculated that, as a system for sensing potential DAMPs in the hemolymph, the dronc mutants constitutively activate a proteolytic cascade that leads to Spz proteolytic processing. We demonstrated that Toll signaling activation required the action of Persephone, a CLIP domain serine protease that usually reacts to microbial proteolytic activities. Our findings show that the Persephone proteolytic cascade plays a crucial role in mediating DAMP-induced systemic responses in apoptosis-deficient Drosophila mutants.

  15. 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

  16. Understanding Death in Children With Epilepsy.

    PubMed

    Donner, Elizabeth J; Camfield, Peter; Brooks, Linda; Buchhalter, Jeffrey; Camfield, Carol; Loddenkemper, Tobias; Wirrell, Elaine

    2017-01-31

    Death in children with epilepsy is profoundly disturbing, with lasting effects on the family, community, and health care providers. The overall risk of death for children with epilepsy is about ten times that of the general population. However, the risk of premature death for children without associated neurological comorbidities is similar to that of the general population, and most deaths are related to the cause of the epilepsy or associated neurologic disability, not seizures. The most common cause of seizure-related death in children with epilepsy is sudden unexpected death in epilepsy (SUDEP). SUDEP is relatively uncommon in childhood, but the risk increases if epilepsy persists into adulthood. Although the direct cause of SUDEP remains unknown, most often death follows a generalized convulsive seizure and the risk of SUDEP is strongly related to drug-resistant epilepsy and frequent generalized tonic-clonic seizures. The most effective SUDEP prevention strategy is to reduce the frequency of seizures, although a number of seizure detection devices are under development and in the future may prove to be useful for seizure detection for those at particularly high risk. There are distinct benefits for health care professionals to discuss mortality with the family soon after the diagnosis of epilepsy. An individual approach is appropriate. When a child with epilepsy dies, particularly if the death was unexpected, family grief may be profound. Physicians and other health care professionals have a critical role in supporting families that lose a child to epilepsy. This review will provide health care providers with information needed to discuss the risk of death in children with epilepsy and support families following a loss.

  17. Toll-like receptor signaling in primary immune deficiencies

    PubMed Central

    Maglione, Paul J.; Simchoni, Noa; Cunningham-Rundles, Charlotte

    2015-01-01

    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 (IRAK)-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 (HSV-1) encephalitis. Other PIDs induce functional alterations of TLR signaling pathways, such as common variable immunodeficiency in which plasmacytoid dendritic cell (pDC) 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

  18. 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.

  19. Comparative studies of Toll-like receptor signalling using zebrafish.

    PubMed

    Kanwal, Zakia; Wiegertjes, Geert F; Veneman, Wouter J; Meijer, Annemarie H; Spaink, Herman P

    2014-09-01

    Zebrafish model systems for infectious disease are increasingly used for the functional analysis of molecular pattern recognition processes. These studies benefit from the high conservation level of all innate immune factors in vertebrates. Zebrafish studies are strategically well positioned for this because of the ease of comparisons with studies in other fish species of which the immune system also has been intensively studied, but that are currently still less amendable to detailed genetic or microscopic studies. In this paper we focus on Toll-like receptor (TLR) signalling factors, which currently are the best characterized in mammalian systems. We review the knowledge on TLR signalling in the context of recent advances in zebrafish studies and discuss possibilities for future approaches that can complement studies in cell cultures and rodent models. A focus in these comparisons is the role of negative control mechanisms in immune responses that appear very important in a whole organism to keep adverse systemic responses in check. We also pay much attention to comparisons with studies in common carp that is highly related to zebrafish and that because of its large body mass can complement immune studies in zebrafish.

  20. The Role of Toll-Like Receptors in Hematopoietic Malignancies

    PubMed Central

    Monlish, Darlene A.; Bhatt, Sima T.; Schuettpelz, Laura G.

    2016-01-01

    Toll-like receptors (TLRs) are a family of pattern recognition receptors that shape the innate immune system by identifying pathogen-associated molecular patterns and host-derived damage-associated molecular patterns. TLRs are widely expressed on both immune cells and non-immune cells, including hematopoietic stem and progenitor cells, effector immune cell populations, and endothelial cells. In addition to their well-known role in the innate immune response to acute infection or injury, accumulating evidence supports a role for TLRs in the development of hematopoietic and other malignancies. Several hematopoietic disorders, including lymphoproliferative disorders and myelodysplastic syndromes, which possess a high risk of transformation to leukemia, have been linked to aberrant TLR signaling. Furthermore, activation of TLRs leads to the induction of a number of proinflammatory cytokines and chemokines, which can promote tumorigenesis by driving cell proliferation and migration and providing a favorable microenvironment for tumor cells. Beyond hematopoietic malignancies, the upregulation of a number of TLRs has been linked to promoting tumor cell survival, proliferation, and metastasis in a variety of cancers, including those of the colon, breast, and lung. This review focuses on the contribution of TLRs to hematopoietic malignancies, highlighting the known direct and indirect effects of TLR signaling on tumor cells and their microenvironment. In addition, the utility of TLR agonists and antagonists as potential therapeutics in the treatment of hematopoietic malignancies is discussed. PMID:27733853

  1. The evolution of vertebrate Toll-like receptors

    USGS Publications Warehouse

    Roach, J.C.; Glusman, G.; Rowen, L.; Kaur, A.; Purcell, M.K.; Smith, K.D.; Hood, L.E.; Aderem, A.

    2005-01-01

    The complete sequences of Takifugu Toll-like receptor (TLR) loci and gene predictions from many draft genomes enable comprehensive molecular phylogenetic analysis. Strong selective pressure for recognition of and response to pathogen-associated molecular patterns has maintained a largely unchanging TLR recognition in all vertebrates. There are six major families of vertebrate TLRs. This repertoire is distinct from that of invertebrates. TLRs within a family recognize a general class of pathogen-associated molecular patterns. Most vertebrates have exactly one gene ortholog for each TLR family. The family including TLR1 has more species-specific adaptations than other families. A major family including TLR11 is represented in humans only by a pseudogene. Coincidental evolution plays a minor role in TLR evolution. The sequencing phase of this study produced finished genomic sequences for the 12 Takifugu rubripes TLRs. In addition, we have produced > 70 gene models, including sequences from the opossum, chicken, frog, dog, sea urchin, and sea squirt. ?? 2005 by The National Academy of Sciences of the USA.

  2. Toll-like receptors in skin infections and inflammatory diseases.

    PubMed

    Lai, Yuping; Gallo, Richard L

    2008-09-01

    The skin is the ultimate example of the function of innate immunity, it alerts the host of danger by many systems including sensing pathogen-associated molecule patterns (PAMPs) through Toll-like receptors and other pattern recognition receptors (PRRs), yet normally provides defense without inflammation. The skin responds rapidly to invading microbes by producing antimicrobial peptides or other antimicrobial intermediates before cytokine release results in inflammation. To achieve maximal immune responses for clearing invading microbes, the activation of select PRRs in skin then initiates and shapes adaptive immune responses through the activation of dendritic cells and recruitment of T cell subsets. Importantly, cross-talk between TLRs can influence this system in several ways including augmenting or suppressing the immune response. As a consequence of their pivotal role, TLR responses need to be tightly controlled by associated negative regulators or negative feedback loops to prevent detrimental effects from TLRs overactivation. This review focuses on describing the involvement of TLRs in the development of skin infections and inflammatory diseases, and highlights the potential application of TLR agonists or antagonists in these skin diseases.

  3. 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.

  4. Origin of Toll-like receptor-mediated innate immunity.

    PubMed

    Kanzok, Stefan M; Hoa, Ngo T; Bonizzoni, Mariangela; Luna, Coralia; Huang, Yaming; Malacrida, Anna R; Zheng, Liangbiao

    2004-04-01

    Toll-related receptors (TLR) have been found in four animal phyla: Nematoda, Arthropoda, Echinodermata, and Chordata. No TLR has been identified thus far in acoelomates. TLR genes play a pivotal role in the innate immunity in both fruit fly and mammals. The prevailing view is that TLR-mediated immunity is ancient. The two pseudocoelomate TLRs, one each from Caenorhabditis elegans and Strongyloides stercoralis, were distinct from the coelomate ones. Further, the only TLR gene (Tol-1) in Ca. elegans did not appear to play a role in innate immunity. We argue that TLR-mediated innate immunity developed only in the coelomates, after they split from pseudocoelomates and acoelomates. We hypothesize that the function of TLR-mediated immunity is to prevent microbial infection in the body cavity present only in the coelomates. Phylogenetic analysis showed that almost all arthropod TLRs form a separate cluster from the mammalian counterparts. We further hypothesize that TLR-mediated immunity developed independently in the protostomia and deuterostomia coelomates.

  5. α-Synuclein Alters Toll-Like Receptor Expression

    PubMed Central

    Béraud, Dawn; Twomey, Margaret; Bloom, Benjamin; Mittereder, Andrew; Ton, Vy; Neitzke, Katherine; Chasovskikh, Sergey; Mhyre, Timothy R.; Maguire-Zeiss, Kathleen A.

    2011-01-01

    Parkinson's disease, an age-related neurodegenerative disorder, is characterized by the loss of dopamine neurons in the substantia nigra, the accumulation of α-synuclein in Lewy bodies and neurites, and neuroinflammation. While the exact etiology of sporadic Parkinson's disease remains elusive, a growing body of evidence suggests that misfolded α-synuclein promotes inflammation and oxidative stress resulting in neurodegeneration. α-Synuclein has been directly linked to microglial activation in vitro and increased numbers of activated microglia have been reported in an α-synuclein overexpressing mouse model prior to neuronal loss. However, the mechanism by which α-synuclein incites microglial activation has not been fully described. Microglial activation is governed in part, by pattern recognition receptors that detect foreign material and additionally recognize changes in homeostatic cellular conditions. Upon proinflammatory pathway initiation, activated microglia contribute to oxidative stress through release of cytokines, nitric oxide, and other reactive oxygen species, which may adversely impact adjacent neurons. Here we show that microglia are directly activated by α-synuclein in a classical activation pathway that includes alterations in the expression of toll-like receptors. These data suggest that α-synuclein can act as a danger-associated molecular pattern. PMID:21747756

  6. Mechanisms of disease: Toll-like receptors in cardiovascular disease.

    PubMed

    Frantz, Stefan; Ertl, Georg; Bauersachs, Johann

    2007-08-01

    The innate immune system detects highly conserved, relatively invariant structural motifs of pathogens. Toll-like receptors (TLRs) have been identified as the primary innate immune receptors. TLRs distinguish between different patterns of pathogens and activate a rapid innate immune response; however, TLRs can also be activated by host-derived molecules. In addition to being expressed in immune cells, TLRs are expressed in other tissues, such as those of the cardiovascular system. TLRs could, therefore, be a key link between cardiovascular disease development and the immune system. Indeed, evidence that TLR activation contributes to the development and progression of atherosclerosis, cardiac dysfunction in sepsis, and congestive heart failure, is convincing. Although much has been learned about TLR activation in cellular components of the cardiovascular system, the role individual TLR family members have in the pathophysiology of cardiovascular diseases and hence in clinical practice remains to be defined. Here we review the rapid progress that has been made in this field, which has improved our understanding of vascular as well as myocardial TLR function in basic and clinical science.

  7. Toll-like receptors in pathophysiology of liver diseases

    PubMed Central

    Kiziltas, Safak

    2016-01-01

    Toll-like receptors (TLRs) are pattern recognition receptors that participate in host defense by recognizing pathogen-associated molecular patterns alongside inflammatory processes by recognizing damage associated molecular patterns. Given constant exposure to pathogens from gut, strict control of TLR-associated signaling pathways is essential in the liver, which otherwise may lead to inappropriate production of pro-inflammatory cytokines and interferons and may generate a predisposition to several autoimmune and chronic inflammatory diseases. The liver is considered to be a site of tolerance induction rather than immunity induction, with specificity in hepatic cell functions and distribution of TLR. Recent data emphasize significant contribution of TLR signaling in chronic liver diseases via complex immune responses mediating hepatocyte (i.e., hepatocellular injury and regeneration) or hepatic stellate cell (i.e., fibrosis and cirrhosis) inflammatory or immune pathologies. Herein, we review the available data on TLR signaling, hepatic expression of TLRs and associated ligands, as well as the contribution of TLRs to the pathophysiology of hepatic diseases. PMID:27917262

  8. Trial Watch: Toll-like receptor agonists in oncological indications.

    PubMed

    Aranda, Fernando; Vacchelli, Erika; Obrist, Florine; Eggermont, Alexander; Galon, Jérôme; Sautès-Fridman, Catherine; Cremer, Isabelle; Henrik Ter Meulen, Jan; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

    2014-01-01

    Toll-like receptors (TLRs) are an evolutionarily conserved group of enzymatically inactive, single membrane-spanning proteins that recognize a wide panel of exogenous and endogenous danger signals. Besides constituting a crucial component of the innate immune response to bacterial and viral pathogens, TLRs appear to play a major role in anticancer immunosurveillance. In line with this notion, several natural and synthetic TLR ligands have been intensively investigated for their ability to boost tumor-targeting immune responses elicited by a variety of immunotherapeutic and chemotherapeutic interventions. Three of these agents are currently approved by the US Food and Drug Administration (FDA) or equivalent regulatory agencies for use in cancer patients: the so-called bacillus Calmette-Guérin, monophosphoryl lipid A, and imiquimod. However, the number of clinical trials testing the therapeutic potential of both FDA-approved and experimental TLR agonists in cancer patients is stably decreasing, suggesting that drug developers and oncologists are refocusing their interest on alternative immunostimulatory agents. Here, we summarize recent findings on the use of TLR agonists in cancer patients and discuss how the clinical evaluation of FDA-approved and experimental TLR ligands has evolved since the publication of our first Trial Watch dealing with this topic.

  9. 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

  10. Toll-like receptor signaling in cell proliferation and survival

    PubMed Central

    Li, Xinyan; Jiang, Song; Tapping, Richard I.

    2009-01-01

    Toll-like receptors (TLRs) are important sensors of foreign microbial components as well as products of damaged or inflamed self tissues. Upon sensing these molecules, TLRs initiate a series of downstream signaling events that drive cellular responses including the production of cytokines, chemokines and other inflammatory mediators. This outcome results from the intracellular assembly of protein complexes that drive phosphorylation and other signaling cascades ultimately leading to chromatin remodeling and transcription factor activation. In addition to driving inflammatory responses, TLRs also regulate cell proliferation and survival which serves to expand useful immune cells and integrate inflammatory responses and tissue repair processes. In this context, central TLR signaling molecules, such as the mitogen-activated protein kinases (MAPK) and phosphoinositide 3-kinase (PI3K), play key roles. In addition, four major groups of transcription factors which are targets of TLR activation also control cell fate. This review focuses on the role of TLR signaling as it relates to cell proliferation and survival. This topic not only has important implications for understanding host defense and tissue repair, but also cancer which is often associated with conditions of chronic inflammation. PMID:19775907

  11. The role of toll like receptors in pregnancy.

    PubMed

    Amirchaghmaghi, Elham; Taghavi, Seyed Abdolvahab; Shapouri, Farnaz; Saeidi, Shaghayegh; Rezaei, Abbas; Aflatoonian, Reza

    2013-10-01

    For many years, the innate immunity was of less interest than the adaptive immunity because it was perceived to have secondary importance in the functionality of the immune system. During the past decades, with the advancement of knowledge about innate immune system, interest in innate immunity has grown dramatically and thus its function has been extensively studied. Innate immunity plays fundamental roles in the initiation and induction of adaptive immune responses. It consists of several cells and receptors including natural killer (NK) cells, macrophages (MQs), dendritic cells (DCs) and pattern recognition receptors (PRRs). Two decades ago, Toll like receptors (TLRs) family was known as one of the important PRRs with unique functions especially in protection against invading pathogens. Since the female reproductive tract has access to the outside environment and has a unique interaction with different pathogens whether invading microorganisms or normal flora, allogenic sperm and semi allogenic fetus, it has an essential need for effective immune responses. It has therefore been suggested that TLRs may play important roles in the immune regulation of the female reproductive tract. In addition, it has been demonstrated that immune disturbance may be responsible for some adverse pregnancy outcomes such as preeclampsia (PE), recurrent spontaneous abortion (RSA) and intrauterine growth restriction (IUGR). Our focus in this review is to show the importance of TLRs in pregnancy with emphasis on the expression of these receptors in different tissues related to pregnancy.

  12. The Role of Toll Like Receptors in Pregnancy

    PubMed Central

    Amirchaghmaghi, Elham; Taghavi, Seyed Abdolvahab; Shapouri, Farnaz; Saeidi, Shaghayegh; Rezaei, Abbas; Aflatoonian, Reza

    2013-01-01

    For many years, the innate immunity was of less interest than the adaptive immunity because it was perceived to have secondary importance in the functionality of the immune system. During the past decades, with the advancement of knowledge about innate immune system, interest in innate immunity has grown dramatically and thus its function has been extensively studied. Innate immunity plays fundamental roles in the initiation and induction of adaptive immune responses. It consists of several cells and receptors including natural killer (NK) cells, macrophages (MQs), dendritic cells (DCs) and pattern recognition receptors (PRRs). Two decades ago, Toll like receptors (TLRs) family was known as one of the important PRRs with unique functions especially in protection against invading pathogens. Since the female reproductive tract has access to the outside environment and has a unique interaction with different pathogens whether invading microorganisms or normal flora, allogenic sperm and semi allogenic fetus, it has an essential need for effective immune responses. It has therefore been suggested that TLRs may play important roles in the immune regulation of the female reproductive tract. In addition, it has been demonstrated that immune disturbance may be responsible for some adverse pregnancy outcomes such as preeclampsia (PE), recurrent spontaneous abortion (RSA) and intrauterine growth restriction (IUGR). Our focus in this review is to show the importance of TLRs in pregnancy with emphasis on the expression of these receptors in different tissues related to pregnancy. PMID:24520479

  13. Role of Toll-like receptors in diabetic nephropathy.

    PubMed

    Mudaliar, Harshini; Pollock, Carol; Panchapakesan, Usha

    2014-05-01

    Diabetic nephropathy is the leading cause of kidney failure and its increasing prevalence and incidence has imposed global socio-economic stress on healthcare systems worldwide. Although historically considered a metabolic disorder, recent studies have established that inflammatory responses are central to the pathogenesis of diabetic nephropathy. TLRs (Toll-like receptors) are a family of pattern recognition receptors responsible for the initiation of inflammatory and immune responses. The regulation of TLR2 and TLR4 have been implicated in the pathogenesis of various kidney diseases, and emerging evidence shows their involvement in the perpetuation of inflammation in the diabetic kidney. The present review focuses on the relative contributions of TLR2 and TLR4 in recognizing endogenous ligands relevant to diabetic nephropathy and their subsequent activation of NF-κB (nuclear factor κB), which results in the synthesis and secretion of pro-inflammatory cytokines and chemokines. Moreover, we discuss the pro-inflammatory signalling pathways of TLR2 and TLR4, in which their interruption or blockade may prove to be important therapeutic targets, potentially translated into clinical treatments for diabetic nephropathy. Currently, inhibitors to TLR2 and TLR4 are undergoing clinical trials in various inflammatory models of disease, but none in patients with diabetic nephropathy. Given the existing literature, there is a fundamental necessity to undertake trials in patients with diabetic nephropathy with a focus on renal end points.

  14. Phosphoinositide turnover in Toll-like receptor signaling and trafficking

    PubMed Central

    Tu Le, Oanh Thi; Ngoc Nguyen, Tu Thi; Lee, Sang Yoon

    2014-01-01

    Lipid components in biological membranes are essential for maintaining cellular function. Phosphoinositides, the phosphorylated derivatives of phosphatidylinositol (PI), regulate many critical cell processes involving membrane signaling, trafficking, and reorganization. Multiple metabolic pathways including phosphoinositide kinases and phosphatases and phospholipases tightly control spatio-temporal concentration of membrane phosphoinositides. Metabolizing enzymes responsible for PI 4,5-bisphosphate (PI(4,5)P2) production or degradation play a regulatory role in Toll-like receptor (TLR) signaling and trafficking. These enzymes include PI 4-phosphate 5-kinase, phosphatase and tensin homolog, PI 3-kinase, and phospholipase C. PI(4,5)P2 mediates the interaction with target cytosolic proteins to induce their membrane translocation, regulate vesicular trafficking, and serve as a precursor for other signaling lipids. TLR activation is important for the innate immune response and is implicated in diverse pathophysiological disorders. TLR signaling is controlled by specific interactions with distinct signaling and sorting adaptors. Importantly, TLR signaling machinery is differentially formed depending on a specific membrane compartment during signaling cascades. Although detailed mechanisms remain to be fully clarified, phosphoinositide metabolism is promising for a better understanding of such spatio-temporal regulation of TLR signaling and trafficking. [BMB Reports 2014; 47(7): 361-368] PMID:24856829

  15. Potentiation and tolerance of toll-like receptor priming in human endothelial cells.

    PubMed

    Koch, Stephen R; Lamb, Fred S; Hellman, Judith; Sherwood, Edward R; Stark, Ryan J

    2017-02-01

    Repeated challenge of lipopolysaccharide (LPS) alters the response to subsequent LPS exposures via modulation of toll-like receptor 4 (TLR4). Whether activation of other TLRs can modulate TLR4 responses, and vice versa, remains unclear. Specifically with regards to endothelial cells, a key component of innate immunity, the impact of TLR cross-modulation is unknown. We postulated that TLR2 priming (via Pam3Csk4) would inhibit TLR4-mediated responses while TLR3 priming (via Poly I:C) would enhance subsequent TLR4-inflammatory signaling. We studied human umbilical vein endothelial cells (HUVECs) and neonatal human dermal microvascular endothelial cells (HMVECs). Cells were primed with a combination of Poly I:C (10 μg/ml), Pam3Csk4 (10 μg/ml), or LPS (100 ng/ml), then washed and allowed to rest. They were then rechallenged with either Poly I:C, Pam3Csk4 or LPS. Endothelial cells showed significant tolerance to repeated LPS challenge. Priming with Pam3Csk4 also reduced the response to secondary LPS challenge in both cell types, despite a reduced proinflammatory response to Pam3Csk4 in HMVECs compared to HUVECs. Poly I:C priming enhanced inflammatory and interferon producing signals upon Poly I:C or LPS rechallenge, respectively. Poly I:C priming induced interferon regulatory factor 7, leading to enhancement of interferon production. Finally, both Poly I:C and LPS priming induced significant changes in receptor-interacting serine/threonine-protein kinase 1 activity. Pharmacological inhibition of receptor-interacting serine/threonine-protein kinase 1 or interferon regulatory factor 7 reduced the potentiated phenotype of TLR3 priming on TLR4 rechallenge. These results demonstrate that in human endothelial cells, prior activation of TLRs can have a significant impact on subsequent exposures and may contribute to the severity of the host response.

  16. Cocaine-related deaths.

    PubMed

    Lora-Tamayo, C; Tena, T; Rodriguez, A

    1994-07-15

    Cocaine availability has been increasing in Spain in the past few years. A review of all the toxicological analyses carried out at the Madrid Department of the Instituto Nacional de Toxicología, with subjects who had died of drugs from 1990 to 1992, found 533 persons who had cocaine in their blood and/or tissues; 450 (84%) deaths involved cocaine and heroin together whereas 83 (16%) deaths involved cocaine with an absence of heroin. This paper reports the circumstances, cocaine and benzoylecgonine concentrations in the blood and other toxicological findings for the two major groups of deaths where cocaine was found with an absence of heroin, i.e., possible overdose cases (35 cases) and traffic accidents (23 cases).

  17. Amphetamine derivative related deaths.

    PubMed

    Lora-Tamayo, C; Tena, T; Rodríguez, A

    1997-02-28

    Amphetamine its methylendioxy (methylendioxyamphetamine methylenedioxymethylamphetamine, methylenedioxyethylamphetamine) and methoxy derivatives (p-methoxyamphetamine and p-methoxymethylamphetamine) are widely abused in Spanish society. We present here the results of a systematic study of all cases of deaths brought to the attention of the Madrid department of the Instituto Nacional de Toxicologia from 1993 to 1995 in which some of these drugs have been found in the cadaveric blood. The cases were divided into three categories: amphetamine and derivatives, amphetamines and alcohol, amphetamines and other drugs. Data on age, sex, clinical symptoms, morphological findings, circumstances of death, when known, and concentration of amphetamine derivatives, alcohol and other drugs in blood are given for each group. The information provided here may prove to be useful for the forensic interpretation of deaths which are directly or indirectly related to abuse of amphetamine derivatives.

  18. [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.

  19. Byron on Death

    DTIC Science & Technology

    1991-01-01

    of alienation from other men, but also kinship with identical elements of nature presented in the same sequence: air, earth , water . Add to those...question of the death of the innocent is as important in Heaven and Earth as in Cain. As the waters rise at the end of the later drama, a mother...What is there in this milk of mine, that death Should stir all heaven and earth up to destroy My boy, And roll the waters o’er his placid breath

  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.

  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.

  2. The role of Toll-like receptors and vitamin D in diabetes mellitus type 1--a review.

    PubMed

    Adamczak, D M; Nowak, J K; Frydrychowicz, M; Kaczmarek, M; Sikora, J

    2014-08-01

    It is widely accepted that type 1 diabetes mellitus (T1DM) is an autoimmune disease resulting from an interaction between immunologic, genetic and environmental factors. However, the exact mechanism leading to the development of T1DM remains incomplete. There is a large body of evidence pointing towards the important role of toll-like receptor (TLR) activation and vitamin D deficiency in T1DM pathogenesis. In this article, we review the available data on the influence of TLRs' level of activation and vitamin D status on the risk of the development of T1DM in humans and rodent models. We also summarize the current information regarding the interactions between TLRs' level of activation, vitamin D status and various environmental factors, such as enteroviral infections, the gut microbiota and breastfeeding substitution, among others. Our results stipulate that vitamin D seems to protect against T1DM by reducing the TLRs' level of activation.

  3. Toll-like receptor 4 activation promotes cardiac arrhythmias by decreasing the transient outward potassium current (Ito) through an IRF3-dependent and MyD88-independent pathway.

    PubMed

    Monnerat-Cahli, Gustavo; Alonso, Hiart; Gallego, Monica; Alarcón, Micaela Lopez; Bassani, Rosana A; Casis, Oscar; Medei, Emiliano

    2014-11-01

    Cardiac arrhythmias are one of the main causes of death worldwide. Several studies have shown that inflammation plays a key role in different cardiac diseases and Toll-like receptors (TLRs) seem to be involved in cardiac complications. In the present study, we investigated whether the activation of TLR4 induces cardiac electrical remodeling and arrhythmias, and the signaling pathway involved in these effects. Membrane potential was recorded in Wistar rat ventricle. Ca(2+) transients, as well as the L-type Ca(2+) current (ICaL) and the transient outward K(+) current (Ito), were recorded in isolated myocytes after 24 h exposure to the TLR4 agonist, lipopolysaccharide (LPS, 1 μg/ml). TLR4 stimulation in vitro promoted a cardiac electrical remodeling that leads to action potential prolongation associated with arrhythmic events, such as delayed afterdepolarization and triggered activity. After 24 h LPS incubation, Ito amplitude, as well as Kv4.3 and KChIP2 mRNA levels were reduced. The Ito decrease by LPS was prevented by inhibition of interferon regulatory factor 3 (IRF3), but not by inhibition of interleukin-1 receptor-associated kinase 4 (IRAK4) or nuclear factor kappa B (NF-κB). Extrasystolic activity was present in 25% of the cells, but apart from that, Ca(2+) transients and ICaL were not affected by LPS; however, Na(+)/Ca(2+) exchanger (NCX) activity was apparently increased. We conclude that TLR4 activation decreased Ito, which increased AP duration via a MyD88-independent, IRF3-dependent pathway. The longer action potential, associated with enhanced Ca(2+) efflux via NCX, could explain the presence of arrhythmias in the LPS group.

  4. High-dose irradiation in combination with toll-like receptor 9 agonist CpG oligodeoxynucleotide 7909 downregulates PD-L1 expression via the NF-κB signaling pathway in non-small cell lung cancer cells

    PubMed Central

    Chen, Xue; Zhang, Qi; Luo, Youjun; Gao, Caixia; Zhuang, Xibing; Xu, Guoxiong; Qiao, Tiankui

    2016-01-01

    Objectives Irradiation resistance appears as local recurrence and distant metastasis in advanced stages of non-small cell lung cancer (NSCLC). High-dose irradiation combined with immunotherapy improved overall survival and local control of NSCLC. This study explored the underlying molecular mechanism by which the effect of high-dose irradiation plus toll-like receptor 9 (TLR9) agonist CpG oligodeoxynucleotide (CpG ODN) 7909 on NSCLC. Materials and methods NSCLC H460 cells were exposed to constant high-dose irradiation (6.37 Gy) in irradiation (IR) group and the irradiation plus CpG group. Gene expression was assessed using quantitative reverse transcriptase-polymerase chain reaction and Western blot. Knockdown of nuclear factor kappa B (NF-κB) p65 expression was conducted using p65 siRNA. Results Expression of programmed death-ligand 1 (PD-L1) mRNA was significantly decreased in IR combined with CpG ODN 7909 group compared with the control or IR-alone groups (P<0.05). TLR9 expression was also obviously increased in the combination group compared with the control (P<0.05). Moreover, expression of NF-κB p65 was apparently reduced in the combination group compared with the control (P<0.05). However, expression of PD-L1 was significantly decreased after knockdown of p65 in IR group (P<0.05), but increased in the combination group (P<0.05) and slightly increased in CpG ODN-alone group (P<0.05), which was opposite to that without p65 knockdown group. Conclusion This study demonstrated that radiotherapy combined with CpG ODN 7909 was able to downregulate PD-L1 expression through inhibition via the NF-κB signaling pathway. PMID:27799798

  5. 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…

  6. [Death of Napoleon Bonaparte].

    PubMed

    Camici, M

    2003-06-01

    The causa mortis of Napoleon Bonaparte has been vexata quaestio for a long time. The author tries to outline a picture of Napoleon from a sanitary point of view. From the report of doctor Francesco Antonmarchi who performed the autopsy, the author tries to understans the cause of death: gastric perforation due to malignant ulcer and subsequent peritonitis with pulmonary tubercolosis.

  7. Counseling and Death.

    ERIC Educational Resources Information Center

    Barry, John R.

    Increasingly, helpers are asked to counsel the dying and their relatives. The research and other literature are reviewed for information and ideas that might be helpful to a counselor; for example, research and speculation about fears of death are examined. While an awareness of such information may reassure the counselor who tries to counsel in…

  8. 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)

  9. Lifespan Attitudes toward Death.

    ERIC Educational Resources Information Center

    Walker, Gail; Maiden, Robert

    To more fully understand how attitudes toward death and dying develop and change across the lifespan, 90 male and female subjects between the ages of 2 and 18 years and 90 male and female subjects between the ages of 18 and 97 were administered questionnaires and interviews about dying. The results revealed that children's attitudes were…

  10. 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

  11. Death and Grief

    MedlinePlus

    ... response to a death or loss. Grief can affect our body, mind, emotions, and spirit. People might notice or show grief in several ways: Physical reactions: These might be things like changes in appetite or sleep, an upset stomach, tight chest, crying, tense muscles, ...

  12. 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.…

  13. Effects of Death Education on Fear of Death and Attitudes towards Death and Life.

    ERIC Educational Resources Information Center

    Leviton, Dan; Fretz, Bruce

    1978-01-01

    Students in a death education course were compared with students of sex education and introductory psychology. After the death education course, students viewed death as more approachable, and wished to experience death in a more interpersonal as compared to a technological context. (Author)

  14. The activation of liver X receptors inhibits toll-like receptor-9-induced foam cell formation.

    PubMed

    Sorrentino, Rosalinda; Morello, Silvana; Chen, Shuang; Bonavita, Eduardo; Pinto, Aldo

    2010-04-01

    Toll-like receptors (TLRs) are related to foam cell formation (FCF), key event in the establishment/progression of atherosclerosis. The activation of TLR2 and TLR4 can increase FCF. The aim of this study was to evaluate the role of TLR9 in FCF. Murine macrophages were treated with CpG-ODN, TLR9 agonist, and oxidized particles of LDL (Paz-PC) and FCF was analyzed by means of Oil Red O staining. The administration of CpG-ODN plus Paz-PC onto macrophages increased the amount of lipid droplets, correlated to increased levels of tumor necrosis factor (TNF)-alpha, IFNbeta, and IP-10. The underlying mechanism by which TLR9 ligation influenced Paz-PC in the FCF was NF-kappaB- and IRF7-dependent, as observed by higher levels of phosphorylated IkappaBalpha, increased nuclear translocation of the p65 subunit, lower levels of the total IKKalpha protein and higher release of interferon-dependent cytokines, such as IP-10. Liver X receptors (LXRs) regulate lipid cellular transport and negatively modulate TLR-dependent signaling pathways. Indeed, the addition of GW3965, synthetic LXRs agonist, significantly reduced FCF after CpG-ODN plus Paz-PC stimulation. In this condition, we observed decreased levels of the nuclear translocation of the p65 subunit, related to the higher presence of LXRalpha into the nucleus. TNF-alpha, IP-10, and IFNbeta levels were reduced by the administration of GW3965 following CpG-ODN and Paz-PC treatment. In conclusion, the activation of TLR9 facilitates the formation of foam cells in an NF-kappaB- and IRF7-dependent manner, countered by the activation of LXRs. This study further support LXRs as potential anti-atherosclerotic target.

  15. Cardiolipins Act as a Selective Barrier to Toll-Like Receptor 4 Activation in the Intestine

    PubMed Central

    Coats, Stephen R.; Hashim, Ahmed; Paramonov, Nikolay A.; Curtis, Michael A.

    2016-01-01

    ABSTRACT Intestinal homeostasis mechanisms must protect the host intestinal tissue from endogenous lipopolysaccharides (LPSs) produced by the intestinal microbiota. In this report, we demonstrate that murine intestinal fecal lipids effectively block Toll-like receptor 4 (TLR4) responses to naturally occurring Bacteroidetes sp. LPS. Cardiolipin (CL) represents a significant proportion of the total intestinal and fecal lipids and, furthermore, potently antagonizes TLR4 activation by reducing LPS binding at the lipopolysaccharide binding protein (LBP), CD14, and MD-2 steps of the TLR4 signaling pathway. It is further demonstrated that intestinal lipids and CL are less effective at neutralizing more potent Enterobacteriaceae-type LPS, which is enriched in feces obtained from mice with dextran sodium sulfate (DSS)-treated inflammatory bowel disease. The selective inhibition of naturally occurring LPS structures by intestinal lipids may represent a novel homeostasis mechanism that blocks LPS activation in response to symbiotic but not dysbiotic microbial communities. IMPORTANCE The guts of animals harbor a variety of Gram-negative bacteria associated with both states of intestinal health and states of disease. Environmental factors, such as dietary habits, can drive the microbial composition of the host animal's intestinal bacterial community toward a more pathogenic state. Both beneficial and harmful Gram-negative bacteria are capable of eliciting potentially damaging inflammatory responses from the host intestinal tissues via a lipopolysaccharide (LPS)-dependent pathway. Physical mucosal barriers and antibodies produced by the intestinal immune system protect against the undesired inflammatory effects of LPS, although it is unknown why some bacteria are more effective at overcoming the protective barriers than others. This report describes the discovery of a lipid-type protective barrier in the intestine that reduces the deleterious effects of LPSs from beneficial

  16. Transgenic cloned sheep overexpressing ovine toll-like receptor 4.

    PubMed

    Deng, Shoulong; Li, Guiguan; Zhang, Jinlong; Zhang, Xiaosheng; Cui, Maosheng; Guo, Yong; Liu, Guoshi; Li, Guangpeng; Feng, Jianzhong; Lian, Zhengxing

    2013-07-01

    An ovine fetal fibroblast cell line highly expressing TLR4 was established by inserting TLR4 into a reconstructive p3S-LoxP plasmid. Transgenic sheep overexpressing TLR4 were produced by transferring TLR4-transfected fetal fibroblasts into metaphase (M)II-stage enucleated oocytes (using SCNT). Because reconstructed embryos derived from MII-stage enucleated oocytes matured in vivo using a delayed-activated method had a higher pregnancy rate (18.52%) than that from MII-stage enucleated oocytes matured in vitro, the former procedure was used. Nine TLR4-transgenic live births were confirmed using polymerase chain reaction and Southern blot analysis. Increased expression of TLR4 at mRNA and protein levels in ear tissues of transgenic lambs were verified using reverse transcription polymerase chain reaction and immunohistochemistry, respectively. More toll-like receptor 4 protein was expressed by peripheral blood monocytes and/or macrophages collected from 3-month-old TLR4-transgenic than nontransgenic lambs at 0, 1, and 4 hours after lipopolysaccharide stimulation. Furthermore, interferon-γ and tumor necrosis factor α secreted by monocytes and/or macrophages of TLR4-transgenic lambs were significantly higher at 1 hour. Therefore, lipopolysaccharide-induced inflammatory responses from monocytes and/or macrophages occurred sooner in TLR4-transgenic lambs, consistent with an enhanced host immune response. In conclusion, transgenic sheep overexpressing TLR4 are a primary model to investigate the role of transgenic animals in disease resistance and have potential for breeding sheep with disease resistance.

  17. 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

  18. Leishmania RNA virus: when the host pays the toll

    PubMed Central

    Hartley, Mary-Anne; Ronet, Catherine; Zangger, Haroun; Beverley, Stephen M.; Fasel, Nicolas

    2012-01-01

    The presence of an RNA virus in a South American subgenus of the Leishmania parasite, L. (Viannia), was detected several decades ago but its role in leishmanial virulence and metastasis was only recently described. In Leishmania guyanensis, the nucleic acid of Leishmania RNA virus (LRV1) acts as a potent innate immunogen, eliciting a hyper-inflammatory immune response through toll-like receptor 3 (TLR3). The resultant inflammatory cascade has been shown to increase disease severity, parasite persistence, and perhaps even resistance to anti-leishmanial drugs. Curiously, LRVs were found mostly in clinical isolates prone to infectious metastasis in both their human source and experimental animal model, suggesting an association between the viral hyperpathogen and metastatic complications such as mucocutaneous leishmaniasis (MCL). MCL presents as chronic secondary lesions in the mucosa of the mouth and nose, debilitatingly inflamed and notoriously refractory to treatment. Immunologically, this outcome has many of the same hallmarks associated with the reaction to LRV: production of type 1 interferons, bias toward a chronic Th1 inflammatory state and an impaired ability of host cells to eliminate parasites through oxidative stress. More intriguing, is that the risk of developing MCL is found almost exclusively in infections of the L. (Viannia) subtype, further indication that leishmanial metastasis is caused, at least in part, by a parasitic component. LRV present in this subgenus may contribute to the destructive inflammation of metastatic disease either by acting in concert with other intrinsic “metastatic factors” or by independently preying on host TLR3 hypersensitivity. Because LRV amplifies parasite virulence, its presence may provide a unique target for diagnostic and clinical intervention of metastatic leishmaniasis. Taking examples from other members of the Totiviridae virus family, this paper reviews the benefits and costs of endosymbiosis, specifically

  19. Toll-like receptor polymorphisms in allogeneic hematopoietic cell transplantation.

    PubMed

    Kornblit, Brian; Enevold, Christian; Wang, Tao; Spellman, Stephen; Haagenson, Mike; Lee, Stephanie J; Müller, Klaus

    2015-02-01

    To assess the impact of the genetic variation in toll-like receptors (TLRs) on outcome after allogeneic myeloablative conditioning hematopoietic cell transplantation (HCT), we investigated 29 single nucleotide polymorphisms 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 ≤ .001. Male hemizygosity and female homozygosity for the minor allele were significantly associated with disease-free survival (hazard ratio [HR], 1.47 [95% confidence interval {CI}, 1.16 to 1.85]; P = .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 to 1.83], P = .010; female donor: HR, 2.78 [95% CI, 1.43 to 5.41], P = .003), disease-free survival (male donor: HR, 1.45 [95% CI, 1.12 to 1.87], P = .005; female donor: HR, 2.34 [95% CI, 1.18 to 4.65], P = .015), and treatment-related mortality (male donor: HR, 1.49 [95% CI, 1.09 to 2.04], P = .012; female donor: HR, 3.12 [95% CI, 1.44 to 6.74], P = .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.

  20. Toll-like Receptor 7 Rapidly Relaxes Human Airways

    PubMed Central

    Scott, Gregory D.; Proskocil, Becky J.; Fryer, Allison D.; Jacoby, David B.; Kaufman, Elad H.

    2013-01-01

    Rationale: Toll-like receptors (TLRs) 7 and 8 detect respiratory virus single-stranded RNA and trigger an innate immune response. We recently described rapid TLR7-mediated bronchodilation in guinea pigs. Objectives: To characterize TLR7 expression and TLR7-induced airway relaxation in humans and in eosinophilic airway inflammation in guinea pigs. To evaluate the relaxant effects of other TLRs. Methods: Human airway smooth muscle strips were contracted with methacholine in vitro, and responses to TLR7 and TLR8 agonists were assessed. TLR7-mediated nitric oxide production was measured using a fluorescent indicator, and TLR7 expression was characterized using immunofluorescence. TLR7 signaling was also evaluated in ovalbumin-challenged guinea pigs. Measurements and Main Results: The TLR7 agonist imiquimod (R837) caused rapid dose-dependent relaxation of methacholine-contracted human airways in vitro. This was blocked by the TLR7 antagonist IRS661 and by inhibiting nitric oxide production but not by inhibiting prostaglandin production. TLR7 activation markedly increased fluorescence of a nitric oxide detector. TLR7 was expressed on airway nerves, but not airway smooth muscle, implicating airway nerves as the source of TLR7-induced nitric oxide production. TLR7-mediated relaxation persisted in inflamed guinea pigs airways in vivo. The TLR8 agonists polyuridylic acid and polyadenylic acid also relaxed human airways, and this was not blocked by the TLR7 antagonist or by blocking nitric oxide or prostaglandin production. No other TLRs relaxed the airways. Conclusions: TLR7 is expressed on airway nerves and mediates relaxation of human and animal airways through nitric oxide production. TLR7-mediated bronchodilation may be a new therapeutic strategy in asthma. PMID:23924358

  1. 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

  2. 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.

  3. An Effector Peptide Family Required for Drosophila Toll-Mediated Immunity

    PubMed Central

    Wasserman, Steven A.

    2015-01-01

    In Drosophila melanogaster, recognition of an invading pathogen activates the Toll or Imd signaling pathway, triggering robust upregulation of innate immune effectors. Although the mechanisms of pathogen recognition and signaling are now well understood, the functions of the immune-induced transcriptome and proteome remain much less well characterized. Through bioinformatic analysis of effector gene sequences, we have defined a family of twelve genes – the Bomanins (Boms) – that are specifically induced by Toll and that encode small, secreted peptides of unknown biochemical activity. Using targeted genome engineering, we have deleted ten of the twelve Bom genes. Remarkably, inactivating these ten genes decreases survival upon microbial infection to the same extent, and with the same specificity, as does eliminating Toll pathway function. Toll signaling, however, appears unaffected. Assaying bacterial load post-infection in wild-type and mutant flies, we provide evidence that the Boms are required for resistance to, rather than tolerance of, infection. In addition, by generating and assaying a deletion of a smaller subset of the Bom genes, we find that there is overlap in Bom activity toward particular pathogens. Together, these studies deepen our understanding of Toll-mediated immunity and provide a new in vivo model for exploration of the innate immune effector repertoire. PMID:25915418

  4. EP2 Receptor Signaling Regulates Microglia Death

    PubMed Central

    Yang, Myung-Soon; Jiang, Jianxiong; Ganesh, Thota; Joe, Eunhye; Dingledine, Raymond

    2015-01-01

    The timely resolution of inflammation prevents continued tissue damage after an initial insult. In the brain, the death of activated microglia by apoptosis has been proposed as one mechanism to resolve brain inflammation. How microglial death is regulated after activation is still unclear. We reported that exposure to lipopolysaccharide (LPS) and interleukin (IL)-13 together initially activates and then kills rat microglia in culture by a mechanism dependent on cyclooxygenase-2 (COX-2). We show here that activation of the E prostanoid receptor 2 (EP2, PTGER2) for prostaglandin E2 mediates microglial death induced by LPS/IL-13, and that EP2 activation by agonist alone kills microglia. Both EP2 antagonists and reactive oxygen scavengers block microglial death induced by either LPS/IL-13 or EP2 activation. By contrast, the homeostatic induction of heme oxygenase 1 (Hmox1) by LPS/IL-13 or EP2 activation protects microglia. Both the Hmox1 inducer cobalt protoporphyrin and a compound that releases the Hmox1 product carbon monoxide (CO) attenuated microglial death produced by LPS/IL-13. Whereas CO reduced COX-2 protein expression, EP2 activation increased Hmox1 and COX-2 expression at both the mRNA and protein level. Interestingly, caspase-1 inhibition prevented microglial death induced by either LPS/IL-13 or low (but not high) concentrations of butaprost, suggestive of a predominantly pyroptotic mode of death. Butaprost also caused the expression of activated caspase-3 in microglia, pointing to apoptosis. These results indicate that EP2 activation, which initially promotes microglial activation, later causes delayed death of activated microglia, potentially contributing to the resolution phase of neuroinflammation. PMID:25715797

  5. Maternal endotoxin-induced preterm birth in mice: fetal responses in toll-like receptors, collectins, and cytokines.

    PubMed

    Salminen, Annamari; Paananen, Reija; Vuolteenaho, Reetta; Metsola, Juhani; Ojaniemi, Marja; Autio-Harmainen, Helena; Hallman, Mikko

    2008-03-01

    Major cause of prematurity is spontaneous preterm birth (PTB) associated with intrauterine inflammation. Our aim was to establish a model of endotoxin Lipopolysaccharide-induced PTB of live-born pups and to study early immune activation in fetal and maternal compartments. Expression of several proteins that bind microbes (Toll-like receptors TLR4, TLR2; surfactant proteins SP-A, SP-D) was analyzed. At 16 or 17 d of gestation, C57BL/6 dams received a single dose of intraperitoneal LPS, leading to PTB within 17 h. Cytokine levels increased in maternal serum, followed by a modest increase in fetal serum and in amniotic fluid. In uterus, placenta, and fetal membranes, LPS mostly increased the expressions of TLR, SPs, and cytokines. The number of TLR2-positive macrophages increased in labyrinthine placenta. In fetal lung, intestine, liver, and brain there were modest changes in cytokine expressions. In fetal lung, SP and TLR mRNAs decreased and TLR2-positive macrophages redistributed around vessels. LPS-induced fetal deaths associated with early age (16 d gestation) rather than with proinflammatory activation. Here we propose that maternal LPS response leads to PTB and acute decrease of immune proteins in epithelial lining of fetal lung. Instead, acceleration of lung maturity has been previously observed in intraamniotic inflammation.

  6. 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.

  7. Death from Nitrous Oxide.

    PubMed

    Bäckström, Björn; Johansson, Bengt; Eriksson, Anders

    2015-11-01

    Nitrous oxide is an inflammable gas that gives no smell or taste. It has a history of abuse as long as its clinical use, and deaths, although rare, have been reported. We describe two cases of accidental deaths related to voluntary inhalation of nitrous oxide, both found dead with a gas mask covering the face. In an attempt to find an explanation to why the victims did not react properly to oncoming hypoxia, we performed experiments where a test person was allowed to breath in a closed system, with or without nitrous oxide added. Vital signs and gas concentrations as well as subjective symptoms were recorded. The experiments indicated that the explanation to the fact that neither of the descendents had reacted to oncoming hypoxia and hypercapnia was due to the inhalation of nitrous oxide. This study raises the question whether nitrous oxide really should be easily, commercially available.

  8. Cell death and tendinopathy.

    PubMed

    Yuan, Jun; Wang, Min-Xia; Murrell, George A C

    2003-10-01

    Apoptosis and necrosis are presently recognized as the two major types of physiological and pathological cell death. Apoptosis is a tightly regulated cell deletion process that differs morphologically and biochemically from necrotic cell death. Tendinopathy is defined as a tendon injury that originates from intrinsic and extrinsic etiological factors. Excessive apoptosis has recently been described in degenerative tendon. The increased number of apoptotic tendon cells in degenerative tendon tissue could affect the rate of collagen synthesis and repair. Impaired or dysfunctional protein synthesis may lead to weaker tendon tissue and eventually increase the risk for tendon rupture. Clearly, there are many details to insert into this pathway, but there is hope that if the fine details of the pathway can be fleshed out, then strategies may be able to be developed to break the cycle at one or more points and prevent or treat tendinopathy more effectively.

  9. 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

  10. 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.

  11. 23 CFR 661.49 - Can IRRBP funds be spent on Interstate, State Highway, and Toll Road IRR bridges?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ..., and Toll Road IRR bridges? 661.49 Section 661.49 Highways FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION ENGINEERING AND TRAFFIC OPERATIONS INDIAN RESERVATION ROAD BRIDGE PROGRAM § 661.49 Can IRRBP funds be spent on Interstate, State Highway, and Toll Road IRR bridges? Yes....

  12. 23 CFR 661.49 - Can IRRBP funds be spent on Interstate, State Highway, and Toll Road IRR bridges?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ..., and Toll Road IRR bridges? 661.49 Section 661.49 Highways FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION ENGINEERING AND TRAFFIC OPERATIONS INDIAN RESERVATION ROAD BRIDGE PROGRAM § 661.49 Can IRRBP funds be spent on Interstate, State Highway, and Toll Road IRR bridges? Yes....

  13. 26 CFR 49.4254-2 - Payment for toll telephone service or telegraph service in coin-operated telephones.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 16 2010-04-01 2010-04-01 true Payment for toll telephone service or telegraph service in coin-operated telephones. 49.4254-2 Section 49.4254-2 Internal Revenue INTERNAL REVENUE SERVICE... Communications § 49.4254-2 Payment for toll telephone service or telegraph service in coin-operated...

  14. 26 CFR 49.4254-2 - Payment for toll telephone service or telegraph service in coin-operated telephones.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 16 2013-04-01 2013-04-01 false Payment for toll telephone service or telegraph service in coin-operated telephones. 49.4254-2 Section 49.4254-2 Internal Revenue INTERNAL REVENUE SERVICE... Communications § 49.4254-2 Payment for toll telephone service or telegraph service in coin-operated...

  15. 26 CFR 49.4254-2 - Payment for toll telephone service or telegraph service in coin-operated telephones.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 16 2011-04-01 2011-04-01 false Payment for toll telephone service or telegraph service in coin-operated telephones. 49.4254-2 Section 49.4254-2 Internal Revenue INTERNAL REVENUE SERVICE... Communications § 49.4254-2 Payment for toll telephone service or telegraph service in coin-operated...

  16. 26 CFR 49.4254-2 - Payment for toll telephone service or telegraph service in coin-operated telephones.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 16 2012-04-01 2012-04-01 false Payment for toll telephone service or telegraph service in coin-operated telephones. 49.4254-2 Section 49.4254-2 Internal Revenue INTERNAL REVENUE SERVICE... Communications § 49.4254-2 Payment for toll telephone service or telegraph service in coin-operated...

  17. 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

  18. 76 FR 6190 - Open Meeting of the Taxpayer Advocacy Panel Small Business/Self Employed Correspondence Exam Toll...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-02-03

    ... Advocacy Panel Small Business/Self Employed Correspondence Exam Toll Free Project Committee AGENCY... Taxpayer Advocacy Panel Small Business/ Self Employed Correspondence Exam Toll Free Project Committee will... Act, 5 U.S.C. App. (1988) that an open meeting of the Taxpayer Advocacy Panel Small...

  19. 76 FR 2196 - Open Meeting of the Taxpayer Advocacy Panel Small Business/Self Employed Correspondence Exam Toll...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-12

    ... Internal Revenue Service Open Meeting of the Taxpayer Advocacy Panel Small Business/Self Employed...: An open meeting of the Taxpayer Advocacy Panel Small Business/ Self Employed Correspondence Exam Toll... Business/Self Employed Correspondence Exam Toll Free will be held Tuesday, February 22, 2011, at 9...

  20. Toll receptors instruct axon and dendrite targeting and participate in synaptic partner matching in a Drosophila olfactory circuit.

    PubMed

    Ward, Alex; Hong, Weizhe; Favaloro, Vincenzo; Luo, Liqun

    2015-03-04

    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.

  1. From Death to Death Certificate: What do the Dead say?

    PubMed

    Gill, James R

    2017-03-01

    This is an overview of medicolegal death investigation and death certification. Postmortem toxicological analysis, particularly for ethanol and drugs of abuse, plays a large role in the forensic investigation of natural and unnatural deaths. Postmortem drug concentrations must be interpreted in light of the autopsy findings and circumstances. Interpretations of drug and ethanol concentrations are important for death certification, but they also may be important for other stakeholders such as police, attorneys, public health practitioners, and the next-of-kin.

  2. Fear of death.

    PubMed

    Penson, Richard T; Partridge, Rosamund A; Shah, Muhammad A; Giansiracusa, David; Chabner, Bruce A; Lynch, Thomas J

    2005-02-01

    Shortly before his death in 1995, Kenneth B. Schwartz, a cancer patient at Massachusetts General Hospital (MGH) founded The Kenneth B. Schwartz Center at MGH. The Schwartz Center is a nonprofit organization dedicated to supporting and advancing compassionate health care delivery, which provides hope to the patient and support to caregivers and encourages the healing process. The center sponsors the Schwartz Center Rounds, a monthly multidisciplinary forum where caregivers reflect on important psychosocial issues faced by patients, their families, and their caregivers, and gain insight and support from fellow staff members. For many, cancer is synonymous with death. Fearing death is a rational response. For too long, medicine has ignored this primeval fear. Increasingly, clinicians recognize and address end-of-life issues, facing patients' and our own emotional vulnerabilities in order to connect and explore problems and fears. Listening and learning from the patient guides us as we acknowledge much of the mystery that still surrounds the dying process. Rarely is there a simple or right answer. An empathetic response to suffering patients is the best support. Support is vital in fostering the adjustment of patients. A silent presence may prove more helpful than well-meant counsel for many patients. Through an examination of eight caregiver narratives of their patients' experiences, the role of the health care provider in the dying process, particularly in regard to challenging fear, is reviewed.

  3. Introgression of Neandertal- and Denisovan-like Haplotypes Contributes to Adaptive Variation in Human Toll-like Receptors

    PubMed Central

    Dannemann, Michael; Andrés, Aida M.; Kelso, Janet

    2016-01-01

    Pathogens and the diseases they cause have been among the most important selective forces experienced by humans during their evolutionary history. Although adaptive alleles generally arise by mutation, introgression can also be a valuable source of beneficial alleles. Archaic humans, who lived in Europe and Western Asia for more than 200,000 years, were probably well adapted to this environment and its local pathogens. It is therefore conceivable that modern humans entering Europe and Western Asia who admixed with them obtained a substantial immune advantage from the introgression of archaic alleles. Here we document a cluster of three Toll-like receptors (TLR6-TLR1-TLR10) in modern humans that carries three distinct archaic haplotypes, indicating repeated introgression from archaic humans. Two of these haplotypes are most similar to the Neandertal genome, and the third haplotype is most similar to the Denisovan genome. The Toll-like receptors are key components of innate immunity and provide an important first line of immune defense against bacteria, fungi, and parasites. The unusually high allele frequencies and unexpected levels of population differentiation indicate that there has been local positive selection on multiple haplotypes at this locus. We show that the introgressed alleles have clear functional effects in modern humans; archaic-like alleles underlie differences in the expression of the TLR genes and are associated with reduced microbial resistance and increased allergic disease in large cohorts. This provides strong evidence for recurrent adaptive introgression at the TLR6-TLR1-TLR10 locus, resulting in differences in disease phenotypes in modern humans. PMID:26748514

  4. The Treatment of PVCs and Prevention of Sudden Cardiac Death

    PubMed Central

    Nattel, Stanley

    1991-01-01

    Premature ventricular complexes (PVCs) have traditionally been suppressed using antiarrhythmic drugs. Recent studies have failed to show that reducing the number of PVCs can prevent sudden death; moreover, treatment with some antiarrhythmic agents can increase the risk. There is a close link between the severity of ischemic heart disease and sudden death. PMID:21234088

  5. 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…

  6. 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…

  7. Induction of Direct Antimicrobial Activity Through Mammalian Toll-Like Receptors

    NASA Astrophysics Data System (ADS)

    Thoma-Uszynski, Sybille; Stenger, Steffen; Takeuchi, Osamu; Ochoa, Maria Teresa; Engele, Matthias; Sieling, Peter A.; Barnes, Peter F.; Röllinghoff, Martin; Bölcskei, Pal L.; Wagner, Manfred; Akira, Shizuo; Norgard, Michael V.; Belisle, John T.; Godowski, Paul J.; Bloom, Barry R.; Modlin, Robert L.

    2001-02-01

    The mammalian innate immune system retains from Drosophila a family of homologous Toll-like receptors (TLRs) that mediate responses to microbial ligands. Here, we show that TLR2 activation leads to killing of intracellular Mycobacterium tuberculosis in both mouse and human macrophages, through distinct mechanisms. In mouse macrophages, bacterial lipoprotein activation of TLR2 leads to a nitric oxide-dependent killing of intracellular tubercle bacilli, but in human monocytes and alveolar macrophages, this pathway was nitric oxide-independent. Thus, mammalian TLRs respond (as Drosophila Toll receptors do) to microbial ligands and also have the ability to activate antimicrobial effector pathways at the site of infection.

  8. 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

  9. Subversion of Toll-like receptor signaling by a unique family of bacterial Toll/interleukin-1 receptor domain-containing proteins.

    PubMed

    Cirl, Christine; Wieser, Andreas; Yadav, Manisha; Duerr, Susanne; Schubert, Sören; Fischer, Hans; Stappert, Dominik; Wantia, Nina; Rodriguez, Nuria; Wagner, Hermann; Svanborg, Catharina; Miethke, Thomas

    2008-04-01

    Pathogenic microbes have evolved sophisticated molecular strategies to subvert host defenses. Here we show that virulent bacteria interfere directly with Toll-like receptor (TLR) function by secreting inhibitory homologs of the Toll/interleukin-1 receptor (TIR) domain. Genes encoding TIR domain containing-proteins (Tcps) were identified in Escherichia coli CFT073 (TcpC) and Brucella melitensis (TcpB). We found that TcpC is common in the most virulent uropathogenic E. coli strains and promotes bacterial survival and kidney pathology in vivo. In silico analysis predicted significant tertiary structure homology to the TIR domain of human TLR1, and we show that the Tcps impede TLR signaling through the myeloid differentiation factor 88 (MyD88) adaptor protein, owing to direct binding of Tcps to MyD88. Tcps represent a new class of virulence factors that act by inhibiting TLR- and MyD88-specific signaling, thus suppressing innate immunity and increasing virulence.

  10. Diverse Toll-like receptors mediate cytokine production by Fusobacterium nucleatum and Aggregatibacter actinomycetemcomitans in macrophages.

    PubMed

    Park, Se-Ra; Kim, Dong-Jae; Han, Seung-Hyun; Kang, Min-Jung; Lee, Jun-Young; Jeong, Yu-Jin; Lee, Sang-Jin; Kim, Tae-Hyoun; Ahn, Sang-Gun; Yoon, Jung-Hoon; Park, Jong-Hwan

    2014-05-01

    Toll-like receptors (TLRs) orchestrate a repertoire of immune responses in macrophages against various pathogens. Fusobacterium nucleatum and Aggregatibacter actinomycetemcomitans are two important periodontal pathogens. In the present study, we investigated TLR signaling regulating cytokine production of macrophages in response to F. nucleatum and A. actinomycetemcomitans. TLR2 and TLR4 are redundant in the production of cytokines (interleukin-6 [IL-6] and tumor necrosis factor alpha [TNF-α]) in F. nucleatum- and A. actinomycetemcomitans-infected macrophages. The production of cytokines by macrophages in response to F. nucleatum and A. actinomycetemcomitans infection was impaired in MyD88-deficient macrophages. Moreover, cytokine concentrations were lower in MyD88-deficient macrophages than in TLR2/TLR4 (TLR2/4) double-deficient cells. An endosomal TLR inhibitor, chloroquine, reduced cytokine production in TLR2/4-deficient macrophages in response to F. nucleatum and A. actinomycetemcomitans, and DNA from F. nucleatum or A. actinomycetemcomitans induced IL-6 production in bone marrow-derived macrophages (BMDMs), which was abolished by chloroquine. Western blot analysis revealed that TLR2/4 and MyD88 were required for optimal activation of NF-κB and mitogen-activated protein kinases (MAPKs) in macrophages in response to F. nucleatum and A. actinomycetemcomitans, with different kinetics. An inhibitor assay showed that NF-κB and all MAPKs (p38, extracellular signal-regulated kinase [ERK], and Jun N-terminal protein kinase [JNK]) mediate F. nucleatum-induced production of cytokines in macrophages, whereas NF-κB and p38, but not ERK and JNK, are involved in A. actinomycetemcomitans-mediated cytokine production. These findings suggest that multiple TLRs may participate in the cytokine production of macrophages against periodontal bacteria.

  11. Histone Deacetylase 7 Promotes Toll-like Receptor 4-dependent Proinflammatory Gene Expression in Macrophages*

    PubMed Central

    Shakespear, Melanie R.; Hohenhaus, Daniel M.; Kelly, Greg M.; Kamal, Nabilah A.; Gupta, Praveer; Labzin, Larisa I.; Schroder, Kate; Garceau, Valerie; Barbero, Sheila; Iyer, Abishek; Hume, David A.; Reid, Robert C.; Irvine, Katharine M.; Fairlie, David P.; Sweet, Matthew J.

    2013-01-01

    Broad-spectrum inhibitors of histone deacetylases (HDACs) constrain Toll-like receptor (TLR)-inducible production of key proinflammatory mediators. Here we investigated HDAC-dependent inflammatory responses in mouse macrophages. Of the classical Hdacs, Hdac7 was expressed at elevated levels in inflammatory macrophages (thioglycollate-elicited peritoneal macrophages) as compared with bone marrow-derived macrophages and the RAW264 cell line. Overexpression of a specific, alternatively spliced isoform of Hdac7 lacking the N-terminal 22 amino acids (Hdac7-u), but not the Refseq Hdac7 (Hdac7-s), promoted LPS-inducible expression of Hdac-dependent genes (Edn1, Il-12p40, and Il-6) in RAW264 cells. A novel class IIa-selective HDAC inhibitor reduced recombinant human HDAC7 enzyme activity as well as TLR-induced production of inflammatory mediators in thioglycollate-elicited peritoneal macrophages. Both LPS and Hdac7-u up-regulated the activity of the Edn1 promoter in an HDAC-dependent fashion in RAW264 cells. A hypoxia-inducible factor (HIF) 1 binding site in this promoter was required for HDAC-dependent TLR-inducible promoter activity and for Hdac7- and HIF-1α-mediated trans-activation. Coimmunoprecipitation assays showed that both Hdac7-u and Hdac7-s interacted with HIF-1α, whereas only Hdac7-s interacted with the transcriptional repressor CtBP1. Thus, Hdac7-u positively regulates HIF-1α-dependent TLR signaling in macrophages, whereas an interaction with CtBP1 likely prevents Hdac7-s from exerting this effect. Hdac7 may represent a potential inflammatory disease target. PMID:23853092

  12. Toll-like receptor responses to Peste des petits ruminants virus in goats and water buffalo.

    PubMed

    Dhanasekaran, Sakthivel; Biswas, Moanaro; Vignesh, Ambothi R; Ramya, R; Raj, Gopal Dhinakar; Tirumurugaan, Krishnaswamy G; Raja, Angamuthu; Kataria, Ranjit S; Parida, Satya; Elankumaran, Subbiah; Subbiah, Elankumaran

    2014-01-01

    Ovine rinderpest or goat plague is an economically important and contagious viral disease of sheep and goats, caused by the Peste des petits ruminants virus (PPRV). Differences in susceptibility to goat plague among different breeds and water buffalo exist. The host innate immune system discriminates between pathogen associated molecular patterns and self antigens through surveillance receptors known as Toll like receptors (TLR). We investigated the role of TLR and cytokines in differential susceptibility of goat breeds and water buffalo to PPRV. We examined the replication of PPRV in peripheral blood mononuclear cells (PBMC) of Indian domestic goats and water buffalo and demonstrated that the levels of TLR3 and TLR7 and downstream signalling molecules correlation with susceptibility vs resistance. Naturally susceptible goat breeds, Barbari and Tellichery, had dampened innate immune responses to PPRV and increased viral loads with lower basal expression levels of TLR 3/7. Upon stimulation of PBMC with synthetic TLR3 and TLR7 agonists or PPRV, the levels of proinflammatory cytokines were found to be significantly higher while immunosuppressive interleukin (IL) 10 levels were lower in PPRV resistant Kanni and Salem Black breeds and water buffalo at transcriptional level, correlating with reduced viralloads in infected PBMC. Water buffalo produced higher levels of interferon (IFN) α in comparison with goats at transcriptional and translational levels. Pre-treatment of Vero cells with human IFNα resulted in reduction of PPRV replication, confirming the role of IFNα in limiting PPRV replication. Treatment with IRS66, a TLR7 antagonist, resulted in the reduction of IFNα levels, with increased PPRV replication confirming the role of TLR7. Single nucleotide polymorphism analysis of TLR7 of these goat breeds did not show any marked nucleotide differences that might account for susceptibility vs resistance to PPRV. Analyzing other host genetic factors might provide

  13. Local Interleukin-1-Driven Joint Pathology Is Dependent on Toll-Like Receptor 4 Activation

    PubMed Central

    Abdollahi-Roodsaz, Shahla; Joosten, Leo A.B.; Koenders, Marije I.; van den Brand, Ben T.; van de Loo, Fons A.J.; van den Berg, Wim B.

    2009-01-01

    Toll-like receptors (TLRs) may contribute to the pathogenesis of chronic inflammatory destructive diseases through the recognition of endogenous ligands produced on either inflammation or degeneration of the extracellular matrix. The presence of endogenous TLR agonists has been reported in rheumatoid joints. In the present study, we investigated the significance of TLR2 and TLR4 activation by locally- produced endogenous ligands in the severity of joint inflammation and destruction. Local joint pathology independent of systemic immune activation was induced by overexpression of interleukin (IL)-1 and TNF in naive joints using adenoviral gene transfer. Here, we report that at certain doses, IL-1-induced local joint inflammation, cartilage proteoglycan depletion, and bone erosion are dependent on TLR4 activation, whereas TLR2 activation is not significantly involved. In comparison, tumor necrosis factor α-driven joint pathology seemed to be less dependent on TLR2 and TLR4. The severity of IL-1-induced bone erosion and irreversible cartilage destruction was markedly reduced in TLR4−/− mice, even though the degree of inflammation was similar, suggesting uncoupled processes. Furthermore, the expression of cathepsin K, a marker for osteoclast activity, induced by IL-1β was dependent on TLR4. Overexpression of IL-1β in the joint as well as ex vivo IL-1 stimulation of patellae provoked the release of endogenous TLR4 agonists capable of inducing TLR4-mediated cytokine production. These data emphasize the potential relevance of TLR4 activation in rheumatoid arthritis, particularly with respect to IL-1-mediated joint pathology. PMID:19834062

  14. Expression and functionality of Toll-like receptor 3 in the megakaryocytic lineage

    PubMed Central

    D’Atri, L. P.; Etulain, J.; Rivadeneyra, L.; Lapponi, M. J.; Centurion, M.; Cheng, K.; Yin, H.; Schattner, M.

    2015-01-01

    Summary Background In addition to their key role in hemostasis, platelets and megakaryocytes also regulate immune and inflammatory responses, in part through their expression of Toll-like receptors (TLRs). Among the TLRs, TLR3 recognizes double-stranded (ds) RNA associated with viral infection. Thrombocytopenia is a frequent complication of viral infection. However, the expression and functionality of TLR3 in megakaryocytes and platelets is not yet well understood. Objective To study the expression and functionality of TLR3 in the megakaryocytic lineage. Methods and Results RT-PCR, flow cytometric, and immunofluorescence assays showed that TLR3 is expressed in CD34+ cells, megakaryocytes, and platelets. Immunoblotting assays showed that stimulation of megakaryocytes with two synthetic agonists of TLR3, Poly(I:C) and Poly(A:U), activated the NF-κB, PI3K/Akt, ERK1/2, and p38 pathways. TLR3-megakaryocyte activation resulted in reduced platelet production in vitro and IFN-β release through the PI3K/Akt and NF-κB signaling pathways. TLR3 ligands potentiated the aggregation mediated by classical platelet agonists. This effect was also observed for ATP release, but not for P-selectin or CD40L membrane exposure, indicating that TLR3 activation was not involved in alpha granule release. In addition, TLR3 agonists induced activation of the NF-κB, PI3K/Akt, and ERK1/2 pathways in platelets. Reduction of platelet production and platelet fibrinogen binding mediated by Poly(I:C) or Poly(A:U) were prevented by the presence of an inhibitor of TLR3/dsRNA complex. Conclusions Our findings indicate that functional TLR3 is expressed in CD34+ cells, megakaryocytes, and platelets, and suggest a potential role for this receptor in the megakaryo/thrombopoiesis alterations that occur in viral infections. PMID:25594115

  15. Toll-like receptor 2-mediated alternative activation of microglia is protective after spinal cord injury.

    PubMed

    Stirling, David P; Cummins, Karen; Mishra, Manoj; Teo, Wulin; Yong, V Wee; Stys, Peter

    2014-03-01

    Improving neurological outcome after spinal cord injury is a major clinical challenge because axons, once severed, do not regenerate but 'dieback' from the lesion site. Although microglia, the immunocompetent cells of the brain and spinal cord respond rapidly to spinal cord injury, their role in subsequent injury or repair remains unclear. To assess the role of microglia in spinal cord white matter injury we used time-lapse two-photon and spectral confocal imaging of green fluorescent protein-labelled microglia, yellow fluorescent protein-labelled axons, and Nile Red-labelled myelin of living murine spinal cord and revealed dynamic changes in white matter elements after laser-induced spinal cord injury in real time. Importantly, our model of acute axonal injury closely mimics the axonopathy described in well-characterized clinically relevant models of spinal cord injury including contusive-, compressive- and transection-based models. Time-lapse recordings revealed that microglia were associated with some acute pathophysiological changes in axons and myelin acutely after laser-induced spinal cord injury. These pathophysiological changes included myelin and axonal spheroid formation, spectral shifts in Nile Red emission spectra in axonal endbulbs detected with spectral microscopy, and 'bystander' degeneration of axons that survived the initial injury, but then succumbed to secondary degeneration. Surprisingly, modulation of microglial-mediated release of neurotoxic molecules failed to protect axons and myelin. In contrast, sterile stimulation of microglia with the specific toll-like receptor 2 agonist Pam2CSK4 robustly increased the microglial response to ablation, reduced secondary degeneration of central myelinated fibres, and induced an alternative (mixed M1:M2) microglial activation profile. Conversely, Tlr2 knock out: Thy1 yellow fluorescent protein double transgenic mice experienced greater axonal dieback than littermate controls. Thus, promoting an alternative

  16. Activation of Toll-like Receptor 4 (TLR4) Attenuates Adaptive Thermogenesis via Endoplasmic Reticulum Stress*

    PubMed Central

    Okla, Meshail; Wang, Wei; Kang, Inhae; Pashaj, Anjeza; Carr, Timothy; Chung, Soonkyu

    2015-01-01

    Adaptive thermogenesis is the cellular process transforming chemical energy into heat in response to cold. A decrease in adaptive thermogenesis is a contributing factor to obesity. However, the molecular mechanisms responsible for the compromised adaptive thermogenesis in obese subjects have not yet been elucidated. In this study we hypothesized that Toll-like receptor 4 (TLR4) activation and subsequent inflammatory responses are key regulators to suppress adaptive thermogenesis. To test this hypothesis, C57BL/6 mice were either fed a palmitate-enriched high fat diet or administered with chronic low-dose LPS before cold acclimation. TLR4 stimulation by a high fat diet or LPS were both associated with reduced core body temperature and heat release. Impairment of thermogenic activation was correlated with diminished expression of brown-specific markers and mitochondrial dysfunction in subcutaneous white adipose tissue (sWAT). Defective sWAT browning was concomitant with elevated levels of endoplasmic reticulum (ER) stress and autophagy. Consistently, TLR4 activation by LPS abolished cAMP-induced up-regulation of uncoupling protein 1 (UCP1) in primary human adipocytes, which was reversed by silencing of C/EBP homologous protein (CHOP). Moreover, the inactivation of ER stress by genetic deletion of CHOP or chemical chaperone conferred a resistance to the LPS-induced suppression of adaptive thermogenesis. Collectively, our data indicate the existence of a novel signaling network that links TLR4 activation, ER stress, and mitochondrial dysfunction, thereby antagonizing thermogenic activation of sWAT. Our results also suggest that TLR4/ER stress axis activation may be a responsible mechanism for obesity-mediated defective brown adipose tissue activation. PMID:26370079

  17. Toll-Like Receptor 2 Is Required for Inflammatory Process Development during Leishmania infantum Infection

    PubMed Central

    Sacramento, Laís A.; da Costa, Jéssica L.; de Lima, Mikhael H. F.; Sampaio, Pedro A.; Almeida, Roque P.; Cunha, Fernando Q.; Silva, João S.; Carregaro, Vanessa

    2017-01-01

    Visceral leishmaniasis (VL) is a chronic and fatal disease caused by Leishmania infantum in Brazil. Leukocyte recruitment to infected tissue is a crucial event for the control of infections such as VL. Among inflammatory cells, neutrophils are recruited to the site of Leishmania infection, and these cells may control parasite replication through oxidative or non-oxidative mechanisms. The recruitment, activation and functions of the neutrophils are coordinated by pro-inflammatory cytokines and chemokines during recognition of the parasite by pattern recognition receptors (PRRs). Here, we demonstrated that the Toll-like receptor 2 (TLR2) signaling pathway contributes to the development of the innate immune response during L. infantum infection. The protective mechanism is related to the appropriate recruitment of neutrophils to the inflammatory site. Neutrophil migration is coordinated by DCs that produce CXCL1 and provide a prototypal Th1 and Th17 environment when activated via TLR2. Furthermore, infected TLR2−/− mice failed to induce nitric oxide synthase (iNOS) expression in neutrophils but not in macrophages. In vitro, infected TLR2−/− neutrophils presented deficient iNOS expression, nitric oxide (NO) and TNF-α production, decreased expression of CD11b and reduced L. infantum uptake capacity. The non-responsive state of neutrophils is associated with increased amounts of IL-10. Taken together, these data clarify new mechanisms by which TLR2 functions in promoting the development of the adaptive immune response and effector mechanisms of neutrophils during L. infantum infection. PMID:28280488

  18. The procedure for death notification--"In Person, In Time…".

    PubMed

    Sobczak, Krzysztof

    2013-01-01

    Informing of a patient's death is difficult for physicians as well as patient's families. Breaking bad news is part of clinical experience of physicians and existential experience of patient's close relatives. The professional manner of death notification may effectively reduce the level of stress and other negative emotions in both parties involved. Special information procedures defining cardinal rules of professional death notification have been devised to help physicians in this process. One of them, created in the United States in the 1990s, is the communication protocol - "In Person, In Time" - Recommended Procedures for Death Notification", discussed in the present paper.

  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.

  20. 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…

  1. Helping Students Cope with Death.

    ERIC Educational Resources Information Center

    Rodabough, Tillman

    1980-01-01

    Classroom teachers need to understand the broad differences that exist between a child's perception of death and that of an adult and should be prepared to confront and cope with the effects of death and grief upon students. Children's perceptions of death and ways in which the teacher can help the child with his grief are described. (JN)

  2. 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…

  3. 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…

  4. 75 deaths in asthmatics prescribed home nebulisers.

    PubMed Central

    Sears, M R; Rea, H H; Fenwick, J; Gillies, A J; Holst, P E; O'Donnell, T V; Rothwell, R P

    1987-01-01

    The circumstances surrounding the deaths of 75 asthmatic patients who had been prescribed a domiciliary nebuliser driven by an air compressor pump for administration of high dose beta sympathomimetic drugs were investigated as part of the New Zealand national asthma mortality study. Death was judged unavoidable in 19 patients who seemed to have precipitous attacks despite apparently good long term management. Delays in seeking medical help because of overreliance on beta agonist delivered by nebuliser were evident in 12 cases and possible in a further 11, but these represented only 8% of the 271 verified deaths from asthma in New Zealanders aged under 70 during the period. Evidence for direct toxicity of high dose beta agonist was not found. Nevertheless, the absence of serum potassium and theophylline concentrations and of electrocardiographic monitoring in the period immediately preceding death precluded firm conclusions whether arrhythmias might have occurred due to these factors rather than to hypoxia alone. In most patients prescribed domiciliary nebulisers death was associated with deficiencies in long term and short term care similar to those seen in patients without nebulisers. Discretion in prescribing home nebulisers, greater use of other appropriate drugs, including adequate corticosteroids, and careful supervision and instruction of patients taking beta agonist by nebuliser should help to reduce the mortality from asthma. Images p480-a PMID:3103732

  5. Death, dying, and domination.

    PubMed

    Spindelman, Marc

    2008-06-01

    This Article critiques conventional liberal arguments for the right to die on liberal grounds. It contends that these arguments do not go far enough to recognize and address private, and in particular structural, forms of domination. It presents an alternative that does, which is thus more respectful of true freedom in the context of death and dying, and also more consistent with liberalism. After discussing obstacles to the achievement of a right to die that encompasses freedom from both public and private domination, the Article closes with a significant reform project within bioethics that might help bring it about.

  6. The immune responses triggered by CpG ODNs in shrimp Litopenaeus vannamei are associated with LvTolls.

    PubMed

    Sun, Rui; Wang, Mengqiang; Wang, Lingling; Yue, Feng; Yi, Qilin; Huang, Mengmeng; Liu, Rui; Qiu, Limei; Song, Linsheng

    2014-03-01

    CpG oligodeoxynucleotides (ODNs) represent a kind of pathogen-associated molecular patterns (PAMPs) as well as a novel adjuvant that activate the innate immune system through interaction with Toll-like receptor 9 (TLR9) in mammals. In the present study, the synthetic oligodeoxynucleotides, CpG ODN 2395, was employed to investigate the interactive mode of CpG ODNs with three known Tolls (LvToll1-3) from shrimp Litopenaeus vannamei. The mature peptides of extracellular domains of LvTolls (LvToll-ECDs) were recombinant expressed and their binding activities to CpG ODN 2395 were further examined by ELISA. rLvToll1-ECD and rLvToll3-ECD exhibited affinity to CpG ODN 2395 in a dose-dependent manner when their concentrations ranged from 0.25 to 2.00 μmol/L, while rLvToll2-ECD did not show any binding activities to CpG ODN 2395 in tested concentrations. Additionally, after the stimulation of CpG ODN 2395, the luciferase activities of HEK293T cells transfected with LvToll1-mosaic or LvToll3-mosaic were significantly increased to 2.38-fold (p<0.01) and 1.56-fold (p<0.01), while that in the HEK293T cells transfected with LvToll2-mosaic declined to 0.41-fold. The TNF-α activities were significantly enhanced (p<0.01), and a significant increase (p<0.05) of the NO production was observed at 12h post CpG ODN 2395 stimulation. Moreover, the induced TNF-α activities and increased NO production triggered by CpG ODN 2395 were abolished after the treatment of chloroquine (CQ). The uptake of CpG ODN 2395 by shrimp haemocytes was investigated using the laser scanning confocal microscope, and CpG ODN 2395 was observed to be internalized by the haemocytes and distributed in the cytoplasm with aggregated signals around the nucleuses. It suggested that the interactions of CpG ODNs with LvToll1 and LvToll3 as well as the mature of endosomes in the haemocytes of shrimp L. vannamei were indispensable for the triggering of immune responses by CpG ODNs, and the results provided a foundation

  7. A Role for Toll-like Receptor 3 Variants in Host Susceptibility to Enteroviral Myocarditis and Dilated Cardiomyopathy*

    PubMed Central

    Gorbea, Carlos; Makar, Kimberly A.; Pauschinger, Matthias; Pratt, Gregory; Bersola, Jeathrina L. F.; Varela, Jacquelin; David, Ryan M.; Banks, Lori; Huang, Chien-Hua; Li, Hua; Schultheiss, Heinz-Peter; Towbin, Jeffrey A.; Vallejo, Jesús G.; Bowles, Neil E.

    2010-01-01

    The innate antiviral response is mediated, at least in part, by Toll-like receptors (TLRs). TLR3 signaling is activated in response to viral infection, and the absence of TLR3 in mice significantly increases mortality after infection with enteroviruses that cause myocarditis and/or dilated cardiomyopathy. We screened TLR3 in patients diagnosed with enteroviral myocarditis/cardiomyopathy and identified a rare variant in one patient as well as a significantly increased occurrence of a common polymorphism compared with controls. Expression of either variant resulted in significantly reduced TLR3-mediated signaling after stimulation with synthetic double-stranded RNA. Furthermore, Coxsackievirus B3 infection of cell lines expressing mutated TLR3 abrogated activation of the type I interferon pathway, leading to increased viral replication. TLR3-mediated type I interferon signaling required cellular autophagy and was suppressed by 3-methyladenine and bafilomycin A1, by inhibitors of lysosomal proteolysis, and by reduced expression of Beclin 1, Atg5, or microtubule-associated protein 1 light chain 3β (MAP1LC3β). However, TLR3-mediated signaling was restored upon exogenous expression of Beclin 1 or a variant MAP1LC3β fusion protein refractory to RNA interference. These data suggest that individuals harboring these variants may have a blunted innate immune response to enteroviral infection, leading to reduced viral clearance and an increased risk of cardiac pathology. PMID:20472559

  8. PDT: death pathways

    NASA Astrophysics Data System (ADS)

    Kessel, David

    2007-02-01

    Cellular targets of photodynamic therapy include mitochondria, lysosomes, the endoplasmic reticulum (ER) and the plasma membrane. PDT can evoke necrosis, autophagy and apoptosis, or combinations of these, depending on the PDT dose, the site(s) of photodamage and the cellular phenotype. It has been established that loss of viability occurs even when the apoptotic program is inhibited. Studies assessing effects of ER or mitochondrial photodamage, involving loss of Bcl-2 function, indicate that low-dose PDT elicited a rapid autophagic response in L1210 cells. This was attributed to the ability of autophagy to recycle photodamaged organelles, and there was partial protection from loss of viability. This effect was not observed in L1210/Atg7, where autophagy was silenced. At higher PDT doses, apoptotic cells were observed within 60 min in both cell lines, but more so in L1210. The ability of L1210 cells to undergo autophagy did not offer protection from cell death at the higher PDT dose. Previous studies had indicated that autophagy can contribute to cell death, since L1210 cells that do not undergo an initial apoptotic response often contain multiple autophagic vacuoles 24 hr later. With L1210/Atg7, apoptosis alone may account for the loss of viability at an LD 90 PDT dose.

  9. Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Chronic low-grade inflammation is a hallmark of obesity and thought to contribute to the development of obesity-related insulin resistance. Toll-like receptor 4 (Tlr4) is a key mediator of pro-inflammatory responses. Mice lacking Tlr4s are protected from diet-induced insulin resistance and inflammat...

  10. Online Education as a Toll Good: An Examination of the South Carolina Virtual School Program

    ERIC Educational Resources Information Center

    Rauh, Jonathan

    2011-01-01

    Education has long been considered merit good; however, inequitable distribution has made it more akin to a toll good. This was most recently demonstrated by Henry, Fortner, and Thompson (2010). Choice requirements designed to remedy the inequitable distribution of education, have largely been confined to brick and mortar schools. Subsequently,…

  11. Burn Enhances Toll-Like Receptor Induced Responses by Circulating Leukocytes

    DTIC Science & Technology

    2012-04-30

    mole- cules shared among members of a particular class of microbes (e.g., LPS from Gram-negative pathogens and ssRNA from RNA viruses), a wide range...lipoproteins of Mycobacterium tuberculosis . Cell Immunol 2009; 258: 29-37. [10] Cairns B, Maile R, Barnes CM, Frelinger JA and Meyer AA. Increased Toll

  12. 77 FR 8328 - Open Meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-14

    ... soliciting public comments, ideas and suggestions on improving customer service at the Internal Revenue... Internal Revenue Service Open Meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee AGENCY: Internal Revenue Service (IRS) Treasury. ACTION: Notice of meeting. SUMMARY: An open meeting of...

  13. 77 FR 21156 - Open Meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-09

    ... soliciting public comments, ideas and suggestions on improving customer service at the Internal Revenue... Internal Revenue Service Open Meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee AGENCY: Internal Revenue Service (IRS), Treasury. ACTION: Notice of Meeting. SUMMARY: An open meeting of...

  14. 77 FR 37102 - Open Meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-06-20

    ... improving customer service at the Internal Revenue Service. DATES: The meeting will be held Tuesday, July 3... No: 2012-14968] DEPARTMENT OF THE TREASURY Internal Revenue Service Open Meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee AGENCY: Internal Revenue Service (IRS), Treasury. ACTION:...

  15. 77 FR 47165 - Open Meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-07

    ... soliciting public comments, ideas, and suggestions on improving customer service at the Internal Revenue... Internal Revenue Service Open Meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee AGENCY: Internal Revenue Service (IRS), Treasury. ACTION: Notice of meeting. SUMMARY: An open meeting of...

  16. 77 FR 30590 - Open meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee.

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-23

    ... soliciting public comments, ideas and suggestions on improving customer service at the Internal Revenue... Internal Revenue Service Open meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee. AGENCY: Internal Revenue Service (IRS) Treasury. ACTION: Notice of meeting. SUMMARY: An open meeting of...

  17. 77 FR 40411 - Open Meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-09

    ... soliciting public comments, ideas and suggestions on improving customer service at the Internal Revenue... Internal Revenue Service Open Meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee AGENCY: Internal Revenue Service (IRS), Treasury. ACTION: Notice of meeting. SUMMARY: An open meeting of...

  18. 76 FR 77892 - Open Meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-14

    ... soliciting public comments, ideas and suggestions on improving customer service at the Internal Revenue... Internal Revenue Service Open Meeting of the Taxpayer Advocacy Panel Toll-Free Project Committee AGENCY: Internal Revenue Service (IRS) Treasury. ACTION: Notice of meeting. SUMMARY: An open meeting of...

  19. Analysis of a National Toll Free Suicide Crisis Line in South Africa

    ERIC Educational Resources Information Center

    Meehan, Sue-Ann; Broom, Yvonne

    2007-01-01

    The first national toll free suicide crisis line for South Africa was launched in October 2003 with the aim of providing a service dedicated to the prevention of suicide in this country. The intervention was motivated by South Africa's suicide rate which had risen higher than the global suicide rate, with the majority of attempted suicides…

  20. Combating Drug Abuse by Targeting Toll-Like Receptor 4 (TLR4)

    DTIC Science & Technology

    2013-10-01

    to preserve the desired effects of   3   opioids ( pain -relief) while diminishing unwanted effects (analgesic tolerance and reward...significant progress anticipated in the coming project period. 15. SUBJECT TERMS toll like receptor 4 (TLR4); TLR4 agonists non- opioid (+)-naloxone and...naltrexone; drug abuse; glial activation; therapeutic approach to treating drug abuse; opioids ; cocaine 16. SECURITY CLASSIFICATION OF: 17

  1. Mapping of the toll like receptor family in channel catfish, Ictalurus punctatus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The Toll Like Receptors (TLRs) are key elements of the innate response to pathogens. They recognize Pathogen Associated Molecular Patterns (PAMPs) and activate the host defense responses. As such, they are candidate genes for disease resistance. In teleost, eight homologs of the endothermic vertebra...

  2. DIESEL EXHAUST ENHANCES TOLL-LIKE RECEPTOR 3 EXPRESSION AND SIGNALING IN RESPIRATORY EPITHELIAL CELLS

    EPA Science Inventory

    Our previous studies have shown that prior exposure of respiratory epithelial cells to an aqueous-trapped solution of DE (DEas) enhances the susceptibility to Influenza infections. Here we examined the effect of DEas on the toll-like receptor 3 (TLR3) pathway, which is responsib...

  3. The Emotional Toll of Obligation and Teachers' Disengagement from the Profession

    ERIC Educational Resources Information Center

    Janzen, Melanie D.; Phelan, Anne M.

    2015-01-01

    Obligation, or the binding responsibility to respond to the other, both lends teaching its moral integrity, but also takes an enormous emotional toll on those who teach. Obligation is of particular importance today given that education is increasingly being restructured by ideologies of the market and managerialism that seek to minimize the moral…

  4. Learning from child death review in the USA, England, Australia, and New Zealand.

    PubMed

    Fraser, James; Sidebotham, Peter; Frederick, John; Covington, Teresa; Mitchell, Edwin A

    2014-09-06

    Despite pronounced reductions in child mortality in industrialised countries, variations exist within and between countries. Many child deaths are preventable, and much could be done to further reduce mortality. For the family, their community, and professionals caring for them, every child's death is a tragedy. Systematic review of all child deaths is grounded in respect for the rights of children and their families, and aimed towards the prevention of future child deaths. In a Series of three papers, we discuss child death in high-income countries in the context of evolving child death review processes. This paper outlines the background to and development of child death review in the USA, England, Australia, and New Zealand. We consider the purpose, process, and outputs of child death review, and discuss how these factors can contribute to a greater understanding of children's deaths and to knowledge for the prevention of future child deaths.

  5. Increases in heroin overdose deaths - 28 States, 2010 to 2012.

    PubMed

    Rudd, Rose A; Paulozzi, Len J; Bauer, Michael J; Burleson, Richard W; Carlson, Rick E; Dao, Dan; Davis, James W; Dudek, Jennifer; Eichler, Beth Ann; Fernandes, Jessie C; Fondario, Anna; Gabella, Barbara; Hume, Beth; Huntamer, Theron; Kariisa, Mbabazi; Largo, Thomas W; Miles, JoAnne; Newmyer, Ashley; Nitcheva, Daniela; Perez, Beatriz E; Proescholdbell, Scott K; Sabel, Jennifer C; Skiba, Jessica; Slavova, Svetla; Stone, Kathy; Tharp, John M; Wendling, Tracy; Wright, Dagan; Zehner, Anne M

    2014-10-03

    Nationally, death rates from prescription opioid pain reliever (OPR) overdoses quadrupled during 1999-2010, whereas rates from heroin overdoses increased by <50%. Individual states and cities have reported substantial increases in deaths from heroin overdose since 2010. CDC analyzed recent mortality data from 28 states to determine the scope of the heroin overdose death increase and to determine whether increases were associated with changes in OPR overdose death rates since 2010. This report summarizes the results of that analysis, which found that, from 2010 to 2012, the death rate from heroin overdose for the 28 states increased from 1.0 to 2.1 per 100,000, whereas the death rate from OPR overdose declined from 6.0 per 100,000 in 2010 to 5.6 per 100,000 in 2012. Heroin overdose death rates increased significantly for both sexes, all age groups, all census regions, and all racial/ethnic groups other than American Indians/Alaska Natives. OPR overdose mortality declined significantly among males, persons aged <45 years, persons in the South, and non-Hispanic whites. Five states had increases in the OPR death rate, seven states had decreases, and 16 states had no change. Of the 18 states with statistically reliable heroin overdose death rates (i.e., rates based on at least 20 deaths), 15 states reported increases. Decreases in OPR death rates were not associated with increases in heroin death rates. The findings indicate a need for intensified prevention efforts aimed at reducing overdose deaths from all types of opioids while recognizing the demographic differences between the heroin and OPR-using populations. Efforts to prevent expansion of the number of OPR users who might use heroin when it is available should continue.

  6. Blue Monday phenomenon among men: suicide deaths in Japan.

    PubMed

    Ohtsu, Tadahiro; Kokaze, Akatsuki; Osaki, Yoneatsu; Kaneita, Yoshitaka; Shirasawa, Takako; Ito, Taku; Sekii, Hideaki; Kawamoto, Teruyoshi; Hashimoto, Masayasu; Ohida, Takashi

    2009-10-01

    The number of suicide deaths in Japan has continued to be high, and is a pressing social problem. Although the weekly distribution of suicide deaths has been documented, no nationwide analysis has yet been conducted. In the present study, the ratios of the number of suicide deaths per day, by day of the week, and on weekdays relative to holidays were calculated using the data for all suicide deaths recorded in 2003. The suicide deaths recorded on holidays were treated as the reference, and a confidence interval of 95% (95% CI) was used. We calculated the suicide death ratios among men and women of all ages (men:23,396, women:8,713, total:32,109) and also among those of productive age (age:15-64 years, men:18,552, women:5,481, total:24,033). Among men of all ages, the suicide death ratio on Mondays was found to be significantly high at 1.49 (95% CI:1.04-2.14), and the ratios were found to decrease over the course of the week from Monday to Friday. On each weekday, the suicide death ratios among men of productive age were found to be higher than those among men of all ages. Among women, the suicide death ratios on any weekday were found to be higher than 1, but there was no significant difference between the days. Among both men and women, the number of suicide deaths on holidays was lower than that on weekdays. This study revealed that the number of suicide deaths recorded per day on Mondays is 1.5 times higher than that on holidays among men. This suggests that the structure of the work week may possibly influence suicide deaths among men. Future discussions regarding the arrangement and distribution of weekly holidays should be conducted in order to reduce the number of suicide deaths.

  7. Toll-pathway in tiger shrimp (Penaeus monodon) responds to white spot syndrome virus infection: evidence through molecular characterisation and expression profiles of MyD88, TRAF6 and TLR genes.

    PubMed

    Deepika, A; Sreedharan, K; Paria, Anutosh; Makesh, M; Rajendran, K V

    2014-12-01

    The Toll-pathway plays key roles in regulating the innate immune response in invertebrates. Myeloid differentiation factor 88 (MyD88) and Tumour necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) are key molecules in this signalling pathway. To investigate the role of Toll-pathway in innate immune response of shrimp, Penaeus monodon, MyD88 (PmMyD88) and TRAF6 (PmTRAF6) were identified and characterised. PmMyD88 cDNA is 1716 bp long with an open reading frame (ORF) of 1449 bp encoding a putative protein of 482 amino acids, with a death domain, a TIR domain and C-terminal extension domain. PmTRAF6 cDNA is 2563 bp long with an ORF of 1785 bp (594 amino acids) with an N-terminal RING-type zinc finger domain, two TRAF-type zinc finger domains, a coiled region and a MATH domain. In healthy shrimp, PmMyD88, PmTRAF6 and PmToll were detected in 15 tissues with the highest expression in midgut, eyestalk and lymphoid organ, respectively. Responses of these genes to WSSV in experimentally-infected P. monodon as well as in cultured haemocytes and also effect of poly I:C on the gene expression in vitro was investigated at six time-points in seven tissues. PmToll showed significant up-regulation at all time-points of infection in six tissues and until 24 h post-infection in vitro. However, poly I:C-induced haemocytes showed up-regulation of the gene until 48 h post-exposure. WSSV caused significant up-regulation of PmMyD88 in most of the tissues tested. The virus challenge as well as poly I:C induction in vitro also resulted in significant up-regulation of the gene. Up-regulated expression of PmTRAF6 was detected in haemocytes and lymphoid organ at late stage of infection. In vitro virus challenge showed significant up-regulation of PmTRAF6 at almost all time-points whereas no significant change in the expression was observed on poly I:C induction. The responses of these key genes, observed in the present study, suggest that Toll-pathway as a whole may play a crucial

  8. Activation of Toll-like receptor 3 induces apoptosis of oral squamous carcinoma cells in vitro and in vivo.

    PubMed

    Luo, Qingqiong; Hu, Shuiqing; Yan, Ming; Sun, Zujun; Chen, Wantao; Chen, Fuxiang

    2012-08-01

    Toll-like receptors are well known as molecular sensors of pathogen-associated molecular patterns. They control activation of the innate immune response and subsequently shape the adaptive immune response. Recent publications have demonstrated that Toll-like receptors also play important roles in multiple human cancers, yet their function in oral squamous cell carcinoma remains unclear. In this study, we showed that both oral squamous cell carcinoma cell lines and tissues from oral squamous carcinoma patients express relatively high levels of Toll-like receptor 3. We also found that synthetic dsRNA-polyinosinic-polycytidilic acid, a Toll-like receptor 3 ligand, induced apoptosis of oral squamous carcinoma cells mainly via Toll-like receptor 3, through interferon-β production and activation of caspases 3 and 9. Moreover, in an oral squamous cell carcinoma xenograft mouse model, we demonstrated for the first time that activation of Toll-like receptor 3 inhibited oral squamous cell carcinoma tumor growth in vivo. Therefore, the direct proapoptotic activity of Toll-like receptor 3 in human oral squamous carcinoma cells may make this protein a viable therapeutic target in the treatment of oral squamous cell carcinoma.

  9. Ubiquitin-mediated Regulation of Cell Death, Inflammation and Defense of Homeostasis

    PubMed Central

    Meier, Pascal; Morris, Otto; Broemer, Meike

    2016-01-01

    Cell death and inflammation are ancient processes of fundamental biological importance in both normal physiology and human disease pathologies. The recent observation that apoptosis regulatory components have dual roles in cell death and inflammation suggests that these proteins function, not primarily to kill, but to coordinate tissue repair and remodeling. This perspective unifies cell death components as positive regulators of tissue repair that replaces malfunctioning or damaged tissues and enhances the resilience of epithelia to insult. It is now recognized that cells that die by apoptosis do not do so silently, but release a variety of paracrine signals to communicate with their cellular environment to ensure tissue regeneration, and wound healing. Moreover, inflammatory signalling pathways, such as those emanating from the TNF-receptor or Toll-related receptors, take part in cell competition to eliminate developmentally aberrant clones. Ubiquitylation has emerged as crucial mediator of signal transduction in cell death and inflammation. Here we focus on recent advances on ubiquitin-mediated regulation of cell death and inflammation, and how this is used to regulate the defense of homeostasis. PMID:26431569

  10. A family of human receptors structurally related to Drosophila Toll

    PubMed Central

    Rock, Fernando L.; Hardiman, Gary; Timans, Jackie C.; Kastelein, Robert A.; Bazan, J. Fernando

    1998-01-01

    The discovery of sequence homology between the cytoplasmic domains of Drosophila Toll and human interleukin 1 receptors has sown the conviction that both molecules trigger related signaling pathways tied to the nuclear translocation of Rel-type transcription factors. This conserved signaling scheme governs an evolutionarily ancient immune response in both insects and vertebrates. We report the molecular cloning of a class of putative human receptors with a protein architecture that is similar to Drosophila Toll in both intra- and extracellular segments. Five human Toll-like receptors—named TLRs 1–5—are probably the direct homologs of the fly molecule and, as such, could constitute an important and unrecognized component of innate immunity in humans. Intriguingly, the evolutionary retention of TLRs in vertebrates may indicate another role—akin to Toll in the dorsoventralization of the Drosophila embryo—as regulators of early morphogenetic patterning. Multiple tissue mRNA blots indicate markedly different patterns of expression for the human TLRs. By using fluorescence in situ hybridization and sequence-tagged site database analyses, we also show that the cognate Tlr genes reside on chromosomes 4 (TLRs 1, 2, and 3), 9 (TLR4), and 1 (TLR5). Structure prediction of the aligned Toll-homology domains from varied insect and human TLRs, vertebrate interleukin 1 receptors and MyD88 factors, and plant disease-resistance proteins recognizes a parallel β/α fold with an acidic active site; a similar structure notably recurs in a class of response regulators broadly involved in transducing sensory information in bacteria. PMID:9435236

  11. [Characteristics and influencing factors of air pollution in and out of the highway toll gates].

    PubMed

    Chen, Ke-Jun; Chen, Ke-Liang; Zhang, Lan-Jun; Leng, Guang-Yi

    2007-08-01

    During June and July 2003, CO, NO2, THC and PM10 were sampled at the four highway toll gates in Chongqing. Air temperature, air pressure, wind velocity and traffic flow were also monitored simultaneously. The relation between air pollution parameters and influencing factors was analyzed by applying the methods of bivariate correlation and partial correlation. As shown in the monitoring result, the outdoor average concentrations of CO and PM10 exceed indoor ones, but NO2 and THC are reverse. The average concentrations of CO and NO2 at the toll gates don't exceed the indoor and outdoor air quality standards except for the toll gate in Chongqing and Chayuan. One-hour average concentrations of outdoor and indoor THC are 7.728 mg/m3 and 7.216 mg/m3 respectively, and exceed ten times of the indoor air quality standard. One-hour average concentrations of indoor and outdoor PM10 change acutely respectively, and the their maximum concentrations are 0.631 mg/m3 and 0.217 mg/m3 which exceed indoor air quality standard and the second class of ambient air quality standard. Polluting state of Chongqing toll is the worst among the four sampled tolls, and three indexes are bigger than others. Indoor and outdoor air pollutants have correlativity. Correlations of CO, PM10 and NO2 are significant at the 0.01 level respectively, and correlations between indoor and outdoor THC are significant at the 0.05 level. In the influencing factors analysis, traffic flow is significantly correlative with NO2, THC and PM10 (p < 0.01 or 0.01 < p < 0.05), and not significantly correlative with CO (p > 0.01). Air pressure and ambient temperature are predominating factors which influencing the concentration variation, and wind speed is a minor meteorological factor influencing the fluctuations of the data.

  12. Are serum eosinophilic cationic protein levels of toll collectors affected by diesel exhaust exposure?

    PubMed Central

    Bilgin, Cahit; Arbak, Peri; Yavuz, Ozlem; Balbay, Ege Gulec; Balbay, Oner; Annakkaya, Ali Nihat

    2016-01-01

    Objective: There are few studies on the diesel exhaust particulates (DEP) / eosinophilic cationic protein (ECP) level relationship. This study aimed to detect ECP levels in a highly DE exposed group, named as toll collectors. Methods: In a cross-sectional study, levels of serum ECP, rates of respiratory symptoms, mean levels of respiratory functions, smoking status, and variations in peak expiratory flow (PEF) during weekends and working days were compared for 68 toll collectors (TC) (range of age, 24-48 years) and 28 controls (range of age, 25-61 years). All subjects in the study group were men. Results: No significant difference was observed in terms of symptoms and smoking rates between the toll collectors and control group. The number of toll collectors [12/68 (17.7%) vs 1/28 (3.5%)] with diurnal PEF variability in the working period was higher than that of controls (p=0.058). Mean ECP level of toll collectors was higher than that of controls (32.8 vs 21.4 ng/L), but the difference was not significant. Mean ECP levels were higher in subjects experiencing diurnal PEF variability during work and off-work periods (34.9 vs 28.3 ng/L, p=0.410). Conclusions: Serial PEF measurements combined with serum ECP measurements did not add a new tool to detect the sensitivity of workers dealing with DE. Much more diesel exhaust exposed workers should be included to search for cheap and available methods when evaluating airway. PMID:27882015

  13. Dead Cert: Measuring Cell Death.

    PubMed

    Crowley, Lisa C; Marfell, Brooke J; Scott, Adrian P; Boughaba, Jeanne A; Chojnowski, Grace; Christensen, Melinda E; Waterhouse, Nigel J

    2016-12-01

    Many cells in the body die at specific times to facilitate healthy development or because they have become old, damaged, or infected. Defects in cells that result in their inappropriate survival or untimely death can negatively impact development or contribute to a variety of human pathologies, including cancer, AIDS, autoimmune disorders, and chronic infection. Cell death may also occur following exposure to environmental toxins or cytotoxic chemicals. Although this is often harmful, it can be beneficial in some cases, such as in the treatment of cancer. The ability to objectively measure cell death in a laboratory setting is therefore essential to understanding and investigating the causes and treatments of many human diseases and disorders. Often, it is sufficient to know the extent of cell death in a sample; however, the mechanism of death may also have implications for disease progression, treatment, and the outcomes of experimental investigations. There are a myriad of assays available for measuring the known forms of cell death, including apoptosis, necrosis, autophagy, necroptosis, anoikis, and pyroptosis. Here, we introduce a range of assays for measuring cell death in cultured cells, and we outline basic techniques for distinguishing healthy cells from apoptotic or necrotic cells-the two most common forms of cell death. We also provide personal insight into where these assays may be useful and how they may or may not be used to distinguish apoptotic cell death from other death modalities.

  14. Death Valley, California

    NASA Technical Reports Server (NTRS)

    1994-01-01

    This is an image of Death Valley, California, centered at 36.629 degrees north latitude, 117.069 degrees west longitude. The image shows Furnace Creek alluvial fan and Furnace Creek Ranch at the far right, and the sand dunes near Stove Pipe Wells at the center. The dark fork-shaped feature between Furnace Creek fan and the dunes is a smooth flood-plain which encloses Cottonball Basin. The bright dots near the center of the image are corner refectors that have been set-up to calibrate the radar as the Shuttle passes overhead with the SIR-C/X-SAR system. The Jet Propulsion Laboratory alternative photo number is P-43883.

  15. Death by water intoxication.

    PubMed

    Gardner, John W

    2002-05-01

    With recent emphasis on increased water intake during exercise for the prevention of dehydration and exertional heat illness, there has been an increase in cases of hyponatremia related to excessive water intake. This article reviews several recent military cases and three deaths that have occurred as a result of overhydration, with resultant hyponatremia and cerebral edema. All of these cases are associated with more than 5 L (usually 10-20 L) of water intake during a period of a few hours. The importance of maintaining adequate hydration in exertional heat illness prevention cannot be overemphasized, but excessive fluid intake may lead to life-threatening hyponatremia. Current guidelines provide safety by limiting fluid intake during times of heavy sweating to 1 to 1.5 L per hour.

  16. A sustained increase in plasma NEFA upregulates the Toll-like receptor network in human muscle

    PubMed Central

    Hussey, Sophie E.; Lum, Helen; Alvarez, Andrea; Cipriani, Yolanda; Garduño-Garcia, José de Jesús; Anaya, Luis; Dube, John; Musi, Nicolas

    2014-01-01

    Aims/hypothesis Insulin-sensitive tissues (muscle, liver) of individuals with obesity and type 2 diabetes mellitus are in a state of low-grade inflammation, characterised by increased Toll-like receptor (TLR) expression and TLR-driven signalling. However, the cause of this mild inflammatory state is unclear. We tested the hypothesis that a prolonged mild increase in plasma NEFA will increase TLR expression and TLR-driven signalling (nuclear factor κB [NFκB] and mitogen-activated kinase [MAPK]) and impair insulin action in muscle of lean healthy individuals. Methods Twelve lean, normal-glucose-tolerant participants were randomised to receive a 48 h infusion (30 ml/h) of saline or Intralipid followed by a euglycaemic–hyperinsulinaemic clamp. Vastus lateralis muscle biopsies were performed before and during the clamp. Results Lipid infusion impaired insulin-stimulated IRS-1 tyrosine phosphorylation and reduced peripheral insulin sensitivity (p < 0.01). The elevation in circulating NEFA increased expression of TLR3, TLR4 and TLR5, and several MAPK (MAPK8, MAP4K4, MAP2K3) and inhibitor of κB kinase-NFκB (CHUK [IKKA], c-REL [REL] and p65 [RELA, NFKB3,p65]) signalling genes (p < 0.05). The lipid infusion also increased extracellular signal-regulated kinase (ERK) phosphorylation (p < 0.05) and tended to reduce the content of nuclear factor of light polypeptide gene enhancer in B cells inhibitor α (p = 0.09). The muscle content of most diacyglycerol, ceramide and acylcarnitine species was unaffected. In summary, insulin resistance induced by prolonged low-dose lipid infusion occurs together with increased TLR-driven inflammatory signalling and impaired insulin-stimulated IRS-1 tyrosine phosphorylation. Conclusions/interpretation A sustained, mild elevation in plasma NEFA is sufficient to increase TLR expression and TLR-driven signalling (NFκB and MAPK) in lean individuals. The activation of this pathway by NEFA may be involved in the pathogenesis of insulin

  17. Variants in toll-like receptors 2 and 9 influence susceptibility to pulmonary tuberculosis in Caucasians, African-Americans, and West Africans

    PubMed Central

    Velez, Digna Rosa; Wejse, Christian; Stryjewski, Martin E.; Abbate, Eduardo; Hulme, William F.; Myers, Jamie L.; Estevan, Rosa; Patillo, Sara G.; Olesen, Rikke; Tacconelli, Alessandra; Sirugo, Giorgio; Gilbert, John R.; Hamilton, Carol D.; Scott, William K.

    2010-01-01

    Tuberculosis (TB) is a global public health problem and a source of preventable deaths each year, with 8.8 million new cases of TB and 1.6 million deaths worldwide in 2005. Approximately, 10% of infected individuals develop pulmonary or extrapulmonary TB, suggesting that host defense factors influence development of active disease. Toll-like receptor’ (TLR) polymorphisms have been associated with regulation of TLR expression and development of active TB. In the present study, 71 polymorphisms in TLR1, TLR2, TLR4, TLR6, and TLR9 were examined from 474 (295 cases and 179 controls) African-Americans, 381 (237 cases and 144 controls) Caucasians, and from 667 (321 cases and 346 controls) Africans from Guinea-Bissau for association with pulmonary TB using generalized estimating equations and logistic regression. Statistically significant associations were observed across populations at TLR9 and TLR2. The strongest evidence for association came at an insertion (I)/deletion (D) polymorphism (−196 to −174) in TLR2 that associated with TB in both Caucasians (II vs. ID&DD, OR=0.41 [95% CI 0.24–0.68], p=0.0007) and Africans (II vs. ID&DD, OR=0.70 [95% CI 0.51–0.95], p=0.023). Our findings in three independent population samples indicate that variations in TLR2 and TLR9 might play important roles in determining susceptibility to TB. PMID:19771452

  18. Protective Effect of Ginsenosides Rg1 and Re on Lipopolysaccharide-Induced Sepsis by Competitive Binding to Toll-Like Receptor 4

    PubMed Central

    Su, Fei; Xue, Yin; Wang, Yuemin; Zhang, Lili; Chen, Wangxue

    2015-01-01

    We previously demonstrated that ginsenosides Rg1 and Re enhanced the immune response in C3H/HeB mice but not in C3H/HeJ mice carrying a mutation in the Tlr4 gene. The results of the present study showed that both Rg1 and Re inhibited mRNA expression and production of proinflammatory mediators that included tumor necrosis factor α, interleukin-1β, interleukin-6, cyclooxygenase-2, and inducible nitric oxide synthase from lipopolysaccharide (LPS)-stimulated macrophages. Rg1 was found to be distributed both extracellularly and intracellularly but Re was located only extracellularly to compete with LPS for binding to Toll-like receptor 4. Preinjection of Rg1 and Re into rats suppressed LPS-induced increases in body temperature, white blood cell counts, and levels of serum proinflammatory mediators. Preinjection of Rg1 and Re into mice prevented the LPS-induced decreases in total white blood cell counts and neutrophil counts, inhibited excessive expression of multiple proinflammatory mediators, and successfully rescued 100% of the mice from sepsis-associated death. More significantly, when administered after lethal LPS inoculation, Rg1, but not Re, still showed a potent antisepsis effect and protected 90% of the mice from death. The better protection efficacy of Rg1 could result from its intracellular distribution, suggesting that Rg1 may be an ideal antisepsis agent. PMID:26149990

  19. Ten Leading Causes of Death and Injury

    MedlinePlus

    ... Brain Injury Violence Prevention Ten Leading Causes of Death and Injury Recommend on Facebook Tweet Share Compartir ... Injury Deaths, United States - 2013 Leading Causes of Death Charts Causes of Death by Age Group 2014 [ ...

  20. Inhibition of caspases prevents ototoxic and ongoing hair cell death

    NASA Technical Reports Server (NTRS)

    Matsui, Jonathan I.; Ogilvie, Judith M.; Warchol, Mark E.

    2002-01-01

    Sensory hair cells die after acoustic trauma or ototoxic insults, but the signal transduction pathways that mediate hair cell death are not known. Here we identify several important signaling events that regulate the death of vestibular hair cells. Chick utricles were cultured in media supplemented with the ototoxic antibiotic neomycin and selected pharmacological agents that influence signaling molecules in cell death pathways. Hair cells that were treated with neomycin exhibited classically defined apoptotic morphologies such as condensed nuclei and fragmented DNA. Inhibition of protein synthesis (via treatment with cycloheximide) increased hair cell survival after treatment with neomycin, suggesting that hair cell death requires de novo protein synthesis. Finally, the inhibition of caspases promoted hair cell survival after neomycin treatment. Sensory hair cells in avian vestibular organs also undergo continual cell death and replacement throughout mature life. It is unclear whether the loss of hair cells stimulates the proliferation of supporting cells or whether the production of new cells triggers the death of hair cells. We examined the effects of caspase inhibition on spontaneous hair cell death in the chick utricle. Caspase inhibitors reduced the amount of ongoing hair cell death and ongoing supporting cell proliferation in a dose-dependent manner. In isolated sensory epithelia, however, caspase inhibitors did not affect supporting cell proliferation directly. Our data indicate that ongoing hair cell death stimulates supporting cell proliferation in the mature utricle.