Science.gov

Sample records for reduced death toll

  1. Uncovering the 2010 Haiti earthquake death toll

    NASA Astrophysics Data System (ADS)

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

    2013-05-01

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

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

    PubMed Central

    Das, Saudamini; Vincent, Jeffrey R.

    2009-01-01

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

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

    PubMed

    Das, Saudamini; Vincent, Jeffrey R

    2009-05-01

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

  4. Distributions of observed death tolls govern sensitivity to human fatalities.

    PubMed

    Olivola, Christopher Y; Sagara, Namika

    2009-12-29

    How we react to humanitarian crises, epidemics, and other tragic events involving the loss of human lives depends largely on the extent to which we are moved by the size of their associated death tolls. Many studies have demonstrated that people generally exhibit a diminishing sensitivity to the number of human fatalities and, equivalently, a preference for risky (vs. sure) alternatives in decisions under risk involving human losses. However, the reason for this tendency remains unknown. Here we show that the distributions of event-related death tolls that people observe govern their evaluations of, and risk preferences concerning, human fatalities. In particular, we show that our diminishing sensitivity to human fatalities follows from the fact that these death tolls are approximately power-law distributed. We further show that, by manipulating the distribution of mortality-related events that people observe, we can alter their risk preferences in decisions involving fatalities. Finally, we show that the tendency to be risk-seeking in mortality-related decisions is lower in countries in which high-mortality events are more frequently observed. Our results support a model of magnitude evaluation based on memory sampling and relative judgment. This model departs from the utility-based approaches typically encountered in psychology and economics in that it does not rely on stable, underlying value representations to explain valuation and choice, or on choice behavior to derive value functions. Instead, preferences concerning human fatalities emerge spontaneously from the distributions of sampled events and the relative nature of the evaluation process. PMID:20018778

  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. 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

  7. Smoking Still Takes Big Toll in U.S. Cancer Deaths

    MedlinePlus

    ... gov/news/fullstory_161641.html Smoking Still Takes Big Toll in U.S. Cancer Deaths Habit is linked ... new study finds. Researchers tracking 2014 federal government data found that more than 167,000 cancer deaths ...

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

    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.—Arroyo, D. S., Soria, J. A., Gaviglio, E. A., Garcia-Keller, C., Cancela, L. M., Rodriguez-Galan, M. C., Wang, J. M., Iribarren, P. Toll-like receptor 2 ligands promote microglial cell death by inducing autophagy. PMID:23073832

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

    PubMed

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

    2016-06-01

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

  12. 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. PMID:23073832

  13. 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

  14. Reducing deaths from pregnancy and childbirth. Asia.

    PubMed

    Pillai, G

    1993-01-01

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

  15. [Practical use of the molecular-genetic technologies in solving the tasks of forensic medical identification of remains in emergencies with huge human death toll].

    PubMed

    Ivanov, P L; Shcherbakova, E V; Pigolkin, Iu I

    2004-01-01

    Previously, we have developed different variants, for the expert use, of information technologies, i.e. of computer automated analytical systems, to ensure an effective analysis of huge bulwarks of molecular-genetic expert findings. The results obtained in the above research significantly advanced the possibilities of expert evaluation related with personality identification under the conditions of a big death toll; they also cleaned the ground for the introduction of such methodological approaches in the practice of investigations of emergency accidents involving huge death tolls. Described within the present case study is a practical experience of forensic medical identification of unrecognized remains in air crashes with huge human death tolls implemented through computer-assisted complex molecular-genetic tests on the basis of indirect DNA identification involving the establishment of blood relationship.

  16. Chromosomal instability triggers cell death via local signalling through the innate immune receptor Toll

    PubMed Central

    Liu, Dawei; Shaukat, Zeeshan; Saint, Robert B.; Gregory, Stephen L.

    2015-01-01

    Chromosomal instability (CIN) is a hallmark of cancer and has been implicated in cancer initiation, progression and the development of resistance to traditional cancer therapy. Here we identify a new property of CIN cells, showing that inducing CIN in proliferating Drosophila larval tissue leads to the activation of innate immune signalling in CIN cells. Manipulation of this immune pathway strongly affects the survival of CIN cells, primarily via JNK, which responds to both Toll and TNFα/Eiger. This pathway also activates Mmp1, which recruits hemocytes to the CIN tissue to provide local amplification of the immune response that is needed for effective elimination of CIN cells. PMID:26462024

  17. Death toll exceeded 70,000 in Europe during the summer of 2003.

    PubMed

    Robine, Jean-Marie; Cheung, Siu Lan K; Le Roy, Sophie; Van Oyen, Herman; Griffiths, Clare; Michel, Jean-Pierre; Herrmann, François Richard

    2008-02-01

    Daily numbers of deaths at a regional level were collected in 16 European countries. Summer mortality was analyzed for the reference period 1998-2002 and for 2003. More than 70,000 additional deaths occurred in Europe during the summer 2003. Major distortions occurred in the age distribution of the deaths, but no harvesting effect was observed in the months following August 2003. Global warming constitutes a new health threat in an aged Europe that may be difficult to detect at the country level, depending on its size. Centralizing the count of daily deaths on an operational geographical scale constitutes a priority for Public Health in Europe.

  18. 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.

  19. 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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

  2. 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.

  3. 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…

  4. 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

  5. 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

  6. 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.

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-02-01

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

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

    PubMed

    Belmi, Peter; Pfeffer, Jeffrey

    2016-05-01

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

  10. How surgical innovation reduced death and suffering from prostate cancer.

    PubMed

    Walsh, Patrick C

    2013-01-01

    Radical prostatectomy for the cure of prostate cancer never gained widespread popularity because of severe side effects: all men were impotent, many were totally incontinent, and when performed by the retropubic approach, bleeding was often life threatening. When I arrived at Johns Hopkins in 1974 as the new director of the Brady Urological Institute, I embarked upon a series of anatomic studies to determine the source of this morbidity. Using the operating room as an anatomy laboratory and performing dissections in stillborn male infants, it was possible to define important, previously unrecognized anatomic structures. Application of these discoveries to the surgical technique made it possible to preserve sexual function, reduce urinary continence to a minimum, and perform the procedure in a relative bloodless field. Armed with the ability to cure prostate cancer more safely with surgery and with fewer side effects, radical prostatectomy was rapidly adopted and in the following decade death from prostate cancer declined by 40%.

  11. 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…

  12. Sudden infant death syndrome: neonatal hypodynamia (reduced exercise level).

    PubMed

    Reid, G M

    2001-03-01

    Sudden infant death syndrome (SIDS) has been described as a silent unexpected death during sleep. Infants with near-miss SIDS have shown a higher heart rate and diminished heart rate variability during sleep. Non-rapid-eye-movement (NREM) sleep rate variability was related to respiration. A decreased heart rate variability was also observed in infants with respiratory distress syndrome (RDS) or prenatal hypoxia. It was hypothesized that decreased heart rate variability and decreased body measurement during sleep were related to a decreased arousal response. Cardiac output is greater in the supine position. Acetylcholine slows the heart beat. Postural changes modify the acute baroreflex control of the heart rate. The cerebellum also contributes to the reflex anti-orthostatic (supine) cardiovascular response to postural change. Delayed myelination of various areas of the brain occurred in SIDS victims and it was suggested that the defect in central respiratory control could be a motor rather than a sensory problem, and that the search for abnormalities should be extended to regions in the cerebellum and pre-frontal-temporal-limbic systems. The cerebellum exercises control over motor neuron impulses from the cerebral cortex to lower structures. An extended period of neonatal decreased body movement has its counterpart in the astronaut exposed to the deconditioning effect of zero gravity. Hypodynamia induces hyperglycemia, insulin resistance, renal inositoluria and impaired nerve conduction. Myoinositol is 20 times higher in fetal-like tissue than in adults. The insecticide lindane (gammexane) is an inositol antagonist. Lindane administration to neonatal rats induced low levels of specific components of myelin proteins in oligodendrocytes in the brain. The activity of these specific enzymes was reduced in oligodendrocytes in the brain of SIDS victims. It is hypothesized that lindane administration to laboratory neonatal animals is a laboratory model for studying

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

    NASA Astrophysics Data System (ADS)

    McAneney, J.

    2014-12-01

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

  14. 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.

  15. Crosstalk between complement and Toll-like receptor activation in relation to donor brain death and renal ischemia-reperfusion injury.

    PubMed

    Damman, Jeffrey; Daha, Mohamed R; van Son, Willem J; Leuvenink, Henri G; Ploeg, Rutger J; Seelen, Marc A

    2011-04-01

    Two central pathways of innate immunity, complement and Toll-like receptors (TLRs), play an important role in the pathogenesis of renal injury inherent to kidney transplantation. Recent findings indicate close crosstalk between complement and TLR signaling pathways. It is suggested that mitogen activated protein kinases (MAPKs) might be the key molecules linking both the complement and TLR pathways together. Complement and TLRs are important mediators of renal ischemia-reperfusion injury (IRI). Besides IRI, complement C3 can also be upregulated and activated in the kidney before transplantation as a direct result of brain death (BD) in the donor. This local upregulation and activation of complement in the donor kidney has been proven to be detrimental for renal allograft outcome. Also TLR4 and several of its major ligands are upregulated by donor BD compared to living donors. Important and in line with the observations above, kidney transplant recipients have a benefit when receiving a kidney from a TLR4 Asp299Gly/Thr399Ile genotypic donor. The role of complement and TLRs and crosstalk between these two innate immune systems in relation to renal injury during donor BD and ischemia-reperfusion are focus of this review. Future strategies to target complement and TLR activation in kidney transplantation are considered.

  16. 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

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

    PubMed

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

    2016-07-19

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

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

    MedlinePlus

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

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

    PubMed

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

    2012-04-01

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

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

    PubMed

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

    2012-04-01

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

  1. 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.

  2. Reducing Burnout in the Hospice and the Death Education Movement.

    ERIC Educational Resources Information Center

    LaGrand, Louis E.

    1980-01-01

    Several possibilities are proposed for reducing stress: (1) cognitive modification; (2) exercise outlets; (3) relaxation techniques; and (4) stimulus control. Both awareness and social support among professionals are emphasized as resources to be utilized in designing individual stress-management programs. (Author)

  3. [Death].

    PubMed

    Ribas, Jordi Domingo

    2003-12-01

    Intercultural factors are essential for reflection. In this article, the authors deals with a more direct vision on the special edition about Grief and Mourning, about the topic which lies in the depths of all of our consciences: death and the question what lies beyond death? The author provides us elements to reflect about concepts, some accepted in various cases, rejected in others, but always polemical, which help us to penetrate farther into the real mystery of life: death and what follows death.

  4. 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.

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

    PubMed Central

    Le, Hai Van; Kim, Jae Young

    2016-01-01

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

  6. Impact of new highways on road deaths: a case study in risk assessment.

    PubMed

    Richter, E D; Ben-Michael, E; Reingold, S M; Weinberger, Z; Ginsberg, G

    2000-01-01

    Epidemiologists have generally avoided to assess risk for road deaths from high-speed highways. We examined the validity of the claim that the Trans-Israel Highway, a six-lane 320 km toll road with higher design speed, and raised speed limits (120 kph), will reduce road deaths. We used models showing that death tolls vary with the fourth power of rise in driving speed. Risk assessments was derived from estimates of increase in the highway-induced traffic, the impact of higher speed limits (from 110 to 120 kph) and the so-called spillover effect from speed habituation. We predict a large rise in the number of killed or injured, even if the death risks per vkm is low on the Highway itself. With the Trans-Israel Highway, death tolls--some 550 fatalities per year in 1995, could rise to as high as 900-1000 per year in 2010. Congestion produced by induced traffic will partially offset these effects. By contrast, death tolls from alternative strategies based on sustainable transportation policies could be reduced to less than 300 deaths per year. Risk assessment based on explicitly defined assumptions predicts high death tolls from the nationwide impact of raised speed on the Highway and its connecting roads. There is a need for new frameworks which impose the Code of Helsinki type requirements for the assessment and authorization of social decisions with adverse public health impacts.

  7. Impact of new highways on road deaths: a case study in risk assessment.

    PubMed

    Richter, E D; Ben-Michael, E; Reingold, S M; Weinberger, Z; Ginsberg, G

    2000-01-01

    Epidemiologists have generally avoided to assess risk for road deaths from high-speed highways. We examined the validity of the claim that the Trans-Israel Highway, a six-lane 320 km toll road with higher design speed, and raised speed limits (120 kph), will reduce road deaths. We used models showing that death tolls vary with the fourth power of rise in driving speed. Risk assessments was derived from estimates of increase in the highway-induced traffic, the impact of higher speed limits (from 110 to 120 kph) and the so-called spillover effect from speed habituation. We predict a large rise in the number of killed or injured, even if the death risks per vkm is low on the Highway itself. With the Trans-Israel Highway, death tolls--some 550 fatalities per year in 1995, could rise to as high as 900-1000 per year in 2010. Congestion produced by induced traffic will partially offset these effects. By contrast, death tolls from alternative strategies based on sustainable transportation policies could be reduced to less than 300 deaths per year. Risk assessment based on explicitly defined assumptions predicts high death tolls from the nationwide impact of raised speed on the Highway and its connecting roads. There is a need for new frameworks which impose the Code of Helsinki type requirements for the assessment and authorization of social decisions with adverse public health impacts. PMID:10846845

  8. [Uncertain whether weight-reducing diet lowers the risk of early death in hypertensive patients].

    PubMed

    Køster-Rasmussen, Rasmus; Simonsen, Mette Kildevæld; de Fine Olivarius, Niels

    2012-08-27

    The Cochrane review "Long-term effects of weight-reducing diets in hypertensive patients" fails to evaluate the primary outcomes of mortality and morbidity. It is uncertain whether weight loss in general reduces the risk of cardiovascular disease and death as the relation between intentional weight loss and mortality is biased by reverse causation. Weight loss is a potent risk factor of weight regain and weight cycling is associated to early death. Recommendations on weight loss should be individualized and focused on promotion of a healthy and active lifestyle rather than counting kilos.

  9. Apolipoprotein A-I Attenuates Palmitate-Mediated NF-κB Activation by Reducing Toll-Like Receptor-4 Recruitment into Lipid Rafts

    PubMed Central

    Tateya, Sanshiro; Schwartz, Jay; Tang, Chongren; Mitra, Poulami; Oram, John F.; Chait, Alan; Kim, Francis

    2012-01-01

    While high-density lipoprotein (HDL) is known to protect against a wide range of inflammatory stimuli, its anti-inflammatory mechanisms are not well understood. Furthermore, HDL's protective effects against saturated dietary fats have not been previously described. In this study, we used endothelial cells to demonstrate that while palmitic acid activates NF-κB signaling, apolipoprotein A–I, (apoA-I), the major protein component of HDL, attenuates palmitate-induced NF-κB activation. Further, vascular NF-κB signaling (IL-6, MCP-1, TNF-α) and macrophage markers (CD68, CD11c) induced by 24 weeks of a diabetogenic diet containing cholesterol (DDC) is reduced in human apoA-I overexpressing transgenic C57BL/6 mice compared to age-matched WT controls. Moreover, WT mice on DDC compared to a chow diet display increased gene expression of lipid raft markers such as Caveolin-1 and Flotillin-1, and inflammatory Toll-like receptors (TLRs) (TLR2, TLR4) in the vasculature. However apoA-I transgenic mice on DDC show markedly reduced expression of these genes. Finally, we show that in endothelial cells TLR4 is recruited into lipid rafts in response to palmitate, and that apoA-I prevents palmitate-induced TLR4 trafficking into lipid rafts, thereby blocking NF-κB activation. Thus, apoA-I overexpression might be a useful therapeutic tool against vascular inflammation. PMID:22479476

  10. Toll-Like Receptor 7 Agonist Therapy with Imidazoquinoline Enhances Cancer Cell Death and Increases Lymphocytic Infiltration and Proinflammatory Cytokine Production in Established Tumors of a Renal Cell Carcinoma Mouse Model

    PubMed Central

    Kauffman, Eric C.; Liu, Huixian; Schwartz, Michael J.; Scherr, Douglas S.

    2012-01-01

    Imidazoquinolines are synthetic toll-like receptor 7 and 8 agonists and potent dendritic cell activators with established anticancer activity. Here we test the hypothesis that imidazoquinoline has in vivo efficacy within established renal cell carcinoma (RCC) tumors. Immunocompetent mice bearing syngeneic RCC xenografts were treated with imidazoquinoline or placebo at two separate time points. Harvested tumors were assayed by TUNEL/caspase-3/Ki67 immunostains to evaluate cell death/apoptosis/proliferation, and CD3/B220/CD45 immunostains to evaluate T-cell lymphocyte/B-cell lymphocyte/pan-leukocyte tumor infiltration. ELISA measurement of tumor and serum levels of proinflammatory cytokines, IL-6 and MCP-1, was performed. A single imidazoquinoline dose significantly decreased RCC tumor growth by 50% and repeat dosing compounded the effect, without observed weight loss or other toxicity. Tumor immunostaining revealed significant increases in cell death and apoptosis without changes in cell proliferation, supporting induction of apoptosis as the primary mechanism of tumor growth suppression. Imidazoquinoline treatment also significantly enhanced peritumoral aggregation and intratumoral infiltration by T-cell lymphocytes, while increasing intratumoral (but not serum) levels of proinflammatory cytokines. In conclusion, imidazoquinoline treatment enhances T-cell lymphocyte infiltration and proinflammatory cytokine production within established mouse RCC tumors, while suppressing tumor growth via induction of cancer cell apoptosis. These findings support a therapeutic role for imidazoquinoline in RCC. PMID:22481916

  11. The Vi Capsular Antigen of Salmonella enterica Serotype Typhi Reduces Toll-Like Receptor-Dependent Interleukin-8 Expression in the Intestinal Mucosa

    PubMed Central

    Raffatellu, Manuela; Chessa, Daniela; Wilson, R. Paul; Dusold, Richard; Rubino, Salvatore; Bäumler, Andreas J.

    2005-01-01

    Human infections with nontyphoidal Salmonella serotypes, such as S. enterica serotype Typhimurium, are characterized by a massive neutrophil influx in the colon and terminal ileum. In contrast, neutrophils are scarce in intestinal infiltrates of typhoid fever patients. Here, we show that in S. enterica serotype Typhi, the causative agent of typhoid fever, expression of the Vi capsular antigen reduced expression of the neutrophil chemoattractant interleukin-8 (IL-8) in host cells. Capsulated bacteria elicited IL-8 expression in polarized human epithelial cells (T84) and human macrophage-like cells (THP-1) in vitro at significantly reduced levels compared to noncapsulated bacteria. Experiments with a human cell line (HEK293) transfected with human Toll-like receptors (TLRs) demonstrated that in the presence of TLR5 or TLR4/MD2/CD14, a noncapsulated serotype Typhi mutant was able to induce the expression of IL-8, while this host response was significantly reduced when cells were infected with the capsulated serotype Typhi wild type. The relevance of these in vitro observations for the interaction of serotype Typhi with its human host was further studied ex vivo using human colonic tissue explants. Expression of IL-8 was detected in human colonic tissue explants infected with serotype Typhimurium or a noncapsulated serotype Typhi mutant. In contrast, infection with the serotype Typhi wild type did not elicit IL-8 expression in colonic tissue explants. Collectively, these data suggest that the scarcity of neutrophils in intestinal infiltrates of typhoid fever patients is due to a capsule-mediated reduction of TLR-dependent IL-8 production in the intestinal mucosa. PMID:15908363

  12. 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

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

    PubMed

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

    2016-08-01

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

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

    PubMed

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

    2013-05-24

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

  15. The Fab Fragment of a Humanized Anti-Toll Like Receptor 4 (TLR4) Monoclonal Antibody Reduces the Lipopolysaccharide Response via TLR4 in Mouse Macrophage.

    PubMed

    Cai, Binggang; Wang, Maorong; Zhu, Xuhui; Xu, Jing; Zheng, Wenkai; Zhang, Yiqing; Zheng, Feng; Feng, Zhenqing; Zhu, Jin

    2015-01-01

    Lipopolysaccharides (LPS) can induce acute inflammation, sepsis, or chronic inflammatory disorders through the Toll receptor 4 (TLR4) signaling pathway. The TLR4/MD2 (myeloid differentiation protein 2) complex plays a major role in the immune response to LPS. However, there is not a good method to suppress the immune response induced by LPS via this complex in macrophages. In this article, we aimed to evaluate the effects of humanized anti-TLR4 monoclonal antibodies on LPS-induced responses in mouse macrophages. The peritoneal macrophages of mice were incubated with anti-TLR4 monoclonal antibodies and stimulated with LPS. The expression levels of cytokines were analyzed by quantitative polymerase chain reaction and enzyme-linked immunosorbent assays. Additionally, activation of various signaling pathways was evaluated by Western blotting. The results showed that the humanized anti-TLR4 monoclonal antibody blocked the inflammatory cytokines expression at both the mRNA and protein level. We also found that the Fab fragment significantly inhibited the nuclear factor kappaB signaling pathway by reducing the phosphorylation of the inhibitor of kappaBalpha and decreasing the translocation of p65, resulting in the suppression of p38, extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase 1/2, and IFN-β regulatory factor 3 phosphorylation. Therefore, our study showed that this humanized anti-TLR4 monoclonal antibody could effectively protect against LPS-induced responses by blocking the TLR4 signaling pathway in mouse peritoneal macrophages.

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

    PubMed

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

    2015-07-01

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

  17. Lactate Reduces Organ Injury in Toll-like Receptor- and Inflammasome-Mediated Inflammation via GPR81-mediated Suppression of Innate Immunity

    PubMed Central

    Hoque, Rafaz; Farooq, Ahmad; Ghani, Ayaz; Gorelick, Fred; Mehal, Wajahat Zafar

    2014-01-01

    BACKGROUND & AIMS The NLRP3 inflammasome induces inflammation in response to organ injury, but little is known about its regulation. Toll-like receptors (TLRs) provide the first signal required for activation of the inflammasome and stimulate aerobic glycolysis to generate lactate. We examined whether lactate and the lactate receptor, GPR81, regulate TLR induction of signal 1 and limit inflammasome activation and organ injury. METHODS Primary mouse macrophages and human monocytes were incubated with TLR4 agonists and lactate and assayed for levels of pro-IL1β, NLRP3, and CASP1; release of IL1β; and activation of NFκB and caspase 1. Small interfering (si)RNAs were used to reduce levels of GPR81andARRB2, and an NFκB luciferase reporter transgene was transfected in RAW 264.7 cells. Cell lysates were analyzed by immunoprecipitation with an antibody against GPR81. Acute hepatitis was induced in C56BL/6N mice by administration of lipopolysaccharaide (LPS) and D-galactosamine. Acute pancreatitis was induced by administration of LPS and caerulein. Some mice were given intraperitoneal injections of sodium lactate or siRNA against Gpr81. Activation of NFκB in tissue macrophages was assessed in mice that express a reporter transgene. RESULTS In macrophages and monocytes, increasing concentrations of lactate reduced TLR4-mediated induction of Il1B, Nlrp3, and Casp1; activation of NFκB; release of IL1β; and cleavage of CASP1. GPR81 and ARRB2 physically interacted and were required for these effects. Administration of lactate reduced inflammation and organ injury in mice with immune hepatitis; this reduction required Gpr81 dependence in vivo. Lactate also prevented activation of NFκB in macrophages of mice, and when given following injury, reduced the severity of acute pancreatitis and acute liver injury. CONCLUSIONS Lactate negatively regulates TLR induction of the NLRP3 inflammasome and production of IL1β, via ARRB2 and GPR81. Lactate could be a promising

  18. Enhanced recovery program for hip and knee replacement reduces death rate

    PubMed Central

    2011-01-01

    Background and purpose Multimodal techniques can aid early rehabilitation and discharge of patients following primary joint replacement. We hypothesized that this not only reduces the economic burden of joint replacement by reducing length of stay, but also helps in reduction of early complications. Patients and methods We evaluated 4,500 consecutive unselected total hip replacements and total knee replacements regarding length of hospital stay, mortality, and perioperative complications. The first 3,000 underwent a traditional protocol while the other 1,500 underwent an enhanced recovery protocol involving behavioral, pharmacological, and procedural modifications. Results There was a reduction in 30-day death rate (0.5% to 0.1%, p = 0.02) and 90-day death rate (0.8% to 0.2%, p = 0.01). The median length of stay decreased from 6 days to 3 days (p < 0.001), resulting in a saving of 5,418 bed days. Requirement for blood transfusion was reduced (23% to 9.8%, p < 0.001). There was a trend of a reduced rate of 30-day myocardial infarction (0.8% to 0.5%. p = 0 .2) and stroke (0.5% to 0.2%, p = 0.2). The 60-day deep vein thrombosis figures (0.8% to 0.6%, p = 0.5) and pulmonary embolism figures (1.2% to 1.1%, p = 0.9) were similar. Re-admission rate remained unchanged during the period of the study (4.7% to 4.8%, p = 0.8). Interpretation This large observational study of unselected consecutive hip and knee arthroplasty patients shows a substantial reduction in death rate, reduced length of stay, and reduced transfusion requirements after the introduction of a multimodal enhanced recovery protocol. PMID:21895500

  19. 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

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

    PubMed

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

    2015-12-01

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

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

    PubMed

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

    2012-02-01

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

  2. 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.

  3. 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

  4. A community prevention trial to reduce alcohol-involved accidental injury and death: overview.

    PubMed

    Holder, H D; Saltz, R F; Grube, J W; Voas, R B; Gruenewald, P J; Treno, A J

    1997-06-01

    The 5-year "Preventing Alcohol Trauma: A Community Trial" project in the United States was designed to reduce alcohol-involved injuries and death in three experimental communities. The project consisted of five mutually reinforcing components: (1) Community Mobilization Component to develop community organization and support, (2) Responsible Beverage Service Component to establish standards for servers and owner/managers of on-premise alcohol outlets to reduce their risk of having intoxicated and/or underage customers in bars and restaurants, (3) Drinking and Driving Component to increase local DWI enforcement efficiency and to increase the actual and perceived risk that drinking drivers would be detected, (4) Underage Drinking Component to reduce retail availability of alcohol to minors, and (5) Alcohol Access Component to use local zoning powers and other municipal controls of outlet number and density to reduce the availability of alcohol. This paper gives an overview of the rationale and causal model, the research design and outline of each intervention component for the entire prevention trial. PMID:9231442

  5. 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…

  6. 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

  7. 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

  8. 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.

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

    PubMed

    Sugarman, Stephen D

    2009-12-01

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

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

    PubMed

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

    2010-09-01

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

  11. 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.

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

    PubMed

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

    2010-04-01

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

  13. 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. PMID:27087188

  14. 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.

  15. Reduced Endoplasmic Reticulum Luminal Calcium Links Saturated Fatty Acid-Mediated Endoplasmic Reticulum Stress and Cell Death in Liver Cells

    PubMed Central

    Wei, Yuren; Wang, Dong; Gentile, Christopher L.; Pagliassotti, Michael J.

    2010-01-01

    Chronic exposure to elevated free fatty acids, in particular long chain saturated fatty acids, provokes endoplasmic reticulum (ER) stress and cell death in a number of cell types. The perturbations to the ER that instigate ER stress and activation of the unfolded protein in response to fatty acids in hepatocytes have not been identified. The present study employed H4IIE liver cells and primary rat hepatocytes to examine the hypothesis that saturated fatty acids induce ER stress via effects on ER luminal calcium stores. Exposure of H4IIE liver cells and primary hepatocytes to palmitate and stearate reduced thapsigargin-sensitive calcium stores and biochemical markers of ER stress over similar time courses (6h). These changes preceded cell death, which was only observed at later time points (16h). Co-incubation with oleate prevented the reduction in calcium stores, induction of ER stress markers and cell death observed in response to palmitate. Inclusion of calcium chelators, BAPTA-AM or EGTA, reduced palmitate- and stearate-mediated enrichment of cytochrome c in post-mitochondrial supernatant fractions and cell death. These data suggest that redistribution of ER luminal calcium contributes to long chain saturated fatty acid-mediated ER stress and cell death. PMID:19444596

  16. 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…

  17. Suppressed Microglial E Prostanoid Receptor 1 Signaling Selectively Reduces TNFα and IL-6 Secretion from Toll-like Receptor 3 Activation

    PubMed Central

    Li, Xianwu; Cudaback, Eiron; Keene, C. Dirk; Breyer, Richard M.; Montine, Thomas J.

    2010-01-01

    Activation of innate immunity via Toll-like receptors (TLRs) is associated with neurodegenerative diseases, and some effectors, like tumor necrosis factor alpha (TNFα) and interleukin 6 (IL-6), directly contribute to neurodegeneration. We tested the hypothesis that prostaglandin (PG) E2 receptor subtype 1 (EP1) was necessary for induction of microglial cytokines following activation of innate immunity. Primary murine microglia had cytokine secretion by activators of TLR3 > TLR9 >TLR4 > TLR2. TLR3 activation induced early expression of cyclooxygenase 2 (COX2) and delayed expression of membranous PGE synthase and secretion of PGE2. Non-selective and COX2-selective inhibitors blocked TLR3 induction of TNFα and IL-6. Moreover, of the eight out of twenty cytokines and chemokines induced by TLR3 activation, only TNFα and IL-6 were significantly dependent on EP1 signaling as determined using microglia from mice homozygous deficient for EP1 gene or wild type (WT) microglia co-incubated with an EP1 antagonist. These results were confirmed by blocking intracellular Ca2+ release with 2-aminoethoxy-diphenyl borate (2-APB) or Xestospongin C (XC), inhibitors of IP3 receptors. Our results show that suppression of microglial EP1 signaling achieves much of the desired effect of COX inhibitors by selectively blocking TLR3-induced microglial secretion of two major effectors of paracrine neuron damage. In combination with the ability of EP1 suppression to ameliorate excitotoxicity, these data point to blockade of EP1 as an attractive candidate therapeutic for neurodegenerative diseases. PMID:21319223

  18. 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. |

  19. Smac-mimetic-induced epithelial cell death reduces the growth of renal cysts.

    PubMed

    Fan, Lucy X; Zhou, Xia; Sweeney, William E; Wallace, Darren P; Avner, Ellis D; Grantham, Jared J; Li, Xiaogang

    2013-12-01

    Past efforts to pharmacologically disrupt the development and growth of renal cystic lesions focused primarily on normalizing the activity of a specific signaling molecule, but the effects of stimulating apoptosis in the proliferating epithelial cells have not been well studied. Although benign, ADPKD renal cysts created by the sustained proliferation of epithelial cells resemble tumors, and malignant cell death can be achieved by cotreatment with TNF-α and a mimetic of second mitochondria-derived activator of caspase (Smac). Notably, TNF-α accumulates to high levels in ADPKD cyst fluid. Here, we report that an Smac-mimetic selectively induces TNF-α-dependent cystic renal epithelial cell death, leading to the removal of cystic epithelial cells from renal tissues and delaying cyst formation. In vitro, a Smac-mimetic (GT13072) induced the degradation of cIAP1 that is required but not sufficient for cell death. Cotreatment with TNF-α augmented the formation and activation of the RIPK1-dependent death complex and the degradation and cleavage of FLIP, an inhibitor of caspase-8, in renal cystic epithelial cells. This approach produced death specifically in Pkd1 mutant epithelial cells, with no effect on normal renal epithelial cells. Moreover, treatment with the Smac-mimetic slowed cyst and kidney enlargement and preserved renal function in two genetic strains of mice with Pkd1 mutations. Thus, our mechanistic data characterize an apoptotic pathway, activated by the selective synergy of an Smac-mimetic and TNF-α in renal cyst fluid, that attenuates cyst development, providing an innovative translational platform for the rational development of novel therapeutics for ADPKD.

  20. Minocycline attenuates microglial response and reduces neuronal death after cardiac arrest and cardiopulmonary resuscitation in mice.

    PubMed

    Wang, Qian-yan; Sun, Peng; Zhang, Qing; Yao, Shang-long

    2015-04-01

    The possible role of minocycline in microglial activation and neuronal death after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) in mice was investigated in this study. The mice were given potassium chloride to stop the heart beating for 8 min to achieve CA, and they were subsequently resuscitated with epinephrine and chest compressions. Forty adult C57BL/6 male mice were divided into 4 groups (n=10 each): sham-operated group, CA/CPR group, CA/CPR+minocycline group, and CA/CPR+vehicle group. Animals in the latter two groups were intraperitoneally injected with minocycline (50 mg/kg) or vehicle (normal saline) 30 min after recovery of spontaneous circulation (ROSC). Twenty-four h after CA/CPR, the brains were removed for histological evaluation of the hippocampus. Microglial activation was evaluated by detecting the expression of ionized calcium-binding adapter molecule-1 (Iba1) by immunohistochemistry. Neuronal death was analyzed by hematoxylin and eosin (H&E) staining and the levels of tumor necrosis factor-alpha (TNF-α) in the hippocampus were measured by enzyme-linked immunosorbent assay (ELISA). The results showed that the neuronal death was aggravated, most microglia were activated and TNF-α levels were enhanced in the hippocampus CA1 region of mice subjected to CA/CPR as compared with those in the sham-operated group (P<0.05). Administration with minocycline 30 min after ROSC could significantly decrease the microglial response, TNF-α levels and neuronal death (P<0.05). It was concluded that early administration with minocycline has a strong therapeutic potential for CA/CPR-induced brain injury.

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

    PubMed Central

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

    2011-01-01

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

  2. 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.

  3. KCa2 channels activation prevents [Ca2+]i deregulation and reduces neuronal death following glutamate toxicity and cerebral ischemia

    PubMed Central

    Dolga, A M; Terpolilli, N; Kepura, F; Nijholt, I M; Knaus, H-G; D'Orsi, B; Prehn, J H M; Eisel, U L M; Plant, T; Plesnila, N; Culmsee, C

    2011-01-01

    Exacerbated activation of glutamate receptor-coupled calcium channels and subsequent increase in intracellular calcium ([Ca2+]i) are established hallmarks of neuronal cell death in acute and chronic neurological diseases. Here we show that pathological [Ca2+]i deregulation occurring after glutamate receptor stimulation is effectively modulated by small conductance calcium-activated potassium (KCa2) channels. We found that neuronal excitotoxicity was associated with a rapid downregulation of KCa2.2 channels within 3 h after the onset of glutamate exposure. Activation of KCa2 channels preserved KCa2 expression and significantly reduced pathological increases in [Ca2+]i providing robust neuroprotection in vitro and in vivo. These data suggest a critical role for KCa2 channels in excitotoxic neuronal cell death and propose their activation as potential therapeutic strategy for the treatment of acute and chronic neurodegenerative disorders. PMID:21509037

  4. 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. PMID:23579320

  5. 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.

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

    PubMed

    Edwards, Marc

    2014-01-01

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

  7. 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

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

    PubMed

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

    2016-04-01

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

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

    PubMed

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

    2016-01-01

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

  10. 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

  11. 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.

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

    MedlinePlus

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

  13. Intestinal Blautia Is Associated with Reduced Death from Graft-versus-Host Disease.

    PubMed

    Jenq, Robert R; Taur, Ying; Devlin, Sean M; Ponce, Doris M; Goldberg, Jenna D; Ahr, Katya F; Littmann, Eric R; Ling, Lilan; Gobourne, Asia C; Miller, Liza C; Docampo, Melissa D; Peled, Jonathan U; Arpaia, Nicholas; Cross, Justin R; Peets, Tatanisha K; Lumish, Melissa A; Shono, Yusuke; Dudakov, Jarrod A; Poeck, Hendrik; Hanash, Alan M; Barker, Juliet N; Perales, Miguel-Angel; Giralt, Sergio A; Pamer, Eric G; van den Brink, Marcel R M

    2015-08-01

    The relationship between intestinal microbiota composition and acute graft-versus-host disease (GVHD) after allogeneic blood/marrow transplantation (allo-BMT) is not well understood. Intestinal bacteria have long been thought to contribute to GVHD pathophysiology, but recent animal studies in nontransplant settings have found that anti-inflammatory effects are mediated by certain subpopulations of intestinal commensals. Hypothesizing that a more nuanced relationship may exist between the intestinal bacteria and GVHD, we evaluated the fecal bacterial composition of 64 patients 12 days after BMT. We found that increased bacterial diversity was associated with reduced GVHD-related mortality. Furthermore, harboring increased amounts of bacteria belonging to the genus Blautia was associated with reduced GVHD lethality in this cohort and was confirmed in another independent cohort of 51 patients from the same institution. Blautia abundance was also associated with improved overall survival. We evaluated the abundance of Blautia with respect to clinical factors and found that loss of Blautia was associated with treatment with antibiotics that inhibit anaerobic bacteria and receiving total parenteral nutrition for longer durations. We conclude that increased abundance of commensal bacteria belonging to the Blautia genus is associated with reduced lethal GVHD and improved overall survival.

  14. Sustained Toll-Like Receptor 9 Activation Promotes Systemic and Cardiac Inflammation, and Aggravates Diastolic Heart Failure in SERCA2a KO Mice

    PubMed Central

    Dhondup, Yangchen; Sjaastad, Ivar; Scott, Helge; Sandanger, Øystein; Zhang, Lili; Haugstad, Solveig Bjærum; Aronsen, Jan Magnus; Ranheim, Trine; Holmen, Sigve Dhondup; Alfsnes, Katrine; Ahmed, Muhammad Shakil; Attramadal, Håvard; Gullestad, Lars; Aukrust, Pål; Christensen, Geir; Yndestad, Arne; Vinge, Leif Erik

    2015-01-01

    Aim Cardiac inflammation is important in the pathogenesis of heart failure. However, the consequence of systemic inflammation on concomitant established heart failure, and in particular diastolic heart failure, is less explored. Here we investigated the impact of systemic inflammation, caused by sustained Toll-like receptor 9 activation, on established diastolic heart failure. Methods and Results Diastolic heart failure was established in 8–10 week old cardiomyocyte specific, inducible SERCA2a knock out (i.e., SERCA2a KO) C57Bl/6J mice. Four weeks after conditional KO, mice were randomized to receive Toll-like receptor 9 agonist (CpG B; 2μg/g body weight) or PBS every third day. After additional four weeks, echocardiography, phase contrast magnetic resonance imaging, histology, flow cytometry, and cardiac RNA analyses were performed. A subgroup was followed, registering morbidity and death. Non-heart failure control groups treated with CpG B or PBS served as controls. Our main findings were: (i) Toll-like receptor 9 activation (CpG B) reduced life expectancy in SERCA2a KO mice compared to PBS treated SERCA2a KO mice. (ii) Diastolic function was lower in SERCA2a KO mice with Toll-like receptor 9 activation. (iii) Toll-like receptor 9 stimulated SERCA2a KO mice also had increased cardiac and systemic inflammation. Conclusion Sustained activation of Toll-like receptor 9 causes cardiac and systemic inflammation, and deterioration of SERCA2a depletion-mediated diastolic heart failure. PMID:26461521

  15. 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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

    Hu, Yanfeng

    2016-09-01

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

  18. Thermal treatment of bentonite reduces aflatoxin b1 adsorption and affects stem cell death.

    PubMed

    Nones, Janaína; Nones, Jader; Riella, Humberto Gracher; Poli, Anicleto; Trentin, Andrea Gonçalves; Kuhnen, Nivaldo Cabral

    2015-10-01

    Bentonites are clays that highly adsorb aflatoxin B1 (AFB1) and, therefore, protect human and animal cells from damage. We have recently demonstrated that bentonite protects the neural crest (NC) stem cells from the toxicity of AFB1. Its protective effects are due to the physico-chemical properties and chemical composition altered by heat treatment. The aim of this study is to prepare and characterize the natural and thermal treatments (125 to 1000 °C) of bentonite from Criciúma, Santa Catarina, Brazil and to investigate their effects in the AFB1 adsorption and in NC cell viability after challenging with AFB1. The displacement of water and mineralogical phases transformations were observed after the thermal treatments. Kaolinite disappeared at 500 °C and muscovite and montmorillonite at 1000 °C. Slight changes in morphology, chemical composition, and density of bentonite were observed. The adsorptive capacity of the bentonite particles progressively reduced with the increase in temperature. The observed alterations in the structure of bentonite suggest that the heat treatments influence its interlayer distance and also its adsorptive capacity. Therefore, bentonite, even after the thermal treatment (125 to 1000 °C), is able to increase the viability of NC stem cells previously treated with AFB1. Our results demonstrate the effectiveness of bentonite in preventing the toxic effects of AFB1.

  19. Inhibition of type 2A secretory phospholipase A2 reduces death of cardiomyocytes in acute myocardial infarction.

    PubMed

    van Dijk, Annemieke; Krijnen, Paul A J; Vermond, Rob A; Pronk, Amanda; Spreeuwenberg, Marieke; Visser, Frans C; Berney, Richard; Paulus, Walter J; Hack, C Erik; van Milligen, Florine J; Niessen, Hans W M

    2009-06-01

    During acute myocardial infarction (AMI), ischemia leads to necrotic areas surrounded by border zones of reversibly damaged cardiomyocytes, showing membrane flip-flop. During reperfusion type IIA secretory phopholipase A(2) (sPLA(2)-IIA) induces direct cell-toxicity and facilitates binding of other inflammatory mediators on these cardiomyocytes. Therefore, we hypothesized that the specific sPLA(2)-IIA-inhibitor PX-18 would reduce cardiomyocyte death and infarct size in vivo. Wistar rats were treated with PX-18 starting minutes after reperfusion, and at day 1 and 2 post AMI. After 28 days hearts were analyzed. Furthermore, the effect of PX-18 on membrane flip-flop and apoptosis was investigated in vitro. PX-18 significantly inhibited sPLA(2)-IIA activity and reduced infarct size (reduction 73 +/- 9%, P < 0.05), compared to the vehicle-treated group, without impairing wound healing. In vitro, PX-18 significantly reduced reversible membrane flip-flop and apoptosis in cardiomyocytes. However, no sPLA(2)-IIA activity could be detected, suggesting that PX-18 also exerted a protective effect independent of sPLA(2)-IIA. In conclusion, PX-18 is a potent therapeutic to reduce infarct size by inhibiting sPLA(2)-IIA, and possibly also by inhibiting apoptosis of cardiomyocytes in a sPLA(2)-IIA independent manner.

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

    PubMed

    Cross, Suzanne; Bell, Jacqueline S; Graham, Wendy J

    2010-02-01

    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.

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

    PubMed

    Saligari, Jessica; Evans, Richard

    2016-04-01

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

  2. 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.

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

    PubMed

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

    2016-02-22

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

  4. 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

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

    ERIC Educational Resources Information Center

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

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

  6. Death Education and Death Fear Reduction

    ERIC Educational Resources Information Center

    Mueller, Mary Louise

    1976-01-01

    The study examined the possibility of reducing the fear of death in early adolescents through a 12-lesson unit designed to assist the student to achieve an attitude of integration toward life and death. (NQ)

  7. 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.

  8. Poverty Takes Bigger Toll on A Man's Health If He's Black

    MedlinePlus

    ... Drugs & Supplements Videos & Tools Español You Are Here: Home → Latest Health News → Article URL of this page: https://medlineplus.gov/news/fullstory_159937.html Poverty Takes Bigger Toll on a Man's Health If He's Black: Study Low income raises risk of early death ...

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

    PubMed

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

    2015-10-01

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

  10. Pelle Modulates dFoxO-Mediated Cell Death in Drosophila

    PubMed Central

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

    2015-01-01

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

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

    SciTech Connect

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

    2014-07-25

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

  12. 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

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

    PubMed Central

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

    2015-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2014-07-01

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

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

    PubMed

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

    2014-07-10

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

  16. 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.

  17. 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.

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

    PubMed Central

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

    2016-01-01

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

  19. 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...

  20. 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...

  1. 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...

  2. 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...

  3. 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...

  4. 47 CFR 42.6 - Retention of telephone toll records.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... whether it is billing its own toll service customers for toll calls or billing customers for another... Section 42.6 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES... telephone toll records. Each carrier that offers or bills toll telephone service shall retain for a...

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

    PubMed Central

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

    2015-01-01

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

  6. 47 CFR 63.65 - Closure of public toll station where another toll station of applicant in the community will...

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... of public toll station where another toll station of applicant in the community will continue service... 47 Telecommunication 3 2011-10-01 2011-10-01 false Closure of public toll station where another toll station of applicant in the community will continue service. 63.65 Section 63.65...

  7. 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

    ... of public toll station where another toll station of applicant in the community will continue service... 47 Telecommunication 3 2010-10-01 2010-10-01 false Closure of public toll station where another toll station of applicant in the community will continue service. 63.65 Section 63.65...

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

    PubMed

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

    2016-04-01

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

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

    Cancer.gov

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

  10. Is whole grain intake associated with reduced total and cause-specific death rates in older women? The Iowa Women's Health Study.

    PubMed Central

    Jacobs, D R; Meyer, K A; Kushi, L H; Folsom, A R

    1999-01-01

    OBJECTIVES: This study sought to determine whether nutrient-rich whole grains reduce mortality risk. METHODS: The study included 38,740 Iowa women, aged 55 to 69 years. A food frequency questionnaire was used to obtain data on grain intake. RESULTS: Median whole grain intake quintiles ranged from a median of 0.2 to more than 3 servings per day. Women with higher intakes had healthier lifestyles and less baseline disease. The total death rate decreased in increasing quintiles, and the pattern repeated for cancer, cardiovascular disease, and other causes combined. Adjusted for lifestyle and baseline disease, the relative hazard rate ratio for total death was about 0.85 in daily consumers of whole grain. Findings persisted in strata of baseline healthy and diseased and were not explained by dietary fiber. Rates of total mortality, but not cardiovascular disease mortality, were higher among frequent consumers of refined grain. CONCLUSIONS: Total mortality risk was inversely associated with whole grain intake and positively associated with refined grain intake. Refined grains contributed more than 20% of energy intake, and whole grains contributed 1%. Substitution of whole for refined grain may reduce chronic disease risk in the United States. PMID:10076480

  11. Glutathione and glutaredoxin act as a backup of human thioredoxin reductase 1 to reduce thioredoxin 1 preventing cell death by aurothioglucose.

    PubMed

    Du, Yatao; Zhang, Huihui; Lu, Jun; Holmgren, Arne

    2012-11-01

    Thioredoxin reductase 1 (TrxR1) in cytosol is the only known reductant of oxidized thioredoxin 1 (Trx1) in vivo so far. We and others found that aurothioglucose (ATG), a well known active-site inhibitor of TrxR1, inhibited TrxR1 activity in HeLa cell cytosol but had no effect on the viability of the cells. Using a redox Western blot analysis, no change was observed in redox state of Trx1, which was mainly fully reduced with five sulfhydryl groups. In contrast, auranofin killed cells and oxidized Trx1, also targeting mitochondrial TrxR2 and Trx2. Combining ATG with ebselen gave a strong synergistic effect, leading to Trx1 oxidation, reactive oxygen species accumulation, and cell death. We hypothesized that there should exist a backup system to reduce Trx1 when only TrxR1 activity was lost. Our results showed that physiological concentrations of glutathione, NADPH, and glutathione reductase reduced Trx1 in vitro and that the reaction was strongly stimulated by glutaredoxin1. Simultaneous depletion of TrxR activity by ATG and glutathione by buthionine sulfoximine led to overoxidation of Trx1 and loss of HeLa cell viability. In conclusion, the glutaredoxin system and glutathione have a backup role to keep Trx1 reduced in cells with loss of TrxR1 activity. Monitoring the redox state of Trx1 shows that cell death occurs when Trx1 is oxidized, followed by general protein oxidation catalyzed by the disulfide form of thioredoxin.

  12. 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.

  13. 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.

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

    PubMed

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

    2012-06-01

    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 H(2)O(2). 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.

  15. 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

  16. Thiram-induced cytotoxicity is accompanied by a rapid and drastic oxidation of reduced glutathione with consecutive lipid peroxidation and cell death.

    PubMed

    Cereser, C; Boget, S; Parvaz, P; Revol, A

    2001-06-21

    The toxic effect of thiram, a widely used dithiocarbamate fungicide, was investigated in cultured human skin fibroblasts. Cell survival assays demonstrated that thiram induced a dose-dependent decrease in the viable cell recovery. Thiram exposure resulted in a rapid depletion of intracellular reduced glutathione (GSH) content with a concomitant increase in oxidized glutathione (GSSG) concentration. Alteration of glutathione levels was accompanied by a dose-dependent decrease in the activity of glutathione reductase (GR), a key enzyme for the regeneration of GSH from GSSG. Thiram-exposed cells exhibited increased lipid peroxidation reflected by enhanced thiobarbituric acid reactive substances (TBARS) production, suggesting that GSH depletion and the lower GR activity gave rise to increased oxidative processes. To investigate the role of decreased GSH content in the toxicity of thiram, GSH levels were modulated prior to exposure. Pretreatment of fibroblasts with N-acetyl-L-cysteine (NAC), a GSH biosynthesis precursor, prevented both lipid peroxidation and cell death induced by thiram exposure. In contrast, thiram cytotoxicity was exacerbated by the previous depletion of cellular GSH by L-buthionine-(S,R)-sulfoximine (BSO). Taken together, these results strongly suggest that thiram induces GSH depletion, leading to oxidative stress and finally cell death.

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

    PubMed

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

    2016-03-01

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

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

    PubMed

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

    2013-03-13

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

  19. Cyanidin 3-O-glucoside reduces Helicobacter pylori VacA-induced cell death of gastric KATO III cells through inhibition of the SecA pathway.

    PubMed

    Kim, Sa-Hyun; Woo, Hyunjun; Park, Min; Rhee, Ki-Jong; Moon, Cheol; Lee, Dongsup; Seo, Woo Duck; Kim, Jong Bae

    2014-01-01

    Two key virulence factors of Helicobacter pylori are the secreted virulent proteins of vacuolating toxin A (VacA) and cytotoxin associated protein A (CagA) which lead to damages of gastric epithelial cells. We previously identified that the cyanidin 3-O-glucoside (C3G) inhibits the secretion of both VacA and CagA. In the current report, we show that C3G inhibits VacA secretion in a dose-dependent manner by inhibiting secretion system subunit protein A (SecA) synthesis. As SecA is involved in translocation of bacterial proteins, we predicted that inhibition of the SecA pathway by C3G should decrease H. pylori-induced cell death. To test this hypothesis, the human gastric cell line KATO III cells were co-cultured with H. pylori 60190 (VacA(+)/CagA(+)) and C3G. We found that C3G treatment caused a decrease in activation of the pro-apoptotic proteins caspase-3/-8 in H. pylori-infected cells leading to a decrease in cell death. Our data suggest that consumption of foods containing anthocyanin may be beneficial in reducing cell damage due to H. pylori infection. PMID:24904230

  20. Cyanidin 3-O-Glucoside Reduces Helicobacter pylori VacA-Induced Cell Death of Gastric KATO III Cells through Inhibition of the SecA Pathway

    PubMed Central

    Kim, Sa-Hyun; Woo, Hyunjun; Park, Min; Rhee, Ki-Jong; Moon, Cheol; Lee, Dongsup; Seo, Woo Duck; Kim, Jong Bae

    2014-01-01

    Two key virulence factors of Helicobacter pylori are the secreted virulent proteins of vacuolating toxin A (VacA) and cytotoxin associated protein A (CagA) which lead to damages of gastric epithelial cells. We previously identified that the cyanidin 3-O-glucoside (C3G) inhibits the secretion of both VacA and CagA. In the current report, we show that C3G inhibits VacA secretion in a dose-dependent manner by inhibiting secretion system subunit protein A (SecA) synthesis. As SecA is involved in translocation of bacterial proteins, we predicted that inhibition of the SecA pathway by C3G should decrease H. pylori-induced cell death. To test this hypothesis, the human gastric cell line KATO III cells were co-cultured with H. pylori 60190 (VacA+/CagA+) and C3G. We found that C3G treatment caused a decrease in activation of the pro-apoptotic proteins caspase-3/-8 in H. pylori-infected cells leading to a decrease in cell death. Our data suggest that consumption of foods containing anthocyanin may be beneficial in reducing cell damage due to H. pylori infection. PMID:24904230

  1. 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

  2. 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

  3. Early initiation of antiretroviral therapy: the current best way to reduce liver-related deaths in HIV/hepatitis C virus-coinfected patients.

    PubMed

    Shafran, Stephen D

    2007-04-15

    Approximately 25% to 35% of HIV-infected persons in developed countries are coinfected with hepatitis C virus (HCV). HCV liver disease is accelerated by HIV coinfection, especially at low CD4 cell counts. Highly active antiretroviral therapy (HAART) dramatically reduces HIV-related mortality, and liver disease has emerged as a major cause of death in HIV/HCV-coinfected persons. Anti-HCV therapy with pegylated interferon plus ribavirin can cure HCV infection in up to 40% of coinfected patients; however, only approximately 10% of coinfected patients are considered candidates. Hence, HCV therapy cures approximately 4% of coinfected patients. Eleven cohort studies have shown that HAART is associated with a reduced rate of progression of HCV liver disease, and 4 of these studies have demonstrated a reduction in liver-related mortality. Although offering HCV therapy to the few eligible HIV/HCV-coinfected patients is important, early initiation of HAART in coinfected patients has a greater public health impact in reducing liver-related mortality than in curing HCV infection in approximately 4% of these patients.

  4. Death imagery and death anxiety.

    PubMed

    McDonald, R T; Hilgendorf, W A

    1986-01-01

    This study investigated the relationship between positive/negative death imagery and death anxiety. Subjects were 179 undergraduate students at a large, private, midwestern university. Results reveal that on five measures of death anxiety the subjects with low death anxiety scores had significantly more positive death images than did those with high death anxiety scores. The few subjects who imagined death to be young (N = 14) had a significantly more positive image of death than those who perceived it to be an old person. Death was seen as male by 92% of the male respondents and 74% of the female respondents. Significant differences in death imagery and death anxiety were found between subjects enrolled in an introductory psychology course and those enrolled in a thanatology course. No sex differences in death anxiety or positive/negative death imagery were found.

  5. Induction of latency-associated peptide (transforming growth factor-β1) expression on CD4+ T cells reduces Toll-like receptor 4 ligand-induced tumour necrosis factor-α production in a transforming growth factor-β-dependent manner

    PubMed Central

    Boswell, Sandra; Sharif, Shayan; Alisa, Akeel; Pereira, Stephen P; Williams, Roger; Behboudi, Shahriar

    2011-01-01

    CD4+ T cells expressing the latent form of transforming growth factor-β [latency-associated peptide (LAP) (TGF-β1)] play an important role in the modulation of immune responses. Here, we identified a novel peptide ligand (GPC81–95) with an intrinsic ability to induce membrane-bound LAP (TGF-β1) expression on a subpopulation of human CD4+ T cells (using flow cytometry; ranging from 0·8% to 2·6%) and stimulate peripheral blood mononuclear cells to release LAP (TGF-β1) (using ELISPOT assay; ranging from 0·03% to 0·16%). In spite of this low percentage of responding cells, GPC81–95 significantly reduced Toll-like receptor 4 ligand-induced tumour necrosis factor-α production in a TGF-β1- and CD4+ T-cell-dependent manner. The results demonstrate that GPC81–95 is a useful tool to study the functional properties of a subpopulation of LAP (TGF-β1)+ CD4+ T cells and suggest a pathway that can be exploited to suppress inflammatory response. PMID:21426338

  6. 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.

  7. 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...

  8. 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...

  9. 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...

  10. 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...

  11. 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...

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

    PubMed Central

    Allmark, Peter; Tod, Angela M.

    2014-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-08-01

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

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

    PubMed

    Allmark, Peter; Tod, Angela M

    2014-03-01

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

  16. 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)

  17. Cause of Death in Women of Reproductive Age in Rural Nepal Obtained Through Community-Based Surveillance: Is Reducing Maternal Mortality the Right Priority for Women's Health Programs?

    PubMed

    Pyakurel, Ram; Sharma, Nirmala; Paudel, Deepak; Coghill, Anna; Sinden, Laura; Bost, Liberty; Larkin, Melissa; Burrus, Carla Jean; Roy, Khrist

    2015-01-01

    We used a community surveillance system to gather information regarding pregnancy outcomes and the cause of death for women of reproductive age (WRA) in Kanchanpur, Nepal. A total of 784 mother groups participated in the collection of pregnancy outcomes and mortality data. Of the 273 deaths among WRA, the leading causes of death reported were chronic diseases (94, 34.4%) poisoning, snake bites, and suicide (grouped together; 55, 20.1%), and accidents (29, 10.6%), while maternal mortality accounted for 7%. Nevertheless, the calculated maternal mortality ratio was quite high (259.3 per 100,000 live births).

  18. A Water-Ethanol Extract from the Willow Bracket Mushroom, Phellinus igniarius (Higher Basidiomycetes), Reduces Transient Cerebral Ischemia-Induced Neuronal Death.

    PubMed

    Kim, Jin Hee; Choi, Bo Young; Kim, Hyun Jung; Kim, In Yeol; Lee, Bo Eun; Sohn, Min; Park, Hyoung Jin; Suh, Sang Won

    2015-01-01

    This study investigated the potential neuroprotective effect of a mushroom extract from Phellinus igniarius (Piwep) after transient cerebral ischemia. Ph. Igniarius, which has a history of traditional medicinal use, contains immunomodulatory compounds that have been described to have effects on the human immune system. Using a model of transient cerebral ischemia induced by both common carotid artery occlusion and hypovolemia, a water-ethanol extract precipitate of Ph. Igniarius (Piwep) was delivered intraperitoneally immediately after the insult and was injected subsequently every other day for the experimental course. Neuronal death was examined by Fluoro-Jade B staining 1 week after the insult. Piwep injection lead to decreased hippocampal neuronal death, suppression of oxidative injury, activation of microglia, and disruption of the blood-brain barrier. We conclude that Piwep potently inhibits hippocampal neuronal death following ischemia and may have a high therapeutic potential for ameliorating stroke-induced neuron death in the clinical setting.

  19. A Water-Ethanol Extract from the Willow Bracket Mushroom, Phellinus igniarius (Higher Basidiomycetes), Reduces Transient Cerebral Ischemia-Induced Neuronal Death.

    PubMed

    Kim, Jin Hee; Choi, Bo Young; Kim, Hyun Jung; Kim, In Yeol; Lee, Bo Eun; Sohn, Min; Park, Hyoung Jin; Suh, Sang Won

    2015-01-01

    This study investigated the potential neuroprotective effect of a mushroom extract from Phellinus igniarius (Piwep) after transient cerebral ischemia. Ph. Igniarius, which has a history of traditional medicinal use, contains immunomodulatory compounds that have been described to have effects on the human immune system. Using a model of transient cerebral ischemia induced by both common carotid artery occlusion and hypovolemia, a water-ethanol extract precipitate of Ph. Igniarius (Piwep) was delivered intraperitoneally immediately after the insult and was injected subsequently every other day for the experimental course. Neuronal death was examined by Fluoro-Jade B staining 1 week after the insult. Piwep injection lead to decreased hippocampal neuronal death, suppression of oxidative injury, activation of microglia, and disruption of the blood-brain barrier. We conclude that Piwep potently inhibits hippocampal neuronal death following ischemia and may have a high therapeutic potential for ameliorating stroke-induced neuron death in the clinical setting. PMID:26756300

  20. 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

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

    PubMed

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

    2016-06-01

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

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

    PubMed

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

    2016-06-01

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

  3. 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.

  4. 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...

  5. 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...

  6. 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...

  7. 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...

  8. 23 CFR 950.5 - Requirement to use electronic toll collection technology.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

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

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

    PubMed

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

    2016-06-01

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

  10. Designing and Implementing an Innovative SMS-based alert system (RapidSMS-MCH) to monitor pregnancy and reduce maternal and child deaths in Rwanda

    PubMed Central

    Ngabo, Fidele; Nguimfack, Judith; Nwaigwe, Friday; Mugeni, Catherine; Muhoza, Denis; Wilson, David R; Kalach, John; Gakuba, Richard; Karema, Corrine; Binagwaho, Agnes

    2012-01-01

    Introduction With the continuous growth of mobile network coverage and unprecedented penetration of mobile devices in the developing world, several mHealth initiatives are being implemented in developing countries. This paper aims to describe requirements for designing and implementing a mobile phone-based communication system aiming at monitoring pregnancy and reducing bottlenecks in communication associated with maternal and newborn deaths; and document challenges and lessons learned. Methods An SMS-based system was developed to improve maternal and child health (MCH) using RapidSMS®, a free and open-sourced software development framework. To achieve the expected results, the RapidSMS-MCH system was customized to allow interactive communication between a community health worker (CHW)following mother-infant pairs in their community, a national centralized database, the health facility and in case of an emergency alert, the ambulance driver. The RapidSMS-MCH system was piloted in Musanze district, Nothern province of Rwanda over a 12-month period. Results A total of 432 CHW were trained and equipped with mobile phones. A total of 35,734 SMS were sent by 432 CHW from May 2010 to April 2011. A total of 11,502 pregnancies were monitored. A total of 362 SMS alerts for urgent and life threatening events were registered. We registered a 27% increase in facility based delivery from 72% twelve months before to 92% at the end of the twelve months pilot phase. Major challenges were telephone maintenance and replacement. Disctrict heath team capacity to manage and supervise the system was strengthened by the end of pilot phase. Highly committed CHWs and effective coordination by the District health team were critical enablers. Conclusion We successully designed and implemented a mobile phone SMS-based system to track pregnancy and maternal and child outcomes in limited resources setting. Implementation of mobile-phone systems at community level could contribute to improving

  11. High death rates in health care workers and teachers in Malawi.

    PubMed

    Harries, A D; Hargreaves, N J; Gausi, F; Kwanjana, J H; Salaniponi, F M

    2002-01-01

    High death rates are reported in health care workers (HCWs) and teachers in urban areas of Malawi. The present study was carried out to determine the annual death rate in HCWs and primary school teachers working in semi-urban and rural areas of Malawi, and to try to ascertain the main causes of death. Forty district and mission hospitals in Malawi were visited. A record was made of the number of clinical and nursing-based HCWs in each hospital in 1999, the number of deaths in that calendar year and reported causes of death. A record was also made of the number of teachers working in 4 primary schools nearest to each hospital in 1999, the number of deaths in that calendar year and reported causes of death. There were 2979 HCWs, of whom 60 (2.0%) died. There were 4367 teachers of whom 101 (2.3%) died. Annual death rates, calculated per 100,000 people, were significantly higher in male HCWs compared with female HCWs (2495 versus 1770, RR 1.17, 95% CI 1.14-1.20, P < 0.001), and significantly higher in female teachers compared with male teachers (2521 versus 1934, RR 1.14, 95% CI 1.11-1.17, P < 0.001). In male HCWs and teachers the highest death rates were in those aged 35-44 years. In female HCWs and teachers, the highest death rates were in those aged 25-34 years and 35-44 years, respectively. Reported causes of death in HCWs were tuberculosis (TB) in 47%, chronic illness in 45% and acute illness in the remainder, while in teachers the causes were TB in 27%, chronic illness in 49% and acute illness in 25%. Chronic illness, thought to be due to AIDS, and TB were the common causes of death. The current high death rates from AIDS and TB will have a crippling toll on the health and education sectors, and effective ways of reducing these death rates must be found.

  12. 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.

  13. 47 CFR 63.504 - Contents of applications to close a public toll station where no other such toll station of the...

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 3 2013-10-01 2013-10-01 false Contents of applications to close a public toll station where no other such toll station of the applicant in the community will continue service and where telephone toll service is not otherwise available to the public through a telephone exchange connected with the toll lines of a...

  14. 47 CFR 63.504 - Contents of applications to close a public toll station where no other such toll station of the...

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 3 2012-10-01 2012-10-01 false Contents of applications to close a public toll station where no other such toll station of the applicant in the community will continue service and where telephone toll service is not otherwise available to the public through a telephone exchange connected with the toll lines of a...

  15. 47 CFR 63.504 - Contents of applications to close a public toll station where no other such toll station of the...

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 3 2014-10-01 2014-10-01 false Contents of applications to close a public toll station where no other such toll station of the applicant in the community will continue service and where telephone toll service is not otherwise available to the public through a telephone exchange connected with the toll lines of a...

  16. 47 CFR 63.504 - Contents of applications to close a public toll station where no other such toll station of the...

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 3 2010-10-01 2010-10-01 false Contents of applications to close a public toll station where no other such toll station of the applicant in the community will continue service and where telephone toll service is not otherwise available to the public through a telephone exchange connected with the toll lines of a...

  17. 47 CFR 63.504 - Contents of applications to close a public toll station where no other such toll station of the...

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 3 2011-10-01 2011-10-01 false Contents of applications to close a public toll station where no other such toll station of the applicant in the community will continue service and where telephone toll service is not otherwise available to the public through a telephone exchange connected with the toll lines of a...

  18. Disseminated cysticercosis: clinical spectrum, Toll-like receptor-4 gene polymorphisms and role of albendazole: A prospective follow-up of 60 cases with a review of 56 published cases.

    PubMed

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

    2016-09-01

    . 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

  19. Death duties

    PubMed Central

    Myers, Kathryn A.; Eden, David

    2007-01-01

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

  20. Toll-like receptor 1 variation increases the risk of transplant-related mortality in hematologic malignancies.

    PubMed

    Uchino, Kaori; Mizuno, Shohei; Mizutani, Motonori; Horio, Tomohiro; Hanamura, Ichiro; Espinoza, J Luis; Matsuo, Keitaro; Onizuka, Makoto; Kashiwase, Koichi; Morishima, Yasuo; Fukuda, Takahiro; Kodera, Yoshihisa; Doki, Noriko; Miyamura, Koichi; Mori, Takehiko Mori Takehiko; Takami, Akiyoshi

    2016-09-01

    Toll-like receptor 1 (TLR1) genetic variant (rs5743551, -7202A>G) has been reported to be associated with susceptibility to various infectious diseases. We retrospectively examined the impact of TLR1 variation on transplant outcomes in a cohort of 320 patients who underwent unrelated HLA-matched bone marrow transplantation (BMT) for hematologic malignancies. A multivariate analysis showed that the G/G genotype in the recipients and the donors was associated with a significantly lower 3-year transplant-related mortality (TRM). The recipient G/G genotype also resulted in a better 3-year progression-free survival. This study suggests that the recipient and donor TLR1 G/G genotypes are comparably associated with a reduced risk of death that was not related to relapse. Thus, TLR1 genotyping may be useful for selecting the donor, managing patients in a risk-adapted manner, and creating therapeutic strategies to prevent complications after hematopoietic stem cell transplantation. PMID:27369862

  1. 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 Section 52.111 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS Arizona § 52.111 Toll free number...

  2. 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 Section 52.111 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS Arizona § 52.111 Toll free number...

  3. 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 Section 52.111 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS Arizona § 52.111 Toll free number...

  4. 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 Section 52.111 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS Arizona § 52.111 Toll free number...

  5. 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 Section 52.111 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS Arizona § 52.111 Toll free number...

  6. 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.

  7. 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...

  8. 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...

  9. 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...

  10. 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...

  11. 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...

  12. Neonatal Death

    MedlinePlus

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

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

    PubMed Central

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

    2015-01-01

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

  14. Toll-like Receptors in Tumor Immunotherapy

    PubMed Central

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

    2007-01-01

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

  15. Three novel Toll genes (PtToll1-3) identified from a marine crab, Portunus trituberculatus: Different tissue expression and response to pathogens.

    PubMed

    Zhou, Su-Ming; Yuan, Xue-Mei; Liu, Shun; Li, Meng; Tao, Zhen; Wang, Guo-Liang

    2015-10-01

    The Toll signaling pathway is one of the most important regulators of the immune response in both vertebrates and invertebrates. Herein, three novel Toll (PtToll1-3) cDNA sequences were cloned from the swimming crab, Portunus trituberculatus. PtToll1 has 1003 amino acid residues and consists of an extracellular domain containing 15 leucine-rich repeats (LRRs) and a cytoplasmic Toll/interleukin-1 receptor (TIR) domain of 139 residues. PtToll2 encodes 1196 peptides, with an extracellular domain containing 28 LRRs and a cytoplasmic TIR domain. PtToll3 is 1229 residues long and contains 26 LRRs and a cytoplasmic TIR domain. Based on sequence and phylogenetic analyses, PtToll1 distinctly clustered with almost all crustacean Tolls, except Litopenaeus vannamei Toll3. However, PtToll2 and PtToll3 were separated from most reported crustacean Tolls, which mostly clustered with Drosophila melanogaster (Dm) Toll8, L. vannamei Toll3, and DmToll6. Reverse transcription PCR and real-time quantitative PCR analyses showed that PtToll1 and PtToll3 were constitutively expressed in all tissues tested, but PtToll2 mRNA was only highly enriched in gills. Upon challenges with Vibrio alginolyticus, Candida lusitaniae, or white spot syndrome virus (WSSV), the three Tolls exhibited different responses: the PtToll1 transcript was up-regulated in response to C. lusitaniae or V. alginolyticus challenge, but did not respond to WSSV challenge; both PtToll2 and PtToll3 mRNAs were down-regulated 12 h after C. lusitaniae or V. alginolyticus infection. However, WSSV elicited the expression of PtToll2 at 6 h post-infection, but suppressed transcription of PtToll3 at 24 h post-infection. The study provides valuable data for understanding the role of Toll pathways in the host defense against microbial pathogens, which will facilitate future studies on host-pathogen interactions in crabs. PMID:26238349

  16. Essential Roles of Toll-Like Receptors in Atherosclerosis.

    PubMed

    Lin, Juntang; Kakkar, Vijay; Lu, Xinjie

    2016-01-01

    Atherosclerosis is driven by inflammation with an involvement of innate and adaptive immune responses. Toll-like receptors, the well-defined pattern recognition receptors of the immune system, play a central role in macrophage activation. Toll-like receptors recognize pathogen-associated molecular patterns expressed by a wide range of infectious agents and provide a strong link between local innate and adaptive immunity. Activation of these receptors triggers an intracellular signaling cascade mediated through myeloid differentiation factor 88 or toll/interleukin-1 receptor-domain-containing adapter-inducing interferon-β, leading to the secretion of proand anti-inflammatory cytokines. Engagement of Toll-like receptors with their ligands induces leukocyte recruitment and enhances matrix metalloproteinase expression within atherosclerotic lesions. Recently certain Toll-like receptors have shown a protective role in atherosclerosis. TLRs, therefore, represent an important link between inflammation and atheroma, making them attractive targets for the treatment of atherosclerosis. This review will briefly describe the general biological structure and potential roles of Toll-like receptors as therapeutic targets for the treatment of atherosclerosis and highlight the potential challenges on Toll-like receptor- based therapy in cardiovascular disease. PMID:26639096

  17. Toll-like receptors and liver disease.

    PubMed

    Kesar, Vivek; Odin, Joseph A

    2014-02-01

    Toll-like receptors (TLRs) are pattern recognition receptors that play an important role in host defence by recognizing pathogen-associated molecular patterns (PAMP). Recent studies indicate that TLR signalling plays an important role in progression of chronic liver diseases. Ongoing clinical trials suggest that therapeutic manipulation of TLR pathways may offer novel means of reversing chronic liver diseases. Upon activation by their respective ligands, TLRs initiate an intracellular pro-inflammatory/anti-inflammatory signalling cascade via recruitment of various adaptor proteins. TLR associated signalling pathways are tightly regulated to keep a check on inappropriate production of pro-inflammatory cytokines and interferons thereby preventing various autoimmune and inflammatory processes. Herein, we review the current state of knowledge of hepatic distribution, signalling pathways and therapeutic modulation of TLRs in chronic liver diseases. PMID:24118797

  18. The tolls and dangers of atherosclerotic disease.

    PubMed

    Monaco, Claudia

    2012-01-01

    Inflammation drives atherosclerosis. Toll-like receptor-2 and -4 are so far the strongest candidates for initiating innate immune signalling in atherosclerosis. Their signalling has implications for lesion development, foam cell formation, inflammation, matrix degradation and ischemia-reperfusion. The repertoire of TLR agonists is expanding. They collectively represent a conglomerate of structurally diverse molecular patterns requiring a high level of versatility in their sensing. Such versatility is achieved through cooperation of TLR heterodimers, co-receptors, and binding proteins. Several endogenous and exogenous molecular patterns engaging TLRs are associated with atherosclerosis development and complications. In this review, I describe how such molecular patterns are sensed, how they signal and what the consequences in the atherosclerotic plaque might be. The effect of TLR antagonising compounds in human and murine atherosclerosis is also addressed.

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

    PubMed

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

    2016-06-01

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

  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

    2016-06-01

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

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

    MedlinePlus

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

  2. Hard Times May Exact a Toll on Brain Health

    MedlinePlus

    ... https://medlineplus.gov/news/fullstory_161283.html Hard Times May Exact a Toll on Brain Health Poverty ... a cause-and-effect relationship between hard economic times and brain health and aging. The findings were ...

  3. 31. TACOMA NARROWS BRIDGE, LOOKING WEST ACROSS TOLL PLAZA, 29 ...

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

    31. TACOMA NARROWS BRIDGE, LOOKING WEST ACROSS TOLL PLAZA, 29 AUGUST 1940. (ELDRIDGE, CLARK M. TACOMA NARROWS BRIDGE, TACOMA, WASHINGTON, FINAL REPORT ON DESIGN AND CONSTRUCTION, 1941) - Tacoma Narrows Bridge, Spanning Narrows at State Route 16, Tacoma, Pierce County, WA

  4. 30. TACOMA NARROWS BRIDGE, LOOKING EAST THROUGH TOLL LANES, 29 ...

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

    30. TACOMA NARROWS BRIDGE, LOOKING EAST THROUGH TOLL LANES, 29 AUGUST 1940. (ELDRIDGE, CLARK H. TACOMA NARROWS BRIDGE, TACOMA, WASHINGTON, FINAL REPORT ON DESIGN AND CONSTRUCTION, 1941) - Tacoma Narrows Bridge, Spanning Narrows at State Route 16, Tacoma, Pierce County, WA

  5. Fitful Sleep May Take Toll on Older Women's Hearts

    MedlinePlus

    ... html Fitful Sleep May Take Toll on Older Women's Hearts Before and after menopause, less sleep linked ... 2016 (HealthDay News) -- The sleep woes that many women suffer during menopause may be more than a ...

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-06-01

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

  8. 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.

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

    PubMed

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

    2015-08-01

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

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

    PubMed Central

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

    2014-01-01

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

  11. 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.

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

    PubMed

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

    2016-02-01

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

  13. 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.

  14. Inhibition of the kinase ITK in a mouse model of asthma reduces cell death and fails to inhibit the inflammatory response.

    PubMed

    Sun, Yonglian; Peng, Ivan; Webster, Joshua D; Suto, Eric; Lesch, Justin; Wu, Xiumin; Senger, Kate; Francis, George; Barrett, Kathy; Collier, Jenna L; Burch, Jason D; Zhou, Meijuan; Chen, Yuan; Chan, Connie; Eastham-Anderson, Jeff; Ngu, Hai; Li, Olga; Staton, Tracy; Havnar, Charles; Jaochico, Allan; Jackman, Janet; Jeet, Surinder; Riol-Blanco, Lorena; Wu, Lawren C; Choy, David F; Arron, Joseph R; McKenzie, Brent S; Ghilardi, Nico; Ismaili, Moulay Hicham Alaoui; Pei, Zhonghua; DeVoss, Jason; Austin, Cary D; Lee, Wyne P; Zarrin, Ali A

    2015-12-01

    Interleukin-2 (IL-2)-inducible T cell kinase (ITK) mediates T cell receptor (TCR) signaling primarily to stimulate the production of cytokines, such as IL-4, IL-5, and IL-13, from T helper 2 (TH2) cells. Compared to wild-type mice, ITK knockout mice are resistant to asthma and exhibit reduced lung inflammation and decreased amounts of TH2-type cytokines in the bronchoalveolar lavage fluid. We found that a small-molecule selective inhibitor of ITK blocked TCR-mediated signaling in cultured TH2 cells, including the tyrosine phosphorylation of phospholipase C-γ1 (PLC-γ1) and the secretion of IL-2 and TH2-type cytokines. Unexpectedly, inhibition of the kinase activity of ITK during or after antigen rechallenge in an ovalbumin-induced mouse model of asthma failed to reduce airway hyperresponsiveness and inflammation. Rather, in mice, pharmacological inhibition of ITK resulted in T cell hyperplasia and the increased production of TH2-type cytokines. Thus, our studies predict that inhibition of the kinase activity of ITK may not be therapeutic in patients with asthma.

  15. [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.

  16. Activation of lung toll-like receptors does not exacerbate sickness responses to lipopolysaccharide in mice.

    PubMed

    Walker, Adam K; Hsieh, Jennifer; Luu, Katherine V; Radwan, Aiat A; Valverde, Gabriella R; Dickey, Burton F; Tuvim, Michael J; Dantzer, Robert

    2014-05-01

    Pneumonia represents a leading cause of death. Recently, a novel treatment strategy for pneumonia has involved enhancing the host pulmonary innate immune response by pre-exposure to aerosolized toll-like receptor (TLR)9 and TLR2/6 agonists, known as O/P. O/P inhalation in mice has been demonstrated to stimulate innate lung immunity, and thus increase survival against subsequent pneumonia infection while producing barely detectable increases in systemic cytokines. Here, we examined the safety of O/P treatment when used in mice that are inflamed systemically. Swiss-Webster mice were treated with two doses of aerosolized O/P (1× or 8×) vs phosphate buffered saline (PBS) either immediately before intraperitoneal injection of 0.1mg/kg lipopolysaccharide (LPS) or PBS (equivolume) or 2h after. Sickness responses (reduced body weight, food intake, activity and social interaction) were examined at 2 and 5.5h post-treatment. Immediately following behavioral testing, mice were euthanized, perfused with PBS, and brains, spleens, livers and lungs snap frozen for assessment of pro-inflammatory cytokine mRNAs. While O/P treatment alone increased lung IL-1β, IFNγ and TNF-α, no such effects were observed in the brain, spleen or liver. Furthermore, there was no evidence that O/P treatment administered before or after LPS had any synergizing effect to potentiate the cytokine response to LPS in any compartment measured. Supportive of these findings were the measures of sickness behaviors that did not show any increased sickness response in O/P-treated mice exposed to LPS, suggestive that the cytokine signal produced in the lungs from O/P inhalation did not propagate to the brain and synergize with LPS-induced neuroinflammation. These findings support the safety of the use of O/P inhalation as a preventative measure against pneumonia and demonstrate a unique ability of the lungs to compartmentalize pulmonary inflammation and limit propagation of the cytokine signal to the brain.

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

    PubMed Central

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

    2005-01-01

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

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

    PubMed

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

    2015-12-01

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

  19. Butin (7,3′,4′-Trihydroxydihydroflavone) Reduces Oxidative Stress-Induced Cell Death via Inhibition of the Mitochondria-Dependent Apoptotic Pathway

    PubMed Central

    Zhang, Rui; Lee, In Kyung; Piao, Mei Jing; Kim, Ki Cheon; Kim, Areum Daseul; Kim, Hye Sun; Chae, Sungwook; Kim, Hee Sun; Hyun, Jin Won

    2011-01-01

    Recently, we demonstrated that butin (7,3′,4′-trihydroxydihydroflavone) protected cells against hydrogen peroxide (H2O2)-induced apoptosis by: (1) scavenging reactive oxygen species (ROS), activating antioxidant enzymes such superoxide dismutase and catalase; (2) decreasing oxidative stress-induced 8-hydroxy-2′-deoxyguanosine levels via activation of oxoguanine glycosylase 1, and (3), reducing oxidative stress-induced mitochondrial dysfunction. The objective of this study was to determine the cytoprotective effects of butin on oxidative stress-induced mitochondria-dependent apoptosis, and possible mechanisms involved. Butin significantly reduced H2O2-induced loss of mitochondrial membrane potential as determined by confocal image analysis and flow cytometry, alterations in Bcl-2 family proteins such as decrease in Bcl-2 expression and increase in Bax and phospho Bcl-2 expression, release of cytochrome c from mitochondria into the cytosol and activation of caspases 9 and 3. Furthermore, the anti-apoptotic effect of butin was exerted via inhibition of mitogen-activated protein kinase kinase-4, c-Jun NH2-terminal kinase (JNK) and activator protein-1 cascades induced by H2O2 treatment. Finally, butin exhibited protective effects against H2O2-induced apoptosis, as demonstrated by decreased apoptotic bodies, sub-G1 hypodiploid cells and DNA fragmentation. Taken together, the protective effects of butin against H2O2-induced apoptosis were exerted via blockade of membrane potential depolarization, inhibition of the JNK pathway and mitochondria-involved caspase-dependent apoptotic pathway. PMID:21747713

  20. 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

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

    PubMed

    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

    2015-02-12

    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 (PS1(M146L)xAPP(751sl)) 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.

  2. 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

  3. 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

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

    PubMed

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

    2016-08-01

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

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

    PubMed

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

    2014-02-01

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

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

    PubMed

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

    2014-02-01

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

  7. BmToll9, an Arthropod conservative Toll, is likely involved in the local gut immune response in the silkworm, Bombyx mori.

    PubMed

    Wu, Shan; Zhang, Xiaofeng; Chen, Xiaomei; Cao, Pingsheng; Beerntsen, Brenda T; Ling, Erjun

    2010-02-01

    The Toll family of transmembrane proteins mediates signaling during the innate immune response in most animals. Toll9 is widespread in insects and has a unique signature, QHR, in its Toll/interleukin-1 receptor (TIR) domain. The introns in the TIR region are highly conserved among insects, suggesting the antiquity of Toll9 genes. Toll9 of Bombyx mori (BmToll9) was analysed by quantitative real-time RT-PCR. BmToll9 is constitutively expressed in egg, larval and adult stages prior to microbial challenge. BmToll9 is strongly expressed in the different parts of the gut, but weakly expressed in haemocytes, trachea, fat body, malpighian tubule and epidermis, and scarcely expressed in the silk glands. The injection of sterilized 0.85% NaCl solution inhibited BmToll9 expression in most tissues especially during the early responses. Staphylococcus aureus had no or limited effect on the expression of BmToll9 in the silkworm gut and fat body. But in epidermis, trachea, malpighian tubules and haemocytes, the expression of BmToll9 was significantly increased after S. aureus challenge. Infection of Escherichia coli significantly increased the BmToll9 expression in different parts of the gut as well as in epidermis, malpighian tubule and haemocytes. At 48h after feeding of the fungus, Beauveria bassiana, BmToll9 expression was significantly increased. Tissues responses to the injected and ingested bacteria showed that BmToll9 is probably involved in the local gut immune response in the silkworm.

  8. BmToll9, an Arthropod conservative Toll, is likely involved in the local gut immune response in the silkworm, Bombyx mori.

    PubMed

    Wu, Shan; Zhang, Xiaofeng; Chen, Xiaomei; Cao, Pingsheng; Beerntsen, Brenda T; Ling, Erjun

    2010-02-01

    The Toll family of transmembrane proteins mediates signaling during the innate immune response in most animals. Toll9 is widespread in insects and has a unique signature, QHR, in its Toll/interleukin-1 receptor (TIR) domain. The introns in the TIR region are highly conserved among insects, suggesting the antiquity of Toll9 genes. Toll9 of Bombyx mori (BmToll9) was analysed by quantitative real-time RT-PCR. BmToll9 is constitutively expressed in egg, larval and adult stages prior to microbial challenge. BmToll9 is strongly expressed in the different parts of the gut, but weakly expressed in haemocytes, trachea, fat body, malpighian tubule and epidermis, and scarcely expressed in the silk glands. The injection of sterilized 0.85% NaCl solution inhibited BmToll9 expression in most tissues especially during the early responses. Staphylococcus aureus had no or limited effect on the expression of BmToll9 in the silkworm gut and fat body. But in epidermis, trachea, malpighian tubules and haemocytes, the expression of BmToll9 was significantly increased after S. aureus challenge. Infection of Escherichia coli significantly increased the BmToll9 expression in different parts of the gut as well as in epidermis, malpighian tubule and haemocytes. At 48h after feeding of the fungus, Beauveria bassiana, BmToll9 expression was significantly increased. Tissues responses to the injected and ingested bacteria showed that BmToll9 is probably involved in the local gut immune response in the silkworm. PMID:19723534

  9. [The need for death education].

    PubMed

    Deeken, A

    1992-08-01

    "Death Education" is at the same time "Life Education." For many years I have endeavored to create an awareness of the need for death education in Japan. In this paper I would like to stress the necessity of death education for the following three groups. 1. For medical personnel. Three objectives of death education: 1) Learn to understand the fears and anxieties of the patients facing death and try to reduce their excessive fears and anxieties. 2) Familiarize yourself with the ethical issues related to terminal care and try to establish a warm relationship based on trust and continue communication with the dying patient till the end. 2. For patients. 1) Be aware that the time of your life is limited and try to discover the preciousness of the remaining time. Meditate on the uniqueness of your own death. 2) Finish your unfinished business, reevaluate your human relationships and benefit from a life review therapy. 3) Remove the taboo on death, arrange your own funeral and consider the possibility of another life after death. 3. For the patient's family and friends. 1) Continue warm communication with the dying patient till the end. 2) Prepare for your own bereavement and grief. 3) Try to make your own grief process an opportunity for personal growth. When a cure is no longer possible for a dying patient, the focus of our endeavors should be loving care of the person. Death education can help us to provide better terminal care during the final stage of life.

  10. 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

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

    PubMed

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

    2016-01-01

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

  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. Interleukin 1/Toll-like Receptor-induced Autophosphorylation Activates Interleukin 1 Receptor-associated Kinase 4 and Controls Cytokine Induction in a Cell Type-specific Manner

    PubMed Central

    Cushing, Leah; Stochaj, Wayne; Siegel, Marshall; Czerwinski, Robert; Dower, Ken; Wright, Quentin; Hirschfield, Margaret; Casanova, Jean-Laurent; Picard, Capucine; Puel, Anne; Lin, Lih-Ling; Rao, Vikram R.

    2014-01-01

    IRAK4 is a central kinase in innate immunity, but the role of its kinase activity is controversial. The mechanism of activation for IRAK4 is currently unknown, and little is known about the role of IRAK4 kinase in cytokine production, particularly in different human cell types. We show IRAK4 autophosphorylation occurs by an intermolecular reaction and that autophosphorylation is required for full catalytic activity of the kinase. Phosphorylation of any two of the residues Thr-342, Thr-345, and Ser-346 is required for full activity, and the death domain regulates the activation of IRAK4. Using antibodies against activated IRAK4, we demonstrate that IRAK4 becomes phosphorylated in human cells following stimulation by IL-1R and Toll-like receptor agonists, which can be blocked pharmacologically by a dual inhibitor of IRAK4 and IRAK1. Interestingly, in dermal fibroblasts, although complete inhibition of IRAK4 kinase activity does not inhibit IL-1-induced IL-6 production, NF-κB, or MAPK activation, there is complete ablation of these processes in IRAK4-deficient cells. In contrast, the inhibition of IRAK kinase activity in primary human monocytes reduces R848-induced IL-6 production with minimal effect on NF-κB or MAPK activation. Taken together, these studies define the mechanism of IRAK4 activation and highlight the differential role of IRAK4 kinase activity in different human cell types as well as the distinct roles IRAK4 scaffolding and kinase functions play. PMID:24567333

  14. National Automatic Toll Collection System - Pilot Project (Part 1)

    NASA Astrophysics Data System (ADS)

    Nowacki, Gabriel; Mitraszewska, Izabella; Kamiński, Tomasz; Niedzicka, Anna; Smoczyńska, Ewa; Ucińska, Monika; Kallweit, Thomas; Rozesłaniec, Robert

    2011-09-01

    This article presents selected issues concerning functional structure of the National Automatic Toll Collection System. The system includes the following elements: two on-board intelligent devices - OBU, two control gates, laboratory model of a National Centre for Automatic Toll Collection (NATCS). Poland and other EU member states should implement the European Electronic Tolling Service - EETS in accordance with the European Commission's decision of 6 October 2009. EETS should be available within three years (2012) for all vehicles over 3.5 tonnes and vehicles carrying more than 9 persons including the driver. This service will be available for other vehicles within five years (2014). Motor Transport Institute has created the structure of NATCS, as a hybrid pilot project to be used in researches on the implementation of the interoperable system in EU. The tests results will be presented in the article - part 2.

  15. 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.

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

    PubMed

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

    2014-05-01

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

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

    PubMed

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

    2014-05-01

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

  18. 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…

  19. 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

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

    PubMed

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

    2015-10-01

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

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

    Code of Federal Regulations, 2012 CFR

    2012-04-01

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

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

    Code of Federal Regulations, 2013 CFR

    2013-04-01

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

  3. Henry Hudson Bridge toll plaza, upper level, looking west. Pipe ...

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

    Henry Hudson Bridge toll plaza, upper level, looking west. Pipe railing parapets and pedestrian walkway on left. Inwood Hill Park in background. - Henry Hudson Parkway, Extending 11.2 miles from West 72nd Street to Bronx-Westchester border, New York County, NY

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

    Code of Federal Regulations, 2010 CFR

    2010-04-01

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

  5. Systemic cancer immunotherapy with Toll-like receptor 7 agonists

    PubMed Central

    Hotz, Christian; Bourquin, Carole

    2012-01-01

    Toll-like receptor (TLR) 7 agonists represent a promising strategy for the immunotherapy of cancer. We have recently investigated the influence of TLR tolerance on the efficacy of systemic tumor treatment with TLR7 ligands. We propose that considering the kinetics of receptor sensitivity highly improves the outcome of cancer immunotherapy. PMID:22720251

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

    Code of Federal Regulations, 2011 CFR

    2011-04-01

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

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

    PubMed

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

    2016-07-01

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

  8. 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 ...

  9. 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.

  10. 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.

  11. 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. PMID:27542619

  12. Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits

    PubMed Central

    Tang, Sung-Chun; Arumugam, Thiruma V.; Xu, Xiangru; Cheng, Aiwu; Mughal, Mohamed R.; Jo, Dong Gyu; Lathia, Justin D.; Siler, Dominic A.; Chigurupati, Srinivasulu; Ouyang, Xin; Magnus, Tim; Camandola, Simonetta; Mattson, Mark P.

    2007-01-01

    The innate immune system senses the invasion of pathogenic microorganisms and tissue injury through Toll-like receptors (TLR), a mechanism thought to be limited to immune cells. We now report that neurons express several TLRs, and that the levels of TLR2 and -4 are increased in neurons in response to IFN-γ stimulation and energy deprivation. Neurons from both TLR2 knockout and -4 mutant mice were protected against energy deprivation-induced cell death, which was associated with decreased activation of a proapoptotic signaling cascade involving jun N-terminal kinase and the transcription factor AP-1. TLR2 and -4 expression was increased in cerebral cortical neurons in response to ischemia/reperfusion injury, and the amount of brain damage and neurological deficits caused by a stroke were significantly less in mice deficient in TLR2 or -4 compared with WT control mice. Our findings establish a proapoptotic signaling pathway for TLR2 and -4 in neurons that may render them vulnerable to ischemic death. PMID:17693552

  13. Commentary: Pursuing justice in death penalty trials.

    PubMed

    Watson, Clarence; Eth, Spencer; Leong, Gregory B

    2012-01-01

    The capital trial, by its nature, is fraught with emotionally disturbing elements that jurors must face when deciding the ultimate fate of a guilty defendant. A confluence of mitigating and aggravating factors influences a capital jury's decision to impose a sentence of death. The presence or absence of defendant remorse in these cases may make all the difference in whether a capital defendant's life is spared. This commentary examines the onerous emotional toll encountered by capital jurors in light of the findings of Corwin and colleagues regarding defendant remorse and juror's need for affect. The commentary also presents practical and ethics-related considerations that should be kept in mind when reflecting on their study.

  14. Commentary: Pursuing justice in death penalty trials.

    PubMed

    Watson, Clarence; Eth, Spencer; Leong, Gregory B

    2012-01-01

    The capital trial, by its nature, is fraught with emotionally disturbing elements that jurors must face when deciding the ultimate fate of a guilty defendant. A confluence of mitigating and aggravating factors influences a capital jury's decision to impose a sentence of death. The presence or absence of defendant remorse in these cases may make all the difference in whether a capital defendant's life is spared. This commentary examines the onerous emotional toll encountered by capital jurors in light of the findings of Corwin and colleagues regarding defendant remorse and juror's need for affect. The commentary also presents practical and ethics-related considerations that should be kept in mind when reflecting on their study. PMID:22396341

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

    PubMed Central

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

    2015-01-01

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

  16. Toll-like receptor and tumour necrosis factor dependent endotoxin-induced acute lung injury

    PubMed Central

    Togbe, Dieudonnée; Schnyder-Candrian, Silvia; Schnyder, Bruno; Doz, Emilie; Noulin, Nicolas; Janot, Laure; Secher, Thomas; Gasse, Pamela; Lima, Carla; Coelho, Fernando Rodrigues; Vasseur, Virginie; Erard, François; Ryffel, Bernhard; Couillin, Isabelle; Moser, Rene

    2007-01-01

    Recent studies on endotoxin/lipopolysaccharide (LPS)-induced acute inflammatory response in the lung are reviewed. The acute airway inflammatory response to inhaled endotoxin is mediated through Toll-like receptor 4 (TLR4) and CD14 signalling as mice deficient for TLR4 or CD14 are unresponsive to endotoxin. Acute bronchoconstriction, tumour necrosis factor (TNF), interleukin (IL)-12 and keratinocyte-derived chemokine (KC) production, protein leak and neutrophil recruitment in the lung are abrogated in mice deficient for the adaptor molecules myeloid differentiation factor 88 (MyD88) and Toll/Interleukin-1 receptor (TIR)-domain-containing adaptor protein (TIRAP), but independent of TIR-domain-containing adaptor-inducing interferon-beta (TRIF). In particular, LPS-induced TNF is required for bronchoconstriction, but dispensable for inflammatory cell recruitment. Lipopolysaccharide induces activation of the p38 mitogen-activated protein kinase (MAPK). Inhibition of pulmonary MAPK activity abrogates LPS-induced TNF production, bronchoconstriction, neutrophil recruitment into the lungs and broncho-alveolar space. In conclusion, TLR4-mediated, bronchoconstriction and acute inflammatory lung pathology to inhaled endotoxin are dependent on TLR4/CD14/MD2 expression using the adapter proteins TIRAP and MyD88, while TRIF, IL-1R1 or IL-18R signalling pathways are dispensable. Further downstream in this axis of signalling, TNF blockade reduces only acute bronchoconstriction, while MAPK inhibition abrogates completely endotoxin-induced inflammation. PMID:18039275

  17. Lifestyle and Host Defense Mechanisms of the Dung Beetle, Euoniticellus intermedius: The Toll Signaling Pathway

    PubMed Central

    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. PMID:24735102

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

    PubMed

    Lee, Ju Young

    2012-01-01

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

  19. Children and Death.

    ERIC Educational Resources Information Center

    Brennan, Andrew J. J.

    Health professionals and educators should develop their abilities to educate about death and to comfort the bereaved. Due to lower death rates, the lack of philosophical religious views, and distorted perceptions of death contributed by television, death has become a mystery instead of a segment of the common experience. Particularly when a child…

  20. 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.

  1. Cervical cancer: a preventable death.

    PubMed

    Nour, Nawal M

    2009-01-01

    Cervical cancer kills 260,000 women annually, and nearly 85% of these deaths occur in developing nations, where it is the leading cause of cancer deaths in women. Disparities of health and poverty play a large role in this high mortality rate. Whereas routine Papanicolaou and human papillomavirus (HPV) testing has dramatically reduced cervical cancer deaths in Western nations, without proper infrastructure, facilities, and medical training, the rates of cervical cancer in developing nations will remain high. Studies on HPV DNA testing and the low-technology method of "screen and treat" are promising. In addition, reducing the cost and increasing the availability of HPV vaccines in developing nations brings hope and promise to the next generation of women. PMID:20111660

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

    PubMed

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

    2013-10-01

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

  3. 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

  4. 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.

  5. 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

  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. PMID:26034855

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

    PubMed

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

    2016-06-23

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

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

    PubMed

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

    1999-04-01

    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. Adjuvants containing natural and synthetic Toll-like receptor 4 ligands.

    PubMed

    Ireton, Gregory C; Reed, Steven G

    2013-07-01

    The last decade has seen an increased focus on the development of adjuvants for vaccines, and several novel adjuvants are now in licensed products or in late-stage clinical development. These advancements have been aided by the discovery of receptors and signaling pathways of the innate immune system and an increased understanding of how these innate responses influence the adaptive immune response. Successful vaccine development relies on knowledge of which adjuvants to use and the proper formulation of adjuvants and antigens to achieve safe, stable and immunogenic vaccines. In this review, the authors focus on the current use of natural and synthetic lipopolysaccharide analogues that retain their adjuvant properties with reduced toxicity compared with the parent compound for use in emerging vaccines. The authors review how these compounds initiate signal transduction through Toll-like receptor 4, insights from structure-function studies and how formulation parameters can influence their effectiveness as vaccine adjuvants.

  10. 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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-07-01

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

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

    PubMed

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

    2013-09-01

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

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

    PubMed Central

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

    2013-01-01

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

  15. Sudden Infant Death Syndrome

    MedlinePlus

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

  16. Toll-like receptor-mediated signaling cascade as a regulator of the inflammation network during alcoholic liver disease

    PubMed Central

    Ceccarelli, Sara; Nobili, Valerio; Alisi, Anna

    2014-01-01

    Chronic abuse of alcohol leads to various histological abnormalities in the liver. These are conditions collectively known as alcoholic liver disease (ALD). Currently, ALD is considered to be one of the major causes of death worldwide. An impaired intestinal barrier with related endotoxemia is among the various pathogenetic factors. This is mainly characterized by circulating levels of lipopolysaccharide (LPS), considered critical for the onset of intra-hepatic inflammation. This in turn promotes hepatocellular damage and fibrosis in ALD. Elevated levels of LPS exert their effects by binding to Toll-like receptors (TLRs) which are expressed by all liver-resident cells. The activation of TLR signaling triggers an overproduction and release of some cytokines, which promote an autocatalytic cascade of other pro-inflammatory signals. In this review, we provide an overview of the mechanisms that sustain LPS-mediated activation of TLR signaling, reporting current experimental and clinical evidence of its role during inflammation in ALD. PMID:25469012

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

    PubMed

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

    2015-08-13

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

  18. Suicide on death row.

    PubMed

    Lester, David; Tartaro, Christine

    2002-09-01

    The suicide rate on death row for the period 1976 through 1999 was found to be high (113 per 100,000 per year), some five times higher than the suicide rate for the male population of the United States. The death row suicide rate was predicted by features of the death row population (negatively with the population on death row) and by social indicators of the society as a whole (negatively with birth and divorce rates and positively with marriage rates).

  19. No life without death.

    PubMed

    Krammer, Peter H; Kamiński, Marcin; Kiessling, Michael; Gülow, Karsten

    2007-01-01

    Apoptosis-programed cell death-is the most common form of death in the body. Once apoptosis is induced, proper execution of the cell death program requires the coordinated activation and execution of multiple molecular processes. Here, we describe the pathways and the basic components of the death-inducing machinery. Since apoptosis is a key regulator of tissue homeostasis, an imbalance of apoptosis results in severe diseases like cancer, autoimmunity, and AIDS.

  20. Dreams of Death.

    ERIC Educational Resources Information Center

    Barrett, Deirdre

    1989-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2011-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2015-12-09

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

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

    PubMed Central

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

    2014-01-01

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

  7. Macrophage activation: role of toll-like receptors, nitric oxide, and nuclear factor kappa B.

    PubMed

    Billack, Blase

    2006-10-15

    Macrophages play an important role in host-defense and inflammation. In response to an immune challenge, macrophages become activated and produce proinflammatory mediators that contribute to nonspecific immunity. The mediators released by activated macrophages include: superoxide anion; reactive nitrogen intermediates, such as nitric oxide and peroxynitrite; bioactive lipids; and cytokines. Although essential to the immune response, overproduction of certain macrophage-derived mediators during an immune challenge or inflammatory response can result in tissue injury and cellular death. The present report is focused on understanding some of the molecular mechanisms used by macrophages to produce reactive nitrogen intermediates in response to immunostimulatory agents such as heat shock protein 60 and bacterial lipopolysaccharide. The role of Toll-like receptors and transcription factors such as nuclear factor kappa B (NFkappaB) in the innate immune response is also described. A basic understanding of the underlying molecular mechanisms responsible for macrophage activation should serve as a foundation for novel drug development aimed at modulating macrophage activity.

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

    PubMed

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

    2015-01-01

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

  9. Clarifying the discussion on brain death.

    PubMed

    Dagi, F T; Kaufman, R

    2001-10-01

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

  10. High serum homocysteine levels correlate with a decrease in the blood flow velocity of the ophthalmic artery in highway toll collectors.

    PubMed

    Memişoğullari, Ramazan; Yüksel, Harun; Coskun, Abdurrahman; Yüksel, Hatice Kurt; Yazgan, Omer; Bilgin, Cahit

    2007-07-01

    Highway workers, such as policemen, automotive service companies, and toll collectors, are placed at risk of the accelerated atherosclerotic process, since recent studies have suggested that exposure to exhaust particles and ambient air pollution increases carotid intima-media thickness and reduces ocular blood flow velocity. Therefore, we assessed the relationship between serum homocysteine, a potential parameter for atherosclerosis, and the ocular blood flow velocity and the resistivity index in highway toll collectors. The peak systolic and end diastolic flow velocities and the resistivity index were measured in 22 toll collectors and 24 control subjects by color Doppler ultrasonography. The resistivity index, which is an indirect measure of the atherosclerotic process, was calculated: resistivity index = (peak systolic velocity - end diastolic velocity)/peak systolic velocity. Serum homocysteine levels were determined by fluorometric high-performance liquid chromatography. In the highway toll collectors, the serum homocysteine level (14.4 +/- 4.8 micromol/l; p < 0.005) and the resistivity index of the ophthalmic artery (0.741 +/- 0.015; p < 0.05) were higher and the ophthalmic blood flow velocity (33.0 +/- 3.0 cm/s; p < 0.001) was lower than those in the controls (10.6 +/- 3.1 micromol/l; 0.728 +/- 0.023; 36.8 +/- 2.2 cm/s; respectively). There were significant correlations between the serum homocysteine level and ophthalmic artery resistivity index in both highway toll collectors (p < 0.001) and controls (p < 0.005). Exposure to exhaust particles might increase the serum homocysteine level, which in turn could lead to the decreased ocular blood flow and the increased resistivity index. PMID:17592212

  11. Toll-like Receptor 4 in CNS Pathologies

    PubMed Central

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

    2010-01-01

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

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

    PubMed

    Krieg, Arthur M

    2006-06-01

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

  13. Malaria tolerance--for whom the cell tolls?

    PubMed

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

    2006-08-01

    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 antitoxic vaccine strategies, as well as interactions between different malaria species and between malaria and other human parasites.

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2015-01-01

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

  16. 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

  17. 77 FR 67735 - Open Meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-11-13

    ... Internal Revenue Service Open Meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee... the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee will be conducted. The Taxpayer... Act, 5 U.S.C. App. (1988) that an open meeting of the Taxpayer Advocacy Panel Toll-Free Phone...

  18. 78 FR 56269 - Open Meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-12

    ... Internal Revenue Service Open Meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee... the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee will be conducted. The Taxpayer...) that an open meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee will be...

  19. 78 FR 3500 - Open Meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee.

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-01-16

    ... Internal Revenue Service Open Meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee... the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee will be conducted. The Taxpayer.... (1988) that an open meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee...

  20. 78 FR 29207 - Open Meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-17

    ... Internal Revenue Service Open Meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee... the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee will be conducted. The Taxpayer... open meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee will be held...

  1. 78 FR 69939 - Open Meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-21

    ... Internal Revenue Service Open Meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee... the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee will be conducted. The Taxpayer...) that an open meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee will be...

  2. 78 FR 11277 - Open Meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-02-15

    ... Internal Revenue Service Open Meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee... the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee will be conducted. The Taxpayer... open meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee will be held...

  3. 78 FR 36304 - Open Meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-17

    ... Internal Revenue Service Open Meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee... the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee will be conducted. The Taxpayer... open meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee will be held...

  4. 78 FR 15126 - Open Meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-08

    ... Internal Revenue Service Open Meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee... the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee will be conducted. The Taxpayer... open meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee will be held...

  5. 77 FR 74920 - Open Meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-12-18

    ... Internal Revenue Service Open Meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee... the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee will be conducted. The Taxpayer.... (1988) that an open meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee...

  6. 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... Communications § 49.4254-2 Payment for toll telephone service or telegraph service in coin-operated telephones. Where the tax on a toll telephone or radio telephone message or conversation, or a telegraph, cable,...

  7. 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... Communications § 49.4254-2 Payment for toll telephone service or telegraph service in coin-operated telephones. Where the tax on a toll telephone or radio telephone message or conversation, or a telegraph, cable,...

  8. 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…

  9. Dynamic Arginine Methylation of Tumor Necrosis Factor (TNF) Receptor-associated Factor 6 Regulates Toll-like Receptor Signaling*

    PubMed Central

    Tikhanovich, Irina; Kuravi, Sudhakiranmayi; Artigues, Antonio; Villar, Maria T.; Dorko, Kenneth; Nawabi, Atta; Roberts, Benjamin; Weinman, Steven A.

    2015-01-01

    Arginine methylation is a common post-translational modification, but its role in regulating protein function is poorly understood. This study demonstrates that, TNF receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase involved in innate immune signaling, is regulated by reversible arginine methylation in a range of primary and cultured cells. Under basal conditions, TRAF6 is methylated by the methyltransferase PRMT1, and this inhibits its ubiquitin ligase activity, reducing activation of toll-like receptor signaling. In response to toll-like receptor ligands, TRAF6 is demethylated by the Jumonji domain protein JMJD6. Demethylation is required for maximal activation of NF-κB. Loss of JMJD6 leads to reduced response, and loss of PRMT1 leads to basal pathway activation with subsequent desensitization to ligands. In human primary cells, variations in the PRMT1/JMJD6 ratio significantly correlate with TRAF6 methylation, basal activation of NF-κB, and magnitude of response to LPS. Reversible arginine methylation of TRAF6 by the opposing effects of PRMT1 and JMJD6 is, therefore, a novel mechanism for regulation of innate immune pathways. PMID:26221041

  10. Molecular characterization and expression analysis of Toll-like receptor 21 cDNA from Paralichthys olivaceus.

    PubMed

    Gao, Hong; Wu, Lian; Sun, Jin-Sheng; Geng, Xu-Yun; Pan, Bao-Ping

    2013-10-01

    Toll-like receptor (TLR) is believed to play crucial role in host defense of pathogenic microbes in innate immune system. In the present study, the full-length cDNA of Paralichthys olivaceus Toll-like receptor 21 (Po-TLR21) was cloned by homology cloning and rapid amplification of cDNA ends (RACE) technique. The Po-TLR21 cDNA sequence was 3687 bp, containing an open reading frame of 2922 bp encoding 973 amino acids. TMHMM and SMART program analysis indicated that protein contained one transmembrane domain, eighteen leucine-rich repeats (LRRs), and one Toll/IL-1 receptor homology domain (TIR). Multiple alignment analysis of the Po-TLR21 protein-coding sequence with other known TLR21 from grouper, pufferfish, zebrafish, cod, catfish, carp and chicken showed the homology of 67%, 63%, 54%, 52%, 51%, 49%, and 39%, respectively. The Po-TLR21 mRNA expression patterns were measured by real-time PCR. The results revealed that TLR21 is widely expressed in various tested healthy tissues, and highly expressed in spleen and gill. In vivo immunostimulation experiments revealed that expression of TLR21 is modulated by Vibrio anguillarum (V. anguillarum), CpG oligodeoxynucleotides (CpG ODN) and poly I:C. Moreover, the inhibitor of homodimerization of myeloid differentiation factor 88 (MyD88) could significantly reduce the up-regulation of TLR21, MyD88, and tumor necrosis factor (TNF) expression in CpG ODN or poly I:C-treated head kidney cells in vitro. These results indicate that TLR21 may be involved in the pathogen recognition in the early innate immune. PMID:23880453

  11. 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…

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

    ERIC Educational Resources Information Center

    Greyson, Bruce

    1986-01-01

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

  13. 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

  14. The Effect of an Instructional Module on Death and Dying on the Death Anxiety of Emergency Medical Technician Trainees.

    ERIC Educational Resources Information Center

    Coleman, Ted

    1993-01-01

    Examined whether instructional unit on death and dying during emergency medical technician course reduced death anxiety in trainees. Found no significant differences between treatment group (n=28) that received unit and control group (n=25) that did not on pre-, post-, or delayed-tests. Death education apparently had no more influence on death…

  15. 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

  16. 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…

  17. 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…

  18. Near-death experiences.

    PubMed

    Blackmore, S J

    1996-02-01

    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.

  19. 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…

  20. 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…

  1. 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

  2. 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

  3. Reflections on Death Education

    ERIC Educational Resources Information Center

    Riskey, Raymond J.

    1977-01-01

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

  4. SUICIDE ON DEATH ROW.

    PubMed

    Tartaro, Christine; Lester, David

    2015-12-01

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

  5. 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)

  6. 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.

  7. Natural death while driving.

    PubMed

    Oström, M; Eriksson, A

    1987-07-01

    Of sudden natural deaths while driving, 126 occurred during 1980 through 1985 in the northern half of Sweden. The mean age of the 69 car driver victims was 59 years, considerably higher than that of traumatic car deaths, and all but 2 were males. The mean age of 57 operators of other vehicles was 66 years, and of these, 6 were women. Seven car drivers were stricken during commercial employment. Most accidents occurred during daytime and the distribution of the weekdays was fairly even. Ischemic heart disease accounted for 112 deaths, and other cardiovascular diseases for an additional 9 deaths. Only 1/5 of the victims experienced previous symptoms of disease. Out of at least 31 other persons at risk in the car deaths, only 2 passengers suffered minor injuries. The trauma in the deceased was in most cases minor in both car and other vehicle deaths. Property damage was also minimal. At least 1/3 of the drivers were able to stop the car before becoming unconscious. In none of the car cases was alcohol detected in the blood, while alcohol was identified in at least 2 of the other vehicle victims. The findings here agree with previous studies that natural deaths at the wheel are fairly uncommon, and that the risk for other persons is not significant. The value of adequate postmortem examinations of drivers dying in traffic is stressed--natural deaths can otherwise be overlooked. PMID:3612079

  8. 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…

  9. 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

  10. Antiinfective applications of toll-like receptor 9 agonists.

    PubMed

    Krieg, Arthur M

    2007-07-01

    The innate immune system detects pathogens by the presence of highly conserved pathogen-expressed molecules, which trigger host immune defenses. Toll-like receptor (TLR) 9 detects unmethylated CpG dinucleotides in bacterial or viral DNA, and can be stimulated for therapeutic applications with synthetic oligodeoxynucleotides containing immune stimulatory "CpG motifs." TLR9 activation induces both innate and adaptive immunity. The TLR9-induced innate immune activation can be applied in the prevention or treatment of infectious diseases, and the adaptive immune-enhancing effects can be harnessed for improving vaccines. This article highlights the current understanding of the mechanism of action of CpG oligodeoxynucleotides, and provides an overview of the preclinical data and early human clinical trial results, applying these TLR9 agonists in the field of infectious diseases. PMID:17607015

  11. Toll-like receptors are key players in neurodegeneration

    PubMed Central

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

    2011-01-01

    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. PMID:21616174

  12. Unique features of chicken Toll-like receptors.

    PubMed

    Keestra, A Marijke; de Zoete, Marcel R; Bouwman, Lieneke I; Vaezirad, Mahdi M; van Putten, Jos P M

    2013-11-01

    Toll-like receptors (TLRs) are a major class of innate immune pattern recognition receptors that have a key role in immune homeostasis and the defense against infections. The research explosion that followed the discovery of TLRs more than a decade ago has boosted fundamental knowledge on the function of the immune system and the resistance against disease, providing a rational for clinical modulation of the immune response. In addition, the conserved nature of the ancient TLR system throughout the animal kingdom has enabled a comparative biology approach to understand the evolution, structural architecture, and function of TLRs. In the present review we focus on TLR biology in the avian species, and, especially, on the unique functional properties of the chicken TLR repertoire. PMID:23628643

  13. 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

  14. Death in Denmark.

    PubMed

    Evans, M

    1990-12-01

    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.

  15. [Congenital components of immunity: Toll-like receptors in the normal state and in immunopathology].

    PubMed

    Koval'chuk, L V; Khoreva, M V; Varivoda, A S

    2005-01-01

    This review deals with rapidly accumulating information on a highly important components of the congenital immune system: Toll-like receptors playing a leading role in the recognition of microbial patterns. The data on the main structural and functional features of Toll-like receptors and their distribution in the body are summarized. The main signal paths are characterized and the key molecules which take part in the transduction are pointed out. Special attention is paid to the activating action of lipopolysaccharides through TLR4. Pathological processes developing as the result of damages in the structure and function of Toll-like receptors in humans and experimental animals are determined.

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

    PubMed

    Tangmansakulchai, Kulvadee; Abubakar, Zuroida; Kitiyanant, Narisorn; Suwanjang, Wilasinee; Leepiyasakulchai, Chaniya; Govitrapong, Piyarat; Chetsawang, Banthit

    2016-09-01

    Calpain is an intracellular Ca(2+)-dependent protease, and the activation of calpain has been implicated in neurodegenerative diseases. Calpain activity can be regulated by calpastatin, an endogenous specific calpain inhibitor. Several lines of evidence have demonstrated a potential role of calpastatin in preventing calpain-mediated pathogenesis. Additionally, several studies have revealed that calpain activation and mitochondrial damage are involved in the cell death process; however, recent evidence has not clearly indicated a neuroprotective mechanism of calpastatin against calpain-dependent mitochondrial impairment in the process of neuronal cell death. Therefore, the purpose of this study was to investigate the potential ability of calpastatin to inhibit calpain activation and mitochondrial impairment in oxidative stress-induced neuron degeneration. Calpastatin was stably overexpressed in human neuroblastoma SH-SY5Y cells. In non-calpastatin overexpressing SH-SY5Y cells, hydrogen peroxide significantly decreased cell viability, superoxide dismutase activity, mitochondrial membrane potential, ATP production and mitochondrial fusion protein (Opa1) levels in the mitochondrial fraction but increased reactive oxygen species formation, calpain and calcineurin activation, mitochondrial fission protein (Fis1 and Drp1) levels in the mitochondrial fraction and apoptotic cells. Nevertheless, these toxic effects were abolished in hydrogen peroxide-treated calpastatin-overexpressing SH-SY5Y cells. The results of the present study demonstrate the potential ability of calpastatin to diminish calpain and calcineurin activation and mitochondrial impairment in neurons that are affected by oxidative damage. PMID:27453331

  17. Effects of Death Education on Conscious and Unconscious Death Anxiety.

    ERIC Educational Resources Information Center

    Hayslip, Bert, Jr.; And Others

    1994-01-01

    Adults (n=162) varying in extent of participation in didactic or experiential forms of death education versus those who had no such exposure to death and dying-related issues completed measures of conscious and unconscious death fears. Findings suggest that didactic death education was effective in altering death anxiety, although effects were…

  18. Podocyte apoptosis is prevented by blocking the Toll-like receptor pathway

    PubMed Central

    Saurus, P; Kuusela, S; Lehtonen, E; Hyvönen, M E; Ristola, M; Fogarty, C L; Tienari, J; Lassenius, M I; Forsblom, C; Lehto, M; Saleem, M A; Groop, P-H; Holthöfer, H; Lehtonen, S

    2015-01-01

    High serum lipopolysaccharide (LPS) activity in normoalbuminuric patients with type 1 diabetes (T1D) predicts the progression of diabetic nephropathy (DN), but the mechanisms behind this remain unclear. We observed that treatment of cultured human podocytes with sera from normoalbuminuric T1D patients with high LPS activity downregulated 3-phosphoinositide-dependent kinase-1 (PDK1), an activator of the Akt cell survival pathway, and induced apoptosis. Knockdown of PDK1 in cultured human podocytes inhibited antiapoptotic Akt pathway, stimulated proapoptotic p38 MAPK pathway, and increased apoptosis demonstrating an antiapoptotic role for PDK1 in podocytes. Interestingly, PDK1 was downregulated in the glomeruli of diabetic rats and patients with type 2 diabetes before the onset of proteinuria, further suggesting that reduced expression of PDK1 associates with podocyte injury and development of DN. Treatment of podocytes in vitro and mice in vivo with LPS reduced PDK1 expression and induced apoptosis, which were prevented by inhibiting the Toll-like receptor (TLR) signaling pathway with the immunomodulatory agent GIT27. Our data show that LPS downregulates the cell survival factor PDK1 and induces podocyte apoptosis, and that blocking the TLR pathway with GIT27 may provide a non-nephrotoxic means to prevent the progression of DN. PMID:25950482

  19. Paclitaxel induces acute pain via directly activating toll like receptor 4.

    PubMed

    Yan, Xisheng; Maixner, Dylan W; Yadav, Ruchi; Gao, Mei; Li, Pei; Bartlett, Michael G; Weng, Han-Rong

    2015-12-01

    Paclitaxel, a powerful anti-neoplastic drug, often causes pathological pain, which significantly reduces the quality of life in patients. Paclitaxel-induced pain includes pain that occurs immediately after paclitaxel treatment (paclitaxel-associated acute pain syndrome, P-APS) and pain that persists for weeks to years after cessation of paclitaxel treatment (paclitaxel induced chronic neuropathic pain). Mechanisms underlying P-APS remain unknown. In this study, we found that paclitaxel causes acute pain in rodents in a dose-dependent manner. The paclitaxel-induced acute pain occurs within 2 hrs after a single intravenous injection of paclitaxel. This is accompanied by low levels of paclitaxel penetrating into the cerebral spinal fluid and spinal dorsal horn. We demonstrated that an intrathecal injection of paclitaxel induces mechanical allodynia in a dose-dependent manner. Paclitaxel causes activation of toll like receptor 4 (TLR4) in the spinal dorsal horn and dorsal root ganglions. Through activating TLR4, paclitaxel increases glutamatergic synaptic activities and reduces glial glutamate transporter activities in the dorsal horn. Activations of TLR4 are necessary in the genesis of paclitaxel-induced acute pain. The cellular and molecular signaling pathways revealed in this study could provide rationales for the development of analgesics and management strategies for P-APS in patients. PMID:25775962

  20. Age-associated inflammation and Toll-like receptor dysfunction prime the lungs for pneumococcal pneumonia

    PubMed Central

    Hinojosa, Ernesto; Boyd, Angela R.; Orihuela, Carlos J.

    2011-01-01

    Background Aging is associated with increased inflammation and risk for community-acquired pneumonia (CAP). Streptococcus pneumoniae co-opts the NFkB-regulated proteins Polymeric immunoglobulin receptor (pIgR) and Platelet-activating factor receptor (PAFr) to attach and invade cells. We sought to determine if aging and chronic inflammation was associated with increased pIgR & PAFr in the lungs and increased susceptibility to S. pneumoniae. Methods Lung protein and mRNA levels were quantitated using Western blot and quantitative PCR. NFkB activation was measured by electrophoretic mobility shift assay. Cytokine levels were measured by cytometric bead analysis. To model chronic inflammation mice were implanted with osmotic pumps that delivered tumor necrosis factor (TNF)α. Results Aged mice and those infused with TNFα had increased levels of pIgR & PAFr in their lungs and were more susceptible to S. pneumoniae. During pneumonia, aged mice had reduced levels of pIgR & PAFr and less NFkB activation despite greater bacterial burden. We determined that aged mice had decreased amounts of lung Toll-like receptors (TLR)-1, 2, and 4 and reduced capacity to respond to S. pneumoniae with pro-inflammatory cytokine production. Conclusions Aged mice, and potentially elderly humans, are more susceptible to pneumonia because of a priming effect of chronic inflammation and TLR dysfunction. PMID:19586419

  1. [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.

  2. 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

  3. Unnatural sudden infant death

    PubMed Central

    Meadow, R.

    1999-01-01

    AIM—To identify features to help paediatricians differentiate between natural and unnatural infant deaths.
METHOD—Clinical features of 81 children judged by criminal and family courts to have been killed by their parents were studied. Health and social service records, court documents, and records from meetings with parents, relatives, and social workers were studied.
RESULTS—Initially, 42 children had been certified as dying from sudden infant death syndrome (SIDS), and 29 were given another cause of natural death. In 24 families, more than one child died; 58died before the age of 6 months and most died in the afternoon or evening. Seventy per cent had experienced unexplained illnesses; over half were admitted to hospital within the previous month, and 15 had been discharged within 24 hours of death. The mother, father, or both were responsible for death in 43, five, and two families, respectively. Most homes were disadvantaged—no regular income, receiving income support—and mothers smoked. Half the perpetrators had a history of somatising or factitious disorder. Death was usually by smothering and 43% of children had bruises, petechiae, or blood on the face.
CONCLUSIONS—Although certain features are indicative of unnatural infant death, some are also associated with SIDS. Despite the recent reduction in numbers of infants dying suddenly, inadequacies in the assessment of their deaths exist. Until a thorough postmortem examination is combined with evaluation of the history and circumstances of death by an experienced paediatrician, most cases of covert fatal abuse will go undetected. The term SIDS requires revision or abandonment.

 PMID:10325752

  4. 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

  5. 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

  6. Eaten to death

    PubMed Central

    Nelson, Charles; Baehrecke, Eric H.

    2014-01-01

    Macro-autophagy (hereafter referred to as autophagy) delivers cytoplasmic material to the lysosome for degradation, and has been implicated in many cellular processes, including stress, infection, survival, and death. While the regulation and role that autophagy plays in stress, infection, and survival is apparent, the regulation of and role that autophagy has during cell death remains relatively unclear. In this review, we highlight what is known about the role that autophagy can play during physiological cell death, and discuss the implications of better understanding cellular destruction that involves autophagy. PMID:25323556

  7. [Brain death and thanatology].

    PubMed

    Zwierlein, E

    1993-09-01

    New technologies in medicine dramatically open a twilight-zone of ignorance between life and death. The argument shows that the present definition of brain death as the death of a human person is a convention with a specific philosophy behind. You will meet the problem with more accuracy when referring to an ethics of intransparence that allows an individual decision with respect to certain qualified conditions. Only from this starting-point the informed ex ante consent for an organ donation seems to become the only conclusive but at the same time justified decision.

  8. Death writ large.

    PubMed

    Kastenbaum, Robert

    2004-05-01

    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 processes. Obstacles to developing a systematic macrothanatology are identified. The 9-11-01 terrorist attacks on America are discussed as an example of mass death with complex correlates and consequences. Other examples are taken from the realms of war, disease, disaster, and extinction.

  9. Reduction of avian influenza virus shedding by administration of Toll-like receptor ligands to chickens.

    PubMed

    Barjesteh, Neda; Shojadoost, Bahram; Brisbin, Jennifer T; Emam, Mehdi; Hodgins, Douglas C; Nagy, Éva; Sharif, Shayan

    2015-09-11

    Avian influenza viruses (AIV) are of concern to the poultry industry. Outbreaks of AIV highlight the urgent need for effective control measures. Prophylactic strategies should be explored that rapidly elicit immunity against the virus. Toll-like receptors (TLRs) are innate immune molecules that can induce anti-viral responses, therefore the application of TLR ligands as prophylactic agents in chickens is gaining more attention. We hypothesized that treatment of chickens with TLR ligands reduces the shedding of AIV from infected birds. In addition, the effects of TLR ligand dose and route of administration on the efficiency of TLR ligands to reduce AIV shedding were examined. Chickens were treated with TLR2, 4, 7 and 21 ligands using different doses and routes of administration, 18h before AIV infection. Moreover, the expression of several candidate genes, such as type I interferons, PKR, OAS, viperin and IFITM3 was quantified at 3, 8 and 18h post-treatment with TLR ligands. The results revealed that route of administration and dosage affect the efficacy of TLR ligands to reduce virus shedding. Furthermore, varying effects were observed when different ligands were applied. Our results demonstrated that all TLR ligand treatments reduced AIV shedding, with the CpG-ODN 1826 being the most efficacious to reduce oral virus shedding, whereas LPS from Escherichia coli 026:B6 resulted in the largest reduction in cloacal virus shedding. Moreover, TLR ligands induced the expression of genes involved in antiviral responses such as type I interferons and interferon-stimulated genes in chicken trachea and cecal tonsils. These results raise the possibility of treatment of chickens with TLR ligands as anti-viral agents.

  10. Arabidopsis ACCELERATED CELL DEATH2 modulates programmed cell death.

    PubMed

    Yao, Nan; Greenberg, Jean T

    2006-02-01

    The Arabidopsis thaliana chloroplast protein ACCELERATED CELL DEATH2 (ACD2) modulates the amount of programmed cell death (PCD) triggered by Pseudomonas syringae and protoporphyrin IX (PPIX) treatment. In vitro, ACD2 can reduce red chlorophyll catabolite, a chlorophyll derivative. We find that ACD2 shields root protoplasts that lack chlorophyll from light- and PPIX-induced PCD. Thus, chlorophyll catabolism is not obligatory for ACD2 anti-PCD function. Upon P. syringae infection, ACD2 levels and localization change in cells undergoing PCD and in their close neighbors. Thus, ACD2 shifts from being largely in chloroplasts to partitioning to chloroplasts, mitochondria, and, to a small extent, cytosol. ACD2 protects cells from PCD that requires the early mitochondrial oxidative burst. Later, the chloroplasts of dying cells generate NO, which only slightly affects cell viability. Finally, the mitochondria in dying cells have dramatically altered movements and cellular distribution. Overproduction of both ACD2 (localized to mitochondria and chloroplasts) and ascorbate peroxidase (localized to chloroplasts) greatly reduces P. syringae-induced PCD, suggesting a pro-PCD role for mitochondrial and chloroplast events. During infection, ACD2 may bind to and/or reduce PCD-inducing porphyrin-related molecules in mitochondria and possibly chloroplasts that generate reactive oxygen species, cause altered organelle behavior, and activate a cascade of PCD-inducing events.

  11. 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.…

  12. Hour of Exercise a Day May Offset Sitting's Toll on Health

    MedlinePlus

    ... news/fullstory_160102.html Hour of Exercise a Day May Offset Sitting's Toll on Health Study found ... News) -- Just one hour of physical activity a day -- something as simple as a brisk walk or ...

  13. 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 ...

  14. 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)

  15. 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)

  16. Death and Wheatgrass

    ERIC Educational Resources Information Center

    Coleman, Jon T.

    2005-01-01

    The death of his father prompts the author and university professor to reflect on the acts of grieving and teaching. He offers a tribute to his deceased father while commenting on the importance of teaching in his life.

  17. Autoerotic deaths: four cases.

    PubMed

    Cooke, C T; Cadden, G A; Margolius, K A

    1994-07-01

    We describe the circumstances and post mortem medical findings of 4 unusual fatalities where death occurred during autoerotic practice. Three cases occurred in young to middle-aged men--hanging, electrocution and inhalation of a zucchini. The manner of death in each was accidental. The fourth case was an elderly man who died of ischemic heart disease, apparently whilst masturbating with a vacuum cleaner and a hair dryer.

  18. 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

  19. Autophagic cell death exists

    PubMed Central

    Clarke, Peter G.H.; Puyal, Julien

    2012-01-01

    The term autophagic cell death (ACD) initially referred to cell death with greatly enhanced autophagy, but is increasingly used to imply a death-mediating role of autophagy, as shown by a protective effect of autophagy inhibition. In addition, many authors require that autophagic cell death must not involve apoptosis or necrosis. Adopting these new and restrictive criteria, and emphasizing their own failure to protect human osteosarcoma cells by autophagy inhibition, the authors of a recent Editor’s Corner article in this journal argued for the extreme rarity or nonexistence of autophagic cell death. We here maintain that, even with the more stringent recent criteria, autophagic cell death exists in several situations, some of which were ignored by the Editor’s Corner authors. We reject their additional criterion that the autophagy in ACD must be the agent of ultimate cell dismantlement. And we argue that rapidly dividing mammalian cells such as cancer cells are not the most likely situation for finding pure ACD. PMID:22652592

  20. 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

  1. 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.

  2. Characterization, expression analysis and localization pattern of toll-like receptor 1 (tlr1) and toll-like receptor 2 (tlr2) genes in grass carp Ctenopharyngodon idella.

    PubMed

    He, L B; Wang, H; Luo, L F; Jiang, S H; Liu, L Y; Li, Y M; Huang, R; Liao, L J; Zhu, Z Y; Wang, Y P

    2016-08-01

    In this study, the toll-like receptor 1 (tlr1) and toll-like receptor 2 (tlr2) genes of grass carp Ctenopharyngodon idella were cloned and characterized. tlr1 and tlr2 were found to be highly expressed in immune system organs such as spleen, middle kidney and heart kidney. The expression level of tlr1 and tlr2 was found to be up-regulated at the later stage of viral challenge process. Moreover, subcellular localization indicated that Tlr1 and Tlr2 shared similar localization pattern and both of them may locate in the plasma membrane of transfected cells. PMID:27221024

  3. Toll-like receptor signaling in colorectal cancer: carcinogenesis to cancer therapy.

    PubMed

    Li, Ting-Ting; Ogino, Shuji; Qian, Zhi Rong

    2014-12-21

    Toll-like receptors (TLRs) are germ line encoded innate immune sensors that recognize conserved microbial structures and host alarmins, and signal expression of major histocompatibility complex proteins, costimulatory molecules, and inflammatory mediators by macrophages, neutrophils, dendritic cells, and other cell types. These protein receptors are characterized by their ability to respond to invading pathogens promptly by recognizing particular TLR ligands, including flagellin and lipopolysaccharide of bacteria, nucleic acids derived from viruses, and zymosan of fungi. There are 2 major TLR pathways; one is mediated by myeloid differentiation factor 88 (MYD88) adaptor proteins, and the other is independent of MYD88. The MYD88-dependent pathway involves early-phase activation of nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-κB1) and all the TLRs, except TLR3, have been shown to activate this pathway. TLR3 and TLR4 act via MYD88-independent pathways with delayed activation of NF-κB signaling. TLRs play a vital role in activating immune responses. TLRs have been shown to mediate inflammatory responses and maintain epithelial barrier homeostasis, and are highly likely to be involved in the activation of a number of pathways following cancer therapy. Colorectal cancer (CRC) is one of the most common cancers, and accounts for almost half a million deaths annually worldwide. Inflammation is considered a risk factor for many common malignancies including cancers of the colorectum. The key molecules involved in inflammation-driven carcinogenesis include TLRs. As sensors of cell death and tissue remodeling, TLRs may have a universal role in cancer; stimulation of TLRs to activate the innate immune system has been a legitimate therapeutic strategy for some years. TLRs 3/4/7/8/9 are all validated targets for cancer therapy, and a number of companies are developing agonists and vaccine adjuvants. On the other hand, antagonists may favor inhibition

  4. The Drosophila Toll pathway controls but does not clear Candida glabrata infections.

    PubMed

    Quintin, Jessica; Asmar, Joelle; Matskevich, Alexey A; Lafarge, Marie-Céline; Ferrandon, Dominique

    2013-03-15

    The pathogenicity of Candida glabrata to patients remains poorly understood for lack of convenient animal models to screen large numbers of mutants for altered virulence. In this study, we explore the minihost model Drosophila melanogaster from the dual perspective of host and pathogen. As in vertebrates, wild-type flies contain C. glabrata systemic infections yet are unable to kill the injected yeasts. As for other fungal infections in Drosophila, the Toll pathway restrains C. glabrata proliferation. Persistent C. glabrata yeasts in wild-type flies do not appear to be able to take shelter in hemocytes from the action of the Toll pathway, the effectors of which remain to be identified. Toll pathway mutant flies succumb to injected C. glabrata. In this immunosuppressed background, cellular defenses provide a residual level of protection. Although both the Gram-negative binding protein 3 pattern recognition receptor and the Persephone protease-dependent detection pathway are required for Toll pathway activation by C. glabrata, only GNBP3, and not psh mutants, are susceptible to the infection. Both Candida albicans and C. glabrata are restrained by the Toll pathway, yet the comparative study of phenoloxidase activation reveals a differential activity of the Toll pathway against these two fungal pathogens. Finally, we establish that the high-osmolarity glycerol pathway and yapsins are required for virulence of C. glabrata in this model. Unexpectedly, yapsins do not appear to be required to counteract the cellular immune response but are needed for the colonization of the wild-type host.

  5. Toll-Like Receptor 4 Is a Regulator of Monocyte and Electroencephalographic Responses to Sleep Loss

    PubMed Central

    Wisor, Jonathan P.; Clegern, William C.; Schmidt, Michelle A.

    2011-01-01

    Study Objectives: Sleep loss triggers changes in inflammatory signaling pathways in the brain and periphery. The mechanisms that underlie these changes are ill-defined. The Toll-like receptor 4 (TLR4) activates inflammatory signaling cascades in response to endogenous and pathogen-associated ligands known to be elevated in association with sleep loss. TLR4 is therefore a possible mediator of some of the inflammation-related effects of sleep loss. Here we describe the baseline electroencephalographic sleep phenotype and the biochemical and electroencephalographic responses to sleep loss in TLR4-deficient mice. Design, Measurements and Results: TLR4-deficient mice and wild type controls were subjected to electroencephalographic and electromyographic recordings during spontaneous sleep/wake cycles and during and after sleep restriction sessions of 3, 6, and 24-h duration, during which sleep was disrupted by an automated sleep restriction system. Relative to wild type control mice, TLR4-deficient mice exhibited an increase in the duration of the primary daily waking bout occurring at dark onset in a light/dark cycle. The amount of time spent in non-rapid eye movement sleep by TLR4-deficient mice was reduced in proportion to increased wakefulness in the hours immediately after dark onset. Subsequent to sleep restriction, EEG measures of increased sleep drive were attenuated in TLR4-deficient mice relative to wild-type mice. TLR4 was enriched 10-fold in brain cells positive for the cell surface marker CD11b (cells of the monocyte lineage) relative to CD11b-negative cells in wild type mouse brains. To assess whether this population was affected selectively by TLR4 knockout, flow cytometry was used to count F4/80- and CD45-positive cells in the brains of sleep deprived and time of day control mice. While wild-type mice exhibited a significant reduction in the number of CD11b-positive cells in the brain after 24-h sleep restriction, TLR4-deficient mice did not. Conclusion

  6. [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.

  7. 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

  8. 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

  9. The CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy.

    PubMed

    Tanga, Flobert Y; Nutile-McMenemy, Nancy; DeLeo, Joyce A

    2005-04-19

    Neuropathic pain remains a prevalent and persistent clinical problem because of our incomplete understanding of its pathogenesis. This study demonstrates for the first time, to our knowledge, a critical role for CNS innate immunity by means of microglial Toll-like receptor 4 (TLR4) in the induction phase of behavioral hypersensitivity in a mouse and rat model of neuropathy. We hypothesized that after L5 nerve transection, CNS neuroimmune activation and subsequent cytokine expression are triggered by the stimulation of microglial membrane-bound TLR4. To test this hypothesis, experiments were undertaken to assess tactile and thermal hypersensitivity in genetically altered (i.e., TLR4 knockout and point-mutant) mice after L5 nerve transection. In a complementary study, TLR4 antisense oligodeoxynucleotide (ODN) was administered intrathecally to L5 spinal nerve injured rats to reduce the expression of spinal TLR4. Both the genetically altered mice and the rats treated with TLR4 antisense ODN displayed significantly attenuated behavioral hypersensitivity and decreased expression of spinal microglial markers and proinflammatory cytokines as compared with their respective control groups. This finding shows that TLR4 contributes to the initiation of CNS neuroimmune activation after L5 nerve transection. Further understanding of this early, specific, innate CNS/microglial response and how it leads to sustained glial/neuronal hypersensitivity may point to new therapies for the prevention and treatment of neuropathic pain syndromes. PMID:15809417

  10. The CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy

    PubMed Central

    Tanga, Flobert Y.; Nutile-McMenemy, Nancy; DeLeo, Joyce A.

    2005-01-01

    Neuropathic pain remains a prevalent and persistent clinical problem because of our incomplete understanding of its pathogenesis. This study demonstrates for the first time, to our knowledge, a critical role for CNS innate immunity by means of microglial Toll-like receptor 4 (TLR4) in the induction phase of behavioral hypersensitivity in a mouse and rat model of neuropathy. We hypothesized that after L5 nerve transection, CNS neuroimmune activation and subsequent cytokine expression are triggered by the stimulation of microglial membrane-bound TLR4. To test this hypothesis, experiments were undertaken to assess tactile and thermal hypersensitivity in genetically altered (i.e., TLR4 knockout and point-mutant) mice after L5 nerve transection. In a complementary study, TLR4 antisense oligodeoxynucleotide (ODN) was administered intrathecally to L5 spinal nerve injured rats to reduce the expression of spinal TLR4. Both the genetically altered mice and the rats treated with TLR4 antisense ODN displayed significantly attenuated behavioral hypersensitivity and decreased expression of spinal microglial markers and proinflammatory cytokines as compared with their respective control groups. This finding shows that TLR4 contributes to the initiation of CNS neuroimmune activation after L5 nerve transection. Further understanding of this early, specific, innate CNS/microglial response and how it leads to sustained glial/neuronal hypersensitivity may point to new therapies for the prevention and treatment of neuropathic pain syndromes. PMID:15809417

  11. 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.

  12. Does superstition help? A study of the role of superstitions and death beliefs on death anxiety amongst Chinese undergraduates in Hong Kong.

    PubMed

    Wong, Shui Hung

    2012-01-01

    Past research has shown that traditional Chinese death beliefs, which mostly consisted of superstitious thoughts, are related to death anxiety. However, other studies have shown that superstitions may help people cope with uncertainty and, therefore, reduce uncertainty-induced anxiety. The role of superstitions, whether related to heightened death anxiety or reduced death anxiety, is unclear. This study attempted to address the knowledge gap by examining the relationships among superstitions and Chinese death beliefs on death anxiety in the Chinese context. One hundred twenty-four undergraduates in Hong Kong completed measures of superstition (R-PBS), death anxiety (MFODS), and Chinese death beliefs scale. Superstition was found to be predictor of death anxiety, as expected. With superstitions highly prevalent in Chinese societies, the study has practical implications in end-of-life care, bereavement support, and death education in the Chinese context.

  13. Constraint and Adaptation in newt Toll-Like Receptor Genes

    PubMed Central

    Babik, Wiesław; Dudek, Katarzyna; Fijarczyk, Anna; Pabijan, Maciej; Stuglik, Michał; Szkotak, Rafał; Zieliński, Piotr

    2015-01-01

    Acute die-offs of amphibian populations worldwide have been linked to the emergence of viral and fungal diseases. Inter and intraspecific immunogenetic differences may influence the outcome of infection. Toll-like receptors (TLRs) are an essential component of innate immunity and also prime acquired defenses. We report the first comprehensive assessment of TLR gene variation for urodele amphibians. The Lissotriton newt TLR repertoire includes representatives of 13 families and is compositionally most similar to that of the anuran Xenopus. Both ancient and recent gene duplications have occurred in urodeles, bringing the total number of TLR genes to at least 21. Purifying selection has predominated the evolution of newt TLRs in both long (∼70 Ma) and medium (∼18 Ma) timescales. However, we find evidence for both purifying and positive selection acting on TLRs in two recently diverged (2–5 Ma) allopatric evolutionary lineages (Lissotriton montandoni and L. vulgaris graecus). Overall, both forms of selection have been stronger in L. v. graecus, while constraint on most TLR genes in L. montandoni appears relaxed. The differences in selection regimes are unlikely to be biased by demographic effects because these were controlled by means of a historical demographic model derived from an independent data set of 62 loci. We infer that TLR genes undergo distinct trajectories of adaptive evolution in closely related amphibian lineages, highlight the potential of TLRs to capture the signatures of different assemblages of pathogenic microorganisms, and suggest differences between lineages in the relative roles of innate and acquired immunity. PMID:25480684

  14. 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.

  15. Subverting Toll-Like Receptor Signaling by Bacterial Pathogens

    PubMed Central

    McGuire, Victoria A.; Arthur, J. Simon C.

    2015-01-01

    Pathogenic bacteria are detected by pattern-recognition receptors (PRRs) expressed on innate immune cells, which activate intracellular signal transduction pathways to elicit an immune response. Toll-like receptors are, perhaps, the most studied of the PRRs and can activate the mitogen-activated protein kinase (MAPK) and Nuclear Factor-κB (NF-κB) pathways. These pathways are critical for mounting an effective immune response. In order to evade detection and promote virulence, many pathogens subvert the host immune response by targeting components of these signal transduction pathways. This mini-review highlights the diverse mechanisms that bacterial pathogens have evolved to manipulate the innate immune response, with a particular focus on those that target MAPK and NF-κB signaling pathways. Understanding the elaborate strategies that pathogens employ to subvert the immune response not only highlights the importance of these proteins in mounting effective immune responses, but may also identify novel approaches for treatment or prevention of infection. PMID:26648936

  16. 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

  17. Toll-like receptors: potential targets for lupus treatment.

    PubMed

    Wu, Yan-wei; Tang, Wei; Zuo, Jian-ping

    2015-12-01

    Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the loss of tolerance to self-nuclear antigens. Accumulating evidence shows that Toll-like receptors (TLRs), previously proven to be critical for host defense, are implicated in the pathogenesis of autoimmune diseases by recognition of self-molecules. Genome-wide association studies, experimental mouse models and clinical sample studies have provided evidence for the involvement of TLRs, including TLR2/4, TLR5, TLR3 and TLR7/8/9, in SLE pathogenesis. A number of downstream proteins in the TLR signaling cascade (such as MyD88, IRAKs and IFN-α) are identified as potential therapeutic targets for SLE treatment. Numerous antagonists targeting TLR signaling, including oligonucleotides, small molecular inhibitors and antibodies, are currently under preclinical studies or clinical trials for SLE treatment. Moreover, the emerging new manipulation of TLR signaling by microRNA (miRNA) regulation shows promise for the future treatment of SLE.

  18. Computational Approaches to Toll-Like Receptor 4 Modulation.

    PubMed

    Billod, Jean-Marc; Lacetera, Alessandra; Guzmán-Caldentey, Joan; Martín-Santamaría, Sonsoles

    2016-01-01

    Toll-like receptor 4 (TLR4), along with its accessory protein myeloid differentiation factor 2 (MD-2), builds a heterodimeric complex that specifically recognizes lipopolysaccharides (LPS), which are present on the cell wall of Gram-negative bacteria, activating the innate immune response. Some TLR4 modulators are undergoing preclinical and clinical evaluation for the treatment of sepsis, inflammatory diseases, cancer and rheumatoid arthritis. Since the relatively recent elucidation of the X-ray crystallographic structure of the extracellular domain of TLR4, research around this fascinating receptor has risen to a new level, and thus, new perspectives have been opened. In particular, diverse computational techniques have been applied to decipher some of the basis at the atomic level regarding the mechanism of functioning and the ligand recognition processes involving the TLR4/MD-2 system at the atomic level. This review summarizes the reported molecular modeling and computational studies that have recently provided insights into the mechanism regulating the activation/inactivation of the TLR4/MD-2 system receptor and the key interactions modulating the molecular recognition process by agonist and antagonist ligands. These studies have contributed to the design and the discovery of novel small molecules with promising activity as TLR4 modulators. PMID:27483231

  19. 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.

  20. Allergens and Activation of the Toll-Like Receptor Response.

    PubMed

    Monie, Tom P; Bryant, Clare E

    2016-01-01

    Pattern recognition receptors (PRRs) provide a crucial function in the detection of exogenous and endogenous danger signals. The Toll-like receptors (TLRs) were the first family of PRRs to be discovered and have been extensively studied since. Whilst TLRs remain the best characterized family of PRRs there is still much to be learnt about their mode of activation and the mechanisms of signal transduction they employ. Much of our understanding of these processes has been gathered through the use of cell based signaling assays utilizing specific gene-reporters or cytokine secretion based readouts. More recently it has become apparent that the repertoire of ligands recognized by these receptors may be wider than originally assumed and that their activation may be sensitized, or at least modulated by the presence of common household allergens such as the cat dander protein Fel d 1, or the house dust mite allergen Der p 2. In this chapter we provide an overview of the cell culture and stimulation processes required to study TLR signaling in HEK293 based assays and in bone marrow-derived macrophages. PMID:26803639

  1. Chapter 3. Toll-like receptors (TLRs) in Brain Abscess

    PubMed Central

    Esen, Nilufer; Kielian, Tammy

    2014-01-01

    Brain abscesses arise from a localized parenchymal infection, typically elicited by pyogenic bacteria such as S. aureus. Despite improvements in detection and treatment strategies, brain abscesses continue to occur, with an increased prevalence in developing countries and immune compromised patients. Adding to the seriousness of these infections is the recent emergence of antibiotic-resistant strains of bacteria, which are becoming more commonly associated with brain abscesses. Recent studies using a mouse experimental brain abscess model have revealed a complex role for Toll-like receptors (TLRs) in disease pathogenesis. Interestingly, TLR2 has limited impact on the innate immune response during the acute stage of brain abscess formation induced by S. aureus but influences adaptive immunity. In contrast, mice deficient in MyD88, a central adaptor molecule for the majority of TLRs in addition to the IL-1R and IL-18R, demonstrate severe defects in innate immunity coupled with exaggerated tissue destruction. It is envisioned that understanding the roles for TLRs in both resident CNS glia as well as infiltrating immune cells will provide insights as to how the immune response to bacterial infection can be tailored to achieve effective pathogen destruction without inducing excessive bystander damage of surrounding non-infected brain parenchyma. A discussion of recent findings in this field is presented along with outstanding questions and the concept of a pathogen-necrosis-autoantigen triad for the amplification for TLR signaling is introduced. PMID:19688327

  2. 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.

  3. Toll-like receptors: potential targets for lupus treatment

    PubMed Central

    Wu, Yan-wei; Tang, Wei; Zuo, Jian-ping

    2015-01-01

    Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the loss of tolerance to self-nuclear antigens. Accumulating evidence shows that Toll-like receptors (TLRs), previously proven to be critical for host defense, are implicated in the pathogenesis of autoimmune diseases by recognition of self-molecules. Genome-wide association studies, experimental mouse models and clinical sample studies have provided evidence for the involvement of TLRs, including TLR2/4, TLR5, TLR3 and TLR7/8/9, in SLE pathogenesis. A number of downstream proteins in the TLR signaling cascade (such as MyD88, IRAKs and IFN-α) are identified as potential therapeutic targets for SLE treatment. Numerous antagonists targeting TLR signaling, including oligonucleotides, small molecular inhibitors and antibodies, are currently under preclinical studies or clinical trials for SLE treatment. Moreover, the emerging new manipulation of TLR signaling by microRNA (miRNA) regulation shows promise for the future treatment of SLE. PMID:26592511

  4. Toll-Like Receptor 4 Deficiency Impairs Motor Coordination

    PubMed Central

    Zhu, Jian-Wei; Li, Yi-Fei; Wang, Zhao-Tao; Jia, Wei-Qiang; Xu, Ru-Xiang

    2016-01-01

    The cerebellum plays an essential role in balance and motor coordination. Purkinje cells (PCs) are the sole output neurons of the cerebellar cortex and are critical for the execution of its functions, including motor coordination. Toll-like receptor (TLR) 4 is involved in the innate immune response and is abundantly expressed in the central nervous system; however, little is known about its role in cerebellum-related motor functions. To address this question, we evaluated motor behavior in TLR4 deficient mice. We found that TLR4−∕− mice showed impaired motor coordination. Morphological analyses revealed that TLR4 deficiency was associated with a reduction in the thickness of the molecular layer of the cerebellum. TLR4 was highly expressed in PCs but not in Bergmann glia or cerebellar granule cells; however, loss of TLR4 decreased the number of PCs. These findings suggest a novel role for TLR4 in cerebellum-related motor coordination through maintenance of the PC population. PMID:26909014

  5. Association of Toll-like receptor 2 polymorphisms with gout

    PubMed Central

    CAI, YAN; PENG, YI-HUA; TANG, ZHONG; GUO, XIAO-LAN; QING, YU-FENG; LIANG, SU-HUA; JIANG, HONG; DANG, WANG-TAI; MA, QIANG; HE, CHENG; ZHOU, JING-GUO

    2014-01-01

    Gout is the most common autoinflammatory arthritis characterized by elevated serum urate and recurrent attacks of intra-articular crystal deposition of monosodium urate (MSU) in tissues. The pathogenesis of gout has not been fully determined, although certain genetic factors are involved in the development of gout. Accumulated data suggested that MSU crystal-induced inflammation is a paradigm of innate immunity. As Toll-like receptors (TLRs) are the underlying mechanisms of the innate immune response, the present study aimed to investigate whether TLR2 polymorphisms are associated with gout. Two single-nucleotide polymorphisms (Arg677Trp and Arg753Gln, rs5743708) in TLR2 were genotyped by polymerase chain reaction-restriction fragment length polymorphism and the −196 to −174 del polymorphism was investigated using the allele-specific polymerase chain reaction in 431 individuals (215 patients with gout and 216 healthy controls). TLR2 Arg677Trp and Arg753Gln genotyping indicated that all the positive samples were of the wild-type genotype. No significant differences in genotype (χ2=1.686, P=0.430) and allele (χ2=1.430, P=0.232) frequencies of the −196 to −174 del polymorphism between the patients with gout and the control groups was observed. Our results suggested that the TLR2 Arg677Trp, Arg753Gln and the −196 to −174 del polymorphisms were not associated with susceptibility to primary gouty arthritis. PMID:24649113

  6. Toll-like receptor 4 limits transmission of Bordetella bronchiseptica.

    PubMed

    Rolin, Olivier; Smallridge, Will; Henry, Michael; Goodfield, Laura; Place, David; Harvill, Eric T

    2014-01-01

    Transmission of pathogens has been notoriously difficult to study under laboratory conditions leaving knowledge gaps regarding how bacterial factors and host immune components affect the spread of infections between hosts. We describe the development of a mouse model of transmission of a natural pathogen, Bordetella bronchiseptica, and its use to assess the impact of host immune functions. Although B. bronchiseptica transmits poorly between wild-type mice and mice lacking other immune components, it transmits efficiently between mice deficient in Toll-Like Receptor 4 (TLR4). TLR4-mutant mice were more susceptible to initial colonization, and poorly controlled pathogen growth and shedding. Heavy neutrophil infiltration distinguished TLR4-deficient responses, and neutrophil depletion did not affect respiratory CFU load, but decreased bacterial shedding. The effect of TLR4 response on transmission may explain the extensive variation in TLR4 agonist potency observed among closely related subspecies of Bordetella. This transmission model will enable mechanistic studies of how pathogens spread from one host to another, the defining feature of infectious disease.

  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. Adolescent Russian roulette deaths.

    PubMed

    Collins, Kim A

    2010-03-01

    Adolescence, between the ages of 10 and 19 years, is a unique period both physically and emotionally. During this time of life, individuals are known to experiment and engage in risky behavior, sometimes with unforeseen morbidity and mortality. We also see suicide emerge as a manner of death in this age group. The most common method is gunshot wound and sometimes in the form of Russian roulette. Few studies have looked at deaths by Russian roulette, the victims, and scenarios. In particular, no study examines the adolescent victim of Russian roulette. To better understand and classify this entity, adolescent Russian roulette autopsy cases over a 20-year period were examined looking at the victims, scenarios, autopsy findings, cause and manner of death, and the weapons. All victims were males, ages 13 to 19 years, with a Black-to-White ratio of 1:1. No victim had a previous psychiatric history. Toxicology was positive for alcohol and/or marijuana in 50% of the victims. Friends were present when the victim shot himself which occurred in the home the majority of the time. In all but 1 case, premeditation of the game was involved as the victim provided the weapon for the roulette. The cause of death was gunshot wound to the head (6 to the right side, 1 to the mouth, 1 to the forehead), and the manner of death was suicide in 6 cases and accident in 2 cases. A review of the literature discusses the adolescent victim, suicide, and Russian roulette.

  9. 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.…

  10. 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)

  11. A "good death" for whom? Quality of spouse's death and psychological distress among older widowed persons.

    PubMed

    Carr, Deborah

    2003-06-01

    Ethicists, policy makers, and care providers are increasingly concerned with helping the dying elderly to experience a "good death." A "good death" is characterized by physical comfort, social support, acceptance, and appropriate medical care, and it should minimize psychological distress for the dying and their families. I identify the predictors of death quality and evaluate how the quality of an older adult's death affects the surviving spouse's psychological adjustment six months after the loss. Analyses use Changing Lives of Older Couples (CLOC) data, a prospective study of married persons ages 65 and older. Positive spousal relationships during the final days increase survivors' yearning yet reduce their anger. Having a spouse die a painful death is associated with elevated anxiety, yearning, and intrusive thoughts. The perception of physician negligence is associated with elevated anger. These findings suggest that improved end-of-life care and pain management will benefit both the dying and their bereaved spouses. PMID:12866391

  12. Heme-Mediated Induction of CXCL10 and Depletion of CD34+ Progenitor Cells Is Toll-Like Receptor 4 Dependent.

    PubMed

    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.

  13. Toll-Like Receptor 4 Signaling Pathway Mediates Inhalant Organic Dust-Induced Bone Loss.

    PubMed

    Staab, Elizabeth; Thiele, Geoffrey M; Clarey, Dillon; Wyatt, Todd A; Romberger, Debra J; Wells, Adam D; Dusad, Anand; Wang, Dong; Klassen, Lynell W; Mikuls, Ted R; Duryee, Michael J; Poole, Jill A

    2016-01-01

    Agriculture workers have increased rates of airway and skeletal disease. Inhalant exposure to agricultural organic dust extract (ODE) induces bone deterioration in mice; yet, mechanisms underlying lung-bone crosstalk remain unclear. Because Toll-like receptor 2 (TLR2) and TLR4 are important in mediating the airway consequences of ODE, this study investigated their role in regulating bone responses. First, swine facility ODE stimulated wild-type (WT) bone marrow macrophages to form osteoclasts, and this finding was inhibited in TLR4 knock-out (KO), but not TLR2 KO cells. Next, using an established intranasal inhalation exposure model, WT, TLR2 KO and TLR4 KO mice were treated daily with ODE or saline for 3 weeks. ODE-induced airway neutrophil influx and cytokine/chemokine release were similarly reduced in TLR2 and TLR4 KO animals as compared to WT mice. Utilizing micro-computed tomography (CT), analysis of tibia showed loss of bone mineral density, volume and deterioration of bone micro-architecture and mechanical strength induced by ODE in WT mice were significantly reduced in TLR4 but not TLR2 KO animals. Bone marrow osteoclast precursor cell populations were analyzed by flow cytometry from exposed animals. In WT animals, exposure to inhalant ODE increased osteoclast precursor cell populations as compared to saline, an effect that was reduced in TLR4 but not TLR2 KO mice. These results show that TLR2 and TLR4 pathways mediate ODE-induced airway inflammation, but bone deterioration consequences following inhalant ODE treatment is strongly dependent upon TLR4. Thus, the TLR4 signaling pathway appears critical in regulating the lung-bone inflammatory axis to microbial component-enriched organic dust exposures. PMID:27479208

  14. Toll-Like Receptor 4 Signaling Pathway Mediates Inhalant Organic Dust-Induced Bone Loss

    PubMed Central

    Staab, Elizabeth; Thiele, Geoffrey M.; Clarey, Dillon; Wyatt, Todd A.; Romberger, Debra J.; Wells, Adam D.; Dusad, Anand; Wang, Dong; Klassen, Lynell W.; Mikuls, Ted R.; Duryee, Michael J.; Poole, Jill A.

    2016-01-01

    Agriculture workers have increased rates of airway and skeletal disease. Inhalant exposure to agricultural organic dust extract (ODE) induces bone deterioration in mice; yet, mechanisms underlying lung-bone crosstalk remain unclear. Because Toll-like receptor 2 (TLR2) and TLR4 are important in mediating the airway consequences of ODE, this study investigated their role in regulating bone responses. First, swine facility ODE stimulated wild-type (WT) bone marrow macrophages to form osteoclasts, and this finding was inhibited in TLR4 knock-out (KO), but not TLR2 KO cells. Next, using an established intranasal inhalation exposure model, WT, TLR2 KO and TLR4 KO mice were treated daily with ODE or saline for 3 weeks. ODE-induced airway neutrophil influx and cytokine/chemokine release were similarly reduced in TLR2 and TLR4 KO animals as compared to WT mice. Utilizing micro-computed tomography (CT), analysis of tibia showed loss of bone mineral density, volume and deterioration of bone micro-architecture and mechanical strength induced by ODE in WT mice were significantly reduced in TLR4 but not TLR2 KO animals. Bone marrow osteoclast precursor cell populations were analyzed by flow cytometry from exposed animals. In WT animals, exposure to inhalant ODE increased osteoclast precursor cell populations as compared to saline, an effect that was reduced in TLR4 but not TLR2 KO mice. These results show that TLR2 and TLR4 pathways mediate ODE-induced airway inflammation, but bone deterioration consequences following inhalant ODE treatment is strongly dependent upon TLR4. Thus, the TLR4 signaling pathway appears critical in regulating the lung-bone inflammatory axis to microbial component-enriched organic dust exposures. PMID:27479208

  15. The Impact of Death Education on Fear of Death and Death Anxiety Among Human Services Students.

    PubMed

    McClatchey, Irene Searles; King, Steve

    2015-01-01

    Human services professionals will undoubtedly work with the dying and bereaved populations at one time or other. Yet, they are poorly prepared to do so since death education, that is, lessons about the human and emotional aspects of death, its implications, and subsequent bereavement issues, is often not part of their curriculum. This nonequivalent comparison group study (N = 86) examined death fear and death anxiety among human services students before and after receiving death education using the Multidimensional Fear of Death Scale. The results showed a statistically significant decrease in death anxiety among the group of students who participated in death education compared to those who did not.

  16. [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.

  17. [Sudden infant death syndrome].

    PubMed

    Espinosa Morett, A; Shkurovich, M; Carlos Ugartechea, J; Mallet Arelano, A; Salmón Rodríguez, L E

    1976-01-01

    This report is based on a review of the present situation of the sudden infant death syndrome through the presentation of four cases studied at the Unidad de Pediatría, Hospital General de México, S.S.A. All cases were in apparent good health before death. All babies were less than ten months of age. In three cases, necropsy was not performed, and the other one did not show significant abnormalities at the post-mortem examination. A complete review of the literature was made including: historical, epidemiological, genetic, clinical and pathological aspects. Special emphasis is made on the pathophysiology of the syndrome during MOR phase of sleep and muscular hypertrophy of the lungs arteriolae suggesting chronic hypoxia which are the most relevant theories in the sudden infant death syndrome. Psychological aspects and the family management by the physician and detection of possible future victims of the syndrome are finally discussed. PMID:973858

  18. 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).

  19. Infant deaths in slings.

    PubMed

    Madre, Chrystèle; Rambaud, Caroline; Avran, David; Michot, Charlotte; Sachs, Philippe; Dauger, Stéphane

    2014-12-01

    Although the incidence of sudden unexpected death in infancy (SUDI) decreased markedly after campaigns to promote supine positioning during sleeping, it has remained unchanged over the last decade. Epidemiological data suggest a role for new causes such as suffocation, asphyxia, and entrapment. Health authorities in several countries have issued warnings about slings used to carry infants. However, few reports of infant deaths in slings have been published in medical journals. Our paediatric intensive care unit has admitted two infants who experienced cardiorespiratory arrest while carried in a sling. Diagnostic investigations including a post-mortem examination established asphyxia as the mechanism of death. In conclusion, baby slings may carry a risk of SUDI, either by compression of the baby into a forward-flexed position or by direct suffocation. European recommendations for the cautious use of baby slings should be disseminated to families and professionals involved in caring for infants, as done recently in Australia, Canada, and the USA. PMID:24343674

  20. Death on Denali

    PubMed Central

    Wilson, Rodman; Mills, William J.; Rogers, Donald R.; Propst, Michael T.

    1978-01-01

    Between 1903 and 1975 about 1 percent of climbers on Mount McKinley (Denali) and Mount Foraker in Alaska died. In 1976 a total of ten (1.7 percent) of 587 mountaineers died, but this rate of death was not significantly higher than previously. Nineteen percent of climbers in 1976 suffered major or minor injuries, illness or death. Acute mountain sickness (AMS), frostbite and fractures were common. Thirty-three rescues or retrievals of bodies were mounted at a cost of more than $82,000. Inexperience (particularly with arctic mountaineering), poor leadership, faulty equipment and undue reliance on rescue by helicopter contributed to the alarming incidence of accident, illness and death on big peaks in Mount McKinley National Park in 1976. PMID:664648

  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. [Near death experiences].

    PubMed

    Rubia Vila, Francisco José

    2012-01-01

    Near Death Experiences are those accounted by people who after being clinically dead return to life spontaneously or after reanimation. These experiences have been used traditionally to support the belief in the existence of the soul and of life after death. However, today neuroscience tries to explain these experiences from the scientific point of view, i.e. explaining them based on their brain substrates. Their resemblance to mystic experiences and to altered states of consciousness seems to indicate that they may be produced by hyperactivity of limbic structures caused by anoxia or hypercapnia. PMID:24294729

  3. [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.

  4. Teaching about the Death Penalty.

    ERIC Educational Resources Information Center

    Ryan, John Paul; Eden, John Michael

    1998-01-01

    Examines the reasons for the death penalty, the reasons why the death penalty attracts so much attention, whether the death penalty is applied consistently, and the evidence that the application of the death penalty may be racially biased. Provides an accompanying article on "Teaching Ideas" by Ronald A. Banaszak. (CMK)

  5. Toll of Tobacco in the United States of America

    MedlinePlus

    ... et al., “Estimates of Smoking-Attributable Deaths at Ages 15-54, Motherless or Fatherless Youths, and Resulting Social Security Costs in the United States in 1994,” Preventive Medicine 30(5):353-360, May 2000. Tobacco marketing. U.S. Federal Trade Commission (FTC). Cigarette Report for ...

  6. 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.

  7. 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

  8. 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…

  9. Digital Language Death

    PubMed Central

    Kornai, András

    2013-01-01

    Of the approximately 7,000 languages spoken today, some 2,500 are generally considered endangered. Here we argue that this consensus figure vastly underestimates the danger of digital language death, in that less than 5% of all languages can still ascend to the digital realm. We present evidence of a massive die-off caused by the digital divide. PMID:24167559

  10. Children's Concepts of Death.

    ERIC Educational Resources Information Center

    Kane, Barbara

    1979-01-01

    A total of 122 middle-class White boys and girls aged 3 through 12 years were interviewed to determine the nature and the development of their concepts of death and the impact of experience on those concepts. (Author/BH)

  11. 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.…

  12. 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…

  13. Death Penalty in America.

    ERIC Educational Resources Information Center

    Clifford, Amie L.

    1997-01-01

    Examines the legal and moral issues, controversies, and unique trial procedures involved with the death penalty. Discusses the 1972 landmark Supreme Court decision that resulted in many states abolishing this punishment, only to reintroduce it later with different provisions. Reviews the controversial case of Sam Sheppard. (MJP)

  14. 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)

  15. Death in Contemporary America.

    ERIC Educational Resources Information Center

    Feifel, Herman, Ed.

    1982-01-01

    In five articles, considers the history and nature of death in America. Discusses dilemmas that face the helping professions as a consequence of improving medical capability. Highlights the effects of social change upon the mourning experience. Discusses the hospice movement. (RC)

  16. Psychiatry on death row.

    PubMed

    Hussain, A H; Tozman, S

    1978-03-01

    The authors present the personal experiences of an attending physician in a Death Row in Ceylon (Sri-Lanka). Aspects of the execution scenario are presented and discussed with its implications for the protagonists: the condemned, witnesses, standers-by, authorities and society-at large.

  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. 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. PMID:25464115

  19. 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

  20. Toll-like Receptors of the Ascidian Ciona intestinalis

    PubMed Central

    Sasaki, Naoko; Ogasawara, Michio; Sekiguchi, Toshio; Kusumoto, Shoichi; Satake, Honoo

    2009-01-01

    Key transmembrane proteins in the innate immune system, Toll-like receptors (TLRs), have been suggested to occur in the genome of non-mammalian organisms including invertebrates. However, authentic invertebrate TLRs have been neither structurally nor functionally investigated. In this paper, we originally present the structures, localization, ligand recognition, activities, and inflammatory cytokine production of all TLRs of the ascidian Ciona intestinalis, designated as Ci-TLR1 and Ci-TLR2. The amino acid sequence of Ci-TLR1 and Ci-TLR2 were found to possess unique structural organization with moderate sequence similarity to functionally characterized vertebrate TLRs. ci-tlr1 and ci-tlr2 genes were expressed predominantly in the stomach and intestine as well as in hemocytes. Ci-TLR1 and Ci-TLR2 expressed in HEK293 cells, unlike vertebrate TLRs, were localized to both the plasma membrane and endosomes. Intriguingly, both Ci-TLR1 and Ci-TLR2 stimulate NF-κB induction in response to multiple pathogenic ligands such as double-stranded RNA, and bacterial cell wall components that are differentially recognized by respective vertebrate TLRs, revealing that Ci-TLRs recognize broader pathogen-associated molecular patterns than vertebrate TLRs. The Ci-TLR-stimulating pathogenic ligands also induced the expression of Ci-TNFα in the intestine and stomach where Ci-TLRs are expressed. These results provide evidence that the TLR-triggered innate immune systems are essentially conserved in ascidians, and that Ci-TLRs possess “hybrid” biological and immunological functions, compared with vertebrate TLRs. Moreover, it is presumed that chordate TLR ancestors also acquired the Ci-TLR-like multiple cellular localization and pathogen-associated molecular pattern recognition. PMID:19651780

  1. Death understanding and fear of death in young children.

    PubMed

    Slaughter, Virginia; Griffiths, Maya

    2007-10-01

    The purpose of this study was to test whether the developmental acquisition of a mature concept of death, that is, understanding death as a biological event, affects young children's fear of death. Ninety children between the ages of 4 and 8 participated in an interview study in which their understanding of death and their fear of death were both assessed. Levels of general anxiety were also measured via parent report. A regression analysis indicated that more mature death understanding was associated with lower levels of death fear, when age and general anxiety were controlled. These data provide some empirical support for the widely held belief that discussing death and dying in biological terms is the best way to alleviate fear of death in young children.

  2. Regulation of angiogenesis, mural cell recruitment and adventitial macrophage behavior by Toll-like receptors.

    PubMed

    Aplin, Alfred C; Ligresti, Giovanni; Fogel, Eric; Zorzi, Penelope; Smith, Kelly; Nicosia, Roberto F

    2014-01-01

    The angiogenic response to injury can be studied by culturing rat or mouse aortic explants in collagen gels. Gene expression studies show that aortic angiogenesis is preceded by an immune reaction with overexpression of Toll-like receptors (TLRs) and TLR-inducible genes. TLR1, 3, and 6 are transiently upregulated at 24 h whereas TLR2, 4, and 8 expression peaks at 24 h but remains elevated during angiogenesis and vascular regression. Expression of TLR5, 7 and 9 steadily increases over time and is highest during vascular regression. Studies with isolated cells show that TLRs are expressed at higher levels in aortic macrophages compared to endothelial or mural cells with the exception of TLR2 and TLR9 which are more abundant in the aortic endothelium. LPS and other TLR ligands dose dependently stimulate angiogenesis and vascular endothelial growth factor production. TLR9 ligands also influence the behavior of nonendothelial cell types by blocking mural cell recruitment and inducing formation of multinucleated giant cells by macrophages. TLR9-induced mural cell depletion is associated with reduced expression of the mural cell recruiting factor PDGFB. The spontaneous angiogenic response of the aortic rings to injury is reduced in cultures from mice deficient in myeloid differentiation primary response 88 (MyD88), a key adapter molecule of TLRs, and following treatment with an inhibitor of the NFκB pathway. These results suggest that the TLR system participates in the angiogenic response of the vessel wall to injury and may play an important role in the regulation of inflammatory angiogenesis in reactive and pathologic processes.

  3. Toll mediated infection response is altered by gravity and spaceflight in Drosophila.

    PubMed

    Taylor, Katherine; Kleinhesselink, Kurt; George, Michael D; Morgan, Rachel; Smallwood, Tangi; Hammonds, Ann S; Fuller, Patrick M; Saelao, Perot; Alley, Jeff; Gibbs, Allen G; Hoshizaki, Deborah K; von Kalm, Laurence; Fuller, Charles A; Beckingham, Kathleen M; Kimbrell, Deborah A

    2014-01-01

    Space travel presents unlimited opportunities for exploration and discovery, but requires better understanding of the biological consequences of long-term exposure to spaceflight. Immune function in particular is relevant for space travel. Human immune responses are weakened in space, with increased vulnerability to opportunistic infections and immune-related conditions. In addition, microorganisms can become more virulent in space, causing further challenges to health. To understand these issues better and to contribute to design of effective countermeasures, we used the Drosophila model of innate immunity to study immune responses in both hypergravity and spaceflight. Focusing on infections mediated through the conserved Toll and Imd signaling pathways, we found that hypergravity improves resistance to Toll-mediated fungal infections except in a known gravitaxis mutant of the yuri gagarin gene. These results led to the first spaceflight project on Drosophila immunity, in which flies that developed to adulthood in microgravity were assessed for immune responses by transcription profiling on return to Earth. Spaceflight alone altered transcription, producing activation of the heat shock stress system. Space flies subsequently infected by fungus failed to activate the Toll pathway. In contrast, bacterial infection produced normal activation of the Imd pathway. We speculate on possible linkage between functional Toll signaling and the heat shock chaperone system. Our major findings are that hypergravity and spaceflight have opposing effects, and that spaceflight produces stress-related transcriptional responses and results in a specific inability to mount a Toll-mediated infection response. PMID:24475130

  4. 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

  5. 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.

  6. Do "near death experiences" occur only near death?

    PubMed

    Gabbard, G O; Twemlow, S W; Jones, F C

    1981-06-01

    Near deaths experiences are being reported with increasing frequency, but whether the constellation of factors comprising these experiences is unique to near death situations is unknown. This investigation compared near death experiences to other out-of-body experiences to determine if there are unique features associated with near death experiences. Our results indicate that there are no characteristics which are exclusive to near death situations, but our analysis of t-tests is highly suggestive of a number of distinguishing features which differentiate near death experiences from other out-of-body experiences.

  7. Near-death experiences and the psychology of death.

    PubMed

    Tassell-Matamua, Natasha A

    Little is known about the psychological phenomenology of death. Reported across known history and in all cultures by those who have died or been close to death, NDEs challenge objective-mechanistic models by suggesting the phenomenology of death may involve a variety of complex psychological processes. This article discusses three notable characteristics of the NDE--loss of the fear of death, psychological sequelae, and complex conscious abilities--supporting this claim. The implications these have for advancing societal understandings of death are discussed, and their pragmatic application for professions where death is frequently encountered, such as palliative care, is addressed.

  8. Mast cell toll-like receptor 2 signaling is crucial for effective killing of Francisella tularensis1

    PubMed Central

    Rodriguez, Annette R.; Yu, Jieh-Juen; Guentzel, M. N.; Navara, Christopher S.; Klose, Karl E.; Forsthuber, Thomas G.; Chambers, James P.; Berton, Michael T.; Arulanandam, Bernard P

    2012-01-01

    Toll-like receptor (TLR) signaling is critical for early host defense against pathogens, but the contribution of mast cell TLR-mediated mechanisms and subsequent effector functions during pulmonary infection is largely unknown. We have previously demonstrated that mast cells, through the production of IL-4, effectively control Francisella tularensis replication. In this study, the highly human virulent strain of F. tularensis SCHU S4 and the Live Vaccine Strain (LVS) were utilized to investigate the contribution of mast cell-TLR regulation of Francisella. Mast cells required TLR2 for effective bacterial killing, regulation of the hydrolytic enzyme cathepsin L, and for coordination and trafficking of MHCII and lysosomal associated membrane protein 2 (LAMP2). Infected TLR2−/− mast cells, in contrast to WT and TLR4−/−, lacked detectable IL-4 and displayed increased cell death with a 2–3 log increase of F. tularensis replication, but could be rescued with recombinant IL-4 treatment. Importantly, MHCII and LAMP2 localization with labeled F. tularensis in the lungs was greater in WT than in TLR2−/− mice. These results provide evidence for the important effector contribution of mast cells and TLR2-mediated signaling on early innate processes in the lung following pulmonary F. tularensis infection and provide additional insight into possible mechanisms by which intracellular pathogens modulate respiratory immune defenses. PMID:22529298

  9. Toll-Like Receptor-3 Is Dispensable for the Innate MicroRNA Response to West Nile Virus (WNV)

    PubMed Central

    Chugh, Pauline E.; Damania, Blossom A.; Dittmer, Dirk P.

    2014-01-01

    The innate immune response to West Nile virus (WNV) infection involves recognition through toll-like receptors (TLRs) and RIG-I-like receptors (RLRs), leading to establishment of an antiviral state. MiRNAs (miRNAs) have been shown to be reliable biomarkers of TLR activation. Here, we sought to evaluate the contribution of TLR3 and miRNAs to the host response to WNV infection. We first analyzed HEK293-NULL and HEK293-TLR3 cells for changes in the innate immune response to infection. The presence of TLR3 did not seem to affect WNV load, infectivity or phosphorylation of IRF3. Analysis of experimentally validated NFκB-responsive genes revealed a WNV-induced signature largely independent of TLR3. Since miRNAs are involved in viral pathogenesis and the innate response to infection, we sought to identify changes in miRNA expression upon infection in the presence or absence of TLR3. MiRNA profiling revealed 70 miRNAs induced following WNV infection in a TLR3-independent manner. Further analysis of predicted gene targets of WNV signature miRNAs revealed genes highly associated with pathways regulating cell death, viral pathogenesis and immune cell trafficking. PMID:25127040

  10. microRNA-26a modulates inflammatory response induced by toll-like receptor 4 stimulation in microglia.

    PubMed

    Kumar, Asit; Bhatia, Harsharan Singh; de Oliveira, Antonio Carlos Pinheiro; Fiebich, Bernd L

    2015-12-01

    MiRNAs, a family of small non-coding RNAs, have emerged as novel post-transcriptional regulators of numerous cellular responses. Although the involvement of miRNAs in the regulation of neuroinflammation in various neurological diseases has been previously studied, their role in the production of inflammatory mediators during microglia activation is poorly understood. In this study, the role of miR-26a has been investigated in the modulation of inflammatory response in cultured microglia. Using real-time PCR, the expression of miR-26a was studied in toll-like receptors 4 stimulated primary mouse microglia. miR-26a expression was found to be rapidly reduced after the stimulation of toll-like receptors 4 in microglia. Over-expression of miR-26a significantly decreased the production of inflammatory cytokines such as tumor necrosis factor α and IL-6, whereas knockdown of miR-26a increased the expression of these mediators. Furthermore, using in silico analysis, we identified that the activating transcription factor (ATF) 2 is directly targeted by miR-26a. This finding was confirmed by loss and gain of function studies. Similar to the effect of miR-26a over-expression, knockdown of activating transcription factor 2 inhibited the production of proinflammatory cytokines, particularly IL-6. Taken together, our results suggest the involvement of miR-26a in the regulation of the production of proinflammatory cytokines in microglia. We proposed that in microglia, activation of toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS) down-regulates miR-26a. The down-regulation of this miR increases expression of activating transcription factor 2 (ATF2). This event, in addition to the activation of ATF2 by c-Jun N-terminal kinase (JNK), increases interleukin-6 (IL-6) production. On the other hand, miR-26a also increases the production of tumor necrosis factor α (TNFα) by a mechanism independent of ATF2.

  11. Phosphatidylinositol 4-phosphate 5-kinase α facilitates Toll-like receptor 4-mediated microglial inflammation through regulation of the Toll/interleukin-1 receptor domain-containing adaptor protein (TIRAP) location.

    PubMed

    Nguyen, Tu Thi Ngoc; Kim, Yong Min; Kim, T Doohun; Le, Oanh Thi Tu; Kim, Jae Jin; Kang, Ho Chul; Hasegawa, Hiroshi; Kanaho, Yasunori; Jou, Ilo; Lee, Sang Yoon

    2013-02-22

    Phosphatidylinositol (PI) 4,5-bisphosphate (PIP(2)), generated by PI 4-phosphate 5-kinase (PIP5K), regulates many critical cellular events. PIP(2) is also known to mediate plasma membrane localization of the Toll/IL-1 receptor domain-containing adaptor protein (TIRAP), required for the MyD88-dependent Toll-like receptor (TLR) 4 signaling pathway. Microglia are the primary immune competent cells in brain tissue, and TLR4 is important for microglial activation. However, a functional role for PIP5K and PIP(2) in TLR4-dependent microglial activation remains unclear. Here, we knocked down PIP5Kα, a PIP5K isoform, in a BV2 microglial cell line using stable expression of lentiviral shRNA constructs or siRNA transfection. PIP5Kα knockdown significantly suppressed induction of inflammatory mediators, including IL-6, IL-1β, and nitric oxide, by lipopolysaccharide. PIP5Kα knockdown also attenuated signaling events downstream of TLR4 activation, including p38 MAPK and JNK phosphorylation, NF-κB p65 nuclear translocation, and IκB-α degradation. Complementation of the PIP5Kα knockdown cells with wild type but not kinase-dead PIP5Kα effectively restored the LPS-mediated inflammatory response. We found that PIP5Kα and TIRAP colocalized at the cell surface and interacted with each other, whereas kinase-dead PIP5Kα rendered TIRAP soluble. Furthermore, in LPS-stimulated control cells, plasma membrane PIP(2) increased and subsequently declined, and TIRAP underwent bi-directional translocation between the membrane and cytosol, which temporally correlated with the changes in PIP(2). In contrast, PIP5Kα knockdown that reduced PIP(2) levels disrupted TIRAP membrane targeting by LPS. Together, our results suggest that PIP5Kα promotes TLR4-associated microglial inflammation by mediating PIP(2)-dependent recruitment of TIRAP to the plasma membrane.

  12. An inquiry about clinical death--considering spiritual pain.

    PubMed

    Deeken, Alfons

    2009-06-01

    According to a paper published by the International Work Group on Death, Dying and Bereavement, "Each person has a spiritual dimension." That means each person has spiritual energy and spiritual needs. In facing death, a patient suffers spiritual pain and needs spiritual care. This paper describes what spirituality and spiritual pain mean. It identifies nine types of fears and anxieties about death which become a source of spiritual pain: 1. Fear of pain; 2. Fear of loneliness; 3. Fear of unpleasant experiences; 4. Fear of becoming a burden to the family and to society; 5. Anxiety towards the unknown; 6. Fear of death resulting from fear of life; 7. Fear of death as a feeling that one's life task is still incomplete; 8. Fear of death as fear of personal extinction; 9. Fear of death as fear of judgment and punishment after death. Five types of spiritual pain that seem to be frequent among patients facing death are discussed: 1. Loss of self-determination; 2. Loss of meaning; 3. Guilt feelings; 4. Loneliness and isolation; 5. Loss of hope. Three ways of preventing or reducing excessive fear of death and of lowering the various types of spiritual pain are suggested: 1. Death education; 2. Presence at the bedside; 3. Humor as an expression of love. PMID:19597307

  13. Mortality surveillance: 2004 to 2005 Florida hurricane-related deaths.

    PubMed

    Ragan, Patricia; Schulte, Joann; Nelson, Stephen J; Jones, Ken T

    2008-06-01

    During 2004 and 2005, Florida was struck by 8 hurricanes, resulting in 213 deaths. The Department of Health and Florida medical examiners monitor hurricane mortality surveillance. This study analyzed hurricane-related deaths reported by the Florida Medical Examiners Commission for 2004 to 2005. The objectives of this study were to (1) describe the Florida hurricane-related mortality for 2004 and 2005, (2) accurately characterize the hurricane-related deaths, and (3) identify strategies to prevent or reduce future hurricane deaths. For 2004, there were 144 total hurricane-related deaths. The majority (59%) occurred in the postimpact phase, with accidents accounting for 76% of deaths. Among these, over half were caused by trauma, followed by drowning, other injury, electrocution, and carbon monoxide poisoning. For 2005, there were 69 hurricane-related deaths. Sixty-one percent of deaths occurred in the postimpact phase, with accidents accounting for 86% of all deaths. Among these, over half were due to trauma, with drowning and carbon monoxide poisoning being the other major contributors. Most hurricane-related deaths are due to unintentional injury and therefore, preventable. Seventy-nine percent of deaths are in those aged 40 and older. Prevention messages should target high-risk, postimpact activities, especially in older adults.

  14. An inquiry about clinical death--considering spiritual pain.

    PubMed

    Deeken, Alfons

    2009-06-01

    According to a paper published by the International Work Group on Death, Dying and Bereavement, "Each person has a spiritual dimension." That means each person has spiritual energy and spiritual needs. In facing death, a patient suffers spiritual pain and needs spiritual care. This paper describes what spirituality and spiritual pain mean. It identifies nine types of fears and anxieties about death which become a source of spiritual pain: 1. Fear of pain; 2. Fear of loneliness; 3. Fear of unpleasant experiences; 4. Fear of becoming a burden to the family and to society; 5. Anxiety towards the unknown; 6. Fear of death resulting from fear of life; 7. Fear of death as a feeling that one's life task is still incomplete; 8. Fear of death as fear of personal extinction; 9. Fear of death as fear of judgment and punishment after death. Five types of spiritual pain that seem to be frequent among patients facing death are discussed: 1. Loss of self-determination; 2. Loss of meaning; 3. Guilt feelings; 4. Loneliness and isolation; 5. Loss of hope. Three ways of preventing or reducing excessive fear of death and of lowering the various types of spiritual pain are suggested: 1. Death education; 2. Presence at the bedside; 3. Humor as an expression of love.

  15. 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. PMID:26258592

  16. Death by necrosis

    PubMed Central

    Syntichaki, Popi; Tavernarakis, Nektarios

    2002-01-01

    Cells suffer necrotic death when exposed to extreme environmental conditions, adverse and excessive stimuli, or when deleterious mutations are encoded in their genetic material. Unlike apoptosis, which involves a highly regulated and elaborate network of biochemical events and cascades, necrosis has been considered generally to be a chaotic decadence process that effects the inexorable demise of cells otherwise not destined to die. This grim prospect is now slowly being overturned, mostly by exciting new findings in two simple model organisms, Caenorhabditis elegans and Drosophila melanogaster. Despite the wide spectrum of necrosis-initiating conditions, evidence is accumulating that execution of necrotic or neurodegenerative cell death may be carried out by a finite common set of mechanisms. PMID:12101090

  17. 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.

  18. 78 FR 78517 - Open Meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-26

    ... Internal Revenue Service Open Meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee... the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee will be conducted. The Taxpayer Advocacy Panel is soliciting public comments, ideas, and suggestions on improving customer service at...

  19. 78 FR 64063 - Open Meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-10-25

    ... Internal Revenue Service Open Meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee... the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee will be conducted. The Taxpayer Advocacy Panel is soliciting public comments, ideas, and suggestions on improving customer service at...

  20. 78 FR 41193 - Open Meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-09

    ... Internal Revenue Service Open Meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee... the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee will be conducted. The Taxpayer Advocacy Panel is soliciting public comments, ideas and suggestions on improving customer service at...

  1. 78 FR 22947 - Open Meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-04-17

    ... Internal Revenue Service Open Meeting of the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee... the Taxpayer Advocacy Panel Toll-Free Phone Line Project Committee will be conducted. The Taxpayer Advocacy Panel is soliciting public comments, ideas and suggestions on improving customer service at...

  2. 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 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....

  3. 23 CFR 661.49 - Can IRRBP funds be spent on Interstate, State Highway, and Toll Road IRR bridges?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ..., 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....

  4. 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....

  5. 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....

  6. 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

    2015-03-01

    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.

  7. A systematic review of CD14 and toll-like receptors in relation to asthma in Caucasian children.

    PubMed

    Klaassen, Ester Mm; Thönissen, Brenda Ejt; van Eys, Guillaume; Dompeling, Edward; Jöbsis, Quirijn

    2013-03-15

    The aetiology of childhood asthma is complex. An early dysfunction in the immunological development of the innate immune system in combination with environmental factors possibly triggers asthma. CD14 and toll-like receptors are important components of the innate immune system. The aim of this systematic review was to obtain a better insight into the relation between CD14 and toll-like receptors and childhood asthma in Caucasians. We searched PubMed and EMBASE for relevant articles. In total, 44 articles were included. The quality of the selected studies was independently assessed by the first two authors using the Newcastle-Ottawa quality assessment scale. Toll-like receptor 2, toll-like receptor 6, toll-like receptor 9, and toll-like receptor 10 appear to have some association with childhood asthma in Caucasians. The evidence for a relation of CD14 with childhood asthma is limited. In conclusion, there is no convincing evidence yet for a role of CD14 and toll-like receptors in relation to childhood asthma. Future studies should include haplotype analysis and take environmental factors into account to further clarify the role of CD14 and toll-like receptors on childhood asthma.

  8. 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...

  9. 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

    ... INTERIOR LAND AND WATER INDIAN RESERVATION ROADS PROGRAM Indian Reservation Roads Program Policy and... operating a toll facility? Information on designing and operating a toll highway, bridge or tunnel is available from the International Bridge, Tunnel and Turnpike Association. The Association publishes...

  10. 25 CFR 170.131 - How can a tribe find out more about designing and operating a toll facility?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... INTERIOR LAND AND WATER INDIAN RESERVATION ROADS PROGRAM Indian Reservation Roads Program Policy and... operating a toll facility? Information on designing and operating a toll highway, bridge or tunnel is available from the International Bridge, Tunnel and Turnpike Association. The Association publishes...

  11. 25 CFR 170.130 - How can tribes use Federal highway funds for toll and ferry facilities?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... LAND AND WATER INDIAN RESERVATION ROADS PROGRAM Indian Reservation Roads Program Policy and Eligibility..., design, construct, and operate toll highways, bridges, and tunnels, as well as ferry boats and ferry.... To initiate construction of a . . . A tribe must . . . (1) Toll highway, bridge, or tunnel (i)...

  12. 25 CFR 170.130 - How can tribes use Federal highway funds for toll and ferry facilities?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... LAND AND WATER INDIAN RESERVATION ROADS PROGRAM Indian Reservation Roads Program Policy and Eligibility..., design, construct, and operate toll highways, bridges, and tunnels, as well as ferry boats and ferry.... To initiate construction of a . . . A tribe must . . . (1) Toll highway, bridge, or tunnel (i)...

  13. 25 CFR 170.131 - How can a tribe find out more about designing and operating a toll facility?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... INTERIOR LAND AND WATER INDIAN RESERVATION ROADS PROGRAM Indian Reservation Roads Program Policy and... operating a toll facility? Information on designing and operating a toll highway, bridge or tunnel is available from the International Bridge, Tunnel and Turnpike Association. The Association publishes...

  14. 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

    ... INTERIOR LAND AND WATER INDIAN RESERVATION ROADS PROGRAM Indian Reservation Roads Program Policy and... operating a toll facility? Information on designing and operating a toll highway, bridge or tunnel is available from the International Bridge, Tunnel and Turnpike Association. The Association publishes...

  15. 25 CFR 170.130 - How can tribes use Federal highway funds for toll and ferry facilities?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... LAND AND WATER INDIAN RESERVATION ROADS PROGRAM Indian Reservation Roads Program Policy and Eligibility..., design, construct, and operate toll highways, bridges, and tunnels, as well as ferry boats and ferry.... To initiate construction of a . . . A tribe must . . . (1) Toll highway, bridge, or tunnel (i)...

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

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... LAND AND WATER INDIAN RESERVATION ROADS PROGRAM Indian Reservation Roads Program Policy and Eligibility..., design, construct, and operate toll highways, bridges, and tunnels, as well as ferry boats and ferry.... To initiate construction of a . . . A tribe must . . . (1) Toll highway, bridge, or tunnel (i)...

  17. 25 CFR 170.131 - How can a tribe find out more about designing and operating a toll facility?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... INTERIOR LAND AND WATER INDIAN RESERVATION ROADS PROGRAM Indian Reservation Roads Program Policy and... operating a toll facility? Information on designing and operating a toll highway, bridge or tunnel is available from the International Bridge, Tunnel and Turnpike Association. The Association publishes...

  18. 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

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF ENERGY Federal Energy Regulatory Commission Zone J Tolling Co., LLC; Supplemental Notice That Initial Market- Based Rate...-referenced proceeding of Zone J Tolling Co., LLC's application for market-based rate authority, with...

  19. 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.

  20. 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

  1. Macrophage Activation Redirects Yersinia-Infected Host Cell Death from Apoptosis to Caspase-1-Dependent Pyroptosis

    PubMed Central

    Bergsbaken, Tessa; Cookson, Brad T

    2007-01-01

    Infection of macrophages by Yersinia species results in YopJ-dependent apoptosis, and naïve macrophages are highly susceptible to this form of cell death. Previous studies have demonstrated that macrophages activated with lipopolysaccharide (LPS) prior to infection are resistant to YopJ-dependent cell death; we found this simultaneously renders macrophages susceptible to killing by YopJ− Yersinia pseudotuberculosis (Yptb). YopJ− Yptb-induced macrophage death was dependent on caspase-1 activation, resulting in rapid permeability to small molecules, followed by membrane breakdown and DNA damage, and accompanied by cleavage and release of proinflammatory interleukin-18. Induction of caspase-1-dependent death, or pyroptosis, required the bacterial type III translocon but none of its known translocated proteins. Wild-type Yptb infection also triggered pyroptosis: YopJ-dependent activation of proapoptotic caspase-3 was significantly delayed in activated macrophages and resulted in caspase-1-dependent pyroptosis. The transition to susceptibility was not limited to LPS activation; it was also seen in macrophages activated with other Toll-like receptor (TLR) ligands and intact nonviable bacteria. Yptb infection triggered macrophage activation and activation of caspase-1 in vivo. Y. pestis infection of activated macrophages also stimulated caspase-1 activation. These results indicate that host signaling triggered by TLR and other activating ligands during the course of Yersinia infection redirects both the mechanism of host cell death and the downstream consequences of death by shifting from noninflammatory apoptosis to inflammatory pyroptosis. PMID:17983266

  2. 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

  3. Role of mitochondria ROS generation in ethanol-induced NLRP3 inflammasome activation and cell death in astroglial cells

    PubMed Central

    Alfonso-Loeches, Silvia; Ureña-Peralta, Juan R.; Morillo-Bargues, Maria José; Oliver-De La Cruz, Jorge; Guerri, Consuelo

    2014-01-01

    Toll-like receptors (TLRs) and NOD-like receptors (NLRs) are innate immunity sensors that provide an early/effective response to pathogenic or injury conditions. We have reported that ethanol-induced TLR4 activation triggers signaling inflammatory responses in glial cells, causing neuroinflammation and brain damage. However, it is uncertain if ethanol is able to activate NLRs/inflammasome in astroglial cells, which is the mechanism of activation, and whether there is crosstalk between both immune sensors in glial cells. Here we show that chronic ethanol treatment increases the co-localization of caspase-1 with GFAP+ cells, and up-regulates IL-1β and IL-18 in the frontal medial cortex in WT, but not in TLR4 knockout mice. We further show that cultured cortical astrocytes expressed several inflammasomes (NLRP3, AIM2, NLRP1, and IPAF), although NLRP3 mRNA is the predominant form. Ethanol, as ATP and LPS treatments, up-regulates NLRP3 expression, and causes caspase-1 cleavage and the release of IL-1β and IL-18 in astrocytes supernatant. Ethanol-induced NLRP3/caspase-1 activation is mediated by mitochondrial (m) reactive oxygen species (ROS) generation because when using a specific mitochondria ROS scavenger, the mito-TEMPO (500 μM) or NLRP3 blocking peptide (4 μg/ml) or a specific caspase-1 inhibitor, Z-YVAD-FMK (10 μM), abrogates mROS release and reduces the up-regulation of IL-1β and IL-18 induced by ethanol or LPS or ATP. Confocal microscopy studies further confirm that ethanol, ATP or LPS promotes NLRP3/caspase-1 complex recruitment within the mitochondria to promote cell death by caspase-1-mediated pyroptosis, which accounts for ≈73% of total cell death (≈22%) and the remaining (≈25%) die by caspase-3-dependent apoptosis. Suppression of the TLR4 function abrogates most ethanol effects on NLRP3 activation and reduces cell death. These findings suggest that NLRP3 participates, in ethanol-induced neuroinflammation and highlight the NLRP3/TLR4 crosstalk in

  4. 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.

  5. 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…

  6. 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…

  7. Insulin withdrawal-induced cell death in adult hippocampal neural stem cells as a model of autophagic cell death.

    PubMed

    Baek, Seung-Hoon; Kim, Eun-Kyoung; Goudreau, John L; Lookingland, Keith J; Kim, Seong Who; Yu, Seong-Woon

    2009-02-01

    The term "autophagic cell death" was coined to describe a form of cell death associated with the massive formation of autophagic vacuoles without signs of apoptosis. However, questions about the actual role of autophagy and its molecular basis in cell death remain to be elucidated. We recently reported that adult hippocampal neural stem (HCN) cells undergo autophagic cell death following insulin withdrawal. Insulin-deprived HCN cells exhibit morphological and biochemical markers of autophagy, including accumulation of Beclin 1 and the type II form of microtubule-associated protein 1 light chain 3 (LC3) without evidence of apoptosis. Suppression of autophagy by knockdown of Atg7 reduces cell death, whereas promotion of autophagy with rapamycin augments cell death in insulin-deficient HCN cells. These data reveal a causative role of autophagy in insulin withdrawal-induced HCN cell death. HCN cells have intact apoptotic capability despite the lack of apoptosis following insulin withdrawal. Our study demonstrates that autophagy is the default cell death mechanism in insulin-deficient HCN cells, and provides a genuine model of autophagic cell death in apoptosis-intact cells. Novel insight into molecular mechanisms of this underappreciated form of programmed cell death should facilitate the development of therapeutic methods to cope with human diseases caused by dysregulated cell death.

  8. Motor Vehicle Related Child Deaths: A Plea for Action.

    ERIC Educational Resources Information Center

    Toledo, Jose R.; And Others

    This paper reviews the literature concerning motor related child deaths, emphasizes that automobile related incidents are the major cause of death in children below 14 and over 1 year of age, and provides suggestions about what pediatricians can do to reduce highway fatalities among children. Special attention is given to investigations of the use…

  9. Lessons from the confidential enquiry into maternal deaths, Malaysia.

    PubMed

    Ravichandran, J; Ravindran, J

    2014-09-01

    Malaysia has successfully reduced maternal mortality through several efforts which, in the broad sense, include (i) the overall socio-economic development of the country; (ii) strengthened health services; and (iii) specific efforts and initiatives for the reduction of maternal mortality, one of which is the audit of maternal deaths by the confidential enquiry into maternal deaths.

  10. The Collett-Lester Fear of Death Scale: a correction.

    PubMed

    Lester, David; Abdel-Khalek, Ahmed

    2003-01-01

    A revision of the Collett-Lester Fear of Death Scale is presented, eliminating a deviant item that reduced the reliability of the scale. Using a sample of 191 undergraduates, four 7-item subscales were derived with adequate reliabilities and factorial congruence for 2 of the subscales (Fear of Death of Self and Fear of Dying of Self).

  11. Modelling predictions of cancer deaths in Northern Ireland

    PubMed Central

    French, D; Catney, D; Gavin, AT

    2006-01-01

    Background An ageing population has service planners concerned about future levels of disease which are age dependent. Predictions of mortality for colorectal, lung and breast cancers, which account for 30% of cancer cases and 40% of cancers deaths, were calculated for 2010 and 2015, based on trends in death rates and the predicted change in the demography of the Northern Ireland population. Methods The US National Cancer Institute's “Joinpoint” program was used to check for structural breaks in the time series of cancer death rates from 1984 to 2004. The prediction models applied to the data allowed variations in trends across age groups to be taken into account. A linear model was used for increasing or constant trends and a log linear model was used where the trend was decreasing. The models assume the number of deaths in each stratum, defined by age-sex and time-period, is Poisson distributed, with the average value determined by a log or linear function. Results Recent trends in rates of cancers studied were downwards except for female lung. Predictions include decreased colorectal cancer deaths in females and lung cancer deaths in males. In females, lung cancer deaths are predicted to more than double by the year 2015 (473 deaths), based on the 1984 level. Colorectal death rates in males are predicted to drop, but the number of deaths will increase by more than 10%, due to demographic change. Numbers of breast cancer deaths are likely to rise slightly, despite falling age standardised death rates, due to an ageing population. Conclusions This work has provided estimates of early future trends, useful to service planners, and highlights the need for tobacco control, to reduce numbers of lung cancer deaths in females. The recently announced control of environmental tobacco legislation is one welcome development which should reduce lung cancer mortality in Northern Ireland. PMID:16755941

  12. Toll/Interleukin-1 Receptor Domain Dimers as the Platform for Activation and Enhanced Inhibition of Toll-like Receptor Signaling*

    PubMed Central

    Fekonja, Ota; Benčina, Mojca; Jerala, Roman

    2012-01-01

    TIR (Toll/IL-1 receptor) domains mediate interactions between TLR (Toll-like) or IL-1 family receptors and signaling adapters. While homotypic TIR domain interactions mediate receptor activation they are also usurped by microbial TIR domain containing proteins for immunosuppression. Here we show the role of a dimerized TIR domain platform for the suppression as well as for the activation of MyD88 signaling pathway. Coiled-coil dimerization domain, present in many bacterial TCPs, potently augments suppression of TLR/IL-1R signaling. The addition of a strong coiled-coil dimerization domain conferred the superior inhibition against the wide spectrum of TLRs and prevented the constitutive activation by a dimeric TIR platform. We propose a molecular model of MyD88-mediated signaling based on the dimerization of TIR domains as the limiting step. PMID:22829600

  13. Local interleukin-1-driven joint pathology is dependent on toll-like receptor 4 activation.

    PubMed

    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

    2009-11-01

    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 alpha-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-1beta was dependent on TLR4. Overexpression of IL-1beta 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.

  14. Toll-like Receptors as a Target of Food-derived Anti-inflammatory Compounds*

    PubMed Central

    Shibata, Takahiro; Nakashima, Fumie; Honda, Kazuya; Lu, Yu-Jhang; Kondo, Tatsuhiko; Ushida, Yusuke; Aizawa, Koichi; Suganuma, Hiroyuki; Oe, Sho; Tanaka, Hiroshi; Takahashi, Takashi; Uchida, Koji

    2014-01-01

    Toll-like receptors (TLRs) play a key role in linking pathogen recognition with the induction of innate immunity. They have been implicated in the pathogenesis of chronic inflammatory diseases, representing potential targets for prevention/treatment. Vegetable-rich diets are associated with the reduced risk of several inflammatory disorders. In the present study, based on an extensive screening of vegetable extracts for TLR-inhibiting activity in HEK293 cells co-expressing TLR with the NF-κB reporter gene, we found cabbage and onion extracts to be the richest sources of a TLR signaling inhibitor. To identify the active substances, we performed activity-guiding separation of the principal inhibitors and identified 3-methylsulfinylpropyl isothiocyanate (iberin) from the cabbage and quercetin and quercetin 4′-O-β-glucoside from the onion, among which iberin showed the most potent inhibitory effect. It was revealed that iberin specifically acted on the dimerization step of TLRs in the TLR signaling pathway. To gain insight into the inhibitory mechanism of TLR dimerization, we developed a novel probe combining an isothiocyanate-reactive group and an alkyne functionality for click chemistry and detected the probe bound to the TLRs in living cells, suggesting that iberin disrupts dimerization of the TLRs via covalent binding. Furthermore, we designed a variety of iberin analogues and found that the inhibition potency was influenced by the oxidation state of the sulfur. Modeling studies of the iberin analogues showed that the oxidation state of sulfur might influence the global shape of the isothiocyanates. These findings establish the TLR dimerization step as a target of food-derived anti-inflammatory compounds. PMID:25294874

  15. Insights into Soluble Toll-Like Receptor 2 as a Downregulator of Virally Induced Inflammation

    PubMed Central

    Henrick, Bethany M.; Yao, Xiao-Dan; Taha, Ameer Y.; German, J. Bruce; Rosenthal, Kenneth Lee

    2016-01-01

    The ability to distinguish pathogens from self-antigens is one of the most important functions of the immune system. However, this simple self versus non-self assignment belies the complexity of the immune response to threats. Immune responses vary widely and appropriately according to a spectrum of threats and only recently have the mechanisms for controlling this highly textured process emerged. A primary mechanism by which this controlled decision-making process is achieved is via Toll-like receptor (TLR) signaling and the subsequent activation of the immune response coincident with the presence of pathogenic organisms or antigens, including lipid mediators. While immune activation is important, the appropriate regulation of such responses is also critical. Recent findings indicate a parallel pathway by which responses to both viral and bacterial infections is controlled via the secretion of soluble TLR2 (sTLR2). sTLR2 is able to bind a wide range of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). sTLR2 has been detected in many bodily fluids and is thus ubiquitous in sites of pathogen appearance. Interestingly, growing evidence suggests that sTLR2 functions to sequester PAMPs and DAMPs to avoid immune activation via detection of cellular-expressed TLRs. This immune regulatory function would serve to reduce the expression of the molecules required for cellular entry, and the recruitment of target cells following infection with bacteria and viruses. This review provides an overview of sTLR2 and the research regarding the mechanisms of its immune regulatory properties. Furthermore, the role of this molecule in regulating immune activation in the context of HIV infection via sTLR2 in breast milk provides actionable insights into therapeutic targets across a variety of infectious and inflammatory states. PMID:27531999

  16. 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

  17. 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

  18. 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.

  19. 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

  20. Toll-Like Receptor Responses to Peste des petits ruminants Virus in Goats and Water Buffalo

    PubMed Central

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

  1. Toll-like receptor 4 in butylated hydroxytoluene-induced mouse pulmonary inflammation and tumorigenesis.

    PubMed

    Bauer, Alison K; Dixon, Darlene; DeGraff, Laura M; Cho, Hye-Youn; Walker, Christopher R; Malkinson, Alvin M; Kleeberger, Steven R

    2005-12-01

    Because chronic pulmonary diseases predispose to lung neoplasia, the identification of the molecular mechanisms involved could provide novel preventive, diagnostic, and therapeutic strategies. Toll-like receptors (TLRs) transduce exogenous and endogenous signals into the production of inflammatory cytokines to coordinate adaptive immune responses. To determine the role of Tlr4 in chronic lung inflammation, we compared lung permeability, leukocyte infiltration, and nuclear factor kappa B (NFkappaB) and activator protein 1 (AP-1) DNA binding in butylated hydroxytoluene (BHT)-treated (four weekly injections of 125-200 mg/kg each) inbred mouse strains with functional Tlr4 (OuJ and BALB) and mutated Tlr4 (HeJ and BALB(Lps-d)). We also measured primary tumor formation in these mice after single-carcinogen injection (3-methylcholanthrene; 10 microg/kg), followed by BHT treatment (six weekly injections of 125-200 mg/kg each). Mice with functional Tlr4 had reduced lung permeability, leukocyte inflammation, and primary tumor formation (BALB(Lps-d), mean = 22.3 tumors/mouse, versus BALB, mean = 13.9 tumors/mouse, difference = 8.4 tumors/mouse, 95% confidence interval = 4.6 to 12.1 tumors/mouse; P = .025) compared with mice with mutated Tlr4. NFkappaB DNA binding activity was higher in OuJ than in HeJ mice; however, AP-1 activity was elevated in HeJ mice. To our knowledge, this is the first model to demonstrate a modulatory role for Tlr4 in chronic lung inflammation and tumorigenesis.

  2. Childhood Deaths from Physical Abuse.

    ERIC Educational Resources Information Center

    Kasim, Mohd. Sham; and Others

    1995-01-01

    This paper describes 30 cases of childhood deaths caused by physical abuse in Kuala Lumpur, Malaysia. Data presented include ethnic origins, age, causes of death, identity of perpetrators, and marital situation of parents. (DB)

  3. The time of death's badness.

    PubMed

    Johansson, Jens

    2012-10-01

    Those who endorse the view that death is in some cases bad for the deceased--a view that, as I shall explain, has considerable bearing on many bioethical issues--need to address the following, Epicurean question: When is death bad for the one who dies? The two most popular answers are "before death" (priorism) and "after death" (subsequentism). Part of the support for these two views consists in the idea that a third answer, "at no time" (atemporalism), makes death unsatisfyingly different from other evils. I argue that this objection is mistaken, and that priorism and subsequentism face problems that atemporalism avoids. Moreover, I argue that if it is nonetheless insisted that we must find a time at which my death is bad for me, we can appeal to periods that begin before my death and end after my death. I end with some implications for posthumous harm.

  4. Life, Death, and Second Chances

    MedlinePlus

    ... Home Current Issue Past Issues Special Section Life, Death, and Second Chances Past Issues / Fall 2007 Table ... New Asthma Guidelines: What You Should Know / Life, Death, and Second Chances / Asthma Research: The NIH-NJRC ...

  5. Sudden Infant Death Syndrome (SIDS)

    MedlinePlus

    ... Information Clinical Trials Resources and Publications Sudden Infant Death Syndrome (SIDS): Condition Information Skip sharing on social ... Share this: Page Content SIDS is the sudden death of an infant younger than 1 year of ...

  6. 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

  7. Death in Denmark: a reply.

    PubMed

    Lamb, D

    1991-06-01

    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.

  8. Changing epidemiology of trauma deaths leads to a bimodal distribution

    PubMed Central

    Gunst, Mark; Ghaemmaghami, Vafa; Gruszecki, Amy; Urban, Jill; Frankel, Heidi

    2010-01-01

    Injury mortality was classically described with a trimodal distribution, with immediate deaths at the scene, early deaths due to hemorrhage, and late deaths from organ failure. We hypothesized that the development of trauma systems has improved prehospital care, early resuscitation, and critical care and altered this pattern. This population-based study of all trauma deaths in an urban county with a mature trauma system reviewed data for 678 patients (median age, 33 years; 81% male; 43% gunshot, 20% motor vehicle crashes). Deaths were classified as immediate (scene), early (in hospital, ≤4 hours from injury), or late (>4 hours after injury). Multinomial regression was used to identify independent predictors of immediate and early versus late deaths, adjusted for age, gender, race, intention, mechanism, toxicology, and cause of death. Results showed 416 (61%) immediate, 199 (29%) early, and 63 (10%) late deaths. Compared with the classical description, the percentage of immediate deaths remained unchanged, and early deaths occurred much earlier (median 52 vs 120 minutes). However, unlike the classic trimodal distribution, the late peak was greatly diminished. Intentional injuries, alcohol intoxication, asphyxia, and injuries to the head and chest were independent predictors of immediate death. Alcohol intoxication and injuries to the chest were predictors of early death, while pelvic fractures and blunt assaults were associated with late deaths. In conclusion, trauma deaths now have a predominantly bimodal distribution. Near elimination of the late peak likely represents advancements in resuscitation and critical care that have reduced organ failure. Further reductions in mortality will likely come from prevention of intentional injuries and injuries associated with alcohol intoxication. PMID:20944754

  9. Self-related consequences of death fear and death denial.

    PubMed

    Cozzolino, Philip J; Blackie, Laura E R; Meyers, Lawrence S

    2014-01-01

    This study explores self-related outcomes (e.g., esteem, self-concept clarity, existential well-being) as a function of the interaction between self-reported levels of death fear and death denial. Consistent with the idea that positive existential growth can come from individuals facing, rather than denying, their mortality (Cozzolino, 2006 ), the authors observed that not fearing and denying death can bolster important positive components of the self. That is, individuals low in death denial and death fear evidenced an enhanced self that is valued, clearly conceived, efficacious, and that has meaning and purpose.

  10. DEATH CONCERN AND DEATH OBSESSION IN IRANIAN NURSES.

    PubMed

    Dadfar, Mahboubeh; Lester, David

    2015-06-01

    The goal of the present study was to examine whether nurses had increased death concern and death obsession compared to non-nursing staff. A Death Concern Scale and a Death Obsession Scale, translated into Persian, were administered to 56 female Iranian nurses (55% in their 30s) and compared to 56 female hospital staff members (45% in their 30s). The two groups did not differ significantly in their scores on either scale. It is, therefore, recommended that death education programs in hospitals be given to all staff, nursing and non-nursing.

  11. Death of an Adult Child

    MedlinePlus

    ... iGive.com Purchase Through AmazonSmile Contact Us Donate Death of an Adult Child The death of any child, regardless of cause or age, ... the situations that may have caused their child’s death. Judgmental statements from others indicating that the child ...

  12. 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)

  13. Winning the Race with Death.

    ERIC Educational Resources Information Center

    Goodman, Lisl M.

    The hypothesis of a negative relationship between level of self-actualization and fear of death was based on the assumption that people are not afraid of death per se but of the incompleteness of their lives. Fear of death was furthermore assumed to inhibit orientation toward the future, thereby restricting movement toward achievement and…

  14. 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…

  15. 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…

  16. 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…

  17. Changing Breton Responses to Death.

    ERIC Educational Resources Information Center

    Badone, Ellen

    1988-01-01

    Based on fieldwork conducted in Brittany, France, during 1983 and 1984, discusses changes in Breton responses to death which have accompanied modernization and economic development. Suggests that familiarity with death and acceptance of it are being replaced by the "denial of death" characteristic of contemporary Western culture. Notes parallel…

  18. Body cooling after death.

    PubMed

    Kuehn, L A; Tikuisis, P; Livingstone, S; Limmer, R

    1980-09-01

    In the analyses of cases of death in cold air environments, it is often of interest to determine the time required for the body of the individual to cool to ambient temperature. Usually such determinations have been based on Newton's law of cooling. This paper describes a case history in which this technique was experimentally tested and consequently abandoned in favour of a more complex biophysical model which more accurately described the thermo-physical events inherent in body cooling. This model is recommended for determination of the times required for various body parts to cool to ambient environmental temperatures.

  19. Computer implants and death.

    PubMed

    Gert, Bernard

    2009-01-01

    Although a patient whose whole brain has ceased to function may have his heart, lungs, and other organs continue to function if they are connected to the appropriate machines, the patient is still dead and the machines can be disconnected. In the future, nanotechnology, or other technology, may allow putting implants in the brainstem that can keep a patient's heart, lungs and other organs functioning, even though the whole natural brain has ceased to function. It would be useful to consider how this technology might affect the criterion of death before it is actually available.

  20. Sudden death of entanglement.

    PubMed

    Yu, Ting; Eberly, J H

    2009-01-30

    A new development in the dynamical behavior of elementary quantum systems is the surprising discovery that correlation between two quantum units of information called qubits can be degraded by environmental noise in a way not seen previously in studies of dissipation. This new route for dissipation attacks quantum entanglement, the essential resource for quantum information as well as the central feature in the Einstein-Podolsky-Rosen so-called paradox and in discussions of the fate of Schrödinger's cat. The effect has been labeled ESD, which stands for early-stage disentanglement or, more frequently, entanglement sudden death. We review recent progress in studies focused on this phenomenon.