Mounting evidence indicates that escalating doses of allopurinol are unnecessary for cardiovascular protection: Comment on Coburn et al.

PubMed

Bredemeier, Markus

2018-05-09

We read with interest the study by Coburn et al. (1), a methodologically sound propensity-score matched cohort study evaluating the effect of dose escalation of allopurinol on cardiovascular (CV) and overall mortality. The results indicate that increasing doses carry a higher risk of mortality, but the authors comment that failure in achieving doses up to 600 mg may have contributed to the absence of protective effect. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

76 FR 71459 - Prohexadione Calcium; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-18

... available. In one study, maternal toxicity manifested as increased mortality, abortions, and decreases in... the dose that caused maternal toxicity. The abortions were attributed to the maternal toxicity (i.e.../Residential). absorption rate 25%. Residential. 200 mg/kg/day based on increased mortality, abortions, and...

In vitro effects of Apixaban on 5 different cancer cell lines

PubMed Central

Guasti, Luigina; Moretto, Paola; Vigetti, Davide; Ageno, Walter; Dentali, Francesco; Maresca, Andrea M.; Campiotti, Leonardo; Grandi, Anna M.; Passi, Alberto

2017-01-01

Background Cancer is associated with hypercoagulability. However, several data suggest that anticoagulant drugs may have an effect on tumor development and progression mediated by both coagulation dependent processes and non-coagulation dependent processes. Therefore, we investigated the in vitro effects of Apixaban on cell proliferation, mortality, cell migration, gene expression and matrix metalloproteinase in 5 different cancer cell lines. Methods The following cancer cell lines, and 2 normal fibroblast cultures (lung and dermal fibroblasts), were studied: OVCAR3 (ovarian cancer), MDA MB 231 (breast cancer), CaCO-2 (colon cancer), LNCaP (prostate cancer) and U937 (histiocytic lymphoma). Proliferation and cell mortality were assessed in control cells and Apixaban treated cultures (dose from 0.1 to 5 μg/ml, 0 to 96-h). Necrosis/Apoptosis (fluorescence microscopy), cell migration (24-h after scratch test), matrix metalloproteinase (MMP) activity and mRNA expression (RT PCR) of p16, p21, p53 and HAS were also assessed. Results High-dose (5 μg/ml) Apixaban incubation was associated with a significantly reduced proliferation in 3 cancer cell lines (OVCAR3, CaCO-2 and LNCaP) and with increased cancer cell mortality in all, except LNCaP, cancer lines. Apoptosis seems to account for the increased mortality. The migration capacity seems to be impaired after high-dose Apixaban incubation in OVCAR3 and CaCO-2 cells. Data on mRNA expression suggest a consistent increase in tumor suppression gene p16 in all cell lines. Conclusions Our data suggest that high-dose Apixaban may be able to interfere with cancer cell in vitro, reducing proliferation and increasing cancer cell mortality through apoptosis in several cancer cell lines. PMID:29023465

The effect of Haemophilus influenzae type B and pneumococcal conjugate vaccines on childhood meningitis mortality: a systematic review.

PubMed

Davis, Stephanie; Feikin, Daniel; Johnson, Hope L

2013-01-01

Two of the most prevalent causes of severe bacterial meningitis in children, Haemophilus influenzae type B (Hib) and Streptococcus pneumoniae, are preventable by existing vaccines increasingly available in developing countries. Our objective was to estimate the dose-specific effect of Hib and pneumococcal conjugate vaccines (PCV) on childhood meningitis mortality in low-income countries for use in the Lives Saved Tool (LiST). We systematically searched and reviewed published vaccine efficacy trials and observational studies reporting the effect of Hib or PCV vaccines on organism-specific meningitis, bacterial meningitis and all-cause meningitis incidence and mortality among children less than five years old in low- and middle-income countries. Data collection and quality assessments were performed using standardized guidelines. For outcomes available across multiple studies (≥ 2) and approximating meningitis mortality, we pooled estimates reporting dose-specific effects using random effects meta-analytic methods, then combined these with meningitis etiology data to determine the preventable fraction of childhood meningitis mortality for inclusion in LiST. We identified 18 studies of Hib conjugate vaccines reporting relevant meningitis morbidity and mortality outcomes (2 randomized controlled trials [RCTs], 16 observational studies) but few provided dose-specific effects. A meta-analysis of four case-control studies examined the dose-specific effect of Hib conjugate vaccines on Hib meningitis morbidity (1 dose: RR=0.64, 95% CI 0.38-1.06; 2 doses: RR=0.09, 95% CI 0.03-0.27; 3 doses: RR=0.06, 95% CI 0.02-0.22), consistent with results from single RCTs. Pooled estimates of two RCTs provided evidence for the effect of three doses of PCV on vaccine-serotype meningitis morbidity (RR=0.16, 95% CI 0.02-1.20). We considered these outcomes of severe disease as proxy estimates for meningitis mortality and combined the estimates of protective effects with meningitis etiology data to provide an estimate of the preventable fraction of childhood meningitis mortality with three doses of Hib (38-43%) and pneumococcal conjugate vaccines (28-35%) for use in LiST. Few RCTs or vaccine effectiveness studies evaluated the dose-specific impact of Hib and PCV vaccines on childhood meningitis mortality, necessitating use of proxy measures to estimate population impact in LiST. Our analysis indicates that approximately three-quarters of meningitis deaths are preventable with existing Hib and PCV vaccines.

Self-reported nonadherence to antiretroviral therapy as a predictor of viral failure and mortality.

PubMed

Glass, Tracy R; Sterne, Jonathan A C; Schneider, Marie-Paule; De Geest, Sabina; Nicca, Dunja; Furrer, Hansjakob; Günthard, Huldrych F; Bernasconi, Enos; Calmy, Alexandra; Rickenbach, Martin; Battegay, Manuel; Bucher, Heiner C

2015-10-23

To determine the effect of nonadherence to antiretroviral therapy (ART) on virologic failure and mortality in naive individuals starting ART. Prospective observational cohort study. Eligible individuals enrolled in the Swiss HIV Cohort Study, started ART between 2003 and 2012, and provided adherence data on at least one biannual clinical visit. Adherence was defined as missed doses (none, one, two, or more than two) and percentage adherence (>95, 90-95, and <90) in the previous 4 weeks. Inverse probability weighting of marginal structural models was used to estimate the effect of nonadherence on viral failure (HIV-1 viral load >500 copies/ml) and mortality. Of 3150 individuals followed for a median 4.7 years, 480 (15.2%) experienced viral failure and 104 (3.3%) died, 1155 (36.6%) reported missing one dose, 414 (13.1%) two doses and, 333 (10.6%) more than two doses of ART. The risk of viral failure increased with each missed dose (one dose: hazard ratio [HR] 1.15, 95% confidence interval 0.79-1.67; two doses: 2.15, 1.31-3.53; more than two doses: 5.21, 2.96-9.18). The risk of death increased with more than two missed doses (HR 4.87, 2.21-10.73). Missing one to two doses of ART increased the risk of viral failure in those starting once-daily (HR 1.67, 1.11-2.50) compared with those starting twice-daily regimens (HR 0.99, 0.64-1.54, interaction P = 0.09). Consistent results were found for percentage adherence. Self-report of two or more missed doses of ART is associated with an increased risk of both viral failure and death. A simple adherence question helps identify patients at risk for negative clinical outcomes and offers opportunities for intervention.

Erythropoietin, Iron Depletion and Relative Thrombocytosis: A Possible Explanation for Hemoglobin-Survival Paradox in Chronic Kidney Disease

PubMed Central

Streja, Elani; Kovesdy, Csaba P; Greenland, Sander; Kopple, Joel D.; McAllister, Charles J; Nissenson, Allen R; Kalantar-Zadeh, Kamyar

2017-01-01

Background High doses of human recombinant erythropoietin (rHuEPO) to achieve hemoglobin levels above 13 g/dL in chronic kidney disease appear associated with elevated mortality. Study Design We conducted logistic regression and survival analyses in a retrospective cohort of maintenance hemodialysis (MHD) patients to examine the hypothesis that the induced iron depletion with resultant relative thrombocytosis may be a possible contributor to the link between the high rHuEPO dose associated hemoglobin ≥13 g/dL and mortality. Setting & Participants The national database of a large dialysis organization (DaVita) with 40,787 MHD patients during July to December 2001 and their survival up to July 2004 were examined. Predictors Hemoglobin level, platelet count and administered rHuEPO dose during each calendar quarter. Outcomes & other Measurements Case-mix adjusted 3-year all-cause mortality; and measures of iron stores including serum ferritin and iron saturation ratio (ISAT). Results Higher platelet count was associated with lower iron stores and higher prescribed rHuEPO dose. Compared to hemoglobin of 12-13 g/dL, hemoglobin ≥13 g/dL was associated with increased mortality in the presence of relative thrombocytosis, i.e., platelet count ≥300,000/μl, (case-mix adjusted death-rate ratio [RR]: 1.21, 95% confidence limits [CL]: 1.02–1.44, P=0.03) as opposed to the absence of relative thrombocytosis (RR: 1.04, 95% CL: 0.98–1.08, P=0.13). Prescribed rHuEPO dose >20,000 units/week was associated with higher likelihood of iron depletion (ISAT<20%) and relative thrombocytosis (case-mix adjusted odds ratio: 2.53 [CL: 2.37–2.69] and 1.36 [CL: 1.30–1.42], respectively, p<0.001) and increased mortality over 3 years (death-rate ratio of 1.59, CL: 1.54, 1.65, p<0.001). Limitations Our results may incorporate uncontrolled confounding. Achieved hemoglobin may have different mortality-predictability than targeted hemoglobin. Conclusions Iron depletion and associated relative thrombocytosis might contribute to increased mortality when administering high rHuEPO doses to achieve hemoglobin ≥13 g/dL in MHD patients. Randomized trials are needed to test these observational associations. PMID:18760517

Effect of low-to-moderate-dose corticosteroids on mortality of hospitalized adolescents and adults with influenza A(H1N1)pdm09 viral pneumonia.

PubMed

Li, Hui; Yang, Shi-Gui; Gu, Li; Zhang, Yao; Yan, Xi-Xin; Liang, Zong-An; Zhang, Wei; Jia, Hong-Yu; Chen, Wei; Liu, Meng; Yu, Kai-Jiang; Xue, Chun-Xue; Hu, Ke; Zou, Qi; Li, Lan-Juan; Cao, Bin; Wang, Chen

2017-07-01

The effect of corticosteroids on influenza A(H1N1)pdm09 viral pneumonia patients remains controversial, and the impact of dosage has never been studied. Using data of hospitalized adolescent and adult patients with influenza A(H1N1)pdm09 viral pneumonia, prospectively collected from 407 hospitals in mainland China, the effects of low-to-moderate-dose (25-150 mg d -1 ) and high-dose (>150 mg d -1 ) corticosteroids on 30-day mortality, 60-day mortality, and nosocomial infection were assessed with multivariate Cox regression and propensity score-matched case-control analysis. In total, 2141 patients (median age: 34 years; morality rate: 15.9%) were included. Among them, 1160 (54.2%) had PaO 2 /FiO 2 <300 mm Hg on admission, and 1055 (49.3%) received corticosteroids therapy. Corticosteroids, without consideration of dose, did not influence either 30-day or 60-day mortality. Further analysis revealed that, as compared with the no-corticosteroid group, low-to-moderate-dose corticosteroids were related to reduced 30-day mortality (adjusted hazard ratio [aHR] 0.64 [95% CI 0.43-0.96, P=.033]). In the subgroup analysis among patients with PaO 2 /FiO 2 <300 mm Hg, low-to-moderate-dose corticosteroid treatment significantly reduced both 30-day mortality (aHR 0.49 [95% CI 0.32-0.77]) and 60-day mortality (aHR 0.51 [95% CI 0.33-0.78]), while high-dose corticosteroid therapy yielded no difference. For patients with PaO 2 /FiO 2 ≥300 mm Hg, corticosteroids (irrespective of dose) showed no benefit and even increased 60-day mortality (aHR 3.02 [95% CI 1.06-8.58]). Results were similar in the propensity model analysis. Low-to-moderate-dose corticosteroids might reduce mortality of influenza A(H1N1)pdm09 viral pneumonia patients with PaO 2 /FiO 2 <300 mm Hg. Mild patients with PaO 2 /FiO 2 ≥300 mm Hg could not benefit from corticosteroid therapy. © 2017 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.

A cut-off of daily sedentary time and all-cause mortality in adults: a meta-regression analysis involving more than 1 million participants.

PubMed

Ku, Po-Wen; Steptoe, Andrew; Liao, Yung; Hsueh, Ming-Chun; Chen, Li-Jung

2018-05-25

The appropriate limit to the amount of daily sedentary time (ST) required to minimize mortality is uncertain. This meta-analysis aimed to quantify the dose-response association between daily ST and all-cause mortality and to explore the cut-off point above which health is impaired in adults aged 18-64 years old. We also examined whether there are differences between studies using self-report ST and those with device-based ST. Prospective cohort studies providing effect estimates of daily ST (exposure) on all-cause mortality (outcome) were identified via MEDLINE, PubMed, Scopus, Web of Science, and Google Scholar databases until January 2018. Dose-response relationships between daily ST and all-cause mortality were examined using random-effects meta-regression models. Based on the pooled data for more than 1 million participants from 19 studies, the results showed a log-linear dose-response association between daily ST and all-cause mortality. Overall, more time spent in sedentary behaviors is associated with increased mortality risks. However, the method of measuring ST moderated the association between daily ST and mortality risk (p < 0.05). The cut-off of daily ST in studies with self-report ST was 7 h/day in comparison with 9 h/day for those with device-based ST. Higher amounts of daily ST are log-linearly associated with increased risk of all-cause mortality in adults. On the basis of a limited number of studies using device-based measures, the findings suggest that it may be appropriate to encourage adults to engage in less sedentary behaviors, with fewer than 9 h a day being relevant for all-cause mortality.

Late Infection-Related Mortality in Asplenic Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study.

PubMed

Weil, Brent R; Madenci, Arin L; Liu, Qi; Howell, Rebecca M; Gibson, Todd M; Yasui, Yutaka; Neglia, Joseph P; Leisenring, Wendy M; Smith, Susan A; Tonorezos, Emily S; Friedman, Danielle N; Constine, Louis S; Tinkle, Christopher L; Diller, Lisa R; Armstrong, Gregory T; Oeffinger, Kevin C; Weldon, Christopher B

2018-06-01

Purpose Infection-related outcomes associated with asplenia or impaired splenic function in survivors of childhood cancer remains understudied. Methods Late infection-related mortality was evaluated in 20,026 5-year survivors of childhood cancer (diagnosed < 21 years of age from 1970 to 1999; median age at diagnosis, 7.0 years [range, 0 to 20 years]; median follow-up, 26 years [range, 5 to 44 years]) using cumulative incidence and piecewise-exponential regression models to estimate adjusted relative rates (RRs). Splenic radiation was approximated using average dose (direct and/or indirect) to the left upper quadrant of the abdomen (hereafter, referred to as splenic radiation). Results Within 5 years of diagnosis, 1,354 survivors (6.8%) had a splenectomy and 9,442 (46%) had splenic radiation without splenectomy. With 62 deaths, the cumulative incidence of infection-related late mortality was 1.5% (95% CI, 0.7% to 2.2%) at 35 years after splenectomy and 0.6% (95% CI, 0.4% to 0.8%) after splenic radiation. Splenectomy (RR, 7.7; 95% CI, 3.1 to 19.1) was independently associated with late infection-related mortality. Splenic radiation was associated with increasing risk for late infection-related mortality in a dose-response relationship (0.1 to 9.9 Gy: RR, 2.0; 95% CI, 0.9 to 4.5; 10 to 19.9 Gy: RR, 5.5; 95% CI, 1.9 to 15.4; ≥ 20 Gy: RR, 6.0; 95% CI, 1.8 to 20.2). High-dose alkylator chemotherapy exposure was also independently associated with an increased risk of infection-related mortality (RR, 1.9; 95% CI, 1.1 to 3.4). Conclusion Splenectomy and splenic radiation significantly increase risk for late infection-related mortality. Even low- to intermediate-dose radiation exposure confers increased risk, suggesting that the spleen is highly radiosensitive. These findings should inform long-term follow-up guidelines for survivors of childhood cancer and should lead clinicians to avoid or reduce radiation exposure involving the spleen whenever possible.

The sequence of vaccinations and increased female mortality after high-titre measles vaccine: trials from rural Sudan and Kinshasa.

PubMed

Aaby, Peter; Ibrahim, Salah A; Libman, Michael D; Jensen, Henrik

2006-04-05

West African studies have hypothesized that increased female mortality after high-titre measles vaccine (HTMV) was due to subsequent diphtheria-tetanus-pertussis (DTP) and inactivated polio vaccine (IPV) vaccinations. We tested two deductions from this hypothesis in HTMV studies from rural Sudan and Kinshasa; first, there should be no excess female mortality for HTMV recipients when DTP was not given after HTMV and second, excess female mortality should only be found among those children who received DTP after HTMV. The Sudanese trial randomised 510 children to Edmonston-Zagreb (EZ) HTMV, Connaught HTMV or a control vaccine (meningococcal). Both the Connaught HTMV and the control group received standard measles vaccine at 9 months. In the Kinshasa study 1023 children received one dose of HTMV at 6 months or two doses at 312 and 912 months of age. First, the Sudan trial is one of the few randomised studies of measles vaccine; the EZ HTMV group had lower mortality between 5 and 9 months of age than controls, the mortality ratio (MR) being 0.00 (p = 0.030). This effect was not due to prevention of measles infection. Second, both studies provided evidence that HTMV per se was associated with low mortality. In a combined analysis comparing both HTMV groups with controls, the HTMV groups had a MR of 0.09 (0.01-0.71) between 5 and 9 months of age. In Kinshasa, the HTMV recipients who did not receive simultaneous DTP had an annual mortality rate of only 1.0% between 6 months and 3 years of age. Third, the female-male MR was related to subsequent DTP vaccinations. In Kinshasa, the female-male MR was only 0.40 (0.13-1.27) among the HTMV recipients who did not receive further doses of DTP. In Sudan, the female-male mortality ratio in the EZ group was 3.89 (95% CI 1.02-14.83) and the female-male MR increased with number of doses of DTP likely to have been given during follow-up (trend, p = 0.043). Fourth, in Kinshasa, mortality was higher among children who had received HTMV and DTP simultaneously than among children who had received HTMV alone (MR = 5.38 (1.37-21.2)). Measles vaccine is associated with non-specific beneficial effects. When not given with DTP, HTMV per se was associated with low mortality. Increased female mortality was not found among children who did not receive DTP after HTMV. Hence, our deductions were supported and the sequence or combination of vaccinations may have an effect on sex-specific mortality patterns in low-income countries.

Smoking increases risks of all-cause and breast cancer specific mortality in breast cancer individuals: a dose-response meta-analysis of prospective cohort studies involving 39725 breast cancer cases

PubMed Central

Wang, Kang; Li, Feng; Zhang, Xiang; Li, Zhuyue; Li, Hongyuan

2016-01-01

Smoking is associated with the risks of mortality from breast cancer (BC) or all causes in BC survivors. Two-stage dose-response meta-analysis was conducted. A search of PubMed and Embase was performed, and a random-effect model was used to yield summary hazard ratios (HRs). Eleven prospective cohort studies were included. The summary HR per 10 cigarettes/day, 10 pack-years, 10 years increase were 1.10 (95% confidence interval (CI) = 1.04–1.16), 1.09 (95% CI = 1.06–1.12), 1.10 (95% CI = 1.06–1.14) for BC specific mortality, and 1.15 (95% CI = 1.10–1.19), 1.15 (95% CI = 1.10–1.20), 1.17 (95% CI = 1.11–1.23) for all-cause mortality, respectively. The linear or non-linear associations between smoking and risks of mortality from BC or all causes were revealed. Subgroup analyses suggested a positive association between ever or former smoking and the risk of all-cause mortality in BC patients, especially in high doses consumption. In conclusion, higher smoking intensity, more cumulative amount of cigarettes consumption and longer time for smoking is associated with elevated risk of mortality from BC and all causes in BC individuals. The results regarding smoking cessation and “ever or former” smokers should be treated with caution due to limited studies. PMID:27863414

External radiation dose and cancer mortality among French nuclear workers: considering potential confounding by internal radiation exposure.

PubMed

Fournier, L; Laurent, O; Samson, E; Caër-Lorho, S; Laroche, P; Le Guen, B; Laurier, D; Leuraud, K

2016-11-01

French nuclear workers have detailed records of their occupational exposure to external radiation that have been used to examine associations with subsequent cancer mortality. However, some workers were also exposed to internal contamination by radionuclides. This study aims to assess the potential for bias due to confounding by internal contamination of estimates of associations between external radiation exposure and cancer mortality. A cohort of 59,004 workers employed for at least 1 year between 1950 and 1994 by CEA (Commissariat à l'Energie Atomique), AREVA NC, or EDF (Electricité de France) and badge-monitored for external radiation exposure were followed through 2004 to assess vital status and cause of death. A flag based on a workstation-exposure matrix defined four levels of potential for internal contamination. Standardized mortality ratios were assessed for each level of the internal contamination indicator. Poisson regression was used to quantify associations between external radiation exposure and cancer mortality, adjusting for potential internal contamination. For solid cancer, the mortality deficit tended to decrease as the levels of potential for internal contamination increased. For solid cancer and leukemia excluding chronic lymphocytic leukemia, adjusting the dose-response analysis on the internal contamination indicator did not markedly change the excess relative risk per Sievert of external radiation dose. This study suggests that in this cohort, neglecting information on internal dosimetry while studying the association between external dose and cancer mortality does not generate a substantial bias. To investigate more specifically the health effects of internal contamination, an effort is underway to estimate organ doses due to internal contamination.

The increase in animal mortality risk following exposure to sparsely ionizing radiation is not linear quadratic with dose

DOE PAGES

Haley, Benjamin M.; Paunesku, Tatjana; Grdina, David J.; ...

2015-12-09

The US government regulates allowable radiation exposures relying, in large part, on the seventh report from the committee to estimate the Biological Effect of Ionizing Radiation (BEIR VII), which estimated that most contemporary exposures- protracted or low-dose, carry 1.5 fold less risk of carcinogenesis and mortality per Gy than acute exposures of atomic bomb survivors. This correction is known as the dose and dose rate effectiveness factor for the life span study of atomic bomb survivors (DDREF LSS). As a result, it was calculated by applying a linear-quadratic dose response model to data from Japanese atomic bomb survivors and amore » limited number of animal studies.« less

The increase in animal mortality risk following exposure to sparsely ionizing radiation is not linear quadratic with dose

DOE Office of Scientific and Technical Information (OSTI.GOV)

Haley, Benjamin M.; Paunesku, Tatjana; Grdina, David J.

The US government regulates allowable radiation exposures relying, in large part, on the seventh report from the committee to estimate the Biological Effect of Ionizing Radiation (BEIR VII), which estimated that most contemporary exposures- protracted or low-dose, carry 1.5 fold less risk of carcinogenesis and mortality per Gy than acute exposures of atomic bomb survivors. This correction is known as the dose and dose rate effectiveness factor for the life span study of atomic bomb survivors (DDREF LSS). As a result, it was calculated by applying a linear-quadratic dose response model to data from Japanese atomic bomb survivors and amore » limited number of animal studies.« less

The effect of Haemophilus influenzae type B and pneumococcal conjugate vaccines on childhood meningitis mortality: a systematic review

PubMed Central

2013-01-01

Background Two of the most prevalent causes of severe bacterial meningitis in children, Haemophilus influenzae type B (Hib) and Streptococcus pneumoniae, are preventable by existing vaccines increasingly available in developing countries. Our objective was to estimate the dose-specific effect of Hib and pneumococcal conjugate vaccines (PCV) on childhood meningitis mortality in low-income countries for use in the Lives Saved Tool (LiST). Methods We systematically searched and reviewed published vaccine efficacy trials and observational studies reporting the effect of Hib or PCV vaccines on organism-specific meningitis, bacterial meningitis and all-cause meningitis incidence and mortality among children less than five years old in low- and middle-income countries. Data collection and quality assessments were performed using standardized guidelines. For outcomes available across multiple studies (≥2) and approximating meningitis mortality, we pooled estimates reporting dose-specific effects using random effects meta-analytic methods, then combined these with meningitis etiology data to determine the preventable fraction of childhood meningitis mortality for inclusion in LiST. Results We identified 18 studies of Hib conjugate vaccines reporting relevant meningitis morbidity and mortality outcomes (2 randomized controlled trials [RCTs], 16 observational studies) but few provided dose-specific effects. A meta-analysis of four case-control studies examined the dose-specific effect of Hib conjugate vaccines on Hib meningitis morbidity (1 dose: RR=0.64, 95% CI 0.38-1.06; 2 doses: RR=0.09, 95% CI 0.03-0.27; 3 doses: RR=0.06, 95% CI 0.02-0.22), consistent with results from single RCTs. Pooled estimates of two RCTs provided evidence for the effect of three doses of PCV on vaccine-serotype meningitis morbidity (RR=0.16, 95% CI 0.02-1.20). We considered these outcomes of severe disease as proxy estimates for meningitis mortality and combined the estimates of protective effects with meningitis etiology data to provide an estimate of the preventable fraction of childhood meningitis mortality with three doses of Hib (38-43%) and pneumococcal conjugate vaccines (28-35%) for use in LiST. Conclusions Few RCTs or vaccine effectiveness studies evaluated the dose-specific impact of Hib and PCV vaccines on childhood meningitis mortality, necessitating use of proxy measures to estimate population impact in LiST. Our analysis indicates that approximately three-quarters of meningitis deaths are preventable with existing Hib and PCV vaccines. PMID:24564188

Maternal Tetanus Toxoid Vaccination and Neonatal Mortality in Rural North India

PubMed Central

Singh, Abhishek; Pallikadavath, Saseendran; Ogollah, Reuben; Stones, William

2012-01-01

Objectives Preventable neonatal mortality due to tetanus infection remains common. We aimed to examine antenatal vaccination impact in a context of continuing high neonatal mortality in rural northern India. Methods and Findings Using the third round of the Indian National Family Health Survey (NFHS) 2005–06, mortality of most recent singleton births was analysed in discrete-time logistic model with maternal tetanus vaccination, together with antenatal care utilisation and supplementation with iron and folic acid. 59% of mothers reported receiving antenatal care, 48% reported receiving iron and folic acid supplementation and 68% reported receiving two or more doses of tetanus toxoid (TT) vaccination. The odds of all-cause neonatal death were reduced following one or more antenatal dose of TT with odds ratios (OR) of 0.46 (95% CI 0.26 to 0.78) after one dose and 0.45 (95% CI 0.31 to 0.66) after two or more doses. Reported utilisation of antenatal care and iron-folic acid supplementation did not influence neonatal mortality. In the statistical model, 16% (95% CI 5% to 27%) of neonatal deaths could be attributed to a lack of at least two doses of TT vaccination during pregnancy, representing an estimated 78,632 neonatal deaths in absolute terms. Conclusions Substantial gains in newborn survival could be achieved in rural North India through increased coverage of antenatal TT vaccination. The apparent substantial protective effect of a single antenatal dose of TT requires further study. It may reflect greater population vaccination coverage and indicates that health programming should prioritise universal antenatal coverage with at least one dose. PMID:23152814

Maternal tetanus toxoid vaccination and neonatal mortality in rural north India.

PubMed

Singh, Abhishek; Pallikadavath, Saseendran; Ogollah, Reuben; Stones, William

2012-01-01

Preventable neonatal mortality due to tetanus infection remains common. We aimed to examine antenatal vaccination impact in a context of continuing high neonatal mortality in rural northern India. Using the third round of the Indian National Family Health Survey (NFHS) 2005-06, mortality of most recent singleton births was analysed in discrete-time logistic model with maternal tetanus vaccination, together with antenatal care utilisation and supplementation with iron and folic acid. 59% of mothers reported receiving antenatal care, 48% reported receiving iron and folic acid supplementation and 68% reported receiving two or more doses of tetanus toxoid (TT) vaccination. The odds of all-cause neonatal death were reduced following one or more antenatal dose of TT with odds ratios (OR) of 0.46 (95% CI 0.26 to 0.78) after one dose and 0.45 (95% CI 0.31 to 0.66) after two or more doses. Reported utilisation of antenatal care and iron-folic acid supplementation did not influence neonatal mortality. In the statistical model, 16% (95% CI 5% to 27%) of neonatal deaths could be attributed to a lack of at least two doses of TT vaccination during pregnancy, representing an estimated 78,632 neonatal deaths in absolute terms. Substantial gains in newborn survival could be achieved in rural North India through increased coverage of antenatal TT vaccination. The apparent substantial protective effect of a single antenatal dose of TT requires further study. It may reflect greater population vaccination coverage and indicates that health programming should prioritise universal antenatal coverage with at least one dose.

Effects of in utero and lactational exposure to triphenyltin chloride on pregnancy outcome and postnatal development in rat offspring.

PubMed

Grote, Konstanze; Hobler, Carolin; Andrade, Anderson J M; Grande, Simone Wichert; Gericke, Christine; Talsness, Chris E; Appel, Klaus E; Chahoud, Ibrahim

2007-09-05

The organotin compound (OTC) triphenyltin (TPT) is used extensively as a herbicide, pesticide and fungicide in agriculture as well as, together with tributyltin (TBT), in marine antifouling paints. We studied the effects of in utero exposure to 2 or 6 mg triphenyltinchloride (TPTCl)/kgb.w. on pregnancy outcome and postnatal development in rat offspring. Gravid Wistar rats were treated per gavage from gestational day 6 until the end of lactation. In the 6 mg TPTCl dose group gestational mortality in dams as well as an increased incidence of anticipated and delayed parturition was observed. Furthermore, treatment resulted in a significant increase in perinatal mortality, a decrease in lactational body weight gain as well as in delayed physical maturation of offspring. Similarily, exposure to 2mg TPTCl/kgb.w. resulted in a significant increase in perinatal mortality and in delayed eye opening. Lactational body weight gain and other landmarks of physical maturation were unaffected in the low dose group. We conclude, that in utero exposure to TPTCl at the described dose levels severely affected pregnancy outcome and perinatal survival of offspring. These results were unexpected, as in two earlier studies with pubertal rats TPTCl at the same dose levels no signs of general toxicity were observed.

Seasonal Variation in Solar Ultra Violet Radiation and Early Mortality in Extremely Preterm Infants.

PubMed

Salas, Ariel A; Smith, Kelly A; Rodgers, Mackenzie D; Phillips, Vivien; Ambalavanan, Namasivayam

2015-11-01

Vitamin D production during pregnancy promotes fetal lung development, a major determinant of infant survival after preterm birth. Because vitamin D synthesis in humans is regulated by solar ultraviolet B (UVB) radiation, we hypothesized that seasonal variation in solar UVB doses during fetal development would be associated with variation in neonatal mortality rates. This cohort study included infants born alive with gestational age (GA) between 23 and 28 weeks gestation admitted to a neonatal unit between 1996 and 2010. Three infant cohort groups were defined according to increasing intensities of solar UVB doses at 17 and 22 weeks gestation. The primary outcome was death during the first 28 days after birth. Outcome data of 2,319 infants were analyzed. Mean birth weight was 830 ± 230 g and median gestational age was 26 weeks. Mortality rates were significantly different across groups (p = 0.04). High-intensity solar UVB doses were associated with lower mortality when compared with normal intensity solar UVB doses (hazard ratio: 0.70; 95% confidence interval: 0.54-0.91; p = 0.01). High-intensity solar UVB doses during fetal development seem to be associated with risk reduction of early mortality in preterm infants. Prospective studies are needed to validate these preliminary findings. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Age-Based Methods to Explore Time-Related Variables in Occupational Epidemiology Studies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Janice P. Watkins, Edward L. Frome, Donna L. Cragle

2005-08-31

Although age is recognized as the strongest predictor of mortality in chronic disease epidemiology, a calendar-based approach is often employed when evaluating time-related variables. An age-based analysis file, created by determining the value of each time-dependent variable for each age that a cohort member is followed, provides a clear definition of age at exposure and allows development of diverse analytic models. To demonstrate methods, the relationship between cancer mortality and external radiation was analyzed with Poisson regression for 14,095 Oak Ridge National Laboratory workers. Based on previous analysis of this cohort, a model with ten-year lagged cumulative radiation doses partitionedmore » by receipt before (dose-young) or after (dose-old) age 45 was examined. Dose-response estimates were similar to calendar-year-based results with elevated risk for dose-old, but not when film badge readings were weekly before 1957. Complementary results showed increasing risk with older hire ages and earlier birth cohorts, since workers hired after age 45 were born before 1915, and dose-young and dose-old were distributed differently by birth cohorts. Risks were generally higher for smokingrelated than non-smoking-related cancers. It was difficult to single out specific variables associated with elevated cancer mortality because of: (1) birth cohort differences in hire age and mortality experience completeness, and (2) time-period differences in working conditions, dose potential, and exposure assessment. This research demonstrated the utility and versatility of the age-based approach.« less

Proton pump inhibitors and risk of 1-year mortality and rehospitalization in older patients discharged from acute care hospitals.

PubMed

Maggio, Marcello; Corsonello, Andrea; Ceda, Gian Paolo; Cattabiani, Chiara; Lauretani, Fulvio; Buttò, Valeria; Ferrucci, Luigi; Bandinelli, Stefania; Abbatecola, Angela Marie; Spazzafumo, Liana; Lattanzio, Fabrizia

2013-04-08

The use of proton pump inhibitors (PPIs) has rapidly increased during the past several years. However, concern remains about risks associated with their long-term use in older populations. To investigate the relationship between the use of PPIs and the risk of death or the combined end point of death or rehospitalization in older patients discharged from acute care hospitals. We investigated the relationship between PPI use and study outcomes using time-dependent Cox proportional hazards regression in patients 65 years or older discharged from acute care medical wards from April 1 to June 30, 2007. Eleven acute care medical wards. Four hundred ninety-one patients (mean [SD] age, 80.0 [5.9] years). Mortality and the combined end point of death or rehospitalization. RESULTS The use of PPIs was independently associated with mortality (hazard ratio, 1.51 [95% CI, 1.03-2.77]) but not with the combined end point (1.49 [0.98-2.17]). An increased risk of mortality was observed among patients exposed to high-dose PPIs vs none (hazard ratio, 2.59 [95% CI, 1.22-7.16]). In older patients discharged from acute care hospitals, the use of high-dose PPIs is associated with increased 1-year mortality. Randomized controlled studies including older frail patients are needed. In the meantime, physicians need to use caution and balance benefits and harms in long-term prescription of high-dose PPIs.

Pathology effects at radiation doses below those causing increased mortality

NASA Technical Reports Server (NTRS)

Carnes, Bruce A.; Gavrilova, Natalia; Grahn, Douglas

2002-01-01

Mortality data from experiments conducted at the Argonne National Laboratory (ANL) on the long-term effects of external whole-body irradiation on B6CF(1) mice were used to investigate radiation-induced effects at intermediate doses of (60)Co gamma rays or fission-spectrum neutrons either delivered as a single exposure or protracted over 60 once-weekly exposures. Kaplan-Meier analyses were used to identify the lowest dose in the ANL data (within radiation quality, pattern of exposure, and sex) at which radiation-induced mortality caused by primary tumors could be detected (approximately 1-2 Gy for gamma rays and 10-15 cGy for neutrons). Doses at and below these levels were then examined for radiation-induced shifts in the spectrum of pathology detected at death. To do this, specific pathology events were pooled into larger assemblages based on whether they were cancer, cardiovascular disease or non-neoplastic diseases detected within the lungs and pleura, liver and biliary tract, reproductive organs, or urinary tract. Cancer and cardiovascular disease were further subdivided into categories based on whether they caused death, contributed to death, or were simply observed at death. Counts of how often events falling within each of these combined pathology categories occurred within a mouse were then used as predictor variables in logistic regression to determine whether irradiated mice could be distinguished from control mice. Increased pathology burdens were detected in irradiated mice at doses lower than those causing detectable shifts in mortality-22 cGy for gamma rays and 2 cGy for neutrons. These findings suggest that (1) models based on mortality data alone may underestimate radiation effects, (2) radiation may have adverse health consequences (i.e. elevated health risks) even when mortality risks are not detected, and (3) radiation-induced pathologies other than cancer do occur, and they involve multiple organ systems.

Prevention of febrile neutropenia: use of prophylactic antibiotics.

PubMed

Cullen, M; Baijal, S

2009-09-01

Febrile neutropenia (FN) causes significant morbidity and mortality in patients receiving cytotoxic chemotherapy and can lead to reduced chemotherapy dose intensity and increased overall treatment costs. Antibiotic prophylaxis reduces the incidence of FN. Recent research and meta-analyses confirm that prophylactic fluoroquinolones decrease FN and infection-related mortality in patients with acute leukaemia and those receiving high-dose chemotherapy. Fluoroquinolone prophylaxis also lowers the incidence of FN and all-cause mortality following the first cycle of myelosuppressive chemotherapy for solid tumours. Levofloxacin has been the agent studied most thoroughly in this context. Although there is no convincing evidence that colonisation of individuals with resistant organisms due to antibiotic prophylaxis increases FN or mortality, such concerns must be taken seriously and the use of prophylaxis should be limited responsibly for patients with the greatest chance of benefit. Fluoroquinolone prophylaxis is well tolerated and cost-effective and should be offered to patients receiving chemotherapy for haematological malignancies and high-dose chemotherapy for solid tumours in which prolonged (>7 days) neutropenia is expected. It should also be considered for those receiving chemotherapy for solid tumours and lymphomas during the first cycle of chemotherapy when grade 4 neutropenia is anticipated.

Prevention of febrile neutropenia: use of prophylactic antibiotics

PubMed Central

Cullen, M; Baijal, S

2009-01-01

Febrile neutropenia (FN) causes significant morbidity and mortality in patients receiving cytotoxic chemotherapy and can lead to reduced chemotherapy dose intensity and increased overall treatment costs. Antibiotic prophylaxis reduces the incidence of FN. Recent research and meta-analyses confirm that prophylactic fluoroquinolones decrease FN and infection-related mortality in patients with acute leukaemia and those receiving high-dose chemotherapy. Fluoroquinolone prophylaxis also lowers the incidence of FN and all-cause mortality following the first cycle of myelosuppressive chemotherapy for solid tumours. Levofloxacin has been the agent studied most thoroughly in this context. Although there is no convincing evidence that colonisation of individuals with resistant organisms due to antibiotic prophylaxis increases FN or mortality, such concerns must be taken seriously and the use of prophylaxis should be limited responsibly for patients with the greatest chance of benefit. Fluoroquinolone prophylaxis is well tolerated and cost-effective and should be offered to patients receiving chemotherapy for haematological malignancies and high-dose chemotherapy for solid tumours in which prolonged (>7 days) neutropenia is expected. It should also be considered for those receiving chemotherapy for solid tumours and lymphomas during the first cycle of chemotherapy when grade 4 neutropenia is anticipated. PMID:19756000

The effects of steroids during sepsis depend on dose and severity of illness: an updated meta-analysis

PubMed Central

Minneci, P. C.; Deans, K. J.; Eichacker, P. Q.; Natanson, C.

2012-01-01

A previous meta-analysis determined that the effects of steroids during sepsis were dose-dependent; since then, additional trials have been published. The current analysis updates our previous analysis examining the effects of steroids during sepsis. A literature search from 2004 to 2008 identified seven randomized controlled trials in adult patients; these were added to 14 previously identified trials. The effects of steroids on mortality were highly variable among the 21 trials (p <0.001, I2 = 60%). In trials published before 1989, which involved short courses of high-dose steroids, steroids increased mortality (n = 8, I2 = 14%, OR of death 1.39 (95% CI 1.04–1.86), p 0.03). In trials published after 1997, which involved longer courses of lower-dose steroids, steroids consistently improved shock reversal (n = 7, I2 = 0%, OR of shock reversal 1.66 [95% CI 1.25–2.20), p <0.001), but demonstrated a more heterogeneous beneficial effect on mortality (n = 12, I2 = 25%, OR of death 0.64 (95% CI 0.45–0.93), p 0.02). An inverse linear relationship between severity of illness and the effects of steroids on mortality was identified across all trials (p 0.03) and within the subgroup of trials published after 1997 (p 0.03); steroids were harmful in less severely ill patient populations and beneficial in more severely ill patient populations. There was no effect of response to adrenocorticotrophic hormone (ACTH) stimulation testing concerning the effects of steroids and no increase in steroid-associated adverse events. Low-dose steroids appear to improve mortality rates in patients with septic shock who are at high risk of death; however, additional trials in this subpopulation are necessary to definitively determine the role of low-dose steroids during sepsis. PMID:19416302

In HFREF patients, sacubitril/valsartan, given at relatively low doses, does not lead to increased mortality or hospitalization : A retrospective cohort study.

PubMed

De Vecchis, R; Ariano, C; Di Biase, G; Noutsias, M

2018-03-08

In heart failure with reduced left ventricular ejection fraction (HFREF) patients, the dosage of sacubitril/valsartan is modulated according to a gradual increase regimen. Nevertheless, if patients exhibit tolerability problems, a provisional reduction of the dose of sacubitril/valsartan or even its interruption are recommended. This study provides estimates of respective proportions of patients receiving minimum or intermediate doses of sacubitril/valsartan. In addition, a comparison was made to detect possible differences regarding all-cause mortality and heart failure hospitalization in patients treated with the recommended optimum dose compared to those receiving submaximum maintenance doses of sacubitril/valsartan. Patients treated with sacubitril/valsartan in addition to beta-blocker and mineralocorticoid receptor blocker were 68. Among them, 20 patients (29.4%), were identified as having clinical features that were contraindications to the administration of sacubitril/valsartan at full dose. The subsequent decision was to maintain an intermediate dose in 11 patients and to reduce the dose to the minimum level allowed, i.e., 24 mg/26 mg twice daily in nine patients. After a median follow-up of 5.25 months, no differences were found concerning the risk of all-cause death by comparing patients treated with reduced versus those subjected to target doses of sacubitril/valsartan (odds ratio [OR] = 1.666; 95% confidence interval [CI] = 0.256-10.823; p = 0.6266). Patients taking reduced doses had a similar risk of heart failure hospitalizations when compared to patients treated with the target dose (OR = 0.789; 95% CI: 0.077-8.0808; p = 1.00). During a median follow-up of 5.25 months, in the group of patients who had proven to be intolerant to the maximum dose of sacubitril/valsartan, use of reduced doses of the drug did not result in increased all-cause mortality or heart failure hospitalization compared to patients treated with sacubitril/valsartan at the target dose.

Pre-Bombing Population Density in Hiroshima and Nagasaki: Its Measurement and Impact on Radiation Risk Estimates in the Life Span Study of Atomic Bomb Survivors.

PubMed

French, Benjamin; Funamoto, Sachiyo; Sugiyama, Hiromi; Sakata, Ritsu; Cologne, John; Cullings, Harry M; Mabuchi, Kiyohiko; Preston, Dale L

2018-03-29

In the Life Span Study of atomic bomb survivors, differences in urbanicity between high-dose and low-dose survivors could confound the association between radiation dose and adverse outcomes. We obtained data on the pre-bombing population distribution in Hiroshima and Nagasaki, and quantified the impact of adjustment for population density on radiation risk estimates for mortality (1950-2003) and incident solid cancer (1958-2009). Population density ranged from 4,671-14,378 and 5,748-19,149 people/km2 in urban regions of Hiroshima and Nagasaki, respectively. Radiation risk estimates for solid cancer mortality were attenuated by 5.1%, but those for all-cause mortality and incident solid cancer were unchanged. There was no overall association between population density and adverse outcomes, but there was evidence that the association between density and mortality differed by age at exposure. Among survivors 10-14 years old in 1945, there was a positive association between population density and risk of all-cause mortality (relative risk, 1.053 per 5,000 people/km2 increase, 95% confidence interval: 1.027, 1.079) and solid cancer mortality (relative risk, 1.069 per 5,000 people/km2 increase, 95% confidence interval: 1.025, 1.115). Our results suggest that radiation risk estimates from the Life Span Study are not sensitive to unmeasured confounding by urban-rural differences.

Comparative toxicity and micronuclei formation in Tribolium castaneum, Callosobruchus maculatus and Sitophilus oryzae exposed to high doses of gamma radiation.

PubMed

Ahmadi, Mehrdad; Mozdarani, Hossein; Abd-Alla, Adly M M

2015-07-01

The effects of gamma radiation on mortality and micronucleus formation in Tribolium castaneum Herbst, Callosobruchus maculatus (F.) and Sitophilus oryzae (L.) genital cells were evaluated. Two groups of healthy and active adult insects 1-3 and 8-10 days old were irradiated with various doses (50-200 Gy) gamma ray. Seven days post-irradiation; mortality rates and micronucleus formation were assessed in genital cells of the irradiated insects. The results show that with increasing gamma doses, the mortality rate of each species increased and T. castaneum and S. oryzae showed the low and high sensitivity respectively. It was shown that the micronucleus appearance in the tested insects had correlation with amount and intensity of radiation doses. Moreover our results indicate different levels in the genotoxicity of gamma radiation among the insects' genital cells under study. The frequency of micronuclei in genital cells of 1-3 days old insects exposed to 50 and 200 Gy were 12.6 and 38.8 Mn/1000 cells in T. castaneum, 20.8 and 46.8 Mn/1000 cells in C. maculatus and 16.8 and 57.2 Mn/1000 cells in S. oryzae respectively. A high sensitivity of the genital cells to irradiation exposure was seen in S. oryzae correlated with its high mortality rate compared with the other two species. These results might be indicative of inflicting chromosomal damage expressed as micronucleus in high mortality rates observed in the pest population; an indication of genotoxic effects of radiation on the studied species. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cancer mortality among coke oven workers.

PubMed Central

Redmond, C K

1983-01-01

The OSHA standard for coke oven emissions, which went into effect in January 1977, sets a permissible exposure limit to coke oven emissions of 150 micrograms/m3 benzene-soluble fraction of total particulate matter (BSFTPM). Review of the epidemiologic evidence for the standard indicates an excess relative risk for lung cancer as high as 16-fold in topside coke oven workers with 15 years of exposure or more. There is also evidence for a consistent dose-response relationship in lung cancer mortality when duration and location of employment at the coke ovens are considered. Dose-response models fitted to these same data indicate that, while excess risks may still occur under the OSHA standard, the predicted levels of increased relative risk would be about 30-50% if a linear dose-response model is assumed and 3-7% if a quadratic model is assumed. Lung cancer mortality data for other steelworkers suggest the predicted excess risk has probably been somewhat overestimated, but lack of information on important confounding factors limits further dose-response analysis. PMID:6653539

THE STATE OF IMMUNITY IN GUINEA-PIGS IMMUNIZED WITH LIVE BRUCELLOSIS VACCINE AND EXPOSED TO RADIATION

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shevtsova, Z.V.

1960-01-01

On immunization with 19-BA live brucellosis vaccine on the 3rd and 10th days after exposure to radiation in a dose of 200 r, guinea pigs died 4 and 2 times more frequently than unvaccinated guinea pigs. If immunization was carried out on the 30th day after irradiation the mortality among irradiated animals showed only a slight increase compared with the mortality among unvaccinated control animals. Immunization carried out before exposure to radiation had no influence upon the mortality of the animals caused by radiation sickness. Guinea pigs immunized after exposure to radiation were insusceptible when infected with the doses ofmore » virulent strains of Brucella usually employed to challenge immunity (2-4 infective doses). If, however, the animals were infected with a dose twice as high (8 infective doses) the degree of immunity proved to be lower in guinea pigs exposed to radiation, than in guinea pigs immunized and not exposed to radiation. Exposure of guinea pigs to radiation at a time when immunity had already developed had no influence upon the degree of immunity on infection with 4 infective doses of the virulent strain. (auth)« less

Innate resistance of mice to experimental infection with Naegleria fowleri.

PubMed Central

Haggerty, R M; John, D T

1978-01-01

The mouse system provides an excellent model for studying host resistance to Naegleria fowleri, the agent of primary amoebic meningoencephalitis. Innate resistance to infection with N. fowleri was examined with respect to infecting dose and the age, sex, and strain of mice. Intravenous inoculation with 10(7) amoebae per mouse produced 100% mortality in 9 days, whereas inoculation with fewer amoebae reduced the cumulative mortality. Male and female DUB/ICR mice of varying ages were inoculated intravenously with 2.5 X 10(5) N. fowleri per g of body weight. The youngest mice died first, with 100% mortality for both males and females, and mortality decreased with increasing age. Female mice were significantly more resistant to infection than males. Five strains of mice weighing approximately 20 g were inoculated intravenously with weight-adjusted doses; mortality ranged from 10% in C57BL/6 mice to 95% in A/HeCr mice. PMID:669800

A dose-response of consuming high fructose corn syrup-sweetened beverages on lipid/lipoprotein risk factors for cardiovascular disease in young adults

USDA-ARS?s Scientific Manuscript database

National Health and Nutrition Examination Survey data show increased risk of cardiovascular disease (CVD) mortality with increased intake of added sugar across quintiles. Objective: To determine the dose response effects of consuming beverages sweetened with high fructose corn syrup (HFCS) at zero, ...

Hemodialysis patients receiving a greater Kt dose than recommended have reduced mortality and hospitalization risk.

PubMed

Maduell, Francisco; Ramos, Rosa; Varas, Javier; Martin-Malo, Alejandro; Molina, Manuel; Pérez-Garcia, Rafael; Marcelli, Daniele; Moreso, Francesc; Aljama, Pedro; Merello, Jose Ignacio

2016-12-01

Achieving an adequate dialysis dose is one of the key goals for dialysis treatments. Here we assessed whether patients receiving the current cleared plasma volume (Kt), individualized for body surface area per recommendations, had improved survival and reduced hospitalizations at 2 years of follow-up. Additionally, we assessed whether patients receiving a greater dose gained more benefit. This prospective, observational, multicenter study included 6129 patients in 65 Fresenius Medical Care Spanish facilities. Patients were classified monthly into 1 of 10 risk groups based on the difference between achieved and target Kt. Patient groups with a more negative relationship were significantly older with a higher percentage of diabetes mellitus and catheter access. Treatment dialysis time, effective blood flow, and percentage of on-line hemodiafiltration were significantly higher in groups with a higher dose. The mortality risk profile showed a progressive increase when achieved minus target Kt became more negative but was significantly lower in the group with 1 to 3 L clearance above target Kt and in groups with greater increases above target Kt. Additionally, hospitalization risk appeared significantly reduced in groups receiving 9 L or more above the minimum target. Thus, prescribing an additional 3 L or more above the minimum Kt dose could potentially reduce mortality risk, and 9 L or more reduce hospitalization risk. As such, future prospective studies are required to confirm these dose effect findings. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

AP214, an analogue of α-melanocyte-stimulating hormone, ameliorates sepsis-induced acute kidney injury and mortality

PubMed Central

Doi, Kent; Hu, Xuzhen; Yuen, Peter S.T.; Leelahavanichkul, Asada; Yasuda, Hideo; Kim, Soo Mi; Schnermann, Jürgen; Jonassen, Thomas E.N.; Frøkiær, Jørgen; Nielsen, Søren; Star, Robert A.

2008-01-01

Sepsis remains a serious problem in critically ill patients with the mortality increasing to over half when there is attendant acute kidney injury. α-Melanocyte-stimulating hormone is a potent anti-inflammatory cytokine that inhibits many forms of inflammation including that with acute kidney injury. We tested whether a new α-melanocyte-stimulating hormone analogue (AP214), which has increased binding affinity to melanocortin receptors, improves sepsis-induced kidney injury and mortality using a cecal ligation and puncture mouse model. In the lethal cecal ligation-puncture model of sepsis, severe hypotension and bradycardia resulted and AP214 attenuated acute kidney injury of the lethal model with a bell-shaped dose-response curve. An optimum AP214 dose reduced acute kidney injury even when it was administered 6 hr after surgery and it significantly improved blood pressure and heart rate. AP214 reduced serum TNF-α and IL-10 levels with a bell-shaped dose-response curve. Additionally; NF-κB activation in the kidney and spleen, and splenocyte apoptosis were decreased by the treatment. AP214 significantly improved survival in both lethal and sublethal models. We have shown that AP214 improves hemodynamic failure, acute kidney injury, mortality and splenocyte apoptosis attenuating pro- and anti-inflammatory actions due to sepsis. PMID:18354376

Daytime Napping and the Risk of Cardiovascular Disease and All-Cause Mortality: A Prospective Study and Dose-Response Meta-Analysis

PubMed Central

Yamada, Tomohide; Hara, Kazuo; Shojima, Nobuhiro; Yamauchi, Toshimasa; Kadowaki, Takashi

2015-01-01

Study Objectives: To summarize evidence about the association between daytime napping and the risk of cardiovascular disease and all-cause mortality, and to quantify the potential dose-response relation. Design: Meta-analysis of prospective cohort studies. Methods and Results: Electronic databases were searched for articles published up to December 2014 using the terms nap, cardiovascular disease, and all-cause mortality. We selected well-adjusted prospective cohort studies reporting risk estimates for cardiovascular disease and all-cause mortality related to napping. Eleven prospective cohort studies were identified with 151,588 participants (1,625,012 person-years) and a mean follow-up period of 11 years (60% women, 5,276 cardiovascular events, and 18,966 all-cause deaths). Pooled analysis showed that a long daytime nap (≥ 60 min/day) was associated with a higher risk of cardiovascular disease (rate ratio [RR]: 1.82 [1.22–2.71], P = 0.003, I2 = 37%) compared with not napping. All-cause mortality was associated with napping for ≥ 60 min/day (RR: 1.27 [1.11–1.45], P < 0.001, I2 = 0%) compared with not napping. In contrast, napping for < 60 min/day was not associated with cardiovascular disease (P = 0.98) or all-cause mortality (P = 0.08). Meta-analysis demonstrated a significant J-curve dose-response relation between nap time and cardiovascular disease (P for nonlinearity = 0.01). The RR initially decreased from 0 to 30 min/day. Then it increased slightly until about 45 min/day, followed by a sharp increase at longer nap times. There was also a positive linear relation between nap time and all-cause mortality (P for non-linearity = 0.97). Conclusions: Nap time and cardiovascular disease may be associated via a J-curve relation. Further studies are needed to confirm the efficacy of a short nap. Citation: Yamada T, Hara K, Shojima N, Yamauchi T, Kadowaki T. Daytime napping and the risk of cardiovascular disease and all-cause mortality: a prospective study and dose-response meta-analysis. SLEEP 2015;38(12):1945–1953. PMID:26158892

Lung damage following bone marrow transplantation. II. The contribution of cyclophosphamide

DOE Office of Scientific and Technical Information (OSTI.GOV)

Varekamp, A.E.; de Vries, A.J.; Zurcher, C.

1987-10-01

The effect of high-dose cyclophosphamide (Cy), either alone or in combination with irradiation, upon the development of interstitial pneumonitis (IP) after bone marrow transplantation (BMT) was investigated in a Brown Norway rat model. The parameters that were examined included ventilation rate, mortality, and histopathology. No damage to the lungs was observed in rats given Cy alone in supralethal dosages plus BMT, and mortality resulted from severe aplasia of hemopoietic and lymphoid tissues with multifocal hemorrhages, secondary infections, and sepsis. Two separate periods of mortality were observed within the first 180 days following whole thorax irradiation with a high dose ratemore » (HDR; 0.8 Gy/min) or a low dose rate (LDR; 0.05 Gy/min). The addition of Cy prior to irradiation resulted in an increased mortality in the first period (before day 100) in all experimental groups. The influence of Cy on mortality at 180 days however, was different for the HDR and LDR experiments. The LD50-180 after HDR irradiation, dose range 8 to 18 Gy, was not significantly altered by the addition of Cy (100 mg/kg) 1 day prior to irradiation, whereas Cy (100 mg/kg) 1 day prior to LDR irradiation, dose range: 16 to 24 Gy, caused an enhancement of radiation damage with a decrease of the LD50-180 by 1.33 Gy. The dose modification factor (DMF) was 1.07. This enhancement was no longer significant after splitting up the dose of Cy in two dosages of 50 mg/kg given on 2 consecutive days prior to irradiation with a LDR. The extrapolation of the data in this rat model to available dose-response curves on IP after BMT and radiation pneumonitis in humans, implied that non-infectious IP is a radiation pneumonitis that is only slightly enhanced by Cy.« less

Refuting the ticagrelor-aspirin black box warning: and proposing a ticagrelor early-PCI black box warning.

PubMed

DiNicolantonio, James J; Serebruany, Victor L; Tomek, Ales

2013-10-03

Ticagrelor, a novel reversible antiplatelet agent, has a black box warning to avoid maintenance doses of aspirin>100mg. However, a significant ticagrelor-early percutaneous coronary intervention (PCI) interaction exists. To discuss the inappropriateness of the black box warning for aspirin doses>100mg with ticagrelor and the appropriateness (and need) for a black box warning for ticagrelor patients needing early (within 24 hours of randomization) PCI. The FDA Complete Response Review for ticagrelor indicates that aspirin doses ≥ 300 mg/daily was not a significant interaction. In the ticagrelor-aspirin ≥ 300 mg cohort, all-cause mortality (through study end) and cardiovascular (CV) mortality (through study end) were not significantly increased (HR=1.27; 95% CI, 0.84-1.93, p=0.262 and HR=1.39; 95% CI:0.87-2.2, p=0.170), respectively. However, in patients treated with early (within 24 hours) PCI, ticagrelor significantly increased all-cause mortality (30 day: HR=1.89; 95% CI: 1.26-2.81, p=0.002, and through study end, HR=1.41; 95% CI,1.08-1.84, p=0.012) and increased CV mortality (30 day: HR=1.31; 95% CI: 0.97-1.77, p=0.075, and through study end, HR=1.35; 95% CI, 0.995-1.82, p=0.054) compared to clopidogrel. Early-PCI was more prevalent in the US versus outside-US regions (61% versus 49%). The black box warning for the use of maintenance aspirin doses over 100mg/daily with ticagrelor is inappropriate and ignores the more important, credible, and highly significant ticagrelor-early PCI adverse interaction in PLATO. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Challenging the FDA black box warning for high aspirin dose with ticagrelor in patients with diabetes.

PubMed

DiNicolantonio, James J; Serebruany, Victor L

2013-03-01

Ticagrelor, a novel reversible antiplatelet agent, has a Food and Drug Administration (FDA) black box warning to avoid maintenance doses of aspirin (ASA) >100 mg/daily. This restriction is based on the hypothesis that ASA doses >100 mg somehow decreased ticagrelor's benefit in the Platelet Inhibition and Patient Outcomes (PLATO) U.S. cohort. However, these data are highly postrandomized, come from a very small subgroup in PLATO (57% of patients in the U.S. site), and make no biological sense. Moreover, the ticagrelor-ASA interaction was not significant by any multivariate Cox regression analyses. The Complete Response Review for ticagrelor indicates that for U.S. PLATO patients, an ASA dose >300 mg was not a significant interaction for vascular outcomes. In the ticagrelor-ASA >300 mg cohort, all-cause and vascular mortality were not significantly increased (hazard ratio [HR] 1.27 [95% CI 0.84-1.93], P = 0.262 and 1.39 [0.87-2.2], P = 0.170), respectively. Furthermore, for major adverse cardiovascular events (MACEs), 30-day all-cause mortality, and 30-day vascular mortality, the strongest interaction is the diabetes-ASA interaction. That is, patients who had diabetes had significantly fewer MACEs through study end (0.49 [0.34-0.63], P < 0.0001), significantly less 30-day all-cause mortality (0.33 [0.20-0.56], P < 0.0001), and significantly less 30-day vascular mortality (0.35 [0.22-0.55], P < 0.0001), respectively, when given high-dose (300-325 mg) ASA, regardless of treatment (clopidogrel or ticagrelor) assignment. The black box warning for the use of maintenance ASA doses >100 mg with ticagrelor is inappropriate for patients with diabetes and not evidence based.

Dose-response relationships between internally-deposited uranium and select health outcomes in gaseous diffusion plant workers, 1948-2011.

PubMed

Yiin, James H; Anderson, Jeri L; Bertke, Stephen J; Tollerud, David J

2018-05-09

To examine dose-response relationships between internal uranium exposures and select outcomes among a cohort of uranium enrichment workers. Cox regression was conducted to examine associations between selected health outcomes and cumulative internal uranium with consideration for external ionizing radiation, work-related medical X-rays and contaminant radionuclides technetium ( 99 Tc) and plutonium ( 239 Pu) as potential confounders. Elevated and monotonically increasing mortality risks were observed for kidney cancer, chronic renal diseases, and multiple myeloma, and the association with internal uranium absorbed organ dose was statistically significant for multiple myeloma. Adjustment for potential confounders had minimal impact on the risk estimates. Kidney cancer, chronic renal disease, and multiple myeloma mortality risks were elevated with increasing internal uranium absorbed organ dose. The findings add to evidence of an association between internal exposure to uranium and cancer. Future investigation includes a study of cancer incidence in this cohort. © 2018 Wiley Periodicals, Inc.

The non-cancer mortality experience of male workers at British Nuclear Fuels plc, 1946–2005

PubMed Central

McGeoghegan, Dave; Binks, Keith; Gillies, Michael; Jones, Steve; Whaley, Steve

2008-01-01

Background Recent studies of the Hiroshima and Nagasaki A-bomb survivors, together with some (but not all) cohorts exposed occupationally or medically to ionizing radiation, have found an increasing trend in mortality from non-malignant disease with increasing radiation dose. The aim of this study was to establish whether such a trend could be found in a large cohort of employees in the UK nuclear industry. Methods The cohort comprised 64 937 individuals ever employed at the study sites between 1946 and 2002, followed up to 2005; radiation exposures as measured by personal dosimeters (‘film badges’) were available for 42 426 individuals classified as ‘radiation workers’. Poisson regression models were used to investigate the relationship between excess mortality rates and cumulative radiation exposure, using both relative and additive risk models. Results The cohort shows a pronounced ‘healthy worker’ effect. Overall, socio-economic status as indicated by employment status has a greater influence on mortality than does radiation exposure status. For male radiation workers, there is an apparent dose response for mortality from circulatory system disease [P < 0.001, ERR = 0.65 (90% CI 0.36–0.98) Sv−1]. However there is evidence for inhomogeneity in the apparent dose response (P = 0.016), arising principally at cumulative doses in excess of 300 mSv, when the four categories of employment and radiation exposure status are examined separately. Conclusions We have found evidence for an association between mortality from non-cancer causes of death, particularly circulatory system disease, and external exposure to ionizing radiation in this cohort. However, the tentative nature of biological mechanisms that might explain such an effect at low chronic doses and the above inhomogeneities in apparent dose–response, mean that the results of our analysis are not consistent with any simple causal interpretation. Further work is required to explain these inhomogeneities, and on the possible role of factors associated with socio-economic status and shift working, before any further conclusions can be drawn. PMID:18319298

Gamma rays induce DNA damage and oxidative stress associated with impaired growth and reproduction in the copepod Tigriopus japonicus.

PubMed

Han, Jeonghoon; Won, Eun-Ji; Lee, Bo-Young; Hwang, Un-Ki; Kim, Il-Chan; Yim, Joung Han; Leung, Kenneth Mei Yee; Lee, Yong Sung; Lee, Jae-Seong

2014-07-01

Nuclear radioisotope accidents are potentially ecologically devastating due to their impact on marine organisms. To examine the effects of exposure of a marine organism to radioisotopes, we irradiated the intertidal copepod Tigriopus japonicus with several doses of gamma radiation and analyzed the effects on mortality, fecundity, and molting by assessing antioxidant enzyme activities and gene expression patterns. No mortality was observed at 96h, even in response to exposure to a high dose (800Gy) of radiation, but mortality rate was significantly increased 120h (5 days) after exposure to 600 or 800Gy gamma ray radiation. We observed a dose-dependent reduction in fecundity of ovigerous females; even the group irradiated with 50Gy showed a significant reduction in fecundity, suggesting that gamma rays are likely to have a population level effect. In addition, we observed growth retardation, particularly at the nauplius stage, in individuals after gamma irradiation. In fact, nauplii irradiated with more than 200Gy, though able to molt to copepodite stage 1, did not develop into adults. Upon gamma radiation, T. japonicus showed a dose-dependent increase in reactive oxygen species (ROS) levels, the activities of several antioxidant enzymes, and expression of double-stranded DNA break damage genes (e.g. DNA-PK, Ku70, Ku80). At a low level (sub-lethal dose) of gamma irradiation, we found dose-dependent upregulation of p53, implying cellular damage in T. japonicus in response to sub-lethal doses of gamma irradiation, suggesting that T. japonicus is not susceptible to sub-lethal doses of gamma irradiation. Additionally, antioxidant genes, phase II enzyme (e.g. GSTs), and cellular chaperone genes (e.g. Hsps) that are involved in cellular defense mechanisms also showed the same expression patterns for sublethal doses of gamma irradiation (50-200Gy). These findings indicate that sublethal doses of gamma radiation can induce oxidative stress-mediated DNA damage and increase the expression of antioxidant enzymes and proteins with chaperone-related functions, thereby significantly affecting life history parameters such as fecundity and molting in the copepod T. japonicus. Copyright © 2014 Elsevier B.V. All rights reserved.

Studies of the mortality of atomic bomb survivors, Report 14, 1950-2003: an overview of cancer and noncancer diseases.

PubMed

Ozasa, Kotaro; Shimizu, Yukiko; Suyama, Akihiko; Kasagi, Fumiyoshi; Soda, Midori; Grant, Eric J; Sakata, Ritsu; Sugiyama, Hiromi; Kodama, Kazunori

2012-03-01

This is the 14th report in a series of periodic general reports on mortality in the Life Span Study (LSS) cohort of atomic bomb survivors followed by the Radiation Effects Research Foundation to investigate the late health effects of the radiation from the atomic bombs. During the period 1950-2003, 58% of the 86,611 LSS cohort members with DS02 dose estimates have died. The 6 years of additional follow-up since the previous report provide substantially more information at longer periods after radiation exposure (17% more cancer deaths), especially among those under age 10 at exposure (58% more deaths). Poisson regression methods were used to investigate the magnitude of the radiation-associated risks, the shape of the dose response, and effect modification by gender, age at exposure, and attained age. The risk of all causes of death was positively associated with radiation dose. Importantly, for solid cancers the additive radiation risk (i.e., excess cancer cases per 10(4) person-years per Gy) continues to increase throughout life with a linear dose-response relationship. The sex-averaged excess relative risk per Gy was 0.42 [95% confidence interval (CI): 0.32, 0.53] for all solid cancer at age 70 years after exposure at age 30 based on a linear model. The risk increased by about 29% per decade decrease in age at exposure (95% CI: 17%, 41%). The estimated lowest dose range with a significant ERR for all solid cancer was 0 to 0.20 Gy, and a formal dose-threshold analysis indicated no threshold; i.e., zero dose was the best estimate of the threshold. The risk of cancer mortality increased significantly for most major sites, including stomach, lung, liver, colon, breast, gallbladder, esophagus, bladder and ovary, whereas rectum, pancreas, uterus, prostate and kidney parenchyma did not have significantly increased risks. An increased risk of non-neoplastic diseases including the circulatory, respiratory and digestive systems was observed, but whether these are causal relationships requires further investigation. There was no evidence of a radiation effect for infectious or external causes of death.

A reanalysis of cancer mortality in Canadian nuclear workers (1956-1994) based on revised exposure and cohort data.

PubMed

Zablotska, L B; Lane, R S D; Thompson, P A

2014-01-07

A 15-country study of nuclear workers reported significantly increased radiation-related risks of all cancers excluding leukaemia, with Canadian data a major factor behind the pooled results. We analysed mortality (1956-1994) in the updated Canadian cohort and provided revised risk estimates. Employment records were searched to verify and revise exposure data and to restore missing socioeconomic status. Excess relative risks per sievert (ERR/Sv) of recorded radiation dose and 95% confidence intervals (CIs) were estimated using Poisson regression. A significant heterogeneity of the dose-response for solid cancer was identified (P=0.02), with 3088 early (1956-1964) Atomic Energy of Canada Limited (AECL) workers having a significant increase (ERR/Sv=7.87, 95% CI: 1.88, 19.5), and no evidence of radiation risk for 42,228 workers employed by three nuclear power plant companies and post-1964 AECL (ERR/Sv=-1.20, 95% CI: <-1.47, 2.39). Radiation risks of leukaemia were negative in early AECL workers and non-significantly increased in other workers. In analyses with separate terms for tritium and gamma doses, there was no evidence of increased risk from tritium exposure. All workers had mortality lower than the general population. Significantly increased risks for early AECL workers are most likely due to incomplete transfer of AECL dose records to the National Dose Registry. Analyses of the remainder of the Canadian nuclear workers (93.2%) provided no evidence of increased risk, but the risk estimate was compatible with estimates that form the basis of radiation protection standards. Study findings suggest that the revised Canadian cohort, with the exclusion of early AECL workers, would likely have an important effect on the 15-country pooled risk estimate of radiation-related risks of all cancer excluding leukaemia by substantially reducing the size of the point estimate and its significance.

Relative resistance of Pacific salmon to infectious salmon anaemia virus

USGS Publications Warehouse

Rolland, J.B.; Winton, J.R.

2003-01-01

Infectious salmon anaemia (ISA) is a major disease of Atlantic salmon, Salmo salar, caused by an orthomyxovirus (ISAV). Increases in global aqua culture and the international movement of fish made it important to determine if Pacific salmon are at risk. Steelhead trout, Oncorhynchus mykiss, and chum, O. keta, Chinook, O. tshawytscha, coho, O. kisutch, and Atlantic salmon were injected intraperitoneally with a high, medium, or low dose of a Norwegian strain of ISAV. In a second challenge, the same species, except chum salmon, were injected with a high dose of either a Canadian or the Norwegian strain. Average cumulative mortality of Atlantic salmon in trial 1 was 12% in the high dose group, 20% in the medium dose group and 16% in the low dose group. The average cumulative mortality of Atlantic salmon in trial 2 was 98%. No signs typical of ISA and no ISAV-related mortality occurred among any of the groups of Oncorhynchus spp. in either experiment, although ISAV was reisolated from some fish sampled at intervals post-challenge. The results indicate that while Oncorhynchus spp. are quite resistant to ISAV relative to Atlantic salmon, the potential for ISAV to adapt to Oncorhynchus spp. should not be ignored.

Evidence for a cost of immunity when the crustacean Daphnia magna is exposed to the bacterial pathogen Pasteuria ramosa.

PubMed

Little, Tom J; Killick, Stuart C

2007-11-01

The deployment of the immune system has the obvious potential to ameliorate infection outcomes, but immune responses can also harm hosts by either damaging host tissues or monopolizing resources, leading to enhanced mortality. To gain insight into such a 'cost of immunity' when the crustacean Daphnia magna is challenged with the bacterium Pasteuria ramosa, we measured survivorship among hosts that resisted infection following exposure to various strains and doses of the parasite. In the first of two experiments, these exposures were: single exposures with relatively non-aggressive strains, double exposures with non-aggressive strains, and exposure to aggressive strains. Mortality increased across this gradient of exposure. In a second experiment, we varied the dose of the most aggressive P. ramosa strain and found that resisting infection when a large dose was applied resulted in greater mortality than when a medium or low dose was applied. Assuming that resistance is accomplished with an immune response, and that more aggressive parasites and/or larger doses of parasites are more immunostimulatory, these data are compatible with a cost of immunity. Indeed, in terms of survival, resisting parasites can be more harmful than infection.

Evidence supporting radiation hormesis in atomic bomb survivor cancer mortality data.

PubMed

Doss, Mohan

2012-12-01

A recent update on the atomic bomb survivor cancer mortality data has concluded that excess relative risk (ERR) for solid cancers increases linearly with dose and that zero dose is the best estimate for the threshold, apparently validating the present use of the linear no threshold (LNT) model for estimating the cancer risk from low dose radiation. A major flaw in the standard ERR formalism for estimating cancer risk from radiation (and other carcinogens) is that it ignores the potential for a large systematic bias in the measured baseline cancer mortality rate, which can have a major effect on the ERR values. Cancer rates are highly variable from year to year and between adjacent regions and so the likelihood of such a bias is high. Calculations show that a correction for such a bias can lower the ERRs in the atomic bomb survivor data to negative values for intermediate doses. This is consistent with the phenomenon of radiation hormesis, providing a rational explanation for the decreased risk of cancer observed at intermediate doses for which there is no explanation based on the LNT model. The recent atomic bomb survivor data provides additional evidence for radiation hormesis in humans.

A Method for Evaluating Insecticide Efficacy against Bed Bug, Cimex lectularius, Eggs and First Instars.

PubMed

Campbell, Brittany E; Miller, Dini M

2017-03-15

Standard toxicity evaluations of insecticides against insect pests are primarily conducted on adult insects. Evaluations are based on a dose-response or concentration-response curve, where mortality increases as the dose or concentration of an insecticide is increased. Standard lethal concentration (LC50) and lethal dose (LD50) tests that result in 50% mortality of a test population can be challenging for evaluating toxicity of insecticides against non-adult insect life stages, such as eggs and early instar or nymphal stages. However, this information is essential for understanding insecticide efficacy in all bed bug life stages, which affects control and treatment efforts. This protocol uses a standard dipping bioassay modified for bed bug eggs and a contact insecticidal assay for treating nymphal first instars. These assays produce a concentration-response curve to further quantify LC50 values for insecticide evaluations.

Toxic effects of the neem oil (Azadirachta indica) formulation on the stink bug predator, Podisus nigrispinus (Heteroptera: Pentatomidae).

PubMed

Zanuncio, José Cola; Mourão, Sheila Abreu; Martínez, Luis Carlos; Wilcken, Carlos Frederico; Ramalho, Francisco S; Plata-Rueda, Angelica; Soares, Marcus Alvarenga; Serrão, José Eduardo

2016-09-06

This research investigated the effects of neem oil on mortality, survival and malformations of the non-target stink bug predator, Podisus nigrispinus. Neurotoxic and growth inhibitor insecticides were used to compare the lethal and sublethal effects from neem oil on this predator. Six concentrations of neem oil were topically applied onto nymphs and adults of this predator. The mortality rates of third, fourth, and fifth instar nymphs increased with increasing neem oil concentrations, suggesting low toxicity to P. nigrispinus nymphs. Mortality of adults was low, but with sublethal effects of neem products on this predator. The developmental rate of P. nigrispinus decreased with increasing neem oil concentrations. Longevity of fourth instar nymphs varied from 3.74 to 3.05 d, fifth instar from 5.94 to 4.07 d and adult from 16.5 and 15.7 d with 0.5 and 50% neem doses. Podisus nigrispinus presented malformations and increase with neem oil concentrations. The main malformations occur in wings, scutellum and legs of this predator. The neem oil at high and sub lethal doses cause mortality, inhibits growth and survival and results in anomalies on wings and legs of the non-traget predator P. nigrispinus indicating that its use associated with biological control should be carefully evaluated.

The use of preoperative aspirin in cardiac surgery: A systematic review and meta-analysis.

PubMed

Aboul-Hassan, Sleiman Sebastian; Stankowski, Tomasz; Marczak, Jakub; Peksa, Maciej; Nawotka, Marcin; Stanislawski, Ryszard; Kryszkowski, Bartosz; Cichon, Romuald

2017-12-01

Despite the fact that aspirin is of benefit to patients following coronary artery bypass grafting (CABG), continuation or administration of preoperative aspirin before CABG or any cardiac surgical procedure remains controversial. Therefore, we performed a systematic review and meta-analysis to assess the influence of preoperative aspirin administration on patients undergoing cardiac surgery. Medline database was searched using OVID SP interface. Similar searches were performed separately in EMBASE, PubMed, and Cochrane Central Registry of Controlled Trials. Twelve randomized controlled trials and 28 observational studies met our inclusion criteria and were included in the meta-analysis. The use of preoperative aspirin in patients undergoing CABG at any dose is associated with reduced early mortality as well as a reduced incidence of postoperative acute kidney injury (AKI). Low-dose aspirin (≤160 mg/d) is associated with a decreased incidence of perioperative myocardial infarction (MI). Administration of preoperative aspirin at any dose in patients undergoing cardiac surgery increases postoperative bleeding. Despite this effect of preoperative aspirin, it did not increase the rates of surgical re-exploration due to excessive postoperative bleeding nor did it increase the rates of packed red blood cell transfusions (PRBC) when preoperative low-dose aspirin (≤160 mg/d) was administered. Preoperative aspirin increases the risk for postoperative bleeding. However, this did not result in an increased need for chest re-exploration and did not increase the rates of PRBC transfusion when preoperative low-dose (≤160 mg/d) aspirin was administered. Aspirin at any dose is associated with decreased mortality and AKI and low-dose aspirin (≤160 mg/d) decreases the incidence of perioperative MI. © 2017 Wiley Periodicals, Inc.

Morbidity and mortality reduction by supplemental vitamin A or beta-carotene in CBA mice given total-body gamma-radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seifter, E.; Rettura, G.; Padawer, J.

Male CBA mice received graded doses (450-750 rad) of total-body gamma-radiation (TBR) from a dual-beam /sup 137/Cs irradiator. Commencing directly after TBR, 2 days later, or 6 days later, groups of mice received supplemental vitamin A (Vit A) or beta-carotene (beta-Car), compounds previously found to reduce radiation disease in mice subjected to partial-body X-irradiation. Given directly after TBR, supplemental Vit A decreased mortality, evidenced by increases in the radiation dose required to kill 50% of the mice within 30 days (LD50/30). In one experiment, Vit A increased the LD50/30 from 555 to 620 rad; in another experiment, Vit A increasedmore » the dose from 505 to 630 rad. Similarly, in a third experiment, supplemental beta-Car increased the LD50/30 from 510 to 645 rad. Additionally, each compound increased the survival times, even of those mice that died within 30 days. In addition to reduction of mortality and prolongation of survival time, supplemental Vit A moderated weight loss, adrenal gland hyperemia, thymus involution, and lymphopenia--all signs of radiation toxicity. Delaying the supplementation for 2 days after irradiation did not greatly reduce the efficacy of Vit A; however, delaying supplementation for 6 days decreased its effect almost completely.« less

Impact of obesity on outcomes after definitive dose-escalated intensity-modulated radiotherapy for localized prostate cancer.

PubMed

Wang, Lora S; Murphy, Colin T; Ruth, Karen; Zaorsky, Nicholas G; Smaldone, Marc C; Sobczak, Mark L; Kutikov, Alexander; Viterbo, Rosalia; Horwitz, Eric M

2015-09-01

Previous publications have demonstrated conflicting results regarding body mass index (BMI) and prostate cancer (CaP) outcomes after definitive radiotherapy (RT) before the dose escalation era. The goal of the current study was to determine whether increasing BMI was associated with outcomes in men with localized CaP who were treated with dose-escalated RT. The authors identified patients with localized (T1b-T4N0M0) CaP who were treated with definitive intensity-modulated RT and image-guided RT from 2001 through 2010. BMI was analyzed as a continuous variable. Adjusting for confounders, multivariable competing risk and Cox proportional hazards regression models were used to assess the association between BMI and the risk of biochemical failure (BF), distant metastases (DM), cause-specific mortality (CSM), and overall mortality. Of the 1442 patients identified, approximately 20% had a BMI <25 kg/m(2) , 48% had a BMI of 25 to 29.9 kg/m(2) , 23% had a BMI of 30 to 34.9 kg/m(2) , 6% had a BMI of 35 to 39.9 kg/m(2) , and 4% had a BMI of ≥40 kg/m(2) . The median follow-up was 47.6 months (range, 1-145 months), with a median age of 68 years (range, 36-89 years). The median dose was 78 grays (range, 76-80 grays) and 30% of patients received androgen deprivation therapy. Increasing BMI was found to be inversely associated with age (P<.001) and pretreatment prostate-specific antigen level (P = .018). On multivariable analysis, increasing BMI was associated with an increased risk of BF (hazard ratio [HR], 1.03; 95% confidence interval [95% CI], 1.00-1.07 [P = .042]), DM (HR, 1.07; 95% CI, 1.02-1.11 [P = .004]), CSM (HR, 1.15; 95% CI, 1.07-1.23 [P<.001]), and overall mortality (HR, 1.05; 95% CI, 1.02-1.08 [P = .004]). For patients with CaP receiving dose-escalated intensity-modulated RT with daily image-guidance, increasing BMI appears to be associated with an increased risk of BF, DM, CSM, and overall mortality. © 2015 American Cancer Society.

A screen of pharmaceutical drugs for their ability to cause short-term morbidity and mortality in the common bed bug, Cimex lectularius L.

PubMed

Sheele, Johnathan M; Ridge, Gale E; Du, Wenjing; Mallipeddi, Nikhil; Vallabhaneni, Mayur

2017-10-01

The common bed bug, Cimex lectularius L., is a hematophagous ectoparasite that preferentially feeds on humans. Pharmaceuticals present in a person's blood may adversely affect C. lectularius when it feeds. We fed >10,000 C. lectularius on blood samples containing more than 400 different drug doses and drug combinations using an in vitro feeding system to determine insect mortality. The majority of drug doses approximated the peak plasma concentration in humans taking those drugs. Twenty-one drugs were found to cause >17% 12-14-day mortality compared to 8.5% mortality in the control (p < 0.05), but postliminary testing of three of the drugs, famotidine, ethambutol, and primaquine, did not demonstrate an increase in C. lectularius mortality. We also tested 23 drugs for their effects on C. lectularius fecundity. The results may have implications for understanding C. lectularius population dynamics in an infestation.

EFFECT OF RADIATION ON RESPONSE TO ANESTHETIC AGENTS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zauder, H.L.; Orkin, L.R.

1963-07-01

An attempt was made to determine if prior irradiation modified the response to anesthesia or if any anesthetic or anesthetics are associated with an abnormally high or low mortality, following irradiation. Swiss mice were irradiated by a conventional radiotherapy machine utilizing 250-kv x rays with 1- mm aluiminum and 0.5 mm copper filtration. The half-value layer was 1.5 mm of copper, and with a target-skin distance of 70 cm; the dose rate in air was 52 r/ min. A dose-response curve, relating mortality at 30 days to the amount of radiation delivered gave an LD/sub 5/ of 350 r, LD/submore » 25/ of 450 r, and LD/sub 95/ of 750 r. A chamber for the anesthetization of small animals with a known, reproducible concentration of anesthetic agent was designed providing for constant circulation of the gas mixtures, explosive or nonexplosive. Utilizing this apparatus, groups of mice were andesthetized with 6% divinyl ether, 6% diethyl ether, 1.5% halothane, 1.8% trichlorethylene, and 18% cyclopropane. With the latter, oxygen was added to the chamber in sufficient quandtity to provide a concentration of 20 to 25%. Pentobarbital (Nembutal) 30 mg/kg, thiopental sodium (Pentothal) 70 mg/kg, or meperidine hydrochloride (Demerol) 25 mg/kg was injected intraperitoneally into mice with and without prior x radiation. There was no mortality associated with these dosages in the control animals. All drugs were administered to the irradiated animals on the 1st to 28th day postirradiation. In mice irradiated with an LD/sub 5/ (350 r) and anesthetized subsequently with divinyl ether, diethyl ether, or halothane, an increase in the mortality over control values was observed. This increase was greatest following divinyl ether; its administration 7 or more days following irradiation resulted in the death of 10 to 30% of the animals during the 45-min period of anesthetization. After 350 r, meperidine and pentobarbital did not increase montality, but thiopental increased markedly the number of deaths when administered on the 2nd, 4th, or 21st day postirradiation. After 450 r the mortality rate was increased markedly, but cyclopropane was associated with the least increase. As with the volatile agents, mortality following the parenterally administered agents increased as the dose of radiation increased, but no difference wss demonstrated between pentobarbital and its thio derivative. Sleeping time following both drugs was increased 3-fold over that in controls. The mortality following anesthesia in mice who received 750-r (LD/sub 95/) made it impossible to anesthetize these animals beyond the 7th day postirradiation. Again, a significant number of deaths under anesthesia occurred with divinyl ether, and sleeping time following the barbiturates was prolonged, but not beyond the 3-fold increase which was seen at 450 r. It is concluded that divinyl ether is associated with the highest overall mortality and cyclopropane with the lowest; decreasing the concentration of diethyl ether decreases the mortality. The cause of the increased mortality is unknown, since gross and microscopic examinations of autopsy material failed to reveal any differences accounting for these results. (BBB)« less

Mortality from duck plague virus in immunosuppressed adult mallard ducks

USGS Publications Warehouse

Goldberg, Diana R.; Yuill, Thomas M.; Burgess, E.C.

1990-01-01

Environmental contaminants contain chemicals that, if ingested, could affect the immunological status of wild birds, and in particular, their resistance to infectious disease. Immunosuppression caused by environmental contaminants, could have a major impact on waterfowl populations, resulting in increased susceptibility to contagious disease agents. Duck plague virus has caused repeated outbreaks in waterfowl resulting in mortality. In this study, several doses of cyclophosphamide (CY), a known immunosuppressant, were administered to adult mallards (Anas platyrhynchos) to determine if a resultant decrease in resistance to a normally sub-lethal strain of duck plague virus would occur, and induce mortality in these birds. Death occurred in birds given CY only, and in birds given virus and CY, but not in those given virus only. There was significantly greater mortality and more rapid deaths in the duck plague virus-infected groups than in groups receiving only the immunosuppressant. A positively correlated dose-response effect was observed with CY mortalities, irrespective of virus exposure. A fuel oil and a crude oil, common environmental contaminants with immunosuppressive capabilities, were tested to determine if they could produce an effect similar to that of CY. Following 28 days of oral oil administration, the birds were challenged with a sub-lethal dose of duck plague virus. No alteration in resistance to the virus (as measured by mortality) was observed, except in the positive CY control group.

Mortality from duck plague virus in immunosuppressed adult mallard ducks

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goldberg, D.R.; Yuill, T.M.; Burgess, E.C.

Environmental contaminants contain chemicals that, if ingested, could affect the immunological status of wild birds, and in particular, their resistance to infectious disease. Immunosuppression caused by environmental contaminants, could have a major impact on waterfowl populations, resulting in increased susceptibility to contagious disease agents. Duck plague virus has caused repeated outbreaks in waterfowl resulting in mortality. In this study, several doses of cyclophosphamide (CY), a known immunosuppressant, were administered to adult mallards (Anas platyrhynchos) to determine if a resultant decrease in resistance to a normally sub-lethal strain of duck plague virus would occur, and induce mortality in these birds. Deathmore » occurred in birds given CY only, and in birds given virus and CY, but not in those given virus only. There was significantly greater mortality and more rapid deaths in the duck plague virus-infected groups than in groups receiving only the immunosuppressant. A positively correlated dose-response effect was observed with CY mortalities, irrespective of virus exposure. A fuel oil and a crude oil, common environmental contaminants with immunosuppressive capabilities, were tested to determine if they could produce an effect similar to that of CY. Following 28 days of oral oil administration, the birds were challenged with a sub-lethal dose of duck plague virus. No alteration in resistance to the virus (as measured by mortality) was observed, except in the positive CY control group.« less

Mortality among Canadian military personnel exposed to low-dose radiation.

PubMed

Raman, S; Dulberg, C S; Spasoff, R A; Scott, T

1987-05-15

We carried out a cohort study of mortality among 954 Canadian military personnel exposed to low-dose ionizing radiation during nuclear reactor clean-up operations at Chalk River Nuclear Laboratories, Chalk River, Ont., and during observation of atomic test blasts in the United States and Australia in the 1950s. Two controls matched for age, service, rank and trade were selected for each exposed subject. Mortality among the exposed and control groups was ascertained by means of record linkage with the Canadian Mortality Data Base. Survival analysis with life-table techniques did not reveal any difference in overall mortality between the exposed and control groups. Analysis of cause-specific mortality showed similar mortality patterns in the two groups; there was no elevation in the exposed group in the frequency of death from leukemia or thyroid cancer, the causes of death most often associated with radiation exposure. Analysis of survival by recorded gamma radiation dose also did not show any effect of radiation dose on mortality. The findings are in agreement with the current scientific literature on the risk of death from exposure to low-dose radiation.

Diuretic downsides--but in low doses they still seem among the best authenticated antihypertensives.

PubMed

Opie, L H

2000-08-01

Diuretics in low doses have the greatest support among current available antihypertensives in that they have been shown to reduce total mortality, coronary mortality, stroke, and congestive heart failure in an important meta-analysis by Psaty. Recently, Messerli has linked longterm diuretic use to renal cell carcinoma in women. In some patients, diuretic use leads to increasing blood cholesterol and blood sugar levels. Impotence is a recognized side effect, with rates rising about twofold with low-dose chlorthalidone and fourfold with a higher dose. Certain population groups such as younger (<60 years) white males often do not respond to low-dose diuretic therapy with an adequate blood pressure fall. In females of a similar age group, Messerli calculates that prolonged diuretic therapy will prevent only one stroke and no coronary events nor any deaths for every renal cell carcinoma that is provoked. Despite these evident problems, the outcome data on hard endpoints in trials with initial low-dose diuretic therapy remain valid and convincing. Thus, it is argued, low- but not high-dose diuretics retain their primacy in the ranking of antihypertensive therapy.

Assessment of the risk of solar ultraviolet radiation to amphibians. III. Prediction of impacts in selected northern midwestern wetlands.

PubMed

Diamond, Stephen A; Peterson, Gregory S; Tietge, Joseph E; Ankley, Gerald T

2002-07-01

Solar ultraviolet radiation, especially UVB (280-320 nm), has been hypothesized to be at least partially responsible for adverse effects (e.g., declines and malformations) in amphibian species throughout the world. Evaluation of this hypothesis has been limited by the paucity of high-quality UV dose-response data and reliable estimates of typical UV doses that occur in amphibian habitats. In this preliminary risk assessment for effects of UV radiation on amphibians, dose-response relationships quantified in outdoor experiments were compared with UV exposure estimates for 26 wetlands in northern Minnesota and Wisconsin. A comparison of wetland doses, derived from model prediction, historical data, and dissolved organic carbon (DOC) characterization, with experimental effects levels for green (R. clamitans), northern leopard (R. pipiens), and mink (R. septentrionalis) frogs indicated that the risk of mortality and malformations due to UV exposure is low for the majority of wetlands evaluated. Wetland UV dose, averaged over the entire breeding season, exceeded effects doses for mortality for all three species in two of the 26 wetlands examined and for one species in an additional wetland. On the basis of evidence that shorter term doses caused mortality in amphibian larvae, 3-day doses were also evaluated. In three of the wetlands examined, 3-day doses in excess of 85% of full sunlight (the level that appeared to trigger effects in controlled experimentation) occurred at frequencies ranging 22-100% for all three species and at frequencies ranging from 15% to 58% for R. pipiens and R. septentrionalis in three additional wetlands. Risk of malformation in R. pipiens was apparent in five of the 26 wetlands evaluated. Overall, estimated UVB doses in 21 of the wetlands never exceeded experimental effects doses for mortality or malformations. These results suggest that most amphibians are not currently at significant risk for UVB effects in northern Minnesota and Wisconsin wetlands. However, continued reduction of ozone and other global climate change effects may increase UV doses in wetlands, suggesting that the risk of UV to amphibians should continue to be monitored and studied.

Nine-year mortality experience in proton-exposed Macaca mulatta

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krupp, J.H.

1976-08-01

Macaca mulatta exposed at 2 yr of age to proton irradiation have been observed for mortality and latent effects since 1964. This report of progress covering the first 9 yr postexposure shows an interesting occurrence of neoplasia in the 55 MeV proton-exposed animals and an increased incidence of endometriosis in whole-body penetrating proton exposures. For doses of 400 rad and less, no significant deviation from control mortality is apparent, 9 yr postexposure.

Effects of low doses and low dose rates of external ionizing radiation: Cancer mortality among nuclear industry workers in three countries

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cardis, E.; Kato, I.; Lave, C.

Studies of the mortality among nuclear industry workforces have been carried out, and nationally combined analyses performed, in the U.S., the UK and Canada. This paper presents the results of internationally combined analyses of mortality data on 95,673 workers (85.4% men) monitored for external exposure to ionizing radiation and employed for 6 months or longer in the nuclear industry of one of the three countries. These analyses were undertaken to obtain a more precise direct assessment of the carcinogenic effects of protracted low-level exposure to external, predominantly {gamma}, radiation. The combination of the data from the various studies increases themore » power to study associations between radiation dose and mortality from all causes or from all cancers. Mortality from leukemia, excluding chronic lymphocytic leukemia (CLL)-the cause of death most strongly and consistently related to radiation dose in studies of atomic bomb survivors and other populations exposed at high dose rates-was significantly associated with cumulative external radiation dose (one-sided P value = 0.046; 119 deaths). Among the 31 other specific types of cancer studied, a significant association was observed only for multiple myeloma (one-sided P value = 0.037; 44 deaths), and this was attributable primarily to the associations reported previously between this disease and radiation dose in the Hanford (U.S.) and Sellafield (UK) cohorts. The excess relative risk (ERR) estimates for all cancers excluding leukemia, and leukemia excluding CLL, the two main groupings of causes of death for which risk estimates have been derived from studies of atomic bomb survivors, were -0.07 per Sv [90% confidence interval (CI):-0.4,0.3] and 2.18 per Sv (90% CI:0.1,5.7), respectively. These values correspond to a relative risk of 0.99 for all cancers excluding leukemia and 1.22 for leukemia excluding CLL for a cumulative protracted dose of 100 mSv compared to O mSv. 53 refs., 1 fig., 8 tabs.« less

Biomarkers in critically ill patients with systemic inflammatory response syndrome or sepsis supplemented with high-dose selenium.

PubMed

Brodska, Helena; Valenta, Jiri; Malickova, Karin; Kohout, Pavel; Kazda, Antonin; Drabek, Tomas

2015-01-01

Low levels of selenium (Se) and glutathione peroxidase (GSHPx), a key selenoenzyme, were documented in systemic inflammatory response syndrome (SIRS) and sepsis, both associated with high mortality. Se supplementation had mixed effects on outcome. We hypothesized that Se supplementation could have a different impact on biomarkers and 28-day mortality in patients with SIRS vs. sepsis. Adult patients with SIRS or sepsis were randomized to either high-dose (Se+, n = 75) or standard-dose (Se-, n = 75) Se supplementation. Plasma Se, whole blood GSHPx activity, C-reactive protein (CRP), procalcitonin (PCT), prealbumin, albumin and cholesterol levels were measured serially up to day 14. There was no difference in mortality between Se- (24/75) vs. Se+ group (19/75; p = 0.367) or between SIRS and septic patients (8/26 vs. 35/124; p = 0.794). There was a trend to reduced mortality in SIRS patients in the Se+ vs. Se- group (p = 0.084). Plasma Se levels increased in the Se+ group only in patients with sepsis but not in patients with SIRS. Plasma Se levels correlated with GSHPx. In SIRS/Se+ group, Se correlated only with GSHPx. In SIRS/Se- group, Se correlated with cholesterol but not with other biomarkers. In sepsis patients, Se levels correlated with cholesterol, GSHPx and prealbumin. Cholesterol levels were higher in survivors in the Se- group. Se levels correlated with GSHPx activity and other nutritional biomarkers with significant differences between SIRS and sepsis groups. High-dose Se supplementation did not affect mortality but a strong trend to decreased mortality in SIRS patients warrants further studies in this population. Copyright © 2015 Elsevier GmbH. All rights reserved.

Elevated levels of circulating thyroid hormone do not cause the medical sequelae of hyperthyroidism.

PubMed

Kelly, Tammas; Denmark, Lawrence; Lieberman, Daniel Z

2016-11-03

Clinicians have been reluctant to use high dose thyroid (HDT) to treat affective disorders because high circulating levels of thyroid hormone have traditionally been equated with hyperthyroidism, and understood as the cause of the medical sequelae of hyperthyroidism, such as osteoporosis and cardiac abnormalities. This conclusion is not supported by (HDT) research. A literature review of research related to the morbidity and mortality of HDT treatment was performed. There exists a large body of research involving the use of HDT treatment to prevent the recurrence of differentiated thyroid cancer and to treat affective disorders. A review of this literature finds a lack of support for HDT as a cause of osteoporosis, nor is there support for an increase in morbidity or mortality associated with HDT. This finding contrasts with the well-established morbidity and mortality associated with Graves' disease, thyroiditis, and other endogenous forms of hyperthyroidism. The lack of evidence that exogenous HDT causes osteoporosis, cardiac abnormalities or increases mortality compared with the significant morbidity and mortality of hyperthyroidism requires an alternative cause for the medical sequelae of hyperthyroidism. One possibility is an autoimmune mechanism. High circulating levels of thyroid hormone is not the cause of the sequela of hyperthyroidism. The reluctance to using high dose thyroid is unwarranted. Copyright © 2016 Elsevier Inc. All rights reserved.

Daytime Napping and the Risk of Cardiovascular Disease and All-Cause Mortality: A Prospective Study and Dose-Response Meta-Analysis.

PubMed

Yamada, Tomohide; Hara, Kazuo; Shojima, Nobuhiro; Yamauchi, Toshimasa; Kadowaki, Takashi

2015-12-01

To summarize evidence about the association between daytime napping and the risk of cardiovascular disease and all-cause mortality, and to quantify the potential dose-response relation. Meta-analysis of prospective cohort studies. Electronic databases were searched for articles published up to December 2014 using the terms nap, cardiovascular disease, and all-cause mortality. We selected well-adjusted prospective cohort studies reporting risk estimates for cardiovascular disease and all-cause mortality related to napping. Eleven prospective cohort studies were identified with 151,588 participants (1,625,012 person-years) and a mean follow-up period of 11 years (60% women, 5,276 cardiovascular events, and 18,966 all-cause deaths). Pooled analysis showed that a long daytime nap (≥ 60 min/day) was associated with a higher risk of cardiovascular disease (rate ratio [RR]: 1.82 [1.22-2.71], P = 0.003, I(2) = 37%) compared with not napping. All-cause mortality was associated with napping for ≥ 60 min/day (RR: 1.27 [1.11-1.45], P < 0.001, I(2) = 0%) compared with not napping. In contrast, napping for < 60 min/day was not associated with cardiovascular disease (P = 0.98) or all-cause mortality (P = 0.08). Meta-analysis demonstrated a significant J-curve dose-response relation between nap time and cardiovascular disease (P for nonlinearity = 0.01). The RR initially decreased from 0 to 30 min/day. Then it increased slightly until about 45 min/day, followed by a sharp increase at longer nap times. There was also a positive linear relation between nap time and all-cause mortality (P for non-linearity = 0.97). Nap time and cardiovascular disease may be associated via a J-curve relation. Further studies are needed to confirm the efficacy of a short nap. © 2015 Associated Professional Sleep Societies, LLC.

High-Dose Daptomycin Therapy for Left-Sided Infective Endocarditis: a Prospective Study from the International Collaboration on Endocarditis

PubMed Central

Bayer, Arnold S.; Miró, Josè M.; Park, Lawrence P.; Guimarães, Armenio C.; Skoutelis, Athanasios; Fortes, Claudio Q.; Durante-Mangoni, Emanuele; Hannan, Margaret M.; Nacinovich, Francisco; Fernández-Hidalgo, Nuria; Grossi, Paolo; Tan, Ru-San; Holland, Thomas; Fowler, Vance G.; Corey, Ralph G.; Chu, Vivian H.

2013-01-01

The use of daptomycin in Gram-positive left-sided infective endocarditis (IE) has significantly increased. The purpose of this study was to assess the influence of high-dose daptomycin on the outcome of left-sided IE due to Gram-positive pathogens. This was a prospective cohort study based on 1,112 cases from the International Collaboration on Endocarditis (ICE)-Plus database and the ICE-Daptomycin Substudy database from 2008 to 2010. Among patients with left-sided IE due to Staphylococcus aureus, coagulase-negative staphylococci, and Enterococcus faecalis, we compared those treated with daptomycin (cohort A) to those treated with standard-of-care (SOC) antibiotics (cohort B). The primary outcome was in-hospital mortality. Time to clearance of bacteremia, 6-month mortality, and adverse events (AEs) ascribable to daptomycin were also assessed. There were 29 and 149 patients included in cohort A and cohort B, respectively. Baseline comorbidities did not differ between the two cohorts, except for a significantly higher prevalence of diabetes and previous episodes of IE among patients treated with daptomycin. The median daptomycin dose was 9.2 mg/kg of body weight/day. Two-thirds of the patients treated with daptomycin had failed a previous antibiotic regimen. In-hospital and 6-month mortalities were similar in the two cohorts. In cohort A, median time to clearance of methicillin-resistant S. aureus (MRSA) bacteremia was 1.0 day, irrespective of daptomycin dose, representing a significantly faster bacteremia clearance compared to SOC (1.0 versus 5.0 days; P < 0.01). Regimens with higher daptomycin doses were not associated with increased incidence of AEs. In conclusion, higher-dose daptomycin may be an effective and safe alternative to SOC in the treatment of left-sided IE due to common Gram-positive pathogens. PMID:24080644

Bioincompatibility of dialyzer membranes may have a negative impact on outcome of acute renal failure, independent of the dose of dialysis delivered: a retrospective multicenter analysis.

PubMed

Schiffl, H; Lang, S M; Haider, M

1998-01-01

The mortality rate of critically ill patients with acute renal failure (ARF) has remained high. The impact of vigorous intermittent hemodialysis (IHD) on the outcome of ARF has not been validated. In this retrospective multicenter analysis, 154 patients with ARF were treated daily (intensive) or on alternate days (conventional) using complement and cell activating cuprophane (bioincompatible) or high-flux polysulfone dialyzer membranes with insignificant effects on circulating complement or cells (biocompatible). At initiation of IHD, all four groups were similar in patient characteristics and ARF factors. The use of synthetic membranes resulted in a reduced mortality rate (18% vs 45%; p < 0.001) and shorter duration of ARF (8 vs 15 sessions; p < 0.001). Daily IHD with cellulose based membranes tended to increase mortality rates compared with conventional cuprophane dialysis (37% vs 53%). Intensive IHD with polysulfone membranes resulted in a further decrease in overall mortality rates (15% vs 22%). This retrospective analysis shows that bioincompatibility of dialyzer membranes may be more important for the outcome of patients with ARF than the dose of dialysis. Its impact on outcome occurs independently of the dose of dialysis delivered.

Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose Mortality.

PubMed

Dasgupta, Nabarun; Funk, Michele Jonsson; Proescholdbell, Scott; Hirsch, Annie; Ribisl, Kurt M; Marshall, Steve

2016-01-01

Previous studies examining opioid dose and overdose risk provide limited granularity by milligram strength and instead rely on thresholds. We quantify dose-dependent overdose mortality over a large spectrum of clinically common doses. We also examine the contributions of benzodiazepines and extended release opioid formulations to mortality. Prospective observational cohort with one year follow-up. One year in one state (NC) using a controlled substances prescription monitoring program, with name-linked mortality data. Residential population of North Carolina (n = 9,560,234), with 2,182,374 opioid analgesic patients. Exposure was dispensed prescriptions of solid oral and transdermal opioid analgesics; person-years calculated using intent-to-treat principles. Outcome was overdose deaths involving opioid analgesics in a primary or additive role. Poisson models were created, implemented using generalized estimating equations. Opioid analgesics were dispensed to 22.8% of residents. Among licensed clinicians, 89.6% prescribed opioid analgesics, and 40.0% prescribed ER formulations. There were 629 overdose deaths, half of which had an opioid analgesic prescription active on the day of death. Of 2,182,374 patients prescribed opioids, 478 overdose deaths were reported (0.022% per year). Mortality rates increased gradually across the range of average daily milligrams of morphine equivalents. 80.0% of opioid analgesic patients also received benzodiazepines. Rates of overdose death among those co-dispensed benzodiazepines and opioid analgesics were ten times higher (7.0 per 10,000 person-years, 95 percent CI: 6.3, 7.8) than opioid analgesics alone (0.7 per 10,000 person years, 95 percent CI: 0.6, 0.9). Dose-dependent opioid overdose risk among patients increased gradually and did not show evidence of a distinct risk threshold. There is urgent need for guidance about combined classes of medicines to facilitate a better balance between pain relief and overdose risk. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. 2016. This work is written by US Government employees and is in the public domain in the US.

Low-Dose Aspirin Use Does Not Increase Survival in 2 Independent Population-Based Cohorts of Patients With Esophageal or Gastric Cancer.

PubMed

Spence, Andrew D; Busby, John; Johnston, Brian T; Baron, John A; Hughes, Carmel M; Coleman, Helen G; Cardwell, Chris R

2018-03-01

Preclinical studies have shown aspirin to have anticancer properties and epidemiologic studies have associated aspirin use with longer survival times of patients with cancer. We studied 2 large cohorts to determine the association between aspirin use and cancer-specific mortality in patients with esophageal or gastric cancer. We performed a population-based study using cohorts of patients newly diagnosed with esophageal or gastric cancer, identified from cancer registries in England from 1998 through 2012 and the Scottish Cancer Registry from 2009 through 2012. Low-dose aspirin prescriptions were identified from linkages to the United Kingdom Clinical Research Practice Datalink in England and the Prescribing Information System in Scotland. Deaths were identified from linkage to national mortality records, with follow-up until September 2015 in England and January 2015 in Scotland. Time-dependent Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer-specific mortality by low-dose aspirin use after adjusting for potential confounders. Meta-analysis was used to pool results across the 2 cohorts. The combined English and Scottish cohorts contained 4654 patients with esophageal cancer and 3833 patients with gastric cancer, including 3240 and 2392 cancer-specific deaths, respectively. The proportions surviving 1 year, based on cancer-specific mortality, were similar in aspirin users vs non-users after diagnosis with esophageal cancer (48% vs 50% in England and 49% vs 46% in Scotland, respectively) or gastric cancer (58% vs 57% in England and 59% vs 55% in Scotland, respectively). There was no association between postdiagnosis use of low-dose aspirin and cancer-specific mortality among patients with esophageal cancer (pooled adjusted HR, 0.98; 95% CI, 0.89-1.09) or gastric cancer (pooled adjusted HR, 0.96; 95% CI, 0.85-1.08). Long-term aspirin use was not associated with cancer-specific mortality after diagnosis of esophageal cancer (pooled adjusted HR, 1.03; 95% CI, 0.85-1.25) or gastric cancer (pooled adjusted HR, 1.06; 95% CI, 0.85-1.32). In analyses of 2 large independent cohorts in the United Kingdom, low-dose aspirin usage was not associated with increased survival of patients diagnosed with esophageal or gastric cancer. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

Diuretics in primary hypertension - Reloaded.

PubMed

Mishra, Sundeep

Diuretics have long been cherished as drugs of choice for uncomplicated primary hypertension. Robust mortality and morbidity data is available for diuretics to back this strategy. Off-late the interest for diuretics has waned off perhaps due to availability of more effective drugs but more likely due to perceived lack of tolerance and side-effect profile of high-dose of diuretics required for mortality benefit. Low-dose diuretics particularly thiazide diuretics are safer but lack the mortality benefit shown by high-dose. However, indapamide and low dose chlorthalidone have fewer side-effects but continue to provide mortality benefit. Copyright © 2016. Published by Elsevier B.V.

Cancer mortality risk among military participants of a 1958 atmospheric nuclear weapons test.

PubMed Central

Watanabe, K K; Kang, H K; Dalager, N A

1995-01-01

OBJECTIVES. This study was undertaken to determine if Navy veterans who participated in an atmospheric nuclear test in 1958 were at increased risk of death from certain cancers. METHODS. Cancer mortality risk of 8554 Navy veterans who participated in an atmospheric nuclear test in the Pacific was compared with that of 14,625 Navy veterans who did not participate in any test. Radiation dosage information was obtained from film badges for 88% of the test participants. RESULTS. The median radiation dose for the test participants was 388 mrem (3.88 millisieverts [mSv]). Among participants who received the highest radiation dose (> 1000 mrem, or 10 mSv), an increased mortality risk for all causes (relative risk [RR] = 1.23; 95% confidence interval [CI] = 1.04, 1.45), all cancers (RR = 1.42; 95% CI = 1.03, 1.96), and liver cancer (RR = 6.42; 95% CI = 1.17, 35.3) was observed. The risk for cancer of the digestive organs was elevated among test participants (rate ratio = 1.47; 95% CI = 1.06, 2.04) but with no significant dose-response trend. Many of the cancers of a priori interest were not significantly elevated in the overall test participant group or in the group that received the highest radiation dose. CONCLUSIONS. Most of the cancers suspected of being radiogenic were not significantly elevated among the test participants. Nevertheless, increased risks for certain cancers cannot be ruled out at this time. Veterans who participated in the nuclear weapons tests should continue to be monitored. PMID:7702116

Mortality Among a Cohort of U.S. Commercial Airline Cockpit Crew

PubMed Central

Yong, Lee C.; Pinkerton, Lynne E.; Yiin, James H.; Anderson, Jeri L.; Deddens, James A.

2015-01-01

Background We evaluated mortality among 5,964 former U.S. commercial cockpit crew (pilots and flight engineers). The outcomes of a priori interest were non-chronic lymphocytic leukemia, central nervous system (CNS) cancer (including brain), and malignant melanoma. Methods Vital status was ascertained through 2008. Life table and Cox regression analyses were conducted. Cumulative exposure to cosmic radiation was estimated from work history data. Results Compared to the U.S. general population, mortality from all causes, all cancer, and cardiovascular diseases was decreased, but mortality from aircraft accidents was highly elevated. Mortality was elevated for malignant melanoma but not for non-chronic lymphocytic leukemia. CNS cancer mortality increased with an increase in cumulative radiation dose. Conclusions Cockpit crew had a low all-cause, all-cancer, and cardiovascular disease mortality but elevated aircraft accident mortality. Further studies are needed to clarify the risk of CNS and other radiation-associated cancers in relation to cosmic radiation and other workplace exposures. PMID:24700478

Toxic effects of the neem oil (Azadirachta indica) formulation on the stink bug predator, Podisus nigrispinus (Heteroptera: Pentatomidae)

PubMed Central

Zanuncio, José Cola; Mourão, Sheila Abreu; Martínez, Luis Carlos; Wilcken, Carlos Frederico; Ramalho, Francisco S.; Plata-Rueda, Angelica; Soares, Marcus Alvarenga; Serrão, José Eduardo

2016-01-01

This research investigated the effects of neem oil on mortality, survival and malformations of the non-target stink bug predator, Podisus nigrispinus. Neurotoxic and growth inhibitor insecticides were used to compare the lethal and sublethal effects from neem oil on this predator. Six concentrations of neem oil were topically applied onto nymphs and adults of this predator. The mortality rates of third, fourth, and fifth instar nymphs increased with increasing neem oil concentrations, suggesting low toxicity to P. nigrispinus nymphs. Mortality of adults was low, but with sublethal effects of neem products on this predator. The developmental rate of P. nigrispinus decreased with increasing neem oil concentrations. Longevity of fourth instar nymphs varied from 3.74 to 3.05 d, fifth instar from 5.94 to 4.07 d and adult from 16.5 and 15.7 d with 0.5 and 50% neem doses. Podisus nigrispinus presented malformations and increase with neem oil concentrations. The main malformations occur in wings, scutellum and legs of this predator. The neem oil at high and sub lethal doses cause mortality, inhibits growth and survival and results in anomalies on wings and legs of the non-traget predator P. nigrispinus indicating that its use associated with biological control should be carefully evaluated. PMID:27596436

Ventilator-associated pneumonia: the influence of bacterial resistance, prescription errors, and de-escalation of antimicrobial therapy on mortality rates.

PubMed

Souza-Oliveira, Ana Carolina; Cunha, Thúlio Marquez; Passos, Liliane Barbosa da Silva; Lopes, Gustavo Camargo; Gomes, Fabiola Alves; Röder, Denise Von Dolinger de Brito

2016-01-01

Ventilator-associated pneumonia is the most prevalent nosocomial infection in intensive care units and is associated with high mortality rates (14-70%). This study evaluated factors influencing mortality of patients with Ventilator-associated pneumonia (VAP), including bacterial resistance, prescription errors, and de-escalation of antibiotic therapy. This retrospective study included 120 cases of Ventilator-associated pneumonia admitted to the adult adult intensive care unit of the Federal University of Uberlândia. The chi-square test was used to compare qualitative variables. Student's t-test was used for quantitative variables and multiple logistic regression analysis to identify independent predictors of mortality. De-escalation of antibiotic therapy and resistant bacteria did not influence mortality. Mortality was 4 times and 3 times higher, respectively, in patients who received an inappropriate antibiotic loading dose and in patients whose antibiotic dose was not adjusted for renal function. Multiple logistic regression analysis revealed the incorrect adjustment for renal function was the only independent factor associated with increased mortality. Prescription errors influenced mortality of patients with Ventilator-associated pneumonia, underscoring the challenge of proper Ventilator-associated pneumonia treatment, which requires continuous reevaluation to ensure that clinical response to therapy meets expectations. Copyright © 2016. Published by Elsevier Editora Ltda.

Density Dependence and Growth Rate: Evolutionary Effects on Resistance Development to Bt (Bacillus thuringiensis).

PubMed

Martinez, Jeannette C; Caprio, Michael A; Friedenberg, Nicholas A

2018-02-09

It has long been recognized that pest population dynamics can affect the durability of a pesticide, but dose remains the primary component of insect resistance management (IRM). For transgenic pesticidal traits such as Bt (Bacillus thuringiensis Berliner (Bacillales: Bacillaceae)), dose (measured as the mortality of susceptibles caused by a toxin) is a relatively fixed characteristic and often falls below the standard definition of high dose. Hence, it is important to understand how pest population dynamics modify durability and what targets they present for IRM. We used a deterministic model of a generic arthropod pest to examine how timing and strength of density dependence interacted with population growth rate and Bt mortality to affect time to resistance. As in previous studies, durability typically reached a minimum at intermediate doses. However, high population growth rates could eliminate benefits of high dose. The timing of density dependence had a more subtle effect. If density dependence operated simultaneously with Bt mortality, durability was insensitive to its strengths. However, if density dependence was driven by postselection densities, decreasing its strength could increase durability. The strength of density dependence could affect durability of both single traits and pyramids, but its influence depended on the timing of density dependence and size of the refuge. Our findings suggest the utility of a broader definition of high dose, one that incorporates population-dynamic context. That maximum growth rates and timing and strength of interactions causing density dependent mortality can all affect durability, also highlights the need for ecologically integrated approaches to IRM research. © The Author(s) 2017. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Increased non-relapse mortality due to high-dose cytarabine plus CY/TBI in BMT/PBSCT for acute lymphoblastic leukaemia in adults.

PubMed

Arai, Yasuyuki; Kondo, Tadakazu; Shigematsu, Akio; Tanaka, Junji; Ohashi, Kazuteru; Fukuda, Takahiro; Kawakita, Toshiro; Mori, Takehiko; Hoshino, Takumi; Onizuka, Makoto; Ozawa, Yukiyasu; Yoshida, Shuro; Ueda, Yasunori; Mizuno, Ishikazu; Atsuta, Yoshiko; Mizuta, Shuichi

2017-07-01

The efficacy of high-dose cytarabine (HDCA) plus cyclophosphamide/total-body irradiation (CY/TBI) has been proved in cord blood transplantation (CBT) for acute lymphoblastic leukaemia (ALL), but not in bone marrow or peripheral blood stem cell transplantation (BMT/PBSCT). In this cohort study, we compared the prognosis of CY/TBI (N = 1244) and HDCA/CY/TBI (N = 316) regimens in BMT/PBSCT for ALL. The addition of HDCA decreased post-transplant relapse, while significantly increasing non-relapse mortality (risk ratio, 1·33), and overall survival was not improved. The positive effects of HDCA reported in CBT cannot be extrapolated to BMT/PBSCT, and HDCA may not be recommended in these procedures. © 2017 John Wiley & Sons Ltd.

Low-, medium- and high-dose steroids with or without aminocaproic acid in adult hematopoietic SCT patients with diffuse alveolar hemorrhage.

PubMed

Rathi, N K; Tanner, A R; Dinh, A; Dong, W; Feng, L; Ensor, J; Wallace, S K; Haque, S A; Rondon, G; Price, K J; Popat, U; Nates, J L

2015-03-01

Diffuse alveolar hemorrhage (DAH) is a poorly understood complication of transplantation carrying a high mortality. Patients commonly deteriorate and require intensive care unit (ICU) admission. Treatment with high-dose steroids and aminocaproic acid (ACA) has been suggested. The current study examined 119 critically ill adult hematopoietic transplant patients treated for DAH. Patients were subdivided into low-, medium- and high-dose steroid groups with or without ACA. All groups had similar baseline characteristics and severity of illness scores. Primary objectives were 30, 60, 100 day, ICU and hospital mortality. Overall mortality (n=119) on day 100 was high at 85%. In the steroids and ACA cohort (n=82), there were no significant differences in 30, 60, 100, day, ICU and hospital mortality between the dosing groups. In the steroids only cohort (n=37), the low-dose steroid group had a lower ICU and hospital mortality (P=0.02). Adjunctive treatment with ACA did not produce differences in outcomes. In the multivariate analysis, medium- and high-dose steroids were associated with a higher ICU mortality (P=0.01) as compared with the low-dose group. Our data suggest that treatment strategies may need to be reanalyzed to avoid potentially unnecessary and potentially harmful therapies.

Higher anti-depressant dose and major adverse outcomes in moderate chronic kidney disease: a retrospective population-based study

PubMed Central

2014-01-01

Background Many older patients have chronic kidney disease (CKD), and a lower dose of anti-depressants paroxetine, mirtazapine and venlafaxine is recommended in patients with CKD to prevent drug accumulation from reduced elimination. Using information available in large population-based healthcare administrative databases, we conducted this study to determine if ignoring the recommendation and prescribing a higher versus lower dose of anti-depressants associates with a higher risk of adverse events. Methods We conducted a population-based cohort study to describe the 30-day risk of delirium in older adults who initiated a higher vs. lower dose of these three anti-depressants in routine care. We defined delirium using the best proxy available in our data sources - hospitalization with an urgent head computed tomography (CT) scan. We determined if CKD status modified the association between anti-depressant dose and outcome, and examined the secondary outcome of 30 day all-cause mortality. We used multivariable logistic regression analyses to estimate adjusted odds ratios (relative risk (RR)) and 95% confidence intervals. Results We identified adults (mean age 75) in Ontario who started a new study anti-depressant at a higher dose (n = 36,651; 31%) or lower dose (n = 81,160; 69%). Initiating a higher vs. lower dose was not associated with an increased risk of hospitalization with head CT (1.09% vs. 1.27% (adjusted RR 0.90; 95% CI, 0.80 to 1.02), but was associated with a lower risk of all-cause mortality (0.76% vs. 0.97% RR 0.82; 95% CI, 0.71 to 0.95). Neither of these relative risks were modified by the presence of CKD (p = 0.16, 0.68, respectively). Conclusions We did not observe an increase in two adverse outcomes when study anti-depressants were initiated at a higher dose in elderly patients with moderate CKD. Contrary to our hypothesis, the 30-day risk of mortality was lower when a higher versus lower dose of anti-depressant was initiated in these patients, a finding which requires corroboration and further study. PMID:24884589

A reanalysis of cancer mortality in Canadian nuclear workers (1956–1994) based on revised exposure and cohort data

PubMed Central

Zablotska, L B; Lane, R S D; Thompson, P A

2014-01-01

Background: A 15-country study of nuclear workers reported significantly increased radiation-related risks of all cancers excluding leukaemia, with Canadian data a major factor behind the pooled results. We analysed mortality (1956–1994) in the updated Canadian cohort and provided revised risk estimates. Methods: Employment records were searched to verify and revise exposure data and to restore missing socioeconomic status. Excess relative risks per sievert (ERR/Sv) of recorded radiation dose and 95% confidence intervals (CIs) were estimated using Poisson regression. Results: A significant heterogeneity of the dose–response for solid cancer was identified (P=0.02), with 3088 early (1956–1964) Atomic Energy of Canada Limited (AECL) workers having a significant increase (ERR/Sv=7.87, 95% CI: 1.88, 19.5), and no evidence of radiation risk for 42 228 workers employed by three nuclear power plant companies and post-1964 AECL (ERR/Sv=−1.20, 95% CI: <−1.47, 2.39). Radiation risks of leukaemia were negative in early AECL workers and non-significantly increased in other workers. In analyses with separate terms for tritium and gamma doses, there was no evidence of increased risk from tritium exposure. All workers had mortality lower than the general population. Conclusion: Significantly increased risks for early AECL workers are most likely due to incomplete transfer of AECL dose records to the National Dose Registry. Analyses of the remainder of the Canadian nuclear workers (93.2%) provided no evidence of increased risk, but the risk estimate was compatible with estimates that form the basis of radiation protection standards. Study findings suggest that the revised Canadian cohort, with the exclusion of early AECL workers, would likely have an important effect on the 15-country pooled risk estimate of radiation-related risks of all cancer excluding leukaemia by substantially reducing the size of the point estimate and its significance. PMID:24231946

Effectiveness of an improved form of insecticide-based diatomaceous earth against four stored grain pests on different grain commodities.

PubMed

Saeed, Nadia; Farooq, Muhammad; Shakeel, Muhammad; Ashraf, Misbah

2018-04-07

The effectiveness of Grain-Guard, an improved form of diatomaceous earth (DE), with low risk to the environment, was evaluated against the storage pests Liposcelis paeta, Cryptolestes ferrugineus, Rhyzopertha dominica, and Tribolium castaneum on four grain commodities, wheat, rice, maize and sorghum. The overall mortality of stored grain pests increased with the rise of application rate and exposure intervals of diatomaceous earth and decreased over 120 days of post-treatment period. Our results revealed that mortality of adults 14 days post-disclosure was > 80% on wheat at the start of post-treatment than rice, maize, and sorghum, respectively. During the first 60 days of post-treatment, adult mortality increased, whereas later on, a steady decrease in adult mortality was observed. Considerable differences in dose rates were observed on mortality levels along with grain commodities. Following 14 days of exposure, all adults of four species were dead on wheat at 100 ppm and on rice at 150 ppm except maize and sorghum. The suppression of progeny was noticeably higher at the beginning of post-treatment duration while after 60-days of post-treatment, progeny numbers started to increase with the rise in post-treatment durations. This new improved DE formulation was found to be effective at dose rates that are extensively lower than required with previous DE formulations and will contribute to lower the risk of health and environment.

Relationships between iron dose, hospitalizations and mortality in incident haemodialysis patients: a propensity-score matched approach.

PubMed

Varas, Javier; Ramos, Rosa; Aljama, Pedro; Pérez-García, Rafael; Moreso, Francesc; Pinedo, Miguel; Ignacio Merello, José; Stuard, Stefano; Canaud, Bernard; Martín-Malo, Alejandro

2018-01-01

Intravenous iron management is common in the haemodialysis population. However, the safest dosing strategy remains uncertain, in terms of the risk of hospitalization and mortality. We aimed to determine the effects of cumulative monthly iron doses on mortality and hospitalization. This multicentre observational retrospective propensity-matched score study included 1679 incident haemodialysis patients. We measured baseline demographic variables, haemodialysis clinical parameters and laboratory analytical values. We compared outcomes among quartiles of cumulative iron dose (mg/kg/month). We implemented propensity-score matching (PSM) to reduce confounding due to indication. In the PSM cohort (330 patients), we compared outcomes between groups that received cumulative iron doses above and below 5.66 mg/kg/month. Kaplan-Meier analyses showed that the high iron dose group had significantly worse survival than the low iron dose group. A univariate analysis indicated that the monthly iron dose could significantly predict mortality. However, a multivariate regression did not confirm that finding. The multivariate regression analysis revealed that iron doses  >5.58 mg/kg/month were not associated with elevated mortality risk, but they were associated with elevated risks of all-cause and cardiovascular-related hospitalizations. These results were ratified in the PSM population. Intravenous iron administration is advisable for maintaining haemoglobin levels in patients that receive haemodialysis. Our data suggested that large monthly iron doses, adjusted for body weight, were associated with more hospitalizations, but not with mortality or infection-related hospitalizations. © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Critical periods for marihuana-induced intrauterine growth retardation in the rat.

PubMed

Abel, E L; Bush, R; Dintcheff, B A; Ernst, C A

1981-01-01

Pregnant rats were intubated with marihuana extract (20, 200 mg/kg) throughout gestation. Control animals were intubated with vehicle (olive oil). Control animals and animals treated with the lower dose of drug were pair-fed and pair-watered to animals treated with the high dose. At parturition, pups were counted, weighed, culled, and assigned to nondrug-treated dams. Marihuana reduced food and water consumption and maternal weight gain. Pup weight at birth was reduced and neonatal mortality was increased in offspring exposed during the third week of gestation or throughout gestation. Litter size, postnatal mortality and weight at weaning were not significantly affected.

Childhood mortality after a high dose of vitamin A in a high risk population.

PubMed Central

Daulaire, N. M.; Starbuck, E. S.; Houston, R. M.; Church, M. S.; Stukel, T. A.; Pandey, M. R.

1992-01-01

OBJECTIVES--To determine whether a single high dose of vitamin A given to all children in communities with high mortality and malnutrition could affect mortality and to assess whether periodic community wide supplementation could be readily incorporated into an ongoing primary health programme. DESIGN--Opportunistic controlled trial. SETTING--Jumla district, Nepal. SUBJECTS--All children aged under 5 years; 3786 in eight subdistricts given single dose of vitamin A and 3411 in remaining eight subdistricts given no supplementation. MAIN OUTCOME MEASURES--Mortality and cause of death in the five months after supplementation. RESULTS--Risk of death for children aged 1-59 months in supplemented communities was 26% lower (relative risk 0.74, 95% confidence interval 0.55 to 0.99) than in unsupplemented communities. The reduction in mortality was greatest among children aged 6-11 months: death rate (deaths/1000 child years at risk) was 133.8 in supplemented children and 260.8 in unsupplemented children (relative risk 0.51, 0.30 to 0.89). The death rate from diarrhoea was also reduced (63.5 supplemented v 97.5 unsupplemented; relative risk 0.65, 0.44 to 0.95). The extra cost per death averted was about $11. CONCLUSION--The results support a role for Vitamin A in increasing child survival. The supplementation programme was readily integrated with the ongoing community health programme at little extra cost. PMID:1739794

Dose-response relationship between dietary magnesium intake and cardiovascular mortality: A systematic review and dose-based meta-regression analysis of prospective studies.

PubMed

Fang, Xin; Liang, Chun; Li, Mei; Montgomery, Scott; Fall, Katja; Aaseth, Jan; Cao, Yang

2016-12-01

Although epidemiology studies have reported the relationship, including a dose-response relationship, between dietary magnesium intake and risk of cardiovascular disease (CVD), the risk for CVD mortality is inconclusive and the evidence for a dose-response relationship has not been summarized. We conducted a systematic review and meta-analysis of prospective studies to summarize the evidence regarding the association of dietary magnesium intake with risk of CVD mortality and describe their dose-response relationship. We identified relevant studies by searching major scientific literature databases and grey literature resources from their inception to August 2015, and reviewed references lists of retrieved articles. We included population-based studies that reported mortality risks, i.e. relative risks (RRs), odds ratios (ORs) or hazard ratios (HRs) of CVD mortality or cause-specific CVD death. Linear dose-response relationships were assessed using random-effects meta-regression. Potential nonlinear associations were evaluated using restricted cubic splines. Out of 3002 articles, 9 articles from 8 independent studies met the eligibility criteria. These studies comprised 449,748 individuals and 10,313 CVD deaths. Compared with the lowest dietary magnesium consumption group in the population, the risk of CVD mortality was reduced by 16% in women and 8% in men. No significant linear dose-response relationship was found between increment in dietary magnesium intake and CVD mortality across all the studies. After adjusting for age and BMI, the risk of CVD mortality was reduced by 24-25% per 100mg/d increment in dietary magnesium intake in women of all the participants and in all the US participants. Although the combined data confirm the role of dietary magnesium intake in reducing CVD mortality, the dose-response relationship was only found among women and in US population. Copyright © 2016 Elsevier GmbH. All rights reserved.

Sublethal dose of phoxim and Bombyx mori nucleopolyhedrovirus interact to elevate silkworm mortality.

PubMed

Gu, ZhiYa; Li, FanChi; Hu, JingSheng; Ding, Chao; Wang, Chaoqian; Tian, JiangHai; Xue, Bin; Xu, KaiZun; Shen, WeiDe; Li, Bing

2017-03-01

Silkworm (Bombyx mori) is an economically important insect. It is relatively less resistant to certain chemicals and environment exposures such as pesticides and pathogens. After pesticide exposures, the silkworms are more susceptible to microbial infections. The mechanism underlying the susceptibility might be related to immune response and oxidative stress. A sublethal dose of phoxim combined with Bombyx mori nucleopolyhedrovirus (BmNPV) elevated the silkworm mortality at 96 h. We found a higher content of H 2 O 2 and increased levels of genes related to oxidative stress and immune response after treatment with a sublethal dose of phoxim for 24 h or 48 h. However, such response decreased with longer pesticide treatment. Mortality increased by 44% when B. mori was exposed to combined treatment with BmNPV and phoxim rather than BmNPV alone. The level of examined immune-related and oxidative-stress-related genes significantly decreased in the combined treatment group compared with the BmNPV group. Our results indicated that, with long-term exposure to pesticides such as OPs, even at sublethal dose, the oxidative stress response and immune responses in silkworm were inhibited, which may lead to further immune impairment and accumulation of oxidative stress, resulting in susceptibility to the virus and harm to the silkworm. Our study provided insights for understanding the susceptibility to pathogen after pesticide exposures, which may promote the development of better pesticide controls to avoid significant economic losses. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

Toxic effects of orally ingested oil from the Deepwater Horizon spill on laughing gulls.

PubMed

Horak, K E; Bursian, S J; Ellis, C K; Dean, K M; Link, J E; Hanson-Dorr, K C; Cunningham, F L; Harr, K E; Pritsos, C A; Pritsos, K L; Healy, K A; Cacela, D; Shriner, S A

2017-12-01

The explosion of the Deepwater Horizon oil rig released, millions of gallons of oil into the environment, subsequently exposing wildlife, including numerous bird species. To determine the effects of MC252 oil to species relevant to the Gulf of Mexico, studies were done examining multiple exposure scenarios and doses. In this study, laughing gulls (Leucophaeus atricilla, LAGU) were offered fish injected with MC252 oil at target doses of 5 or 10mL/kg bw per day. Dosing continued for 27 days. Of the adult, mixed-sex LAGUs used in the present study, ten of 20 oil exposed LAGUs survived to the end of the study; a total of 10 of the oil exposed LAGUs died or were euthanized within 20 days of initiation of the study. Endpoints associated with oxidative stress, hepatic total glutathione (tGSH), oxidized glutathione (GSSG) and reduced glutathione (rGSH) significantly increased as mean dose of oil increased, while the rGSH:GSSG ratio showed a non-significant negative trend with oil dose. A significant increase in 3-methyl histidine was found in oil exposed birds when compared to controls indicative of muscle wastage and may have been associated with the gross observation of diminished structural integrity in cardiac tissue. Consistent with previous oil dosing studies in birds, significant changes in liver, spleen, and kidney weight when normalized to body weight were observed. These studies indicate that mortality in response to oil dosing is relatively common and the mortality exhibited by the gulls is consistent with previous studies examining oil toxicity. Whether survival effects in the gull study were associated with weight loss, physiologic effects of oil toxicity, or a behavioral response that led the birds to reject the dosed fish is unknown. Published by Elsevier Inc.

Trends in opioid use and dosing among socio-economically disadvantaged patients

PubMed Central

Gomes, Tara; Juurlink, David N; Dhalla, Irfan A; Mailis-Gagnon, Angela; Paterson, J Michael; Mamdani, Muhammad M

2011-01-01

Background Opioid therapy for patients with chronic nonmalignant pain remains controversial, primarily because of safety concerns and the potential for abuse. The objective of this study was to examine trends in opioid utilization for nonmalignant pain among recipients of social assistance and to explore the relation between dose of analgesic and mortality. Methods Using a cross-sectional study design, we characterized annual trends in prescriptions for and daily dose of opioid analgesics between 2003 and 2008 for beneficiaries (aged 15 to 64 years) of Ontario’s public drug plan. We defined moderate, high and very high dose thresholds as daily doses of up to 200, 201 to 400, and more than 400 mg oral morphine (or equivalent), respectively. In an exploratory cohort study, we followed, over a 2-year period, patients who received at least one prescription for an opioid in 2004 to investigate the relation between opioid dose and opioid-related mortality. Results Over the study period, opioid prescribing rates rose by 16.2%, and 180 974 individuals received nearly 1.5 million opioid prescriptions in 2008. Also by 2008, the daily dose dispensed exceeded 200 mg morphine equivalent for almost a third (32.6%) of recipients of long-acting oxycodone but only 20.3% of those treated with fentanyl or other long-acting opioids. Among patients for whom high or very high doses of opioids were dispensed in 2004, 19.3% of deaths during the subsequent 2 years were opioid-related, occurring at a median age of 46 years. Two-year opioid-related mortality rates were 1.63 per 1000 population (95% confidence interval [CI] 1.42–1.85) among people with moderate-dose prescriptions, 7.92 per 1000 population (95% CI 5.25–11.49) among those with high-dose prescriptions, and 9.94 per 1000 population (95% CI 2.78–25.12) among those with very-high-dose prescriptions. Interpretation Among socio-economically disadvantaged patients in Ontario, the use and dose of opioids for nonmalignant pain has increased substantially, driven primarily by the use of long-acting oxycodone and, to a lesser extent, fentanyl. The findings of our exploratory study suggested a strong association between opioid-related mortality and the dose of opioid dispensed. PMID:22046214

Radiation Exposure and Mortality from Cardiovascular Disease and Cancer in Early NASA Astronauts.

PubMed

Elgart, S Robin; Little, Mark P; Chappell, Lori J; Milder, Caitlin M; Shavers, Mark R; Huff, Janice L; Patel, Zarana S

2018-05-31

Understanding space radiation health effects is critical due to potential increased morbidity and mortality following spaceflight. We evaluated whether there is evidence for excess cardiovascular disease or cancer mortality in early NASA astronauts and if a correlation exists between space radiation exposure and mortality. Astronauts selected from 1959-1969 were included and followed until death or February 2017, with 39 of 73 individuals still alive at that time. Calculated standardized mortality rates for tested outcomes were significantly below U.S. white male population rates, including all-cardiovascular disease (n = 7, SMR = 33; 95% CI, 14-65) and all-cancer (n = 7, SMR = 43; 95% CI, 18-83), as anticipated in a healthy worker population. Space radiation doses for cohort members ranged from 0-78 mGy. No significant associations between space radiation dose and mortality were found using logistic regression with an internal reference group, adjusting for medical radiation. Statistical power of the logistic regression was <6%, remaining <12% even when expected risk level or observed deaths were assumed to be 10 times higher than currently reported. While no excess radiation-associated cardiovascular or cancer mortality risk was observed, findings must be tempered by the statistical limitations of this cohort; notwithstanding, this small unique cohort provides a foundation for assessment of astronaut health.

Alcohol and liver disease in Europe--Simple measures have the potential to prevent tens of thousands of premature deaths.

PubMed

Sheron, Nick

2016-04-01

In the World Health Organisation European Region, more than 2,370,000 years of life are lost from liver disease before the age of 50; more than lung cancer, trachea, bronchus, oesophageal, stomach, colon, rectum and pancreatic cancer combined. Between 60-80% of these deaths are alcohol related, a disease for which no pharmaceutical therapy has yet been shown to improve long-term survival. The toxicity of alcohol is dose related at an individual level, and is dose related at a population level; overall liver mortality is largely determined by population alcohol consumption. Trends in alcohol consumption correlate closely with trends in overall liver mortality, with 3-5-fold decreases or increases in liver mortality in different European countries over the last few decades. The evidence base for alcohol control measures aimed at reducing population alcohol consumption has been subjected to rigorous evaluation; most recently by the Organisation for Economic Co-Operation and Development (OECD). Effective alcohol policy measures reduce alcohol mortality, including mortality from liver disease. The most effective and cost effective measures have been summarised by the OECD and the World Health Organisation: regular incremental above inflation tax increases, a minimum price for alcohol, effective protection of children from alcohol marketing and low level interventions from clinicians. Simple, cheap and effective changes to alcohol policy by European Institutions and member states have the potential to dramatically reduce liver mortality in Europe. Copyright © 2016. Published by Elsevier B.V.

Risk analysis: divergent models and convergent interpretations

NASA Technical Reports Server (NTRS)

Carnes, B. A.; Gavrilova, N.

2001-01-01

Material presented at a NASA-sponsored workshop on risk models for exposure conditions relevant to prolonged space flight are described in this paper. Analyses used mortality data from experiments conducted at Argonne National Laboratory on the long-term effects of external whole-body irradiation on B6CF1 mice by 60Co gamma rays and fission neutrons delivered as a single exposure or protracted over either 24 or 60 once-weekly exposures. The maximum dose considered was restricted to 1 Gy for neutrons and 10 Gy for gamma rays. Proportional hazard models were used to investigate the shape of the dose response at these lower doses for deaths caused by solid-tissue tumors and tumors of either connective or epithelial tissue origin. For protracted exposures, a significant mortality effect was detected at a neutron dose of 14 cGy and a gamma-ray dose of 3 Gy. For single exposures, radiation-induced mortality for neutrons also occurred within the range of 10-20 cGy, but dropped to 86 cGy for gamma rays. Plots of risk relative to control estimated for each observed dose gave a visual impression of nonlinearity for both neutrons and gamma rays. At least for solid-tissue tumors, male and female mortality was nearly identical for gamma-ray exposures, but mortality risks for females were higher than for males for neutron exposures. As expected, protracting the gamma-ray dose reduced mortality risks. Although curvature consistent with that observed visually could be detected by a model parameterized to detect curvature, a relative risk term containing only a simple term for total dose was usually sufficient to describe the dose response. Although detectable mortality for the three pathology end points considered typically occurred at the same level of dose, the highest risks were almost always associated with deaths caused by tumors of epithelial tissue origin.

Effect of high-dose vs standard-dose multivitamin supplementation at the initiation of HAART on HIV disease progression and mortality in Tanzania: a randomized controlled trial.

PubMed

Isanaka, Sheila; Mugusi, Ferdinand; Hawkins, Claudia; Spiegelman, Donna; Okuma, James; Aboud, Said; Guerino, Chalamilla; Fawzi, Wafaie W

2012-10-17

Large randomized trials have previously shown that high-dose micronutrient supplementation can increase CD4 counts and reduce human immunodeficiency virus (HIV) disease progression and mortality among individuals not receiving highly active antiretroviral therapy (HAART); however, the safety and efficacy of such supplementation has not been established in the context of HAART. To test the hypothesis that high-dose multivitamin supplementation vs standard-dose multivitamin supplementation decreases the risk of HIV disease progression or death and improves immunological, virological, and nutritional parameters in patients with HIV initiating HAART. A randomized, double-blind, controlled trial of high-dose vs standard-dose multivitamin supplementation for 24 months in 3418 patients with HIV initiating HAART between November 2006 and November 2008 in 7 clinics in Dar es Salaam, Tanzania. INTERVENTION The provision of daily oral supplements of vitamin B complex, vitamin C, and vitamin E at high levels or standard levels of the recommended dietary allowance. The composite of HIV disease progression or death from any cause. The study was stopped early in March 2009 because of evidence of increased levels of alanine transaminase (ALT) in patients receiving the high-dose multivitamin supplement. At the time of stopping, 3418 patients were enrolled (median follow-up, 15 months), and there were 2374 HIV disease progression events and 453 observed deaths (2460 total combined events). Compared with standard-dose multivitamin supplementation, high-dose supplementation did not reduce the risk of HIV disease progression or death. The absolute risk of HIV progression or death was 72% in the high-dose group vs 72% in the standard-dose group (risk ratio [RR], 1.00; 95% CI, 0.96-1.04). High-dose supplementation had no effect on CD4 count, plasma viral load, body mass index, or hemoglobin level concentration, but increased the risk of ALT elevations (1239 events per 1215 person-years vs 879 events per 1236 person-years; RR, 1.44; 95% CI, 1.11-1.87) vs standard-dose supplementation. CONCLUSION In adults receiving HAART, use of high-dose multivitamin supplements compared with standard-dose multivitamin supplements did not result in a decrease in HIV disease progression or death but may have resulted in an increase in ALT levels. Clinicaltrials.gov Identifier: NCT00383669.

Dose-response meta-analysis of poultry intake and colorectal cancer incidence and mortality.

PubMed

Shi, Yan; Yu, Pei-Wu; Zeng, Dong-Zhu

2015-03-01

Poultry intake has been inconsistently associated with incidence or mortality of colorectal cancer (CRC) in epidemiologic studies. The purpose of this study was to assess their relationships by performing a dose-response meta-analysis. We conducted a search of PubMed database between January 1966 and July 2013 for prospective studies that reported relative risks (RRs) with 95 % confidence interval (CIs) of CRC for at least three categories of poultry intake. Dose-response relationships were examined with the generalized least-squares trend estimation. Study-specific results were pooled with a random-effects model. Subgroup, sensitivity, and meta-regression analyses were also conducted to explore heterogeneity. Sixteen studies on poultry intake and CRC incidence, and four studies regarding poultry intake and CRC mortality were identified. These studies involved a total of 13,949 incident CRC cases and 983 CRC deaths. The RRs of CRC for higher compared with lower intake of poultry were reported in these studies, and the reported levels of poultry intake varied substantially. Results of the dose-response meta-analysis conferred a RR of 0.89 (95 % CI 0.81-0.97) for an increase in poultry intake of 50 g/day. The results were not sensitive to any individual studies and were similar for colon and rectal cancer. Poultry intake was not associated with CRC mortality (RR for 50 g/day = 0.97, 95 % CI 0.79-1.20). This meta-analysis indicates that poultry intake may be moderately associated with reduced incidence of CRC.

Rosuvastatin protects against angiotensin II-induced renal injury in a dose-dependent fashion.

PubMed

Park, Joon-Keun; Mervaala, Eero Ma; Muller, Dominik N; Menne, Jan; Fiebeler, Anette; Luft, Friedrich C; Haller, Hermann

2009-03-01

We showed earlier that statin treatment ameliorates target-organ injury in a transgenic model of angiotensin (Ang) II-induced hypertension. We now test the hypothesis that rosuvastatin (1, 10, and 50 mg/kg/day) influences leukocyte adhesion and infiltration, prevents induction of inducible nitric oxide synthase (iNOS), and ameliorates target-organ damage in a dose-dependent fashion. We treated rats harboring the human renin and human angiotensinogen genes (dTGR) from week 4 to 8 (n = 20 per group). Untreated dTGR developed severe hypertension, cardiac hypertrophy, and renal damage, with a 100-fold increased albuminuria and focal cortical necrosis. Mortality of untreated dTGR at age 8 weeks was 59%. Rosuvastatin treatment decreased mortality dose-dependently. Blood pressure was not affected. Albuminuria was reduced dose-dependently. Interstitial adhesion molecule (ICAM)-1 expression was markedly reduced by rosuvastatin, as were neutrophil and monocyte infiltration. Immunohistochemistry showed an increased endothelial and medial iNOS expression in small vessels, infiltrating cells, afferent arterioles, and glomeruli of dTGR. Immunoreactivity was stronger in cortex than medulla. Rosuvastatin markedly reduced the iNOS expression in both cortex and medulla. Finally, matrix protein (type IV collagen, fibronectin) expression was also dose- dependently reduced by rosuvastatin. Our findings indicate that rosuvastatin dose- dependently ameliorates angiotensin II-induced-organ damage and almost completely prevents inflammation at the highest dose. The data implicate 3-hydroxy-3-methylglutaryl coenzyme A function in signaling events leading to target-organ damage.

Coffee consumption and risk of all-cause, cardiovascular, and cancer mortality in smokers and non-smokers: a dose-response meta-analysis.

PubMed

Grosso, Giuseppe; Micek, Agnieszka; Godos, Justyna; Sciacca, Salvatore; Pajak, Andrzej; Martínez-González, Miguel A; Giovannucci, Edward L; Galvano, Fabio

2016-12-01

Coffee consumption has been associated with several benefits toward human health. However, its association with mortality risk has yielded contrasting results, including a non-linear relation to all-cause and cardiovascular disease (CVD) mortality and no association with cancer mortality. As smoking habits may affect the association between coffee and health outcomes, the aim of the present study was to update the latest dose-response meta-analysis of prospective cohort studies on the association between coffee consumption and mortality risk and conduct stratified analyses by smoking status and other potential confounders. A systematic search was conducted in electronic databases to identify relevant studies, risk estimates were retrieved from the studies, and dose-response analysis was modeled by using restricted cubic splines. A total of 31 studies comprising 1610,543 individuals and 183,991 cases of all-cause, 34,574 of CVD, and 40,991 of cancer deaths were selected. Analysis showed decreased all-cause [relative risk (RR) = 0.86, 95 % confidence interval (CI) = 0.82, 0.89)] and CVD mortality risk (RR = 0.85, 95 % CI = 0.77, 0.93) for consumption of up to 4 cups/day of coffee, while higher intakes were associated with no further lower risk. When analyses were restricted only to non-smokers, a linear decreased risk of all-cause (RR = 0.94, 95 % CI = 0.93, 0.96), CVD (RR = 0.94, 95 % CI = 0.91, 0.97), and cancer mortality (RR = 0.98, 95 % CI = 0.96, 1.00) for 1 cup/day increase was found. The search for other potential confounders, including dose-response analyses in subgroups by gender, geographical area, year of publication, and type of coffee, showed no relevant differences between strata. In conclusion, coffee consumption is associated with decreased risk of mortality from all-cause, CVD, and cancer; however, smoking modifies the observed risk when studying the role of coffee on human health.

Single toxin dose-response models revisited

DOE Office of Scientific and Technical Information (OSTI.GOV)

Demidenko, Eugene, E-mail: eugened@dartmouth.edu

The goal of this paper is to offer a rigorous analysis of the sigmoid shape single toxin dose-response relationship. The toxin efficacy function is introduced and four special points, including maximum toxin efficacy and inflection points, on the dose-response curve are defined. The special points define three phases of the toxin effect on mortality: (1) toxin concentrations smaller than the first inflection point or (2) larger then the second inflection point imply low mortality rate, and (3) concentrations between the first and the second inflection points imply high mortality rate. Probabilistic interpretation and mathematical analysis for each of the fourmore » models, Hill, logit, probit, and Weibull is provided. Two general model extensions are introduced: (1) the multi-target hit model that accounts for the existence of several vital receptors affected by the toxin, and (2) model with a nonzero mortality at zero concentration to account for natural mortality. Special attention is given to statistical estimation in the framework of the generalized linear model with the binomial dependent variable as the mortality count in each experiment, contrary to the widespread nonlinear regression treating the mortality rate as continuous variable. The models are illustrated using standard EPA Daphnia acute (48 h) toxicity tests with mortality as a function of NiCl or CuSO{sub 4} toxin. - Highlights: • The paper offers a rigorous study of a sigmoid dose-response relationship. • The concentration with highest mortality rate is rigorously defined. • A table with four special points for five morality curves is presented. • Two new sigmoid dose-response models have been introduced. • The generalized linear model is advocated for estimation of sigmoid dose-response relationship.« less

The dose-response of time served in prison on mortality: New York State, 1989-2003.

PubMed

Patterson, Evelyn J

2013-03-01

I investigated the differential impact of the dose-response of length of stay on postprison mortality among parolees. Using 1989-2003 New York State parole administrative data from the Bureau of Justice Statistics on state correctional facilities, I employed multinomial logistic regression analyses and formal demographic techniques that used the life table of the populations to deduce changes in life expectancy. Each additional year in prison produced a 15.6% increase in the odds of death for parolees, which translated to a 2-year decline in life expectancy for each year served in prison. The risk was highest upon release from prison and declined over time. The time to recovery, or the lowest risk level, was approximately two thirds of the time served in prison. Incarceration reduces life span. Future research should investigate the pathways to this higher mortality and the possibilities of recovery.

Escalation to High Dose Defibrotide in Patients with Hepatic Veno-Occlusive Disease

PubMed Central

Triplett, Brandon M.; Kuttab, Hani I.; Kang, Guolian; Leung, Wing

2015-01-01

Hepatic veno-occlusive disease (VOD) is a serious complication of high-dose chemotherapy regimens, such as those utilized in hematopoietic cell transplantation recipients. Defibrotide is considered a safe and effective treatment when dosed at 25 mg/kg/day. However, patients who develop VOD still have increased mortality despite the use of defibrotide. Data are limited on the use of doses above 60 mg/kg/day for persistent VOD. In this prospective clinical trial, 34 patients received escalating doses of defibrotide. For patients with persistent VOD despite doses of 60 mg/kg/day, doses were increased to a maximum of 110 mg/kg/day. There was no observed increase in toxicity until doses rose beyond 100 mg/kg/day. Patients receiving doses between 10–100 mg/kg/day experienced an average of 3 bleeding episodes per 100 days of treatment, while those receiving doses >100 mg/kg/day experienced 13.2 bleeding episodes per 100 days (p=0.008). Moreover, dose reductions due to toxicity were needed at doses of 110 mg/kg/day more often than at lower doses. Defibrotide may be safely escalated to doses well above the current standard without an increase in bleeding risk. However, the efficacy of this dose escalation strategy remains unclear, as outcomes were similar to published cohorts of patients receiving standard doses of defibrotide for VOD. PMID:26278046

Mortality among military participants at the 1957 PLUMBBOB nuclear weapons test series and from leukemia among participants at the SMOKY test.

PubMed

Caldwell, Glyn G; Zack, Matthew M; Mumma, Michael T; Falk, Henry; Heath, Clark W; Till, John E; Chen, Heidi; Boice, John D

2016-09-01

Health effects following low doses of ionizing radiation are uncertain. Military veterans at the Nevada test site (NTS) during the SMOKY atmospheric nuclear weapons test in 1957 were reported to be at increased risk for leukemia in 1979, but this increase was not evaluated with respect to radiation dose. The SMOKY test was one of 30 tests in 1957 within the PLUMBBOB test series. These early studies led to public laws where atomic veterans could qualify for compensation for presumptive radiogenic diseases. A retrospective cohort study was conducted of 12219 veterans at the PLUMBBOB test series, including 3020 at the SMOKY nuclear test. Mortality follow-up was through 2010 and observed causes of death were compared with expected causes based on general population rates. Radiation dose to red bone marrow was based on individual dose reconstructions, and Cox proportional hazards models were used to evaluate dose response for all leukemias other than chronic lymphocytic leukemia (non-CLL leukemia). Vital status was determined for 95.3% of the 12 219 veterans. The dose to red bone marrow was low (mean 3.2 mGy, maximum 500 mGy). Military participants at the PLUMBBOB nuclear test series remained relatively healthy after 53 years and died at a lower rate than the general population. In contrast, and in comparison with national rates, the SMOKY participants showed significant increases in all causes of death, respiratory cancer, leukemia, nephritis and nephrosis, and accidents, possibly related in part to lifestyle factors common to enlisted men who made up 81% of the SMOKY cohort. Compared with national rates, a statistically significant excess of non-CLL leukemia was observed among SMOKY participants (Standardized Mortality Ratio  =  1.89, 95% 1.24-2.75, n  =  27) but not among PLUMBBOB participants after excluding SMOKY (SMR  =  0.87, 95% 0.64-1.51, n  =  47). Leukemia risk, initially reported to be significantly increased among SMOKY participants, remained elevated, but this risk diminished over time. Despite an intense dose reconstruction, the risk for leukemia was not found to increase with increasing levels of radiation dose to the red bone marrow. Based on a linear model, the estimated excess relative risk per mGy is  -0.05 (95% CI -0.14, 0.04). An explanation for the observed excess of leukemia remains unresolved but conceivably could be related to chance due to small numbers, subtle biases in the study design and/or high tobacco use among enlisted men. Larger studies should elucidate further the possible relationship between fallout radiation, leukemia and cancer among atomic veterans.

Mortality among Military Participants at the 1957 PLUMBBOB Nuclear Weapons Test Series and on Leukemia among Participants at the SMOKY Test

PubMed Central

Caldwell, Glyn G.; Zack, Matthew M.; Mumma, Michael T.; Falk, Henry; Heath, Clark W.; Till, John E.; Chen, Heidi; Boice, John D.

2016-01-01

Health effects following low doses of ionizing radiation are uncertain. Military veterans at the Nevada Test Site (NTS) during the SMOKY atmospheric nuclear weapons test in 1957 were reported to be at increased risk for leukemia in 1979, but this increase was not evaluated with respect to radiation dose. The SMOKY test was one of 30 tests in 1957 within the PLUMBBOB test series. These early studies led to public laws where atomic veterans could qualify for compensation for presumptive radiogenic diseases. A retrospective cohort study was conducted of 12,219 veterans at PLUMBBOB test series, including 3,020 at the SMOKY nuclear test. Mortality follow-up was through 2010 and observed causes of death were compared with expected causes based on general population rates. Radiation dose to red bone marrow was based on individual dose reconstructions, and Cox proportional hazards models were used to evaluate dose response for all leukemias other than chronic lymphocytic leukemia (non-CLL leukemia). Vital status was determined for 95.3% of the 12,219 veterans. The dose to red bone marrow was low (mean 3.2 mGy, maximum 500 mGy). Military participants at the PLUMBBOB nuclear test series remained relatively healthy after 53 years and died at a lower rate than the general population. In contrast, and in comparison with national rates, the SMOKY participants showed significant increases in all causes of death, respiratory cancer, leukemia, nephritis and nephrosis, and accidents, possibly related in part to lifestyle factors common to enlisted men who made up 81% of the SMOKY cohort. Compared with national rates, a statistically significant excess of non-CLL leukemia was observed among SMOKY participants (Standardized Mortality Ratio=1.89, 95% 1.24–2.75, n=27) but not among PLUMBBOB participants after excluding SMOKY (SMR=0.87, 95% 0.64–1.51, n=47). Leukemia risk, initially reported to be significantly increased among SMOKY participants, remained elevated, but this risk diminished over time. Despite an intense dose reconstruction, the risk for leukemia was not found to increase with increasing levels of radiation dose to the red bone marrow. Based on a linear model, the estimated excess relative risk per mGy is −0.05 (95% CI −0.14, 0.04). An explanation for the observed excess of leukemia remains unresolved but conceivably could be related to chance due to small numbers, subtle biases in the study design and/or high tobacco use among enlisted men. Larger studies should elucidate further the possible relationship between fallout radiation, leukemia and cancer among atomic veterans. PMID:27355245

Are diuretics harmful in the management of acute kidney injury?

PubMed

Ejaz, A Ahsan; Mohandas, Rajesh

2014-03-01

To assess the role of diuretics in acute kidney injury (AKI) and their effectiveness in preventing AKI, achieving fluid balance, and decreasing progression to chronic kidney disease (CKD). Diuretics are associated with increased risk for AKI. The theoretical advantage of diuretic-induced preservation of renal medullary oxygenation to prevent AKI has not been proven. A higher cumulative diuretic dose during the dialysis period can cause hypotension and increase mortality in a dose-dependent manner. Data on the use of forced euvolemic diuresis to prevent AKI remains controversial. Positive fluid balance has emerged as an independent predictor of adverse outcomes. Post-AKI furosemide dose had a favorable effect on mortality due in part to the reduction of positive fluid balance. There are exciting experimental data suggesting that spironolactone may prevent AKI once an ischemic insult has occurred and thus prevent the progression to CKD. Diuretics are ineffective and even detrimental in the prevention and treatment of AKI, and neither shorten the duration of AKI, nor reduce the need for renal replacement therapy. Diuretics have an important role in volume management in AKI, but they are not recommended for the prevention of AKI. There is increased emphasis on the prevention of progression of AKI to CKD.

Towards improved quantification of post-fire conifer mortality and recovery: Impacts of fire radiative flux on seedling and mature tree mortality, physiology, and growth

NASA Astrophysics Data System (ADS)

Sparks, A. M.; Kolden, C.; Smith, A. M.

2016-12-01

Fire activity, in terms of intensity, frequency, and total area burned, is expected to increase with changing climate. A challenge for landscape level assessment of fire effects, termed burn severity, is that current assessments provide very little information regarding vegetation physiological performance and recovery, limiting our understanding of fire effects on ecosystem services such as carbon storage/cycling. To address these limitations, we evaluated an alternative dose-response methodology for quantifying fire effects that attempts to bridge fire combustion dynamics and ecophysiology. Specifically, we conducted a highly controlled, laboratory assessment of seedling response to increasing doses of fire radiative energy applied through surface fires, for two western U.S. conifer species. Seedling physiology and spectral reflectance were acquired pre- and up to 1 year post-fire. Post-fire mortality, physiological performance, and spectral reflectance were strongly related with fire radiative energy density (FRED: J m-2) dose. To examine how these relationships change with tree size and age, we conducted small prescribed fires at the tree scale (35 m2) in a mature conifer stand. Radial growth and resin duct defenses were assessed on the mature conifer trees following the prescribed fires. Differences in dose-response relationships between seedlings and mature trees indicate the importance of fire behavior (e.g., flaming-dominated versus smoldering-dominated combustion) in characterizing these relationships. Ultimately, these results suggest that post-fire impacts on growth of surviving seedlings and mature trees require modes of heat transfer to impact tree canopies.

Updated mortality analysis of radiation workers at Rocketdyne (Atomics International), 1948-2008

DOE Office of Scientific and Technical Information (OSTI.GOV)

Boice, John; Cohen, Sarah; Mumma, Michael

Updated analyses of mortality data are presented on 5,801 radiation workers, including 2,232 monitored for radionuclide intakes, and 41,169 non-radiation workers employed 1948-1999 at Rocketdyne (Atomics International). The worker population is unique in that lifetime occupational doses from all places of employment were sought and incorporated into the analyses. Further, radiation doses from intakes of 14 different radionuclides were calculated for 16 organs or tissues using biokinetic models of the International Commission on Radiation Protection (ICRP). The mean dose from external radiation was 13.5 mSv (maximum 1 Sv), and the mean lung dose from external and internal radiation combined wasmore » 19.0 mSv (maximum 3.6 Sv). An additional nine years of follow-up, from December 31,1999 through 2008, increased the person-years of observation by 21.7% to 196,674 (mean 33.9 years) and the number of cancer deaths by 50% to 684. Analyses included comparisons with the general population and the computation of standardized mortality ratios (SMRs), and internal comparisons using proportional hazards models. All cancers taken together (SMR 0.88; 95% CI 0.81-0.95), lung cancer (SMR 0.87; 95% CI 0.76-1.00) and leukemia other than chronic lymphocytic leukemia (CLL) (SMR 1.04; 95% 0.67-1.53) were not significantly elevated. Cox regression analyses revealed no significant dose-response trends for any cancer. For all cancers excluding leukemia, the relative risk (RR) at 100 mSv was estimated as 0.98 (95% CI 0.82-1.17) and for all leukemia other than CLL it was 1.06 (95% CI 0.50-2.23). Uranium was the primary radionuclide contributing to internal exposures, but significant increases in lung and kidney disease were not seen. The extended follow-up re-enforces the findings in the previous study in failing to observe a detectable increase in cancer deaths associated with radiation, but strong conclusions still cannot be drawn because of small numbers and relatively low career doses. Larger combined studies of early workers in the United States following similar methodologies are warranted to refine and clarify radiation risks following protracted exposures.« less

Radiation therapy planning with photons and protons for early and advanced breast cancer: an overview

PubMed Central

Weber, Damien C; Ares, Carmen; Lomax, Antony J; Kurtz, John M

2006-01-01

Postoperative radiation therapy substantially decreases local relapse and moderately reduces breast cancer mortality, but can be associated with increased late mortality due to cardiovascular morbidity and secondary malignancies. Sophistication of breast irradiation techniques, including conformal radiotherapy and intensity modulated radiation therapy, has been shown to markedly reduce cardiac and lung irradiation. The delivery of more conformal treatment can also be achieved with particle beam therapy using protons. Protons have superior dose distributional qualities compared to photons, as dose deposition occurs in a modulated narrow zone, called the Bragg peak. As a result, further dose optimization in breast cancer treatment can be reasonably expected with protons. In this review, we outline the potential indications and benefits of breast cancer radiotherapy with protons. Comparative planning studies and preliminary clinical data are detailed and future developments are considered. PMID:16857055

First report of toxicity of Xylopiaparviflora (A. Rich.) Benth (Annonaceae) root bark's essential oil against cowpea seed bruchid, Callososbruchus maculatus Fabricius (Coleoptera: Chrysomelidae: Bruchinae).

PubMed

Babarinde, Samuel Adelani; Pitan, Olufemi Olutoyin Richard; Olatunde, Ganiyu Olatunji; Ajala, Michael Oluwole

2015-01-01

The fumigant toxicity of Xylopia parviflora (A. Rich.) Benth (Annonaceae) root bark's essential oil (EO) against cowpea seed bruchid, Callosobruchus maculatus, was investigated in the laboratory. Dose had significant (P < 0.0001) effect on mortality at 6 hours after treatment (HAT) at a concentration of 6.25 μL/mL air which exerted 81.70% mortality, while there was no mortality in all other lower doses. At 12 HAT, 75.05% and 90.00% mortality were observed at doses of 3.15 and 6.25 μL/mL air, respectively. It was significantly (P < 0.05) higher than the mortality (50.58%) observed when 0.78 μL/mL air was applied. The lethal time for 50% of assayed adults (LT50) obtained when the bruchid was exposed to X. parviflora EO at a dose of 6.25 μL/mL air (2.71 h) was significantly lower than LT50 obtained at exposure of bruchid to other lower doses of 0.78-3.15 μL/mL air.

Spirulina platensis Lacks Antitumor Effect against Solid Ehrlich Carcinoma in Female Mice

PubMed Central

Barakat, Waleed; Elshazly, Shimaa M.; Mahmoud, Amr A. A.

2015-01-01

Spirulina is a blue-green alga used as a dietary supplement. It has been shown to possess anti-inflammatory, antioxidant, and hepatoprotective properties. This study was designed to evaluate the antitumor effect of spirulina (200 and 800 mg/kg) against a murine model of solid Ehrlich carcinoma compared to a standard chemotherapeutic drug, 5-fluorouracil (20 mg/kg). Untreated mice developed a palpable solid tumor after 13 days. Unlike fluorouracil, spirulina at the investigated two dose levels failed to exert any protective effect. In addition, spirulina did not potentiate the antitumor effect of fluorouracil when they were administered concurrently. Interestingly, their combined administration resulted in a dose-dependent increase in mortality. The present study demonstrates that spirulina lacks antitumor effect against this model of solid Ehrlich carcinoma and increased mortality when combined with fluorouracil. However, the implicated mechanism is still elusive. PMID:26366170

Accelerometer-determined physical activity and all-cause mortality in a national prospective cohort study of hypertensive adults.

PubMed

Loprinzi, Paul D

2016-05-01

Research in the general population suggests an inverse association between physical activity and all-cause mortality. Less research on this topic has been conducted among hypertensive adults, but the limited studies also suggest an inverse association between physical activity and all-cause mortality among hypertensive adults. At this point, sex-specific differences are not well understood, and all of the physical activity-mortality studies among hypertensive adults have employed a self-report measure of physical activity. Therefore, the purpose of this study was to examine the sex-specific association between objectively measured physical activity and all-cause mortality among a national sample of hypertensive adults. Data from the 2003 to 2006 National Health and Nutrition Examination Survey, with follow-up through 2011, were employed. Hypertension status was defined using measured blood pressure and use of blood pressure-lowering medication. Physical activity was assessed via accelerometry. After adjustments, for every 60-min increase in physical activity, hypertensive adults had a 19% (hazard rate = 0.81; 95% confidence interval: 0.72-0.91) reduced risk of all-cause mortality. There was also evidence of a dose-response relationship. Compared with those in the lowest tertile, those in the middle and upper tertiles had a 31 and 42% reduced all-cause mortality risk, respectively. There was no evidence of a sex-specific interaction effect. Among hypertensive adults, objectively measured physical activity is associated with all-cause mortality risk in a dose-response manner.

Furosemide Prescription During the Dry State Is a Predictor of Long-Term Survival of Stable, Optimally Medicated Patients With Systolic Heart Failure.

PubMed

Sargento, Luis; Simões, Andre Vicente; Longo, Susana; Lousada, Nuno; Reis, Roberto Palma Dos

2017-05-01

Furosemide is associated with poor prognosis in patients with heart failure and reduced ejection fraction (HFrEF). To evaluate the association between daily furosemide dose prescribed during the dry state and long-term survival in stable, optimally medicated outpatients with HFrEF. Two hundred sixty-six consecutive outpatients with left ventricular ejection fraction <40%, clinically stable in the dry state and on optimal heart failure therapy, were followed up for 3 years in a heart failure unit. The end point was all-cause death. There were no changes in New York Heart Association class and therapeutics, including diuretics, and no decompensation or hospitalization during 6 months. Furosemide doses were categorized as low or none (0-40 mg/d), intermediate (41-80 mg/d), and high (>80 mg). Cox regression was adjusted for significant confounders. The 3-year mortality rate was 33.8%. Mean dose of furosemide was 57.3 ± 21.4 mg/d. A total of 47.6% of patients received the low dose, 42.1% the intermediate dose, and 2.3% the high dose. Receiver operating characteristics for death associated with furosemide dose showed an area under the curve of 0.74 (95% confidence interval [CI]: 0.68-0.79; P < .001), and the best cutoff was >40 mg/d. An increasing daily dose of furosemide was associated with worse prognosis. Those receiving the intermediate dose (hazard ratio [HR] = 4.1; 95% CI: 2.57-6.64; P < .001) or high dose (HR = 19.8; 95% CI: 7.9-49.6; P < .001) had a higher risk of mortality compared to those receiving a low dose. Patients receiving >40 mg/d, in a propensity score-matched cohort, had a greater risk of mortality than those receiving a low dose (HR = 4.02; 95% CI: 1.8-8.8; P = .001) and those not receiving furosemide (HR = 3.9; 95% CI: 0.07-14.2; P = .039). Furosemide administration during the dry state in stable, optimally medicated outpatients with HFrEF is unfavorably associated with long-term survival. The threshold dose was 40 mg/d.

Long-term Cardiac Mortality After Hypofractionated Radiation Therapy in Breast Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tjessem, Kristin Holm, E-mail: krtjes@ous-hf.no; Johansen, Safora; Malinen, Eirik

Purpose: To explore very-long-term mortality from ischemic heart disease (IHD) after locoregional radiation therapy of breast cancer (BC) in relation to degree of hypofractionation and other treatment variables. Methods and Materials: Two hypofractionated regimens used for locoregional radiation therapy for BC from 1975 to 1991 were considered. Patients received 4.3 Gy × 2/week (10 fractions; target dose 43 Gy; n=1107) or 2.5 Gy × 5/week (20 fractions; target dose 50 Gy; n=459). To estimate cardiac doses, radiation fields were reconstructed in a planning system. Time to death from IHD was the endpoint, comparing the groups with each other and withmore » age-matched, cancer-free control individuals, modeled with the Cox proportional hazards model. Results: Patients given 4.3 Gy × 10 had an increased risk of dying of IHD compared with both the 2.5 Gy group (hazard ratio [HR] = 2.37; 95% confidence interval [CI]: 1.06-5.32; P=.036) and the control group (HR = 1.59; 95% CI: 1.13-2.23; P=.008). Photon beams for parasternal fields gave an increased risk of dying of IHD compared with electron beams (HR = 2.56; 95% CI: 1.12-5.84; P=.025). Multivariate analysis gave an increased risk for the 4.3-Gy versus 2.5-Gy regimen with borderline significance (HR = 2.90; 95% CI: 0.97-8.79; P=.057) but not for parasternal irradiation. Conclusions: The degree of hypofractionation and parasternal photon beams contributed to increased cardiac mortality in this patient cohort. Differences emerged after 12 to 15 years, indicating the need of more studies with observation time of 2 decades.« less

Opioid Prescription, Morbidity, and Mortality in United States Dialysis Patients.

PubMed

Kimmel, Paul L; Fwu, Chyng-Wen; Abbott, Kevin C; Eggers, Anne W; Kline, Prudence P; Eggers, Paul W

2017-12-01

Aggressive pain treatment was advocated for ESRD patients, but new Centers for Disease Control and Prevention guidelines recommend cautious opioid prescription. Little is known regarding outcomes associated with ESRD opioid prescription. We assessed opioid prescriptions and associations between opioid prescription and dose and patient outcomes using 2006-2010 US Renal Data System information in patients on maintenance dialysis with Medicare Part A, B, and D coverage in each study year ( n =671,281, of whom 271,285 were unique patients). Opioid prescription was confirmed from Part D prescription claims. In the 2010 prevalent cohort ( n =153,758), we examined associations of opioid prescription with subsequent all-cause death, dialysis discontinuation, and hospitalization controlled for demographics, comorbidity, modality, and residence. Overall, >60% of dialysis patients had at least one opioid prescription every year. Approximately 20% of patients had a chronic (≥90-day supply) opioid prescription each year, in 2010 usually for hydrocodone, oxycodone, or tramadol. In the 2010 cohort, compared with patients without an opioid prescription, patients with short-term (1-89 days) and chronic opioid prescriptions had increased mortality, dialysis discontinuation, and hospitalization. All opioid drugs associated with mortality; most associated with worsened morbidity. Higher opioid doses correlated with death in a monotonically increasing fashion. We conclude that opioid drug prescription is associated with increased risk of death, dialysis discontinuation, and hospitalization in dialysis patients. Causal relationships cannot be inferred, and opioid prescription may be an illness marker. Efforts to treat pain effectively in patients on dialysis yet decrease opioid prescriptions and dose deserve consideration. Copyright © 2017 by the American Society of Nephrology.

Endotoxin-induced intravascular coagulation in rabbits: effect of tissue plasminogen activator vs urokinase of PAI generation, fibrin deposits and mortality.

PubMed

Paloma, M J; Páramo, J A; Rocha, E

1995-12-01

We have evaluated the effect of plasminogen activators (t-PA and urokinase) on an experimental model of disseminated intravascular coagulation (DIC) in rabbits by injection of 20 micrograms/kg/h of E. coli lipopolysaccharide during 6 h t-PA (0.2 mg/kg and 0.7 mg/kg), urokinase (3000 U/kg/h) and saline (control) were given simultaneously with endotoxin. Results indicated that urokinase and low dose of t-PA significantly reduced the increase of plasminogen activator inhibitor (PAI) activity observed 2 h after endotoxin (p < 0.001). High t-PA dose also diminished the PAI levels at 6 h (p < 0.001). A significant reduction of fibrin deposits in kidneys was observed din both t-PA treated groups as compared with findings in the group of rabbits infused with saline solution (p < 0.005), whereas urokinase had no significant effect on the extent of fibrin deposition. Finally, the mortality rate in the control group (70%) was reduced to 50% in rabbits receiving high doses of t-PA. In conclusion, treatment with t-PA resulted in reduced PAI generation, fibrin deposits and mortality in endotoxin-treated rabbits.

Escalation to High-Dose Defibrotide in Patients with Hepatic Veno-Occlusive Disease.

PubMed

Triplett, Brandon M; Kuttab, Hani I; Kang, Guolian; Leung, Wing

2015-12-01

Hepatic veno-occlusive disease (VOD) is a serious complication of high-dose chemotherapy regimens, such as those used in hematopoietic cell transplantation recipients. Defibrotide is considered a safe and effective treatment when dosed at 25 mg/kg/day. However, patients who develop VOD still have increased mortality despite the use of defibrotide. Data are limited on the use of doses above 60 mg/kg/day for persistent VOD. In this prospective clinical trial 34 patients received escalating doses of defibrotide. For patients with persistent VOD despite doses of 60 mg/kg/day, doses were increased to a maximum of 110 mg/kg/day. Increased toxicity was not observed until doses rose beyond 100 mg/kg/day. Patients receiving doses between 10 and 100 mg/kg/day experienced an average of 3 bleeding episodes per 100 days of treatment, whereas those receiving doses >100 mg/kg/day experienced 13.2 bleeding episodes per 100 days (P = .008). Moreover, dose reductions due to toxicity were needed at doses of 110 mg/kg/day more often than at lower doses. Defibrotide may be safely escalated to doses well above the current standard without an increase in bleeding risk. However, the efficacy of this dose-escalation strategy remains unclear, because outcomes were similar to published cohorts of patients receiving standard doses of defibrotide for VOD. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Effects of ethanol on methyl mercury toxicity in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tamashiro, H.; Arakaki, M.; Akagi, H.

1986-01-01

This study was designed to investigate the effect of different doses of ethanol on the morbidity, mortality, and distribution of mercury in the tissues of groups of rats treated orally once daily with methyl mercury chloride (MMC: 5 mg/kg d) for 10 consecutive days. Ethanol potentiated the toxicity of methyl mercury in terms of neurological manifestations (hindleg crossings and abnormal gait) and mortality. The magnitude of effect depended on the concentration of ethanol administered. The concentration of mercury in the kidney and brain also increased with the dose of ethanol given. These findings indicate that epidemiologic studies designed to evaluatemore » methyl mercury toxicity must take into account the multiple environmental burdens that can affect the population cumulatively and simultaneously.« less

Effect of High-Dose vs Standard-Dose Multivitamin Supplementation at the Initiation of HAART on HIV Disease Progression and Mortality in Tanzania

PubMed Central

Isanaka, Sheila; Mugusi, Ferdinand; Hawkins, Claudia; Spiegelman, Donna; Okuma, James; Aboud, Said; Guerino, Chalamilla; Fawzi, Wafaie W.

2013-01-01

Context Large randomized trials have previously shown that high-dose micronutrient supplementation can increase CD4 counts and reduce human immunodeficiency virus (HIV) disease progression and mortality among individuals not receiving highly active antiretroviral therapy (HAART); however, the safety and efficacy of such supplementation has not been established in the context of HAART. Objective To test the hypothesis that high-dose multivitamin supplementation vs standard-dose multivitamin supplementation decreases the risk of HIV disease progression or death and improves immunological, virological, and nutritional parameters in patients with HIV initiating HAART. Design, Setting, and Participants A randomized, double-blind, controlled trial of high-dose vs standard-dose multivitamin supplementation for 24 months in 3418 patients with HIV initiating HAART between November 2006 and November 2008 in 7 clinics in Dar es Salaam, Tanzania. Intervention The provision of daily oral supplements of vitamin B complex, vitamin C, and vitamin E at high levels or standard levels of the recommended dietary allowance. Main Outcome Measure The composite of HIV disease progression or death from any cause. Results The study was stopped early in March 2009 because of evidence of increased levels of alanine transaminase (ALT) in patients receiving the high-dose multivitamin supplement. At the time of stopping, 3418 patients were enrolled (median follow-up, 15 months), and there were 2374 HIV disease progression events and 453 observed deaths (2460 total combined events). Compared with standard-dose multivitamin supplementation, high-dose supplementation did not reduce the risk of HIV disease progression or death. The absolute risk of HIV progression or death was 72% in the high-dose group vs 72% in the standard-dose group (risk ratio [RR], 1.00; 95% CI, 0.96–1.04). High-dose supplementation had no effect on CD4 count, plasma viral load, body mass index, or hemoglobin level concentration, but increased the risk of ALT elevations (1239 events per 1215 person-years vs 879 events per 1236 person-years; RR, 1.44; 95% CI, 1.11–1.87) vs standard-dose supplementation. Conclusion In adults receiving HAART, use of high-dose multivitamin supplements compared with standard-dose multivitamin supplements did not result in a decrease in HIV disease progression or death but may have resulted in an increase in ALT levels. Trial Registration clinicaltrials.gov Identifier: NCT00383669 PMID:23073950

Toxicological evaluation of morning glory seed: subchronic 90-day feeding study.

PubMed

Dugan, G M; Gumbmann, M R

1990-08-01

Diets containing 0.8, 2.53 and 8.0% field variety morning glory seed were fed to male and female rats (20 per group) in a 90-day subchronic feeding study. Gross clinical observations, body weight, and feed and water intake were recorded weekly. At 90 days, all surviving rats were autopsied, organs were weighed, and blood chemistry analyses, haematology, and bone-marrow evaluation for evidence of clastogenic effects were performed. Tissues from control (0% seed) and high-dose (8.0% seed) rats were examined histologically. Effects of morning glory seed were noted mainly in the high-dose group of both sexes. These included increases in mortality, feed consumption (on a body-weight basis), water consumption, serum alkaline phosphatase and potassium, white blood cell count, and brain and liver weights (as a percentage of body weight); body-weight gain and serum glucose were decreased. Significant changes seen in high-dose females alone were: increased haemoglobin, serum constituents (urea nitrogen, glutamic-pyruvic transaminase, glutamic-oxaloacetic transaminase, and ornithine carbamyl transferase), and organ weights (heart, kidney, spleen and pancreas as a percentage of body weight), and decreases in serum albumin, total protein, albumin:globulin ratio, and calcium. Significant changes occurring in high-dose males alone were: increased testicular weight (as a percentage of body weight), increased serum phosphorus, and decreased serum cholesterol. Liver degeneration in the high-dose females was greater than that in the controls. Mortality at 8.0% seed in the diet was 40% in males and 10% in females. At 0.8% seed, the only parameter that differed significantly from that of the controls was a final body-weight reduction in females without a corresponding reduction in feed consumption.

Influence of Age and Dose of African Swine Fever Virus Infections on Clinical Outcome and Blood Parameters in Pigs.

PubMed

Post, Jacob; Weesendorp, Eefke; Montoya, Maria; Loeffen, Willie L

African swine fever (ASF) is a fatal disease for domestic pigs, leading to serious economic losses in countries where ASF is endemic. Despite extensive research, efficient vaccines against ASF are lacking. Since peripheral blood cells are important mediators for vaccines, we study the impact of ASF on blood parameters in pigs with different ages and infected with different doses of ASF virus. Four different groups were studied: (1) 12 weeks of age/low virus dose; (2) 12 weeks of age/high virus dose; (3) 18 weeks of age/low virus dose; and (4) 18 weeks of age/high virus dose. By varying in age and/or ASFV inoculation dose, we monitor blood parameters during different degrees of disease. Thirty percent of the pigs survived the infection with a moderately virulent strain of African swine fever virus (ASFV). Animals that did survive infection were generally older, independent from the inoculation dose used. A firm reduction in many different cell types at 3-5 days postinfection (DPI) was accompanied by an increase in body temperature, followed by clinical signs and mortality from day 6 PI. While blood parameters generally normalized in survivors, γδ T cells and IL-10 levels could be related to mortality. These conclusions should be considered in new approaches for protection against ASF.

Effect of a single dose of Saccharomyces cerevisiae var. boulardii on the occurrence of porcine neonatal diarrhoea.

PubMed

Hancox, L R; Le Bon, M; Richards, P J; Guillou, D; Dodd, C E R; Mellits, K H

2015-11-01

Piglet neonatal diarrhoea is an important issue in modern pig production and is linked to increased mortality and poor growth rates, affecting long-term pig health, increasing use of medication and cost of production. Saccharomyces cerevisiae var. boulardii (SB) is a probiotic yeast with documented clinical efficacy in the prevention and treatment of diarrhoeal diseases in humans. The objectives of the current study were to evaluate the effect of SB on occurrence and severity of neonatal diarrhoea in piglets, mortality and growth rate. Forty-six litters (606 piglets) were randomly allocated to a control or SB treatment (n=23 per treatment). Within 24 h of farrowing, piglets assigned to the SB treatment received a single oral dose of a paste containing 3.3×10(9) CFU of SB CNCM I-107(9). Piglets from the control litters received a placebo paste. Piglet weight, mortality and diarrhoea were recorded up to day 7 of age. It was shown that numbers of diarrhoea days were significantly correlated with increased mortality rate and reduced weight gain (P<0.05). SB treatment had no effect on growth or mortality in diarrhoeic litters. However, SB-supplemented litters had significantly lower faecal scores, indicating firmer faeces (P<0.01) and fewer numbers of diarrhoeic days (P<0.01) during the 1(st) week of life. Reduction in the number of diarrhoeic litters compared with the control group was observed following the probiotic administration (P<0.05). These results highlight the detrimental effects of neonatal diarrhoea on pre-weaning performance and suggest that SB, by reducing diarrhoea duration and severity, has the potential of improving enteric health in the early stages of life in pigs.

Preoperative steroid administration: effect on morbidity among patients undergoing intestinal bowel resection for Crohńs disease.

PubMed

Bruewer, Matthias; Utech, Markus; Rijcken, Emile J M; Anthoni, Christoph; Laukoetter, Mike G; Kersting, Sabine; Senninger, Norbert; Krieglstein, Christian F

2003-12-01

Long-term steroid therapy may predispose to increased perioperative morbidity in patients undergoing surgery with bowel anastomoses. The aim of our study was to review our data to determine if the steroid dosage is associated with the incidence of early complications after bowel resection in patients with prolonged steroid therapy for Crohńs disease (CD). Altogether, 397 patients underwent bowel resection with primary intestinal anastomoses for CD between 1982 and 2000 in our institution. The mortality and morbidity rates, anastomotic leakage, wound infections, intraabdominal abscesses, reoperation rate, and length of postoperative hospitalization in patients who were having high-dose (>/= 20 mg of prednisolone per day, n = 73) and low-dose (< 20 mg prednisolone per day, n = 146) steroid therapy for more than 1 month before surgery were compared with those of patients ( n = 177) who were not receiving steroids. Statistical analysis was performed using Fisher's exact test and Student's t-test, with p < 0.05 considered significant. The three groups were similar in terms of gender, duration since first diagnosis, American Society of Anesthesiologists classification, and obesity. Mortality, morbidity, anastomotic leakage, wound infections, intraabdominal abscesses, reoperation rate, and average postoperative stay were not statistically different in patients with high-dose, low-dose, or no steroid therapy. The only factor associated with increased morbidity was a low preoperative hemoglobin level. Our results demonstrate that, in patients who are undergoing bowel resection for CD, even high-dose prolonged preoperative systemic steroid therapy is not associated with increased postoperative complications.

The biological impacts of ingested radioactive materials on the pale grass blue butterfly

NASA Astrophysics Data System (ADS)

Nohara, Chiyo; Hiyama, Atsuki; Taira, Wataru; Tanahara, Akira; Otaki, Joji M.

2014-05-01

A massive amount of radioactive materials has been released into the environment by the Fukushima Dai-ichi Nuclear Power Plant accident, but its biological impacts have rarely been examined. Here, we have quantitatively evaluated the relationship between the dose of ingested radioactive cesium and mortality and abnormality rates using the pale grass blue butterfly, Zizeeria maha. When larvae from Okinawa, which is likely the least polluted locality in Japan, were fed leaves collected from polluted localities, mortality and abnormality rates increased sharply at low doses in response to the ingested cesium dose. This dose-response relationship was best fitted by power function models, which indicated that the half lethal and abnormal doses were 1.9 and 0.76 Bq per larva, corresponding to 54,000 and 22,000 Bq per kilogram body weight, respectively. Both the retention of radioactive cesium in a pupa relative to the ingested dose throughout the larval stage and the accumulation of radioactive cesium in a pupa relative to the activity concentration in a diet were highest at the lowest level of cesium ingested. We conclude that the risk of ingesting a polluted diet is realistic, at least for this butterfly, and likely for certain other organisms living in the polluted area.

The biological impacts of ingested radioactive materials on the pale grass blue butterfly.

PubMed

Nohara, Chiyo; Hiyama, Atsuki; Taira, Wataru; Tanahara, Akira; Otaki, Joji M

2014-05-15

A massive amount of radioactive materials has been released into the environment by the Fukushima Dai-ichi Nuclear Power Plant accident, but its biological impacts have rarely been examined. Here, we have quantitatively evaluated the relationship between the dose of ingested radioactive cesium and mortality and abnormality rates using the pale grass blue butterfly, Zizeeria maha. When larvae from Okinawa, which is likely the least polluted locality in Japan, were fed leaves collected from polluted localities, mortality and abnormality rates increased sharply at low doses in response to the ingested cesium dose. This dose-response relationship was best fitted by power function models, which indicated that the half lethal and abnormal doses were 1.9 and 0.76 Bq per larva, corresponding to 54,000 and 22,000 Bq per kilogram body weight, respectively. Both the retention of radioactive cesium in a pupa relative to the ingested dose throughout the larval stage and the accumulation of radioactive cesium in a pupa relative to the activity concentration in a diet were highest at the lowest level of cesium ingested. We conclude that the risk of ingesting a polluted diet is realistic, at least for this butterfly, and likely for certain other organisms living in the polluted area.

Stress-dose hydrocortisone reduces critical illness-related corticosteroid insufficiency associated with severe traumatic brain injury in rats

PubMed Central

2013-01-01

Introduction The spectrum of critical illness-related corticosteroid insufficiency (CIRCI) in severe traumatic brain injury (TBI) is not fully defined and no effective treatments for TBI-induced CIRCI are available to date. Despite growing interest in the use of stress-dose hydrocortisone as a potential therapy for CIRCI, there remains a paucity of data regarding its benefits following severe TBI. This study was designed to investigate the effects of stress-dose hydrocortisone on CIRCI development and neurological outcomes in a rat model of severe traumatic brain injury. Methods Rats were subjected to lateral fluid percussion injury of 3.2-3.5 atmosphere. These rats were then treated with either a stress-dose hydrocortisone (HC, 3 mg/kg/d for 5 days, 1.5 mg/kg on day 6, and 0.75 mg on day 7), a low-dose methylprednisolone (MP, 1 mg/kg/d for 5 days, 0.5 mg/kg on day 6, and 0.25 mg on day 7) or control saline solution intraperitoneally daily for 7 days after injury. Results We investigated the effects of stress-dose HC on the mortality, CIRCI occurrence, and neurological deficits using an electrical stimulation test to assess corticosteroid response and modified neurological severity score (mNSS). We also studied pathological changes in the hypothalamus, especially in the paraventricular nuclei (PVN), after stress-dose HC or a low dose of MP was administered, including apoptosis detected by a TUNEL assay, blood–brain barrier (BBB) permeability assessed by brain water content and Evans Blue extravasation into the cerebral parenchyma, and BBB integrity evaluated by CD31 and claudin-5 expression. We made the following observations. First, 70% injured rats developed CIRCI, with a peak incidence on post-injury day 7. The TBI-associated CIRCI was closely correlated with an increased mortality and delayed neurological recovery. Second, post-injury administration of stress-dose HC, but not MP or saline increased corticosteroid response, prevented CIRCI, reduced mortality, and improved neurological function during the first 14 days post injury dosing. Thirdly, these beneficial effects were closely related to improved vascular function by the preservation of tight junctions in surviving endothelial cells, and reduced neural apoptosis in the PVN of hypothalamus. Conclusions Our findings indicate that post-injury administration of stress-dose HC, but not MP reduces CIRCI and improves neurological recovery. These improvements are associated with reducing the damage to the tight junction of vascular endothelial cells and blocking neuronal apoptosis in the PVN of the hypothalamus. PMID:24131855

Fluid Balance, Diuretic Use, and Mortality in Acute Kidney Injury

PubMed Central

Estrella, Michelle M.; Coresh, Josef; Brower, Roy G.; Liu, Kathleen D.

2011-01-01

Summary Background and objectives Management of volume status in patients with acute kidney injury (AKI) is complex, and the role of diuretics is controversial. The primary objective was to elucidate the association between fluid balance, diuretic use, and short-term mortality after AKI in critically ill patients. Design, setting, participants, & measurements Using data from the Fluid and Catheter Treatment Trial (FACTT), a multicenter, randomized controlled trial evaluating a conservative versus liberal fluid-management strategy in 1000 patients with acute lung injury (ALI), we evaluated the association of post-renal injury fluid balance and diuretic use with 60-day mortality in patients who developed AKI, as defined by the AKI Network criteria. Results 306 patients developed AKI in the first 2 study days and were included in our analysis. There were 137 in the fluid-liberal arm and 169 in the fluid-conservative arm (P = 0.04). Baseline characteristics were similar between groups. Post-AKI fluid balance was significantly associated with mortality in both crude and adjusted analysis. Higher post-AKI furosemide doses had a protective effect on mortality but no significant effect after adjustment for post-AKI fluid balance. There was no threshold dose of furosemide above which mortality increased. Conclusions A positive fluid balance after AKI was strongly associated with mortality. Post-AKI diuretic therapy was associated with 60-day patient survival in FACTT patients with ALI; this effect may be mediated by fluid balance. PMID:21393482

High mortality of Red Sea zooplankton under ambient solar radiation.

PubMed

Al-Aidaroos, Ali M; El-Sherbiny, Mohsen M O; Satheesh, Sathianeson; Mantha, Gopikrishna; Agustī, Susana; Carreja, Beatriz; Duarte, Carlos M

2014-01-01

High solar radiation along with extreme transparency leads to high penetration of solar radiation in the Red Sea, potentially harmful to biota inhabiting the upper water column, including zooplankton. Here we show, based on experimental assessments of solar radiation dose-mortality curves on eight common taxa, the mortality of zooplankton in the oligotrophic waters of the Red Sea to increase steeply with ambient levels of solar radiation in the Red Sea. Responses curves linking solar radiation doses with zooplankton mortality were evaluated by exposing organisms, enclosed in quartz bottles, allowing all the wavelengths of solar radiation to penetrate, to five different levels of ambient solar radiation (100%, 21.6%, 7.2%, 3.2% and 0% of solar radiation). The maximum mortality rates under ambient solar radiation levels averaged (±standard error of the mean, SEM) 18.4±5.8% h(-1), five-fold greater than the average mortality in the dark for the eight taxa tested. The UV-B radiation required for mortality rates to reach ½ of maximum values averaged (±SEM) 12±5.6 h(-1)% of incident UVB radiation, equivalent to the UV-B dose at 19.2±2.7 m depth in open coastal Red Sea waters. These results confirm that Red Sea zooplankton are highly vulnerable to ambient solar radiation, as a consequence of the combination of high incident radiation and high water transparency allowing deep penetration of damaging UV-B radiation. These results provide evidence of the significance of ambient solar radiation levels as a stressor of marine zooplankton communities in tropical, oligotrophic waters. Because the oligotrophic ocean extends across 70% of the ocean surface, solar radiation can be a globally-significant stressor for the ocean ecosystem, by constraining zooplankton use of the upper levels of the water column and, therefore, the efficiency of food transfer up the food web in the oligotrophic ocean.

Myeloperoxidase-derived 2-chlorofatty acids contribute to human sepsis mortality via acute respiratory distress syndrome.

PubMed

Meyer, Nuala J; Reilly, John P; Feng, Rui; Christie, Jason D; Hazen, Stanley L; Albert, Carolyn J; Franke, Jacob D; Hartman, Celine L; McHowat, Jane; Ford, David A

2017-12-07

Sepsis-associated acute respiratory distress syndrome (ARDS) is characterized by neutrophilic inflammation and poor survival. Since neutrophil myeloperoxidase (MPO) activity leads to increased plasma 2-chlorofatty acid (2-ClFA) levels, we hypothesized that plasma concentrations of 2-ClFAs would associate with ARDS and mortality in subjects with sepsis. In sequential consenting patients with sepsis, free 2-ClFA levels were significantly associated with ARDS, and with 30-day mortality, for each log increase in free 2-chlorostearic acid. Plasma MPO was not associated with either ARDS or 30-day mortality but was correlated with 2-ClFA levels. Addition of plasma 2-ClFA levels to the APACHE III score improved prediction for ARDS. Plasma 2-ClFA levels correlated with plasma levels of angiopoietin-2, E selectin, and soluble thrombomodulin. Endothelial cells treated with 2-ClFA responded with increased adhesion molecule surface expression, increased angiopoietin-2 release, and dose-dependent endothelial permeability. Our results suggest that 2-ClFAs derived from neutrophil MPO-catalyzed oxidation contribute to pulmonary endothelial injury and have prognostic utility in sepsis-associated ARDS.

Long-term mortality and cancer risk in irradiated rhesus monkeys

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wood, D.H.

1989-01-01

Lifetime observations on a group of 358 rhesus monkeys indicate that life expectancy loss from exposure to protons in the energy range encountered in the Van Allen belts and solar proton events is influenced primarily by the dose rather than by the energy of radiation. After 24 years, life expectancy losses from similar surface doses of low-LET (138-2300 MeV) and high-LET (32-55 MeV) protons are not significantly different, but the high-LET protons are associated with more deaths in the early years, while the low-LET protons contribute more to mortality in later years. In males, the most significant cause of lifemore » shortening is nonleukemia cancers. In females, radiation increased the risk of endometriosis (an abnormal proliferation of the lining of the uterus) which resulted in significant mortality in the years before early detection and treatment methods were employed. The findings support the 1989 guidelines of the NCRP for maximum permissible radiation exposures in astronauts.« less

Marital history from age 15 to 40 years and subsequent 10-year mortality: a longitudinal study of Danish males born in 1953.

PubMed

Lund, Rikke; Holstein, Bjørn Evald; Osler, Merete

2004-04-01

The aims of the present study are to analyse the association between marital status at age 24, 29, 34, and 39 years and subsequent mortality in a cohort of men born in 1953 (sensitive period); to study the impact of number of years married, number of years divorced/widowed, and number of marital break-ups on mortality (cumulative effect), and to examine whether these effects were independent of marital status at age 39 (proximity effect). Prospective birth cohort study with follow-up of mortality from 1992 to 2002. Participants were 10891 men born within the metropolitan area of Copenhagen, Denmark. Marital status in 1992 as well as start and termination of all previous marital status events from 1968 to 1992 were retrieved from the Danish Civil Registration System. Were hazard ratios (HR) for all-cause mortality from age 40 to 49 years. We found a strong protective effect of being married compared with never being married or divorced/widowed at every age. The association increased in strength with increasing age. Number of years divorced was associated with increased mortality risk in a dose-dependent manner at age 34 and 39 years. One or more marital break-ups was associated with higher mortality, whereas increasing number of years married was associated with lower mortality. Inclusion of current marital status attenuated the strength of the associations but most of them remained statistically significant. Marital status and cumulated marital periods, especially cumulated periods divorced/widowed are strong independent predictors of mortality among younger males.

Cancer mortality following radium treatment for uterine bleeding

DOE Office of Scientific and Technical Information (OSTI.GOV)

Inskip, P.D.; Monson, R.R.; Wagoner, J.K.

1990-09-01

Cancer mortality in relation to radiation dose was evaluated among 4153 women treated with intrauterine radium (226Ra) capsules for benign gynecologic bleeding disorders between 1925 and 1965. Average follow up was 26.5 years (maximum = 59.9 years). Overall, 2763 deaths were observed versus 2687 expected based on U.S. mortality rates (standardized mortality ratio (SMR) = 1.03). Deaths due to cancer, however, were increased (SMR = 1.30), especially cancers of organs close to the radiation source. For organs receiving greater than 5 Gy, excess mortality of 100 to 110% was noted for cancers of the uterus and bladder 10 or moremore » years following irradiation, while a deficit was seen for cancer of the cervix, one of the few malignancies not previously shown to be caused by ionizing radiation. Part of the excess of uterine cancer, however, may have been due to the underlying gynecologic disorders being treated. Among cancers of organs receiving average or local doses of 1 to 4 Gy, excesses of 30 to 100% were found for leukemia and cancers of the colon and genital organs other than uterus; no excess was seen for rectal or bone cancer. Among organs typically receiving 0.1 to 0.3 Gy, a deficit was recorded for cancers of the liver, gall bladder, and bile ducts combined, death due to stomach cancer occurred at close to the expected rate, a 30% excess was noted for kidney cancer (based on eight deaths), and there was a 60% excess of pancreatic cancer among 10-year survivors, but little evidence of dose-response. Estimates of the excess relative risk per Gray were 0.006 for uterus, 0.4 for other genital organs, 0.5 for colon, 0.2 for bladder, and 1.9 for leukemia. Contrary to findings for other populations treated by pelvic irradiation, a deficit of breast cancer was not observed (SMR = 1.0). Dose to the ovaries may have been insufficient to protect against breast cancer.« less

Intraperitoneal Continuous-Rate Infusion for the Maintenance of Anesthesia in Laboratory Mice (Mus musculus)

PubMed Central

Erickson, Rebecca L; Terzi, Matthew C; Jaber, Samer M; Hankenson, F Claire; McKinstry-Wu, Andrew; Kelz, Max B; Marx, James O

2016-01-01

Intraperitoneal injectable anesthetics are often used to achieve surgical anesthesia in laboratory mice. Because bolus redosing of injectable anesthetics can cause unacceptably high mortality, we evaluated intraperitoneal continuous-rate infusion (CRI) of ketamine with or without xylazine for maintaining surgical anesthesia for an extended period of time. Anesthesia was induced in male C57BL/6J mice by using ketamine (80 mg/kg) and xylazine (8 mg/kg) without or with acepromazine at 0.1 mg/kg or 0.5 mg/kg. At 10 min after induction, CRI for 90 min was initiated and comprised 25%, 50%, or 100% of the initial ketamine dose per hour or 50% of the initial doses of both ketamine and xylazine. Anesthetic regimens were compared on the basis of animal immobility, continuous surgical depth of anesthesia as determined by the absence of a pedal withdrawal reflex, and mortality. Consistent with previous studies, the response to anesthetics was highly variable. Regimens that provided the longest continuous surgical plane of anesthesia with minimal mortality were ketamine–xylazine–acepromazine (0.1 mg/kg) with CRI of 100% of the initial ketamine dose and ketamine–xylazine–acepromazine (0.5 mg/kg) with CRI of 50% of the initial ketamine and xylazine doses. In addition, heart rate and respiratory rate did not increase consistently in response to a noxious stimulus during CRI anesthesia, even when mice exhibited a positive pedal withdrawal reflex, suggesting that these parameters are unreliable indicators of anesthetic depth during ketamine–xylazine anesthesia in mice. We conclude that intraperitoneal CRI anesthesia in mice prolongs injectable anesthesia more consistently and with lower mortality than does bolus redosing. PMID:27657709

2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity in yellow perch (Perca flavescens)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Spitsbergen, J.M.; Kleeman, J.M.; Peterson, R.E.

1988-01-01

Growth, mortality and morphologic lesions in juvenile, hatchery-reared yellow perch, Perca flavescens, were studied after treatment with graded single doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, 1-125 ..mu..g/kg, intraperitoneally). TCDD doses of 25 and 125 ..mu..g/kg caused 95% mortality by 28 d after treatment, without decreasing body weight. A TCDD dose of 5 ..mu..g/kg resulted in progressive loss of body weight with cumulative mortality of 80% by 80 d posttreatment. Periodic handling stress did not affect the time course of mortality or cumulative percent lethality in TCDD-treated perch. Fin necrosis, petechial cutaneous hemorrhage, and ascites occurred in perch treated with 5 ..mu..g/kg ormore » more of TCDD. Thymic atrophy, decreased hematopoiesis in the head kidney, fibrinous pericarditis, focal myocardial necrosis, submucosal gastric edema, and hyperplasia of the epithelium of gill filaments and lamellae occurred in perch dosed with 25 or 125 ..mu..g/kg. Dose-related splenic lymphoid depletion occurred in perch receiving 5 ..mu..g/kg or more TCDD, and hepatocycte lipidosis occurred in groups treated with doses of 1 ..mu..g/kg or more TCDD. Thus yellow perch are as responsive to the acute toxic effects of TCDD as some of the more sensitive mammalian species, and neither loss of body weight nor histologic lesions in TCDD-treated perch are sufficient to explain mortality.« less

Developmental toxicity of CdTe QDs in zebrafish embryos and larvae

NASA Astrophysics Data System (ADS)

Duan, Junchao; Yu, Yongbo; Li, Yang; Yu, Yang; Li, Yanbo; Huang, Peili; Zhou, Xianqing; Peng, Shuangqing; Sun, Zhiwei

2013-07-01

Quantum dots (QDs) have widely been used in biomedical and biotechnological applications. However, few studies focus on the assessing toxicity of QDs exposure in vivo. In this study, zebrafish embryos were treated with CdTe QDs (4 nm) during 4-96 h post-fertilization (hpf). Mortality, hatching rate, malformation, heart rate, and QDs uptake were detected. We also measured the larval behavior to analyze whether QDs had persistent effects on larvae locomotor activity at 144 hpf. The results showed that as the exposure dosages increased, the hatching rate and heart rate of zebrafish embryos were decreased, while the mortality increased. Exposure to QDs caused embryonic malformations, including head malformation, pericardial edema, yolk sac edema, bent spine, and yolk not depleted. QDs fluorescence was mainly localized in the intestines region. The larval behavior testing showed that the total swimming distance was decreased in a dose-dependent manner. The lowest dose (2.5 nM QDs) produced substantial hyperactivity while the higher doses groups (5, 10, and 20 nM QDs) elicited remarkably hypoactivity in dark periods. In summary, the data of this article indicated that QDs caused embryonic developmental toxicity, resulted in persistent effects on larval behavior.

Appropriate doses of non-vitamin K antagonist oral anticoagulants in high-risk subgroups with atrial fibrillation: Systematic review and meta-analysis.

PubMed

Kim, In-Soo; Kim, Hyun-Jung; Kim, Tae-Hoon; Uhm, Jae-Sun; Joung, Boyoung; Lee, Moon-Hyoung; Pak, Hui-Nam

2018-04-26

We evaluated the dose-dependent efficacy, safety, and all-cause mortality of non-vitamin K antagonist oral anticoagulants (NOACs) in "atrial fibrillation (AF) patients who were OAC-naïve," or "AF patients with prior-stroke history" with those who were known to be high-risk subgroups under OAC. After a systematic database search (Medline, EMBASE, CENTRAL, SCOPUS, and Web of Science), five phase-III randomized trials comparing NOACs and warfarin in "OAC-naïve/OAC-experienced," or "with/without prior-stroke history" subgroups were included. The outcomes were pooled using a random-effects model to determine the relative risk (RR) for stroke/systemic thromboembolism (SSTE), major bleeding, intracranial hemorrhage, and all-cause mortality. 1. In OAC-naïve patients, standard-dose NOACs showed superior efficacy and safety with lower mortality [RR 0.90 (0.84-0.97), p=0.008, I 2 =0%] compared to warfarin. 2. For OAC-experienced patients, low-dose NOACs showed equivalent efficacy but reduced risk of major bleeding [RR 0.61 (0.40-0.91), p=0.02, I 2 =89%], and had lower all-cause mortality [RR 0.86 (0.75-0.99), p=0.04, I 2 =38%] compared to warfarin. 3. For patients with prior-stroke history, low-dose NOACs showed equivalent efficacy, but reduced risk of major bleeding [RR 0.58 (0.48-0.70), p<0.001, I 2 =0%] and all-cause mortality [RR 0.76 (0.66-0.88), p<0.001, I 2 =0%] compared to warfarin. 4. Among patients without prior-stroke history, standard-dose NOAC was superior to warfarin for both SSTE prevention [RR 0.78 (0.66-0.91), p=0.002, I 2 =43%] and all-cause mortality [RR 0.91 (0.85-0.97), p=0.004, I 2 =0%]. In conclusion, standard-dose NOAC showed lower all-cause mortality than warfarin in OAC-naïve patients with AF, and low-dose NOAC was better than warfarin among the patients with prior-stroke history in terms of all-cause mortality. Copyright © 2018 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Utilization of ICU Data to Improve 30 and 60 Day HENRE Mortality Models, Revision 1

DTIC Science & Technology

2017-05-12

Acute Radiation Syndrome , Mortality, Burn Combined Injury, Lethality, Small Intestine, Ordinary...a large dose of radiation in a short period of time (high dose rate) causes acute radiation syndrome (ARS). Depending on the radiation dose, an...individual may experience the hematopoietic acute radiation syndrome (H-ARS) or the gastrointestinal acute radiation syndrome (GI-ARS) (reviewed in

Efficacy and Safety of Frozen Blood for Transfusion in Trauma Patients - A Multi-Center Trial

DTIC Science & Technology

2015-04-01

threshold are based on a randomized controlled trial by Hébert et al . that showed that critically ill patients who are not actively bleeding should not...causes of increased morbidity and mortality in several studies [23-28]. In a large study, Malone et al . assessed the effect of blood transfusion on...strong independent predictor of mortality. Another study published by Murrell et al . did not find an association between the dose of aged blood and

Cancer mortality in residents of the terrain-shielded area exposed to fallout from the Nagasaki atomic bombing

PubMed Central

Mine, Mariko; Kondo, Hisayoshi; Matsuda, Naoki; Shibata, Yoshisada; Takamura, Noboru

2018-01-01

Abstract The health effects of radiation exposure from the atomic bomb fallout remain unclear. The objective of the present study is to elucidate the association between low-dose radiation exposure from the atomic bomb fallout and cancer mortality among Nagasaki atomic bomb survivors. Of 77 884 members in the Nagasaki University Atomic Bomb Survivors Cohort, 610 residents in the terrain-shielded area with fallout were selected for this analysis; 1443 residents in the terrain-shielded area without fallout were selected as a control group; and 3194 residents in the direct exposure area were also selected for study. Fifty-two deaths due to cancer in the terrain-shielded fallout area were observed during the follow-up period from 1 January 1970 to 31 December 2012. The hazard ratio for cancer mortality in the terrain-shielded fallout area was 0.90 (95% confidence interval: 0.65–1.24). No increase in the risk of cancer mortality was observed, probably because the dose of the radiation exposure was low for residents in the terrain-shielded fallout areas of the Nagasaki atomic bomb, and also because the number of study subjects was small. PMID:29036510

Atomic bomb health benefits.

PubMed

Luckey, T D

2008-01-01

Media reports of deaths and devastation produced by atomic bombs convinced people around the world that all ionizing radiation is harmful. This concentrated attention on fear of miniscule doses of radiation. Soon the linear no threshold (LNT) paradigm was converted into laws. Scientifically valid information about the health benefits from low dose irradiation was ignored. Here are studies which show increased health in Japanese survivors of atomic bombs. Parameters include decreased mutation, leukemia and solid tissue cancer mortality rates, and increased average lifespan. Each study exhibits a threshold that repudiates the LNT dogma. The average threshold for acute exposures to atomic bombs is about 100 cSv. Conclusions from these studies of atomic bomb survivors are: One burst of low dose irradiation elicits a lifetime of improved health.Improved health from low dose irradiation negates the LNT paradigm.Effective triage should include radiation hormesis for survivor treatment.

Effect of temperature and commodity on insecticidal efficacy of spinosad dust against Sitophilus oryzae (Coleoptera: Curculionidae) and Rhyzopertha dominica (Coleoptera: Bostrychidae).

PubMed

Athanassiou, Christos G; Kavallieratos, Nickolas G; Chintzoglou, George J; Peteinatos, Gerassimos G; Boukouvala, Maria C; Petrou, Stamatina S; Panoussakis, Emmanouel C

2008-06-01

The insecticidal effect of spinosad dust, a formulation that contains 0.125% spinosad, was evaluated against adults of Sitophilus oryzae (L.) and Rhyzopertha dominica (F.) at three temperature levels (20, 25, and 30 degrees C) and four commodities (wheat, Triticum aestivum L.; barley, Hordeum vulgare L.; rice, Oryza sativa L.; and maize, Zea mays L.). For this purpose, quantities of the above-mentioned grains were treated with spinosad at two dose rates (20 and 50 ppm of the formulation, corresponding to 0.025 and 0.06 ppm AI, respectively), and mortality of the exposed adults in the treated grains was measured after 7 and 14 d, whereas progeny production was assessed 65 d later. Generally, for both species, mortality increased with dose, exposure interval, and temperature. For S. oryzae, adult survival and progeny production were lower on wheat than the other grains. After 14 d of exposure, mortality of S. oryzae adults on wheat treated with 50 ppm ranged between 61 and 98%, whereas in the other three commodities it did not exceed 42%. Mortality of R. dominica after 14 d on grains treated 50 ppm ranged between 91 and 100%. For this species, progeny production from exposed parental adults was low in all commodities regardless of temperature. Results indicate that spinosad dust can be used as an alternative to traditional grain protectants, but its effectiveness is highly determined by the target species, commodity, dose, and temperature.

Lack of developmental and reproductive toxicity of 2,3,3',4,4'-pentachlorobiphenyl (PCB-105) in Ring-Necked Pheasants

USGS Publications Warehouse

Hornung, M.W.; Miller, L.; Goodman, B.; Melancon, M.J.; Peterson, R.E.

1998-01-01

Mono-ortho PCBs are global contaminants of wildlife with the potential to produce toxicity by an aryl hydrocarbon receptor (AhR)-mediated mechanism. To determine the potency of 2,3,3',4,4'pentachlorobiphenyl (PCB-105) for producing reproductive and developmental toxicity, adult ring-necked pheasant hens (Phasianus colchicus) were orally dosed with 0, 0.06, 0.6 or 6 mg PCB105/kg hen/week for 10 weeks to achieve cumulative doses of 0, 0.6, 6, or 60 mg PCB -105/hen after which hens were bred with untreated roosters once per week for 8 weeks. Except at week 6 of the egglaying period when cumulative egg production in the 6mg PCB 105/hen group was greater than controls, fertilized egg production was not significantly different between treatment groups. Embryo mortality and chick mortality were not significantly different between treatment groups. Total body and heart weights of all chicks 1 day posthatch (dph) were not different between groups, however liver weights of chicks from the 60mg/kg treatment groups were greater than controls at 1 dph. The first chick to hatch from each hen was reared to 21 dph and among these birds the total body, liver and heart weights were not different between groups. There were no dose-related malformations of the beak or limbs, and no signs of subcutaneous edema, ascites, or pericardial edema in chicks at 1 or 21 dph. Hepatic microsomal monooxygenase activities [ethoxyresorufin-O-dealkylase (EROD), benzyloxyresorufin-O-dealkylase (BROD), and methyloxyresorufin-O-dealkylase (MROD)] were significantly elevated in chicks at 1 dph from hens given a cumulative PCB105 dose of 6 mg/kg and in chicks at 21 dph from hens given a cumulative PCB dose of 60 mg/kg. These results indicate that a cumulative PCB-105 dose up to 60 mg/kg hen does not decrease the production of fertilized eggs or increase embryo or chick mortality in ring-necked pheasants, but does increase chick hepatic monooxygenase activity.

Developmental toxicity of diphenyl ether herbicides in birds

USGS Publications Warehouse

Hoffman, D.J.; Rattner, B.A.; Bunck, C.M.

1991-01-01

Diphenyl ether herblcldes, includlng nitrofen, have been identified as mammalian teratogens and cause perinatal mortality. American kestrel (Falco sparverius) nestlings were orally dosed for 10 days w1th 5 ul/g of corn oil (controls) or one of the diphenyl ether herbicides (nitrofen, bifenox, or oxyfluorofen). At 500 mg/kg, nitrofen resulted in complete mortality, bifenox in high (66%) mortality, and oxyfluorofen in no mortality. Nitrofen, at 250 mg/kg, reduced nestling growth, as reflected by decreased body weight and bone length. Bifenox at 250 mg/kg had less effect on growth than nitrofen but crown rump, humerus, radiusulna and femur lengths were significantly less than controls. Liver welght (percent of body welght) increased with 50 mg/kg nitrofen. Other manifestations of hepatotoxicity following nitrofen ingestion included increased hepatic GSH peroxidase activity with 0 mg/kg nitrofen, and increased plasma enzyme activities for ALT, AST. and LDHL with 250 mg/kg. Blfenox lngestion (50 mg/kg) resulted in increased hepatlc GSH peroxidase activity. Nitrofen exposure increased total plasma thyroxlne (T4) concentratlon. These findings suggest that altricial nestllng kestrels are more sensitive to diphenyl ether herbicides than precocial young or adult birds.

Particulate air pollution and daily mortality in Detroit.

PubMed

Schwartz, J

1991-12-01

Particulate air pollution has been associated with increased mortality during episodes of high pollution concentrations. The relationship at lower concentrations has been more controversial, as has the relative role of particles and sulfur dioxide. Replication has been difficult because suspended particle concentrations are usually measured only every sixth day in the U.S. This study used concurrent measurements of total suspended particulates (TSP) and airport visibility from every sixth day sampling for 10 years to fit a predictive model for TSP. Predicted daily TSP concentrations were then correlated with daily mortality counts in Poisson regression models controlling for season, weather, time trends, overdispersion, and serial correlation. A significant correlation (P less than 0.0001) was found between predicted TSP and daily mortality. This correlation was independent of sulfur dioxide, but not vice versa. The magnitude of the effect was very similar to results recently reported from Steubenville, Ohio (using actual TSP measurements), with each 100 micrograms/m3 increase in TSP resulting in a 6% increase in mortality. Graphical analysis indicated a dose-response relationship with no evidence of a threshold down to concentrations below half of the National Ambient Air Quality Standards for particulate matter.

Crisis management in the treatment of childhood acute lymphoblastic leukemia: putting right what can go wrong (emergency complications of disease and treatment).

PubMed

Hough, Rachael; Vora, Ajay

2017-12-08

The improvement in overall survival in children with acute lymphoblastic leukemia (ALL) over the last 5 decades has been considerable, with around 90% now surviving long term. The risk of relapse has been reduced to such an extent that the risk of treatment-related mortality is now approaching that of mortality caused by relapse. Toxicities may also lead to the suboptimal delivery of chemotherapy (treatment delays, dose reductions, dose omissions), potentially increasing relapse risk, and short- and long-term morbidity, adding to the "burden of therapy" in an increasing number of survivors. Thus, the need to reduce toxicity in pediatric ALL is becoming increasingly important. This work focuses on the risk factors, pathogenesis, clinical features, and emergency management of the life-threatening complications of ALL at presentation and during subsequent chemotherapy, including leucostasis, tumor lysis syndrome, infection, methotrexate encephalopathy, thrombosis, and pancreatitis. Potential strategies to abrogate these toxicities in the future are also discussed. © 2016 by The American Society of Hematology. All rights reserved.

Improved hospital mortality with a low MET dose: the importance of a modified early warning score and communication tool.

PubMed

Mullany, D V; Ziegenfuss, M; Goleby, M A; Ward, H E

2016-11-01

Rapid response systems have been mandated for the recognition and management of the deteriorating patient. Increasing medical emergency team (MET) dose may be associated with improved outcomes. Large numbers of MET calls may divert resources from the program providing the service unless additional personnel are provided. To describe the implementation and outcomes of a multifaceted rapid response system (RRS) in a teaching hospital, we conducted an observational study. The RRS consisted of the introduction of a MET together with 1) redesign of the ward observation chart with the vital sign variables colour-coded to identify variation from normal; 2) mandated minimum frequency of vital sign measurement; 3) three formal levels of escalation based on the degree of physiological instability as measured by a modified early warning score (MEWS); 4) COMPASS© education and e-learning package with a two-hour face-to-face small group tutorial; 5) practise in escalation and communication using the ISBAR (Identify, Situation, Background, Assessment, Response/Recommendation) communication tool. The primary outcome measures were all-cause hospital mortality rate and hospital standardised mortality ratio (HSMR) compared to peer hospitals calculated by the Health Round Table. There were 161,153 separations and 1,994 hospital deaths from July 2008 to December 2012. The MET call rate was 11.3 per 1000 separations in 2012. There was a decline in all-cause hospital mortality from 13.8 to 11 deaths/1000 separations. The HSMR decreased from 95.7 in 2008 to 66 in the second half of 2012 (below the three standard deviation control limit). A low MET dose may be associated with improved hospital mortality when combined with a MEWS and an intervention to improve communication.

Initial management of pneumonia and sepsis: factors associated with improved outcome.

PubMed

Menéndez, R; Torres, A; Reyes, S; Zalacain, R; Capelastegui, A; Aspa, J; Borderías, L; Martín-Villasclaras, J J; Bello, S; Alfageme, I; de Castro, F R; Rello, J; Molinos, L; Ruiz-Manzano, J

2012-01-01

Processes of care and adherence to guidelines have been associated with improved survival in community-acquired pneumonia (CAP). In sepsis, bundles of processes of care have also increased survival. We aimed to audit compliance with guideline-recommended processes of care and its impact on outcome in hospitalised CAP patients with sepsis. We prospectively studied 4,137 patients hospitalised with CAP in 13 hospitals. The processes of care evaluated were adherence to antibiotic prescription guidelines, first dose within 6 h and oxygen assessment. Outcome measures were mortality and length of stay (LOS). Oxygen assessment was measured in 3,745 (90.5%) patients; 3,024 (73.1%) patients received antibiotics according to guidelines and 3,053 (73.8%) received antibiotics within 6 h. In CAP patients with sepsis, the strongest independent factor for survival was antibiotic adherence (OR 0.4). In severe sepsis, only compliance to antibiotic adherence plus first dose within 6 h was associated with lower mortality (OR 0.60), adjusted for fine prognostic scale and hospital. Antibiotic adherence was related to shorter hospital stay. In sepsis, antibiotic adherence is the strongest protective factor of care associated with survival and LOS. In severe sepsis, combined antibiotic adherence and first dose within 6 h may reduce mortality.

Effects of the hindlimb-unloading model of spaceflight conditions on resistance of mice to infection with Klebsiella pneumoniae

NASA Technical Reports Server (NTRS)

Belay, Tesfaye; Aviles, Hernan; Vance, Monique; Fountain, Kimberly; Sonnenfeld, Gerald

2002-01-01

BACKGROUND: It has been well documented in several studies that many immunologic parameters are altered in experimental animals and human subjects who have flown in space. However, it is not fully known whether these immunologic changes could result in increased susceptibility to infection. Hindlimb (antiorthostatic) unloading of rodents has been used successfully to simulate some of the effects of spaceflight on physiologic systems. OBJECTIVE: The objective of this study was to determine the effect of hindlimb unloading on the outcome of Klebsiella pneumoniae infection in mice. METHODS: Hindlimb-unloaded, hindlimb-restrained, and control mice were intraperitoneally infected with one 50% lethal dose of K pneumoniae 2 days after suspension. Mortality and bacterial load in several organs were compared among the groups. RESULTS: Unloaded mice showed significantly increased mortality and reduced mean time to death compared with that seen in the control groups. Kinetics of bacterial growth with smaller infective doses revealed that control mice were able to clear bacteria from the organs after 30 hours. In contrast, unloaded mice had continued bacterial growth at the same time point. CONCLUSION: The results of this study suggest that hindlimb unloading might enhance the dissemination of K pneumoniae, leading to increased mortality. The complex physiologic changes observed during hindlimb unloading, including stress, have a key role in the pathophysiology of this infection.

In utero exposure to radiation and haematological malignancies: pooled analysis of Southern Urals cohorts

PubMed Central

Schüz, Joachim; Deltour, Isabelle; Krestinina, Lyudmila Y; Tsareva, Yulia V; Tolstykh, Evgenia I; Sokolnikov, Mikhail E; Akleyev, Alexander V

2017-01-01

Background: It is scientifically uncertain whether in utero exposure to low-dose ionising radiation increases the lifetime risk of haematological malignancies. Methods: We pooled two cohorts from the Southern Urals comprising offspring of female workers of a large nuclear facility (the Mayak Production Association) and of women living in areas along the Techa River contaminated by nuclear accidents/waste from the same facility, with detailed dosimetry. Results: The combined cohort totalled 19 536 subjects with 700 504 person-years at risk over the period of incidence follow-up, and slightly more over the period of mortality follow-up, yielding 58 incident cases and 36 deaths up to age 61 years. Risk was increased in subjects who received in utero doses of ⩾80 mGy (excess relative risk (ERR): 1.27; 95% confidence interval (CI): −0.20 to 4.71), and the risk increased consistently per 100 mGy of continuous exposure in utero (ERR: 0.77; CI: 0.02 to 2.56). No association was apparent in mortality-based analyses. Results for leukaemia and lymphoma were similar. A very weak positive association was observed between incidence and postnatal exposure. Conclusions: In summary, the results suggest a positive association between in utero exposure to ionising radiation and risk of haematological malignancies, but the small number of outcomes and inconsistent incidence and mortality findings preclude firm conclusions. PMID:27855443

Disposition of Perfluorooctanoic Acid (PFOA) in Pregnant and Lactating CD-1 Mice and Their Pups

EPA Science Inventory

Previous studies in mice prenatally-exposed to PFOA demonstrate growth and developmental effects, including impaired body weight gain and mammary gland development, delayed eye opening, and increased mortality. Those dose dependent effects appeared to worsen if offspring exposed ...

Role of timing and dose of energy received in patients with acute lung injury on mortality in the Intensive Nutrition in Acute Lung Injury Trial (INTACT): a post hoc analysis.

PubMed

Braunschweig, Carol L; Freels, Sally; Sheean, Patricia M; Peterson, Sarah J; Perez, Sandra Gomez; McKeever, Liam; Lateef, Omar; Gurka, David; Fantuzzi, Giamila

2017-02-01

Our trial INTACT (Intensive Nutrition in Acute Lung Injury Trial) was designed to compare the impact of feeding from acute lung injury (ALI) diagnosis to hospital discharge, an interval that, to our knowledge, has not yet been explored. It was stopped early because participants who were randomly assigned to energy intakes at nationally recommended amounts via intensive medical nutrition therapy experienced significantly higher mortality hazards than did those assigned to standard nutrition support care that provided energy at 55% of recommended concentrations. We assessed the influence of dose and timing of feeding on hospital mortality. Participants (n = 78) were dichotomized as died or discharged alive. Associations between the energy and protein received overall, early (days 1-7), and late (days ≥8) and the hazards of hospital mortality were evaluated between groups with multivariable analysis methods. Higher overall energy intake predicted significantly higher mortality (OR: 1.14, 95% CI: 1.02, 1.27). Among participants enrolled for ≥8 d (n = 66), higher early energy intake significantly increased the HR for mortality (HR: 1.17, 95% CI: 1.07, 1.28), whereas higher late energy intake was significantly protective (HR: 0.91, 95% CI: 0.83, 1.0). Results were similar for early but not late protein (grams per kilogram) exposure (early-exposure HR: 8.9, 95% CI: 2.3, 34.3; late-exposure HR: 0.15, 95% CI: 0.02, 1.1). Threshold analyses indicated early mean intakes ≥18 kcal/kg significantly increased subsequent mortality. Providing kilocalories per kilogram or grams of protein per kilogram early post-ALI diagnosis at recommended levels was associated with significantly higher hazards for mortality, whereas higher late energy intakes reduced mortality hazards. This time-varying effect violated the Cox proportionality assumption, indicating that feeding trials in similar populations should extend beyond 7 d and use time-varying statistical methods. Future trials are required for corroboration. INTACT was registered at clinicaltrials.gov as NCT01921101. © 2017 American Society for Nutrition.

Trichloroethylene Is Associated with Kidney Cancer Mortality: A Population-based Analysis.

PubMed

Alanee, Shaheen; Clemons, Joseph; Zahnd, Whitney; Sadowski, Daniel; Dynda, Danuta

2015-07-01

To examine the association between the distribution of trichloroethylene (TCE) exposure and mortality from kidney cancer (Kca) across United States counties. Multiple linear regression was used to assess the association of TCE discharges from industrial sites and age-adjusted incidence and mortality rates for Kca during 2005 through 2010, controlling for confounders. A total of 163 counties were included in analysis. We observed an excess risk of Kca mortality associated with higher amounts of environmental TCE releases. A significant dose-response relationship was observed between TCE releases and Kca mortality in females. Smoking, education, income, hypertension, and obesity were significant predictors of incidence and mortality, consistent with previous research on the epidemiology of Kca. TCE exposure may increase the risk of mortality from Kca, an association not highlighted before. There is a need for policy measures to limit TCE discharge to the environment if these results are validated. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Early initiation of low-dose hydrocortisone treatment for septic shock in adults: A randomized clinical trial.

PubMed

Lv, Qing-Quan; Gu, Xiao-Hua; Chen, Qi-Hong; Yu, Jiang-Quan; Zheng, Rui-Qiang

2017-12-01

Physiologic dose hydrocortisone is part of the suggested adjuvant therapies for patients with septic shock. However, the association between the corticosteroid therapy and mortality in patients with septic shock is still not clear. Some authors considered that the mortality is related to the time frame between development of septic shock and start of low dose hydrocortisone. Thus we designed a placebo-controlled, randomized clinical trial to assess the importance of early initiation of low dose hydrocortisone for the final outcome. A total of 118 patients with septic shock were recruited in the study. All eligible patients were randomized to receive hydrocortisone (n=58) or normal saline (n=60). The study medication (hydrocortisone and normal saline) was initiated simultaneously with vasopressors. The primary end-point was 28-day mortality. The secondary end-points were the reversal of shock, in-hospital mortality and the duration of ICU and hospital stay. The proportion of patients with reversal of shock was similar in the two groups (P=0.602); There were no significant differences in 28-day or hospital all-cause mortality; length of stay in the ICU or hospital between patients treated with hydrocortisone or normal saline. The early initiation of low-dose of hydrocortisone did not decrease the risk of mortality, and the length of stay in the ICU or hospital in adults with septic shock. www.clinicaltrials.govNCT02580240. Copyright © 2017 Elsevier Inc. All rights reserved.

Mortality of atomic bomb survivors predicted from laboratory animals

NASA Technical Reports Server (NTRS)

Carnes, Bruce A.; Grahn, Douglas; Hoel, David

2003-01-01

Exposure, pathology and mortality data for mice, dogs and humans were examined to determine whether accurate interspecies predictions of radiation-induced mortality could be achieved. The analyses revealed that (1) days of life lost per unit dose can be estimated for a species even without information on radiation effects in that species, and (2) accurate predictions of age-specific radiation-induced mortality in beagles and the atomic bomb survivors can be obtained from a dose-response model for comparably exposed mice. These findings illustrate the value of comparative mortality analyses and the relevance of animal data to the study of human health effects.

Mortality from cardiovascular diseases in the Semipalatinsk historical cohort, 1960-1999, and its relationship to radiation exposure.

PubMed

Grosche, Bernd; Lackland, Daniel T; Land, Charles E; Simon, Steven L; Apsalikov, Kazbek N; Pivina, Ludmilla M; Bauer, Susanne; Gusev, Boris I

2011-11-01

The data on risk of mortality from cardiovascular disease due to radiation exposure at low or medium doses are inconsistent. This paper reports an analysis of the Semipalatinsk historical cohort exposed to radioactive fallout from nuclear testing in the vicinity of the Semipalatinsk Nuclear Test Site, Kazakhstan. The cohort study, which includes 19,545 persons of exposed and comparison villages in the Semipalatinsk region, had been set up in the 1960s and comprises 582,656 person-years of follow-up between 1960 and 1999. A dosimetric approach developed by the U.S. National Cancer Institute (NCI) has been used. Radiation dose estimates in this cohort range from 0 to 630 mGy (whole-body external). Overall, the exposed population showed a high mortality from cardiovascular disease. Rates of mortality from cardiovascular disease in the exposed group substantially exceeded those of the comparison group. Dose-response analyses were conducted for both the entire cohort and the exposed group only. A dose-response relationship that was found when analyzing the entire cohort could be explained completely by differences between the baseline rates in exposed and unexposed groups. When taking this difference into account, no statistically significant dose-response relationship for all cardiovascular disease, for heart disease, or for stroke was found. Our results suggest that within this population and at the level of doses estimated, there is no detectable risk of radiation-related mortality from cardiovascular disease.

Whole body protection against lethal ionizing radiation in mice by REC-2001: a semi-purified fraction of Podophyllum hexandrum.

PubMed

Lata, M; Prasad, J; Singh, S; Kumar, R; Singh, L; Chaudhary, P; Arora, R; Chawla, R; Tyagi, S; Soni, N L; Sagar, R K; Devi, M; Sharma, R K; Puri, S C; Tripathi, R P

2009-01-01

The current study has concentrated on assessment of the radioprotective potential of REC-2001, a semi-purified fraction of rhizomes of Podophyllum hexandrum, in Swiss albino Strain 'A' mice exposed to 10 Gy whole-body gamma radiation. Animals were treated with 10 and 15 mg/kg b wt (i.p.) of REC-2001 1h prior to exposure to a lethal dose of gamma-radiation (10 Gy) and observed upto 30 days. For analysis of maximum tolerable dose (MTD), LD(50) and acute toxic dose, different concentrations of the extract were administered to animals and their mortality and morbidity status was observed upto 72 h and one week, respectively. Dose reduction factor (DRF) was determined by exposing REC-2001 pre-treated mice to supra-lethal doses of gamma-radiation. Endogenous spleen colony forming units (CFU), DNA strand breaks in thymocytes (alkaline halo assay) and lipid degradation was studied to understand the mechanism of radioprotection. A single dose of REC-2001 (10 and 15 mg/kg b wt i.p.) exhibited >90% survival in the pre-treated irradiated group versus no survival in radiation control group. Single doses of upto 75 mg/kg b wt (i.p.) did not cause any mortality (MTD) in mice. REC-2001, a dose of 90 mg/kg b wt, resulted in 50% mortality (LD(50)), while the LD(100) was 115 mg/kg b wt REC-2001 exhibited a DRF of 1.62. CFU counts in the REC-2001 treated group were found significantly high (5.33/spleen) as compared to controls. Exposure of thymocytes to 10 Gy radiation resulted in increased halo diameter (45+/-3 microm) in comparison to untreated controls (8+/-1 microm). REC-2001 administration (500 microg/ml) decreased the halo diameter to 15+/-2 microm. Radiation-induced lipid degradation was also inhibited by REC-2001. The present study has revealed that REC-2001 is a promising radioprotective fraction that can be effectively used against lethal doses of gamma-radiation after further investigations in higher animal models.

A review of the epidemiologic literature on the role of environmental arsenic exposure and cardiovascular diseases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, C.-H.; Hsiao, C.K.; Chen, C.-L.

2007-08-01

Cardiovascular disease is the leading cause of mortality worldwide. Arsenic is a ubiquitous metalloid in the crust of the earth. Chronic arsenic poisoning is becoming an emerging epidemic in Asia. Epidemiological studies have shown that chronic arsenic poisoning through ingestion of arsenic-contaminated water is associated with various cardiovascular diseases in dose-response relationships. These cardiovascular disorders include carotid atherosclerosis detected by ultrasonography, impaired microcirculation, prolonged QT interval and increased QT dispersion in electrocardiography, and clinical outcomes such as hypertension, blackfoot disease (a unique peripheral vascular disease endemic in southwestern Taiwan), coronary artery disease and cerebral infarction. Chronic arsenic poisoning is anmore » independent risk factor for cardiovascular disease. The adverse cardiovascular effects of long-term arsenic exposure may be persistent and/or irreversible. Arsenic-induced cardiovascular diseases in human population may result from the interaction among genetic, environment and nutritional factors. The major adverse cardiovascular effect of chronic arsenic poisoning has been established qualitatively and quantitatively in the high arsenic exposure areas, but the low-dose effect of arsenic on cardiovascular diseases remains to be explored. Cardiovascular death is the major cause of mortality worldwide, and a small increased risk may imply a large quantity of excess mortality.« less

Long-term toxicity and carcinogenicity studies of cake made from chlorinated flour. 2. Studies in mice.

PubMed

Ginocchio, A V; Fisher, N; Hutchinson, J B; Berry, R; Hardy, J

1983-08-01

Male and female Theiller's Original strain mice were fed for 16 and 17 months respectively on diets in which cake, prepared from flours treated with 0, 1250 or 2500 ppm chlorine, formed 79% by weight on a 12.6% moisture basis. Body weights and food intakes were unaffected by flour treatment but all of the animals on cake diets showed significant increases in body weight compared with controls on a standard diet and became obese. Mortalities in the males were not related to treatment, but in the females there was excess mortality in the treated groups compared with the cake control group, after 13 months in the 1250 group and after 15 months in the 2500 group. No consistent treatment-related effects were observed in the haematological, biochemical and renal-function studies. Dose-related increases in heart and kidney weights and a dose-related decrease in ovary weight were seen in females. No evidence of carcinogenicity resulting from flour treatment was obtained but the early ending of the study, necessitated by high mortalities, greatly diminished the value of this finding. Concentrations of covalently bound chlorine in the perirenal fat were positively correlated with treatment level, but were considerably below those present in the lipid content of the diets on which the mice were fed.

[Disseminated intravascular coagulation induced by endotoxin in rabbits: effect of treatment with t-PA and urokinase].

PubMed

Paloma, M J; Páramo, J A; Rifón, J; Rocha, E

1992-12-01

To assess the therapeutic efficacy of agents capable of stimulating the fibrinolytic system, such as tissue plasminogen activator (t-PA) and urokinase (UK) on endotoxin-induced disseminated intravascular coagulation (DIC) in the rabbit. DIC was induced by intravenous administration of endotoxin, 20 micrograms/kg/hr during 6 hr. Four different groups were established: a) control group, receiving only saline solution; b) t-PA group receiving 0.2 mg/kg; c) t-PA group receiving 0.7 mg/kg, and d) UK group, which was given 3,000 IU/kg/hr for 6 hr. Blood samples were drawn before and after 2 hr and 6 hr of endotoxin administration. Platelet count, and fibrinogen, factor XII and antithrombin III concentrations, were assessed in each sample. Mean, standard deviation and percentage of increase or decrease with respect to the basal value, this considered 100%, were used to evaluate the findings. For comparison of values, Student's t and Mann Whitney's U were used; the Fisher test was used for mortality studies. No statistical differences appeared for any of the values in the rabbits under basal conditions. The rabbits in the control group developed DIC. No doses of t-PA modified the changes appearing in blood coagulation. UK reduced the fibrinogen and factor XII consumption induced by endotoxin. The mortality rate in the control group reached 70%. High-dose t-PA decreased such figure to 50%, while low-dose t-PA or UK failed to reduce mortality. High-dose t-PA has beneficial effects on endotoxin-induced DIC in rabbits. UK failed to achieve such effect at the doses given in this experimental DIC model.

Atomic Bomb Health Benefits

PubMed Central

Luckey, T. D.

2008-01-01

Media reports of deaths and devastation produced by atomic bombs convinced people around the world that all ionizing radiation is harmful. This concentrated attention on fear of miniscule doses of radiation. Soon the linear no threshold (LNT) paradigm was converted into laws. Scientifically valid information about the health benefits from low dose irradiation was ignored. Here are studies which show increased health in Japanese survivors of atomic bombs. Parameters include decreased mutation, leukemia and solid tissue cancer mortality rates, and increased average lifespan. Each study exhibits a threshold that repudiates the LNT dogma. The average threshold for acute exposures to atomic bombs is about 100 cSv. Conclusions from these studies of atomic bomb survivors are: One burst of low dose irradiation elicits a lifetime of improved health.Improved health from low dose irradiation negates the LNT paradigm.Effective triage should include radiation hormesis for survivor treatment. PMID:19088902

Leukemia risk associated with chronic external exposure to ionizing radiation in a French cohort of nuclear workers.

PubMed

Metz-Flamant, C; Samson, E; Caër-Lorho, S; Acker, A; Laurier, D

2012-11-01

Leukemia is one of the earliest cancer effects observed after acute exposure to relatively high doses of ionizing radiation. Leukemia mortality after external exposure at low doses and low-dose rates has been investigated at the French Atomic Energy Commission (CEA) and Nuclear Fuel Company (AREVA NC) after an additional follow-up of 10 years. The cohort included radiation-monitored workers employed for at least one year during 1950-1994 at CEA or AREVA NC and followed during 1968-2004. Association between external exposure and leukemia mortality was estimated with excess relative risk (ERR) models and time-dependent modifying factors were investigated with time windows. The cohort included 36,769 workers, followed for an average of 28 years, among whom 73 leukemia deaths occurred. Among the workers with a positive recorded dose, the mean cumulative external dose was 21.7 mSv. Results under a 2-year lag assumption suggested that the risk of leukemia (except chronic lymphatic leukemia) increased significantly by 8% per 10 mSv. The magnitude of the association for myeloid leukemia was larger. The higher ERR/Sv for doses received 2-14 years earlier suggest that time since exposure modifies the effect. The ERR/Sv also appeared higher for doses received at exposure rates ≥20 mSv per year. These results are consistent with those found in other studies of nuclear workers. However, confidence intervals are still wide. Further analyses should be conducted in pooled cohorts of nuclear workers.

Effects of azadirachtin on the biology of Lutzomyia longipalpis (Diptera: Psychodidae: Phlebotominae) adult female, the main vector of American visceral leishmaniasis.

PubMed

De Andrade-Coelho, Cláudia Alves; De Souza, Nataly Araujo; Silva, Vanderlei Campos; Souza, Adelson A; Gonzalez, Marcelo Salabert; Rangel, Elizabeth Ferreira

2014-07-01

The effects of azadirachtin A added to the sucrose diet of the adult females on the mortality, oviposition, and hatching of the sand fly vector of American visceral leishmaniasis Lutzomyia longipalpis (Lutz & Neiva, 1912) were investigated. Concentrations of 0.1, 1.0, and 10.0 microg/mg of azadirachtin significantly increased insect mortality in comparison with control insects. The same dose also significantly reduced oviposition but not hatching. After a long development period, significantly fewer adult insects were obtained from eggs hatching by azadirachtin-treated females in a dose-response manner. These results indicate that azadirachtin is a potent sterilizer that could be used against the development of Lu. longipalpis populations and as a tool for studying physiological and biochemical processes in phlebotomine species.

Hemodynamic management and outcome of patients treated for cerebral vasospasm with intraarterial nicardipine and/or milrinone.

PubMed

Schmidt, Ulrich; Bittner, Edward; Pivi, Silvia; Marota, John J A

2010-03-01

Vasospasm is a potentially devastating complication after aneurysmal subarachnoid hemorrhage. Although endovascular treatment with intraarterial nicardipine and milrinone is an accepted clinical treatment strategy, there is little information either on hemodynamic management during treatment or on outcome and consequences of the hemodynamic management. We tested 2 hypotheses: (1) intraarterial administration of nicardipine and milrinone to treat cerebral vasospasm would require increased administration of vasoconstrictor to support arterial blood pressure at target levels; and (2) high-dose vasopressors administered to increase blood pressure in these patients would lead to systemic acidosis and end-organ ischemic damage. We conducted a single-center, retrospective review of consecutive patients with clinically symptomatic vasospasm after aneurysmal subarachnoid hemorrhage that failed medical management with "triple H therapy" and subsequently received intraarterial nicardipine and/or milrinone between March 2005 and July 2007. Of 160 endovascular interventions in 73 patients (aged 52 +/- 10 years; 50 women), 96 received only nicardipine, 5 only milrinone, and 59 both drugs. General anesthesia with muscle relaxation was performed for 93% of procedures. During treatment, both the number and dose of vasopressors required to maintain arterial blood pressure at target levels increased; the median dose of phenylephrine increased from 200 (n = 121) to 325 microg/min (n = 122), norepinephrine increased from 12 (n = 60) to 24.5 microg/min (n = 87), and vasopressin infusions increased from 7 to 24. Nonetheless, arterial blood pressure decreased 13% during treatment. In >90% of procedures, the postprocedure angiogram showed improved vessel caliber. A single patient demonstrated troponin T increase; no patients had a decrease in renal function, bowel or peripheral ischemia, systemic acidosis, or acute stroke. Overall mortality was 11%. Intraarterial administration of nicardipine and/or milrinone requires use of vasopressors to maintain arterial blood pressure. Despite high doses of vasoconstrictors, treatment has low mortality, minimal end-organ ischemic damage or systemic acidosis, and results in improved caliber of cerebral vessels affected by vasospasm.

Cancer mortality in German carbon black workers 1976–98

PubMed Central

Wellmann, J; Weiland, S K; Neiteler, G; Klein, G; Straif, K

2006-01-01

Background Few studies have investigated cancer risks in carbon black workers and the findings were inconclusive. Methods The current study explores the mortality of a cohort of 1535 male German blue‐collar workers employed at a carbon black manufacturing plant for at least one year between 1960 and 1998. Vital status and causes of death were assessed for the period 1976–98. Occupational histories and information on smoking were abstracted from company records. Standardised mortality ratios (SMR) and Poisson regression models were calculated. Results The SMRs for all cause mortality (observed deaths (obs) 332, SMR 120, 95% CI 108 to 134), and mortality from lung cancer (obs 50, SMR 218, 95% CI 161 to 287) were increased using national rates as reference. Comparisons to regional rates from the federal state gave SMRs of 120 (95% CI 107 to 133) and 183 (95% CI 136 to 241), respectively. However, there was no apparent dose response relationship between lung cancer mortality and several indicators of occupational exposure, including years of employment and carbon black exposure. Conclusions The mortality from lung cancer among German carbon black workers was increased. The high lung cancer SMR can not fully be explained by selection, smoking, or other occupational risk factors, but the results also provide little evidence for an effect of carbon black exposure. PMID:16497850

Serum high density lipoprotein cholesterol, alcohol, and coronary mortality in male smokers.

PubMed Central

Paunio, M.; Virtamo, J.; Gref, C. G.; Heinonen, O. P.

1996-01-01

OBJECTIVE--To determine whether the increase in mortality from coronary heart disease with high concentration (> 1.75 mmol/l) of high density lipoprotein cholesterol could be due to alcohol intake. DESIGN--Cohort study. SETTING--Placebo group of the alpha tocopherol, beta carotene cancer prevention (ATBC) study of south western population in Finland. PARTICIPANTS--7052 male smokers aged 50-69 years enrolled to the ATBC study in the 1980s. MAIN OUTCOME MEASURES--The relative and absolute rates adjusted for risk factors for clinically or pathologically verified deaths from coronary heart disease for different concentrations of high density lipoprotein cholesterol with and without stratification for alcohol intake. Similar rates were also calculated for different alcohol consumption groups. RESULTS--During the average follow up period of 6.7 years 258 men died from verified coronary heart disease. Coronary death rate steadily decreased with increasing concentration of high density lipoprotein cholesterol until a high concentration. An increase in the rate was observed above 1.75 mmol/l. This increase occurred among those who reported alcohol intake. Mortality was associated with alcohol intake in a J shaped dose response, and those who reported consuming more than five drinks a day (heavy drinkers) had the highest death rate. Mortality was higher in heavy drinkers than in non-drinkers or light or moderate drinkers in all high density lipoprotein categories from 0.91 mmol/l upward. CONCLUSIONS--Mortality from coronary heart disease increases at concentrations of high density lipoprotein cholesterol over 1.75 mmol/l. The mortality was highest among heavy drinkers, but an increase was found among light drinkers also. PMID:8634563

Current clinical use of reteplase for thrombolysis. A pharmacokinetic-pharmacodynamic perspective.

PubMed

Martin, U; Kaufmann, B; Neugebauer, G

1999-04-01

Clinical evaluation of a new thrombolytic agent should start with a dose that provides adequate efficacy and has an acceptably low bleeding risk; this results in a narrow therapeutic window at the upper end of the dose-response curve. Angiographic patency of the infarct-related artery is still the clinical surrogate end-point for mortality in phase II dose-ranging studies. There is experimental and clinical evidence that the area under the concentration-time curve (AUC) for plasminogenolytic activity of a thrombolytic agent is positively correlated with patency of the infarct-related artery. Dose-ranging studies of the novel recombinant plasminogen activator reteplase in healthy volunteers enabled computation of a linear regression curve by which a clinical starting dose could be calculated for an adapted target AUC that would be clinically effective. Pharmacokinetic analysis also revealed that the half-life of reteplase is 4 times longer than that of the reference thrombolytic alteplase, thus allowing bolus injection. The suggested single bolus starting dose of 10U was supported by results from studies in a canine model of coronary thrombolysis. The feedback of insufficiently high patency rates compared with the increased efficacy of front-loaded and accelerated alteplase demanded optimisation strategies for reteplase. Animal experiments suggested that a double bolus regimen of reteplase would be preferable to doubling the single bolus dose. Pharmacokinetic modelling suggested a time interval of 30 min between the 2 bolus injections. Selection of the tested double bolus regimens was conservative and empirical. First, the previously tested single bolus of 15U was divided to 10 + 5U; secondly, the second bolus dose was increased to 10U. This strategy proved to be successful. The current dosage recommendation for reteplase is a double bolus intravenous injection of 10 + 10U, each over 2 min, 30 min apart. This produces a reduction in mortality in patients with acute myocardial infarction that is equivalent to that produced by front-loaded and accelerated infusion of alteplase.

Altered mental status in older adults with histamine2-receptor antagonists: a population-based study.

PubMed

Tawadrous, Davy; Dixon, Stephanie; Shariff, Salimah Z; Fleet, Jamie; Gandhi, Sonja; Jain, Arsh K; Weir, Matthew A; Gomes, Tara; Garg, Amit X

2014-10-01

Standard doses of histamine2-receptor antagonists (H2RAs) may induce altered mental status in older adults, especially in those with chronic kidney disease (CKD). Population-based cohort study of older adults who started a new H2RA between 2002 and 2011 was conducted. Ninety percent received the current standard H2RA dose in routine care. There was no significant difference in 27 baseline patient characteristics. The primary outcome was hospitalization with an urgent head computed tomography (CT) scan (proxy for altered mental status), and the secondary outcome was all-cause mortality also within 30days of a new H2RA prescription. Standard vs. low H2RA dose was associated with a higher risk of hospitalization with an urgent head CT scan (0.98% vs. 0.74%, absolute risk difference 0.24% [95% CI 0.11% to 0.36%], relative risk 1.33 [95% CI 1.12 to 1.58]). This risk was not modified by the presence of CKD (interaction P value=0.71). Standard vs. low H2RA dose was associated with a higher risk of mortality (1.07% vs.0.74%; absolute risk difference 0.34% [95% CI 0.20% to 0.46%], relative risk 1.46 [95% CI 1.23 to 1.73]). Compared to a lower dose, initiation of the current standard dose of H2RA in older adults is associated with a small absolute increase in the 30-day risk of altered mental status (using neuroimaging as a proxy), even in the absence of CKD. This risk may be avoided by initiating older adults on low doses of H2RAs for gastroesophogeal reflux disease, and increasing dosing as necessary for symptom control. Copyright © 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Behavioral effects of ketamine and toxic interactions with psychostimulants

PubMed Central

Hayase, Tamaki; Yamamoto, Yoshiko; Yamamoto, Keiichi

2006-01-01

Background The anesthetic drug ketamine (KT) has been reported to be an abused drug and fatal cases have been observed in polydrug users. In the present study, considering the possibility of KT-enhanced toxic effects of other drugs, and KT-induced promotion of an overdose without making the subject aware of the danger due to the attenuation of several painful subjective symptoms, the intraperitoneal (i.p.) KT-induced alterations in behaviors and toxic interactions with popular co-abused drugs, the psychostimulants cocaine (COC) and methamphetamine (MA), were examined in ICR mice. Results A single dose of KT caused hyperlocomotion in a low (30 mg/kg, i.p.) dose group, and hypolocomotion followed by hyperlocomotion in a high (100 mg/kg, i.p.) dose group. However, no behavioral alterations derived from enhanced stress-related depression or anxiety were observed in the forced swimming or the elevated plus-maze test. A single non-fatal dose of COC (30 mg/kg, i.p.) or MA (4 mg/kg, i.p.) caused hyperlocomotion, stress-related depression in swimming behaviors in the forced swimming test, and anxiety-related behavioral changes (preference for closed arms) in the elevated plus-maze test. For the COC (30 mg/kg) or MA (4 mg/kg) groups of mice simultaneously co-treated with KT, the psychostimulant-induced hyperlocomotion was suppressed by the high dose KT, and the psychostimulant-induced behavioral alterations in the above tests were reversed by both low and high doses of KT. For the toxic dose COC (70 mg/kg, i.p.)- or MA (15 mg/kg, i.p.)-only group, mortality and severe seizures were observed in some animals. In the toxic dose psychostimulant-KT groups, KT attenuated the severity of seizures dose-dependently. Nevertheless, the mortality rate was significantly increased by co-treatment with the high dose KT. Conclusion Our results demonstrated that, in spite of the absence of stress-related depressive and anxiety-related behavioral alterations following a single dose of KT treatment, and in spite of the KT-induced anticonvulsant effects and attenuation of stress- and anxiety-related behaviors caused by COC or MA, the lethal effects of these psychostimulants were increased by KT. PMID:16542420

Use of high-dose nandrolone aggravates septic shock in a mouse model.

PubMed

Lin, Che; Chen, Shou-Tung; Chien, Su-Yu; Kuo, Shou-Jen; Chen, Dar-Ren

2011-06-01

Nandrolone, an anabolic-androgenic steroid, is widely misused by athletes who wish to rapidly increase muscle mass and performance. An increasing number of reports have indicated that nandrolone may affect and modulate the immune system. This study aimed to investigate the effects of nandrolone on septic shock-caused immune responses and the cellular mechanism of action using a sepsis murine model. Before septic shock induction, BALB/c mice were given a high dose of nandrolone or peanut oil only. After septic shock induction, mice were sacrificed at different time points. Their blood and tissue specimens were analyzed. It was found that the high-dose nandrolone group had significantly increased mortality compared with the control group (p<0.001). The serum malondialdehyde level was significantly increased in the high-dose group compared with the control group. Animals administered a high dose of nandrolone had significantly increased hepatic tumor necrosis factor-α or splenic interferon-γ at 0 and 6 hours. In lung tissue, insulin-like growth factor-1, insulin-like growth factor binding proteins (IGFBPs) and insulin-like growth factor-1 receptor, and IGFBP1 and IGFBP2 mRNA expression were increased in the high-dose nandrolone group at 6 hours. Nandrolone abuse may hasten the death of patients with septic shock and may aggravate septic shock in mice. Copyright © 2011. Published by Elsevier B.V.

A nested case-control study of leukemia mortality and ionizing radiation at the Portsmouth Naval Shipyard.

PubMed

Kubale, Travis L; Daniels, Robert D; Yiin, James H; Couch, James; Schubauer-Berigan, Mary K; Kinnes, Gregory M; Silver, Sharon R; Nowlin, Susan J; Chen, Pi-Hsueh

2005-12-01

A nested case-control study using conditional logistic regression was conducted to evaluate the exposure-response relationship between external ionizing radiation exposure and leukemia mortality among civilian workers at the Portsmouth Naval Shipyard (PNS), Kittery, Maine. The PNS civilian workers received occupational radiation exposure while performing construction, overhaul, repair and refueling activities on nuclear-powered submarines. The study age-matched 115 leukemia deaths with 460 controls selected from a cohort of 37,853 civilian workers employed at PNS between 1952 and 1992. In addition to radiation doses received in the workplace, a secondary analysis incorporating doses from work-related medical X rays and other occupational radiation exposures was conducted. A significant positive association was found between leukemia mortality and external radiation exposure, adjusting for gender, radiation worker status, and solvent exposure duration (OR = 1.08 at 10 mSv of exposure; 95% CI = 1.01, 1.16). Solvent exposure (including benzene and carbon tetrachloride) was also significantly associated with leukemia mortality adjusting for radiation dose, radiation worker status, and gender. Incorporating doses from work-related medical X rays did not change the estimated leukemia risk per unit of dose.

Atomic Bomb Survivors Life-Span Study

PubMed Central

Dobrzyński, Ludwik

2015-01-01

The atomic bomb survivors life-span study (LSS) is often claimed to support the linear no-threshold hypothesis (LNTH) of radiation carcinogenesis. This paper shows that this claim is baseless. The LSS data are equally or better described by an s-shaped dependence on radiation exposure with a threshold of about 0.3 Sievert (Sv) and saturation level at about 1.5 Sv. A Monte-Carlo simulation of possible LSS outcomes demonstrates that, given the weak statistical power, LSS cannot provide support for LNTH. Even if the LNTH is used at low dose and dose rates, its estimation of excess cancer mortality should be communicated as 2.5% per Sv, i.e., an increase of cancer mortality from about 20% spontaneous mortality to about 22.5% per Sv, which is about half of the usually cited value. The impact of the “neutron discrepancy problem” – the apparent difference between the calculated and measured values of neutron flux in Hiroshima – was studied and found to be marginal. Major revision of the radiation risk assessment paradigm is required. PMID:26673526

COMPARATIVE TOXICITY OF SIZE FRACTIONATED AIRBORNE PARTICULATE MATTER OBTAINED FROM DIFFERENT CITIES IN THE USA.

EPA Science Inventory

Hundreds of epidemiological studies have shown that exposure to ambient particulate matter is associated with dose dependent increases in mortality and morbidity in the exposed population. While most of the early reports focused on PM10, independent studies are now showing that ...

GESTATIONAL PFOA EXPOSURE OF MICE IS ASSOCIATED WITH ALTERED MAMMARY GLAND DEVELOPMENT IN DAMS AND FEMALE OFFSPRING

EPA Science Inventory

Perfluorooctanoic acid (PFOA), a ubiquitous and persistent synthetic compound, has been detected in human serum. Previous studies in mice linked prenatal PFOA exposure to increased neonatal mortality and decreased pup weights, in a dose responsive manner. To determine whether dev...

Gestational Exposure to Low Doses of Perfluorooctanoic Acid Increases Adiposity, but not Body Weight, of Adult Offspring

EPA Science Inventory

Perfluorooctanoic acid (PFOA) and other perfluoroalkyl acids have numerous industrial and consumer product applications. Studies in mice have demonstrated lower birth weight and higher neonatal mortality in mice after prenatal dosages exceeding 1 mg/kg/day. However, at dosages lo...

Is copeptin level associated with 1-year mortality after out-of-hospital cardiac arrest? Insights from the Paris registry*.

PubMed

Geri, Guillaume; Dumas, Florence; Chenevier-Gobeaux, Camille; Bouglé, Adrien; Daviaud, Fabrice; Morichau-Beauchant, Tristan; Jouven, Xavier; Mira, Jean-Paul; Pène, Frédéric; Empana, Jean-Philippe; Cariou, Alain

2015-02-01

The availability of circulating biomarkers that helps to identify early out-of-hospital cardiac arrest survivors who are at increased risk of long-term mortality remains challenging. Our aim was to prospectively study the association between copeptin and 1-year mortality in patients with out-of-hospital cardiac arrest admitted in a tertiary cardiac arrest center. Retrospective monocenter study. Tertiary cardiac arrest center in Paris, France. Copeptin was assessed at admission and day 3. Pre- and intrahospital factors associated with 1-year mortality were analyzed by multivariate Cox proportional analysis. None. Two hundred ninety-eight consecutive out-of-hospital cardiac arrest patients (70.3% male; median age, 60.2 yr [49.9-71.4]) were admitted in a tertiary cardiac arrest center in Paris (France). After multivariate analysis, higher admission copeptin was associated with 1-year mortality with a threshold effect (hazard ratio(5th vs 1st quintile) = 1.64; 95% CI, 1.05-2.58; p = 0.03). Day 3 copeptin was associated with 1-year mortality in a dose-dependent manner (hazard ratio(2nd vs 1st quintile) = 1.87; 95% CI, 1.00-3.49; p = 0.05; hazard ratio(3rd vs 1st quintile) = 1.92; 95% CI, 1.02-3.64; p = 0.04; hazard ratio(4th vs 1st quintile) = 2.12; 95% CI, 1.14-3.93; p = 0.02; and hazard ratio(5th vs 1st quintile) = 2.75; 95% CI, 1.47-5.15; p < 0.01; p for trend < 0.01). For both admission and day 3 copeptin, association with 1-year mortality existed for out-of-hospital cardiac arrest of cardiac origin only (p for interaction = 0.05 and < 0.01, respectively). When admission and day 3 copeptin were mutually adjusted, only day 3 copeptin remained associated with 1-year mortality in a dose-dependent manner (p for trend = 0.01). High levels of copeptin were associated with 1-year mortality independently from prehospital and intrahospital risk factors, especially in out-of-hospital cardiac arrest of cardiac origin. Day 3 copeptin was superior to admission copeptin: this could permit identification of out-of-hospital cardiac arrest survivors at increased risk of mortality and allow for close observation of such patients.

Mortality (1950–1999) and cancer incidence (1969–1999) of workers in the Port Hope cohort study exposed to a unique combination of radium, uranium and γ-ray doses

PubMed Central

Zablotska, Lydia B; Lane, Rachel S D; Frost, Stanley E

2013-01-01

Objectives Uranium processing workers are exposed to uranium and radium compounds from the ore dust and to γ-ray radiation, but less to radon decay products (RDP), typical of the uranium miners. We examined the risks of these exposures in a cohort of workers from Port Hope radium and uranium refinery and processing plant. Design A retrospective cohort study with carefully documented exposures, which allowed separation of those with primary exposures to radium and uranium. Settings Port Hope, Ontario, Canada, uranium processors with no mining experience. Participants 3000 male and female workers first employed (1932–1980) and followed for mortality (1950–1999) and cancer incidence (1969–1999). Outcome measures Cohort mortality and incidence were compared with the general Canadian population. Poisson regression was used to evaluate the association between cumulative RDP exposures and γ-ray doses and causes of death and cancers potentially related to radium and uranium processing. Results Overall, workers had lower mortality and cancer incidence compared with the general Canadian population. In analyses restricted to men (n=2645), the person-year weighted mean cumulative RDP exposure was 15.9 working level months (WLM) and the mean cumulative whole-body γ-ray dose was 134.4 millisieverts. We observed small, non-statistically significant increases in radiation risks of mortality and incidence of lung cancer due to RDP exposures (excess relative risks/100 WLM=0.21, 95% CI <−0.45 to 1.59 and 0.77, 95% CI <−0.19 to 3.39, respectively), with similar risks for those exposed to radium and uranium. All other causes of death and cancer incidence were not significantly associated with RDP exposures or γ-ray doses or a combination of both. Conclusions In one of the largest cohort studies of workers exposed to radium, uranium and γ-ray doses, no significant radiation-associated risks were observed for any cancer site or cause of death. Continued follow-up and pooling with other cohorts of workers exposed to by-products of radium and uranium processing could provide valuable insight into occupational risks and suspected differences in risk with uranium miners. PMID:23449746

Combined effects of radiation and caffeine on embryonic development in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kusama, T.; Sugiura, N.; Kai, M.

1989-02-01

The combined effect of radiation and caffeine has been studied in mouse embryos. Radiation and/or caffeine were administered to ICR mice on Day 11 of gestation. Intrauterine death, gross malformation, and fetal body weight were selected as indicators of effects. Doses of whole-body gamma irradiation were 0.5 to 2.5 Gy and those of caffeine were 100 and 250 mg/kg maternal body wt. Intrauterine mortality increased with increasing radiation dose; this trend was more remarkable in combination with caffeine. Gross malformations such as cleft palate and defects of forelegs and hindlegs appeared frequently in the fetuses treated with both radiation andmore » caffeine. Decreased fetal weight was observed even in mice treated with 0.5 Gy of radiation or 100 mg/kg caffeine. There was a linear relationship between dose and reduction of fetal weight. The fetal weight was a sensitive, precise, and easy-to-handle indicator for the effects of growth retardation. Intrauterine mortality and frequencies of cleft palate and defects of forelegs and hindlegs were higher than the sum of those induced by radiation and by caffeine separately. The results indicated that the combined action of radiation and caffeine on intrauterine death and malformations was synergistic.« less

Toxic Effects of Silica Nanoparticles on Zebrafish Embryos and Larvae

PubMed Central

Shi, Huiqin; Tian, Linwei; Guo, Caixia; Huang, Peili; Zhou, Xianqing; Peng, Shuangqing; Sun, Zhiwei

2013-01-01

Silica nanoparticles (SiNPs) have been widely used in biomedical and biotechnological applications. Environmental exposure to nanomaterials is inevitable as they become part of our daily life. Therefore, it is necessary to investigate the possible toxic effects of SiNPs exposure. In this study, zebrafish embryos were treated with SiNPs (25, 50, 100, 200 µg/mL) during 4–96 hours post fertilization (hpf). Mortality, hatching rate, malformation and whole-embryo cellular death were detected. We also measured the larval behavior to analyze whether SiNPs had adverse effects on larvae locomotor activity. The results showed that as the exposure dosages increasing, the hatching rate of zebrafish embryos was decreased while the mortality and cell death were increased. Exposure to SiNPs caused embryonic malformations, including pericardial edema, yolk sac edema, tail and head malformation. The larval behavior testing showed that the total swimming distance was decreased in a dose-dependent manner. The lower dose (25 and 50 µg/mL SiNPs) produced substantial hyperactivity while the higher doses (100 and 200 µg/mL SiNPs) elicited remarkably hypoactivity in dark periods. In summary, our data indicated that SiNPs caused embryonic developmental toxicity, resulted in persistent effects on larval behavior. PMID:24058598

Cancer mortality in residents of the terrain-shielded area exposed to fallout from the Nagasaki atomic bombing.

PubMed

Yokota, Kenichi; Mine, Mariko; Kondo, Hisayoshi; Matsuda, Naoki; Shibata, Yoshisada; Takamura, Noboru

2018-01-01

The health effects of radiation exposure from the atomic bomb fallout remain unclear. The objective of the present study is to elucidate the association between low-dose radiation exposure from the atomic bomb fallout and cancer mortality among Nagasaki atomic bomb survivors. Of 77 884 members in the Nagasaki University Atomic Bomb Survivors Cohort, 610 residents in the terrain-shielded area with fallout were selected for this analysis; 1443 residents in the terrain-shielded area without fallout were selected as a control group; and 3194 residents in the direct exposure area were also selected for study. Fifty-two deaths due to cancer in the terrain-shielded fallout area were observed during the follow-up period from 1 January 1970 to 31 December 2012. The hazard ratio for cancer mortality in the terrain-shielded fallout area was 0.90 (95% confidence interval: 0.65-1.24). No increase in the risk of cancer mortality was observed, probably because the dose of the radiation exposure was low for residents in the terrain-shielded fallout areas of the Nagasaki atomic bomb, and also because the number of study subjects was small. © The Author 2017. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

Lung Cancer Mortality (1950–1999) among Eldorado Uranium Workers: A Comparison of Models of Carcinogenesis and Empirical Excess Risk Models

PubMed Central

Eidemüller, Markus; Jacob, Peter; Lane, Rachel S. D.; Frost, Stanley E.; Zablotska, Lydia B.

2012-01-01

Lung cancer mortality after exposure to radon decay products (RDP) among 16,236 male Eldorado uranium workers was analyzed. Male workers from the Beaverlodge and Port Radium uranium mines and the Port Hope radium and uranium refinery and processing facility who were first employed between 1932 and 1980 were followed up from 1950 to 1999. A total of 618 lung cancer deaths were observed. The analysis compared the results of the biologically-based two-stage clonal expansion (TSCE) model to the empirical excess risk model. The spontaneous clonal expansion rate of pre-malignant cells was reduced at older ages under the assumptions of the TSCE model. Exposure to RDP was associated with increase in the clonal expansion rate during exposure but not afterwards. The increase was stronger for lower exposure rates. A radiation-induced bystander effect could be a possible explanation for such an exposure response. Results on excess risks were compared to a linear dose-response parametric excess risk model with attained age, time since exposure and dose rate as effect modifiers. In all models the excess relative risk decreased with increasing attained age, increasing time since exposure and increasing exposure rate. Large model uncertainties were found in particular for small exposure rates. PMID:22936975

Interactions between methylmercury and selenomethionine injected into mallard eggs

USGS Publications Warehouse

Klimstra, J.D.; Yee, J.L.; Heinz, G.H.; Hoffman, D.J.; Stebbins, K.R.

2012-01-01

Methylmercury chloride and seleno-L-methionine were injected separately or in combinations into mallard eggs (Anas platyrhynchos), and embryo mortality and teratogenic effects (deformities) were modeled using a logistic regression model. Methylmercury was injected at doses that resulted in concentrations of 0, 0.2, 0.4, 0.8, and 1.6 µg/g Hg in the egg on a wet weight basis and selenomethionine at doses that resulted in concentrations of 0, 0.1, 0.2, 0.4, and 0.6 µg/g Se in the egg, also on a wet weight basis. When selenomethionine and methylmercury were injected separately, hatching probability decreased in both cases. However, when methylmercury was injected at 1.6 µg/g in combination with selenomethionine at 0.2 µg/g, the presence of the methylmercury resulted in less embryo mortality than had been seen with 0.2 µg/g Se by itself, but it increased the number of deformed embryos and hatchlings. Selenomethionine appeared to be more embryotoxic than equivalent doses of methylmercury when injected into eggs, and both injected methylmercury and selenomethionine were more toxic to mallard embryos than when deposited naturally in the egg by the mother. The underlying mechanisms behind the interactions between methylmercury and selenomethionine and why methylmercury appeared to improve hatching probability of Se-dosed eggs yet increased deformities when the two compounds were combined are unclear. These findings warrant further studies to understand these mechanisms in both laboratory and field settings.

Acute and subchronic toxicity of naturally weathered Exxon Valdez crude oil in mallards and ferrets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stubblefield, W.A.; Hancock, G.A.; Ford, W.H.

1995-11-01

The toxic properties of naturally weathered Exxon Valdez crude oil (WEVC) were assessed in a battery of acute and subchronic toxicity tests using mallards, Anas platyrhynchos, and European ferrets, Mustela putorius. Adult mallard acute oral toxicity study results indicated no mortalities or signs o toxicity, i.e., no-observed-adverse-effect level (NOAEL) and median lethal dose (LD50) > 5,000 mg/kg. Acute oral feeding and food avoidance tests with ducklings also indicated no toxicity (NOAEL and LC50 > 50,000 mg/kg diet) with no evidence of food avoidance (FAC50 > 20,000 mg/kg diet). No mortalities or toxic signs were noted in a 14-d feeding studymore » with adult birds at dietary concentrations up to 100,000 mg WEVC/kg diet. Among clinical and physiological end points evaluated, the only significant difference noted was an increase in liver: body weight ratios in the 100,000-mg WEVC/kg diet dose group. No differences in clinical chemistry or hematological parameters were noted, and there were no consistent differences in histological evaluations of organ tissues. Daily oral doses of up to 5,000 mg/kg of WEVC over 5 d resulted in minimal effects on ferrets. Increased serum albumin concentrations were observed in the 5,000-mg/kg dose group females and decreased spleen weights were noted in females of all WEVC treatment groups. No other significant observations were noted.« less

Radiation Exposure and Attributable Cancer Risk in Patients With Esophageal Atresia.

PubMed

Yousef, Yasmine; Baird, Robert

2018-02-01

Cases of esophageal carcinoma have been documented in survivors of esophageal atresia (EA). Children with EA undergo considerable amounts of diagnostic imaging and consequent radiation exposure potentially increasing their lifetime cancer mortality risk. This study evaluates the radiological procedures performed on patients with EA and estimates their cumulative radiation exposure and attributable lifetime cancer mortality risk. Medical records of patients with EA managed at a tertiary care center were reviewed for demographics, EA subtype, and number and type of radiological investigations. Existing normative data were used to estimate the cumulative radiation exposure and lifetime cancer risk per patient. The present study included 53 patients with a mean follow-up of 5.7 years. The overall median and maximum estimated effective radiation dose in the neonatal period was 5521.4 μSv/patient and 66638.6 μSv/patient, respectively. This correlates to a median and maximum estimated cumulative lifetime cancer mortality risk of 1:1530 and 1:130, respectively. Hence, radiation exposure in the neonatal period increased the cumulative cancer mortality risk a median of 130-fold and a maximum of 1575-fold in EA survivors. Children with EA are exposed to significant amounts of radiation and an increased estimated cumulative cancer mortality risk. Efforts should be made to eliminate superfluous imaging.

Mitigation of the hematopoietic and gastrointestinal acute radiation syndrome by octadecenyl thiophosphate, a small molecule mimic of lysophosphatidic acid.

PubMed

Deng, Wenlin; Kimura, Yasuhiro; Gududuru, Veeresh; Wu, Wenjie; Balogh, Andrea; Szabo, Erzsebet; Thompson, Karin Emmons; Yates, C Ryan; Balazs, Louisa; Johnson, Leonard R; Miller, Duane D; Strobos, Jur; McCool, W Shannon; Tigyi, Gabor J

2015-04-01

We have previously demonstrated that the small molecule octadecenyl thiophosphate (OTP), a synthetic mimic of the growth factor-like mediator lysophosphatidic acid (LPA), showed radioprotective activity in a mouse model of total-body irradiation (TBI) when given orally or intraperitoneally 30 min before exposure to 9 Gy γ radiation. In the current study, we evaluated the effects of OTP, delivered subcutaneously, for radioprotection or radiomitigation from -24 h before to up to +72 h postirradiation using a mouse TBI model with therapeutic doses at around 1 mg/kg. OTP was injected at 10 mg/kg without observable toxic side effects in mice, providing a comfortable safety margin. Treatment of C57BL/6 mice with a single dose of OTP over the time period from -12 h before to +26 h after a lethal dose of TBI reduced mortality by 50%. When administered at +48 h to +72 h postirradiation (LD50/30 to LD100/30), OTP reduced mortality by ≥34%. OTP administered at +24 h postirradiation significantly elevated peripheral white blood cell and platelet counts, increased crypt survival in the jejunum, enhanced intestinal glucose absorption and reduced endotoxin seepage into the blood. In the 6.4-8.6 Gy TBI range using LD50/10 as the end point, OTP yielded a dose modification factor of 1.2. The current data indicate that OTP is a potent radioprotector and radiomitigator ameliorating the mortality and tissue injury of acute hematopoietic as well as acute gastrointestinal radiation syndrome.

Reduced lung-cancer mortality with low-dose computed tomographic screening.

PubMed

Aberle, Denise R; Adams, Amanda M; Berg, Christine D; Black, William C; Clapp, Jonathan D; Fagerstrom, Richard M; Gareen, Ilana F; Gatsonis, Constantine; Marcus, Pamela M; Sicks, JoRean D

2011-08-04

The aggressive and heterogeneous nature of lung cancer has thwarted efforts to reduce mortality from this cancer through the use of screening. The advent of low-dose helical computed tomography (CT) altered the landscape of lung-cancer screening, with studies indicating that low-dose CT detects many tumors at early stages. The National Lung Screening Trial (NLST) was conducted to determine whether screening with low-dose CT could reduce mortality from lung cancer. From August 2002 through April 2004, we enrolled 53,454 persons at high risk for lung cancer at 33 U.S. medical centers. Participants were randomly assigned to undergo three annual screenings with either low-dose CT (26,722 participants) or single-view posteroanterior chest radiography (26,732). Data were collected on cases of lung cancer and deaths from lung cancer that occurred through December 31, 2009. The rate of adherence to screening was more than 90%. The rate of positive screening tests was 24.2% with low-dose CT and 6.9% with radiography over all three rounds. A total of 96.4% of the positive screening results in the low-dose CT group and 94.5% in the radiography group were false positive results. The incidence of lung cancer was 645 cases per 100,000 person-years (1060 cancers) in the low-dose CT group, as compared with 572 cases per 100,000 person-years (941 cancers) in the radiography group (rate ratio, 1.13; 95% confidence interval [CI], 1.03 to 1.23). There were 247 deaths from lung cancer per 100,000 person-years in the low-dose CT group and 309 deaths per 100,000 person-years in the radiography group, representing a relative reduction in mortality from lung cancer with low-dose CT screening of 20.0% (95% CI, 6.8 to 26.7; P=0.004). The rate of death from any cause was reduced in the low-dose CT group, as compared with the radiography group, by 6.7% (95% CI, 1.2 to 13.6; P=0.02). Screening with the use of low-dose CT reduces mortality from lung cancer. (Funded by the National Cancer Institute; National Lung Screening Trial ClinicalTrials.gov number, NCT00047385.).

Long-term mortality and cancer risk in irradiated rhesus monkeys

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wood, D.H.

1991-05-01

Continuous, 24-year observations on a group of 358 rhesus monkeys reveal that life shortening from exposure to protons in the energy range encountered in the Van Allen belts and solar proton events is influenced primarily by the dose rather than by the energy of radiation. Life shortening in groups exposed to similar surface doses of 138- to 2300-MeV and 32- to 55-MeV protons are not significantly different, but the low-energy protons are associated with more deaths in the early years, while the high-energy protons contribute more to mortality in later years. In males, the most significant cause of life shorteningmore » is nonleukemia cancers. In females, radiation increased the risk of endometriosis (an abnormal proliferation of the lining of the uterus) which resulted in significant mortality in the years before early detection and treatment methods were employed. Animals exposed to 55-MeV protons had a high incidence of malignant brain tumors with latent periods ranging from 13 months to 20 years. The first fatal cancer among nonirradiated controls occurred 18 years after the study began. Analysis of the dose-response data supports the 1989 guidelines of the NCRP for maximum permissible radiation exposures in astronauts (NCRP, Guidance on Radiation Received in Space Activities, Report No. 98, National Council on Radiation Protection and Measurements, Bethesda, MD, 1989).« less

What is the impact of preoperative aspirin administration on patients undergoing coronary artery bypass grafting?

PubMed

Aboul-Hassan, Sleiman Sebastian; Stankowski, Tomasz; Marczak, Jakub; Cichon, Romuald

2017-02-01

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether continuation of administration of preoperative aspirin until the day of coronary artery bypass grafting (CABG) could minimize postoperative mortality, prevalence of postoperative myocardial infarction (MI) with or without influence on postoperative bleeding, packed red blood cell (PRBC) transfusion and reoperation for bleeding. Altogether, 662 papers were found using the reported search, 7 of which represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Seven studies, included in this review, consisted of five meta-analyses and two randomized controlled trials. One meta-analysis, involving 27 533 patients submitted to CABG, showed that the administration of preoperative aspirin decreased postoperative 30-day mortality by 27%. Another meta-analysis, including 1437 patients, showed that preoperative aspirin decreased the incidence of perioperative MI by 44%, the effect being even more pronounced with low-dose aspirin, which reduced the prevalence of perioperative MI by 63%. One RCT showed that preoperative aspirin is associated with reduced long-term hazard of MI or repeated revascularization. Four meta-analyses and two RCTs showed that preoperative aspirin is associated with increased postoperative bleeding, PRBC transfusion and reoperation for bleeding. However, this was not the case with preoperative administration of low-dose aspirin. The results presented in these studies suggest that preoperative aspirin administration in patients undergoing CABG has a significant benefit in reducing the incidence of perioperative MI and 30-day mortality rate, as well as reduced long-term hazard of MI or repeated revascularization. At a higher dose (>100 mg/day), postoperative bleeding, PRBC transfusion and reoperation for bleeding increased. However, with low-dose aspirin (≤100 mg/day), these benefits were not at the expense of increased postoperative bleeding or transfusion. © The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Horizontal and trophic transfer of diflubenzuron and fipronil among grasshoppers (Melanoplus sanguinipes) and between grasshoppers and darkling beetles (Tenebrionidae).

PubMed

Smith, D I; Lockwood, J A

2003-04-01

The possibility of horizontal transmission of diflubenzuron and fipronil was assessed in rangeland grasshoppers. Laboratory studies of Melanoplus sanguinipes demonstrated that fipronil was horizontally transferred at lethal levels (p < 0.05) via cannibalism through four passages when the initial dose applied to a food source was 250 times the label rate for rangeland grasshopper and locust control (label rate is 4 g AI/ha). Mortality was 100% on the first three passages through cannibalism. At 25 and 1 times the label rate, fipronil was lethal (p < 0.05) only on the first cannibalistic passage. Diflubenzuron generated significant (p < 0.05) mortality via horizontal transmission through two passages when the initial dose applied to a food source was 2,000 times the label rate for rangeland grasshopper control (label rate is 8.71 g AI/ha). There was 100% mortality in the first passage via cannibalism. At 250 and 25 times the label rate, diflubenzuron was lethal only on the first cannibalistic passage. Field applications of these two acridicides followed by collection of cadavers (Amphitornus coloradus and Ageneotettix deorum) that were fed to M. sanguinipes in the laboratory revealed that fipronil (25 times the label rate) generated significant (p < 0.05) mortality through two passages and diflubenzuron (label rate) caused no mortality via necrophagy. Tenebrionid beetles fed grasshopper cadavers collected from the field application of fipronil yielded 45% mortality, compared with 25% mortality in the controls. These findings suggest that horizontal and trophic transfer probably play a nominal ecotoxicological role in rangeland grasshopper control programs with diflubenzuron, but the transfer of fipronil to grasshoppers, scavengers, and natural enemies via necrophagy may increase both the efficacy of control programs and their environmental affects.

Acceleration of atherogenesis in ApoE-/- mice exposed to acute or low-dose-rate ionizing radiation.

PubMed

Mancuso, Mariateresa; Pasquali, Emanuela; Braga-Tanaka, Ignacia; Tanaka, Satoshi; Pannicelli, Alessandro; Giardullo, Paola; Pazzaglia, Simonetta; Tapio, Soile; Atkinson, Michael J; Saran, Anna

2015-10-13

There is epidemiological evidence for increased non-cancer mortality, primarily due to circulatory diseases after radiation exposure above 0.5 Sv. We evaluated the effects of chronic low-dose rate versus acute exposures in a murine model of spontaneous atherogenesis. Female ApoE-/- mice (60 days) were chronically irradiated for 300 days with gamma rays at two different dose rates (1 mGy/day; 20 mGy/day), with total accumulated doses of 0.3 or 6 Gy. For comparison, age-matched ApoE-/- females were acutely exposed to the same doses and sacrificed 300 days post-irradiation. Mice acutely exposed to 0.3 or 6 Gy showed increased atherogenesis compared to age-matched controls, and this effect was persistent. When the same doses were delivered at low dose rate over 300 days, we again observed a significant impact on global development of atherosclerosis, although at 0.3 Gy effects were limited to the descending thoracic aorta. Our data suggest that a moderate dose of 0.3 Gy can have persistent detrimental effects on the cardiovascular system, and that a high dose of 6 Gy poses high risks at both high and low dose rates. Our results were clearly nonlinear with dose, suggesting that lower doses may be more damaging than predicted by a linear dose response.

A dose-response study of consuming high-fructose corn syrup-sweetened beverages on lipid/lipoprotein risk factors for cardiovascular disease in young adults.

PubMed

Stanhope, Kimber L; Medici, Valentina; Bremer, Andrew A; Lee, Vivien; Lam, Hazel D; Nunez, Marinelle V; Chen, Guoxia X; Keim, Nancy L; Havel, Peter J

2015-06-01

National Health and Nutrition Examination Survey data show an increased risk of cardiovascular disease (CVD) mortality with an increased intake of added sugar. We determined the dose-response effects of consuming beverages sweetened with high-fructose corn syrup (HFCS) at zero, low, medium, and high proportions of energy requirements (Ereq) on circulating lipid/lipoprotein risk factors for CVD and uric acid in adults [age: 18-40 y; body mass index (in kg/m(2)): 18-35]. We conducted a parallel-arm, nonrandomized, double-blinded intervention study in which adults participated in 3.5 inpatient days of baseline testing at the University of California Davis Clinical and Translational Science Center's Clinical Research Center. Participants then consumed beverages sweetened with HFCS at 0% (aspartame sweetened, n = 23), 10% (n = 18), 17.5% (n = 16), or 25% (n = 28) of Ereq during 13 outpatient days and during 3.5 inpatient days of intervention testing at the research center. We conducted 24-h serial blood collections during the baseline and intervention testing periods. Consuming beverages containing 10%, 17.5%, or 25% Ereq from HFCS produced significant linear dose-response increases of lipid/lipoprotein risk factors for CVD and uric acid: postprandial triglyceride (0%: 0 ± 4; 10%: 22 ± 8; 17.5%: 25 ± 5: 25%: 37 ± 5 mg/dL, mean of Δ ± SE, P < 0.0001 effect of HFCS-dose), fasting LDL cholesterol (0%: -1.0 ± 3.1; 10%: 7.4 ± 3.2; 17.5%: 8.2 ± 3.1; 25%: 15.9 ± 3.1 mg/dL, P < 0.0001), and 24-h mean uric acid concentrations (0%: -0.13 ± 0.07; 10%: 0.15 ± 0.06; 17.5%: 0.30 ± 0.07; 25%: 0.59 ± 0.09 mg/dL, P < 0.0001). Compared with beverages containing 0% HFCS, all 3 doses of HFCS-containing beverages increased concentrations of postprandial triglyceride, and the 2 higher doses increased fasting and/or postprandial concentrations of non-HDL cholesterol, LDL cholesterol, apolipoprotein B, apolipoprotein CIII, and uric acid. Consuming beverages containing 10%, 17.5%, or 25% Ereq from HFCS produced dose-dependent increases in circulating lipid/lipoprotein risk factors for CVD and uric acid within 2 wk. These results provide mechanistic support for the epidemiologic evidence that the risk of cardiovascular mortality is positively associated with consumption of increasing amounts of added sugars. This trial was registered at clinicaltrials.gov as NCT01103921. © 2015 American Society for Nutrition.

Metoprolol impairs resistance artery function in mice

PubMed Central

El Beheiry, Mostafa H.; Heximer, Scott P.; Voigtlaender-Bolz, Julia; Mazer, C. David; Connelly, Kim A.; Wilson, David F.; Beattie, W. Scott; Tsui, Albert K. Y.; Zhang, Hangjun; Golam, Kabir; Hu, Tina; Liu, Elaine; Lidington, Darcy; Bolz, Steffen-Sebastian

2011-01-01

Acute β-blockade with metoprolol has been associated with increased mortality by undefined mechanisms. Since metoprolol is a relatively high affinity blocker of β2-adrenoreceptors, we hypothesized that some of the increased mortality associated with its use may be due to its abrogation of β2-adrenoreceptor-mediated vasodilation of microvessels in different vascular beds. Cardiac output (CO; pressure volume loops), mean arterial pressure (MAP), relative cerebral blood flow (rCBF; laser Doppler), and microvascular brain tissue Po2 (G2 oxyphor) were measured in anesthetized mice before and after acute treatment with metoprolol (3 mg/kg iv). The vasodilatory dose responses to β-adrenergic agonists (isoproterenol and clenbuterol), and the myogenic response, were assessed in isolated mesenteric resistance arteries (MRAs; ∼200-μm diameter) and posterior cerebral arteries (PCAs ∼150-μm diameter). Data are presented as means ± SE with statistical significance applied at P < 0.05. Metoprolol treatment did not effect MAP but reduced heart rate and stroke volume, CO, rCBF, and brain microvascular Po2, while concurrently increasing systemic vascular resistance (P < 0.05 for all). In isolated MRAs, metoprolol did not affect basal artery tone or the myogenic response, but it did cause a dose-dependent impairment of isoproterenol- and clenbuterol-induced vasodilation. In isolated PCAs, metoprolol (50 μM) impaired maximal vasodilation in response to isoproterenol. These data support the hypothesis that acute administration of metoprolol can reduce tissue oxygen delivery by impairing the vasodilatory response to β2-adrenergic agonists. This mechanism may contribute to the observed increase in mortality associated with acute administration of metoprolol in perioperative patients. PMID:21799135

Toxicity of Lead and Proposed Substitute Shot to Mallards

USGS Publications Warehouse

Longcore, J.R.; Andrews, R.; Locke, L.N.; Bagley, George E.; Young, L.T.

1974-01-01

Poisoning of North American waterfowl resulting from the ingestion of lead shot by ducks, geese, and swans causes an estimated annual mortality of 2 to 3% of the population (Bellrose 1959). To alleviate this problem the search for a suitable substitute for lead has been underway since the early 1950's. Proposed substitutes for lead shot were evaluated in a series of acute toxicity tests with pen-reared mallards (Anas platyrhynchos). Most candidate materials were as toxic to ducks as commercial lead shot. Coating or alloying lead with other metals only delayed mortality among dosed ducks. The reputedly 'disintegrable' lead shot with the water-soluble binder and the lead containing biochemical additives were also as toxic to mallards as the commercial lead shot. Mortality was not significantly different among lead-dosed adult or first-year hen and drake pen-reared mallards; lead-dosed adult, wild mallards of both sexes; and lead-dosed adult, male black ducks (Anas rubripes). The ingestion of one lead shot, size 4, by each of 80 pen-reared mallards caused an average 19% mortality. The presence and type of grit in the gizzard had a measurable effect on erosion of ingested shot and on shot retention among dosed mallards. Significantly fewer lead-dosed ducks died when fed crushed oystershell grit than when fed either quartz grit or no grit.

Increased long term mortality associated with rash after early measles vaccination in rural Senegal.

PubMed

Seng, R; Samb, B; Simondon, F; Cissé, B; Soumaré, M; Jensen, H; Bennett, J; Whittle, H; Aaby, P

1999-01-01

To examine whether clinical symptoms, including rash, were more common after measles immunization compared with placebo and to study the association between postvaccination symptoms and later mortality. Examination of side effects in the 3 weeks after immunization in a trial of high titer and standard titer measles vaccines. Two hundred twenty-four children randomly selected to be included in the surveillance for diarrhea, fever and rash. There was no difference in fever and diarrhea between recipients of high titer vaccines and recipients of placebo. However, high titer recipients tended to have more measles-like rashes than placebo recipients [relative risk, 2.12 (range, 0.90 to 5.03)]. Among recipients of high titer vaccines, children who presented a rash had higher mortality in the following 5 to 7 years than those who did not develop rash [mortality rate ratio, 3.85 (range, 1.52 to 9.79)]. High titer recipients without a rash had the same mortality as children in the placebo group who were given standard doses of measles vaccine at 10 months of age [mortality rate, 0.76 (range, 0.35 to 1.62)]. These observations suggest that in this particular study, rash after high titer measles vaccine may identify children who received a particularly high dose of vaccine or children with more severe and persistent postvaccination immunosuppression. Whether high titer vaccine is more likely than standard titer measles vaccine to provoke such reaction is not known, given that we did not compare side effects after different titers of measles vaccine. Future trials of live measles vaccine should monitor the development of rash.

Mortality associated with administration of high-dose tranexamic acid and aprotinin in primary open-heart procedures: a retrospective analysis.

PubMed

Sander, Michael; Spies, Claudia D; Martiny, Viktoria; Rosenthal, Christoph; Wernecke, Klaus-Dieter; von Heymann, Christian

2010-01-01

Antifibrinolytic agents are commonly used during cardiac surgery to minimize bleeding. Because of safety concerns, aprotinin was withdrawn from the market in 2007. Since then, tranexamic acid (TXA) has become the antifibrinolytic treatment of choice in many heart centers. The safety profile of TXA has not been extensively studied. Therefore, the aim of this study was to evaluate safety and efficiency of TXA compared with aprotinin in cardiac surgery. Since July 1, 2006, TXA has been administered at a dose of 50 mg/kg tranexamic acid before cardiopulmonary bypass (CPB) and 50 mg/kg into the priming fluid of the CPB. Prior to this, all patients were treated with aprotinin at a dose of 50,000 KIU per kilogram body weight. Safety was evaluated with mortality, biomarkers, and the diagnosis of myocardial infarction, ischemic stroke, convulsive seizures, and acute renal failure in the intensive care unit (ICU), intermediate care unit (IMCU), and hospital stay. Efficiency was evaluated by the need for transfusion of blood products and total postoperative blood loss. After informed consent, 893 patients were included in our database (557 consecutive patients receiving aprotinin and 336 patients receiving TXA). A subgroup of 320 patients undergoing open-heart procedures (105 receiving TXA and 215 receiving aprotinin) was analyzed separately. In the aprotinin group, a higher rate of late events of ischemic stroke (3.4% versus 0.9%; P = 0.02) and neurologic disability (5.8% versus 2.4%; P = 0.02) was found. The rate of postoperative convulsive seizures was increased in tendency in patients receiving TXA (2.7% versus 0.9%; P = 0.05). The use of TXA was associated with higher cumulative drainage losses (PANOVA < 0.01; Ptime < 0.01) and a higher rate of repeated thoracotomy for bleeding (6.9% versus 2.4%; P < 0.01). In the subgroup of patients with open-chamber procedures, mortality was higher in the TXA group (16.2% TXA versus 7.5% aprotinin; P = 0.02). Multivariate logistic regression identified EURO score II and CPB time as additional risk factors for this increased mortality. The use of high-dose TXA is questioned, as our data suggest an association between higher mortality and minor efficiency while the safety profile of this drug is not consistently improved. Further confirmatory prospective studies evaluating the efficacy and safety profile of TXA are urgently needed to find a safe dosage for this antifibrinolytic drug.

Long-term epidemiological studies of atomic bomb survivors in Hiroshima and Nagasaki: study populations, dosimetry and summary of health effects.

PubMed

Okubo, Toshiteru

2012-10-01

The Radiation Effects Research Foundation succeeded 28 years' worth of activities of the Atomic Bomb Casualty Commission on long-term epidemiological studies in Hiroshima and Nagasaki. It has three major cohorts of atomic bomb survivors, i.e. the Life Span Study (LSS) of 120,000 people, the In Utero Cohort of 3600 and the Second Generation Study (F(1)) of 77,000. The LSS and F(1) studies include a periodic health examination for each sub-cohort, i.e. the Adult Health Study and the F(1) Clinical Study, respectively. An extensive individual dose estimation was conducted and the system was published as the Dosimetry System established in 2002 (DS02). As results of these studies, increases of cancers in relation to dose were clearly shown. Increases of other mortality causes were also observed, including heart and respiratory diseases. There has been no evidence of genetic effects in the survivors' children, including cancer and other multi-factorial diseases. The increase in the expected mortality number in the next 10 y would allow the analyses of further details of the observed effects related to atomic bomb exposures.

Protective Role of Acetylsalicylic Acid in Experimental Trypanosoma cruzi Infection: Evidence of a 15-epi-Lipoxin A4-Mediated Effect

PubMed Central

Henriquez, Natalia; Faúndez, Mario; Torres, Gloria; Castillo, Christian; Escanilla, Sebastián; Kemmerling, Ulrike; Morello, Antonio; López-Muñoz, Rodrigo A.; Maya, Juan D.

2013-01-01

Chagas' disease, produced by Trypanosoma cruzi, affects more than 8 million people, producing approximately 10,000 deaths each year in Latin America. Migration of people from endemic regions to developed countries has expanded the risk of infection, transforming this disease into a globally emerging problem. PGE2 and other eicosanoids contribute to cardiac functional deficits after infection with T. cruzi. Thus, the inhibition of host cyclooxygenase (COX) enzyme emerges as a potential therapeutic target. In vivo studies about the effect of acetylsalicylic acid (ASA) upon T. cruzi infection are controversial, and always report the effect of ASA at a single dose. Therefore, we aimed to analyze the effect of ASA at different doses in an in vivo model of infection and correlate it with the production of arachidonic acid metabolites. ASA decreased mortality, parasitemia, and heart damage in T. cruzi (Dm28c) infected mice, at the low doses of 25 and 50 mg/Kg. However, this effect disappeared when the high ASA doses of 75 and 100 mg/Kg were used. We explored whether this observation was related to the metabolic shift toward the production of 5-lipoxygenase derivatives, and although we did not observe an increase in LTB4 production in infected RAW cells and mice infected, we did find an increase in 15-epi-LXA4 (an ASA-triggered lipoxin). We also found high levels of 15-epi-LXA4 in T. cruzi infected mice treated with the low doses of ASA, while the high ASA doses decreased 15-epi-LXA4 levels. Importantly, 15-epi-LXA4 prevented parasitemia, mortality, and cardiac changes in vivo and restored the protective role in the treatment with a high dose of ASA. This is the first report showing the production of ASA-triggered lipoxins in T. cruzi infected mice, which demonstrates the role of this lipid as an anti-inflammatory molecule in the acute phase of the disease. PMID:23638194

Urinary cadmium and mortality among inhabitants of a cadmium-polluted area in Japan

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nakagawa, Hideaki; Nishijo, Muneko; Morikawa, Yuko

The influence of cadmium (Cd) body burden on mortality remains controversial. Excess mortality and the dose-response relationship between mortality and urinary cadmium excretion were investigated in this study among environmentally exposed subjects. A 15-year follow-up study was carried out on 3119 inhabitants (1403 men and 1716 women) of the Cd-polluted Kakehashi River basin, whose urinary Cd concentration was examined in a 1981-1982 health impact survey. The mortality risk of high urinary Cd ({>=}10 {mu}g/g Cr) subjects after adjustment for age using Cox's proportional hazard model was higher than that of moderate urinary Cd (<10 {mu}g/g Cr) subjects in both sexes.more » When the subjects were divided into five groups according to the amount of urinary Cd (<3, 3-5, 5-10, 10-20, {>=}20 {mu}g/g Cr), the mortality risk was significantly increased among the subjects with urinary Cd{>=}3 {mu}g/g Cr in proportion to the increases in the amount of urinary Cd concentration after adjustment for age, especially in women. Furthermore, special causes of death among high and moderate urinary Cd were investigated, and mortality risk ratio for heart failure, which is a cause of death often diagnosed in cases with a gradual deterioration culminating in death, was significantly increased in both sexes, compared with the moderate urinary Cd subjects. Also, in women the mortality risk for renal diseases in the high urinary Cd subjects was significantly higher than that in the moderate urinary Cd subjects. These results suggest that a causal association between Cd body burden and mortality exists among inhabitants environmentally exposed to Cd but that no special disease may be induced except renal diseases.« less

Accelerometer-measured dose-response for physical activity, sedentary time, and mortality in US adults.

PubMed

Matthews, Charles E; Keadle, Sarah Kozey; Troiano, Richard P; Kahle, Lisa; Koster, Annemarie; Brychta, Robert; Van Domelen, Dane; Caserotti, Paolo; Chen, Kong Y; Harris, Tamara B; Berrigan, David

2016-11-01

Moderate-to-vigorous-intensity physical activity is recommended to maintain and improve health, but the mortality benefits of light activity and risk for sedentary time remain uncertain. Using accelerometer-based measures, we 1) described the mortality dose-response for sedentary time and light- and moderate-to-vigorous-intensity activity using restricted cubic splines, and 2) estimated the mortality benefits associated with replacing sedentary time with physical activity, accounting for total activity. US adults (n = 4840) from NHANES (2003-2006) wore an accelerometer for ≤7 d and were followed prospectively for mortality. Proportional hazards models were used to estimate adjusted HRs and 95% CIs for mortality associations with time spent sedentary and in light- and moderate-to-vigorous-intensity physical activity. Splines were used to graphically present behavior-mortality relation. Isotemporal models estimated replacement associations for sedentary time, and separate models were fit for low- (<5.8 h total activity/d) and high-active participants to account for nonlinear associations. Over a mean of 6.6 y, 700 deaths occurred. Compared with less-sedentary adults (6 sedentary h/d), those who spent 10 sedentary h/d had 29% greater risk (HR: 1.29; 95% CI: 1.1, 1.5). Compared with those who did less light activity (3 h/d), those who did 5 h of light activity/d had 23% lower risk (HR: 0.77; 95% CI: 0.6, 1.0). There was no association with mortality for sedentary time or light or moderate-to-vigorous activity in highly active adults. In less-active adults, replacing 1 h of sedentary time with either light- or moderate-to-vigorous-intensity activity was associated with 18% and 42% lower mortality, respectively. Health promotion efforts for physical activity have mostly focused on moderate-to-vigorous activity. However, our findings derived from accelerometer-based measurements suggest that increasing light-intensity activity and reducing sedentary time are also important, particularly for inactive adults. © 2016 American Society for Nutrition.

Coffee consumption and mortality from all causes, cardiovascular disease, and cancer: a dose-response meta-analysis.

PubMed

Crippa, Alessio; Discacciati, Andrea; Larsson, Susanna C; Wolk, Alicja; Orsini, Nicola

2014-10-15

Several studies have analyzed the relationship between coffee consumption and mortality, but the shape of the association remains unclear. We conducted a dose-response meta-analysis of prospective studies to examine the dose-response associations between coffee consumption and mortality from all causes, cardiovascular disease (CVD), and all cancers. Pertinent studies, published between 1966 and 2013, were identified by searching PubMed and by reviewing the reference lists of the selected articles. Prospective studies in which investigators reported relative risks of mortality from all causes, CVD, and all cancers for 3 or more categories of coffee consumption were eligible. Results from individual studies were pooled using a random-effects model. Twenty-one prospective studies, with 121,915 deaths and 997,464 participants, met the inclusion criteria. There was strong evidence of nonlinear associations between coffee consumption and mortality for all causes and CVD (P for nonlinearity < 0.001). The largest risk reductions were observed for 4 cups/day for all-cause mortality (16%, 95% confidence interval: 13, 18) and 3 cups/day for CVD mortality (21%, 95% confidence interval: 16, 26). Coffee consumption was not associated with cancer mortality. Findings from this meta-analysis indicate that coffee consumption is inversely associated with all-cause and CVD mortality. © The Author 2014. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

A role for very low-dose recombinant activated factor VII in refractory bleeding after cardiac surgery: Lessons from an observational study.

PubMed

Hoffmann, Till; Assmann, Alexander; Dierksen, Angelika; Roussel, Elisabeth; Ullrich, Sebastian; Lichtenberg, Artur; Albert, Alexander; Sixt, Stephan

2018-04-18

Although off-label use of recombinant activated factor VII against refractory bleeding is incorporated in current guideline recommendations, safety concerns persist predominantly with respect to thromboembolic complications. We analyzed the safety and efficacy of recombinant activated factor VII at a very low dose in cardiosurgical patients with refractory bleeding. This prospective study includes 1180 cardiosurgical patients at risk of bleeding. Goal-directed substitution was based on real-time laboratory testing and clinical scoring of the bleeding intensity. All patients who fulfilled the criteria for enhanced risk of bleeding (n = 281) were consequently included in the present analysis. Patients in whom refractory bleeding developed despite substitution with specific hemostatic compounds (n = 167) received a single shot of very low-dose recombinant activated factor VII (≤20 μg/kg). Mortality and risk of thromboembolic complications, and freedom from stroke and acute myocardial infarction in particular, were analyzed (vs patients without recombinant activated factor VII) by multivariable logistic and Cox regression analyses, as well as Kaplan-Meier estimates. There was no increase in rates of mortality (30-day mortality 4.2% vs 7.0% with P = .418; follow-up survival 85.6% at 13.0 [interquartile range, 8.4-15.7] months vs 80.7% at 10.2 [interquartile range, 7.2-16.1] months with P = .151), thromboembolic complications (6.6% vs 9.6% with P = .637), renal insufficiency, need for percutaneous coronary intervention, duration of ventilation, duration of hospital stay, or rehospitalization in patients receiving very low-dose recombinant activated factor VII compared with patients not receiving recombinant activated factor VII. Complete hemostasis without any need for further hemostatic treatment was achieved after very low-dose recombinant activated factor VII administration in the majority of patients (up to 88.6% vs 0% with P < .001). The key results were confirmed after adjustment by propensity score-based analyses. When combined with early and specific restoration of hemostatic reserves after cardiac surgery, very low-dose recombinant activated factor VII treatment of refractory bleeding is effective and not associated with any apparent increase in adverse events. Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Honey bee (Apis mellifera) drones survive oxidative stress due to increased tolerance instead of avoidance or repair of oxidative damage

USDA-ARS?s Scientific Manuscript database

Oxidative stress can lead to premature aging symptoms and cause acute mortality at higher doses in a range of organisms. Oxidative stress resistance and longevity are mechanistically and phenotypically linked: considerable variation in oxidative stress resistance exists among and within species and ...

Sunlight Has Cardiovascular Benefits Independently of Vitamin D.

PubMed

Weller, Richard B

2016-01-01

High blood pressure (BP) is the leading risk factor for disability adjusted life years lost globally. Epidemiological data show a correlation between increased sun exposure and reduced population BP and cardiovascular mortality. Individuals with high serum vitamin D levels are at reduced risk of hypertension, cardiovascular disease and metabolic syndrome, yet multiple trial data show that oral vitamin D supplementation has no effect on these endpoints. Sunlight is a risk factor for skin cancers, but no link has been shown with increased all-cause mortality. Cohort studies from Scandinavia show a dose-dependent fall in mortality with increased sun-seeking behaviour. Skin contains significant stores of nitrogen oxides, which can be converted to NO by UV radiation and exported to the systemic circulation. Human studies show that this pathway can cause arterial vasodilatation and reduced BP. Murine studies suggest the same mechanism may reduce metabolic syndrome. Sunlight has beneficial effects on cardiovascular risk factors independently of vitamin D. All-cause mortality should be the primary determinant of public health messages. Sunlight is a risk factor for skin cancer, but sun avoidance may carry more of a cost than benefit for overall good health. © 2016 S. Karger AG, Basel.

Estimates of benefits and harms of prophylactic use of aspirin in the general population

PubMed Central

Cuzick, J.; Thorat, M. A.; Bosetti, C.; Brown, P. H.; Burn, J.; Cook, N. R.; Ford, L. G.; Jacobs, E. J.; Jankowski, J. A.; La Vecchia, C.; Law, M.; Meyskens, F.; Rothwell, P. M.; Senn, H. J.; Umar, A.

2015-01-01

Background Accumulating evidence supports an effect of aspirin in reducing overall cancer incidence and mortality in the general population. We reviewed current data and assessed the benefits and harms of prophylactic use of aspirin in the general population. Methods The effect of aspirin for site-specific cancer incidence and mortality, cardiovascular events was collated from the most recent systematic reviews. Studies identified through systematic Medline search provided data regarding harmful effects of aspirin and baseline rates of harms like gastrointestinal bleeding and peptic ulcer. Results The effects of aspirin on cancer are not apparent until at least 3 years after the start of use, and some benefits are sustained for several years after cessation in long-term users. No differences between low and standard doses of aspirin are observed, but there were no direct comparisons. Higher doses do not appear to confer additional benefit but increase toxicities. Excess bleeding is the most important harm associated with aspirin use, and its risk and fatality rate increases with age. For average-risk individuals aged 50–65 years taking aspirin for 10 years, there would be a relative reduction of between 7% (women) and 9% (men) in the number of cancer, myocardial infarction or stroke events over a 15-year period and an overall 4% relative reduction in all deaths over a 20-year period. Conclusions Prophylactic aspirin use for a minimum of 5 years at doses between 75 and 325 mg/day appears to have favourable benefit–harm profile; longer use is likely to have greater benefits. Further research is needed to determine the optimum dose and duration of use, to identify individuals at increased risk of bleeding, and to test effectiveness of Helicobacter pylori screening–eradication before starting aspirin prophylaxis. PMID:25096604

Low-dose hydrocortisone therapy attenuates septic shock in adult patients but does not reduce 28-day mortality: a meta-analysis of randomized controlled trials.

PubMed

Wang, Changsong; Sun, Jiaxiao; Zheng, Juanjuan; Guo, Lei; Ma, Hongyan; Zhang, Yang; Zhang, Fengmin; Li, Enyou

2014-02-01

The role of low-dose hydrocortisone in attenuating septic shock and reducing short-term mortality in adult patients with septic shock is unclear. We conducted a meta-analysis of previous studies to determine whether hydrocortisone could ameliorate the effects of septic shock at 7 and 28 days and reduce 28-day morality. Randomized controlled trials (RCTs) of corticosteroids versus placebo (or supportive treatment alone) were retrieved from electronic searches (Medline, Embase, and Cochrane Library databases; LILACS; and Web of Knowledge) and manual searches (up to May 2012). From a pool of 1949 potentially relevant articles, duplicate independent review identified 10 relevant, RCTs of low-dose hydrocortisone therapy in septic shock. Four pairs of reviewers agreed on the criteria for trial eligibility. One reviewer entered the data into the computer, and 3 reviewers checked the data. Missing data were obtained from the authors of the relevant trials. The primary outcome analyzed was an estimate of 28-day mortality. Eight publications were included in the meta-analysis. Low-dose hydrocortisone therapy did not reduce 28-day mortality (N = 1063; odds ratio (OR) = 0.891, 95% confidence interval (CI), 0.69-1.15). Low-dose hydrocortisone therapy ameliorated shock at 7 days (6 RCTs, N = 964, OR = 2.078, 95% CI, 1.58-2.73, P < 0.0001, and I = 26.9%) and 28 days (6 RCTs, N = 947, OR = 1.495, 95% CI, 1.12-1.99, P = 0.006, and I = 0.0%). Although low-dose hydrocortisone therapy ameliorates septic shock at 7 and 28 days, it does not reduce 28-day mortality.

Age at exposure to ionising radiation and cancer mortality among Hanford workers: follow up through 1994

PubMed Central

Wing, S; Richardson, D

2005-01-01

Background: Studies of workers at the plutonium production factory in Hanford, WA have led to conflicting conclusions about the role of age at exposure as a modifier of associations between ionising radiation and cancer. Aims: To evaluate the influence of age at exposure on radiation risk estimates in an updated follow up of Hanford workers. Methods: A cohort of 26 389 workers hired between 1944 and 1978 was followed through 1994 to ascertain vital status and causes of death. External radiation dose estimates were derived from personal dosimeters. Poisson regression was used to estimate associations between mortality and cumulative external radiation dose at all ages, and in specific age ranges. Results: A total of 8153 deaths were identified, 2265 of which included cancer as an underlying or contributory cause. Estimates of the excess relative risk per Sievert (ERR/Sv) for cumulative radiation doses at all ages combined were negative for all cause and leukaemia and positive for all cancer and lung cancer. Cumulative doses accrued at ages below 35, 35–44, and 45–54 showed little association with mortality. For cumulative dose accrued at ages 55 and above (10 year lag), the estimated ERR/Sv for all cancers was 3.24 (90% CI: 0.80 to 6.17), primarily due to an association with lung cancer (ERR/Sv: 9.05, 90% CI: 2.96 to 17.92). Conclusions: Associations between radiation and cancer mortality in this cohort are primarily a function of doses at older ages and deaths from lung cancer. The association of older age radiation exposures and cancer mortality is similar to observations from several other occupational studies. PMID:15961623

Vitamin A for the treatment of children with measles--a systematic review.

PubMed

D'Souza, Rennie M; D'Souza, Ron

2002-12-01

Vitamin A deficiency is a recognized risk factor for severe measles. WHO and UNICEF have recommended vitamin A for the treatment of measles but there are children still dying from measles. A systematic review, including the use of meta-analysis was done of randomized controlled trials comparing vitamin A with placebo obtained from a systematic search of the medical literature to determine whether vitamin A prevents mortality and pneumonia-specific mortality in children with measles. We identified five trials conducted in Africa, four in hospitals and one in a community that met the inclusion criteria. There were 445 children aged 6 months to 13 years supplemented with vitamin A and 478 with placebo. There was a 39 per cent reduction in overall mortality when vitamin A was used for the treatment of measles but this was not statistically significant (relative risk 0.61; 95 per cent confidence interval 0.32-1.12). When stratified by dose, 200 000 IU of vitamin A given for 2 days was associated with a reduction in overall mortality (0.36, 0.14-0.82) and pneumonia-specific mortality (0.33, 0.08-0.92) in hospitalized children in areas with high case fatality. Greater reduction in mortality was observed in children under the age of 2 years (0.17, 0.03-0.61). On the other hand, a single dose of 200 000 IU of vitamin A was not associated with reduced mortality (1.25, 0.48-3.1). There were no trials comparing a single dose with two doses of vitamin A. There were not enough studies to separate out the individual effects of age, dose, formulation, hospitalization and case fatality in the study area. We conclude that 200 000 IU of vitamin A repeated on 2 days should be used for the treatment of measles as recommended by WHO in children admitted to hospitals in areas where the case fatality is high.

Solid cancer mortality associated with chronic external radiation exposure at the French atomic energy commission and nuclear fuel company.

PubMed

Metz-Flamant, C; Samson, E; Caër-Lorho, S; Acker, A; Laurier, D

2011-07-01

Studies of nuclear workers make it possible to directly quantify the risks associated with ionizing radiation exposure at low doses and low dose rates. Studies of the CEA (Commissariat à l'Energie Atomique) and AREVA Nuclear Cycle (AREVA NC) cohort, currently the most informative such group in France, describe the long-term risk to nuclear workers associated with external exposure. Our aim is to assess the risk of mortality from solid cancers among CEA and AREVA NC nuclear workers and its association with external radiation exposure. Standardized mortality ratios (SMRs) were calculated and internal Poisson regressions were conducted, controlling for the main confounding factors [sex, attained age, calendar period, company and socioeconomic status (SES)]. During the period 1968-2004, there were 2,035 solid cancers among the 36,769 CEA-AREVA NC workers. Cumulative external radiation exposure was assessed for the period 1950-2004, and the mean cumulative dose was 12.1 mSv. Mortality rates for all causes and all solid cancers were both significantly lower in this cohort than in the general population. A significant excess of deaths from pleural cancer, not associated with cumulative external dose, was observed, probably due to past asbestos exposure. We observed a significant excess of melanoma, also unassociated with dose. Although cumulative external dose was not associated with mortality from all solid cancers, the central estimated excess relative risk (ERR) per Sv of 0.46 for solid cancer mortality was higher than the 0.26 calculated for male Hiroshima and Nagasaki A-bomb survivors 50 years or older and exposed at the age of 30 years or older. The modification of our results after stratification for SES demonstrates the importance of this characteristic in occupational studies, because it makes it possible to take class-based lifestyle differences into account, at least partly. These results show the great potential of a further joint international study of nuclear workers, which should improve knowledge about the risks associated with chronic low doses and provide useful risk estimates for radiation protection.

Outcomes in patients with chronic kidney disease not on dialysis receiving extended dosing regimens of darbepoetin alfa: long-term results of the EXTEND observational cohort study

PubMed Central

Galle, Jan-Christoph; Addison, Janet; Suranyi, Michael G.; Claes, Kathleen; Di Giulio, Salvatore; Guerin, Alain; Herlitz, Hans; Kiss, István; Farouk, Mourad; Manamley, Nick; Wirnsberger, Gerhard; Winearls, Christopher

2016-01-01

Background Extended dosing of the erythropoiesis-stimulating agent (ESA) darbepoetin alfa (DA) once biweekly or monthly reduces anaemia treatment burden. This observational study assessed outcomes and dosing patterns in patients with chronic kidney disease not on dialysis (CKD-NoD) commencing extended dosing of DA. Methods Adult CKD-NoD patients starting extended dosing of DA in Europe or Australia in June 2006 or later were followed up until December 2012. Outcomes included haemoglobin (Hb) concentration, ESA dosing, mortality rates and receipt of dialysis and renal transplantation. Subgroup analyses were conducted for selected outcomes. Results Of 6035 enrolled subjects, 5723 (94.8%) met analysis criteria; 1795 (29.7%) received dialysis and 238 (3.9%) underwent renal transplantation. Mean (standard deviation) Hb concentration at commencement of extended dosing was 11.0 (1.5) g/dL. Mean [95% confidence interval (CI)] Hb 12 months after commencement of extended dosing (primary outcome) was 11.6 g/dL (11.5, 11.6) overall and was similar across countries, with no differences between subjects previously treated with an ESA versus ESA-naïve subjects, subjects with versus without prior renal transplant or diabetics versus non-diabetics. Weekly ESA dose gradually decreased following commencement of extended DA dosing and was similar across subgroups. The decrease in weekly DA dose was accompanied by an increase in the proportion of patients receiving iron therapy. Hb concentrations declined following changes in ESA labels and treatment guidelines. The mortality rate (95% CI) was 7.06 (6.68, 7.46) deaths per 100 years of follow-up. Subjects alive at study end had stable Hb concentrations in the preceding year, while those who died had lower and declining Hb concentrations in their last year. Conclusions Long-term, extended dosing of DA maintained Hb concentrations in patients already treated with an ESA and corrected and maintained Hb in ESA-naïve patients. PMID:27190334

Impact of BMI on clinical outcomes of NOAC therapy in daily care - Results of the prospective Dresden NOAC Registry (NCT01588119).

PubMed

Tittl, L; Endig, S; Marten, S; Reitter, A; Beyer-Westendorf, I; Beyer-Westendorf, J

2018-07-01

Direct acting non-Vitamin K antagonist oral anticoagulants (NOAC) are characterized by a fixed dosing regimen. Despite the potential for relative underdosing due to large distribution volumes, dose adjustments for patients with high body mass index (BMI) are not recommended. Since efficacy and safety data in obese patients are scarce, we evaluated the impact of BMI on clinical outcomes in daily care patients treated with NOAC for stroke prevention in atrial fibrillation or venous thromboembolism. Using prospectively collected data from a non-interventional registry, cardiovascular (CV), major bleeding events (MB) and all-cause mortality were evaluated according to BMI classes. All outcome events were centrally adjudicated using standard scientific definitions. Between November 1st 2011 and December 31st 2016, 3432 patients were enrolled into the registry (61.3% rivaroxaban; 20% apixaban; 10.1% dabigatran, 8.6% edoxaban; mean follow-up 998.1 ± 542.9 days; median 1004 days). With increasing BMI (range 13.7-57.2 kg/m 2 ), the proportion of patients receiving standard (vs. reduced) NOAC dose increased from 64.7% (underweight) to 78.9% (obesity). Although obese patients had more cardiovascular risk factors compared to normal weight patients, on-treatment rates of clinical outcomes (CV, MB, all-cause-mortality) were lowest in overweight and obese patients. In a large set of real-life NOAC recipients we found no indication that high BMI is associated with inferior NOAC effectiveness or safety, which is in line with recent epidemiological data of a "BMI paradox" that indicates a somewhat protective effect of higher BMI regarding unfavourable outcomes also in patients receiving fixed dose NOAC anticoagulation without dose adjustment for higher BMI. Copyright © 2018 Elsevier B.V. All rights reserved.

Rifaximin diminishes neutropenia following potentially lethal whole-body radiation.

PubMed

Jahraus, Christopher D; Schemera, Bettina; Rynders, Patricia; Ramos, Melissa; Powell, Charles; Faircloth, John; Brawner, William R

2010-07-01

Terrorist attacks involving radiological or nuclear weapons are a substantial geopolitical concern, given that large populations could be exposed to potentially lethal doses of radiation. Because of this, evaluating potential countermeasures against radiation-induced mortality is critical. Gut microflora are the most common source of systemic infection following exposure to lethal doses of whole-body radiation, suggesting that prophylactic antibiotic therapy may reduce mortality after radiation exposure. The chemical stability, easy administration and favorable tolerability profile of the non-systemic antibiotic, rifaximin, make it an ideal potential candidate for use as a countermeasure. This study evaluated the use of rifaximin as a countermeasure against low-to-intermediate-dose whole-body radiation in rodents. Female Wistar rats (8 weeks old) were irradiated with 550 cGy to the whole body and were evaluated for 30 d. Animals received methylcellulose, neomycin (179 mg/kg/d) or variably dosed rifaximin (150-2000 mg/kg/d) one hour after irradiation and daily throughout the study period. Clinical assessments (e.g. body weight) were made daily. On postirradiation day 30, blood samples were collected and a complete blood cell count was performed. Animals receiving high doses of rifaximin (i.e. 1000 or 2000 mg/kg/d) had a greater increase in weight from the day of irradiation to postirradiation day 30 compared with animals that received placebo or neomycin. For animals with an increase in average body weight from irradiation day within 80-110% of the group average, methylcellulose rendered an absolute neutrophil count (ANC) of 211, neomycin rendered an ANC of 334, rifaximin 300 mg/kg/d rendered an ANC of 582 and rifaximin 1000 mg/kg/d rendered an ANC of 854 (P = 0.05 for group comparison). Exposure to rifaximin after near-lethal whole-body radiation resulted in diminished levels of neutropenia.

Determination of florfenicol dose rate in feed for control of mortality in nile tilapia Oreochromis nilotica infected with streptococcus iniae

USDA-ARS?s Scientific Manuscript database

A dose titration study was conducted to determine the dosage of florfenicol (FFC) in feed to control Streptococcus iniae-associated mortality in Nile tilapia Oreochromis niloticus. Six tanks were assigned to each of five treatments: (1) not challenged with S. iniae and fed unmedicated feed; (2) chal...

Reduced mortality after severe head injury will increase the demands for rehabilitation services.

PubMed

Eker, C; Schalén, W; Asgeirsson, B; Grände, P O; Ranstam, J; Nordström, C H

2000-07-01

In 1989, a new therapy to reduce intracranial pressure in severely head-injured patients was introduced in Lund. The new treatment reduced mortality significantly. The present study describes the quality of life for the survivors. The study includes 53 patients treated during 1989-1994, according to a new treatment protocol for increased intracranial pressure ('Lund concept' group). During 1982-1986, 38 patients were managed according to a protocol including high dose thiopentone ('Thiopentone' group). The two groups are compared regarding neurophysical and psychiatric symptoms as well as aspects regarding the patient's role, performance, interpersonal relationship, frictions, feelings and satisfaction in work, areas of social and leisure activities, and extended family. Mortality was reduced from 47% to 8%, but the number of patients with a persistent vegetative state and/or remaining severe disability did not increase. However, the number of patients with persisting emotional and intellectual deficits increased significantly. The new treatment regime has dramatically increased the number of survivors after severe head trauma. Although most patients have a favourable outcome, there are more patients with remaining sequelae and disabilities, and the demand for qualified rehabilitation has increased.

Health Impacts from Acute Radiation Exposure

DOE Office of Scientific and Technical Information (OSTI.GOV)

Strom, Daniel J.

2003-09-30

Absorbed doses above1-2 Gy (100-200 rads) received over a period of a day or less lead to one or another of the acute radiation syndromes. These are the hematopoietic syndrome, the gastrointestinal (GI) syndrome, the cerebrovascular (CV) syndrome, the pulmonary syndrome, or the cutaneous syndrome. The dose that will kill about 50% of the exposed people within 60 days with minimal medical care, LD50-60, is around 4.5 Gy (450 rads) of low-LET radiation measured free in air. The GI syndrome may not be fatal with supportive medical care and growth factors below about 10 Gy (1000 rads), but above thismore » is likely to be fatal. Pulmonary and cutaneous syndromes may or may not be fatal, depending on many factors. The CV syndrome is invariably fatal. Lower acute doses, or protracted doses delivered over days or weeks, may lead to many other health outcomes than death. These include loss of pregnancy, cataract, impaired fertility or temporary or permanent sterility, hair loss, skin ulceration, local tissue necrosis, developmental abnormalities including mental and growth retardation in persons irradiated as children or fetuses, radiation dermatitis, and other symptoms listed in Table 2 on page 12. Children of parents irradiated prior to conception may experience heritable ill-health, that is, genetic changes from their parents. These effects are less strongly expressed than previously thought. Populations irradiated to high doses at high dose rates have increased risk of cancer incidence and mortality, taken as about 10-20% incidence and perhaps 5-10% mortality per sievert of effective dose of any radiation or per gray of whole-body absorbed dose low-LET radiation. Cancer risks for non-uniform irradiation will be less.« less

Cancer mortality and morbidity among plutonium workers at the Sellafield plant of British Nuclear Fuels

PubMed Central

Omar, R Z; Barber, J A; Smith, P G

1999-01-01

The mortality of all 14 319 workers employed at the Sellafield plant of British Nuclear Fuels between 1947 and 1975 was studied up to the end of 1992, and cancer incidence was examined from 1971 to 1986, in relation to their exposures to plutonium and to external radiation. The cancer mortality rate was 5% lower than that of England and Wales and 3% less than that of Cumbria. The significant excesses of deaths from cancer of the pleura and thyroid found in an earlier study persist with further follow-up (14 observed, 4.0 expected for pleura; 6 observed, 2.2 expected for thyroid). All of the deaths from pleural cancer were among radiation workers. For neither site was there a significant association between the risk of the cancer and accumulated radiation dose. There were significant deficits of deaths from cancers of mouth and pharynx, liver and gall bladder, and larynx and leukaemia when compared with the national rates. Among all radiation workers, there was a significant positive association between accumulated external radiation dose and mortality from cancers of ill-defined and secondary sites (10-year lag, P = 0.04), leukaemia (no lag, P = 0.03; 2-year lag, P = 0.05), multiple myeloma (20-year lag, P = 0.02), all lymphatic and haematopoietic cancers (20-year lag, P = 0.03) and all causes of death combined (20-year lag, P = 0.008). Among plutonium workers, there were significant excesses of deaths from cancer of the breast (6 observed, 2.6 expected) and ill-defined and secondary cancers (29 observed, 20.1 expected). No significant positive trends were observed between the risk of deaths from cancers of any specific site, or all cancers combined, and cumulative plutonium and external radiation doses. For no cancer site was there a significant excess of cancer registrations compared with rates for England and Wales. Analysis of trends in cancer incidence showed significant increases in risk with cumulative plutonium plus external radiation doses for all lymphatic and haematopoietic neoplasms for 0-, 10- and 20-year lag periods. Taken as a whole, our findings do not suggest that workers at Sellafield who have been exposed to plutonium are at an overall significantly increased risk of cancer compared with other radiation workers. © 1999 Cancer Research Campaign PMID:10098774

Cancer mortality and morbidity among plutonium workers at the Sellafield plant of British Nuclear Fuels.

PubMed

Omar, R Z; Barber, J A; Smith, P G

1999-03-01

The mortality of all 14 319 workers employed at the Sellafield plant of British Nuclear Fuels between 1947 and 1975 was studied up to the end of 1992, and cancer incidence was examined from 1971 to 1986, in relation to their exposures to plutonium and to external radiation. The cancer mortality rate was 5% lower than that of England and Wales and 3% less than that of Cumbria. The significant excesses of deaths from cancer of the pleura and thyroid found in an earlier study persist with further follow-up (14 observed, 4.0 expected for pleura; 6 observed, 2.2 expected for thyroid). All of the deaths from pleural cancer were among radiation workers. For neither site was there a significant association between the risk of the cancer and accumulated radiation dose. There were significant deficits of deaths from cancers of mouth and pharynx, liver and gall bladder, and larynx and leukaemia when compared with the national rates. Among all radiation workers, there was a significant positive association between accumulated external radiation dose and mortality from cancers of ill-defined and secondary sites (10-year lag, P = 0.04), leukaemia (no lag, P = 0.03; 2-year lag, P = 0.05), multiple myeloma (20-year lag, P = 0.02), all lymphatic and haematopoietic cancers (20-year lag, P= 0.03) and all causes of death combined (20-year lag, P= 0.008). Among plutonium workers, there were significant excesses of deaths from cancer of the breast (6 observed, 2.6 expected) and ill-defined and secondary cancers (29 observed, 20.1 expected). No significant positive trends were observed between the risk of deaths from cancers of any specific site, or all cancers combined, and cumulative plutonium and external radiation doses. For no cancer site was there a significant excess of cancer registrations compared with rates for England and Wales. Analysis of trends in cancer incidence showed significant increases in risk with cumulative plutonium plus external radiation doses for all lymphatic and haematopoietic neoplasms for 0-, 10- and 20-year lag periods. Taken as a whole, our findings do not suggest that workers at Sellafield who have been exposed to plutonium are at an overall significantly increased risk of cancer compared with other radiation workers.

Interactions between Entomopathogenic Fungus, Metarhizium anisopliae and Sublethal Doses of Spinosad for Control of House Fly, Musca domestica

PubMed Central

Sharififard, M; Mossadegh, MS; Vazirianzadeh, B; Zarei-Mahmoudabadi, A

2011-01-01

Background: Metarhizium anisopliae strain IRAN 437C is one of the most virulent fungal isolates against house fly, Musca domestica. The objective of this study was to determine the interaction of this isolate with sublethal doses of spinosad against housefly. Methods: In adult bioassay, conidia of entomopathogenic fungus were applied as inoculated bait at 105 and 107 spore per gram and spinosad at 0.5, 1 and 1.5 μg (A.I.) per gram bait. In larval bioassay, conidia were applied as combination of spore with larval bedding at 106 and 108 spore per gram and spinosad at sublethals of 0.002, 0.004 and 0.006 μg (AI) per gram medium. Results: Adult mortality was 48% and 72% for fungus alone but ranged from 66–87% and 89–95% in combination treatments of 105 and 107 spore/g with sublethal doses of spinosad respectively. The interaction between 105 spore/g with sublethals exhibited synergistic effect, but in combination of 107 spore in spite of higher mortality, the interaction was additive. There was significant difference in LT50 among various treatments. LT50 values in all combination treatments were smaller than LT50 values in alone ones. Larval mortality was 36% and 69% for fungus alone but ranged from 58%–78% and 81%–100% in combination treatments of 106 and 108 spore/g medium with sublethals of spinosad respectively. The interaction was synergistic in all combination treatments of larvae. Conclusion: The interaction between M. anispliae and spinosad indicated a synergetic effect that increased the house fly mortality as well as reduced the lethal time. PMID:22808408

Seventeen-year mortality experience of proton radiation in Macaca mulatta

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yochmowitz, M.G.; Wood, D.H.; Salmon, Y.L.

1985-04-01

This is an interim report on the lifetime study of chronic mortality and its causes under investigation in 31 control (20 males, 11 females) and 217 survivors (124 males, 93 females) of an acute 90-day experiment in rhesus monkeys. Single acute whole-body exposures were made using 32-, 55-, 138-, 400-, and 2300-MeV protons in 1964-1965. Doses ranged from 25 to 800 rad and dose rates from 12.5 and 100 rad per minute. For pooled data: (1) mortality was signigicantly higher in irradiated animals (48%) than in controls (19%); (2) mortality in animals exposed to partially penetrating 55-MeV protons was essentiallymore » similar to those given totally penetrating 138-, 400-, and 2300-MeV exposures; (3) proton energies and doses that were effective in producing life shortening were greater than or equal to 55 MeV and greater than or equal to 360-400 rad, respectively; (4) death rates for irradiated animals compared to controls began to increase after approx.8 years, approx.2 years, and approx.1 year for those exposed to 360-400, 500-650, and 800 rad, respectively; (5) of the nine probable causes of death reported, the leading causes were primary infections in both irradiated and control animals, endometriosis, neoplasms, and organ degeneration; and (6) if endometriosis is included with the neoplastic group, deaths from all forms of neoplasms would be 42% in irradiated animals. From the results of this study, it is reasonable to conclude that development of endometriosis in females and neoplasms in males is enhanced significantly by proton irradiation over that of respective controls.« less

TOLERANCE OF IRRADIATED FATS (in German)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lang, K.

1962-05-01

As is known, irradiation of polyene acids causes them to undergo similar changes as occur in auto-oxidation, and auto-oxidized fat can become toxic under certain conditions. Thus experiments were devised to study the effects of feeding fats irradiated by a substantially higher dose than is necessary for the sterilization or pasteurization of foodstuifs; to determine the radiation dose causing symptoms from irradiated fat; and the mechanism of the toxic effect. Sprague-Dawley rats were given soya oil, irradiated with 1-Mev electrons at 0, 2.5, 10, 50, and 100 Mrep doses. The fat made up 20% of the diet, which was supplementedmore » with vitamins. With the 100-Mrep dose, after four weeks a depression in wt gain was observed which was connected with a significant loss in the nutritional efficiency of protein. After 3-month feeding, lethal toxicity was noted and after 6 months 18% of the animals died. Only 88% of the 100Mrep iriadiated oil was absorbed. At the 50-Mrep dose a significant disturbance in the liver function and decrease of plasma proteins were observed. From the 24th week on there was in increasing wt loss and mortality rate; after 32 weeks, 12 male rits out of 40 had died. Animals fed on 10-Mrep irradiated oil also showed a high mortality after 40 weeks. Other symptoms observed were: histologically detectible hypofunction of the thyroid gland, decreased body temperature, decreased oxygen consumption, and bradycardia. Other experiments with 100-Mrep irradiated fish oil showed similar results in 10 weeks. The cause of death could not be determined. Notable was the increased wt of liver, deposits of brown pigment in liver and spleen, which upon treatment with NaOH reacted for iron. Water consumption of rats did not change. Also noted was a marked hypoproteinemia accompanied by a characteristic change of the electrophoretic patterns of serum proteins; gamma globulins increased to 25.9%, as compared with 17.2% in the control group. (BBB)« less

High red meat intake and all-cause cardiovascular and cancer mortality: is the risk modified by fruit and vegetable intake?

PubMed

Bellavia, Andrea; Stilling, Frej; Wolk, Alicja

2016-10-01

High red meat consumption is associated with a shorter survival and higher risk of cardiovascular disease (CVD), cancer, and all-cause mortality. Fruit and vegetable (FV) consumption is associated with a longer survival and lower mortality risk. Whether high FV consumption can counterbalance the negative impact of high red meat consumption is unknown. We evaluated 2 large prospective cohorts of Swedish men and women (the Swedish Mammography Cohort and the Cohort of Swedish Men) to determine whether the association between red meat consumption and the risk of all-cause, CVD, and cancer-specific mortality differs across amounts of FV intake. The study population included 74,645 Swedish men and women. Red meat and FV consumption were assessed through a self-administered questionnaire. We estimated HRs of all-cause, CVD, and cancer mortality according to quintiles of total red meat consumption. We next investigated possible interactions between red meat and FV consumption and evaluated the dose-response associations at low, medium, and high FV intake. Compared with participants in the lowest quintile of total red meat consumption, those in the highest quintile had a 21% increased risk of all-cause mortality (HR: 1.21; 95% CI: 1.13, 1.29), a 29% increased risk of CVD mortality (HR: 1.29; 95% CI: 1.14, 1.46), and no increase in the risk of cancer mortality (HR: 1.00; 95% CI: 0.88, 1.43). Results were remarkably similar across amounts of FV consumption, and no interaction between red meat and FV consumption was detected. High intakes of red meat were associated with a higher risk of all-cause and CVD mortality. The increased risks were consistently observed in participants with low, medium, and high FV consumption. The Swedish Mammography Cohort and the Cohort of Swedish Men were registered at clinicaltrials.gov as NCT01127698 and NCT01127711, respectively. © 2016 American Society for Nutrition.

Exercise Dose in Clinical Practice

PubMed Central

Wasfy, Meagan; Baggish, Aaron L.

2016-01-01

There is wide variability in the physical activity patterns of the patients in contemporary clinical cardiovascular practice. This review is designed to address the impact of exercise dose on key cardiovascular risk factors and on mortality. We begin by examining the body of literature that supports a dose-response relationship between exercise and cardiovascular disease risk factors including plasma lipids, hypertension, diabetes mellitus, and obesity. We next explore the relationship between exercise dose and mortality by reviewing the relevant epidemiological literature underlying current physical activity guideline recommendations. We then expand this discussion to critically examine recent data pertaining to the impact of exercise dose at the lowest and highest ends of the spectrum. Finally, we provide a framework for how the key concepts of exercise dose can be integrated into clinical practice. PMID:27267537

Exercise Dose in Clinical Practice.

PubMed

Wasfy, Meagan M; Baggish, Aaron L

2016-06-07

There is wide variability in the physical activity patterns of the patients in contemporary clinical cardiovascular practice. This review is designed to address the impact of exercise dose on key cardiovascular risk factors and on mortality. We begin by examining the body of literature that supports a dose-response relationship between exercise and cardiovascular disease risk factors, including plasma lipids, hypertension, diabetes mellitus, and obesity. We next explore the relationship between exercise dose and mortality by reviewing the relevant epidemiological literature underlying current physical activity guideline recommendations. We then expand this discussion to critically examine recent data pertaining to the impact of exercise dose at the lowest and highest ends of the spectrum. Finally, we provide a framework for how the key concepts of exercise dose can be integrated into clinical practice. © 2016 American Heart Association, Inc.

Burden of mortality and years of life lost due to ambient PM10 pollution in Wuhan, China.

PubMed

Zhang, Yunquan; Peng, Minjin; Yu, Chuanhua; Zhang, Lan

2017-11-01

Ambient particulate matter (PM) has been mainly linked with mortality and morbidity when assessing PM-associated health effects. Up-to-date epidemiologic evidence is very sparse regarding the relation between PM and years of life lost (YLL). The present study aimed to estimate the burden of YLL and mortality due to ambient PM pollution. Individual records of all registered deaths and daily data on PM 10 and meteorology during 2009-2012 were obtained in Wuhan, central China. Using a time-series study design, we applied generalized additive model to assess the short-term association of 10-μg/m 3 increase in PM 10 with daily YLL and mortality, adjusting for long-term trend and seasonality, mean temperature, relative humidity, public holiday, and day of the week. A linear-no-threshold dose-response association was observed between daily ambient PM 10 and mortality outcomes. PM 10 pollution along lag 0-1 days was found to be mostly strongly associated with mortality and YLL. The effects of PM 10 on cause-specific mortality and YLL showed generally similar seasonal patterns, with stronger associations consistently occurring in winter and/or autumn. Compared with males and younger persons, females and the elderly suffered more significantly from both increased YLL and mortality due to ambient PM 10 pollution. Stratified analyses by education level (0-6 and 7 + years) demonstrated great mortality impact on both subgroups, whereas only low-educated persons were strongly affected by PM 10 -associated burden of YLL. Our study confirmed that short-term PM 10 exposure was linearly associated with significant increases in both mortality incidence and years of life lost. Given the non-threshold adverse effects on mortality burden, the on-going efforts to reduce particulate air pollution would substantially benefit public health in China. Copyright © 2017 Elsevier Ltd. All rights reserved.

Missing doses in the life span study of Japanese atomic bomb survivors.

PubMed

Richardson, David B; Wing, Steve; Cole, Stephen R

2013-03-15

The Life Span Study of atomic bomb survivors is an important source of risk estimates used to inform radiation protection and compensation. Interviews with survivors in the 1950s and 1960s provided information needed to estimate radiation doses for survivors proximal to ground zero. Because of a lack of interview or the complexity of shielding, doses are missing for 7,058 of the 68,119 proximal survivors. Recent analyses excluded people with missing doses, and despite the protracted collection of interview information necessary to estimate some survivors' doses, defined start of follow-up as October 1, 1950, for everyone. We describe the prevalence of missing doses and its association with mortality, distance from hypocenter, city, age, and sex. Missing doses were more common among Nagasaki residents than among Hiroshima residents (prevalence ratio = 2.05; 95% confidence interval: 1.96, 2.14), among people who were closer to ground zero than among those who were far from it, among people who were younger at enrollment than among those who were older, and among males than among females (prevalence ratio = 1.22; 95% confidence interval: 1.17, 1.28). Missing dose was associated with all-cancer and leukemia mortality, particularly during the first years of follow-up (all-cancer rate ratio = 2.16, 95% confidence interval: 1.51, 3.08; and leukemia rate ratio = 4.28, 95% confidence interval: 1.72, 10.67). Accounting for missing dose and late entry should reduce bias in estimated dose-mortality associations.

Missing Doses in the Life Span Study of Japanese Atomic Bomb Survivors

PubMed Central

Richardson, David B.; Wing, Steve; Cole, Stephen R.

2013-01-01

The Life Span Study of atomic bomb survivors is an important source of risk estimates used to inform radiation protection and compensation. Interviews with survivors in the 1950s and 1960s provided information needed to estimate radiation doses for survivors proximal to ground zero. Because of a lack of interview or the complexity of shielding, doses are missing for 7,058 of the 68,119 proximal survivors. Recent analyses excluded people with missing doses, and despite the protracted collection of interview information necessary to estimate some survivors' doses, defined start of follow-up as October 1, 1950, for everyone. We describe the prevalence of missing doses and its association with mortality, distance from hypocenter, city, age, and sex. Missing doses were more common among Nagasaki residents than among Hiroshima residents (prevalence ratio = 2.05; 95% confidence interval: 1.96, 2.14), among people who were closer to ground zero than among those who were far from it, among people who were younger at enrollment than among those who were older, and among males than among females (prevalence ratio = 1.22; 95% confidence interval: 1.17, 1.28). Missing dose was associated with all-cancer and leukemia mortality, particularly during the first years of follow-up (all-cancer rate ratio = 2.16, 95% confidence interval: 1.51, 3.08; and leukemia rate ratio = 4.28, 95% confidence interval: 1.72, 10.67). Accounting for missing dose and late entry should reduce bias in estimated dose-mortality associations. PMID:23429722

[Beta lactam antibiotics and the question of dose regimen for severe infection. Prolonged infusion theoretically appealing--yet no evidence of clinical benefit].

PubMed

Leander, Gunilla; Eliasson, Erik; Hanberger, Håkan; Giske, Christian

2015-03-24

Patients with severe sepsis/septic shock have a high mortality. Beta-lactam antibiotics are normally first line treatment. This antimicrobial class has been associated with time-dependent efficacy. It is therefore plausible that administration as prolonged infusion will increase the therapeutic effect, as compared to short term bolus injections, which is the most common practice today. We have reviewed 14 randomized controlled studies to investigate whether prolonged infusion provides lower mortality and/or increased clinical cure. In summary, convincing advantages with prolonged infusion could not be found, however randomized studies are heterogeneous, and it cannot be excluded that some subgroups of critically ill patients could benefit from such treatment.

Mortality in bullous pemphigoid and prognostic factors in 1st and 3rd year of follow-up in specialized centre in Poland.

PubMed

Kalinska-Bienias, Agnieszka; Lukowska-Smorawska, Katarzyna; Jagielski, Pawel; Kowalewski, Cezary; Wozniak, Katarzyna

2017-11-01

Bullous pemphigoid (BP) is associated with higher mortality and coexisting comorbidities, some of them affecting poor prognosis. The aim of the study was to identify prognostic factors causing greater mortality both in the 1st and 3rd year of follow-up and to determine the 1-, 2-, 3-year mortality rates, standardized mortality ratio (SMR) in Polish BP patients. All patients with BP (a cohort of 205 patients, mean age 76.2 years) diagnosed between 5 January 2000 and 10 December 2013 in a referral unit for autoimmune bullous diseases at the university hospital in Poland were included retrospectively. Mortality data were obtained from the Centre for Document Personalization at the Minister of Interior and Administration. Our original observation was that prednisone in moderate dose (0.5 mg kg -1 ) in monotherapy was an independent risk factor of fatal prognosis in the 1st year of follow-up, assessed using multivariate analysis. We confirmed the strong correlation between neurological diseases and greater mortality. Both in the 1st and 3rd year of follow-up, dementia and Parkinson disease resulted in increased mortality. We also found that arrhythmias significantly increased mortality in the 1st and 3rd year of follow-up. The prognostic factors in BP changed over time of follow-up. In the 3rd year of observation, the age above 77, longer hospitalization and BP severity were associated with greater mortality. We observed poorer prognosis in BP patients than age-matched general Polish population. The 1-, 2-, 3-year mortality rates were 22.4, 31.2, 39.5% and SMR was 3.8 (95% CI 3.4-3.7).

Cancer mortality among atomic bomb survivors exposed as children.

PubMed

Goto, Hitomi; Watanabe, Tomoyuki; Miyao, Masaru; Fukuda, Hiromi; Sato, Yuzo; Oshida, Yoshiharu

2012-05-01

To compare cancer mortality among A-bomb survivors exposed as children with cancer mortality among an unexposed control group (the entire population of Japan, JPCG). The subjects were the Hiroshima and Nagasaki A-bomb survivor groups (0-14 years of age in 1945) reported in life span study report 12 (follow-up years were from 1950 to 1990), and a control group consisting of the JPCG. We estimated the expected number of deaths due to all causes and cancers of various causes among the exposed survivors who died in the follow-up interval, if they had died with the same mortality as the JPCG (0-14 years of age in 1945). We calculated the standardized mortality ratio (SMR) of A-bomb survivors in comparison with the JPCG. SMRs were significantly higher in exposed boys overall for all deaths, all cancers, leukemia, and liver cancer, and for exposed girls overall for all cancers, solid cancers, liver cancer, and breast cancer. In boys, SMRs were significantly higher for all deaths and liver cancer even in those exposed to very low doses, and for all cancers, solid cancers, and liver cancer in those exposed to low doses. In girls, SMRs were significantly higher for liver cancer and uterine cancer in those exposed to low doses, and for leukemia, solid cancers, stomach cancer, and breast cancer in those exposed to high doses. We calculated the SMRs for the A-bomb survivors versus JPCG in childhood and compared them with a true non-exposed group. A notable result was that SMRs in boys exposed to low doses were significantly higher for solid cancer.

Detection and distribution of ostreid herpesvirus 1 in experimentally infected Pacific oyster spat.

PubMed

Segarra, Amélie; Baillon, Laury; Faury, Nicole; Tourbiez, Delphine; Renault, Tristan

2016-01-01

High mortality rates are reported in spat and larvae of Pacific oyster Crassostrea gigas and associated with ostreid herpesvirus 1 (OsHV-1) detection in France. Although the viral infection has been experimentally reproduced in oyster larvae and spat, little knowledge is currently available concerning the viral entry and its distribution in organs and tissues. This study compares OsHV-1 DNA and RNA detection and localization in experimentally infected oysters using two virus doses: a low dose that did not induce any mortality and a high dose inducing high mortality. Real time PCR demonstrated significant differences in terms of viral DNA amounts between the two virus doses. RNA transcripts were detected in oysters receiving the highest dose of viral suspension whereas no transcript was observed in oysters injected with the low dose. This study also allowed observing kinetics of viral DNA and RNA detection in different tissues of oyster spat. Finally, viral detection was significantly different in function of tissues (p<0.005), time (p<0.005) with an interaction between tissues and time (p<0.005) for each probe. Copyright © 2015 Elsevier Inc. All rights reserved.

The question of nonlinearity in the dose-response relation between particulate matter air pollution and mortality: can Akaike's Information Criterion be trusted to take the right turn?

PubMed

Roberts, Steven; Martin, Michael A

2006-12-15

The shape of the dose-response relation between particulate matter air pollution and mortality is crucial for public health assessment, and departures of this relation from linearity could have important regulatory consequences. A number of investigators have studied the shape of the particulate matter-mortality dose-response relation and concluded that the relation could be adequately described by a linear model. Some of these researchers examined the hypothesis of linearity by comparing Akaike's Information Criterion (AIC) values obtained under linear, piecewise linear, and spline alternative models. However, at the current time, the efficacy of the AIC in this context has not been assessed. The authors investigated AIC as a means of comparing competing dose-response models, using data from Cook County, Illinois, for the period 1987-2000. They found that if nonlinearities exist, the AIC is not always successful in detecting them. In a number of the scenarios considered, AIC was equivocal, picking the correct simulated dose-response model about half of the time. These findings suggest that further research into the shape of the dose-response relation using alternative model selection criteria may be warranted.

Effects of UVB radiation on grazing of two cladocerans from high-altitude Andean lakes

PubMed Central

Rejas, Danny

2017-01-01

Climate change and water extraction may result in increased exposition of the biota to ultraviolet-B radiation (UVB) in high-altitude Andean lakes. Although exposition to lethal doses in these lakes is unlikely, sub-lethal UVB doses may have strong impacts in key compartments such as zooplankton. Here, we aimed at determining the effect of sub-lethal UVB doses on filtration rates of two cladoceran species (Daphnia pulicaria and Ceriodaphnia dubia). We firstly estimated the Incipient Limiting Concentration (ILC) and the Gut Passage Time (GPT) for both species. Thereafter we exposed clones of each species to four increasing UVB doses (treatments): i) DUV-0 (Control), ii) DUV-1 (0.02 MJ m2), iii) DUV-2 (0.03 MJ m2) and iv) DUV-3 (0.15 MJ m2); and estimated their filtration rates using fluorescent micro-spheres. Our results suggest that increasing sub-lethal doses of UVB radiation may strongly disturb the structure and functioning of high-altitude Andean lakes. Filtration rates of D. pulicaria were not affected by the lowest dose applied (DUV-1), but decreased by 50% in treatments DUV-2 and DUV-3. Filtration rates for C. dubia were reduced by more than 80% in treatments DUV-1 and DUV-2 and 100% of mortality occurred at the highest UVB dose applied (DUV-3). PMID:28379975

Effect of oral infection with Kashmir bee virus and Israeli acute paralysis virus on bumblebee (Bombus terrestris) reproductive success.

PubMed

Meeus, Ivan; de Miranda, Joachim R; de Graaf, Dirk C; Wäckers, Felix; Smagghe, Guy

2014-09-01

Israeli acute paralysis virus (IAPV) together with Acute bee paralysis virus (ABPV) and Kashmir bee virus (KBV) constitute a complex of closely related dicistroviruses. They are infamous for their high mortality after injection in honeybees. These viruses have also been reported in non-Apis hymenopteran pollinators such as bumblebees, which got infected with IAPV when placed in the same greenhouse with IAPV infected honeybee hives. Here we orally infected Bombus terrestris workers with different doses of either IAPV or KBV viral particles. The success of the infection was established by analysis of the bumblebees after the impact studies: 50days after infection. Doses of 0.5×10(7) and 1×10(7) virus particles per bee were infectious over this period, for IAPV and KBV respectively, while a dose of 0.5×10(6) IAPV particles per bee was not infectious. The impact of virus infection was studied in micro-colonies consisting of 5 bumblebees, one of which becomes a pseudo-queen which proceeds to lay unfertilized (drone) eggs. The impact parameters studied were: the establishment of a laying pseudo-queen, the timing of egg-laying, the number of drones produced, the weight of these drones and worker mortality. In this setup KBV infection resulted in a significant slower colony startup and offspring production, while only the latter can be reported for IAPV. Neither virus increased worker mortality, at the oral doses used. We recommend further studies on how these viruses transmit between different pollinator species. It is also vital to understand how viral prevalence can affect wild bee populations because disturbance of the natural host-virus association may deteriorate the already critically endangered status of many bumblebee species. Copyright © 2014 Elsevier Inc. All rights reserved.

Body mass index and mortality in men with prostate cancer.

PubMed

Cantarutti, Anna; Bonn, Stephanie E; Adami, Hans-Olov; Grönberg, Henrik; Bellocco, Rino; Bälter, Katarina

2015-08-01

Body Mass index (BMI) has been shown to affect risk and mortality of several cancers. Prostate cancer and obesity are major public health concerns for middle-aged and older men. Previous studies of pre-diagnostic BMI have found an increased risk of prostate cancer mortality in obese patients. To study the associations between BMI at time of prostate cancer diagnosis and prostate cancer specific and overall mortality. BMI was analyzed both as a continuous variable and categorized into four groups based on the observed distribution in the cohort (BMI < 22.5, 22.5 < 25, 25 < 27.5 and ≥27.5 kg/m2). The association between BMI and mortality was assessed using stratified Cox proportional hazards models and by fitting regression splines for dose response analysis in 3,161 men diagnosed with prostate cancer. After 11 years of follow up via linkage to the population-based cause of death registry, we identified 1,161 (37%) deaths off which 690 (59%) were due to prostate cancer. High BMI (BMI ≥ 27.5 kg/m2) was associated with a statistically significant increased risk of prostate cancer specific mortality (HR:1.44, 95% CI: 1.09-1.90) and overall mortality (HR:1.33, 95% CI: 1.09-1.63) compared to the reference group (BMI 22.5 < 25 kg/m2). Additionally, men with a low BMI (<22.5 kg/m2 ), had a statistically significant increased risk of prostate cancer specific mortality (HR:1.33, 95% CI: 1.02-1.74) and overall mortality (HR:1.36, 95% CI: 1.11-1.67) compared to the reference. However, this effect disappeared when men who died within the first two years of follow-up were excluded from the analyses while the increased risk of prostate cancer specific mortality and overall mortality remained statistically significant for men with a BMI ≥ 27.5 kg/m2 (HR:1.44, 95% CI: 1.09-1.90 and HR: 1.33, 95% CI: 1.09-1.63, respectively). This study showed that a high BMI at time of prostate cancer diagnosis was associated with increased overall mortality. © 2015 Wiley Periodicals, Inc.

Phenotypic Dichotomy Following Developmental Exposure to Perfluorooctanic Acid (PFOA) Exposure in CD-1 Mice: Low Doses Induce Elevated Serum, Leptin, Insulin, and Overweight in Mid-Life.

EPA Science Inventory

The synthetic surfactant, perfluorooctanoic acid (PFOA) is a proven developmental toxicant in mice, causing prenatal pregnancy loss, increased neonatal mortality, delayed eye opening, and abnormal mammary gland growth in animals exposed during fetal life. PFOA is found in the ser...

The Association Between Perceived Stress and Mortality Among People With Multimorbidity: A Prospective Population-Based Cohort Study.

PubMed

Prior, Anders; Fenger-Grøn, Morten; Larsen, Karen Kjær; Larsen, Finn Breinholt; Robinson, Kirstine Magtengaard; Nielsen, Marie Germund; Christensen, Kaj Sparle; Mercer, Stewart W; Vestergaard, Mogens

2016-08-01

Multimorbidity is common and is associated with poor mental health and high mortality. Nevertheless, no studies have evaluated whether mental health may affect the survival of people with multimorbidity. We investigated the association between perceived stress and mortality in people with multimorbidity by following a population-based cohort of 118,410 participants from the Danish National Health Survey 2010 for up to 4 years. Information on perceived stress and lifestyle was obtained from the survey. We assessed multimorbidity using nationwide register data on 39 conditions and identified 4,229 deaths for the 453,648 person-years at risk. Mortality rates rose with increasing levels of stress in a dose-response relationship (P-trend < 0.0001), independently of multimorbidity status. Mortality hazard ratios (highest stress quintile vs. lowest) were 1.51 (95% confidence interval (CI): 1.25, 1.84) among persons without multimorbidity, 1.39 (95% CI: 1.18, 1.64) among those with 2 or 3 conditions, and 1.43 (95% CI: 1.18, 1.73) among those with 4 or more conditions, when adjusted for disease severities, lifestyle, and socioeconomic status. The numbers of excess deaths associated with high stress were 69 among persons without multimorbidity, 128 among those with 2 or 3 conditions, and 255 among those with 4 or more conditions. Our findings suggested that perceived stress contributes significantly to higher mortality rates in a dose-response pattern, and more stress-associated deaths occurred in people with multimorbidity. © The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

A highly infective plant-associated bacterium influences reproductive rates in pea aphids

PubMed Central

Hendry, Tory A.; Clark, Kelley J.; Baltrus, David A.

2016-01-01

Pea aphids, Acyrthosiphon pisum, have the potential to increase reproduction as a defence against pathogens, though how frequently this occurs or how infection with live pathogens influences this response is not well understood. Here we determine the minimum infective dose of an environmentally common bacterium and possible aphid pathogen, Pseudomonas syringae, to determine the likelihood of pathogenic effects to pea aphids. Additionally, we used P. syringae infection to investigate how live pathogens may alter reproductive rates. We found that oral bacterial exposure decreased subsequent survival of aphids in a dose-dependent manner and we estimate that ingestion of less than 10 bacterial cells is sufficient to increase aphid mortality. Pathogen dose was positively related to aphid reproduction. Aphids exposed to low bacterial doses showed decreased, although statistically indistinguishable, fecundity compared to controls. Aphids exposed to high doses reproduced significantly more than low dose treatments and also more, but not significantly so, than controls. These results are consistent with previous studies suggesting that pea aphids may use fecundity compensation as a response to pathogens. Consequently, even low levels of exposure to a common plant-associated bacterium may therefore have significant effects on pea aphid survival and reproduction. PMID:26998321

A highly infective plant-associated bacterium influences reproductive rates in pea aphids.

PubMed

Hendry, Tory A; Clark, Kelley J; Baltrus, David A

2016-02-01

Pea aphids, Acyrthosiphon pisum, have the potential to increase reproduction as a defence against pathogens, though how frequently this occurs or how infection with live pathogens influences this response is not well understood. Here we determine the minimum infective dose of an environmentally common bacterium and possible aphid pathogen, Pseudomonas syringae, to determine the likelihood of pathogenic effects to pea aphids. Additionally, we used P. syringae infection to investigate how live pathogens may alter reproductive rates. We found that oral bacterial exposure decreased subsequent survival of aphids in a dose-dependent manner and we estimate that ingestion of less than 10 bacterial cells is sufficient to increase aphid mortality. Pathogen dose was positively related to aphid reproduction. Aphids exposed to low bacterial doses showed decreased, although statistically indistinguishable, fecundity compared to controls. Aphids exposed to high doses reproduced significantly more than low dose treatments and also more, but not significantly so, than controls. These results are consistent with previous studies suggesting that pea aphids may use fecundity compensation as a response to pathogens. Consequently, even low levels of exposure to a common plant-associated bacterium may therefore have significant effects on pea aphid survival and reproduction.

Clinical course of sepsis in children with acute leukemia admitted to the pediatric intensive care unit.

PubMed

Singer, Kanakadurga; Subbaiah, Perla; Hutchinson, Raymond; Odetola, Folafoluwa; Shanley, Thomas P

2011-11-01

To describe the clinical course, resource use, and mortality of patients with leukemia admitted to the pediatric intensive care unit with sepsis and nonsepsis diagnoses over a 10-yr period. Retrospective analysis. Tertiary medical-surgical pediatric intensive care unit at C.S. Mott Children's Hospital, University of Michigan. All patients with leukemia admitted to the pediatric intensive care unit from January 1, 1998, to December 31, 2008. None; chart review. Clinical course was characterized by demographics, leukemia diagnosis, phase of therapy, leukocyte count on admission, presence of sepsis, steroid administration, intensity of care, and Pediatric Risk of Mortality score on admission to the pediatric intensive care unit. The primary outcome was survival to pediatric intensive care unit discharge. Among 68 single admissions to the pediatric intensive care unit with leukemia during the study period, 33 (48.5%) were admitted with sepsis. Admission to the pediatric intensive care unit for sepsis was associated with greater compromise of hemodynamic and renal function and use of stress dose steroids (p = .016), inotropic and/or vasopressor drugs (p = .01), and renal replacement therapy (p = .028) than nonsepsis admission. There was higher mortality among children with sepsis than other diagnoses (52% vs. 17%, p = .004). Also, mortality among children with sepsis was higher among those with acute lymphoblastic leukemia (60% vs. 44%) compared with acute myelogenous leukemia. Administration of stress dose steroids was associated with higher mortality (50% vs. 17%, p = .005) and neutropenia. Patients with acute lymphoblastic leukemia and sepsis showed the greatest mortality and resource use. Patients with acute leukemia and sepsis had a much higher mortality rate compared with previously described sepsis mortality rates for the general pediatric intensive care unit patient populations. Patients who received steroids had an increased mortality rate, but given the retrospective nature of this study, we maintain a position of equipoise with regard to this association. Variation in mortality and resource use by leukemia type suggests further research is needed to develop targeted intervention strategies to enhance patient outcomes.

Intensified treatment with high dose Rifampicin and Levofloxacin compared to standard treatment for adult patients with Tuberculous Meningitis (TBM-IT): protocol for a randomized controlled trial

PubMed Central

2011-01-01

Background Tuberculous meningitis is the most severe form of tuberculosis. Mortality for untreated tuberculous meningitis is 100%. Despite the introduction of antibiotic treatment for tuberculosis the mortality rate for tuberculous meningitis remains high; approximately 25% for HIV-negative and 67% for HIV positive patients with most deaths occurring within one month of starting therapy. The high mortality rate in tuberculous meningitis reflects the severity of the condition but also the poor antibacterial activity of current treatment regimes and relatively poor penetration of these drugs into the central nervous system. Improving the antitubercular activity in the central nervous system of current therapy may help improve outcomes. Increasing the dose of rifampicin, a key drug with known poor cerebrospinal fluid penetration may lead to higher drug levels at the site of infection and may improve survival. Of the second generation fluoroquinolones, levofloxacin may have the optimal pharmacological features including cerebrospinal fluid penetration, with a ratio of Area Under the Curve (AUC) in cerebrospinal fluid to AUC in plasma of >75% and strong bactericidal activity against Mycobacterium tuberculosis. We propose a randomized controlled trial to assess the efficacy of an intensified anti-tubercular treatment regimen in tuberculous meningitis patients, comparing current standard tuberculous meningitis treatment regimens with standard treatment intensified with high-dose rifampicin and additional levofloxacin. Methods/Design A randomized, double blind, placebo-controlled trial with two parallel arms, comparing standard Vietnamese national guideline treatment for tuberculous meningitis with standard treatment plus an increased dose of rifampicin (to 15 mg/kg/day total) and additional levofloxacin. The study will include 750 patients (375 per treatment group) including a minimum of 350 HIV-positive patients. The calculation assumes an overall mortality of 40% vs. 30% in the two arms, respectively (corresponding to a target hazard ratio of 0.7), a power of 80% and a two-sided significance level of 5%. Randomization ratio is 1:1. The primary endpoint is overall survival, i.e. time from randomization to death during a follow-up period of 9 months. Secondary endpoints are: neurological disability at 9 months, time to new neurological event or death, time to new or recurrent AIDS-defining illness or death (in HIV-positive patients only), severe adverse events, and rate of treatment interruption for adverse events. Discussion Currently very few options are available for the treatment of TBM and the mortality rate remains unacceptably high with severe disabilities seen in many of the survivors. This trial is based on the hypothesis that current anti-mycobacterial treatment schedules for TBM are not potent enough and that outcomes will be improved by increasing the CSF penetrating power of this regimen by optimising dosage and using additional drugs with better CSF penetration. Trial registration International Standard Randomised Controlled Trial Number ISRCTN61649292 PMID:21288325

Intensified treatment with high dose rifampicin and levofloxacin compared to standard treatment for adult patients with tuberculous meningitis (TBM-IT): protocol for a randomized controlled trial.

PubMed

Heemskerk, Dorothee; Day, Jeremy; Chau, Tran Thi Hong; Dung, Nguyen Huy; Yen, Nguyen Thi Bich; Bang, Nguyen Duc; Merson, Laura; Olliaro, Piero; Pouplin, Thomas; Caws, Maxine; Wolbers, Marcel; Farrar, Jeremy

2011-02-02

Tuberculous meningitis is the most severe form of tuberculosis. Mortality for untreated tuberculous meningitis is 100%. Despite the introduction of antibiotic treatment for tuberculosis the mortality rate for tuberculous meningitis remains high; approximately 25% for HIV-negative and 67% for HIV positive patients with most deaths occurring within one month of starting therapy. The high mortality rate in tuberculous meningitis reflects the severity of the condition but also the poor antibacterial activity of current treatment regimes and relatively poor penetration of these drugs into the central nervous system. Improving the antitubercular activity in the central nervous system of current therapy may help improve outcomes. Increasing the dose of rifampicin, a key drug with known poor cerebrospinal fluid penetration may lead to higher drug levels at the site of infection and may improve survival. Of the second generation fluoroquinolones, levofloxacin may have the optimal pharmacological features including cerebrospinal fluid penetration, with a ratio of Area Under the Curve (AUC) in cerebrospinal fluid to AUC in plasma of >75% and strong bactericidal activity against Mycobacterium tuberculosis. We propose a randomized controlled trial to assess the efficacy of an intensified anti-tubercular treatment regimen in tuberculous meningitis patients, comparing current standard tuberculous meningitis treatment regimens with standard treatment intensified with high-dose rifampicin and additional levofloxacin. A randomized, double blind, placebo-controlled trial with two parallel arms, comparing standard Vietnamese national guideline treatment for tuberculous meningitis with standard treatment plus an increased dose of rifampicin (to 15 mg/kg/day total) and additional levofloxacin. The study will include 750 patients (375 per treatment group) including a minimum of 350 HIV-positive patients. The calculation assumes an overall mortality of 40% vs. 30% in the two arms, respectively (corresponding to a target hazard ratio of 0.7), a power of 80% and a two-sided significance level of 5%. Randomization ratio is 1:1. The primary endpoint is overall survival, i.e. time from randomization to death during a follow-up period of 9 months. Secondary endpoints are: neurological disability at 9 months, time to new neurological event or death, time to new or recurrent AIDS-defining illness or death (in HIV-positive patients only), severe adverse events, and rate of treatment interruption for adverse events. Currently very few options are available for the treatment of TBM and the mortality rate remains unacceptably high with severe disabilities seen in many of the survivors. This trial is based on the hypothesis that current anti-mycobacterial treatment schedules for TBM are not potent enough and that outcomes will be improved by increasing the CSF penetrating power of this regimen by optimising dosage and using additional drugs with better CSF penetration. International Standard Randomised Controlled Trial Number ISRCTN61649292.

Hepatic lipidosis in turkeys.

PubMed

Gazdzinski, P; Squires, E J; Julian, R J

1994-01-01

Two flocks of 14,000 twenty-week-old turkey hens each experienced increased mortality due to hepatic lipidosis. Some hens showed signs of dyspnea and cyanosis before death. Necropsy revealed dark muscles and enlarged livers with pale areas and numerous hemorrhages. Petechial and ecchymotic hemorrhages were also found on the abdominal fat and epicardium. Lung congestion and edema were prominent. In the heart and blood vessels, the blood was uncoagulated. Mortality was elevated for 12 days and resulted in the death of 0.7% of the turkey hens in one flock and 1.7% in the other. Vitamin E administered in water at a dose of 25 IU per hen appeared to reduce mortality. The nutritional and environmental factors that may contribute to the development of hepatic lipidosis in turkeys are discussed.

G-CSF-primed BM for allogeneic SCT: revisited.

PubMed

Pessach, I; Resnick, I; Shimoni, A; Nagler, A

2015-07-01

G-SCF-mobilized PBSC (GPB) grafts have a higher cell dose and somewhat more committed progenitor cells than steady-state BM (SBM), resulting in faster engraftment and faster immunological reconstitution. On the other hand, transplant related mortality (TRM), disease-free survival (DFS) and overall survival (OS) are similar both for PB and for BM. In contrast to SBM, G-CSF-primed BM (GBM) grafts stimulate HSC proliferation, increasing cell dose and thus resulting in faster engraftment because of higher cell dose infused, or because of treatment with G-CSF. Furthermore, GBM may induce tolerance and functional modulations in donor hematopoiesis and immunity, further reducing GVHD incidence, which is already lower with SBM compared with GPB grafts. Overall, a growing body of clinical evidence suggests that GBM transplants may share the advantages of GPB transplantations, without the associated increased risk of GVHD, and might be an attractive graft source for allogeneic SCTs.

Aliskiren toxicity in juvenile rats is determined by ontogenic regulation of intestinal P-glycoprotein expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hoffmann, Peter, E-mail: peterk.hoffmann@novartis.com; Beckman, David; McLean, Lee Anne

Juvenile rat toxicity studies with the direct renin inhibitor aliskiren were initiated to support treatment in the pediatric population. In Study 1, aliskiren was administered orally to juvenile rats at doses of 0, 30, 100 or 300 mg/kg/day with repeated dosing from postpartum day (PPD) 8 to PPD 35/36. In-life, clinical pathology, anatomic pathology, and toxicokinetics evaluations were performed. In Study 2, single oral doses of aliskiren (0, 100 or 300 mg/kg) were given to 14-, 21-, 24-, 28-, 31- or 36-day-old rats; in-life data and toxicokinetics were evaluated. Study 3 was a single dose (3 mg/kg i.v.) pharmacokinetic studymore » in juvenile rats on PPD 8, 14, 21 and 28. In Study 4, naïve rats were used to investigate ontogenic changes of the multidrug-resistant protein 1 (MDR1) and the organic anion transporting polypeptide (OATP) mRNA in several organs. Oral administration of aliskiren at 100 and 300 mg/kg caused unexpected mortality and severe morbidity in 8-day-old rats. Aliskiren plasma and tissue concentrations were increased in rats aged 21 days and younger. Expression of MDR1 and OATP mRNA in the intestine, liver and brain was significantly lower in very young rats. In conclusion, severe toxicity and increased exposure in very young rats after oral administration of aliskiren are considered to be the result of immature drug transporter systems. Immaturity of MDR1 in enterocytes appears to be the most important mechanism responsible for the high exposure. - Highlights: • Aliskiren was orally administered to juvenile rats. • Unexpected severe toxicity and acute mortality occurred in rats aged 8 days. • Toxicity was associated with increased aliskiren plasma and tissue exposure. • Developmental changes of exposure correlated with ontogeny of transporters. • Immaturity of MDR1 in enterocytes causes increased exposure in very young rats.« less

Population-based surveillance of neonatal herpes simplex virus infection in Australia, 1997-2011.

PubMed

Jones, Cheryl A; Raynes-Greenow, Camille; Isaacs, David

2014-08-15

Neonatal herpes simplex virus (HSV) infection is uncommon, but mortality after disseminated disease and morbidity after encephalitis are high. For the last decade, increased dose and duration of acyclovir has been advised to prevent disease progression and recurrence. We sought to determine prospectively the epidemiologic, clinical, and secular trends of this condition in Australia. This was prospective national active surveillance for neonatal HSV disease through the Australian Paediatric Surveillance Unit from 1997 to 2011. Case notification triggered a questionnaire requesting de-identified data from the pediatric clinician. We identified 131 confirmed cases of neonatal HSV disease in 15 years from 261 notifications (95% response). The reported incidence (3.27 cases per 100 000 live births overall; 95% confidence interval [CI], 2.73-3.86) was stable. Overall mortality was 18.8% (95% CI, 12.1-25.5); the mortality rate was significantly lower in the latter part of the study period, 2005-2011, compared with 1997-2004 (P = .04). There were significantly more young mothers (<20 years of age) compared with Australian birth record data (18.5% vs 4.8%; P < .001). HSV-1 infection was more common than HSV-2 (62.7% vs 37.3%; P < .001), and the rate of HSV-1 infections increased significantly over the surveillance period (P < .05). From 2002, most infants received high-dose acyclovir. The time from symptom onset to initiation of therapy in survivors did not change over time. Mortality from neonatal HSV infection has fallen but remains high. HSV-1 is the major serotype causing neonatal disease in Australia. Young mothers represent an important target group for prevention. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Japanese haemodialysis anaemia management practices and outcomes (1999–2006): results from the DOPPS

PubMed Central

Akizawa, Tadao; Pisoni, Ronald L.; Akiba, Takashi; Saito, Akira; Fukuhara, Shunichi; Asano, Yasushi; Hasegawa, Takeshi; Port, Friedrich K.; Kurokawa, Kiyoshi

2008-01-01

Background. Japanese haemodialysis (HD) patients not only have a very low mortality and hospitalization risk but also low haemoglobin (Hb) levels. Internationally, anaemia is associated with mortality, hospitalization and health-related quality of life (QoL) measures of HD patients. Methods. Longitudinal data collected from 1999 to 2006 from 60 to 64 representative Japanese dialysis units participating in the Dialysis Outcomes and Practice Patterns Study (DOPPS) were used to describe anaemia management practices and outcomes for Japanese HD patients. Results. From 1999 to 2006, patient mean Hb increased from 9.7 g/dl to 10.4 g/dl, and the percentage of facilities with median Hb ≥10 g/dl increased from 27% to 75%. Hb was measured in the supine position for 90% of patients, resulting in substantially lower reported Hb values than those seen in other countries. As of 2006, erythropoietin (Epo) was prescribed to 83% of HD patients; mean Epo dose was 5231 units/week; intravenous (IV) iron use was 33% and median IV iron dose was 160 mg/month. Many patient- and facility-level factors were significantly related to higher Hb. A consistent overall pattern of lower mortality risk with higher baseline Hb levels was seen (RR = 0.89 per 1 g/dl higher Hb, P = 0.003). Facilities with median Hb ≥10.4 displayed a lower mortality risk (RR = 0.77, P = 0.03) versus facility median Hb <10.4 g/dl. Lower Hb levels were not significantly related to hospitalization risk, but were associated with lower QoL scores. Conclusions. These results provide detailed information on anaemia management practices in Japan and the relationships of anaemia control with outcomes, with implications of anaemia management worldwide. PMID:18577535

Mortality among workers monitored for radiation exposure at the French nuclear fuel company.

PubMed

Metz-Flamant, C; Rogel, A; Caër, S; Samson, E; Laurier, D; Acker, A; Tirmarche, M

2009-01-01

A cohort of 9,285 nuclear workers employed at the French company AREVA NC specializing in the nuclear fuel cycle was established. Vital status, causes of death, employment characteristics and annual exposure to ionizing radiation were reconstructed for each individual over the time period 1977-2004. Standardized mortality ratios (SMRs) were computed using national mortality rates as an external reference. Tests for trends in mortality with duration of employment and cumulative external dose were performed. The all-cause and all-cancer mortality was significantly lower than expected from the French population. No significant excess among cancer sites studied was observed. Significant positive trends with cumulative dose were observed for colon and liver cancer and for respiratory diseases. Isolated significant trends should be carefully interpreted and considered in line with the large number of trend tests performed.

Hepatitis B virus-related mortality in rheumatoid arthritis patients undergoing long-term low-dose glucocorticoid treatment: A population-based study.

PubMed

Yang, Sheng-Shun; Hung, Chin-Tun; Li, Shu-Fen; Lee, Horng-Mo; Chung, Yueh-Chin; Chen, Hsin-Hua; Chang, Shu-Chuan

2017-09-04

Glucocorticoids (GC) are commonly used in rheumatoid arthritis (RA) patients which bears a risk of hepatitis B virus (HBV) reactivation. The purpose of this study was to investigate the risk of HBV-related mortality under long-term low-dose GCs in Taiwanese RA patients. We retrospectively analyzed 45,423 RA patients using National Health Insurance Research Database from January 1999 to December 2011. Of them, 2204 patients had the diagnosis of HBV and were classified into four groups according to GCs regimens. Outcome comparison by Cox model analysis for liver-related mortality was performed. In this cohort, 90.5% were older than 40. One hundred and five patients had been treated with short-term large-dose GCs (Group A); 862 patients received GCs ≥20 mg/day for ≥3 days or a variable dose but did not meet Group C criteria (Group B); 689 patients were continuously treated with low-dose (<20 mg/day) GCs for ≥3 months for at least one session (Group C); and 548 patients had never been exposed to GCs (Group D). Two hundred and sixty-one patients had been exposed to antiviral agents, which was significantly higher in Group C. Fifty-eight patients (2.63%) died of acute hepatic failure, while no statistically significant difference between each groups (p = 0.074). Groups C and D comparison by two-sample test showed that long-term low-dose GC treatment was not associated with liver-related death after adjusting for malignancy. Long-term low-dose GC treatment was not associated with liver-related mortality in RA with concomitant HBV patients probably due to commonly applied antiviral therapy by rheumatologists. Copyright © 2017. Published by Elsevier B.V.

Out-of-hospital mortality among patients receiving methadone for noncancer pain.

PubMed

Ray, Wayne A; Chung, Cecilia P; Murray, Katherine T; Cooper, William O; Hall, Kathi; Stein, C Michael

2015-03-01

Growing methadone use in pain management has raised concerns regarding its safety relative to other long-acting opioids. Methadone hydrochloride may increase the risk for lethal respiratory depression related to accidental overdose and life-threatening ventricular arrhythmias. To compare the risk of out-of-hospital death in patients receiving methadone for noncancer pain with that in comparable patients receiving sustained-release (SR) morphine sulfate. A retrospective cohort study was conducted using Tennessee Medicaid records from 1997 through 2009. The cohort included patients receiving morphine SR or methadone who were aged 30 to 74 years, did not have cancer or another life-threatening illness, and were not in a hospital or nursing home. At cohort entry, 32 742 and 6014 patients had filled a prescription for morphine SR or methadone, respectively. The patients' median age was 48 years, 57.9% were female, and comparable proportions had received cardiovascular, psychotropic, and other musculoskeletal medications. Nearly 90% of the patients received the opioid for back pain or other musculoskeletal pain. The median doses prescribed for morphine SR and methadone were 90 mg/d and 40 mg/d, respectively. The primary study end point was out-of-hospital mortality, given that opioid-related deaths typically occur outside the hospital. There were 477 deaths during 28 699 person-years of follow-up (ie, 166 deaths per 10 000 person-years). After control for study covariates, patients receiving methadone had a 46% increased risk of death during the follow-up period, with an adjusted hazard ratio (HR) of 1.46 (95% CI, 1.17-1.83; P < .001), resulting in 72 (95% CI, 27-130) excess deaths per 10 000 person-years of follow-up. Methadone doses of 20 mg/d or less, the lowest dose quartile, were associated with an increased risk of death (HR, 1.59; 95% CI, 1.01-2.51, P = .046) relative to a comparable dose of morphine SR (<60 mg/d). The increased risk of death observed for patients receiving methadone in this retrospective cohort study, even for low doses, supports recommendations that it should not be a drug of first choice for noncancer pain.

Estimating the Risks of Breast Cancer Radiotherapy: Evidence From Modern Radiation Doses to the Lungs and Heart and From Previous Randomized Trials

PubMed Central

Correa, Candace; Duane, Frances K.; Aznar, Marianne C.; Anderson, Stewart J.; Bergh, Jonas; Dodwell, David; Ewertz, Marianne; Gray, Richard; Jagsi, Reshma; Pierce, Lori; Pritchard, Kathleen I.; Swain, Sandra; Wang, Zhe; Wang, Yaochen; Whelan, Tim; Peto, Richard; McGale, Paul

2017-01-01

Purpose Radiotherapy reduces the absolute risk of breast cancer mortality by a few percentage points in suitable women but can cause a second cancer or heart disease decades later. We estimated the absolute long-term risks of modern breast cancer radiotherapy. Methods First, a systematic literature review was performed of lung and heart doses in breast cancer regimens published during 2010 to 2015. Second, individual patient data meta-analyses of 40,781 women randomly assigned to breast cancer radiotherapy versus no radiotherapy in 75 trials yielded rate ratios (RRs) for second primary cancers and cause-specific mortality and excess RRs (ERRs) per Gy for incident lung cancer and cardiac mortality. Smoking status was unavailable. Third, the lung or heart ERRs per Gy in the trials and the 2010 to 2015 doses were combined and applied to current smoker and nonsmoker lung cancer and cardiac mortality rates in population-based data. Results Average doses from 647 regimens published during 2010 to 2015 were 5.7 Gy for whole lung and 4.4 Gy for whole heart. The median year of irradiation was 2010 (interquartile range [IQR], 2008 to 2011). Meta-analyses yielded lung cancer incidence ≥ 10 years after radiotherapy RR of 2.10 (95% CI, 1.48 to 2.98; P < .001) on the basis of 134 cancers, indicating 0.11 (95% CI, 0.05 to 0.20) ERR per Gy whole-lung dose. For cardiac mortality, RR was 1.30 (95% CI, 1.15 to 1.46; P < .001) on the basis of 1,253 cardiac deaths. Detailed analyses indicated 0.04 (95% CI, 0.02 to 0.06) ERR per Gy whole-heart dose. Estimated absolute risks from modern radiotherapy were as follows: lung cancer, approximately 4% for long-term continuing smokers and 0.3% for nonsmokers; and cardiac mortality, approximately 1% for smokers and 0.3% for nonsmokers. Conclusion For long-term smokers, the absolute risks of modern radiotherapy may outweigh the benefits, yet for most nonsmokers (and ex-smokers), the benefits of radiotherapy far outweigh the risks. Hence, smoking can determine the net effect of radiotherapy on mortality, but smoking cessation substantially reduces radiotherapy risk. PMID:28319436

Estimating the Risks of Breast Cancer Radiotherapy: Evidence From Modern Radiation Doses to the Lungs and Heart and From Previous Randomized Trials.

PubMed

Taylor, Carolyn; Correa, Candace; Duane, Frances K; Aznar, Marianne C; Anderson, Stewart J; Bergh, Jonas; Dodwell, David; Ewertz, Marianne; Gray, Richard; Jagsi, Reshma; Pierce, Lori; Pritchard, Kathleen I; Swain, Sandra; Wang, Zhe; Wang, Yaochen; Whelan, Tim; Peto, Richard; McGale, Paul

2017-05-20

Purpose Radiotherapy reduces the absolute risk of breast cancer mortality by a few percentage points in suitable women but can cause a second cancer or heart disease decades later. We estimated the absolute long-term risks of modern breast cancer radiotherapy. Methods First, a systematic literature review was performed of lung and heart doses in breast cancer regimens published during 2010 to 2015. Second, individual patient data meta-analyses of 40,781 women randomly assigned to breast cancer radiotherapy versus no radiotherapy in 75 trials yielded rate ratios (RRs) for second primary cancers and cause-specific mortality and excess RRs (ERRs) per Gy for incident lung cancer and cardiac mortality. Smoking status was unavailable. Third, the lung or heart ERRs per Gy in the trials and the 2010 to 2015 doses were combined and applied to current smoker and nonsmoker lung cancer and cardiac mortality rates in population-based data. Results Average doses from 647 regimens published during 2010 to 2015 were 5.7 Gy for whole lung and 4.4 Gy for whole heart. The median year of irradiation was 2010 (interquartile range [IQR], 2008 to 2011). Meta-analyses yielded lung cancer incidence ≥ 10 years after radiotherapy RR of 2.10 (95% CI, 1.48 to 2.98; P < .001) on the basis of 134 cancers, indicating 0.11 (95% CI, 0.05 to 0.20) ERR per Gy whole-lung dose. For cardiac mortality, RR was 1.30 (95% CI, 1.15 to 1.46; P < .001) on the basis of 1,253 cardiac deaths. Detailed analyses indicated 0.04 (95% CI, 0.02 to 0.06) ERR per Gy whole-heart dose. Estimated absolute risks from modern radiotherapy were as follows: lung cancer, approximately 4% for long-term continuing smokers and 0.3% for nonsmokers; and cardiac mortality, approximately 1% for smokers and 0.3% for nonsmokers. Conclusion For long-term smokers, the absolute risks of modern radiotherapy may outweigh the benefits, yet for most nonsmokers (and ex-smokers), the benefits of radiotherapy far outweigh the risks. Hence, smoking can determine the net effect of radiotherapy on mortality, but smoking cessation substantially reduces radiotherapy risk.

Use of alternating and pulsed direct current electrified fields for zebra mussel control

USGS Publications Warehouse

Luoma, James A.; Dean, Jan C.; Severson, Todd J.; Wise, Jeremy K.; Barbour, Matthew

2017-01-01

Alternatives to chemicals for controlling dreissenid mussels are desirable for environmental compatibility, but few alternatives exist. Previous studies have evaluated the use of electrified fields for stunning and/or killing planktonic life stages of dreissenid mussels, however, the available literature on the use of electrified fields to control adult dreissenid mussels is limited. We evaluated the effects of sinusoidal alternating current (AC) and 20% duty cycle square-wave pulsed direct current (PDC) exposure on the survival of adult zebra mussels at water temperatures of 10, 15, and 22 °C. Peak voltage gradients of ~ 17 and 30 Vp/cm in the AC and PDC exposures, respectively, were continuously applied for 24, 48, or 72 h. Peak power densities ranged from 77,999 to 107,199 µW/cm3 in the AC exposures and 245,320 to 313,945 µW/cm3 in the PDC exposures. The peak dose ranged from 6,739 to 27,298 Joules/cm3 and 21,306 to 80,941 Joules/cm3 in the AC and PDC exposures, respectively. The applied power ranged from 16.6 to 68.9 kWh in the AC exposures and from 22.2 to 86.4 kWh in the PDC exposures. Mortality ranged from 2.7 to 92.7% in the AC exposed groups and from 24.0 to 98.7% in PDC exposed groups. Mortality increased with corresponding increases in water temperature and exposure duration, and we observed more zebra mussel mortality in the PDC exposures. Exposures conducted with AC required less of a peak dose (Joules/cm3) but more applied power (kWh) to achieve the same level of adult zebra mussel mortality as corresponding PDC exposures. The results demonstrate that 20% duty cycle square-wave PDC requires less energy than sinusoidal AC to inducing the same level of adult zebra mussel mortality.

Predictive model of early mortality following acute inhalation of PuO/sub 2/ aerosols. [Extrapolation of beagle data to man

DOE Office of Scientific and Technical Information (OSTI.GOV)

Raabe, O.G.; Goldman, M.

Since data on the pulmonary toxicity of plutonium in people are not available, estimates must be based upon available experimental animal data. For this purpose, inhalation studies with beagle dogs exposed to aerosols of /sup 238/PuO/sub 2/ and /sup 239/PuO/sub 2/ were analyzed and a simple model has been proposed to describe apparent dose-response relationships. It was found that for each aerosol and radionuclide form, the cumulative absorbed lung dose that leads to death from lung damage up to 1000 days could be assumed to have a log-normal distribution of values that was independent of time to death. The datamore » was satisfactorily fit to a model in which the time of death postexposure is given by: t = (K/D), with the time to death, the cumulative dose to lung tissue (the killing dose), and anti D the average dose rate to lung tissue from time of exposure to death. The ratios of median K values, normalized to the value for /sup 90/Sr--Y FAP, indicate a relative biological effectiveness (RBE) of 14 for /sup 239/PuO/sub 2/ particles and 5 for /sup 238/PuO/sub 2/ particles. This demonstrates an effect of particle specific activity on relative biological effectiveness for early mortality, since an increase in specific activity of particles leads to a lower apparent RBE.« less

Relationship of tree nut, peanut and peanut butter intake with total and cause-specific mortality: a cohort study and meta-analysis.

PubMed

van den Brandt, Piet A; Schouten, Leo J

2015-06-01

Nut intake has been associated with lower mortality, but few studies have investigated causes of death other than cardiovascular disease, and dose-response relationships remain unclear. We investigated the relationship of nut (tree nut, peanut) and peanut butter intake with overall and cause-specific mortality. In the Netherlands Cohort Study, 120,852 men and women aged 55-69 years provided information on dietary and lifestyle habits in 1986. Mortality follow-up until 1996 consisted of linkage to Statistics Netherlands. Multivariate case-cohort analyses were based on 8823 deaths and 3202 subcohort members with complete data on nuts and potential confounders. We also conducted meta-analyses of our results with those published from other cohort studies. Total nut intake was related to lower overall and cause-specific mortality (cancer, diabetes, cardiovascular, respiratory, neurodegenerative diseases, other causes) in men and women. When comparing those consuming 0.1-<5, 5-<10 and 10+ g nuts/day with non-consumers, multivariable hazard ratios for total mortality were 0.88, 0.74 and 0.77 [95% confidence interval (CI), 0.66-0.89], respectively (Ptrend = 0.003). Cause-specific hazard ratios comparing 10+ vs 0 g/day varied from 0.56 for neurodegenerative to 0.83 for cardiovascular disease mortality. Restricted cubic splines showed nonlinear dose-response relationships with mortality. Peanuts and tree nuts were inversely related to mortality, whereas peanut butter was not. In meta-analyses, summary hazard ratios for highest vs lowest nut consumption were 0.85 for cancer, and 0.71 for respiratory mortality. Nut intake was related to lower overall and cause-specific mortality, with evidence for nonlinear dose-response relationships. Peanut butter was not related to mortality. © The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

Impact of Vibrio parahaemolyticus and white spot syndrome virus (WSSV) co-infection on survival of penaeid shrimp Litopenaeus vannamei

NASA Astrophysics Data System (ADS)

Zhang, Xiaojing; Song, Xiaoling; Huang, Jie

2016-11-01

White spot syndrome virus (WSSV) is an important viral pathogen that infects farmed penaeid shrimp, and the threat of Vibrio parahaemolyticus infection to shrimp farming has become increasingly severe. Viral and bacterial cross or superimposed infections may induce higher shrimp mortality. We used a feeding method to infect Litopenaeus vannamei with WSSV and then injected a low dose of V. parahaemolyticus (WSSV+Vp), or we first infected L. vannamei with a low-dose injection of V. parahaemolyticus and then fed the shrimp WSSV to achieve viral infection (Vp+WSSV). The eff ect of V. parahaemolyticus and WSSV co-infection on survival of L. vannamei was evaluated by comparing cumulative mortality rates between experimental and control groups. We also spread L. vannamei hemolymph on thiosulfate citrate bile salt sucrose agar plates to determine the number of Vibrio, and the WSSV copy number in L. vannamei gills was determined using an absolute quantitative polymerase chain reaction (PCR) method. LvMyD88 and Lvakt gene expression levels were detected in gills of L. vannamei by real-time PCR to determine the cause of the diff erent mortality rates. Our results show that (1) the cumulative mortality rate of L. vannamei in the WSSV+Vp group reached 100% on day 10 after WSSV infection, whereas the cumulative mortality rate of L. vannamei in the Vp+WSSV group and the WSSV-alone control group approached 100% on days 11 and 13 of infection; (2) the number of Vibrio in the L. vannamei group infected with V. parahaemolyticus alone declined gradually, whereas the other groups showed significant increases in the numbers of Vibrio ( P<0.05); (3) the WSSV copy numbers in the gills of the WSSV+Vp, Vp+WSSV, and the WSSV-alone groups increased from 105 to 107 /mg tissue 72, 96, and 144 h after infection, respectively. These results suggest that V. parahaemolyticus infection accelerated proliferation of WSSV in L. vannamei and vice versa. The combined accelerated proliferation of both V. parahaemolyticus and WSSV led to massive death of L. vannamei.

A dose-response study of consuming high-fructose corn syrup–sweetened beverages on lipid/lipoprotein risk factors for cardiovascular disease in young adults123456

PubMed Central

Medici, Valentina; Bremer, Andrew A; Lee, Vivien; Lam, Hazel D; Nunez, Marinelle V; Chen, Guoxia X; Keim, Nancy L; Havel, Peter J

2015-01-01

Background: National Health and Nutrition Examination Survey data show an increased risk of cardiovascular disease (CVD) mortality with an increased intake of added sugar. Objective: We determined the dose-response effects of consuming beverages sweetened with high-fructose corn syrup (HFCS) at zero, low, medium, and high proportions of energy requirements (Ereq) on circulating lipid/lipoprotein risk factors for CVD and uric acid in adults [age: 18–40 y; body mass index (in kg/m2): 18–35]. Design: We conducted a parallel-arm, nonrandomized, double-blinded intervention study in which adults participated in 3.5 inpatient days of baseline testing at the University of California Davis Clinical and Translational Science Center’s Clinical Research Center. Participants then consumed beverages sweetened with HFCS at 0% (aspartame sweetened, n = 23), 10% (n = 18), 17.5% (n = 16), or 25% (n = 28) of Ereq during 13 outpatient days and during 3.5 inpatient days of intervention testing at the research center. We conducted 24-h serial blood collections during the baseline and intervention testing periods. Results: Consuming beverages containing 10%, 17.5%, or 25% Ereq from HFCS produced significant linear dose-response increases of lipid/lipoprotein risk factors for CVD and uric acid: postprandial triglyceride (0%: 0 ± 4; 10%: 22 ± 8; 17.5%: 25 ± 5: 25%: 37 ± 5 mg/dL, mean of Δ ± SE, P < 0.0001 effect of HFCS-dose), fasting LDL cholesterol (0%: −1.0 ± 3.1; 10%: 7.4 ± 3.2; 17.5%: 8.2 ± 3.1; 25%: 15.9 ± 3.1 mg/dL, P < 0.0001), and 24-h mean uric acid concentrations (0%: −0.13 ± 0.07; 10%: 0.15 ± 0.06; 17.5%: 0.30 ± 0.07; 25%: 0.59 ± 0.09 mg/dL, P < 0.0001). Compared with beverages containing 0% HFCS, all 3 doses of HFCS-containing beverages increased concentrations of postprandial triglyceride, and the 2 higher doses increased fasting and/or postprandial concentrations of non–HDL cholesterol, LDL cholesterol, apolipoprotein B, apolipoprotein CIII, and uric acid. Conclusions: Consuming beverages containing 10%, 17.5%, or 25% Ereq from HFCS produced dose-dependent increases in circulating lipid/lipoprotein risk factors for CVD and uric acid within 2 wk. These results provide mechanistic support for the epidemiologic evidence that the risk of cardiovascular mortality is positively associated with consumption of increasing amounts of added sugars. This trial was registered at clinicaltrials.gov as NCT01103921. PMID:25904601

Mortality in a Combined Cohort of Uranium Enrichment Workers

PubMed Central

Yiin, James H.; Anderson, Jeri L.; Daniels, Robert D.; Bertke, Stephen J.; Fleming, Donald A.; Tollerud, David J.; Tseng, Chih-Yu; Chen, Pi-Hsueh; Waters, Kathleen M.

2017-01-01

Objective To examine the patterns of cause-specific mortality and relationship between internal exposure to uranium and specific causes in a pooled cohort of 29,303 workers employed at three former uranium enrichment facilities in the United States with follow-up through 2011. Methods Cause-specific standardized mortality ratios (SMRs) for the full cohort were calculated with the U.S. population as referent. Internal comparison of the dose-response relation between selected outcomes and estimated organ doses was evaluated using regression models. Results External comparison with the U.S. population showed significantly lower SMRs in most diseases in the pooled cohort. Internal comparison showed positive associations of absorbed organ doses with multiple myeloma, and to a lesser degree with kidney cancer. Conclusion In general, these gaseous diffusion plant workers had significantly lower SMRs than the U.S. population. The internal comparison however, showed associations between internal organ doses and diseases associated with uranium exposure in previous studies. PMID:27753121

Utilization of ICU Data to Improve 30 and 60 Day Mortality Models

DTIC Science & Technology

2017-01-06

Acute Radiation Syndrome , Mortality, Burn Combined Injury, Lethality, Small Intestine, Ordinary Differential...short period of time (high dose rate) causes acute radiation syndrome (ARS). Depending on the radiation dose, an individual may experience the...hematopoietic acute radiation syndrome (H-ARS) or the gastrointestinal acute radiation syndrome (GI-ARS) (reviewed in Maciàă I Garau et al., 2011). For acute

An egg injection method for assessing early life stage mortality of polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls in rainbow trout, (Oncorhynchus mykiss)

USGS Publications Warehouse

Walker, M.K.; Hufnagle, L.C.; Clayton, M.K.; Peterson, R.E.

1992-01-01

To characterize the risk that polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and biphenyls (PCBs) pose to salmonid early life stage survival, we developed a method to expose rainbow trout (Oncorhynchus mykiss) eggs to graded doses of PCDD, PCDF, and PCB congeners, using 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as a prototype. Rainbow trout eggs were injected 24–50 h post-fertilization with 0.2 μl of 50 mM phosphatidylcholine (PC) liposomes (control) or 0.2 μl of 5–7 graded doses of TCDD incorporated into 50 mM PC liposomes. Injection volume never exceeded 0.6% egg volume. Immediately following injection, the injection site was sealed with Super glue®, resulting in 92–97% of TCDD dose retained by the egg. Following both egg injection and waterborne egg exposure. TCDD toxicity in rainbow trout was manifested by half-hatching mortality but predominantly by sac fry mortality associated with hemorrhages, pericardial edema, and yolk sac edema. TCDD LD50s, following injection and waterborne exposure of rainbow trout eggs, were 421 (331–489) and 439 (346–519) pg TCDD/g egg (LD50, 95% fiducial limits), respectively. As in rainbow trout, TCDD toxicity in lake trout (Salvelinus namaycush) following the same two routes of exposure was manifested by half-hatching mortality but predominantly by sac fry mortality preceded by hemorrhages and yolk sac edema. LD50s, based on the dose of TCDD in lake trout eggs, were 47 (21–65) and 65 (60–71) pg/g following injection and waterborne exposure, respectively. The egg injection method is ideal for assessing the relationship between early life stage mortality in rainbow trout and graded egg doses of individual PCDD, PCDF, or PCB congeners.

Paraquat detoxication with multiple emulsions.

PubMed

Frasca, S; Couvreur, P; Seiller, M; Pareau, D; Lacour, B; Stambouli, M; Grossiord, J L

2009-10-01

In this study, we show that detoxifying W/O/W multiple emulsions, prepared with an appropriate extractant/trapping couple, represent a promising technology for quick and safe poisoning treatments, with application to the highly toxic herbicide Paraquat, responsible of poisonings from low-dose exposure leading to several deaths every year. In vitro tests led to the choice of an appropriate extractant/trapping couple system with significant detoxication performance. In vivo tests showed (i) that rats receiving high doses of Paraquat, then a detoxifying emulsion, presented an increase from 50% to 100% of the MST (median survival time) and (ii) that no mortality was observed during 30 days with rats dosed with emulsions initially loaded with Paraquat at a concentration much higher than the lethal dose, proving the stability and the inocuity of the detoxifying multiple emulsion in the gastrointestinal tract.

The Three Mile Island Population Registry.

PubMed

Goldhaber, M K; Tokuhata, G K; Digon, E; Caldwell, G G; Stein, G F; Lutz, G; Gur, D

1983-01-01

Shortly after the March 28, 1979, accident at the Three Mile Island (TMI) nuclear plant outside Harrisburg, Pa., the Pennsylvania Department of Health, in conjunction with the Centers for Disease Control and the U.S. Bureau of the Census, conducted a census of the 35,930 persons residing within 5 miles of the plant. With the help of 150 enumerators, demographic and health-related information was collected on each person to provide baseline data for future short- and long-term epidemiologic studies of the effects of the accident. Individual radiation doses were estimated on the basis of residential location and the amount of time each person spent in the 5-mile area during the 10 days after the accident. Health and behavioral resurveys of the population will be conducted approximately every 5 years. Population-mobility, morbidity, and mortality will be studied yearly by matching the TMI Population Registry with postal records, cancer registry records, and death certificate data. Because the radiation dose from TMI was extremely small, any increase in morbidity or mortality attributable to the accident would be so small as not to be measurable by present methods; however, adverse health effects as a result of psychological stress may occur. Also, a temporary increase in reporting of disease could occur because of increased surveillance and attention to health.

The Three Mile Island Population Registry.

PubMed Central

Goldhaber, M K; Tokuhata, G K; Digon, E; Caldwell, G G; Stein, G F; Lutz, G; Gur, D

1983-01-01

Shortly after the March 28, 1979, accident at the Three Mile Island (TMI) nuclear plant outside Harrisburg, Pa., the Pennsylvania Department of Health, in conjunction with the Centers for Disease Control and the U.S. Bureau of the Census, conducted a census of the 35,930 persons residing within 5 miles of the plant. With the help of 150 enumerators, demographic and health-related information was collected on each person to provide baseline data for future short- and long-term epidemiologic studies of the effects of the accident. Individual radiation doses were estimated on the basis of residential location and the amount of time each person spent in the 5-mile area during the 10 days after the accident. Health and behavioral resurveys of the population will be conducted approximately every 5 years. Population-mobility, morbidity, and mortality will be studied yearly by matching the TMI Population Registry with postal records, cancer registry records, and death certificate data. Because the radiation dose from TMI was extremely small, any increase in morbidity or mortality attributable to the accident would be so small as not to be measurable by present methods; however, adverse health effects as a result of psychological stress may occur. Also, a temporary increase in reporting of disease could occur because of increased surveillance and attention to health. PMID:6419276

Terminate Lung Cancer (TLC) Study - A mixed-methods population approach to increase lung cancer screening awareness and low-dose computed tomography in Eastern Kentucky

PubMed Central

Cardarelli, Roberto; Reese, David; Roper, Karen L.; Cardarelli, Kathryn; Feltner, Frances J.; Studts, Jamie L.; Knight, Jennifer R.; Armstrong, Debra; Weaver, Anthony; Shaffer, Dana

2017-01-01

For low dose CT lung cancer screening to be effective in curbing disease mortality, efforts are needed to overcome barriers to awareness and facilitate uptake of the current evidence-based screening guidelines. A sequential mixed-methods approach was employed to design a screening campaign utilizing messages developed from community focus groups, followed by implementation of the outreach campaign intervention in two high-risk Kentucky regions. This study reports on rates of awareness and screening in intervention regions, as compared to a control region. PMID:27866066

Updated Mortality Analysis of Radiation Workers at Rocketdyne (Atomics International), 1948-2008

DOE Office of Scientific and Technical Information (OSTI.GOV)

Boice Jr JD, Colen SS, Mumma MT, Ellis ED, Eckerman DF, Leggett RW, Boecker BB, Brill B, Henderson BE

Updated analyses of mortality data are presented on 46,970 workers employed 1948-1999 at Rocketdyne (Atomics International). Overall, 5,801 workers were involved in radiation activities, including 2,232 who were monitored for intakes of radionuclides, and 41,169 workers were engaged in rocket testing or other non-radiation activities. The worker population is unique in that lifetime occupational doses from all places of employment were sought, updated and incorporated into the analyses. Further, radiation doses from intakes of 14 different radionuclides were calculated for 16 organs or tissues using biokinetic models of the International Commission on Radiation Protection (ICRP). Because only negligible exposures weremore » received by the 247 workers monitored for radiation activities after 1999, the mean dose from external radiation remained essentially the same at 13.5 mSv (maximum 1 Sv) as reported previously, as did the mean lung dose from external and internal radiation combined at 19.0 mSv (maximum 3.6 Sv). An additional 9 years of follow-up, from December 31,1999 through 2008, increased the person-years of observation for the radiation workers by 21.7% to 196,674 (mean 33.9 years) and the number of cancer deaths by 50% to 684. Analyses included external comparisons with the general population and the computation of standardized mortality ratios (SMRs) and internal comparisons using proportional hazards models and the computation of relative risks (RRs). A low SMR for all causes of death (SMR 0.82; 95% CI 0.78-0.85) continued to indicate that the Rocketdyne radiation workers were healthier than the general population and were less likely to die. The SMRs for all cancers taken together (SMR 0.88; 95% CI 0.81-0.95), lung cancer (SMR 0.87; 95% CI 0.76-1.00) and leukemia other than chronic lymphocytic leukemia (CLL) (SMR 1.04; 95% 0.67-1.53) were not significantly elevated. Cox regression analyses revealed no significant dose-response trends for any cancer. For all cancers excluding leukemia, the RR at 100 mSv was estimated as 0.98 (95% CI 0.82-1.17), and for all leukemia other than CLL it was 1.06 (95% CI 0.50-2.23). Uranium was the primary radionuclide contributing to internal exposures, but no significant increases in lung and kidney disease were seen. The extended follow-up reinforces the findings in the previous study in failing to observe a detectable increase in cancer deaths associated with radiation, but strong conclusions still cannot be drawn because of small numbers and relatively low career doses. Larger combined studies of early workers in the United States using similar methodologies are warranted to refine and clarify radiation risks after protracted exposures.« less

External validation of ADO, DOSE, COTE and CODEX at predicting death in primary care patients with COPD using standard and machine learning approaches.

PubMed

Morales, Daniel R; Flynn, Rob; Zhang, Jianguo; Trucco, Emmanuel; Quint, Jennifer K; Zutis, Kris

2018-05-01

Several models for predicting the risk of death in people with chronic obstructive pulmonary disease (COPD) exist but have not undergone large scale validation in primary care. The objective of this study was to externally validate these models using statistical and machine learning approaches. We used a primary care COPD cohort identified using data from the UK Clinical Practice Research Datalink. Age-standardised mortality rates were calculated for the population by gender and discrimination of ADO (age, dyspnoea, airflow obstruction), COTE (COPD-specific comorbidity test), DOSE (dyspnoea, airflow obstruction, smoking, exacerbations) and CODEX (comorbidity, dyspnoea, airflow obstruction, exacerbations) at predicting death over 1-3 years measured using logistic regression and a support vector machine learning (SVM) method of analysis. The age-standardised mortality rate was 32.8 (95%CI 32.5-33.1) and 25.2 (95%CI 25.4-25.7) per 1000 person years for men and women respectively. Complete data were available for 54879 patients to predict 1-year mortality. ADO performed the best (c-statistic of 0.730) compared with DOSE (c-statistic 0.645), COTE (c-statistic 0.655) and CODEX (c-statistic 0.649) at predicting 1-year mortality. Discrimination of ADO and DOSE improved at predicting 1-year mortality when combined with COTE comorbidities (c-statistic 0.780 ADO + COTE; c-statistic 0.727 DOSE + COTE). Discrimination did not change significantly over 1-3 years. Comparable results were observed using SVM. In primary care, ADO appears superior at predicting death in COPD. Performance of ADO and DOSE improved when combined with COTE comorbidities suggesting better models may be generated with additional data facilitated using novel approaches. Copyright © 2018. Published by Elsevier Ltd.

Measles vaccination in the presence or absence of maternal measles antibody: impact on child survival.

PubMed

Aaby, Peter; Martins, Cesário L; Garly, May-Lill; Andersen, Andreas; Fisker, Ane B; Claesson, Mogens H; Ravn, Henrik; Rodrigues, Amabelia; Whittle, Hilton C; Benn, Christine S

2014-08-15

Measles vaccine (MV) has a greater effect on child survival when administered in early infancy, when maternal antibody may still be present. To test whether MV has a greater effect on overall survival if given in the presence of maternal measles antibody, we reanalyzed data from 2 previously published randomized trials of a 2-dose schedule with MV given at 4-6 months and at 9 months of age. In both trials antibody levels had been measured before early measles vaccination. In trial I (1993-1995), the mortality rate was 0.0 per 1000 person-years among children vaccinated with MV in the presence of maternal antibody and 32.3 per 1000 person-years without maternal antibody (mortality rate ratio [MRR], 0.0; 95% confidence interval [CI], 0-.52). In trial II (2003-2007), the mortality rate was 4.2 per 1000 person-years among children vaccinated in presence of maternal measles antibody and 14.5 per 1000 person-years without measles antibody (MRR, 0.29; 95% CI, .09-.91). Possible confounding factors did not explain the difference. In a combined analysis, children who had measles antibody detected when they received their first dose of MV at 4-6 months of age had lower mortality than children with no maternal antibody, the MRR being 0.22 (95% CI, .07-.64) between 4-6 months and 5 years. Child mortality in low-income countries may be reduced by vaccinating against measles in the presence of maternal antibody, using a 2-dose schedule with the first dose at 4-6 months (earlier than currently recommended) and a booster dose at 9-12 months of age. NCT00168558. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.

SCHISTOSOMIASIS: AGE OF SNAILS AND SUSCEPTIBILITY TO X-IRRADIATION

DOE Office of Scientific and Technical Information (OSTI.GOV)

Szumlewicz, A.P.

1964-04-17

Studies on sensitivity of Australorbis glabratus to x rays have defined the chronological and physiological age at which the snail is most sensitive to radiation damage. Results showed that the dose producing 50-percent mortality at 30 days after irradiation increased with age but that at 90 days it was practically constant from 2 to 210 days of age. In view of the avaiIable data on recovery from radiation damage caused by doses from 6000 to 9000 roentgens it is suggested that doses above those causing 50% lethality at 60 days but below those causing 50% lethality for 30 days shouldmore » be considered in setting up radiation barriers to cortrol snails in water-distribution systems. (auth)« less

HbA1c and Risks of All-Cause and Cause-Specific Death in Subjects without Known Diabetes: A Dose-Response Meta-Analysis of Prospective Cohort Studies

PubMed Central

Zhong, Guo-Chao; Ye, Ming-Xin; Cheng, Jia-Hao; Zhao, Yong; Gong, Jian-Ping

2016-01-01

Whether HbA1c levels are associated with mortality in subjects without known diabetes remains controversial. Moreover, the shape of the dose–response relationship on this topic is unclear. Therefore, a dose–response meta-analysis was conducted. PubMed and EMBASE were searched. Summary hazard ratios (HRs) were calculated using a random-effects model. Twelve studies were included. The summary HR per 1% increase in HbA1c level was 1.03 [95% confidence interval (CI) = 1.01–1.04] for all-cause mortality, 1.05 [95% CI = 1.02–1.07) for cardiovascular disease (CVD) mortality, and 1.02 (95% CI = 0.99–1.07) for cancer mortality. After excluding subjects with undiagnosed diabetes, the aforementioned associations remained significant for CVD mortality only. After further excluding subjects with prediabetes, all aforementioned associations presented non-significance. Evidence of a non-linear association between HbA1c and mortality from all causes, CVD and cancer was found (all Pnon-linearity < 0.05). The dose–response curves were relatively flat for HbA1c less than around 5.7%, and rose steeply thereafter. In conclusion, higher HbA1c level is associated with increased mortality from all causes and CVD among subjects without known diabetes. However, this association is driven by those with undiagnosed diabetes or prediabetes. The results regarding cancer mortality should be treated with caution due to limited studies. PMID:27045572

Radiation dose- and sex-dependent cardiovascular mortality in residents of contaminated areas after the Chornobyl NPP accident, 1988-2010 observation period.

PubMed

Buzunov, V O; Prikaschikova, K Ye; Gubina, I G; Kostiuk, G V; Tereschenko, S O

2013-01-01

To estimate the circulatory system disease death rates for people living in areas contaminated after the Chornobyl accident. Epidemiological estimation covered the post-accident period (1988-2010) and was focused on the relationship between death rates and doses accumulated over 1986-2010 or sex of survivors aged under 60 at the time of the accident. We used data from the State Registry of Ukraine on persons affected by the Chornobyl accident. Residents of contaminated areas were grouped into the two cohorts according to cumulative dose values. Cohort 1 numbered 155,592 people (86,787 females and 68,805 males), their radiation doses were 5.6-20.99 mSv; cohort 2 totaled 98,830 people (52,640 females and 46,190 males) with radiation doses 21.00-50.99 mSv. Mean age (X ± δ) of inhabitants of contaminated areas at the time of the accident (April 26, 1986) was 29.5 ± 23.2 years (30.6 ± 22.3 for women and 28.3 ± 23.2 for men) in the cohort 1, and 28.7 ± 17.3 years (29.8 ± 17.7 and 27.5 ± 16.2 respectively) in the cohort 2). These cohorts were subdivided by sex (males and females). Significantly higher (ID per 103 person-years is 8.08 ± 0.10) cardiovascular mortality was revealed among members of the cohort 2 vs. cohort 1 (ID per 103 person-years is 6.29 ± 0.06). Mortality from cardiovascular diseases in both sex groups of the cohort 2 is higher (ID per 103 person-years is 6.80 ± 0.12 in women and 9.43 ± 0.15 - in men) than that of the cohort 1 (ID per 103 person-years is 5.34 ± 0.08 in women, 7.37 ± 0.10 - in men). Whatever accumulated doses the mortality from circulatory diseases was significantly higher in men vs. women. Cardiovascular mortality in population of radiation-contaminated territories depends on the integral radiation exposure and gender. Death rates are clearly higher (p<0.05) in persons having more radiation doses vs. those exposed to less ones. Mortality is significantly higher in males vs. females despite integral radiation doses values. The coronary heart disease, cerebrovascular disease, arterial hypertension, heart diseases, diseases of arteries, arterioles and capillaries) were the main causes of death. Buzunov V. O., Prykashhykova K. Je., Gubina I. G., Kostjuk G. V., Tereshhenko S. O., 2013.

Glutamine and antioxidants in the critically ill patient: a post hoc analysis of a large-scale randomized trial.

PubMed

Heyland, Daren K; Elke, Gunnar; Cook, Deborah; Berger, Mette M; Wischmeyer, Paul E; Albert, Martin; Muscedere, John; Jones, Gwynne; Day, Andrew G

2015-05-01

The recent large randomized controlled trial of glutamine and antioxidant supplementation suggested that high-dose glutamine is associated with increased mortality in critically ill patients with multiorgan failure. The objectives of the present analyses were to reevaluate the effect of supplementation after controlling for baseline covariates and to identify potentially important subgroup effects. This study was a post hoc analysis of a prospective factorial 2 × 2 randomized trial conducted in 40 intensive care units in North America and Europe. In total, 1223 mechanically ventilated adult patients with multiorgan failure were randomized to receive glutamine, antioxidants, both glutamine and antioxidants, or placebo administered separate from artificial nutrition. We compared each of the 3 active treatment arms (glutamine alone, antioxidants alone, and glutamine + antioxidants) with placebo on 28-day mortality. Post hoc, treatment effects were examined within subgroups defined by baseline patient characteristics. Logistic regression was used to estimate treatment effects within subgroups after adjustment for baseline covariates and to identify treatment-by-subgroup interactions (effect modification). The 28-day mortality rates in the placebo, glutamine, antioxidant, and combination arms were 25%, 32%, 29%, and 33%, respectively. After adjusting for prespecified baseline covariates, the adjusted odds ratio of 28-day mortality vs placebo was 1.5 (95% confidence interval, 1.0-2.1, P = .05), 1.2 (0.8-1.8, P = .40), and 1.4 (0.9-2.0, P = .09) for glutamine, antioxidant, and glutamine plus antioxidant arms, respectively. In the post hoc subgroup analysis, both glutamine and antioxidants appeared most harmful in patients with baseline renal dysfunction. No subgroups suggested reduced mortality with supplements. After adjustment for baseline covariates, early provision of high-dose glutamine administered separately from artificial nutrition was not beneficial and may be associated with increased mortality in critically ill patients with multiorgan failure. For both glutamine and antioxidants, the greatest potential for harm was observed in patients with multiorgan failure that included renal dysfunction upon study enrollment. © 2014 American Society for Parenteral and Enteral Nutrition.

Implications of sequence and timing of exposure for synergy between the pyrethroid insecticide alpha-cypermethrin and the entomopathogenic fungus Beauveria bassiana.

PubMed

Meyling, Nicolai V; Arthur, Samuel; Pedersen, Kathrine E; Dhakal, Suraj; Cedergreen, Nina; Fredensborg, Brian L

2018-03-30

Combining low doses of chemical insecticides with entomopathogens constitutes a sustainable pest control method, but the significance of the timing and sequence of exposures needs clarification. We studied lethal effects of combinations of the entomopathogenic fungus Beauveria bassiana (KVL03-122) and the pyrethroid alpha-cypermethrin on the beetle Tenebrio molitor under varying timing and sequence of exposure. Synergy over time was evaluated in relation to the model of independent action (IA). We expected that increased progression of disease caused by B. bassiana would make beetles more susceptible to the insecticide, leading to enhanced synergy. Synergistic effects between B. bassiana and alpha-cypermethrin were observed when B. bassiana was applied first, but only when the interval between applications was >48 h. With 72 h between exposures, mortality had increased to 100% after 8 days, in contrast to the 60% mortality expected. No synergy was observed when the insecticide was applied prior to fungal exposure within 24 h. The sequence and timing of exposure do matter to achieve synergistic mortality by combining B. bassiana and alpha-cypermethrin, and the IA model proved to be a strong tool with which to evaluate the interactions of the two stressors over time. Pest control strategies could include B. bassiana followed by low-dose exposures to alpha-cypermethrin after 2-3 days. © 2018 Society of Chemical Industry. © 2018 Society of Chemical Industry.

Weather and Climate Change Impacts on Human Mortality in Bangladesh

NASA Technical Reports Server (NTRS)

Burkart, Katrin; Lesk, Corey; Bader, Daniel; Horton, Radley; Kinney, Patrick

2016-01-01

Weather and climate profoundly affect human health. Several studies have demonstrated a U-, V-, or J-shaped temperature-mortality relationship with increasing death rates at the lower and particularly upper end of the temperature distribution. The objectives of this study were (1) to analyze the relationship between temperature and mortality in Bangladesh for different subpopulations and (2) to project future heat-related mortality under climate change scenarios. We used (non-)parametric Generalized Additive Models adjusted for trend, season and day of the month to analyze the effect of temperature on daily mortality. We found a decrease in mortality with increasing temperature over a wide range of values; between the 90th and 95th percentile an abrupt increase in mortality was observed which was particularly pronounced for the elderly above the age of 65 years, for males, as well as in urban areas and in areas with a high socio-economic status. Daily historical and future temperature values were obtained from the NASA Earth Exchange Global Daily Downscaled Projections (NEX-GDDP) dataset. This dataset is comprised of downscaled climate scenarios for the globe that are derived from the General Circulation Model (GCM) runs conducted under the Coupled Model Intercomparison Project Phase 5 (CMIP5). The derived dose-response functions were used to estimate the number of heat-related deaths occurring during the 1990s (1980-2005), the 2020s (2011-2040) and the 2050s (2041-2070). We estimated that excess deaths due to heat will triple from the 1990s to the 2050s, with an annual number of 0.5 million excess deaths in 1990 to and expected number of 1.5 millions in 2050.

Toxicity of flavor enhancers to the oriental fruit fly, Bactrocera dorsalis (Hendel) (Diptera: Tephritidae).

PubMed

Zheng, Chunyan; Yang, Dongyu; Li, Zhiqiang; Xu, Yijuan

2018-04-11

The objective of this study was to evaluate the toxicity of flavor enhancers to the oriental fruit fly Bactrocera dorsalis (Hendel). The flavor enhancers glycine, disodium guanylate, succinic acid disodium salt, monosodium glutamate (MSG), disodium inosinate, and L-alanine significantly increased the mortality of B. dorsalis flies. The mortality of flies that fed on glycine, disodium guanylate, succinic acid disodium salt, and MSG was greater than 90%. Additionally, fruit fly mortality increased with increases in both time and concentration. Glycine not only reduced the climbing ability of B. dorsalis but also affected the duration and frequency of its behavioral patterns (flight, walking, grooming and inactivity). Compared with adult flies in the control group, adult B. dorsalis flies that fed on glycine exhibited a significantly increased duration and frequency of inactivity and a decreased duration and frequency of both flight and walking. However, the effect of glycine on grooming activity was not significant. These findings demonstrate the toxic effects of flavor enhancers on B. dorsalis. Glycine also affected the behavior of adult flies at a low dose. Therefore, glycine has potentially toxic to insects and also likely to have a negative impact at sublethal concentrations.

Single- and repeated-dose oral toxicity studies of citicoline free-base (choline cytidine 5'-pyrophosphate) in Sprague-Dawley rats.

PubMed

Schauss, A G; Somfai-Relle, S; Financsek, I; Glavits, R; Parent, S C; Endres, J R; Varga, T; Szücs, Z; Clewell, A

2009-01-01

The dietary supplement Citicoline free-base (choline cytidine 5'-pyrophosphate) was toxicologically evaluated in Sprague-Dawley rats using oral gavage. In an acute 14-day study, 2000 mg/kg was well tolerated. In a 90-day study, 100, 350, and 1000 mg/kg/day doses resulted in no mortality. In males, slight significant increases in serum creatinine (350 and 1000 mg/kg/day), and decreases in urine volume (all treated groups) were observed. In females, slight significant increases in total white blood cell and absolute lymphocyte counts (1000 mg/kg/day), and blood urea nitrogen (BUN) (100 and 350, but not 1000 mg/kg/day) were noted. A dose-related increase in renal tubular mineralization, without degenerative or inflammatory reaction, was found in females (all treated groups) and two males (1000 mg/kg/day). Renal mineralization in rats (especially females) is influenced by calcium:phosphorus ratios in the diet. A high level of citicoline consumption resulted in increased phosphorus intake in the rats, and likely explains this result.

Influence of Renal Impairment on Outcome for Thrombolysis-Treated Acute Ischemic Stroke: ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study) Post Hoc Analysis.

PubMed

Carr, Susan J; Wang, Xia; Olavarria, Veronica V; Lavados, Pablo M; Rodriguez, Jorge A; Kim, Jong S; Lee, Tsong-Hai; Lindley, Richard I; Pontes-Neto, Octavio M; Ricci, Stefano; Sato, Shoichiro; Sharma, Vijay K; Woodward, Mark; Chalmers, John; Anderson, Craig S; Robinson, Thompson G

2017-09-01

Renal dysfunction (RD) is associated with poor prognosis after stroke. We assessed the effects of RD on outcomes and interaction with low- versus standard-dose alteplase in a post hoc subgroup analysis of the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study). A total of 3220 thrombolysis-eligible patients with acute ischemic stroke (mean age, 66.5 years; 37.8% women) were randomly assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) intravenous alteplase within 4.5 hours of symptom onset. Six hundred and fifty-nine (19.8%) patients had moderate-to-severe RD (estimated glomerular filtration rate, <60 mL/min per 1.73 m 2 ) at baseline. The impact of RD on death or disability (modified Rankin Scale scores, 2-6) at 90 days, and symptomatic intracerebral hemorrhage, was assessed in logistic regression models. Compared with patients with normal renal function (>90 mL/min per 1.73 m 2 ), those with severe RD (<30 mL/min per 1.73 m 2 ) had increased mortality (adjusted odds ratio, 2.07; 95% confidence interval, 0.89-4.82; P =0.04 for trend); every 10 mL/min per 1.73 m 2 lower estimated glomerular filtration rate was associated with an adjusted 9% increased odds of death from thrombolysis-treated acute ischemic stroke. There was no significant association with modified Rankin Scale scores 2 to 6 (adjusted odds ratio, 1.03; 95% confidence interval, 0.62-1.70; P =0.81 for trend), modified Rankin Scale 3 to 6 (adjusted odds ratio, 1.20; 95% confidence interval, 0.72-2.01; P =0.44 for trend), or symptomatic intracerebral hemorrhage, or any heterogeneity in comparative treatment effects between low-dose and standard-dose alteplase by RD grades. RD is associated with increased mortality but not disability or symptomatic intracerebral hemorrhage in thrombolysis-eligible and treated acute ischemic stroke patients. Uncertainty persists as to whether low-dose alteplase confers benefits over standard-dose alteplase in acute ischemic stroke patients with RD. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01422616. © 2017 American Heart Association, Inc.

Effect of Punica granatum solvent extracts on immune system and disease resistance in Paralichthys olivaceus against lymphocystis disease virus (LDV).

PubMed

Harikrishnan, Ramasamy; Heo, Jaehyun; Balasundaram, Chellam; Kim, Man-Chul; Kim, Ju-Sang; Han, Yong-Jae; Heo, Moon-Soo

2010-10-01

We report the effect of aqueous, ethanol, and methanol solvent leaf extracts of Punica granatum on innate immune mechanisms, such as phagocytosis activity, respiratory burst activity, alternative complement activity, lysozyme activity and functional immunity in terms of percentage cumulative mortality and Relative Percent Survival (RPS) in olive flounder Paralichthys olivaceus naturally infected with lymphocystis disease virus (LDV) after 8 weeks. Infected fish were intraperitoneally administered with 0, 5, 50, and 100 mg kg(-1) body weight of solvent extracts. In groups treated with 50 and 100 mg kg(-1) body weight, the chosen innate immune parameters significantly increased after 8 weeks when compared to 0 mg kg(-1) dose, but not with 5 mg kg(-1). Administration of P. granatum solvent extracts for 8 weeks significantly reduced the percentage mortality with the consequent increase in RPS. The results suggest that intraperitoneal administration of the leaf extracts of P. granatum at 50 or 100 mg kg(-1) dose clearly enhance the innate immune responses and disease resistance after 8 weeks in P. olivaceus against natural LDV infection. Published by Elsevier Ltd.

Synthesis of 2,4-dihydroxychalcone derivatives as potential antidepressant effect.

PubMed

Guan, L-P; Zhao, D-H; Chang, Y; Wen, Z-S; Tang, L-M; Huang, F-F

2013-01-01

In this study, twelve 2,4-dihydroxychalcone derivatives were synthesized and evaluated for antidepressant activities using the forced swimming test (FST). The pharmacological test showed that 6 compounds significantly reduced the immobility times in the FST at a dose of 10 mg/kg, indicative of antidepressant activity. Among the derivatives, compounds designated 3d and 3 h exhibited the best antidepressant activity, with reduced immobility time by 32.05% and 34.33%, respectively. In the 5-hydroxytryptophan-induced head-twitch test and yohimbine-induced mortality test, compounds 3d and 3 h increased head-twitch and increased the mortality rate. The mechanisms of the antidepressant effects of compounds 3d and 3 h may be related with the 5-HTP and NE nervous system. © Georg Thieme Verlag KG Stuttgart · New York.

Long-term follow-up of the residents of the Three Mile Island accident area: 1979-1998.

PubMed

Talbott, Evelyn O; Youk, Ada O; McHugh-Pemu, Kathleen P; Zborowski, Jeanne V

2003-03-01

The Three Mile Island (TMI) nuclear power plant accident (1979) prompted the Pennsylvania Department of Health to initiate a cohort mortality study in the TMI accident area. This study is significant because of the long follow-up (1979-1998), large cohort size (32,135), and evidence from earlier reports indicating increased cancer risks. Standardized mortality ratios (SMRs) were calculated to assess the mortality experience of the cohort compared with a local population. Relative risk (RR) regression modeling was performed to assess cause-specific mortality associated with radiation-related exposure variables after adjustment for individual smoking and lifestyle factors. Overall cancer mortality in this cohort was similar to the local population [SMRs = 103.7 (male); 99.8 (female)]. RR modeling showed neither maximum gamma nor likely gamma exposure was a significant predictor of all malignant neoplasms; bronchus, trachea, and lung; or heart disease mortality after adjusting for known confounders. The RR estimates for maximum gamma exposure (less than or equal to 8, 8-19, 20-34, greater than or equal to 35 mrem) in relation to all lymphatic and hematopoietic tissue (LHT) are significantly elevated (RRs = 1.00, 1.16, 2.54, 2.45, respectively) for males and are suggestive of a potential dose-response relationship, although the test for trend was not significant. An upward trend of RRs and SMRs for levels of maximum gamma exposure in relation to breast cancer in females (RRs = 1.00, 1.08, 1.13, 1.31; SMRs = 104.2, 113.2, 117.9) was also noted. Although the surveillance within the TMI cohort provides no consistent evidence that radioactivity released during the nuclear accident has had a significant impact on the overall mortality experience of these residents, several elevations persist, and certain potential dose-response relationships cannot be definitively excluded.

An experimental vaccine against Aeromonas hydrophila can induce protection in rainbow trout, Oncorhynchus mykiss (Walbaum)

USGS Publications Warehouse

LaPatra, S.E.; Plant, K.P.; Alcorn, S.; Ostland, V.; Winton, J.

2010-01-01

A candidate vaccine against Aeromonas hydrophila in rainbow trout, Oncorhynchus mykiss, was developed using a bacterial lysate. To test the strength of protection, A. hydrophila challenge models were compared using injection into both the intraperitoneal (IP) cavity and the dorsal sinus (DS) with selected doses of live bacteria washed in saline or left untreated. Unlike the IP route, injection into the DS with either saline washed or unwashed cells resulted in consistent cumulative mortality and a dose response that could be used to establish a standard challenge having an LD50 of approximately 3 × 107 colony forming units per fish. Survivors of the challenge suffered significantly lower mortality upon re-challenge than naïve fish, suggesting a high level of acquired resistance was elicited by infection. Passive immunization using serum from hyper-immunized fish also resulted in significantly reduced mortality indicating protection can be transferred and that some portion of resistance may be antibody mediated. Vaccination of groups of rainbow trout with A. hydrophila lysate resulted in significant protection against a high challenge dose but only when injected along with Freund’s complete adjuvant. At a low challenge dose, mortality in all groups was low, but the bacterial lysate alone appeared to offer some protection.

Cancer Mortality Following Radiotherapy for Benign Gynecologic Disorders

PubMed Central

Sakata, Ritsu; Kleinerman, Ruth A.; Mabuchi, Kiyohiko; Stovall, Marilyn; Smith, Susan A.; Weathers, Rita; Wactawski-Wende, Jean; Cookfair, Diane L.; Boice, John D.; Inskip, Peter D.

2012-01-01

The purpose of this study is to quantify cancer mortality in relationship to organ-specific radiation dose among women irradiated for benign gynecologic disorders. Included in this study are 12,955 women treated for benign gynecologic disorders at hospitals in the Northeastern U.S. between 1925 and 1965; 9,770 women treated by radiation and 3,186 women treated by other methods. The average age at treatment was 45.9 years (range, 13–88 years), and the average follow-up period was 30.1 years (maximum, 69.9 years). Radiation doses to organs and active bone marrow were reconstructed by medical physicists using original radiotherapy records. The highest doses were received by the uterine cervix (median, 120 Gy) and uterine corpus (median, 34 Gy), followed by the bladder, rectum and colon (median, 1.7–7.2 Gy), with other abdominal organs receiving median doses ≤1 Gy and organs in the chest and head receiving doses <0.1 Gy. Standardized mortality rate ratios relative to the general U.S. population were calculated. Radiation-related risks were estimated in internal analyses using Poisson regression models. Mortality was significantly elevated among irradiated women for cancers of the uterine corpus, ovary, bladder, rectum, colon and brain, as well as for leukemia (exclusive of chronic lymphocytic leukemia) but not for cancer of the cervix, Hodgkin or non-Hodgkin lymphoma, multiple myeloma, or chronic lymphocytic leukemia. Evidence of a dose-response was seen for cancers of the ovary [excess relative risk (ERR) 0.31/Gy, P < 0.001], bladder (ERR = 0.21/Gy, P = 0.02) and rectum (ERR = 0.23/Gy, P = 0.05) and suggested for colon (ERR = 0.09/Gy, P = 0.10), but not for cancers of the uterine corpus or brain nor for non-chronic lymphocytic leukemia. Relative risks of mortality due to cancers of the stomach, pancreas, liver and kidney were close to 1.0, with no evidence of dose-response over the range of 0–1.5 Gy. Breast cancer was not significantly associated with dose to the breast or ovary. Mortality due to cancers of heavily irradiated organs remained elevated up to 40 years after irradiation. Significantly elevated radiation-related risk was seen for cancers of organs proximal to the radiation source or fields (bladder, rectum and ovary), as well as for non-chronic lymphocytic leukemia. Our results corroborate those from previous studies that suggest that cells of the uterine cervix and lymphopoietic system are relatively resistant to the carcinogenic effects of radiation. Studies of women irradiated for benign gynecologic disorders, together with studies of women treated with higher doses of radiation for uterine cancers, provide quantitative information on cancer risks associated with a broad range of pelvic radiation exposures. PMID:22856888

A Locomotor Deficit Induced by Sublethal Doses of Pyrethroid and Neonicotinoid Insecticides in the Honeybee Apis mellifera.

PubMed

Charreton, Mercédès; Decourtye, Axel; Henry, Mickaël; Rodet, Guy; Sandoz, Jean-Christophe; Charnet, Pierre; Collet, Claude

2015-01-01

The toxicity of pesticides used in agriculture towards non-targeted organisms and especially pollinators has recently drawn the attention from a broad scientific community. Increased honeybee mortality observed worldwide certainly contributes to this interest. The potential role of several neurotoxic insecticides in triggering or potentiating honeybee mortality was considered, in particular phenylpyrazoles and neonicotinoids, given that they are widely used and highly toxic for insects. Along with their ability to kill insects at lethal doses, they can compromise survival at sublethal doses by producing subtle deleterious effects. In this study, we compared the bee's locomotor ability, which is crucial for many tasks within the hive (e.g. cleaning brood cells, feeding larvae…), before and after an acute sublethal exposure to one insecticide belonging to the two insecticide classes, fipronil and thiamethoxam. Additionally, we examined the locomotor ability after exposure to pyrethroids, an older chemical insecticide class still widely used and known to be highly toxic to bees as well. Our study focused on young bees (day 1 after emergence) since (i) few studies are available on locomotion at this stage and (ii) in recent years, pesticides have been reported to accumulate in different hive matrices, where young bees undergo their early development. At sublethal doses (SLD48h, i.e. causing no mortality at 48 h), three pyrethroids, namely cypermethrin (2.5 ng/bee), tetramethrin (70 ng/bee), tau-fluvalinate (33 ng/bee) and the neonicotinoid thiamethoxam (3.8 ng/bee) caused a locomotor deficit in honeybees. While the SLD48h of fipronil (a phenylpyrazole, 0.5 ng/bee) had no measurable effect on locomotion, we observed high mortality several days after exposure, an effect that was not observed with the other insecticides. Although locomotor deficits observed in the sublethal range of pyrethroids and thiamethoxam would suggest deleterious effects in the field, the case of fipronil demonstrates that toxicity evaluation requires information on multiple endpoints (e.g. long term survival) to fully address pesticides risks for honeybees. Pyrethroid-induced locomotor deficits are discussed in light of recent advances regarding their mode of action on honeybee ion channels and current structure-function studies.

A Locomotor Deficit Induced by Sublethal Doses of Pyrethroid and Neonicotinoid Insecticides in the Honeybee Apis mellifera

PubMed Central

Charreton, Mercédès; Decourtye, Axel; Henry, Mickaël; Rodet, Guy; Sandoz, Jean-Christophe; Charnet, Pierre; Collet, Claude

2015-01-01

The toxicity of pesticides used in agriculture towards non-targeted organisms and especially pollinators has recently drawn the attention from a broad scientific community. Increased honeybee mortality observed worldwide certainly contributes to this interest. The potential role of several neurotoxic insecticides in triggering or potentiating honeybee mortality was considered, in particular phenylpyrazoles and neonicotinoids, given that they are widely used and highly toxic for insects. Along with their ability to kill insects at lethal doses, they can compromise survival at sublethal doses by producing subtle deleterious effects. In this study, we compared the bee’s locomotor ability, which is crucial for many tasks within the hive (e.g. cleaning brood cells, feeding larvae…), before and after an acute sublethal exposure to one insecticide belonging to the two insecticide classes, fipronil and thiamethoxam. Additionally, we examined the locomotor ability after exposure to pyrethroids, an older chemical insecticide class still widely used and known to be highly toxic to bees as well. Our study focused on young bees (day 1 after emergence) since (i) few studies are available on locomotion at this stage and (ii) in recent years, pesticides have been reported to accumulate in different hive matrices, where young bees undergo their early development. At sublethal doses (SLD48h, i.e. causing no mortality at 48h), three pyrethroids, namely cypermethrin (2.5 ng/bee), tetramethrin (70 ng/bee), tau-fluvalinate (33 ng/bee) and the neonicotinoid thiamethoxam (3.8 ng/bee) caused a locomotor deficit in honeybees. While the SLD48h of fipronil (a phenylpyrazole, 0.5 ng/bee) had no measurable effect on locomotion, we observed high mortality several days after exposure, an effect that was not observed with the other insecticides. Although locomotor deficits observed in the sublethal range of pyrethroids and thiamethoxam would suggest deleterious effects in the field, the case of fipronil demonstrates that toxicity evaluation requires information on multiple endpoints (e.g. long term survival) to fully address pesticides risks for honeybees. Pyrethroid-induced locomotor deficits are discussed in light of recent advances regarding their mode of action on honeybee ion channels and current structure-function studies. PMID:26659095

No effect of an additional early dose of measles vaccine on hospitalization or mortality in children: A randomized controlled trial.

PubMed

Schoeps, Anja; Nebié, Eric; Fisker, Ane Baerent; Sié, Ali; Zakane, Alphonse; Müller, Olaf; Aaby, Peter; Becher, Heiko

2018-04-05

Non-specific effects (NSEs) of vaccines have increasingly gained attention in recent years. Recent studies suggest that live vaccines, such as measles vaccine (MV), have beneficial effects on health, while inactivated vaccines, such as the diphtheria-tetanus-pertussis (DTP) vaccine, may have harmful effects. If this is the case, it should improve child health to move MV closer to the last vaccination with DTP. The objective of this study was to investigate the NSEs of an additional early dose of MV on hospitalization or mortality. Children were randomized to receive either the standard MV at 9 months (control) or an additional early dose of MV 4 weeks after the third dose of DTP-containing Pentavalent vaccine and the standard MV at 9 months (intervention). In this analysis of a secondary outcome in the trial, we investigated the effect of the intervention on a composite endpoint of over-night hospitalization with or without recovery, or death without previous hospitalization, in children between 4.5 and 36 months of age in the Nouna HDSS in Burkina Faso. We used Cox proportional hazards regression with repeated events and time since study enrolment as underlying time-scale. Among 2258 children in the intervention and 2238 children in the control group we observed a total of 464 episodes of hospitalization or mortality. There was no difference between intervention and control group (HR = 1.00, 95% Confidence Interval (CI) 0.83-1.20). Results from the per-protocol and intention-to-treat analysis were similar. Although no significant, results suggest a possible beneficial effect of early MV in children that had not been exposed to an OPV campaign after enrolment (HR = 0.83, 95% CI 0.55-1.29). We did not detect any effect of early MV on subsequent hospitalization or mortality. However, possible effects of early MV could have been obscured by NSEs of the frequent OPV campaigns. Registration: The trial was registered at ClinicalTrials.gov, NCT01644721. Copyright © 2018 Elsevier Ltd. All rights reserved.

Response of common grackles to dietary concentrations of four organophosphate pesticides

USGS Publications Warehouse

Grue, C.E.

1982-01-01

Behavioral and physiological responses of common grackles to dietary concentrations of dicrotophos, fenitrothion, fenthion, and methyl parathion suggest mortality was largely due to pesticide-induced anorexia. Mortality was dose related, though consumption of treated diets was reduced such that birds on different geometrically arranged concentrations of the same pesticide ingested about the same amount of toxicant. Grackles that died lost an average of 28 to 36% of their initial body weight; visible fat was absent and muscle tissue was reduced on the sternum. Mortality of birds exposed to dicrotophos increased between May and August, although chemical intake remained relatively constant, and was associated with a natural decrease in fat and flesh condition in response to increased ambient temperatures and post-nuptial molt. Food consumption in songbirds exposed to organophosphates may be reduced significantly up to 12 hr after exposure ceases because of an unknown effect of these chemicals on their feeding behavior, but not repellency. The results caution against using median lethal dietary concentrations for other than ranking chemicals based on their relative toxicity, particularly in establishing safe environmental levels, and suggest that anorexia and physiological condition may be important factors in mortality of wild birds exposed to organophosphates.

Lung cancer incidence and mortality in National Lung Screening Trial participants who underwent low-dose CT prevalence screening: a retrospective cohort analysis of a randomised, multicentre, diagnostic screening trial.

PubMed

Patz, Edward F; Greco, Erin; Gatsonis, Constantine; Pinsky, Paul; Kramer, Barnett S; Aberle, Denise R

2016-05-01

Annual low-dose CT screening for lung cancer has been recommended for high-risk individuals, but the necessity of yearly low-dose CT in all eligible individuals is uncertain. This study examined rates of lung cancer in National Lung Screening Trial (NLST) participants who had a negative prevalence (initial) low-dose CT screen to explore whether less frequent screening could be justified in some lower-risk subpopulations. We did a retrospective cohort analysis of data from the NLST, a randomised, multicentre screening trial comparing three annual low-dose CT assessments with three annual chest radiographs for the early detection of lung cancer in high-risk, eligible individuals (aged 55-74 years with at least a 30 pack-year history of cigarette smoking, and, if a former smoker, had quit within the past 15 years), recruited from US medical centres between Aug 5, 2002, and April 26, 2004. Participants were followed up for up to 5 years after their last annual screen. For the purposes of this analysis, our cohort consisted of all NLST participants who had received a low-dose CT prevalence (T0) screen. We determined the frequency, stage, histology, study year of diagnosis, and incidence of lung cancer, as well as overall and lung cancer-specific mortality, and whether lung cancers were detected as a result of screening or within 1 year of a negative screen. We also estimated the effect on mortality if the first annual (T1) screen in participants with a negative T0 screen had not been done. The NLST is registered with ClinicalTrials.gov, number NCT00047385. Our cohort consisted of 26 231 participants assigned to the low-dose CT screening group who had undergone their T0 screen. The 19 066 participants with a negative T0 screen had a lower incidence of lung cancer than did all 26 231 T0-screened participants (371·88 [95% CI 337·97-408·26] per 100 000 person-years vs 661·23 [622·07-702·21]) and had lower lung cancer-related mortality (185·82 [95% CI 162·17-211·93] per 100 000 person-years vs 277·20 [252·28-303·90]). The yield of lung cancer at the T1 screen among participants with a negative T0 screen was 0·34% (62 screen-detected cancers out of 18 121 screened participants), compared with a yield at the T0 screen among all T0-screened participants of 1·0% (267 of 26 231). We estimated that if the T1 screen had not been done in the T0 negative group, at most, an additional 28 participants in the T0 negative group would have died from lung cancer (a rise in mortality from 185·82 [95% CI 162·17-211·93] per 100 000 person-years to 212·14 [186·80-239·96]) over the course of the trial. Participants with a negative low-dose CT prevalence screen had a lower incidence of lung cancer and lung cancer-specific mortality than did all participants who underwent a prevalence screen. Because overly frequent screening has associated harms, increasing the interval between screens in participants with a negative low-dose CT prevalence screen might be warranted. None. Copyright © 2016 Elsevier Ltd. All rights reserved.

Outcomes in patients with chronic kidney disease not on dialysis receiving extended dosing regimens of darbepoetin alfa: long-term results of the EXTEND observational cohort study.

PubMed

Galle, Jan-Christoph; Addison, Janet; Suranyi, Michael G; Claes, Kathleen; Di Giulio, Salvatore; Guerin, Alain; Herlitz, Hans; Kiss, István; Farouk, Mourad; Manamley, Nick; Wirnsberger, Gerhard; Winearls, Christopher

2016-12-01

Extended dosing of the erythropoiesis-stimulating agent (ESA) darbepoetin alfa (DA) once biweekly or monthly reduces anaemia treatment burden. This observational study assessed outcomes and dosing patterns in patients with chronic kidney disease not on dialysis (CKD-NoD) commencing extended dosing of DA. Adult CKD-NoD patients starting extended dosing of DA in Europe or Australia in June 2006 or later were followed up until December 2012. Outcomes included haemoglobin (Hb) concentration, ESA dosing, mortality rates and receipt of dialysis and renal transplantation. Subgroup analyses were conducted for selected outcomes. Of 6035 enrolled subjects, 5723 (94.8%) met analysis criteria; 1795 (29.7%) received dialysis and 238 (3.9%) underwent renal transplantation. Mean (standard deviation) Hb concentration at commencement of extended dosing was 11.0 (1.5) g/dL. Mean [95% confidence interval (CI)] Hb 12 months after commencement of extended dosing (primary outcome) was 11.6 g/dL (11.5, 11.6) overall and was similar across countries, with no differences between subjects previously treated with an ESA versus ESA-naïve subjects, subjects with versus without prior renal transplant or diabetics versus non-diabetics. Weekly ESA dose gradually decreased following commencement of extended DA dosing and was similar across subgroups. The decrease in weekly DA dose was accompanied by an increase in the proportion of patients receiving iron therapy. Hb concentrations declined following changes in ESA labels and treatment guidelines. The mortality rate (95% CI) was 7.06 (6.68, 7.46) deaths per 100 years of follow-up. Subjects alive at study end had stable Hb concentrations in the preceding year, while those who died had lower and declining Hb concentrations in their last year. Long-term, extended dosing of DA maintained Hb concentrations in patients already treated with an ESA and corrected and maintained Hb in ESA-naïve patients. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA.

Similar clinical benefits from below-target and target dose enalapril in patients with heart failure in the SOLVD Treatment trial.

PubMed

Lam, Phillip H; Dooley, Daniel J; Fonarow, Gregg C; Butler, Javed; Bhatt, Deepak L; Filippatos, Gerasimos S; Deedwania, Prakash; Forman, Daniel E; White, Michel; Fletcher, Ross D; Arundel, Cherinne; Blackman, Marc R; Adamopoulos, Chris; Kanonidis, Ioannis E; Aban, Inmaculada B; Patel, Kanan; Aronow, Wilbert S; Allman, Richard M; Anker, Stefan D; Pitt, Bertram; Ahmed, Ali

2018-02-01

To examine associations of below-target and target dose of enalapril, an angiotensin-converting enzyme (ACE) inhibitor, with outcomes in patients with heart failure and reduced ejection fraction (HFrEF) in the Studies of Left Ventricular Dysfunction (SOLVD) Treatment trial. Two thousand five hundred and sixty-nine patients with HFrEF (ejection fraction ≤35%) were randomized to below-target (5-10 mg/day) dose placebo (n = 1284) or enalapril (n = 1285). One month post-randomization, blind up-titration to target (20 mg/day) dose was attempted for both study drugs in 2458 patients. Among the 1444 patients who achieved dose up-titration (placebo, n = 748; enalapril, n = 696; mean dose for both groups, 20.0 mg/day), target dose enalapril (vs. target dose placebo) was associated with a 9% absolute lower risk of the combined endpoint of heart failure hospitalization or all-cause mortality [adjusted hazard ratio (HR) 0.70; 95% confidence interval (CI) 0.60-0.81; P < 0.001] during 4 years of follow-up. Among the 1014 patients who could not achieve target dose (placebo, n = 486; enalapril, n = 528; mean dose for both groups, 8.8 mg/day), below-target dose enalapril (vs. below-target dose placebo) was associated with a 12% absolute lower risk of the combined endpoint of heart failure hospitalization or all-cause mortality (adjusted HR 0.68; 95% CI 0.57-0.81; P < 0.001). Among the 1224 patients receiving enalapril, target (vs. below-target) dose had no association with the combined endpoint of heart failure hospitalization or all-cause mortality (adjusted HR 1.04; 95% CI 0.87-1.23; P = 0.695). In patients with HFrEF, the clinical benefits of ACE inhibitors appear to be similar at both below-target and target doses. © 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.

Stomach Cancer Risk After Treatment for Hodgkin Lymphoma

PubMed Central

Morton, Lindsay M.; Dores, Graça M.; Curtis, Rochelle E.; Lynch, Charles F.; Stovall, Marilyn; Hall, Per; Gilbert, Ethel S.; Hodgson, David C.; Storm, Hans H.; Johannesen, Tom Børge; Smith, Susan A.; Weathers, Rita E.; Andersson, Michael; Fossa, Sophie D.; Hauptmann, Michael; Holowaty, Eric J.; Joensuu, Heikki; Kaijser, Magnus; Kleinerman, Ruth A.; Langmark, Frøydis; Pukkala, Eero; Vaalavirta, Leila; van den Belt-Dusebout, Alexandra W.; Fraumeni, Joseph F.; Travis, Lois B.; Aleman, Berthe M.; van Leeuwen, Flora E.

2013-01-01

Purpose Treatment-related stomach cancer is an important cause of morbidity and mortality among the growing number of Hodgkin lymphoma (HL) survivors, but risks associated with specific HL treatments are unclear. Patients and Methods We conducted an international case-control study of stomach cancer nested in a cohort of 19,882 HL survivors diagnosed from 1953 to 2003, including 89 cases and 190 matched controls. For each patient, we quantified cumulative doses of specific alkylating agents (AAs) and reconstructed radiation dose to the stomach tumor location. Results Stomach cancer risk increased with increasing radiation dose to the stomach (Ptrend < .001) and with increasing number of AA-containing chemotherapy cycles (Ptrend = .02). Patients who received both radiation to the stomach ≥ 25 Gy and high-dose procarbazine (≥ 5,600 mg/m2) had strikingly elevated stomach cancer risk (25 cases, two controls; odds ratio [OR], 77.5; 95% CI, 14.7 to 1452) compared with those who received radiation < 25 Gy and procarbazine < 5,600 mg/m2 (Pinteraction < .001). Risk was also elevated (OR, 2.8; 95% CI, 1.3 to 6.4) among patients who received radiation to the stomach ≥ 25 Gy but procarbazine < 5,600 mg/m2; however, no procarbazine-related risk was evident with radiation < 25 Gy. Treatment with dacarbazine also increased stomach cancer risk (12 cases, nine controls; OR, 8.8; 95% CI, 2.1 to 46.6), after adjustment for radiation and procarbazine doses. Conclusion Patients with HL who received subdiaphragmatic radiotherapy had dose-dependent increased risk of stomach cancer, with marked risks for patients who also received chemotherapy containing high-dose procarbazine. For current patients, risks and benefits of exposure to both procarbazine and subdiaphragmatic radiotherapy should be weighed carefully. For patients treated previously, GI symptoms should be evaluated promptly. PMID:23980092

Early prediction of norepinephrine dependency and refractory septic shock with a multimodal approach of vascular failure.

PubMed

Conrad, Marie; Perez, Pierre; Thivilier, Carine; Levy, Bruno

2015-08-01

The purpose of the study is to improve our ability to detect catecholamine dependency and refractory septic shock. Fifty-one patients with septic shock were studied within the first 4 hours of norepinephrine administration. Patients were divided into 2 groups according to their evolution in the intensive care unit, namely, group A, shock reversal, and group B, no shock reversal. Reversal of shock was defined as the maintenance of a systolic blood pressure greater than or equal to 90 mm Hg without vasopressor support for 24 hours or more. Vascular reactivity was tested using incremental doses of phenylephrine. Muscle tissue oxygen saturation and its changes during a vascular occlusion test were measured. Group B patients had a higher Sequential Organ Failure Assessment (SOFA) score and lactate level and more frequently received norepinephrine and renal replacement. Overall mortality was 100% in group B (16/16) and 20% (7/35) in group A. Phenylephrine increased mean arterial pressure in a dose-dependent manner more significantly in group A patients than in group B (P = .0004). Basal tissue oxygen saturation and the recovery slope after vascular occlusion test were lower in group B. In multivariate analysis, 4 parameters remained independently associated with mortality: the increase in mean arterial pressure at phenylephrine 6 μg/kg per minute, the recovery slope, SOFA score, and norepinephrine doses at H0. The intensity of septic shock-induced vascular hyporesponsiveness to vasopressor is tightly linked to septic shock severity and evolution and may potentially be identified early with simple to obtain parameters such as near-infrared spectroscopy value, SOFA score, or norepinephrine dose. Copyright © 2015 Elsevier Inc. All rights reserved.

Effects of two doses of anti-T lymphocyte globulin-Fresenius given after full-match sibling stem cell transplantation in acute myeloblastic leukemia patients who underwent myeloablative fludarabine/busulfan conditioning.

PubMed

Boga, Can; Yeral, Mahmut; Gereklioglu, Ciğdem; Asma, Suheyl; Maytalman, Erkan; Aytan, Pelin; Kozanoglu, Ilknur; Sariturk, Cagla; Ozdogu, Hakan

2018-02-20

Anti-T lymphocyte globulin Fresenius (rATG-F; ATG-Fresenius) and antithymocyte globulin (thymoglobulin), which are included in transplant protocols, are used to reduce the risk of chronic graft-versus-host disease (cGVHD) or suppress allograft rejection. Available clinical studies have been conducted in heterogenous patient populations and with different administration protocols including stem cell sources. Additionally, the pharmacokinetics of ATG is variable, and the clinically effective dose of rATG-F, in particular, is not exactly known. The aim of the study was to investigate the clinical outcomes of acute myeloid leukemia (AML) patients who underwent hemopoietic peripheral stem cell transplantation from full-matched sibling donors and given two different doses of r-ATG-F. This was a single-center, retrospective chart review conducted between July 2005 and July 2016. Sixty-nine consecutive AML patients who underwent transplant with fludarabine- and busulfan-based conditioning were included in the study. Patients in Group 1 received 15 mg/kg body weight rATG-F to 2013 (n = 46), and Group 2 received 30 mg/kg of rATG-F dose begining in 2013 to reduce to cGVHD (n = 23). Cyclosporine and methotrexate were used to treat acute GVHD (aGVHD) prophylaxis. Outcome parameters were compared between the groups. Although the recommended dose r-ATG-F had led to a decrease in the cumulative incidence of cGVHD (27 [58.7%] vs. 8 [34.8%]; p = .03), it also increased the infection rate at 1 year (3 [6.5%] vs. 4 [17.4%]; p = .02). The two groups were similar in terms of engraftment time, aGVHD, relapse, nonrelapse mortality, and rATG-F-related toxicity. A Cox regression model revealed that aGVHD III-IV was associated with increased nonrelapse mortality at 1 year (hazard ratio = 18.2; 95% confidence interval, 1.667-199.255; p = <.02). No patients developed rATG-F-related severe adverse events (Common Terminology Criteria grade 4 or 5). Dose difference of rATG-F did not influence survival parameters; however, increasing the dose to 30 mg/kg seems to be effective for reducing cGVHD with an increase in infection rate requiring close monitoring of infections in AML patients who received myeloablative fludarabine/busulfan conditioning. Copyright © 2018 King Faisal Specialist Hospital & Research Centre. Published by Elsevier B.V. All rights reserved.

Temporal changes in occupational sitting time in the Danish workforce and associations with all-cause mortality: results from the Danish work environment cohort study.

PubMed

van der Ploeg, Hidde P; Møller, Simone Visbjerg; Hannerz, Harald; van der Beek, Allard J; Holtermann, Andreas

2015-06-02

Prolonged sitting has been negatively associated with a range of non-communicably diseases. However, the role of occupational sitting is less clear, and little is known on the changes of occupational sitting in a working population over time. The present study aimed to determine 1) temporal changes in occupational sitting time between 1990 and 2010 in the Danish workforce; 2) the association and possible dose-response relationship between occupational sitting time and all-cause mortality. This study analysed data from the Danish Work Environment Cohort Study (DWECS), which is a cohort study of the Danish working population conducted in five yearly intervals between 1990 and 2010. Occupational sitting time is self-reported in the DWECS. To determine the association with all-cause mortality, the DWECS was linked to the Danish Register of Causes of Death via the Central Person Register. Between 1990 and 2010 the proportion of the Danish workforce who sat for at least three quarters of their work time gradually increased from 33.1 to 39.1%. All-cause mortality analyses were performed with 149,773 person-years of observation and an average follow-up of 12.61 years, during which 533 deaths were registered. None of the presented analyses found a statistically significant association between occupational sitting time and all-cause mortality. The hazard ratio for all-cause mortality was 0.97 (95% CI: 0.79; 1.18) when ≥24 hr/wk occupational sitting time was compared to <24 hr/wk for the 1990-2005 waves. Occupational sitting time increased by 18% in the Danish workforce, which seemed to be limited to people with high socio-economic status. If this increase is accompanied by increases in total sitting time, this development has serious public health implications, given the detrimental associations between total sitting time and mortality. The current study was inconclusive on the specific role that occupational sitting might play in the increased all-cause mortality risk associated with the total volume of sitting.

Recurrent spontaneous motor seizures after repeated low-dose systemic treatment with kainate: assessment of a rat model of temporal lobe epilepsy.

PubMed

Hellier, J L; Patrylo, P R; Buckmaster, P S; Dudek, F E

1998-06-01

Human temporal lobe epilepsy is associated with complex partial seizures that can produce secondarily generalized seizures and motor convulsions. In some patients with temporal lobe epilepsy, the seizures and convulsions occur following a latent period after an initial injury and may progressively increase in frequency for much of the patient's life. Available animal models of temporal lobe epilepsy are produced by acute treatments that often have high mortality rates and/or are associated with a low proportion of animals developing spontaneous chronic motor seizures. In this study, rats were given multiple low-dose intraperitoneal (i.p.) injections of kainate in order to minimize the mortality rate usually associated with single high-dose injections. We tested the hypothesis that these kainate-treated rats consistently develop a chronic epileptic state (i.e. long-term occurrence of spontaneous, generalized seizures and motor convulsions) following a latent period after the initial treatment. Kainate (5 mg/kg per h, i.p.) was administered to rats every hour for several hours so that class III-V seizures were elicited for > or = 3 h, while control rats were treated similarly with saline. This treatment protocol had a relatively low mortality rate (15%). After acute treatment, rats were observed for the occurrence of motor seizures for 6-8 h/week. Nearly all of the kainate-treated rats (97%) had two or more spontaneous motor seizures months after treatment. With this observation protocol, the average latency for the first spontaneous motor seizure was 77+/-38 (+/-S.D.) days after treatment. Although variability was observed between rats, seizure frequency initially increased with time after treatment, and nearly all of the kainate-treated rats (91%) had spontaneous motor seizures until the time of euthanasia (i.e. 5-22 months after treatment). Therefore, multiple low-dose injections of kainate, which cause recurrent motor seizures for > or = 3 h, lead to the development of a chronic epileptic state that is characterized by (i) a latent period before the onset of chronic motor seizures, and (ii) a high but variable seizure frequency that initially increases with time after the first chronic seizure. This modification of the kainate-treatment protocol is efficient and relatively simple, and the properties of the chronic epileptic state appear similar to severe human temporal lobe epilepsy. Furthermore, the observation that seizure frequency initially increased as a function of time after kainate treatment supports the hypothesis that temporal lobe epilepsy can be a progressive syndrome.

Filgrastim Improves Survival in Lethally Irradiated Nonhuman Primates

PubMed Central

Farese, Ann M.; Cohen, Melanie V.; Katz, Barry P.; Smith, Cassandra P.; Gibbs, Allison; Cohen, Daniel M.; MacVittie, Thomas J.

2015-01-01

Treatment of individuals exposed to potentially lethal doses of radiation is of paramount concern to health professionals and government agencies. We evaluated the efficacy of filgrastim to increase survival of nonhuman primates (NHP) exposed to an approximate mid-lethal dose (LD50/60) (7.50 Gy) of LINAC-derived photon radiation. Prior to total-body irradiation (TBI), nonhuman primates were randomized to either a control (n =22) or filgrastim-treated (n =24) cohorts. Filgrastim (10 μg/kg/d) was administered beginning 1 day after TBI and continued daily until the absolute neutrophil count (ANC) was >1,000/μL for 3 consecutive days. All nonhuman primates received medical management as per protocol. The primary end point was all cause overall mortality over the 60 day in-life study. Secondary end points included mean survival time of decedents and all hematologic-related parameters. Filgrastim significantly (P < 0.004) reduced 60 day overall mortality [20.8% (5/24)] compared to the controls [59.1% (13/22)]. Filgrastim significantly decreased the duration of neutropenia, but did not affect the absolute neutrophil count nadir. Febrile neutropenia (ANC <500/μL and body temperature ≥103°F) was experienced by 90.9% (20/22) of controls compared to 79.2% (19/24) of filgrastim-treated animals (P = 0.418). Survival was significantly increased by 38.3% over controls. Filgrastim, administered at this dose and schedule, effectively mitigated the lethality of the hematopoietic subsyndrome of the acute radiation syndrome. PMID:23210705

Optimal dose selection of N-methyl-N-nitrosourea for the rat comet assay to evaluate DNA damage in organs with different susceptibility to cytotoxicity.

PubMed

Kitamoto, Sachiko; Matsuyama, Ryoko; Uematsu, Yasuaki; Ogata, Keiko; Ota, Mika; Yamada, Toru; Miyata, Kaori; Funabashi, Hitoshi; Saito, Koichi

2015-07-01

The in vivo rodent alkaline comet assay (comet assay) is a promising technique to evaluate DNA damage in vivo. However, there is no agreement on a method to evaluate DNA damage in organs where cytotoxicity is observed. As a part of the Japanese Center for the Validation of Alternative Methods (JaCVAM)-initiative international validation study of the comet assay, we examined DNA damage in the liver, stomach, and bone marrow of rats given three oral doses of N-methyl-N-nitrosourea (MNU) up to the maximum tolerated dose based on systemic toxicity. MNU significantly increased the % tail DNA in all the organs. Histopathological analysis showed no cytotoxic effect on the liver, indicating clearly that MNU has a genotoxic potential in the liver. In the stomach, however, the cytotoxic effects were very severe at systemically non-toxic doses. Low-dose MNU significantly increased the % tail DNA even at a non-cytotoxic dose, indicating that MNU has a genotoxic potential also in the stomach. Part of the DNA damage at cytotoxic doses was considered to be a secondary effect of severe cell damage. In the bone marrow, both the % tail DNA and incidence of micronucleated polychromatic erythrocytes significantly increased at non-hematotoxic doses, which were different from the non-cytotoxic doses for liver and stomach. These findings indicate that an optimal dose for detecting DNA damage may vary among organs and that careful attention is required to select an optimum dose for the comet assay based on systemic toxicity such as mortality and clinical observations. The present study shows that when serious cytotoxicity is suggested by increased % hedgehogs in the comet assay, histopathological examination should be included for the evaluation of a positive response. Copyright © 2015 Elsevier B.V. All rights reserved.

Antimicrobial drug use and risk factors associated with treatment incidence and mortality in Swiss veal calves reared under improved welfare conditions.

PubMed

Lava, M; Schüpbach-Regula, G; Steiner, A; Meylan, M

2016-04-01

Ninety-one Swiss veal farms producing under a label with improved welfare standards were visited between August and December 2014 to investigate risk factors related to antimicrobial drug use and mortality. All herds consisted of own and purchased calves, with a median of 77.4% of purchased calves. The calves' mean age was 29±15days at purchasing and the fattening period lasted at average 120±28 days. The mean carcass weight was 125±12kg. A mean of 58±33 calves were fattened per farm and year, and purchased calves were bought from a mean of 20±17 farms of origin. Antimicrobial drug treatment incidence was calculated with the defined daily dose methodology. The mean treatment incidence (TIADD) was 21±15 daily doses per calf and year. The mean mortality risk was 4.1%, calves died at a mean age of 94±50 days, and the main causes of death were bovine respiratory disease (BRD, 50%) and gastro-intestinal disease (33%). Two multivariable models were constructed, for antimicrobial drug treatment incidence (53 farms) and mortality (91 farms). No quarantine, shared air space for several groups of calves, and no clinical examination upon arrival at the farm were associated with increased antimicrobial treatment incidence. Maximum group size and weight differences >100kg within a group were associated with increased mortality risk, while vaccination and beef breed were associated with decreased mortality risk. The majority of antimicrobial treatments (84.6%) were given as group treatments with oral powder fed through an automatic milk feeding system. Combination products containing chlortetracycline with tylosin and sulfadimidine or with spiramycin were used for 54.9%, and amoxicillin for 43.7% of the oral group treatments. The main indication for individual treatment was BRD (73%). The mean age at the time of treatment was 51 days, corresponding to an estimated weight of 80-100kg. Individual treatments were mainly applied through injections (88.5%), and included administration of fluoroquinolones in 38.3%, penicillines (amoxicillin or benzylpenicillin) in 25.6%, macrolides in 13.1%, tetracyclines in 12.0%, 3th and 4th generation cephalosporines in 4.7%, and florfenicol in 3.9% of the cases. The present study allowed for identifying risk factors for increased antimicrobial drug treatment and mortality. This is an important basis for future studies aiming at reducing treatment incidence and mortality in veal farms. Our results indicate that improvement is needed in the selection of drugs for the treatment of veal calves according to the principles of prudent use of antibiotics. Copyright © 2016 Elsevier B.V. All rights reserved.

Long-term safety of cilostazol in patients with peripheral artery disease: the CASTLE study (Cilostazol: A Study in Long-term Effects).

PubMed

Hiatt, William R; Money, Samuel R; Brass, Eric P

2008-02-01

Cilostazol, a phosphodiesterase III inhibitor, is indicated to treat the symptoms of intermittent claudication and increase walking distance in patients with peripheral arterial disease (PAD). At the time of approval, the United States Food and Drug Administration required an additional long-term safety study to evaluate the effect cilostazol on mortality. A total of 1899 subjects with a clinical diagnosis of PAD and symptoms of claudication were screened for participation in a randomized, double-blinded, placebo-controlled safety study of cilostazol. The intent-to-treat (ITT) population, which was the primary analysis (n = 1435), was defined as all randomized patients who received at least one dose of study medication and included patients who were followed up >30 days after discontinuation of study drug. A total of 717 patients received cilostazol and 718 received placebo. Cilostazol was administered at a primary dose of 100 mg twice daily. The dose could be reduced to 50 mg twice daily if patients experienced an adverse event that might have been drug related. Long-term adherence to study medication was poor, with >60% of participants discontinuing therapy by 36 months. The mortality analysis therefore focused on deaths during the period on-treatment, defined as the period during which the study drug was taken plus a 30-day follow-up period after dosing. Total patient-years of exposure were 1046 on-treatment for cilostazol and 1090 for placebo. On-treatment, there were 18 deaths on cilostazol and 19 deaths on placebo for a hazard ratio of 0.99 (95% confidence interval [CI], 0.52-1.88). Cardiovascular deaths on-treatment occurred in 14 patients on cilostazol and 14 on placebo. In the full ITT population at 36 months, there were 101 deaths, 49 on cilostazol and 52 on placebo, with hazard ratio of 0.94 (95% CI, 0.64-1.39). Thus, most deaths occurred >30 days after study drug discontinuation. Serious bleeding events affected 18 patients taking cilostazol in the on-treatment population and 22 taking placebo. The rates of bleeding events were similar in patients who used aspirin, aspirin plus clopidogrel, or anticoagulants at anytime during the course of the study This long-term study demonstrated no safety signal for cilostazol on all-cause or cardiovascular mortality. The study, however, was underpowered to detect a small adverse impact of cilostazol on mortality (hazard ratio upper bound of the 95% CI was 1.88 in the on-treatment population). Serious bleeding events appeared not to be increased by cilostazol.

Dietary magnesium intake and the risk of cardiovascular disease, type 2 diabetes, and all-cause mortality: a dose-response meta-analysis of prospective cohort studies.

PubMed

Fang, Xuexian; Wang, Kai; Han, Dan; He, Xuyan; Wei, Jiayu; Zhao, Lu; Imam, Mustapha Umar; Ping, Zhiguang; Li, Yusheng; Xu, Yuming; Min, Junxia; Wang, Fudi

2016-12-08

Although studies have examined the association between dietary magnesium intake and health outcome, the results are inconclusive. Here, we conducted a dose-response meta-analysis of prospective cohort studies in order to investigate the correlation between magnesium intake and the risk of cardiovascular disease (CVD), type 2 diabetes (T2D), and all-cause mortality. PubMed, EMBASE, and Web of Science were searched for articles that contained risk estimates for the outcomes of interest and were published through May 31, 2016. The pooled results were analyzed using a random-effects model. Forty prospective cohort studies totaling more than 1 million participants were included in the analysis. During the follow-up periods (ranging from 4 to 30 years), 7678 cases of CVD, 6845 cases of coronary heart disease (CHD), 701 cases of heart failure, 14,755 cases of stroke, 26,299 cases of T2D, and 10,983 deaths were reported. No significant association was observed between increasing dietary magnesium intake (per 100 mg/day increment) and the risk of total CVD (RR: 0.99; 95% CI, 0.88-1.10) or CHD (RR: 0.92; 95% CI, 0.85-1.01). However, the same incremental increase in magnesium intake was associated with a 22% reduction in the risk of heart failure (RR: 0.78; 95% CI, 0.69-0.89) and a 7% reduction in the risk of stroke (RR: 0.93; 95% CI, 0.89-0.97). Moreover, the summary relative risks of T2D and mortality per 100 mg/day increment in magnesium intake were 0.81 (95% CI, 0.77-0.86) and 0.90 (95% CI, 0.81-0.99), respectively. Increasing dietary magnesium intake is associated with a reduced risk of stroke, heart failure, diabetes, and all-cause mortality, but not CHD or total CVD. These findings support the notion that increasing dietary magnesium might provide health benefits.

Amiodarone therapy in chronic heart failure and myocardial infarction: a review of the mortality trials with special attention to STAT-CHF and the GESICA trials. Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina.

PubMed

Pinto, J V; Ramani, K; Neelagaru, S; Kown, M; Gheorghiade, M

1997-01-01

Amiodarone appears to reduce sudden death in patients with left ventricular dysfunction resulting from an acute MI or a primary dilated cardiomyopathy, particularly if complex ventricular arrhythmias are present. Amiodarone's beneficial effect on mortality in these patients could be unrelated to its antiarrhythmic effects. Multiple factors could account for the improvement in mortality such as the drug's antiischemic effects, neuromodulating effects, its effect on left ventricular function and on heart rate. Moreover, patients with LV dysfunction who have survived an episode of sudden death would potentially benefit from amiodarone therapy. Future trials are needed to determine the precise subsets(s) of patients who would benefit from the drug and the most efficacious dosing regimen for the drug. Based on available data, amiodarone is the only antiarrhythmic agent which has not been shown to increase mortality in patients with chronic heart failure.

Improving the biocontrol potential of Steinernema feltiae against Delia radicum through dosage, application technique and timing.

PubMed

Beck, Bert; Spanoghe, Pieter; Moens, Maurice; Brusselman, Eva; Temmerman, Femke; Pollet, Sabien; Nuyttens, David

2014-05-01

The potential of the entomopathogenic nematode (EPN) Steinernema feltiae Filipjev as a biocontrol agent against the cabbage maggot Delia radicum (L.), was assessed in three field tests, focusing on EPN dosage, application technique and timing. Spraying cabbage plant trays with different doses of infective juveniles (IJs) (50,000, 100,000 and 200,000 per plant) generated a similar reduction of plant mortality. Spraying plant trays with 200,000 IJs of Steinernema feltiae per plant temporarily reduced the number of maggots around the plants' roots, while neither spraying a lower dose (50,000 IJs/plant) nor soil drenching with 200,000 or 50,000 IJs/plant) reduced maggot numbers. When applied as a plant tray spray, IJs of S. feltiae took 1-2 weeks to spread through the soil surrounding the roots. The pathogenicity of the EPNs, as evaluated by a Galleria mellonella bait test, was highest (up to 100% mortality) until up to five weeks after application, and declined to control levels after 4-7 weeks. Follow-up drench applications with EPNs, applied one and/or two weeks after the first EPN application, did not influence control of Delia radicum. Plant tray spraying provides better placement of Steinernema feltiae than soil drench treatments for control of Delia radicum. Plant mortality was not dose-dependent in the presented trials, unlike the reduction of maggot numbers. Further research into timing and application technique of follow-up treatments with S. feltiae is required to increase efficacy to commercial standards. © 2013 Society of Chemical Industry.

Thiamine in septic shock patients with alcohol use disorders: An observational pilot study.

PubMed

Holmberg, Mathias Johan; Moskowitz, Ari; Patel, Parth Vijay; Grossestreuer, Anne Victoria; Uber, Amy; Stankovic, Nikola; Andersen, Lars Wiuff; Donnino, Michael William

2018-02-01

Alcohol-use disorders (AUDs) have been associated with increased sepsis-related mortality. As patients with AUDs are often thiamine deficient, we investigated practice patterns relating to thiamine administration in patients with AUDs presenting with septic shock and explored the association between receipt of thiamine and mortality. We performed a retrospective cohort study of patients presenting with septic shock between 2008 and 2014 at a single tertiary care center. We identified patients with an AUD diagnosis, orders for microbial cultures and use of antibiotics, vasopressor dependency, and lactate levels≥4mmol/L. We excluded those who received thiamine later than 48h of sepsis onset. We included 53 patients. Thirty-four (64%) patients received thiamine. Five patients (15%) received their first thiamine dose in the emergency department. The median time to thiamine administration was 9 (quartiles: 4, 18) hours. The first thiamine dose was most often given parenterally (68%) and for 100mg (88%). In those receiving thiamine, 15/34 (44%) died, compared to 15/19 (79%) of those not receiving thiamine, p=0.02. A considerable proportion of patients with AUDs admitted for septic shock do not receive thiamine. Thiamine administration in this patient population was associated with decreased mortality. Copyright © 2017 Elsevier Inc. All rights reserved.

Hypnotic drug risks of mortality, infection, depression, and cancer: but lack of benefit

PubMed Central

Kripke, Daniel F.

2016-01-01

This is a review of hypnotic drug risks and benefits, reassessing and updating advice presented to the Commissioner of the Food and Drug Administration (United States FDA). Almost every month, new information appears about the risks of hypnotics (sleeping pills). This review includes new information on the growing USA overdose epidemic, eight new epidemiologic studies of hypnotics’ mortality not available for previous compilations, and new emphasis on risks of short-term hypnotic prescription. The most important risks of hypnotics include excess mortality, especially overdose deaths, quiet deaths at night, infections, cancer, depression and suicide, automobile crashes, falls, and other accidents, and hypnotic-withdrawal insomnia. The short-term use of one-two prescriptions is associated with greater risk per dose than long-term use. Hypnotics are usually prescribed without approved indication, most often with specific contraindications, but even when indicated, there is little or no benefit. The recommended doses objectively increase sleep little if at all, daytime performance is often made worse, not better, and the lack of general health benefits is commonly misrepresented in advertising. Treatments such as the cognitive behavioral treatment of insomnia and bright light treatment of circadian rhythm disorders might offer safer and more effective alternative approaches to insomnia. PMID:27303633

Assessing Aromatic-Hydrocarbon Toxicity to Fish Early Life Stages Using Passive-Dosing Methods and Target-Lipid and Chemical-Activity Models.

PubMed

Butler, Josh D; Parkerton, Thomas F; Redman, Aaron D; Letinski, Daniel J; Cooper, Keith R

2016-08-02

Aromatic hydrocarbons (AH) are known to impair fish early life stages (ELS). However, poorly defined exposures often confound ELS-test interpretation. Passive dosing (PD) overcomes these challenges by delivering consistent, controlled exposures. The objectives of this study were to apply PD to obtain 5 d acute embryo lethality and developmental data and 30 d chronic embryo-larval survival and growth-effects data using zebrafish with different AHs; to analyze study and literature toxicity data using target-lipid (TLM) and chemical-activity (CA) models; and to extend PD to a mixture and test the assumption of AH additivity. PD maintained targeted exposures over a concentration range of 6 orders of magnitude. AH toxicity increased with log Kow up to pyrene (5.2). Pericardial edema was the most sensitive sublethal effect that often preceded embryo mortality, although some AHs did not produce developmental effects at concentrations causing mortality. Cumulative embryo-larval mortality was more sensitive than larval growth, with acute-to-chronic ratios of <10. More-hydrophobic AHs did not exhibit toxicity at aqueous saturation. The relationship and utility of the TLM-CA models for characterizing fish ELS toxicity is discussed. Application of these models indicated that concentration addition provided a conservative basis for predicting ELS effects for the mixture investigated.

Clinical features of gastroduodenal injury associated with long-term low-dose aspirin therapy

PubMed Central

Iwamoto, Junichi; Saito, Yoshifumi; Honda, Akira; Matsuzaki, Yasushi

2013-01-01

Low-dose aspirin (LDA) is clinically used for the prevention of cardiovascular and cerebrovascular events with the advent of an aging society. On the other hand, a very low dose of aspirin (10 mg daily) decreases the gastric mucosal prostaglandin levels and causes significant gastric mucosal damage. The incidence of LDA-induced gastrointestinal mucosal injury and bleeding has increased. It has been noticed that the incidence of LDA-induced gastrointestinal hemorrhage has increased more than that of non-aspirin non-steroidal anti-inflammatory drug (NSAID)-induced lesions. The pathogenesis related to inhibition of cyclooxygenase (COX)-1 includes reduced mucosal flow, reduced mucus and bicarbonate secretion, and impaired platelet aggregation. The pathogenesis related to inhibition of COX-2 involves reduced angiogenesis and increased leukocyte adherence. The pathogenic mechanisms related to direct epithelial damage are acid back diffusion and impaired platelet aggregation. The factors associated with an increased risk of upper gastrointestinal (GI) complications in subjects taking LDA are aspirin dose, history of ulcer or upper GI bleeding, age > 70 years, concomitant use of non-aspirin NSAIDs including COX-2-selective NSAIDs, and Helicobacter pylori (H. pylori) infection. Moreover, no significant differences have been found between ulcer and non-ulcer groups in the frequency and severity of symptoms such as nausea, acid regurgitation, heartburn, and bloating. It has been shown that the ratios of ulcers located in the body, fundus and cardia are significantly higher in bleeding patients than the ratio of gastroduodenal ulcers in patients taking LDA. Proton pump inhibitors reduce the risk of developing gastric and duodenal ulcers. In contrast to NSAID-induced gastrointestinal ulcers, a well-tolerated histamine H2-receptor antagonist is reportedly effective in prevention of LDA-induced gastrointestinal ulcers. The eradication of H. pylori is equivalent to treatment with omeprazole in preventing recurrent bleeding. Continuous aspirin therapy for patients with gastrointestinal bleeding may increase the risk of recurrent bleeding but potentially reduces the mortality rates, as stopping aspirin therapy is associated with higher mortality rates. It is very important to prevent LDA-induced gastroduodenal ulcer complications including bleeding, and every effort should be exercised to prevent the bleeding complications. PMID:23555156

Dose-dependent increases in flow-mediated dilation following acute cocoa ingestion in healthy older adults

PubMed Central

Feehan, Robert P.; Kunselman, Allen R.; Preston, Amy G.; Miller, Debra L.; Lott, Mary E. J.

2011-01-01

An inverse relation exists between intake of flavonoid-rich foods, such as cocoa, and cardiovascular-related mortality. Favorable effects of flavonoids on the endothelium may underlie these associations. We performed a randomized, double-blind, placebo-controlled study to test the hypothesis that acute cocoa ingestion dose dependently increases endothelium-dependent vasodilation, as measured by an increase in brachial artery flow-mediated dilation (FMD), in healthy older adults. Measurements were obtained before (preingestion) and after (1- and 2-h postingestion) ingestion of 0 (placebo), 2, 5, 13, and 26 g of cocoa in 23 adults (63 ± 2 yr old, mean ± SE). Changes in brachial artery FMD 1- and 2-h postingestion compared with preingestion were used to determine the effects of cocoa. FMD was unchanged 1 (Δ−0.3 ± 0.2%)- and 2-h (Δ0.1 ± 0.1%) after placebo (0 g cocoa). In contrast, FMD increased both 1-h postingestion (2 g cocoa Δ0.0 ± 0.2%, 5 g cocoa Δ0.8 ± 0.3%, 13 g cocoa Δ1.0 ± 0.3%, and 26 g cocoa Δ1.6 ± 0.3%: P < 0.05 compared with placebo for 5, 13, and 26 g cocoa) and 2-h postingestion (2 g cocoa Δ0.5 ± 0.3%, 5 g cocoa Δ1.0 ± 0.3%, 13 g cocoa Δ1.4 ± 0.2%, and 26 g cocoa Δ2.5 ± 0.4%: P < 0.05 compared with placebo for 5, 13, and 26 g cocoa) on the other study days. A serum marker of cocoa ingestion (total epicatechin) correlated with increased FMD 1- and 2-h postingestion (r = 0.44–0.48; both P < 0.05). Collectively, these results indicate that acute cocoa ingestion dose dependently increases brachial artery FMD in healthy older humans. These responses may help to explain associations between flavonoid intake and cardiovascular-related mortality in humans. PMID:21903881

Childhood mortality impact and costs of integrating vitamin A supplementation into immunization campaigns.

PubMed Central

Ching, P; Birmingham, M; Goodman, T; Sutter, R; Loevinsohn, B

2000-01-01

Country-specific activity and coverage data were used to estimate the childhood mortality impact (deaths averted) and costs of integrating vitamin A supplements into immunization campaigns conducted in 1998 and 1999. More than 94 million doses of vitamin A were administered in 41 countries in 1998, helping to avert nearly 169,000 deaths. During 1999, delivery of more than 97 million doses in 50 countries helped avert an estimated 242,000 deaths. The estimated incremental cost per death averted was US$72 (range: 36-142) in 1998 and US$64 (range: 32-126) in 1999. The estimated average total cost of providing supplementation per death averted was US$310 (range: 157-609) in 1998 and US$276 (range: 139-540) in 1999. Costs per death averted varied by campaign, depending on the number and proportion of the child population reached, number of doses received per child, and child mortality rates. PMID:11029982

Extended release amoxicillin/clavulanate: optimizing a product for respiratory infections based on pharmacodynamic principles.

PubMed

Jacobs, Michael R

2005-06-01

Acute bacterial respiratory tract infections cause a great deal of human morbidity and mortality. Treatment guidelines for these infections include macrolides, doxycycline, beta-lactams and beta-lactam/beta-lactamase inhibitor combinations such as amoxicillin/clavulanic acid to provide coverage for the common respiratory pathogens, including penicillin and macrolide nonsusceptible Streptococcus pneumoniae, as well as beta-lactamase-producing Haemophilus influenzae and Moraxella catarrhalis. In response to recent guidelines recommending higher dose amoxicillin to extend coverage to a higher percentage of S. pneumoniae, a new formulation of amoxicillin/clavulanic acid was developed. This formulation includes a higher amoxicillin dose, with part of the amoxicillin dose being in an extended release formulation, without increasing the clavulanate dose, for twice-daily oral treatment of these infections. Clinical studies of community-acquired pneumonia and acute rhinosinusitis have shown that the new formulation is well tolerated and highly efficacious, with clinical outcomes equivalent to comparators.

Long-term antipsychotic and benzodiazepine use and brain volume changes in schizophrenia: The Northern Finland Birth Cohort 1966 study.

PubMed

Huhtaniska, Sanna; Jääskeläinen, Erika; Heikka, Tuomas; Moilanen, Jani S; Lehtiniemi, Heli; Tohka, Jussi; Manjón, José V; Coupé, Pierrick; Björnholm, Lassi; Koponen, Hannu; Veijola, Juha; Isohanni, Matti; Kiviniemi, Vesa; Murray, Graham K; Miettunen, Jouko

2017-08-30

High doses of antipsychotics have been associated with loss in cortical and total gray matter in schizophrenia. However, previous imaging studies have not taken benzodiazepine use into account, in spite of evidence suggesting adverse effects such as cognitive impairment and increased mortality. In this Northern Finland Birth Cohort 1966 study, 69 controls and 38 individuals with schizophrenia underwent brain MRI at the ages of 34 and 43 years. At baseline, the average illness duration was over 10 years. Brain structures were delineated using an automated volumetry system, volBrain, and medication data on cumulative antipsychotic and benzodiazepine doses were collected using medical records and interviews. We used linear regression with intracranial volume and sex as covariates; illness severity was also taken into account. Though both medication doses associated to volumetric changes in subcortical structures, after adjusting for each other and the average PANSS total score, higher scan-interval antipsychotic dose associated only to volume increase in lateral ventricles and higher benzodiazepine dose associated with volume decrease in the caudate nucleus. To our knowledge, there are no previous studies reporting associations between benzodiazepine dose and brain structural changes. Further studies should focus on how these observations correspond to cognition and functioning. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Developmental toxicity of diphenyl ether herbicides in nestling American kestrels

USGS Publications Warehouse

Hoffman, D.J.; Spann, J.W.; LeCaptain, L.J.; Bunck, C.M.; Rattner, B.A.

1991-01-01

Beginning the day after hatching, American kestrel (Falco sparverius) nestlings were orally dosed for 10 consecutive days with 5 microliters/g of corn oil (controls) or one of the diphenyl ether herbicides (nitrofen, bifenox, or oxyfluorfen) at concentrations of 10, 50, 250, or 500 mg/kg in corn oil. At 500 mg/kg, nitrofen resulted in complete nestling mortality, bifenox in high (66%) mortality, and oxyfluorfen in no mortality. Nitrofen at 250 mg/kg reduced nestling growth as reflected by decreased body weight, crownrump length, and bone lengths including humerus, radiusulna, femur, and tibiotarsus. Bifenox at 250 mg/kg had less effect on growth than nitrofen, but crownrump, humerus, radiusulna, and femur were significantly shorter than controls. Liver weight as a percent of body weight increased with 50 and 250 mg/kg nitrofen. Other manifestations of impending hepatotoxicity following nitrofen ingestion included increased hepatic GSH peroxidase activity in all nitrofentreated groups, and increased plasma enzyme activities for ALT, AST, and LDHL in the 250mg/kg group. Bifenox ingestion resulted in increased hepatic GSH peroxidase activity in the 50and 250mg/kg groups. Nitrofen exposure also resulted in an increase in total plasma thyroxine (T4) concentration. These findings suggest that altricial nestlings are more sensitive to diphenyl ether herbicides than young or adult birds of precocial species.

Effect of probiotic culture water on growth, mortality, and feed conversion ratio of Vaname shrimp (Litopenaeus vannamei Boone)

NASA Astrophysics Data System (ADS)

Bachruddin, M.; Sholichah, M.; Istiqomah, S.; Supriyanto, A.

2018-04-01

This study was aimed to determine the effect of various dose of probiotics in the culture water to the growth and mortality of Vaname shrimp. This study consist of treatment control and treatment of various dose of probiotics. Control (0 mL/10 L water), P1 (1 mL/10 L water), P2 (2 mL/10 L water), P3 (3 mL/10 L water) and P4 (4 mL/10 L water) treatment, given to the Vaname shrimps with intervals once per week. This probiotic consist of Lactobacillus plantarum, Lactobacillus fermentum, Bacillus subtilis, Bacillus licheniformis, Bacillus megaterium, Nitrobacter sp., and Nitrosomonas sp. Dependent variables in this study are weight of shrimp, length of shrimp, mortality and feed conversion ratio. The results had different of various dose probiotics application in the water showed significance for each treatment on growth and mortality of Vaname shrimp. The best results were shown in treatment P2 (2 mL/10 water) with mean value of Vaname shrimp weight is 7.447 ± 1.193 g/shrimp, the length is 10,390 ± 0,469 cm/shrimp, mortality is 41%, and the value of FCR is 0.91.

Dietary toxicity of field-contaminated invertebrates to marine fish: effects of metal doses and subcellular metal distribution.

PubMed

Dang, Fei; Rainbow, Philip S; Wang, Wen-Xiong

2012-09-15

There is growing awareness of the toxicological effects of metal-contaminated invertebrate diets on the health of fish populations in metal-contaminated habitats, yet the mechanisms underlying metal bioaccumulation and toxicity are complex. In the present study, marine fish Terapon jurbua terepon were fed a commercial diet supplemented with specimens of the polychaete Nereis diversicolor or the clam Scrobicularia plana, collected from four metal-impacted estuaries (Tavy, Restronguet Creek, West Looe, Gannel) in southwest England, as environmentally realistic metal sources. A comparative toxicological evaluation of both invertebrates showed that fish fed S. plana for 21 d exhibited evident mortality compared to those fed N. diversicolor. Furthermore, a spatial effect on mortality was observed. Differences in metal doses rather than subcellular metal distributions between N. diversicolor and S. plana appeared to be the cause of such different mortalities. Partial least squares regression was used to evaluate the statistical relationship between multiple-metal doses and fish mortality, revealing that Pb, Fe, Cd and Zn in field-collected invertebrates co-varied most strongly with the observed mortality. This study provides a step toward exploring the underlying mechanism of dietary toxicity and identifying the potential causality in complex metal mixture exposures in the field. Copyright © 2012 Elsevier B.V. All rights reserved.

Quantifying Barotrauma Risk to Juvenile Fish during Hydro-turbine Passage

DOE Office of Scientific and Technical Information (OSTI.GOV)

Richmond, Marshall C.; Serkowski, John A.; Ebner, Laurie L.

2014-03-15

We introduce a method for hydro turbine biological performance assessment (BioPA) to bridge the gap between field and laboratory studies on fish injury and turbine engineering design. Using this method, a suite of biological performance indicators is computed based on simulated data from a computational fluid dynamics (CFD) model of a proposed hydro turbine design. Each performance indicator is a measure of the probability of exposure to a certain dose of an injury mechanism. If the relationship between the dose of an injury mechanism (stressor) and frequency of injury (dose-response) is known from laboratory or field studies, the likelihood ofmore » fish injury for a turbine design can be computed from the performance indicator. By comparing the values of the indicators from various turbine designs, engineers and biologists can identify the more-promising designs and operating conditions to minimize hydraulic conditions hazardous to passing fish. In this paper, the BioPA method is applied to estimate barotrauma induced mortal injury rates for Chinook salmon exposed to rapid pressure changes in Kaplan-type hydro turbines. Following the description of the general method, application of the BioPA to estimate the probability of mortal injury from exposure to rapid decompression is illustrated using a Kaplan hydro turbine at the John Day Dam on the Columbia River in the Pacific Northwest region of the USA. The estimated rates of mortal injury increased from 0.3% to 1.7% as discharge through the turbine increased from 334 to 564 m3/s for fish assumed to be acclimated to a depth of 5 m. The majority of pressure nadirs occurred immediately below the runner blades, with the lowest values in the gap at the blade tips and just below the leading edge of the blades. Such information can help engineers focus on problem areas when designing new turbine runners to be more fish-friendly than existing units.« less

Subsequent Malignancies in Children Treated for Hodgkin's Disease: Associations With Gender and Radiation Dose

DOE Office of Scientific and Technical Information (OSTI.GOV)

Constine, Louis S.; Department of Pediatrics, James P. Wilmot Cancer Center at University of Rochester, Rochester, NY; Tarbell, Nancy

2008-09-01

Purpose: Subsequent malignant neoplasms (SMNs) are a dominant cause of morbidity and mortality in children treated for Hodgkin's disease (HD). We evaluated select demographic and therapeutic factors associated with SMNs, specifically gender and radiation dose. Methods and Materials: A total of 930 children treated for HD at five institutions between 1960 and 1990 were studied. Mean age at diagnosis was 13.6 years, and mean follow-up was 16.8 years (maximum, 39.4 years). Treatment included radiation alone (43%), chemotherapy alone (9%), or both (48%). Results: We found that SMNs occurred in 102 (11%) patients, with a 25-year actuarial rate of 19%. Withmore » 15,154 patient years of follow-up, only 7.18 cancers were expected (standardized incidence ratio [SIR] = 14.2; absolute excess risk [AER] = 63 cases/10,000 years). The SIR for female subjects, 19.93, was significantly greater than for males, 8.41 (p < 0.0001). After excluding breast cancer, the SIR for female patients was 15.4, still significantly greater than for male patients (p = 0.0012). Increasing radiation dose was associated with an increasing SIR (p = 0.0085). On univariate analysis, an increased risk was associated with female gender, increasing radiation dose, and age at treatment (12-16 years). Using logistic regression, mantle radiation dose increased risk, and this was 2.5-fold for female patients treated with more than 35 Gy primarily because of breast cancer. Conclusions: Survivors of childhood HD are at risk for SMNs, and this risk is greater for female individuals even after accounting for breast cancer. Although SMNs occur in the absence of radiation therapy, the risk increases with RT dose.« less

A moderate dose of red wine, but not de-alcoholized red wine increases coronary flow reserve.

PubMed

Kiviniemi, Tuomas O; Saraste, Antti; Toikka, Jyri O; Saraste, Markku; Raitakari, Olli T; Pärkkä, Jussi P; Lehtimäki, Terho; Hartiala, Jaakko J; Viikari, Jorma; Koskenvuo, Juha W

2007-12-01

Red wine consumption is associated with reduced cardiovascular disease mortality. Its cardioprotective properties may be partly related to its ability to improve endothelial function. The purpose of this randomized controlled cross-over study was to determine whether moderate doses of red wine and de-alcoholized red wine improve coronary flow velocity reserve (CFR). Using transthoracic Doppler echocardiography, 176 CFR measurements were made in 22 healthy men before and after ingestion of a moderate (4.0+/-0.4 dl) and an escalating high dose (total amount 8.1+/-0.9 dl) of alcohol-containing red wine and de-alcoholized red wine, which contained similar amounts of phenolic substances. The difference in plasma antioxidant capacity was determined by colorimetric assay kit. Red wine increased CFR from 3.8+/-1.4 to 4.5+/-1.4 (p<0.01) and 4.0+/-1.2 (p=NS) after moderate and high doses, respectively; whereas de-alcoholized red wine had no significant effects on CFR (4.0+/-0.7, 4.3+/-1.3 and 4.5+/-1.4, respectively). Plasma antioxidant capacity increased significantly after high dose of red wine (27.5+/-14.7%, p<0.001), but not after de-alcoholized red wine (0.5+/-10.5%, p=NS) despite similar amounts of phenolic substances. Differences between CFR and plasma antioxidant capacities before and after drinking had no significant association. A moderate dose of red wine, but not de-alcoholized red wine increases CFR. The increase of CFR is probably mediated by other than direct antioxidant properties of polyphenols, because the simultaneous increase of CFR and plasma antioxidant capacity were not associated.

Subsequent malignancies in children treated for Hodgkin's disease: associations with gender and radiation dose.

PubMed

Constine, Louis S; Tarbell, Nancy; Hudson, Melissa M; Schwartz, Cindy; Fisher, Susan G; Muhs, Ann G; Basu, Swati K; Kun, Larry E; Ng, Andrea; Mauch, Peter; Sandhu, Ajay; Culakova, Eva; Lyman, Gary; Mendenhall, Nancy

2008-09-01

Subsequent malignant neoplasms (SMNs) are a dominant cause of morbidity and mortality in children treated for Hodgkin's disease (HD). We evaluated select demographic and therapeutic factors associated with SMNs, specifically gender and radiation dose. A total of 930 children treated for HD at five institutions between 1960 and 1990 were studied. Mean age at diagnosis was 13.6 years, and mean follow-up was 16.8 years (maximum, 39.4 years). Treatment included radiation alone (43%), chemotherapy alone (9%), or both (48%). We found that SMNs occurred in 102 (11%) patients, with a 25-year actuarial rate of 19%. With 15,154 patient years of follow-up, only 7.18 cancers were expected (standardized incidence ratio [SIR] = 14.2; absolute excess risk [AER] = 63 cases/10,000 years). The SIR for female subjects, 19.93, was significantly greater than for males, 8.41 (p < 0.0001). After excluding breast cancer, the SIR for female patients was 15.4, still significantly greater than for male patients (p = 0.0012). Increasing radiation dose was associated with an increasing SIR (p = 0.0085). On univariate analysis, an increased risk was associated with female gender, increasing radiation dose, and age at treatment (12-16 years). Using logistic regression, mantle radiation dose increased risk, and this was 2.5-fold for female patients treated with more than 35 Gy primarily because of breast cancer. Survivors of childhood HD are at risk for SMNs, and this risk is greater for female individuals even after accounting for breast cancer. Although SMNs occur in the absence of radiation therapy, the risk increases with RT dose.

A 5-month toxicity study of the ethanol extract of the leaves of Heliotropium indicum in Sprague Dawley rats after oral administration.

PubMed

Owolabi, M A; Oribayo, O O; Ukpo, G E; Mbaka, G O; Akindehin, O E

2015-01-01

Heliotropium indicum Linn. (Boraginaceae) is used in Nigerian traditional medicine to treat tuberculosis with treatment lasting for 3 months; however, information on its toxicity is scarce. This study investigated the safety of the leaves of Heliotropium indicum after a 5 month oral administration. The leaves of H. indicum were dried; extracted in 70% ethanol and concentrated to dryness. Swiss mice were administered orally with single doses of the extract (0.5 to 12.0 g/kg b.wt /day); mortality was examined for up to 14 days. In another study, the plant material (0.5 to 2.0 g/kg b.wt /day) were administered daily by oral gavage to Sprague Dawley rats. Body weight was monitored weekly, hematological, biochemical and organ parameters were determined at the end of the 1st, 2nd and 5th months of extract administration. The oral administration of the ethanol extract of H. indicum caused dose-dependent mortality. The LD50 was 9.78 g/kg b.wt for the Swiss mice; no harmful effect was observed on the liver and kidney except the testes which exhibited considerable inflammatory changes at the highest dose of 2.0 g/kg b.wt./day after the 5th month treatment. No significant difference (P>0.05) was shown in the enzyme study, marginal increase occurred in some haematological parameters. The increase in body weight of the treated rats after its initial reduction was consistent and significantly different (P<0.05) from their initial body weight. Prolonged administration of the crude leaf extract of H. indicum is considered to be safe and nontoxic at the doses studied. However, there is a probability of a negative effect on the testes at a higher dose of the extract.

Immunomodulatory activity of methanolic extract of Morus alba Linn. (mulberry) leaves.

PubMed

Bharani, Shendige Eswara Rao; Asad, Mohammed; Dhamanigi, Sunil Samson; Chandrakala, Gowda Kallenahalli

2010-01-01

The leaves of Morus alba Linn. (Family: Moraceae) commonly known as mulberry are mainly used as food for the silkworms and they are sometimes eaten as vegetable or used as cattle fodder in different parts of the world. The effect of Morus alba on the immune system was evaluated by using different experimental models such as carbon clearance test, cyclophosphamide induced neutropenia, neutrophil adhesion test, effect on serum immunoglobulins, mice lethality test and indirect haemagglutination test. Methanolic extract of Morus alba was administered orally at low dose and high dose of 100 mg/kg and 1 g/kg respectively and Ocimum sanctum (100 mg/kg, po) was used as standard drug. Morus alba extract in both doses increased the levels of serum immunoglobulins and prevented the mortality induced by bovine Pasteurella multocida in mice. It also increased the circulating antibody titre in indirect haemagglutination test. On the other hand, it showed significant increase in the phagocytic index in carbon clearance assay, a significant protection against cyclophosphamide induced neutropenia and increased the adhesion of neutrophils in the neutrophil adhesion test. Hence, it was concluded that Morus alba increases both humoral immunity and cell mediated immunity.

Meta-analysis: low-dose intake of vitamin E combined with other vitamins or minerals may decrease all-cause mortality.

PubMed

Jiang, Shan; Pan, Zhenyu; Li, Hui; Li, Fenglan; Song, Yanyan; Qiu, Yu

2014-01-01

It has been suggested that vitamin E alone or combined with other vitamins or minerals can prevent oxidative stress and slow oxidative injury-related diseases, such as cardiovascular disease and cancer. A comprehensive search of PubMed/MEDLINE, EMBASE and the Cochrane Library was performed. Relative risk was used as an effect measure to compare the intervention and control groups. A total of 33 trials were included in the meta-analysis. Neither vitamin E intake alone (RR=1.01; 95% CI, 0.97 to 1.04; p=0.77) nor vitamin E intake combined with other agents (RR=0.97; 95% CI, 0.89 to 1.06; p=0.55) was correlated with all-cause mortality. Subgroup analyses revealed that low-dose vitamin E supplementation combined with other agents is associated with a statistically significant reduction in all-cause mortality (RR=0.92; 95% CI, 0.86 to 0.98; p=0.01), and vitamin E intake combined with other agents is associated with a statistically significant reduction in mortality rates among individuals without probable or confirmed diseases (RR=0.92; 95% CI, 0.86 to 0.99; p=0.02). Neither vitamin E intake alone nor combined with other agents is associated with a reduction in all-cause mortality. But a low dose (<400 IU/d) of vitamin E combined with other agents is correlated with a reduction in all-cause mortality, and vitamin E intake combined with other agents is correlated with a reduction in the mortality rate among individuals without probable or confirmed diseases.

Association Between Incomplete Neoadjuvant Radiotherapy and Survival for Patients With Locally Advanced Rectal Cancer

PubMed Central

Sun, Zhifei; Adam, Mohamed A.; Kim, Jina; Palta, Manisha; Czito, Brian G.; Migaly, John; Mantyh, Christopher R.

2017-01-01

Importance Failing to complete chemotherapy adversely affects survival in patients with colorectal cancer. However, the effect of incomplete delivery of neoadjuvant radiotherapy is unclear. Objective To determine whether incomplete radiotherapy delivery is associated with worse clinical outcomes and survival. Design, Setting, and Participants Data on 17 600 patients with stage II to III rectal adenocarcinoma from the 2006-2012 National Cancer Database who received neoadjuvant chemoradiotherapy followed by surgical resection were included. Multivariable regression methods were used to compare resection margin positivity, permanent colostomy rate, 30-day readmission, 90-day mortality, and overall survival between patients who received complete (45.0-50.4 Gy) and incomplete (<45.0 Gy) doses of radiation as preoperative therapy. Main Outcomes and Measures The primary outcome measure was overall survival; short-term perioperative and oncologic outcomes encompassing margin positivity, permanent ostomy rate, postoperative readmission, and postoperative mortality were also assessed. Results Among 17 600 patients included, 10 862 were men, with an overall median age of 59 years (range, 51-68 years). Of these, 874 patients (5.0%) received incomplete doses of neoadjuvant radiation. The median radiation dose received among those who did not achieve complete dosing was 34.2 Gy (interquartile range, 19.8-40.0 Gy). Female sex (adjusted odds ratio [OR] 0.69; 95% CI, 0.59-0.81; P < .001) and receiving radiotherapy at a different hospital than the one where surgery was performed (OR, 0.72; 95% CI, 0.62-0.85; P < .001) were independent predictors of failing to achieve complete dosing; private insurance status was predictive of completing radiotherapy (OR, 1.60; 95% CI, 1.16-2.21; P = .004). At 5-year follow-up, overall survival was improved among patients who received a complete course of radiotherapy (3086 [estimated survival probability, 73.2%] vs 133 [63.0%]; P < .001). After adjustment for demographic, clinical, and tumor characteristics, patients receiving a complete vs incomplete radiation dose had a similar resection margin positivity (OR, 0.99; 95% CI, 0.72-1.35; P = .92), permanent colostomy rate (OR, 0.96; 95% CI, 0.70-1.32; P = .81), 30-day readmission rate (OR, 0.92; 95% CI, 0.67-1.27; P = .62), and 90-day mortality (OR, 0.72; 95% CI, 0.33-1.54; P = .41). However, a complete radiation dose had a significantly lower risk of long-term mortality (adjusted hazard ratio, 0.70; 95% CI, 0.59-0.84; P < .001). Conclusions and Relevance Achieving a target radiation dose of 45.0 to 50.4 Gy is associated with a survival benefit in patients with locally advanced rectal cancer. Aligning all aspects of multimodal oncology care may increase the probability of completing neoadjuvant therapy. PMID:28273303

Model-based meta-analysis to evaluate optimal doses of direct oral factor Xa inhibitors in atrial fibrillation patients

PubMed Central

Yoshioka, Hideki; Sato, Hiromi; Hatakeyama, Hiroto

2018-01-01

The noninferiority of direct oral factor Xa (FXa) inhibitors (rivaroxaban, apixaban, and edoxaban) in treatment of atrial fibrillation were demonstrated compared with warfarin by several large clinical trials; however, subsequent meta-analyses reported a higher risk of major bleeding with rivaroxaban than with the other FXa inhibitors. In the present study, we first estimated the changes of prothrombin time (PT) in 5 randomized trials based on reported population pharmacokinetic and pharmacodynamic models and then carried out a model-based meta-analysis to obtain models describing the relationship between PT changes and the event rates of ischemic stroke/systemic embolism (SE) and of major bleeding. By using the models, we simulated the optimal therapeutic doses for each FXa inhibitor. It was suggested that dose reduction of rivaroxaban from the current 20 mg/d to 10 mg/d would decrease patient deaths from major bleeding (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.64-0.74) with little increase in those for ischemic stroke/SE (HR, 1.11; 95% CI, 1.07-1.20). The overall decrease in the mortality caused by both events was estimated as 5.81 per 10 000 patient-years (95% CI, 3.92-8.16), with an HR of 0.87 (95% CI, 0.83-0.91). For apixaban and edoxaban, no distinct change in the overall mortality was simulated by dose modification. This study suggested that the current dose of rivaroxaban might be excessive and would need to be reduced to decrease the excess risk of major bleeding. PMID:29760204

Sterile insect technique as a tool for increasing the efficacy of gypsy moth biocontrol

Treesearch

Julius Novotny; Milan Zubrik

2003-01-01

Characteristics such as the duration of the larval stage and attraction of larvae to oviposition by an endoparasitic wasp were evaluated between groups of irradiated and non irradiated gypsy moth larvae. Untreated larvae required a shorter time to reach the adult stage (both male and female). The mortality of larvae was highest at the highest irradiation dose. Pupae...

Body Composition in Relation to Clinical Outcomes in Renal Cell Cancer: A Systematic Review and Meta-analysis.

PubMed

Vrieling, Alina; Kampman, Ellen; Knijnenburg, Nathalja C; Mulders, Peter F; Sedelaar, J P Michiel; Baracos, Vickie E; Kiemeney, Lambertus A

2016-12-04

Several studies suggest that body composition (ie, body proportions of muscle and fat defined by computed tomography) is associated with clinical outcomes of several cancer types, including renal cell cancer (RCC). To conduct a systematic review and meta-analysis of the evidence on body composition in relation to clinical outcomes in RCC. Literature was reviewed through October 2016 using PubMed and Embase. We included studies investigating computed tomography-measured cross-sectional areas of visceral adipose tissue (VAT), perinephric fat, subcutaneous adipose tissue (SAT), skeletal muscle index (SMI), and skeletal muscle radiodensity (SMD) in relation to perioperative outcomes, treatment toxicity, and survival in RCC patients. We included 28 studies with a total of 6608 patients. Binary classification of body composition was used in most studies. In metastatic RCC (mRCC) patients treated with antiangiogenic drugs, dose-limiting toxicity was more frequent in patients with low versus high SMI (four studies, risk difference = 16%, 95% confidence interval [CI]: 2-31%, p = 0.03, I 2 = 26%). Low versus high SMI (six studies, hazard ratio = 1.48, 95% CI: 1.08-2.03, p = 0.02, I 2 = 28%) and SMD (four studies, HR = 1.56, 95% CI: 1.20-2.03, p = 0.0008, I 2 = 0%) were associated with an increased risk of overall mortality in mRCC. Low versus high VAT and perinephric fat were not consistently associated with perioperative outcomes and survival. No associations for SAT were found. Low SMI is associated with increased dose-limiting toxicity, and low SMI and SMD are associated with increased overall mortality in mRCC. The association of VAT, perinephric fat, and SAT with clinical outcomes needs further investigation, also in localized RCC. We reviewed studies assessing the association of body composition with clinical outcomes in renal cell cancer. We demonstrated higher risk of dose-limiting toxicity and overall mortality for metastatic renal cell cancer patients with low versus high skeletal muscle index or skeletal muscle radiodensity, but observed inconsistent associations with visceral adipose tissue and perinephric fat. Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

The effect of neonatal vitamin A supplementation on morbidity and mortality at 12 months: a randomized trial

PubMed Central

Smith, Emily R; Muhihi, Alfa; Mshamu, Salum; Sudfeld, Christopher R; Noor, Ramadhani Abdallah; Spiegelman, Donna; Shapiro, Roger L; Masanja, Honorati; Fawzi, Wafaie

2016-01-01

Abstract Background: Neonatal vitamin A supplementation (NVAS) is an intervention hypothesized to reduce infant morbidity and mortality. The objective of this study was to assess the efficacy of neonatal vitamin A supplementation in reducing infant morbidity and mortality and assess potential sources of heterogeneity of the effect of NVAS. Methods: We completed an individually randomized, double-blind, placebo-controlled trial in Tanzania. Infants were randomized within 3 days of birth to a single dose of vitamin A (50 000 IU) or placebo. We assessed infants at 1 and 3 days after supplementation, as well as 1, 3, 6 and 12 months after supplementation. We included all live births in the analysis and used relative risks (RR) and 95% confidence intervals (CI) to assess the risks of mortality and hospitalization by 12 months. We used general estimating equations to assess the incidence of morbidities during infancy. Results: A total of 31 999 infants were enrolled in the study between August 2010 and March 2013. At 12 months, vitamin A did not reduce all-cause infant mortality (RR 1.04; 95% CI 0.92-1.16), nor affect hospitalization (RR 1.09; 95% CI 0.97-1.22) or all-cause morbidity (RR 1.00; 95% CI 0.96-1.05). Postpartum maternal vitamin A supplementation modified the effect of neonatal vitamin A supplementation on mortality at 12 months (P-value, test for interaction = 0.04). Among infants born to women who received a mega-dose of vitamin A after delivery, NVAS appeared to increase the risk of death (RR 1.12; 95% CI 0.98-1.29), whereas the risk of death among infants born to women who did not receive a mega-dose was reduced (RR 0.86; 95% CI 0.70-1.06). We noted no modification of the effect of NVAS by infant gender, birthweight or maternal HIV status. Conclusion: NVAS did not affect the risk of death or incidence of common childhood morbidities. However, this study sheds light on potential sources of heterogeneity of the effect of neonatal vitamin A supplementation which should be further examined in a pooled analysis of all NVAS trials. PMID:27789674

Effects of intra-aortic balloon counterpulsation in a model of septic shock.

PubMed

Solomon, Steven B; Minneci, Peter C; Deans, Katherine J; Feng, Jing; Eichacker, Peter Q; Banks, Steven M; Danner, Robert L; Natanson, Charles; Solomon, Michael A

2009-01-01

Fluid refractory septic shock can develop into a hypodynamic cardiovascular state in both children and adults. Despite management of these patients with empirical inotropic therapy (with or without a vasodilator), mortality remains high. The effect of cardiovascular support using intra-aortic balloon counterpulsation was investigated in a hypodynamic, mechanically ventilated canine sepsis model in which cardiovascular and pulmonary support were titrated based on treatment protocols. Each week, three animals (n = 33, 10-12 kg) were administered intrabronchial Staphylococcus aureus challenge and then randomized to receive intra-aortic balloon counterpulsation for 68 hrs or no intra-aortic balloon counterpulsation (control). Bacterial doses were increased over the study (4-8 x 10(9) cfu/kg) to assess the effects of intra-aortic balloon counterpulsation during sepsis with increasing risk of death. Compared with lower bacterial doses (4-7 x 10(9) colony-forming units/kg), control animals challenged with the highest dose (8 x 10(9) colony-forming units/kg) had a greater risk of death (mortality rate 86% vs. 17%), with worse lung injury ([A - a]O2), and renal dysfunction (creatinine). These sicker animals required higher norepinephrine infusion rates to maintain blood pressure (and higher FIO2) and positive end-expiratory pressure levels to maintain oxygenation (p < or = 0.04 for all). In animals receiving the highest bacterial dose, intra-aortic balloon counterpulsation improved survival time (23.4 +/- 10 hrs longer; p = 0.003) and lowered norepinephrine requirements (0.43 +/- 0.17 microg/kg/min; p = 0.002) and systemic vascular resistance index (1.44 +/- 0.57 dynes/s/cm5/kg; p = 0.0001) compared with controls. Despite these beneficial effects, intra-aortic balloon counterpulsation was associated with an increase in blood urea nitrogen (p = 0.002) and creatinine (p = 0.12). In animals receiving lower doses of bacteria, intra-aortic balloon counterpulsation had no significant effects on survival or renal function. In a canine model of severe septic shock with a low cardiac index, intra-aortic balloon counterpulsation prolongs survival time and lowers vasopressor requirements.

Arsenic exposure from drinking water, and all-cause and chronic-disease mortalities in Bangladesh (HEALS): a prospective cohort study.

PubMed

Argos, Maria; Kalra, Tara; Rathouz, Paul J; Chen, Yu; Pierce, Brandon; Parvez, Faruque; Islam, Tariqul; Ahmed, Alauddin; Rakibuz-Zaman, Muhammad; Hasan, Rabiul; Sarwar, Golam; Slavkovich, Vesna; van Geen, Alexander; Graziano, Joseph; Ahsan, Habibul

2010-07-24

Millions of people worldwide are chronically exposed to arsenic through drinking water, including 35-77 million people in Bangladesh. The association between arsenic exposure and mortality rate has not been prospectively investigated by use of individual-level data. We therefore prospectively assessed whether chronic and recent changes in arsenic exposure are associated with all-cause and chronic-disease mortalities in a Bangladeshi population. In the prospective cohort Health Effects of Arsenic Longitudinal Study (HEALS), trained physicians unaware of arsenic exposure interviewed in person and clinically assessed 11 746 population-based participants (aged 18-75 years) from Araihazar, Bangladesh. Participants were recruited from October, 2000, to May, 2002, and followed-up biennially. Data for mortality rates were available throughout February, 2009. We used Cox proportional hazards model to estimate hazard ratios (HRs) of mortality, with adjustment for potential confounders, at different doses of arsenic exposure. 407 deaths were ascertained between October, 2000, and February, 2009. Multivariate adjusted HRs for all-cause mortality in a comparison of arsenic at concentrations of 10.1-50.0 microg/L, 50.1-150.0 microg/L, and 150.1-864.0 microg/L with at least 10.0 microg/L in well water were 1.34 (95% CI 0.99-1.82), 1.09 (0.81-1.47), and 1.68 (1.26-2.23), respectively. Results were similar with daily arsenic dose and total arsenic concentration in urine. Recent change in exposure, measurement of total arsenic concentrations in urine repeated biennially, did not have much effect on the mortality rate. Chronic arsenic exposure through drinking water was associated with an increase in the mortality rate. Follow-up data from this cohort will be used to assess the long-term effects of arsenic exposure and how they might be affected by changes in exposure. However, solutions and resources are urgently needed to mitigate the resulting health effects of arsenic exposure. US National Institutes of Health. Copyright 2010 Elsevier Ltd. All rights reserved.

Impact of persistence and non-persistence in leisure time physical activity on coronary heart disease and all-cause mortality: The Copenhagen City Heart Study.

PubMed

Schnohr, Peter; O'Keefe, James H; Lange, Peter; Jensen, Gorm Boje; Marott, Jacob Louis

2017-10-01

Aims The aim of this study was to investigate the impact of persistence and non-persistence in leisure time physical activity on coronary heart disease and all-cause mortality. Methods and results In the Copenhagen City Heart Study, we prospectively followed 12,314 healthy subjects for 33 years of maximum follow-up with at least two repeated measures of physical activity. The association between persistence and non-persistence in leisure time physical activity, coronary heart disease and all-cause mortality were assessed by multivariable Cox regression analyses. Coronary heart disease mortality for persistent physical activity in leisure compared to persistent sedentary activity were: light hazard ratio (HR) 0.76; 95% confidence interval (CI) 0.63-0.92, moderate HR 0.52; 95% CI 0.41-0.67, and high physical activity HR 0.51; 95% CI, 0.30-0.88. The differences in longevity were 2.8 years for light, 4.5 years for moderate and 5.5 years for high physical activity. A substantial increase in physical activity was associated with lower coronary heart disease mortality (HR 0.75; 95% CI 0.52-1.08) corresponding to 2.4 years longer life, whereas a substantial decrease in physical activity was associated with higher coronary heart disease mortality (HR 1.61; 95% CI 1.11-2.33) corresponding to 4.2 years shorter life than the unchanged group. A similar pattern was observed for all-cause mortality. Conclusion We found inverse dose-response relationships between persistent leisure time physical activity and both coronary heart disease and all-cause mortality. A substantial increase in physical activity was associated with a significant gain in longevity, whereas a decrease in physical activity was associated with even greater loss of longevity.

Dose-Dependent Effects of Statins for Patients with Aneurysmal Subarachnoid Hemorrhage: Meta-Regression Analysis.

PubMed

To, Minh-Son; Prakash, Shivesh; Poonnoose, Santosh I; Bihari, Shailesh

2018-05-01

The study uses meta-regression analysis to quantify the dose-dependent effects of statin pharmacotherapy on vasospasm, delayed ischemic neurologic deficits (DIND), and mortality in aneurysmal subarachnoid hemorrhage. Prospective, retrospective observational studies, and randomized controlled trials (RCTs) were retrieved by a systematic database search. Summary estimates were expressed as absolute risk (AR) for a given statin dose or control (placebo). Meta-regression using inverse variance weighting and robust variance estimation was performed to assess the effect of statin dose on transformed AR in a random effects model. Dose-dependence of predicted AR with 95% confidence interval (CI) was recovered by using Miller's Freeman-Tukey inverse. The database search and study selection criteria yielded 18 studies (2594 patients) for analysis. These included 12 RCTs, 4 retrospective observational studies, and 2 prospective observational studies. Twelve studies investigated simvastatin, whereas the remaining studies investigated atorvastatin, pravastatin, or pitavastatin, with simvastatin-equivalent doses ranging from 20 to 80 mg. Meta-regression revealed dose-dependent reductions in Freeman-Tukey-transformed AR of vasospasm (slope coefficient -0.00404, 95% CI -0.00720 to -0.00087; P = 0.0321), DIND (slope coefficient -0.00316, 95% CI -0.00586 to -0.00047; P = 0.0392), and mortality (slope coefficient -0.00345, 95% CI -0.00623 to -0.00067; P = 0.0352). The present meta-regression provides weak evidence for dose-dependent reductions in vasospasm, DIND and mortality associated with acute statin use after aneurysmal subarachnoid hemorrhage. However, the analysis was limited by substantial heterogeneity among individual studies. Greater dosing strategies are a potential consideration for future RCTs. Copyright © 2018 Elsevier Inc. All rights reserved.

Cancer in populations living in regions with radioecological problems in Bulgaria.

PubMed

Chobanova, N; Genchev, G; Yagova, A; Georgieva, L

2003-01-01

To analyse the incidence and mortality of some malignant diseases among the population living in regions of past uranium extraction in Bulgaria. A retrospective study on cancer incidence and mortality in the population living around two regions with radioecological problems was conducted. According to the expected individual annual effective doses for the population, regions with expected highest radiation risk (average effective dose > 10 mSv per year) were the villages Yana, Eleshnitza and Seslavtzi (group A), and with expected relatively high radiation risk (average effective dose > 5 mSv per year) were the town of Buhovo, and the villages Dolni Bogrov and Gorni Bogrov (group B). The ecologically clean village German was chosen as a control settlement. The incidence and mortality of gastrointestinal tract cancers, bronchus and lung cancer, breast cancer, thyroid cancer, and myeloid leukaemia for the period 1995- 2001 were studied. The incidence of the gastrointestinal tract cancers in the population of German was significantly lower than those for Bulgaria and for group B. The mortality from this disease of groups A, B and Bulgaria were significantly higher than in the control settlement. Standardized mortality of lung cancer in the population of the villages with highest and relatively high radiation risk was significantly higher than in German and Bulgaria. The incidence and mortality changes of diseases studied are a consequence of the impact of many factors. Moreover, they do not characterize the impact of the radiation factor.

Developmental toxicity evaluation of Bendectin in CD rats.

PubMed

Tyl, R W; Price, C J; Marr, M C; Kimmel, C A

1988-06-01

Bendectin, composed of doxylamine succinate and pyridoxine HCl (1:1), is an antinauseant previously prescribed for nausea and vomiting during pregnancy. The present study examined the maternal and developmental effects of Bendectin (0, 200, 500, or 800 mg/kg/day, po) administered to timed-pregnant CD rats (36-41/group) during organogenesis (gestational days [gd] 6-15). At death (gd 20), all live fetuses were examined for external, visceral, and skeletal abnormalities. At 500 and 800 mg/kg/day, maternal toxicity included reduced food consumption during treatment and for the gestation period, increased water consumption in the posttreatment period, reduced weight gain during treatment, and sedation; water consumption was reduced during treatment and for the gestation period, and maternal mortality (17.1%) was observed only at the high dose. Developmental toxicity included reduced prenatal viability (800 mg/kg/day) and reduced fetal body weight/litter (500 and 800 mg/kg/day). In addition, reduced ossification of metacarpals (800 mg/kg/day), phalanges of the forelimbs (500 and 800 mg/kg/day), and of caudal vertebral centra (all doses) was observed. No increase in percent malformed live fetuses/litter was observed. The proportion of litters with one or more malformed fetuses was higher than vehicle controls only at 800 mg/kg/day, with short 13th rib (to which the test species is predisposed) as the predominant observation. By contrast, a positive control agent (nitrofen, 50 mg/kg/day, po, 14 dams) produced 85% malformed fetuses/litter with the predominant malformation being diaphragmatic hernia. In conclusion, the incidence of litters with one or more malformed fetuses was increased only at a dose of Bendectin which produced maternal mortality (17.1%) and other indices of maternal and developmental toxicity (see Discussion).

DDE increased the toxicity of parathion to coturnix quail

USGS Publications Warehouse

Ludke, J.L.

1977-01-01

Adult male Japanese quail (Coturnix coturnix) were exposed to DDE or chlordane in the diet and subsequently dosed with parathion or paraoxon. Pretreatment with 5 or 50 ppm DDE in the diet for 12 weeks resulted in increased cholinesterase (ChE) activity in plasma, but not in the brain. Dietary concentrations of 5 and 50 ppm DDE caused increased susceptibility of quail that were challenged with parathion or paraoxon. The increased mortality resulting from DDE pretreatment was reflected in brain ChE inhibition. The synergistic action of DDE was apparent after 3 days of exposure to 50 ppm DDE and 1 week of exposure to 5 ppm DDE. Birds exposed for 3 weeks to 5 or 50 ppm DDE retained their DDE-potentiated sensitivity to parathion after 2 weeks on clean diet. Chlordane pretreatment resulted in decreased susceptibility (antagonism) to parathion, but not to paraoxon dosage. Implications of differing responses in ChE and mortality among controls, DDE-, and chlordane-pretreated birds after parathion or paraoxon dosage are discussed.

Mortality from respiratory diseases associated with opium use: a population-based cohort study.

PubMed

Rahmati, Atieh; Shakeri, Ramin; Khademi, Hooman; Poutschi, Hossein; Pourshams, Akram; Etemadi, Arash; Khoshnia, Masoud; Sohrabpour, Amir Ali; Aliasgari, Ali; Jafari, Elham; Islami, Farhad; Semnani, Shahryar; Gharravi, Abdolsamad; Abnet, Christian C; Pharoah, Paul D P; Brennan, Paul; Boffetta, Paolo; Dawsey, Sanford M; Malekzadeh, Reza; Kamangar, Farin

2017-11-01

Recent studies have suggested that opium use may increase mortality from cancer and cardiovascular diseases. However, no comprehensive study of opium use and mortality from respiratory diseases has been published. We aimed to study the association between opium use and mortality from respiratory disease using prospectively collected data. We used data from the Golestan Cohort Study, a prospective cohort study in northeastern Iran, with detailed, validated data on opium use and several other exposures. A total of 50 045 adults were enrolled from 2004 to 2008, and followed annually until June 2015, with a follow-up success rate of 99%. We used Cox proportional hazard regression models to evaluate the association between opium use and outcomes of interest. During the follow-up period, 331 deaths from respiratory disease were reported (85 due to respiratory malignancies and 246 due to non-malignant aetiologies). Opium use was associated with an increased risk of death from any respiratory disease (adjusted HR 95% CI 3.13 (2.42 to 4.04)). The association was dose-dependent with a HR of 3.84 (2.61 to 5.67) for the highest quintile of cumulative opium use versus never use (P trend <0.001). The HRs (95% CI) for the associations between opium use and malignant and non-malignant causes of respiratory mortality were 1.96 (1.18 to 3.25) and 3.71 (2.76 to 4.96), respectively. Long-term opium use is associated with increased mortality from both malignant and non-malignant respiratory diseases. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Risk of solid cancer in low dose-rate radiation epidemiological studies and the dose-rate effectiveness factor.

PubMed

Shore, Roy; Walsh, Linda; Azizova, Tamara; Rühm, Werner

2017-10-01

Estimated radiation risks used for radiation protection purposes have been based primarily on the Life Span Study (LSS) of atomic bomb survivors who received brief exposures at high dose rates, many with high doses. Information is needed regarding radiation risks from low dose-rate (LDR) exposures to low linear-energy-transfer (low-LET) radiation. We conducted a meta-analysis of LDR epidemiologic studies that provide dose-response estimates of total solid cancer risk in adulthood in comparison to corresponding LSS risks, in order to estimate a dose rate effectiveness factor (DREF). We identified 22 LDR studies with dose-response risk estimates for solid cancer after minimizing information overlap. For each study, a parallel risk estimate was derived from the LSS risk model using matching values for sex, mean ages at first exposure and attained age, targeted cancer types, and accounting for type of dosimetric assessment. For each LDR study, a ratio of the excess relative risk per Gy (ERR Gy -1 ) to the matching LSS ERR risk estimate (LDR/LSS) was calculated, and a meta-analysis of the risk ratios was conducted. The reciprocal of the resultant risk ratio provided an estimate of the DREF. The meta-analysis showed a LDR/LSS risk ratio of 0.36 (95% confidence interval [CI] 0.14, 0.57) for the 19 studies of solid cancer mortality and 0.33 (95% CI 0.13, 0.54) when three cohorts with only incidence data also were added, implying a DREF with values around 3, but statistically compatible with 2. However, the analyses were highly dominated by the Mayak worker study. When the Mayak study was excluded the LDR/LSS risk ratios increased: 1.12 (95% CI 0.40, 1.84) for mortality and 0.54 (95% CI 0.09, 0.99) for mortality + incidence, implying a lower DREF in the range of 1-2. Meta-analyses that included only cohorts in which the mean dose was <100 mGy yielded a risk ratio of 1.06 (95% CI 0.30, 1.83) for solid cancer mortality and 0.58 (95% CI 0.10, 1.06) for mortality + incidence data. The interpretation of a best estimate for a value of the DREF depends on the appropriateness of including the Mayak study. This study indicates a range of uncertainty in the value of DREF between 1 and about 2 after protracted radiation exposure. The LDR data provide direct evidence regarding risk from exposures at low dose rates as an important complement to the LSS risk estimates used for radiation protection purposes.

The Effect of X-Irradiation on Goldfish: I. The Effect of X-Irradiation on Survival and Susceptibility of the Goldfish, Carassius auratus, to Infection by Aeromonas salmonicida and Gyrodactylus spp.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shechmeister, I. L.; Watson, L. J.; Cole, V. W.

1962-01-01

Graded doses (l00 to l0000 r) of whole-body x radiation were administered to goldfish, Carassius auratus. The x ray LD/sub 50(30)/ was found to be 2315 r. Survival time decreased with increase in x-ray dose. Exposure to 100 r resulted in 100% mortality in 363 days; all fish exposed to l0,000 r succumbed in 11 to 14 days. Gross pathologic effects resulting from x irradiation are discussed. The transient phenomenon of external pigmentation development due to ionizing radiation was noted. The swim bladder, a hydrostatic organ, was frequently observed to be in a deflated condition after exposure to doses greatermore » than 500 r, resulting in loss of buoyancy. The increase in the susceptibility of irradiated animals to an experimentally induced bacterial infection, Aeromonas salmonicida, and to a naturally acquired ectoparasitic trematode, Gyrodactylus spp., was also observed. (auth)« less

Developing better mouse models to study cisplatin-induced kidney injury.

PubMed

Sharp, Cierra N; Siskind, Leah J

2017-10-01

Cisplatin is a potent chemotherapeutic used for the treatment of many types of cancer. However, its dose-limiting side effect is nephrotoxicity leading to acute kidney injury (AKI). Patients who develop AKI have an increased risk of mortality and are more likely to develop chronic kidney disease (CKD). Unfortunately, there are no therapeutic interventions for the treatment of AKI. It has been suggested that the lack of therapies is due in part to the fact that the established mouse model used to study cisplatin-induced AKI does not recapitulate the cisplatin dosing regimen patients receive. In recent years, work has been done to develop more clinically relevant models of cisplatin-induced kidney injury, with much work focusing on incorporation of multiple low doses of cisplatin administered over a period of weeks. These models can be used to recapitulate the development of CKD after AKI and, by doing so, increase the likelihood of identifying novel therapeutic targets for the treatment of cisplatin-induced kidney injury. Copyright © 2017 the American Physiological Society.

Air pollution and daily mortality in Erfurt, east Germany, 1980-1989.

PubMed Central

Spix, C; Heinrich, J; Dockery, D; Schwartz, J; Völksch, G; Schwinkowski, K; Cöllen, C; Wichmann, H E

1993-01-01

In Erfurt, Germany, unfavorable geography and emissions from coal burning lead to very high ambient pollution (up to about 4000 micrograms/m3 SO2 in 1980-89). To assess possible health effects of these exposures, total daily mortality was obtained for this same period. A multivariate model was fitted, including corrections for long-term fluctuations, influenza epidemics, and meterology, before analyzing the effect of pollution. The best fit for pollution was obtained for log (SO2 daily mean) with a lag of 2 days. Daily mortality increased by 10% for an increase in SO2 from 23 to 929 micrograms/m3 (5% quantile to 95% quantile). A harvesting effect (fewer people die on a given day if more deaths occurred in the last 15 days) may modify this by +/- 2%. The effect for particulates (SP, 1988-89 only) was stronger than the effect of SO2. Log SP (daily mean) increasing from 15 micrograms/m3 to 331 micrograms/m3 (5% quantile to 95% quantile) was associated with a 22% increase in mortality. Depending on harvesting, the observable effect may lie between 14% and 27%. There is no indication of a threshold or synergism. The effects of air pollution are smaller than the effects of influenza epidemics and are of the same size as meterologic effects. The results for the lower end of the dose range are in agreement with linear models fitted in studies of moderate air pollution and episode studies. Images Figure 1. Figure 2. PMID:8137781

Air pollution and daily mortality in Erfurt, east Germany, 1980-1989.

PubMed

Spix, C; Heinrich, J; Dockery, D; Schwartz, J; Völksch, G; Schwinkowski, K; Cöllen, C; Wichmann, H E

1993-11-01

In Erfurt, Germany, unfavorable geography and emissions from coal burning lead to very high ambient pollution (up to about 4000 micrograms/m3 SO2 in 1980-89). To assess possible health effects of these exposures, total daily mortality was obtained for this same period. A multivariate model was fitted, including corrections for long-term fluctuations, influenza epidemics, and meterology, before analyzing the effect of pollution. The best fit for pollution was obtained for log (SO2 daily mean) with a lag of 2 days. Daily mortality increased by 10% for an increase in SO2 from 23 to 929 micrograms/m3 (5% quantile to 95% quantile). A harvesting effect (fewer people die on a given day if more deaths occurred in the last 15 days) may modify this by +/- 2%. The effect for particulates (SP, 1988-89 only) was stronger than the effect of SO2. Log SP (daily mean) increasing from 15 micrograms/m3 to 331 micrograms/m3 (5% quantile to 95% quantile) was associated with a 22% increase in mortality. Depending on harvesting, the observable effect may lie between 14% and 27%. There is no indication of a threshold or synergism. The effects of air pollution are smaller than the effects of influenza epidemics and are of the same size as meterologic effects. The results for the lower end of the dose range are in agreement with linear models fitted in studies of moderate air pollution and episode studies.

Longitudinal Comparison of Thyroxine Pharmacokinetics Between Pregnant and Nonpregnant Women: A Stable Isotope Study

PubMed Central

Soldin, Offie P.; Soldin, Steven J.; Vinks, Alexander A.; Younis, Islam; Landy, Helain J.

2013-01-01

The treatment of maternal hypothyroidism presents clinicians with a unique challenge, because dosing regimens previously developed and validated for nonpregnant women cannot be easily extrapolated to dosing in pregnancy. Thyroid hormone requirement increases by 20% to 40% early during pregnancy, persisting throughout gestation. Accordingly, women with treated hypothyroidism need to increase their levothyroxine dose to prevent maternal hypothyroidism and the associated impaired cognitive development and increased fetal mortality. We investigated the pharmacokinetic properties of levothyroxine during pregnancy through the use of a novel, traceable form of levothyroxine. The objective was to conduct a longitudinal study to determine whether levothyroxine pharmacokinetics differ in the pregnant versus nonpregnant state. We used a unique 13C-levothyroxine-tracer method to distinguish between endogenous and exogenous levothyroxine and studied the pharmacokinetics of a single oral dose of levothyroxine using tandem mass spectrometry. Moreover, we were able to detect single dose amounts of the drug, in picogram/mL concentrations. The area under the curve was 23.0 ng*h/mL in pregnancy and 14.8 ng*h/mL in nonpregnant women (P < 0.03) with median serum half-lives of 32.1 hours and 24.1 hours, respectively (P < 0.04). Further research involves the measurement of free thyroxine on these samples using tandem mass spectrometry. Future work should focus on the mechanisms responsible for the gestational differences in pharmacokinetics and whether these should necessitate dose schedule changes in pregnancy. PMID:20962709

Toxicology of brotizolam

PubMed Central

Hewett, C.; Kreuzer, H.; Köllmer, H.; Niggeschulze, A.; Stötzer, H.

1983-01-01

1 Acute studies. Following oral or intraperitoneal administration, toxicity was very low (LD50 in rodents > 10,000 and > 900 mg/kg, respectively). 2 Subacute and chronic studies in rodents. Signs of toxicity were seen only at doses of 400 mg/kg or more. Histopathological changes were found only in the 78-week study. 3 Subacute studies in dogs (intravenous) and primates (oral). In dogs, doses of 0.1 and 0.3 mg/kg produced ataxia, salivation, and diarrhoea. In monkeys doses of 7 mg/kg or higher produced ataxia, increased appetite, hyperreflexive muscular spasms, increase in liver weight, and lipid depletion of the adrenal cortex. 4 Reproductive studies in the rat and rabbit. Repeated doses of up to 30 mg/kg were not associated with any disturbance in fertility; nor were any embryotoxic or teratogenic effects observed. When dams were treated with 400 mg/kg, litter mortality was markedly increased. 5 Mutagenicity studies. The four different tests performed gave no indication of any mutagenic effect. 6 Local tolerance tests in the rabbit. Brotizolam was well tolerated when administered intramuscularly, intra-arterially, or intravenously. 7 Carcinogenicity studies in rodents. The mouse study showed no evidence of a tumourigenic effect. The rat study is still being evaluated. 8 The toxicological studies demonstrate that brotizolam has an unusually wide therapeutic range. Findings of toxicological significance, most of which were reversible, were first recorded at doses of 7-10 mg/kg, i.e. at more than 100-times the intended human therapeutic dose. PMID:6686462

Low-Dose Tissue Plasminogen Activator in Acute Ischemic Stroke: A Systematic Review and Meta-Analysis.

PubMed

Cheng, Ji-Wei; Zhang, Xiao-Jing; Cheng, Li-Shan; Li, Guo-Yi; Zhang, Li-Jun; Ji, Kang-Xiang; Zhao, Qing; Bai, Yu

2018-02-01

Intravenous thrombolysis using tissue plasminogen activator (tPA) improves significantly the neurologic function in patients with acute ischemic stroke (AIS). However, it brings financial burden to patients and is associated with symptomatic intracranial hemorrhage (SICH). Whether low-dose tPA can effectively reduce SICH and has the same efficacy as standard-dose tPA is still controversial. We searched for English clinical trials published before March, 2017on the comparison of the efficacy and safety between low and standard dose of tPA in the treatment of AIS using MEDLINE, Embase, and Cochrane Library. The modified Rankin scale (mRS) score was used as the primary efficacy outcome. The mRS1 corresponded to 0-1, whereas mRS2 corresponded to 0-2. The SICH and mortality were adopted as primary safety outcomes. Twelve high-quality studies were selected, including 7686 patients (low-dose: 2888, standard-dose: 4798). With no statistical heterogeneity, the fixed effects model was adopted in the analysis. Similarly to standard doses, low-dose tPA improved the mRS scores (mRS1: odds ratio [OR] = .92, 95% confidence interval [CI] .84-1.02; P = .12; mRS2: OR = .97, 95% CI .88-1.08; P = .57). Compared with standard-dose tPA, low-dose tPA reduced the incidence of SICH (by National Institute of Neurological Disorders and Stroke [NINDS] definition: OR = .71, 95% CI .57-0.89; P = .003; by Safe Implementation of Thrombolysis in Stroke Monitoring Study [SITS-MOST] definition: OR = .64, 95% CI .42-0.99; P = .04), while both reduced mortality (OR = .87, 95% CI .74-1.02; P = .08). Low-dose tPA is comparable to standard-dose tPA in improving the neurologic function and reducing mortality in AIS patients. Moreover, low-dose tPA can reduce the incidence of SICH compared with standard-dose tPA. Therefore, low-dose tPA is highly recommended in AIS patients. Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Leukaemia mortality and low-dose ionising radiation in the WISMUT uranium miner cohort (1946-2013).

PubMed

Kreuzer, Michaela; Sobotzki, Christina; Fenske, Nora; Marsh, James W; Schnelzer, Maria

2017-03-01

To examine the risk of death from leukaemia in relation to occupational chronic low-level external and internal radiation exposure in a cohort of 58 972 former German uranium miners with mortality follow-up from 1946 to 2013. The red bone marrow (RBM) dose from low-linear energy transfer (LET) (mainly external γ-radiation) and high-LET (mainly radon gas) radiation was estimated based on a job-exposure matrix and biokinetic/dosimetric models. Linear excess relative risks (ERR) and 95% CIs were estimated via Poisson regression for chronic lymphatic leukaemia (CLL) and non-CLL. The mean cumulative low-LET and high-LET RBM doses among the 86% radiation-exposed workers were 48 and 9 mGy, respectively. There was a positive non-significant dose-response for mortality from non-CLL (n=120) in relation to low-LET (ERR/Gy=2.18; 95% CI -0.41 to 6.37) and high-LET radiation (ERR/Gy=16.65; 95% -1.13 to 46.75). A statistically significant excess was found for the subgroup chronic myeloid leukaemia (n=31) in relation to low-LET radiation (ERR/Gy=7.20; 95% CI 0.48 to 24.54) and the subgroup myeloid leukaemia (n=99) (ERR/Gy=26.02; 95% CI 2.55 to 68.99) for high-LET radiation. The ERR/Gy tended to be about five to ten times higher for high-LET versus low-LET radiation; however, the CIs largely overlapped. Results indicate no association of death from CLL (n=70) with either type of radiation. Our findings indicate an increased risk of death for specific subtypes from non-CLL in relation to chronic low-LET and high-LET radiation, but no such relation for CLL. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

High-Dose Conformal Radiotherapy Reduces Prostate Cancer-Specific Mortality: Results of a Meta-analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Viani, Gustavo Arruda, E-mail: gusviani@gmail.com; Godoi Bernardes da Silva, Lucas; Stefano, Eduardo Jose

2012-08-01

Purpose: To determine in a meta-analysis whether prostate cancer-specific mortality (PCSM), biochemical or clinical failure (BCF), and overall mortality (OM) in men with localized prostate cancer treated with conformal high-dose radiotherapy (HDRT) are better than those in men treated with conventional-dose radiotherapy (CDRT). Methods and Materials: The MEDLINE, Embase, CANCERLIT, and Cochrane Library databases, as well as the proceedings of annual meetings, were systematically searched to identify randomized, controlled studies comparing conformal HDRT with CDRT for localized prostate cancer. Results: Five randomized, controlled trials (2508 patients) that met the study criteria were identified. Pooled results from these randomized, controlled trialsmore » showed a significant reduction in the incidence of PCSM and BCF rates at 5 years in patients treated with HDRT (p = 0.04 and p < 0.0001, respectively), with an absolute risk reduction (ARR) of PCSM and BCF at 5 years of 1.7% and 12.6%, respectively. Two trials evaluated PCSM with 10 years of follow up. The pooled results from these trials showed a statistical benefit for HDRT in terms of PCSM (p = 0.03). In the subgroup analysis, trials that used androgen deprivation therapy (ADT) showed an ARR for BCF of 12.9% (number needed to treat = 7.7, p < 0.00001), whereas trials without ADT had an ARR of 13.6% (number needed to treat = 7, p < 0.00001). There was no difference in the OM rate at 5 and 10 years (p = 0.99 and p = 0.11, respectively) between the groups receiving HDRT and CDRT. Conclusions: This meta-analysis is the first study to show that HDRT is superior to CDRT in preventing disease progression and prostate cancer-specific death in trials that used conformational technique to increase the total dose. Despite the limitations of our study in evaluating the role of ADT and HDRT, our data show no benefit for HDRT arms in terms of BCF in trials with or without ADT.« less

Advances in the management of heart failure: the role of ivabradine

PubMed Central

Müller-Werdan, Ursula; Stöckl, Georg; Werdan, Karl

2016-01-01

A high resting heart rate (≥70–75 b.p.m.) is a risk factor for patients with heart failure (HF) with reduced ejection fraction (EF), probably in the sense of accelerated atherosclerosis, with an increased morbidity and mortality. Beta-blockers not only reduce heart rate but also have negative inotropic and blood pressure-lowering effects, and therefore, in many patients, they cannot be given in the recommended dose. Ivabradine specifically inhibits the pacemaker current (funny current, If) of the sinoatrial node cells, resulting in therapeutic heart rate lowering without any negative inotropic and blood pressure-lowering effect. According to the European Society of Cardiology guidelines, ivabradine should be considered to reduce the risk of HF hospitalization and cardiovascular death in symptomatic patients with a reduced left ventricular EF ≤35% and sinus rhythm ≥70 b.p.m. despite treatment with an evidence-based dose of beta-blocker or a dose below the recommended dose (recommendation class “IIa” = weight of evidence/opinion is in favor of usefulness/efficacy: “should be considered”; level of evidence “B” = data derived from a single randomized clinical trial or large nonrandomized studies). Using a heart rate cutoff of ≥ 75 b.p.m., as licensed by the European Medicines Agency, treatment with ivabradine 5–7.5 mg b.i.d. reduces cardiovascular mortality by 17%, HF mortality by 39% and HF hospitalization rate by 30%. A high resting heart rate is not only a risk factor in HF with reduced EF but also at least a risk marker in HF with preserved EF, in acute HF and also in special forms of HF. In this review, we discuss the proven role of ivabradine in the validated indication “HF with reduced EF” together with interesting preliminary findings, and the potential role of ivabradine in further, specific forms of HF. PMID:27895488

Brachytherapy for cervix cancer: low-dose rate or high-dose rate brachytherapy – a meta-analysis of clinical trials

PubMed Central

Viani, Gustavo A; Manta, Gustavo B; Stefano, Eduardo J; de Fendi, Ligia I

2009-01-01

Background The literature supporting high-dose rate brachytherapy (HDR) in the treatment of cervical carcinoma derives primarily from retrospective series. However, controversy still persists regarding the efficacy and safety of HDR brachytherapy compared to low-dose rate (LDR) brachytherapy, in particular, due to inadequate tumor coverage for stage III patients. Whether LDR or HDR brachytherapy produces better results for these patients in terms of survival rate, local control rate and the treatment complications remain controversial. Methods A meta-analysis of RCT was performed comparing LDR to HDR brachytherapy for cervix cancer treated for radiotherapy alone. The MEDLINE, EMBASE, CANCERLIT and Cochrane Library databases, as well as abstracts published in the annual proceedings were systematically searched. We assessed methodological quality for each outcome by grading the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. We used "recommend" for strong recommendations, and "suggest" for weak recommendations. Results Pooled results from five randomized trials (2,065 patients) of HDR brachytherapy in cervix cancer showed no significant increase of mortality (p = 0.52), local recurrence (p = 0.68), or late complications (rectal; p = 0.7, bladder; p = 0.95 or small intestine; p = 0.06) rates as compared to LDR brachytherapy. In the subgroup analysis no difference was observed for overall mortality and local recurrence in patients with clinical stages I, II and III. The quality of evidence was low for mortality and local recurrence in patients with clinical stage I, and moderate for other clinical stages. Conclusion Our meta-analysis shows that there are no differences between HDR and LDR for overall survival, local recurrence and late complications for clinical stages I, II and III. By means of the GRADE system, we recommend the use of HDR for all clinical stages of cervix cancer. PMID:19344527

Combined low-dose aspirin and warfarin anticoagulant therapy of postoperative atrial fibrillation following mechanical heart valve replacement.

PubMed

Wang, Jian-tang; Dong, Ming-feng; Song, Guang-min; Ma, Zeng-shan; Ma, Sheng-jun

2014-12-01

The safety and efficacy of combined low dose aspirin and warfarin therapy in patients with atrial fibrillation after mechanical heart valve replacement were evaluated. A total of 1016 patients (620 females, mean age of 36.8±7.7 years) admitted for cardiac valve replacement and complicated with atrial fibrillation after surgery were randomly divided into study (warfarin plus 75-100 mg aspirin) or control (warfarin only) groups. International normalized ratio (INR) and prothrombin time were maintained at 1.8-2.5 and 1.5-2.0 times the normal values, respectively. Thromboembolic events and major bleedings were registered during the follow-up period. Patients were followed up for 24±9 months. The average dose of warfarin in the study and control groups was 2.91±0.83 mg and 2.88±0.76 mg, respectively (P>0.05). The incidence of overall thromboembolic events in study group was lower than that in control group (2.16% vs. 4.35%, P=0.049). No statistically significant differences were found in hemorrhage events (3.53% vs. 3.95%, P=0.722) or mortality (0.20% vs. 0.40%, P=0.559) between the two groups. Combined low dose aspirin and warfarin therapy in the patients with atrial fibrillation following mechanical heart valve replacement significantly decreased thromboembolic events as compared with warfarin therapy alone. This combined treatment was not associated with an increase in the risk of major bleeding or mortality.

Measles Vaccination in the Presence or Absence of Maternal Measles Antibody: Impact on Child Survival

PubMed Central

Aaby, Peter; Martins, Cesário L.; Garly, May-Lill; Andersen, Andreas; Fisker, Ane B.; Claesson, Mogens H.; Ravn, Henrik; Rodrigues, Amabelia; Whittle, Hilton C.; Benn, Christine S.

2014-01-01

Background. Measles vaccine (MV) has a greater effect on child survival when administered in early infancy, when maternal antibody may still be present. Methods. To test whether MV has a greater effect on overall survival if given in the presence of maternal measles antibody, we reanalyzed data from 2 previously published randomized trials of a 2-dose schedule with MV given at 4–6 months and at 9 months of age. In both trials antibody levels had been measured before early measles vaccination. Results. In trial I (1993–1995), the mortality rate was 0.0 per 1000 person-years among children vaccinated with MV in the presence of maternal antibody and 32.3 per 1000 person-years without maternal antibody (mortality rate ratio [MRR], 0.0; 95% confidence interval [CI], 0–.52). In trial II (2003–2007), the mortality rate was 4.2 per 1000 person-years among children vaccinated in presence of maternal measles antibody and 14.5 per 1000 person-years without measles antibody (MRR, 0.29; 95% CI, .09–.91). Possible confounding factors did not explain the difference. In a combined analysis, children who had measles antibody detected when they received their first dose of MV at 4–6 months of age had lower mortality than children with no maternal antibody, the MRR being 0.22 (95% CI, .07–.64) between 4–6 months and 5 years. Conclusions. Child mortality in low-income countries may be reduced by vaccinating against measles in the presence of maternal antibody, using a 2-dose schedule with the first dose at 4–6 months (earlier than currently recommended) and a booster dose at 9–12 months of age. Clinical Trials Registration. NCT00168558. PMID:24829213

Ultrasonography-driven combination antibiotic therapy with tigecycline significantly increases survival among patients with neutropenic enterocolitis following cytarabine-containing chemotherapy for the remission induction of acute myeloid leukemia.

PubMed

Pugliese, Novella; Salvatore, Paola; Iula, Dora Vita; Catania, Maria Rosaria; Chiurazzi, Federico; Della Pepa, Roberta; Cerchione, Claudio; Raimondo, Marta; Giordano, Claudia; Simeone, Luigia; Caruso, Simona; Pane, Fabrizio; Picardi, Marco

2017-07-01

Neutropenic enterocolitis (NEC) is an abdominal infection reported primarily in patients with acute myeloid leukemia (AML) following chemotherapy, especially cytarabine, a notable efficacious cytotoxic agent for AML remission. Specific data regarding the impact of different cytarabine schedules and/or antibacterial regimens for NEC are sparse. The aim of the study was to identify the predictors of outcome within 30 days of NEC onset. NEC episodes were retrospectively pinpointed among 440 patients with newly diagnosed AML hospitalized in our Institution, over a 10-year period, for receiving chemotherapy protocols with 100-6000 mg/m 2 daily of cytarabine. Two subgroups, survivors versus nonsurvivors, were compared by using logistic regression analysis. NEC was documented in 100 of 420 (23.8%) analyzed patients: 42.5% had received high-dose cytarabine, whereas 19% and 15% intermediate-dose and standard-dose cytarabine, respectively (P < 0.001). The 30-day NEC attributable mortality rate was 23%. In univariate analysis, antileukemic protocols containing robust dosages of cytarabine were significantly associated with high mortality (P < 0.001); whereas, standard-dose cytarabine and prompt initiation (at the ultrasonographic appearance of intestinal mural thickening) of NEC therapy with antibiotic combinations including tigecycline were significantly associated with low mortality. In multivariate analysis, high-dose cytarabine-containing chemotherapy was the independent predictor of poor outcome (odds ratio [OR]: 0.109; 95% confidence interval [CI]: 0.032-0.364; P < 0.001), whereas ultrasonography-driven NEC therapy with antibiotic regimens including tigecycline was associated with a favorable outcome (OR: 13.161; 95% CI: 1.587-109.17; P = 0.017). Chemotherapy schedules with robust dosages of cytarabine for AML remission are associated with a high rate of NEC incidence and attributable. Vigorous antibacterial therapy, triggered off pathologic ultrasonographic findings, with drug combinations which have broad antimicrobial coverage and good gut penetration, specifically those also including tigecycline, may be effective in improving 30-day survival rate after NEC onset. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Late Mortality Among 5-Year Survivors of Childhood Cancer: A Summary From the Childhood Cancer Survivor Study

PubMed Central

Armstrong, Gregory T.; Liu, Qi; Yasui, Yutaka; Neglia, Joseph P.; Leisenring, Wendy; Robison, Leslie L.; Mertens, Ann C.

2009-01-01

The Childhood Cancer Survivor Study (CCSS) has assembled the largest cohort to date for assessment of late mortality. Vital status and cause of death of all patients eligible for participation in CCSS was determined using the National Death Index and death certificates to characterize the mortality experience of 20,483 survivors, representing 337,334 person-years of observation. A total of 2,821 deaths have occurred as of December 31, 2002. The overall cumulative mortality is 18.1% (95% CI, 17.3 to 18.9) at 30 years from diagnosis. With time, while all-cause mortality rates have been stable, the pattern of late death is changing. Mortality attributable to recurrence or progression of primary disease is decreasing, with increases in rates of mortality attributable to subsequent neoplasms (standardized mortality ratios [SMR], 15.2; 95% CI, 13.9 to 16.6), cardiac death (SMR, 7.0; 95% CI, 5.9 to 8.2), and pulmonary death (SMR, 8.8; 95% CI, 6.8 to 11.2) largely due to treatment-related causes. In addition, the CCSS has identified specific treatment-related risk factors for late mortality. Radiotherapy (relative risk [RR], 2.9; 95% CI, 2.1 to 4.2), alkylating agents (RR, 2.2; 95% CI, 1.6 to 3.0), and epipodophyllotoxins (RR, 2.3; 95% CI, 1.2 to 4.5) increase the risk of death due to subsequent malignancy. Cardiac radiation exposure (RR, 3.3; 95% CI, 2.0 to 5.5) and high dose of anthracycline exposure (RR, 3.1; 95% CI, 1.6 to 5.8) are associated with late cardiac death. By continued longitudinal follow-up of the cohort and expansion of the cohort to include patients diagnosed between 1987 and 1999, the CCSS will remain a primary resource for assessment of late mortality of survivors of childhood cancers. PMID:19332714

Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial.

PubMed

Aaby, Peter; Martins, Cesário L; Garly, May-Lill; Balé, Carlito; Andersen, Andreas; Rodrigues, Amabelia; Ravn, Henrik; Lisse, Ida M; Benn, Christine S; Whittle, Hilton C

2010-11-30

To examine in a randomised trial whether a 25% difference in mortality exists between 4.5 months and 3 years of age for children given two standard doses of Edmonston-Zagreb measles vaccines at 4.5 and 9 months of age compared with those given one dose of measles vaccine at 9 months of age (current policy). Randomised controlled trial. The Bandim Health Project, Guinea-Bissau, which maintains a health and demographic surveillance system in an urban area. 6648 children aged 4.5 months of age who had received three doses of diphtheria-tetanus-pertussis vaccine at least four weeks before enrolment. A large proportion of the children (80%) had previously taken part in randomised trials of neonatal vitamin A supplementation. Children were randomised to receive Edmonston-Zagreb measles vaccine at 4.5 and 9 months of age (group A), no vaccine at 4.5 months and Edmonston-Zagreb measles vaccine at 9 months of age (group B), or no vaccine at 4.5 months and Schwarz measles vaccine at 9 months of age (group C). Main outcome measure Mortality rate ratio between 4.5 and 36 months of age for group A compared with groups B and C. Secondary outcomes tested the hypothesis that the beneficial effect was stronger in the 4.5 to 9 months age group, in girls, and in the dry season, but the study was not powered to test whether effects differed significantly between subgroups. In the intention to treat analysis of mortality between 4.5 and 36 months of age the mortality rate ratio of children who received two doses of Edmonston-Zagreb vaccine at 4.5 and 9 months of age compared with those who received a single dose of Edmonston-Zagreb vaccine or Schwarz vaccine at 9 months of age was 0.78 (95% confidence interval 0.59 to 1.05). In the analyses of secondary outcomes, the intention to treat mortality rate ratio was 0.67 (0.38 to 1.19) between 4.5 and 9 months and 0.83 (0.83 to 1.16) between 9 and 36 months of age. The effect on mortality between 4.5 and 36 months of age was significant for girls (intention to treat mortality rate ratio 0.64 (0.42 to 0.98)), although this was not significantly different from the effect in boys (0.95 (0.64 to 1.42)) (interaction test, P=0.18). The effect did not differ between the dry season and the rainy season. As neonatal vitamin A supplementation is not WHO policy, the analyses were done separately for the 3402 children who did not receive neonatal vitamin A. In these children, the two dose Edmonston-Zagreb measles vaccine schedule was associated with a significantly lower mortality between 4.5 and 36 months of age (intention to treat mortality rate ratio 0.59 (0.39 to 0.89)). The effect was again significant for girls but not statistically significant from the effect in boys. When measles cases were censored, the intention to treat mortality rate ratio was 0.65 (0.43 to 0.99). Although the overall effect did not reach statistical significance, the results may indicate that a two dose schedule with Edmonston-Zagreb measles vaccine given at 4.5 and 9 months of age has beneficial non-specific effects on children's survival, particularly for girls and for children who have not received neonatal vitamin A. This should be tested in future studies in different locations. Clinical trials NCT00168558.

The Associations between Types of Ambient PM2.5 and Under-Five and Maternal Mortality in Africa.

PubMed

Owili, Patrick Opiyo; Lien, Wei-Hung; Muga, Miriam Adoyo; Lin, Tang-Huang

2017-03-30

Exploring the effects of different types of PM 2.5 is necessary to reduce associated deaths, especially in low- and middle-income countries (LMICs). Hence we determined types of ambient PM 2.5 before exploring their effects on under-five and maternal mortality in Africa. The spectral derivate of aerosol optical depth (AOD) from Moderate Resolution Imaging Spectroradiometer (MODIS) products from 2000 to 2015 were employed to determine the aerosol types before using Generalized Linear and Additive Mixed-Effect models with Poisson link function to explore the associations and penalized spline for dose-response relationships. Four types of PM 2.5 were identified in terms of mineral dust, anthropogenic pollutant, biomass burning and mixture aerosols. The results demonstrate that biomass PM 2.5 increased the rate of under-five mortality in Western and Central Africa, each by 2%, and maternal mortality in Central Africa by 19%. Anthropogenic PM 2.5 increased under-five and maternal deaths in Northern Africa by 5% and 10%, respectively, and maternal deaths by 4% in Eastern Africa. Dust PM 2.5 increased under-five deaths in Northern, Western, and Central Africa by 3%, 1%, and 10%, respectively. Mixture PM 2.5 only increased under-five deaths and maternal deaths in Western (incidence rate ratio = 1.01, p < 0.10) and Eastern Africa (incidence rate ratio = 1.06, p < 0.01), respectively. The findings indicate the types of ambient PM 2.5 are significantly associated with under-five and maternal mortality in Africa where the exposure level usually exceeds the World Health Organization's (WHO) standards. Appropriate policy actions on protective and control measures are therefore suggested and should be developed and implemented accordingly.

The Associations between Types of Ambient PM2.5 and Under-Five and Maternal Mortality in Africa

PubMed Central

Owili, Patrick Opiyo; Lien, Wei-Hung; Muga, Miriam Adoyo; Lin, Tang-Huang

2017-01-01

Exploring the effects of different types of PM2.5 is necessary to reduce associated deaths, especially in low- and middle-income countries (LMICs). Hence we determined types of ambient PM2.5 before exploring their effects on under-five and maternal mortality in Africa. The spectral derivate of aerosol optical depth (AOD) from Moderate Resolution Imaging Spectroradiometer (MODIS) products from 2000 to 2015 were employed to determine the aerosol types before using Generalized Linear and Additive Mixed-Effect models with Poisson link function to explore the associations and penalized spline for dose-response relationships. Four types of PM2.5 were identified in terms of mineral dust, anthropogenic pollutant, biomass burning and mixture aerosols. The results demonstrate that biomass PM2.5 increased the rate of under-five mortality in Western and Central Africa, each by 2%, and maternal mortality in Central Africa by 19%. Anthropogenic PM2.5 increased under-five and maternal deaths in Northern Africa by 5% and 10%, respectively, and maternal deaths by 4% in Eastern Africa. Dust PM2.5 increased under-five deaths in Northern, Western, and Central Africa by 3%, 1%, and 10%, respectively. Mixture PM2.5 only increased under-five deaths and maternal deaths in Western (incidence rate ratio = 1.01, p < 0.10) and Eastern Africa (incidence rate ratio = 1.06, p < 0.01), respectively. The findings indicate the types of ambient PM2.5 are significantly associated with under-five and maternal mortality in Africa where the exposure level usually exceeds the World Health Organization’s (WHO) standards. Appropriate policy actions on protective and control measures are therefore suggested and should be developed and implemented accordingly. PMID:28358348

Night-shift work increases morbidity of breast cancer and all-cause mortality: a meta-analysis of 16 prospective cohort studies.

PubMed

Lin, Xiaoti; Chen, Weiyu; Wei, Fengqin; Ying, Mingang; Wei, Weidong; Xie, Xiaoming

2015-11-01

Night-shift work (NSW) has previously been related to incidents of breast cancer and all-cause mortality, but many published studies have reported inconclusive results. The aim of the present study was to quantify a potential dose-effect relationship between NSW and morbidity of breast cancer, and to evaluate the association between NSW and risk of all-cause mortality. The outcomes included NSW, morbidity of breast cancer, cardiovascular mortality, cancer-related mortality, and all-cause mortality. Sixteen investigations were included, involving 2,020,641 participants, 10,004 incident breast cancer cases, 7185 cancer-related deaths, 4820 cardiovascular end points, and 2480 all-cause mortalities. The summary risk ratio (RR) of incident breast cancer for an increase of NSW was 1.057 [95% confidence interval (CI) 1.014-1.102; test for heterogeneity p = 0.358, I(2) = 9.2%]. The combined RR (95% CI) of breast cancer risk for NSW vs daytime work was: 1.029 (0.969-1.093) in the <5-year subgroup, 1.019 (1.001-1.038) for 5-year incremental risk, 1.025 (1.006-1.044) for 5- to 10-year exposure times, 1.074 (1.010-1.142) in the 10- to 20-year subgroup, and 1.088 (1.012-1.169) for >20-year exposure lengths. The overall RR was 1.089 (95% CI 1.016-1.166) in a fixed-effects model (test for heterogeneity p = 0.838, I(2) = 0%) comparing rotating NSW and day work. Night-shift work was associated with an increased risk of cardiovascular death (RR 1.027, 95% CI 1.001-1.053), and all-cause death 1.253 (95% CI 0.786-1.997). In summary, NSW increased the risk of breast cancer morbidity by: 1.9% for 5 years, 2.5% for 5-10 years, 7.4% for 10-20 years, and 8.8% for >20-years of NSW. Additionally, rotating NSW enhanced the morbidity of breast cancer by 8.9%. Moreover, NSW was associated with a 2.7% increase in cardiovascular death. Copyright © 2015. Published by Elsevier B.V.

Organ toxicity and mortality in propofol-sedated rabbits under prolonged mechanical ventilation.

PubMed

Ypsilantis, Petros; Politou, Maria; Mikroulis, Dimitrios; Pitiakoudis, Michail; Lambropoulou, Maria; Tsigalou, Christina; Didilis, Vasilios; Bougioukas, Georgios; Papadopoulos, Nikolaos; Manolas, Constantinos; Simopoulos, Constantinos

2007-07-01

Prolonged administration of propofol at large doses has been implicated in propofol infusion syndrome in intensive care unit patients. In this study we investigated organ toxicity and mortality of propofol sedation at large doses in prolonged mechanically ventilated rabbits and determined the role of propofol's lipid vehicle. Eighteen healthy male rabbits were endotracheally intubated and sedated with propofol 2% (Group P), sevoflurane (Group S) or sevoflurane while receiving Intralipid 10% (Group SI). Sedation lasted 48 h or until death (Group P) or the maximum surviving period of Group P (Groups S and SI). The initial propofol infusion rate (20 mg x kg(-1) x h(-1)) or sevoflurane concentration (1.5%) was adjusted, if needed, to maintain a standard level of sedation. Blood biochemical analysis was performed in serial blood samples and histologic examination in the heart, lungs, liver, gallbladder, kidneys, urinary bladder, and quadriceps femoris muscle at autopsy. The mortality rate was 100% (surviving period, 26-38 h) for Group P, whereas 0% for Groups S and SI. The initial propofol infusion rate had to be increased up to 65.7 +/- 4.6 mg x kg(-1) x h(-1) and sevoflurane concentration up to 4%. Serum liver function indices, lipids and creatine kinase were significantly increased (P < 0.05) in Groups P and SI and lactate was increased only in Group P, whereas amylase was increased in all groups. In Group P, histologic examination revealed myocarditis, pulmonary edema with interstitial pneumonia, hepatitis, steatosis, and focal liver necrosis, cholangitis, gallbladder necrosis, acute tubular necrosis of the kidneys, focal loss of the urinary bladder epithelium, and rhabdomyolysis of skeletal muscles; in Group S, low-grade bronchitis and incipient inflammation of the liver and the kidneys; and in Group SI, low-grade bronchitis, liver steatosis and hepatitis, and incipient inflammation of the gallbladder, kidneys, and urinary bladder. Continuous infusion of 2% propofol at large doses for the sedation of rabbits undergoing prolonged mechanical ventilation induced fatal multiorgan dysfunction syndrome similar to the propofol infusion syndrome seen in humans. Our novel findings including lung, liver, gallbladder, and urinary bladder injury were also noted. The role of propofol's lipid vehicle in the manifestation of the syndrome was minor. Sevoflurane proved to be a safe alternative medication for prolonged sedation.

Linear No-Threshold Model VS. Radiation Hormesis

PubMed Central

Doss, Mohan

2013-01-01

The atomic bomb survivor cancer mortality data have been used in the past to justify the use of the linear no-threshold (LNT) model for estimating the carcinogenic effects of low dose radiation. An analysis of the recently updated atomic bomb survivor cancer mortality dose-response data shows that the data no longer support the LNT model but are consistent with a radiation hormesis model when a correction is applied for a likely bias in the baseline cancer mortality rate. If the validity of the phenomenon of radiation hormesis is confirmed in prospective human pilot studies, and is applied to the wider population, it could result in a considerable reduction in cancers. The idea of using radiation hormesis to prevent cancers was proposed more than three decades ago, but was never investigated in humans to determine its validity because of the dominance of the LNT model and the consequent carcinogenic concerns regarding low dose radiation. Since cancer continues to be a major health problem and the age-adjusted cancer mortality rates have declined by only ∼10% in the past 45 years, it may be prudent to investigate radiation hormesis as an alternative approach to reduce cancers. Prompt action is urged. PMID:24298226

Terminal illness and the increased mortality risk of conventional antipsychotics in observational studies: a systematic review.

PubMed

Luijendijk, Hendrika J; de Bruin, Niels C; Hulshof, Tessa A; Koolman, Xander

2016-02-01

Numerous large observational studies have shown an increased risk of mortality in elderly users of conventional antipsychotics. Health authorities have warned against use of these drugs. However, terminal illness is a potentially strong confounder of the observational findings. So, the objective of this study was to systematically assess whether terminal illness may have biased the observational association between conventional antipsychotics and risk of mortality in elderly patients. Studies were searched in PubMed, CINAHL, Embase, the references of selected studies and articles referring to selected studies (Web of Science). Inclusion criteria were (i) observational studies that estimated (ii) the risk of all-cause mortality in (iii) new elderly users of (iv) conventional antipsychotics compared with atypical antipsychotics or no use. Two investigators assessed the characteristics of the exposure and reference groups, main results, measured confounders and methods used to adjust for unmeasured confounders. We identified 21 studies. All studies were based on administrative medical and pharmaceutical databases. Sicker and older patients received conventional antipsychotics more often than new antipsychotics. The risk of dying was especially high in the first month of use, and when haloperidol was administered per injection or in high doses. Terminal illness was not measured in any study. Instrumental variables that were used were also confounded by terminal illness. We conclude that terminal illness has not been adjusted for in observational studies that reported an increased risk of mortality risk in elderly users of conventional antipsychotics. As the validity of the evidence is questionable, so is the warning based on it. Copyright © 2015 John Wiley & Sons, Ltd.

Early Exposure to Recommended Calorie Delivery in the Intensive Care Unit Is Associated With Increased Mortality in Patients With Acute Respiratory Distress Syndrome.

PubMed

Peterson, Sarah J; Lateef, Omar B; Freels, Sally; McKeever, Liam; Fantuzzi, Giamila; Braunschweig, Carol A

2017-06-01

The Intensive Nutrition in Acute Lung Injury: Clinical Trial (INTACT), designed to evaluate outcomes of calorie delivery from acute respiratory distress syndrome (ARDS) diagnosis through hospital discharge, was stopped due to higher mortality in the intervention group. Post hoc analysis found timing and dose of calorie delivery influenced mortality. The objective of this retrospective cohort study was to determine if early vs late calorie exposure changed the hazard of death among a larger sample of patients with ARDS. Adult patients who met the eligibility criteria for INTACT but did not participate were included. Daily calorie delivery was collected from the date INTACT eligibility was determined to extubation or death. Cox proportional hazards regression was used to model the relationship between hazard of hospital death with average calorie exposure received over increasing study days and after day 7. A total of 298 patients were included; overall mortality was 33%. Among patients who remained intubated at 1 week (n = 202), higher kcal/kg received from intensive care unit (ICU) days 1-6 increased hazards of subsequent death on days 7+ (hazard ratio [HR], 1.04; 95% confidence interval [CI], 1.01-1.06); kcal/kg received after ICU day 7 decreased the hazards of death on day 7+ (HR, 0.53; 95% CI, 0.33-0.84). Higher calorie exposure between ICU days 1 and 7 was associated with higher subsequent hazard of mortality, and provision of high-calorie exposure after day 8 decreased the hazards of death.

Macrolide therapy is associated with reduced mortality in acute respiratory distress syndrome (ARDS) patients.

PubMed

Simonis, Fabienne D; de Iudicibus, Gianfranco; Cremer, Olaf L; Ong, David S Y; van der Poll, Tom; Bos, Lieuwe D; Schultz, Marcus J

2018-01-01

Macrolides have been associated with favorable immunological effects in various inflammatory disease states. We investigated the association between macrolide therapy and mortality in patients with the acute respiratory distress syndrome (ARDS). This was an unplanned secondary analysis of patients with ARDS within a large prospective observational study of critically ill patients in the intensive care units (ICUs) of two university-affiliated hospitals in the Netherlands. The exposure of interest was low-dose macrolide use prescribed for another reason than infection; we excluded patients who received high-dose macrolides for an infection. The primary endpoint was 30-day mortality. The association between macrolide therapy and mortality was determined in the whole cohort, as well as in a propensity score matched cohort; the association was compared between pulmonary versus non-pulmonary ARDS, and between two biological phenotypes based on plasma levels of 20 biomarkers. In total, 873 patients with ARDS were analyzed, of whom 158 patients (18%) received macrolide therapy during stay in ICU for a median duration of 3 (interquartile range, 1-4) days. Erythromycin was the most frequent prescribed macrolide (97%). Macrolide therapy was associated with reduced 30-day mortality in the whole cohort [22.8% vs. 31.6%; crude odds ratio (OR), 0.64 (interquartile range, 0.43-0.96), P=0.03]. The association in the propensity score matched cohort remained significant [22.8% vs. 32.9%; OR, 0.62 (interquartile range, 0.39-0.96), P=0.03]. Propensity matched associations with mortality were different in patients with non-pulmonary ARDS vs. pulmonary ARDS and also varied by biological phenotype. These data together show that low-dose macrolide therapy prescribed for another reason than infection is associated with decreased mortality in patients with ARDS.

Macrolide therapy is associated with reduced mortality in acute respiratory distress syndrome (ARDS) patients

PubMed Central

de Iudicibus, Gianfranco; Cremer, Olaf L.; Ong, David S. Y.; van der Poll, Tom; Bos, Lieuwe D.; Schultz, Marcus J.

2018-01-01

Background Macrolides have been associated with favorable immunological effects in various inflammatory disease states. We investigated the association between macrolide therapy and mortality in patients with the acute respiratory distress syndrome (ARDS). Methods This was an unplanned secondary analysis of patients with ARDS within a large prospective observational study of critically ill patients in the intensive care units (ICUs) of two university-affiliated hospitals in the Netherlands. The exposure of interest was low-dose macrolide use prescribed for another reason than infection; we excluded patients who received high-dose macrolides for an infection. The primary endpoint was 30-day mortality. The association between macrolide therapy and mortality was determined in the whole cohort, as well as in a propensity score matched cohort; the association was compared between pulmonary versus non-pulmonary ARDS, and between two biological phenotypes based on plasma levels of 20 biomarkers. Results In total, 873 patients with ARDS were analyzed, of whom 158 patients (18%) received macrolide therapy during stay in ICU for a median duration of 3 (interquartile range, 1–4) days. Erythromycin was the most frequent prescribed macrolide (97%). Macrolide therapy was associated with reduced 30-day mortality in the whole cohort [22.8% vs. 31.6%; crude odds ratio (OR), 0.64 (interquartile range, 0.43–0.96), P=0.03]. The association in the propensity score matched cohort remained significant [22.8% vs. 32.9%; OR, 0.62 (interquartile range, 0.39–0.96), P=0.03]. Propensity matched associations with mortality were different in patients with non-pulmonary ARDS vs. pulmonary ARDS and also varied by biological phenotype. Conclusions These data together show that low-dose macrolide therapy prescribed for another reason than infection is associated with decreased mortality in patients with ARDS. PMID:29430441

Retrospective evaluation of the effect of red blood cell product age on occurrence of acute transfusion-related complications in dogs: 210 cases (2010-2012).

PubMed

Maglaras, Christina H; Koenig, Amie; Bedard, Deanna L; Brainard, Benjamin M

2017-01-01

To determine whether red blood cell (RBC) product age influences the occurrence of acute transfusion-related complications and mortality in dogs. The hypothesis was that acute transfusion-related complications and mortality would increase with age of product. Retrospective study (2010-2012). University teaching hospital. Two hundred and ten clinical canine patients. None. Medical records were reviewed for dogs receiving RBC-containing products. Patient signalment; reason for transfusion; product type, dose, age, and source; pretransfusion compatibility; rate, route, and method of administration; administration of multiple transfusions; underlying disease; occurrence of transfusion-related complications (eg, fever, hemolysis, gastrointestinal distress, cardiovascular, neurologic, and respiratory complications); various hematologic parameters; and survival were recorded. Data were analyzed for association between potential risk factors and occurrence of transfusion-related complications as well as between transfusion-related complications and survival. Of 333 transfusion events in 210 patients, 84 transfusion-related complications occurred. Fever was most common (41/333), followed by hemolysis (21/333). For every additional day of product age, the odds of hemolysis increased significantly (odds ratio, 1.11; 95% confidence interval, 1.06-1.16; P < 0.0001). Transfusion-related complications when considered as a whole were associated with higher dose of product, longer duration of administration per transfusion event, and immune-mediated disease, but not with source of product or general category of anemia. Administration rate was significantly slower in patients with febrile transfusion-related complications (P < 0.0001). Product age was not associated with increased mortality. Age of stored RBC products is associated with increased risk of transfusion-related hemolysis, but not with fever. Prospective clinical studies evaluating the influence of storage duration on development of in vitro versus in vivo hemolysis are warranted. © Veterinary Emergency and Critical Care Society 2016.

The effect of silver nanoparticles on zebrafish embryonic development and toxicology.

PubMed

Xia, Guangqing; Liu, Tiantian; Wang, Zhenwei; Hou, Yi; Dong, Lihong; Zhu, Junyi; Qi, Jie

2016-06-01

The unique physical and chemical characteristics of nanomaterials, such as the effects of their small size, surface effects, very high rates of reaction, and quantum tunnel effect, have aroused great interest among scholars. However, improper usage has led to an increasing number of nanomaterials entering the environment through various channels, greatly threatening the security of the ecological environment and human health. The urgent need for a scientific assessment of their biosafety can enable nanomaterials to truly benefit humanity. However, the current research in this field is extremely limited with regard to safety standards and waste disposal. In this study, we used silver nanoparticles (nano-Ag) and zebrafish embryos as experimental subjects, and we have reported the deleterious effect on zebrafish embryos treated with different concentrations of nano-Ag, with respect to morphological features (mortality, deformity rate, and heartbeat) and the analysis of expression of relevant genes (sox17, gsc, ntl, otx2); we found a dose-dependent increase in mortality and hatching delay. The results of in situ hybridization indicated that nano-Ag causes a dose-dependent toxicity in embryonic development, and would affect their development and lead to deformity, delayed development, and even death. The safety limit for the concentration of nano-Ag was found to be less than 5 mg/L.

Effects of low-dose acetylsalicylic acid and atherosclerotic vascular diseases on the outcome in patients with severe sepsis or septic shock.

PubMed

Otto, Gordon Philipp; Sossdorf, Maik; Boettel, Janina; Kabisch, Björn; Breuel, Hannes; Winning, Johannes; Lösche, Wolfgang

2013-01-01

Sepsis and its sequelae of multiple organ failure is one of the leading causes of death in the industrial countries. Several studies have shown that patients who are treated with low-dose acetyl salicylic acid (ASA) for secondary prevention of atherothrombosis may have a lower risk to develop organ failure in the case of critical illness. The benefit of ASA is probably due to an inhibition of platelet activation as well as an increase in the formation of anti-inflammatory lipoxin A4. On the other hand, the effect of ASA could be - at least partially - an indirect one, caused by atherosclerotic vascular diseases as the cause of ASA treatment. Atherosclerosis is considered as a moderate systemic inflammation and we hypothesise that this chronic condition could have an impact on the outcome in sepsis. To get more information on the benefit of ASA in critically ill patients and on possible interference with atherosclerotic vascular diseases, we analysed the medical records of 886 septic patients who were admitted to the surgical intensive care unit (ICU) of a university hospital. Logistic regression analysis indicated that patients who were treated during the ICU stay with ASA (100 mg/d) had a significantly lower mortality. Odds ratios (ORs; with 95% confidential intervals) of 0.56 (0.37-0.84) and 0.57 (0.39-0.83) were calculated for ICU and hospital mortality, respectively. In contrast, statin treatment did not have significant effect on mortality. Diagnosis of atherosclerotic vascular diseases according to ICD classification did not influence ICU mortality but lowered hospital mortality (OR = 0.71 (0.52-0.99)). Subgroup analysis provided preliminary evidence that clopidogrel when given as only anti-platelet drug may have a similar benefit as ASA, but the combination of ASA and clopidogrel failed to improve the outcome. The time course of plasma fibrinogen and procalcitonin levels indicate that ASA seems to reduce the activation of haemostasis and increase the resolution of inflammation. It is concluded that prospective interventional studies should be done to test the use of ASA as novel therapeutic approach in critically ill patients.

Career Excess Mortality Risk from Diagnostic Radiological Exams Required for Crewmembers Participating in Long Duration Space Flight

NASA Technical Reports Server (NTRS)

Dodge, C. W.; Gonzalez, S. M.; Picco, C. E.; Johnston, S. L.; Shavers, M. R.; VanBaalen, M.

2008-01-01

NASA requires astronauts to undergo diagnostic x-ray examinations as a condition for their employment. The purpose of these procedures is to assess the astronaut s overall health and to diagnose conditions that could jeopardize the success of long duration space missions. These include exams for acceptance into the astronaut corps, routine periodic exams, as well as evaluations taken pre and post missions. Issues: According to NASA policy these medical examinations are considered occupational radiological exposures, and thus, are included when computing the astronaut s overall radiation dose and associated excess cancer mortality risk. As such, astronauts and administrators are concerned about the amount of radiation received from these procedures due to the possibility that these additional doses may cause astronauts to exceed NASA s administrative limits, thus disqualifying them from future flights. Methods: Radiation doses and cancer mortality risks following required medical radiation exposures are presented herein for representative male and female astronaut careers. Calculation of the excess cancer mortality risk was performed by adapting NASA s operational risk assessment model. Averages for astronaut height, weight, number of space missions and age at selection into the astronaut corps were used as inputs to the NASA risk model. Conclusion: The results show that the level of excess cancer mortality imposed by all required medical procedures over an entire astronaut s career is approximately the same as that resulting from a single short duration space flight (i.e. space shuttle mission). In short the summation of all medical procedures involving ionizing radiation should have no impact on the number of missions an astronaut can fly over their career. Learning Objectives: 1. The types of diagnostic medical exams which astronauts are subjected to will be presented. 2. The level of radiation dose and excess mortality risk to the average male and female astronaut will be presented.

Immunosuppressant dose reduction and long-term rejection risk in renal transplant recipients with severe bacterial pneumonia.

PubMed

Shih, Chia-Jen; Tarng, Der-Cherng; Yang, Wu-Chang; Yang, Chih-Yu

2014-07-01

Due to lifelong immunosuppression, renal transplant recipients (RTRs) are at risk of infectious complications such as pneumonia. Severe pneumonia results in respiratory failure and is life‑threatening. We aimed to examine the influence of immunosuppressant dose reduction on RTRs with bacterial pneumonia and respiratory failure. From January 2001 to January 2011, 33 of 1,146 RTRs at a single centre developed bacterial pneumonia with respiratory failure. All patients were treated using mechanical ventilation and aggressive therapies in the intensive care unit. Average time from kidney transplantation to pneumonia with respiratory failure was 6.8 years. In-hospital mortality rate was 45.5% despite intensive care and aggressive therapies. Logistic regression analysis indicated that a high serum creatinine level at the time of admission to the intensive care unit (odds ratio 1.77 per mg/dL, 95% confidence interval 1.01-3.09; p = 0.045) was a mortality determinant. Out of the 33 patients, immunosuppressive agents were reduced in 17 (51.5%). We found that although immunosuppressant dose reduction tended to improve in-hospital mortality, this was not statistically significant. Nevertheless, during a mean follow-up period of two years, none of the survivors (n = 18) developed acute rejection or allograft necrosis. In RTRs with bacterial pneumonia and respiratory failure, higher serum creatinine levels were a mortality determinant. Although temporary immunosuppressant dose reduction might not reduce mortality, it was associated with a minimal risk of acute rejection during the two-year follow-up. Our results suggest that early immunosuppressant reduction in RTRs with severe pneumonia of indeterminate microbiology may be safe even when pathogens are bacterial in nature.

The optimal age of measles immunisation in low-income countries: a secondary analysis of the assumptions underlying the current policy

PubMed Central

Martins, Cesário L; Garly, May-Lill; Rodrigues, Amabelia; Benn, Christine S; Whittle, Hilton

2012-01-01

Objective The current policy of measles vaccination at 9 months of age was decided in the mid-1970s. The policy was not tested for impact on child survival but was based on studies of seroconversion after measles vaccination at different ages. The authors examined the empirical evidence for the six underlying assumptions. Design Secondary analysis. Data sources and methods These assumptions have not been research issues. Hence, the authors examined case reports to assess the empirical evidence for the original assumptions. The authors used existing reviews, and in December 2011, the authors made a PubMed search for relevant papers. The title and abstract of papers in English, French, Portuguese, Spanish, German and Scandinavian languages were assessed to ascertain whether the paper was potentially relevant. Based on cumulative measles incidence figures, the authors calculated how many measles cases had been prevented assuming everybody was vaccinated at a specific age, how many ‘vaccine failures’ would occur after the age of vaccination and how many cases would occur before the specific age of vaccination. In the combined analyses of several studies, the authors used the Mantel–Haenszel weighted RR stratifying for study or age groups to estimate common trends. Setting and participants African community studies of measles infection. Primary and secondary outcomes Consistency between assumptions and empirical evidence and the predicted effect on mortality. Results In retrospect, the major assumptions were based on false premises. First, in the single study examining this point, seronegative vaccinated children had considerable protection against measles infection. Second, in 18 community studies, vaccinated measles cases (‘vaccine failures’) had threefold lower case death than unvaccinated cases. Third, in 24 community studies, infants had twofold higher case death than older measles cases. Fourth, the only study examining the assumption that ‘vaccine failures’ lead to lack of confidence found the opposite because vaccinated children had milder measles infection. Fifth, a one-dose policy was recommended. However, the two randomised trials of early two-dose measles vaccination compared with one-dose vaccination found significantly reduced mortality until 3 years of age. Thus, current evidence suggests that the optimal age for a single dose of measles vaccine should have been 6 or 7 months resulting in fewer severe unvaccinated cases among infants but more mild ‘vaccine failures’ among older children. Furthermore, the two-dose trials indicate that measles vaccine reduces mortality from other causes than measles infection. Conclusions Many lives may have been lost by not determining the optimal age of measles vaccination. Since seroconversion continues to be the basis for policy, the current recommendation is to increase the age of measles vaccination to 12 months in countries with limited measles transmission. This policy may lead to an increase in child mortality. PMID:22815465

Molecular and cellular profiling of acute responses to total body radiation exposure in ovariectomized female cynomolgus macaques.

PubMed

DeBo, Ryne J; Register, Thomas C; Caudell, David L; Sempowski, Gregory D; Dugan, Gregory; Gray, Shauna; Owzar, Kouros; Jiang, Chen; Bourland, J Daniel; Chao, Nelson J; Cline, J Mark

2015-06-01

The threat of radiation exposure requires a mechanistic understanding of radiation-induced immune injury and recovery. The study objective was to evaluate responses to ionizing radiation in ovariectomized (surgically post-menopausal) female cynomolgus macaques. Animals received a single total-body irradiation (TBI) exposure at doses of 0, 2 or 5 Gy with scheduled necropsies at 5 days, 8 weeks and 24 weeks post-exposure. Blood and lymphoid tissues were evaluated for morphologic, cellular, and molecular responses. Irradiated animals developed symptoms of acute hematopoietic syndrome, and reductions in thymus weight, thymopoiesis, and bone marrow cellularity. Acute, transient increases in plasma monocyte chemoattractant protein 1 (MCP-1) were observed in 5 Gy animals along with dose-dependent alterations in messenger ribonucleic acid (mRNA) signatures in thymus, spleen, and lymph node. Expression of T cell markers was lower in thymus and spleen, while expression of macrophage marker CD68 (cluster of differentiation 68) was relatively elevated in lymphoid tissues from irradiated animals. Ovariectomized female macaques exposed to moderate doses of radiation experienced increased morbidity, including acute, dose-dependent alterations in systemic and tissue-specific biomarkers, and increased macrophage/T cell ratios. The effects on mortality exceeded expectations based on previous studies in males, warranting further investigation.

A historical prospective study of European stainless steel, mild steel, and shipyard welders.

PubMed Central

Simonato, L; Fletcher, A C; Andersen, A; Anderson, K; Becker, N; Chang-Claude, J; Ferro, G; Gérin, M; Gray, C N; Hansen, K S

1991-01-01

A multicentre cohort of 11,092 male welders from 135 companies located in nine European countries has been assembled with the aim of investigating the relation of potential cancer risk, lung cancer in particular, with occupational exposure. The observation period and the criteria for inclusion of welders varied from country to country. Follow up was successful for 96.9% of the cohort and observed numbers of deaths (and for some countries incident cancer cases) were compared with expected numbers calculated from national reference rates. Mortality and cancer incidence ratios were analysed by cause category, time since first exposure, duration of employment, and estimated cumulative dose to total fumes, chromium (Cr), Cr VI, and nickel (Ni). Overall a statistically significant excess was reported for mortality from lung cancer (116 observed v 86.81 expected deaths, SMR = 134). When analysed by type of welding an increasing pattern with time since first exposure was present for both mild steel and stainless steel welders, which was more noticeable for the subcohort of predominantly stainless steel welders. No clear relation was apparent between mortality from lung cancer and duration of exposure to or estimated cumulative dose of Ni or Cr. Whereas the patterns of lung cancer mortality in these results suggest that the risk of lung cancer is higher for stainless steel than mild steel welders the different level of risk for these two categories of welding exposure cannot be quantified with precision. The report of five deaths from pleural mesothelioma unrelated to the type of welding draws attention to the risk of exposure to asbestos in welding activities. PMID:2015204

Progress in global measles control and mortality reduction, 2000-2007.

PubMed

2008-12-05

Despite the availability of a safe and effective vaccine since 1963, measles has been a major killer of children in developing countries (causing an estimated 750,000 deaths as recently as 2000), primarily because of underutilization of the vaccine. At the World Health Assembly in 2008, all World Health Organization (WHO) member states reaffirmed their commitment to achieving a 90% reduction in measles mortality by 2010 compared with 2000, a goal that was established in 2005 as part of the Global Immunization Vision and Strategy (2). This WHO-UNICEF comprehensive strategy for measles mortality reduction (1) focuses on 47 priority countries. The strategy's components include 1) achieving and maintaining high coverage (>90%) with the routinely scheduled first dose of measles-containing vaccine (MCV1) among children aged 1 year; 2) ensuring that all children receive a second opportunity for measles immunization (either through a second routine dose or through periodic supplementary immunization activities [SIAs]); 3) implementing effective laboratory-supported disease surveillance; and 4) providing appropriate clinical management for measles cases. This report updates previously published reports and describes immunization and surveillance activities implemented during 2007. Increased routine measles vaccine coverage and SIAs implemented during 2000--2007 resulted in a 74% decrease in the estimated number of measles deaths globally. An estimated 197,000 deaths from measles occurred in 2007; of these, 136,000 (69%) occurred in the WHO South-East Asian Region. Achievement of the 2010 goal will require full implementation of measles mortality reduction strategies, especially in the WHO South-East Asian Region.

Toxicity and carcinogenicity studies of boric acid in male and female B6C3F1 mice.

PubMed Central

Dieter, M P

1994-01-01

Toxicity and potential carcinogenicity studies of boric acid were investigated in mice to verify in a second rodent species that this was a noncarcinogenic chemical. Earlier chronic studies in rats indicated boric acid was not a carcinogen. The chemical is nominated for testing because over 200 tons are produced annually, there are multiple uses for the product, and there is potential for widespread human exposure, both orally and dermally. Both sexes of B6C3F1 mice were offered diets mixed with boric acid for 14 days, 13 weeks, or 2 years. Dietary doses used in the acute, 14-day study were 0, 0.62, 1.25, 2.5, 5, and 10%; those in the subchronic, 13-week study were 0, 0.12, 0.25, 0.50, 1, and 2%; and doses in the 2-year, chronic study were 0, 0.25, and 0.50% in the diet. Mortality, clinical signs of toxicity, estimates of food consumption, body weight gain, and histopathologic examination of selected tissues constituted the variables measured. In the 14-day study mortality was proportional to dose and time of exposure in both sexes, occurring in dose groups as low as 2.5% and as early as 7 days of exposure. Body weights were depressed more than 10% below controls in the higher dose groups of both sexes. Mortality in the 13-week study was confined to the two highest dose groups in male mice and to the 2%-dose group in females. Body weight depression from 8 to 23% below those of controls occurred in the 0.50% and higher dose groups of both sexes.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7889889

Sedentary behaviour and risk of all-cause, cardiovascular and cancer mortality, and incident type 2 diabetes: a systematic review and dose response meta-analysis.

PubMed

Patterson, Richard; McNamara, Eoin; Tainio, Marko; de Sá, Thiago Hérick; Smith, Andrea D; Sharp, Stephen J; Edwards, Phil; Woodcock, James; Brage, Søren; Wijndaele, Katrien

2018-03-28

 To estimate the strength and shape of the dose-response relationship between sedentary behaviour and all-cause, cardiovascular disease (CVD) and cancer mortality, and incident type 2 diabetes (T2D), adjusted for physical activity (PA). Data Sources: Pubmed, Web of Knowledge, Medline, Embase, Cochrane Library and Google Scholar (through September-2016); reference lists. Study Selection: Prospective studies reporting associations between total daily sedentary time or TV viewing time, and ≥ one outcome of interest. Data Extraction: Two independent reviewers extracted data, study quality was assessed; corresponding authors were approached where needed. Data Synthesis: Thirty-four studies (1,331,468 unique participants; good study quality) covering 8 exposure-outcome combinations were included. For total sedentary behaviour, the PA-adjusted relationship was non-linear for all-cause mortality (RR per 1 h/day: were 1.01 (1.00-1.01) ≤ 8 h/day; 1.04 (1.03-1.05) > 8 h/day of exposure), and for CVD mortality (1.01 (0.99-1.02) ≤ 6 h/day; 1.04 (1.03-1.04) > 6 h/day). The association was linear (1.01 (1.00-1.01)) with T2D and non-significant with cancer mortality. Stronger PA-adjusted associations were found for TV viewing (h/day); non-linear for all-cause mortality (1.03 (1.01-1.04) ≤ 3.5 h/day; 1.06 (1.05-1.08) > 3.5 h/day) and for CVD mortality (1.02 (0.99-1.04) ≤ 4 h/day; 1.08 (1.05-1.12) > 4 h/day). Associations with cancer mortality (1.03 (1.02-1.04)) and T2D were linear (1.09 (1.07-1.12)).  Independent of PA, total sitting and TV viewing time are associated with greater risk for several major chronic disease outcomes. For all-cause and CVD mortality, a threshold of 6-8 h/day of total sitting and 3-4 h/day of TV viewing was identified, above which the risk is increased.

Shaken baby syndrome and a triple-dose strategy for its prevention.

PubMed

Stewart, Tanya Charyk; Polgar, Denise; Gilliland, Jason; Tanner, David A; Girotti, Murray J; Parry, Neil; Fraser, Douglas D

2011-12-01

Inflicted traumatic brain injury associated with Shaken Baby Syndrome (SBS) is a leading cause of injury mortality and morbidity in infants. A triple-dose SBS prevention program was implemented with the aim to reduce the incidence of SBS. The objectives of this study were to describe the epidemiology of SBS, the triple-dose prevention program, and its evaluation. Descriptive and spatial epidemiologic profiles of SBS cases treated at Children's Hospital, London Health Sciences Centre, from 1991 to 2010 were created. Dose 1 (in-hospital education): pre-post impact evaluation of registered nurse training, with a questionnaire developed to assess parents' satisfaction with the program. Dose 2 (public health home visits): process evaluation of additional education given to new parents. Dose 3 (media campaign): a questionnaire developed to rate the importance of factors on a 7-point Likert scale. These factors were used to create weights for statistical modeling and mapping within a geographic information system to target prevention ads. Forty-three percent of severe infant injuries were intentional. A total of 54 SBS cases were identified. The mean age was 6.7 months (standard deviation, 10.9 months), with 61% of infant males. The mean Injury Severity Score was 26.3 (standard deviation, 5.5) with a 19% mortality rate. Registered nurses learned new information on crying patterns and SBS, with a 47% increase in knowledge posttraining (p < 0.001). Over 10,000 parents were educated in-hospital, a 93% education compliance rate. Nearly all parents (93%) rated the program as useful, citing "what to do when the crying becomes frustrating" as the most important message. Only 6% of families needed to be educated during home visits. Locations of families with a new baby, high population density, and percentage of lone parents were found to be the most important factors for selecting media sites. The spatial analysis revealed six areas needed to be targeted for ad locations. SBS is a devastating intentional injury that often results in poor outcomes for the child. Implementing a triple-dose prevention program that provides education on crying patterns, coping strategies, and the dangers of shaking is key to SBS prevention. The program increased knowledge. Parents rated the program as useful. The media campaign allowed us to extend the primary prevention beyond new parents to help create a cultural change in the way crying, the primary trigger for SBS, is viewed. Targeting our intervention increased the likelihood that our message was reaching the population in greatest need.

Mortality among mound workers exposed to polonium-210 and other sources of radiation, 1944-1979.

PubMed

Boice, John D; Cohen, Sarah S; Mumma, Michael T; Ellis, Elizabeth Dupree; Cragle, Donna L; Eckerman, Keith F; Wallace, Phillip W; Chadda, Bandana; Sonderman, Jennifer S; Wiggs, Laurie D; Richter, Bonnie S; Leggett, Richard W

2014-02-01

Polonium-210 is a naturally occurring radioactive element that decays by emitting an alpha particle. It is in the air we breathe and also a component of tobacco smoke. Polonium-210 is used as an anti-static device in printing presses and gained widespread notoriety in 2006 after the poisoning and subsequent death of a Russian citizen in London. More is known about the lethal effects of polonium-210 at high doses than about late effects from low doses. Cancer mortality was examined among 7,270 workers at the Mound nuclear facility near Dayton, OH where polonium-210 was used (1944-1972) in combination with beryllium as a source of neutrons for triggering nuclear weapons. Other exposures included external gamma radiation and to a lesser extent plutonium-238, tritium and neutrons. Vital status and cause of death was determined through 2009. Standardized mortality ratios (SMRs) were computed for comparisons with the general population. Lifetime occupational doses from all places of employment were sought and incorporated into the analysis. Over 200,000 urine samples were analyzed to estimate radiation doses to body organs from polonium and other internally deposited radionuclides. Cox proportional hazards models were used to evaluate dose-response relationships for specific organs and tissues. Vital status was determined for 98.7% of the workers of which 3,681 had died compared with 4,073.9 expected (SMR 0.90; 95% CI 0.88-0.93). The mean dose from external radiation was 26.1 mSv (maximum 939.1 mSv) and the mean lung dose from external and internal radiation combined was 100.1 mSv (maximum 17.5 Sv). Among the 4,977 radiation workers, all cancers taken together (SMR 0.86; 95% CI 0.79-0.93), lung cancer (SMR 0.85; 95% CI 0.74-0.98), and other types of cancer were not significantly elevated. Cox regression analysis revealed a significant positive dose-response trend for esophageal cancer [relative risk (RR) and 95% confidence interval at 100 mSv of 1.54 (1.15-2.07)] and a negative dose-response trend for liver cancer [RR (95% CI) at 100 mSv of 0.55 (0.23-1.32)]. For lung cancer the RR at 100 mSv was 1.00 (95% CI 0.97-1.04) and for all leukemias other than chronic lymphocytic leukemia (CLL) it was 1.04 (95% CI 0.63-1.71). There was no evidence that heart disease was associated with exposures [RR at 100 mSv of 1.06 (0.95-1.18)]. Assuming a relative biological effectiveness factor of either 10 or 20 for polonium and plutonium alpha particle emissions had little effect on the dose-response analyses. Polonium was the largest contributor to lung dose, and a relative risk of 1.04 for lung cancer at 100 mSv could be excluded with 95% confidence. A dose related increase in cancer of the esophagus was consistent with a radiation etiology but based on small numbers. A dose-related decrease in liver cancer suggests the presence of other modifying factors of risk and adds caution to interpretations. The absence of a detectable increase in total cancer deaths and lung cancer in particular associated with occupational exposures to polonium (mean lung dose 159.8 mSv), and to plutonium to a lesser extent (mean lung dose 13.7 mSv), is noteworthy but based on small numbers. Larger combined studies of U.S. workers are needed to clarify radiation risks following prolonged exposures and radionuclide intakes.

Mortality Among Mound Workers Exposed to Polonium-210 and Other Sources of Radiation, 1944–1979

DOE PAGES

Boice, John D.; Cohen, Sarah S.; Mumma, Michael T.; ...

2014-02-14

Polonium-210 is a naturally occurring radioactive element that decays by emitting an alpha particle. It is in the air we breathe and also a component of tobacco smoke. Polonium-210 is used as an anti-static device in printing presses and gained widespread notoriety in 2006 after the poisoning and subsequent death of a Russian citizen in London. More is known about the lethal effects of polonium-210 at high doses than about late effects from low doses. In this paper, cancer mortality was examined among 7,270 workers at the Mound nuclear facility near Dayton, OH where polonium-210 was used (1944–1972) in combinationmore » with beryllium as a source of neutrons for triggering nuclear weapons. Other exposures included external gamma radiation and to a lesser extent plutonium-238, tritium and neutrons. Vital status and cause of death was determined through 2009. Standardized mortality ratios (SMRs) were computed for comparisons with the general population. Lifetime occupational doses from all places of employment were sought and incorporated into the analysis. Over 200,000 urine samples were analyzed to estimate radiation doses to body organs from polonium and other internally deposited radionuclides. Cox proportional hazards models were used to evaluate dose-response relationships for specific organs and tissues. Vital status was determined for 98.7% of the workers of which 3,681 had died compared with 4,073.9 expected (SMR 0.90; 95% CI 0.88–0.93). The mean dose from external radiation was 26.1 mSv (maximum 939.1 mSv) and the mean lung dose from external and internal radiation combined was 100.1 mSv (maximum 17.5 Sv). Among the 4,977 radiation workers, all cancers taken together (SMR 0.86; 95% CI 0.79–0.93), lung cancer (SMR 0.85; 95% CI 0.74–0.98), and other types of cancer were not significantly elevated. Cox regression analysis revealed a significant positive dose-response trend for esophageal cancer [relative risk (RR) and 95% confidence interval at 100 mSv of 1.54 (1.15–2.07)] and a negative dose-response trend for liver cancer [RR (95% CI) at 100 mSv of 0.55 (0.23–1.32)]. For lung cancer the RR at 100 mSv was 1.00 (95% CI 0.97–1.04) and for all leukemias other than chronic lymphocytic leukemia (CLL) it was 1.04 (95% CI 0.63–1.71). There was no evidence that heart disease was associated with exposures [RR at 100 mSv of 1.06 (0.95–1.18)]. Assuming a relative biological effectiveness factor of either 10 or 20 for polonium and plutonium alpha particle emissions had little effect on the dose-response analyses. Polonium was the largest contributor to lung dose, and a relative risk of 1.04 for lung cancer at 100 mSv could be excluded with 95% confidence. A dose related increase in cancer of the esophagus was consistent with a radiation etiology but based on small numbers. A dose-related decrease in liver cancer suggests the presence of other modifying factors of risk and adds caution to interpretations. The absence of a detectable increase in total cancer deaths and lung cancer in particular associated with occupational exposures to polonium (mean lung dose 159.8 mSv), and to plutonium to a lesser extent (mean lung dose 13.7 mSv), is noteworthy but based on small numbers. Finally, larger combined studies of U.S. workers are needed to clarify radiation risks following prolonged exposures and radionuclide intakes.« less

Mortality Among Mound Workers Exposed to Polonium-210 and Other Sources of Radiation, 1944–1979

DOE Office of Scientific and Technical Information (OSTI.GOV)

Boice, John D.; Cohen, Sarah S.; Mumma, Michael T.

Polonium-210 is a naturally occurring radioactive element that decays by emitting an alpha particle. It is in the air we breathe and also a component of tobacco smoke. Polonium-210 is used as an anti-static device in printing presses and gained widespread notoriety in 2006 after the poisoning and subsequent death of a Russian citizen in London. More is known about the lethal effects of polonium-210 at high doses than about late effects from low doses. In this paper, cancer mortality was examined among 7,270 workers at the Mound nuclear facility near Dayton, OH where polonium-210 was used (1944–1972) in combinationmore » with beryllium as a source of neutrons for triggering nuclear weapons. Other exposures included external gamma radiation and to a lesser extent plutonium-238, tritium and neutrons. Vital status and cause of death was determined through 2009. Standardized mortality ratios (SMRs) were computed for comparisons with the general population. Lifetime occupational doses from all places of employment were sought and incorporated into the analysis. Over 200,000 urine samples were analyzed to estimate radiation doses to body organs from polonium and other internally deposited radionuclides. Cox proportional hazards models were used to evaluate dose-response relationships for specific organs and tissues. Vital status was determined for 98.7% of the workers of which 3,681 had died compared with 4,073.9 expected (SMR 0.90; 95% CI 0.88–0.93). The mean dose from external radiation was 26.1 mSv (maximum 939.1 mSv) and the mean lung dose from external and internal radiation combined was 100.1 mSv (maximum 17.5 Sv). Among the 4,977 radiation workers, all cancers taken together (SMR 0.86; 95% CI 0.79–0.93), lung cancer (SMR 0.85; 95% CI 0.74–0.98), and other types of cancer were not significantly elevated. Cox regression analysis revealed a significant positive dose-response trend for esophageal cancer [relative risk (RR) and 95% confidence interval at 100 mSv of 1.54 (1.15–2.07)] and a negative dose-response trend for liver cancer [RR (95% CI) at 100 mSv of 0.55 (0.23–1.32)]. For lung cancer the RR at 100 mSv was 1.00 (95% CI 0.97–1.04) and for all leukemias other than chronic lymphocytic leukemia (CLL) it was 1.04 (95% CI 0.63–1.71). There was no evidence that heart disease was associated with exposures [RR at 100 mSv of 1.06 (0.95–1.18)]. Assuming a relative biological effectiveness factor of either 10 or 20 for polonium and plutonium alpha particle emissions had little effect on the dose-response analyses. Polonium was the largest contributor to lung dose, and a relative risk of 1.04 for lung cancer at 100 mSv could be excluded with 95% confidence. A dose related increase in cancer of the esophagus was consistent with a radiation etiology but based on small numbers. A dose-related decrease in liver cancer suggests the presence of other modifying factors of risk and adds caution to interpretations. The absence of a detectable increase in total cancer deaths and lung cancer in particular associated with occupational exposures to polonium (mean lung dose 159.8 mSv), and to plutonium to a lesser extent (mean lung dose 13.7 mSv), is noteworthy but based on small numbers. Finally, larger combined studies of U.S. workers are needed to clarify radiation risks following prolonged exposures and radionuclide intakes.« less

Statistical considerations in the analysis of data from replicated bioassays

USDA-ARS?s Scientific Manuscript database

Multiple-dose bioassay is generally the preferred method for characterizing virulence of insect pathogens. Linear regression of probit mortality on log dose enables estimation of LD50/LC50 and slope, the latter having substantial effect on LD90/95s (doses of considerable interest in pest management)...

Modeling Population-Level Consequences of Polychlorinated Biphenyl Exposure in East Greenland Polar Bears.

PubMed

Pavlova, Viola; Grimm, Volker; Dietz, Rune; Sonne, Christian; Vorkamp, Katrin; Rigét, Frank F; Letcher, Robert J; Gustavson, Kim; Desforges, Jean-Pierre; Nabe-Nielsen, Jacob

2016-01-01

Polychlorinated biphenyls (PCBs) can cause endocrine disruption, cancer, immunosuppression, or reproductive failure in animals. We used an individual-based model to explore whether and how PCB-associated reproductive failure could affect the dynamics of a hypothetical polar bear (Ursus maritimus) population exposed to PCBs to the same degree as the East Greenland subpopulation. Dose-response data from experimental studies on a surrogate species, the mink (Mustela vision), were used in the absence of similar data for polar bears. Two alternative types of reproductive failure in relation to maternal sum-PCB concentrations were considered: increased abortion rate and increased cub mortality. We found that the quantitative impact of PCB-induced reproductive failure on population growth rate depended largely on the actual type of reproductive failure involved. Critical potencies of the dose-response relationship for decreasing the population growth rate were established for both modeled types of reproductive failure. Comparing the model predictions of the age-dependent trend of sum-PCBs concentrations in females with actual field measurements from East Greenland indicated that it was unlikely that PCB exposure caused a high incidence of abortions in the subpopulation. However, on the basis of this analysis, it could not be excluded that PCB exposure contributes to higher cub mortality. Our results highlight the necessity for further research on the possible influence of PCBs on polar bear reproduction regarding their physiological pathway. This includes determining the exact cause of reproductive failure, i.e., in utero exposure versus lactational exposure of offspring; the timing of offspring death; and establishing the most relevant reference metrics for the dose-response relationship.

Biological Response to SPE Exposures

NASA Technical Reports Server (NTRS)

Wilson, J. W.; Cucinotta, F. A.; Kim, M.; Shinn, J. L.; Jones, T. D.; Chang, C. K.

2004-01-01

It has long been recognized that a single solar particle event (SPE) can produce, over a short period of time, exposures on the order of LD50 for humans under normal physiological conditions. It is further recognized that recovery from injury over the period of exposure would greatly increase the chances of survival (dose rate effects) although such effects were left unquantified. In the present report we use the bioresponse model derived from a broad range of animal and human exposure data for evaluation of troop readiness in tactical nuclear warfare to evaluate the biological risk posed by the solar event of 4 August 1972. The astronaut blood forming organ (BFO) exposure in deep space would have been 2.2 Sv (1.6 Gy) in a space suit, 1.8 Sv (1.3 Gy) in an aluminum pressure vessel, and 0.7 Sv (0.5 Gy) in an equipment room compared to an X-ray mortality threshold of 1.5 Gy (assuming high dose rate). We find BFO dose rate effectiveness factors for this SPE on the order of 3 to 4, greatly reducing the mortality risks for this event. There is an approximate 3 percent chance that an even larger event may occur for which exposures could be 2-4 times higher. Assured survival of the astronaut requires added shelter shielding and a warning system for this event. The required mass of the shelter shield can be greatly reduced by using hydrogenous materials such as polymers, water, food, and other biological materials in its construction. Limitations of the current bioresponse model arise from the exposures taking place in the microgravity environment wherein the immune system is already challenged and the effective mortality threshold may be reduced by a factor of two. Such microgravity effects could greatly affect astronaut risks.

Dosing strategies to optimize currently available anti-MRSA treatment options (Part 1: IV options).

PubMed

Hall, Ronald G; Thatcher, Michael; Wei, Wei; Varghese, Shibin; Varughese, Lincy; Ndiulor, Michelle; Payne, Kenna D

2017-05-01

Methicillin-resistant Staphylococcus aureus (MRSA) continues to be a predominant pathogen resulting in significant morbidity and mortality. Optimal dosing of anti-MRSA agents is needed to help prevent the development of antimicrobial resistance and to increase the likelihood of a favorable clinical outcome. Areas covered: This review summarizes the available data for antimicrobials routinely used for MRSA infections that are not administered orally or topically. We make recommendations and highlight the current gaps in the literature. A PubMed (1966 - Present) search was performed to identify relevant literature for this review. Expert commentary: Improvements in MIC determination and therapeutic drug monitoring are needed to fully implement individualized dosing that optimizes antimicrobial pharmacodynamics.Additional data will become available for these agents in regards to effectiveness for severe MRSA infections and pharmacokinetic data for special patient populations.

Methylene Blue for Vasoplegia When on Cardiopulmonary Bypass During Double-Lung Transplantation.

PubMed

Carley, Michelle; Schaff, Jacob; Lai, Terrance; Poppers, Jeremy

2015-10-15

Vasoplegia syndrome, characterized by hypotension refractory to fluid resuscitation or high-dose vasopressors, low systemic vascular resistance, and normal-to-increased cardiac index, is associated with increased morbidity and mortality after cardiothoracic surgery. Methylene blue inhibits inducible nitric oxide synthase and guanylyl cyclase, and has been used to treat vasoplegia during cardiopulmonary bypass. However, because methylene blue is associated with increased pulmonary vascular resistance, its use in patients undergoing lung transplantion has been limited. Herein, we report the use of methylene blue to treat refractory vasoplegia during cardiopulmonary bypass in a patient undergoing double-lung transplantation.

Measles control strategies in India: position paper of Indian Academy of Pediatrics.

PubMed

Vashishtha, V M; Choudhury, P; Bansal, C P; Gupta, S G

2013-06-08

Measles continues to be a major cause of childhood morbidity and mortality in India. Recent studies estimate that 80,000 Indian children die each year due to measles and its complications, amounting to 4% of under-5 deaths. Immunization against measles directly contributes to the reduction of under five child mortality and hence to the achievement of Millennium Development Goal 4 (MDG 4). The live attenuated measles vaccines are safe, effective and provide long lasting protection. The key strategies being followed globally for measles mortality reduction are high coverage of measles first dose, sensitive laboratory supported surveillance, appropriate case management, and providing second dose of measles vaccine. Prior to 2010, India was the only country in the world that had not introduced a second dose of measles vaccine in its National immunization program. We herein discuss the current status of measles vaccination along with the rationale and challenges of providing a second opportunity for measles vaccination, and the principles of measles catch-up campaigns.

A Critical, Nonlinear Threshold Dictates Bacterial Invasion and Initial Kinetics During Influenza

NASA Astrophysics Data System (ADS)

Smith, Amber M.; Smith, Amanda P.

2016-12-01

Secondary bacterial infections increase morbidity and mortality of influenza A virus (IAV) infections. Bacteria are able to invade due to virus-induced depletion of alveolar macrophages (AMs), but this is not the only contributing factor. By analyzing a kinetic model, we uncovered a nonlinear initial dose threshold that is dependent on the amount of virus-induced AM depletion. The threshold separates the growth and clearance phenotypes such that bacteria decline for dose-AM depletion combinations below the threshold, stay constant near the threshold, and increase above the threshold. In addition, the distance from the threshold correlates to the growth rate. Because AM depletion changes throughout an IAV infection, the dose requirement for bacterial invasion also changes accordingly. Using the threshold, we found that the dose requirement drops dramatically during the first 7d of IAV infection. We then validated these analytical predictions by infecting mice with doses below or above the predicted threshold over the course of IAV infection. These results identify the nonlinear way in which two independent factors work together to support successful post-influenza bacterial invasion. They provide insight into coinfection timing, the heterogeneity in outcome, the probability of acquiring a coinfection, and the use of new therapeutic strategies to combat viral-bacterial coinfections.

A Critical, Nonlinear Threshold Dictates Bacterial Invasion and Initial Kinetics During Influenza.

PubMed

Smith, Amber M; Smith, Amanda P

2016-12-15

Secondary bacterial infections increase morbidity and mortality of influenza A virus (IAV) infections. Bacteria are able to invade due to virus-induced depletion of alveolar macrophages (AMs), but this is not the only contributing factor. By analyzing a kinetic model, we uncovered a nonlinear initial dose threshold that is dependent on the amount of virus-induced AM depletion. The threshold separates the growth and clearance phenotypes such that bacteria decline for dose-AM depletion combinations below the threshold, stay constant near the threshold, and increase above the threshold. In addition, the distance from the threshold correlates to the growth rate. Because AM depletion changes throughout an IAV infection, the dose requirement for bacterial invasion also changes accordingly. Using the threshold, we found that the dose requirement drops dramatically during the first 7d of IAV infection. We then validated these analytical predictions by infecting mice with doses below or above the predicted threshold over the course of IAV infection. These results identify the nonlinear way in which two independent factors work together to support successful post-influenza bacterial invasion. They provide insight into coinfection timing, the heterogeneity in outcome, the probability of acquiring a coinfection, and the use of new therapeutic strategies to combat viral-bacterial coinfections.

Bayesian estimation of dose thresholds

NASA Technical Reports Server (NTRS)

Groer, P. G.; Carnes, B. A.

2003-01-01

An example is described of Bayesian estimation of radiation absorbed dose thresholds (subsequently simply referred to as dose thresholds) using a specific parametric model applied to a data set on mice exposed to 60Co gamma rays and fission neutrons. A Weibull based relative risk model with a dose threshold parameter was used to analyse, as an example, lung cancer mortality and determine the posterior density for the threshold dose after single exposures to 60Co gamma rays or fission neutrons from the JANUS reactor at Argonne National Laboratory. The data consisted of survival, censoring times and cause of death information for male B6CF1 unexposed and exposed mice. The 60Co gamma whole-body doses for the two exposed groups were 0.86 and 1.37 Gy. The neutron whole-body doses were 0.19 and 0.38 Gy. Marginal posterior densities for the dose thresholds for neutron and gamma radiation were calculated with numerical integration and found to have quite different shapes. The density of the threshold for 60Co is unimodal with a mode at about 0.50 Gy. The threshold density for fission neutrons declines monotonically from a maximum value at zero with increasing doses. The posterior densities for all other parameters were similar for the two radiation types.

Bench-to-bedside review: Vasopressin in the management of septic shock

PubMed Central

2011-01-01

This review of vasopressin in septic shock differs from previous reviews by providing more information on the physiology and pathophysiology of vasopressin and vasopressin receptors, particularly because of recent interest in more specific AVPR1a agonists and new information from the Vasopressin and Septic Shock Trial (VASST), a randomized trial of vasopressin versus norepinephrine in septic shock. Relevant literature regarding vasopressin and other AVPR1a agonists was reviewed and synthesized. Vasopressin, a key stress hormone in response to hypotension, stimulates a family of receptors: AVPR1a, AVPR1b, AVPR2, oxytocin receptors and purinergic receptors. Rationales for use of vasopressin in septic shock are as follows: first, a deficiency of vasopressin in septic shock; second, low-dose vasopressin infusion improves blood pressure, decreases requirements for norepinephrine and improves renal function; and third, a recent randomized, controlled, concealed trial of vasopressin versus norepinephrine (VASST) suggests low-dose vasopressin may decrease mortality of less severe septic shock. Previous clinical studies of vasopressin in septic shock were small or not controlled. There was no difference in 28-day mortality between vasopressin-treated versus norepinephrine-treated patients (35% versus 39%, respectively) in VASST. There was potential benefit in the prospectively defined stratum of patients with less severe septic shock (5 to 14 μg/minute norepinephrine at randomization): vasopressin may have lowered mortality compared with norepinephrine (26% versus 36%, respectively, P = 0.04 within stratum). The result was robust: vasopressin also decreased mortality (compared with norepinephrine) if less severe septic shock was defined by the lowest quartile of arterial lactate or by use of one (versus more than one) vasopressor at baseline. Other investigators found greater hemodynamic effects of higher dose of vasopressin (0.06 units/minute) but also unique adverse effects (elevated liver enzymes and serum bilirubin). Use of higher dose vasopressin requires further evaluation of efficacy and safety. There are very few studies of interactions of therapies in critical care - or septic shock - and effects on mortality. Therefore, the interaction of vasopressin infusion, corticosteroid treatment and mortality of septic shock was evaluated in VASST. Low-dose vasopressin infusion plus corticosteroids significantly decreased 28-day mortality compared with corticosteroids plus norepinephrine (44% versus 35%, respectively, P = 0.03; P = 0.008 interaction statistic). Prospective randomized controlled trials would be necessary to confirm this interesting interaction. In conclusion, low-dose vasopressin may be effective in patients who have less severe septic shock already receiving norepinephrine (such as patients with modest norepinephrine infusion (5 to 15 μg/minute) or low serum lactate levels). The interaction of vasopressin infusion and corticosteroid treatment in septic shock requires further study. PMID:21892977

Multi-component assessment of chronic obstructive pulmonary disease: an evaluation of the ADO and DOSE indices and the global obstructive lung disease categories in international primary care data sets

PubMed Central

Jones, Rupert C; Price, David; Chavannes, Niels H; Lee, Amanda J; Hyland, Michael E; Ställberg, Björn; Lisspers, Karin; Sundh, Josefin; van der Molen, Thys; Tsiligianni, Ioanna

2016-01-01

Suitable tools for assessing the severity of chronic obstructive pulmonary disease (COPD) include multi-component indices and the global initiative for chronic obstructive lung disease (GOLD) categories. The aim of this study was to evaluate the dyspnoea, obstruction, smoking, exacerbation (DOSE) and the age, dyspnoea, obstruction (ADO) indices and GOLD categories as measures of current health status and future outcomes in COPD patients. This was an observational cohort study comprising 5,114 primary care COPD patients across three databases from UK, Sweden and Holland. The associations of DOSE and ADO indices with (i) health status using the Clinical COPD Questionnaire (CCQ) and St George’s Respiratory Questionnaire (SGRQ) and COPD Assessment test (CAT) and with (ii) current and future exacerbations, admissions and mortality were assessed in GOLD categories and DOSE and ADO indices. DOSE and ADO indices were significant predictors of future exacerbations: incident rate ratio was 1.52 (95% confidence intervals 1.46–1.57) for DOSE, 1.16 (1.12–1.20) for ADO index and 1.50 (1.33–1.68) and 1.23 (1.10–1.39), respectively, for hospitalisations. Negative binomial regression showed that the DOSE index was a better predictor of future admissions than were its component items. The hazard ratios for mortality were generally higher for ADO index groups than for DOSE index groups. The GOLD categories produced widely differing assessments for future exacerbation risk or for hospitalisation depending on the methods used to calculate them. None of the assessment systems were excellent at predicting future risk in COPD; the DOSE index appears better than the ADO index for predicting many outcomes, but not mortality. The GOLD categories predict future risk inconsistently. The DOSE index and the GOLD categories using exacerbation frequency may be used to identify those at high risk for exacerbations and admissions. PMID:27053297

Multi-component assessment of chronic obstructive pulmonary disease: an evaluation of the ADO and DOSE indices and the global obstructive lung disease categories in international primary care data sets.

PubMed

Jones, Rupert C; Price, David; Chavannes, Niels H; Lee, Amanda J; Hyland, Michael E; Ställberg, Björn; Lisspers, Karin; Sundh, Josefin; van der Molen, Thys; Tsiligianni, Ioanna

2016-04-07

Suitable tools for assessing the severity of chronic obstructive pulmonary disease (COPD) include multi-component indices and the global initiative for chronic obstructive lung disease (GOLD) categories. The aim of this study was to evaluate the dyspnoea, obstruction, smoking, exacerbation (DOSE) and the age, dyspnoea, obstruction (ADO) indices and GOLD categories as measures of current health status and future outcomes in COPD patients. This was an observational cohort study comprising 5,114 primary care COPD patients across three databases from UK, Sweden and Holland. The associations of DOSE and ADO indices with (i) health status using the Clinical COPD Questionnaire (CCQ) and St George's Respiratory Questionnaire (SGRQ) and COPD Assessment test (CAT) and with (ii) current and future exacerbations, admissions and mortality were assessed in GOLD categories and DOSE and ADO indices. DOSE and ADO indices were significant predictors of future exacerbations: incident rate ratio was 1.52 (95% confidence intervals 1.46-1.57) for DOSE, 1.16 (1.12-1.20) for ADO index and 1.50 (1.33-1.68) and 1.23 (1.10-1.39), respectively, for hospitalisations. Negative binomial regression showed that the DOSE index was a better predictor of future admissions than were its component items. The hazard ratios for mortality were generally higher for ADO index groups than for DOSE index groups. The GOLD categories produced widely differing assessments for future exacerbation risk or for hospitalisation depending on the methods used to calculate them. None of the assessment systems were excellent at predicting future risk in COPD; the DOSE index appears better than the ADO index for predicting many outcomes, but not mortality. The GOLD categories predict future risk inconsistently. The DOSE index and the GOLD categories using exacerbation frequency may be used to identify those at high risk for exacerbations and admissions.

Randomized Trial of 2 Versus 1 Dose of Measles Vaccine: Effect on Hospital Admission of Children After 9 Months of Age.

PubMed

Brønd, Marie; Martins, Cesario L; Byberg, Stine; Benn, Christine S; Whittle, Hilton; Garly, May-Lill; Aaby, Peter; Fisker, Ane B

2017-06-15

Two doses of measles vaccine (MV) might reduce the nonmeasles mortality rate more than 1 dose of MV does. The effect of 2 versus 1 dose on morbidity has not been examined. Within a randomized trial of the effect of 2 doses versus 1 dose of MV on mortality in Guinea-Bissau, we investigated the effect on hospital admissions. Children were randomly assigned 1:2 to receive MV at 4.5 and 9 months of age or the currently recommended dose at 9 months. We compared hospital admission rates among children between 9 and 18 months of age in a Cox regression model with age as the underlying time scale. Half of the children had received neonatal vitamin A supplementation (NVAS) in another trial. The beneficial effect of MV at 4.5 and 9 months on mortality was limited to children who had not received NVAS; therefore, we investigated the interaction of MV with NVAS on admission rates. Among 5626 children (2 doses of MV, 1960 children; 1 dose of MV, 3666), we identified 311 hospital admissions of children between 9 and 18 months of age. Overall, compared to 1 dose of MV, 2 doses reduced the risk of hospital admission for children who had not received NVAS (hazard ratio [HR], 0.66 [95% confidence interval (CI), 0.47-0.93]), but we found no effect among NVAS recipients (HR, 1.16 [95% CI, 0.82-1.63]) (P = .02 for interaction). The benefit of 2 doses of MV was limited to children who had not received NVAS. NVAS is not generally recommended; hence, an early 2-dose measles vaccination policy might reduce hospital admissions more than the current policy of providing the first MV at 9 months of age. ClinicalTrials.gov identifier NCT00168558. © The Author 2017. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Acute and sub-chronic toxicity of Cajanus cajan leaf extracts.

PubMed

Tang, Rong; Tian, Ru-Hua; Cai, Jia-Zhong; Wu, Jun-Hui; Shen, Xiao-Ling; Hu, Ying-Jie

2017-12-01

The leaves of Cajanus cajan (L.) Millsp. (Fabaceae) have diverse bioactivities, but little safety data are reported. This study examines the toxicological profiles of C. cajan leaf extracts. The leaves were extracted by water or 90% ethanol to obtain water or ethanol extract (WEC or EEC). EEC was suspended in water and successively fractionated into dichloroform and n-butanol extracts (DEC and BEC). Marker compounds of the extracts were monitored by high-performance liquid chromatography (HPLC). Kunming mice were administered with a single maximum acceptable oral dose (15.0 g/kg for WEC, EEC and BEC and 11.3 g/kg for DEC) to determine death rate or maximal tolerated doses (MTDs). In sub-chronic toxicity investigation, Sprague-Dawley rats were orally given WEC or EEC at 1.5, 3.0 or 6.0 g/kg doses for four weeks and observed for two weeks after dosing to determine toxicological symptoms, histopathology, biochemistry and haematology. Flavonoids and stilbenes in the extracts were assayed. In acute toxicity test, no mortality and noted alterations in weight and behavioural abnormality were observed, and the maximum oral doses were estimated as MTDs. In sub-chronic toxicity study, no mortality and significant variances in haematological and biochemical parameters or organ histopathology were observed, but increased kidney weight in 3.0 g/kg WEC- or 3.0 and 6.0 g/kg EEC-treated female rats, and reduced testes and epididymis weight in EEC-treated male rats were recorded. These changes returned to the level of control after recovery period. Acute and sub-chronic toxicity of Cajanus cajan leaf extracts was not observed.

Homocysteine-Lowering and Cardiovascular Disease Outcomes in Kidney Transplant Recipients: Primary Results from the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial

PubMed Central

Bostom, Andrew G.; Carpenter, Myra A.; Kusek, John W.; Levey, Andrew S.; Hunsicker, Lawrence; Pfeffer, Marc A.; Selhub, Jacob; Jacques, Paul F.; Cole, Edward; Gravens-Mueller, Lisa; House, Andrew A.; Kew, Clifton; McKenney, Joyce L.; Pacheco-Silva, Alvaro; Pesavento, Todd; Pirsch, John; Smith, Stephen; Solomon, Scott; Weir, Matthew

2015-01-01

Background Kidney transplant recipients, like other patients with chronic kidney disease (CKD), experience excess risk of cardiovascular disease (CVD) and elevated total homocysteine (tHcy) concentrations. Observational studies of patients with CKD suggest increased homocysteine is a risk factor for CVD. The impact of lowering total homocysteine (tHcy) levels in kidney transplant recipients is unknown. Methods and Results In a double-blind controlled trial, we randomized 4110 stable kidney transplant recipients to a multivitamin that included either a high dose (n=2056) or low dose (n=2054) of folic acid, vitamin B6, and vitamin B12 to determine whether decreasing tHcy concentrations reduced the rate of the primary composite arteriosclerotic CVD outcome (myocardial infarction, stroke, CVD death, resuscitated sudden death, coronary artery or renal artery revascularization, lower extremity arterial disease, carotid endarterectomy or angioplasty, or abdominal aortic aneurysm repair). Mean follow-up was 4.0 years. Treatment with the high dose multivitamin reduced homocysteine but did not reduce the rates of the primary outcome (n= 547 total events; hazards ratio [95% confidence interval] = 0.99 [0.84–1.17]), or secondary outcomes of all-cause mortality (n=431 deaths; 1.04 [0.86–1.26]) or dialysis-dependent kidney failure (n=343 events; 1.15 [0.93–1.43]) compared to the low dose multivitamin. Conclusions Treatment with a high dose folic acid, B6, and B12 multivitamin in kidney transplant recipients did not reduce a composite cardiovascular disease outcome, all-cause mortality, or dialysis-dependent kidney failure despite significant reduction in homocysteine level. PMID:21482964

Fruit and vegetable consumption and mortality from all causes, cardiovascular disease, and cancer: systematic review and dose-response meta-analysis of prospective cohort studies.

PubMed

Wang, Xia; Ouyang, Yingying; Liu, Jun; Zhu, Minmin; Zhao, Gang; Bao, Wei; Hu, Frank B

2014-07-29

To examine and quantify the potential dose-response relation between fruit and vegetable consumption and risk of all cause, cardiovascular, and cancer mortality. Medline, Embase, and the Cochrane library searched up to 30 August 2013 without language restrictions. Reference lists of retrieved articles. Prospective cohort studies that reported risk estimates for all cause, cardiovascular, and cancer mortality by levels of fruit and vegetable consumption. Random effects models were used to calculate pooled hazard ratios and 95% confidence intervals and to incorporate variation between studies. The linear and non-linear dose-response relations were evaluated with data from categories of fruit and vegetable consumption in each study. Sixteen prospective cohort studies were eligible in this meta-analysis. During follow-up periods ranging from 4.6 to 26 years there were 56,423 deaths (11,512 from cardiovascular disease and 16,817 from cancer) among 833,234 participants. Higher consumption of fruit and vegetables was significantly associated with a lower risk of all cause mortality. Pooled hazard ratios of all cause mortality were 0.95 (95% confidence interval 0.92 to 0.98) for an increment of one serving a day of fruit and vegetables (P=0.001), 0.94 (0.90 to 0.98) for fruit (P=0.002), and 0.95 (0.92 to 0.99) for vegetables (P=0.006). There was a threshold around five servings of fruit and vegetables a day, after which the risk of all cause mortality did not reduce further. A significant inverse association was observed for cardiovascular mortality (hazard ratio for each additional serving a day of fruit and vegetables 0.96, 95% confidence interval 0.92 to 0.99), while higher consumption of fruit and vegetables was not appreciably associated with risk of cancer mortality. This meta-analysis provides further evidence that a higher consumption of fruit and vegetables is associated with a lower risk of all cause mortality, particularly cardiovascular mortality. © Wang et al 2014.

Developmental toxicity of diphenyl ether herbicides in nestling American kestrels.

PubMed

Hoffman, D J; Spann, J W; LeCaptain, L J; Bunck, C M; Rattner, B A

1991-11-01

Beginning the day after hatching, American kestrel (Falco sparverius) nestlings were orally dosed for 10 consecutive days with 5 microliters/g of corn oil (controls) or one of the diphenyl ether herbicides (nitrofen, bifenox, or oxyfluorfen) at concentrations of 10, 50, 250, or 500 mg/kg in corn oil. At 500 mg/kg, nitrofen resulted in complete nestling mortality, bifenox in high (66%) mortality, and oxyfluorfen in no mortality. Nitrofen at 250 mg/kg reduced nestling growth as reflected by decreased body weight, crown-rump length, and bone lengths including humerus, radius-ulna, femur, and tibiotarsus. Bifenox at 250 mg/kg had less effect on growth than nitrofen, but crown-rump, humerus, radius-ulna, and femur were significantly shorter than controls. Liver weight as a percent of body weight increased with 50 and 250 mg/kg nitrofen. Other manifestations of impending hepatotoxicity following nitrofen ingestion included increased hepatic GSH peroxidase activity in all nitrofen-treated groups, and increased plasma enzyme activities for ALT, AST, and LDH-L in the 250-mg/kg group. Bifenox ingestion resulted in increased hepatic GSH peroxidase activity in the 50- and 250-mg/kg groups. Nitrofen exposure also resulted in an increase in total plasma thyroxine (T4) concentration. These findings suggest that altricial nestlings are more sensitive to diphenyl ether herbicides than young or adult birds of precocial species.

Hydrocortisone Therapy in Catecholamine-Resistant Pediatric Septic Shock: A Pragmatic Analysis of Clinician Practice and Association With Outcomes.

PubMed

Nichols, Blake; Kubis, Sherri; Hewlett, Jennifer; Yehya, Nadir; Srinivasan, Vijay

2017-09-01

The 2012 Surviving Sepsis Campaign pediatric guidelines recommend stress dose hydrocortisone in children experiencing catecholamine-dependent septic shock with suspected or proven absolute adrenal insufficiency. We evaluated whether stress dose hydrocortisone therapy in children with catecholamine dependent septic shock correlated with random serum total cortisol levels and was associated with improved outcomes. Retrospective cohort study. Non-cardiac PICU. Critically ill children (1 mo to 18 yr) admitted between January 1, 2013, and December 31, 2013, with catecholamine dependent septic shock who had random serum total cortisol levels measured prior to potential stress dose hydrocortisone therapy. None. The cohort was dichotomized to random serum total cortisol less than 18 mcg/dL and greater than or equal to 18 mcg/dL. Associations of stress dose hydrocortisone with outcomes: PICU mortality, PICU and hospital length of stay, ventilator-free days, and vasopressor-free days were examined. Seventy children with catecholamine-dependent septic shock and measured random serum total cortisol levels were eligible (16% PICU mortality). Although 43% (30/70) had random serum total cortisol less than 18 μg/dL, 60% (42/70) received stress dose hydrocortisone. Children with random serum total cortisol less than 18 μg/dL had lower severity of illness and lower Vasopressor Inotrope Scores than those with random serum total cortisol greater than or equal to 18 μg/dL (all p < 0.05). Children with stress dose hydrocortisone had higher severity of illness and PICU mortality than those without stress dose hydrocortisone (all p < 0.05). Mean random serum total cortisol levels were similar in children with and without stress dose hydrocortisone (21.1 vs 18.7 μg/dL; p = 0.69). In children with random serum total cortisol less than 18 μg/dL, stress dose hydrocortisone was associated with greater PICU and hospital length of stay and fewer ventilator-free days (all p < 0.05). In children with random serum total cortisol greater than 18 μg/dL, stress dose hydrocortisone was associated with greater PICU mortality and fewer ventilator-free days and vasopressor-free days (all p < 0.05). Stress dose hydrocortisone therapy in children with catecholamine-dependent septic shock correlated more with severity of illness than random serum total cortisol levels and was associated with worse outcomes, irrespective of random serum total cortisol levels.

Toxicity of dietary Heliotropium dolosum seed to broiler chickens.

PubMed

Eröksüz, Y; Eröksüz, H; Ozer, H; Canatan, H; Yaman, I; Cevik, A

2001-12-01

Five groups of 20 female broiler chicks were fed different levels of dehulled Heliotropium dolosum seed (w/w%; 0.0, 1.0, 3.0, 5.0 or 10.0%) from 10 to 52 d of age. In all doses the seed caused decreases in daily feed intake, weight gain, and feed efficiency, and biochemical findings, severity of pathologic changes, and mortality rate increased in a dose-dependent manner. Acute toxicity was observed in livers of chicks fed 10% seed. Other test groups had chronic changes. Livers had massive to submassive necrosis, hepatic megalocytosis, bile duct proliferation, fatty change, and periportal fibrosis. Biochemical evaluations revealed hypoalbuminemia, hypoprotienemia and increased ALP activity and billuribin. The seed of Heliotropium dolosum produced biochemical and specific pathologic changes in broiler chicks, as well as decreased food intake and feed efficiency. Higher seed levels induced more pronounced changes.

Polysaccharides induce radioprotection of murine hemopoietic stem cells and increase the LD50/30 days

DOE Office of Scientific and Technical Information (OSTI.GOV)

Maisin, J.R.; Kondi-Tamba, A.; Mattelin, G.

1986-02-01

Intravenous administration of 60 mg/kg of a polysaccharide (MNR, MNZ, GLP/BO4, GLP/BO5) significantly decreases the mortality of mice exposed to a single dose of X rays. The dose reduction factors (DRF) obtained for MNZ, MNR, GLP/BO4, and GLP/BO5 given intraperitoneally 15 min before exposure were 2.16, 1.93, 1.80, and 1.94, respectively. The DRF was not increased when MNZ or GLP/BO4 were combined with injection of AET before X-ray exposure. The LD50 for the CFUs exposed in vivo in mice was 1.13 Gy for the treated mice and 0.75 Gy for the nontreated mice. This corresponds to a DRF of 1.6.more » The DRF calculated from the slope is 1.27.« less

Associations between adjuvant radiotherapy and different causes of death in a German breast cancer cohort.

PubMed

Obi, Nadia; Eulenburg, Christine; Seibold, Petra; Eilber, Ursula; Thöne, Kathrin; Behrens, Sabine; Chang-Claude, Jenny; Flesch-Janys, Dieter

2018-04-01

Studies of cohorts of breast cancer (BC) patients diagnosed before 1990 showed radiotherapy (RT) to be associated with increased cardiovascular (CVD) and lung cancer mortality many years after diagnosis. In the late 1990s, improvements in RT planning techniques reduced radiation doses to normal tissues. Recent studies did not consistently report higher RT-related mortality for CVD and second cancers. Aim of the study was to analyze specific causes of death after 3D-conformal RT in a recent BC cohort. Stage I-III BC patients diagnosed 2001-2005 and enrolled in the population based MARIEplus study were followed-up for 11.9 years (median). Associations between adjuvant RT and cause-specific mortality were analyzed by using competing risks models, yielding subdistribution hazard ratios (SHR) for RT directly related to cumulative incidences. Models were adjusted for differences in baseline characteristics applying inverse-probability-of-treatment-weighting (IPTW). Of the 2951 patients, 2439 (83.0%) received RT. No significant association of RT with lung cancer mortality (SHR IPTW 0.88, 0.35-2.12), other cancer mortality (SHR IPTW 1.04, 95% CI 0.62-1.73) or cardiac mortality was observed (SHR IPTW 1.57, 0.75-3.29). Mortality from lung and other diseases were significantly lower in irradiated women (SHR IPTW 0.39, 95% CI 0.17-0.90 and SHR IPTW 0.58, 95% CI 0.34-0.97, respectively). In line with recent studies, 3D-conformal RT did not significantly increase mortality from non-BC causes in the German MARIEplus cohort. Since long-term data are still sparse and event rates low in BC-cohorts, who received modern RT, investigation of possible late RT effects on mortality beyond 14 years of follow-up is warranted. Copyright © 2017 Elsevier Ltd. All rights reserved.

Non-specific effects of diphtheria-tetanus-pertussis and measles vaccinations? An analysis of surveillance data from Navrongo, Ghana.

PubMed

Welaga, Paul; Nielsen, Jens; Adjuik, Martin; Debpuur, Cornelius; Ross, David A; Ravn, Henrik; Benn, Christine S; Aaby, Peter

2012-12-01

Studies from low-income countries have suggested that routine vaccinations may have non-specific effects on child mortality; measles vaccine (MV) is associated with lower mortality and diphtheria-tetanus-pertussis (DTP) with relatively higher mortality. We used data from Navrongo, Ghana, to examine the impact of vaccinations on child mortality. Vaccination status was assessed at the initiation of a trial of vitamin A supplementation and after 12 and 24 months of follow-up. Within the placebo group, we compared the mortality over the first 4 months and the full 2 years of follow-up for different vaccination status groups with different likelihoods of additional vaccinations during follow-up. The frequency of additional vaccinations was assessed among children whose vaccination card was seen at 12 and 24 months of follow-up. Among children with a vaccination card, more than 75% received missing DTP or MV during the first 12 months of follow-up, whereas only 25% received these vaccines among children with no vaccination card at enrollment. Children without a card at enrollment had a significant threefold higher mortality over the 2-year follow-up period than those fully vaccinated. The small group of children with DTP3-4 but no MV at enrollment had lower mortality than children without a card and had the same mortality as fully vaccinated children. In contrast, children with 1-2 DTP doses but no MV had a higher mortality during the first 4 months than children without a card [MRR = 1.65 (0.95, 2.87)]; compared with the fully vaccinated children, they had significantly higher mortality after 4 months [MRR = 2.38 (1.07, 5.30)] and after 2 years [MRR = 2.41 (1.41, 4.15)]. Children with 0-2 DTP doses at enrollment had higher mortality after 4 months (MRR = 1.67 (0.82, 3.43) and after 2 years [MRR = 1.85 (1.16, 2.95)] than children who had all three doses of DTP at enrollment. As hypothesised, DTP vaccination was associated with higher child mortality than measles vaccination. To optimise vaccination policies, routine vaccinations need to be evaluated in randomised trials measuring the impact on survival. © 2012 Blackwell Publishing Ltd.

Immunomodulatory activity of methanolic leaf extract of Moringa oleifera in animals.

PubMed

Sudha, P; Asdaq, Syed Mohammed Basheeruddin; Dhamingi, Sunil S; Chandrakala, Gowda Kallenahalli

2010-01-01

The aim of the present study was to investigate the immunomodulatory action of methanolic extract of Moringa oleifera (MEMO) in an experimental model of immunity. The cellular immunity was evaluated using neutrophil adhesion test, cyclophosphamide induced neutropenia and carbon clearance assay, whereas, humoral immunity was tested by mice lethality test, serum immunoglobulin estimation and indirect haemagglutination assay in animals. Administration of MEMO (250 and 750 mg/kg, po) and Ocimum sanctum (100 mg/kg, po) significantly increased the levels of serum immunoglobulins and also prevented the mortality induced by bovine Pasteurella multocida in mice. They also increased significantly the circulating antibody titre in indirect haemagglunation test. Moreover, MEMO produced significant increase in adhesion of neutrophils, attenuation of cyclophosphamide-induced neutropenia and an increase in phagocytic index in carbon clearance assay. From the above results, it can be concluded that MEMO stimulate both cellular and humoral immune response. However, low dose of MEMO was found to be more effective than the high dose.

Ionising radiation and risk of death from leukaemia and lymphoma in radiation-monitored workers (INWORKS): an international cohort study.

PubMed

Leuraud, Klervi; Richardson, David B; Cardis, Elisabeth; Daniels, Robert D; Gillies, Michael; O'Hagan, Jacqueline A; Hamra, Ghassan B; Haylock, Richard; Laurier, Dominique; Moissonnier, Monika; Schubauer-Berigan, Mary K; Thierry-Chef, Isabelle; Kesminiene, Ausrele

2015-07-01

There is much uncertainty about the risks of leukaemia and lymphoma after repeated or protracted low-dose radiation exposure typical of occupational, environmental, and diagnostic medical settings. We quantified associations between protracted low-dose radiation exposures and leukaemia, lymphoma, and multiple myeloma mortality among radiation-monitored adults employed in France, the UK, and the USA. We assembled a cohort of 308,297 radiation-monitored workers employed for at least 1 year by the Atomic Energy Commission, AREVA Nuclear Cycle, or the National Electricity Company in France, the Departments of Energy and Defence in the USA, and nuclear industry employers included in the National Registry for Radiation Workers in the UK. The cohort was followed up for a total of 8.22 million person-years. We ascertained deaths caused by leukaemia, lymphoma, and multiple myeloma. We used Poisson regression to quantify associations between estimated red bone marrow absorbed dose and leukaemia and lymphoma mortality. Doses were accrued at very low rates (mean 1.1 mGy per year, SD 2.6). The excess relative risk of leukaemia mortality (excluding chronic lymphocytic leukaemia) was 2.96 per Gy (90% CI 1.17-5.21; lagged 2 years), most notably because of an association between radiation dose and mortality from chronic myeloid leukaemia (excess relative risk per Gy 10.45, 90% CI 4.48-19.65). This study provides strong evidence of positive associations between protracted low-dose radiation exposure and leukaemia. Centers for Disease Control and Prevention, Ministry of Health, Labour and Welfare of Japan, Institut de Radioprotection et de Sûreté Nucléaire, AREVA, Electricité de France, National Institute for Occupational Safety and Health, US Department of Energy, US Department of Health and Human Services, University of North Carolina, Public Health England. Copyright © 2015 Elsevier Ltd. All rights reserved.

Low dose intravenous immunoglobulins and steroids in toxic epidermal necrolysis: a prospective comparative open-labelled study of 36 cases.

PubMed

Jagadeesan, Soumya; Sobhanakumari, K; Sadanandan, Sadeep Melethil; Ravindran, Sheeba; Divakaran, Manjula Velikkakathu; Skaria, Lissy; Kurien, George

2013-01-01

Toxic epidermal necrolysis (TEN) is a severe adverse drug reaction associated with high mortality. Though different modalities of treatment are advocated, there is no consensus regarding specific therapy. Corticosteroids have shown conflicting results and for high dose intravenous immunoglobulins (IVIG), cost is a limiting factor. To find out the effectiveness of combination therapy with low-dose IVIG and steroids versus steroids alone in our TEN patients. After obtaining Ethical Committee approval, 36 consecutive TEN patients (2008-2012) were alternately allocated to 2 groups - Group A was given combination of low-dose IVIG (0.2-0.5 g/kg) and rapidly tapering course of steroids (intravenous dexamethasone 0.1- 0.3 mg/kg/day tapered in 1-2 weeks) while Group B was given same dose of steroids alone. Outcome parameters assessed were time taken for arrest of disease progression, time taken for re-epithelization, duration of hospital stay and mortality rates. Both groups had 18 patients. Baseline characteristics like age, sex ratio, SCORTEN, body surface area involvement and treatment interval were comparable. Time for arrest of disease progression and for re-epithelization was significantly lowered in Group A (P = 0.0001, P = 0.0009 respectively). Though duration of hospital stay and deaths were less in Group A, difference was not statistically significant. SCORTEN based standardized mortality ratio (SMR) analysis revealed that combination therapy reduced the probability of dying by 82% (SMR = 0.18 ± 0.36) and steroids by 37% (SMR = 0.63 ± 0.71). Difference in SMR was statistically significant (P = 0.00001). No significant side effects due to either modality were found in any of the patients. Combination therapy with low-dose IVIG and steroids is more effective in terms of reduced mortality and faster disease resolution when compared to steroids alone in TEN.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Latty, Drew, E-mail: drew.latty@health.nsw.gov.au; Stuart, Kirsty E; Westmead Breast Cancer Institute, Sydney, New South Wales

Radiation treatment to the left breast is associated with increased cardiac morbidity and mortality. The deep inspiration breath-hold technique (DIBH) can decrease radiation dose delivered to the heart and this may facilitate the treatment of the internal mammary chain nodes. The aim of this review is to critically analyse the literature available in relation to breath-hold methods, implementation, utilisation, patient compliance, planning methods and treatment verification of the DIBH technique. Despite variation in the literature regarding the DIBH delivery method, patient coaching, visual feedback mechanisms and treatment verification, all methods of DIBH delivery reduce radiation dose to the heart. Furthermore » research is required to determine optimum protocols for patient training and treatment verification to ensure the technique is delivered successfully.« less

Safety and efficacy of cell-based therapy on critical limb ischemia: A meta-analysis.

PubMed

Ai, Min; Yan, Chang-Fu; Xia, Fu-Chun; Zhou, Shuang-Lu; He, Jian; Li, Cui-Ping

2016-06-01

Critical limb ischemia (CLI) is a major health problem worldwide, affecting approximately 500-1000 people per million per annum. Cell-based therapy has given new hope for the treatment of limb ischemia. This study assessed the safety and efficacy of cellular therapy CLI treatment. We searched the PubMed, Embase and Cochrane databases through October 20, 2015, and selected the controlled trials with cell-based therapy for CLI treatment compared with cell-free treatment. We assessed the results by meta-analysis using a variety of outcome measures, as well as the association of mononuclear cell dosage with treatment effect by dose-response meta-analysis. Twenty-five trials were included. For the primary evaluation index, cell-based therapy significantly reduced the rate of major amputation (odds ratio [OR] 0.44, 95% confidence interval [CI] 0.32-0.60, P = 0.000) and significantly increased the rate of amputation-free survival (OR 2.80, 95% CI 1.70-4.61, P = 0.000). Trial sequence analysis indicated that optimal sample size (n = 3374) is needed to detect a plausible treatment effect in all-cause mortality. Cell-based therapy significantly improves ankle brachial index, increases the rate of ulcer healing, increases the transcutaneous pressure of oxygen, reduces limb pain and improves movement ability. Subgroup analysis indicated heterogeneity is caused by type of control, design bias and transplant route. In the dose-response analysis, there was no significant correlation between cell dosage and the therapeutic effect. Cell-based therapy has a significant therapeutic effect on CLI, but randomized double-blind placebo-controlled trials are needed to improve the credibility of this conclusion. Assessment of all-cause mortality also requires a larger sample size to arrive at a strong conclusion. In dose-response analysis, increasing the dosage of cell injections does not significantly improve the therapeutic effects of cell-based therapy. Copyright © 2016 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Combining vitamin A and vaccines: convenience or conflict?

PubMed

Benn, Christine Stabell

2012-01-01

The present thesis is based on 11 papers from 1995-2010. The studies have mainly taken place at the Bandim Health Project in Guinea-Bissau, West Africa, but a reanalysis of a randomised trial from Ghana is also included. My research has explored the consequences of combining high-dose vitamin A supplementation and childhood vaccines. Vitamin A deficiency is associated with increased mortality. To protect against the consequences of vitamin A deficiency the World Health Organization recommends that high-dose vitamin A supplements be given together with routine vaccines to children between 6 months and 5 years of age in more than 100 low-income countries. The recommendation is based on logistical considerations. The consequences of combining vitamin A and vaccines were not investigated in randomised trials prior to the implementation of this policy - it was assumed that the interventions were independent. My first project aimed to study the effect on the immune response to measles of providing vitamin A together with measles vaccine. We found that the two interventions were not independent. Vitamin A enhanced the antibody response to measles vaccine given at 9 months of age significantly, especially in boys. The effects were sustained over time; the children who had received vitamin A with their measles vaccine were more protected against measles at 6-8 years of age. Though vitamin A supplementation had a beneficial effect on the immune response to measles vaccine, it intrigued me that the effect of vitamin A supplementation on overall mortality was not always beneficial. While vitamin A was beneficial when given after 6 months of age, and two studies had shown a beneficial effect when given at birth, all studies testing the effect between 1-5 months of age had found no effect. These time windows are dominated by three different childhood vaccines: BCG vaccine given at birth, diphtheria-tetanus-pertussis (DTP) vaccine given between 1-5 months of age, and measles vaccine given at 9 months of age. These vaccines have been shown to have strong effects on mortality from infectious diseases in general, so-called non-specific effects. The live BCG and measles vaccine protects against more mortality than can be ascribed to the prevention of tuberculosis and measles, respectively. The inactivated DTP vaccine worryingly has been associated with increased mortality from other infectious diseases. Both positive and negative effects are strongest for girls. I proposed the hypothesis that vitamin A amplifies not only the specific vaccine effects, as we saw for measles vaccine, but also the non-specific effects of vaccines on mortality from other infectious diseases. According to my hypothesis, vitamin A would enhance the non-specific beneficial effects on mortality of BCG and measles vaccine, but also the negative effects of DTP vaccine. Hence, the hypothesis offered an explanation for the mortality-age pattern after vitamin A supplementation. Since it was formulated, I have aimed to test this hypothesis. Since it is associated with ethical problems to randomise children above 6 months of age to vitamin A supplementation, and to randomise children in general to recommended vaccines, we have had to be pragmatic when designing the trials. Hence, our studies have taken many different forms. We conducted an observational study during a vitamin A campaign in which missing vaccines were also provided, and a randomised trial testing the effect of two different doses of vitamin A during another campaign; we tested the effect of providing vitamin A with BCG at birth in two randomised trials, and we reanalysed data from one of the original randomised trials of vitamin A supplementation from the perspective of vaccination status. In all studies the main outcome was mortality. The results document that vitamin A supplements do more than protect against vitamin A deficiency. They support the hypothesis that vitamin A supplements interact with vaccines with important consequences for mortality. First, a smaller dose of vitamin A was more beneficial than a larger dose for girls. Second, the effect of vitamin A given with DTP vaccine was significantly different from the effect of vitamin A given with measles vaccine, and children, who received vitamin A with DTP vaccine, had higher mortality than children, who had received vitamin A alone, or who did not receive anything. Third, vitamin A given with BCG at birth interacted negatively with subsequent DTP vaccines in girls. Fourth, the effect of vitamin A to older children in Ghana depended on vaccination status, being beneficial in boys, but harmful in girls who received DTP vaccine during follow-up. The results also show that boys and girls respond differently to vitamin A and vaccines. It is a common assumption within public health in low-income countries that interventions can be combined without producing unexpected consequences. The work presented in this thesis confronts this assumption; the results show that vitamin A and vaccines should be seen not only as specific interventions with specific and independent effects, but as immuno-modulators, which can interact with important consequences for overall mortality. Combining interventions can be convenient and lead to synergistic health benefits, but we documented several examples, where it also leads to unexpectedly increased mortality. Thus, to optimise the child health intervention policy in low-income countries a shift in paradigm is needed. Health interventions should no longer be seen as merely specific and independent, and the policy should probably not be the same for boys and girls. Though more complex, it is necessary to evaluate all health interventions in terms of their effect on overall mortality - and their potential interactions with other health interventions and potential sex-differential effects should always be investigated. Only in this way can we assure that the children in the poorest countries get the best possible treatment and avoid using large amounts of money and resources on interventions which may, in worst case, kill them.

Initial fluid resuscitation following adjusted body weight dosing is associated with improved mortality in obese patients with suspected septic shock.

PubMed

Taylor, Stephanie Parks; Karvetski, Colleen H; Templin, Megan A; Heffner, Alan C; Taylor, Brice T

2018-02-01

The optimal initial fluid resuscitation strategy for obese patients with septic shock is unknown. We evaluated fluid resuscitation strategies across BMI groups. Retrospective analysis of 4157 patients in a multicenter activation pathway for treatment of septic shock between 2014 and 2016. 1293 (31.3%) patients were obese (BMI≥30). Overall, higher BMI was associated with lower mortality, however this survival advantage was eliminated in adjusted analyses. Patients with higher BMI received significantly less fluid per kilogram at 3h than did patients with lower BMI (p≤0.001). In obese patients, fluid given at 3h mimicked a dosing strategy based on actual body weight (ABW) in 780 (72.2%), adjusted body weight (AdjBW) in 95 (8.8%), and ideal body weight (IBW) in 205 (19.0%). After adjusting for condition- and treatment-related variables, dosing based on AdjBW was associated with improved mortality compared to ABW (OR 0.45; 95% CI [0.19, 1.07]) and IBW (OR 0.29; 95% CI [0.11,0.74]). Using AdjBW to calculate initial fluid resuscitation volume for obese patients with suspected shock may improve outcomes compared to other weight-based dosing strategies. The optimal fluid dosing strategy for obese patients should be a focus of future prospective research. Copyright © 2017 Elsevier Inc. All rights reserved.

The Chernobyl accident — an epidemiological perspective

PubMed Central

Cardis, E.; Hatch, M.

2011-01-01

Twenty-five years have passed since radioactive releases from the Chernobyl nuclear accident led to exposure of millions of people in Europe. Studies of affected populations have provided important new data on the links between radiation and cancer – particularly the risk of thyroid tumours from exposure to iodine isotopes - that are important not only for a fuller scientific understanding of radiation effects, but also for radiation protection. It is now well-documented that children and adolescents exposed to radioiodines from Chernobyl fallout have a sizeable dose-related increase in thyroid cancer, with risk greatest in those youngest at exposure and with a suggestion that deficiency in stable iodine may increase the risk. Data on thyroid cancer risks to other age groups are somewhat less definitive. In addition, there have been reported increases in incidence and mortality from non-thyroid cancers and non-cancer endpoints. Although some studies are difficult to interpret because of methodological limitations, recent investigations of Chernobyl clean-up workers (“liquidators”) have provided evidence of increased risks of leukaemia and other hematological malignancies and of cataracts, and suggestions of an increase in risk of cardiovascular diseases, following low doses and low dose rates of radiation. Further careful follow-up of these populations, including establishment and long-term support of life-span study cohorts, could provide additional important information for the quantification of radiation risks and the protection of persons exposed to low doses of radiation. PMID:21396807

The Chernobyl accident--an epidemiological perspective.

PubMed

Cardis, E; Hatch, M

2011-05-01

Twenty-five years have passed since radioactive releases from the Chernobyl nuclear accident led to the exposure of millions of people in Europe. Studies of affected populations have provided important new data on the links between radiation and cancer-particularly the risk of thyroid tumours from exposure to iodine isotopes-that are important not only for a fuller scientific understanding of radiation effects, but also for radiation protection. It is now well documented that children and adolescents exposed to radioiodines from Chernobyl fallout have a sizeable dose-related increase in thyroid cancer, with the risk greatest in those youngest at exposure and with a suggestion that deficiency in stable iodine may increase the risk. Data on thyroid cancer risks to other age groups are somewhat less definitive. In addition, there have been reported increases in incidence and mortality from non-thyroid cancers and non-cancer end points. Although some studies are difficult to interpret because of methodological limitations, recent investigations of Chernobyl clean-up workers ('liquidators') have provided evidence of increased risks of leukaemia and other haematological malignancies and of cataracts, and suggestions of an increase in the risk of cardiovascular diseases, following low doses and low dose rates of radiation. Further careful follow-up of these populations, including the establishment and long-term support of life-span study cohorts, could provide additional important information for the quantification of radiation risks and the protection of persons exposed to low doses of radiation. Copyright © 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Congenital malformations induced by mescaline, lysergic acid diethylamide, and bromolysergic acid in the hamster.

PubMed

Geber, W F

1967-10-13

Malformations of the brain, spinal cord, liver, and other viscera; body edema; and localized hemorrhages were found in fetal hamsters from mothers injected subcutaneously with a single dose of mescaline, lysergic acid diethylamide, or 2-bromo-D lysergic acid diethylamide on the 8th day of pregnancy. In addition, all three drugs produced an increase in the percentages of small fetuses per litter, of resorptions, and of fetal mortality.

Repellent and Contact Toxicity of Alpinia officinarum Rhizome Extract against Lasioderma serricorne Adults.

PubMed

Lü, Jianhua; Ma, Dan

2015-01-01

The repellent and contact toxicities of Alpinia officinarum rhizome extract on Lasioderma serricorne adults, and its ability to protect stored wheat flour from L. serricorne adults infestation were investigated. The A. officinarum extract exhibited strong repellent and contact toxicities against L. serricorne adults. The toxicities enhanced significantly with the increasing treatment time and treatment dose. The mean percentage repellency value reached 91.3% at class V at the dose of 0.20 μL/cm2 after 48 h of exposure. The corrected mortality reached over 80.0% at the dose of 0.16 μL/cm2 after 48 h of exposure. The A. officinarum extract could significantly reduce L. serricorne infestation level against stored wheat flour. Particularly, the insect infestation was nil in wheat flour packaged with kraft paper bags coated with the A. officinarum extract at the dose of above 0.05 μL/cm2. The naturally occurring A. officinarum extract could be useful for integrated management of L. serricorne.

Repellent and Contact Toxicity of Alpinia officinarum Rhizome Extract against Lasioderma serricorne Adults

PubMed Central

Lü, Jianhua; Ma, Dan

2015-01-01

The repellent and contact toxicities of Alpinia officinarum rhizome extract on Lasioderma serricorne adults, and its ability to protect stored wheat flour from L. serricorne adults infestation were investigated. The A. officinarum extract exhibited strong repellent and contact toxicities against L. serricorne adults. The toxicities enhanced significantly with the increasing treatment time and treatment dose. The mean percentage repellency value reached 91.3% at class V at the dose of 0.20 μL/cm2 after 48 h of exposure. The corrected mortality reached over 80.0% at the dose of 0.16 μL/cm2 after 48 h of exposure. The A. officinarum extract could significantly reduce L. serricorne infestation level against stored wheat flour. Particularly, the insect infestation was nil in wheat flour packaged with kraft paper bags coated with the A. officinarum extract at the dose of above 0.05 μL/cm2. The naturally occurring A. officinarum extract could be useful for integrated management of L. serricorne. PMID:26292097

Time series analysis of personal exposure to ambient air pollution and mortality using an exposure simulator.

PubMed

Chang, Howard H; Fuentes, Montserrat; Frey, H Christopher

2012-09-01

This paper describes a modeling framework for estimating the acute effects of personal exposure to ambient air pollution in a time series design. First, a spatial hierarchical model is used to relate Census tract-level daily ambient concentrations and simulated exposures for a subset of the study period. The complete exposure time series is then imputed for risk estimation. Modeling exposure via a statistical model reduces the computational burden associated with simulating personal exposures considerably. This allows us to consider personal exposures at a finer spatial resolution to improve exposure assessment and for a longer study period. The proposed approach is applied to an analysis of fine particulate matter of <2.5 μm in aerodynamic diameter (PM(2.5)) and daily mortality in the New York City metropolitan area during the period 2001-2005. Personal PM(2.5) exposures were simulated from the Stochastic Human Exposure and Dose Simulation. Accounting for exposure uncertainty, the authors estimated a 2.32% (95% posterior interval: 0.68, 3.94) increase in mortality per a 10 μg/m(3) increase in personal exposure to PM(2.5) from outdoor sources on the previous day. The corresponding estimates per a 10 μg/m(3) increase in PM(2.5) ambient concentration was 1.13% (95% confidence interval: 0.27, 2.00). The risks of mortality associated with PM(2.5) were also higher during the summer months.

The relationship between total cholinesterase activity and mortality in four butterfly species

USGS Publications Warehouse

Bargar, Timothy A.

2012-01-01

The relationship between total cholinesterase activity (TChE) and mortality in four butterfly species (great southern white [Ascia monuste], common buckeye [Junonia coenia], painted lady [Vanessa cardui], and julia butterflies [Dryas julia]) was investigated. Acute contact toxicity studies were conducted to evaluate the response (median lethal dose [LD50] and TChE) of the four species following exposure to the organophosphate insecticide naled. The LD50 for these butterflies ranged from 2.3 to 7.6 μg/g. The average level of TChE inhibition associated with significant mortality ranged from 26 to 67%, depending on the species. The lower bounds of normal TChE activity (2 standard deviations less than the average TChE for reference butterflies) ranged from 8.4 to 12.3 μM/min/g. As a percentage of the average reference TChE activity for the respective species, the lower bounds were similar to the inhibition levels associated with significant mortality, indicating there was little difference between the dose resulting in significant TChE inhibition and that resulting in mortality.

Arsenic in Drinking Water and Mortality for Cancer and Chronic Diseases in Central Italy, 1990-2010

PubMed Central

D’Ippoliti, Daniela; Santelli, Enrica; De Sario, Manuela; Scortichini, Matteo; Davoli, Marina; Michelozzi, Paola

2015-01-01

Background In several volcanic areas of Italy, arsenic levels exceed European regulatory limits (10 μg/L in drinking water). There is still uncertainty about health risks from arsenic at low-medium doses (<100 μg/L). Objectives A large population-based study using an administrative cohort of residents in the Viterbo province (Central Italy), chronically exposed to low-medium arsenic levels via drinking water, was investigated to evaluate the effects of a lifetime exposure to arsenic on mortality from cancers and chronic diseases. Methods The study population consisted of 165,609 residents of 17 municipalities, followed from 1990 until 2010. Average individual arsenic exposure at the first residence (AsI) was estimated through a space-time modeling approach using residential history and arsenic concentrations from water supply. A time-dependent Cumulative Arsenic dose Indicator (CAI) was calculated, accounting for daily water intake and exposure duration. Mortality Hazard Ratios (HR) were estimated by gender for different diseases using Cox proportional models, adjusting for individual and area-level confounders. A flexible non-parametric approach was used to investigate dose-response relationships. Results Mean AsI exposure was 19.3 μg/L, and average exposure duration was 39.5 years. Associations of AsI and CAI indicators with several diseases were found, with greatest risks found for lung cancer in both sexes (HR = 2.61 males; HR = 2.09 females), myocardial infarction, peripheral arterial disease and COPD in males (HR = 2.94; HR = 2.44; HR = 2.54 respectively) and diabetes in females (HR = 2.56). For lung cancer and cardiovascular diseases dose-response relationship is modelled by piecewise linear functions revealing effects even for doses lower than 10 μg/L, and no threshold dose value was identified as safe for health. Conclusions Results provide new evidence for risk assessment of low-medium concentrations of arsenic and contribute to the ongoing debate about the threshold-dose of effect, suggesting that even concentrations below 10 μg/L carry a mortality risk. Policy actions are urgently needed in areas exposed to arsenic like in the Viterbo province, to comply with current EU regulations. PMID:26383851

Radiation induced changes in the cuticular hydrocarbons of the granary weevil and their relationship to dessication and adult mortality. Quarterly report, February 15-May 14, 1986. [Sitophilus granarius

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sriharan, S.

1986-01-01

The weevils (Sitophilus granarius) were irradiated with gamma radiation at dose levels of 15, 30 and 80 krad in /sup 131/Cs irradiator at Tuskegee University. Survival studies showed that the weevils could live up to three weeks after irradiation. The higher dose level did not show any detrimental effect on the survival. The present studies were conducted with weevils of mixed age groups. This may be one factor in reduced mortality.

The effects of nandrolone decanoate on nutritional parameters in hemodialysis patients.

PubMed

Barton Pai, A; Chretien, C; Lau, A H

2002-07-01

Malnutrition with hypoalbuminemia is an independent predictor of mortality in end-stage renal disease patients. Anabolic steroids reduce protein catabolism and therefore may improve nutritional parameters. This study was undertaken to determine the effects of the anabolic steroid nandrolone decanoate on the nutritional status of hemodialysis patients. Secondary endpoints were to examine the effects of androgen therapy on hematocrit and erythropoietin (EPO) dose. Medical records of chronic hemodialysis patients who received nandrolone decanoate for greater than 30 days were reviewed. Data collected included: demographics, dose, frequency, duration of treatment and cumulative dose of nandrolone. Baseline albumin, transferrin, dry weight, phosphorus, creatinine, hematocrit and erythropoietin dose were obtained for comparison with values after treatment. Of the 9 patients evaluated (mean +/- SD: age 55+/-28 years, 4/9 male), 2 patients received nandrolone doses of 25 mg intramuscularly (i.m.) every week, while the remaining 7 patients received 100 mg i.m. every 2 weeks. The mean +/- SD duration of treatment was 96+/-43 days, with a mean +/- SD cumulative dose of 656+/-371 mg. The mean +/- SD baseline albumin was 2.9+/-0.6 mg/dl which increased to 3.3+/-0.4 mg/dl after treatment (p = 0.045). Dry weight increased from a mean +/- SD of 64.4+/-11.7 kg to 66.0+/-10.9 kg after nandrolone therapy (p = 0.028). Mean +/- SD hematocrit at baseline was 28.2+/-4.5% and increased to 33.2+/-5.1% (p = 0.033). The dose of EPO was reduced in 4 patients (44%) during nandrolone therapy. Nandrolone significantly improved markers of nutritional status in our hemodialysis patients. This therapy may also enhance the hematopoietic effects of EPO.

Secondary malignant neoplasms in testicular cancer survivors.

PubMed

Curreri, Stephanie A; Fung, Chunkit; Beard, Clair J

2015-09-01

Testicular cancer is the most common cancer among men aged 15 to 40 years, and the incidence of testicular cancer is steadily increasing. Despite successful treatment outcomes and the rate of survival at 5 to 10 years being 95%, survivors can experience late effects of both their cancer and the treatment they received, including secondary malignant neoplasms (SMNs). We discuss the development of non-germ cell SMNs that develop after diagnosis and treatment of testicular cancer and their effect on mortality. Patients diagnosed with testicular cancer frequently choose postoperative surveillance if they are diagnosed with clinical stage I disease. These patients may experience an increased risk for developing SMNs following radiation exposure from diagnostic imaging. Similarly, radiotherapy for testicular cancer is associated with increased risks of developing both solid tumors and leukemia. Studies have reported that patients exposed to higher doses of radiation have an increased risk of developing SMNs when compared with patients who received lower doses of radiation. Patients treated with chemotherapy also experience an increased risk of developing SMNs following testicular cancer, though the risk following chemotherapy and radiation therapy combined is not well described. A large population-based study concluded that the rate ratios for both cancer-specific and all-cause mortality for SMNs among testicular cancer survivors were not significantly different from those of matched first cancers. Although it is known that patients who receive adjuvant chemotherapy or radiotherapy or who undergo routine diagnostic or follow-up imaging for a primary testicular cancer are at an increased risk for developing SMNs, the extent of this risk is largely unknown. It is critically important that research be conducted to determine this risk and its contributing factors as accurately as possible. Copyright © 2015 Elsevier Inc. All rights reserved.

The association between glucose levels and hospital outcomes in patients with acute exacerbations of chronic obstructive pulmonary disease

PubMed Central

Islam, Ebtesam A.; Limsuwat, Chok; Nantsupawat, Teerapat; Berdine, Gilbert G.; Nugent, Kenneth M.

2015-01-01

BACKGROUND: Corticosteroids used for chronic obstructive pulmonary disease (COPD) exacerbations can cause hyperglycemia in hospitalized patients, and hyperglycemia may be associated with increased mortality, length of stay (LOS), and re-admissions in these patients. MATERIALS AND METHODS: We did three retrospective studies using charts from July 2008 through June 2009, January 2006 through December 2010, and October 2010 through March 2011. We collected demographic and clinical information, laboratory results, radiographic results, and information on LOS, mortality, and re-admission. RESULTS: Glucose levels did not predict outcomes in any of the studied cohorts, after adjustment for covariates in multivariable analysis. The first database included 30 patients admitted to non-intensive care unit (ICU) hospital beds. Six of 20 non-diabetic patients had peak glucoses above 200 mg/dl. Nine of the ten diabetic patients had peak glucoses above 200 mg/dl. The maximum daily corticosteroid dose had no apparent effect on the glucose levels. The second database included 217 patients admitted to ICUs. The initial blood glucose was higher in patients who died than those who survived using bivariate analysis (P = 0.015; odds ratio, OR, 1.01) but not in multivariable analysis. Multivariable logistic regression analysis also demonstrated that glucose levels did not affect LOS. The third database analyzing COPD re-admission rates included 81 patients; the peak glucose levels were not associated with re-admission. CONCLUSIONS: Our data demonstrate that COPD patients treated with corticosteroids developed significant hyperglycemia, but the increase in blood glucose levels did not correlate with the maximum dose of corticosteroids. Blood glucose levels were not associated with mortality, LOS, or re-admission rates. PMID:25829959

Characterizing sudden death and dead-in-bed syndrome in Type 1 diabetes: analysis from two childhood-onset Type 1 diabetes registries.

PubMed

Secrest, A M; Becker, D J; Kelsey, S F; Laporte, R E; Orchard, T J

2011-03-01

Type 1 diabetes mellitus increases the risk for sudden unexplained death, generating concern that diabetes processes and/or treatments underlie these deaths. Young (< 50 years) and otherwise healthy patients who are found dead in bed have been classified as experiencing 'dead-in-bed' syndrome. We thus identified all unwitnessed deaths in two related registries (the Children's Hospital of Pittsburgh and Allegheny County) yielding 1319 persons with childhood-onset (age < 18 years) Type 1 diabetes diagnosed between 1965 and 1979. Cause of death was determined by a Mortality Classification Committee (MCC) of at least two physician epidemiologists, based on the death certificate and additional records surrounding the death. Of the 329 participants who had died, the Mortality Classification Committee has so far reviewed and assigned a final cause of death to 255 (78%). Nineteen (8%) of these were sudden unexplained deaths (13 male) and seven met dead-in-bed criteria. The Mortality Classification Committee adjudicated cause of death in the seven dead-in-bed persons as: diabetic coma (n =4), unknown (n=2) and cardiomyopathy (n=1, found on autopsy). The three dead-in-bed individuals who participated in a clinical study had higher HbA(1c) , lower BMI and higher daily insulin dose compared with both those dying from other causes and those surviving. Sudden unexplained death in Type 1 diabetes seems to be increased 10-fold and associated with male sex, while dead-in-bed individuals have a high HbA(1c) and insulin dose and low BMI. Although sample size is too small for definitive conclusions, these results suggest specific sex and metabolic factors predispose to sudden unexplained death and dead-in-bed death. © 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK.

Effects of estrogen coadministration on epoxiconazole toxicity in rats.

PubMed

Stinchcombe, Stefan; Schneider, Steffen; Fegert, Ivana; Rey Moreno, Maria Cecilia; Strauss, Volker; Gröters, Sibylle; Fabian, Eric; Fussell, Karma C; Pigott, Geoffrey H; van Ravenzwaay, Bennard

2013-06-01

Epoxiconazole (EPX; CAS-No. 133855-98-8) is a triazole class-active substance of plant protection products. At a dose level of 50 mg/kg bw/day, it causes a significantly increased incidence of late fetal mortality when administered to pregnant rats throughout gestation (gestation day [GD] 7-18 or 21), as reported previously (Taxvig et al., 2007, 2008) and confirmed in these studies. Late fetal resorptions occurred in the presence of significant maternal toxicity such as clear reduction of corrected body weight gain, signs of anemia, and, critically, a marked reduction of maternal estradiol plasma levels. Furthermore, estradiol supplementation at dose levels of 0.5 or 1.0 μg/animal/day of estradiol cyclopentylpropionate abolished the EPX-mediated late fetal resorptions. No increased incidences of external malformations were found in rats cotreated with 50 mg/kg bw/day EPX and estradiol cyclopentylpropionate, indicating that the occurrence of malformations was not masked by fetal mortality under the study conditions. Overall, the study data indicate that fetal mortality observed in rat studies with EPX is not the result of direct fetal toxicity but occurs indirectly via depletion of maternal estradiol levels. The clarification of the human relevance of the estrogen-related mechanism behind EPX-mediated late fetal resorptions in rats warrants further studies. In particular, this should involve investigation of the placenta (Rey Moreno et al., 2013), since it is the materno-fetal interface and crucial for fetal maintenance. The human relevance is best addressed in a species which is closer to humans with reference to placentation and hormonal regulation of pregnancy, such as the guinea pig (Schneider et al., 2013). © 2013 Wiley Periodicals, Inc.

Toxicity of dietary Heliotropium circinatum to rats.

PubMed

Eröksüz, H; Eröksüz, Y; Ozer, H; Ceribasi, A O; Tosun, F; Tamer, U; Kizilay, C Akyüz

2003-08-01

Pyrrolizidine alkaloid intoxication was produced in adult, male rats by feeding different levels (0, 1, 3, 5 or 10%) of Heliotropium circinatum for 20 w. Combined GC-MS revealed 0.15% total alkaloid content in the plant material of which 12% and 88% were basic and N-oxide forms, respectively. The specific alkaloids identified were europine (67.33%), heliotrine (16.34%), lasiocarpine (8.12%), heleurine (4.18%), echinatine (1.56%), 7-angeylheliotrine (1.19%), and an unknown alkaloid (1.28%). Neither mortality nor significant clinical changes occurred in test groups. Mild to moderate, dose-related hepatic megalocytosis was the most prominent histopathological finding. In addition to chronic hepatotoxicity, notable medial thickening occurred in the pulmonary arterioles and arteries of the high-dosed groups. This study indicated that H. circinatum plant has limited toxic potential in rats with mild to moderate histological changes and no mortality at the dosing levels, total doses, or time of exposure employed.

Gabapentin dose and the 30-day risk of altered mental status in older adults: A retrospective population-based study

PubMed Central

Dixon, Stephanie N.; Kuwornu, Paul John; Dev, Varun K.; Montero-Odasso, Manuel; Burneo, Jorge; Garg, Amit X.

2018-01-01

Gabapentin is an effective treatment for chronic neuropathic pain but may cause dizziness, drowsiness, and confusion in some older adults. The goal of this study was to assess the association between gabapentin dosing and adverse outcomes by obtaining estimates of the 30-day risk of hospitalization with altered mental status and mortality in older adults (mean age 76 years) in Ontario, Canada initiated on high dose (>600 mg/day; n = 34,159) compared to low dose (≤600 mg/day; n = 76,025) oral gabapentin in routine outpatient care. A population-based, retrospective cohort study assessing new gabapentin use between 2002 to 2014 was conducted. The primary outcome was 30-day hospitalization with an urgent head computed tomography (CT) scan in the absence of evidence of stroke (a proxy for altered mental status). The secondary outcome was 30-day all-cause mortality. The baseline characteristics measured in the two dose groups were similar. Initiation of a high versus low dose of gabapentin was associated with a higher risk of hospitalization with head CT scan (1.27% vs. 1.06%, absolute risk difference 0.21%, adjusted relative risk 1.29 [95% CI 1.14 to 1.46], number needed to treat 477) but not a statistically significant higher risk of mortality (1.25% vs. 1.16%, absolute risk difference of 0.09%, adjusted relative risk of 1.01 [95% CI 0.89 to 1.14]). Overall, the risk of being hospitalized with altered mental status after initiating gabapentin remains low, but may be reduced through the judicious use of gabapentin, use of the lowest dose to control pain, and vigilance for early signs of altered mental status. PMID:29538407

Shipboard testing of the efficacy of SeaKleen as a ballast water treatment to eliminate non-indigenous species aboard a working tanker in Pacific waters.

PubMed

Wright, D A; Dawson, R; Caceres, V; Orano-Dawson, C E; Kananen, G E; Cutler, S J; Cutler, H G

2009-08-01

Trials were conducted aboard the tanker Seabulk Mariner to test a natural product, SeaKleen, as a biocide controlling non-indigenous populations of plankton and bacteria in ballast water. SeaKleen was dosed into matched ballast tanks at two different concentrations, 0.8 mg L(-1) active ingredient (a.i.) and 1.6 mg L(-1) a.i. during ballasting off the Oregon coast during a three-day passage to Prince William Sound, Alaska. Live organism counts from treated ballast water were compared with those from untreated (control tank) water collected from the same source location. Shipboard chemical analyses were made to verify dose and quantify chemical degradation and residuals following dilution. Results indicated that both SeaKleen doses resulted in complete zooplankton and phytoplankton mortality and that the higher dose (1.6 mg L(-1) a.i.) caused a two-log removal of culturable bacteria over a 92 h grow-out period. Spectrophotometry confirmed initial dosing to within 5% of nominal values. Shipboard bioassays were conducted using larval fish (Cyprinodon variegatus), brine shrimp (Artemia salina) and the bioluminescent dinoflagellate Pyrocystis lunula. Exposure of the test organisms to water drawn from treated ballast tanks 48 h after SeaKleen was added to the tanks resulted in 100% mortalities in Cyprinodon and Pyrocystis at both doses. Corresponding mortalities for Artemia larvae were 100% and 60% for high and low SeaKleen doses, respectively. Toxicity testing of treated water, subjected to varying dilutions, indicated that residual toxicity to even the most sensitive organisms would be eliminated once the discharge had dispersed beyond 100 feet from the vessel.

Mortality from Cardiovascular Diseases in the Semipalatinsk Historical Cohort, 1960–1999, and its Relationship to Radiation Exposure

PubMed Central

Grosche, Bernd; Lackland, Daniel T.; Land, Charles E.; Simon, Steven L.; Apsalikov, Kazbek N.; Pivina, Ludmilla M.; Bauere, Susanne; Gusev, Boris I.

2013-01-01

The data on risk of mortality from cardiovascular disease due to radiation exposure at low or medium doses are inconsistent. This paper reports an analysis of the Semipalatinsk historical cohort exposed to radioactive fallout from nuclear testing in the vicinity of the Semipalatinsk Nuclear Test Site, Kazakhstan. The cohort study, which includes 19,545 persons of exposed and comparison villages in the Semipalatinsk region, had been set up in the 1960s and comprises 582,656 person-years of follow-up between 1960 and 1999. A dosimetric approach developed by the U.S. National Cancer Institute (NCI) has been used. Radiation dose estimates in this cohort range from 0 to 630 mGy (wholebody external). Overall, the exposed population showed a high mortality from cardiovascular disease. Rates of mortality from cardiovascular disease in the exposed group substantially exceeded those of the comparison group. Dose–response analyses were conducted for both the entire cohort and the exposed group only. A dose–response relationship that was found when analyzing the entire cohort could be explained completely by differences between the baseline rates in exposed and unexposed groups. When taking this difference into account, no statistically significant dose–response relationship for all cardiovascular disease, for heart disease, or for stroke was found. Our results suggest that within this population and at the level of doses estimated, there is no detectable risk of radiation related mortality from cardiovascular disease. PMID:21787182

[Role of acetylcholine in gelsenicine-induced death in mice].

PubMed

Lai, Zhou-Yi; Wang, Hai-Bo; Lv, Rui-Ling; Tan, Qiu-Chan; Deng, Zhi-Qin; Wang, Yuan; Sun, Xiao-Xue; Wu, Jia-Bao; Zhu, Lin-Yan; Wang, Lei; Chen, Li-Xin; Ye, Wen-Cai; Wang, Li-Wei

2016-06-25

The aim of this study was to investigate the relationship between the acetylcholine concentration in the blood and gelsenicine-induced death in mice. Kunming mice were given intraperitoneal injections of normal saline, gelsenicine or different doses of acetylcholine chloride. Atropine was given to the mice which received gelsenicine or medium dose acetylcholine chloride injection. The blood was sampled immediately when the mice died or survived for 20 min after injection. The acetylcholine concentration and acetylcholinesterase activity in the blood were measured by the testing kits, and the mortality was calculated and analyzed. The results showed that half lethal dose of gelsenicine (0.15 mg/kg) reduced the acetylcholinesterase activity and increased the blood acetylcholine concentration. The blood acetylcholine concentration of the dead mice in the gelsenicine group was increased to 43.0 μg/mL (from 31.1 μg/mL in the control), which was lower than that (53.9 μg/mL) of the dead mice in the medium dose acetylcholine chloride group, but almost equal to that (42.7 μg/mL) of the survival mice in the medium dose acetylcholine chloride group. Atropine could successfully rescue the mice from acetylcholine poisoning, but its efficiency of rescuing the mice from gelsenicine intoxication was weak. These results suggest that gelsenicine can inhibit acetylcholinesterase activity and increase blood acetylcholine concentration, but the accumulation of acetylcholine may not be the only or main cause of the death induced by gelsenicine in mice.

Intrathecal Morphine Attenuates Recovery of Function after a Spinal Cord Injury

PubMed Central

Moreno, Georgina; Woller, Sarah; Puga, Denise; Hoy, Kevin; Balden, Robyn; Grau, James W.

2009-01-01

Abstract Prior work has shown that a high dose (20 mg/kg) of systemic morphine, required to produce significant analgesia in the acute phase of a contusion injury, undermines the long-term health of treated subjects and increases lesion size. Moreover, a single dose of systemic morphine in the early stage of injury (24 h post-injury) led to symptoms of neuropathic pain 3 weeks later, in the chronic phase. The present study examines the locus of the effects using intrathecal morphine administration. Subjects were treated with one of three doses (0, 30, or 90 μg) of intrathecal morphine 24 h after a moderate contusion injury. The 90-μg dose produced significant analgesia when subjects were exposed to noxious stimuli (thermal and incremented shock) below the level of injury. Yet, despite analgesic efficacy, intrathecal morphine significantly attenuated the recovery of locomotor function and increased lesion size rostral to the injury site. A single dose of 30 or 90 μg of intrathecal morphine also decreased weight gain, and more than doubled the incidence of mortality and autophagia when compared to vehicle-treated controls. Morphine is one of the most effective pharmacological agents for the treatment of neuropathic pain and, therefore, is indispensable for the spinally injured. Treatment can, however, adversely affect the recovery process. A morphine-induced attenuation of recovery may result from increases in immune cell activation and, subsequently, pro-inflammatory cytokine concentrations in the contused spinal cord. PMID:19388818

Lung, liver and bone cancer mortality after plutonium exposure in beagle dogs and nuclear workers.

PubMed

Wilson, Dulaney A; Mohr, Lawrence C; Frey, G Donald; Lackland, Daniel; Hoel, David G

2010-01-01

The Mayak Production Association (MPA) worker registry has shown evidence of plutonium-induced health effects. Workers were potentially exposed to plutonium nitrate [(239)Pu(NO(3))(4)] and plutonium dioxide ((239)PuO(2)). Studies of plutonium-induced health effects in animal models can complement human studies by providing more specific data than is possible in human observational studies. Lung, liver, and bone cancer mortality rate ratios in the MPA worker cohort were compared to those seen in beagle dogs, and models of the excess relative risk of lung, liver, and bone cancer mortality from the MPA worker cohort were applied to data from life-span studies of beagle dogs. The lung cancer mortality rate ratios in beagle dogs are similar to those seen in the MPA worker cohort. At cumulative doses less than 3 Gy, the liver cancer mortality rate ratios in the MPA worker cohort are statistically similar to those in beagle dogs. Bone cancer mortality only occurred in MPA workers with doses over 10 Gy. In dogs given (239)Pu, the adjusted excess relative risk of lung cancer mortality per Gy was 1.32 (95% CI 0.56-3.22). The liver cancer mortality adjusted excess relative risk per Gy was 55.3 (95% CI 23.0-133.1). The adjusted excess relative risk of bone cancer mortality per Gy(2) was 1,482 (95% CI 566.0-5686). Models of lung cancer mortality based on MPA worker data with additional covariates adequately described the beagle dog data, while the liver and bone cancer models were less successful.

Delivered dose of renal replacement therapy and mortality in critically ill patients with acute kidney injury

PubMed Central

Vesconi, Sergio; Cruz, Dinna N; Fumagalli, Roberto; Kindgen-Milles, Detlef; Monti, Gianpaola; Marinho, Anibal; Mariano, Filippo; Formica, Marco; Marchesi, Mariano; René, Robert; Livigni, Sergio; Ronco, Claudio

2009-01-01

Introduction The optimal dialysis dose for the treatment of acute kidney injury (AKI) is controversial. We sought to evaluate the relationship between renal replacement therapy (RRT) dose and outcome. Methods We performed a prospective multicentre observational study in 30 intensive care units (ICUs) in eight countries from June 2005 to December 2007. Delivered RRT dose was calculated in patients treated exclusively with either continuous RRT (CRRT) or intermittent RRT (IRRT) during their ICU stay. Dose was categorised into more-intensive (CRRT ≥ 35 ml/kg/hour, IRRT ≥ 6 sessions/week) or less-intensive (CRRT < 35 ml/kg/hour, IRRT < 6 sessions/week). The main outcome measures were ICU mortality, ICU length of stay and duration of mechanical ventilation. Results Of 15,200 critically ill patients admitted during the study period, 553 AKI patients were treated with RRT, including 338 who received CRRT only and 87 who received IRRT only. For CRRT, the median delivered dose was 27.1 ml/kg/hour (interquartile range (IQR) = 22.1 to 33.9). For IRRT, the median dose was 7 sessions/week (IQR = 5 to 7). Only 22% of CRRT patients and 64% of IRRT patients received a more-intensive dose. Crude ICU mortality among CRRT patients were 60.8% vs. 52.5% (more-intensive vs. less-intensive groups, respectively). In IRRT, this was 23.6 vs. 19.4%, respectively. On multivariable analysis, there was no significant association between RRT dose and ICU mortality (Odds ratio (OR) more-intensive vs. less-intensive: CRRT OR = 1.21, 95% confidence interval (CI) = 0.66 to 2.21; IRRT OR = 1.50, 95% CI = 0.48 to 4.67). Among survivors, shorter ICU stay and duration of mechanical ventilation were observed in the more-intensive RRT groups (more-intensive vs. less-intensive for all: CRRT (median): 15 (IQR = 8 to 26) vs. 19.5 (IQR = 12 to 33.5) ICU days, P = 0.063; 7 (IQR = 4 to 17) vs. 14 (IQR = 5 to 24) ventilation days, P = 0.031; IRRT: 8 (IQR = 5.5 to 14) vs. 18 (IQR = 13 to 35) ICU days, P = 0.008; 2.5 (IQR = 0 to 10) vs. 12 (IQR = 3 to 24) ventilation days, P = 0.026). Conclusions After adjustment for multiple variables, these data provide no evidence for a survival benefit afforded by higher dose RRT. However, more-intensive RRT was associated with a favourable effect on ICU stay and duration of mechanical ventilation among survivors. This result warrants further exploration. Trial Registration Cochrane Renal Group (CRG110600093). PMID:19368724

Infectivity and pathogenicity of the oomycete Aphanomyces invadans in Atlantic menhaden Brevoortia tyrannus

USGS Publications Warehouse

Kiryu, Y.; Shields, J.D.; Vogelbein, W.K.; Kator, H.; Blazer, V.S.

2003-01-01

Atlantic menhaden Brevoortia tyrannus develop characteristic skin ulcers in response to infection by the oomycete Aphanomyces invadans. To investigate pathogenicity, we conducted a dose response study. Juvenile menhaden were inoculated subcutaneously with 0, 1, 5, 10, 100, and 500 secondary zoospores per fish and monitored for 37 d post-injection (p.i.). Survival rates declined with increasing zoospore dose, with significantly different survivorship curves for the different doses. Moribund and dead fish exhibited characteristic ulcerous lesions at the injection site starting at 13 d p.i. None of the sham-injected control fish (0 zoospore treatment) died. The LD50 (lethal dose killing 50% of exposed menhaden) for inoculated fish was estimated at 9.7 zoospores; however, some fish receiving an estimated single zoospore developed infections that resulted in death. Menhaden were also challenged by aqueous exposure and confirmed that A. invadans was highly pathogenic by this more environmentally realistic route. Fish that were acclimated to culture conditions for 30 d, and presumably free of skin damage, then aqueously exposed to 100 zoospores ml-1, exhibited 14% lesion prevalence with 11% mortality. Net-handled fish that were similarly infected had a significantly higher lesion prevalence (64%) and mortality (64%). Control fish developed no lesions and did not die. Scanning electron microscopy of fish skin indicated that zoospores adhered to intact epidermis, germinated and penetrated the epithelium with a germ tube. Our results indicate that A. invadans is a primary pathogen of menhaden and is able to cause disease at very low zoospore concentrations.

Fluid Therapy and Outcome: Balance Is Best

PubMed Central

Allen, Sara J.

2014-01-01

Abstract: The use of intravenous fluids is routine in patients undergoing surgery or critical illness; however, controversy still exists regarding optimum fluid therapy. Recent literature has examined the effects of different types, doses, and timing of intravenous fluid therapy. Each of these factors may influence patient outcomes. Crystalloids consist of isotonic saline or balanced electrolyte solutions and widely distribute across extracellular fluid compartments, whereas colloids contain high-molecular-weight molecules suspended in crystalloid carrier solution and do not freely distribute across the extracellular fluid compartments. Colloids vary in composition and associated potential adverse effects. Recent evidence has highlighted safety and ethical concerns regarding the use of colloid solutions in critically ill patients, particularly the use of synthetic starch solutions. which have been associated with increased morbidity and mortality. Crystalloid solutions with a chloride-rich composition (e.g., isotonic saline) have been associated with metabolic acidosis, hyperchloremia, increased incidence of acute kidney injury, and increased requirement for renal replacement therapy. An optimum dose of intravenous fluids remains controversial with no definitive evidence to support restrictive versus liberal approaches. Further high-quality trials are needed to elucidate the optimum fluid therapy for patients, but currently a balanced approach to type, dose, and timing of fluids is recommended. PMID:24779116

Fluid therapy and outcome: balance is best.

PubMed

Allen, Sara J

2014-03-01

The use of intravenous fluids is routine in patients undergoing surgery or critical illness; however, controversy still exists regarding optimum fluid therapy. Recent literature has examined the effects of different types, doses, and timing of intravenous fluid therapy. Each of these factors may influence patient outcomes. Crystalloids consist of isotonic saline or balanced electrolyte solutions and widely distribute across extracellular fluid compartments, whereas colloids contain high-molecular-weight molecules suspended in crystalloid carrier solution and do not freely distribute across the extracellular fluid compartments. Colloids vary in composition and associated potential adverse effects. Recent evidence has highlighted safety and ethical concerns regarding the use of colloid solutions in critically ill patients, particularly the use of synthetic starch solutions, which have been associated with increased morbidity and mortality. Crystalloid solutions with a chloride-rich composition (e.g., isotonic saline) have been associated with metabolic acidosis, hyperchloremia, increased incidence of acute kidney injury, and increased requirement for renal replacement therapy. An optimum dose of intravenous fluids remains controversial with no definitive evidence to support restrictive versus liberal approaches. Further high-quality trials are needed to elucidate the optimum fluid therapy for patients, but currently a balanced approach to type, dose, and timing of fluids is recommended.

Leisure time physical activity and mortality: a detailed pooled analysis of the dose-response relationship.

PubMed

Arem, Hannah; Moore, Steven C; Patel, Alpa; Hartge, Patricia; Berrington de Gonzalez, Amy; Visvanathan, Kala; Campbell, Peter T; Freedman, Michal; Weiderpass, Elisabete; Adami, Hans Olov; Linet, Martha S; Lee, I-Min; Matthews, Charles E

2015-06-01

The 2008 Physical Activity Guidelines for Americans recommended a minimum of 75 vigorous-intensity or 150 moderate-intensity minutes per week (7.5 metabolic-equivalent hours per week) of aerobic activity for substantial health benefit and suggested additional benefits by doing more than double this amount. However, the upper limit of longevity benefit or possible harm with more physical activity is unclear. To quantify the dose-response association between leisure time physical activity and mortality and define the upper limit of benefit or harm associated with increased levels of physical activity. We pooled data from 6 studies in the National Cancer Institute Cohort Consortium (baseline 1992-2003). Population-based prospective cohorts in the United States and Europe with self-reported physical activity were analyzed in 2014. A total of 661,137 men and women (median age, 62 years; range, 21-98 years) and 116,686 deaths were included. We used Cox proportional hazards regression with cohort stratification to generate multivariable-adjusted hazard ratios (HRs) and 95% CIs. Median follow-up time was 14.2 years. Leisure time moderate- to vigorous-intensity physical activity. The upper limit of mortality benefit from high levels of leisure time physical activity. Compared with individuals reporting no leisure time physical activity, we observed a 20% lower mortality risk among those performing less than the recommended minimum of 7.5 metabolic-equivalent hours per week (HR, 0.80 [95% CI, 0.78-0.82]), a 31% lower risk at 1 to 2 times the recommended minimum (HR, 0.69 [95% CI, 0.67-0.70]), and a 37% lower risk at 2 to 3 times the minimum (HR, 0.63 [95% CI, 0.62-0.65]). An upper threshold for mortality benefit occurred at 3 to 5 times the physical activity recommendation (HR, 0.61 [95% CI, 0.59-0.62]); however, compared with the recommended minimum, the additional benefit was modest (31% vs 39%). There was no evidence of harm at 10 or more times the recommended minimum (HR, 0.69 [95% CI, 0.59-0.78]). A similar dose-response relationship was observed for mortality due to cardiovascular disease and to cancer. Meeting the 2008 Physical Activity Guidelines for Americans minimum by either moderate- or vigorous-intensity activities was associated with nearly the maximum longevity benefit. We observed a benefit threshold at approximately 3 to 5 times the recommended leisure time physical activity minimum and no excess risk at 10 or more times the minimum. In regard to mortality, health care professionals should encourage inactive adults to perform leisure time physical activity and do not need to discourage adults who already participate in high-activity levels.

All cause mortality and incidence of cancer in workers in bauxite mines and alumina refineries.

PubMed

Fritschi, Lin; Hoving, Jan Lucas; Sim, Malcolm R; Del Monaco, Anthony; MacFarlane, Ewan; McKenzie, Dean; Benke, Geza; de Klerk, Nicholas

2008-08-15

Bauxite is a reddish clay that is refined to produce alumina, which is then reduced to aluminium. There have been studies examining the health of workers in aluminium smelters, but not workers in bauxite mining and alumina refining. A cohort of employees of 1 large aluminium company since 1983 was assembled (n = 6,485, 5,828 men). Deaths and incident cancers to 2002 were ascertained by linkage to national and state cancer and death registries. SIRs and SMRs were calculated compared to national rates standardizing for calendar year, sex and 5-year age group. The mortality from all causes (SMR 0.68, 95% CI: 0.60-0.77), and from circulatory and respiratory diseases, all cancers combined and injury in the male cohort were lower than in the Australian male population and were similar across work groups and with duration of employment. The only significant increased mortality risk was from pleural mesothelioma. The incidence of all cancers combined was similar to the Australian rate. The cohort had a lower risk of incident lymphohaematopoietic cancer (SIR 0.50, 95% CI: 0.31-0.88) and a higher risk of melanoma (SIR 1.30, 95% CI: 1.00-1.69) although no dose-responses were seen. There was also an increased risk of mesothelioma (SIR 3.49, 95% CI: 1.82-6.71), which was associated with exposures outside the aluminium industry. This study is the first to examine cancer and mortality amongst workers in bauxite mines and alumina refineries and found little evidence for increased cancer incidence or mortality in these workers. (c) 2008 Wiley-Liss, Inc.

Deaths and tumours among rotogravure printers exposed to toluene.

PubMed Central

Svensson, B G; Nise, G; Englander, V; Attewell, R; Skerfving, S; Möller, T

1990-01-01

A cohort of 1020 rotogravure printers exposed to toluene and employed for a minimum period of three months in eight plants during 1925-85 was studied. Air levels of toluene were available since 1943 in one plant and since 1969 in most. Based on these measurements and on present concentrations of toluene in blood and subcutaneous fat, the yearly average air levels in each plant were estimated. They reached a maximum of about 450 ppm in the 1940s and 1950s but were only about 30 ppm by the mid-1980s. Exposure to benzene had occurred up to the beginning of the 1960s. Compared with regional rates, total mortality did not increase during the observation period 1952-86 (129 observed deaths v 125 expected; SMR = 1.03). There was no increase in mortality from non-malignant diseases of the lungs, nervous system, or gastrointestinal and urinary tracts. There was no overall excess of tumours 1958-85 (68 v 54, SMR = 1.26; 95% confidence interval, CI = 0.95-1.7). Among the specific cancers, only those of the respiratory tract were significantly increased (16 v 9; SMR = 1.76, CI = 1.03-2.9). Statistical significance was not attained, however, when only subjects with an exposure period of at least five years and a latency period of at least 10 years were considered. Further, there were no dose response relations with cumulated toluene dose (ppm years). There were no significant increases of tumours at other sites, including leukaemias/lymphomas/myelomas. PMID:2378814

Does Early Resumption of Low-Dose Aspirin After Evacuation of Chronic Subdural Hematoma With Burr-Hole Drainage Lead to Higher Recurrence Rates?

PubMed

Kamenova, Maria; Lutz, Katharina; Schaedelin, Sabine; Fandino, Javier; Mariani, Luigi; Soleman, Jehuda

2016-11-01

Antiplatelet therapy in patients with chronic subdural hematoma (cSDH) presents significant neurosurgical challenges. Given the lack of guidelines regarding perioperative management with antiplatelet therapy, it is difficult to balance the patient's increased cardiovascular risk and prevalence of cSDH. To better understand the risk and recurrence rates related to resuming low-dose acetylsalicylic acid (ASA) by evaluating our patients' resumption of low-dose ASA at various times after burr-hole drainage of the hematoma. In our retrospective study, 140 consecutive patients taking low-dose ASA undergoing surgical evacuation of cSDH were included. Data included baseline characteristics and rates of recurrence, morbidity, and mortality. A multivariate logistic regression model analyzed the association between ASA resumption time and recurrence rates. No statistically significant association was observed between early postoperative resumption of low-dose ASA and recurrence of cSDH (odds ratio, 1.01; 95% confidence interval, 1.001-1.022; P = .06). Corresponding odds ratios and risk differences for restarting ASA treatment on postoperative days 1, 7, 14, 21, 28, 35, or 42 were estimated at 1.53 and 5.9%, 1.42 and 5.1%, 1.33 and 4.1%, 1.23 and 3.2%, 1.15 and 2.2%, 1.07 and 1.1%, and 1.01 and 0.2%, respectively (P > .05). Cardiovascular event rates, surgical morbidity, and mortality did not significantly differ between patients with or without ASA therapy. Given the few published studies regarding ASA use in cranial neurosurgery, our findings elucidate one issue, showing comparable recurrence rates with early or late resumption of low-dose ASA after burr-hole evacuation of cSDH. ASA, acetylsalicylic acidCAD, coronary artery diseaseCI, confidence intervalcSDH, chronic subdural hematomaGCS, Glasgow Coma ScalemRS, modified Rankin ScaleOR, odds ratioRD, risk difference.

The use of a low dose hydrocortisone to prevent pulmonary embolism in patients with multiple trauma.

PubMed

Chaari, Anis; Ghadhoune, Hatem; Chakroune, Olfa; Abid, Hanen; Turki, Olfa; Bahloul, Mabrouk; Bouaziz, Mounir

2013-08-01

Venous thromboembolism events are common in trauma patients. Immediate acute inflammation following injury triggers coagulation cascade and may increase the risk of pulmonary embolism (PE) in this population. We aimed to evaluate whether early low-dose steroids prevent symptomatic PE onset in multiple trauma patients. The medical surgical intensive care unit of Habib Bourguiba University Hospital (Sfax--Tunisia). Comparative study of two cohorts: a retrospective cohort of patients who didn't receive early low-dose steroids (steroid (-) group) and a prospective cohort of patients who received hydrocortisone with a dose of 100 mg/8 h for a scheduled period of 7 days (steroid (+) group). All adult patients admitted in our intensive care unit (ICU) for multiple trauma with predicted duration of mechanical ventilation over 48 h were included. Evaluation of the impact of low-dose steroids on the incidence of symptomatic PE. We included 175 patients: 92 in the steroids (-) group and 83 in the steroids (+) group. PE was diagnosed in 15 patients (8.5 %). The incidence of PE was significantly lower in steroid (+) group (3.6 vs 13 %; p = 0.013). In multivariate analysis, independent factors predicting PE onset were meningeal hemorrhage [OR = 14.7; 95 % CI (2.2-96.3); p = 0.013] and pelvic ring trauma [OR = 8; 95 % CI (1.8-36.4); p = 0.007] whereas low-dose steroids were significantly associated with a protective effect [OR = 0.2; 95 % CI (0.05-0.77); p = 0.019]. There was no significant difference between steroids (+) and steroids (-) groups neither in terms of mean ICU length of stay (LOS) (respectively 11 ± 9.7 and 12.3 ± 10.7 days; p = 0.372) nor in terms of ICU mortality (respectively 29.3 and 24.1 %; p = 0.434). Steroids are effective in reducing the incidence of PE in multiple trauma patients. However, no significant benefice was found on ICU mortality.

[Classical antihypertensive drugs: diuretics].

PubMed

Nagy, Viktor László

2017-03-01

The diuretics are essential medicaments of antihypertensive therapy. They reduce blood pressure and cardiovascular events optimally. With increasing doses of thiazides and thiazide analogs do not come further powerful effect of reducing blood pressure or cardiovascular mortality and morbidity, but clearly elevate the side effects. Because of it, the minimum effective dose level and the fixed-dose combination therapy should be preferred. The use these drugs leads to especially positive outcome in elder patients, isolated systolic hypertension, heart failure, after stroke and in black population. Loop diuretics as antihypertensive therapy can be used only by renal impairment. The use of aldosterone antagonists can have a good effect not only on heart failure but also on prevention of atrial fibrillation. Furthermore, using it in a combination therapy with thiazides, it reduces the risk of hypokalemia. Therefore, the diuretic treatment in hypertension is flourishing again. Orv. Hetil., 2017, 158(11), 403-408.

Safety of oral sulfates in rats and dogs contrasted with phosphate-induced nephropathy in rats.

PubMed

Pelham, Russell W; Russell, Robert G; Padgett, Eric L; Reno, Frederick E; Cleveland, Mark vB

2009-01-01

An oral sulfate salt solution (OSS), under development as a bowel cleansing agent for colonoscopy in humans, is studied in rats and dogs. In rats, amaximumpractical oral OSS dose (5 g/kg/d) is compared with an oral sodium phosphate (OSP) solution, both at about 7 times the clinical dose. OSS induces the intended effects of loose stools and diarrhea. In rats, higher urine sodium and potassium accompany higher clearance rates, considered adaptive to the osmotic load of OSS. OSS for 28 days is well tolerated in rats and dogs. In contrast, OSP causes increased mortality, reduced body weight and food consumption, severe kidney tubular degeneration, and calcium phosphate deposition in rats. These are accompanied by mineralization in the stomach and aorta, along with cardiac and hepatic degeneration and necrosis. The greater safety margin of OSS over OSP at similarmultiples of the clinical dose indicates its suitability for human use.

Androgen Deprivation Therapy Use in the Setting of High-dose Radiation Therapy and the Risk of Prostate Cancer–Specific Mortality Stratified by the Extent of Competing Mortality

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rose, Brent S., E-mail: brose44@gmail.com; Chen, Ming-Hui; Wu, Jing

Purpose: The addition of androgen deprivation therapy (ADT) to radiation therapy (RT) is the standard of care for men with intermediate- and high-risk prostate cancer (PC). However, whether competing mortality (CM) affects the ability of ADT to improve, survival remains unanswered. Methods and Materials: We calculated a CM risk score using a Fine-Gray semiparametric model that included age and cardiometabolic comorbidities from a cohort of 17,669 men treated with high-dose RT with or without supplemental ADT for nonmetastatic PC. Fine and Gray competing risk regression analysis was used to assess whether ADT reduced the risk of PC-specific mortality for menmore » with a low versus a high risk of CM among the 4550 patients within the intermediate- and high-risk cohort after adjustment for established PC prognostic factors, year of treatment, site, and ADT propensity score. Results: After a median follow-up of 8.4 years, 1065 men had died, 89 (8.36%) of PC. Among the men with a low CM score, ADT use was associated with a significant reduction in the risk of PC-specific mortality (adjusted hazard ratio 0.35, 95% confidence interval 0.14-0.87, P=.02) but was not for men with high CM (adjusted hazard ratio 1.33, 95% confidence interval 0.77-2.30, P=.30). Conclusions: Adding ADT to high-dose RT appears to be associated with decreased PC-specific mortality risk in men with a low but not a high CM score. These data should serve to heighten awareness about the importance of considering competing risks when determining whether to add ADT to RT for older men with intermediate- or high-risk PC.« less

Long-term toxicity and carcinogenicity studies of cake made from chlorinated flour. 1. Studies in rats.

PubMed

Fisher, N; Hutchinson, J B; Berry, R; Hardy, J; Ginocchio, A V

1983-08-01

Wistar rats were fed for 104 wk on cake-based diets in which the cake, prepared from unchlorinated flour, or flour treated with 1250 or 2500 ppm chlorine, formed 79% of the diet on a 12.6% moisture basis. A fourth group was fed stock diet 41B. No differences in appearance, health, behaviour or mortalities attributable to the flour treatment were observed. Female but not male mortalities were significantly higher for cake-fed rats than for those fed diet 41B. Dose-related haematological effects were seen at various stages in cake-fed rats. Dose-related increases in plasma alanine and aspartate aminotransferases were noted at 12 months in males but not in females, for whom all the values were elevated. A dose-related diminution in blood sugar at 12 months was seen only in females. A dose-related increase in urinary aspartate aminotransferase was seen only in males. Urinary N-acetylglucosaminidase activity per mg creatinine did not differ significantly between groups. At post mortem a dose-related reduction in spleen weight was found in the females only. The lesions found were those expected in ageing rats, but were observed earlier in rats fed cake. Glomerulonephrosis affected rats fed cake more than those fed diet 41B. Cake diets promoted nephrocalcinosis, unrelated to flour treatment. Increased splenic haematopoiesis occurred in about half of the females in the cake diet groups but less frequently in males or in rats fed diet 41B. Tumours were mainly chromophobe adenomas of the pituitary, common in rats. Insulomas were seen in two males in each of the groups fed on cake made from chlorinated flour, but an earlier form of this tumour was found in all cake groups and its incidence is thus regarded as unrelated to the flour treatment. The incidence of tumours of the reticuloendothelial system was not related to flour treatment. Covalent chlorine concentrations in the perirenal fat of the cake-fed rats were correlated with treatment levels, with values of 50-912 ppm in males and 59-1174 ppm in females. Since concentrations in the lipid of the diet fed to the animals were much higher than these, accumulation of the additive was absent or negligible. The chlorine concentrations in the perirenal fat of male and female rats fed diet 41B were 62 and 72 ppm respectively.

High or low- a trial of low dose anti snake venom in the treatment of poisonous snakebites.

PubMed

Cherian, A M; Girish, T S; Jagannati, Manjeera; Lakshmi, M

2013-06-01

To demonstrate that use of lower doses of anti-snake venom is as effective as high doses and is associated with less complications and lower mortality especially in the wake of rising cost of medical treatment, the people most affected by snakebites being the poor farmers. A prospective descriptive study consisting of 54 snakebite patients fulfilling the inclusion criteria who were admitted to Bangalore Baptist Hospital, Bengaluru, between November 2006 and November 2008 and were treated with a low dose ASV regime. The patients were initially given 2 vials of ASV followed later with 1 vial at a time according to clotting time. Any other supportive measures were undertaken as necessary. In this study the average dose of ASV required was only 6.70 +/- 3.24 vials. The complications--12.9% patients had ARF, and another 12.9% patients had neuropraralysis severe enough to require ventilatory support. There were 2 deaths (mortality of 3.7%) in the study. Low dose ASV regime in poisonous snakebites along with supportive treatment as necessary is as good as high dose regime, and has lesser adverse effects while reducing the cost of treatment too. Hence low dose regime can be used with beneficial results in poisonous snakebites.

Behavioral, clinical, and pathological characterization of acid metalliferous water toxicity in mallards

USGS Publications Warehouse

Isanhart, J.P.; Wu, H.; Pandher, K.; MacRae, R.K.; Cox, S.B.; Hooper, M.J.

2011-01-01

From September to November 2000, United States Fish and Wildlife Service biologists investigated incidents involving 221 bird deaths at 3 mine sites located in New Mexico and Arizona. These bird deaths primarily involved passerine and waterfowl species and were assumed to be linked to consumption of acid metalliferous water (AMW). Because all of the carcasses were found in or near pregnant leach solution ponds, tailings ponds, and associated lakes or storm water retention basins, an acute-toxicity study was undertaken using a synthetic AMW (SAMW) formulation based on the contaminant profile of a representative pond believed to be responsible for avian mortalities. An acute oral-toxicity trial was performed with a mixed-sex group of mallards (Anas platyrhynchos). After a 24-h pretreatment food and water fast, gorge drinking was evident in both SAMW treatment and control groups, with water consumption rates greatest during the initial drinking periods. Seven of nine treated mallards were killed in extremis within 12 h after the initiation of dose. Total lethal doses of SAMW ranged from 69.8 to 270.1 mL/kg (mean ?? SE 127.9 ?? 27.1). Lethal doses of SAMW were consumed in as few as 20 to 40 min after first exposure. Clinical signs of SAMW toxicity included increased serum uric acid, aspartate aminotransferase, creatine kinase, potassium, and P levels. PCV values of SAMW-treated birds were also increased compared with control mallards. Histopathological lesions were observed in the esophagus, proventriculus, ventriculus, and duodenum of SAMW-treated mallards, with the most distinctive being erosion and ulceration of the kaolin of the ventriculus, ventricular hemorrhage and/or congestion, and duodenal hemorrhage. Clinical, pathological, and tissue-residue results from this study are consistent with literature documenting acute metal toxicosis, especially copper (Cu), in avian species and provide useful diagnostic profiles for AMW toxicity or mortality events. Blood and kidney Cu concentrations were 23- and 6-fold greater, respectively, in SAMW mortalities compared with controls, whereas Cu concentrations in liver were not nearly as increased, suggesting that blood and kidney concentrations may be more useful than liver concentrations for diagnosing Cu toxicosis in wild birds. Based on these findings and other reports of AMW toxicity events in wild birds, we conclude that AMW bodies pose a significant hazard to wildlife that come in contact with them. ?? 2011 Springer Science+Business Media, LLC (outside the USA).

Behavioral, clinical, and pathological characterization of acid metalliferous water toxicity in mallards

USGS Publications Warehouse

Isanhart, John P.; Wu, Hongmei; Pandher, Karamjeet; MacRae, Russell K.; Cox, Stephen B.; Hooper, Michael J.

2011-01-01

From September to November 2000, United States Fish and Wildlife Service biologists investigated incidents involving 221 bird deaths at 3 mine sites located in New Mexico and Arizona. These bird deaths primarily involved passerine and waterfowl species and were assumed to be linked to consumption of acid metalliferous water (AMW). Because all of the carcasses were found in or near pregnant leach solution ponds, tailings ponds, and associated lakes or storm water retention basins, an acute-toxicity study was undertaken using a synthetic AMW (SAMW) formulation based on the contaminant profile of a representative pond believed to be responsible for avian mortalities. An acute oral-toxicity trial was performed with a mixed-sex group of mallards (Anas platyrhynchos). After a 24-h pretreatment food and water fast, gorge drinking was evident in both SAMW treatment and control groups, with water consumption rates greatest during the initial drinking periods. Seven of nine treated mallards were killed in extremis within 12 h after the initiation of dose. Total lethal doses of SAMW ranged from 69.8 to 270.1 mL/kg (mean ± SE 127.9 ± 27.1). Lethal doses of SAMW were consumed in as few as 20 to 40 min after first exposure. Clinical signs of SAMW toxicity included increased serum uric acid, aspartate aminotransferase, creatine kinase, potassium, and P levels. PCV values of SAMW-treated birds were also increased compared with control mallards. Histopathological lesions were observed in the esophagus, proventriculus, ventriculus, and duodenum of SAMW-treated mallards, with the most distinctive being erosion and ulceration of the kaolin of the ventriculus, ventricular hemorrhage and/or congestion, and duodenal hemorrhage. Clinical, pathological, and tissue-residue results from this study are consistent with literature documenting acute metal toxicosis, especially copper (Cu), in avian species and provide useful diagnostic profiles for AMW toxicity or mortality events. Blood and kidney Cu concentrations were 23- and 6-fold greater, respectively, in SAMW mortalities compared with controls, whereas Cu concentrations in liver were not nearly as increased, suggesting that blood and kidney concentrations may be more useful than liver concentrations for diagnosing Cu toxicosis in wild birds. Based on these findings and other reports of AMW toxicity events in wild birds, we conclude that AMW bodies pose a significant hazard to wildlife that come in contact with them.

Behavioral, clinical, and pathological characterization of acid metalliferous water toxicity in mallards.

PubMed

Isanhart, John P; Wu, Hongmei; Pandher, Karamjeet; MacRae, Russell K; Cox, Stephen B; Hooper, Michael J

2011-11-01

From September to November 2000, United States Fish and Wildlife Service biologists investigated incidents involving 221 bird deaths at 3 mine sites located in New Mexico and Arizona. These bird deaths primarily involved passerine and waterfowl species and were assumed to be linked to consumption of acid metalliferous water (AMW). Because all of the carcasses were found in or near pregnant leach solution ponds, tailings ponds, and associated lakes or storm water retention basins, an acute-toxicity study was undertaken using a synthetic AMW (SAMW) formulation based on the contaminant profile of a representative pond believed to be responsible for avian mortalities. An acute oral-toxicity trial was performed with a mixed-sex group of mallards (Anas platyrhynchos). After a 24-h pretreatment food and water fast, gorge drinking was evident in both SAMW treatment and control groups, with water consumption rates greatest during the initial drinking periods. Seven of nine treated mallards were killed in extremis within 12 h after the initiation of dose. Total lethal doses of SAMW ranged from 69.8 to 270.1 mL/kg (mean ± SE 127.9 ± 27.1). Lethal doses of SAMW were consumed in as few as 20 to 40 min after first exposure. Clinical signs of SAMW toxicity included increased serum uric acid, aspartate aminotransferase, creatine kinase, potassium, and P levels. PCV values of SAMW-treated birds were also increased compared with control mallards. Histopathological lesions were observed in the esophagus, proventriculus, ventriculus, and duodenum of SAMW-treated mallards, with the most distinctive being erosion and ulceration of the kaolin of the ventriculus, ventricular hemorrhage and/or congestion, and duodenal hemorrhage. Clinical, pathological, and tissue-residue results from this study are consistent with literature documenting acute metal toxicosis, especially copper (Cu), in avian species and provide useful diagnostic profiles for AMW toxicity or mortality events. Blood and kidney Cu concentrations were 23- and 6-fold greater, respectively, in SAMW mortalities compared with controls, whereas Cu concentrations in liver were not nearly as increased, suggesting that blood and kidney concentrations may be more useful than liver concentrations for diagnosing Cu toxicosis in wild birds. Based on these findings and other reports of AMW toxicity events in wild birds, we conclude that AMW bodies pose a significant hazard to wildlife that come in contact with them.

Renal function on admission modifies prognostic impact of diuretics in acute heart failure: a propensity score matched and interaction analysis.

PubMed

Matsue, Yuya; Shiraishi, Atsushi; Kagiyama, Nobuyuki; Yoshida, Kazuki; Kume, Teruyoshi; Okura, Hiroyuki; Suzuki, Makoto; Matsumura, Akihiko; Yoshida, Kiyoshi; Hashimoto, Yuji

2016-12-01

Although intravenous diuretics have been mainstay drugs in patients with acute heart failure (AHF), they have been suggested to have some deleterious effects on prognosis. We postulated that renal function may modify their deleterious effects in AHF patients. The study population consisted of 1094 AHF patients from three hospitals. Renal dysfunction (RD) was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m 2 on admission, and the cohort was divided into a high-dose furosemide (≥100 mg/48 h) and low-dose furosemide group according to the amount of intravenous furosemide used within 48 h from admission. In the whole cohort, in-hospital mortality rate was higher in the high-dose furosemide group than the low-dose furosemide group (12.5 vs. 6.6 %, respectively, P = 0.001). However, this difference in the in-hospital mortality rates was significant only in the RD subgroup (15.6 vs. 7.0 %, respectively, P < 0.001), and not in the non-RD subgroup (2.5 vs. 5.9 %, respectively, P = 0.384). Propensity score-matched analysis was performed to evaluate the impact of high-dose furosemide on prognosis. After propensity score matching, high-dose furosemide was not associated with in-hospital mortality (OR 1.25, 95 % CI 0.73-2.16, P = 0.408). However, there was a qualitative difference in OR for in-hospital mortality between AHF with RD (OR 1.77, 95 % CI 0.96-3.28, P = 0.068) and without RD (OR 0.23, 95 % CI 0.05-1.10, P = 0.064), and there was a significant interaction between eGFR and prognostic impact of high-dose furosemide (P for OR interaction = 0.013). An inverse relationship was observed between eGFR and OR for in-hospital death in the group treated with high-dose furosemide (decreasing OR with better eGFR). The deleterious effect of diuretics was significantly modified with renal function in AHF. This association may be one reason for poorer prognosis of AHF patients complicated with renal impairment.

Monochloroacetic acid lethality in the rat in relation to lactic acid accumulation in the cerebrospinal fluid

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mitroka, J.G.

1989-01-01

Potential antidotes for human exposure to monochloroacetic acid (MCA) were evaluated using a rodent model. Dichloroacetic acid (DCA) and phenobarbital (PB) but not ethanol or phenytoin, were found to be effective antidotes to monochloroacetic acid (MCA) in rats. DCA (110 mg/kg, ip), administered to rats 15 minutes after a LD-80 of MCA (80 mg/kg, iv), consistently reduced mortality to 0%, while PB reduced mortality to less than 20%. Both DCA and PB were found to be similarly effective in mice. The hypothesis that PB reduces mortality in MCA treated rats by altering the metabolic disposition of MCA was evaluated andmore » rejected. Administration of PB to rats treated with a lethal dose of ({sup 14}C)MCA did not alter the concentrations of MCA or its metabolites in plasma or cerebrospinal fluid (CSF), or the extent of covalent binding between radioactivity equivalent to ({sup 14}C)MCA and brain proteins. The relationship between altered blood-brain barrier permeability and death in MCA treated rats was investigated. Treatment with MCA (80 mg/kg, iv) was associated with a significant (50%) increase in the permeability of the rat blood-brain barrier to ({sup 125}I)BSA. The effect was not altered by treatment with PB, however, suggesting that altered blood-brain barrier permeability does not have an important role in the lethal effect of MCA in rats. The effect of MCA on brain carbohydrate metabolism in vivo was investigated. CSF and blood lactic acid concentrations increased in MCA treated rats, and the increase in CSF levels was dose related. In individual MCA treated rats, CSF lactate concentrations paralleled the time course of ataxia and a discrete threshold for death (18 mmol/L) was observed. The relationship between excess brain lactate levels and death in MCA treated rats was investigated further.« less

Low-dose aspirin for prevention of cardiovascular disease in patients on hemodialysis: A 5-y prospective cohort study.

PubMed

Liu, Jun; Pan, Yu; Chen, Lei; Qiao, Qing Yan; Wang, Jing; Pan, Li Hua; Gu, Yan Hong; Gu, Hui Fang; Fu, Shun Kun; Jin, Hui Min

2016-10-01

Introduction Aspirin is an effective antiplatelet drug for preventing cardiovascular events in high-risk subjects. However, for patients with chronic kidney disease and undergoing hemodialysis (HD), its preventive efficacy remains controversial. The present study aimed to determine whether aspirin therapy reduces the risk of cardiovascular disease (CVD) and all-cause mortality in patients on HD. Methods We conducted a 5-y prospective cohort study involving patients on HD. Major exposure variables included prescription of aspirin (100 mg/d) and no aspirin (nonaspirin). The primary outcomes included all-cause death, cardiovascular events, hemorrhage, and ischemic stroke. The secondary outcome included bleeding events defined by the requirement of hospitalization. Findings In this study, 406 patients on regular HD were involved during a 5-y follow-up. Among these, 152 and 254 propensity-matched patients were enrolled in the aspirin and nonaspirin cohort, respectively. The cumulative survival rate was not significantly higher in the aspirin than in the nonaspirin users (log rank χ 2  = 1.080, P = 0.299). Aspirin use was not significantly associated with reduced all-cause mortality, fatal and nonfatal congestive heart failure, as well as acute myocardial infarction and ischemic stroke. The risk of fatal cerebral hemorrhage was not significantly increased in the aspirin users (HR = 1.795, 95% CI 0.666-4.841, P = 0.174). After adjustment for other confounders, aspirin use was also not associated with decreased risk of all-cause mortality and CVD. Discussion The present prospective cohort study suggests that low-dose aspirin use is not associated with a significant decrease in the risks of all-cause mortality, CVD, and stroke in population undergoing HD (ClinicalTrials.gov number, NCT02261025). © 2016 International Society for Hemodialysis.

Non-CD34+ cells, especially CD8+ cytotoxic T cells and CD56+ natural killer cells, rather than CD34 cells, predict early engraftment and better transplantation outcomes in patients with hematologic malignancies after allogeneic peripheral stem cell transplantation.

PubMed

Kim, Dong Hwan; Won, Dong Il; Lee, Nan Young; Sohn, Sang Kyun; Suh, Jang Soo; Lee, Kyu Bo

2006-07-01

The effect of the transplant dose of each cell subset on engraftment kinetics and transplantation outcomes was evaluated in HLA-identical allogeneic peripheral blood stem cell transplantation (PBSCT). Sixty-nine patients were included in this retrospective study. Engraftment kinetics, transplantation outcomes, and immune reconstitution up to 1 year after transplantation were analyzed according to the transplant dose of CD34+ and non-CD34+ cells, including natural killer (NK) cells and CD8+ cytotoxic T (Tc) cells. An accelerated neutrophil engraftment was strongly associated with a higher transplant dose of NK cells (12 versus 16 days, P < .001) and Tc cells (13 versus 16 days, P < .001) but not CD34+ cells (P = .442). Survival analyses revealed a favorable prognosis for patients who received a higher dose of non-CD34+ cell subsets, rather than CD34+ cells, in terms of overall survival (OS; P = .024 for NK cells and .050 for Tc cells) and nonrelapse mortality (NRM; P = .005 for NK cells, .060 for Tc cells). In addition, a higher transplant dose of NK and Tc cells was correlated with a faster lymphoid reconstitution. In multivariate analyses, rapid neutrophil engraftment was correlated with a higher transplant dose of NK cells (P = .001) and Tc cells (P = .004). Moreover, an increased OS was associated with the NK cell dose (P = .007) and chronic graft-versus-host disease (P = .009), whereas a decreased NRM was associated with the NK dose (P = .024). In conclusion, in a PBSCT setting, a higher transplant dose of NK and Tc cells accelerated neutrophil engraftment, improved the immune reconstitution, and decreased NRM, thereby increasing OS after allogeneic PBSCT.

Glutamine and antioxidants: status of their use in critical illness.

PubMed

van Zanten, Arthur R H

2015-03-01

Many studies in critically ill patients have addressed enteral or parenteral supplementation of glutamine and antioxidants to counteract assumed deficiencies and induce immune-modulating effects to reduce infections and improve outcome. Older studies showed marked reductions in mortality, infectious morbidity and length of stay. Recent studies no longer show beneficial effects and in contrast even demonstrated increased mortality. This opiniating review focuses on the latest information and the consequences for the use of glutamine and antioxidants in critically ill patients. Positive effects in systematic reviews and meta-analyses are based on results from older, smaller and mainly single-centre studies. New information has challenged the conditional deficiency hypothesis concerning glutamine in critically ill patients. The recent REDOXS and MetaPlus trials studying the effects of glutamine, selenium and other antioxidants have shown no benefits and increased mortality. Given that the first dictum in medicine is to do no harm, we cannot be confident that immune-modulating nutrient supplementation with glutamine and antioxidants is effective and well tolerated for critically ill patients. Until more data are available, it is probably better not to routinely administer glutamine and antioxidants in nonphysiological doses to mechanically ventilated critically ill patients.

Efficacy and safety of dronedarone: a review of randomized trials.

PubMed

Christiansen, Christine Benn; Torp-Pedersen, Christian; Køber, Lars

2010-01-01

Dronedarone is developed for treatment of atrial fibrillation (AF) or flutter (AFL). It is a noniodinized amiodarone analogue and believed to be without the adverse effects of amiodarone. However, long-term adverse effects are not yet well investigated. This is a review of seven studies on dronedarone. DAFNE established an effective dose to be 400 mg b.i.d. ADONIS and EURIDIS showed significant prevention of AF/AFL recurrence hazard ratio (HR 0.78 and 0.73) compared to placebo. In ATHENA, cardiovascular death/hospitalization was significantly reduced (HR 0.76) in patients with AF and additional risk factors. ANDROMEDA was stopped because dronedarone increased early mortality (HR 2.13) in advanced heart failure (HF). ERATO found that dronedarone significantly reduced heart rate compared to placebo in patients with AF. DIONYSOS showed that amiodarone was superior to dronedarone to maintain sinus rhythm in patients with AF/AFL. Dronedarone is superior to placebo but less efficient than amiodarone in maintaining sinus rhythm in patients with a history of AF. In patients with AF and risk factors dronedarone reduces cardiovascular mortality and morbidity, but in patients with severe HF dronedarone significantly increases mortality.

Dose escalation of definitive radiation is not associated with improved survival for cervical esophageal cancer: a National Cancer Data Base (NCDB) analysis.

PubMed

De, B; Rhome, R; Doucette, J; Buckstein, M

2017-04-01

For cervical esophageal cancer (CEC), National Comprehensive Cancer Network guidelines support RT to 50-50.4 Gy with chemotherapy but acknowledge higher doses may be appropriate. This study uses the National Cancer Database (NCDB) to characterize RT practices and identify if a dose-response relationship exists for overall survival (OS) for definitive treatment of CEC. We queried the NCDB for patients diagnosed with Stage I-III CEC from 2004 to 2013, and selected patients receiving definitive RT with doses between 50 and 74 Gy. Using multivariate logistic regression, the database was analyzed to determine factors associated with use of RT > 50.4 Gy. Patients were then stratified into three dose categories. Predictors of OS were analyzed with univariate and multivariate methods using the Kaplan-Meier curves, the log-rank test, and the Cox proportional hazards analysis. We stratified 789 patients with CEC who were treated with definitive radiation ± chemotherapy: 50-50.4 Gy ('standard'), >50.4 and <66 Gy ('medium'), and 66-74 Gy ('high'). Of these patients, 215 (27%) received standard doses, 375 (48%) received medium doses, and 199 (25%) received high doses. Patients with Medicaid insurance and those with Stage II disease were less likely (P < 0.05) to receive >50.4 Gy. Sex, histology, distance to treatment facility, and academic/community facility type were not significantly associated with receipt of >50.4 Gy. There was no association between dose and OS for the medium or high groups when using univariate analysis or analysis adjusted for demographic, facility, and clinical attributes. Stage III disease and the Charlson-Deyo scores of 1 or 2 were associated with higher mortality (P < 0.05), while female sex and use of chemotherapy were associated with lower mortality (P < 0.01). Nearly three-fourths of CEC patients in the United States are treated with RT > 50.4 Gy. Higher radiation doses were not associated with increased OS in CEC patients in the NCDB. © The Authors 2017. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Therapeutic effect of long-term melatonin treatment on the course and fatal outcome of modeled acute radiation sickness.

PubMed

Vasin, M V; Ushakov, I B; Kovtun, V Yu; Semenova, L A; Koroleva, L V; Galkin, A A; Afanas'ev, R V

2014-04-01

We studied the effect of long-term administration of melatonin to male C57Bl/6 mice starting from day 3 after whole-body γ-irradiation (9.5-10.0 Gy, 7.7-17.1 cGy/min). It was found that replacement of drinking water with melatonin solution (5 mg/liter) did not reduce the amount of fluid intake throughout the period of acute radiation injury. The daily dose of melatonin was 0.9-1.2 mg/kg body weight (this parameter was lower at the peak of the disease and increased during the recovery stage). Melatonin by more than 20% (p<0.05) improved survival of mice exposed to γ-irradiation in a dose of LD97/30, reduced leukopenia during the stage of acute manifestations of the disease and maximum mortality, and increased blood leukocyte count by 40% (p<0.05) by day 12 after irradiation.

Vitamin D supplementation for prevention of mortality in adults.

PubMed

Bjelakovic, Goran; Gluud, Lise Lotte; Nikolova, Dimitrinka; Whitfield, Kate; Wetterslev, Jørn; Simonetti, Rosa G; Bjelakovic, Marija; Gluud, Christian

2014-01-10

Available evidence on the effects of vitamin D on mortality has been inconclusive. In a recent systematic review, we found evidence that vitamin D3 may decrease mortality in mostly elderly women. The present systematic review updates and reassesses the benefits and harms of vitamin D supplementation used in primary and secondary prophylaxis of mortality. To assess the beneficial and harmful effects of vitamin D supplementation for prevention of mortality in healthy adults and adults in a stable phase of disease. We searched The Cochrane Library, MEDLINE, EMBASE, LILACS, the Science Citation Index-Expanded and Conference Proceedings Citation Index-Science (all up to February 2012). We checked references of included trials and pharmaceutical companies for unidentified relevant trials. Randomised trials that compared any type of vitamin D in any dose with any duration and route of administration versus placebo or no intervention in adult participants. Participants could have been recruited from the general population or from patients diagnosed with a disease in a stable phase. Vitamin D could have been administered as supplemental vitamin D (vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol)) or as an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol) or 1,25-dihydroxyvitamin D (calcitriol)). Six review authors extracted data independently. Random-effects and fixed-effect meta-analyses were conducted. For dichotomous outcomes, we calculated the risk ratios (RRs). To account for trials with zero events, we performed meta-analyses of dichotomous data using risk differences (RDs) and empirical continuity corrections. We used published data and data obtained by contacting trial authors.To minimise the risk of systematic error, we assessed the risk of bias of the included trials. Trial sequential analyses controlled the risk of random errors possibly caused by cumulative meta-analyses. We identified 159 randomised clinical trials. Ninety-four trials reported no mortality, and nine trials reported mortality but did not report in which intervention group the mortality occurred. Accordingly, 56 randomised trials with 95,286 participants provided usable data on mortality. The age of participants ranged from 18 to 107 years. Most trials included women older than 70 years. The mean proportion of women was 77%. Forty-eight of the trials randomly assigned 94,491 healthy participants. Of these, four trials included healthy volunteers, nine trials included postmenopausal women and 35 trials included older people living on their own or in institutional care. The remaining eight trials randomly assigned 795 participants with neurological, cardiovascular, respiratory or rheumatoid diseases. Vitamin D was administered for a weighted mean of 4.4 years. More than half of the trials had a low risk of bias. All trials were conducted in high-income countries. Forty-five trials (80%) reported the baseline vitamin D status of participants based on serum 25-hydroxyvitamin D levels. Participants in 19 trials had vitamin D adequacy (at or above 20 ng/mL). Participants in the remaining 26 trials had vitamin D insufficiency (less than 20 ng/mL).Vitamin D decreased mortality in all 56 trials analysed together (5,920/47,472 (12.5%) vs 6,077/47,814 (12.7%); RR 0.97 (95% confidence interval (CI) 0.94 to 0.99); P = 0.02; I(2) = 0%). More than 8% of participants dropped out. 'Worst-best case' and 'best-worst case' scenario analyses demonstrated that vitamin D could be associated with a dramatic increase or decrease in mortality. When different forms of vitamin D were assessed in separate analyses, only vitamin D3 decreased mortality (4,153/37,817 (11.0%) vs 4,340/38,110 (11.4%); RR 0.94 (95% CI 0.91 to 0.98); P = 0.002; I(2) = 0%; 75,927 participants; 38 trials). Vitamin D2, alfacalcidol and calcitriol did not significantly affect mortality. A subgroup analysis of trials at high risk of bias suggested that vitamin D2 may even increase mortality, but this finding could be due to random errors. Trial sequential analysis supported our finding regarding vitamin D3, with the cumulative Z-score breaking the trial sequential monitoring boundary for benefit, corresponding to 150 people treated over five years to prevent one additional death. We did not observe any statistically significant differences in the effect of vitamin D on mortality in subgroup analyses of trials at low risk of bias compared with trials at high risk of bias; of trials using placebo compared with trials using no intervention in the control group; of trials with no risk of industry bias compared with trials with risk of industry bias; of trials assessing primary prevention compared with trials assessing secondary prevention; of trials including participants with vitamin D level below 20 ng/mL at entry compared with trials including participants with vitamin D levels equal to or greater than 20 ng/mL at entry; of trials including ambulatory participants compared with trials including institutionalised participants; of trials using concomitant calcium supplementation compared with trials without calcium; of trials using a dose below 800 IU per day compared with trials using doses above 800 IU per day; and of trials including only women compared with trials including both sexes or only men. Vitamin D3 statistically significantly decreased cancer mortality (RR 0.88 (95% CI 0.78 to 0.98); P = 0.02; I(2) = 0%; 44,492 participants; 4 trials). Vitamin D3 combined with calcium increased the risk of nephrolithiasis (RR 1.17 (95% CI 1.02 to 1.34); P = 0.02; I(2) = 0%; 42,876 participants; 4 trials). Alfacalcidol and calcitriol increased the risk of hypercalcaemia (RR 3.18 (95% CI 1.17 to 8.68); P = 0.02; I(2) = 17%; 710 participants; 3 trials). Vitamin D3 seemed to decrease mortality in elderly people living independently or in institutional care. Vitamin D2, alfacalcidol and calcitriol had no statistically significant beneficial effects on mortality. Vitamin D3 combined with calcium increased nephrolithiasis. Both alfacalcidol and calcitriol increased hypercalcaemia. Because of risks of attrition bias originating from substantial dropout of participants and of outcome reporting bias due to a number of trials not reporting on mortality, as well as a number of other weaknesses in our evidence, further placebo-controlled randomised trials seem warranted.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Harrison, F.L.; Rice, D.W. Jr.; Moore, D.H.

Traditional bioassays are unsuitable for assessing sublethal effects of low levels of radioactivity because mortality and phenotypic responses are not anticipated. We compared the usefulness of chromosomal aberration (CA) and sister chromatid exchange (SCE) induction as measures of low-level radiation effects in a sediment-dwelling marine worm, Neanthes arenaceodentata. Newly hatched larvae were exposed to two radiation exposure regimes. Groups of 100 larvae were exposed to either x rays delivered at high dose rates (0.7 Gy min/sup -1/) or to /sup 60/Co gamma rays delivered at low dose rates (4.8 X 10/sup -5/ to 1.2 X 10/sup -1/ Gy h/sup -1/).more » After irradiation, the larvae were exposed to 3 X 10/sup -5/M bromodeoxyuridine (BrdUrd) for 28 h (x-ray-irradiated larvae) or for 54 h (/sup 60/Co-irradiated larvae). Slides of larval cells were prepared for observation of CAs and SCEs. Frequencies of CAs were determined in first division cells; frequencies of SCEs were determined in second division cells. Results from x-ray irradiation indicated that dose-related increases occur in chromosome and chromatid deletions, but an x-ray dose greater than or equal to 2 Gy was required to observe a significant increase. Worm larvae receiving /sup 60/Co irradiation showed elevated SCE frequencies; a significant increase in SCE frequency was observed at 0.6 Gy. 49 references, 2 figures.« less

Comparison of two indices of exposure to polycyclic aromatic hydrocarbons in a retrospective aluminium smelter cohort.

PubMed

Friesen, Melissa C; Demers, Paul A; Spinelli, John J; Lorenzi, Maria F; Le, Nhu D

2007-04-01

The association between coal tar-derived substances, a complex mixture of polycyclic aromatic hydrocarbons, and cancer is well established. However, the specific aetiological agents are unknown. To compare the dose-response relationships for two common measures of coal tar-derived substances, benzene-soluble material (BSM) and benzo(a)pyrene (BaP), and to evaluate which among these is more strongly related to the health outcomes. The study population consisted of 6423 men with > or =3 years of work experience at an aluminium smelter (1954-97). Three health outcomes identified from national mortality and cancer databases were evaluated: incidence of bladder cancer (n = 90), incidence of lung cancer (n = 147) and mortality due to acute myocardial infarction (AMI, n = 184). The shape, magnitude and precision of the dose-response relationships and cumulative exposure levels for BSM and BaP were evaluated. Two model structures were assessed, where 1n(relative risk) increased with cumulative exposure (log-linear model) or with log-transformed cumulative exposure (log-log model). The BaP and BSM cumulative exposure metrics were highly correlated (r = 0.94). The increase in model precision using BaP over BSM was 14% for bladder cancer and 5% for lung cancer; no difference was observed for AMI. The log-linear BaP model provided the best fit for bladder cancer. The log-log dose-response models, where risk of disease plateaus at high exposure levels, were the best-fitting models for lung cancer and AMI. BaP and BSM were both strongly associated with bladder and lung cancer and modestly associated with AMI. Similar conclusions regarding the associations could be made regardless of the exposure metric.

Clinical signs, pathology and dose-dependent survival of adult wood frogs, Rana sylvatica, inoculated orally with frog virus 3 Ranavirus sp., Iridoviridae.

PubMed

Forzn, Mara J; Jones, Kathleen M; Vanderstichel, Raphal V; Wood, John; Kibenge, Frederick S B; Kuiken, Thijs; Wirth, Wytamma; Ariel, Ellen; Daoust, Pierre-Yves

2015-05-01

Amphibian populations suffer massive mortalities from infection with frog virus 3 FV3, genus Ranavirus, family Iridoviridae, a pathogen also involved in mortalities of fish and reptiles. Experimental oral infection with FV3 in captive-raised adult wood frogs, Rana sylvatica Lithobates sylvaticus, was performed as the first step in establishing a native North American animal model of ranaviral disease to study pathogenesis and host response. Oral dosing was successful LD50 was 10(2.93 2.423.44) p.f.u. for frogs averaging 35mm in length. Onset of clinical signs occurred 614days post-infection p.i. median 11 days p.i. and time to death was 1014 days p.i. median 12 days p.i.. Each tenfold increase in virus dose increased the odds of dying by 23-fold and accelerated onset of clinical signs and death by approximately 15. Ranavirus DNA was demonstrated in skin and liver of all frogs that died or were euthanized because of severe clinical signs. Shedding of virus occurred in faeces 710 days p.i. 34.5days before death and skin sheds 10 days p.i. 01.5days before death of some frogs dead from infection. Most common lesions were dermal erosion and haemorrhages haematopoietic necrosis in bone marrow, kidney, spleen and liver and necrosis in renal glomeruli, tongue, gastrointestinal tract and urinary bladder mucosa. Presence of ranavirus in lesions was confirmed by immunohistochemistry. Intracytoplasmic inclusion bodies probably viral were present in the bone marrow and the epithelia of the oral cavity, gastrointestinal tract, renal tubules and urinary bladder. Our work describes a ranaviruswood frog model and provides estimates that can be incorporated into ranavirus disease ecology models. © 2015 The Authors.

The burden of hyperkalemia in patients with cardiovascular and renal disease.

PubMed

Dunn, Jeffrey D; Benton, Wade W; Orozco-Torrentera, Ernesto; Adamson, Robert T

2015-11-01

Hyperkalemia is a potentially serious condition that can result in life-threatening cardiac arrhythmias and is associated with an increased mortality risk. Patients older than 65 years who have an advanced stage of chronic kidney disease (stage 3 or higher), diabetes, and/or chronic heart failure are at higher risk for hyperkalemia. To reduce disease progression and improve outcomes in these groups of patients, modulation of the renin-angiotensin-aldosterone system (RAAS) is recommended by guidelines. One limiting factor of RAAS inhibitors at proven doses is the increased risk for hyperkalemia associated with their use. Although there are effective therapeutic options for the short-term, acute management of hyperkalemia, the available strategies for chronic control of high potassium levels have limited effectiveness. The management of high potassium in the long term often requires withdrawing or reducing the doses of drugs proven to reduce cardiovascular and renal outcomes (eg, RAAS inhibitors) or implementing excessive and often intolerable dietary restrictions. Furthermore, withholding RAAS inhibitors may lead to incremental healthcare costs associated with poor outcomes, such as end-stage renal disease, hospitalizations due to cardiovascular causes, and cardiovascular mortality. As such, there is an important unmet need for novel therapeutic options for the chronic management of patients at risk for hyperkalemia. Potential therapies in development may change the treatment landscape in the near future.

Measles mortality reduction and pre-elimination in the African region, 2001-2009.

PubMed

Masresha, Balcha G; Fall, Amadou; Eshetu, Messeret; Sosler, Steve; Alleman, Mary; Goodson, James L; Katsande, Reggis; Nshimirimana, Deogratias

2011-07-01

In 2001, countries in the African region adopted the measles-associated mortality reduction strategy recommended by the World Health Organization and the United Nations Children's Fund. With support from partners, these strategies were implemented during 2001-2009. To assess implementation, estimates of the first dose of measles vaccination through routine services (MCVI) and reported coverage for measles supplemental immunization activities (SIAs) were reviewed. Measles surveillance data were analyzed. During 2001-2009, regional MCV1 coverage increased from 56% to 69%, and >425 million children received measles vaccination through 125 SIAs. Measles case-based surveillance was established in 40 of 46 countries; the remaining 6 have aggregated case reporting. From 2001 through 2008, reported measles cases decreased by 92%, from 492,116 to 37,010; however, in 2009, cases increased to 83,625. The implementation of the recommended strategies led to a marked decrease in measles cases in the region; however, the outbreaks occurring since 2008 indicate suboptimal vaccination coverage. To achieve high MCV1 coverage, provide a second dose through either periodic SIAs or routine services, and to ensure further progress toward attaining the regional measles pre-elimination goal by 2012, a renewed commitment from implementing partners and donors is needed. © The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.

Long-Term Outcomes Among Adult Survivors of Childhood Central Nervous System Malignancies in the Childhood Cancer Survivor Study

PubMed Central

Liu, Qi; Yasui, Yutaka; Huang, Sujuan; Ness, Kirsten K.; Leisenring, Wendy; Hudson, Melissa M.; Donaldson, Sarah S.; King, Allison A.; Stovall, Marilyn; Krull, Kevin R.; Robison, Leslie L.; Packer, Roger J.

2009-01-01

Background Adult survivors of childhood central nervous system (CNS) malignancies are at high risk for long-term morbidity and late mortality. However, patterns of late mortality, the long-term risks of subsequent neoplasms and debilitating medical conditions, and sociodemographic outcomes have not been comprehensively characterized for individual diagnostic and treatment groups. Methods We collected information on treatment, mortality, chronic medical conditions, and neurocognitive functioning of adult 5-year survivors of CNS malignancies diagnosed between 1970 and 1986 within the Childhood Cancer Survivor Study. Using competing risk framework, we calculated cumulative mortality according to cause of death and cumulative incidence of subsequent neoplasms according to exposure and dose of cranial radiation therapy (RT). Neurocognitive impairment and socioeconomic outcomes were assessed with respect to dose of CNS radiotherapy to specific brain regions. Cumulative incidence of chronic medical conditions was compared between survivors and siblings using Cox regression models. All tests of statistical significance were two-sided. Results Among all eligible 5-year survivors (n = 2821), cumulative late mortality at 30 years was 25.8% (95% confidence interval [CI] = 23.4% to 28.3%), due primarily to recurrence and/or progression of primary disease. Patients who received cranial RT of 50 Gy or more (n = 813) had a cumulative incidence of a subsequent neoplasm within the CNS of 7.1% (95% CI = 4.5% to 9.6%) at 25 years from diagnosis compared with 1.0% (95% CI = 0% to 2.3%) for patients who had no RT. Survivors had higher risk than siblings of developing new endocrine, neurological, or sensory complications 5 or more years after diagnosis. Neurocognitive impairment was high and proportional to radiation dose for specific tumor types. There was a dose-dependent association between RT to the frontal and/or temporal lobes and lower rates of employment, and marriage. Conclusions Survivors of childhood CNS malignancies are at high risk for late mortality and for developing subsequent neoplasms and chronic medical conditions. Care providers should be informed of these risks so they can provide risk-directed care and develop screening guidelines. PMID:19535780

What Pertussis Mortality Rates Make Maternal Acellular Pertussis Immunization Cost-Effective in Low- and Middle-Income Countries? A Decision Analysis

PubMed Central

Russell, Louise B.; Pentakota, Sri Ram; Toscano, Cristiana Maria; Cosgriff, Ben; Sinha, Anushua

2016-01-01

Background. Despite longstanding infant vaccination programs in low- and middle-income countries (LMICs), pertussis continues to cause deaths in the youngest infants. A maternal monovalent acellular pertussis (aP) vaccine, in development, could prevent many of these deaths. We estimated infant pertussis mortality rates at which maternal vaccination would be a cost-effective use of public health resources in LMICs. Methods. We developed a decision model to evaluate the cost-effectiveness of maternal aP immunization plus routine infant vaccination vs routine infant vaccination alone in Bangladesh, Nigeria, and Brazil. For a range of maternal aP vaccine prices, one-way sensitivity analyses identified the infant pertussis mortality rates required to make maternal immunization cost-effective by alternative benchmarks ($100, 0.5 gross domestic product [GDP] per capita, and GDP per capita per disability-adjusted life-year [DALY]). Probabilistic sensitivity analysis provided uncertainty intervals for these mortality rates. Results. Infant pertussis mortality rates necessary to make maternal aP immunization cost-effective exceed the rates suggested by current evidence except at low vaccine prices and/or cost-effectiveness benchmarks at the high end of those considered in this report. For example, at a vaccine price of $0.50/dose, pertussis mortality would need to be 0.051 per 1000 infants in Bangladesh, and 0.018 per 1000 in Nigeria, to cost 0.5 per capita GDP per DALY. In Brazil, a middle-income country, at a vaccine price of $4/dose, infant pertussis mortality would need to be 0.043 per 1000 to cost 0.5 per capita GDP per DALY. Conclusions. For commonly used cost-effectiveness benchmarks, maternal aP immunization would be cost-effective in many LMICs only if the vaccine were offered at less than $1–$2/dose. PMID:27838677

Differential toxic effects of Carbofuran and Diazinon on time of flight in pigeons (Columba livia): Potential for pesticide effects on migration

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brasel, Jeffrey M.; Environmental Sciences and Health Graduate Program, University of Nevada, Reno, NV 89557; Collier, Abby C.

Cholinesterase inhibiting compounds such as carbamates and organophosphate insecticides have been widely used in agriculture since the ban on organochlorines in the 1970s. Carbofuran, a carbamate, and diazinon, an organophosphate, are among the most commonly implicated cholinesterase inhibitors in episodes of accidental avian toxicity and mortality. Despite the apparent effects of these compounds, little work has been done to study effects of low-level, environmentally relevant doses at the population level in migratory bird species. In this study, homing pigeons were used as surrogate species to assess the differences in the effect of incrementally low doses (0.0, 0.25, 0.5, and 1.0more » mg/kg) of carbofuran and diazinon on time of flight and determine whether there was a threshold dose of either or both xenobiotics when orally administered at these levels. The results indicate that there is a significant dose-dependent increase in flight time in pigeons dosed with carbofuran while diazinon exposed pigeons showed little effect. More profound effects were noted with carbofuran with pigeons falling off the pace of the flock and a dose for highly significant increase in flight time elucidated between 0.5 and 1.0 mg/kg. The results of the studies validate the homing pigeon as a good subject for comparative studies of cholinesterase inhibitors in birds and the need for further research on repeated low-level exposures on populations of avian species.« less

Cost-effectiveness of prenatal food and micronutrient interventions on under-five mortality and stunting: Analysis of data from the MINIMat randomized trial, Bangladesh

PubMed Central

Selling, Katarina Ekholm; Shaheen, Rubina; Khan, Ashraful Islam; Persson, Lars-Åke; Lindholm, Lars

2018-01-01

Introduction Nutrition interventions may have favourable as well as unfavourable effects. The Maternal and Infant Nutrition Interventions in Matlab (MINIMat), with early prenatal food and micronutrient supplementation, reduced infant mortality and were reported to be very cost-effective. However, the multiple micronutrients (MMS) supplement was associated with an increased risk of stunted growth in infancy and early childhood. This unfavourable outcome was not included in the previous cost-effectiveness analysis. The aim of this study is to evaluate whether the MINIMat interventions remain cost-effective in view of both favourable (decreased under-five-years mortality) and unfavourable (increased stunting) outcomes. Method Pregnant women in rural Bangladesh, where food insecurity still is prevalent, were randomized to early (E) or usual (U) invitation to be given food supplementation and daily doses of 30 mg, or 60 mg iron with 400 μg of folic acid, or MMS with 15 micronutrients including 30 mg iron and 400 μg of folic acid. E reduced stunting at 4.5 years compared with U, MMS increased stunting at 4.5 years compared with Fe60, while the combination EMMS reduced infant mortality compared with UFe60. The outcome measure used was disability adjusted life years (DALYs), a measure of overall disease burden that combines years of life lost due to premature mortality (under five-year mortality) and years lived with disability (stunting). Incremental cost effectiveness ratios were calculated using cost data from already published studies. Results By incrementing UFe60 (standard practice) to EMMS, one DALY could be averted at a cost of US$24. Conclusion When both favourable and unfavourable outcomes were included in the analysis, early prenatal food and multiple micronutrient interventions remained highly cost effective and seem to be meaningful from a public health perspective. PMID:29447176

Cost-effectiveness of prenatal food and micronutrient interventions on under-five mortality and stunting: Analysis of data from the MINIMat randomized trial, Bangladesh.

PubMed

Svefors, Pernilla; Selling, Katarina Ekholm; Shaheen, Rubina; Khan, Ashraful Islam; Persson, Lars-Åke; Lindholm, Lars

2018-01-01

Nutrition interventions may have favourable as well as unfavourable effects. The Maternal and Infant Nutrition Interventions in Matlab (MINIMat), with early prenatal food and micronutrient supplementation, reduced infant mortality and were reported to be very cost-effective. However, the multiple micronutrients (MMS) supplement was associated with an increased risk of stunted growth in infancy and early childhood. This unfavourable outcome was not included in the previous cost-effectiveness analysis. The aim of this study is to evaluate whether the MINIMat interventions remain cost-effective in view of both favourable (decreased under-five-years mortality) and unfavourable (increased stunting) outcomes. Pregnant women in rural Bangladesh, where food insecurity still is prevalent, were randomized to early (E) or usual (U) invitation to be given food supplementation and daily doses of 30 mg, or 60 mg iron with 400 μg of folic acid, or MMS with 15 micronutrients including 30 mg iron and 400 μg of folic acid. E reduced stunting at 4.5 years compared with U, MMS increased stunting at 4.5 years compared with Fe60, while the combination EMMS reduced infant mortality compared with UFe60. The outcome measure used was disability adjusted life years (DALYs), a measure of overall disease burden that combines years of life lost due to premature mortality (under five-year mortality) and years lived with disability (stunting). Incremental cost effectiveness ratios were calculated using cost data from already published studies. By incrementing UFe60 (standard practice) to EMMS, one DALY could be averted at a cost of US$24. When both favourable and unfavourable outcomes were included in the analysis, early prenatal food and multiple micronutrient interventions remained highly cost effective and seem to be meaningful from a public health perspective.

The Kidney Disease Outcomes Quality Initiative (K/DOQI) Guideline for Bone Metabolism and Disease in CKD: association with mortality in dialysis patients.

PubMed

Noordzij, Marlies; Korevaar, Johanna C; Boeschoten, Elisabeth W; Dekker, Friedo W; Bos, Willem J; Krediet, Raymond T

2005-11-01

In 2003, the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (K/DOQI) published a guideline recommending tight control of serum calcium, phosphorus, calcium-phosphorus product (Ca x P), and intact parathyroid hormone levels in patients with chronic kidney disease. Within the context of this guideline, we explored associations of these plasma concentrations with all-cause mortality risk in incident dialysis patients in The Netherlands. In a large, prospective, multicenter, cohort study (Netherlands Cooperative Study on the Adequacy of Dialysis), we included 1,629 patients new on hemodialysis or peritoneal dialysis therapy between 1997 and 2004. Multivariate Cox regression models containing calcium level, phosphorus level, intact parathyroid hormone level, age, comorbidity, primary kidney disease, nutritional status, albumin level, dialysis dose, and hemoglobin level were used to examine mortality risks. Mean age was 60 +/- 15 (SD) years, 61% were men, and 64% were treated with hemodialysis. In adjusted time-dependent survival analysis, all-cause mortality risk increased in hemodialysis patients by 40% (hazard ratio [HR], 1.4; 95% confidence interval [CI], 1.1 to 1.7) and in peritoneal dialysis patients by 60% (HR, 1.6; 95% CI, 1.1 to 2.4) for plasma phosphorus levels greater than the target. In addition, having elevated plasma Ca x P product levels increased mortality risk by 40% (HR, 1.4; 95% CI, 1.1 to 1.8) in hemodialysis patients and 50% in peritoneal dialysis patients (HR, 1.5; 95% CI, 1.0 to 2.2). In both patient groups, no significant effects were observed for plasma levels less than the targets. In time-dependent survival analysis, the presence of plasma phosphorus and Ca x P product concentrations greater than K/DOQI targets increased all-cause mortality risk in hemodialysis and peritoneal dialysis patients.

Acute, 28days sub acute and genotoxic profiling of Quercetin-Magnesium complex in Swiss albino mice.

PubMed

Ghosh, Nilanjan; Sandur, Rajendra; Ghosh, Deepanwita; Roy, Souvik; Janadri, Suresh

2017-02-01

Quercetin-Magnesium complex is one of the youngest alkaline rare earth metal (Magnesium) complexes with flavonoids (Quercetin) in organo-metalic family. Earlier studies describe the details of the complex formation, characterization and antioxidant study of the complex but toxicity profile is still under darkness. The present study was taken up to investigate the oral acute toxicity, 28days repeated oral sub-acute toxicity study and genotoxicity study of Quercetin-Magnesium complex in Swiss albino mice. Quercetin-Magnesium complex showed mortality at a dose of 185mg/kg in the Swiss albino mice. In 28days repeated oral toxicity study, Quercetin-Magnesium complex was administered to both sex of Swiss albino mice at dose levels of 150, 130 and 100mg/kg body weight respectively. Where 150mg/kg dose shows increased levels of white blood cells and changes in total protein, serum creatinine and blood urea nitrogen. Histopathological study of Quercetin-Magnesium complex shows minor structural alteration in kidney at 150mg/kg dose. No observed toxic level found in 130mg/kg or below doses. No genotoxic effect found in any doses of the complex. Therefore 130mg/kg or below dose level could be better for further study. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Comparative toxicity of lead shot in black ducks (Anas rubripes) and mallards (Anas platyrhynchos)

USGS Publications Warehouse

Rattner, B.A.; Fleming, W.J.; Bunck, C.M.

1989-01-01

In winter, pen-reared and wild black ducks (Anas rubripes), and game farm and wild mallards (Anas platyrhynchos), maintained on pelleted feed, were sham-dosed or given one number 4 lead shot. After 14 days, dosed birds were redosed with two or four additional lead shot. This dosing regimen also was repeated in summer using pen-reared black ducks and game farm mallards. Based upon mortality, overt intoxication, weight change, delta-aminolevulinic acid dehydratase activity and protoporphyrin concentration, black ducks and mallards were found to be equally tolerant to lead shot. However, captive wild ducks were more sensitive than their domesticated counterparts, as evidenced by greater mortality and weight loss following lead shot administration. This difference may be related to stress associated with captivity and unnatural diet.

Dose Regimens, Variability, and Complications Associated with Using Repeat-Bolus Dosing to Extend a Surgical Plane of Anesthesia in Laboratory Mice

PubMed Central

Jaber, Samer M; Hankenson, F Claire; Heng, Kathleen; McKinstry-Wu, Andrew; Kelz, Max B; Marx, James O

2014-01-01

Extending a surgical plane of anesthesia in mice by using injectable anesthetics typically is accomplished by repeat-bolus dosing. We compared the safety and efficacy of redosing protocols administered either during an anesthetic surgical plane (maintaining a continuous surgical plane, CSP), or immediately after leaving this plane (interrupted surgical plane, ISP) in C57BL/6J mice. Anesthesia was induced with ketamine, xylazine, and acepromazine (80, 8, and 1 mg/kg IP, respectively), and redosing protocols included 25% (0.25K), 50% (0.5K), or 100% (1.0K) of the initial ketamine dose or 25% (0.25KX) or 50% (0.5KX) of the initial ketamine–xylazine dose. In the ISP group, the surgical plane was extended by 13.8 ± 2.1 min (mean ± SEM) after redosing for the 0.25K redose with 50% returning to a surgical plane, 42.7 ± 4.5 min for the 0.5K redose with 88% returning to a surgical plane, and 44.3 ± 15.4 min for the 1.0K redose, 52.8 ± 7.2 min for the 0.25KX redose, and 45.9 ± 2.9 min for the 0.5KX redose, with 100% of mice returning to a surgical plane of anesthesia in these 3 groups. Mortality rates for ISP groups were 0%, 12%, 33%, 12%, and 18%, respectively. Mice in CSP groups had 50% mortality, independent of the repeat-dosing protocol. We recommend redosing mice with either 50% of the initial ketamine dose or 25% of the initial ketamine–xylazine dose immediately upon return of the pedal withdrawal reflex to extend the surgical plane of anesthesia in mice, optimize the extension of the surgical plane, and minimize mortality. PMID:25650976

Assessment of the risk of solar ultraviolet radiation to amphibians. I. Dose-dependent induction of hindlimb malformations in the northern leopard frog (Rana pipiens).

PubMed

Ankley, Gerald T; Diamond, Stephen A; Tietge, Joseph E; Holcombe, Gary W; Jensen, Kathleen M; Defoe, David L; Peterson, Ryan

2002-07-01

A number of environmental stressors have been hypothesized as responsible for recent increases in limb malformations in several species of North American amphibians. The purpose of this study was to generate dose-response data suitable for assessing the potential role of solar ultraviolet (UV) radiation in causing limb malformations in a species in which this phenomenon seemingly is particularly prevalent, the northern leopard frog (Rana pipiens). Frogs were exposed from early embryonic stages through complete metamorphosis to varying natural sunlight regimes, including unaltered (100%) sunlight, sunlight subjected to neutral density filtration to achieve relative intensities of 85%, 75%, 65%, 50%, and 25% of unaltered sunlight, and sunlight filtered with glass or acrylamide to attenuate, respectively, the UVB (290-320 nm) and UVB plus UVA (290-380 nm) portions of the spectrum. The experiments were conducted in a controlled setting, with continual monitoring of UVB, UVA, and visible light to support a robust exposure assessment. Full sunlight caused approximately 50% mortality of the frogs during early larval development; no significant treatment-related mortality occurred under any of the other exposure regimes, including 100% sunlight with glass or acrylamide filtration. There was a dose-dependent (p < 0.0001) induction of hindlimb malformations in the frogs, with the percentage of affected animals ranging from about 97% under unaltered sunlight to 0% in the 25% neutral density treatment. Malformations were comprised mostly of missing or truncated digits, and generally were bilateral as well as symmetrical. Filtration of sunlight with either glass or acrylamide both significantly reduced the incidence of malformed limbs. The estimated sunlight dose resulting in a 50% limb malformation rate (ED50) was 63.5%. The limb ED50 values based on measured sunlight intensities corresponded to average daily doses of 4.5 and 100 Wh x m(-2) for UVB and UVA, respectively. Exposure to sunlight also resulted in increased eye malformations in R. pipiens, however, the dose-response relationship for this endpoint was not monotonic. The results of this study, in conjunction with measured or predicted exposure data from natural settings, provide a basis for quantitative prediction of the risk of solar UV radiation to amphibians.

Effect of vitamin D on all-cause mortality in heart failure (EVITA): a 3-year randomized clinical trial with 4000 IU vitamin D daily.

PubMed

Zittermann, Armin; Ernst, Jana B; Prokop, Sylvana; Fuchs, Uwe; Dreier, Jens; Kuhn, Joachim; Knabbe, Cornelius; Birschmann, Ingvild; Schulz, Uwe; Berthold, Heiner K; Pilz, Stefan; Gouni-Berthold, Ioanna; Gummert, Jan F; Dittrich, Marcus; Börgermann, Jochen

2017-08-01

Circulating 25-hydroxyvitamin D (25OHD) levels <75 nmol/L are associated with a nonlinear increase in mortality risk. Such 25OHD levels are common in heart failure (HF). We therefore examined whether oral vitamin D supplementation reduces mortality in patients with advanced HF. Four hundred HF patients with 25OHD levels <75 nmol/L were randomized to receive 4000 IU vitamin D daily or matching placebo for 3 years. Primary endpoint was all-cause mortality. Key secondary outcome measures included hospitalization, resuscitation, mechanical circulatory support (MCS) implant, high urgent listing for heart transplantation, heart transplantation, and hypercalcaemia. Initial 25OHD levels were on average <40 nmol/L, remained around 40 nmol/L in patients assigned to placebo and plateaued around 100 nmol/L in patients assigned to vitamin D. Mortality was not different in patients receiving vitamin D (19.6%; n = 39) or placebo (17.9%; n = 36) with a hazard ratio (HR) of 1.09 [95% confidence interval (CI): 0.69-1.71; P = 0.726]. The need for MCS implant was however greater in patients assigned to vitamin D (15.4%, n = 28) vs. placebo [9.0%, n = 15; HR: 1.96 (95% CI: 1.04-3.66); P = 0.031]. Other secondary clinical endpoints were similar between groups. The incidence of hypercalcaemia was 6.2% (n = 10) and 3.1% (n = 5) in patients receiving vitamin D or placebo (P = 0.192). A daily vitamin D dose of 4000 IU did not reduce mortality in patients with advanced HF but was associated with a greater need for MCS implants. Data indicate caution regarding long-term supplementation with moderately high vitamin D doses. clinicaltrials.gov Idenitfier: NCT01326650. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.

Do the health benefits of cycling outweigh the risks?

PubMed

Johan de Hartog, Jeroen; Boogaard, Hanna; Nijland, Hans; Hoek, Gerard

2010-08-01

Although from a societal point of view a modal shift from car to bicycle may have beneficial health effects due to decreased air pollution emissions, decreased greenhouse gas emissions, and increased levels of physical activity, shifts in individual adverse health effects such as higher exposure to air pollution and risk of a traffic accident may prevail. We describe whether the health benefits from the increased physical activity of a modal shift for urban commutes outweigh the health risks. We have summarized the literature for air pollution, traffic accidents, and physical activity using systematic reviews supplemented with recent key studies. We quantified the impact on all-cause mortality when 500,000 people would make a transition from car to bicycle for short trips on a daily basis in the Netherlands. We have expressed mortality impacts in life-years gained or lost, using life table calculations. For individuals who shift from car to bicycle, we estimated that beneficial effects of increased physical activity are substantially larger (3-14 months gained) than the potential mortality effect of increased inhaled air pollution doses (0.8-40 days lost) and the increase in traffic accidents (5-9 days lost). Societal benefits are even larger because of a modest reduction in air pollution and greenhouse gas emissions and traffic accidents. On average, the estimated health benefits of cycling were substantially larger than the risks relative to car driving for individuals shifting their mode of transport.

A plausible radiobiological model of cardiovascular disease at low or fractionated doses

NASA Astrophysics Data System (ADS)

Little, Mark; Vandoolaeghe, Wendy; Gola, Anna; Tzoulaki, Ioanna

Atherosclerosis is the main cause of coronary heart disease and stroke, the two major causes of death in developed society. There is emerging evidence of excess risk of cardiovascular disease at low radiation doses in various occupationally-exposed groups receiving small daily radia-tion doses. Assuming that they are causal, the mechanisms for effects of chronic fractionated radiation exposures on cardiovascular disease are unclear. We outline a spatial reaction-diffusion model for atherosclerosis, and perform stability analysis, based wherever possible on human data. We show that a predicted consequence of multiple small radiation doses is to cause mean chemo-attractant (MCP-1) concentration to increase linearly with cumulative dose. The main driver for the increase in MCP-1 is monocyte death, and consequent reduction in MCP-1 degradation. The radiation-induced risks predicted by the model are quantitatively consistent with those observed in a number of occupationally-exposed groups. The changes in equilibrium MCP-1 concentrations with low density lipoprotein cholesterol concentration are also consistent with experimental and epidemiologic data. This proposed mechanism would be experimentally testable. If true, it also has substantive implications for radiological protection, which at present does not take cardiovascular disease into account. The Japanese A-bomb survivor data implies that cardiovascular disease and can-cer mortality contribute similarly to radiogenic risk. The major uncertainty in assessing the low-dose risk of cardiovascular disease is the shape of the dose response relationship, which is unclear in the Japanese data. The analysis of the present paper suggests that linear extrapo-lation would be appropriate for this endpoint.

A 13-week dermal repeat-dose neurotoxicity study of hydrodesulfurized kerosene in rats.

PubMed

Breglia, Rudolph; Bui, Quang; Burnett, Donald; Koschier, Francis; Lapadula, Elizabeth; Podhasky, Paula; Schreiner, Ceinwen; White, Russell

2014-01-01

A 13-week dermal repeat-dose toxicity study was conducted with hydrodesulfurized (HDS) kerosene, a test material that also met the commercial specifications for aviation turbine fuel (jet A). The objectives were to assess the potential for target organ toxicity and neurotoxicity. The HDS kerosene was applied to the shaved backs of Sprague-Dawley CD rats, 12/sex/group, 6 h/d, 5 d/wk in doses of 0 (vehicle control), 165 mg/kg (20% HDS kerosene), 330 mg/kg (40% HDS kerosene), or 495 mg/kg (60% HDS kerosene). Additional rats (12/sex) from the control and the high-dose groups were held without treatment for 4 weeks to assess recovery. Standard parameters of toxicity were investigated during the in-life phase. At necropsy, organs were weighed and selected tissues were processed for microscopic evaluation. Neurobehavioral evaluations included tests of motor activity and functional observations that were conducted pretest, at intervals during the exposure period and after recovery. No test substance-related effects on mortality, clinical observations (except dermal irritation), body weight, or clinical chemistry values were observed. A dose-related increase in skin irritation, confirmed histologically as minimal, was evident at the dosing site. The only statistically significant change considered potentially treatment related was an increase in the neutrophil count in females at 13 weeks. No test article-related effects were observed in the neurobehavioral assessments or gross or microscopic findings in the peripheral or central nervous system tissues in any of the dose groups. Excluding skin irritation, the no observed adverse effect level value for all effects was considered 495 mg/kg/d.

Dietary enhancement of intestinal radioresistance during fractionated irradiation. [. gamma. rays; rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pageau, R.; St-Pierre, C.

1978-10-01

Rats fed laboratory chow or elemental diet 3 were given fractions of 240 rads of /sup 60/Co ..gamma.. radiation abdominally (1200 rads/week) until all animals had died. Changes in appetite, body weight, and mortality were monitored as a function of the cumulative dose received. More radiation was needed in the diet-fed group to achieve both 0 and 100% mortality, a difference of 37% at the mean lethal dose level. Both groups developed similar progressive anorexia but the diet-fed animals lost weight more slowly. Data indicate that basic intestinal radioresistance is enhanced by feeding the elemental diet.

Efficacy of Silicosec, a diatomaceous earth formulation against Tribolium castaneum (Herbst) (Coleoptera: Tenebrionidae).

PubMed

Ziaee, Masumeh; Safaralizadeh, Mohammad H; Shayesteh, Nouraddin

2007-11-01

Laboratory bioassays were carried out to evaluate the insecticidal efficacy of SilicoSec against 7- 14-days-old adults of Tribolium castaneum; old and young larvae with the mean weight of 3.4 +/- 0.1 and 0.6 +/- 0.1 mg, respectively at 27 degrees C and 55 +/- 5% r.h in the dark. Wheat treated with four dose rates of SilicoSec with three replications. Adult's mortality was measured after 2, 7 and 14 days of exposure. After 14 days mortality count, all adults were removed and samples retained under the same conditions for a further 60 days to assess progeny production. In the case of larvae, mortality was counted after 1, 2 and 7 days. After 2 days of exposure no concentration achieved 11% mortality for adults, however; adult's mortality exceeds 89.65% when exposed for 7 days to SilicoSec. Mortality of old and young larvae at 0.6 g kg(-1) after 2 days were 28.88 and 22.22%, respectively and exceed to 60.71 and 69.04% at longer exposure of 7 days. Results indicated that mortality of T. castaneum was influenced by interval exposed to wheat treated with SilicoSec and over this exposure; the increases in application rate of SilicoSec had significant effect on the mortality. Young larvae of red flour beetle were more sensitive to SilicoSec than old larvae and adults were more tolerant. Reproductive potential of adults in the treated wheat was suppressed when compared with untreated wheat. The high retention level of SilicoSec (78.62%) was noted in wheat kernels.

NGO-promoted women's credit program, immunization coverage, and child mortality in rural Bangladesh.

PubMed

Amin, R; Li, Y

1997-01-01

A growing number of non-governmental organizations (NGOs) are adopting the collateral-free credit programs by anchoring them with their social development programs aimed at improved program effectiveness and sustainability. Drawing upon a sample of 3,564 targeted poor households covered by five small NGOs in rural Bangladesh, this study finds that the NGO credit-members as well as those who reside in the NGO program area are higher adopters of child immunization than those in the non-program area. Similarly, the study found that infant and child mortality is lower among the NGO credit members than among the non-members and that under five-year deaths of children progressively decline with the increase in the doses of vaccines. Implications of these findings are discussed in the study.

[SYNERGISM OF PRECONCEPTIVE RADIATION EXPOSURE AND PARENTS' ONCO-PATHOLOGY IN THE RISE OF CARCINOGENIC RISK IN THE OFFSPRINGS OF PROFESSIONAL EMPLOYEES].

PubMed

Telnov, V I; Kabirova, N R; Okatenko, P V

2015-01-01

The problem of carcinogenic risk in offsprings of individuals exposed to radiation is challenging and insufficiently studied. In that there are no evaluations of the interaction between radiation and non-radiation factors. The aim of the study was the analysis of interaction of preconceptive radiation exposure and parents' onco-pathology in cancer mortality in offsprings (F1) of workers (fathers) of the Mayak Production Association exposed to a wide range of doses of radiation over a year prior conception. The number of offspring is 8191 individuals (4180 men and 4011 women). The analysis was performed with the use of fourfold table and eightfold tables. The interaction offactors was estimated on the base of the additive and multiplicative models. The studied factors were independent. The odds ratio (OR) of cancer mortality in the offspring with parents' oncopathology (1.43) was insignificant. OR of cancer mortality in preconceptive radiation exposure in a dose over 110 mGy and without parents' onco-pathology was 2.61 (1.52-4.49), and in their combination--3.86 (1.93-7.71). Index of synergism of preconceptive radiation exposure and parents' onco-patholog in the rise of carcinogenic risk in the offspring was 1.34 and the character of their interaction was multiplicative. Thus, for the first time there was established the interaction between radiation and non-radiation factors in the synergism sort in the increase of carcinogenic risk in the offspring of people exposed to radiation.

Independent Evaluation of the integrated Community Case Management of Childhood Illness Strategy in Malawi Using a National Evaluation Platform Design.

PubMed

Amouzou, Agbessi; Kanyuka, Mercy; Hazel, Elizabeth; Heidkamp, Rebecca; Marsh, Andrew; Mleme, Tiope; Munthali, Spy; Park, Lois; Banda, Benjamin; Moulton, Lawrence H; Black, Robert E; Hill, Kenneth; Perin, Jamie; Victora, Cesar G; Bryce, Jennifer

2016-03-01

We evaluated the impact of integrated community case management of childhood illness (iCCM) on careseeking for childhood illness and child mortality in Malawi, using a National Evaluation Platform dose-response design with 27 districts as units of analysis. "Dose" variables included density of iCCM providers, drug availability, and supervision, measured through a cross-sectional cellular telephone survey of all iCCM-trained providers. "Response" variables were changes between 2010 and 2014 in careseeking and mortality in children aged 2-59 months, measured through household surveys. iCCM implementation strength was not associated with changes in careseeking or mortality. There were fewer than one iCCM-ready provider per 1,000 under-five children per district. About 70% of sick children were taken outside the home for care in both 2010 and 2014. Careseeking from iCCM providers increased over time from about 2% to 10%; careseeking from other providers fell by a similar amount. Likely contributors to the failure to find impact include low density of iCCM providers, geographic targeting of iCCM to "hard-to-reach" areas although women did not identify distance from a provider as a barrier to health care, and displacement of facility careseeking by iCCM careseeking. This suggests that targeting iCCM solely based on geographic barriers may need to be reconsidered. © The American Society of Tropical Medicine and Hygiene.

Leisure-time running reduces all-cause and cardiovascular mortality risk.

PubMed

Lee, Duck-Chul; Pate, Russell R; Lavie, Carl J; Sui, Xuemei; Church, Timothy S; Blair, Steven N

2014-08-05

Although running is a popular leisure-time physical activity, little is known about the long-term effects of running on mortality. The dose-response relations between running, as well as the change in running behaviors over time, and mortality remain uncertain. We examined the associations of running with all-cause and cardiovascular mortality risks in 55,137 adults, 18 to 100 years of age (mean age 44 years). Running was assessed on a medical history questionnaire by leisure-time activity. During a mean follow-up of 15 years, 3,413 all-cause and 1,217 cardiovascular deaths occurred. Approximately 24% of adults participated in running in this population. Compared with nonrunners, runners had 30% and 45% lower adjusted risks of all-cause and cardiovascular mortality, respectively, with a 3-year life expectancy benefit. In dose-response analyses, the mortality benefits in runners were similar across quintiles of running time, distance, frequency, amount, and speed, compared with nonrunners. Weekly running even <51 min, <6 miles, 1 to 2 times, <506 metabolic equivalent-minutes, or <6 miles/h was sufficient to reduce risk of mortality, compared with not running. In the analyses of change in running behaviors and mortality, persistent runners had the most significant benefits, with 29% and 50% lower risks of all-cause and cardiovascular mortality, respectively, compared with never-runners. Running, even 5 to 10 min/day and at slow speeds <6 miles/h, is associated with markedly reduced risks of death from all causes and cardiovascular disease. This study may motivate healthy but sedentary individuals to begin and continue running for substantial and attainable mortality benefits. Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Leisure-Time Running Reduces All-Cause and Cardiovascular Mortality Risk

PubMed Central

Lee, Duck-chul; Pate, Russell R.; Lavie, Carl J.; Sui, Xuemei; Church, Timothy S.; Blair, Steven N.

2014-01-01

Background Although running is a popular leisure-time physical activity, little is known about the long-term effects of running on mortality. The dose-response relations between running, as well as the change in running behaviors over time and mortality remain uncertain. Objectives We examined the associations of running with all-cause and cardiovascular mortality risks in 55,137 adults, aged 18 to 100 years (mean age, 44). Methods Running was assessed on the medical history questionnaire by leisure-time activity. Results During a mean follow-up of 15 years, 3,413 all-cause and 1,217 cardiovascular deaths occurred. Approximately, 24% of adults participated in running in this population. Compared with non-runners, runners had 30% and 45% lower adjusted risks of all-cause and cardiovascular mortality, respectively, with a 3-year life expectancy benefit. In dose-response analyses, the mortality benefits in runners were similar across quintiles of running time, distance, frequency, amount, and speed, compared with non-runners. Weekly running even <51 minutes, <6 miles, 1-2 times, <506 metabolic equivalent-minutes, or <6 mph was sufficient to reduce risk of mortality, compared with not running. In the analyses of change in running behaviors and mortality, persistent runners had the most significant benefits with 29% and 50% lower risks of all-cause and cardiovascular mortality, respectively, compared with never-runners. Conclusions Running, even 5-10 minutes per day and slow speeds <6 mph, is associated with markedly reduced risks of death from all causes and cardiovascular disease. This study may motivate healthy but sedentary individuals to begin and continue running for substantial and attainable mortality benefits. PMID:25082581

Occupational exposure to ionising radiation and mortality among workers of the former Spanish Nuclear Energy Board.

PubMed Central

Rodríguez Artalejo, F; Castaño Lara, S; de Andrés Manzano, B; García Ferruelo, M; Iglesias Martín, L; Calero, J R

1997-01-01

OBJECTIVES: Firstly, to ascertain whether mortality among workers of the former Spanish Nuclear Energy Board (Junta de Energía Nuclear-JEN) was higher than that for the Spanish population overall; and secondly, if this were so, to ascertain whether this difference was associated with exposure to ionising radiation. METHODS: A retrospective follow up of a cohort of 5657 workers was carried out for the period 1954-92. Cohort mortality was compared with that for the Spanish population overall, with standardised mortality ratios (SMRs) adjusted for sex, age, and calendar period. Also, Poisson models were used to analyse mortality from lung cancer in the cohort by level of exposure to ionising radiation. RESULTS: Workers' median and mean cumulative exposures were 4.04 and 11.42 mSv, respectively. Mean annual exposure was 1.33 mSv. Excess mortality due to bone tumours was found for the cohort as a whole (six deaths observed; SMR 2.95; 95% confidence interval (95% CI) 1.08 to 6.43). Among miners, excess mortality was found for non-malignant respiratory diseases (SMR 2.94; 95% CI 2.27 to 3.75), and for lung cancer bordering on statistical significance (SMR 1.50; 95% CI 0.96 to 2.23; P = 0.055). Relative risks of dying of lung cancer from ionising radiation in the dose quartiles 2, 3, and 4 versus the lowest dose quartile, were 1.00, 1.64, and 0.94, respectively. CONCLUSIONS: Excess mortality from lung cancer was found among JEN miners. Nevertheless, no clear relation was found between mortality from lung cancer and level of exposure to ionising radiation in the JEN cohort. Continued follow up of the cohort is required to confirm excess mortality from bone tumours. PMID:9155782

Occupational exposure to ionising radiation and mortality among workers of the former Spanish Nuclear Energy Board.

PubMed

Rodríguez Artalejo, F; Castaño Lara, S; de Andrés Manzano, B; García Ferruelo, M; Iglesias Martín, L; Calero, J R

1997-03-01

Firstly, to ascertain whether mortality among workers of the former Spanish Nuclear Energy Board (Junta de Energía Nuclear-JEN) was higher than that for the Spanish population overall; and secondly, if this were so, to ascertain whether this difference was associated with exposure to ionising radiation. A retrospective follow up of a cohort of 5657 workers was carried out for the period 1954-92. Cohort mortality was compared with that for the Spanish population overall, with standardised mortality ratios (SMRs) adjusted for sex, age, and calendar period. Also, Poisson models were used to analyse mortality from lung cancer in the cohort by level of exposure to ionising radiation. Workers' median and mean cumulative exposures were 4.04 and 11.42 mSv, respectively. Mean annual exposure was 1.33 mSv. Excess mortality due to bone tumours was found for the cohort as a whole (six deaths observed; SMR 2.95; 95% confidence interval (95% CI) 1.08 to 6.43). Among miners, excess mortality was found for non-malignant respiratory diseases (SMR 2.94; 95% CI 2.27 to 3.75), and for lung cancer bordering on statistical significance (SMR 1.50; 95% CI 0.96 to 2.23; P = 0.055). Relative risks of dying of lung cancer from ionising radiation in the dose quartiles 2, 3, and 4 versus the lowest dose quartile, were 1.00, 1.64, and 0.94, respectively. Excess mortality from lung cancer was found among JEN miners. Nevertheless, no clear relation was found between mortality from lung cancer and level of exposure to ionising radiation in the JEN cohort. Continued follow up of the cohort is required to confirm excess mortality from bone tumours.

Association of Placebo, Indomethacin, Ibuprofen, and Acetaminophen With Closure of Hemodynamically Significant Patent Ductus Arteriosus in Preterm Infants: A Systematic Review and Meta-analysis.

PubMed

Mitra, Souvik; Florez, Ivan D; Tamayo, Maria E; Mbuagbaw, Lawrence; Vanniyasingam, Thuva; Veroniki, Areti Angeliki; Zea, Adriana M; Zhang, Yuan; Sadeghirad, Behnam; Thabane, Lehana

2018-03-27

Despite increasing emphasis on conservative management of patent ductus arteriosus (PDA) in preterm infants, different pharmacotherapeutic interventions are used to treat those developing a hemodynamically significant PDA. To estimate the relative likelihood of hemodynamically significant PDA closure with common pharmacotherapeutic interventions and to compare adverse event rates. The databases of MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched from inception until August 15, 2015, and updated on December 31, 2017, along with conference proceedings up to December 2017. Randomized clinical trials that enrolled preterm infants with a gestational age younger than 37 weeks treated with intravenous or oral indomethacin, ibuprofen, or acetaminophen vs each other, placebo, or no treatment for a clinically or echocardiographically diagnosed hemodynamically significant PDA. Data were independently extracted in pairs by 6 reviewers and synthesized with Bayesian random-effects network meta-analyses. Primary outcome: hemodynamically significant PDA closure; secondary: included surgical closure, mortality, necrotizing enterocolitis, and intraventricular hemorrhage. In 68 randomized clinical trials of 4802 infants, 14 different variations of indomethacin, ibuprofen, or acetaminophen were used as treatment modalities. The overall PDA closure rate was 67.4% (2867 of 4256 infants). A high dose of oral ibuprofen was associated with a significantly higher odds of PDA closure vs a standard dose of intravenous ibuprofen (odds ratio [OR], 3.59; 95% credible interval [CrI], 1.64-8.17; absolute risk difference, 199 [95% CrI, 95-258] more per 1000 infants) and a standard dose of intravenous indomethacin (OR, 2.35 [95% CrI, 1.08-5.31]; absolute risk difference, 124 [95% CrI, 14-188] more per 1000 infants). Based on the ranking statistics, a high dose of oral ibuprofen ranked as the best pharmacotherapeutic option for PDA closure (mean surface under the cumulative ranking [SUCRA] curve, 0.89 [SD, 0.12]) and to prevent surgical PDA ligation (mean SUCRA, 0.98 [SD, 0.08]). There was no significant difference in the odds of mortality, necrotizing enterocolitis, or intraventricular hemorrhage with use of placebo or no treatment compared with any of the other treatment modalities. A high dose of oral ibuprofen was associated with a higher likelihood of hemodynamically significant PDA closure vs standard doses of intravenous ibuprofen or intravenous indomethacin; placebo or no treatment did not significantly change the likelihood of mortality, necrotizing enterocolitis, or intraventricular hemorrhage. PROSPERO Identifier: CRD42015015797.

Dose-response association of moderate-to-vigorous physical activity with cardiovascular biomarkers and all-cause mortality: Considerations by individual sports, exercise and recreational physical activities.

PubMed

Loprinzi, Paul D

2015-12-01

Previous research demonstrates that moderate-to-vigorous physical activity (MVPA) is associated with reduced all-cause mortality risk. Our understanding of whether individual physical activities are associated with all-cause mortality is less understood. Data from the 1999-2006 NHANES were employed, with follow-up through 2011. 48 different individual physical activities (e.g., swimming, running, bicycling) were assessed, and total MVPA MET-min-month was calculated based on their responses to these 48 individual physical activities. Greater engagement in MVPA was associated with more favorable cardiovascular biomarkers, particularly for men. Even after adjustment for total MVPA, different individual physical activities were associated with cardiovascular biomarkers across gender. When compared to those not meeting guidelines (0-1999 MVPA MET-min-month), a dose-response association between MVPA and mortality was observed, with those engaging in 5 times the guideline level having the lowest risk of all-cause mortality (45% reduced risk). There was no evidence of a harmful effect of very high MVPA (e.g., 20,000+ MVPA MET-min-month). Engaging in MVPA even below the minimum recommendation was associated with survival benefits, and the greatest survival effects occurred at a dose of approximately 5 times the minimum recommendation. Although very high levels (e.g., 10 times the minimum recommendation) of self-reported MVPA did not demonstrate the greatest survival effects, high levels of physical activity did not appear to have harmful effects. Copyright © 2015 Elsevier Inc. All rights reserved.

Lipotropes Protect against Pathogen-Aggravated Stress and Mortality in Low Dose Pesticide-Exposed Fish

PubMed Central

Kumar, Neeraj; Gupta, Subodh; Chandan, Nitish Kumar; Aklakur, Md.; Pal, Asim Kumar; Jadhao, Sanjay Balkrishna

2014-01-01

The decline of freshwater fish biodiversity corroborates the trends of unsustainable pesticide usage and increase of disease incidence in the last few decades. Little is known about the role of nonlethal exposure to pesticide, which is not uncommon, and concurrent infection of opportunistic pathogens in species decline. Moreover, preventative measures based on current knowledge of stress biology and an emerging role for epigenetic (especially methylation) dysregulation in toxicity in fish are lacking. We herein report the protective role of lipotropes/methyl donors (like choline, betaine and lecithin) in eliciting primary (endocrine), secondary (cellular and hemato-immunological and histoarchitectural changes) and tertiary (whole animal) stress responses including mortality (50%) in pesticide-exposed (nonlethal dose) and pathogen-challenged fish. The relative survival with betaine and lecithin was 10 and 20 percent higher. This proof of cause-and-effect relation and physiological basis under simulated controlled conditions indicate that sustained stress even due to nonlethal exposure to single pollutant enhances pathogenic infectivity in already nutritionally-stressed fish, which may be a driver for freshwater aquatic species decline in nature. Dietary lipotropes can be used as one of the tools in resurrecting the aquatic species decline. PMID:24690771

Acute kidney injury after primary angioplasty: effect of different hydration treatments.

PubMed

Manari, Antonio; Magnavacchi, Paolo; Puggioni, Enrico; Vignali, Luigi; Fiaccadori, Enrico; Menozzi, Mila; Tondi, Stefano; Robotti, Stefano; Ferrari, Duilio; Valgimigli, Marco

2014-01-01

We evaluated the effect of different dose hydration protocols, with normal saline or bicarbonate, on the incidence of contrast-induced acute kidney injury (CI-AKI) in patients with ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PPCI). We considered 592 STEMI patients treated with PPCI in 5 Italian centers. Patients were randomized to receive standard or high-dose infusions of normal saline or sodium bicarbonate started immediately before contrast medium administration and continued for the following 12 h. The cumulative incidence of CI-AKI was 18.1% without any difference among treatment groups. Shock, age, ejection fraction 35% or less, and basal serum creatinine were significantly associated with an increased risk of CI-AKI. Follow-up at 12 months was complete in 573 patients. Overall, 25 out of 573 patients died (4.3%). We observed higher short-term mortality rates in patients receiving high-volume hydration. Otherwise, only age, shock and CI-AKI were significantly associated with 1-year mortality. In patients with STEMI undergoing PPCI, high-volume hydration with normal saline or sodium bicarbonate administrated at the time of contrast media administration was not associated with any significant advantage in terms of CI-AKI prevention.

Lipotropes protect against pathogen-aggravated stress and mortality in low dose pesticide-exposed fish.

PubMed

Kumar, Neeraj; Gupta, Subodh; Chandan, Nitish Kumar; Aklakur, Md; Pal, Asim Kumar; Jadhao, Sanjay Balkrishna

2014-01-01

The decline of freshwater fish biodiversity corroborates the trends of unsustainable pesticide usage and increase of disease incidence in the last few decades. Little is known about the role of nonlethal exposure to pesticide, which is not uncommon, and concurrent infection of opportunistic pathogens in species decline. Moreover, preventative measures based on current knowledge of stress biology and an emerging role for epigenetic (especially methylation) dysregulation in toxicity in fish are lacking. We herein report the protective role of lipotropes/methyl donors (like choline, betaine and lecithin) in eliciting primary (endocrine), secondary (cellular and hemato-immunological and histoarchitectural changes) and tertiary (whole animal) stress responses including mortality (50%) in pesticide-exposed (nonlethal dose) and pathogen-challenged fish. The relative survival with betaine and lecithin was 10 and 20 percent higher. This proof of cause-and-effect relation and physiological basis under simulated controlled conditions indicate that sustained stress even due to nonlethal exposure to single pollutant enhances pathogenic infectivity in already nutritionally-stressed fish, which may be a driver for freshwater aquatic species decline in nature. Dietary lipotropes can be used as one of the tools in resurrecting the aquatic species decline.

Analyses of Radiation and Mesothelioma in the US Transuranium and Uranium Registries

PubMed Central

Fulcher, Keri; Nagarajan, Sumitha; McCord, Stacey; Fallahian, Naz Afarin; Hoffman, Heather J.; Haver, Cary; Tolmachev, Sergei

2013-01-01

Objectives. We examined the relationship between radiation and excess deaths from mesothelioma among deceased nuclear workers who were part of the US Transuranium and Uranium Registries. Methods. We performed univariate analysis with SAS Version 9.1 software. We conducted proportionate mortality ratio (PMR) and proportionate cancer mortality ratio (PCMR) analyses using the National Institute for Occupational Safety and Health Life Table Analysis System with the referent group being all deaths in the United States. Results. We found a PMR of 62.40 (P < .05) and a PCMR of 46.92 (P < .05) for mesothelioma. PMRs for the 4 cumulative external radiation dose quartiles were 61.83, 57.43, 74.46, and 83.31. PCMRs were 36.16, 47.07, 51.35, and 67.73. The PMR and PCMR for trachea, bronchus, and lung cancer were not significantly elevated. Conclusions. The relationship between cumulative external radiation dose and the PMR and PCMR for mesothelioma suggests that external radiation at nuclear facilities is associated with an increased risk of mesothelioma. The lack of a significantly elevated PMR and PCMR for trachea, bronchus, and lung cancer suggests that asbestos did not confound this relationship. PMID:23409888

The prognostic value of irradiated lung volumes on the prediction of intra-/ post-operative mortality in patients after neoadjuvant radiochemotherapy for esophageal cancer. A retrospective multicenter study.

PubMed

Kup, Philipp Günther; Nieder, Carsten; Geinitz, Hans; Henkenberens, Christoph; Besserer, Angela; Oechsner, Markus; Schill, Sabine; Mücke, Ralph; Scherer, Vera; Combs, Stephanie E; Adamietz, Irenäus A; Fakhrian, Khashayar

2015-01-01

To assess the association between dosimetric factors of the lung and incidence of intra- and postoperative mortality among esophageal cancer (EC) patients treated with neoadjuvant radiochemotherapy (N-RCT) followed by surgery (S). Inclusion criteria were: age < 85 years, no distant metastases at the time of diagnosis, no induction chemotherapy, conformal radiotherapy, total dose ≤ 50.4 Gy, and available dose volume histogram (DVH) data. One-hundred thirty-five patients met our inclusion criteria. Median age was 62 years. N-RCT consisted of 36 - 50.4 Gy (median 45 Gy), 1.8 - 2 Gy per fraction. Concomitant chemotherapy consisted of 5-Fluoruracil (5-FU) and cisplatin in 113 patients and cisplatin and taxan-derivates in 15 patients. Seven patients received a single cytotoxic agent. In 130 patients an abdominothoracal and in 5 patients a transhiatal resection was performed. The following dosimetric parameters were generated from the total lung DVH: mean dose, V5, V10, V15, V20, V30, V40, V45 and V50. The primary endpoint was the rate of intra- and postoperative mortality (from the start of N-RCT to 60 days after surgical resection). A total of ten postoperative deaths (7%) were observed: 3 within 30 days (2%) and 7 between 30 and 60 days after surgical intervention (5%); no patient died during the operation. In the univariate analysis, weight loss (≥10% in 6 months prior to diagnosis, risk ratio: 1.60, 95%CI: 0.856-2.992, p=0.043), Eastern Cooperative Oncology Group-performance status (ECOG 2 vs. 1, risk ratio: 1.931, 95%CI: 0.898-4.150, p=0.018) and postoperative pulmonary plus non-pulmonary complications (risk ratio: 2.533, 95%CI: 0.978-6.563, p=0.004) were significantly associated with postoperative mortality. There was no significant association between postoperative mortality and irradiated lung volumes. Lung V45 was the only variable which was significantly associated with higher incidence of postoperative pulmonary plus non-pulmonary complications (Exp(B): 1.285, 95%CI 1.029-1.606, p=0.027), but not with the postoperative pulmonary complications (Exp(B): 1.249, 95%CI 0.999-1.561, p=0.051). Irradiated lung volumes did not show relevant associations with intra- and postoperative mortality of patients treated with moderate dose (36 - 50.4 Gy) conventionally fractionated conformal radiotherapy combined with widely used radiosensitizers. Postoperative mortality was significantly associated with greater weight loss, poor performance status and development of postoperative complications, but not with treatment-related factors. Limiting the volume of lung receiving higher radiation doses appears prudent because of the observed association with risk of postoperative complications.

Infusional β-lactam antibiotics in febrile neutropenia: has the time come?

PubMed

Abbott, Iain J; Roberts, Jason A

2012-12-01

Febrile neutropenia presents a clinical challenge in which timely and appropriate antibiotic exposure is crucial. In the context of altered pharmacokinetics and rising bacterial resistance, standard antibiotic doses are unlikely to be sufficient. This review explores the potential utility of altered dosing approaches of β-lactam antibiotics to optimize treatment in febrile neutropenia. There is a dynamic relationship between the antibiotic, the infecting pathogen, and the host. Great advancements have been made in the understanding of the pharmacokinetic changes in critical illness and the pharmacodynamic relationships of antibiotics in these settings. Antibiotic treatment in febrile neutropenia is becoming increasingly difficult. Patients are of higher acuity, receive more intensive chemotherapy regimens leading to prolonged neutropenia, and are often exposed to multiple antibiotic courses. These patients display significant variability in antibiotic clearances and increases in volume of distribution compared with standard ward-based patients. Rising antibiotic resistance and a lack of new antibiotics in production have prompted alternative dosing strategies based on pharmacokinetic/pharmacodynamic data, such as extended or continuous infusions of β-lactam antibiotics, to maximize the likelihood of treatment success. A definitive study that describes a mortality benefit of such dosing regimens remains elusive and the theoretical advantages require testing in well designed clinical trials.

Radiation arteriopathy in the transgenic arteriovenous fistula model.

PubMed

Lawton, Michael T; Arnold, Christine M; Kim, Yung J; Bogarin, Ernesto A; Stewart, Campbell L; Wulfstat, Amanda A; Derugin, Nikita; Deen, Dennis; Young, William L

2008-05-01

The transgenic arteriovenous fistula model, surgically constructed with transgenic mouse aorta interposed in common carotid artery-to-external jugular vein fistulae in nude rats, has a 4-month experimental window because patency and transgenic phenotype are lost over time. We adapted this model to investigate occlusive arteriopathy in brain arteriovenous malformations after radiosurgery by radiating grafted aorta before insertion in the fistula. We hypothesized that high-dose radiation would reproduce the arteriopathy observed clinically within the experimental time window and that deletions of endoglin (ENG) and endothelial nitric oxide synthase (eNOS) genes would modify the radiation response. Radiation arteriopathy in the common carotid arteries of 171 wild-type mice was examined with doses of 25, 80, 120, or 200 Gy (Experiment 1). Radiation arteriopathy in 68 wild-type arteriovenous fistulae was examined histologically and morphometrically with preoperative radiation doses of 0, 25, or 200 Gy (Experiment 2). Radiation arteriopathy in 51 transgenic arteriovenous fistulae (36 ENG and 15 eNOS knock-out fistulae) was examined using preoperative radiation doses of 0, 25, or 200 Gy (Experiment 3). High-dose radiation (200 Gy) of mouse common carotid arteries induced only mild arteriopathy (mean score, 0.66) without intimal hyperplasia and with high mortality (68%). Radiation arteriopathy in wild-type arteriovenous fistulae was severe (mean score, 3.5 at 200 Gy), with intimal hyperplasia and medial disruption at 3 months, decreasing luminal areas with increasing dose, and no mortality. Arteriopathy was robust in transgenic arteriovenous fistulae with ENG +/- and with eNOS +/-, with thick intimal hyperplasia in the former and distinct smooth muscle cell proliferation in the latter. The transgenic arteriovenous fistula model can be adapted to rapidly reproduce radiation arteriopathy observed in resected brain arteriovenous malformations after radiosurgery. High radiation doses accelerate the progression of arteriopathy to fit the 4-month time limitation of the model, allowing transgenic tissues to retain their phenotypes throughout the experimental window. Modified radiation responses in ENG and eNOS knock-out fistulae indicate that arteriopathy after arteriovenous malformation radiosurgery might potentially be enhanced by altered gene expression.

In vitro tests to establish LC50 and discriminating concentrations for fipronil against Rhipicephalus (Boophilus) microplus (Acari: Ixodidae) and their standardization.

PubMed

Castro-Janer, E; Rifran, L; Piaggio, J; Gil, A; Miller, R J; Schumaker, T T S

2009-05-26

Laboratory test was carried out on larvae and adults of the cattle tick, Rhipicephalus (Boophilus) microplus, to determine fipronil toxicity. Adult immersion test (AIT, N=26), larval immersion test (LIT, N=71) and larval packet test (LPT, N=41) were standardized using susceptible strain (Mozo). Dose-response curves were compared with a fipronil resistant strain. Four variables were analyzed from AIT results: mortality, weight of eggs on day 7 and on day 14, index of fertility, and index of fecundity. For larval test, dose mortality curves were analyzed. In spite of the high LC(50) variability, all variables determined for AIT were appropriate to discriminate both strains. AIT and LIT had more sensitivity than LPT, with larger resistance factors. It was used two times LC(99.9) as discriminating doses (DCs) following FAO suggestion. For mortality by AIT, LIT and LPT the DCs were estimated: 4.98ppm, 7.64ppm and 2365.8ppm, respectively, for Mozo strain. DCs mortality values estimated for resistant strain by AIT, LIT and LPT were: 6.96x10(5)ppm, 343.26ppm and 5.7x10(3)ppm, respectively and their respective resistant factors were: 202.4, 5.36 and 1.52. Protocols for AIT, LIT and LPT have been presented in this paper.

Systemic SMAD7 Gene Therapy Increases Striated Muscle Mass and Enhances Exercise Capacity in a Dose-Dependent Manner.

PubMed

Maricelli, Joseph W; Bishaw, Yemeserach M; Wang, Bo; Du, Min; Rodgers, Buel D

2018-03-01

Striated muscle wasting occurs with a variety of disease indications, contributing to mortality and compromising life quality. Recent studies indicate that the recombinant adeno-associated virus (serotype 6) Smad7 gene therapeutic, AVGN7, enhances skeletal and cardiac muscle mass and prevents cancer-induced wasting of both tissues. This is accomplished by attenuating ActRIIb intracellular signaling and, as a result, the physiological actions of myostatin and other ActRIIb ligands. AVGN7 also enhances isolated skeletal muscle twitch force, but is unknown to improve systemic muscle function similarly, especially exercise capacity. A 2-month-long dose-escalation study was therefore conducted using 5 × 10 11 , 1 × 10 12 , and 5 × 10 12 vg/mouse and different tests of systemic muscle function. Body mass, skeletal muscle mass, heart mass, and forelimb grip strength were all increased in a dose-dependent manner, as was the fiber cross-sectional area of tibialis anterior muscles. Maximal oxygen consumption (VO 2 max), a measure of metabolic rate, was similarly enhanced during forced treadmill running, and although the total distance traveled was only elevated by the highest dose, all doses reduced the energy expenditure rate compared to control mice injected with an empty vector. Such improvements in VO 2 max are consistent with physiological cardiac hypertrophy, which is highly beneficial and a normal adaptive response to exercise. This was particularly evident at the lowest dose tested, which had minimal significant effects on skeletal muscle mass and/or function, but increased heart weight and exercise capacity. These results together suggest that AVGN7 enhances striated muscle mass and systemic muscle function. They also define minimally effective and optimal doses for future preclinical trials and toxicology studies and in turn will aid in establishing dose ranges for clinical trials.

Differential antagonism of tetramethylenedisulfotetramine-induced seizures by agents acting at NMDA and GABAA receptors

PubMed Central

Shakarjian, Michael P.; Velíšková, Jana; Stanton, Patric K.; Velíšek, Libor

2012-01-01

Tetramethylenedisulfotetramine (TMDT) is a highly lethal neuroactive rodenticide responsible for many accidental and intentional poisonings in mainland China. Ease of synthesis, water solubility, potency, and difficulty to treat make TMDT a potential weapon for terrorist activity. We characterized TMDT-induced convulsions and mortality in male C57BL/6 mice. TMDT (ip) produced a continuum of twitches, clonic, and tonic-clonic seizures decreasing in onset latency and increasing in severity with increasing dose; 0.4 mg/kg was 100% lethal. The NMDA antagonist, ketamine (35 mg/kg) injected ip immediately after the first TMDT-induced seizure, did not change number of tonic-clonic seizures or lethality, but increased the number of clonic seizures. Doubling the ketamine dose decreased tonic-clonic seizures and eliminated lethality through a 60 min observation period. Treating mice with another NMDA antagonist, MK-801, 0.5 or 1 mg/kg ip, showed similar effects as low and high doses of ketamine, respectively, and prevented lethality, converting status epilepticus EEG activity to isolated interictal discharges. Treatment with these agents 15 min prior to TMDT administration did not increase their effectiveness. Post-treatment with the GABAA receptor allosteric enhancer diazepam (5 mg/kg) greatly reduced seizure manifestations and prevented lethality 60 min post-TMDT, but ictal events were evident in EEG recordings and, hours post-treatment, mice experienced status epilepticus and died. Thus, TMDT is a highly potent and lethal convulsant for which single-dose benzodiazepine treatment is inadequate in managing electrographic seizures or lethality. Repeated benzodiazepine dosing or combined application of benzodiazepines and NMDA receptor antagonists are more likely to be effective in treating TMDT poisoning. PMID:23022509

Arsenic levels in drinking water and mortality of liver cancer in Taiwan.

PubMed

Lin, Hung-Jung; Sung, Tzu-I; Chen, Chi-Yi; Guo, How-Ran

2013-11-15

The carcinogenic effect of arsenic is well documented, but epidemiologic data on liver cancer were limited. To evaluate the dose-response relationship between arsenic in drinking water and mortality of liver cancer, we conducted a study in 138 villages in the southwest coast area of Taiwan. We assessed arsenic levels in drinking water using data from a survey conducted by the government and reviewed death certificates from 1971 to 1990 to identify liver cancer cases. Using village as the unit, we conducted multi-variate regression analyses and then performed post hoc analyses to validate the findings. During the 20-year period, 802 male and 301 female mortality cases of liver cancer were identified. After adjusting for age, arsenic levels above 0.64 mg/L were associated with an increase in the liver cancer mortality in both genders, but no significant effect was observed for lower exposure categories. Post hoc analyses and a review of literature supported these findings. We concluded that exposures to high arsenic levels in drinking water are associated with the occurrence of liver cancer, but such an effect is not prominent at exposure levels lower than 0.64 mg/L. Copyright © 2013 Elsevier B.V. All rights reserved.

Fruit and vegetable intake and the risk of cardiovascular disease, total cancer and all-cause mortality—a systematic review and dose-response meta-analysis of prospective studies

PubMed Central

Aune, Dagfinn; Giovannucci, Edward; Boffetta, Paolo; Fadnes, Lars T; Keum, NaNa; Norat, Teresa; Greenwood, Darren C; Riboli, Elio; Vatten, Lars J; Tonstad, Serena

2017-01-01

Abstract Background: Questions remain about the strength and shape of the dose-response relationship between fruit and vegetable intake and risk of cardiovascular disease, cancer and mortality, and the effects of specific types of fruit and vegetables. We conducted a systematic review and meta-analysis to clarify these associations. Methods: PubMed and Embase were searched up to 29 September 2016. Prospective studies of fruit and vegetable intake and cardiovascular disease, total cancer and all-cause mortality were included. Summary relative risks (RRs) were calculated using a random effects model, and the mortality burden globally was estimated; 95 studies (142 publications) were included. Results: For fruits and vegetables combined, the summary RR per 200 g/day was 0.92 [95% confidence interval (CI): 0.90–0.94, I2 = 0%, n = 15] for coronary heart disease, 0.84 (95% CI: 0.76–0.92, I2 = 73%, n = 10) for stroke, 0.92 (95% CI: 0.90–0.95, I2 = 31%, n = 13) for cardiovascular disease, 0.97 (95% CI: 0.95–0.99, I2 = 49%, n = 12) for total cancer and 0.90 (95% CI: 0.87–0.93, I2 = 83%, n = 15) for all-cause mortality. Similar associations were observed for fruits and vegetables separately. Reductions in risk were observed up to 800 g/day for all outcomes except cancer (600 g/day). Inverse associations were observed between the intake of apples and pears, citrus fruits, green leafy vegetables, cruciferous vegetables, and salads and cardiovascular disease and all-cause mortality, and between the intake of green-yellow vegetables and cruciferous vegetables and total cancer risk. An estimated 5.6 and 7.8 million premature deaths worldwide in 2013 may be attributable to a fruit and vegetable intake below 500 and 800 g/day, respectively, if the observed associations are causal. Conclusions: Fruit and vegetable intakes were associated with reduced risk of cardiovascular disease, cancer and all-cause mortality. These results support public health recommendations to increase fruit and vegetable intake for the prevention of cardiovascular disease, cancer, and premature mortality. PMID:28338764

Clinical outcomes and cost minimization with an alternative dosing regimen for meropenem in a community hospital.

PubMed

Patel, Gita Wasan; Duquaine, Susan M; McKinnon, Peggy S

2007-12-01

To compare outcomes and cost for the traditional United States Food and Drug Administration-approved dosing regimen for meropenem versus an alternative dosing regimen providing similar pharmacodynamic exposure with a lower total daily dose. Retrospective cohort study with a cost-minimization analysis. A 417-bed, privately owned community hospital. One hundred patients who received meropenem 1 g every 8 or 12 hours (traditional dosing regimen) between January 1 and September 30, 2004 (historical controls), and 192 patients who received meropenem 500 mg every 6 or 8 hours (alternative dosing regimen) between October 1, 2004, and September 30, 2005. Demographic and clinical data were collected for all patients. Cost-minimization analysis was performed by using the drug acquisition cost for meropenem. Demographics, sources of infection, distributions of organisms, and Charlson Comorbidity Index scores were similar between patients in the traditionally and alternatively dosed groups. Concomitant therapy, duration of therapy, success rates, lengths of stay, and in-hospital mortality rates were also similar between groups. Median time to the resolution of symptoms was 3 days for traditional dosing and 1.5 days for alternative dosing (p<0.0001). A logistic regression model including the dosing strategy showed that only polymicrobial infections and sepsis were associated with increased failure rates. The median cost for antibiotics was $439.05/patient for traditional dosing and $234.08/patient for alternative dosing (p<0.0001). An alternative dosing regimen for meropenem with a lower total daily dose yielded patient outcomes, including success rates and duration of therapy, equivalent to those of the traditional dosing regimen. Alternative dosing decreased total drug exposure, costs for antibiotics, and time to the resolution of infections.