Protective effects of chlorogenic acid in 3-nitropropionic acid induced toxicity and genotoxicity.

PubMed

Alarcón-Herrera, Norberto; Flores-Maya, Saúl; Bellido, Belén; García-Bores, Ana M; Mendoza, Ernesto; Ávila-Acevedo, Guillermo; Hernández-Echeagaray, Elizabeth

2017-11-01

Mitochondrial inhibition with the toxin 3-Nitropropionic acid (3-NP) has been used to study the underlying mechanisms in striatal neurodegeneration, but few experiments have evaluated its toxicity and genotoxicity of in vivo administration. Furthermore, different antioxidant molecules may prevent degeneration induced by the toxic effects of 3-NP. Therefore, the purpose of this study was to evaluate the toxicity and genotoxicity induced by 3-NP (15 mg/kg) in the micronuclei assay method; also, we assessed chlorogenic acid (CGA, 100 mg/kg) for its anti-toxic and anti-genotoxic effect in damage produced by in vivo treatment with 3-NP. 3-NP induced toxicity and genotoxicity. CGA administered as a co-treatment with 3-NP (3-NP + CA) reduced toxicity by 32.76%, as a pre-treatment for 5 days only, followed by 3-NP treatment (P/CA, 3-NP) inhibiting toxicity by 24.04%, or as a pre-treatment, plus a co-treatment with 3-NP (P/CA, 3-NP + CA) avoided any toxic effect. CGA alone did not exhibit any toxic effect. Only P/CGA, 3-NP + CGA group, avoided toxicity and genotoxicity, suggesting that CGA could be suitable to prevent, reduce or delay toxicity and cell death. Copyright © 2017 Elsevier Ltd. All rights reserved.

40 CFR 797.1950 - Mysid shrimp chronic toxicity test.

Code of Federal Regulations, 2011 CFR

2011-07-01

... control and treatment groups. This time cannot be specified because of possible delays in sexual... control groups; PCONTROL ACT (CONTINUED) ENVIRONMENTAL EFFECTS TESTING GUIDELINES Aquatic Guidelines § 797.1950...

40 CFR 797.1950 - Mysid shrimp chronic toxicity test.

Code of Federal Regulations, 2012 CFR

2012-07-01

... control and treatment groups. This time cannot be specified because of possible delays in sexual... control groups; PCONTROL ACT (CONTINUED) ENVIRONMENTAL EFFECTS TESTING GUIDELINES Aquatic Guidelines § 797.1950...

40 CFR 797.1950 - Mysid shrimp chronic toxicity test.

Code of Federal Regulations, 2013 CFR

2013-07-01

... control and treatment groups. This time cannot be specified because of possible delays in sexual... control groups; PCONTROL ACT (CONTINUED) ENVIRONMENTAL EFFECTS TESTING GUIDELINES Aquatic Guidelines § 797.1950...

40 CFR 797.1950 - Mysid shrimp chronic toxicity test.

Code of Federal Regulations, 2014 CFR

2014-07-01

... control and treatment groups. This time cannot be specified because of possible delays in sexual... control groups; PCONTROL ACT (CONTINUED) ENVIRONMENTAL EFFECTS TESTING GUIDELINES Aquatic Guidelines § 797.1950...

Epigenetic perturbations in the pathogenesis of mustard toxicity; hypothesis and preliminary results

PubMed Central

Korkmaz, Ahmet; Yaren, Hakan; Kunak, Z. Ilker; Uysal, Bulent; Kurt, Bulent; Topal, Turgut; Kenar, Levent; Ucar, Ergun; Oter, Sukru

2008-01-01

Among the most readily available chemical warfare agents, sulfur mustard (SM), also known as mustard gas, has been the most widely used chemical weapon. SM causes debilitating effects that can leave an exposed individual incapacitated for days to months; therefore delayed SM toxicity is of much greater importance than its ability to cause lethality. Although not fully understood, acute toxicity of SM is related to reactive oxygen and nitrogen species, oxidative stress, DNA damage, poly(ADP-ribose) polymerase (PARP) activation and energy depletion within the affected cell. Therefore several antioxidants and PARP inhibitors show beneficial effects against acute SM toxicity. The delayed toxicity of SM however, currently has no clear mechanistic explanation. One third of the 100,000 Iranian casualties are still suffering from the detrimental effects of SM in spite of the extensive treatment. We, therefore, made an attempt whether epigenetic aberrations may contribute to pathogenesis of mustard poisoning. Preliminary evidence reveals that mechlorethamine (a nitrogen mustard derivative) exposure may not only cause oxidative stress, DNA damage, but epigenetic perturbations as well. Epigenetic refers to the study of changes that influence the phenotype without causing alteration of the genotype. It involves changes in the properties of a cell that are inherited but do not involve a change in DNA sequence. It is now known that in addition to mutations, epimutations contribute to a variety of human diseases. Under light of preliminary results, the current hypothesis will focus on epigenetic regulations to clarify mustard toxicity and the use of drugs to correct possible epigenetic defects. PMID:21218122

Differential cardiotoxicity in response to chronic doxorubicin treatment in male spontaneous hypertension-heart failure (SHHF), spontaneously hypertensive (SHR), and Wistar Kyoto (WKY) rats

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

Sharkey, Leslie C., E-mail: shark009@umn.edu; Radin, M. Judith, E-mail: radin.1@osu.edu; Heller, Lois, E-mail: lheller@d.umn.edu

Life threatening complications from chemotherapy occur frequently in cancer survivors, however little is known about genetic risk factors. We treated male normotensive rats (WKY) and strains with hypertension (SHR) and hypertension with cardiomyopathy (SHHF) with 8 weekly doses of doxorubicin (DOX) followed by 12 weeks of observation to test the hypothesis that genetic cardiovascular disease would worsen delayed cardiotoxicity. Compared with WKY, SHR demonstrated weight loss, decreased systolic blood pressure, increased kidney weights, greater cardiac and renal histopathologic lesions and greater mortality. SHHF showed growth restriction, increased kidney weights and renal histopathology but no effect on systolic blood pressure ormore » mortality. SHHF had less severe cardiac lesions than SHR. We evaluated cardiac soluble epoxide hydrolase (sEH) content and arachidonic acid metabolites after acute DOX exposure as potential mediators of genetic risk. Before DOX, SHHF and SHR had significantly greater cardiac sEH and decreased epoxyeicosatrienoic acid (EET) (4 of 4 isomers in SHHF and 2 of 4 isomers in SHR) than WKY. After DOX, sEH was unchanged in all strains, but SHHF and SHR rats increased EETs to a level similar to WKY. Leukotriene D4 increased after treatment in SHR. Genetic predisposition to heart failure superimposed on genetic hypertension failed to generate greater toxicity compared with hypertension alone. The relative resistance of DOX-treated SHHF males to the cardiotoxic effects of DOX in the delayed phase despite progression of genetic disease was unexpected and a key finding. Strain differences in arachidonic acid metabolism may contribute to variation in response to DOX toxicity. - Highlights: • Late doxorubicin toxicity evaluated in normal, hypertensive, and cardiomyopathic rats. • Hypertension enhances the delayed toxicity of doxorubicin. • Genetic predisposition to cardiomyopathy did not further enhance toxicity. • Epoxyeicosatrienoic acids increased in response to doxorubicin in SHR and SHHF. • Altered leukotriene metabolism may contribute greater toxicity in SHR vs. SHHF rats.« less

Pressure-immobilization bandages delay toxicity in a porcine model of eastern coral snake (Micrurus fulvius fulvius) envenomation.

PubMed

German, Benjamin T; Hack, Jason B; Brewer, Kori; Meggs, William J

2005-06-01

Pressure-immobilization bandages are used in countries where neurotoxic snake envenomations are common. They impede lymphatic egress from the bite site and delay systemic venom toxicity. The effectiveness of these devices has not been evaluated in coral snake envenomations. We investigated the efficacy of pressure-immobilization bandages in delaying the onset of systemic toxicity in a porcine model of coral snake envenomation. A randomized controlled trial of pressure-immobilization bandages was conducted in a university animal care center. Subjects were 12 anesthetized, spontaneously breathing pigs, ranging from 9.1 to 11.4 kg. After injection with 10 mg of Micrurus fulvius fulvius venom in the subcutaneous tissue of the distal foreleg, subjects were randomized to receive no treatment or application of a pressure-immobilization bandage at 1 minute after injection. Treated animals had elastic bandages applied to the extremity and splinting for immobilization. Vital signs and quality of respirations were recorded. Outcome was the onset of respiratory failure or survival to 8 hours. Necropsies and histologic analysis of the envenomation site was performed. One animal from each group was removed because of the discovery of pre-existing respiratory pathology. Four of 5 pigs in the treatment group survived to 8 hours, but none in the control group survived. Mean time to onset of respiratory compromise was 170.4 +/- 33.3 minutes in the control group. None of the pigs had histologic changes at the envenomation site consistent with ischemia or pressure-related injury. Pressure-immobilization bandages delayed the onset of systemic toxicity in our porcine model of M fulvius envenomation.

Exposure to Enriched Environment Decreases Neurobehavioral Deficits Induced by Neonatal Glutamate Toxicity

PubMed Central

Horvath, Gabor; Reglodi, Dora; Vadasz, Gyongyver; Farkas, Jozsef; Kiss, Peter

2013-01-01

Environmental enrichment is a popular strategy to enhance motor and cognitive performance and to counteract the effects of various harmful stimuli. The protective effects of enriched environment have been shown in traumatic, ischemic and toxic nervous system lesions. Monosodium glutamate (MSG) is a commonly used taste enhancer causing excitotoxic effects when given in newborn animals. We have previously demonstrated that MSG leads to a delay in neurobehavioral development, as shown by the delayed appearance of neurological reflexes and maturation of motor coordination. In the present study we aimed at investigating whether environmental enrichment is able to decrease the neurobehavioral delay caused by neonatal MSG treatment. Newborn pups were treated with MSG subcutaneously on postnatal days 1, 5 and 9. For environmental enrichment, we placed rats in larger cages, supplemented with different toys that were altered daily. Normal control and enriched control rats received saline treatment only. Physical parameters such as weight, day of eye opening, incisor eruption and ear unfolding were recorded. Animals were observed for appearance of reflexes such as negative geotaxis, righting reflexes, fore- and hindlimb grasp, fore- and hindlimb placing, sensory reflexes and gait. In cases of negative geotaxis, surface righting and gait, the time to perform the reflex was also recorded daily. For examining motor coordination, we performed grid walking, footfault, rope suspension, rota-rod, inclined board and walk initiation tests. We found that enriched environment alone did not lead to marked alterations in the course of development. On the other hand, MSG treatment caused a slight delay in reflex development and a pronounced delay in weight gain and motor coordination maturation. This delay in most signs and tests could be reversed by enriched environment: MSG-treated pups kept under enriched conditions showed no weight retardation, no reflex delay in some signs and performed better in most coordination tests. These results show that environmental enrichment is able to decrease the neurobehavioral delay caused by neonatal excitotoxicity. PMID:24065102

Chlorhexidine hexametaphosphate as a wound care material coating: antimicrobial efficacy, toxicity and effect on healing.

PubMed

Barbour, Michele E; Maddocks, Sarah E; Grady, Helena J; Roper, James A; Bass, Mark D; Collins, Andrew M; Dommett, Rachel M; Saunders, Margaret

2016-08-01

In this study, chlorhexidine hexametaphosphate (CHX-HMP) is investigated as a persistent antimicrobial coating for wound care materials. CHX-HMP was used as a wound care material coating and compared with chlorhexidine digluconate materials with respect to antimicrobial efficacy, toxicity and wound closure. Antimicrobial efficacy at day 1, 3 and 7 was observed with experimental and commercial materials. CHX-HMP coated materials had less toxic effect on human placental cells than commercial chlorhexidine dressings. CHX-HMP in pluronic gel did not delay healing but reduced wound colonization by E. faecalis. CHX-HMP could become a useful component of wound care materials with sustained antimicrobial efficacy, lower toxicity than chlorhexidine digluconate materials, and reduction in wound colonization without affecting closure.

Cerebral Acetylcholine and Choline Contents and Turnover Following Low-Dose Acetylcholinesterase Inhibitor Treatment in Rats

DTIC Science & Technology

2006-05-01

JH, Jr., Romano JA, King JM (1990) Age-related differences in soman toxicity and in blood and brain regional cholinesterase activity . Brain Res.Bull...of OP AChE inhibitors when given in anticipation of exposure to toxic nerve agents. The mechanism of this protection seems to be the pre- occupation of...has indicated effects on blood AChE activity during and shortly after treatment and delayed effects, 2 to 16 weeks post-treatment, on exploratory

Effects of total body irradiation and cyclosporin a on the lethality of toxic shock syndrome toxin-1 in a rabbit model of toxic shock syndrome.

PubMed

Dinges, Martin M; Gregerson, Dale S; Tripp, Timothy J; McCormick, John K; Schlievert, Patrick M

2003-10-15

Toxic shock syndrome (TSS) may be mediated by superantigen-activated T cells, a theory we tested in rabbits, which are more susceptible to the lethal effects of superantigens, such as TSS toxin-1 (TSST-1), than are mice. Rabbits exposed to 10 cGy of total body irradiation exhibited T cell deficiency, with profound depletion of splenic lymphocytes and circulating CD4(+) lymphocytes, as well as an inability to manifest delayed-type hypersensitivity. Nevertheless, these rabbits remained completely susceptible to TSST-1, indicating that TSS can occur in the setting of marked immunosuppression.

Preservation of Immune Function in Cervical Cancer Patients during Chemoradiation using a Novel Integrative Approach

PubMed Central

Lutgendorf, Susan K.; Mullen-Houser, Elizabeth; Russell, Daniel; DeGeest, Koen; Jacobson, Geraldine; Hart, Laura; Bender, David; Anderson, Barrie; Buekers, Thomas E.; Goodheart, Michael J.; Antoni, Michael H.; Sood, Anil K.; Lubaroff, David M.

2010-01-01

Patients receiving chemoradiation for cervical cancer are at risk for distress, chemoradiation-related side-effects, and immunosuppression. This prospective randomized clinical trial examined effects of a complementary therapy, Healing Touch (HT), versus relaxation training (RT) and usual care (UC) for 1) supporting cellular immunity, 2) improving mood and quality of life (QOL), and 3) reducing treatment-associated toxicities and treatment delay in cervical cancer patients receiving chemoradiation. Sixty women with stages IB1 to IVA cervical cancer were randomly assigned to receive UC or 4×/weekly individual sessions of either HT or RT immediately following radiation during their 6-week chemoradiation treatment. Patients completed psychosocial assessments and blood sampling before chemoradiation at baseline, weeks 4 and 6. Multilevel regression analyses using orthogonal contrasts tested for differences between treatment conditions over time. HT patients had a minimal decrease in natural killer cell cytotoxicity (NKCC) over the course of treatment whereas NKCC of RT and UC patients declined sharply during chemoradiation (group by time interaction: p=0.018). HT patients showed greater decreases in 2 different indicators of depressed mood (CESD depressed mood subscale and POMS depression scale) compared to RT and UC (group by time interactions: p < 0.05). No between group differences were observed in QOL, treatment delay, or clinically-rated toxicities. HT may benefit cervical cancer patients by moderating effects of chemoradiation on depressed mood and cellular immunity. Effects of HT on toxicities, treatment delay, QOL, and fatigue were not observed. Long-term clinical implications of findings are not known. PMID:20600809

Ketoconazole modulates the infectivity of Ichthyophonus sp. (Mesomycetozoa) in vivo in experimentally injected European sea bass.

PubMed

Hontoria, Francisco; González, Ma Angeles; Sitjà-Bobadilla, Ariadna; Palenzuela, Oswaldo; Alvarez-Pellitero, Pilar

2013-09-03

In vitro studies have confirmed the inhibitory effect of the azol-derivative ketoconazole (KZ) on the growth of Ichthyophonus, an important pathogen causing epizootics in wild and cultured fish. We evaluated the effect of KZ in vivo in European sea bass Dicentrarchus labrax experimentally infected with the same Ichthyophonus isolate. Liposomes were used to vehiculate different doses of KZ to increase the effect on Ichthyophonus and lower the toxicity of the drug, and KZ toxicity was assessed in cultured sea bass juveniles. We also studied the effect of liposome-vehiculated KZ included in medicated food on ichthyophoniasis. KZ causes clear toxic effects in D. labrax juveniles at doses >80 mg kg-1, apparent in the reduced survival of fish and histological alterations to livers, kidneys and spleens. Fish injected with Ichthyophonus and treated with KZ dosages of ≤80 mg kg-1 d-1 presented lower ichthyophoniasis prevalence, fewer organs infected per fish, and fewer spores in the affected organs than the untreated fish. KZ seems to delay the onset of infection, but cannot stop further progression once established. However, this behaviour is not clearly reflected in the biometric and haematological data collected from these fish. We hypothesise that KZ's delaying effect would increase, if lower infective doses (more similar to natural situations) were used. The drug administration vehicle (liposomes vs. emulsions) did not affect the results. Our data confirm the potential utility of KZ in treating ichthyophoniasis and reveal its low toxicity for sea bass. Nevertheless, the optimal dose and appropriate application protocol remain to be determined.

Research on the influence of ozone dissolved in the fuel-water emulsion on the parameters of the CI engine

NASA Astrophysics Data System (ADS)

Wojs, M. K.; Orliński, P.; Kamela, W.; Kruczyński, P.

2016-09-01

The article presents the results of empirical research on the impact of ozone dissolved in fuel-water emulsion on combustion process and concentration of toxic substances in CI engine. The effect of ozone presence in the emulsion and its influence on main engine characteristics (power, torque, fuel consumption) and selected parameters that characterize combustion process (levels of pressures and temperatures in combustion chamber, period of combustion delay, heat release rate, fuel burnt rate) is shown. The change in concentration of toxic components in exhausts gases when engine is fueled with ozonized emulsion was also identified. The empirical research and their analysis showed significant differences in the combustion process when fuel-water emulsion containing ozone was used. These differences include: increased power and efficiency of the engine that are accompanied by reduction in time of combustion delay and beneficial effects of ozone on HC, PM, CO and NOX emissions.

Can exercise ameliorate treatment toxicity during the initial phase of testosterone deprivation in prostate cancer patients? Is this more effective than delayed rehabilitation?

PubMed Central

2012-01-01

Background There has been substantial increase in use of androgen deprivation therapy as adjuvant management of prostate cancer. However, this leads to a range of musculoskeletal toxicities including reduced bone mass and increased skeletal fractures compounded with rapid metabolic alterations, including increased body fat, reduced lean mass, insulin resistance and negative lipoprotein profile, increased incidence of cardiovascular and metabolic morbidity, greater distress and reduced quality of life. Numerous research studies have demonstrated certain exercise prescriptions to be effective at preventing or even reversing these treatment toxicities. However, all interventions to date have been of rehabilitative intent being implemented after a minimum of 3 months since initiation of androgen deprivation, by which time considerable physical and psychological health problems have manifested. The pressing question is whether it is more efficacious to commence exercise therapy at the same time as initiating androgen deprivation, so treatment induced adverse effects can be immediately attenuated or indeed prevented. Methods/design We are proposing a multi-site randomized controlled trial with partial crossover to examine the effects of timing of exercise implementation (immediate or delayed) on preserving long-term skeletal health, reversing short- and long-term metabolic and cardiovascular risk factors, and supporting mental health in men receiving androgen deprivation therapy. 124 men who are about to initiate androgen deprivation for prostate cancer will be randomized to immediate or delayed groups. Immediate will commence a 6-month exercise program within 7–10 days of their first dose. Delayed will receive usual care for 6 months and then commence the exercise program for 6 months (partial cross-over). Immediate will be free to adopt the lifestyle of their choosing following the initial 6-month intervention. Measurements for primary and secondary endpoints will take place at baseline, 6 months and 12 months. Discussion This project is unique as it explores a fundamental question of when exercise implementation will be of most benefit and addresses both physical and psychological consequences of androgen deprivation initiation. The final outcome may be adjunct treatment which will reduce if not prevent the toxicities of androgen deprivation, ultimately resulting in reduced morbidity and mortality for men with prostate cancer. Trial registration ACTRN12612000097842 PMID:23013489

Preventing and Managing Toxicities of High-Dose Methotrexate.

PubMed

Howard, Scott C; McCormick, John; Pui, Ching-Hon; Buddington, Randall K; Harvey, R Donald

2016-12-01

: High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m 2 , is used to treat a range of adult and childhood cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI) in 2%-12% of patients. Nephrotoxicity results from crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. AKI and other toxicities of high-dose methotrexate can lead to significant morbidity, treatment delays, and diminished renal function. Risk factors for methotrexate-associated toxicity include a history of renal dysfunction, volume depletion, acidic urine, and drug interactions. Renal toxicity leads to impaired methotrexate clearance and prolonged exposure to toxic concentrations, which further worsen renal function and exacerbate nonrenal adverse events, including myelosuppression, mucositis, dermatologic toxicity, and hepatotoxicity. Serum creatinine, urine output, and serum methotrexate concentration are monitored to assess renal clearance, with concurrent hydration, urinary alkalinization, and leucovorin rescue to prevent and mitigate AKI and subsequent toxicity. When delayed methotrexate excretion or AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase are usually sufficient to allow renal recovery without the need for dialysis. Prompt recognition and effective treatment of AKI and associated toxicities mitigate further toxicity, facilitate renal recovery, and permit patients to receive other chemotherapy or resume HDMTX therapy when additional courses are indicated. High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m 2 , is used for a range of cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI), attributable to crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. When AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase allow renal recovery without the need for dialysis. This article, based on a review of the current associated literature, provides comprehensive recommendations for prevention of toxicity and, when necessary, detailed treatment guidance to mitigate AKI and subsequent toxicity. ©AlphaMed Press.

Preventing and Managing Toxicities of High-Dose Methotrexate

PubMed Central

McCormick, John; Pui, Ching-Hon; Buddington, Randall K.; Harvey, R. Donald

2016-01-01

High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m2, is used to treat a range of adult and childhood cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI) in 2%–12% of patients. Nephrotoxicity results from crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. AKI and other toxicities of high-dose methotrexate can lead to significant morbidity, treatment delays, and diminished renal function. Risk factors for methotrexate-associated toxicity include a history of renal dysfunction, volume depletion, acidic urine, and drug interactions. Renal toxicity leads to impaired methotrexate clearance and prolonged exposure to toxic concentrations, which further worsen renal function and exacerbate nonrenal adverse events, including myelosuppression, mucositis, dermatologic toxicity, and hepatotoxicity. Serum creatinine, urine output, and serum methotrexate concentration are monitored to assess renal clearance, with concurrent hydration, urinary alkalinization, and leucovorin rescue to prevent and mitigate AKI and subsequent toxicity. When delayed methotrexate excretion or AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase are usually sufficient to allow renal recovery without the need for dialysis. Prompt recognition and effective treatment of AKI and associated toxicities mitigate further toxicity, facilitate renal recovery, and permit patients to receive other chemotherapy or resume HDMTX therapy when additional courses are indicated. Implications for Practice: High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m2, is used for a range of cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI), attributable to crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. When AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase allow renal recovery without the need for dialysis. This article, based on a review of the current associated literature, provides comprehensive recommendations for prevention of toxicity and, when necessary, detailed treatment guidance to mitigate AKI and subsequent toxicity. PMID:27496039

Suppression of Somatic Expansion Delays the Onset of Pathophysiology in a Mouse Model of Huntington’s Disease

PubMed Central

Budworth, Helen; Harris, Faye R.; Williams, Paul; Lee, Do Yup; Holt, Amy; Pahnke, Jens; Szczesny, Bartosz; Acevedo-Torres, Karina; Ayala-Peña, Sylvette; McMurray, Cynthia T.

2015-01-01

Huntington’s Disease (HD) is caused by inheritance of a single disease-length allele harboring an expanded CAG repeat, which continues to expand in somatic tissues with age. The inherited disease allele expresses a toxic protein, and whether further somatic expansion adds to toxicity is unknown. We have created an HD mouse model that resolves the effects of the inherited and somatic expansions. We show here that suppressing somatic expansion substantially delays the onset of disease in littermates that inherit the same disease-length allele. Furthermore, a pharmacological inhibitor, XJB-5-131, inhibits the lengthening of the repeat tracks, and correlates with rescue of motor decline in these animals. The results provide evidence that pharmacological approaches to offset disease progression are possible. PMID:26247199

Clinical and diagnostic features of delayed hypoxic leukoencephalopathy.

PubMed

Shprecher, David R; Flanigan, Kevin M; Smith, A Gordon; Smith, Shawn M; Schenkenberg, Thomas; Steffens, John

2008-01-01

Delayed hypoxic leukoencephalopathy is an underrecognized syndrome of delayed demyelination, which is important to consider when delayed onset of neuropsychiatric symptoms follows a hypoxic event. The authors describe clinical and diagnostic features of three such cases, review the pathophysiology of delayed hypoxic leukoencephalopathy, and discuss features which may help distinguish it from toxic leukoencephalopathy.

A review on delayed toxic effects of sulfur mustard in Iranian veterans

PubMed Central

2012-01-01

Iranian soldiers were attacked with chemical bombs, rockets and artillery shells 387 times during the 8-years war by Iraq (1980–1988). More than 1,000 tons of sulfur mustard gas was used in the battlefields by the Iraqis against Iranian people. A high rate of morbidities occurred as the result of these attacks. This study aimed to evaluate the delayed toxic effects of sulfur mustard gas on Iranian victims. During a systematic search, a total of 193 (109 more relevant to the main aim) articles on sulfur mustard gas were reviewed using known international and national databases. No special evaluation was conducted on the quality of the articles and their publication in accredited journals was considered sufficient. High rate of morbidities as the result of chemical attacks by sulfur mustard among Iranian people occurred. Iranian researchers found a numerous late complications among the victims which we be listed as wide range of respiratory, ocular, dermatological, psychological, hematological, immunological, gastrointestinal and endocrine complications, all influenced the quality of life of exposed victims. The mortality rate due to this agent was 3%. Although, mortality rate induced by sulfur mustard among Iranian people was low, variety and chronicity of toxic effects and complications of this chemical agent were dramatic. PMID:23351810

Immediate versus delayed self-reporting of symptoms and side effects during chemotherapy: does timing matter?

PubMed

Coolbrandt, Annemarie; Van den Heede, Koen; Vanhove, Ellen; De Bom, Ann; Milisen, Koen; Wildiers, Hans

2011-04-01

The aim of this study was to examine how patients recall symptoms at a delayed self-report. Accurate insight into toxicity symptoms during chemotherapy is essential so that nurses and doctors can assess therapeutic tolerance and adjust supportive care accordingly. A non-experimental, longitudinal design was employed. Using the Therapy-Related Symptoms Checklist (TRSC), respondents (n = 142) reported their initial symptoms during the first 7 days of the chemotherapy cycle at two different times: (1) each day of the first seven days after the chemotherapy administration (immediate self-report), and (2) at their next hospital visit for chemotherapy (delayed self-report). We compared the number and severity of symptoms and side effects reported in the immediate and delayed self-reports. Respondents reported significantly fewer symptoms and fewer severe symptoms in the delayed self-report. For 22 out of 25 symptoms the delayed-reported grade was significantly lower than the immediate-reported maximum grade. Compared to the immediate-reported median grade, significant differences occurred in only 10 out of the 25 symptoms. In all cases, except fatigue, the delayed-reported grade was significantly higher than the immediate-reported median grade. This study indicates that delayed self-report of chemotherapy side effects is not an appropriate measure of actual symptoms and side effects experienced by patients. Delayed self-report gives a weaker insight into actual symptom burden. Fatigue is at particular risk to be minimized at the delayed self-report. Therefore it is recommended to assess chemotherapy-related symptoms and side effects by means of immediate self-report. Copyright © 2010 Elsevier Ltd. All rights reserved.

Sub-lethal and lethal toxicities of elevated CO2 on embryonic, juvenile, and adult stages of marine medaka Oryzias melastigma.

PubMed

Lee, Changkeun; Kwon, Bong-Oh; Hong, Seongjin; Noh, Junsung; Lee, Junghyun; Ryu, Jongseong; Kang, Seong-Gil; Khim, Jong Seong

2018-06-06

The potential leakage from marine CO 2 storage sites is of increasing concern, but few studies have evaluated the probable adverse effects on marine organisms. Fish, one of the top predators in marine environments, should be an essential representative species used for water column toxicity testing in response to waterborne CO 2 exposure. In the present study, we conducted fish life cycle toxicity tests to fully elucidate CO 2 toxicity mechanism effects. We tested sub-lethal and lethal toxicities of elevated CO 2 concentrations on marine medaka (Oryzias melastigma) at different developmental stages. At each developmental stage, the test species was exposed to varying concentrations of gaseous CO 2 (control air, 5%, 10%, 20%, and 30%), with 96 h of exposure at 0-4 d (early stage), 4-8 d (middle stage), and 8-12 d (late stage). Sub-lethal and lethal effects, including early developmental delays, cardiac edema, tail abnormalities, abnormal pigmentation, and mortality were monitored daily during the 14 d exposure period. At the embryonic stage, significant sub-lethal and lethal effects were observed at pH < 6.30. Hypercapnia can cause long-term and/or delayed developmental embryonic problems, even after transfer back to clean seawater. At fish juvenile and adult stages, significant mortality was observed at pH < 5.70, indicating elevated CO 2 exposure might cause various adverse effects, even during short-term exposure periods. It should be noted the early embryonic stage was found more sensitive to CO 2 exposure than other developmental stages of the fish life cycle. Overall, the present study provided baseline information for potential adverse effects of high CO 2 concentration exposure on fish developmental processes at different life cycle stages in marine ecosystems. Copyright © 2018 Elsevier Ltd. All rights reserved.

Developmental Toxicity of Endocrine Disrupters Bisphenol A and Vinclozolin in a Terrestrial Isopod

PubMed Central

van Gestel, C. A. M.; Soares, A. M. V. M.

2010-01-01

Studies of the effects of endocrine-disrupting compounds (EDCs) on invertebrates are still largely underrepresented. This work aims to fill this gap by assessing the effects of bisphenol A (BPA) and vinclozolin (Vz) on the terrestrial isopod Porcellio scaber (common rough woodlouse). Male adult and sexually undifferentiated juvenile woodlice were exposed to the toxicants. Effects on molting regime and growth were investigated independently for males and female woodlice after sexual differentiation. Both chemicals elicited developmental toxicity to P. scaber by causing overall decreased growth. Nevertheless, BPA induced molting, whereas Vz delayed it. Although the LC50 values for juvenile and adult survival were fairly similar, juvenile woodlice showed an increased chronic sensitivity to both chemicals, and female woodlice were most the sensitive to BPA. We recommend the use of adults, juveniles, female, and male woodlice, as well as a large range of toxicant concentrations, to provide valuable information regarding differential dose responses, effects, and threshold values for EDCs. PMID:20148245

Developmental toxicity of endocrine disrupters bisphenol A and vinclozolin in a terrestrial isopod.

PubMed

Lemos, M F L; van Gestel, C A M; Soares, A M V M

2010-08-01

Studies of the effects of endocrine-disrupting compounds (EDCs) on invertebrates are still largely underrepresented. This work aims to fill this gap by assessing the effects of bisphenol A (BPA) and vinclozolin (Vz) on the terrestrial isopod Porcellio scaber (common rough woodlouse). Male adult and sexually undifferentiated juvenile woodlice were exposed to the toxicants. Effects on molting regime and growth were investigated independently for males and female woodlice after sexual differentiation. Both chemicals elicited developmental toxicity to P. scaber by causing overall decreased growth. Nevertheless, BPA induced molting, whereas Vz delayed it. Although the LC50 values for juvenile and adult survival were fairly similar, juvenile woodlice showed an increased chronic sensitivity to both chemicals, and female woodlice were most the sensitive to BPA. We recommend the use of adults, juveniles, female, and male woodlice, as well as a large range of toxicant concentrations, to provide valuable information regarding differential dose responses, effects, and threshold values for EDCs.

Atypical antipsychotic (clozapine) self-poisoning in late pregnancy presenting with absent fetal heart rate variability without acidosis and delayed peristalsis in the newborn baby: a case report.

PubMed

Novikova, N; Chitnis, M; Linder, V; Hofmeyr, G J

2009-08-01

A case of an attempted suicide with atypical antipsychotic (clozapine) in late pregnancy is reported. Toxic effects of clozapine in the mother as well as in the fetus and newborn were observed. It should be remembered as a rare cause of unexplained loss of consciousness in pregnant women, a cause of abnormalities on fetal cardiotocogram as well as a cause of delayed peristalsis in a newborn baby.

Contrasting effects of hypoxia on copper toxicity during development in the three-spined stickleback (Gasterosteus aculeatus).

PubMed

Fitzgerald, Jennifer A; Katsiadaki, Ioanna; Santos, Eduarda M

2017-03-01

Hypoxia is a global problem in aquatic systems and often co-occurs with pollutants. Despite this, little is known about the combined effects of these stressors on aquatic organisms. The objective of this study was to investigate the combined effects of hypoxia and copper, a toxic metal widespread in the aquatic environment. We used the three-spined stickleback (Gasterosteus aculeatus) as a model because of its environmental relevance and amenability for environmental toxicology studies. We focused on embryonic development as this is considered to be a sensitive life stage to environmental pollution. We first investigated the effects of hypoxia alone on stickleback development to generate the information required to design subsequent studies. Our data showed that exposure to low oxygen concentrations (24.7 ± 0.9% air saturation; AS) resulted in strong developmental delays and increased mortalities, whereas a small decrease in oxygen (75.0 ± 0.5%AS) resulted in premature hatching. Stickleback embryos were then exposed to a range of copper concentrations under hypoxia (56.1 ± 0.2%AS) or normoxia (97.6 ± 0.1%AS), continuously, from fertilisation to free swimming larvae. Hypoxia caused significant changes in copper toxicity throughout embryonic development. Prior to hatching, hypoxia suppressed the occurrence of mortalities, but after hatching hypoxia significantly increased copper toxicity. Interestingly, when exposures were conducted only after hatching, the onset of copper-induced mortalities was delayed under hypoxia compared to normoxia, but after 48 h, copper was more toxic to hatched embryos under hypoxia. This is the second species for which the protective effect of hypoxia on copper toxicity prior to hatching, followed by its exacerbating effect after hatching is demonstrated, suggesting the hypothesis that this pattern may be common for teleost species. Our research highlights the importance of considering the interactions between multiple stressors, as understanding these interactions is essential to facilitate the accurate prediction of the consequences of exposure to complex stressors in a rapidly changing environment. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Behavioral Effects and Tunneling Responses of Eastern Subterranean Termites (Isoptera: Rhinotermitidae) Exposed to Chlorantraniliprole-Treated Soils.

PubMed

Saran, Raj K; Ziegler, Melissa; Kudlie, Sara; Harrison, Danielle; Leva, David M; Scherer, Clay; Coffelt, Mark A

2014-10-01

Intrinsic toxicities of chlorantraniliprole, fipronil, and imidacloprid were evaluated with topical applications on worker termites. Worker termites were exposed to substrates treated with formulated chlorantraniliprole to study contact toxicity, tunneling, and postexposure behaviors. The intrinsic toxicities (LD50, ng/termite) of chlorantraniliprole (1.25, 0.96, and 0.44) and fipronil (0.12, 0.11, and 0.13) at 11 d were similar for workers from three termite colonies. Imidacloprid toxicity (LD50) values were highly variable among the workers from three different colonies, values at 11 d ranging from 0.7 to 75 ng/termite. Termite workers exposed to sand and soils treated with chlorantraniliprole at 50 ppm exhibited delayed mortality and, for most of the exposure times, it took >5 d to observe 90-100% mortality in termite workers. Exposure to chlorantraniliprole-treated sand (50 ppm) for as little as 1 min stopped feeding and killed 90-100% of the workers. Tunneling (≈ 2 h) in different soil types treated with chlorantraniliprole at 50 ppm, even those with high organic matter (6.3%) and clay content (30%), caused immediate feeding cessation in worker termites and mortality in the next 7-14 d. Worker termites exposed for 1 and 60 min to sand treated with chlorantraniliprole (50 ppm) were able to walk normally for 4 h after exposure in most cases. Delayed toxicity, increased aggregation, and grooming were observed in exposed termites and discussed in the context of horizontal transfer effects within termite colonies. © 2014 Entomological Society of America.

Suppression of somatic expansion delays the onset of pathophysiology in a mouse model of Huntington’s Disease

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

Budworth, Helen; Harris, Faye R.; Williams, Paul

Huntington’s Disease (HD) is caused by inheritance of a single disease-length allele harboring an expanded CAG repeat, which continues to expand in somatic tissues with age. The inherited disease allele expresses a toxic protein, and whether further somatic expansion adds to toxicity is unknown. We have created an HD mouse model that resolves the effects of the inherited and somatic expansions. We show here that suppressing somatic expansion substantially delays the onset of disease in littermates that inherit the same disease-length allele. Furthermore, a pharmacological inhibitor, XJB-5-131, inhibits the lengthening of the repeat tracks, and correlates with rescue of motormore » decline in these animals. The results provide evidence that pharmacological approaches to offset disease progression are possible.« less

Suppression of somatic expansion delays the onset of pathophysiology in a mouse model of Huntington’s Disease

DOE PAGES

Budworth, Helen; Harris, Faye R.; Williams, Paul; ...

2015-08-06

Huntington’s Disease (HD) is caused by inheritance of a single disease-length allele harboring an expanded CAG repeat, which continues to expand in somatic tissues with age. The inherited disease allele expresses a toxic protein, and whether further somatic expansion adds to toxicity is unknown. We have created an HD mouse model that resolves the effects of the inherited and somatic expansions. We show here that suppressing somatic expansion substantially delays the onset of disease in littermates that inherit the same disease-length allele. Furthermore, a pharmacological inhibitor, XJB-5-131, inhibits the lengthening of the repeat tracks, and correlates with rescue of motormore » decline in these animals. The results provide evidence that pharmacological approaches to offset disease progression are possible.« less

Simulated developmental and reproductive impacts on amphibian populations and implications for assessing long-term effects

EPA Science Inventory

Fish endpoints measured in early life stage toxicity tests are often used as representative of larval amphibian sensitivity in Ecological Risk Assessment (ERA). This application potentially overlooks the impact of developmental delays on amphibian metamorphosis, and thereby red...

Intranasal melatonin nanoniosomes: pharmacokinetic, pharmacodynamics and toxicity studies.

PubMed

Priprem, Aroonsri; Johns, Jeffrey R; Limsitthichaikoon, Sucharat; Limphirat, Wanwisa; Mahakunakorn, Pramote; Johns, Nutjaree Prateepawanit

2017-06-01

Intranasal melatonin encapsulated in nanosized niosomes was preclinically evaluated. A formula of melatonin niosomes (MN) was selected through physicochemical and cytotoxic data for pharmacokinetic, pharmacodynamics and toxicity studies in male Wistar rats. Intranasal MN was bioequivalent to intravenous injection of melatonin, providing therapeutic level doses. Acute and subchronic toxicity screening showed no abnormal signs, symptoms or hematological effects in any animals. Transient nasal irritations with no inflammation were observed with intranasal MN, leading it to be categorized as relatively harmless. The intranasal MN could deliver melatonin to the brain to induce sleep and provide delayed systemic circulation, relative to intravenous injection and also distribute to peripheral tissue.

A Cultivated Form of a Red Seaweed (Chondrus crispus), Suppresses β-Amyloid-Induced Paralysis in Caenorhabditis elegans.

PubMed

Sangha, Jatinder Singh; Wally, Owen; Banskota, Arjun H; Stefanova, Roumiana; Hafting, Jeff T; Critchley, Alan T; Prithiviraj, Balakrishnan

2015-10-20

We report here the protective effects of a methanol extract from a cultivated strain of the red seaweed, Chondrus crispus, against β-amyloid-induced toxicity, in a transgenic Caenorhabditis elegans, expressing human Aβ1-42 gene. The methanol extract of C. crispus (CCE), delayed β-amyloid-induced paralysis, whereas the water extract (CCW) was not effective. The CCE treatment did not affect the transcript abundance of amy1; however, Western blot analysis revealed a significant decrease of Aβ species, as compared to untreated worms. The transcript abundance of stress response genes; sod3, hsp16.2 and skn1 increased in CCE-treated worms. Bioassay guided fractionation of the CCE yielded a fraction enriched in monogalactosyl diacylglycerols (MGDG) that significantly delayed the onset of β-amyloid-induced paralysis. Taken together, these results suggested that the cultivated strain of C. crispus, whilst providing dietary nutritional value, may also have significant protective effects against β-amyloid-induced toxicity in C. elegans, partly through reduced β-amyloid species, up-regulation of stress induced genes and reduced accumulation of reactive oxygen species (ROS).

Comparison of the toxicity of silver, gold and platinum nanoparticles in developing zebrafish embryos.

PubMed

Asharani, P V; Lianwu, Yi; Gong, Zhiyuan; Valiyaveettil, Suresh

2011-03-01

Nanoparticles have diverse applications in electronics, medical devices, therapeutic agents and cosmetics. While the commercialization of nanoparticles is rapidly expanding, their health and environmental impact is not well understood. Toxicity assays of silver, gold, and platinum nanoparticles, using zebrafish embryos to study their developmental effects were carried out. Gold (Au-NP, 15-35 nm), silver (Ag-NP, 5-35 nm) and platinum nanoparticles (Pt-NP, 3-10 nm) were synthesized using polyvinyl alcohol (PVA) as a capping agent. Toxicity was recorded in terms of mortality, hatching delay, phenotypic defects and metal accumulation. The addition of Ag-NP resulted in a concentration-dependant increase in mortality rate. Both Ag-NP and Pt-NP induced hatching delays, as well as a concentration dependant drop in heart rate, touch response and axis curvatures. Ag-NP also induced other significant phenotypic changes including pericardial effusion, abnormal cardiac morphology, circulatory defects and absence or malformation of the eyes. In contrast, Au-NP did not show any indication of toxicity. Uptake and accumulation of nanoparticles in embryos was confirmed by inductively coupled plasma optical emission spectroscopy (ICP-OES), which revealed detectable levels in embryos within 72 hpf. Ag-NP and Au-NP were taken up by the embryos in relatively equal amounts whereas lower Pt concentrations were observed in embryos exposed to Pt-NP. This was probably due to the small size of the Pt nanoparticles compared to Ag-NP and Au-NP, thus resulting in fewer metal atoms being retained in the embryos. Among the nanoparticles studied, Ag-NPs were found to be the most toxic and Au-NPs the non-toxic. The toxic effects exhibited by the zebrafish embryos as a consequence of nanoparticle exposure, accompanied by the accumulation of metals inside the body calls for urgent further investigations in this field.

Delayed seizure associated with paclitaxel-Cremophor el in a patient with early-stage breast cancer.

PubMed

O'Connor, Tracey L; Kossoff, Ellen

2009-08-01

Paclitaxel, a microtubule stabilizer, is an effective agent for treating cancer of the breast, ovary, head and neck, and lung. Because paclitaxel is insoluble in water, it is formulated with the micelle-forming Cremophor EL. Neurologic toxicity is well described with both the drug and this carrier, with most toxicities manifesting as peripheral neuropathy, motor neuropathy, autonomic neuropathy, and myopathy. Toxic effects on the central nervous system, such as seizures or encephalopathy, have been rarely reported; however, the seizures reported were closely related to the time of infusion. We describe a 41-year-old woman with no history of seizures who was treated with paclitaxel for breast cancer. Four days after the drug was infused, she developed a generalized tonic-clonic seizure that could not be attributed to other causes. The patient was treated with phenytoin and was able to complete her adjuvant chemotherapy with nab-paclitaxel without further events. Her condition was neurologically stable without phenytoin for the next 6 months. Use of the Naranjo adverse drug reaction probability scale indicated a possible association (score of 3) between the delayed seizure and paclitaxel or its solvent, Cremophor EL. Clinicians should be aware of the potential for seizure activity in patients who receive paclitaxel formulated with Cremophor EL.

Reproductive toxicity evaluation of dietary butyl benzyl phthalate (BBP) in rats.

PubMed

Tyl, Rochelle W; Myers, Christina B; Marr, Melissa C; Fail, Patricia A; Seely, John C; Brine, Dolores R; Barter, Robert A; Butala, John H

2004-01-01

Butyl benzyl phthalate (BBP) was administered in the diet at 0, 750, 3750, and 11,250 ppm ad libitum to 30 rats per sex per dose for two offspring generations, one litter/breeding pair/generation, through weaning of F2 litters. Adult F0 systemic toxicity and adult F1 systemic and reproductive toxicity were present at 11,250 ppm (750 mg/kg per day). At 11,250 ppm, there were reduced F1 and F2 male anogenital distance (AGD) and body weights/litter during lactation, delayed acquisition of puberty in F1 males and females, retention of nipples and areolae in F1 and F2 males, and male reproductive system malformations. At 3750 ppm (250 mg/kg per day), only reduced F1 and F2 offspring male AGD was present. There were no effects on parents or offspring at 750 ppm (50 mg/kg per day). The F1 parental systemic and reproductive toxicity no observable adverse effect level (NOAEL) was 3750 ppm. The offspring toxicity NOAEL was 3750 ppm. The offspring toxicity no observable effect level (NOEL) was 750 ppm, based on the presence of reduced AGD in F1 and F2 males at birth at 3750 ppm, but no effects on reproductive development, structures, or functions.

In vivo toxic effects of 4-methoxy-5-hydroxy-canthin-6-one in zebrafish embryos via copper dyshomeostasis and oxidative stress.

PubMed

Gong, Guiyi; Jiang, Lingling; Lin, Qinghua; Liu, Wenyuan; He, Ming-Fang; Zhang, Jie; Feng, Feng; Qu, Wei; Xie, Ning

2018-01-01

Dysfunction of copper homeostasis can lead to a host of disorders, which might be toxic sometimes. 4-Methoxy-5-hydroxy-canthin-6-one (CAN) is one of the major constituents from Picrasma quassioides and responsible for its therapeutic effects. In this work, we evaluated the toxic effect of CAN (7.5μM) on zebrafish embryos. CAN treatment decreased survival, delayed hatching time and induced malformations (loss of pigmentation, pericardial edema, as well as hematologic and neurologic abnormalities). Besides, exogenous copper supplementation rescued the pigmentation and cardiovascular defects in CAN-treated embryos. Further spectroscopic studies revealed a copper-chelating activity of CAN. Then its regulation on the expressions of copper homeostasis related genes also be analyzed. In addition, CAN lowered the total activity of SOD, elevated the ROS production and altered the oxidative related genes transcriptions, which led to oxidative stress. In conclusion, we demonstrated that CAN (7.5μM) might exert its toxic effects in zebrafish embryos by causing copper dyshomeostasis and oxidative stress. It will give insight into the risk assessment and prevention of CAN-mediated toxicity. Copyright © 2017 Elsevier Inc. All rights reserved.

Delayed and time-cumulative toxicity of imidacloprid in bees, ants and termites

PubMed Central

Rondeau, Gary; Sánchez-Bayo, Francisco; Tennekes, Henk A.; Decourtye, Axel; Ramírez-Romero, Ricardo; Desneux, Nicolas

2014-01-01

Imidacloprid, one of the most commonly used insecticides, is highly toxic to bees and other beneficial insects. The regulatory challenge to determine safe levels of residual pesticides can benefit from information about the time-dependent toxicity of this chemical. Using published toxicity data for imidacloprid for several insect species, we construct time-to-lethal-effect toxicity plots and fit temporal power-law scaling curves to the data. The level of toxic exposure that results in 50% mortality after time t is found to scale as t1.7 for ants, from t1.6 to t5 for honeybees, and from t1.46 to t2.9 for termites. We present a simple toxicological model that can explain t2 scaling. Extrapolating the toxicity scaling for honeybees to the lifespan of winter bees suggests that imidacloprid in honey at 0.25 μg/kg would be lethal to a large proportion of bees nearing the end of their life. PMID:24993452

Prolonged neurophysiologic effects of levetiracetam after oral administration in humans.

PubMed

Epstein, Charles M; Girard-Siqueira, Lhys; Ehrenberg, Joshua Andrew

2008-07-01

To determine whether neurophysiological effects of levetiracetam (LEV) outlast its serum half-life of approximately 7 h. Demonstration of prolonged effects would help to explain the efficacy of LEV at conventional dosing intervals that are longer than the serum half-life. Following an oral dose of LEV 3 g in 12 normal volunteers, we compared transcranial magnetic stimulation (TMS) measures of motor threshold (MT) and recruitment with LEV serum levels and subjective ratings of toxicity over 48 h. Subjects used a two-dimensional visual-analog scale to estimate the time course of any side effects. LEV serum levels and subjective toxicity both peaked around 1 h after oral administration. MT elevation was delayed in comparison to peak serum levels and subjective toxicity. MT was maximally elevated at 6-9 h, and recruitment maximally reduced at 0.6-9 h. Changes in both measures had recovered by approximately 50% at 24 h. Despite the time difference between toxicity and TMS changes, toxicity estimates correlated with the maximum increase in MT. There is a substantial time lag between LEV serum levels and TMS measures of neuronal effects, and a similar temporal dissociation between subjective toxicity and maximum TMS change. The time course of neurophysiological effects, as measured by TMS, may help to explain the sustained clinical efficacy of LEV despite a short peripheral half-life.

Serum Creatinine Versus Plasma Methotrexate Levels to Predict Toxicities in Children Receiving High-dose Methotrexate.

PubMed

Tiwari, Priya; Thomas, M K; Pathania, Subha; Dhawan, Deepa; Gupta, Y K; Vishnubhatla, Sreenivas; Bakhshi, Sameer

2015-01-01

Facilities for measuring methotrexate (MTX) levels are not available everywhere, potentially limiting administration of high-dose methotrexate (HDMTX). We hypothesized that serum creatinine alteration after HDMTX administration predicts MTX clearance. Overall, 122 cycles in 50 patients of non-Hodgkin lymphoma or acute lymphoblastic leukemia aged ≤18 years receiving HDMTX were enrolled prospectively. Plasma MTX levels were measured at 12, 24, 36, 48, 60, and 72 hours; serum creatinine was measured at baseline, 24, 48, and 72 hours. Correlation of plasma MTX levels with creatinine levels and changes in creatinine from baseline (Δ creatinine) were evaluated. Plasma MTX levels at 72 hours showed positive correlation with serum creatinine at 48 hours (P = .011) and 72 hours (P = .013) as also Δ creatinine at 48 hours (P = .042) and 72 hours (P = .045). However, cut-off value of either creatinine or Δ creatinine could not be established to reliably predict delayed MTX clearance. Greater than 50% Δ creatinine at 48 and 72 hours significantly predicted grade 3/4 leucopenia (P = .036 and P = .001, respectively) and thrombocytopenia (P = .012 and P = .009, respectively) but not mucositis (P = .827 and P = .910, respectively). Delayed MTX elimination did not predict any grade 3/4 toxicity. In spite of demonstration of significant correlation between serum creatinine and Δ creatinine with plasma MTX levels at 72 hours, cut-off value of either variable to predict MTX delay could not be established. Thus, either of these cannot be used as a surrogate for plasma MTX estimation. Interestingly, Δ creatinine effectively predicted hematological toxicities, which were not predicted by delayed MTX clearance.

Plerixafor Improves Primary Tumor Response and Reduces Metastases in Cervical Cancer Treated with Radio-Chemotherapy.

PubMed

Chaudary, Naz; Pintilie, Melania; Jelveh, Salomeh; Lindsay, Patricia; Hill, Richard P; Milosevic, Michael

2017-03-01

Purpose: There is an important need to improve the effectiveness of radio-chemotherapy (RTCT) for cervical cancer. The CXCL12/CXCR4 pathway can influence RT response by recruiting normal myeloid cells to the tumor microenvironment that in turn can exert radioprotective effects, and may promote metastases. The objective of this study was to explore the efficacy and toxicity of combining RTCT with CXCL12/CXCR4 inhibition in cervical cancer. Experimental Design: CXCR4 expression was measured in 115 patients with cervical cancer. Two primary orthotopic cervical cancer xenografts (OCICx) with different levels of CXCR4 expression were treated with RT (30 Gy: 15 daily fractions) and weekly cisplatin (4 mg/kg), with or without the CXCR4 inhibitor Plerixafor (5 mg/kg/day). The endpoints were tumor growth delay and lymph node metastases. Acute intestinal toxicity was assessed using a crypt cell assay. Results: There was a fivefold variation in CXCR4 mRNA expression in the patient samples, and good correlation between the expression in patients and in the xenografts. The combination of RTCT and Plerixafor produced substantial tumor growth delay and reduced lymph node metastases compared with RTCT alone in both of the xenograft models. There was a trend toward reduced acute intestinal toxicity with the addition of Plerixafor to RTCT. There were no changes in normal organ morphology to suggest increased late toxicity. Conclusions: This study demonstrates that the addition of Plerixafor to standard RTCT improves primary tumor response and reduces metastases in cervical cancer with no increase in toxicity. This combination warrants further investigation in phase I/II clinical trials. Clin Cancer Res; 23(5); 1242-9. ©2016 AACR . ©2016 American Association for Cancer Research.

Delayed toxicity of two chitinolytic enzyme inhibitors (psammaplin a and pentoxifylline) against eastern subterranean termites (Isoptera: Rhinotermitidae).

PubMed

Hiusen, Timothy J; Kamble-Shripat, T

2013-08-01

By using a no-choice feeding bioassay, delayed toxicity and concentration-dependent mortality of two chitinolytic enzyme inhibitors, pentoxifylline and psammaplin A, were evaluated by determining LT50, LT90, and LT99 (lethal time) against the economically important eastern subterranean termite, Reticulitermes flavipes (Kollar). Pentoxifylline- and psammaplin A-incorporated diets (filter paper) were assayed at 0.01, 0.02, 0.04, 0.08, and 0.21% and 0.0375, 0.075, 0.15, and 0.3% active ingredient (wt:wt), respectively. Acetone-only treated filter paper served as diet for the control treatments. Termite workers were allowed to feed on diet until 100% test population mortality occurred (80-95 d). Both chitinase inhibitors were shown to be toxic to R. flavipes. Concentration-dependent toxicity occurred within the pentoxifylline treatments over the range of 0.01-0.08%, with 0.08% treatments producing an LT50 of 32.2 d. However, mortality in response to psammaplin A treatments lacked concentration-dependent toxicity. Treatment with 0.3% psammaplin A produced an LT50 of 21.3 d. Mortality in response to lower psammaplin A treatments displayed no concentration-dependent trends. This study provides the first report on delayed toxicity of chitinolytic enzyme inhibitors against eastern subterranean termites (order Isoptera) and toxicological data on pentoxifylline and psammaplin A over a range of concentrations.

Adverse effects of methylmercury: environmental health research implications.

PubMed

Grandjean, Philippe; Satoh, Hiroshi; Murata, Katsuyuki; Eto, Komyo

2010-08-01

The scientific discoveries of health risks resulting from methylmercury exposure began in 1865 describing ataxia, dysarthria, constriction of visual fields, impaired hearing, and sensory disturbance as symptoms of fatal methylmercury poisoning. Our aim was to examine how knowledge and consensus on methylmercury toxicity have developed in order to identify problems of wider concern in research. We tracked key publications that reflected new insights into human methylmercury toxicity. From this evidence, we identified possible caveats of potential significance for environmental health research in general. At first, methylmercury research was impaired by inappropriate attention to narrow case definitions and uncertain chemical speciation. It also ignored the link between ecotoxicity and human toxicity. As a result, serious delays affected the recognition of methylmercury as a cause of serious human poisonings in Minamata, Japan. Developmental neurotoxicity was first reported in 1952, but despite accumulating evidence, the vulnerability of the developing nervous system was not taken into account in risk assessment internationally until approximately 50 years later. Imprecision in exposure assessment and other forms of uncertainty tended to cause an underestimation of methylmercury toxicity and repeatedly led to calls for more research rather than prevention. Coupled with legal and political rigidity that demanded convincing documentation before considering prevention and compensation, types of uncertainty that are common in environmental research delayed the scientific consensus and were used as an excuse for deferring corrective action. Symptoms of methylmercury toxicity, such as tunnel vision, forgetfulness, and lack of coordination, also seemed to affect environmental health research and its interpretation.

Ethanol fumigation combined with and without nitrogen gas delays potato greening and inhibits Glycoalkaloid generation under light

USDA-ARS?s Scientific Manuscript database

Postharvest potato greening under light accompanied by the generation of toxic glycoalkaloids results in a potential serious health risk and great postharvest losses. This study examined the inhibiting effects of ethanol fumigation and ethanol fumigation combined with N2 treatment on potato greening...

Incorporating seeds in activated carbon pellets limits herbicide effects to seeded bunchgrasses when controlling exotic annuals

USDA-ARS?s Scientific Manuscript database

Revegetation of exotic annual grass-invaded rangeland with pre-emergent herbicides is challenging because seeding is delayed until herbicide toxicity has diminished, but at this time, exotic annuals can be re-invading. Incorporating seeds into activated carbon pellets may allow seeding to occur at t...

Effect of delayed toxicity of chemical barriers to control Argentine ants (Hymenoptera: Formicidae).

PubMed

Soeprono, Andrew M; Rust, Michael K

2004-12-01

Brief exposures of Argentine ants to four different insecticide treatments, bifenthrin, beta-cyfluthrin, bifenthrin + beta-cyfluthrin, and fipronil, were conducted to determine Kaplan-Meier product limit survivorship percentiles (SPs) at 21-23 and 27-29 degrees C. Bifenthrin, beta-cyfluthrin, and bifenthrin + beta-cyfluthrin provided rapid kill at 21-23 degrees C with SP10 values ranging from 11.2 to 33.7 min. Fipronil provided delayed toxicity at 21-23 degrees C with SP10 values ranging from 270 to 960 min. At 27-29 degrees C, all of the SP10 values significantly decreased. Field tests in which Argentine ants were induced to forage across insecticide-treated surfaces were used to determine the effect that speed of action has on foraging and recruitment ability, and whether these insecticides are repellent. The slower-acting fipronil allowed a greater amount of foraging and consequently a greater fraction of the colony to be exposed, whereas fast-acting bifenthrin, beta-cyfluthrin, and bifenthrin + beta-cyfluthrin inhibited recruitment, resulting in fewer ants being exposed and killed. Implications for controlling ants by using perimeter barrier treatments are discussed.

The Combined Effect of Methyl- and Ethyl-Paraben on Lifespan and Preadult Development Period of Drosophila melanogaster (Diptera: Drosophilidae)

PubMed Central

Chen, Qi; Pan, Chenguang; Li, Yajuan; Zhang, Min; Gu, Wei

2016-01-01

Parabens are widely used as preservative substances in foods, pharmaceuticals, industrial products, and cosmetics. But several studies have cautioned that parabens have estrogenic or endocrine-disrupting properties. Drosophila melanogaster is an ideal model in vivo to detect the toxic effects of chemistry. The study was designed to assess the potential additive toxic effects of methylparaben (MP) and ethylparaben (EP) mixture (MP + EP) on lifespan and preadult development period in D. melanogaster. The data revealed that the MP + EP can reduce the longevity of flies compared with the control group, consistent with a significant reduction in malondialdehyde levels and an increase in superoxide dismutase activities. Furthermore, MP + EP may have a greater toxic effect on longevity of flies than separate using with the same concentration. Additionally, parabens had a nonmonotonic dose–response effect on D. melanogaster preadult development period, showing that MP + EP delayed preadult development period compared with control group while individual MP or EP significantly shortened (P < 0.01) at low concentration (300 mg/l). In conclusion, MP + EP had the potential additive toxicity on lifespan and preadult development period for D. melanogaster. PMID:28076277

Screening of Toxic Effects of Bisphenol A and Products of Its Degradation: Zebrafish (Danio rerio) Embryo Test and Molecular Docking.

PubMed

Makarova, Katerina; Siudem, Pawel; Zawada, Katarzyna; Kurkowiak, Justyna

2016-10-01

Bisphenol A (BPA) acts as an endocrine-disrupting compound even at a low concentration. Degradation of BPA could lead to the formation of toxic products. In this study, we compare the toxicity of BPA and seven intermediate products of its degradation. The accuracy of three molecular docking programs (Surflex, Autodock, and Autodock Vina) in predicting the binding affinities of selected compounds to human (ERα, ERβ, and ERRγ) and zebrafish (ERα, ERRγA, and ERRγB) estrogen and estrogen-related receptors was evaluated. The docking experiments showed that 4-isopropylphenol could have similar toxicity to that of BPA due to its high affinity to ERRγ and ERRγB and high octanol-water partitioning coefficient. The least toxic compounds were hydroquinone and phenol. Those compounds as well as BPA were screened in the zebrafish (Danio rerio) embryo test. 4-isopropylphenol had the strongest toxic effect on zebrafish embryos and caused 100% lethality shortly after exposure. BPA caused the delay in development, multiple deformations, and low heartbeats (30 bps), whereas hydroquinone had no impact on the development of the zebrafish embryo. Thus, the results of zebrafish screening are in good agreement with our docking experiment. The molecular docking could be used to screen the toxicity of other xenoestrogens and their products of degradation.

Short-term exposure to low doses of rotenone induces developmental, biochemical, behavioral, and histological changes in fish.

PubMed

Melo, Karina Motta; Oliveira, Rhaul; Grisolia, Cesar Koppe; Domingues, Inês; Pieczarka, Julio Cesar; de Souza Filho, José; Nagamachi, Cleusa Yoshiko

2015-09-01

Rotenone, a natural compound derived from plants of the genera Derris and Lonchocarpus, is used worldwide as a pesticide and piscicide. This study aims to assess short-term toxicity of rotenone to early-life stages of the fish Danio rerio and Poecilia reticulata using a wide and integrative range of biomarkers (developmental, biochemical, behavioral, and histopathological). Moreover, the species sensitivity distribution (SSD) approach was used to compare rotenone acute toxicity to fish species. Toxicity tests were based on the OECD protocols, fish embryo toxicity test (for D. rerio embryos), and fish acute toxicity test (for P. reticulata juveniles). D. rerio embryos were used to estimate lethal concentrations and analyze embryonic and enzymatic alterations (activity of catalase, glutathione-S-transferase, and cholinesterase), while P. reticulata juveniles were used for the assessment of histological damage in the gills and liver. Rotenone induced significant mortality in zebrafish embryos with a 96-h lethal concentration 50% (LC50) = 12.2 μg/L. Rotenone was embryotoxic, affecting the development of D. rerio embryos, which showed cardiac edema; tail deformities; loss of equilibrium; and a general delay characterized by lack of tail detachment, delayed somite formation, yolk sac absorption, and lack of pigmentation. Biochemical biomarker inhibition was observed for concentrations ≥1 μg/L for CAT and glutathione-S-transferase (GST) and for cholinesterase (ChE) in concentration from 10 μg/L. Behavioral changes were observed for P. reticulata juveniles exposed to concentrations equal to or above 25 μg/L of rotenone; moreover, histological damage in the liver and gills of fish exposed to concentrations equal to or above 2.5 μg/L could be observed. A hazard concentration 5% (HC5) of 3.2 μg/L was estimated considering the acute toxicity data for different fish species (n = 49). Lethal and sublethal effects of rotenone raise a concern about its effects on nontarget fish species, especially because rotenone and its metabolite rotenolone are frequently reported in the microgram range in natural environments for several days after field applications. Rotenone should be used with caution. Given the high toxicity and wide range of sublethal effects here reported, further studies in a chronic exposure scenario are recommended.

Adverse Effects of Methylmercury: Environmental Health Research Implications

PubMed Central

Grandjean, Philippe; Satoh, Hiroshi; Murata, Katsuyuki; Eto, Komyo

2010-01-01

Background The scientific discoveries of health risks resulting from methylmercury exposure began in 1865 describing ataxia, dysarthria, constriction of visual fields, impaired hearing, and sensory disturbance as symptoms of fatal methylmercury poisoning. Objective Our aim was to examine how knowledge and consensus on methylmercury toxicity have developed in order to identify problems of wider concern in research. Data sources and extraction We tracked key publications that reflected new insights into human methylmercury toxicity. From this evidence, we identified possible caveats of potential significance for environmental health research in general. Synthesis At first, methylmercury research was impaired by inappropriate attention to narrow case definitions and uncertain chemical speciation. It also ignored the link between ecotoxicity and human toxicity. As a result, serious delays affected the recognition of methylmercury as a cause of serious human poisonings in Minamata, Japan. Developmental neurotoxicity was first reported in 1952, but despite accumulating evidence, the vulnerability of the developing nervous system was not taken into account in risk assessment internationally until approximately 50 years later. Imprecision in exposure assessment and other forms of uncertainty tended to cause an underestimation of methylmercury toxicity and repeatedly led to calls for more research rather than prevention. Conclusions Coupled with legal and political rigidity that demanded convincing documentation before considering prevention and compensation, types of uncertainty that are common in environmental research delayed the scientific consensus and were used as an excuse for deferring corrective action. Symptoms of methylmercury toxicity, such as tunnel vision, forgetfulness, and lack of coordination, also seemed to affect environmental health research and its interpretation. PMID:20529764

Novel Regenerative Peptide TP508 Mitigates Radiation-Induced Gastrointestinal Damage By Activating Stem Cells and Preserving Crypt Integrity

PubMed Central

Kantara, Carla; Moya, Stephanie M.; Houchen, Courtney W.; Umar, Shahid; Ullrich, Robert L.; Singh, Pomila; Carney, Darrell H.

2015-01-01

In recent years, increasing threats of radiation exposure and nuclear disasters have become a significant concern for the United States and countries worldwide. Exposure to high doses of radiation triggers a number of potentially lethal effects. Among the most severe is the gastrointestinal (GI) toxicity syndrome caused by the destruction of the intestinal barrier, resulting in bacterial translocation, systemic bacteremia, sepsis and death. The lack of effective radioprotective agents capable of mitigating radiation-induced damage has prompted a search for novel countermeasures that can mitigate the effects of radiation post-exposure, accelerate tissue repair in radiation-exposed individuals, and prevent mortality. We report that a single injection of regenerative peptide TP508 (rusalatide acetate, Chrysalin®) 24h after lethal radiation exposure (9Gy, LD100/15) appears to significantly increase survival and delay mortality by mitigating radiation-induced intestinal and colonic toxicity. TP508 treatment post-exposure prevents the disintegration of gastrointestinal crypts, stimulates the expression of adherens junction protein E-cadherin, activates crypt cell proliferation, and decreases apoptosis. TP508 post-exposure treatment also up-regulates the expression of DCLK1 and LGR5 markers of stem cells that have been shown to be responsible for maintaining and regenerating intestinal crypts. Thus, TP508 appears to mitigate the effects of GI toxicity by activating radioresistant stem cells and increasing the stemness potential of crypts to maintain and restore intestinal integrity. These results suggest that TP508 may be an effective emergency nuclear countermeasure that could be delivered within 24h post-exposure to increase survival and delay mortality, giving victims time to reach clinical sites for advanced medical treatment. PMID:26280221

Antivenom therapy for snakebites in children: is there evidence?

PubMed

Schmidt, James M

2005-04-01

A new Fab fragment antivenom (CroFab) for the treatment of crotaline envenomation, the predominant venomous snakebite in the United States, has drastically changed snakebite management since its release in December 2000. This review examines the evidence supporting the use of CroFab, with particular attention on the pediatric population. The published experience with CroFab in humans consists of six studies and some case reports. These publications demonstrate that CroFab is highly efficacious in treating both the local and systemic toxic effects of crotaline envenomation. They identify an important phenomenon of recurrent or delayed toxicity in some patients. The studies report a very low incidence of acute or delayed hypersensitivity reactions to the antivenom. They suggest comparable efficacy and safety of CroFab in the pediatric population as in adults. Based on limited data, CroFab has been shown to be a safe and efficacious antivenom for use in children as well as adults. Further studies are needed to refine our understanding of its efficacy, safety, indications, and dosing.

The small-molecule TNF-α inhibitor, UTL-5g, delays deaths and increases survival rates for mice treated with high doses of cisplatin

PubMed Central

Media, Joseph; Chen, Ben; Valeriote, Fredrick

2013-01-01

Purpose UTL-5g is a novel small-molecule chemoprotector that lowers hepatotoxicity, nephrotoxicity, and myelotoxicity induced by cisplatin through TNF-α inhibition among other factors. The objective of this study was to investigate whether UTL-5g can reduce the overall acute toxicity of cisplatin and increase cisplatin tolerability in mice. Materials and Methods BDF1 female mice were treated individually with UTL-5g (suspended in Ora-Plus) by oral gavage at 60 mg/kg, 30 min before i.p. injection of cisplatin at 10, 15, and 20 mg/kg respectively on Day 0. Starting from Day 1, individual mice were again treated daily by the same dose of UTL-5g for 4 consecutive days. Survivals and bodyweights were monitored. Results UTL-5g treatment increased the survival rate and delayed the time to death for mice treated with 150% of the maximum tolerated dose (MTD) of cisplatin (15 mg/kg). Likewise, at 200% of the MTD of cisplatin (20 mg/kg), treatment of UTL-5g increased the survival rate and delayed the time to death. Treatment of UTL-5g did not have a significant effect on weight-loss induced by cisplatin indicating that bodyweight may not be a sensitive enough measure for chemoprotection of UTL-5g against cisplatin. Conclusions In summary, UTL-5g delayed deaths and increased survival rates of mice treated by high doses of cisplatin indicating that UTL-5g is capable of reducing the overall acute toxicity of cisplatin and increased cisplatin tolerability in mice; this is in line with the specific chemoprotective effects of UTL-5g previously reported. Further investigation of UTL-5g in combination with cisplatin is warranted. PMID:23881213

The small-molecule TNF-α inhibitor, UTL-5g, delays deaths and increases survival rates for mice treated with high doses of cisplatin.

PubMed

Shaw, Jiajiu; Media, Joseph; Chen, Ben; Valeriote, Fredrick

2013-09-01

UTL-5g is a novel small-molecule chemoprotector that lowers hepatotoxicity, nephrotoxicity, and myelotoxicity induced by cisplatin through TNF-α inhibition among other factors. The objective of this study was to investigate whether UTL-5g can reduce the overall acute toxicity of cisplatin and increase cisplatin tolerability in mice. BDF1 female mice were treated individually with UTL-5g (suspended in Ora-Plus) by oral gavage at 60 mg/kg, 30 min before i.p. injection of cisplatin at 10, 15, and 20 mg/kg, respectively, on Day 0. Starting from Day 1, individual mice were again treated daily by the same dose of UTL-5g for 4 consecutive days. Survivals and body weights were monitored. UTL-5g treatment increased the survival rate and delayed the time to death for mice treated with 150 % of the maximum tolerated dose (MTD) of cisplatin (15 mg/kg). Likewise, at 200 % of the MTD of cisplatin (20 mg/kg), treatment of UTL-5g increased the survival rate and delayed the time to death. Treatment of UTL-5g did not have a significant effect on weight loss induced by cisplatin, indicating that body weight may not be a sensitive-enough measure for chemoprotection of UTL-5g against cisplatin. In summary, UTL-5g delayed deaths and increased survival rates of mice treated by high doses of cisplatin, indicating that UTL-5g is capable of reducing the overall acute toxicity of cisplatin and increased cisplatin tolerability in mice; this is in line with the specific chemoprotective effects of UTL-5g previously reported. Further investigation of UTL-5g in combination with cisplatin is warranted.

Sodium benzoate induced developmental defects, oxidative stress and anxiety-like behaviour in zebrafish larva.

PubMed

Gaur, Himanshu; Purushothaman, Srinithi; Pullaguri, Narasimha; Bhargava, Yogesh; Bhargava, Anamika

2018-07-20

Sodium benzoate (SB) is a common food preservative. Its FDA described safety limit is 1000 ppm. Lately, increased use of SB has prompted investigations regarding its effects on biological systems. Data regarding toxicity of SB is divergent and controversial with studies reporting both harmful and beneficial effects. Therefore, we did a systematic dose dependent toxicity study of SB using zebrafish vertebrate animal model. We also investigated oxidative stress and anxiety-like behaviour in zebrafish larva treated with SB. Our results indicate that SB induced developmental (delayed hatching), morphological (pericardial edema, yolk sac edema and tail bending), biochemical (oxidative stress) and behavioural (anxiety-like behaviour) abnormalities in developing zebrafish larva. LC 50 of SB induced toxicity was approximately 400 ppm after 48 h of SB exposure. Our study strongly supports its harmful effects on vertebrates at increasing doses. Thus, we suggest caution in the excessive use of this preservative in processed and convenience foods. Copyright © 2018 Elsevier Inc. All rights reserved.

Bacterial bioluminescence response to long-term exposure to reverse osmosis treated effluents from dye industries.

PubMed

Ravindran, J; Manikandan, B; Shirodkar, P V; Francis, K X; Mani Murali, R; Vethamony, P

2014-10-01

The bacterial bioluminescence assay is one of the novel means for toxicity detection. The bioluminescence response of 2 marine bioluminescent bacteria was tested upon their long-term exposure to 9 different reverse osmosis (RO) rejects with varying chemical composition sampled from various dye industries. Bioluminescent bacteria were cultured in the RO reject samples, at different concentrations, and their growth rate and luminescence was measured for 24 h. The RO reject samples caused sublethal effects upon exposure and retarded the growth of bacteria, confirming their toxic nature. Further, continuation of the exposure showed that the initial luminescence, though reduced, recovered and increased beyond the control cultures irrespective of cell density, and finally decreased once again. The present study emphasizes the need of evolving a long-term exposure assay and shows that the method followed in this study is suitable to evaluate the toxicants that exert delayed toxicity, using lower concentrations of toxicants as well as coloured samples.

Possible long term effects of chemical warfare using visual evoked potentials.

PubMed

Riazi, Abbas; Hafezi, Rhamatollah; Babaei, Mahmoud; Naderi, Mostafa

2014-09-01

Some studies have already addressed the effects of occupational organic solvent exposure on the visually evoked potentials (VEPs). Visual system is an important target for Sulphur Mustard (SM) toxicity. A number of Iranian victims of Sulphur Mustard (SM) agent were apprehensive about the delay effect of SM on their vision and a possible delay effect of SM on their visual cortex. This investigation was performed on 34 individuals with a history of chemical exposure and a control group of 15 normal people. The Toennies electro-diagnosis device was used and its signals were saved as the latencies. The mean of N75, N140 and P100 of victims of chemical warfare (VCWs) and control group indicated no significant results (P>0.05). The VCWs did not show any visual symptoms and there was no clear deficit in their VEPs.

40 CFR 799.9365 - TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity screening...

Code of Federal Regulations, 2011 CFR

2011-07-01

... the control and the top dose group for observation of reversibility, persistence or delayed occurrence... toxicity. (2) Dosage. (i) Generally, at least three test groups and a control group should be used. If... administering the test substance, the control group should receive the vehicle in the highest volume used. (ii...

40 CFR 799.9365 - TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity screening...

Code of Federal Regulations, 2012 CFR

2012-07-01

... the control and the top dose group for observation of reversibility, persistence or delayed occurrence... toxicity. (2) Dosage. (i) Generally, at least three test groups and a control group should be used. If... administering the test substance, the control group should receive the vehicle in the highest volume used. (ii...

40 CFR 799.9365 - TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity screening...

Code of Federal Regulations, 2010 CFR

2010-07-01

... the control and the top dose group for observation of reversibility, persistence or delayed occurrence... toxicity. (2) Dosage. (i) Generally, at least three test groups and a control group should be used. If... administering the test substance, the control group should receive the vehicle in the highest volume used. (ii...

40 CFR 799.9365 - TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity screening...

Code of Federal Regulations, 2013 CFR

2013-07-01

... the control and the top dose group for observation of reversibility, persistence or delayed occurrence... toxicity. (2) Dosage. (i) Generally, at least three test groups and a control group should be used. If... administering the test substance, the control group should receive the vehicle in the highest volume used. (ii...

40 CFR 799.9365 - TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity screening...

Code of Federal Regulations, 2014 CFR

2014-07-01

... the control and the top dose group for observation of reversibility, persistence or delayed occurrence... toxicity. (2) Dosage. (i) Generally, at least three test groups and a control group should be used. If... administering the test substance, the control group should receive the vehicle in the highest volume used. (ii...

Enhanced effect of geldanamycin nanocomposite against breast cancer cells growing in vitro and as xenograft with vanquished normal cell toxicity

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

Prabhu, Suma

Despite enormous advances in remedies developed for breast cancer, an effective therapeutic strategy by targeting malignant cells with the least normal tissue toxicity is yet to be developed. Hsp90 is considered to be an important therapeutic target to inhibit cell proliferation. Geldanamycin (GDM), a potent inhibitor of Hsp90 was withdrawn from clinical trials due to its undesirable hepatotoxicity. We report a superparamagnetic iron oxide (SPION) based polymeric nanocomposite of GDM augmenting anticancer competence with decreased hepatic toxicity. The particle size of nanocomposite was ascertained to be 76 ± 10 nm with acceptable stability. A comparative dose dependent in vitro validationmore » of cytotoxicity showed an enhanced cellular damage and necrosis in breast cancer (MCF-7) cell line at a low dose of 5.49 nM (in GDM nanocomposite) in contrast to 20 nM of pure GDM, while normal breast epithelial cells (MCF-10A) were least affected. Besides, in vivo study (in breast cancer xenografts) substantiated 2.7 fold delay in tumor progression mediated by redundancy in the downstream functions of p-Akt and MAPK-Erk leading to apoptosis with negligible hepatotoxicity. Pure GDM disrupted the function and morphology of liver with lesser therapeutic efficacy than the GDM nanocomposite. These findings deduce that GDM based polymeric magnetite nanocomposite play a vital role in efficacious therapy while vanquishing normal cells and hepatic toxicity and thereby promising it to be reinstated in clinics. - Highlights: • GDM nanocomposite shows selective cell kill of cancerous breast cells. • Nanocomposite delays the growth of tumor in comparison to pure GDM treatment. • GDM promotes apoptosis by down-regulation of p-Akt and MAPK-Erk. • GDM nanocomposite nullifies the hepatotoxicity generally exhibited by pure GDM.« less

Clinical aspects of percutaneous poisoning by the chemical warfare agent VX: effects of application site and decontamination.

PubMed

Hamilton, Murray G; Hill, Ira; Conley, John; Sawyer, Thomas W; Caneva, Duane C; Lundy, Paul M

2004-11-01

O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothioate (VX) is an extremely toxic organophosphate nerve agent that has been weaponized and stockpiled in a number of different countries, and it has been used in recent terrorist events. It differs from other well-known organophosphate nerve agents in that its primary use is as a contact poison rather than as an inhalation hazard. For this reason, we examined the effects of application site and skin decontamination on VX toxicity in anesthetized domestic swine after topical application. VX applied to the surface of the ear rapidly resulted in signs of toxicity consistent with the development of cholinergic crisis, including apnea and death. VX on the epigastrium resulted in a marked delayed development of toxic signs, reduced toxicity, and reduction in the rate of cholinesterase depression compared with animals exposed on the ear. Skin decontamination (15 minutes post-VX on the ear) arrested the development of clinical signs and prevented further cholinesterase inhibition and death. These results confirm earlier work that demonstrates the importance of exposure site on the resultant toxicity of this agent and they also show that decontamination postexposure has the potential to be an integral and extremely important component of medical countermeasures against this agent.

Strong Delayed Interactive Effects of Metal Exposure and Warming: Latitude-Dependent Synergisms Persist Across Metamorphosis.

PubMed

Debecker, Sara; Dinh, Khuong V; Stoks, Robby

2017-02-21

As contaminants are often more toxic at higher temperatures, predicting their impact under global warming remains a key challenge for ecological risk assessment. Ignoring delayed effects, synergistic interactions between contaminants and warming, and differences in sensitivity across species' ranges could lead to an important underestimation of the risks. We addressed all three mechanisms by studying effects of larval exposure to zinc and warming before, during, and after metamorphosis in Ischnura elegans damselflies from high- and low-latitude populations. By integrating these mechanisms into a single study, we could identify two novel patterns. First, during exposure zinc did not affect survival, whereas it induced mild to moderate postexposure mortality in the larval stage and at metamorphosis, and very strongly reduced adult lifespan. This severe delayed effect across metamorphosis was especially remarkable in high-latitude animals, as they appeared almost insensitive to zinc during the larval stage. Second, the well-known synergism between metals and warming was manifested not only during the larval stage but also after metamorphosis, yet notably only in low-latitude damselflies. These results highlight that a more complete life-cycle approach that incorporates the possibility of delayed interactions between contaminants and warming in a geographical context is crucial for a more realistic risk assessment in a warming world.

The Combined Effect of Methyl- and Ethyl-Paraben on Lifespan and Preadult Development Period of Drosophila melanogaster (Diptera: Drosophilidae).

PubMed

Chen, Qi; Pan, Chenguang; Li, Yajuan; Zhang, Min; Gu, Wei

2016-01-01

Parabens are widely used as preservative substances in foods, pharmaceuticals, industrial products, and cosmetics. But several studies have cautioned that parabens have estrogenic or endocrine-disrupting properties. Drosophila melanogaster is an ideal model in vivo to detect the toxic effects of chemistry. The study was designed to assess the potential additive toxic effects of methylparaben (MP) and ethylparaben (EP) mixture (MP + EP) on lifespan and preadult development period in D. melanogaster The data revealed that the MP + EP can reduce the longevity of flies compared with the control group, consistent with a significant reduction in malondialdehyde levels and an increase in superoxide dismutase activities. Furthermore, MP + EP may have a greater toxic effect on longevity of flies than separate using with the same concentration. Additionally, parabens had a nonmonotonic dose-response effect on D. melanogaster preadult development period, showing that MP + EP delayed preadult development period compared with control group while individual MP or EP significantly shortened (P < 0.01) at low concentration (300 mg/l). In conclusion, MP + EP had the potential additive toxicity on lifespan and preadult development period for D. melanogaster. © The Author 2016. Published by Oxford University Press on behalf of the Entomological Society of America.

Acute and chronic systemic chromium toxicity.

PubMed

Gad, S C

1989-10-01

Although chromium and compounds containing it have been recognized as having potential severe adverse effects on health for more than 160 years, understanding of the systemic toxicology and true hazard of these compounds is still not complete. A review of the current state of knowledge is attempted in this paper, with appropriate attention given to the complications of multiple valence states and solubility. Selected chromium compounds, particularly hexavalent ones, are carcinogens, corrosives, delayed contact sensitizers, and have the kidney as their primary target organ. But chromium is also an essential element for humans. The body clearly possesses some effective detoxification mechanisms for some degree of exposure to hexavalent chrome compounds. The significant features of acute and chronic chromium toxicity are presented in view of these considerations.

Accumulation and developmental toxicity of hexabromocyclododecanes (HBCDs) on the marine copepod Tigriopus japonicus.

PubMed

Shi, Dalin; Lv, Dongmei; Liu, Wanxin; Shen, Rong; Li, Dongmei; Hong, Haizheng

2017-01-01

The brominated flame retardants hexabromocyclododecanes (HBCDs) are ubiquitous environmental contaminants, widely distributed in aquatic systems including the marine environment and marine organisms. HBCDs are toxic to the development of both freshwater and marine fish. However, the impacts of HBCDs on marine invertebrates are not well known. In this study, the marine copepod, Tigriopus japonicus, was used to assess the bioaccumulation and developmental toxicity of technical HBCD (tHBCD) through water-borne exposure. The uptake rate constant of tHBCD by T. japonicus was high, which resulted in high bioaccumulation potential. The bioconcentration factors of tHBCD were 8.73 × 10 4 and 6.34 × 10 4  L kg -1 in T. japonicus, calculated using the kinetic and steady-state methods, respectively. Exposure of T. japonicus nauplii to tHBCD caused significant growth delay. The lowest-observable-effect-concentrations of tHBCD induced developmental delay were 30 and 8 μg L -1 for the F0 and F1 generations, respectively, which suggested that the F1 generation was more sensitive to tHBCD than the F0 generation and warranted multiple-generation toxicity tests for future studies. Furthermore, exposure of the adult copepods to tHBCD induced the transcription of oxidative stress response genes and apoptotic genes, e.g., SOD,CAT, GST, OGG1, P53 and Caspase-3. It was therefore speculated that tHBCD exposure induced the generation of reactive oxygen species in T. japonicus, which activated the oxidative stress defense genes and meanwhile resulted in oxidative DNA damage. The damaged DNA activated the transcription of p53 and triggered the caspase-mediated apoptosis pathway, which may be the reason for the tHBCD induced developmental delay in T. japonicus nauplii. Copyright © 2016 Elsevier Ltd. All rights reserved.

Acute kidney injury and hyperbilirubinemia in a young male after ingestion of Tribulus terrestris.

PubMed

Ryan, Margaret; Lazar, Ira; Nadasdy, Gyongyi M; Nadasdy, Tibor; Satoskar, Anjali A

2015-03-01

Acute tubular necrosis (ATN), especially from toxic injury is frequently accompanied by tubular casts and crystals. Myeloma casts, myoglobin, red blood cell and granular casts are well described. However, bile casts in tubules are rarely seen. We describe a case of Tribulus terrestris toxicity in a young healthy male, presenting with severe hyperbilirubinemia followed by acute renal failure and bile containing casts in the tubules. Tribulus terrestris is an herb often used by athletes as a nutritional supplement for performance enhancement. Although it is thought to be relatively safe, serious side effects have been reported before. Our aim is to increase awareness of the potential toxicities of performance enhancing herbal medications. These are often sold over-the-counter and therefore casually used, especially by young healthy individuals. Beneficial effects are controversial. Under-reporting by patients and infrequent documentation by health-care providers can delay diagnosis. We elaborately describe the kidney biopsy findings in Tribulus terrestris toxicity, and also provide a concise overview of the spectrum of tubular casts and their staining patterns, found in various kidney diseases.

Detoxification depot for beta-amyloid peptides.

PubMed

Sundaram, Ranjini K; Kasinathan, Chinnaswamy; Stein, Stanley; Sundaram, Pazhani

2008-02-01

Alzheimer's Disease (AD) is caused by the deposition of insoluble and toxic amyloid peptides (Abeta) in the brain leading to memory loss and other associated neurodegenerative symptoms. To date there is limited treatment options and strategies for treating AD. Studies have shown that clearance of the amyloid plaques from the brain and thus from the blood could be effective in stopping and or delaying the progression of the disease. Small peptides derived from the Abeta-42 sequence, in particular KLVFF, have shown to be effective binders of Abeta peptides and thus could be useful in delaying progression of the disease. We have taken advantage of this property by generating the retro-inverso (RI) version of this peptide, ffvlk, in different formats. We are presenting a new detox gel system using poly ethylene glycol (PEG), polymerized and cross linked with the RI peptides. We hypothesize that detox gel incorporating RI peptides will act like a 'sink' to capture the Abeta peptides from the surrounding environment. We tested these detox gels for their ability to capture biotinylated Abeta-42 peptides in vitro. The results showed that the detox gels bound Abeta-42 peptides effectively and irreversibly. Gels incorporating the tetramer RI peptide exhibited maximum binding capacity. The detox gel could be a potential candidate for treatment strategies to deplete the brain of toxic amyloid peptides.

Pregnenolone protects the PC-12 cell line against amyloid beta peptide toxicity but its sulfate ester does not.

PubMed

Akan, Pinar; Kizildag, Servet; Ormen, Murat; Genc, Sermin; Oktem, Mehmet Ali; Fadiloglu, Meral

2009-01-15

Pregnenolone (P), the main precursor of the steroids, and its sulfate ester, pregnenolone sulfate (PS), are the major neurosteroids produced in the neural tissue. Many neuroendocrinological studies stressed the neuroprotective role of neurosteroids although it has been suggested that the inhibition of P and PS synthesis can delay neuronal cell death. The potential roles of P and PS in vital neuronal functions and in amyloid beta peptide (Abeta) toxicity are not clearly identified. This work aims to investigate the effects of P and PS on cell viability and Abeta peptide toxicity in a concentration and exposure time-dependent manner in rat PC-12 cells. The cells were treated with 20muM Abeta peptide 25-35 and variable concentrations of P and PS ranging from 0.5muM to 100muM. To examine the effects of steroid treatment on Abeta peptide toxicity, 0.5muM (low) and 50muM (high) neurosteroids were used. The cell viability and lactate dehydrogenase release of cells were evaluated after 24, 48 and 72h. Morphological changes of cells were also examined. The treatment with higher than 1muM concentrations of P and PS significantly decreased the cell viability comparing to untreated cells. At lower concentrations, P and PS had no toxic actions until 72h. The Abeta treatment resulted in a significant decrease in cell viability comparing to untreated cells. P showed a dose-dependent protective effect against Abeta peptide in PC-12 cells. But its sulfate ester did not have the same effect on Abeta peptide toxicity, even it significantly decreased cell viability in Abeta-treated cells. Consequently, the discrepant effects of P and PS on Abeta peptide toxicity may provide insight on the pathogenesis of Alzheimer's disease.

The efficacy of Pistacia Terebinthus soap in the treatment of cetuximab-induced skin toxicity.

PubMed

Tastekin, Didem; Tambas, Makbule; Kilic, Kemal; Erturk, Kayhan; Arslan, Deniz

2014-12-01

This open-labeled phase II, efficacy-finding study evaluated the efficiency and safety of Pistacia terebinthus soap in metastatic colorectal cancer patients who developed cetuximab induced skin toxicity. Patients who received cetuximab plus chemotherapy and developed Grade 2 or 3 skin toxicity were treated twice daily with a soap made of oil extracted from Pistacia terebinthus. During treatment, no topical or oral antibiotics, corticosteroids or other moisturizers were used. Patients were examined 1 week later and their photographs were taken. Fifteen mCRC patients who developed skin toxicity while receiving first-line CTX in combination with chemotherapy were included into the study. Eight patients were male and the median age was 58 (25-70). Sixty percent of the patients (n:9) had Grade 3 skin toxicity. Complete response rates in patients with Grade 2 and Grade 3 skin toxicities were 100 and 33%, respectively. In the remaining patients with Grade 3 toxicity the skin toxicity regressed to Grade 1. The objective response rate was 100%, and no delay, dose reduction or discontinuation of CTX treatment due to skin toxicity was necessary. Skin toxicity reoccurred in all patients when patients stopped administering the soap and therefore they used it throughout the cetuximab treatment. Pistacia terebinthus soap seemed to be used safely and effectively in the treatment of skin toxicity induced by Cetuximab.

Ecotoxicology of phenylphosphonothioates.

PubMed Central

Francis, B M; Hansen, L G; Fukuto, T R; Lu, P Y; Metcalf, R L

1980-01-01

The phenylphosphonothioate insecticides EPN and leptophos, and several analogs, were evaluated with respect to their delayed neurotoxic effects in hens and their environmental behavior in a terrestrial-aquatic model ecosystem. Acute toxicity to insects was highly correlated with sigma sigma of the substituted phenyl group (regression coefficient r = -0.91) while acute toxicity to mammals was slightly less well correlated (regression coefficient r = -0.71), and neurotoxicity was poorly correlated with sigma sigma (regression coefficient r = -0.35). Both EPN and leptophos were markedly more persistent and bioaccumulative in the model ecosystem than parathion. Desbromoleptophos, a contaminant and metabolite of leptophos, was seen to be a highly stable and persistent terminal residue of leptophos. PMID:6159210

Effect of pulmonary surfactant on the dissolution, stability and uptake of zinc oxide nanowires by human respiratory epithelial cells

PubMed Central

Theodorou, Ioannis G.; Ruenraroengsak, Pakatip; Gow, Andrew; Schwander, Stephan; Zhang, Junfeng (Jim); Chung, Kian Fan; Tetley, Teresa D.; Ryan, Mary P.; Porter, Alexandra E.

2017-01-01

Inhaled nanoparticles have high deposition rates in the alveolar region of the lung but the effects of pulmonary surfactant (PS) on nanoparticle bioreactivity are unclear. Here, the impact of PS on the stability and dissolution of ZnO nanowires (ZnONWs) was investigated, and linked with their bioreactivity in vitro with human alveolar epithelial type 1-like cells (TT1). Pre-incubation of ZnONWs with Curosurf® (a natural porcine PS) decreased their dissolution at acidic pH, through the formation of a phospholipid corona. Confocal live cell microscopy confirmed that Curosurf® lowered intracellular dissolution, thus delaying the onset of cell death compared to bare ZnONWs. Despite reducing dissolution, Curosurf® significantly increased the uptake of ZnONWs within TT1 cells, ultimately increasing their toxicity after 24h. Although serum, improved ZnONW dispersion in suspension similar to Curosurf®, it had no effect on ZnONW internalization and toxicity, indicating a unique role of PS in promoting particle uptake. In the absence of PS, ZnONW length had no effect on dissolution kinetics or degree of cellular toxicity, indicating a less important role of length in determining ZnONW bioreactivity. This work provides unique findings on the effects of PS on the stability and toxicity of ZnONWs, which could be important in the study of pulmonary toxicity and epithelial-endothelial translocation of nanoparticles in general. PMID:27441789

Outcome and toxicity associated with a dose-intensified, maintenance-free CHOP-based chemotherapy protocol in canine lymphoma: 130 cases.

PubMed

Sorenmo, Karin; Overley, B; Krick, E; Ferrara, T; LaBlanc, A; Shofer, F

2010-09-01

A dose-intensified/dose-dense chemotherapy protocol for canine lymphoma was designed and implemented at the Veterinary Hospital of the University of Pennsylvania. In this study, we describe the clinical characteristics, prognostic factors, efficacy and toxicity in 130 dogs treated with this protocol. The majority of the dogs had advanced stage disease (63.1% stage V) and sub-stage b (58.5%). The median time to progression (TTP) and lymphoma-specific survival were 219 and 323 days, respectively. These results are similar to previous less dose-intense protocols. Sub-stage was a significant negative prognostic factor for survival. The incidence of toxicity was high; 53.9 and 45% of the dogs needed dose reductions and treatment delays, respectively. Dogs that required dose reductions and treatment delays had significantly longer TTP and lymphoma-specific survival times. These results suggest that dose density is important, but likely relative, and needs to be adjusted according to the individual patient's toxicity for optimal outcome.

Bacterial toxicity assessment of drinking water treatment residue (DWTR) and lake sediment amended with DWTR.

PubMed

Yuan, Nannan; Wang, Changhui; Pei, Yuansheng

2016-11-01

Drinking water treatment residue (DWTR) seems to be very promising for controlling lake sediment pollution. Logically, acquisition of the potential toxicity of DWTR will be beneficial for its applications. In this study, the toxicity of DWTR and sediments amended with DWTR to Aliivibrio fischeri was evaluated based on the Microtox(®) solid and leachate phase assays, in combination with flow cytometry analyses and the kinetic luminescent bacteria test. The results showed that both solid particles and aqueous/organic extracts of DWTR exhibited no toxicity to the bacterial luminescence and growth. The solid particles of DWTR even promoted bacterial luminescence, possibly because DWTR particles could act as a microbial carrier and provide nutrients for bacteria growth. Bacterial toxicity (either luminescence or growth) was observed from the solid phase and aqueous/organic extracts of sediments with or without DWTR addition. Further analysis showed that the solid phase toxicity was determined to be related mainly to the fixation of bacteria to fine particles and/or organic matter, and all of the observed inhibition resulting from aqueous/organic extracts was identified as non-significant. Moreover, DWTR addition not only had no adverse effect on the aqueous/organic extract toxicity of the sediment but also reduced the solid phase toxicity of the sediment. Overall, in practical application, the solid particles, the water-soluble substances transferred to surface water or the organic substances in DWTR had no toxicity or any delayed effect on bacteria in lakes, and DWTR can therefore be considered as a non-hazardous material. Copyright © 2016 Elsevier Ltd. All rights reserved.

TOXIC ACTIVITY AND DELAYED EFFECTS OF FIVE BOTANICAL OILS ON THE FOLLOWING GENERATIONS OF AGROTIS IPSILON (HUFNAGEL) (INSECTA: LEPIDOPTERA: NOCTUIDAE) AFTER PARENTS TREATMENT.

PubMed

Mesbah, H A; El-Sayed, N A; El-Kady, M B; Mourad, A K; Kordy, A M; Henaidy, Z M

2014-01-01

The present study is carried out to evaluate the toxic efficiency and delayed effects of five botanical oils on the greasy cut worm Agrotis ipsilon (Lepidoptera: Noctuidae), as a trial for the attainment of a possible use of an alternative safe and effective phytochemicals against the insect-pest. So as to minimize or prevent the repeated usage of conventional insecticides, then reduce the environmental pollution as well as the occurring hazards to man and domestic animal due to the use of the pesticides alone. Four tested concentrations (0.5, 1.0, 1.5 and 2.5% v/v) from each of camphor, red basil, menthol, rose and anise oils, were bioassayed by treating the offered castor oil bean leaves, to the 4th instar larvae along 48h, under the laboratory higrothermic conditions of 25±2 °C and 65±5% R.H. The obtained results showed that the five tested oils were found to have more or less toxic activity and drastic effects on the inspected parameters of fitness components of the treated parent generation of the insect, in particular, pupae, emerged adult moths and laid eggs/female. In this respect camphor and red basil oils were highly effective, followed by menthol oil, anise oil and the least effective one was rose oil. Moreover, the assessed unprofitable delayed effects on the going on of the biological performance within the treated insects showed the adverse effects on the fitness components of the consequent generations (fs) post (p) one treatment with each of the bioassyed oils. The prevalence of adverse effects and disturbance in the going on biological performance through the period of (p) generation; which is followed by the distinct failure of insect development in (f1) generation were recorded for each of the tested menthol oil at 0.5 and 1.5% (v/v); camphor oil at 1.5 and 2.5% and red basil oil at 2.5% (v/v). While anise and rose oils were somewhat less efficient causing the distinct failure of the following generations up to the 3rd and/or the 6th ones. That observed distinct failure of the insect development could be attributed to the rapid or/and slow cumulative effect of the induced recessive lethal genes in both influenced sexes along the interval of the following developed generations (fs) after (p) one treatment, causing apparent adverse disturbance of the normal biological performance, which finally appears at the beginning of the failed generation.

Systemic cytokine response in moribund mice of streptococcal toxic shock syndrome model.

PubMed

Saito, Mitsumasa; Kajiwara, Hideko; Iida, Ken-ichiro; Hoshina, Takayuki; Kusuhara, Koichi; Hara, Toshiro; Yoshida, Shin-ichi

2011-02-01

Streptococcus pyogenes causes severe invasive disease in humans, including streptococcal toxic shock syndrome (STSS). We previously reported a mouse model that is similar to human STSS. When mice were infected intramuscularly with 10(7) CFU of S. pyogenes, all of them survived acute phase of infection. After 20 or more days of infection, a number of them died suddenly accompanied by S. pyogenes bacteremia. We call this phenomenon "delayed death". We analyzed the serum cytokine levels of mice with delayed death, and compared them with those of mice who died in the acute phase of intravenous S. pyogenes infection. The serum levels of TNF-α and IFN-γ in mice of delayed death were more than 100 times higher than those in acute death mice. IL-10 and IL-12, which were not detected in acute death, were also significantly higher in mice of delayed death. IL-6 and MCP-1 (CCL-2) were elevated in both groups of mice. It was noteworthy that not only pro-inflammatory cytokines but also anti-inflammatory cytokines were elevated in delayed death. We also found that intravenous TNF-α injection accelerated delayed death, suggesting that an increase of serum TNF-α induced S. pyogenes bacteremia in our mouse model. Copyright © 2010 Elsevier Ltd. All rights reserved.

Effectiveness of urban shelter-in-place—II: Residential districts

NASA Astrophysics Data System (ADS)

Chan, Wanyu R.; Nazaroff, William W.; Price, Phillip N.; Gadgil, Ashok J.

In the event of a short-term, large-scale toxic chemical release to the atmosphere, shelter-in-place (SIP) may be used as an emergency response to protect public health. We modeled hypothetical releases using realistic, empirical parameters to explore how key factors influence SIP effectiveness for single-family dwellings in a residential district. Four classes of factors were evaluated in this case study: (a) time scales associated with release duration, SIP implementation delay, and SIP termination; (b) building air-exchange rates, including air infiltration and ventilation; (c) the degree of sorption of toxic chemicals to indoor surfaces; and (d) the shape of the dose-response relationship for acute adverse health effects. Houses with lower air leakage are more effective shelters, and thus variability in the air leakage of dwellings is associated with varying degrees of SIP protection in a community. Sorption on indoor surfaces improves SIP effectiveness by lowering the peak indoor concentrations and reducing the amount of contamination in the indoor air. Nonlinear dose-response relationships imply substantial reduction in adverse health effects from lowering the peak exposure concentration. However, if the scenario is unfavorable for indefinite sheltering (e.g. sheltering in leaky houses for protection against a nonsorbing chemical with a linear dose-response), the community must implement SIP without delay and exit from shelter when it first becomes safe to do so. Otherwise, the community can be subjected to even greater risk than if they did not take shelter indoors.

Lethal and sub-lethal effects of cyproconazole on freshwater organisms: a case study with Chironomus riparius and Dugesia tigrina.

PubMed

Saraiva, Althiéris S; Sarmento, Renato A; Golovko, Oksana; Randak, Tomas; Pestana, João L T; Soares, Amadeu M V M

2018-04-01

The fungicide cyproconazole (CPZ) inhibits the biosynthesis of ergosterol, an essential sterol component in fungal cell membrane and can also affect non-target organisms by its inhibitory effects on P450 monooxygenases. The predicted environmental concentration of CPZ is up to 49.05 μg/L and 145.89 μg/kg in surface waters and sediments, respectively, and information about CPZ toxicity towards non-target aquatic organisms is still limited. This study aimed to address the lack of ecotoxicological data for CPZ, and thus, an evaluation of the lethal and sub-lethal effects of CPZ was performed using two freshwater invertebrates (the midge Chironomus riparius and the planarian Dugesia tigrina). The estimated CPZ 48 h LC 50 (95% CI) was 17.46 mg/L for C. riparius and 47.38 mg/L for D. tigrina. The emergence time (EmT 50 ) of C. riparius was delayed by CPZ exposure from 0.76 mg/L. On the other hand, planarians showed higher tolerance to CPZ exposure. Sub-lethal effects of CPZ on planarians included reductions in locomotion (1.8 mg/L), delayed photoreceptors regeneration (from 0.45 mg/L), and feeding inhibition (5.6 mg/L). Our results confirm the moderate toxicity of CPZ towards aquatic invertebrates but sub-lethal effects observed also suggest potential chronic effects of CPZ with consequences for population dynamics.

Embryonic exposure to model naphthenic acids delays growth and hatching in the pond snail Lymnaea stagnalis.

PubMed

Johnston, Christina U; Clothier, Lindsay N; Quesnel, Dean M; Gieg, Lisa M; Chua, Gordon; Hermann, Petra M; Wildering, Willem C

2017-02-01

Naphthenic acids (NAs), a class of structurally diverse carboxylic acids with often complex ring structures and large aliphatic tail groups, are important by-products of many petrochemical processes including the oil sands mining activity of Northern Alberta. While it is evident that NAs have both acute and chronic harmful effects on many organisms, many aspects of their toxicity remain to be clarified. Particularly, while substantive data sets have been collected on NA toxicity in aquatic prokaryote and vertebrate model systems, to date, nothing is known about the toxic effects of these compounds on the embryonic development of aquatic invertebrate taxa, including freshwater mollusks. This study examines under laboratory conditions the toxicity of NAs extracted from oil sands process water (OSPW) and the low-molecular weight model NAs cyclohexylsuccinic acid (CHSA), cyclohexanebutyric acid (CHBA), and 4-tert-butylcyclohexane carboxylic acid (4-TBCA) on embryonic development of the snail Lymnaea stagnalis, a common freshwater gastropod with a broad Palearctic distribution. Evidence is provided for concentration-dependent teratogenic effects of both OSPW-derived and model NAs with remarkably similar nominal threshold concentrations between 15 and 20 mg/L and 28d EC 50 of 31 mg/L. In addition, the data provide evidence for substantial toxicokinetic differences between CHSA, CHBA and 4-TBCA. Together, our study introduces Lymnaea stagnalis embryonic development as an effective model to assay NA-toxicity and identifies molecular architecture as a potentially important toxicokinetic parameter in the toxicity of low-molecular weight NA in embryonic development of aquatic gastropods. Copyright © 2016 Elsevier Ltd. All rights reserved.

Toxicity studies on agents Gb and Gd (Phase 2): Delayed neuropathy study of soman in SPF white leghorn chickens. Final technical report, July 1985-August 1991

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

Bucci, T.J.; Parker, R.M.; Gosnell, P.A.

1992-05-01

A dose rangefinding study, a delayed neuropathy study, and a neurotoxic esterase study, were performed in White Leghorn chickens using the organophosphate ester Soman. The hens used for the Rangefinding study were dosed once orally with 500, 250, 100, 50, 25, or 0 microns g/Kg GD, on Day 1. They were pretreated and protected daily through Day 7 with atropine. Surviving hens were euthanized with sodium pentobarbital on Day 21. The maximum tolerated dose (MTD) to be used in the Delayed Neuropathy Study was chosen based upon the rangefinding data. Fifty hens were assigned to a Single Dose Delayed Neuropathymore » study. Groups of ten hens were given 14.2 (MTD), 7.1 (MTD/2), 3.5 (MTD/4), 0 (negative control) microns/Kg GD or 51 0 mg/Kg tri-ortho-cresyl phosphate (TOCP) (positive control). Rangefinding study. They were evaluated for signs of neurologic toxicity/ataxia. Necropsy examination was performed on all animals. Sections of cerebellum, medulla, spinal cord (cervical, thoracic, and lumbar), both sciatic nerves and their tibial branch were examined microscopically.... Delayed neuropathy; Agents; Soman; Chickens.« less

Disruption of testosterone homeostasis as a mode of action for the reproductive toxicity of triazole fungicides in the male rat.

PubMed

Goetz, Amber K; Ren, Hongzu; Schmid, Judith E; Blystone, Chad R; Thillainadarajah, Inthirany; Best, Deborah S; Nichols, Harriette P; Strader, Lillian F; Wolf, Douglas C; Narotsky, Michael G; Rockett, John C; Dix, David J

2007-01-01

Triazole fungicides associated with a range of reported male reproductive effects in experimental animals were selected to assess potential toxic modes of action. Wistar Han rats were fed myclobutanil (M: 100, 500, or 2000 ppm), propiconazole (P: 100, 500, or 2500 ppm), or triadimefon (T: 100, 500, or 1800 ppm) from gestation day 6 to postnatal day (PND) 120. One male per litter was necropsied on PND1, 22, 50, or 92. Measurements included anogenital distance (AGD) at PND0, body and organ weights, serum hormone levels, age at preputial separation (PPS), sperm morphology and motility, and fertility and fecundity. AGD was increased by the high dose of all three triazoles, indicating hypervirilization. Triadimefon delayed PPS, consistent with delayed puberty, at 1800 ppm. Relative liver weights were increased at PND1, 50, and 92 by all three triazoles. Hepatocellular hypertrophy was present at PND50 from propiconazole and triadimefon and at PND92 from all three high-dose triazole treatments. Relative pituitary weights were decreased at PND92 by middle- and high-dose myclobutanil treatment. Absolute testis weights were increased at PND1 by myclobutanil, at PND22 by myclobutanil and triadimefon, and at PND50 by propiconazole and triadimefon treatment. Relative ventral prostate weights were increased at PND92 by myclobutanil and triadimefon treatment. Serum testosterone was increased at PND50 by triadimefon and at PND92/99 by all three triazole treatments. Insemination and fertility were impaired by myclobutanil and triadimefon treatment. In addition to the reproductive system effects, total serum thyroxine levels were decreased at PND92 by high-dose triadimefon. These reproductive effects are consistent with the disruption of testosterone homeostasis as a key event in the mode of action for triazole-induced reproductive toxicity.

Contact toxicity and residual effects of selected insecticides against the adult Paederus fuscipes (Coleoptera: Staphylinidae).

PubMed

Bong, Lee-Jin; Neoh, Kok-Boon; Jaal, Zairi; Lee, Chow-Yang

2013-12-01

The contact toxicity of four insecticide formulations (deltamethrin, fipronil, fenitrothion, and imidacloprid) applied on three different substrates (tile, plywood, and concrete) against the adult rove beetle, Paederus fuscipes Curtis, was evaluated. The relative order of speed of killing effects was as follows: deltamethrin > imidacloprid > fipronil > fenitrothion. Although deltamethrin showed the fastest action against P. fuscipes, the recovery rate of rove beetles at 48 h posttreatment was moderate (approximately 25%) on the tile surface to high (approximately 80%) on the plywood surface. Thus, it is likely that the insects did not pick up the lethal dose especially on porous surfaces. In contrast, fipronil demonstrated delayed toxicity that might promote maximal uptake by the insects. More than 80% mortality was registered for tile and plywood surfaces up to 4 wk after exposure. High mortality (almost 100%) was recorded for imidacloprid-exposed P. fuscipes at 48 h posttreatment, but only on the tile surface. Among the four insecticides tested, fenitrothion was the least effective against P. fuscipes because low percentage to no mortality was recorded in the fenitrothion treatment.

Competition magnifies the impact of a pesticide in a warming world by reducing heat tolerance and increasing autotomy.

PubMed

Op de Beeck, Lin; Verheyen, Julie; Stoks, Robby

2018-02-01

There is increasing concern that standard laboratory toxicity tests may be misleading when assessing the impact of toxicants, because they lack ecological realism. Both warming and biotic interactions have been identified to magnify the effects of toxicants. Moreover, while biotic interactions may change the impact of toxicants, toxicants may also change the impact of biotic interactions. However, studies looking at the impact of biotic interactions on the toxicity of pesticides and vice versa under warming are very scarce. Therefore, we tested how warming (+4 °C), intraspecific competition (density treatment) and exposure to the pesticide chlorpyrifos, both in isolation and in combination, affected mortality, cannibalism, growth and heat tolerance of low- and high-latitude populations of the damselfly Ischnura elegans. Moreover, we addressed whether toxicant exposure, potentially in interaction with competition and warming, increased the frequency of autotomy, a widespread antipredator mechanism. Competition increased the toxicity of chlorpyrifos and made it become lethal. Cannibalism was not affected by chlorpyrifos but increased at high density and under warming. Chlorpyrifos reduced heat tolerance but only when competition was high. This is the first demonstration that a biotic interaction can be a major determinant of 'toxicant-induced climate change sensitivity'. Competition enhanced the impact of chlorpyrifos under warming for high-latitude larvae, leading to an increase in autotomy which reduces fitness in the long term. This points to a novel pathway how transient pesticide pulses may cause delayed effects on populations in a warming world. Our results highlight that the interplay between biotic interactions and toxicants have a strong relevance for ecological risk assessment in a warming polluted world. Copyright © 2017 Elsevier Ltd. All rights reserved.

Assessing the toxic effects of DMSO on cord blood to determine exposure time limits and the optimum concentration for cryopreservation.

PubMed

Fry, L J; Querol, S; Gomez, S G; McArdle, S; Rees, R; Madrigal, J A

2015-08-01

Advantages of using cord blood (CB) over other sources of haematopoietic progenitor cells, such as bone marrow, include the ability to cryopreserve and bank the samples until requested for a transplant. Cryopreservation requires the addition of a cryoprotectant to prevent the formation of intracellular ice during freezing. Dimethyl sulphoxide (DMSO) is commonly used at a concentration of 10% (v/v); however, there is evidence to suggest this chemical is toxic to cells as well as to patients after infusion. The toxic effects of DMSO were assessed through cell viability and in vitro functional assays in fresh and post-thaw CB samples before determining the maximum exposure time and optimal concentration for cryopreservation. A dose-dependent toxicity of DMSO was observed in fresh samples with 40% removing all viable and functional haematopoietic progenitor cells (HPC). In fresh and post-thaw analysis, minimal toxic effect was observed when cryopreservation was delayed for up to 1 h after 10% DMSO addition. After thawing, DMSO washout was superior to dilution or unmanipulated when maintained for long periods (advantage observed 1 h after thawing). Finally, the optimum concentration for cryopreserving CB was found to be 7.5 to 10% with detrimental effects observed outside of this range. These results support the use of 7.5-10% as the optimal DMSO concentration and the maximum exposure time should be limited to <1 h prior to freezing and 30 min post-thaw. © 2015 International Society of Blood Transfusion.

Cardiac Development in Zebrafish and Human Embryonic Stem Cells Is Inhibited by Exposure to Tobacco Cigarettes and E-Cigarettes

PubMed Central

Palpant, Nathan J.; Hofsteen, Peter; Pabon, Lil; Reinecke, Hans; Murry, Charles E.

2015-01-01

Background Maternal smoking is a risk factor for low birth weight and other adverse developmental outcomes. Objective We sought to determine the impact of standard tobacco cigarettes and e-cigarettes on heart development in vitro and in vivo. Methods Zebrafish (Danio rerio) were used to assess developmental effects in vivo and cardiac differentiation of human embryonic stem cells (hESCs) was used as a model for in vitro cardiac development. Results In zebrafish, exposure to both types of cigarettes results in broad, dose-dependent developmental defects coupled with severe heart malformation, pericardial edema and reduced heart function. Tobacco cigarettes are more toxic than e-cigarettes at comparable nicotine concentrations. During cardiac differentiation of hESCs, tobacco smoke exposure results in a delayed transition through mesoderm. Both types of cigarettes decrease expression of cardiac transcription factors in cardiac progenitor cells, suggesting a persistent delay in differentiation. In definitive human cardiomyocytes, both e-cigarette- and tobacco cigarette-treated samples showed reduced expression of sarcomeric genes such as MLC2v and MYL6. Furthermore, tobacco cigarette-treated samples had delayed onset of beating and showed low levels and aberrant localization of N-cadherin, reduced myofilament content with significantly reduced sarcomere length, and increased expression of the immature cardiac marker smooth muscle alpha-actin. Conclusion These data indicate a negative effect of both tobacco cigarettes and e-cigarettes on heart development in vitro and in vivo. Tobacco cigarettes are more toxic than E-cigarettes and exhibit a broader spectrum of cardiac developmental defects. PMID:25978043

Developmental toxicity of PAH mixtures in fish early life stages. Part II: adverse effects in Japanese medaka.

PubMed

Le Bihanic, Florane; Clérandeau, Christelle; Le Menach, Karyn; Morin, Bénédicte; Budzinski, Hélène; Cousin, Xavier; Cachot, Jérôme

2014-12-01

In aquatic environments, polycyclic aromatic hydrocarbons (PAHs) mostly occur as complex mixtures, for which risk assessment remains problematic. To better understand the effects of PAH mixture toxicity on fish early life stages, this study compared the developmental toxicity of three PAH complex mixtures. These mixtures were extracted from a PAH-contaminated sediment (Seine estuary, France) and two oils (Arabian Light and Erika). For each fraction, artificial sediment was spiked at three different environmental concentrations roughly equivalent to 0.5, 4, and 10 μg total PAH g(-1) dw. Japanese medaka embryos were incubated on these PAH-spiked sediments throughout their development, right up until hatching. Several endpoints were recorded at different developmental stages, including acute endpoints, morphological abnormalities, larvae locomotion, and genotoxicity (comet and micronucleus assays). The three PAH fractions delayed hatching, induced developmental abnormalities, disrupted larvae swimming activity, and damaged DNA at environmental concentrations. Differences in toxicity levels, likely related to differences in PAH proportions, were highlighted between fractions. The Arabian Light and Erika petrogenic fractions, containing a high proportion of alkylated PAHs and low molecular weight PAHs, were more toxic to Japanese medaka early life stages than the pyrolytic fraction. This was not supported by the toxic equivalency approach, which appeared unsuitable for assessing the toxicity of the three PAH fractions to fish early life stages. This study highlights the potential risks posed by environmental mixtures of alkylated and low molecular weight PAHs to early stages of fish development.

Revisiting the definition of dose-limiting toxicities in paediatric oncology phase I clinical trials: An analysis from the Innovative Therapies for Children with Cancer Consortium.

PubMed

Bautista, Francisco; Moreno, Lucas; Marshall, Lynley; Pearson, Andrew D J; Geoerger, Birgit; Paoletti, Xavier

2017-11-01

Dose-escalation trials aim to identify the maximum tolerated dose and, importantly, the recommended phase II dose (RP2D) and rely on the occurrence of dose-limiting toxicities (DLTs) during the first treatment cycle. Molecularly targeted agents (MTAs) often follow continuous and prolonged administrations, displaying a distinct toxicity profile compared to conventional chemotherapeutics, and classical DLT criteria might not be appropriate to evaluate MTAs' toxicity. We investigated this issue in children. The Innovative Therapies for Children with Cancer Consortium (ITCC) phase I trials of novel anticancer agents between 2004 and 2015 were analysed. Data from investigational product, trial design, items defining DLT/RP2D were extracted. A survey on dose-escalation process, DLTs and RP2D definition was conducted among the ITCC clinical trials committee members. Thirteen phase I trials with 15 dose-escalation cohorts were analysed. They explored 11 MTAs and 2 novel cytotoxics; 12 evaluated DLT during cycle 1. Definition of DLT was heterogeneous: Grade III-IV haematologic toxicities that were transient or asymptomatic and grade III-IV non-haematological toxicities manageable with adequate supportive care were often excluded, whereas some included dose intensity or grade II toxicities into DLT. None of the studies considered delayed toxicity into the RP2D definition. DLTs should be homogeneously defined across trials, limiting the number of exceptions due to specific toxicities. Dose escalation should still be based on safety data from cycle 1, but delayed and overall toxicities, pharmacokinetic parameters and pharmacodynamic data should be considered to refine the final RP2D. The evaluation of long-term toxicity in the developing child cannot be adequately addressed in early trials. Copyright © 2017 Elsevier Ltd. All rights reserved.

Additives to local anesthetics for peripheral nerve blocks: Evidence, limitations, and recommendations.

PubMed

Bailard, Neil S; Ortiz, Jaime; Flores, Roland A

2014-03-01

The therapeutic rationale, clinical effectiveness, and potential adverse effects of medications used in combination with local anesthetics for peripheral nerve block therapy are reviewed. A wide range of agents have been tested as adjuncts to peripheral nerve blocks, which are commonly performed for regional anesthesia during or after hand or arm surgery, neck or spine surgery, and other procedures. Studies to determine the comparative merits of nerve block adjuncts are complicated by the wide variety of coadministered local anesthetics and sites of administration and by the heterogeneity of primary endpoints. Sodium bicarbonate has been shown to speed the onset of mepivacaine nerve blocks but delay the onset of others. Epinephrine has been shown to prolong sensory nerve blockade and delay systemic uptake of local anesthetics, thus reducing the risk of anesthetic toxicity. Tramadol, buprenorphine, dexamethasone, and clonidine appear to be effective additives in some situations. Midazolam, magnesium, dexmedetomidine, and ketamine cannot be routinely recommended as nerve block additives due to a dearth of supportive data, modest efficacy, and (in the case of ketamine) significant adverse effects. Recent studies suggest that administering additives intravenously or intramuscularly can provide many of the benefits of perineural administration while reducing the potential for neurotoxicity, contamination, and other hazards. Some additives to local anesthetics can hasten the onset of nerve block, prolong block duration, or reduce toxicity. On the other hand, poorly selected or unnecessary additives may not have the desired effect and may even expose patients to unnecessary risks.

Inhalation toxicology. V., Evaluation of relative toxicity to rats of thermal decomposition products from two aircraft seat fire-blocking materials.

DOT National Transportation Integrated Search

1985-11-01

Two fire-blocking layer (FBL) materials, designed to delay the thermal decomposition of polyurethane foam seat cushions during an aircraft cabin fire, were evaluated for the relative toxicity of their gaseous combustion products. Each materials was t...

In Vivo Protection against Strychnine Toxicity in Mice by the Glycine Receptor Agonist Ivermectin

PubMed Central

Radwan, Rasha

2014-01-01

The inhibitory glycine receptor, a ligand-gated ion channel that mediates fast synaptic inhibition in mammalian spinal cord and brainstem, is potently and selectively inhibited by the alkaloid strychnine. The anthelminthic and anticonvulsant ivermectin is a strychnine-independent agonist of spinal glycine receptors. Here we show that ivermectin is an effective antidote of strychnine toxicity in vivo and determine time course and extent of ivermectin protection. Mice received doses of 1 mg/kg and 5 mg/kg ivermectin orally or intraperitoneally, followed by an intraperitoneal strychnine challenge (2 mg/kg). Ivermectin, through both routes of application, protected mice against strychnine toxicity. Maximum protection was observed 14 hours after ivermectin administration. Combining intraperitoneal and oral dosage of ivermectin further improved protection, resulting in survival rates of up to 80% of animals and a significant delay of strychnine effects in up to 100% of tested animals. Strychnine action developed within minutes, much faster than ivermectin, which acted on a time scale of hours. The data agree with a two-compartment distribution of ivermectin, with fat deposits acting as storage compartment. The data demonstrate that toxic effects of strychnine in mice can be prevented if a basal level of glycinergic signalling is maintained through receptor activation by ivermectin. PMID:25317421

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

Xu, Ting; Zhao, Jing; Hu, Ping

Pentachlorophenol (PCP) is a prevalent pollutant in the environment and has been demonstrated to be a serious toxicant to humans and animals. However, little is known regarding the molecular mechanism underlying its toxic effects on vertebrate early development. To explore the impacts and underlying mechanisms of PCP on early development, zebrafish (Danio rerio) embryos were exposed to PCP at concentrations of 0, 20 and 50 μg/L, and microscopic observation and cDNA microarray analysis were subsequently conducted at gastrulation stage. The morphological observations revealed that PCP caused a developmental delay of zebrafish embryos in a concentration-dependent manner. Transcriptomic data showed thatmore » 50 μg/L PCP treatment resulted in significant changes in gene expression level, and the genes involved in energy metabolism and cell behavior were identified based on gene functional enrichment analysis. The energy production of embryos was influenced by PCP via the activation of glycolysis along with the inhibition of oxidative phosphorylation (OXPHOS). The results suggested that PCP acts as an inhibitor of OXPHOS at 8 hpf (hours postfertilization). Consistent with the activated glycolysis, the cell cycle activity of PCP-treated embryos was higher than the controls. These characteristics are similar to the Warburg effect, which occurs in human tumors. The microinjection of exogenous ATP confirmed that an additional energy supply could rescue PCP-treated embryos from the developmental delay due to the energy deficit. Taken together, our results demonstrated that PCP causes a Warburg-like effect on zebrafish embryos during gastrulation, and the affected embryos had the phenotype of developmental delay. - Highlights: • We treat zebrafish embryos with PCP at gastrula stage. • PCP acts as an oxidative phosphorylation inhibitor, not an uncoupler, in gastrulation. • Exogenous ATP injection will rescue the development of effected embryos. • The transcriptome of PCP-treated embryo exhibits a Warburg-like effect in tumor cell.« less

Solid-state, ambient-operation thermally activated delayed fluorescence from flexible, non-toxic gold-nanocluster thin films: towards the development of biocompatible light-emitting devices

NASA Astrophysics Data System (ADS)

Talite, M. J. A.; Lin, H. T.; Jiang, Z. C.; Lin, T. N.; Huang, H. Y.; Heredia, E.; Flores, A.; Chao, Y. C.; Shen, J. L.; Lin, C. A. J.; Yuan, C. T.

2016-08-01

Luminescent gold nanoclusters (AuNCs) with good biocompatibility have gained much attention in bio-photonics. In addition, they also exhibit a unique photo-physical property, namely thermally activated delayed fluorescence (TADF), by which both singlet and triplet excitons can be harvested. The combination of their non-toxic material property and unique TADF behavior makes AuNCs biocompatible nano-emitters for bio-related light-emitting devices. Unfortunately, the TADF emission is quenched when colloidal AuNCs are transferred to solid states under ambient environment. Here, a facile, low-cost and effective method was used to generate efficient and stable TADF emissions from solid AuNCs under ambient environment using polyvinyl alcohol as a solid matrix. To unravel the underlying mechanism, temperature-dependent static and transient photoluminescence measurements were performed and we found that two factors are crucial for solid TADF emission: small energy splitting between singlet and triplet states and the stabilization of the triplet states. Solid TADF films were also deposited on the flexible plastic substrate with patterned structures, thus mitigating the waveguide-mode losses. In addition, we also demonstrated that warm white light can be generated based on a co-doped single emissive layer, consisting of non-toxic, solution-processed TADF AuNCs and fluorescent carbon dots under UV excitation.

Optimal antidiarrhea treatment for antitumor agent irinotecan hydrochloride (CPT-11)-induced delayed diarrhea.

PubMed

Takasuna, K; Hagiwara, T; Watanabe, K; Onose, S; Yoshida, S; Kumazawa, E; Nagai, E; Kamataki, T

2006-10-01

An antitumor camptothecin derivative CPT-11 has proven a broad spectrum of solid tumor malignancy, but its severe diarrhea has often limited its more widespread use. We have demonstrated from a rat model that intestinal beta-glucuronidase may play a key role in the development of CPT-11-induced delayed diarrhea by the deconjugation of the luminal SN-38 glucuronide, and the elimination of the intestinal microflora by antibiotics or dosing of TJ-14, a Kampo medicine that contains beta-glucuronidase inhibitor baicalin, exerted a protective effect. In the present study, we assessed the efficacy of several potential treatments in our rat model to clarify which is the most promising treatment for CPT-11-induced delayed diarrhea. Oral dosing (twice daily from days -1 to 4) of streptomycin 20 mg/kg and penicillin 10 mg/kg (Str/Pen), neomycin 20 mg/kg and bacitracin 10 mg/kg (Neo/Bac), both of which inhibited almost completely the fecal beta-glucuronidase activity, or TJ-14 1,000 mg/kg improved the decrease in body weight and the delayed diarrhea symptoms induced by CPT-11 (60 mg/kg i.v. from days 1 to 4) to a similar extent. The efficacy was less but significant in activated charcoal (1,000 mg/kg p.o. twice daily from days -1 to 4). In a separate experiment using rats bearing breast cancer (Walker 256-TC), TJ-14, Neo/Bac, and charcoal at the same dose regimen improved CPT-11-induced intestinal toxicity without reducing CPT-11's antitumor activity. In contrast, oral dosing (twice a day) of cyclosporin A (50 mg/kg), a P-glycoprotein and cMOAT/MRP2 inhibitor or valproic acid (200 mg/kg), a UDP-glucuronosyltranferase inhibitor, exacerbated the intestinal toxicity without modifying CPT-11's antitumor activity. The result clearly demonstrated the ability of Neo/Bac, Str/Pen, and TJ-14, less but significant ability of activated charcoal, to ameliorate CPT-11-induced delayed-onset diarrhea, suggesting the treatments decreasing the exposure of the intestines to the luminal SN-38 are valuable for improvement of CPT-11-induced intestinal toxicity. In contrast, the treatments affecting the biliary excretion of CPT-11 and its metabolites might have undesirable results.

Toxicity evaluation of convection-enhanced delivery of small-molecule kinase inhibitors in naïve mouse brainstem.

PubMed

Zhou, Zhiping; Ho, Sharon L; Singh, Ranjodh; Pisapia, David J; Souweidane, Mark M

2015-04-01

Diffuse intrinsic pontine gliomas (DIPGs) are inoperable and lethal high-grade gliomas lacking definitive therapy. Platelet-derived growth factor receptor (PDGFR) and its downstream signaling molecules are the most commonly overexpressed oncogenes in DIPG. This study tested the effective concentration of PDGFR pathway inhibitors in cell culture and then toxicity of these small-molecule kinase inhibitors delivered to the mouse brainstem via convection-enhanced delivery (CED) for potential clinical application. Effective concentrations of small-molecule kinase inhibitors were first established in cell culture from a mouse brainstem glioma model. Sixteen mice underwent CED, a local drug delivery technique, of saline or of single and multidrug combinations of dasatinib (2 M), everolimus (20 M), and perifosine (0.63 mM) in the pons. Animals were kept alive for 3 days following the completion of infusion. No animals displayed any immediate or delayed neurological deficits postoperatively. Histological analysis revealed edema, microgliosis, acute inflammation, and/or axonal injury in the experimental animals consistent with mild acute drug toxicity. Brainstem CED of small-molecule kinase inhibitors in the mouse did not cause serious acute toxicities. Future studies will be necessary to evaluate longer-term safety to prepare for potential clinical application.

Efficacy of some plant oils alone and/or combined with different insecticides on the cotton leaf-worm Spodoptera littoralis (Boisd.) (Lepidoptera: Noctuidae) in Egypt.

PubMed

Mesbah, H A; Mourad, A K; Rokaia, A Z M

2006-01-01

The present work was conducted to evaluate the efficiency of two essential oils ((Flax or "Linseed" and Sesame ), five volatile plant oils ( Camphor, Red basil, Rose, Menthol and Clove ), four pesticides (Methoxyfenozide; Permethrin; Profenofos and Spinosad) and their mixtures on the cotton leaf-worm Spodoptera littoralis (Boisd.). This study was also devoted to minimize the usage of conventional insecticides, reduce the environmental pollution, and protect human-beings and domestic animals from hazards due to pesticides applications. In the meantime, the delayed effect of these tested plant oils on the developing immatures and moths of the cotton leaf-worm, Spodoptera littoralis was determined. Most of the evaluated plant oils were found to have an insecticidal effect on the 4th instar larvae of the cotton leaf-worm, S. littoralis. Both the essential Sesame oil and Clove volatile oil showed rather weak toxic effect corresponding to the same concentrations and periods of the bioassay tests. Comparing the toxicity of the tested plant oils, it was affirmed that both Rose and Red basil volatile oils were the highest efficient natural phytocompounds against the treated larvae and alternatively ranked either the 1st and/or the 2nd rank, throughout the different periods of the bioassay tests, followed by the other three tested oils which were more or less efficient phytocompounds. According to the toxicity index, all the tested oils were less toxic than the superior Red basil volatile oil after 48 h. post treatment followed by the gradual decrease in toxicity of Rose, Flax and Menthol, respectively. The development of the treated 4th larval instar was blocked due to treatment with the tested plant oils. With no exception, all the efficiently tested essential and/or volatile oils acted principally as Insect Growth Inhibitors (IGIs) rather than antifeedants causing disruption of the insect development, abnormal larvae, pupae and adults that were lead finally to death. The tested mixtures of Clove and Sesame oils increased the percentage of larval mortality in comparison to their use alone against the treated 4th larval instar.Contrarily, antagonism was revealed for the mixture of Sesame/Flax oils, the calculated value of LC50 greatly increased compared to the corresponding values of their individual evaluation after 48 h. from initiating the treatment. The delayed effect of tested plant oils was inspected on certain parameters of the fitness components of the subject insect and was mainly determined for the rates of hatched eggs and emerged moths. Remarkably, the Methoxyfenozide treated 4th larval instar became passive, or ceased feeding on the treated leaves and were unable to complete normally the moulting process, which partially took place in most'of the other treated individuals. The treated larvae with the tested lower concentrations, hardly succeeded in completing moulting process. The survived larvae failed to complete the next moulting at the end of the treatments. The toxic effect of Spinosad was more apparent against the treated larvae after 72 h from application. The calculated LC50 values indicated the gradual increase of its toxic effect in the subsequent prolonged intervals of the test. Spinosad showed its activity either by contact or ingestion and caused larval characteristic symptoms. Permethrin exhibited superior toxic efficacy overall the other tested chemicals, during the period from 72 up to 96 h post treatment. The gradual increase of the toxic effect of Permethrin indicated an efficient continuous persistence of nervous toxicity. According to the specific properties of Profenofos, results revealed that the toxicity by ingestion was more potential than by contact and explained the reason of developing toxicity with the increase of bioassay inspection period. The comparative toxic efficiency of the tested insecticides proved that Permethrin was the most effective one, giving LC50 values of 2.92 and 1.53 ppm after 72 and 96 h. bioassay, respectively, followed by Profenofos, Methoxyfenozide and Spinosad, successively. In addition, the calculated values of toxicity index also proved that all the tested compounds were less toxic than Permethrin (as a standard compound ). It is worth mentioning that the combined action of the mixed pesticides with four efficient volatile plant oils showed synergistic action against the 4th larval instar of S. littoralis.

Impairment of Bony Crypt Development Associated With Hexavalent Chromium Exposure During Tooth Eruption.

PubMed

Sánchez, Luciana M; Lewicki, Marianela; De Lucca, Romina C; Ubios, Ángela M

2015-12-01

Improperly treated hexavalent chromium-containing industrial wastes contaminate drinking water, potentially affecting children taking breast milk or baby bottles prepared with infant formula. Thus, the aim of the present work was to determine the effect of this toxic on bone activity in the developing alveolus during tooth eruption of suckling Wistar rats intoxicated with potassium dichromate. Experimental animals received a daily dose of 12.5mg/kg body weight of potassium dichromate by gavage for 10 days; controls received an equivalent volume of saline solution. Histologic and histomorphometric studies of the mandible were performed. The data were statistically analyzed using Student's t test; statistical significance was set at a value of p <0.05. Experimental animals exhibited delayed tooth eruption, decreased periodontal width and bone volume, a lower percentage of bone formation surfaces, and higher percentage of quiescent surfaces (p<0.05) compared to controls. The delay in tooth eruption observed after exposure to hexavalent chromium is the result of a lower rate of bone remodeling in the developing alveolus. The obtained results show the importance of controlling toxic substances in drinking water, since their effects may alter the growth and development of subjects who were exposed during early infancy. Sociedad Argentina de Investigación Odontológica.

Real-time, interactive, visually updated simulator system for telepresence

NASA Technical Reports Server (NTRS)

Schebor, Frederick S.; Turney, Jerry L.; Marzwell, Neville I.

1991-01-01

Time delays and limited sensory feedback of remote telerobotic systems tend to disorient teleoperators and dramatically decrease the operator's performance. To remove the effects of time delays, key components were designed and developed of a prototype forward simulation subsystem, the Global-Local Environment Telerobotic Simulator (GLETS) that buffers the operator from the remote task. GLETS totally immerses an operator in a real-time, interactive, simulated, visually updated artificial environment of the remote telerobotic site. Using GLETS, the operator will, in effect, enter into a telerobotic virtual reality and can easily form a gestalt of the virtual 'local site' that matches the operator's normal interactions with the remote site. In addition to use in space based telerobotics, GLETS, due to its extendable architecture, can also be used in other teleoperational environments such as toxic material handling, construction, and undersea exploration.

Effect of trifluoperazine on toxicity, HIF-1α induction and hepatocyte regeneration in acetaminophen toxicity in mice1

PubMed Central

Chaudhuri, Shubhra; McCullough, Sandra S.; Hennings, Leah; Brown, Aliza T.; Li, Shun-Hwa; Simpson, Pippa M.; Hinson, Jack A.; James, Laura P.

2012-01-01

Oxidative stress and mitochondrial permeability transition (MPT) are important mechanisms in acetaminophen (APAP) toxicity. The MPT inhibitor trifluoperazine (TFP) reduced MPT, oxidative stress, and toxicity in freshly isolated hepatocytes treated with APAP. Since hypoxia inducible factor-one alpha (HIF-1α is induced very early in APAP toxicity, a role for oxidative stress in the induction has been postulated. In the present study, the effect of TFP on toxicity and HIF-1α induction in B6C3F1 male mice treated with APAP was examined. Mice received TFP (10 mg/kg, oral gavage) prior to APAP (200 mg/kg IP) and at 7 and 36 h after APAP. Measures of metabolism (hepatic glutathione and APAP protein adducts) were comparable in the two groups of mice. Toxicity was decreased in the APAP/TFP mice at 2, 4, and 8 h, compared to the APAP mice. At 24 and 48 h, there were no significant differences in toxicity between the two groups. TFP lowered HIF-1α induction but also reduced the expression of proliferating cell nuclear antigen, a marker of hepatocyte regeneration. TFP can also inhibit phospholipase A2, and cytosolic and secretory PLA2 activity levels were reduced in the APAP/TFP mice compared to the APAP mice. TFP also lowered prostaglandin E2 expression, a known mechanism of cytoprotection. In summary, the MPT inhibitor TFP delayed the onset of toxicity and lowered HIF-1α induction in APAP treated mice. TFP also reduced PGE2 expression and hepatocyte regeneration, likely through a mechanism involving PLA2. PMID:22902588

Hysteresis in coral reefs under macroalgal toxicity and overfishing.

PubMed

Bhattacharyya, Joydeb; Pal, Samares

2015-03-01

Macroalgae and corals compete for the available space in coral reef ecosystems.While herbivorous reef fish play a beneficial role in decreasing the growth of macroalgae, macroalgal toxicity and overfishing of herbivores leads to proliferation of macroalgae. The abundance of macroalgae changes the community structure towards a macroalgae-dominated reef ecosystem. We investigate coral-macroalgal phase shifts by means of a continuous time model in a food chain. Conditions for local asymptotic stability of steady states are derived. It is observed that in the presence of macroalgal toxicity and overfishing, the system exhibits hysteresis through saddle-node bifurcation and transcritical bifurcation. We examine the effects of time lags in the liberation of toxins by macroalgae and the recovery of algal turf in response to grazing of herbivores on macroalgae by performing equilibrium and stability analyses of delay-differential forms of the ODE model. Computer simulations have been carried out to illustrate the different analytical results.

Potential protective effect of L-cysteine against the toxicity of acrylamide and furan in exposed Xenopus laevis embryos: an interaction study.

PubMed

Williams, John Russell; Rayburn, James R; Cline, George R; Sauterer, Roger; Friedman, Mendel

2014-08-06

The embryo toxicities of two food-processing-induced toxic compounds, acrylamide and furan, with and without added L-cysteine were examined individually and in mixtures using the frog embryo teratogenesis assay-Xenopus (FETAX). The following measures of developmental toxicity were used: (a) 96 h LC50, the median concentration causing 50% embryo lethality; (b) 96 h EC50, the median concentration causing 50% malformations of the surviving embryos; and (c) teratogenic index (96 h LC50/96 h EC50), an estimate of teratogenic risk. Calculations of toxic units (TU) were used to assess possible antagonism, synergism, or response addition of several mixtures. The evaluated compounds demonstrated counterintuitive effects. Furan had lower than expected toxicity in Xenopus embryos and, unlike acrylamide, does not seem to be teratogenic. However, the short duration of the tests may not show the full effects of furan if it is truly primarily genotoxic and carcinogenic. L-Cysteine showed unexpected properties in the delay of hatching of the embryos. The results from the interaction studies between combination of two or three components (acrylamide plus L-cysteine; furan plus L-cysteine; acrylamide plus furan; acrylamide plus furan and L-cysteine) show that furan and acrylamide seem to have less than response addition at 1:1 toxic unit ratio in lethality. Acrylamide and L-cysteine show severe antagonism even at low 19 acrylamide/1 L-cysteine TU ratios. Data from the mixture of acrylamide, furan, and L-cysteine show a slight antagonism, less than would have been expected from binary mixture exposures. Bioalkylation mechanisms and their prevention are discussed. There is a need to study the toxicological properties of mixtures of acrylamide and furan concurrently formed in heat-processed food.

Developmental toxicity of PAH mixtures in fish early life stages. Part I: adverse effects in rainbow trout.

PubMed

Le Bihanic, Florane; Morin, Bénédicte; Cousin, Xavier; Le Menach, Karyn; Budzinski, Hélène; Cachot, Jérôme

2014-12-01

A new gravel-contact assay using rainbow trout, Oncorhynchus mykiss, embryos was developed to assess the toxicity of polycyclic aromatic hydrocarbons (PAHs) and other hydrophobic compounds. Environmentally realistic exposure conditions were mimicked with a direct exposure of eyed rainbow trout embryos incubated onto chemical-spiked gravels until hatching at 10 °C. Several endpoints were recorded including survival, hatching delay, hatching success, biometry, developmental abnormalities, and DNA damage (comet and micronucleus assays). This bioassay was firstly tested with two model PAHs, fluoranthene and benzo[a]pyrene. Then, the method was applied to compare the toxicity of three PAH complex mixtures characterized by different PAH compositions: a pyrolytic extract from a PAH-contaminated sediment (Seine estuary, France) and two petrogenic extracts from Arabian Light and Erika oils, at two environmental concentrations, 3 and 10 μg g(-1) sum of PAHs. The degree and spectrum of toxicity were different according to the extract considered. Acute effects including embryo mortality and decreased hatching success were observed only for Erika oil extract. Arabian Light and pyrolytic extracts induced mainly sublethal effects including reduced larvae size and hemorrhages. Arabian Light and Erika extracts both induced repairable DNA damage as revealed by the comet assay versus the micronucleus assay. The concentration and proportion of methylphenanthrenes and methylanthracenes appeared to drive the toxicity of the three PAH fractions tested, featuring a toxic gradient as follows: pyrolytic < Arabian Light < Erika. The minimal concentration causing developmental defects was as low as 0.7 μg g(-1) sum of PAHs, indicating the high sensitivity of the assay and validating its use for toxicity assessment of particle-bound pollutants.

Ultrastructural study of the effect of cyclophosphamide on the growth area of incisor teeth of DBA/2 and C57BL/6 mice.

PubMed

Anton, E

1996-04-01

The effect of a single dose of 300 mg/kg of cyclophosphamide (CY) on the ultrastructure of the basal area of lower incisor teeth was investigated in two strains of mice (DBA/2 and C57BL/6) which are very differently affected by the delayed toxicity of CY. As in the rat, CY produced necrosis in the primitive mesenchymal cells and preodontoblasts of the pulp. Moreover, important changes were noticed in the associated layers of the enamel organ (presumptive stratum intermedium cells and stellate reticulum); thus, most of the cells displayed degenerative changes including extensive vacuolization, cytoplasm sequestration and variable nuclear alterations ranging from relative integrity to complete disorganization. In contrast, non-dividing columnar odontoblasts and ameloblasts were not affected by the drug. The alterations appeared as early as 21 hours after CY and progressed in the following 2 and 3 days. Normality of the formative tooth end was regained 7 days after CY. These results indicate that in addition to the effect on the pulp, CY produces severe cytopathological changes in the cells of the stratum intermedium and stellate reticulum of the enamel organ. The different sensitivity of DBA/2 and C57BL/6 mice to the delayed toxicity of CY does not seem to be related to its effect on odontogenesis since both strains showed the same response to CY in this respect.

Toxicity of PHOS-CHEK LC-95A and 259F fire retardants to ocean- and stream-type Chinook salmon and their potential to recover before seawater entry.

PubMed

Dietrich, Joseph P; Van Gaest, Ahna L; Strickland, Stacy A; Hutchinson, Greg P; Krupkin, Alex B; Arkoosh, Mary R

2014-08-15

Long-term fire retardants are used to prevent the spread of wildland fire, but have inadvertently entered aquatic habitats and resulted in fish kills. We examined the toxicity of two fire retardant products; PHOS-CHEK 259F and LC-95A, on Chinook salmon with two different life histories, ocean-type and stream-type, at different stages of their development. Ocean-type Chinook outmigrate to the ocean as subyearlings; while, stream-type salmon overwinter in freshwater and outmigrate as yearlings. Ocean-type and stream-type salmon were exposed to the fire retardants prior to their parr to smolt transition (presmolts) as subyearlings (stream-type and ocean-type) and yearlings (stream-type only), as well as during their transition (smolts). The salmon were exposed to eight concentrations of each retardant and a control for 96h to determine acute toxicity. Lethal concentration curves were modeled by logistic regression for each life history and life stage exposed to the two fire retardants. Among all life histories and life stages tested, PHOS-CHEK 259F was most toxic to stream-type salmon at smolt stage and PHOS-CHEK LC-95A was most toxic to ocean-type salmon at smolt stage. To determine the delayed effects of product exposures on fish health as well as for the potential of recovery, 24-hour seawater challenges were performed immediately after fire retardant exposure, as well as after a recovery period. Previous PHOS-CHEK exposure reduced survival during seawater challenge among salmon from both life histories undergoing the parr-smolt transition and was more pronounced after PHOS-CHEK LC-95A exposure. However, this delayed effect was not observed 34 or more days after either PHOS-CHEK exposure. We conclude that accidental PHOS-CHEK LC-95A or 259F drops during salmon outmigration would have adverse impacts that extend beyond the acute mortality that occurs within the immediate drop and dilution areas. Published by Elsevier B.V.

Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial

PubMed Central

Brown, Paul D.; Pugh, Stephanie; Laack, Nadia N.; Wefel, Jeffrey S.; Khuntia, Deepak; Meyers, Christina; Choucair, Ali; Fox, Sherry; Suh, John H.; Roberge, David; Kavadi, Vivek; Bentzen, Soren M.; Mehta, Minesh P.; Watkins-Bruner, Deborah

2013-01-01

Background To determine the protective effects of memantine on cognitive function in patients receiving whole-brain radiotherapy (WBRT). Methods Adult patients with brain metastases received WBRT and were randomized to receive placebo or memantine (20 mg/d), within 3 days of initiating radiotherapy for 24 weeks. Serial standardized tests of cognitive function were performed. Results Of 554 patients who were accrued, 508 were eligible. Grade 3 or 4 toxicities and study compliance were similar in the 2 arms. There was less decline in delayed recall in the memantine arm at 24 weeks (P = .059), but the difference was not statistically significant, possibly because there were only 149 analyzable patients at 24 weeks, resulting in only 35% statistical power. The memantine arm had significantly longer time to cognitive decline (hazard ratio 0.78, 95% confidence interval 0.62–0.99, P = .01); the probability of cognitive function failure at 24 weeks was 53.8% in the memantine arm and 64.9% in the placebo arm. Superior results were seen in the memantine arm for executive function at 8 (P = .008) and 16 weeks (P = .0041) and for processing speed (P = .0137) and delayed recognition (P = .0149) at 24 weeks. Conclusions Memantine was well tolerated and had a toxicity profile very similar to placebo. Although there was less decline in the primary endpoint of delayed recall at 24 weeks, this lacked statistical significance possibly due to significant patient loss. Overall, patients treated with memantine had better cognitive function over time; specifically, memantine delayed time to cognitive decline and reduced the rate of decline in memory, executive function, and processing speed in patients receiving WBRT. RTOG 0614, ClinicalTrials.gov number CT00566852. PMID:23956241

Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial.

PubMed

Brown, Paul D; Pugh, Stephanie; Laack, Nadia N; Wefel, Jeffrey S; Khuntia, Deepak; Meyers, Christina; Choucair, Ali; Fox, Sherry; Suh, John H; Roberge, David; Kavadi, Vivek; Bentzen, Soren M; Mehta, Minesh P; Watkins-Bruner, Deborah

2013-10-01

To determine the protective effects of memantine on cognitive function in patients receiving whole-brain radiotherapy (WBRT). Adult patients with brain metastases received WBRT and were randomized to receive placebo or memantine (20 mg/d), within 3 days of initiating radiotherapy for 24 weeks. Serial standardized tests of cognitive function were performed. Of 554 patients who were accrued, 508 were eligible. Grade 3 or 4 toxicities and study compliance were similar in the 2 arms. There was less decline in delayed recall in the memantine arm at 24 weeks (P = .059), but the difference was not statistically significant, possibly because there were only 149 analyzable patients at 24 weeks, resulting in only 35% statistical power. The memantine arm had significantly longer time to cognitive decline (hazard ratio 0.78, 95% confidence interval 0.62-0.99, P = .01); the probability of cognitive function failure at 24 weeks was 53.8% in the memantine arm and 64.9% in the placebo arm. Superior results were seen in the memantine arm for executive function at 8 (P = .008) and 16 weeks (P = .0041) and for processing speed (P = .0137) and delayed recognition (P = .0149) at 24 weeks. Memantine was well tolerated and had a toxicity profile very similar to placebo. Although there was less decline in the primary endpoint of delayed recall at 24 weeks, this lacked statistical significance possibly due to significant patient loss. Overall, patients treated with memantine had better cognitive function over time; specifically, memantine delayed time to cognitive decline and reduced the rate of decline in memory, executive function, and processing speed in patients receiving WBRT. RTOG 0614, ClinicalTrials.gov number CT00566852.

Toxic effects of endrin and toxaphene on the southern leopard frog Rana sphenocephala

USGS Publications Warehouse

Hall, R.J.; Swineford, D.

1980-01-01

Eggs, larvae and sub-adults of the southern leopard frog Rana sphenocephala were exposed to endrin and toxaphene. Exposure was in water by a continuous-flow technique, following standards that have been used successfully in the study of fish and invertebrates. R. sphenocephala is more sensitive to both pesticides than are higher vertebrates but is slightly less sensitive than fish. Eggs seem to be resistant to the effects of both pesticides and are probably poor indicators of environmental hazard. The toxic level of endrin is about equal in larvae and transformed frogs (LC50, 0?005-0?015 ppm). Toxaphene is less toxic to sub-adults (LC50, 0?37-0?790 ppm) than to larvae (LC50, 0?032-0?054 ppm). Delayed mortality, behavioural aberrations and effects on growth have been seen in toxaphene-dosed larvae observed over 30-day periods. Behavioural effects are more severe than those reported in other groups of animals. Effects on growth resulting from a 96-h exposure begin in the 0?013-0?018 ppm range. The maximum accumulation of residues observed for each chemical represented bioconcentration factors of about 100. Endrin residues are apparently lost more readily than toxaphene residues; relative depuration rates correlate well with the time course of toxic action in each chemical. Although less sensitive to these pesticides than fish, amphibians may not be protected in their natural habitats. Future studies of the effects of toxicants on amphibians should employ larvae if only one stage can be tested, should expose subjects for at least 96 h and should continue observations for a total of at least 30 days.

Stability of citrate-capped silver nanoparticles in exposure media and their effects on the development of embryonic zebrafish (Danio rerio)

PubMed Central

Park, Kwangsik; Tuttle, George; Sinche, Federico; Harper, Stace L.

2014-01-01

The stability of citrate-capped silver nanoparticles (AgNPs) and the embryonic developmental toxicity were evaluated in the fish test water. Serious aggregation of AgNPs was observed in undiluted fish water (DM-100) in which high concentration of ionic salts exist. However, AgNPs were found to be stable for 7 days in DM-10, prepared by diluting the original fish water (DM-100) with deionized water to 10%. The normal physiology of zebrafish embryos were evaluated in DM-10 to see if DM-10 can be used as a control vehicle for the embryonic fish toxicity test. As results, DM-10 without AgNPs did not induce any significant adverse effects on embryonic development of zebrafish determined by mortality, hatching, malformations and heart rate. When embryonic toxicity of AgNPs was tested in both DM-10 and in DM-100, AgNPs showed higher toxicity in DM-10 than in DM-100. This means that the big-sized aggregates of AgNPs were low toxic compared to the nano-sized AgNPs. AgNPs induced delayed hatching, decreased heart rate, pericardial edema, and embryo death. Accumulation of AgNPs in the embryo bodies was also observed. Based on this study, citrate-capped AgNPs are not aggregated in DM-10 and it can be used as a control vehicle in the toxicity test of fish embryonic development. PMID:23325492

[Efectiveness of topical therapies in patients with breast cancer that experience radiodermatitis. A systematic review].

PubMed

Fernández-Castro, Mercedes; Martín-Gil, Belén

2015-01-01

After radiation therapy most patients experience acute skin toxicity to some degree. The purpose of this systematic review is to assess the available evidence concerning the effectivity of topical therapies on patients with breast cancer that experience radiodermatitis after radiotherapy. The review included clinical trials aimed to evaluate topical therapies for prevention or treatment of acute radiodermatitis in women with breast cancer, which were published between 2009 and 2014. The bibliographic search was carried out in the following databases: PubMed, Cinahl, Cochrane Plus, IBECS and LILACS. The studies were selected independently by peer reviewers using the Critical Appraisal Skills Programme in its Spanish version. 86 bibliographical references were identified. Twenty full-text articles of clinical trials were assessed and two were excluded because they were not completed; 12 of clinical trials evaluated topical treatment with creams and ointments, three with corticosteroid creams and other three with dressings. The effectivity of human epidermal growth factor cream, linoleic acid emulsion, topical silver sulfadiazine, corticosteroids creams and polyurethane dressings has been shown in these clinical trials. Given that radiodermatitis is a dynamic process, these topical agents were effective in different stages of skin toxicity. Some of them delayed the onset, others decreased the development and severity of acute skin toxicity degree and others improved the subjective symptoms (itching, pain, burning). Only polyurethane dressings suggest effectiveness in all stages of skin toxicity, in prevention, management of the different skin toxicity degrees and improvement of wellbeing. Copyright © 2015. Published by Elsevier España, S.L.U.

Toxic cocaine- and convulsant-induced modification of forced swimming behaviors and their interaction with ethanol: comparison with immobilization stress

PubMed Central

Hayase, Tamaki; Yamamoto, Yoshiko; Yamamoto, Keiichi

2002-01-01

Background Swimming behaviors in the forced swimming test have been reported to be depressed by stressors. Since toxic convulsion-inducing drugs related to dopamine [cocaine (COC)], benzodiazepine [methyl 6,7-dimethoxy-4-ethyl-β-carboline-carboxylate (DMCM)], γ-aminobutyric acid (GABA) [bicuculline (BIC)], and glutamate [N-methyl-D-aspartate (NMDA)] receptors can function as stressors, the present study compared their effects on the forced swimming behaviors with the effects of immobilization stress (IM) in rats. Their interactions with ethanol (EtOH), the most frequently coabused drug with COC which also induces convulsions as withdrawal symptoms but interferes with the convulsions caused by other drugs, were also investigated. Results Similar to the IM (10 min) group, depressed swimming behaviors (attenuated time until immobility and activity counts) were observed in the BIC (5 mg/kg IP) and DMCM (10 mg/kg IP) groups at the 5 h time point, after which no toxic behavioral symptoms were observed. However, they were normalized to the control levels at the 12 h point, with or without EtOH (1.5 g/kg IP). In the COC (60 mg/kg IP) and NMDA (200 mg/kg IP) groups, the depression occurred late (12 h point), and was normalized by the EtOH cotreatment. At the 5 h point, the COC treatment enhanced the swimming behaviors above the control level. Conclusions Although the physiological stress (IM), BIC, and DMCM also depressed the swimming behaviors, a delayed occurrence and EtOH-induced recovery of depressed swimming were observed only in the COC and NMDA groups. This might be correlated with the previously-reported delayed responses of DA and NMDA neurons rather than direct effects of the drugs, which could be suppressed by EtOH. Furthermore, the characteristic psychostimulant effects of COC seemed to be correlated with an early enhancement of swimming behaviors. PMID:12425723

Toxicological safety assessment of genetically modified Bacillus thuringiensis with additional N-acyl homoserine lactonase gene.

PubMed

Peng, Donghai; Zhou, Chenfei; Chen, Shouwen; Ruan, Lifang; Yu, Ziniu; Sun, Ming

2008-01-01

The aim of the present study is to evaluate the toxicology safety to mammals of a genetically modified (GM) Bacillus thuringiensis with an additional N-acyl homoserine lactones gene (aiiA), which possesses insecticidal activity together with restraint of bacterial pathogenicity and is intended for use as a multifunctional biopesticide. Safety assessments included an acute oral toxicity test and 28-d animal feeding study in Wistar rats, primary eye and dermal irritation in Zealand White rabbits, and delayed contact hypersensitivity in guinea pigs. Tests were conducted using spray-dried powder preparation. This GM product showed toxicity neither in oral acute toxicity test nor in 28-d animal feeding test at a dose of 5,000 mg/kg body weight. During the animal feeding test, there were no significant differences in growth, food and water consumption, hematology, blood biochemical indices, organ weights, and histopathology finding between rats in controls and tested groups. Tested animals in primary eye and dermal irritation and delayed contact hypersensitivity test were also devoid of any toxicity compared to controls. All the above results demonstrated that the GM based multifunctional B. thuringiensis has low toxicity and low eye and dermal irritation and would not cause hypersensitivity to laboratory mammals and therefore could be regarded as safe for use as a pesticide.

Retinal and visual system: occupational and environmental toxicology.

PubMed

Fox, Donald A

2015-01-01

Occupational chemical exposure often results in sensory systems alterations that occur without other clinical signs or symptoms. Approximately 3000 chemicals are toxic to the retina and central visual system. Their dysfunction can have immediate, long-term, and delayed effects on mental health, physical health, and performance and lead to increased occupational injuries. The aims of this chapter are fourfold. First, provide references on retinal/visual system structure, function, and assessment techniques. Second, discuss the retinal features that make it especially vulnerable to toxic chemicals. Third, review the clinical and corresponding experimental data regarding retinal/visual system deficits produced by occupational toxicants: organic solvents (carbon disulfide, trichloroethylene, tetrachloroethylene, styrene, toluene, and mixtures) and metals (inorganic lead, methyl mercury, and mercury vapor). Fourth, discuss occupational and environmental toxicants as risk factors for late-onset retinal diseases and degeneration. Overall, the toxicants altered color vision, rod- and/or cone-mediated electroretinograms, visual fields, spatial contrast sensitivity, and/or retinal thickness. The findings elucidate the importance of conducting multimodal noninvasive clinical, electrophysiologic, imaging and vision testing to monitor toxicant-exposed workers for possible retinal/visual system alterations. Finally, since the retina is a window into the brain, an increased awareness and understanding of retinal/visual system dysfunction should provide additional insight into acquired neurodegenerative disorders. © 2015 Elsevier B.V. All rights reserved.

Perfluorooctanoic acid (PFOA)-induced developmental toxicity in the mouse is dependent on expression of peroxisome proliferator activated receptor-alpha (PPAR-α)

EPA Science Inventory

PFOA is a member of a family of perfluorinated chemicals that have a variety of applications. PFOA persists in the environment and is found in wildlife and humans. In mice, PFOA is developmentally toxic producing mortality, delayed eye opening, growth deficits, and altered puber...

Synergistic Antitumor Effect of Oligogalacturonides and Cisplatin on Human Lung Cancer A549 Cells.

PubMed

Huang, Cian-Song; Huang, Ai-Chun; Huang, Ping-Hsiu; Lo, Diana; Wang, Yuh-Tai; Wu, Ming-Chang

2018-06-14

Cisplatin (DPP), a clinically potent antineoplastic agent, is limited by its severe adverse effects. The aim of this study was to investigate the effect of oligogalacturonides (OGA) and DDP on human lung cancer A549 cells. The combined use of OGA and DDP had a synergistic effect on the growth inhibition of A549 cells, changed the cell cycle distribution, and enhanced apoptotic response, especially in sequential combination treatment group of DDP 12 h + OGA 12 h. Western blot analyses showed that the combination treatment of OGA and DDP upregulated Bax, p53, and Caspase-3 and downregulated Bcl-2 proteins. More importantly, DDP-induced toxicity was attenuated by OGA and DDP combination treatment in normal HEK293 cells. Our data suggests that the combined use of OGA from natural sources and DDP could be an important new adjuvant therapy for lung cancer as well as offer important insights for reducing kidney toxicity of DDP and delaying the development of DDP resistance.

Effects of 3-Nitro-1,2,4-triazol-5-one on Survival, Growth and Metamorphosis in the Northern Leopard Frog, Lithobates pipiens.

PubMed

Pillard, David A; Eck, William S; Johnson, Mark S; Packard, Stephanie

2017-11-01

New explosive formulations are being developed to be less sensitive to impact and inadvertent explosion, increasing safety for the warfighter. Since testing and training make environmental releases imminent, the toxicity of 3-nitro-1,2,4-triazol-5-one (NTO), a component of Insensitive Munitions eXplosive (IMX) formulations, was assessed in a one-generation study to the northern leopard frog (Lithobates ( = Rana) pipiens). Because NTO in water creates acidic conditions, acute studies were conducted with non-pH-adjusted NTO, while a long-term (70-d) study was conducted with neutralized NTO. In the acute study, 48-h and 7-d LC 50 s were ~250 mg NTO/L. In the long-term study, tadpoles were dead by day 2 in 11,350 mg/L NTO, and by day 63 in 8382 mg/L. The 70-d LC 50 was 3670 mg (neutralized) NTO/L. The number of organisms reaching complete metamorphosis was reduced by NTO; the lowest IC 25 was 1999 mg NTO/L for the Number Completing Metamorphosis. The NOECs for Time to Front Limb Eruption or Time to Metamorphosis were the same at 1346 mg/L. Histopathology did not significantly distinguish between NTO-exposed and unexposed animals, although possible effects on the density of spermatogonia in NTO-exposed males was suggested. The test data indicate that acute toxicity to ambient NTO can be attributed primarily to its acidic nature; relatively low chronic toxicity of neutralized NTO is due to delays in metamorphosis. The consequence from this latter observation may be ecologically significant as delays of even a few days could increase mortality through predation and/or loss of the aquatic medium in temporary water bodies.

Delayed photolysis of liposomes: a strategy for the precision timing of bolus drug release using ex-vivo photochemical sensitization

NASA Astrophysics Data System (ADS)

Kozikowski, Raymond T.; Sorg, Brian S.

2012-03-01

Chemotherapy is a standard treatment for metastatic cancer. However drug toxicity limits the dosage that can safely be used, thus reducing treatment efficacy. Drug carrier particles, like liposomes, can help reduce toxicity by shielding normal tissue from drug and selectively depositing drug in tumors. Over years of development, liposomes have been optimized to avoid uptake by the Reticuloendothelial System (RES) as well as effectively retain their drug content during circulation. As a result, liposomes release drug passively, by slow leakage, but this uncontrolled drug release can limit treatment efficacy as it can be difficult to achieve therapeutic concentrations of drug at tumor sites even with tumor-specific accumulation of the carriers. Lipid membranes can be photochemically lysed by both Type I (photosensitizer-substrate) and Type II (photosensitizer-oxygen) reactions. It has been demonstrated in red blood cells (RBCs) in vitro that these photolysis reactions can occur in two distinct steps: a light-initiated reaction followed by a thermally-initiated reaction. These separable activation steps allow for the delay of photohemolysis in a controlled manner using the irradiation energy, temperature and photosensitizer concentration. In this work we have translated this technique from RBCs to liposomal nanoparticles. To that end, we present in vitro data demonstrating this delayed bolus release from liposomes, as well as the ability to control the timing of this event. Further, we demonstrate for the first time the improved delivery of bioavailable cargo selectively to target sites in vivo.

A field experiment to assess impact of chemically dispersed oil on Arabian Gulf corals

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

Le Gore, R.S.; Cuddeback, J.E.; Hofmann, J.E.

1983-03-01

Field experiments were conducted on a coral reef at Jurayd Island (Saudi Arabia) in the Arabian Gulf to study the effects of chemically dispersed oil on local corals. Portions of the reef were exposed to predetermined concentrations of oil alone, dispersant alone, and oil-plus-dispersant mixtures. Areas of the reef not exposed to any of the toxicants were used as controls. Arabian Light Crude and Corexit 9527 dispersant were the test toxicants. Two series of experiments were conducted beginning in September 1981, one with a 24-hour exposure period and the other with a 5-day (120-hour) exposure period. Corals were stained formore » growth rate studies and extensively photographed to document any observed effects. Corals were examined for biological impacts immediately after the exposures, and then at 3-month intervals for 1 year. Water temperature, salinity, dissolved oxygen, and hydrocarbon content were recorded during the exposure periods. Coral growth appeared unaffected by exposure to the toxicants. Some Acropora species corals exposed to dispersed oil for 5 days exhibited delayed effects, which became apparent during the relatively cold winter season.« less

Toxicity profile and treatment delays in NOPHO ALL2008-comparing adults and children with Philadelphia chromosome-negative acute lymphoblastic leukemia.

PubMed

Toft, Nina; Birgens, Henrik; Abrahamsson, Jonas; Griškevičius, Laimonas; Hallböök, Helene; Heyman, Mats; Klausen, Tobias Wirenfeldt; Jónsson, Ólafur Gísli; Palk, Katrin; Pruunsild, Kaie; Quist-Paulsen, Petter; Vaitkeviciene, Goda; Vettenranta, Kim; Asberg, Ann; Helt, Louise Rold; Frandsen, Thomas; Schmiegelow, Kjeld

2016-02-01

Cure rates improve when adolescents and young adults with acute lymphoblastic leukemia (ALL) are treated according to pediatric protocols. Assumed risks of toxicities and associated delays in treatment have played a role in setting upper age limits. The aim of this study was to examine the toxicity profile and treatment delays in NOPHO ALL2008 comparing children and adults. We collected information on 19 treatment-related toxicities, systematically captured at 3-month intervals throughout therapy, and time intervals between 12 consecutive treatment phases for 1076 patients aged 1-45 yrs treated according to the Nordic/Baltic ALL2008 protocol. No adults died during induction. The duration of induction therapy and postinduction treatment phases did not differ between children and adults, except for patients 18-45 yrs being significantly delayed during two of nine high-risk blocks (median number of days for patients 1-9, 10-17, and 18-45 yrs; the glucocorticosteroid/antimetabolite-based block B1: 24, 26, and 29 d, respectively, P = 0.001, and Block 5 (in most cases also a B block): 29, 29, and 37 d, respectively, P = 0.02). A higher incidence of thrombosis with increasing age was found; highest odds ratio 5.4 (95% CI: (2.6;11.0)) for patients 15-17 yrs compared with children 1-9 yrs (P < 0.0001). Risk of avascular osteonecrosis was related to age with the highest OR for patients 10-14 yrs (OR = 10.4 (95% CI: (4.4;24.9)), P < 0.0001). Adults followed and tolerated the NOPHO ALL2008 protocol virtually as well as children, although thrombosis and avascular osteonecrosis was most common among adolescents. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Iron Promotes the Toxicity of Amyloid β Peptide by Impeding Its Ordered Aggregation*

PubMed Central

Liu, Beinan; Moloney, Aileen; Meehan, Sarah; Morris, Kyle; Thomas, Sally E.; Serpell, Louise C.; Hider, Robert; Marciniak, Stefan J.; Lomas, David A.; Crowther, Damian C.

2011-01-01

We have previously shown that overexpressing subunits of the iron-binding protein ferritin can rescue the toxicity of the amyloid β (Aβ) peptide in our Drosophila model system. These data point to an important pathogenic role for iron in Alzheimer disease. In this study, we have used an iron-selective chelating compound and RNAi-mediated knockdown of endogenous ferritin to further manipulate iron in the brain. We confirm that chelation of iron protects the fly from the harmful effects of Aβ. To understand the pathogenic mechanisms, we have used biophysical techniques to see how iron affects Aβ aggregation. We find that iron slows the progression of the Aβ peptide from an unstructured conformation to the ordered cross-β fibrils that are characteristic of amyloid. Finally, using mammalian cell culture systems, we have shown that iron specifically enhances Aβ toxicity but only if the metal is present throughout the aggregation process. These data support the hypothesis that iron delays the formation of well ordered aggregates of Aβ and so promotes its toxicity in Alzheimer disease. PMID:21147772

Iron promotes the toxicity of amyloid beta peptide by impeding its ordered aggregation.

PubMed

Liu, Beinan; Moloney, Aileen; Meehan, Sarah; Morris, Kyle; Thomas, Sally E; Serpell, Louise C; Hider, Robert; Marciniak, Stefan J; Lomas, David A; Crowther, Damian C

2011-02-11

We have previously shown that overexpressing subunits of the iron-binding protein ferritin can rescue the toxicity of the amyloid β (Aβ) peptide in our Drosophila model system. These data point to an important pathogenic role for iron in Alzheimer disease. In this study, we have used an iron-selective chelating compound and RNAi-mediated knockdown of endogenous ferritin to further manipulate iron in the brain. We confirm that chelation of iron protects the fly from the harmful effects of Aβ. To understand the pathogenic mechanisms, we have used biophysical techniques to see how iron affects Aβ aggregation. We find that iron slows the progression of the Aβ peptide from an unstructured conformation to the ordered cross-β fibrils that are characteristic of amyloid. Finally, using mammalian cell culture systems, we have shown that iron specifically enhances Aβ toxicity but only if the metal is present throughout the aggregation process. These data support the hypothesis that iron delays the formation of well ordered aggregates of Aβ and so promotes its toxicity in Alzheimer disease.

Evaluation in zebrafish model of the toxicity of rhodamine B-conjugated crotamine, a peptide potentially useful for diagnostics and therapeutics.

PubMed

Chan, Judy Yuet-Wa; Zhou, Hefeng; Kwan, Yiu Wa; Chan, Shun Wan; Radis-Baptista, Gandhi; Lee, Simon Ming-Yuen

2017-11-01

Crotamine is defensin-like cationic peptide from rattlesnake venom that possesses anticancer, antimicrobial, and antifungal properties. Despite these promising biological activities, toxicity is a major concern associated with the development of venom-derived peptides as therapeutic agents. In the present study, we used zebrafish as a system model to evaluate the toxicity of rhodamine B-conjugated (RhoB) crotamine derivative. The lethal toxic concentration of RhoB-crotamine was as low as 4 μM, which effectively kill zebrafish larvae in less than 10 min. With non-lethal concentrations (<1 μM), crotamine caused malformation in zebrafish embryos, delayed or completely halted hatching, adversely affected embryonic developmental programming, decreased the cardiac functions, and attenuated the swimming distance of zebrafish. The RhoB-crotamine translocated across vitelline membrane and accumulated in zebrafish yolk sac. These results demonstrate the sensitive responsivity of zebrafish to trial crotamine analogues for the development of novel therapeutic peptides with improved safety, bioavailability, and efficacy profiles. © 2017 Wiley Periodicals, Inc.

Embryonic Zebrafish Model - A Well-Established Method for Rapidly Assessing the Toxicity of Homeopathic Drugs: - Toxicity Evaluation of Homeopathic Drugs Using Zebrafish Embryo Model.

PubMed

Gupta, Himanshu R; Patil, Yogesh; Singh, Dipty; Thakur, Mansee

2016-12-01

Advancements in nanotechnology have led to nanoparticle (NP) use in various fields of medicine. Although the potential of NPs is promising, the lack of documented evidence on the toxicological effects of NPs is concerning. A few studies have documented that homeopathy uses NPs. Unfortunately, very few sound scientific studies have explored the toxic effects of homeopathic drugs. Citing this lack of high-quality scientific evidence, regulatory agencies have been reluctant to endorse homeopathic treatment as an alternative or adjunct treatment. This study aimed to enhance our insight into the impact of commercially-available homeopathic drugs, to study the presence of NPs in those drugs and any deleterious effects they might have, and to determine the distribution pattern of NPs in zebrafish embryos ( Danio rerio ). Homeopathic dilutions were studied using high-resolution transmission electron microscopy with selected area electron diffraction (SAED). For the toxicity assessment on Zebrafish, embryos were exposed to a test solution from 4 - 6 hours post-fertilization, and embryos/larvae were assessed up to 5 days post-fertilization (dpf) for viability and morphology. Toxicity was recorded in terms of mortality, hatching delay, phenotypic defects and metal accumulation. Around 5 dpf was found to be the optimum developmental stage for evaluation. The present study aimed to conclusively prove the presence of NPs in all high dilutions of homeopathic drugs. Embryonic zebrafish were exposed to three homeopathic drugs with two potencies (30CH, 200CH) during early embryogenesis. The resulting morphological and cellular responses were observed. Exposure to these potencies produced no visibly significant malformations, pericardial edema, and mortality and no necrotic and apoptotic cellular death. Our findings clearly demonstrate that no toxic effects were observed for these three homeopathic drugs at the potencies and exposure times used in this study. The embryonic zebrafish model is recommended as a well-established method for rapidly assessing the toxicity of homeopathic drugs.

Drug-drug interaction between methotrexate and levetiracetam resulting in delayed methotrexate elimination.

PubMed

Bain, Emily; Birhiray, Ruemu E; Reeves, David J

2014-02-01

To report a case of delayed methotrexate (MTX) elimination while receiving concomitant levetiracetam. A 46-year-old man with relapsed osteosarcoma of the base of the skull receiving high-dose MTX tolerated his first cycle of MTX with elimination to nontoxic MTX levels (≤0.1 µmol/L) within 90 hours. After hospital discharge, the patient experienced seizures secondary to brain metastasis and started on levetiracetam, which was continued as maintenance therapy. The patient experienced delayed MTX elimination during cycles 2, 3, and 4 while receiving levetiracetam. On average, elimination to nontoxic MTX levels took 130 hours (106-144 hours). Before the fifth cycle of MTX, lorazepam was substituted for the levetiracetam. MTX was eliminated to nontoxic levels within 95 hours. During all cycles, the patient received standard supportive care and serum creatinine remained stable. No other drugs known to interact with MTX were administered. This possible drug interaction has only been reported once in the pediatric population. With a score of 6 on the Drug Interaction Probability Scale for evaluating causation of drug interactions, it is probable that the delayed MTX elimination was caused by an interaction with levetiracetam. Coadministration of levetiracetam and MTX may result in delayed elimination of MTX, increasing the likelihood of toxicity. Consideration should be given to temporarily switching from levetiracetam to another antiepileptic (ie, lorazepam) to prevent this interaction. This is particularly important in those experiencing delayed elimination with prior cycles of concomitant MTX and levetiracetam or those at greater risk for MTX toxicity.

Preliminary experience of whole-brain radiation therapy (WBRT) in breast cancer patients with brain metastases previously treated with bevacizumab-based chemotherapy.

PubMed

Chira, Ciprian; Jacob, Julian; Derhem, Najib; Bollet, Marc A; Campana, François; Marchand, Virginie; Pierga, Jean-Yves; Fourquet, Alain; Kirova, Youlia M

2011-11-01

We report our experience of bevacizumab-based chemotherapy (BBCT) followed by whole-brain radiation therapy (WBRT) for breast cancer (BC) patients (pts) with inoperable brain metastases (BM) or who refused surgery. This is a retrospective study of seven metastatic BC pts treated at the Institut Curie with at least one course of BBCT before WBRT, with a delay of ≤ 12 months between the two treatments. Toxicity was scored according to the common terminology criteria for adverse events (v4. 2010). Median age was 56 years (41-65). Median follow-up was 5.9 months (0.4-24.6). The median dose of bevacizumab was 10 mg/kg. Median number of cycles BBCT was six (5-17). Different chemotherapy regimens were used, the most common combination was paclitaxel-bevacizumab. WBRT was delivered in ten fractions, five fractions/week, for two weeks, to a total of 30 Gy. One pt underwent stereotactic radio surgery (SRS) after WBRT. No pt received BBCT during RT. Most common reported side-effects were nausea (n = 4), headache (n = 3), vomiting (n = 1), and vertigo (n = 3). All pts had mild or moderate grade ≤ 2 neurologic toxicity. There were no radiological signs of necrosis or cerebral ischemia. BBCT before WBRT was not associated with severe brain toxicity. Because of the limited number of pts, the different BBCT regimens, and important delays between treatments, these results must be confirmed prospectively.

Pollution dilemma in Asian population: CNG and wound healing.

PubMed

Ejaz, Sohail; Chekarova, Irina; Ahmad, Mukhtar; Nasir, Amir; Ashraf, Muhammad; Lim, Chae Woong

2009-11-01

Automobile exhaust constituents contribute significantly to air pollution in urban areas and compressed natural gas (CNG) is considered one of the most promising fuel alternatives for the future. CNG-powered four-stroke engine auto-rickshaws are ubiquitous in South Asian cities as taxi and for commercial transportation. Automotive exhaust contains several toxins, which are overwhelmingly toxic to the processes of wound healing. By utilizing the in vivo mouse model of wound healing, this report analyzes the effects of CNG-powered four-stroke auto-rickshaws smoke solution (4SARSS) on different events of wound healing; dermal matrix regeneration, re-epithelialization and neovascularization. A total of 72 adult mice, divided in eight groups were exposed to 4SARSS for 12 days. A highly significant reduction (P<0.001) in wound closure was observed among all 4SARSS treated groups, at each time point of the experiment. An immature development in both the neoepidermis and the neodermis was observed among all 4SARSS treated wounds with defective re-epithelialization, dermal matrix regeneration and maturation of collagen bundles. Abbott curve, angular spectrum, 3D surface topographies, and histological investigations of wounds explicated highly significant activation (P<0.001) of delayed-neovascularization among 4SARSS treated wounds. All these annotations advocate excessive toxicity of emission from CNG-powered auto-rickshaws to the process of wound healing and people occupationally exposed to this toxic emissions may suffer varying degree of delayed wound healing. Crown Copyright © 2009. Published by Elsevier B.V. All rights reserved.

Inhaled Diesel Emissions Generated with Cerium Oxide Nanoparticle Fuel Additive Induce Adverse Pulmonary and Systemic Effects

PubMed Central

Snow, Samantha J.; McGee, John; Miller, Desinia B.; Bass, Virginia; Schladweiler, Mette C.; Thomas, Ronald F.; Krantz, Todd; King, Charly; Ledbetter, Allen D.; Richards, Judy; Weinstein, Jason P.; Conner, Teri; Willis, Robert; Linak, William P.; Nash, David; Wood, Charles E.; Elmore, Susan A.; Morrison, James P.; Johnson, Crystal L.; Gilmour, Matthew Ian; Kodavanti, Urmila P.

2014-01-01

Diesel exhaust (DE) exposure induces adverse cardiopulmonary effects. Cerium oxide nanoparticles added to diesel fuel (DECe) increases fuel burning efficiency but leads to altered emission characteristics and potentially altered health effects. Here, we evaluated whether DECe results in greater adverse pulmonary effects compared with DE. Male Sprague Dawley rats were exposed to filtered air, DE, or DECe for 5 h/day for 2 days. N-acetyl glucosaminidase activity was increased in bronchial alveolar lavage fluid (BALF) of rats exposed to DECe but not DE. There were also marginal but insignificant increases in several other lung injury biomarkers in both exposure groups (DECe > DE for all). To further characterize DECe toxicity, rats in a second study were exposed to filtered air or DECe for 5 h/day for 2 days or 4 weeks. Tissue analysis indicated a concentration- and time-dependent accumulation of lung and liver cerium followed by a delayed clearance. The gas-phase and high concentration of DECe increased lung inflammation at the 2-day time point, indicating that gas-phase components, in addition to particles, contribute to pulmonary toxicity. This effect was reduced at 4 weeks except for a sustained increase in BALF γ-glutamyl transferase activity. Histopathology and transmission electron microscopy revealed increased alveolar septa thickness due to edema and increased numbers of pigmented macrophages after DECe exposure. Collectively, these findings indicate that DECe induces more adverse pulmonary effects on a mass basis than DE. In addition, lung accumulation of cerium, systemic translocation to the liver, and delayed clearance are added concerns to existing health effects of DECe. PMID:25239632

An extended one-generation reproductive toxicity test of 1,2,4-Triazol-5-one (NTO) in rats.

PubMed

Lent, Emily May; Crouse, Lee C B; Jackovitz, Allison M; Carroll, Erica E; Johnson, Mark S

2016-01-01

Nitrotriazolone (1,2,4-triazol-5-one; NTO), an insensitive, energetic material used in explosive formulations, induced testicular toxicity and oligospermia in repeated-dose oral toxicity tests in rats. To evaluate whether NTO produces additional reproductive and developmental effects, a modified extended one-generation reproductive toxicity test was conducted. Rats were provided ad libitum access to NTO in drinking water at 0-, 144-, 720-, or 3600-mg/L NTO. Treatment of the parental generation began 2 (females) and 4 (males) wk premating and continued until weaning of litters. Direct dosing of offspring (F1) occurred from weaning through puberty. Pups were counted and weighed on postnatal day (PND) 0/1. Anogenital distance (AGD) was measured on PND 4 and males were examined for presence of nipples on PND 13. F1 offspring were examined daily for attainment of puberty. NTO did not markedly affect measures of fertility, including mating indices, gestation index, litter size, and sex ratio. Seminiferous tubule degeneration or atrophy was observed in P1 and F1 3600-mg/L NTO males. F1 males in the 3600 mg/L group exhibited reduced reproductive organ mass (testes, epididymides, and accessory sex organs). Nipple retention was increased in NTO exposed F1 males compared to controls. Attainment of puberty was delayed by 2.6 d in the 3600-mg/L NTO-exposed males relative to controls. Comparison of the effects of NTO with those of antiandrogens suggests absence of malformations of the genital tract in NTO-exposed males. This study supports previous findings indicating that NTO is a testicular toxicant with male developmental effects that may be secondary to testicular toxicity.

Postconditioning Effectively Prevents Trimethyltin Induced Neuronal Damage in the Rat Brain.

PubMed

Lalkovicova, Maria; Burda, Jozef; Nemethova, Miroslava; Burda, Rastislav; Danielisova, Viera

Trimethyltin (TMT) is a toxic substance formerly used as a catalyst in the production of organic substances, as well as in industry and agriculture. TMT poisoning has caused death or severe injury in many dozens of people. The toxicity of TMT is mediated by dose dependent selective damage to the limbic system in humans and other animals, specifically the degeneration of CA1 neurons in the hippocampus. The typical symptoms include memory loss and decreased learning ability. Using knowledge gained in previous studies of global ischaemia, we used delayed postconditioning after TMT intoxication (8 mg/kg i.p.), consisting of applying a stressor (BR, bradykinin 150 μg/kg i.p.) 24 or 48 hours after the injection of TMT. We found that BR had preventive effects on neurodegenerative changes as well as learning and memory deficits induced by TMT intoxication.

Cancer Prevention with Promising Natural Products: Mechanisms of Action and Molecular Targets

PubMed Central

Pratheeshkumar, Poyil; Sreekala, Chakkenchath; Zhang, Zhuo; Budhraja, Amit; Ding, Songze; Son, Young-Ok; Wang, Xin; Hitron, Andrew; Hyun-Jung, Kim; Wang, Lei; Lee, Jeong-Chae; Shi, Xianglin

2016-01-01

Cancer is the second leading cause of death worldwide. There is greater need for more effective and less toxic therapeutic and preventive strategies. Natural products are becoming an important research area for novel and bioactive molecules for drug discovery. Phytochemicals and dietary compounds have been used for the treatment of cancer throughout history due to their safety, low toxicity, and general availability. Many active phytochemicals are in human clinical trials. Studies have indicated that daily consumption of dietary phytochemicals have cancer protective effects against carcinogens. They can inhibit, delay, or reverse carcinogenesis by inducing detoxifying and antioxidant enzymes systems, regulating inflammatory and proliferative signaling pathways, and inducing cell cycle arrest and apoptosis. Epidemiological studies have also revealed that high dietary intakes of fruits and vegetables reduce the risk of cancer. This review discusses potential natural cancer preventive compounds, their molecular targets, and their mechanisms of actions. PMID:22583402

Neurosteroids for the potential protection of humans against organophosphate toxicity.

PubMed

Reddy, Doodipala Samba

2016-08-01

This article describes the therapeutic potential of neurosteroids as anticonvulsant antidotes for chemical intoxication caused by organophosphate pesticides and nerve agents or gases like sarin and soman. Toxic manifestations following nerve agent exposure, as evident in chemical attacks in Japan and Syria, include hypersecretion, respiratory distress, tremors, convulsions leading to status epilepticus (SE), and death. Benzodiazepines, such as diazepam, are the current anticonvulsants of choice for controlling nerve agent-induced life-threatening seizures, SE, and brain injury. Benzodiazepines can control acute seizures when given early, but they are less effective for delayed treatment of SE, which is characterized by rapid desensitization of synaptic GABA A receptors, benzodiazepine resistance, and brain injury. Neurosteroid-sensitive extrasynaptic GABA A receptors, however, remain unaffected by such events. Thus, anticonvulsant neurosteroids may produce more effective protection than benzodiazepines against a broad spectrum of chemical agents, even when given late after nerve agent exposure. © 2016 New York Academy of Sciences.

An F1-extended one-generation reproductive toxicity study in Crl:CD(SD) rats with 2,4-dichlorophenoxyacetic acid.

PubMed

Marty, Mary Sue; Neal, Barbara H; Zablotny, Carol L; Yano, Barry L; Andrus, Amanda K; Woolhiser, Michael R; Boverhof, Darrell R; Saghir, Shakil A; Perala, Adam W; Passage, Julie K; Lawson, Marie A; Bus, James S; Lamb, James C; Hammond, Larry

2013-12-01

2,4-Dichlorophenoxyacetic acid (2,4-D) was assessed for systemic toxicity, reproductive toxicity, developmental neurotoxicity (DNT), developmental immunotoxicity (DIT), and endocrine toxicity. CD rats (27/sex/dose) were exposed to 0, 100, 300, 600 (female), or 800 (male) ppm 2,4-D in diet. Nonlinear toxicokinetic behavior was shown at high doses; the renal clearance saturation threshold for 2,4-D was exceeded markedly in females and slightly exceeded in males. Exposure was 4 weeks premating, 7 weeks postmating for P1 males and through lactation for P1 females. F1 offspring were examined for survival and development, and at weaning, pups were divided in cohorts, by sex and dose, and by systemic toxicity (10), DNT (10), DIT (20), and reproductive toxicity (≥ 23). Remaining weanlings were evaluated for systemic toxicity and neuropathology (10-12). Body weight decreased during lactation in high-dose P1 females and in F1 pups. Kidney was the primary target organ, with slight degeneration of proximal convoluted tubules observed in high-dose P1 males and in high-dose F1 males and females. A slight intergenerational difference in kidney toxicity was attributed to increased intake of 2,4-D in F1 offspring. Decreased weanling testes weights and delayed preputial separation in F1 males were attributed to decreased body weights. Endocrine-related effects were limited to slight thyroid hormone changes and adaptive histopathology in high-dose GD 17 dams seen only at a nonlinear toxicokinetic dose. 2,4-D did not cause reproductive toxicity, DNT, or DIT. The "No Observed Adverse Effect Level" for systemic toxicity was 300 ppm in both males (16.6 mg/kg/day) and females (20.6 mg/kg/day), which is approximately 6700- to 93 000-fold higher than that reported for 2,4-D exposures in human biomonitoring studies.

An F1-Extended One-Generation Reproductive Toxicity Study in Crl:CD(SD) Rats With 2,4-Dichlorophenoxyacetic Acid

PubMed Central

Marty, Mary Sue

2013-01-01

2,4-Dichlorophenoxyacetic acid (2,4-D) was assessed for systemic toxicity, reproductive toxicity, developmental neurotoxicity (DNT), developmental immunotoxicity (DIT), and endocrine toxicity. CD rats (27/sex/dose) were exposed to 0, 100, 300, 600 (female), or 800 (male) ppm 2,4-D in diet. Nonlinear toxicokinetic behavior was shown at high doses; the renal clearance saturation threshold for 2,4-D was exceeded markedly in females and slightly exceeded in males. Exposure was 4 weeks premating, 7 weeks postmating for P1 males and through lactation for P1 females. F1 offspring were examined for survival and development, and at weaning, pups were divided in cohorts, by sex and dose, and by systemic toxicity (10), DNT (10), DIT (20), and reproductive toxicity (≥ 23). Remaining weanlings were evaluated for systemic toxicity and neuropathology (10–12). Body weight decreased during lactation in high-dose P1 females and in F1 pups. Kidney was the primary target organ, with slight degeneration of proximal convoluted tubules observed in high-dose P1 males and in high-dose F1 males and females. A slight intergenerational difference in kidney toxicity was attributed to increased intake of 2,4-D in F1 offspring. Decreased weanling testes weights and delayed preputial separation in F1 males were attributed to decreased body weights. Endocrine-related effects were limited to slight thyroid hormone changes and adaptive histopathology in high-dose GD 17 dams seen only at a nonlinear toxicokinetic dose. 2,4-D did not cause reproductive toxicity, DNT, or DIT. The “No Observed Adverse Effect Level” for systemic toxicity was 300 ppm in both males (16.6mg/kg/day) and females (20.6mg/kg/day), which is approximately 6700- to 93 000-fold higher than that reported for 2,4-D exposures in human biomonitoring studies. PMID:24072463

Late hematologic toxicity following treatment of rattlesnake envenomation with crotalidae polyvalent immune Fab antivenom.

PubMed

Ruha, Anne-Michelle; Curry, Steven C; Albrecht, Clay; Riley, Brad; Pizon, Anthony

2011-01-01

North American rattlesnake envenomations commonly produce defibrination, coagulopathy and/or thrombocytopenia, which may be reversed following treatment with Crotalidae Polyvalent Immune Fab Ovine (FabAV). Despite initial resolution with FabAV, late onset or recurrence of venom-induced hematologic effects may occur. Time at which onset of late hematotoxicity may first be detected is unknown. The purpose of this study was to identify the incidence and time of onset of recurrent or new late hypofibrinogenemia, coagulopathy, or thrombocytopenia in a cohort of rattlesnake envenomation patients seen in outpatient follow-up after treatment with FabAV, and to report hematologic outcomes in these patients. Review of 66 charts of patients with rattlesnake envenomation who were treated with FabAV, and subsequently had outpatient follow-up evaluation at least 48 h after last FabAV, was performed. Demographic information, rattlesnake and bite characteristics, dose and timing of antivenom administration, adverse events, in-patient laboratory values, length of hospital stay, and follow-up laboratory values were collected. The primary outcome parameters were recurrent or delayed onset coagulopathy, hypofibrinogenemia, or thrombocytopenia identified no sooner than 48 h after last dose of FabAV. Prior to control of the envenomation with FabAV, 42 patients (63.6%) experienced hematologic toxicity. At follow-up, 21 patients (32%) were found to have late coagulopathy, hypofibrinogenemia, or thrombocytopenia. Of twenty-three patients (35%) with more than one follow-up visit, fifteen had normal laboratory findings at the first follow-up visit. Five of these 15 patients (8% of total study group; 33% of this subgroup) with normal hematologic studies at first follow-up exhibited late hematologic toxicity at second follow-up. Severe late hematologic toxicity developed in five of 66 (8%) patients. One patient was retreated with FabAV for late severe thrombocytopenia. Recurrent and delayed onset of hematologic toxicity in rattlesnake envenomation victims treated with FabAV is common. Follow-up more than three days after treatment is necessary to detect all cases of late hematologic toxicity. Copyright © 2010 Elsevier Ltd. All rights reserved.

Assessment of the lethal and sublethal effects of 20 environmental chemicals in zebrafish embryos and larvae by using OECD TG 212.

PubMed

Horie, Yoshifumi; Yamagishi, Takahiro; Takahashi, Hiroko; Shintaku, Youko; Iguchi, Taisen; Tatarazako, Norihisa

2017-10-01

Fish embryo toxicity tests are used to assess the lethal and sublethal effects of environmental chemicals in aquatic organisms. Previously, we used a short-term toxicity test published by the Organization for Economic Co-operation and Development (test no. 212: Fish, Short-term Toxicity Test on Embryo and Sac-Fry Stages [OECD TG 212]) to assess the lethal and sublethal effects of aniline and several chlorinated anilines in zebrafish embryos and larvae. To expand upon this previous study, we used OECD TG 212 in zebrafish embryos and larvae to assess the lethal and sublethal effects of 20 additional environmental chemicals that included active pharmaceutical ingredients, pesticides, metals, aromatic compounds or chlorinated anilines. Zebrafish embryos (Danio rerio) were exposed to the test chemicals until 8 days post-fertilization. A delayed lethal effect was induced by 16 of the 20 test chemicals, and a positive correlation was found between heart rate turbulence and mortality. We also found that exposure to the test chemicals at concentrations lower than the lethal concentration induced the sublethal effects of edema, body curvature and absence of swim-bladder inflation. In conclusion, the environmental chemicals assessed in the present study induced both lethal and sublethal effects in zebrafish embryos and larvae, as assessed by using OECD TG 212. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Characterization of the effects of methylmercury on Caenorhabditis elegans

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

Helmcke, Kirsten J.; Syversen, Tore; Miller, David M.

2009-10-15

The rising prevalence of methylmercury (MeHg) in seafood and in the global environment provides an impetus for delineating the mechanism of the toxicity of MeHg. Deleterious effects of MeHg have been widely observed in humans and in other mammals, the most striking of which occur in the nervous system. Here we test the model organism, Caenorhabditis elegans (C. elegans), for MeHg toxicity. The simple, well-defined anatomy of the C. elegans nervous system and its ready visualization with green fluorescent protein (GFP) markers facilitated our study of the effects of methylmercuric chloride (MeHgCl) on neural development. Although MeHgCl was lethal tomore » C. elegans, induced a developmental delay, and decreased pharyngeal pumping, other traits including lifespan, brood size, swimming rate, and nervous system morphology were not obviously perturbed in animals that survived MeHgCl exposure. Despite the limited effects of MeHgCl on C. elegans development and behavior, intracellular mercury (Hg) concentrations ({<=} 3 ng Hg/mg protein) in MeHgCl-treated nematodes approached levels that are highly toxic to mammals. If MeHgCl reaches these concentrations throughout the animal, this finding indicates that C. elegans cells, particularly neurons, may be less sensitive to MeHgCl toxicity than mammalian cells. We propose, therefore, that C. elegans should be a useful model for discovering intrinsic mechanisms that confer resistance to MeHgCl exposure.« less

Chemical meningitis related to intra-CSF liposomal cytarabine.

PubMed

Durand, Bénédicte; Zairi, Fahed; Boulanger, Thomas; Bonneterre, Jacques; Mortier, Laurent; Le Rhun, Emilie

2017-10-01

Therapeutic options of leptomeningeal metastases include intra-cerebrospinal fluid (CSF) chemotherapy. Among intra-CSF agents, liposomal cytarabine has advantages but can induce specific toxicities. A BRAF-V600E-mutated melanoma leptomeningeal metastases patient, treated by dabrafenib and liposomal cytarabine, presented after the first injection of liposomal cytarabine with hyperthermia and headaches. Despite sterile CSF/blood analyses, extended intravenous antibiotics were given and the second injection was delayed. The diagnosis of chemical meningitis was finally made. Dose reduction and appropriate symptomatic treatment permitted the administration of 15 injections of liposomal cytarabine combined with dabrafenib. A confirmation of the diagnosis of chemical meningitis is essential in order (1) not to delay intra-CSF or systemic chemotherapy or (2) to limit the administration of unnecessary but potentially toxic antibiotics.

Bilirubin and its oxidation products damage brain white matter

PubMed Central

Lakovic, Katarina; Ai, Jinglu; D'Abbondanza, Josephine; Tariq, Asma; Sabri, Mohammed; Alarfaj, Abdullah K; Vasdev, Punarjot; Macdonald, Robert Loch

2014-01-01

Brain injury after intracerebral hemorrhage (ICH) occurs in cortex and white matter and may be mediated by blood breakdown products, including hemoglobin and heme. Effects of blood breakdown products, bilirubin and bilirubin oxidation products, have not been widely investigated in adult brain. Here, we first determined the effect of bilirubin and its oxidation products on the structure and function of white matter in vitro using brain slices. Subsequently, we determined whether these compounds have an effect on the structure and function of white matter in vivo. In all, 0.5 mmol/L bilirubin treatment significantly damaged both the function and the structure of myelinated axons but not the unmyelinated axons in brain slices. Toxicity of bilirubin in vitro was prevented by dimethyl sulfoxide. Bilirubin oxidation products (BOXes) may be responsible for the toxicity of bilirubin. In in vivo experiments, unmyelinated axons were found more susceptible to damage from bilirubin injection. These results suggest that unmyelinated axons may have a major role in white-matter damage in vivo. Since bilirubin and BOXes appear in a delayed manner after ICH, preventing their toxic effects may be worth investigating therapeutically. Dimethyl sulfoxide or its structurally related derivatives may have a potential therapeutic value at antagonizing axonal damage after hemorrhagic stroke. PMID:25160671

Exposure to Zearalenone During Early Pregnancy Causes Estrogenic Multitoxic Effects in Mice.

PubMed

Kunishige, Kohji; Kawate, Noritoshi; Inaba, Toshio; Tamada, Hiromichi

2017-03-01

Although zearalenone (ZEN; Sigma Chemicals, St Louis, Missouri) is a well-known mycotoxin with estrogenic activity, the toxic effects of ZEN during pregnancy are unknown. This study compared the effects of daily subcutaneous injections of ZEN (2, 4, or 8 mg/kg) with those of 17β-estradiol (E2; [Sigma Chemicals] 0.8, 1.6, or 3.2 μg/kg) in mice. Injections were administered on gestational days (GDs) 1 to 5, the period including implantation which is sensitive to hormonal balance. The effects of ZEN or E2 were evaluated by comparing the number of live fetuses, their weight, and absorbed conceptuses on GD 18, with those in vehicle-treated controls. In addition, implantation, embryos in the oviducts and those in uteri without implantation sites were investigated on GD 5. In mice treated with the highest dose of ZEN or E2, decidual responses and plasma progesterone concentrations were measured on GDs 5 and 6, respectively, and delayed implantation was investigated on GDs 9 and 14. The results showed that treatment with ZEN, in a manner similar to that seen for E2, led to obstruction of essential processes for establishing and maintaining pregnancy, such as embryo migration from oviducts to uteri, the decidual response, and activation of luteal function. Zearalenone also induced delayed implantation and loss of conceptuses and at low doses caused a retarded growth of the fetuses after normal implantation. It was therefore concluded that ZEN causes multiple estrogenic toxic actions when administered during early pregnancy in mice.

Genetic and toxinological characterization of North Atlantic strains of the dinoflagellate Ostreopsis and allelopathic interactions with toxic and non-toxic species from the genera Prorocentrum, Coolia and Gambierdiscus.

PubMed

García-Portela, María; Riobó, Pilar; Franco, José Mariano; Bañuelos, Rosa Mª; Rodríguez, Francisco

2016-12-01

The genus Ostreopsis includes several toxic species that can develop blooms in benthic ecosystems, with potential harmful consequences for human health and marine invertebrates. Despite of this, little is known about the allelopathic interactions between these organisms and other co-occurring microalgae that exploit similar spatial and nutrient resources in benthic ecosystems. The aim of this study was to follow these interactions in cultures of two Ostreopsis ribotypes with different toxin profiles (O. cf. ovata contained ovatoxins-a, b, c and e, while only ovatoxin-d was found in O .sp. "Lanzarote-type"), mixed with species of three benthic dinoflagellate genera (Coolia, Prorocentrum and Gambierdiscus), isolated from the same area (North East Atlantic, Canary Islands). In a first experiment, the potential allelopathic effects on growth rates were followed, in mixed cultures of Coolia monotis (a non toxic species) exposed to the clarified medium and to cells of O. sp."Lanzarote-type" and O. cf. ovata. Growth delayed in C. monotis was observed specially in clarified medium, while the O. sp. "Lanzarote-type" strain attained much lower densities in mixed cultures. In a second experiment, we examined the potential effects of clarified media from O. sp."Lanzarote-type" and O. cf. ovata on the adherence capacity in two toxic species (Prorocentrum hoffmannianum and Gambierdiscus excentricus). Contrasting effects were found: a significant increase of adherence capacity in P. hoffmannianum vs attachment decline in G. excentricus, that experienced also severe deleterious effects (cell lysis). Our results suggest the existence of weak to moderate allelopathic interactions between the studied organisms, although the outcome is dependent on the species involved. Copyright © 2016 Elsevier B.V. All rights reserved.

Two-generation reproductive toxicity study of tributyltin chloride in female rats.

PubMed

Ogata, R; Omura, M; Shimasaki, Y; Kubo, K; Oshima, Y; Aou, S; Inoue, N

2001-05-25

A two-generation reproductive toxicity study of the effects of tributyltin chloride (TBTCl) was conducted in female rats using dietary concentrations of 5, 25, and 125 ppm TBTCl. Reproductive outcomes of dams (number and body weight of pups and the percentage of live pups) and the growth of female pups (the day of eye opening and body weight gain) were significantly decreased in the 125 ppm TBTCl group. A delay in vaginal opening and impaired estrous cyclicity were also observed in the 125 ppm TBTCl group. However, an increase in anogenital distance was found in all TBTCl groups on postnatal d 1. A dose-effect relationship was observed in TBTCl-induced changes in anogenital distance. These results indicate that the whole-life exposure to TBTCl affects the sexual development and reproductive function of female rats. In addition, the TBTCl-induced increase in anogenital distance seems to suggest it may exert a masculinizing effect on female neonates. However, the concentrations of TBTCl used in this study are not environmentally relevant.

Sublethal effects of atrazine on embryo-larval development of Rhinella arenarum (Anura: Bufonidae).

PubMed

Svartz, Gabriela V; Herkovits, Jorge; Pérez-Coll, Cristina S

2012-05-01

Atrazine (ATR), one of the most widely used herbicides in the world, affects not only target organisms but also the biota in general. Here, the teratogenic and neurotoxic effects of ATR on Rhinella arenarum (South American toad) embryos, and larvae were evaluated by means of standardized bioassays during acute and chronic exposures. The herbicide had a significant incidence of malformations, with a Teratogenic Index (TI) of 3.28. The main effects were delayed development, reduced body size, microcephaly, axial flexures, wavy tail and edema. In addition, delayed development, reduced development of forelimbs, and edema were recorded at metamorphosis stages. Scanning electron microscopy allowed observing different degrees of cellular dissociation and persistent cilliar cells in specific regions like the adhesive structure and tail fin. Results obtained by ATR 24 h pulse exposures at six developmental stages pointed out blastula as the most susceptible developmental stage both for immediate and delayed adverse effects. A noteworthy recovery capacity from acute toxic effects was recorded from the neural plate stage onwards. Regarding neurotoxic effects, abnormal, and erratic swimming and spasmodic contractions were recorded. Both the teratogenic and neurotoxic effects reported in this study demonstrate the importance of evaluating sublethal effects in non-target organisms as they could imply reduced fitness of individuals and eventually a population decline. The Hazard Quotients (HQ) for ATR ranged from 0.14 to 10.80, and the fact that some of these values are above USEPA's level of concern indicate that ATR is likely a risk to R. arenarum.

Predictive modeling of nanomaterial exposure effects in biological systems

PubMed Central

Liu, Xiong; Tang, Kaizhi; Harper, Stacey; Harper, Bryan; Steevens, Jeffery A; Xu, Roger

2013-01-01

Background Predictive modeling of the biological effects of nanomaterials is critical for industry and policymakers to assess the potential hazards resulting from the application of engineered nanomaterials. Methods We generated an experimental dataset on the toxic effects experienced by embryonic zebrafish due to exposure to nanomaterials. Several nanomaterials were studied, such as metal nanoparticles, dendrimer, metal oxide, and polymeric materials. The embryonic zebrafish metric (EZ Metric) was used as a screening-level measurement representative of adverse effects. Using the dataset, we developed a data mining approach to model the toxic endpoints and the overall biological impact of nanomaterials. Data mining techniques, such as numerical prediction, can assist analysts in developing risk assessment models for nanomaterials. Results We found several important attributes that contribute to the 24 hours post-fertilization (hpf) mortality, such as dosage concentration, shell composition, and surface charge. These findings concur with previous studies on nanomaterial toxicity using embryonic zebrafish. We conducted case studies on modeling the overall effect/impact of nanomaterials and the specific toxic endpoints such as mortality, delayed development, and morphological malformations. The results show that we can achieve high prediction accuracy for certain biological effects, such as 24 hpf mortality, 120 hpf mortality, and 120 hpf heart malformation. The results also show that the weighting scheme for individual biological effects has a significant influence on modeling the overall impact of nanomaterials. Sample prediction models can be found at http://neiminer.i-a-i.com/nei_models. Conclusion The EZ Metric-based data mining approach has been shown to have predictive power. The results provide valuable insights into the modeling and understanding of nanomaterial exposure effects. PMID:24098077

Toxicity of silver nanoparticles in zebrafish models

NASA Astrophysics Data System (ADS)

Asharani, P. V.; Lian Wu, Yi; Gong, Zhiyuan; Valiyaveettil, Suresh

2008-06-01

This study was initiated to enhance our insight on the health and environmental impact of silver nanoparticles (Ag-np). Using starch and bovine serum albumin (BSA) as capping agents, silver nanoparticles were synthesized to study their deleterious effects and distribution pattern in zebrafish embryos (Danio rerio). Toxicological endpoints like mortality, hatching, pericardial edema and heart rate were recorded. A concentration-dependent increase in mortality and hatching delay was observed in Ag-np treated embryos. Additionally, nanoparticle treatments resulted in concentration-dependent toxicity, typified by phenotypes that had abnormal body axes, twisted notochord, slow blood flow, pericardial edema and cardiac arrhythmia. Ag+ ions and stabilizing agents showed no significant defects in developing embryos. Transmission electron microscopy (TEM) of the embryos demonstrated that nanoparticles were distributed in the brain, heart, yolk and blood of embryos as evident from the electron-dispersive x-ray analysis (EDS). Furthermore, the acridine orange staining showed an increased apoptosis in Ag-np treated embryos. These results suggest that silver nanoparticles induce a dose-dependent toxicity in embryos, which hinders normal development.

Cranberry Extract Standardized for Proanthocyanidins Alleviates β-Amyloid Peptide Toxicity by Improving Proteostasis Through HSF-1 in Caenorhabditis elegans Model of Alzheimer's Disease.

PubMed

Guo, Hong; Cao, Min; Zou, Sige; Ye, Boping; Dong, Yuqing

2016-12-01

A growing body of evidence suggests that nutraceuticals with prolongevity properties may delay the onset of Alzheimer's disease (AD). We recently demonstrated that a proanthocyanidins-standardized cranberry extract has properties that prolong life span and promote innate immunity in Caenorhabditis elegans In this article, we report that supplementation of this cranberry extract delayed Aβ toxicity-triggered body paralysis in the C elegans AD model. Genetic analyses indicated that the cranberry-mediated Aβ toxicity alleviation required heat shock transcription factor (HSF)-1 rather than DAF-16 and SKN-1. Moreover, cranberry supplementation increased the transactivity of HSF-1 in an IIS-dependent manner. Further studies found that the cranberry extract relies on HSF-1 to significantly enhance the solubility of proteins in aged worms, implying an improved proteostasis in AD worms. Considering that HSF-1 plays a pivotal role in maintaining proteostasis, our results suggest that cranberry maintains the function of proteostasis through HSF-1, thereby protecting C elegans against Aβ toxicity. Together, our findings elucidated the mechanism whereby cranberry attenuated Aβ toxicity in C elegans and stressed the significance of proteostasis in the prevention of age-related diseases from a practical point of view. © The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Oxygen toxicity.

PubMed

Stogner, S W; Payne, D K

1992-12-01

The objective of this article is to provide an overview of the biochemistry of oxygen metabolism, including the formation of free radicals and the role of endogenous antioxidants. Pathophysiologic correlates underlying the clinical manifestations of oxygen toxicity are reviewed and management strategies are outlined. References from basic science and clinical journals were selected from the authors' files and from a search of a computerized database of the biomedical literature. Articles selected for review included both historical and current literature concerning the biochemistry and pathophysiology of oxygen toxicity in animals and humans. The benefits of oxygen therapy have been known for many years; however, its potential toxicity has not been recognized until the last two decades. The lungs, the eyes, and, under certain conditions, the central nervous system are the organs most affected by prolonged exposure to hyperoxic environments. Free radical formation during cellular metabolism under hyperoxic conditions is recognized as the biochemical basis of oxygen injury to cells and organs. Endogenous antioxidants are a primary means of detoxifying reactive oxygen species and preventing hyperoxia-induced cellular damage. When this defense fails or is overwhelmed by the excessive production of hyperoxia-induced free-radical species, distinctive morphologic changes occur at the cellular level. The amount of hyperoxia required to cause cellular damage and the time course of these changes vary from species to species and from individual to individual within the same species. Age, nutritional status, presence of underlying diseases, and certain drugs may influence the development of oxygen toxicity. There is currently no reliably effective drug for preventing or delaying the development of oxygen toxicity in humans. Use of the lowest effective oxygen concentration, the avoidance of certain drugs, and attention to nutritional and metabolic factors remain the best means currently available to avoid or minimize oxygen toxicity. Research is continuing into more effective ways to prevent, diagnose, and treat this disorder.

Toxicity of inorganic and organic selenium to Daphnia magna (cladocera) and Chironomus riparius (diptera)

USGS Publications Warehouse

Ingersoll, Christopher G.; Dwyer, F.J.; May, T.W.

1990-01-01

Elevated concentrations of selenium (Se) have been previously measured in biota sampled from the Kesterson National Wildlife Refuge (KNWR) in the San Joaquin Valley of central California. We conducted acute and chronic toxicity tests with the cladoceran Daphnia magna and the midge Chironomus riparius to determine the toxicity or bioaccumulation of waterborne Se in a reconstituted water similar to the San Joaquin River. Daphnids were more acutely sensitive than midges to the toxic effects of inorganic Se. An organic form of Se (seleno-[L]-methionine) was extremely toxic to daphnids, but was relatively nontoxic to midges. In long-term exposure to a 6:1 mixture of selenate to selenite (a mixture representative of KNWR), the emergence time of adult midges was delayed at Se concentrations ≥ 837 μg/L. Daphnid reproduction and intrinsic rate of natural increase (r) were reduced at Se concentrations ≥ 348 μg/L and growth of adults was reduced at ≥ 156 μg/L. Whole body Mg, K and Na concentrations in daphnids were not affected by chronic Se exposure; however, whole body Ca concentration increased at intermediate Se exposure concentrations. In addition, whole body Cl concentration was reduced at 711 μg Se/L. Daphnids accumulated potentially toxic concentrations of Se from water that may adversely affect fish or waterfowl through the food chain.

Is imidacloprid an effective alternative for controlling pyrethroid-resistant populations of Triatoma infestans (Hemiptera: Reduviidae) in the Gran Chaco ecoregion?

PubMed

Carvajal, Guillermo; Picollo, María Inés; Toloza, Ariel Ceferino

2014-09-01

The prevention of Chagas disease is based primarily on the chemical control of Triatoma infestans (Klug) using pyrethroid insecticides. However, high resistance levels, correlated with control failures, have been detected in Argentina and Bolivia. A previous study at our laboratory found that imidacloprid could serve as an alternative to pyrethroid insecticides. We studied the delayed toxicity of imidacloprid and the influence of the blood feeding condition of the insect on the toxicity of this insecticide; we also studied the effectiveness of various commercial imidacloprid formulations against a pyrethroid-resistant T. infestans population from the Gran Chaco ecoregion. Variations in the toxic effects of imidacloprid were not observed up to 72 h after exposure and were not found to depend on the blood feeding condition of susceptible and resistant individuals. Of the three different studied formulations of imidacloprid on glass and filter paper, only the spot-on formulation was effective. This formulation was applied to pigeons at doses of 1, 5, 20 and 40 mg/bird. The nymphs that fed on pigeons treated with 20 mg or 40 mg of the formulation showed a higher mortality rate than the control group one day and seven days post-treatment (p < 0.01). A spot-on formulation of imidacloprid was effective against pyrethroid-resistant T. infestans populations at the laboratory level.

Is imidacloprid an effective alternative for controlling pyrethroid-resistant populations of Triatoma infestans (Hemiptera: Reduviidae) in the Gran Chaco ecoregion?

PubMed Central

Carvajal, Guillermo; Picollo, María Inés; Toloza, Ariel Ceferino

2014-01-01

The prevention of Chagas disease is based primarily on the chemical control of Triatoma infestans (Klug) using pyrethroid insecticides. However, high resistance levels, correlated with control failures, have been detected in Argentina and Bolivia. A previous study at our laboratory found that imidacloprid could serve as an alternative to pyrethroid insecticides. We studied the delayed toxicity of imidacloprid and the influence of the blood feeding condition of the insect on the toxicity of this insecticide; we also studied the effectiveness of various commercial imidacloprid formulations against a pyrethroid-resistant T. infestans population from the Gran Chaco ecoregion. Variations in the toxic effects of imidacloprid were not observed up to 72 h after exposure and were not found to depend on the blood feeding condition of susceptible and resistant individuals. Of the three different studied formulations of imidacloprid on glass and filter paper, only the spot-on formulation was effective. This formulation was applied to pigeons at doses of 1, 5, 20 and 40 mg/bird. The nymphs that fed on pigeons treated with 20 mg or 40 mg of the formulation showed a higher mortality rate than the control group one day and seven days post-treatment (p < 0.01). A spot-on formulation of imidacloprid was effective against pyrethroid-resistant T. infestans populations at the laboratory level. PMID:25141281

In vitro microbial inhibition and cellular response to novel biodegradable composite wound dressings with controlled release of antibiotics.

PubMed

Elsner, J J; Berdicevsky, I; Zilberman, M

2011-01-01

About 70% of all people with severe burns die from related infections, despite advances in treatment regimens and the best efforts of nurses and doctors. Although silver-eluting wound dressings are available for addressing this problem, there is growing evidence of the deleterious effects of such dressings in delaying the healing process owing to cellular toxicity. A new concept of antibiotic-eluting composite wound dressings is described here. These dressings are based on a polyglyconate mesh coated with a porous poly-(dl-lactic-co-glycolic acid) matrix loaded with antibiotic drugs. The effect of antibiotic release on bacterial inhibition was studied, and cell cytotoxicity was examined. The dressings resulted in a 99.99% decrease in the viable counts of Pseudomonas aeruginosa and Staphylococcus albus at very high initial inoculations of 10⁷-10⁸ CFU ml⁻¹ after only 1 day, while such a decrease in Staphylococcus aureus was obtained within 3 days. Bacterial inhibition zones around the dressing material were found to persist for 2 weeks, indicating a long-lasting antimicrobial effect. Despite severe toxicity to bacteria, the dressing material was found to have no toxic effect on cultured fibroblasts, indicating that the new antibiotic-eluting wound dressings represent an effective option for selective treatment of bacterial infections. Copyright © 2010 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Developmental immunotoxicity of chemicals in rodents and its possible regulatory impact.

PubMed

Hessel, Ellen V S; Tonk, Elisa C M; Bos, Peter M J; van Loveren, Henk; Piersma, Aldert H

2015-01-01

Around 25% of the children in developed countries are affected with immune-based diseases. Juvenile onset diseases such as allergic, inflammatory and autoimmune diseases have shown increasing prevalences in the last decades. The role of chemical exposures in these phenomena is unclear. It is thought that the developmental immune system is more susceptible to toxicants than the mature situation. Developmental immunotoxicity (DIT) testing is nowadays not or minimally included in regulatory toxicology requirements. We reviewed whether developmental immune parameters in rodents would provide relatively sensitive endpoints of toxicity, whose inclusion in regulatory toxicity testing might improve hazard identification and risk assessment of chemicals. For each of the nine reviewed toxicants, the developing immune system was found to be at least as sensitive or more sensitive than the general (developmental) toxicity parameters. Functional immune (antigen-challenged) parameters appear more affected than structural (non-challenged) immune parameters. Especially, antibody responses to immune challenges with keyhole limpet hemocyanine or sheep red blood cells and delayed-type hypersensitivity responses appear to provide sensitive parameters of developmental immune toxicity. Comparison with current tolerable daily intakes (TDI) and their underlying overall no observed adverse effect levels showed that for some of the compounds reviewed, the TDI may need reconsideration based on developmental immune parameters. From these data, it can be concluded that the developing immune system is very sensitive to the disruption of toxicants independent of study design. Consideration of including functional DIT parameters in current hazard identification guidelines and wider application of relevant study protocols is warranted.

Embryonic Zebrafish Model - A Well-Established Method for Rapidly Assessing the Toxicity of Homeopathic Drugs

PubMed Central

Gupta, Himanshu R; Patil, Yogesh; Singh, Dipty

2016-01-01

Objectives: Advancements in nanotechnology have led to nanoparticle (NP) use in various fields of medicine. Although the potential of NPs is promising, the lack of documented evidence on the toxicological effects of NPs is concerning. A few studies have documented that homeopathy uses NPs. Unfortunately, very few sound scientific studies have explored the toxic effects of homeopathic drugs. Citing this lack of high-quality scientific evidence, regulatory agencies have been reluctant to endorse homeopathic treatment as an alternative or adjunct treatment. This study aimed to enhance our insight into the impact of commercially-available homeopathic drugs, to study the presence of NPs in those drugs and any deleterious effects they might have, and to determine the distribution pattern of NPs in zebrafish embryos (Danio rerio). Methods: Homeopathic dilutions were studied using high-resolution transmission electron microscopy with selected area electron diffraction (SAED). For the toxicity assessment on Zebrafish, embryos were exposed to a test solution from 4 - 6 hours post-fertilization, and embryos/larvae were assessed up to 5 days post-fertilization (dpf) for viability and morphology. Toxicity was recorded in terms of mortality, hatching delay, phenotypic defects and metal accumulation. Around 5 dpf was found to be the optimum developmental stage for evaluation. Results: The present study aimed to conclusively prove the presence of NPs in all high dilutions of homeopathic drugs. Embryonic zebrafish were exposed to three homeopathic drugs with two potencies (30CH, 200CH) during early embryogenesis. The resulting morphological and cellular responses were observed. Exposure to these potencies produced no visibly significant malformations, pericardial edema, and mortality and no necrotic and apoptotic cellular death. Conclusion: Our findings clearly demonstrate that no toxic effects were observed for these three homeopathic drugs at the potencies and exposure times used in this study. The embryonic zebrafish model is recommended as a well-established method for rapidly assessing the toxicity of homeopathic drugs. PMID:28127503

Initial Results of a Phase I Dose-Escalation Trial of Concurrent and Maintenance Erlotinib and Reirradiation for Recurrent and New Primary Head-and-Neck Cancer

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

Rusthoven, Kyle E.; Feigenberg, Steven J.; Raben, David

2010-11-15

Purpose: To present the first report of a Phase I trial evaluating concurrent and maintenance erlotinib and reirradiation in patients with recurrent or secondary primary head-and-neck cancer (HNC). Methods and Materials: Patients with recurrent or new primary HNC with an interval of at least 6 months since prior radiation were eligible. Patients were treated in 3 sequential cohorts: Cohort I, 100 mg of erlotinib daily with reirradiation at 61.6 Gy in 28 fractions; Cohort II, 150 mg of erlotinib with 61.6 Gy in 28 fractions; and Cohort III, 150 mg of erlotinib with 66 Gy in 30 fractions. Maintenance erlotinibmore » started immediately after reirradiation at 150 mg daily and was continued for 2 years or until disease progression or dose-limiting toxicity. Dose-limiting toxicities were defined as any Grade 4 or 5 toxicity or a toxicity-related delay in radiation therapy of greater than 7 days. Results: Fourteen patients were accrued, 3 to Cohort I, 4 to Cohort II, and 7 to Cohort III. Thirteen patients were evaluable for toxicity. Median follow-up was 8.4 months overall and 15.1 months for surviving patients. One patient had a dose-limiting toxicity in Cohort III. This patient declined initial percutaneous endoscopic gastrostomy tube placement, was hospitalized with Grade 3 dysphagia and aspiration, and required a delay in radiation therapy of greater than 7 days. No Grade 4 acute toxicity was observed. Acute Grade 3 toxicity occurred in 9 of 13 patients. No erlotinib-related toxicity of Grade 3 or greater was observed during maintenance therapy. One patient had Grade 5 carotid hemorrhage 6 months after reirradiation, and another patient had Grade 3 osteoradionecrosis. Conclusions: Reirradiation (66 Gy in 2.2 Gy fractions) with concurrent and maintenance erlotinib (150 mg daily) for recurrent or new primary HNC is feasible.« less

A Phase I Dose Escalation Study of Hypofractionated IMRT Field-in-Field Boost for Newly Diagnosed Glioblastoma Multiforme

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

Monjazeb, Arta M., E-mail: arta.monjazeb@ucdmc.ucdavis.edu; Ayala, Deandra; Jensen, Courtney

2012-02-01

Objectives: To describe the results of a Phase I dose escalation trial for newly diagnosed glioblastoma multiforme (GBM) using a hypofractionated concurrent intensity-modulated radiotherapy (IMRT) boost. Methods: Twenty-one patients were enrolled between April 1999 and August 2003. Radiotherapy consisted of daily fractions of 1.8 Gy with a concurrent boost of 0.7 Gy (total 2.5 Gy daily) to a total dose of 70, 75, or 80 Gy. Concurrent chemotherapy was not permitted. Seven patients were enrolled at each dose and dose limiting toxicities were defined as irreversible Grade 3 or any Grade 4-5 acute neurotoxicity attributable to radiotherapy. Results: All patientsmore » experienced Grade 1 or 2 acute toxicities. Acutely, 8 patients experienced Grade 3 and 1 patient experienced Grade 3 and 4 toxicities. Of these, only two reversible cases of otitis media were attributable to radiotherapy. No dose-limiting toxicities were encountered. Only 2 patients experienced Grade 3 delayed toxicity and there was no delayed Grade 4 toxicity. Eleven patients requiring repeat resection or biopsy were found to have viable tumor and radiation changes with no cases of radionecrosis alone. Median overall and progression-free survival for this cohort were 13.6 and 6.5 months, respectively. One- and 2-year survival rates were 57% and 19%. At recurrence, 15 patients received chemotherapy, 9 underwent resection, and 5 received radiotherapy. Conclusions: Using a hypofractionated concurrent IMRT boost, we were able to safely treat patients to 80 Gy without any dose-limiting toxicity. Given that local failure still remains the predominant pattern for GBM patients, a trial of dose escalation with IMRT and temozolomide is warranted.« less

Stereotactic body radiation therapy with concurrent full-dose gemcitabine for locally advanced pancreatic cancer: a pilot trial demonstrating safety

PubMed Central

2013-01-01

Background Concurrent chemoradiation is a standard option for locally advanced pancreatic cancer (LAPC). Concurrent conventional radiation with full-dose gemcitabine has significant toxicity. Stereotactic body radiation therapy (SBRT) may provide the opportunity to administer radiation in a shorter time frame with similar efficacy and reduced toxicity. This Pilot study assessed the safety of concurrent full-dose gemcitabine with SBRT for LAPC. Methods Patients received gemcitabine, 1000 mg/m2 for 6 cycles. During week 4 of cycle 1, patients received SBRT (25 Gy delivered in five consecutive daily fractions of 5 Gy prescribed to the 75-83% isodose line). Acute and late toxicities were assessed using NIH CTCAE v3. Tumor response was assessed by RECIST. Patients underwent an esophagogastroduodenoscopy at baseline, 2, and 6 months to assess the duodenal mucosa. Quality of life (QoL) data was collected before and after treatment using the QLQ-C30 and QLQ-PAN26 questionnaires. Results Between September 2009 and February 2011, 11 patients enrolled with one withdrawal during radiation therapy. Patients had grade 1 to 2 gastrointestinal toxicity from the start of SBRT to 2 weeks after treatment. There were no grade 3 or greater radiation-related toxicities or delays for cycle 2 of gemcitabine. On endoscopy, there were no grade 2 or higher mucosal toxicities. Two patients had a partial response. The median progression free and overall survival were 6.8 and 12.2 months, respectively. Global QoL did not change between baseline and immediately after radiation treatment. Conclusions SBRT with concurrent full dose gemcitabine is safe when administered to patients with LAPC. There is no delay in administration of radiation or chemotherapy, and radiation is completed with minimal toxicity. PMID:23452509

A look at treatment strategies for relapsed multiple myeloma.

PubMed

Cetani, Giusy; Boccadoro, Mario; Oliva, Stefania

2018-05-16

Multiple myeloma treatment considerably improved during the past decade, thanks to novel effective drugs, a better understanding of myeloma biology and clonal heterogeneity, and an improved management of toxicities. The choice of regimen at relapse is usually based on prior response, toxicities, age and comorbidities of relapsed patients. Areas covered: A review was performed of the most recent and effective therapeutic strategies for the relapsed myeloma setting, by documenting the latest clinical evidence from phase II and III clinical trials. Of note, new drugs, such as carfilzomib, ixazomib, pomalidomide, daratumumab and elotuzumab, alone or in combinations in doublet or triplet regimens, have greatly increased the treatment armamentarium against myeloma. Expert Commentary: Impressive results have been obtained with new drugs in relapsed patients. Besides number of prior therapies and previous response, other factors play a crucial role in the selection of therapy. Re-challenge with previous drugs can be adopted if previous responses lasted at least 6 months and therapy had induced low toxicity. Patients' risk status can further help to appropriately select therapy at relapse, and clinical trials will allow physicians to use newer targeted therapies and immune-therapies, thus delaying palliative approaches to later relapse stages.

Evaluation of electric arc furnace-processed steel slag for dermal corrosion, irritation, and sensitization from dermal contact.

PubMed

Suh, Mina; Troese, Matthew J; Hall, Debra A; Yasso, Blair; Yzenas, John J; Proctor, Debora M

2014-12-01

Electric arc furnace (EAF) steel slag is alkaline (pH of ~11-12) and contains metals, most notably chromium and nickel, and thus has potential to cause dermal irritation and sensitization at sufficient dose. Dermal contact with EAF slag occurs in many occupational and environmental settings because it is used widely in construction and other industrial sectors for various applications including asphaltic paving, road bases, construction fill, and as feed for cement kilns construction. However, no published study has characterized the potential for dermal effects associated with EAF slag. To assess dermal irritation, corrosion and sensitizing potential of EAF slag, in vitro and in vivo dermal toxicity assays were conducted based on the Organisation for Economic Co-operation and Development (OECD) guidelines. In vitro dermal corrosion and irritation testing (OECD 431 and 439) of EAF slag was conducted using the reconstructed human epidermal (RHE) tissue model. In vivo dermal toxicity and delayed contact sensitization testing (OECD 404 and 406) were conducted in rabbits and guinea pigs, respectively. EAF slag was not corrosive and not irritating in any tests. The results of the delayed contact dermal sensitization test indicate that EAF slag is not a dermal sensitizer. These findings are supported by the observation that metals in EAF slag occur as oxides of low solubility with leachates that are well below toxicity characteristic leaching procedure (TCLP) limits. Based on these results and in accordance to the OECD guidelines, EAF slag is not considered a dermal sensitizer, corrosive or irritant. Copyright © 2014 John Wiley & Sons, Ltd.

Comparative analysis of biological effect of corannulene and graphene on developmental and sleep/wake profile of zebrafish larvae.

PubMed

Li, Xiang; Zhang, Yuan; Li, Xu; Feng, DaoFu; Zhang, ShuHui; Zhao, Xin; Chen, DongYan; Zhang, ZhiXiang; Feng, XiZeng

2017-06-01

Little is known about the biological effect of non-planar polycyclic aromatic hydrocarbons (PAH) such as corannulene on organisms. In this study, we compared the effect of corannulene (non-planar PAH) and graphene (planar PAH) on embryonic development and sleep/wake behaviors of larval zebrafish. First, the toxicity of graded doses of corannulene (1, 10, and 50μg/mL) was tested in developing zebrafish embryos. Corannulene showed minimal developmental toxicity only induced an epiboly delay. Further, a significant decrease in locomotion/increase in sleep was observed in larvae treated with the highest dose (50μg/mL) of corannulene while no significant locomotion alterations were induced by graphene. Finally, the effect of corannulene or graphene on the hypocretin (hcrt) system and sleep/wake regulators such as hcrt, hcrt G-protein coupled receptor (hcrtr), and arylalkylamine N-acetyltransferase-2 (aanat2) was evaluated. Corannulene increased sleep and reduced locomotor activity and the expression of hcrt and hcrtr mRNA while graphene did not obviously disturb the sleep behavior and gene expression patterns. These results suggest that the corannulene has the potential to cause hypnosis-like behavior in larvae and provides a fundamental comparative understanding of the effects of corannulene and graphene on biology systems. Little is known about the biological effect of non-planar polycyclic aromatic hydrocarbons (PAH) such as corannulene on organisms. Here, we compare the effect of corannulene (no-planar PAH) and graphene (planar PAH) on embryonic development and sleep/wake behaviors of larval zebrafish. And we aim to investigate the effect of curvature on biological system. First, toxicity of corannulene over the range of doses (1μg/mL, 10μg/mL and 50μg/mL) was tested in developing zebrafish embryos. Corannulene has minimal developmental toxicity, only incurred epiboly delay. Subsequently, a significant decrease in locomotion/increase in sleep at the highest dose (50μg/mL) was detected in corannulene treated larvae while no significant locomotion alterations was induced by graphene. Finally, the impact of corannulene or graphene on hypocretin system and sleep/wake regulator such as hcrt, hcrtr and aanat2 was evaluated. Corannulene increased sleep, reduced locomotor activity and the expression of hcrt and hcrtr mRNA while graphene did not obviously disturb the sleep behaviors and gene expression patterns. This result may indicate the potential effect of corannulene to cause hypnosia-like behavior in larvae and provide the fundamental understanding for the biological effect of curvature on biology system. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Lithium toxicity

MedlinePlus

... diagnose at first. This delay can lead to long-term problems. If dialysis is done quickly, the person may feel much better. But symptoms such as memory and mood problems may be permanent. Acute on ...

Toxicity hazard of organophosphate insecticide malathion identified by in vitro methods.

PubMed

Jira, David; Janousek, Stanislav; Pikula, Jiri; Vitula, Frantisek; Kejlova, Kristina

2012-01-01

Malathion is generally not classified as toxic. However, the toxicity seems to be species-dependent. Local and systemic toxicity data for birds are rare, but a decrease of wild bird densities in areas where malathion was applied was reported. Aim of the study was to extend knowledge on malathion toxicity on cellular and organ level and to evaluate embryotoxicity and genotoxicity for birds using the chick embryo model HET-CAM. Skin and eye irritation was determined using reconstructed skin and eye cornea tissues and the chorioallantoic membrane of chick embryo to simulate conjunctiva. Cytotoxicity in 3T3 Balb/c fibroblast culture was determined to estimate acute systemic toxicity. Chick embryo model was further employed to evaluate acute embryotoxicity for birds (mortality and genotoxicity). Data were analysed by means of general linear models. Malathion is not a skin and eye irritant. Cytotoxicity in vitro test provided LD50 value of 616 mg/kg suggesting higher toxic potential than is generally published based on in vivo tests on laboratory rodents. Embryotoxicity studies revealed dose and age dependent mortality of chick embryos. Genotoxicity was identified by means of micronucleus test in erythroid cells isolated from chorioallantois vascular system of chick embryos. Using in vitro alternative toxicological methods, a higher toxic potential of malathion was demonstrated than is generally declared. An increased health and environmental hazard may occur in areas with intensive agricultural production. The environmental consequences of delayed effects and embryotoxicity for bird populations in areas exposed to organophosphate insecticides, such as malathion, are obvious.

An ethanolic extract of black cohosh causes hematological changes but not estrogenic effects in female rodents

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

Mercado-Feliciano, Minerva; Cora, Michelle C.; Witt, Kristine L.

2012-09-01

Black cohosh rhizome (Actaea racemosa) is used as a remedy for pain and gynecological ailments; modern preparations are commonly sold as ethanolic extracts available as dietary supplements. Black cohosh was nominated to the National Toxicology Program (NTP) for toxicity testing due to its widespread use and lack of safety data. Several commercially available black cohosh extracts (BCE) were characterized by the NTP, and one with chemical composition closest to formulations available to consumers was used for all studies. Female B6C3F1/N mice and Wistar Han rats were given 0, 15 (rats only), 62.5 (mice only), 125, 250, 500, or 1000 mg/kg/daymore » BCE by gavage for 90 days starting at weaning. BCE induced dose-dependent hematological changes consistent with a non-regenerative macrocytic anemia and increased frequencies of peripheral micronucleated red blood cells (RBC) in both species. Effects were more severe in mice, which had decreased RBC counts in all treatment groups and increased micronucleated RBC at doses above 125 mg/kg. Dose-dependent thymus and liver toxicity was observed in rats but not mice. No biologically significant effects were observed in other organs. Puberty was delayed 2.9 days at the highest treatment dose in rats; a similar magnitude delay in mice occurred in the 125 and 250 mg/kg groups but not at the higher doses. An additional uterotrophic assay conducted in mice exposed for 3 days to 0.001, 0.01, 0.1, 1, 10, 100 and 500 mg/kg found no estrogenic or anti-estrogenic activity. These are the first studies to observe adverse effects of BCE in rodents. -- Highlights: ► Mice and rats were dosed with black cohosh extract for 90 days starting at weaning. ► Hematological changes were consistent with a non-regenerative macrocytic anemia. ► Peripheral micronucleated red blood cell frequencies increased. ► Puberty was delayed 2.9 days in rats. ► No estrogenic/anti-estrogenic activity was seen in the uterotrophic assay.« less

Comparative toxicity of several metal oxide nanoparticle aqueous suspensions to Zebrafish (Danio rerio) early developmental stage.

PubMed

Zhu, Xiaoshan; Zhu, Lin; Duan, Zhenghua; Qi, Ruiqi; Li, Yan; Lang, Yupeng

2008-02-15

With the emergence of manufactured nanomaterials, it is urgent to carry out researches on their potential environmental impacts and biological effects. To better understand the potential ecotoxicological impacts of metal oxide nanoparticles released to aquatic environments, the zebrafish 96-h embryo-larval bioassay was used to assess and compare the developmental toxicities of nanoscale zinc oxide (nZnO), titanium dioxide (nTiO(2)) and alumina (nAl(2)O(3)) aqueous suspensions. Toxicological endpoints such as zebrafish embryos or larvae survival, hatching rate and malformation were noted and described within 96 h of exposure. Meanwhile, a comparative experiment with their bulk counterparts (i.e., ZnO/bulk, TiO(2)/bulk and Al(2)O(3)/bulk) was conducted to understand the effect of particle size on their toxicities. The results showed that: (i) both nZnO and ZnO/bulk aqueous suspensions delayed zebrafish embryo and larva development, decreased their survival and hatching rates, and caused tissue damage. The 96-h LC(50) of nZnO and ZnO/bulk aqueous suspensions on the zebrafish survival are 1.793 mg/L and 1.550 mg/L respectively; and the 84-h EC(50) on the zebrafish embryo hatching rate are 2.065 mg/L and 2.066 mg/L respectively. Serious tissue ulceration was found on zebrafish larvae exposed to nZnO and ZnO/bulk aqueous suspensions. (ii) In contrast, neither nTiO(2) and TiO(2)/bulk nor nAl(2)O(3) and Al(2)O(3)/bulk showed any toxicity to zebrafish embryos and larvae under the same experimental condition. It revealed that the metal oxide nanoparticles with different chemical composition have different zebrafish developmental toxicities. (iii) Exposures of nTiO(2), nZnO and nAl(2)O(3) produced toxic effects on zebrafish embryos and larvae, which was not different from the effects caused by exposing to their bulk counterparts. This is the first study about the developmental toxicity of metal oxide nanoparticles, and the results demonstrate that nZnO is very toxic to zebrafish embryos and larvae, which highlights the need to evaluate the potential eco-toxicity of these manufactured nanomaterials (MNMs).

Methylisothiazolinone toxicity and inhibition of wound healing and regeneration in planaria.

PubMed

Van Huizen, Alanna V; Tseng, Ai-Sun; Beane, Wendy S

2017-10-01

Methylisothiazolinone (MIT) is a common biocide used in cosmetic and industrial settings. Studies have demonstrated that MIT is a human sensitizer, to the extent that in 2013 MIT was named allergen of the year. Recently, we showed that MIT exposure in Xenopus laevis (the African clawed frog) inhibits wound healing and tail regeneration. However, it is unknown whether MIT affects these processes in other animals. Here, we investigated the effects of MIT exposure in planaria-non-parasitic freshwater flatworms able to regenerate all tissues after injury. Using a common research strain of Dugesia japonica, we determined that intact planarians exposed to 15μM MIT displayed both neuromuscular and epithelial-integrity defects. Furthermore, regenerating (head and tail) fragments exposed to 15μM MIT failed to close wounds or had significantly delayed wound healing. Planarian wounds normally close within 1h after injury. However, most MIT-exposed animals retained open wounds at 24h and subsequently died, and those few animals that were able to undergo delayed wound healing without dying exhibited abnormal regeneration. For instance, head regeneration was severely delayed or inhibited, with anterior structures such as eyes failing to form in newly produced tissues. These data suggest that MIT directly affects both wound healing and regeneration in planarians. Next, we investigated the ability of thiol-containing antioxidants to rescue planarian wound closure during MIT exposure. The data reveal both n-acetyl cysteine and glutathione were each able to fully rescue MIT inhibition of wound healing. Lastly, we established MIT toxicity levels by determining the LC 50 of 5 different planarian species: D. japonica, Schmidtea mediterranea, Girardia tigrina, Girardia dorotocephala, and Phagocata gracilis. Our LC 50 data revealed that concentrations as low as 39μM (4.5ppm) are lethal to planarians, with concentrations of just 5μM inhibiting wound healing, and suggest that phylogeny is predictive of species toxicity levels. Together these results indicate MIT may have broad wound healing effects on aquatic species in general and are not limited to X. laevis alone. Future studies should investigate the impact of MIT on wound healing in other organisms, including non-aquatic organisms and mammals. Copyright © 2017 Elsevier B.V. All rights reserved.

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

Chaudhuri, Shubhra, E-mail: SCHAUDHURI@uams.edu; Arkansas Children's Hospital Research Institute, Little Rock, AR; McCullough, Sandra S., E-mail: mcculloughsandras@uams.edu

Oxidative stress and mitochondrial permeability transition (MPT) are important mechanisms in acetaminophen (APAP) toxicity. The MPT inhibitor trifluoperazine (TFP) reduced MPT, oxidative stress, and toxicity in freshly isolated hepatocytes treated with APAP. Since hypoxia inducible factor-one alpha (HIF-1α) is induced very early in APAP toxicity, a role for oxidative stress in the induction has been postulated. In the present study, the effect of TFP on toxicity and HIF-1α induction in B6C3F1 male mice treated with APAP was examined. Mice received TFP (10 mg/kg, oral gavage) prior to APAP (200 mg/kg IP) and at 7 and 36 h after APAP. Measuresmore » of metabolism (hepatic glutathione and APAP protein adducts) were comparable in the two groups of mice. Toxicity was decreased in the APAP/TFP mice at 2, 4, and 8 h, compared to the APAP mice. At 24 and 48 h, there were no significant differences in toxicity between the two groups. TFP lowered HIF-1α induction but also reduced the expression of proliferating cell nuclear antigen, a marker of hepatocyte regeneration. TFP can also inhibit phospholipase A{sub 2}, and cytosolic and secretory PLA{sub 2} activity levels were reduced in the APAP/TFP mice compared to the APAP mice. TFP also lowered prostaglandin E{sub 2} expression, a known mechanism of cytoprotection. In summary, the MPT inhibitor TFP delayed the onset of toxicity and lowered HIF-1α induction in APAP treated mice. TFP also reduced PGE{sub 2} expression and hepatocyte regeneration, likely through a mechanism involving PLA{sub 2}. -- Highlights: ► Trifluoperazine reduced acetaminophen toxicity and lowered HIF-1α induction. ► Trifluoperazine had no effect on the metabolism of acetaminophen. ► Trifluoperazine reduced hepatocyte regeneration. ► Trifluoperazine reduced phospholipase A{sub 2} activity and prostaglandin E{sub 2} levels.« less

Minocycline protects, rescues and prevents knockdown transgenic parkin Drosophila against paraquat/iron toxicity: Implications for autosomic recessive juvenile parkinsonism.

PubMed

Ortega-Arellano, Hector Flavio; Jimenez-Del-Rio, Marlene; Velez-Pardo, Carlos

2017-05-01

Autosomal recessive Juvenile Parkinsonism (AR-JP) is a chronic, progressive neurodegenerative disorder caused by mutation in the PARKIN gene, and invariably associated with dopaminergic (DAergic) neuronal loss and brain iron accumulation. Since current medical therapy is symptomatic and lacks significant disease-modifying effects, other treatment approaches are urgently needed it. In the present work, we investigate the role of minocycline (MC) in paraquat (PQ)/iron-induced neurotoxicity in the Drosophila TH>parkin-RNAi/+ (w[*]; UAS-parkin-RNAi; TH-GAL4) fly and have shown the following: (i) MC increased life span and restored the locomotor activity of knockdown (KD) transgenic parkin flies in comparison with the control (vehicle) group; (ii) MC at low (0.1 and 0.3mM) and middle (0.5mM) concentrations protected, rescued and prevented KD parkin Drosophila against PQ toxicity. However, MC at high (1mM) concentration aggravated the toxic effect of PQ; (iii) MC protected and rescued DAergic neurons against the PQ toxic effect according to tyrosine hydroxylase (TH)>green-fluorescent protein (GFP) reporter protein microscopy and anti-TH Western blotting analysis; (iv) MC protected DAergic neurons against PQ/iron toxicity; (v) MC significantly abridged lipid peroxidation (LPO) in the protection, rescue and prevention treatment in TH>parkin-RNAi/+ flies against PQ or iron alone or combined (PQ/iron)-induced neuronal oxidative stress (OS). Our results suggest that MC exerts neuroprotection against PQ/iron-induced OS in DAergic neurons most probably by the scavenging activity of reactive oxygen species (ROS), and by chelating iron. Therefore, MC might be a potential therapeutic drug to delay, revert, or prevent AR-JP. Copyright © 2017 Elsevier B.V. All rights reserved.

Metal stress in zooplankton diapause production: post-hatching response.

PubMed

Aránguiz-Acuña, Adriana; Pérez-Portilla, Pablo

2017-04-01

Aquatic organisms commonly respond to harsh conditions by forming diapausing stages, which enable populations to survive adverse periods forming egg banks. Production of diapausing eggs is frequently observed in monogonont rotifers, previously changing from asexual to partial sexual reproduction (mixis). In despite that zooplankton are frequently used in ecotoxicological assessment because of their sensitivity to various toxicants and their important role in the ecosystems, toxicity evaluations often consider the directly exposed population produced by parthenogenetic reproduction, exclusively. We assessed experimentally effects of exposure to metals on mixis delay and fitness of hatchlings of the rotifer Brachionus plicatilis obtained from a brackish water lagoon with high metal content, especially copper. We show that sub-lethal concentrations of copper affected traits related to sexual reproduction and diapausing egg production in the rotifer. Copper addition did not delay the start of mixis, suggesting that rapid initiation of mixis is promoted in risky environments, according to the hypothesis of mixis as an escape strategy. Higher investment in mixis was obtained when individuals were exposed to metal. Addition of copper negatively affected the hatching success of diapausing eggs and performance of hatchlings. Nevertheless, these effects were greater for individuals formed in non-metal conditions, suggesting an adaptive advantage of populations from natural sediments exposed to copper. These results highlight the ecological and evolutionary consequences of the presence of metals in freshwater environments by modulating diapause adaptive efficacy and the selective process in egg banks.

Toxic Shock Syndrome Caused by Methicillin-Resistant Staphylococcus aureus (MRSA) After Expander-Based Breast Reconstruction.

PubMed

Suga, Hirotaka; Shiraishi, Tomohiro; Takushima, Akihiko; Harii, Kiyonori

2016-01-01

Toxic shock syndrome is a rare but life-threatening complication after plastic surgery procedures. We experienced 2 cases of toxic shock syndrome after expander-based breast reconstruction caused by methicillin-resistant Staphylococcus aureus. The first patient took a severe clinical course due to the delayed diagnosis and treatment, and the second patient recovered rapidly after the early diagnosis and treatment based on our experience of the first case. Fever, rash, and gastrointestinal symptoms (diarrhea and/or vomiting) were characteristic and important for the early diagnosis of toxic shock syndrome. Considering the increased prevalence of methicillin-resistant Staphylococcus aureus, we should suspect methicillin-resistant Staphylococcus aureus in cases of toxic shock syndrome that occur postoperatively, and the empiric administration of vancomycin should be initiated in such cases.

The combined toxicological effects of titanium dioxide nanoparticles and bisphenol A on zebrafish embryos

PubMed Central

2014-01-01

Environmental pollutants co-exist and exhibit interaction effects that are different from those associated with a single pollutant. As one of the more commonly manufactured nanomaterials, titanium dioxide nanoparticles (TiO2-NPs) are most likely to bind to other contaminants in water. In this paper, we aimed to study the combined toxicological effects of TiO2-NPs and bisphenol A (BPA) on organism. First, in vitro adsorption experiments were conducted to determine the adsorptive interaction between TiO2-NPs and BPA. Second, zebrafish embryo toxicity tests were performed to monitor for changes in the toxicological effects associated with the two chemicals. The study results demonstrated that adsorptive interactions exist between the two chemicals and increased toxicity effects which included an advanced toxicological effect time, decreased survival, increased morphological abnormalities, and delayed embryo hatching. Also, we suggest that the mode of combined action has a synergistic effect. Based on this, we postulate that concomitant exposure to TiO2-NPs and BPA increased BPA bioavailability and uptake into cells and organisms. Further studies are required to understand the mechanisms of interactions of this mixture. PMID:25177222

Zinc oxide nanoparticles alter hatching and larval locomotor activity in zebrafish (Danio rerio).

PubMed

Chen, Te-Hao; Lin, Chia-Chi; Meng, Pei-Jie

2014-07-30

Zinc oxide nanoparticles (ZnO NP) are extensively used in various consumer products such as sunscreens and cosmetics, with high potential of being released into aquatic environments. In this study, fertilized zebrafish (Danio rerio) eggs were exposed to various concentrations of ZnO NP suspensions (control, 0.1, 0.5, 1, 5, and 10mg/L) or their respective centrifuged supernatants (0.03, 0.01, 0.08, 0.17, 0.75, and 1.21mg/L dissolved Zn ions measured) until reaching free swimming stage. Exposure to ZnO NP suspensions and their respective centrifuged supernatants caused similar hatching delay, but did not cause larval mortality or malformation. Larval activity level, mean velocity, and maximum velocity were altered in the groups exposed to high concentrations of ZnO NP (5-10mg/L) but not in the larvae exposed to the supernatants. To evaluate possible mechanism of observed effects caused by ZnO NP, we also manipulated the antioxidant environment by co-exposure to an antioxidant compound (N-acetylcysteine, NAC) or an antioxidant molecule suppressor (buthionine sulfoximine, BSO) with 5mg/L ZnO NP. Co-exposure to NAC did not alter the effects of ZnO NP on hatchability, but co-exposure to BSO caused further hatching delay. For larval locomotor activity, co-exposure to NAC rescued the behavioral effect caused by ZnO NP, but co-exposure to BSO did not exacerbate the effect. Our data indicated that toxicity of ZnO NP cannot be solely explained by dissolved Zn ions, and oxidative stress may involve in ZnO NP toxicity. Copyright © 2013 Elsevier B.V. All rights reserved.

Maritime Evaluation of Aerosol Fire Knock Down Tools. Part 2: Toxicity and Corrosion Potential

DTIC Science & Technology

2014-02-01

determined using paramagnetic sensor technology, while CO and CO2 concentrations were measured, respectively, via gas filter correlation and single...time response of each sensor in the unit. Since it is important to account for this delay in response during analysis and interpretation of measured...within, the compartment as well as confinement and extinguishment of the fire. 1 The initial response of the NOx analyzer and delay in sensor

Inhibition of methyldigoxin-induced arrhythmias by pentadecapeptide BPC 157: a relation with NO-system.

PubMed

Balenovic, Dijana; Bencic, Martina Lovric; Udovicic, Mario; Simonji, Karol; Hanzevacki, Jadranka Separovic; Barisic, Ivan; Kranjcevic, Stjepan; Prkacin, Ingrid; Coric, Vedran; Brcic, Luka; Coric, Marijana; Brcic, Iva; Borovic, Suzana; Radic, Bozo; Drmic, Domagoj; Vrcic, Hrvoje; Seiwerth, Sven; Sikiric, Predrag

2009-08-07

Pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, MW 1419) reversed congestive heart failure and various arrhythmias, influenced the NO-system and showed no proarrhythmic effect. In therapy analogy, we challenged rats with digitalis, to show attenuation by BPC 157 and the relation between the NO-system and digitalis toxicity. (i). BPC 157 prophylactic effect. Development of cumulative intravenous digitalis toxicity, BPC 157 (50 microg, 10 microg, 10 ng/kg applied intravenously immediately before a methyldigoxin increment regimen (2.0/1.5/1.5/1.0 mg/kg at 15 min-intervals, total dose 6.0 mg/kg/45 min)) reduced the number of ventricular premature beats, prolonged the time before onset of ventricular tachycardia, reduced ventricular tachycardia and AV-block duration (microg-regimes) or reduced mainly the AV-block duration (ng-regimen). (ii). BPC 157 therapy. Advanced methyldigoxin toxicity (6.0 mg/kg i.v. bolus). BPC 157 applied at the 20th second of the grade 3 AV-block shortened AV-blocks, mitigated a further digitalis toxicity course. Ventricular tachycardias were either avoided (50 microg), or markedly reduced (10 microg, 10 ng). Fatal outcome was either avoided (50 microg), reduced (10 microg), or only delayed (10 ng) (iii) BPC 157, L-NAME, l-arginine, L-NAME+l-arginine application. L-NAME-application (5 mg/kg i.p.) aggravated methyldigoxin-arrhythmias. l-arginine (200 mg/kg i.p.) alone had no effect but blunted L-NAME-exaggeration (L-NAME+l-arginine). In this respect, BPC 157 (50 microg/kg i.p.) was prophylactically and therapeutically more effective: the antagonism of L-NAME with BPC 157 produced an effect similar to BPC 157 alone. In conclusion, digitalis-induced arrhythmias in rats could be prevented and counteracted by pentadecapeptide BPC 157, mainly through an interaction with the NO-system.

Effect of Piperonyl Butoxide on the Toxicity of Four Classes of Insecticides to Navel Orangeworm (Amyelois transitella) (Lepidoptera: Pyralidae).

PubMed

Demkovich, Mark; Dana, Catherine E; Siegel, Joel P; Berenbaum, May R

2015-12-01

Amyelois transitella (Walker) (Lepidoptera: Pyralidae), the navel orangeworm, is a highly polyphagous economic pest of almond, pistachio, and walnut crops in California. Increasing demand for these crops and their rising economic value has resulted in substantial increases of insecticide applications to reduce damage to acceptable levels. The effects of piperonyl butoxide (PBO), a methylenedioxyphenyl compound that can act as a synergist by inhibiting cytochrome P450-mediated detoxification on insecticide metabolism by A. transitella, were examined in a series of feeding bioassays with first-instar A. transitella larvae from a laboratory strain. PBO, however, can have a variety of effects on metabolism, including inhibition of glutathione-S-transferases and esterases and induction of P450s. In our study, PBO synergized the toxicity of acetamiprid, λ-cyhalothrin, and spinosad, suggesting possible involvement of P450s in their detoxification. In contrast, PBO interacted antagonistically with the organophosphate insecticide chlorpyrifos, reducing its toxicity, an effect consistent with inhibition of P450-mediated bioactivation of this pesticide. The toxicity of the anthranilic diamide insecticide chlorantraniliprole was not altered by PBO, suggestive of little or no involvement of P450-mediated metabolism in its detoxification. Because a population of navel orangeworm in Kern County, CA, has already acquired resistance to the pyrethroid insecticide bifenthrin through enhanced P450 activity, determining the effect of adding a synergist such as PBO on detoxification of all insecticide classes registered for use in navel orangeworm management can help to develop rotation practices that may delay resistance acquisition or to implement alternative management practices where resistance is likely to evolve. © The Authors 2015. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Nanoparticulated docetaxel exerts enhanced anticancer efficacy and overcomes existing limitations of traditional drugs.

PubMed

Choi, Jinhyang; Ko, Eunjung; Chung, Hye-Kyung; Lee, Jae Hee; Ju, Eun Jin; Lim, Hyun Kyung; Park, Intae; Kim, Kab-Sig; Lee, Joo-Hwan; Son, Woo-Chan; Lee, Jung Shin; Jung, Joohee; Jeong, Seong-Yun; Song, Si Yeol; Choi, Eun Kyung

2015-01-01

Nanoparticulation of insoluble drugs improves dissolution rate, resulting in increased bioavailability that leads to increased stability, better efficacy, and reduced toxicity of drugs. Docetaxel (DTX), under the trade name Taxotere™, is one of the representative anticancer chemotherapeutic agents of this era. However, this highly lipophilic and insoluble drug has many adverse effects. Our novel and widely applicable nanoparticulation using fat and supercritical fluid (NUFS™) technology enabled successful nanoscale particulation of DTX (Nufs-DTX). Nufs-DTX showed enhanced dissolution rate and increased aqueous stability in water. After confirming the preserved mechanism of action of DTX, which targets microtubules, we showed that Nufs-DTX exhibited similar effects in proliferation and clonogenic assays using A549 cells. Interestingly, we observed that Nufs-DTX had a greater in vivo tumor growth delay effect on an A549 xenograft model than Taxotere™, which was in agreement with the improved drug accumulation in tumors according to the biodistribution result, and was caused by the enhanced permeability and retention (EPR) effect. Although both Nufs-DTX and Taxotere™ showed negative results for our administration dose in the hematologic toxicity test, Nufs-DTX showed much less toxicity than Taxotere™ in edema, paralysis, and paw-withdrawal latency on a hot plate analysis that are regarded as indicators of fluid retention, peripheral neuropathy, and thermal threshold, respectively, for toxicological tests. In summary, compared with Taxotere™, Nufs-DTX, which was generated by our new platform technology using lipid, supercritical fluid, and carbon dioxide (CO2), maintained its biochemical properties as a cytotoxic agent and had better tumor targeting ability, better in vivo therapeutic effect, and less toxicity, thereby overcoming the current hurdles of traditional drugs.

Mitigation in Multiple Effects of Graphene Oxide Toxicity in Zebrafish Embryogenesis Driven by Humic Acid.

PubMed

Chen, Yuming; Ren, Chaoxiu; Ouyang, Shaohu; Hu, Xiangang; Zhou, Qixing

2015-08-18

Graphene oxide (GO) is a widely used carbonaceous nanomaterial. To date, the influence of natural organic matter (NOM) on GO toxicity in aquatic vertebrates has not been reported. During zebrafish embryogenesis, GO induced a significant hatching delay and cardiac edema. The intensive interactions of GO with the chorion induces damage to chorion protuberances, excessive generation of (•)OH, and changes in protein secondary structure. In contrast, humic acid (HA), a ubiquitous form of NOM, significantly relieved the above adverse effects. HA reduced the interactions between GO and the chorion and mitigated chorion damage by regulating the morphology, structures, and surface negative charges of GO. HA also altered the uptake and deposition of GO and decreased the aggregation of GO in embryonic yolk cells and deep layer cells. Furthermore, HA mitigated the mitochondrial damage and oxidative stress induced by GO. This work reveals a feasible antidotal mechanism for GO in the presence of NOM and avoids overestimating the risks of GO in the natural environment.

Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.

PubMed

Puzanov, I; Diab, A; Abdallah, K; Bingham, C O; Brogdon, C; Dadu, R; Hamad, L; Kim, S; Lacouture, M E; LeBoeuf, N R; Lenihan, D; Onofrei, C; Shannon, V; Sharma, R; Silk, A W; Skondra, D; Suarez-Almazor, M E; Wang, Y; Wiley, K; Kaufman, H L; Ernstoff, M S

2017-11-21

Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs' therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy, and effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies. There is an urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met for a full-day workshop to develop recommendations to standardize management of irAEs. Here we present their consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy.

Toxicity of single-wall carbon nanotubes functionalized with polyethylene glycol in zebrafish (Danio rerio) embryos.

PubMed

Girardi, Felipe A; Bruch, Gisele E; Peixoto, Carolina S; Dal Bosco, Lidiane; Sahoo, Sangram K; Gonçalves, Carla O F; Santos, Adelina P; Furtado, Clascídia A; Fantini, Cristiano; Barros, Daniela M

2017-02-01

Single-wall carbon nanotubes functionalized with polyethylene glycol (SWCNT-PEG) are promising materials for biomedical applications such as diagnostic devices and controlled drug-release systems. However, several questions about their toxicological profile remain unanswered. Thus, the aim of this study was to investigate the action of SWCNT-PEG in Danio rerio zebrafish embryos at the molecular, physiological and morphological levels. The SWCNT used in this study were synthesized by the high-pressure carbon monoxide process, purified and then functionalized with distearoyl phosphatidylethanolamine block copolymer-PEG (molecular weight 2 kDa). The characterization process was carried out with low-resolution transmission electron microscopy, thermogravimetric analysis and Raman spectroscopy. Individual zebrafish embryos were exposed to the SWCNT-PEG. Toxic effects occurred only at the highest concentration tested (1 ppm) and included high mortality rates, delayed hatching and decreased total larval length. For all the concentrations tested, the alkaline comet assay revealed no genotoxicity, and Raman spectroscopy measurements on the histological slices revealed no intracellular nanotubes. The results shown here demonstrate that SWCNT-PEG has low toxicity in zebrafish embryos, but more studies are needed to understand what mechanisms are involved. However, the presence of residual metals is possibly among the primary mechanisms responsible for the toxic effects observed, because the purification process was not able to remove all metal contamination, as demonstrated by the thermogravimetric analysis. More attention must be given to the toxicity of these nanomaterials before they are used in biomedical applications. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Environmental toxicants and male reproductive function

PubMed Central

Wong, Elissa W.P; Lie, Pearl P.Y; Li, Michelle W.M; Su, Linlin; Siu, Erica R; Yan, Helen H.N; Mannu, Jayakanthan; Mathur, Premendu P; Bonanomi, Michele; Silvestrini, Bruno; Mruk, Dolores D

2011-01-01

Environmental toxicants, such as cadmium and bisphenol A (BPA) are endocrine disruptors. In utero, perinatal or neonatal exposure of BPA to rats affect the male reproductive function, such as the blood-testis barrier (BTB) integrity. This effect of BPA on BTB integrity in immature rats is likely mediated via a loss of gap junction function at the BTB, failing to coordinate tight junction and anchoring junction function at the site to maintain the immunological barrier integrity. This in turn activates the extracellular signal-regulated kinases 1/2 (Erk1/2) downstream and an increase in protein endocytosis, destabilizing the BTB. The cadmium-induced disruption of testicular dysfunction is mediated initially via its effects on the occludin/ZO-1/focal adhesion kinase (FAK) complex at the BTB, causing redistribution of proteins at the Sertoli-Sertoli cell interface, leading to the BTB disruption. The damaging effects of these toxicants to testicular function are mediated by mitogen-activated protein kinases (MAPK) downstream, which in turn perturbs the actin bundling and accelerates the actin-branching activity, causing disruption of the Sertoli cell tight junction (TJ)-barrier function at the BTB and perturbing spermatid adhesion at the apical ectoplasmic specialization (apical ES, a testis-specific anchoring junction type) that leads to premature release of germ cells from the testis. However, the use of specific inhibitors against MAPK was shown to block or delay the cadmium-induced testicular injury, such as BTB disruption and germ cell loss. These findings suggest that there may be a common downstream p38 and/or Erk1/2 MAPK-based signaling pathway involving polarity proteins and actin regulators that is shared between different toxicants that induce male reproductive dysfunction. As such, the use of inhibitors and/or antagonists against specific MAPKs can possibly be used to “manage” the illnesses caused by these toxicants and/or “protect” industrial workers being exposed to high levels of these toxicants in their work environment. PMID:21866273

Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial.

PubMed

Vora, Ajay; Goulden, Nick; Wade, Rachel; Mitchell, Chris; Hancock, Jeremy; Hough, Rachael; Rowntree, Clare; Richards, Sue

2013-03-01

Minimal residual disease (MRD) is the most sensitive and specific predictor of relapse risk in children with acute lymphoblastic leukaemia (ALL) during remission. We assessed whether treatment intensity could be adjusted for children and young adults according to MRD risk stratification. Between Oct 1, 2003 and June 30, 2011, consecutive children and young adults (aged 1-25 years) with ALL from the UK and Ireland were recruited. Eligible patients were categorised into clinical standard, intermediate, and high risk groups on the basis of a combination of National Cancer Institute (NCI) criteria, cytogenetics, and early response to induction therapy, which was assessed by bone marrow blast counts taken at days 8 (NCI high-risk patients) and 15 (NCI standard-risk patients) after induction began. Clinical standard-risk and intermediate-risk patients were assessed for MRD. Those classified as MRD low risk (undetectable MRD at the end of induction [day 29] or detectable MRD at day 29 that became undetectable by week 11) were randomly assigned to receive one or two delayed intensification courses. Patients had received induction, consolidation, and interim maintenance therapy before they began delayed intensification. Delayed intensification consisted of pegylated asparaginase on day 4; vincristine, dexamethasone (alternate weeks), and doxorubicin for 3 weeks; and 4 weeks of cyclophosphamide and cytarabine. Computer randomisation was done with stratification by MRD result and balancing for sex, age, and white blood cell count at diagnosis by method of minimisation. Patients, clinicians, and data analysts were not masked to treatment allocation. The primary outcome was event-free survival (EFS), which was defined as time to relapse, secondary tumour, or death. Our aim was to rule out a 7% reduction in EFS in the group given one delayed intensification course relative to that given two delayed intensification courses. Analyses were by intention to treat. This trial is registered, number ISRCTN07355119. Of 3207 patients registered in the trial overall, 521 MRD low-risk patients were randomly assigned to receive one (n=260) or two (n=261) delayed intensification courses. Median follow-up of these patients was 57 months (IQR 42-72). We recorded no significant difference in EFS between the group given one delayed intensification (94·4% at 5 years, 95% CI 91·1-97·7) and that given two delayed intensifications (95·5%, 92·8-98·2; unadjusted odds ratio 1·00, 95% CI 0·43-2·31; two-sided p=0·99). The difference in 5-year EFS between the two groups was 1·1% (95% CI -5·6 to 2·5). 11 patients (actuarial relapse at 5 years 5·6%, 95% CI 2·3-8·9) given one delayed intensification and six (2·4%, 0·2-4·6) given two delayed intensifications relapsed (p=0·23). Three patients (1·2%, 0-2·6) given two delayed intensifications died of treatment-related causes compared with none in the group given one delayed intensification (p=0·08). We recorded no significant difference between groups for serious adverse events and grade 3 or 4 toxic effects; however, the second delayed intensification course was associated with one (<1%) treatment-related death, and 74 episodes of grade 3 or 4 toxic effects in 45 patients (17%). Treatment reduction is feasible for children and young adults with ALL who are predicted to have a low risk of relapse on the basis of rapid clearance of MRD by the end of induction therapy. Medical Research Council and Leukaemia and Lymphoma Research. Copyright © 2013 Elsevier Ltd. All rights reserved.

Reproductive toxicity of a mixture of regulated drinking-water disinfection by-products in a multigenerational rat bioassay.

PubMed

Narotsky, Michael G; Klinefelter, Gary R; Goldman, Jerome M; DeAngelo, Anthony B; Best, Deborah S; McDonald, Anthony; Strader, Lillian F; Murr, Ashley S; Suarez, Juan D; George, Michael H; Hunter, E Sidney; Simmons, Jane Ellen

2015-06-01

Trihalomethanes (THMs) and haloacetic acids (HAAs) are regulated disinfection by-products (DBPs); their joint reproductive toxicity in drinking water is unknown. We aimed to evaluate a drinking water mixture of the four regulated THMs and five regulated HAAs in a multigenerational reproductive toxicity bioassay. Sprague-Dawley rats were exposed (parental, F1, and F2 generations) from gestation day 0 of the parental generation to postnatal day (PND) 6 of the F2 generation to a realistically proportioned mixture of THMs and HAAs at 0, 500×, 1,000×, or 2,000× of the U.S. Environmental Protection Agency's maximum contaminant levels (MCLs). Maternal water consumption was reduced at ≥ 1,000×; body weights were reduced at 2,000×. Prenatal and postnatal survival were unaffected. F1 pup weights were unaffected at birth but reduced at 2,000× on PND6 and at ≥ 1,000× on PND21. Postweaning F1 body weights were reduced at 2,000×, and water consumption was reduced at ≥ 500×. Males at 2,000× had a small but significantly increased incidence of retained nipples and compromised sperm motility. Onset of puberty was delayed at 1,000× and 2,000×. F1 estrous cycles and fertility were unaffected, and F2 litters showed no effects on pup weight or survival. Histologically, P0 (parental) dams had nephropathy and adrenal cortical pathology at 2,000×. A mixture of regulated DBPs at up to 2,000× the MCLs had no adverse effects on fertility, pregnancy maintenance, prenatal survival, postnatal survival, or birth weights. Delayed puberty at ≥ 1,000× may have been secondary to reduced water consumption. Male nipple retention and compromised sperm motility at 2,000× may have been secondary to reduced body weights.

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.

ABCB1-1Delta polymorphism can predict hematologic toxicity in dogs treated with vincristine.

PubMed

Mealey, K L; Fidel, J; Gay, J M; Impellizeri, J A; Clifford, C A; Bergman, P J

2008-01-01

Dogs that harbor the naturally occurring ABCB1-1Delta polymorphism experience increased susceptibility to avermectin-induced neurological toxicosis as a result of deficient P-glycoprotein function. Whether or not the ABCB1-1Delta polymorphism affects susceptibility to toxicity of other P-glycoprotein substrate drugs has not been studied. Dogs that possess the ABCB1-1Delta mutation are more likely to develop hematologic toxicity associated with vincristine than ABCB1 wild-type dogs. Thirty-four dogs diagnosed with lymphoma were included in this study. Cheek swab samples were obtained from dogs diagnosed with lymphoma that were to be treated with vincristine. DNA was extracted from cheek swabs and the ABCB1 genotype was determined. Hematologic adverse drug reactions were recorded for each dog and graded according to the Veterinary Comparative Oncology Group's criteria for adverse event reporting (Consensus Document). In order to avoid possible bias, ABCB1 genotype results for a particular patient were not disclosed to oncologists until an initial adverse event report had been submitted. Dogs heterozygous or homozygous for the ABCB1-1Delta mutation were significantly more likely to develop hematologic toxicity, specifically neutropenia (P= .0005) and thrombocytopenia (P= .0001), after treatment with vincristine than ABCB1 wild-type dogs. At currently recommended dosages (0.5-0.7 mg/M(2)), vincristine is likely to cause hematologic toxicity in dogs with the ABCB1-1Delta mutation, resulting in treatment delays and unacceptable morbidity and mortality. Assessing the ABCB1-1Delta genotype before vincristine administration and decreasing the dosage may prevent toxicity and treatment delays resulting from neutropenia or thrombocytopenia.

Thermal Stress and Toxicity | Science Inventory | US EPA

EPA Pesticide Factsheets

Elevating ambient temperature above thermoneutrality exacerbates toxicity of most air pollutants, insecticides, and other toxic chemicals. On the other hand, safety and toxicity testing of toxicants and drugs is usually performed in mice and rats maintained at subthermoneutral temperatures of —22 °C. When exposed to chemical toxicants under these relatively cool conditions, rodents typically undergo a regulated hypothermic response, characterized by preference for cooler ambient temperatures and controlled reduction in core temperature. Reducing core temperature delays the clearance of most toxicants from the body; however, a mild hypothermia also improves recovery and survival from the toxicant. Raising ambient temperature to thermoneutrality and above increases the rate of clearance of the toxicant but also exacerbates toxicity. Furthermore, heat stress combined with work or exercise is likely to worsen toxicity. Body temperature of large mammals, including humans, does not decrease as much in response to exposure to a toxicant. However, heat stress tan nonetheless worsen toxic outcome in humans through a variety of mechanisms. For example, heat-induced sweating and elevation in skin blood flow accelerates uptake of some insecticides. Epidemiological studies suggest that thermal stress may exacerbate the toxicity of airborne pollutants such as ozone and particulate matter. Overall, translating results of studies in rodents to that of humans is a formidable

Delayed ossification in Wistar rats induced by Morinda citrifolia L. exposure during pregnancy.

PubMed

Marques, Nelson Fernando Quallio; Marques, Ana Paula Bombonatto Mariano; Iwano, Ana Lívia; Golin, Munisa; De-Carvalho, Rosangela Ribeiro; Paumgartten, Francisco José Roma; Dalsenter, Paulo Roberto

2010-03-02

Different products of plant Morinda citrifolia L. (noni) have been marketed and used around the world based on properties described by Polynesian people that use them for more than 2000 years. Marketing of these products is based on their presumptive phytotherapic properties. However there is little scientific evidence about their safety, especially when used during pregnancy. Evaluate the possible developmental toxicity of the noni fruit aqueous extract and commercial product of TAHITIAN NONI juice in rats exposed during pregnancy. Pregnant Wistar rats were exposed by gavage to 7, 30 and 300 mg/kg bw (body weight) of noni aqueous extract or to 0.4, 2 and 20 mL/kg bw (body weight) of noni juice between day 7 and day 15 of pregnancy. Caesarean sections were performed on day 20 of pregnancy and reproductive parameters were evaluated. Implantations sites and postimplantation losses were recorded. Fetuses were weighted and examined for externally visible anomalies. After, the fetuses were cleared with KOH and the bones stained with alizarin red. Skeletal alterations of the skull, vertebral column, ribs, forelimbs, hindlimbs, sternum, sings of delayed ossification and variations were examined in accordance with pre-defined criteria and identified using harmonized and internationally accepted nomenclature recommended by the International Federation of Teratology Societies. Exposure with extract and juice of Morinda citrifolia did not induce maternal toxicity at the tested doses, but induced delayed ossification in fetuses. The exposure of pregnant rats to aqueous extract or juice Morinda citrifolia during organogenesis period may induce adverse effects on the normal development of fetuses. These findings indicate the need for further studies with noni derivates preceding their use in pregnant women. Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.

Inhaled diesel emissions generated with cerium oxide nanoparticle fuel additive induce adverse pulmonary and systemic effects.

PubMed

Snow, Samantha J; McGee, John; Miller, Desinia B; Bass, Virginia; Schladweiler, Mette C; Thomas, Ronald F; Krantz, Todd; King, Charly; Ledbetter, Allen D; Richards, Judy; Weinstein, Jason P; Conner, Teri; Willis, Robert; Linak, William P; Nash, David; Wood, Charles E; Elmore, Susan A; Morrison, James P; Johnson, Crystal L; Gilmour, Matthew Ian; Kodavanti, Urmila P

2014-12-01

Diesel exhaust (DE) exposure induces adverse cardiopulmonary effects. Cerium oxide nanoparticles added to diesel fuel (DECe) increases fuel burning efficiency but leads to altered emission characteristics and potentially altered health effects. Here, we evaluated whether DECe results in greater adverse pulmonary effects compared with DE. Male Sprague Dawley rats were exposed to filtered air, DE, or DECe for 5 h/day for 2 days. N-acetyl glucosaminidase activity was increased in bronchial alveolar lavage fluid (BALF) of rats exposed to DECe but not DE. There were also marginal but insignificant increases in several other lung injury biomarkers in both exposure groups (DECe > DE for all). To further characterize DECe toxicity, rats in a second study were exposed to filtered air or DECe for 5 h/day for 2 days or 4 weeks. Tissue analysis indicated a concentration- and time-dependent accumulation of lung and liver cerium followed by a delayed clearance. The gas-phase and high concentration of DECe increased lung inflammation at the 2-day time point, indicating that gas-phase components, in addition to particles, contribute to pulmonary toxicity. This effect was reduced at 4 weeks except for a sustained increase in BALF γ-glutamyl transferase activity. Histopathology and transmission electron microscopy revealed increased alveolar septa thickness due to edema and increased numbers of pigmented macrophages after DECe exposure. Collectively, these findings indicate that DECe induces more adverse pulmonary effects on a mass basis than DE. In addition, lung accumulation of cerium, systemic translocation to the liver, and delayed clearance are added concerns to existing health effects of DECe. Published by Oxford University Press on behalf of the Society of Toxicology 2014. This work is written by US Government employees and is in the public domain in the US.

Developmental toxicity of bisphenol A diglycidyl ether (epoxide resin badge) during the early life cycle of a native amphibian species.

PubMed

Hutler Wolkowicz, Ianina; Svartz, Gabriela V; Aronzon, Carolina M; Pérez Coll, Christina

2016-12-01

Bisphenol A diglycidyl ether (BADGE) is used in packaging materials, in epoxy adhesives, and as an additive for plastics, but it is also a potential industrial wastewater contaminant. The aim of the present study was to evaluate the adverse effects of BADGE on Rhinella arenarum by means of standardized bioassays at embryo-larval development. The results showed that BADGE was more toxic to embryos than to larvae at all exposure times. At acute exposure, lethality rates of embryos exposed to concentrations of 0.0005 mg/L BADGE and greater were significantly higher than rates in the vehicle control, whereas lethality rates of larvae were significantly higher in concentrations of 10 mg/L BADGE and greater. The toxicity then increased significantly, with 96-h median lethal concentrations (LC50s) of 0.13 mg/L and 6.9 mg/L BADGE for embryos and larvae, respectively. By the end of the chronic period, the 336-h LC50s were 0.04 mg/L and 2.2 mg/L BADGE for embryos and larvae, respectively. This differential sensitivity was also ascertained by the 24-h pulse exposure experiments, in which embryos showed a stage-dependent toxicity, with blastula being the most sensitive stage and S.23 the most resistant. The most important sublethal effects in embryos were cell dissociation and delayed development, whereas the main abnormalities observed in larvae related to neurotoxicity, as scare response to stimuli and narcotic effect. Environ Toxicol Chem 2016;35:3031-3038. © 2016 SETAC. © 2016 SETAC.

Exogenous Hydrogen Peroxide Contributes to Heme Oxygenase-1 Delaying Programmed Cell Death in Isolated Aleurone Layers of Rice Subjected to Drought Stress in a cGMP-Dependent Manner

PubMed Central

Wang, Guanghui; Xiao, Yu; Deng, Xiaojiang; Zhang, Heting; Li, Tingge; Chen, Huiping

2018-01-01

Hydrogen peroxide (H2O2) is a reactive oxygen species (ROS) that plays a dual role in plant cells. Here, we discovered that drought (20% polyethylene glycol-6000, PEG)-triggered decreases of HO-1 transcript expression and HO activity. However, exogenous H2O2 contributed toward the increase in HO-1 gene expression and activity of the enzyme under drought stress. Meanwhile, the HO-1 inducer hematin could mimic the effects of the H2O2 scavengers ascorbic acid (AsA) and dimethylthiourea (DMTU) and the H2O2 synthesis inhibitor diphenyleneiodonium (DPI) for scavenging or diminishing drought-induced endogenous H2O2. Conversely, the zinc protoporphyrin IX (ZnPPIX), an HO-1-specific inhibitor, reversed the effects of hematin. We further analyzed the endogenous H2O2 levels and HO-1 transcript expression levels of aleurone layers treated with AsA, DMTU, and DPI in the presence of exogenous H2O2 under drought stress, respectively. The results showed that in aleurone layers subjected to drought stress, when the endogenous H2O2 level was inhibited, the effect of exogenous H2O2 on the induction of HO-1 was enhanced. Furthermore, exogenous H2O2-activated HO-1 effectively enhanced amylase activity. Application of 8-bromoguanosine 3′,5′-cyclic guanosine monophosphate (8-Br-cGMP) (the membrane permeable cGMP analog) promoted the effect of exogenous H2O2-delayed PCD of aleurone layers in response to drought stress. More importantly, HO-1 delayed the programmed cell death (PCD) of aleurone layers by cooperating with nitric oxide (NO), and the delayed effect of NO on PCD was achieved via mediation by cGMP under drought stress. In short, in rice aleurone layers, exogenous H2O2 (as a signaling molecule) triggered HO-1 and delayed PCD via cGMP which possibly induced amylase activity under drought stress. In contrast, as a toxic by-product of cellular metabolism, the drought-generated H2O2 promoted cell death. PMID:29449858

Exogenous Hydrogen Peroxide Contributes to Heme Oxygenase-1 Delaying Programmed Cell Death in Isolated Aleurone Layers of Rice Subjected to Drought Stress in a cGMP-Dependent Manner.

PubMed

Wang, Guanghui; Xiao, Yu; Deng, Xiaojiang; Zhang, Heting; Li, Tingge; Chen, Huiping

2018-01-01

Hydrogen peroxide (H 2 O 2 ) is a reactive oxygen species (ROS) that plays a dual role in plant cells. Here, we discovered that drought (20% polyethylene glycol-6000, PEG)-triggered decreases of HO-1 transcript expression and HO activity. However, exogenous H 2 O 2 contributed toward the increase in HO-1 gene expression and activity of the enzyme under drought stress. Meanwhile, the HO-1 inducer hematin could mimic the effects of the H 2 O 2 scavengers ascorbic acid (AsA) and dimethylthiourea (DMTU) and the H 2 O 2 synthesis inhibitor diphenyleneiodonium (DPI) for scavenging or diminishing drought-induced endogenous H 2 O 2 . Conversely, the zinc protoporphyrin IX (ZnPPIX), an HO-1-specific inhibitor, reversed the effects of hematin. We further analyzed the endogenous H 2 O 2 levels and HO-1 transcript expression levels of aleurone layers treated with AsA, DMTU, and DPI in the presence of exogenous H 2 O 2 under drought stress, respectively. The results showed that in aleurone layers subjected to drought stress, when the endogenous H 2 O 2 level was inhibited, the effect of exogenous H 2 O 2 on the induction of HO-1 was enhanced. Furthermore, exogenous H 2 O 2 -activated HO-1 effectively enhanced amylase activity. Application of 8-bromoguanosine 3',5'-cyclic guanosine monophosphate (8-Br-cGMP) (the membrane permeable cGMP analog) promoted the effect of exogenous H 2 O 2 -delayed PCD of aleurone layers in response to drought stress. More importantly, HO-1 delayed the programmed cell death (PCD) of aleurone layers by cooperating with nitric oxide (NO), and the delayed effect of NO on PCD was achieved via mediation by cGMP under drought stress. In short, in rice aleurone layers, exogenous H 2 O 2 (as a signaling molecule) triggered HO-1 and delayed PCD via cGMP which possibly induced amylase activity under drought stress. In contrast, as a toxic by-product of cellular metabolism, the drought-generated H 2 O 2 promoted cell death.

Response of murine tumours to combinations of CCNU with misonidazole and other radiation sensitizers.

PubMed Central

Siemann, D. W.

1982-01-01

The effect of combinations of the conventional chemotherapeutic agent 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) and nitroimidazole radiation sensitizers was evaluated in female C3H mice. Tumour response to single-agent or combination therapy was assessed in a tumour growth-delay assay. In the KHT sarcoma the simultaneous addition of misonidazole (MISO) was found to increase significantly the tumour growth delay resulting from CCNU treatment. The observed enhancement ratios (ER) increased with MISO dose, and ranged from 1.3 to 1.9 for sensitizer doses of 0.25-1.0 mg/g. The combination of CCNU and 1.0 or 0.5 mg/g MISO in the RIF-1 tumour or the MT-1 tumour produced ERs of approximately 2.0 and approximately 1.5 respectively. In the KHT sarcoma a series of other nitroimidazole sensitizers, including Ro-05-9963, SR-2555, SR-2508 and metronidazole (METRO), were also evaluated at equimolar doses (5 mmol/kg) in combination with a 20mg/kg dose of CCNU. Unlike MISO, these compounds in general failed to enhance the CCNU cytotoxicity in this tumour model. However, SR-2508 did enhance the response of the RIF-1 tumour to large single doses of CCNU, though not as much as MISO. Normal-tissue toxicity was determined using peripheral white blood cell (WBC) counts 3 days after treatment. CCNU doses of 10-50 mg/kg given either alone or in simultaneous combination with 0.5 or 1.0 mg/g MISO were studied. WBC toxicity increased with CCNU dose, but the addition of MISO at either dose did not significantly enhance this normal-tissue toxicity. PMID:6460517

Acute and delayed toxicity of gemcitabine administered during isolated lung perfusion: a preclinical dose-escalation study in pigs.

PubMed

Pagès, Pierre-Benoit; Derangere, Valentin; Bouchot, Olivier; Magnin, Guy; Charon-Barra, Céline; Lokiec, François; Ghiringhelli, François; Bernard, Alain

2015-08-01

Colorectal cancer is the third most commonly diagnosed cancer worldwide, with up to 25% of patients presenting with metastases at the time of diagnosis. Despite pulmonary metastasectomy many patients go on to develop pulmonary recurrence, which might be linked to the presence of lung micrometastases. In this setting, the adjuvant administration of high-dose chemotherapy by isolated lung perfusion (ILP) has shown encouraging results. However, the tolerance to and efficacy of modern gemcitabine (GEM)-based chemotherapy regimens during adjuvant ILP remain unknown. We conducted a dose-escalating preclinical study to evaluate the immediate and delayed toxicity of GEM in a pig model to define dose-limiting toxicity (DLT) and maximum tolerated concentration. Twenty-three pigs were given increasing concentrations of GEM during ILP, and were awakened at the end of the procedure. The concentrations of GEM were 40, 80, 160, 320, 640 and 1280 µg/ml. Serum and lung samples were taken to measure GEM concentrations. Pulmonary damage was evaluated by histological examination and cleaved caspase-3 detection. Immediate and delayed (1 month) toxicity were recorded. All of the animals underwent successful ILP with GEM. No systemic leak was observed. The three pigs that received a concentration of GEM of 1280 µg/ml died of hypoxia after lung recirculation at the end of the procedure. Eleven pigs survived for 1 month. Major lung toxicity was observed for the concentration of GEM of 640 µg/ml, both at the end of the procedure and after 1 month. DLT was defined at the concentration of 640 µg/ml and the maximum tolerated dose (MTD) was defined at the concentration of 320 µg/ml. ILP with GEM is a safe and reproducible technique in this large-animal model, which includes 1 month of survival. The MTD in this pig model was a concentration of GEM of 320 µg/ml. © The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Paper-based chromatic toxicity bioassay by analysis of bacterial ferricyanide reduction.

PubMed

Pujol-Vila, F; Vigués, N; Guerrero-Navarro, A; Jiménez, S; Gómez, D; Fernández, M; Bori, J; Vallès, B; Riva, M C; Muñoz-Berbel, X; Mas, J

2016-03-03

Water quality assessment requires a continuous and strict analysis of samples to guarantee compliance with established standards. Nowadays, the increasing number of pollutants and their synergistic effects lead to the development general toxicity bioassays capable to analyse water pollution as a whole. Current general toxicity methods, e.g. Microtox(®), rely on long operation protocols, the use of complex and expensive instrumentation and sample pre-treatment, which should be transported to the laboratory for analysis. These requirements delay sample analysis and hence, the response to avoid an environmental catastrophe. In an attempt to solve it, a fast (15 min) and low-cost toxicity bioassay based on the chromatic changes associated to bacterial ferricyanide reduction is here presented. E. coli cells (used as model bacteria) were stably trapped on low-cost paper matrices (cellulose-based paper discs, PDs) and remained viable for long times (1 month at -20 °C). Apart from bacterial carrier, paper matrices also acted as a fluidic element, allowing fluid management without the need of external pumps. Bioassay evaluation was performed using copper as model toxic agent. Chromatic changes associated to bacterial ferricyanide reduction were determined by three different transduction methods, i.e. (i) optical reflectometry (as reference method), (ii) image analysis and (iii) visual inspection. In all cases, bioassay results (in terms of half maximal effective concentrations, EC50) were in agreement with already reported data, confirming the good performance of the bioassay. The validation of the bioassay was performed by analysis of real samples from natural sources, which were analysed and compared with a reference method (i.e. Microtox). Obtained results showed agreement for about 70% of toxic samples and 80% of non-toxic samples, which may validate the use of this simple and quick protocol in the determination of general toxicity. The minimum instrumentation requirements and the simplicity of the bioassay open the possibility of in-situ water toxicity assessment with a fast and low-cost protocol. Copyright © 2016 Elsevier B.V. All rights reserved.

Protection against the Acute and Delayed Toxicity of Mustards and Mustard-Like Compounds.

DTIC Science & Technology

1983-09-01

Edition, A. G. Gilman, L. S. Goodman, and A. Gilman (eds.), Macmillan, New York, 1980, pp. 1256-1313. * 2. Ludlum, D. B., Alkylating Agents and the...chemical warfare agents . They are acutely toxic to the skin, respiratory tract, eyes, bone marrow, and, in large doses, to other organs as well...related to the alkylating activity of sulfur mustards and, specifically, to alkylation of DNA (1). Investigations of related compounds have led to the

Effects of mipafox, paraoxon, chlorpyrifos and its metabolite chlorpyrifos-oxon on the expression of biomarker genes of differentiation in D3 mouse embryonic stem cells.

PubMed

Sogorb, Miguel A; Fuster, Encarnación; Del Río, Eva; Estévez, Jorge; Vilanova, Eugenio

2016-11-25

Chlorpyrifos (CPS) is an organophosphorus compound (OP) capable of causing well-known cholinergic and delayed syndromes through the inhibition of acetylcholinesterase and Neuropathy Target Esterase (NTE), respectively. CPS is also able to induce neurodevelopmental toxicity in animals. NTE is codified by the Pnpla6 gene and plays a central role in differentiation and neurodifferentiation. We tested, in D3 mouse embryonic stem cells under differentiation, the effects of the NTE inhibition by the OPs mipafox, CPS and its main active metabolite chlorpyrifos-oxon (CPO) on the expression of genes Vegfa, Bcl2, Amot, Nes and Jun, previously reported to be under- or overexpressed after Pnpla6 silencing in this same cellular model. Mipafox did not significantly alter the expression of such genes at concentrations that significantly inhibited NTE. However, CPS and CPO at concentrations that caused NTE inhibition at similar levels to mipafox statistically and significantly altered the expression of most of these genes. Paraoxon (another OP with capability to inhibit esterases but not NTE) caused similar effects to CPS and CPO. These findings suggest that the molecular mechanism for the neurodevelopmental toxicity induced by CPS is not based on NTE inhibition, and that other unknown esterases might be potential targets of neurodevelopmental toxicity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Zebrafish and clean water technology: assessing soil bioretention as a protective treatment for toxic urban runoff.

PubMed

McIntyre, J K; Davis, J W; Incardona, J P; Stark, J D; Anulacion, B F; Scholz, N L

2014-12-01

Urban stormwater contains a complex mixture of contaminants that can be acutely toxic to aquatic biota. Green stormwater infrastructure (GSI) is a set of evolving technologies intended to reduce impacts on natural systems by slowing and filtering runoff. The extent to which GSI methods work as intended is usually assessed in terms of water quantity (hydrology) and quality (chemistry). Biological indicators of GSI effectiveness have received less attention, despite an overarching goal of protecting the health of aquatic species. Here we use the zebrafish (Danio rerio) experimental model to evaluate bioinfiltration as a relatively inexpensive technology for treating runoff from an urban highway with dense motor vehicle traffic. Zebrafish embryos exposed to untreated runoff (48-96h; six storm events) displayed an array of developmental abnormalities, including delayed hatching, reduced growth, pericardial edema, microphthalmia (small eyes), and reduced swim bladder inflation. Three of the six storms were acutely lethal, and sublethal toxicity was evident across all storms, even when stormwater was diluted by as much as 95% in clean water. As anticipated from exposure to cardiotoxic polycyclic aromatic hydrocarbons (PAHs), untreated runoff also caused heart failure, as indicated by circulatory stasis, pericardial edema, and looping defects. Bioretention treatment dramatically improved stormwater quality and reversed nearly all forms of developmental toxicity. The zebrafish model therefore provides a versatile experimental platform for rapidly assessing GSI effectiveness. Copyright © 2014 Elsevier B.V. All rights reserved.

Repeated sub-chronic oral toxicity study of xylooligosaccharides (XOS) in dogs.

PubMed

Gao, Yonglin; Wang, Yunzhi; Li, Yanshen; Han, Rui; Li, Chunmei; Xiao, Lin; Cho, Susan; Ma, Yukui; Fang, Chao; Lee, Albert W

2017-06-01

In this study, Beagle dogs were administered xylooligosaccharide (XOS, CAS # 87099-0) at doses of 0, 1250, 2500, and 5000 mg/kg/day by oral gavage for 26 weeks. A 4-week recovery period was added to observe delayed or reversible toxicity. Measurements included body weight, food consumption, clinical observations, temperature, electrocardiogram (ECG), urinalysis, blood chemistry, hematology, organ weight, gross necropsy, and histopathological examination. Except for transient diarrhea or vomiting, no treatment-related adverse effects were noted. In the mid-dose groups, transitional diarrhea was observed in the initial 1-2 weeks. In the high-dose groups, diarrhea and/or vomiting were observed episodically over the duration of treatment. However, they disappeared after XOS was withdrawn in the recovery period. Although there was a tendency toward less weight gain in the high-dose group animal group, this is typical in animals and humans fed non-digestible carbohydrates. This chronic toxicity study demonstrated that the no observed adverse effect level (NOAEL) of XOS is 2500 mg/kg body weight (BW)/day. Based on body surface area (conversion factor of 0.54 for dogs to human), this corresponds to daily doses of 1350 mg/kg BW or 81-108 g XOS in human adults weighing 60-80 kg. Copyright © 2017. Published by Elsevier Inc.

Abrin Toxicity and Bioavailability after Temperature and pH Treatment.

PubMed

Tam, Christina C; Henderson, Thomas D; Stanker, Larry H; He, Xiaohua; Cheng, Luisa W

2017-10-13

Abrin, one of most potent toxins known to man, is derived from the rosary pea (jequirity pea), Abrus precatorius and is a potential bioterror weapon. The temperature and pH stability of abrin was evaluated with an in vitro cell free translation (CFT) assay, a Vero cell culture cytotoxicity assay, and an in vivo mouse bioassay. pH treatment of abrin had no detrimental effect on its stability and toxicity as seen either in vitro or in vivo. Abrin exposure to increasing temperatures did not completely abrogate protein translation. In both the cell culture cytotoxicity model and the mouse bioassay, abrin's toxic effects were completely abrogated if the toxin was exposed to temperatures of 74 °C or higher. In the cell culture model, 63 °C-treated abrin had a 30% reduction in cytotoxicity which was validated in the in vivo mouse bioassay with all mice dying but with a slight time-to-death delay as compared to the non-treated abrin control. Since temperature inactivation did not affect abrin's ability to inhibit protein synthesis (A-chain), we hypothesize that high temperature treatment affected abrin's ability to bind to cellular receptors (affecting B-chain). Our results confirm the absolute need to validate in vitro cytotoxicity assays with in vivo mouse bioassays.

Abrin Toxicity and Bioavailability after Temperature and pH Treatment

PubMed Central

Tam, Christina C.; Henderson, Thomas D.; Stanker, Larry H.; He, Xiaohua; Cheng, Luisa W.

2017-01-01

Abrin, one of most potent toxins known to man, is derived from the rosary pea (jequirity pea), Abrus precatorius and is a potential bioterror weapon. The temperature and pH stability of abrin was evaluated with an in vitro cell free translation (CFT) assay, a Vero cell culture cytotoxicity assay, and an in vivo mouse bioassay. pH treatment of abrin had no detrimental effect on its stability and toxicity as seen either in vitro or in vivo. Abrin exposure to increasing temperatures did not completely abrogate protein translation. In both the cell culture cytotoxicity model and the mouse bioassay, abrin’s toxic effects were completely abrogated if the toxin was exposed to temperatures of 74 °C or higher. In the cell culture model, 63 °C-treated abrin had a 30% reduction in cytotoxicity which was validated in the in vivo mouse bioassay with all mice dying but with a slight time-to-death delay as compared to the non-treated abrin control. Since temperature inactivation did not affect abrin’s ability to inhibit protein synthesis (A-chain), we hypothesize that high temperature treatment affected abrin’s ability to bind to cellular receptors (affecting B-chain). Our results confirm the absolute need to validate in vitro cytotoxicity assays with in vivo mouse bioassays. PMID:29027937

¹H NMR-based metabolic profiling of naproxen-induced toxicity in rats.

PubMed

Jung, Jeeyoun; Park, Minhwa; Park, Hye Jin; Shim, Sun Bo; Cho, Yang Ha; Kim, Jinho; Lee, Ho-Sub; Ryu, Do Hyun; Choi, Donwoong; Hwang, Geum-Sook

2011-01-15

The dose-dependent perturbations in urinary metabolite concentrations caused by naproxen toxicity were investigated using ¹H NMR spectroscopy coupled with multivariate statistical analysis. Histopathologic evaluation of naproxen-induced acute gastrointestinal damage in rats demonstrated a significant dose-dependent effect. Furthermore, principal component analysis (PCA) of ¹H NMR from rat urine revealed a dose-dependent metabolic shift between the vehicle-treated control rats and rats treated with low-dose (10 mg/kg body weight), moderate-dose (50 mg/kg), and high-dose (100 mg/kg) naproxen, coinciding with their gastric damage scores after naproxen administration. The resultant metabolic profiles demonstrate that the naproxen-induced gastric damage exhibited energy metabolism perturbations that elevated their urinary levels of citrate, cis-aconitate, creatine, and creatine phosphate. In addition, naproxen administration decreased choline level and increased betaine level, indicating that it depleted the main protective constituent of the gastric mucosa. Moreover, naproxen stimulated the decomposition of tryptophan into kynurenate, which inhibits fibroblast growth factor-1 and delays ulcer healing. These findings demonstrate that ¹H NMR-based urinary metabolic profiling can facilitate noninvasive and rapid diagnosis of drug side effects and is suitable for elucidating possible biological pathways perturbed by drug toxicity. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Neuregulin-1 is Neuroprotective in a Rat Model of Organophosphate-Induced Delayed Neuronal Injury

PubMed Central

Li, Yonggang; Lein, Pamela J.; Liu, Cuimei; Bruun, Donald A.; Giulivi, Cecilia; Ford, Gregory; Tewolde, Teclemichael; Ross-Inta, Catherine; Ford, Byron D.

2012-01-01

Current medical countermeasures against organophosphate (OP) nerve agents are effective in reducing mortality, but do not sufficiently protect the CNS from delayed brain damage and persistent neurological symptoms. In this study, we examined the efficacy of neuregulin-1 (NRG-1) in protecting against delayed neuronal cell death following acute intoxication with the OP diisopropylfluorophosphate (DFP). Adult male Sprague Dawley rats were pretreated with pyridostigmine (0.1 mg/kg BW, i.m.) and atropine methylnitrate (20 mg/kg BW, i.m.) prior to DFP (9 mg/kg BW, i.p.) intoxication to increase survival and reduce peripheral signs of cholinergic toxicity but not prevent DFP-induced seizures or delayed neuronal injury. Pretreatment with NRG-1 did not protect against seizures in rats exposed to DFP. However, neuronal injury was significantly reduced in most brain regions by pretreatment with NRG-1 isoforms NRG-EGF (3.2 μg/kg BW, i.a) or NRG-GGF2 (48 μg/kg BW, i.a.) as determined by FluroJade-B labeling in multiple brain regions at 24 h post-DFP injection. NRG-1 also blocked apoptosis and oxidative stress-mediated protein damage in the brains of DFP-intoxicated rats. Administration of NRG-1 at 1 h after DFP injection similarly provided significant neuroprotection against delayed neuronal injury. These findings identify NRG-1 as a promising adjuvant therapy to current medical countermeasures for enhancing neuroprotection against acute OP intoxication. PMID:22583949

Safety of Radioembolization with {sup 90}Yttrium Resin Microspheres Depending on Coiling or No-Coiling of Aberrant/High-Risk Vessels

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

Paprottka, P. M., E-mail: philipp.paprottka@med.lmu.de, E-mail: philipp.paprottka@med.uni-muenchen.de; Paprottka, K. J., E-mail: karolin.paprottka@med.lmu.de; Walter, A., E-mail: alexandra.Walter@campus.lmu.de

2015-08-15

PurposeTo evaluate the safety of radioembolization (RE) with {sup 90}Yttrium ({sup 90}Y) resin microspheres depending on coiling or no-coiling of aberrant/high-risk vessels.Materials and MethodsEarly and late toxicity after 566 RE procedures were analyzed retrospectively in accordance with the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE v3.0). For optimal safety, aberrant vessels were either coil embolized (n = 240/566, coiling group) or a more peripheral position of the catheter tip was chosen to treat right or left liver lobes (n = 326/566, no-coiling group).ResultsClinically relevant late toxicities (≥Grade 3) were observed in 1 % of our overall cohort. The no-coiling group had significantlymore » less “any” (P = 0.0001) or “clinically relevant” (P = 0.0003) early toxicity. There was no significant difference (P > 0.05) in delayed toxicity in the coiling versus the no-coiling group. No RE-induced liver disease was noted after all 566 procedures.ConclusionRE with {sup 90}Y resin microspheres is a safe and effective treatment option. Performing RE without coil embolization of aberrant vessels prior to treatment could be an alternative for experienced centers.« less

Cells-nano interactions and molecular toxicity after delayed hypersensitivity, in guinea pigs on exposure to hydroxyapatite nanoparticles.

PubMed

Geetha, C S; Remya, N S; Leji, K B; Syama, S; Reshma, S C; Sreekanth, P J; Varma, H K; Mohanan, P V

2013-12-01

The aim of the study was to evaluate the cells-nanoparticle interactions and molecular toxicity after delayed hypersensitivity in Guinea pigs, exposed to hydroxyapatite nanoparticles (HANP). The study focuses on synthesizing and characterizing HANPs and gaining an insight into the cytotoxicity, molecular toxicity, hypersensitivity and oxidative stress caused by them in vitro and in vivo. HANP was synthesized by chemical method and characterized by standard methods. Cytotoxicity was assessed on L929 cells by MTT assay and in vitro studies were carried out on rat liver homogenate. In vivo study was carried out by topical exposure of Guinea pigs with HANP, repeatedly, and evaluating the skin sensitization potential, blood parameters, oxidative stress in liver and brain and DNA damage (8-hydroxyl-2-deoxyguanosine: 8-OHdG) in liver. The results of the study indicated that there was no cytotoxicity (up to 600μg/mL) and oxidative damage (up to 100μg/mL), when exposed to HANPs. It was also evident that, there was no skin sensitization and oxidative damage when HANP were exposed to Guinea pigs. Copyright © 2013 Elsevier B.V. All rights reserved.

Delayed myelosuppression with acute exposure to hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and environmental degradation product hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX) in rats

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

Jaligama, Sridhar; Kale, Vijay M.; Wilbanks, Mitchell S.

2013-02-01

Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), a widely used munitions compound, and hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX), its N-nitroso product of anaerobic microbial nitroreduction, are contaminants of military sites. Previous studies have shown MNX to be the most acutely toxic among the nitroreduced degradation products of RDX and to cause mild anemia at high dose. The present study compares hematotoxicity with acute oral exposure to MNX with parent RDX. Both RDX and MNX caused a modest decrease in blood hemoglobin and ∼ 50% loss of granulocytes (NOAELs = 47 mg/kg) in female Sprague–Dawley rats observed 14 days post-exposure. We explored the possibility that blood cell loss observedmore » after 14 days was delayed in onset because of toxicity to bone marrow (BM) progenitors. RDX and MNX decreased granulocyte/macrophage-colony forming cells (GM-CFCs) at 14, but not 7, days (NOAELs = 24 mg/kg). The earliest observed time at which MNX decreased GM-CFCs was 10 days post-exposure. RDX and MNX likewise decreased BM burst-forming units-erythroid (BFU-Es) at 14, but not 7, days. Granulocyte–erythrocyte–monocyte–megakaryocyte (GEMM)-CFCs were unaffected by RDX and MNX at 7 days suggesting precursor depletion did not account for GM-CFC and BFU-E loss. MNX added to the culture media was without effect on GM-CFC formation indicating no direct inhibition. Flow cytometry showed no differential loss of BM multilineage progenitors (Thy1.1{sup +}) or erythroid (CD71{sup +}) precursors with MNX suggesting myeloid and erythroid lineages were comparably affected. Collectively, these data indicate that acute exposure to both RDX and MNX caused delayed suppression of myelo- and erythropoiesis with subsequent decrease of peripheral granulocytes and erythrocytes. Highlights: ► Acute oral exposure to munitions RDX causes myelosuppression. ► Environmental degradation product MNX is comparable in effect. ► RDX and MNX are cytotoxic to both myeloid and erythroid progenitor cells. ► Myelosuppression is delayed in onset by > 7 days after single exposure.« less

Electrogastrography in experimental pigs: the influence of gastrointestinal injury induced by dextran sodium sulphate on porcine gastric erythromycin-stimulated myoelectric activity.

PubMed

Tachecí, Ilja; Kvetina, Jaroslav; Kunes, Martin; Edakkanambeth Varayil, Jithinraj; Ali, Shahzad Marghoob; Pavlik, Michal; Kopacova, Marcela; Rejchrt, Stanislav; Bures, Jan; Pleskot, Miloslav

2011-01-01

Electrogastrography (EGG) is a non-invasive investigation of gastric myoelectrical activity. The aim of study was to evaluate the impact of erythromycin on EGG in gastrointestinal toxic injury induced by dextran sodium sulphate (DSS) in experimental pigs. The experiments were carried out on 12 adult pigs (weighing 30-35 kg). EGG was recorded using Digitrapper equipment (Synectics Medical AB, Stockholm). Running spectrum activity was used for EGG evaluation. There were two groups of animals: Group I: 6 controls with erythromycin administration (1,600 mg intragastrically); Group II: 6 animals treated with DSS (for 5 days, 0.25 g/kg per day in a dietary bolus) followed by erythromycin administration. Baseline and subsequent six separate 30-minute EGG-recordings (from time 0 to 360 min) were accomplished in each animal. A total of 84 records were analysed. Baseline dominant frequency of slow waves was fully comparable in both groups. In Group I, there was a significant increase in dominant frequency after erythromycin administration (maximum between 240-360 min). There was a flat non-significant and delayed increase in dominant frequency after erythromycin administration in Group II. The difference between Group I and II at particular time intervals was not significant but a diverse trend was evident. EGG recording enables us to register a gastric myoelectrical effect of prokinetic drugs. Erythromycin induced a significant increase in the dominant frequency of slow waves. DSS caused toxic injury to the porcine gastrointestinal tract responsible for the delayed and weaker myoelectrical effect of erythromycin in experimental animals.

Preoperative Short-Course Concurrent Chemoradiation Therapy Followed by Delayed Surgery for Locally Advanced Rectal Cancer: A Phase 2 Multicenter Study (KROG 10-01)

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

Yeo, Seung-Gu; Department of Radiation Oncology, Soonchunhyang University College of Medicine, Cheonan; Oh, Jae Hwan

Purpose: A prospective phase 2 multicenter trial was performed to investigate the efficacy and safety of preoperative short-course concurrent chemoradiation therapy (CRT) followed by delayed surgery for patients with locally advanced rectal cancer. Methods and Materials: Seventy-three patients with cT3-4 rectal cancer were enrolled. Radiation therapy of 25 Gy in 5 fractions was delivered over 5 consecutive days using helical tomotherapy. Concurrent chemotherapy was administered on the same 5 days with intravenous bolus injection of 5-fluorouracil (400 mg/m{sup 2}/day) and leucovorin (20 mg/m{sup 2}/day). After 4 to 8 weeks, total mesorectal excision was performed. The primary endpoint was the pathologicmore » downstaging (ypStage 0-I) rate, and secondary endpoints included tumor regression grade, tumor volume reduction rate, and toxicity. Results: Seventy-one patients completed the planned preoperative CRT and surgery. Downstaging occurred in 20 (28.2%) patients, including 1 (1.4%) with a pathologic complete response. Favorable tumor regression (grade 4-3) was observed in 4 (5.6%) patients, and the mean tumor volume reduction rate was 62.5 ± 21.3%. Severe (grade ≥3) treatment toxicities were reported in 27 (38%) patients from CRT until 3 months after surgery. Conclusions: Preoperative short-course concurrent CRT followed by delayed surgery for patients with locally advanced rectal cancer demonstrated poor pathologic responses compared with conventional long-course CRT, and it yielded considerable toxicities despite the use of an advanced radiation therapy technique.« less

Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity

PubMed Central

Klement, Giannoula; Baruchel, Sylvain; Rak, Janusz; Man, Shan; Clark, Katherine; Hicklin, Daniel J.; Bohlen, Peter; Kerbel, Robert S.

2000-01-01

Various conventional chemotherapeutic drugs can block angiogenesis or even kill activated, dividing endothelial cells. Such effects may contribute to the antitumor efficacy of chemotherapy in vivo and may delay or prevent the acquisition of drug-resistance by cancer cells. We have implemented a treatment regimen that augments the potential antivascular effects of chemotherapy, that is devoid of obvious toxic side effects, and that obstructs the development of drug resistance by tumor cells. Xenografts of 2 independent neuroblastoma cell lines were subjected to either continuous treatment with low doses of vinblastine, a monoclonal neutralizing antibody (DC101) targeting the flk-1/KDR (type 2) receptor for VEGF, or both agents together. The rationale for this combination was that any antivascular effects of the low-dose chemotherapy would be selectively enhanced in cells of newly formed vessels when survival signals mediated by VEGF are blocked. Both DC101 and low-dose vinblastine treatment individually resulted in significant but transient xenograft regression, diminished tumor vascularity, and direct inhibition of angiogenesis. Remarkably, the combination therapy resulted in full and sustained regressions of large established tumors, without an ensuing increase in host toxicity or any signs of acquired drug resistance during the course of treatment, which lasted for >6 months. This article may have been published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org. J. Clin. Invest. 105:R15–R24 (2000). PMID:10772661

Cardiotoxic effects of chemotherapy: A review of both cytotoxic and molecular targeted oncology therapies and their effect on the cardiovascular system.

PubMed

Babiker, Hani M; McBride, Ali; Newton, Michael; Boehmer, Leigh M; Drucker, Adrienne Goeller; Gowan, Mollie; Cassagnol, Manouchkathe; Camenisch, Todd D; Anwer, Faiz; Hollands, James M

2018-06-01

Cardiotoxic effects of chemotherapy and targeted drugs are ubiquitous and challenging in the field of oncology therapeutics. The broad spectrum of toxicities ranging from ischemic, hypertensive, cardiomyopathic, and arrhythmic complications can present as a significant challenge for clinicians treating cancer patients. If early diagnosis and intervention of cardiotoxic complications is missed, this can lead to delay or abrogation of planned treatment, which can potentially culminate to significant morbidity due to not only the cardiotoxic complications but also the progression of cancer. Hence, full knowledge of cardiovascular complications of chemotherapeutic agents, essential diagnostics tests to order, and appropriate management is paramount to oncologist, oncology pharmacists, and scientific clinical investigators. The aforementioned is particularly true in the current oncology era of plenteous early clinical trials studying several pathway/molecular-targeting agents with an increased cardiotoxic potential and the rapid expedited approval of those drugs by the FDA. Herein, we present a review discussing cardiotoxic effects of drugs and guidelines for management of the toxicities to assist the medical field in general managing patients with cancer. Copyright © 2018 Elsevier B.V. All rights reserved.

Toxicity of effluents from gasoline stations oil-water separators to early life stages of zebrafish Danio rerio.

PubMed

Alves, Romulo Nepomuceno; Mariz, Célio Freire; Paulo, Driele Ventura de; Carvalho, Paulo S M

2017-07-01

Used petroleum hydrocarbons and gasoline stations runoff are significant sources of polycyclic aromatic hydrocarbons (PAHs) to aquatic ecosystems. Samples of the final effluent of oil-water-separators were collected at gasoline stations in the metropolitan region of Recife, Brazil, before release to sewage or rainwater systems. Effluent soluble fractions (ESF) were prepared and bioassays were performed according to the Fish Embryo Toxicity Test. The test involved exposing zebrafish Danio rerio embryos to dilutions of the ESFs for 96 h, with daily examination of lethality and sublethal morphological effects integrated through the General Morphology Score (GMS), based on the achievement of developmental hallmarks. Frequencies of abnormalities were recorded after exposures. ESF LC50-96h (lethal concentration to 50% of exposed embryos) in the most toxic effluent achieved 8.9% (v/v), equivalent to 11 μg phenanthrene equivalents L -1 . GMS scores indicated significantly delayed embryo-larval development at ESF dilutions of 10% and 20% from effluents of all gas stations. Major abnormalities detected after the 96 h exposure included the presence of a yolk sac not fully absorbed coupled with the lack of an inflated swim bladder, lack of both pectoral fins, and the failure to develop a protruding mouth. Effective equivalent PAH concentrations that induce a 50% frequency of larvae without an inflated swim bladder (EC50) were 4.9 μg phenanthrene L -1 , 21.8 μg naphthalene L -1 , and 34.1 μg chrysene L -1 . This study shows that PAHs in ESFs from gas stations oil water separators are toxic to zebrafish, contributing to the toxicity of urban storm waters. Copyright © 2017 Elsevier Ltd. All rights reserved.

The classification and application of toxic Chinese materia medica.

PubMed

Liu, Xinmin; Wang, Qiong; Song, Guangqing; Zhang, Guangping; Ye, Zuguang; Williamson, Elizabeth M

2014-03-01

Many important drugs in the Chinese materia medica (CMM) are known to be toxic, and it has long been recognized in classical Chinese medical theory that toxicity can arise directly from the components of a single CMM or may be induced by an interaction between combined CMM. Traditional Chinese Medicine presents a unique set of pharmaceutical theories that include particular methods for processing, combining and decocting, and these techniques contribute to reducing toxicity as well as enhancing efficacy. The current classification of toxic CMM drugs, traditional methods for processing toxic CMM and the prohibited use of certain combinations, is based on traditional experience and ancient texts and monographs, but accumulating evidence increasingly supports their use to eliminate or reduce toxicity. Modern methods are now being used to evaluate the safety of CMM; however, a new system for describing the toxicity of Chinese herbal medicines may need to be established to take into account those herbs whose toxicity is delayed or otherwise hidden, and which have not been incorporated into the traditional classification. This review explains the existing classification and justifies it where appropriate, using experimental results often originally published in Chinese and previously not available outside China. Copyright © 2013 John Wiley & Sons, Ltd.

Impact of TBI on late effects in children treated by megatherapy for Stage IV neuroblastoma. A study of the French Society of Pediatric oncology

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

Flandin, Isabelle; Department of Radiotherapy/Oncology, Hospital Lyon Sud, Lyon; Hartmann, Olivier

2006-04-01

Purpose: To determine the contribution of total body irradiation (TBI) to late sequelae in children treated with high-dose chemotherapy and autologous bone marrow transplantation for Stage IV neuroblastoma. Patients and Methods: We compared two populations that were similar with regard to age, stage, pre-autologous bone marrow transplantation chemotherapy (CT) regimen, period of treatment, and follow-up (12 years). The TBI group (n = 32) received TBI as part of the megatherapy procedure (1982-1993), whereas the CT group (n 30) received conditioning without TBI (1985-1992). Analysis 12 years later focused on growth, weight and corpulence (body mass index) delay; hormonal deficiencies; liver,more » kidney, heart, ear, eye, and dental sequelae; school performance; and the incidence of secondary tumors. Results: Impact of TBI was most marked in relation to growth and weight delay, although the mean delay was not severe, probably because of treatment with growth hormones. Other consequences of TBI were thyroid insufficiency, cataracts, and a high incidence of secondary tumors. Hearing loss and dental agenesis were more prominent in the group treated with CT alone. No differences were observed in school performance. Conclusion: The most frequent side effects of TBI were cataracts, thyroid insufficiency, and growth delay, but more worrying is the risk of secondary tumors. Because of the young mean age of patients and the toxicity of TBI regimens without any survival advantage, regimens without TBI are preferable in the management of Stage IV neuroblastoma.« less

Development and application of the adverse outcome pathway framework for understanding and predicting chronic toxicity: I. Challenges and research needs in ecotoxicology.

PubMed

Groh, Ksenia J; Carvalho, Raquel N; Chipman, James K; Denslow, Nancy D; Halder, Marlies; Murphy, Cheryl A; Roelofs, Dick; Rolaki, Alexandra; Schirmer, Kristin; Watanabe, Karen H

2015-02-01

To elucidate the effects of chemicals on populations of different species in the environment, efficient testing and modeling approaches are needed that consider multiple stressors and allow reliable extrapolation of responses across species. An adverse outcome pathway (AOP) is a concept that provides a framework for organizing knowledge about the progression of toxicity events across scales of biological organization that lead to adverse outcomes relevant for risk assessment. In this paper, we focus on exploring how the AOP concept can be used to guide research aimed at improving both our understanding of chronic toxicity, including delayed toxicity as well as epigenetic and transgenerational effects of chemicals, and our ability to predict adverse outcomes. A better understanding of the influence of subtle toxicity on individual and population fitness would support a broader integration of sublethal endpoints into risk assessment frameworks. Detailed mechanistic knowledge would facilitate the development of alternative testing methods as well as help prioritize higher tier toxicity testing. We argue that targeted development of AOPs supports both of these aspects by promoting the elucidation of molecular mechanisms and their contribution to relevant toxicity outcomes across biological scales. We further discuss information requirements and challenges in application of AOPs for chemical- and site-specific risk assessment and for extrapolation across species. We provide recommendations for potential extension of the AOP framework to incorporate information on exposure, toxicokinetics and situation-specific ecological contexts, and discuss common interfaces that can be employed to couple AOPs with computational modeling approaches and with evolutionary life history theory. The extended AOP framework can serve as a venue for integration of knowledge derived from various sources, including empirical data as well as molecular, quantitative and evolutionary-based models describing species responses to toxicants. This will allow a more efficient application of AOP knowledge for quantitative chemical- and site-specific risk assessment as well as for extrapolation across species in the future. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Post-exposure treatment of VX poisoned guinea pigs with the engineered phosphotriesterase mutant C23: a proof-of-concept study.

PubMed

Worek, Franz; Seeger, Thomas; Reiter, Georg; Goldsmith, Moshe; Ashani, Yacov; Leader, Haim; Sussman, Joel L; Aggarwal, Nidhi; Thiermann, Horst; Tawfik, Dan S

2014-11-18

The highly toxic organophosphorus (OP) nerve agent VX is characterized by a remarkable biological persistence which limits the effectiveness of standard treatment with atropine and oximes. Existing OP hydrolyzing enzymes show low activity against VX and hydrolyze preferentially the less toxic P(+)-VX enantiomer. Recently, a phosphotriesterase (PTE) mutant, C23, was engineered towards the hydrolysis of the toxic P(-) isomers of VX and other V-type agents with relatively high in vitro catalytic efficiency (kcat/KM=5×10(6)M(-1)min(-1)). To investigate the suitability of the PTE mutant C23 as a catalytic scavenger, an in vivo guinea pig model was established to determine the efficacy of post-exposure treatment with C23 alone against VX intoxication. Injection of C23 (5mgkg(-1) i.v.) 5min after s.c. challenge with VX (∼2LD50) prevented systemic toxicity. A lower C23 dose (2mgkg(-1)) reduced systemic toxicity and prevented mortality. Delayed treatment (i.e., 15min post VX) with 5mgkg(-1) C23 resulted in survival of all animals and only in moderate systemic toxicity. Although C23 did not prevent inhibition of erythrocyte acetylcholinesterase (AChE) activity, it partially preserved brain AChE activity. C23 therapy resulted in a rapid decrease of racemic VX blood concentration which was mainly due to the rate of degradation of the toxic P(-)-VX enantiomer that correlates with the C23 blood levels and its kcat/KM value. Although performed under anesthesia, this proof-of-concept study demonstrated for the first time the ability of a catalytic bioscavenger to prevent systemic VX toxicity when given alone as a single post-exposure treatment, and enables an initial assessment of a time window for this approach. In conclusion, the PTE mutant C23 may be considered as a promising starting point for the development of highly effective catalytic bioscavengers for post-exposure treatment of V-agents intoxication. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

The mammary gland is a sensitive pubertal target in CD-1 and C57Bl/6 mice following perinatal perfluorooctanoic acid (PFOA) exposure

PubMed Central

Tucker, Deirdre K.; Macon, Madisa B.; Strynar, Mark J.; Dagnino, Sonia; Andersen, Erik; Fenton, Suzanne E.

2015-01-01

Perfluorooctanoic acid (PFOA) is a known developmental toxicant in mice, with varied strain outcomes depending on dose and period of exposure. The impact of PFOA on female mouse pubertal development at low doses (≤1 mg/kg), however, has yet to be determined. Therefore, female offspring from CD-1 and C57Bl/6 dams exposed to PFOA, creating serum concentrations similar to humans, were examined for pubertal onset, including mammary gland development. Mouse pups demonstrated a shorter PFOA elimination half-life than that reported for adult mice. Prenatal exposure to PFOA caused significant mammary developmental delays in exposed female offspring in both strains. Delays started during puberty and persisted into young adulthood; severity was dose-dependent. In contrast, an evaluation of serum hormone levels and pubertal timing onset in the same offspring revealed no effects of PFOA compared to controls in either strain. Therefore, our data suggest that the mammary gland is more sensitive to the effects of early low level PFOA exposures compared to other pubertal endpoints, regardless of strain. PMID:25499722

Should We Pay Attention to the Delay Before Admission to a Pediatric Intensive Care Unit for Children With Cancer? Impact on 1-Month Mortality. A Report From the French Children's Oncology Study Group, GOCE.

PubMed

Fausser, Jeanne-L; Tavenard, Aude; Rialland, Fanny; Le Moine, Philippe; Minckes, Odile; Jourdain, Anne; Tirel, Olivier; Pellier, Isabelle; Gandemer, Virginie

2017-07-01

Acute complications requiring admission to pediatric intensive care unit (PICU) are frequent for children with cancer. Our objective was to determine early prognostic factors of mortality in a cohort of children with cancer hospitalized in PICU for acute complications and particularly to assess whether the delay before admission to a PICU is an early predictor of mortality. We conduct a retrospective multicenter analysis. All patients transferred in PICU for acute complications between January 2002 and December 2012 were included. One-month mortality of the 224 patients analyzed was 24.5%. Delay before PICU admission was a significant prognostic factor of 1-month mortality with nonsurvivors experiencing a longer median delay than survivors (24 vs. 12 h, respectively, P<0.05). Time from diagnosis to PICU admission (P<0.001), hematopoietic stem cell transplant (P<0.05), the duration of neutropenia (P<0.01), infection type (P<0.001), number of organ dysfunctions (P<0.001), and reaching any grade 4 toxicity before PICU admission (P<0.001) also affected mortality rate at 1-month post-PICU discharge. In the multivariate analysis, only reaching any grade 4 toxicity before PICU admission influenced 1-month mortality (odds ratio, 2.30; 95% confidence interval, 1.07-4.96; P<0.05). These results suggest that PICU admission before severe impairment leads to a better outcome for children with cancer.

Toxic responses of Sox2 gene in the regeneration of the earthworm Eisenia foetida exposed to Retnoic acid.

PubMed

Tao, Jing; Rong, Wei; Diao, Xiaoping; Zhou, Hailong

2018-01-01

Exogenous retinoic acid delays and disturbs the regeneration of Eisenia foetida. The stem cell pluripotency factor, Sox2, can play a crucial role in cell reprogramming and dedifferentiation. In this study, we compared the regeneration of Eisenia foetida in different segments after amputation and the effects of retinoic acid on the regeneration of different segments. The results showed that the regeneration speed of the head and tail was slightly faster than the middle part, and retinoic acid disrupted and delayed the regeneration of the earthworm. The qRT-PCR and Western blot analysis showed that the expression of the Sox2 gene and Sox2 protein was highest on the seventh day in different segments (p<0.05). After treatment with retinoic acid, the expression level of the Sox2 gene and Sox2 protein was significantly reduced (p<0.05). The results indicated that the regeneration of earthworms and the formation of blastema are related to the expression of the Sox2 gene and protein. Retinoic acid delays and interferes with the regeneration of the earthworm by affecting the expression levels of the Sox2 gene and protein. Copyright © 2017 Elsevier Inc. All rights reserved.

Spermatotoxicity of dichloroacetic acid

EPA Science Inventory

The testicular toxicity of dichloroacetic acid (DCA), a disinfection byproduct of drinking water, was evaluated in adult male rats given both single and multiple (up to 14 d) oral doses. Delayed spermiation and altered resorption of residual bodies were observed in rats given sin...

Neuregulin-1 is neuroprotective in a rat model of organophosphate-induced delayed neuronal injury

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

Li, Yonggang; Lein, Pamela J.; Liu, Cuimei

2012-07-15

Current medical countermeasures against organophosphate (OP) nerve agents are effective in reducing mortality, but do not sufficiently protect the CNS from delayed brain damage and persistent neurological symptoms. In this study, we examined the efficacy of neuregulin-1 (NRG-1) in protecting against delayed neuronal cell death following acute intoxication with the OP diisopropylflurophosphate (DFP). Adult male Sprague–Dawley rats were pretreated with pyridostigmine (0.1 mg/kg BW, i.m.) and atropine methylnitrate (20 mg/kg BW, i.m.) prior to DFP (9 mg/kg BW, i.p.) intoxication to increase survival and reduce peripheral signs of cholinergic toxicity but not prevent DFP-induced seizures or delayed neuronal injury. Pretreatmentmore » with NRG-1 did not protect against seizures in rats exposed to DFP. However, neuronal injury was significantly reduced in most brain regions by pretreatment with NRG-1 isoforms NRG-EGF (3.2 μg/kg BW, i.a) or NRG-GGF2 (48 μg/kg BW, i.a.) as determined by FluroJade-B labeling in multiple brain regions at 24 h post-DFP injection. NRG-1 also blocked apoptosis and oxidative stress-mediated protein damage in the brains of DFP-intoxicated rats. Administration of NRG-1 at 1 h after DFP injection similarly provided significant neuroprotection against delayed neuronal injury. These findings identify NRG-1 as a promising adjuvant therapy to current medical countermeasures for enhancing neuroprotection against acute OP intoxication. -- Highlights: ► NRG-1 blocked DFP induced neuronal injury. ► NRG-1 did not protect against seizures in rats exposed to DFP. ► NRG-1 blocked apoptosis and oxidative stress in the brains of DFP-intoxicated rats. ► Administration of NRG-1 at 1 h after DFP injection prevented delayed neuronal injury.« less

Carlina acaulis Exhibits Antioxidant Activity and Counteracts Aβ Toxicity in Caenorhabditis elegans.

PubMed

Link, Pille; Roth, Kevin; Sporer, Frank; Wink, Michael

2016-07-02

Carlina acaulis is a medicinal plant that has shown antioxidant activity in in vitro studies, but to date no corresponding in vivo data is available. Therefore, in the present study the antioxidant activity and its impact in counteracting Aβ toxicity were studied in the Caenorhabditis elegans model. A dichloromethane extract of the roots of C. acaulis was prepared and characterised via gas-liquid-chromatography/mass-spectrometry (GLC-MS). The in vitro antioxidant activity was confirmed via 2,2-diphenyl-1-picrylhydracyl assay. The extract was further separated by thin layer chromatography into two fractions, one of which was a fraction of the dichloromethane extract of C. acaulis containing mostly Carlina oxide (CarOx). Different strains of C. elegans were employed to study the expression of hsp-16.2p::GFP as a marker for oxidative stress, delocalisation of the transcription factor DAF-16 as a possible mechanism of antioxidant activity, the effect of the drug under lethal oxidative stress, and the effect against beta-amyloid (Aβ) toxicity in a paralysis assay. The C. acaulis extract and CarOx showed high antioxidant activity (stress reduction by 47% and 64%, respectively) in C. elegans and could activate the transcription factor DAF-16 which directs the expression of anti-stress genes. In paralysis assay, only the total extract was significantly active, delaying paralysis by 1.6 h. In conclusion, in vivo antioxidant activity was shown for C. acaulis for the first time in the C. elegans model. The active antioxidant compound is Carlina oxide. This activity, however, is not sufficient to counteract Aβ toxicity. Other mechanisms and possibly other active compounds are involved in this effect.

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.

Safety of dermal diphoterine application: an active decontamination solution for chemical splash injuries.

PubMed

Hall, Alan H; Cavallini, Maurizio; Mathieu, Laurence; Maibach, Howard I

2009-01-01

Diphoterine (Laboratoire Prevor, Valmondois, France) is an active, amphoteric, polyvalent, chelating, slightly hypertonic decontamination solution for chemical splashes to the skin and eyes. It chemically binds a large number of chemical substances present on the skin surface without causing a significant release of heat (exothermic reactions). Because of its amphoteric properties, it can bind chemically opposite substances such as acids and bases or oxidizers and reducing agents. No adverse effects have been observed in an ongoing postmarketing surveillance program during many years of use in European industrial facilities. Diphoterine has more recently been used in hospitals for delayed management of chemical burns to the skin and eyes. There is interest in having protocols for both immediate and delayed diphoterine use for skin decontamination. Whereas studies of diphoterine efficacy, clinical and in vitro or ex vivo, have been published or are in the process of being prepared for publication, no review has yet been published focusing solely on the safety of this decontamination solution. Therefore, all available studies on the safety of diphoterine are described here, including recent studies demonstrating no harmful effects on the skin. Diphoterine can be used, even on damaged skin, without toxic, irritant, allergenic, or sensitizing effects.

Inhalant-Abuse Myocarditis Diagnosed by Cardiac Magnetic Resonance.

PubMed

Dinsfriend, William; Rao, Krishnasree; Matulevicius, Susan

2016-06-01

Multiple reports of toxic myocarditis from inhalant abuse have been reported. We now report the case of a 23-year-old man found to have toxic myocarditis from inhalation of a hydrocarbon. The diagnosis was made by means of cardiac magnetic resonance imaging with delayed enhancement. The use of cardiac magnetic resonance to diagnose myocarditis has become increasingly common in clinical medicine, although there is not a universally accepted criterion for diagnosis. We appear to be the first to document a case of toxic myocarditis diagnosed by cardiac magnetic resonance. In patients with a history of drug abuse who present with clinical findings that suggest myocarditis or pericarditis, cardiac magnetic resonance can be considered to support the diagnosis.

Effect of pre-fixation delay and freezing on mink testicular endpoints for environmental research.

PubMed

Spörndly-Nees, Ellinor; Ekstedt, Elisabeth; Magnusson, Ulf; Fakhrzadeh, Azadeh; Luengo Hendriks, Cris L; Holm, Lena

2015-01-01

There is growing interest in using wild animals to monitor the real-life cocktail effect of environmental chemicals on male reproduction. However, practical difficulties, such as long distances to the laboratory, generally prolong the time between euthanisation and specimen handling. For instance, tissue fixation is often performed on frozen material or on material where deterioration has started, which may affect tissue morphology. This study examined the effect of pre-fixation delay and freezing on mink testicular endpoints in order to determine robust endpoints in suboptimally handled specimens. Sexually mature farmed mink (n=30) selected at culling were divided into six groups and subjected to different time intervals between euthanisation and fixation or freezing: 0 hours (fixed immediately post mortem), 6 hours, 18 hours, 30 hours, 42 hours, or frozen 6 hours post mortem and thawed overnight. Unaffected endpoints when pre-fixation storage was extended to 30 hours included: area and diameter of the seminiferous tubules, length and weight of the testes, and acrosomes marked with Gata-4. Epithelial height, Sertoli cells marked with Gata-4 and cell morphology were affected endpoints after 6 hours of storage. Freezing the tissue prior to fixation severely altered cell morphology and reduced testicular weight, tubular diameter and area. Morphological changes seen after 6 hours included shredded germ cells and excess cytoplasm in seminiferous tubular lumen, chromatin rearrangements and increased germ cell death. Extended delay before fixation and freezing affected many endpoints in the mink testicular tissue. Some of these endpoints may mimic chemically induced effects, which is important to consider when evaluating specimens from wild animals for environmental toxicity.

Mustard vesicating agent-induced toxicity in the skin tissue and silibinin as a potential countermeasure.

PubMed

Tewari-Singh, Neera; Agarwal, Rajesh

2016-06-01

Exposure to the vesicating agents sulfur mustard (SM) and nitrogen mustard (NM) causes severe skin injury with delayed blistering. Depending upon the dose and time of their exposure, edema and erythema develop into blisters, ulceration, necrosis, desquamation, and pigmentation changes, which persist weeks and even years after exposure. Research advances have generated data that have started to explain the probable mechanism of action of vesicant-induced skin toxicity; however, despite these advances, effective and targeted therapies are still deficient. This review highlights studies on two SM analogs, 2-chloroethyl ethyl sulfide (CEES) and NM, and CEES- and NM-induced skin injury mouse models that have substantially added to the knowledge on the complex pathways involved in mustard vesicating agent-induced skin injury. Furthermore, employing these mouse models, studies under the National Institutes of Health Countermeasures Against Chemical Threats program have identified the flavanone silibinin as a novel therapeutic intervention with the potential to be developed as an effective countermeasure against skin injury following exposure to mustard vesicating agents. © 2016 New York Academy of Sciences.

Mustard vesicating agents–induced toxicity in the skin tissue and silibinin as a potential countermeasure

PubMed Central

Tewari-Singh, Neera; Agarwal, Rajesh

2016-01-01

Exposure to the vesicating agents sulfur mustard (SM) and nitrogen mustard (NM) causes severe skin injury with delayed blistering. Depending upon the dose and time of their exposure, edema and erythema develop into blisters, ulceration, necrosis, desquamation, and pigmentation changes, which persist weeks and even years after exposure. Research advances have generated data that have started to explain the probable mechanism of action of vesicant-induced skin toxicity; however, despite these advances, effective and targeted therapies are still deficient. This review highlights studies on two SM analogs, chloroethyl ethyl sulfide (CEES) and NM, and CEES- and NM-induced skin injury mouse models that have substantially added to the knowledge on the complex pathways involved in mustard vesicating agent–induced skin injury. Furthermore, employing these mouse models, studies under the National Institutes of Health Countermeasures Against Chemical Threats program have identified the flavanone silibinin as a novel therapeutic intervention with the potential to be developed as an effective countermeasure against skin injury following exposure to mustard vesicating agents. PMID:27326543

The Installation Restoration Program Toxicology Guide. Volume 2

DTIC Science & Technology

1987-05-01

the number of extra responses made during exposure. An increase in response time 5/87 3V.WI UW V VýWVVWtW’.W1 VWJW.W W W VWVWW.WVVW MRVW W \\V -VW W i Ri...toxicity as shown by a decreased maternal weight gain. Minor anomalies in fetal development included an extra lumbar rib and delayed ossification of... lumbar spurs (57 vs. 18 in the control group) and a delayed vertebrae centra ossification (19 vs. 4 in the control group). No teratogenic response was

Cola beverage and delayed elimination of methotrexate

PubMed Central

Santucci, Raoul; Levêque, Dominique; Herbrecht, Raoul

2010-01-01

AIMS To report a case of severe delayed methotrexate elimination attributable to consumption of a cola beverage. METHODS To investigate unexplained low urinary pH in a lymphoma patient treated with high-dose methotrexate. RESULTS Unexpected urinary acidity, despite administration of large amounts of sodium bicarbonate, could be attributed to repeated consumption of a cola beverage. It resulted in a delayed elimination of methotrexate and acute renal failure. Discontinuation of cola drinks, increase in calcium folinate rescue and in sodium bicarbonate allowed satisfactory elimination of methotrexate on day 12 after infusion and recovery from renal impairment without other severe toxicity. No other cause of delay in methotrexate elimination could be identified. CONCLUSIONS Cola beverages have a low pH due to their phosphoric acid content that is excreted by renal route. We recommend patients receiving high dose methotrexate abstain from any cola drink within 24 h before and during methotrexate administration and until complete elimination of the drug. PMID:21545633

Effects of perinatal exposure to low doses of tributyltin chloride on pregnancy outcome and postnatal development in mouse offspring.

PubMed

Si, Jiliang; Li, Jie; Zhang, Fengmei; Li, Guozhen; Xin, Quanbin; Dai, Bingqin

2012-10-01

Tributyltin (TBT), an endocrine-disrupting chemical, is well known to induce imposex in female gastropods. In this study, we assessed the effects of low doses of tributyltin chloride (TBTCl) on dams and their offspring. Pregnant mice were administered by gavage with 0, 1, 10, or 100 μg TBTCl/kg body weight/day from day 6 of pregnancy through the period of lactation. There were no TBT treatment-related deaths or clinical signs of toxicity for dams, and no treatment-related effects on body weight, litter sizes, gestational length of dams, and sex ratio, lactational body weight, postnatal survival, age at eruption of incisors, and eye opening of pups. However, at 100 μg/kg, TBTCl retarded the testes descent of male offspring. Behavioral tests showed a significant delay in cliff-drop aversion response in offspring of 10 and 100 μg/kg groups, but no significant difference in the righting reflex between control and TBT-exposed offspring was detectable. These results indicate that neurobehavioral toxicity seems to be one sensitive indicator to assess the risk of low doses of TBT. Copyright © 2011 Wiley Periodicals, Inc.

Developmental Toxicity of the Organic Fraction from Hydraulic Fracturing Flowback and Produced Waters to Early Life Stages of Zebrafish ( Danio rerio).

PubMed

He, Yuhe; Sun, Chenxing; Zhang, Yifeng; Folkerts, Erik J; Martin, Jonathan W; Goss, Greg G

2018-03-20

Hydraulic fracturing (HF) has emerged as a major recovery method of unconventional oil and gas reservoirs and concerns have been raised regarding the environmental impact of releases of Flowback and Produced Water (FPW) to aquatic ecosystems. To investigate potential effects of HF-FPW on fish embryo development, HF-FPW samples were collected from two different wells and the organic fractions were isolated from both aqueous and particle phases to eliminate the confounding effects of high salinity. Each organic extract was characterized by non-target analysis with HPLC-Orbitrap-MS, with targeted analysis for polycyclic aromatic hydrocarbons provided as markers of petroleum-affected water. The organic profiles differed between samples, including PAHs and alkyl PAHs, and major substances identified by non-target analysis included polyethylene glycols, alkyl ethoxylates, octylphenol ethoxylates, and other high molecular weight (C 49-79 ) ethylene oxide polymeric material. Zebrafish embryos were exposed to various concentrations of FPW organic extracts to investigate acute (7-day) and developmental toxicity in early life stages. The acute toxicity (LD 50 ) of the extracted FPW fractions ranged from 2.8× to 26× the original organic content. Each extracted FPW fraction significantly increased spinal malformation, pericardial edema, and delayed hatch in exposed embryos and altered the expression of a suite of target genes related to biotransformation, oxidative stress, and endocrine-mediation in developing zebrafish embryos. These results provide novel information on the variation of organic profiles and developmental toxicity among different sources and fractions of HF-FPWs.

Modulation of prion polymerization and toxicity by rationally designed peptidomimetics.

PubMed

Srivastava, Ankit; Sharma, Sakshi; Sadanandan, Sandhya; Gupta, Sakshi; Singh, Jasdeep; Gupta, Sarika; Haridas, V; Kundu, Bishwajit

2017-01-01

Misfolding and aggregation of cellular prion protein is associated with a large array of neurological disorders commonly called the transmissible spongiform encephalopathies. Designing inhibitors against prions has remained a daunting task owing to limited information about mechanism(s) of their pathogenic self-assembly. Here, we explore the anti-prion properties of a combinatorial library of bispidine-based peptidomimetics (BPMs) that conjugate amino acids with hydrophobic and aromatic side chains. Keeping the bispidine unit unaltered, a series of structurally diverse BPMs were synthesized and tested for their prion-modulating properties. Administration of Leu- and Trp-BPMs delayed and completely inhibited the amyloidogenic conversion of human prion protein (HuPrP), respectively. We found that each BPM induced the HuPrP to form unique oligomeric nanostructures differing in their biophysical properties, cellular toxicities and response to conformation-specific antibodies. While Leu-BPMs were found to stabilize the oligomers, Trp-BPMs effected transient oligomerization, resulting in the formation of non-toxic, non-fibrillar aggregates. Yet another aromatic residue, Phe, however, accelerated the aggregation process in HuPrP. Molecular insights obtained through MD (molecular dynamics) simulations suggested that each BPM differently engages a conserved Tyr 169 residue at the α2-β2 loop of HuPrP and affects the stability of α2 and α3 helices. Our results demonstrate that this new class of molecules having chemical scaffolds conjugating hydrophobic/aromatic residues could effectively modulate prion aggregation and toxicity. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

Aluminium exposure disrupts elemental homeostasis in Caenorhabditis elegans†

PubMed Central

Page, Kathryn E.; White, Keith N.; McCrohan, Catherine R.

2013-01-01

Aluminium (Al) is highly abundant in the environment and can elicit a variety of toxic responses in biological systems. Here we characterize the effects of Al on Caenorhabditis elegans by identifying phenotypic abnormalities and disruption in whole-body metal homeostasis (metallostasis) following Al exposure in food. Widespread changes to the elemental content of adult nematodes were observed when chronically exposed to Al from the first larval stage (L1). Specifically, we saw increased barium, chromium, copper and iron content, and a reduction in calcium levels. Lifespan was decreased in worms exposed to low levels of Al, but unexpectedly increased when the Al concentration reached higher levels (4.8 mM). This bi-phasic phenotype was only observed when Al exposure occurred during development, as lifespan was unaffected by Al exposure during adulthood. Lower levels of Al slowed C. elegans developmental progression, and reduced hermaphrodite self-fertility and adult body size. Significant developmental delay was observed even when Al exposure was restricted to embryogenesis. Similar changes in Al have been noted in association with Al toxicity in humans and other mammals, suggesting that C. elegans may be of use as a model for understanding the mechanisms of Al toxicity in mammalian systems. PMID:22534883

Dacarbazine as single-agent therapy for relapsed lymphoma in dogs.

PubMed

Griessmayr, P C; Payne, S E; Winter, J E; Barber, L G; Shofer, F S

2009-01-01

Multidrug resistance is the most common cause of treatment failure in dogs with multicentric lymphoma. 5-(3,3-Dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC) is an atypical alkylator used as standard treatment in human Hodgkin's lymphoma, and has been effective in combination treatment to treat resistant lymphoma in dogs. However, no data are available on the use of DTIC as a single agent in the treatment of relapsed canine lymphoma. Single-agent DTIC is effective and safe in treating dogs with lymphoma that relapsed or failed to respond to previous chemotherapy. Forty client-owned dogs with relapsed lymphoma. Dogs were eligible for the retrospective study if they had a histologically or cytologically confirmed diagnosis of lymphoma and had relapsed. Dogs received DTIC (800-1,000 mg/m(2) every 2-3 weeks as a 4-5-hour IV infusion) and were evaluated for response rate and duration. Hematologic and gastrointestinal toxicity was assessed. The overall response rate for dogs being treated with DTIC was 35% (14 dogs) with a median progression-free interval of 43 days. Thirteen dogs had a partial response and 1 dog had a complete response. Stable disease was achieved in 3 dogs. Mild gastrointestinal toxicity was reported in 3 dogs posttreatment. Thrombocytopenia was the principal toxicity observed 7-14 days after the treatment. Treatments were delayed because of thrombocytopenia. DTIC, when used alone, is effective in the treatment of dogs with relapsed lymphoma.

Delayed Complications and Long-term Management of Sulfur Mustard Poisoning: Recent Advances by Iranian Researchers (Part I of II)

PubMed Central

Darchini-Maragheh, Emadodin; Balali-Mood, Mahdi

2018-01-01

Chemical warfare agents are the most brutal weapons among the weapons of mass destruction. Sulfur mustard (SM) is a potent toxic alkylating agent known as “the King of the Battle Gases”. SM has been the most widely used chemical weapon during the wars. It was widely used in World War I. Thereafter, it was extensively employed by the Iraqi troops against the Iranian military personnel and even civilians in the border cities of Iran and Iraq in the period between 1983 and 1988. Long-term incapacitating properties, significant environmental persistence, lack of an effective antidote, and relative ease of manufacturing have kept SM a potential agent for both terrorist and military uses. Even 3 decades after SM exposure, numerous delayed complications among Iranian victims are still being reported by researchers. The most common delayed complications have been observed in the respiratory tracts of chemically injured Iranian war veterans. Also, skin lesions and eye disorders have been observed in most Iranian SM-exposed war veterans in the delayed phase of SM intoxication. Thus, extensive research has been conducted on Iranian war veterans during the past decades. Nevertheless, major gaps still continue to exist in the SM literature. Part I of this paper will discuss the delayed complications and manifestations of exposure to SM among Iranian victims of the Iran–Iraq conflict. Part II, which will appear in the next issue of Iran J Med Sci, will discuss the long-term management and therapy of SM-exposed patients. PMID:29749980

Can the observed association between serum perfluoroalkyl substances and delayed menarche be explained on the basis of puberty-related changes in physiology and pharmacokinetics?

PubMed

Wu, Huali; Yoon, Miyoung; Verner, Marc-André; Xue, Jianping; Luo, Man; Andersen, Melvin E; Longnecker, Matthew P; Clewell, Harvey J

2015-09-01

An association between serum levels of two perfluoroalkyl substances (PFAS) and delayed age at menarche was reported in a cross-sectional study of adolescents. Because perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) have half-lives of years, growth dilution and the development of a new route of excretion (menstruation) could account for some or all of the reported association. To assess how much of the epidemiologic association between PFAS and delayed menarche can be explained by the correlation of growth and maturation with PFAS body burden. We developed a Monte Carlo (MC) physiologically-based pharmacokinetic (PBPK) model of PFAS to simulate plasma PFAS levels in a hypothetical female population aged 2 to 20years old. Realistic distributions of physiological parameters as well as timing of growth spurts and menarche were incorporated in the model. The association between PFAS level and delayed menarche in the simulated data was compared with the reported association. The prevalence of menarche, distributions of age-dependent physiological parameters, and quartiles of serum PFAS concentrations in the simulated subjects were comparable to those reported in the epidemiologic study. The delay of menarche in days per natural log increase in PFAS concentrations in the simulated data were about one third as large as the observed values. The reported relationship between PFAS and age at menarche appears to be at least partly explained by pharmacokinetics rather than a toxic effect of these substances. Copyright © 2015 Elsevier Ltd. All rights reserved.

Subchronic toxicity, immunoregulation and anti-breast tumor effect of Nordamnacantal, an anthraquinone extracted from the stems of Morinda citrifolia L.

PubMed

Abu, Nadiah; Zamberi, Nur Rizi; Yeap, Swee Keong; Nordin, Noraini; Mohamad, Nurul Elyani; Romli, Muhammad Firdaus; Rasol, Nurulfazlina Edayah; Subramani, Tamilselvan; Ismail, Nor Hadiani; Alitheen, Noorjahan Banu

2018-01-27

Morinda citrifolia L. that was reported with immunomodulating and cytotoxic effects has been traditionally used to treat multiple illnesses including cancer. An anthraquinone derived from fruits of Morinda citrifolia L., nordamnacanthal, is a promising agent possessing several in vitro biological activities. However, the in vivo anti-tumor effects and the safety profile of nordamnacanthal are yet to be evaluated. In vitro cytotoxicity of nordamnacanthal was tested using MTT, cell cycle and Annexin V/PI assays on human MCF-7 and MDA-MB231 breast cancer cells. Mice were orally fed with nordamnacanthal daily for 28 days for oral subchronic toxicity study. Then, the in vivo anti-tumor effect was evaluated on 4T1 murine cancer cells-challenged mice. Changes of tumor size and immune parameters were evaluated on the untreated and nordamnacanthal treated mice. Nordamnacanthal was found to possess cytotoxic effects on MDA-MB231, MCF-7 and 4T1 cells in vitro. Moreover, based on the cell cycle and Annexin V results, nordamnacanthal managed to induce cell death in both MDA-MB231 and MCF-7 cells. Additionally, no mortality, signs of toxicity and changes of serum liver profile were observed in nordamnacanthal treated mice in the subchronic toxicity study. Furthermore, 50 mg/kg body weight of nordamncanthal successfully delayed the progression of 4T1 tumors in Balb/C mice after 28 days of treatment. Treatment with nordamnacanthal was also able to increase tumor immunity as evidenced by the immunophenotyping of the spleen and YAC-1 cytotoxicity assays. Nordamnacanthal managed to inhibit the growth and induce cell death in MDA-MB231 and MCF-7 cell lines in vitro and cease the tumor progression of 4T1 cells in vivo. Overall, nordamnacanthal holds interesting anti-cancer properties that can be further explored.

Synergistic stress exacerbation in hippocampal neurons: Evidence favoring the dual hit hypothesis of neurodegeneration

PubMed Central

Heinemann, Scott D.; Posimo, Jessica M.; Mason, Daniel M.; Hutchison, Daniel F.; Leak, Rehana K.

2016-01-01

The dual hit hypothesis of neurodegeneration states that severe stress sensitizes vulnerable cells to subsequent challenges so that the two hits are synergistic in their toxic effects. Although the hippocampus is vulnerable to a number of neurodegenerative disorders, there are no models of synergistic cell death in hippocampal neurons in response to combined proteotoxic and oxidative stressors, the two major characteristics of these diseases. Therefore, we developed a relatively high-throughput dual hit model of stress synergy in primary hippocampal neurons. In order to increase the rigor of our study and strengthen our interpretations, we employed three independent, unbiased viability assays at multiple timepoints. Stress synergy was elicited when hippocampal neurons were treated with the proteasome inhibitor MG132 followed by exposure to the oxidative toxicant paraquat, but only after 48h. MG132 and paraquat only elicited additive effects 24h after the final hit and even loss of heat shock protein 70 activity and glutathione did not promote stress synergy at this early timepoint. Dual hits of MG132 elicited modest glutathione loss and slightly synergistic toxic effects 48h after the second hit, but only at some concentrations and only according to two viability assays (metabolic fitness and cytoskeletal integrity). The thiol N-acetyl cysteine protected hippocampal neurons against dual MG132/MG132 hits but not dual MG132/paraquat hits. Our findings support the view that proteotoxic and oxidative stress propel and propagate each other in hippocampal neurons, leading to synergistically toxic effects, but not as the default response and only after a delay. The neuronal stress synergy observed here lies in contrast to astrocytic responses to dual hits, because astrocytes that survive severe proteotoxic stress resist additional cell loss following second hits. In conclusion, we present a new model of hippocampal vulnerability in which to test therapies, because neuroprotective treatments that are effective against severe, synergistic stress are more likely to succeed in the clinic. PMID:26934478

Effects of Thiamethoxam-Treated Seed on Mexican Bean Beetle (Coleoptera: Coccinellidae), Nontarget Arthropods, and Crop Performance in Southwestern Virginia Snap Beans.

PubMed

Nottingham, L; Kuhar, T P; Kring, T; Herbert, D A; Arancibia, R; Schultz, P

2017-12-08

Thiamethoxam is a neonicotinoid insecticide commonly applied directly to the seeds (seed-treatment) of commercial snap beans, Phaseolus vulgaris L. While previous studies have examined target and nontarget effects of thiamethoxam seed-treatments in snap beans and other crops, to our knowledge, none have been conducted in agroecosystems predominated by the pest Mexican bean beetle, Epilachna varivestis Mulsant (Coleoptera: Coccinellidae). This study examined the effects of thiamethoxam-treated snap beans on E. varivestis, other arthropods, and crop performance in southwestern Virginia. Greenhouse experiments were conducted to evaluate residual toxicity of treated snap beans to E. varivestis and a key predator, Podisus maculiventris (Say) (Hemiptera: Pentatomidae). Treated plants were highly toxic to E. varivestis at 13 d, moderately toxic from 16 to 20 d, and minimally toxic at 24 d. P. maculiventris was unaffected by exposure to treated plants or by feeding on E. varivestis that consumed treated plants. Small plot field experiments in 2014 and 2015 showed no significant effects of thiamethoxam seed-treatments on E. varivestis densities, other arthropods, crop injury, or yield. In 2016, planting was delayed by persistent rain, resulting in early E. varivestis colonization. In this year, thiamethoxam-treated plants had significantly lower densities and feeding injury from E. varivestis, followed by significantly higher yields. Natural enemies were unaffected by seed-treatments in all field experiments. These experiments demonstrated that thiamethoxam seed-treatments provide control of E. varivestis when beetles infest fields within 2 to 3 wk after planting; but otherwise provide negligible advantages. Negative effects from thiamethoxam seed-treatments on nontarget arthropods appear minimal for snap beans in this region. © The Authors 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.

Role of cytokines (TNF-alpha, IL-1beta and KC) in the pathogenesis of CPT-11-induced intestinal mucositis in mice: effect of pentoxifylline and thalidomide.

PubMed

Melo, Maria Luisa P; Brito, Gerly A C; Soares, Rudy C; Carvalho, Sarah B L M; Silva, Johan V; Soares, Pedro M G; Vale, Mariana L; Souza, Marcellus H L P; Cunha, Fernando Q; Ribeiro, Ronaldo A

2008-04-01

Irinotecan (CPT-11) is an inhibitor of DNA topoisomerase I and is clinically effective against several cancers. A major toxic effect of CPT-11 is delayed diarrhea; however, the exact mechanism by which the drug induces diarrhea has not been established. Elucidate the mechanisms of induction of delayed diarrhea and determine the effects of the cytokine production inhibitor pentoxifylline (PTX) and thalidomide (TLD) in the experimental model of intestinal mucositis, induced by CPT-11. Intestinal mucositis was induced in male Swiss mice by intraperitoneal administration of CPT-11 (75 mg/kg) daily for 4 days. Animals received subcutaneous PTX (1.7, 5 and 15 mg/kg) or TLD (15, 30, 60 mg/kg) or 0.5 ml of saline daily for 5 and 7 days, starting 1 day before the first CPT-11 injection. The incidence of delayed diarrhea was monitored by scores and the animals were sacrificed on the 5th and 7th experimental day for histological analysis, immunohistochemistry for TNF-alpha and assay of myeloperoxidase (MPO) activity, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and KC ELISA. CPT-11 caused significant diarrhea, histopathological alterations (inflammatory cell infiltration, loss of crypt architecture and villus shortening) and increased intestinal tissue MPO activity, TNF-alpha, IL-1beta and KC level and TNF-alpha immuno-staining. PTX inhibited delayed diarrhea of mice submitted to intestinal mucositis and reduced histopathological damage, intestinal MPO activity, tissue level of TNF-alpha, IL-1beta and KC and TNF-alpha immuno-staining. TLD significantly reduced the lesions induced by CPT-11 in intestinal mucosa, decreased MPO activity, TNF-alpha tissue level and TNF-alpha immuno-staining, but did not reduce the severity of diarrhea. These results suggest an important role of TNF-alpha, IL-1beta and KC in the pathogenesis of intestinal mucositis induced by CPT-11.

Detection of toxic industrial chemicals in water supplies using surface-enhanced Raman spectroscopy

NASA Astrophysics Data System (ADS)

Spencer, Kevin M.; Sylvia, James M.; Spencer, Sarah A.; Clauson, Susan L.

2010-04-01

An effective method to create fear in the populace is to endanger the water supply. Homeland Security places significant importance on ensuring drinking water integrity. Beyond terrorism, accidental supply contamination from a spill or chemical residual increases is a concern. A prominent class of toxic industrial chemicals (TICs) is pesticides, which are prevalent in agricultural use and can be very toxic in minute concentrations. Detection of TICs or warfare agents must be aggressive; the contaminant needs to be rapidly detected and identified to enable isolation and remediation of the contaminated water while continuing a clean water supply for the population. Awaiting laboratory analysis is unacceptable as delay in identification and remediation increases the likelihood of infection. Therefore, a portable or online water quality sensor is required that can produce rapid results. In this presentation, Surface-Enhanced Raman Spectroscopy (SERS) is discussed as a viable fieldable sensor that can be immersed directly into the water supply and can provide results in <5 minutes from the time the instrument is turned on until analysis is complete. The ability of SERS to detect several chemical warfare agent degradation products, simulants and toxic industrial chemicals in distilled water, tap water and untreated water will be shown. In addition, results for chemical warfare agent degradation products and simulants will be presented. Receiver operator characteristic (ROC) curves will also be presented.

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.

Suppressive effects of fisetin on mice T lymphocytes in vitro and in vivo.

PubMed

Song, Bocui; Guan, Shuang; Lu, Jing; Chen, Zhibao; Huang, Guoren; Li, Gen; Xiong, Ying; Zhang, Shuang; Yue, Zhanpeng; Deng, Xuming

2013-11-01

Most of the immunosuppressive drugs have satisfactory therapeutic effects on organ transplantation and autoimmune disease. However, their clinical application is limited by side effects. Therefore, new and safe immunosuppressive drugs against acute and chronic rejections are eagerly awaited. Fisetin, a flavonoid present in various types of vegetables and fruits, has few side effects and low level of toxicity, which would be a desirable clinical feature. In the present study, we investigated the immunosuppressive effects and underlying mechanisms of fisetin against T-cell activation in vitro and in vivo. We measured the effect of fisetin on T-lymphocyte proliferation, T-cell subsets, cell cycle progression, cytokine production, and nuclear factor activation in vitro, as well as its influence on T cell-mediated delayed-type hypersensitivity reaction in vivo. In vitro, the results showed that fisetin significantly suppressed mouse splenocytes proliferation, Th1 and Th2 cytokine production, cell cycle and the ratio of CD4(+)/CD8(+) T cells. Furthermore, fisetin exerts an immunosuppressive effect in mouse T lymphocytes through the suppression of nuclear factor kappa B activation and nuclear factor of activated T cells signaling in a dose-dependent manner. In vivo, fisetin treatment also significantly inhibited the dinitrofluorobenzene-induced delayed-type hypersensitivity reactions in mice. Fisetin had strong immunosuppressive activity in vitro and in vivo, suggesting a potential role for fisetin as an immunosuppressive agent. Copyright © 2013. Published by Elsevier Inc.

Results of the First American Prospective Study of Intravenous Iron in Oral Iron-Intolerant Iron-Deficient Gravidas.

PubMed

Auerbach, Michael; James, Stephanie E; Nicoletti, Melissa; Lenowitz, Steven; London, Nicola; Bahrain, Huzefa F; Derman, Richard; Smith, Samuel

2017-12-01

Anemia affects up to 42% of gravidas. Neonatal iron deficiency is associated with low birth weight, delayed growth and development, and increased cognitive and behavioral abnormalities. While oral iron is convenient, up to 70% report significant gastrointestinal toxicity. Intravenous iron formulations allowing replacement in one visit with favorable side-effect profiles decrease rates of anemia with improved hemoglobin responses and maternal fetal outcomes. Seventy-four oral iron-intolerant, second- and third-trimester iron-deficient gravidas were questioned for oral iron intolerance and treated with intravenous iron. All received 1000 mg of low-molecular-weight iron dextran in 250 mL normal saline. Fifteen minutes after a test dose, the remainder was infused over the balance of 1 hour. Subjects were called at 1, 2, and 7 days to assess delayed reactions. Four weeks postinfusion or postpartum, hemoglobin levels and iron parameters were measured. Paired t test was used for hemoglobin and iron; 58/73 women were questioned about interval growth and development of their babies. Seventy-three of 74 enrolled subjects completed treatment. Sixty had paired pre- and posttreatment data. The mean pre- and posthemoglobin concentrations were 9.7 and 10.8 g/dL (P < .00001), transferrin saturations 11.7% and 22.6% (P = .0003), and ferritins 14.5 and 126.3 ng/mL, respectively (P < .000001). Six experienced minor infusion reactions. All resolved. Data for 58 infants were available; one was low on its growth charts for 11 months. The remaining 57 were normal. None were diagnosed with iron deficiency anemia. Intravenous iron has less toxicity and is more effective, supporting moving it closer to frontline therapy. Copyright © 2017 Elsevier Inc. All rights reserved.

Ultraviolet B radiation induces impaired lifecycle traits and modulates expression of cytochrome P450 (CYP) genes in the copepod Tigriopus japonicus.

PubMed

Puthumana, Jayesh; Lee, Min-Chul; Park, Jun Chul; Kim, Hui-Su; Hwang, Dae-Sik; Han, Jeonghoon; Lee, Jae-Seong

2017-03-01

To evaluate the effects of ultraviolet B (UV-B) radiation at the developmental, reproductive, and molecular levels in aquatic invertebrates, we measured UV-B-induced acute toxicity, impairments in developmental and reproductive traits, and UV-B interaction with the entire family of cytochrome P450 (CYP) genes in the intertidal benthic copepod Tigriopus japonicus. We found a significant, dose-dependent reduction (P<0.05) in the survival of T. japonicus that began as a developmental delay and decreased fecundity. The 48h LD10 and LD50 were 1.35 and 1.84kJ/m 2 , and the CYP inhibitor (PBO) elevated mortality, confirming the involvement of CYP genes in UV-B induced toxicity. Low-dose UV-B (1.5kJ/m 2 ) induced developmental delays, and higher doses (6-18kJ/m 2 ) caused reproductive impairments in ovigerous females. The significant up-regulation of CYP genes belonging to clans 2/3/MT/4/20 in T. japonicus exposed to UV-B (12kJ/m 2 ) confirmed molecular interaction between UV-B and CYP genes. Moreover, orphan CYPs, such as CYP20A1, provide good insight on the deorphanization of invertebrate CYPs. Overall, these results demonstrate the involvement of UV-B radiation in the expression of all the CYP genes in T. japonicus and their susceptibility to UV-B radiation. This will provide a better understanding of the mechanistic effects of UV-B in copepods through the predicted AhR-mediated up-regulation of CYP genes. Copyright © 2017 Elsevier B.V. All rights reserved.

Immobilization of Russian VX skin depots by localized cooling: implications for decontamination and medical countermeasures.

PubMed

Mikler, J; Tenn, C; Worek, F; Reiter, G; Thiermann, H; Garrett, M; Bohnert, S; Sawyer, T W

2011-09-25

The chemical weapon nerve agent known as Russian VX (VR) is a potent organophosphorus (OP) compound that is much less studied than its VX analogue with respect to toxicity, as well as to the effectiveness of several known countermeasures against it. An anaesthetized domestic swine model was utilized to assess several approaches in mitigating its toxicity, including the utility of cooling VR treated skin to increase the therapeutic window for treatment. The 6h LD₅₀ for VR topically applied on the ear was 100 μg/kg. Treatment of VR exposed animals (5 × LD₅₀) with pralidoxime (2PAM) very poorly regenerated inhibited blood cholinesterase activity, but was partially effective in preventing signs of OP poisoning and increasing survival. In contrast, treatment with the Hagedorn oxime HI-6 reactivated cholinesterase, eliminated all signs of poisoning and prevented death. Decontamination with the Reactive Skin Decontaminant Lotion (RSDL) 15 min after VR exposure was completely effective in preventing death. Cooling of the VR exposure sites for 2 or 6h prevented signs of OP poisoning and death during the cooling period. However, these animals died very quickly after the cessation of cooling, unless they were treated with oxime or decontaminated with RSDL. Blood analyses showed that cooling of agent exposure sites delayed the entry of VR into the bloodstream. Medical treatment with HI-6 and to a lesser extent 2PAM, or decontamination with RSDL are effective in protecting against the toxic effects of cutaneous exposure to VR. Immobilizing this agent (and related compounds) within the dermal reservoir by cooling the exposure sites, dramatically increases the therapeutic window in which these medical countermeasures are effective. Crown Copyright © 2011. Published by Elsevier Ireland Ltd. All rights reserved.

Hypothermia as an Adjunct Therapy to Vesicant-induced Skin Injury

PubMed Central

Sawyer, Thomas W; Nelson, Peggy

2008-01-01

Objective: The notion that cooling vesicant-exposed tissue may ameliorate or prevent resultant injury is not a novel concept. During both World Wars, studies were conducted that investigated this potential mode of therapy with sulfur mustard and seemed to conclude that there might be merit in pursuing this research direction. However, it does not appear that these studies were followed up vigorously, and the literature that describes this work is not readily accessible. In this report, we compare the toxicities of lewisite and sulfur mustard in vitro and in vivo and also provide an overview of historical and recent work on the effect of temperature on the toxicity of these vesicating chemical warfare agents.Methods: Tissue culture and animal studies were utilized to examine the effects of hypothermia on vesicant-induced toxicity. Results: Cytotoxicity was either significantly delayed (lewisite) or prevented (sulfur mustard) when cultures were maintained at 25°C. However, the effects of hypothermia on sulfur mustard–induced cell death were reversible when the cells were returned to 37°C. Despite these in vitro results, animal studies demonstrated that the therapeutic cooling of both mustard sulfur–exposed and lewisite-exposed skin resulted in dramatic and permanent protection against injury. Cooling also increased the therapeutic window in which drugs were effective against vesicant agents in tissue culture and lewisite-induced skin injury. Conclusions: The simple and noninvasive application of cooling measures may not only provide significant therapeutic relief to vesicant-exposed skin but also increase the therapeutic window in which medical countermeasures against vesicant agents are useful. PMID:18516227

Loss of Atg16 delays the alcohol-induced sedation response via regulation of Corazonin neuropeptide production in Drosophila.

PubMed

Varga, Kata; Nagy, Péter; Arsikin Csordás, Katarina; Kovács, Attila L; Hegedűs, Krisztina; Juhász, Gábor

2016-10-06

Autophagy defects lead to the buildup of damaged proteins and organelles, reduced survival during starvation and infections, hypersensitivity to stress and toxic substances, and progressive neurodegeneration. Here we show that, surprisingly, Drosophila mutants lacking the core autophagy gene Atg16 are not only defective in autophagy but also exhibit increased resistance to the sedative effects of ethanol, unlike Atg7 or Atg3 null mutant flies. This mutant phenotype is rescued by the re-expression of Atg16 in Corazonin (Crz)-producing neurosecretory cells that are known to promote the sedation response during ethanol exposure, and RNAi knockdown of Atg16 specifically in these cells also delays the onset of ethanol-induced coma. We find that Atg16 and Crz colocalize within these neurosecretory cells, and both Crz protein and mRNA levels are decreased in Atg16 mutant flies. Thus, Atg16 promotes Crz production to ensure a proper organismal sedation response to ethanol.

Evaluation of the Effectiveness of Sugammadex for Digoxin Intoxication: An Experimental Study.

PubMed

Ozbilgin, Sule; Yurtlu, Derya Aslan; Küçükoztaş, Beyza; Kamacı, Gonca; Korkut, Sezen; Yurtlu, Bülent Serhan; Ensari Güneli, M; Hancı, Volkan; Günerli, Ali

2018-03-16

Previous studies have shown that cyclodextrin group medicines bind to various drugs. The hypothesis of our study is to determine whether sugammadex could bind to digoxin and delay the cardiovascular toxicity of that drug. Twenty-eight sedated Wistar rats were infused with digoxin at 3 mg/h (0.25 mg/ml). Five minutes after the start of infusion, animals were treated with a bolus of either 16 mg/kg (Sgdx16), 100 mg/kg (Sgdx100), or 1000 mg/kg (Sgdx1000) sugammadex. The control group infusion did not contain sugammadex. Heart rate, electrocardiography, and respiratory rate were monitored. The primary endpoint was time to asystole. Digoxin infusion continued until the animals arrested. The time to asystole for the Sgdx1000 group was significantly longer compared to that for the control group (p < 0.05). The mean lethal dose of digoxin was 5.35 ± 2.06 mg/kg in the saline-treated rats. On the other hand, the mean lethal dose of digoxin was 8.54 ± 1.51 mg/kg in the sugammadex 1000 group (p < 0.05). The mean lethal dose of digoxin was significantly higher than control group (p < 0.05). We found that the 1000 mg/kg dose of sugammadex delayed digoxin cardiotoxicity in a rat model of digoxin toxicity. We conclude that further research must be conducted on the interaction between digoxin and sugammadex.

Preclinical systemic toxicity evaluation of chitosan-solid lipid nanoparticle-encapsulated aspirin and curcumin in combination with free sulforaphane in BALB/c mice

PubMed Central

Thakkar, Arvind; Chenreddy, Sushma; Thio, Astrid; Khamas, Wael; Wang, Jeffrey; Prabhu, Sunil

2016-01-01

Our previous studies have established the efficacy of chemopreventive regimens of aspirin and curcumin (CUR) encapsulated within solid lipid nanoparticles (SLNs) in combination with free sulforaphane (ACS combination) to prevent or delay the initiation and progression of pancreatic cancer, classified as one of the deadliest diseases with very low chances of survival upon diagnosis. Although toxicity of individual drugs and SLN has been studied previously, there are no studies in current literature that evaluate the potential toxicity of a combined regimen of ACS, especially when encapsulated within chitosan-SLNs (c-SLNs). Hence, objective of the current study was to investigate the potential toxic effects of ACS c-SLN combined chemopreventive regimens following acute (3 days), subacute (28 days), and subchronic (90 days) administrations by oral gavage in BALB/c mice. Mice were administered the following regimens: saline, blank c-SLN, low-dose ACS c-SLN (2+4.5+0.16 mg/kg), medium-dose ACS c-SLN (20+45+1.6 mg/kg), and high-dose ACS c-SLN (60+135+4.8 mg/kg). The potential toxicity was evaluated based on animal survival, body weight, hematology, blood chemistry, and organ histopathology. During 3-day, 28-day, and 90-day study periods, no animal deaths were observed. Treatment with ACS c-SLNs did not cause alteration in complete blood counts and blood chemistry data. Histopathological examination of various organ sections (pancreas, heart, liver, kidney, and brain) appeared normal. Based on the results of this study, no signs of toxicity in acute, subacute, and subchronic studies following oral administration of ACS c-SLNs were found indicating that the oral dosing regimens were safe at the levels tested for long-term administration to prevent the onset of pancreatic cancer. PMID:27499621

Pharmacogenetics of toxicity of 5-fluorouracil, doxorubicin and cyclophosphamide chemotherapy in breast cancer patients

PubMed Central

Tecza, Karolina; Pamula-Pilat, Jolanta; Lanuszewska, Joanna; Butkiewicz, Dorota; Grzybowska, Ewa

2018-01-01

The differences in patients’ response to the same medication, toxicity included, are one of the major problems in breast cancer treatment. Chemotherapy toxicity makes a significant clinical problem due to decreased quality of life, prolongation of treatment and reinforcement of negative emotions associated with therapy. In this study we evaluated the genetic and clinical risk factors of FAC chemotherapy-related toxicities in the group of 324 breast cancer patients. Selected genes and their polymorphisms were involved in FAC drugs transport (ABCB1, ABCC2, ABCG2,SLC22A16), metabolism (ALDH3A1, CBR1, CYP1B1, CYP2C19, DPYD, GSTM1, GSTP1, GSTT1, MTHFR,TYMS), DNA damage recognition, repair and cell cycle control (ATM, ERCC1, ERCC2, TP53, XRCC1). The multifactorial risk models that combine genetic risk modifiers and clinical characteristics were constructed for 12 toxic symptoms. The majority of toxicities was dependent on the modifications in components of more than one pathway of FAC drugs, while the impact level of clinical factors was comparable to the genetic ones. For the carriers of multiple high risk factors the chance of developing given symptom was significantly elevated which proved the factor-dosage effect. We found the strongest associations between concurrent presence of clinical factors - overall and recurrent anemia, nephrotoxicity and early nausea and genetic polymorphisms in genes responsible for DNA repair, drugs metabolism and transport pathways. These results indicate the possibility of selection of the patients with expected high tolerance to FAC treatment and consequently with high chance of chemotherapy completion without the dose reduction, treatment delays and decline in the quality of life. PMID:29507678

Refractory Cardiogenic Shock During Tramadol Poisoning: A Case Report.

PubMed

Belin, Nicolas; Clairet, Anne-Laure; Chocron, Sidney; Capellier, Gilles; Piton, Gaël

2017-04-01

Tramadol is a weak opioid analgesic indicated for the treatment of moderate to severe pain. Tramadol intoxication can be lethal, and this drug is frequently involved in voluntary overdose. Classically, tramadol intoxication is associated with neurological and respiratory side effects. In contrast, cardiac effects are poorly documented in the literature. We report a case of severe tramadol intoxication, with plasma concentration 20 times the toxic threshold, complicated by refractory cardiogenic shock, successfully treated by extra corporeal life support (ECLS) with a favorable cardiac outcome and ECLS weaning at day 10. Seizure, clonus, and nonreactive mydriasis were present during 4 days, and complete awakening was delayed to day 15. Poisoning caused by high doses of tramadol can lead to refractory cardiogenic shock, and ECLS can be considered as effective rescue therapy in this context.

Inhalant-Abuse Myocarditis Diagnosed by Cardiac Magnetic Resonance

PubMed Central

Rao, Krishnasree; Matulevicius, Susan

2016-01-01

Multiple reports of toxic myocarditis from inhalant abuse have been reported. We now report the case of a 23-year-old man found to have toxic myocarditis from inhalation of a hydrocarbon. The diagnosis was made by means of cardiac magnetic resonance imaging with delayed enhancement. The use of cardiac magnetic resonance to diagnose myocarditis has become increasingly common in clinical medicine, although there is not a universally accepted criterion for diagnosis. We appear to be the first to document a case of toxic myocarditis diagnosed by cardiac magnetic resonance. In patients with a history of drug abuse who present with clinical findings that suggest myocarditis or pericarditis, cardiac magnetic resonance can be considered to support the diagnosis. PMID:27303242

Impacts of the phenylpyrazole insecticide fipronil on larval fish: time-series gene transcription responses in fathead minnow (Pimephales promelas) following short-term exposure.

PubMed

Beggel, Sebastian; Werner, Inge; Connon, Richard E; Geist, Juergen P

2012-06-01

The utilization of molecular endpoints in ecotoxicology can provide rapid and valuable information on immediate organismal responses to chemical stressors and is increasingly used for mechanistic interpretation of effects at higher levels of biological organization. This study contributes knowledge on the sublethal effects of a commonly used insecticide, the phenylpyrazole fipronil, on larval fathead minnow (Pimephales promelas), utilizing a quantitative transcriptomic approach. Immediately after 24h of exposure to fipronil concentrations of ≥31 μg.L(-1), highly significant changes in gene transcription were observed for aspartoacylase, metallothionein, glucocorticoid receptor, cytochrome P450 3A126 and vitellogenin. Different mechanisms of toxicity were apparent over the course of the experiment, with short-term responses indicating neurotoxic effects. After 6 days of recovery, endocrine effects were observed with vitellogenin being up-regulated 90-fold at 61 μg.L(-1) fipronil. Principal component analysis demonstrated a significant increase in gene transcription changes over time and during the recovery period. In conclusion, multiple mechanisms of action were observed in response to fipronil exposure, and unknown delayed effects would have been missed if transcriptomic responses had only been measured at a single time-point. These challenges can be overcome by the inclusion of multiple endpoints and delayed effects in experimental designs. Copyright © 2012 Elsevier B.V. All rights reserved.

A localizing circumferential compression device increases survival after coral snake envenomation to the torso of an animal model.

PubMed

Hack, Jason B; Deguzman, Jocelyn M; Brewer, Kori L; Meggs, William J; O'Rourke, Dorcas

2011-07-01

Pressure immobilization bandages have been shown to delay onset of systemic toxicity after Eastern coral snake (Micrurus fulvius) envenomation to the distal extremity. To assess the efficacy of a novel compression device in delaying onset of systemic toxicity after truncal envenomations with Eastern coral snake (Micrurus fulvius) venom in a porcine model. With University approval, nine juvenile pigs (11 kg to 22 kg) were sedated, anesthetized, and intubated but not paralyzed to ensure continuous spontaneous respirations in a university animal laboratory. Each animal was injected subcutaneously with 10 mg of M. fulvius venom in a pre-selected area of the trunk. After 1 min, six animals had the application of a novel, localizing circumferential compression (LoCC) device applied to the bite site (treatment group) and three animals had no treatment (control group). The device was composed of a rigid polymer clay form molded into a hollow fusiform shape with an internal dimension of 8 × 5 × 3 cm and an elastic belt wrapped around the animal securing the device in place. Vital signs were recorded at 30-min intervals. End points included a respiratory rate below 3 breaths/min, oxygen saturation < 80%, or survival to 8 h. Survival to 8 h was analyzed using Fisher's exact test, with p < 0.05 indicating significance. Survival analysis was performed using the Mantel-Cox test to assess time to death with outcomes represented in a Kaplan-Meier Cumulative survival plot. Five of the six pigs in the treatment group survived 8 h (293-480 min). None of the control pigs survived to 8 h (Fisher's exact p = 0.04), with mean time of respiratory failure 322 min (272-382 min). Survival analysis showed a significant delay in time to event in the treatment group compared to the control group (p = 0.04). The LoCC device used in this study delayed the onset of systemic toxicity and significantly increased survival time after artificial truncal envenomation by Eastern coral snake venom. Copyright © 2011 Elsevier Inc. All rights reserved.

The role of oxidative stress in organophosphate and nerve agent toxicity

PubMed Central

Pearson, Jennifer N.; Patel, Manisha

2016-01-01

Organophosphate nerve agents exert their toxicity through inhibition of acetylcholinesterase. The excessive stimulation of cholinergic receptors rapidly causes neuronal damage, seizures, death, and long-term neurological impairment in those that survive. Owing to the lethality of organophosphorus agents and the growing risk they pose, medical interventions that prevent organophosphate toxicity and the delayed injury response are much needed. Studies have shown that oxidative stress occurs in models of subacute, acute, and chronic exposure to organophosphate agents. Key findings of these studies include alterations in mitochondrial function and increased free radical–mediated injury, such as lipid peroxidation. This review focuses on the role of reactive oxygen species in organophosphate neurotoxicity and its dependence on seizure activity. Understanding the sources, mechanisms, and pathological consequences of organophosphate-induced oxidative stress can lead to the development of rational therapies for treating toxic exposures. PMID:27371936

Development of a co-culture of keratinocytes and immune cells for in vitro investigation of cutaneous sulfur mustard toxicity.

PubMed

Balszuweit, Frank; Menacher, Georg; Bloemeke, Brunhilde; Schmidt, Annette; Worek, Franz; Thiermann, Horst; Steinritz, Dirk

2014-11-05

Sulfur mustard (SM) is a chemical warfare agent causing skin blistering, ulceration and delayed wound healing. Inflammation and extrinsic apoptosis are known to have an important role in SM-induced cytotoxicity. As immune cells are involved in those processes, they may significantly modulate SM toxicity, but the extent of those effects is unknown. We adapted a co-culture model of immortalized keratinocytes (HaCaT) and immune cells (THP-1) and exposed this model to SM. Changes in necrosis, apoptosis and inflammation, depending on SM challenge, absence or presence and number of THP-1 cells were investigated. THP-1 were co-cultured for 24h prior to SM exposure in order to model SM effects on immune cells continuously present in the skin. Our results indicate that the presence of THP-1 strongly increased necrosis, apoptosis and inflammation. This effect was already significant when the ratio of THP-1 and HaCaT cells was similar to the ratio of Langerhans immune cells and keratinocytes in vivo. Any further increases in the number of THP-1 had only slight additional effects on SM-induced cytotoxicity. In order to assess the effects of immune cells migrating into skin areas damaged by SM, we added non-exposed THP-1 to SM-exposed HaCaT. Those THP-1 had only slight effects on SM-induced cytotoxicity. Notably, in HaCaT exposed to 300μM SM, necrosis and inflammation were slightly reduced by adding intact THP-1. This effect was dependent on the number of immune cells, steadily increasing with the number of unexposed THP-1 added. In summary, we have demonstrated that (a) the presented co-culture is a robust model to assess SM toxicity and can be used to test the efficacy of potential antidotes in vitro; (b) immune cells, damaged by SM strongly amplified cytotoxicity, (c) in contrast, unexposed THP-1 (simulating migration of immune cells into affected areas after exposure in vivo) had no pronounced adverse, but exhibited some protective effects. Thus, protecting immune cells from SM toxicity may help to reduce overall injury. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Delayed myelosuppression with acute exposure to hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and environmental degradation product hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX) in rats.

PubMed

Jaligama, Sridhar; Kale, Vijay M; Wilbanks, Mitchell S; Perkins, Edward J; Meyer, Sharon A

2013-02-01

Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), a widely used munitions compound, and hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX), its N-nitroso product of anaerobic microbial nitroreduction, are contaminants of military sites. Previous studies have shown MNX to be the most acutely toxic among the nitroreduced degradation products of RDX and to cause mild anemia at high dose. The present study compares hematotoxicity with acute oral exposure to MNX with parent RDX. Both RDX and MNX caused a modest decrease in blood hemoglobin and ~50% loss of granulocytes (NOAELs=47 mg/kg) in female Sprague-Dawley rats observed 14 days post-exposure. We explored the possibility that blood cell loss observed after 14 days was delayed in onset because of toxicity to bone marrow (BM) progenitors. RDX and MNX decreased granulocyte/macrophage-colony forming cells (GM-CFCs) at 14, but not 7, days (NOAELs=24 mg/kg). The earliest observed time at which MNX decreased GM-CFCs was 10 days post-exposure. RDX and MNX likewise decreased BM burst-forming units-erythroid (BFU-Es) at 14, but not 7, days. Granulocyte-erythrocyte-monocyte-megakaryocyte (GEMM)-CFCs were unaffected by RDX and MNX at 7 days suggesting precursor depletion did not account for GM-CFC and BFU-E loss. MNX added to the culture media was without effect on GM-CFC formation indicating no direct inhibition. Flow cytometry showed no differential loss of BM multilineage progenitors (Thy1.1(+)) or erythroid (CD71(+)) precursors with MNX suggesting myeloid and erythroid lineages were comparably affected. Collectively, these data indicate that acute exposure to both RDX and MNX caused delayed suppression of myelo- and erythropoiesis with subsequent decrease of peripheral granulocytes and erythrocytes. Copyright © 2012 Elsevier Inc. All rights reserved.

Organophosphate-induced changes in the PKA regulatory function of Swiss Cheese/NTE lead to behavioral deficits and neurodegeneration.

PubMed

Wentzell, Jill S; Cassar, Marlène; Kretzschmar, Doris

2014-01-01

Organophosphate-induced delayed neuropathy (OPIDN) is a Wallerian-type axonopathy that occurs weeks after exposure to certain organophosphates (OPs). OPs have been shown to bind to Neuropathy Target Esterase (NTE), thereby inhibiting its enzymatic activity. However, only OPs that also induce the so-called aging reaction cause OPIDN. This reaction results in the release and possible transfer of a side group from the bound OP to NTE and it has been suggested that this induces an unknown toxic function of NTE. To further investigate the mechanisms of aging OPs, we used Drosophila, which expresses a functionally conserved orthologue of NTE named Swiss Cheese (SWS). Treating flies with the organophosporous compound tri-ortho-cresyl phosphate (TOCP) resulted in behavioral deficits and neurodegeneration two weeks after exposure, symptoms similar to the delayed effects observed in other models. In addition, we found that primary neurons showed signs of axonal degeneration within an hour after treatment. Surprisingly, increasing the levels of SWS, and thereby its enzymatic activity after exposure, did not ameliorate these phenotypes. In contrast, reducing SWS levels protected from TOCP-induced degeneration and behavioral deficits but did not affect the axonopathy observed in cell culture. Besides its enzymatic activity as a phospholipase, SWS also acts as regulatory PKA subunit, binding and inhibiting the C3 catalytic subunit. Measuring PKA activity in TOCP treated flies revealed a significant decrease that was also confirmed in treated rat hippocampal neurons. Flies expressing additional PKA-C3 were protected from the behavioral and degenerative phenotypes caused by TOCP exposure whereas primary neurons were not. In addition, knocking-down PKA-C3 caused similar behavioral and degenerative phenotypes as TOCP treatment. We therefore propose a model in which OP-modified SWS cannot release PKA-C3 and that the resulting loss of PKA-C3 activity plays a crucial role in developing the delayed symptoms of OPIDN but not in the acute toxicity.

Acute soman poisoning in primates neither pretreated nor receiving immediate therapy: value of gacyclidine (GK-11) in delayed medical support.

PubMed

Lallement, G; Clarençon, D; Galonnier, M; Baubichon, D; Burckhart, M F; Peoc'h, M

1999-03-01

Organophosphorus (OP) nerve agents are still used as warfare and terrorism compounds. Classical delayed treatment of victims of organophosphate poisoning includes combined i.v. administration of a cholinesterase reactivator (an oxime), a muscarinic cholinergic receptor antagonist (atropine) and a benzodiazepine anticonvulsant (diazepam). The objective of this study was to evaluate, in a realistic setting, the therapeutic benefit of administration of GK-11 (gacyclidine), an antiglutamatergic compound, as a complement to the above therapy against organophosphate poisoning. Gacyclidine was injected (i.v.) in combination with atropine/diazepam/pralidoxime at man-equivalent doses after a 45- or 30-min latency period to intoxicated primates (2 LD50). The effects of gacyclidine on the animals' survival, electroencephalographic (EEG) activity, signs of toxicity, recovery after challenge and central nervous system histology were examined. The present data demonstrated that atropine/diazepam/pralidoxime alone or combined with gacyclidine did not prevent signs of soman toxicity when treatment was delayed 45 min after poisoning. Atropine/diazepam/pralidoxime also did not control seizures or prevent neuropathology in primates exhibiting severe signs of poisoning when treatment was commenced 30 min after intoxication. However, in this latter case, EEG recordings revealed that additional treatment with gacyclidine was able to stop soman-induced seizures and restore normal EEG activity. This drug also totally prevented the neuropathology observed 5 weeks after soman exposure in animals treated with atropine/diazepam/pralidoxime alone. Overall, in the case of severe OP-poisoning, gacyclidine represents a promising adjuvant therapy to the currently available polymedication to ensure optimal management of organophosphate poisoning in man. This drug is presently being evaluated in a human clinical trial for a different neuroprotective indication. However, it should always be kept in mind that, in the case of severe OP-poisoning, medical intervention must be conducted as early as possible.

Organophosphate-Induced Changes in the PKA Regulatory Function of Swiss Cheese/NTE Lead to Behavioral Deficits and Neurodegeneration

PubMed Central

Kretzschmar, Doris

2014-01-01

Organophosphate-induced delayed neuropathy (OPIDN) is a Wallerian-type axonopathy that occurs weeks after exposure to certain organophosphates (OPs). OPs have been shown to bind to Neuropathy Target Esterase (NTE), thereby inhibiting its enzymatic activity. However, only OPs that also induce the so-called aging reaction cause OPIDN. This reaction results in the release and possible transfer of a side group from the bound OP to NTE and it has been suggested that this induces an unknown toxic function of NTE. To further investigate the mechanisms of aging OPs, we used Drosophila, which expresses a functionally conserved orthologue of NTE named Swiss Cheese (SWS). Treating flies with the organophosporous compound tri-ortho-cresyl phosphate (TOCP) resulted in behavioral deficits and neurodegeneration two weeks after exposure, symptoms similar to the delayed effects observed in other models. In addition, we found that primary neurons showed signs of axonal degeneration within an hour after treatment. Surprisingly, increasing the levels of SWS, and thereby its enzymatic activity after exposure, did not ameliorate these phenotypes. In contrast, reducing SWS levels protected from TOCP-induced degeneration and behavioral deficits but did not affect the axonopathy observed in cell culture. Besides its enzymatic activity as a phospholipase, SWS also acts as regulatory PKA subunit, binding and inhibiting the C3 catalytic subunit. Measuring PKA activity in TOCP treated flies revealed a significant decrease that was also confirmed in treated rat hippocampal neurons. Flies expressing additional PKA-C3 were protected from the behavioral and degenerative phenotypes caused by TOCP exposure whereas primary neurons were not. In addition, knocking-down PKA-C3 caused similar behavioral and degenerative phenotypes as TOCP treatment. We therefore propose a model in which OP-modified SWS cannot release PKA-C3 and that the resulting loss of PKA-C3 activity plays a crucial role in developing the delayed symptoms of OPIDN but not in the acute toxicity. PMID:24558370

Organophosphorus Compounds at 80: Some Old and New Issues.

PubMed

Costa, Lucio G

2018-03-01

One of the major classes of pesticides is that of the organophosphates (OPs). Initial developments date back almost 2 centuries but it was only in the mid-1940s that OPs reached a prominent status as insecticides, a status that, albeit declining, is still ongoing. OPs are highly toxic to nontarget species including humans, the primary effects being an acute cholinergic toxicity (responsible for thousands of poisoning each year) and a delayed polyneuropathy. Several issues of current debate and investigation on the toxicology of OPs are discussed in this brief review. These include (1) possible additional targets of OPs, (2) OPs as developmental neurotoxicants, (3) OPs and neurodegenerative diseases, (4) OPs and the "aerotoxic syndrome," (5) OPs and the microbiome, and (6) OPs and cancer. Some of these issues have been debated and studied for some time, while others are newer, suggesting that the study of the toxicology of OPs will remain an important scientific and public health issue for years to come.

Synthesis of valproic acid amides of a melatonin derivative, a piracetam and amantadine for biological tests.

PubMed

Chatterjie, N; Alexander, G; Wang, H

2001-10-01

Three new amide derivatives of valproic acid have been synthesized and characterized by spectrophotometric studies. The rationale for the preparation of such agents has been based on the observation that chemical combination of the anticonvulsant pharmacophore, valproic acid with amine moieties produces more effective and less toxic amides. The amine components selected in this work also exhibit neuroactivity with the prospect of these agents being biologically active in controlling not just seizures and but also possessing neuroprotective properties. We report here the synthesis and properties of the valproylamides of 5-methoxytryptamine, related to melatonin (1), of N-substituted 2-pyrrolidinone related to piracetam (2), and of adamantylamine related to amantadine (3). In preliminary tests these compounds showed low toxicity and a variety of anticonvulsive properties, including a delay in onset of activity. These compounds and their derivatives are now available to be tested additionally for control of subclinical seizures, enhancement of cognition, behavior modification and alleviation of symptoms and disorders due to neuronal damage.

Comparison of oral toxicological properties of botulinum neurotoxin serotypes A and B.

PubMed

Cheng, Luisa W; Henderson, Thomas D

2011-07-01

Botulinum neurotoxins (BoNTs) are among the most potent biological toxins for humans. Of the seven known serotypes (A-G) of BoNT, serotypes A, B and E cause most of the foodborne intoxications in humans. BoNTs in nature are associated with non-toxic accessory proteins known as neurotoxin-associated proteins (NAPs), forming large complexes that have been shown to play important roles in oral toxicity. Using mouse intraperitoneal and oral models of botulism, we determined the dose response to both BoNT/B holotoxin and complex toxins, and compared the toxicities of BoNT/B and BoNT/A complexes. Although serotype A and B complexes have similar NAP composition, BoNT/B formed larger-sized complexes, and was approximately 90 times more lethal in mouse oral intoxications than BoNT/A complexes. When normalized by mean lethal dose, mice orally treated with high doses of BoNT/B complex showed a delayed time-to-death when compared with mice treated with BoNT/A complex. Furthermore, we determined the effect of various food matrices on oral toxicity of BoNT/A and BoNT/B complexes. BoNT/B complexes showed lower oral bioavailability in liquid egg matrices when compared to BoNT/A complexes. In summary, our studies revealed several factors that can either enhance or reduce the toxicity and oral bioavailability of BoNTs. Dissecting the complexities of the different BoNT serotypes and their roles in foodborne botulism will lead to a better understanding of toxin biology and aid future food risk assessments. Published by Elsevier Ltd.

Tumor Regression and Delayed Onset Toxicity Following B7-H4 CAR T Cell Therapy

PubMed Central

Smith, Jenessa B; Lanitis, Evripidis; Dangaj, Denarda; Buza, Elizabeth; Poussin, Mathilde; Stashwick, Caitlin; Scholler, Nathalie; Powell, Daniel J

2016-01-01

B7-H4 protein is frequently overexpressed in ovarian cancer. Here, we engineered T cells with novel B7-H4-specific chimeric antigen receptors (CARs) that recognized both human and murine B7-H4 to test the hypothesis that B7-H4 CAR T cell therapy can be applied safely in preclinical models. B7-H4 CAR T cells specifically secreted IFN-γ and lysed B7-H4(+) targets. In vivo, B7-H4 CAR T cells displayed antitumor reactivity against B7-H4(+) human ovarian tumor xenografts. Unexpectedly, B7-H4 CAR T cell treatment reproducibly showed delayed, lethal toxicity 6–8 weeks after therapy. Comprehensive assessment of murine B7-H4 protein distribution uncovered expression in ductal and mucosal epithelial cells in normal tissues. Postmortem analysis revealed the presence of widespread histologic lesions that correlated with B7-H4(+) expression, and were inconsistent with graft versus host disease. Lastly, expression patterns of B7-H4 protein in normal human tissue were comparable to distribution in mice, advancing our understanding of B7-H4. We conclude that B7-H4 CAR therapy mediates control of cancer outgrowth. However, long-term engraftment of B7-H4 CAR T cells mediates lethal, off-tumor toxicity that is likely due to wide expression of B7-H4 in healthy mouse organs. This model system provides a unique opportunity for preclinical evaluation of safety approaches that limit CAR-mediated toxicity after tumor destruction in vivo. PMID:27439899

Randomized trial comparing two methods of re-irradiation after salvage surgery in head and neck squamous cell carcinoma: Once daily split-course radiotherapy with concomitant chemotherapy or twice daily radiotherapy with cetuximab.

PubMed

Tao, Yungan; Faivre, Laura; Laprie, Anne; Boisselier, Pierre; Ferron, Christophe; Jung, Guy Michel; Racadot, Séverine; Gery, Bernard; Even, Caroline; Breuskin, Ingrid; Bourhis, Jean; Janot, François

2018-05-18

A previous randomized trial in recurrent Head and Neck squamous-cell carcinoma (HNSCC) has shown re-irradiation combined with chemotherapy after salvage surgery significantly improved disease-free survival (DFS). The objective of this randomized trial was to compare two methods of re-irradiation in terms of toxicity and survival. Patients with recurrence/second primary in previously irradiated area were randomly allocated to receive either 60 Gy over 11 weeks with concomitant 5FU - hydroxyurea (VP-arm), or 60 Gy (1.2 Gy twice daily) over 5 weeks with cetuximab (HFR-arm). Primary endpoint was treatment interruption >15 days (acute toxicity). Twenty-six patients were included in VP-arm and 27 in HFR-arm. One patient in VP-arm experienced >15 days interruption due to toxicity, and none in HFR-arm. In both arms, all patients received at least 60 Gy. In VP-arm, 8/26 patients had chemotherapy delay and/or dose reduction. In HFR-arm, 4/27 patients had <6 cycles cetuximab. There was no significant difference in overall survival (Median OS: 37.4 months vs 21.9 months, p = 0.12). Toxicities and DFS were not different between 2 arms. Twice daily schedule of re-irradiation of 60 Gy/5 weeks with cetuximab was tolerable and no significant difference in treatment delays occurred between two arms. Copyright © 2018 Elsevier B.V. All rights reserved.

Development of virtual bait stations to control Argentine ants (Hymenoptera: Formicidae) in environmentally sensitive habitats.

PubMed

Choe, Dong-Hwan; Vetter, Richard S; Rust, Michael K

2010-10-01

A novel bait station referred to as a virtual bait station was developed and tested against field populations of the invasive Argentine ant, Linepithema humile (Mayr) (Hymenoptera: Formicidae), at White Beach, Camp Pendleton, in Oceanside, CA. White Beach is a nesting habitat for an endangered seabird, the California least tern (Sterna antillarum browni Mearns). The beach is heavily infested with Argentine ants, one of the threats for the California least tern chicks. Conventional pest control strategies are prohibited because of the existence of the protected bird species and the site's proximity to the ocean. The bait station consisted of a polyvinyl chloride pipe that was treated on the inside with fipronil insecticide at low concentrations to obtain delayed toxicity against ants. The pipe was provisioned with an inverted bottle of 25% sucrose solution, then capped, and buried in the sand. Foraging ants crossed the treated surface to consume the sucrose solution. The delayed toxicity of fipronil deposits allowed the ants to continue foraging on the sucrose solution and to interact with their nestmates, killing them within 3-5 d after exposure. Further modification of the bait station design minimized the accumulation of dead ants in the sucrose solution, significantly improving the longevity and efficacy of the bait station. The virtual bait station exploits the foraging behavior of the ants and provides a low impact approach to control ants in environmentally sensitive habitats. It excluded all insects except ants, required only milligram quantities of toxicant, and eliminated the problem of formulating toxicants into aqueous sugar baits.

Pilot Study of Adding Vincristine, Topotecan, and Cyclophosphamide to Interval-Compressed Chemotherapy in Newly Diagnosed Patients With Localized Ewing Sarcoma: A Report From the Children's Oncology Group.

PubMed

Mascarenhas, Leo; Felgenhauer, Judy L; Bond, Mason C; Villaluna, Doojduen; Femino, Joseph Dominic; Laack, Nadia N; Ranganathan, Sarangarajan; Meyer, James; Womer, Richard B; Gorlick, Richard; Krailo, Mark D; Marina, Neyssa

2016-03-01

The combination of topotecan and cyclophosphamide is active in relapsed Ewing sarcoma family of tumors (ESFT). The feasibility of adding these agents combined with vincristine (vincristine-topotecan-cyclophosphamide [VTc]) to standard five-drug chemotherapy with vincristine-doxorubicin-cyclophosphamide (VDC) and ifosfamide-etoposide (IE) administered in an interval-compressed (2-week instead of 3-week intervals) schedule was investigated. Newly diagnosed patients with localized ESFT < 31 years, with good performance status and adequate organ function were eligible. Seventeen alternating cycles of chemotherapy with VTc, VDC, and IE were administered at 2-week intervals. Local control (LC) of the primary tumor occurred following six cycles. Primary endpoints were the ability to deliver chemotherapy in an interval-compressed schedule, and the rate of grade 3 or greater nonhematologic toxicity and grade 4 hematologic toxicity, which delayed chemotherapy by ≥2 weeks. Secondary endpoints were event-free survival (EFS) and overall survival (OS). Thirty-five patients with a median age of 11 years were enrolled. The mean time to last dose of chemotherapy prior to LC was 12.6 ± 1.4 weeks and 45.5% of patients received intended chemotherapy without any delay prior to LC. There were no toxic deaths or unexpected toxicities. Five-year EFS was 79.6% (95% confidence interval [CI]: 61.8-89.7%) and 5-year OS was 88% (95% CI: 71.4-95.3%). The addition of VTc to standard therapy was tolerable with sufficient interval compression compared to historical standard 3-week cycles. © 2015 Wiley Periodicals, Inc.

Silibinin Attenuates Sulfur Mustard Analog-Induced Skin Injury by Targeting Multiple Pathways Connecting Oxidative Stress and Inflammation

PubMed Central

Tewari-Singh, Neera; Jain, Anil K.; Inturi, Swetha; Agarwal, Chapla; White, Carl W.; Agarwal, Rajesh

2012-01-01

Chemical warfare agent sulfur mustard (HD) inflicts delayed blistering and incapacitating skin injuries. To identify effective countermeasures against HD-induced skin injuries, efficacy studies were carried out employing HD analog 2-chloroethyl ethyl sulfide (CEES)-induced injury biomarkers in skin cells and SKH-1 hairless mouse skin. The data demonstrate strong therapeutic efficacy of silibinin, a natural flavanone, in attenuating CEES-induced skin injury and oxidative stress. In skin cells, silibinin (10 µM) treatment 30 min after 0.35/0.5 mM CEES exposure caused a significant (p<0.05) reversal in CEES-induced decrease in cell viability, apoptotic and necrotic cell death, DNA damage, and an increase in oxidative stress. Silibinin (1 mg) applied topically to mouse skin 30 min post-CEES exposure (2 mg), was effective in reversing CEES-induced increases in skin bi-fold (62%) and epidermal thickness (85%), apoptotic cell death (70%), myeloperoxidase activity (complete reversal), induction of iNOS, COX-2, and MMP-9 protein levels (>90%), and activation of transcription factors NF-κB and AP-1 (complete reversal). Similarly, silibinin treatment was also effective in attenuating CEES-induced oxidative stress measured by 4-hydroxynonenal and 5,5-dimethyl-2-(8-octanoic acid)-1-pyrolline N-oxide protein adduct formation, and 8-oxo-2-deoxyguanosine levels. Since our previous studies implicated oxidative stress, in part, in CEES-induced toxic responses, the reversal of CEES-induced oxidative stress and other toxic effects by silibinin in this study indicate its pleiotropic therapeutic efficacy. Together, these findings support further optimization of silibinin in HD skin toxicity model to develop a novel effective therapy for skin injuries by vesicants. PMID:23029417

Silibinin attenuates sulfur mustard analog-induced skin injury by targeting multiple pathways connecting oxidative stress and inflammation.

PubMed

Tewari-Singh, Neera; Jain, Anil K; Inturi, Swetha; Agarwal, Chapla; White, Carl W; Agarwal, Rajesh

2012-01-01

Chemical warfare agent sulfur mustard (HD) inflicts delayed blistering and incapacitating skin injuries. To identify effective countermeasures against HD-induced skin injuries, efficacy studies were carried out employing HD analog 2-chloroethyl ethyl sulfide (CEES)-induced injury biomarkers in skin cells and SKH-1 hairless mouse skin. The data demonstrate strong therapeutic efficacy of silibinin, a natural flavanone, in attenuating CEES-induced skin injury and oxidative stress. In skin cells, silibinin (10 µM) treatment 30 min after 0.35/0.5 mM CEES exposure caused a significant (p<0.05) reversal in CEES-induced decrease in cell viability, apoptotic and necrotic cell death, DNA damage, and an increase in oxidative stress. Silibinin (1 mg) applied topically to mouse skin 30 min post-CEES exposure (2 mg), was effective in reversing CEES-induced increases in skin bi-fold (62%) and epidermal thickness (85%), apoptotic cell death (70%), myeloperoxidase activity (complete reversal), induction of iNOS, COX-2, and MMP-9 protein levels (>90%), and activation of transcription factors NF-κB and AP-1 (complete reversal). Similarly, silibinin treatment was also effective in attenuating CEES-induced oxidative stress measured by 4-hydroxynonenal and 5,5-dimethyl-2-(8-octanoic acid)-1-pyrolline N-oxide protein adduct formation, and 8-oxo-2-deoxyguanosine levels. Since our previous studies implicated oxidative stress, in part, in CEES-induced toxic responses, the reversal of CEES-induced oxidative stress and other toxic effects by silibinin in this study indicate its pleiotropic therapeutic efficacy. Together, these findings support further optimization of silibinin in HD skin toxicity model to develop a novel effective therapy for skin injuries by vesicants.

Appropriate antimicrobial therapy in the era of multidrug-resistant human pathogens.

PubMed

Pogue, J M; Kaye, K S; Cohen, D A; Marchaim, D

2015-04-01

The past decade has brought a significant rise in antimicrobial resistance, and the ESKAPE pathogens have become a significant threat to public health. Three epidemiological features that negatively impact patients, which are consistently seen with the ESKAPE pathogens, are the following: 1) there has been a rise in incidence of these organisms as causative human pathogens, 2) there has been a significant increase in antimicrobial resistance in these bacterial species, and 3) the infections caused by these resistant strains are associated with worse outcomes when compared with infections caused by their susceptible counterparts. Significant delays in time to appropriate antimicrobial therapy of up to 5 days have been reported in infections due to these organisms and this is the strongest predictor of mortality with ESKAPE pathogens, particular in critically ill patients, where every hour delay has an incremental survival disadvantage for patients. Strategies to decrease these delays are urgently needed. Although routine broad-spectrum empiric coverage for these organisms would ideally limit this delay, agents with activity against these organisms are sometimes less effective, have significant toxicity risk, and their use can result in the development of resistance. Therefore, strategies to optimize therapy, although limiting unnecessary use of broad-spectrum antimicrobials, are urgently needed. This review will discuss potential strategies to optimize empiric therapy in the age of multi-drug resistance, the limitations of these strategies, and will discuss future directions and opportunities. Copyright © 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Revisiting therapeutic strategies in radiation casualties.

PubMed

Hérodin, Francis; Grenier, Nancy; Drouet, Michel

2007-04-01

Nuclear/radiological threats have evolved and scenarios for terrorist attacks involving radioactive material have been identified as complex situations. Mass casualty scenarios may happen, and individuals may be exposed to intentionally hidden sources of high activity, resulting in delayed diagnosis and treatment of acute radiation syndrome (ARS). Moreover, ARS must be considered as an emergency in order to better anticipate delayed radiation toxicity. In this context, therapeutic strategies in radiation casualties have to be revisited and new pharmacological approaches developed. B6D2F1 mice were total-body irradiated (TBI) with a 9 Gy gamma dose and then received intraperitoneal doses of either early (stem cell factor + FLT-3 ligand + thrombopoietin + interleukin-3 [SFT3] +/- keratinocyte growth factor (KGF); stem cell factor + erythropoietin + Peg-filgrastim [SEG]) or delayed treatments (SFT3 +/- KGF, erythropoietin, or hyaluronic acid). Survival was monitored and bone marrow hematopoiesis evaluated at 300 days following early treatments. SFT3 anti-apoptotic cytokine combination administered early (2 hours and 24 hours) after lethal TBI induced 60% survival versus 5% in controls. Early SEG treatment may be an alternative to SFT3 in terms of survival (55%), but SEG benefit might be obtained at the expense of long-term hematopoiesis. SFT3 + KGF induced 75% survival. No effectiveness was observed, over antimicrobial supportive care, when administration of SFT3 or its tested combinations was delayed at 48 hours. As a potentially multi-organ failure, ARS requires global therapy, beyond the hematopoietic syndrome, which may include pleiotropic cytokines such as KGF.

UGT1A1 gene polymorphism: Impact on toxicity and efficacy of irinotecan-based regimens in metastatic colorectal cancer

PubMed Central

Schulz, Christoph; Heinemann, Volker; Schalhorn, Andreas; Moosmann, Nikolas; Zwingers, Thomas; Boeck, Stefan; Giessen, Clemens; Stemmler, Hans-Joachim

2009-01-01

AIM: To investigate the correlation between uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) gene polymorphisms and irinotecan-associated side effects and parameters of drug efficacy in patients with metastatic colorectal cancer (mCRC) receiving a low-dose weekly irinotecan chemotherapeutic regimen. METHODS: Genotypes were retrospectively evaluated by gene scan analysis on the ABI 310 sequencer of the TATAA box in the promoter region of the UGT1A1 gene in blood samples from 105 patients who had received 1st line irinotecan-based chemotherapy for mCRC. RESULTS: The distribution of the genotypes was as follows: wild type genotype (WT) (6/6) 39.0%, heterozygous genotype (6/7) 49.5%, and homozygous genotype (7/7) 9.5%. The overall response rate (OR) was similar between patients carrying the (6/7, 7/7) or the WT genotype (6/6) (44.3% vs 43.2%, P = 0.75). Neither time to progression [(TTP) 8.1 vs 8.2 mo, P = 0.97] nor overall survival [(OS) 21.2 vs 18.9 mo, P = 0.73] differed significantly in patients who carried the (6/6) when compared to the (6/7, 7/7) genotype. No significant differences in toxicity were observed: Grade 3 and 4 delayed diarrhoea [(6/7, 7/7) vs (6/6); 13.0% vs 6.2%, P = 0.08], treatment delays [(6/7, 7/7) vs (6/6); 25.1% vs 19.3%, P =0.24] or dose reductions [(6/7, 7/7) vs (6/6); 21.5% vs 27.2%, P = 0.07]. CONCLUSION: This analysis demonstrates the non-significant influence of the UGT1A1 gene polymorphism on efficacy and rate of irinotecan-associated toxicity in mCRC patients receiving low-dose irinotecan based chemotherapy. PMID:19859999

Ketoconazole in paracoccidioidomycosis: efficacy of prolonged oral therapy.

PubMed

Restrepo, A; Stevens, D A; Leiderman, E; Fuentes, J; Arana, A; Angel, R; Mejía, G; Gómez, I

1980-08-29

Ketoconazole, a new oral imidazole derivative, was employed for the treatment of five patients with paracoccidioidomycosis. The response was excellent, with objective clinical improvement and healing of both mucocutaneous and pulmonary lesions. Mycological and serological tests, as well as delayed hypersensitivity, were assessed and found to correlate with clinical improvement. Therapy was conducted for 12 months with a dose of 200 mg day in 2 patients; in the remainder the dose was reduced (100 mg day) after the first 6 months and maintained as such for an equal period. No side-effects or toxicity were noted despite prolonged treatment. The advantages of the new therapeutic approach are discussed.

Initial postmarketing experience with crotalidae polyvalent immune Fab for treatment of rattlesnake envenomation.

PubMed

Ruha, Anne-Michelle; Curry, Steven C; Beuhler, Michael; Katz, Ken; Brooks, Daniel E; Graeme, Kimberlie A; Wallace, Kevin; Gerkin, Richard; Lovecchio, Frank; Wax, Paul; Selden, Brad

2002-06-01

We describe our postmarketing experience with patients receiving Crotalidae polyvalent immune Fab (CroFab; FabAV) antivenom for treatment of rattlesnake envenomation. The charts of 28 patients admitted between March 1 and September 9, 2001, with rattlesnake envenomation and treated with FabAV were reviewed for demographic information, time until antivenom treatment, laboratory findings, evidence of hypersensitivity reaction, length of hospital stay, and readmission to the hospital. All patients had swelling, 20 patients had elevated prothrombin times (>14 seconds), 12 patients had low fibrinogen levels (<170 mg/dL), and 6 patients had thrombocytopenia (platelet count <120,000/mm(3)) on presentation. The total dose of FabAV ranged from 10 to 47 vials per patient. Hypofibrinogenemia was resistant to FabAV in some patients. On follow-up, recurrence of coagulopathy was detected in 3 patients, and recurrence of thrombocytopenia was detected in 1 patient. Two patients demonstrated delayed-onset severe thrombocytopenia. Recurrence or delayed-onset toxicity might have been underestimated because of incomplete follow-up in some patients. No acute hypersensitivity reactions occurred. Two patients reported mild symptoms of possible serum sickness on follow-up. FabAV effectively controlled the effects of envenomation; however, initial control of coagulopathy was difficult to achieve in some cases, and recurrence or delayed-onset hematotoxicity was common. When initially managing hematotoxicity, a trend toward normalization of laboratory values might be a more reasonable end point for FabAV treatment than attainment of normal reference values in nonbleeding patients.

Effect of electromagnetic fields on some biomechanical and biochemical properties of rat’s blood

NASA Astrophysics Data System (ADS)

Mohaseb, M. A.; Shahin, F. A.; Ali, F. M.; Baieth, H. A.

2017-06-01

In order to study the effect of electromagnetic fields (0.3 mT, 50 Hz) on some biomechanical and biochemical properties of rats’ blood, healthy thirty male albino rats of 150 ± 10 g were divided into three equal groups namely A, B1, B2. Group A used as a control group, group B1 was continuously exposed to a magnetic field of (0.3 mT, 50 Hz) for a period of 21 days for direct effect studies. Group B2 was continuously exposed to the same magnetic field for the same period of time, then was housed away from the magnetic field for a period of 45 days for delayed effects studies. After examination, the results indicated that the apparent viscosity and the consistency index increased significantly and very high significantly for groub B1 and B2 compared to control at P<0.05. Red blood cell counts (RBCs) membrane elasticity had significantly and very high significantly decreased for groups B1 and B2. Moreover, delayed effects studies indicated that there is deterioration in the bone marrow functions. These results are supported by the blood film image, where irregularities and deformations in the RBCs membranes had been occurred. We conclude that the cell membrane properties are highly affected by the extremely low frequency (ELF) magnetic fields, which proved to be biologically toxic.

Toward a comparative retrospective analysis of rat and rabbit developmental toxicity studies for pharmaceutical compounds.

PubMed

Theunissen, P T; Beken, S; Cappon, G D; Chen, C; Hoberman, A M; van der Laan, J W; Stewart, J; Piersma, A H

2014-08-01

Based on a proposal made at the ICH Workshop in Tallinn, Estonia (2010), the value of the rabbit embryo-fetal development (EFD) versus the rodent EFD was examined by the HESI DART group. A cross-industry data survey provided anonymised EFD and toxicokinetic data from EFD studies on over 400 marketed and unmarketed drugs (over 800 studies) that were entered by experts at RIVM into US EPA’s ToxRefDB style database. The nature and severity of findings at the lowest observed adverse effect level (LOAEL) are being reviewed to quantitate the frequency with which lesser signs of embryo-fetal effects (e.g., delays in ossification, minor changes in frequency of variants) are driving the LOAELs. Interpretation was based on exposure rather than administered dose. This paper provides an update of this ongoing project as discussed during a workshop of the European Teratology Society in Ispra, Italy (2013). This was the first presentation of the initial data set, allowing debate on future directions, to provide a better understanding of the implications of either delaying a rabbit EFD or waiving the need in particular circumstances.

Time course of electrophysiologic effects induced by di-n-butyl-2,2-dichlorovinyl phosphate (DBCV) in the adult hen.

PubMed

Robertson, D G; Mattson, A M; Bestervelt, L L; Richardson, R J; Anderson, R J

1988-01-01

Previous work in our laboratory indicated that di-n-butyl-2,2-dichlorovinyl phosphate (DBCV) produced electrophysiologic changes in hen peripheral nerve that coincided with the development of histopathologic changes and neurologic signs of peripheral neuropathy. The purpose of the present study was to follow the time course for the development of the electrophysiologic changes and to determine whether pretreatment with the phosphinate analog of DBCV (DBCV-P), a nonageable organophosphorus compound, prevented these effects. Although significant electrophysiologic deficits occurred in the tibial and sciatic nerve 24 h after DBCV treatment, the most marked changes coincided with the onset of clinical signs of organophosphorus-induced delayed neuropathy (14-21 d). The sciatic and tibial nerves were equally susceptible to DBCV in producing deficits characterized by changes in the relative refractory period and an increased strength-duration threshold. Pretreatment with DBCV-P prevented the clinical signs and also attenuated the electrophysiologic deficits induced by DBCV treatment. These data suggest that electrophysiologic deficits occur before clinical signs of organophosphorus-induced delayed neuropathy (OPIDN) and may be indicative of a link between neurotoxic esterase (NTE) inhibition and onset of overt clinical toxicity.

CuInS2/ZnS QD exposure induces developmental toxicity, oxidative stress and DNA damage in rare minnow (Gobiocypris rarus) embryos and larvae.

PubMed

Liu, Li; Xiao, Yuan-Yuan; Ji, Yan-Hong; Liu, Ming-Zhi; Chen, Yao; Zeng, Yu-Lian; Zhang, Yao-Guang; Jin, Li

2017-08-01

Chinese rare minnow (Gobiocypris rarus) embryos were used as an experimental model to investigate the effects of CuInS 2 /ZnS quantum dots (QDs) on the early life stages of G. rarus. Normal developmental parameters (survival rate, body length and average heart rate), biomarker genes [stress response (Hsp70), detoxification (Cyp1a), organizer function and axis formation (Wnt8α), and muscle (Mstn)], enzymatic activity and DNA damage were recorded as endpoints in the developing embryos/larvae after exposure until 96h post-fertilization (hpf). Reduced survival rate, decreased heart rate, altered body length, increased malformation rate, decreased hatching rate, advanced hatching time in response to low concentrations (50 and 100nmol/L) and delayed hatching time in response to high concentrations were observed after exposure, as were many other toxic effects, including pericardial edema and bent tails. The 72 hpf LC 50 (median lethal concentration) was determined to be 624.364nmol/L. Treatment with certain concentrations of CuInS 2 /ZnS QDs significantly increased the superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels and significantly induced DNA damage. After treatment with CuInS 2 /ZnS QDs, the embryos showed highly up-regulated expression of Hsp70, Cyp1a and Wnt8a and significantly up-regulated expression of Mstn at 12 hpf. Overall, this study indicates that CuInS 2 /ZnS QDs are potentially toxic to G. rarus embryos. The information presented in this study will be helpful for fully understanding the toxicity induced by CuInS 2 /ZnS QDs in fish embryos. Copyright © 2017 Elsevier Inc. All rights reserved.

Lethal and sublethal toxicity of the industrial chemical epichlorohydrin on Rhinella arenarum (Anura, Bufonidae) embryos and larvae.

PubMed

Hutler Wolkowicz, Ianina R; Aronzon, Carolina M; Pérez Coll, Cristina S

2013-12-15

Lethal and sublethal toxicity of the major chemical used in epoxide compounds, epichlorohydrin (ECH) was evaluated on the early life cycle of the common South American toad, Rhinella arenarum (Anura, Bufonidae). The stages evaluated were (according to Del Conte and Sirlin): early blastula (S.3-S.4), gastrula (S.10-S.12), rotation (S.15), tail bud (S.17), muscular response (S.18), gill circulation (S.20), open mouth (S.21), opercular folds (S.23) and complete operculum (S.25). The LC50 and EC50 values for lethal and sublethal effects were calculated. The early blastula was the most sensitive stage to ECH both for continuously and pulse-exposures (LC50-24h=50.9 mg L(-1)), while S.20 was the most resistant (LC50-24h=104.9 mg L(-1)). Among sublethal effects, early blastula was also the most sensitive stage (LOEC-48 h=20 mg L(-1)) and it has a Teratogenic Index of 2.5, which indicates the teratogenic potential of the substance. The main abnormalities were persistent yolk plugs, cell dissociation, tumors, hydropsy, oral malformations, axial/tail flexures, delayed development and reduced body size. ECH also caused neurotoxicity including scarce response to stimuli, reduction in the food intake, general weakness, spasms and shortening, erratic or circular swimming. Industrial contamination is considered an important factor on the decline of amphibian populations. Considering the available information about ECH's toxicity and its potential hazard to the environment, this work shows the first results of its developmental toxicity on a native amphibian species, Rhinella arenarum. Copyright © 2013 Elsevier B.V. All rights reserved.

Comparative toxicity and efficacy of engineered anthrax lethal toxin variants with broad anti-tumor activities.

PubMed

Peters, Diane E; Hoover, Benjamin; Cloud, Loretta Grey; Liu, Shihui; Molinolo, Alfredo A; Leppla, Stephen H; Bugge, Thomas H

2014-09-01

We have previously designed and characterized versions of anthrax lethal toxin that are selectively cytotoxic in the tumor microenvironment and which display broad and potent anti-tumor activities in vivo. Here, we have performed the first direct comparison of the safety and efficacy of three engineered anthrax lethal toxin variants requiring activation by either matrix-metalloproteinases (MMPs), urokinase plasminogen activator (uPA) or co-localized MMP/uPA activities. C57BL/6J mice were challenged with six doses of engineered toxins via intraperitoneal (I.P.) or intravenous (I.V.) dose routes to determine the maximum tolerated dose for six administrations (MTD6) and dose-limiting toxicities. Efficacy was evaluated using the B16-BL6 syngraft model of melanoma; mice bearing established tumors were treated with six I.P. doses of toxin and tumor measurements and immunohistochemistry, paired with terminal blood work, were used to elaborate upon the anti-tumor mechanism and relative efficacy of each variant. We found that MMP-, uPA- and dual MMP/uPA-activated anthrax lethal toxins exhibited the same dose-limiting toxicity; dose-dependent GI toxicity. In terms of efficacy, all three toxins significantly reduced primary B16-BL6 tumor burden, ranging from 32% to 87% reduction, and they also delayed disease progression as evidenced by dose-dependent normalization of blood work values. While target organ toxicity and effective doses were similar amongst the variants, the dual MMP/uPA-activated anthrax lethal toxin exhibited the highest I.P. MTD6 and was 1.5-3-fold better tolerated than the single MMP- and uPA-activated toxins. Overall, we demonstrate that this dual MMP/uPA-activated anthrax lethal toxin can be administered safely and is highly effective in a preclinical model of melanoma. This modified bacterial cytotoxin is thus a promising candidate for further clinical development and evaluation for use in treating human cancers. Published by Elsevier Inc.

Evaluation of developmental toxicity in rats exposed to the environmental estrogen bisphenol A during pregnancy.

PubMed

Kim, J C; Shin, H C; Cha, S W; Koh, W S; Chung, M K; Han, S S

2001-10-19

Bisphenol A (BPA) is an essential component of epoxy resins used in the lacquer lining of metal food cans, as a component of polycarbonates, and in dental sealants. The present study was conducted in an attempt to evaluate the adverse effects of the environmental estrogen BPA on initiation and maintenance of pregnancy and embryofetal development after maternal exposure during the entire period of pregnancy in Sprague-Dawley rats. The test chemical was administered by gavage to mated females from days 1 to 20 of gestation (sperm in varginal lavage = day 0) at dose levels of 0, 100, 300, and 1000 mg/kg. All females were subjected to caesarean section on day 21 of gestation and their fetuses were examined for external, visceral and skeletal abnormalities. In the 1000 mg/kg group, significant toxic effects including abnormal clinical signs, decreased maternal body weight and body weight gain, and reduced food consumption were observed in pregnant rats. An increase in pregnancy failure was also found in the successfully mated females. In addition, increased number of embryonal deaths, increased postimplantation loss, reduced litter size and fetal body weight, and decreased number of fetal ossification centers of several skeletal districts were seen. On the contrary, no significant changes induced by BPA were detected in the number of corpora lutea and implantation sites and by fetal morphological examinations. In the 300 mg/kg group, suppressed maternal body weight and body weight gain, decreased food intake and reduced body weight of male fetuses were seen. There were no adverse signs of either maternal toxicity or developmental toxicity in the 100 mg/kg group. It was concluded that BPA administration during the entire period of pregnancy in rats produced pregnancy failure, pre- and postimplantation loss, fetal developmental delay and severe maternal toxicity, but no embryo-fetal dysmorphogenesis at an oral exposure level of 1000 mg/kg.

Comparative toxicity and efficacy of engineered anthrax lethal toxin variants with broad anti-tumor activities

PubMed Central

Peters, Diane E.; Hoover, Benjamin; Cloud, Loretta Grey; Liu, Shihui; Molinolo, Alfredo A.; Leppla, Stephen H.; Bugge, Thomas H.

2014-01-01

We have previously designed and characterized versions of anthrax lethal toxin that are selectively cytotoxic in the tumor microenvironment and which display broad and potent anti-tumor activities in vivo. Here, we have performed the first direct comparison of the safety and efficacy of three engineered anthrax lethal toxin variants requiring activation by either matrix-metalloproteinases (MMPs), urokinase plasminogen activator (uPA) or co-localized MMP/uPA activities. C57BL/6J mice were challenged with six doses of engineered toxins via intraperitoneal (I.P.) or intravenous (I.V.) dose routes to determine the maximum tolerated dose for six administrations (MTD6) and dose-limiting toxicities. Efficacy was evaluated using the B16-BL6 syngraft model of melanoma; Mice bearing established tumors were treated with six I.P. doses of toxin and tumor measurements and immunohistochemistry, paired with terminal blood work, were used to elaborate upon the anti-tumor mechanism and relative efficacy of each variant. We found that MMP-, uPA- and dual MMP/uPA- activated anthrax lethal toxins exhibited the same dose-limiting toxicity; dose-dependent GI toxicity. In terms of efficacy, all three toxins significantly reduced primary B16-BL6 tumor burden, ranging from 32%–87% reduction, and they also delayed disease progression as evidenced by dose-dependent normalization of blood work values. While target organ toxicity and effective doses were similar amongst the variants, the dual MMP/uPA-activated anthrax lethal toxin exhibited the highest I.P. MTD6 and was 1.5–3-fold better tolerated than the single MMP- and uPA-activated toxins. Overall, we demonstrate that this dual MMP/uPA-activated anthrax lethal toxin can be administered safely and is highly effective in a preclinical model of melanoma. This modified bacterial cytotoxin is thus a promising candidate for further clinical development and evaluation for use in treating human cancers. PMID:24971906

Cola beverage and delayed elimination of methotrexate.

PubMed

Santucci, Raoul; Levêque, Dominique; Herbrecht, Raoul

2010-11-01

To report a case of severe delayed methotrexate elimination attributable to consumption of a cola beverage. To investigate unexplained low urinary pH in a lymphoma patient treated with high-dose methotrexate. Unexpected urinary acidity, despite administration of large amounts of sodium bicarbonate, could be attributed to repeated consumption of a cola beverage. It resulted in a delayed elimination of methotrexate and acute renal failure. Discontinuation of cola drinks, increase in calcium folinate rescue and in sodium bicarbonate allowed satisfactory elimination of methotrexate on day 12 after infusion and recovery from renal impairment without other severe toxicity. No other cause of delay in methotrexate elimination could be identified. Cola beverages have a low pH due to their phosphoric acid content that is excreted by renal route. We recommend patients receiving high dose methotrexate abstain from any cola drink within 24 h before and during methotrexate administration and until complete elimination of the drug. © 2010 The Authors. British Journal of Clinical Pharmacology © 2010 The British Pharmacological Society.

From lead to manganese through mercury: mythology, science, and lessons for prevention.

PubMed

Alessio, Lorenzo; Campagna, Marcello; Lucchini, Roberto

2007-11-01

Lead (Pb), mercury (Hg), and manganese (Mn) are well-known neurotoxic metals. The knowledge of toxicity was developed through an extensive amount of research, starting with lead and mercury and proceeding today with manganese. Unfortunately, the consequent implementation of preventive measures was generally delayed, causing important negative effects to the exposed populations. A review and historical reconstruction of the research development that yielded modern understanding of lead and mercury neurotoxicity was conducted to derive useful lessons for the prevention of manganese neurotoxicity. Medieval alchemists named planets and metals from gods since they were already aware of the toxicity and the adverse effects caused by lead and mercury. Historical lessons learned from these two metals may help to avoid the repetition of further mistakes regarding other neurotoxic metals like manganese. The knowledge and experience on the toxicokinetics and toxicodynamics of lead and mercury is useful and valuable to identify a proper approach to "safe" exposure levels for manganese. Further information is still needed on the early neurotoxic and neurobehavioral effects after prolonged exposure to very low doses of lead, mercury, and manganese. Nevertheless, according to the precautionary principle, effective preventive measures should be already undertaken to prevent the onset of more severe health effects in the population. This is the most important lesson to be learned and applied from more than 30 years of occupational and environmental neurotoxicology of metals. (c) 2007 Wiley-Liss, Inc.

Therapy Insight: preserving fertility in cyclophosphamide-treated patients with rheumatic disease.

PubMed

Dooley, Mary Anne; Nair, Raj

2008-05-01

Cyclophosphamide remains a necessary treatment for severe rheumatic diseases, despite the continued search for alternative therapies with less gonadal toxicity. The risk of premature gonadal failure and sterility might lead young patients to delay treatment with cyclophosphamide. The patient's age at treatment and the cumulative dose received remain important risk factors for cyclophosphamide-induced gonadal failure in both males and females. Estrogen-containing oral contraceptives for females and testosterone for males are suggested to reduce the gonadal toxicity of cyclophosphamide, although few studies support these interventions. Owing to increased side effects, hormonal therapy is often avoided in patients with edema, hypertension, nephrotic syndrome or antiphospholipid antibodies. Agonists and antagonists of gonadotropin receptors are under study. Gonadotropin-receptor agonists might have beneficial effects in addition to suppression of sex-hormone production. The outcome of attempted cryopreservation of eggs, embryos or ovaries remains uncertain for women seeking to preserve their reproductive potential. Storing male gametes before chemotherapy is widely practiced and technically successful. As recovery of menses or production of testosterone does not predict individual fertility, identification of biomarkers of gonadal function and reserve, including serum levels of several hormones, ultrasonographic measurements of ovarian volume and antral follicle count, are necessary.

Acute Respiratory Distress Syndrome after Onyx Embolization of Arteriovenous Malformation

PubMed Central

Tawil, Isaac; Carlson, Andrew P.; Taylor, Christopher L.

2011-01-01

Purpose. We report a case of a 60-year-old male who underwent sequential Onyx embolizations of a cerebral arteriovenous malformation (AVM) which we implicate as the most likely etiology of subsequent acute respiratory distress syndrome (ARDS). Methods. Case report and literature review. Results. Shortly after the second Onyx embolization procedure, the patient declined from respiratory failure secondary to pulmonary edema. Clinical entities typically responsible for pulmonary edema including cardiac failure, renal failure, iatrogenic volume overload, negative-pressure pulmonary edema, and infectious etiologies were evaluated and excluded. The patient required mechanical ventilatory support for several days, delaying operative resection. The patient met clinical and radiographic criteria for ARDS. After excluding other etiologies of ARDS, we postulate that ARDS developed as a result of Onyx administration. The Onyx copolymer is dissolved in dimethyl sulfoxide (DMSO), a solvent excreted through the lungs and has been implicated in transient pulmonary side effects. Additionally, a direct toxic effect of the Onyx copolymer is postulated. Conclusion. Onyx embolization and DMSO toxicity are implicated as the etiology of ARDS given the lack of other inciting factors and the close temporal relationship. A strong physiologic rationale provides further support. Clinicians should consider this uncommon but important complication. PMID:21687580

Flame retardants: Dust - And not food - Might be the risk.

PubMed

de Boer, J; Ballesteros-Gómez, A; Leslie, H A; Brandsma, S H; Leonards, P E G

2016-05-01

Flame retardants (FRs) are used to delay ignition of materials such as furniture and electric and electronic instruments. Many FRs are persistent and end up in the environment. Environmental studies on flame retardants (FRs) took off in the late 1990s. Polybrominated diphenylethers (PBDEs) appeared to be bioaccumulative and were found in many organisms all over the world. When PBDEs were banned or their production voluntarily terminated, alternatives appeared on the market that often had similar properties or were of more concern due to their toxicity such as halogenated phosphorus-based FRs. Here we show that in spite of the ban on PBDEs more brominated FRs are being produced, an increasing number of other FRs is being applied and FR levels in our homes are much higher than in the outdoor environment. While nowadays we live in better isolated houses and sit in front of the computer or television, on flame retarded upholstery, we are at risk due to the toxic effects of a suite of FRs. The high exposure to these substances indoors calls for better risk assessments that include mixture effects. Copyright © 2015 Elsevier Ltd. All rights reserved.

The mitochondria-targeted antioxidant MitoQ extends lifespan and improves healthspan of a transgenic Caenorhabditis elegans model of Alzheimer disease.

PubMed

Ng, Li Fang; Gruber, Jan; Cheah, Irwin K; Goo, Chong Kit; Cheong, Wei Fun; Shui, Guanghou; Sit, Kim Ping; Wenk, Markus R; Halliwell, Barry

2014-06-01

β-Amyloid (Aβ)-induced toxicity and oxidative stress have been postulated to play critical roles in the pathogenic mechanism of Alzheimer disease (AD). We investigated the in vivo ability of a mitochondria-targeted antioxidant, MitoQ, to protect against Aβ-induced toxicity and oxidative stress in a Caenorhabditis elegans model overexpressing human Aβ. Impairment of electron transport chain (ETC) enzymatic activity and mitochondrial dysfunction are early features of AD. We show that MitoQ extends lifespan, delays Aβ-induced paralysis, ameliorates depletion of the mitochondrial lipid cardiolipin, and protects complexes IV and I of the ETC. Despite its protective effects on lifespan, healthspan, and ETC function, we find that MitoQ does not reduce DCFDA fluorescence, protein carbonyl levels or modulate steadystate ATP levels or oxygen consumption rate. Moreover, MitoQ does not attenuate mitochondrial DNA (mtDNA) oxidative damage. In agreement with its design, the protective effects of MitoQ appear to be targeted specifically to the mitochondrial membrane and our findings suggest that MitoQ may have therapeutic potential for Aβ- and oxidative stress-associated neurodegenerative disorders, particularly AD. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid Leukemia

PubMed Central

Porter, David L.; Levine, Bruce L.; Kalos, Michael; Bagg, Adam; June, Carl H.

2012-01-01

SUMMARY We designed a lentiviral vector expressing a chimeric antigen receptor with specificity for the B-cell antigen CD19, coupled with CD137 (a costimulatory receptor in T cells [4-1BB]) and CD3-zeta (a signal-transduction component of the T-cell antigen receptor) signaling domains. A low dose (approximately 1.5×105 cells per kilogram of body weight) of autologous chimeric antigen receptor–modified T cells reinfused into a patient with refractory chronic lymphocytic leukemia (CLL) expanded to a level that was more than 1000 times as high as the initial engraftment level in vivo, with delayed development of the tumor lysis syndrome and with complete remission. Apart from the tumor lysis syndrome, the only other grade 3/4 toxic effect related to chimeric antigen receptor T cells was lymphopenia. Engineered cells persisted at high levels for 6 months in the blood and bone marrow and continued to express the chimeric antigen receptor. A specific immune response was detected in the bone marrow, accompanied by loss of normal B cells and leukemia cells that express CD19. Remission was ongoing 10 months after treatment. Hypogammaglobulinemia was an expected chronic toxic effect. PMID:21830940

EFFICIENCY OF PREPARED BAITS OF LONE OR/AND ADMIXED FOUR BOTANICAL OILS ON THE VIABILITY OF SUCCESSIVE RAISED GENERATIONS OF AGROTIS IPSILON (HUFNAGEL) (INSECTA: LEPIDOPTERA: NOCTUIDAE) AFTER TREATING THE PARENT ONES.

PubMed

Mesbah, H A; El-Sayed, Nagda A; El-Kady, Magda B; Tayeb, E H; Mourad, A K; Kordy, A M; Henaidy, Zeinab M

2014-01-01

The present study is initiated to determine the toxic and delayed effects of four botanical oils on the greasy cutworm A. ipsilon, aiming to attain an alternative environmentally safe and effective phytochemicals against the insect-pest. Four botanical oils (camphor, red basil, menthol and rose oil) were added at rates of 0.5 and 1.0% (v/w). The tested oils were added alone, and/or admixed at proportional rate of 1:1 in the prepared baits against the exposed 4th instar till the 6th instar larvae of the insect. The study was run under the laboratory higrothermic conditions of 25±2°C and 65±5% R.H. The results showed that the tested baits of camphor, red basil and menthol oils at concentration rates of 0.5 and 1.0% (v/w) adversely affected the inspected parameters of fitness components of the treated individuals of parent (p) generation. They gave more or less fewer numbers of weak unviable adult-moths, which were either sterile or they laid few numbers of infertile eggs and died before the induction of (F1) progeny. That failure could be elucidated by the rapid occurrence of drastic effects on the biological performance of both the influenced sexes of adult-moths along the period of parent's development. Finally it ended by the inhibited induction of (F1) progeny. A delayed effect of the prepared baits of rose oil at 0.5 and 1.0% (v/w), was assessed on the following raised F1, F2, F3 and F4 generations after parent's treatment. The delayed effect was detected as less efficient latent effect on each of these consequently raised generations; characterized by the gradual decrease of the number of alive immatures and adult-moths. The effect was recorded as gradual increase of dead and malformed individuals and adult-moths. In addition to the gradual decrease of deposited and/or hatched eggs up to the 4th generation, which ended by the complete failure of the development. That failure could be also attributed to the cumulated effects of the induced recessive lethal genes in both the influenced sexes during the periods of raised F1, F2 and F3 generations. The recessive lethal genes caused drastic unprofitable effects that appeared at the beginning of the 4th generation that failed. Also, the tested baits (0.5 and 1.0%, v/w) of each of admixed camphor, red basil and menthol oil with rose oil (1:1), greatly affected the developmental parameters of the treated insects. The highest efficient toxicity and an adverse biological performance of the admixed camphor and/or red basil oils with rose oil at 0.5 and 1.0 (v/w), and menthol/rose oil at 0.5% (v/w) on the treated parent generation were detected. The previous treatment gave unviable sterile adults, which died before the induction of (F1) progeny. That recorded failure of (F1) proves the fastest toxic efficiency and a drastic biological performance which were entirely unable to induce (F1) progeny. The tested bait of mixed menthol/rose oils (1.0%, v/w), showed significant reduction in all studied parameters of F1 and F2 fitness components. The tested bait raised sterile unviable adult-moths of (F2) generation which furtherly ended by the distinct failure of (F2) development. This effect may be caused by the cumulative effects of the induced recessive lethal genes in both of the affected sexes through the developmental period of (F1) generation after (P) one treatment, inducing apparent drastic effects, which were revealed at the beginning of (F2) generation. Remarkably, the inspected faster or slower occurred toxicity and drastic biological performance of these admixed botanical oils, may be referred to the synergistic action for most of the evaluated mixtures or/and the additive one for menthol/rose oil (1.0%), which needs further investigation.

Silver nanoparticles disrupt germline stem cell maintenance in the Drosophila testis

NASA Astrophysics Data System (ADS)

Ong, Cynthia; Lee, Qian Ying; Cai, Yu; Liu, Xiaoli; Ding, Jun; Yung, Lin-Yue Lanry; Bay, Boon-Huat; Baeg, Gyeong-Hun

2016-02-01

Silver nanoparticles (AgNPs), one of the most popular nanomaterials, are commonly used in consumer products and biomedical devices, despite their potential toxicity. Recently, AgNP exposure was reported to be associated with male reproductive toxicity in mammalian models. However, there is still a limited understanding of the effects of AgNPs on spermatogenesis. The fruit fly Drosophila testis is an excellent in vivo model to elucidate the mechanisms underlying AgNP-induced defects in spermatogenesis, as germ lineages can be easily identified and imaged. In this study, we evaluated AgNP-mediated toxicity on spermatogenesis by feeding Drosophila with AgNPs at various concentrations. We first observed a dose-dependent uptake of AgNPs in vivo. Concomitantly, AgNP exposure caused a significant decrease in the viability and delay in the development of Drosophila in a dose-dependent manner. Furthermore, AgNP-treated male flies showed a reduction in fecundity, and the resulting testes contained a decreased number of germline stem cells (GSCs) compared to controls. Interestingly, testes exposed to AgNPs exhibited a dramatic increase in reactive oxygen species levels and showed precocious GSC differentiation. Taken together, our study suggests that AgNP exposure may increase ROS levels in the Drosophila testis, leading to a reduction of GSC number by promoting premature GSC differentiation.

Facile preparation of paclitaxel loaded silk fibroin nanoparticles for enhanced antitumor efficacy by locoregional drug delivery.

PubMed

Wu, Puyuan; Liu, Qin; Li, Rutian; Wang, Jing; Zhen, Xu; Yue, Guofeng; Wang, Huiyu; Cui, Fangbo; Wu, Fenglei; Yang, Mi; Qian, Xiaoping; Yu, Lixia; Jiang, Xiqun; Liu, Baorui

2013-12-11

Non-toxic, safe materials and preparation methods are among the most important factors when designing nanoparticles (NPs) for future clinical application. Here we report a novel and facile method encapsulating anticancer drug paclitaxel (PTX) into silk fibroin (SF), a biocompatible and biodegradable natural polymer, without adding any toxic organic solvents, surfactants or other toxic agents. The paclitaxel loaded silk fibroin nanoparticles (PTX-SF-NPs) with a diameter of 130 nm were formed in an aqueous solution at room temperature by self-assembling of SF protein, which demonstrated mainly silk I conformation in the NPs. In cellular uptake experiments, coumarin-6 loaded SF NPs were taken up efficiently by two human gastric cancer cell lines BGC-823 and SGC-7901. In vitro cytotoxicity studies demonstrated that PTX kept its pharmacological activity when incorporating into PTX-SF-NPs, while SF showed no cytotoxicity to cells. The in vivo antitumor effects of PTX-SF-NPs were evaluated on gastric cancer nude mice exnograft model. We found that locoregional delivery of PTX-SF-NPs demonstrated superior antitumor efficacy by delaying tumor growth and reducing tumor weights compared with systemic administration. Furthermore, the organs of mice in NP treated groups didn't show obvious toxicity, indicating the in vivo safety of SF NPs. These results suggest that SF NPs are promising drug delivery carriers, and locoregional delivery of SF NPs could be a potential future clinical cancer treatment regimen.

Organophosphorus pesticides effect on early stages of the axolotl Ambystoma mexicanum (Amphibia: Caudata).

PubMed

Robles-Mendoza, C; García-Basilio, C; Cram-Heydrich, S; Hernández-Quiroz, M; Vanegas-Pérez, C

2009-02-01

Ambystoma mexicanum is an endemic salamander of Xochimilco, a wetland of the basin of Mexico valley. Nowadays, axolotl populations are decreasing due environmental stressors. Particularly, studies about organophosphorus pesticides (OPPs; i.e. chlorpyrifos and malathion) toxicity are of great importance due to their intensive use in agricultural activities in Xochimilco. Thus, the aim of this study was to evaluate under controlled conditions the toxicity of chlorpyrifos (CPF) and malathion (MLT) on embryos and larvae (stage 44 and 54) of A. mexicanum. Embryos and larvae were exposure 96h from 0.5 to 3mg CPFL(-1) and from 10 to 30mg MLTL(-1) in independent tests. Embryos at the end of this period were maintained 9d without pesticide in order to identify possible recuperation. Differences obtained in mortality, hatching success, development, morphological abnormalities, behaviour and activity, suggest that toxicity of CPF and MLT differs in embryos and larval stages. Embryos were less sensitive to OPPs acute exposure than axolotl larvae; additionally, toxicity of CPF in larval stages was greater than MLT. On the other hand, data obtained in axolotl embryos during the period of recuperation to CPF in particular as delay and inhibition of development, malformations and success of hatching, indicated that these responses turned out more sensitive than mortality. This study allowed to identify the toxicological potential of OPPs on early developmental stages of A. mexicanum and it is a valuable contribution for the future management of the axolotl wild population.

Comprehensive assessment of a chlorinated drinking water concentrate in a rat multigenerational reproductive toxicity study.

PubMed

Narotsky, Michael G; Klinefelter, Gary R; Goldman, Jerome M; Best, Deborah S; McDonald, Anthony; Strader, Lillian F; Suarez, Juan D; Murr, Ashley S; Thillainadarajah, Inthirany; Hunter, E Sidney; Richardson, Susan D; Speth, Thomas F; Miltner, Richard J; Pressman, Jonathan G; Teuschler, Linda K; Rice, Glenn E; Moser, Virginia C; Luebke, Robert W; Simmons, Jane Ellen

2013-09-17

Some epidemiological studies report associations between drinking water disinfection byproducts (DBPs) and adverse reproductive/developmental effects, e.g., low birth weight, spontaneous abortion, stillbirth, and birth defects. Using a multigenerational rat bioassay, we evaluated an environmentally relevant "whole" mixture of DBPs representative of chlorinated drinking water, including unidentified DBPs as well as realistic proportions of known DBPs at low-toxicity concentrations. Source water from a water utility was concentrated 136-fold, chlorinated, and provided as drinking water to Sprague-Dawley rats. Timed-pregnant females (P0 generation) were exposed during gestation and lactation. Weanlings (F1 generation) continued exposures and were bred to produce an F2 generation. Large sample sizes enhanced statistical power, particularly for pup weight and prenatal loss. No adverse effects were observed for pup weight, prenatal loss, pregnancy rate, gestation length, puberty onset in males, growth, estrous cycles, hormone levels, immunological end points, and most neurobehavioral end points. Significant, albeit slight, effects included delayed puberty for F1 females, reduced caput epidydimal sperm counts in F1 adult males, and increased incidences of thyroid follicular cell hypertrophy in adult females. These results highlight areas for future research, while the largely negative findings, particularly for pup weight and prenatal loss, are notable.

Secrets of the lac operon. Glucose hysteresis as a mechanism in dietary restriction, aging and disease.

PubMed

Mobbs, Charles V; Mastaitis, Jason W; Zhang, Minhua; Isoda, Fumiko; Cheng, Hui; Yen, Kelvin

2007-01-01

Elevated blood glucose associated with diabetes produces progressive and apparently irreversible damage to many cell types. Conversely, reduction of glucose extends life span in yeast, and dietary restriction reduces blood glucose. Therefore it has been hypothesized that cumulative toxic effects of glucose drive at least some aspects of the aging process and, conversely, that protective effects of dietary restriction are mediated by a reduction in exposure to glucose. The mechanisms mediating cumulative toxic effects of glucose are suggested by two general principles of metabolic processes, illustrated by the lac operon but also observed with glucose-induced gene expression. First, metabolites induce the machinery of their own metabolism. Second, induction of gene expression by metabolites can entail a form of molecular memory called hysteresis. When applied to glucose-regulated gene expression, these two principles suggest a mechanism whereby repetitive exposure to postprandial excursions of glucose leads to an age-related increase in glycolytic capacity (and reduction in beta-oxidation of free fatty acids), which in turn leads to an increased generation of oxidative damage and a decreased capacity to respond to oxidative damage, independent of metabolic rate. According to this mechanism, dietary restriction increases life span and reduces pathology by reducing exposure to glucose and therefore delaying the development of glucose-induced glycolytic capacity.

Uranium: A Dentist's perspective

PubMed Central

Toor, R. S. S.; Brar, G. S.

2012-01-01

Uranium is a naturally occurring radionuclide found in granite and other mineral deposits. In its natural state, it consists of three isotopes (U-234, U-235 and U-238). On an average, 1% – 2% of ingested uranium is absorbed in the gastrointestinal tract in adults. The absorbed uranium rapidly enters the bloodstream and forms a diffusible ionic uranyl hydrogen carbonate complex (UO2HCO3+) which is in equilibrium with a nondiffusible uranyl albumin complex. In the skeleton, the uranyl ion replaces calcium in the hydroxyapatite complex of the bone crystal. Although in North India, there is a risk of radiological toxicity from orally ingested natural uranium, the principal health effects are chemical toxicity. The skeleton and kidney are the primary sites of uranium accumulation. Acute high dose of uranyl nitrate delays tooth eruption, and mandibular growth and development, probably due to its effect on target cells. Based on all previous research and recommendations, the role of a dentist is to educate the masses about the adverse effects of uranium on the overall as well as the dental health. The authors recommended that apart from the discontinuation of the addition of uranium to porcelain, the Public community water supplies must also comply with the Environmental Protection Agency (EPA) standards of uranium levels being not more than 30 ppb (parts per billion). PMID:24478959

Partial life-cycle toxicity and bioconcentration modeling of perfluorooctanesulfonate in the northern leopard frog (Rana pipiens).

PubMed

Ankley, Gerald T; Kuehl, Douglas W; Kahl, Michael D; Jensen, Kathleen M; Butterworth, Brian C; Nichols, John W

2004-11-01

A number of recent monitoring studies have demonstrated elevated concentrations of perfluorooctanesulfonate (PFOS) in humans and wildlife throughout the world. Although no longer manufactured in the United States, the global distribution and relative persistence of PFOS indicates a need to understand its potential ecological effects. Presently, little is known concerning toxicity of PFOS in chronic exposures with aquatic species. Therefore, we evaluated the effects of PFOS on survival and development of the northern leopard frog (Rana pipiens) from early embryogenesis through complete metamorphosis. Exposures were conducted via water at measured PFOS concentrations ranging from 0.03 to 10 mg/L. Animals exposed to 10 mg/L began dying within approximately two weeks of test initiation. Survival was not affected by PFOS at lower concentrations; however, time to metamorphosis was delayed and growth reduced in the 3-mg/L treatment group. Tadpoles readily accumulated PFOS directly from water. Using a one-compartment bioaccumulation model, growth was shown to have a modest impact on steady-state PFOS concentrations. Variability in observed growth rates and the possible contribution of a size-dependent decrease in PFOS elimination rate contributed uncertainty to modeling efforts. Nevertheless, fitted uptake and elimination rate constants were comparable to those determined in earlier studies with juvenile rainbow trout. Overall, our studies suggest that R. pipiens is not exceptionally sensitive to PFOS in terms of either direct toxicity or bioconcentration potential of the chemical.

Essential oils and Beauveria bassiana against Dermanyssus gallinae (Acari: Dermanyssidae): Towards new natural acaricides.

PubMed

Immediato, Davide; Figueredo, Luciana Aguiar; Iatta, Roberta; Camarda, Antonio; de Luna, Rafaela Lira Nogueira; Giangaspero, Annunziata; Brandão-Filho, Sinval Pinto; Otranto, Domenico; Cafarchia, Claudia

2016-10-15

Essential oils (EOs) and entomopathogenic fungi such as Beauveria bassiana (Bb) strains have the potential to be used as alternative insecticides and acaricides for controlling ectoparasites as Dermanyssus gallinae. These compounds have some limitations in their use: the acaricidal effect of EOs is rapid, but short-lived, whilst that of Bb is delayed, but long-lived. To evaluate the effect of both compounds combined against D. gallinae, the non-toxic dose of Eucalyptus globulus, Eucalyptus citriodora, Thymus vulgaris and Eugenia caryophyllata essential oils were firstly calculated for "native" strains of Bb. Subsequently, the effects of the combination of selected EOs with Bb against nymph and adult poultry red mites (PRMs) was assessed. EO concentrations ranging from 0.0015 to 8% v/v (i.e., nine double dilutions) were used to evaluate their effect on germination, sporulation and vegetative growth rates of native strains of Bb. A total of 1440 mites (720 nymphs and 720 adults) were divided into three-treated group (TGs) and one control group (CG). In TGs, mites were exposed to Bb in combination with the selected EO (TG1), EO alone (TG2) or Bb (TG3) alone. In the CG, mites were exposed to 0.1% tween 80 plus EO solvent (CG). E. globulus and E. citriodora were toxic for Bb in concentrations higher than 0.2% and 0.003% respectively, whilst E. caryophyllata and T. vulgaris were toxic at all concentrations tested against Bb. Based on the results of the toxicity assays against Bb, E. globulus was chosen to be tested as acaricide resulting non-toxic for Bb at concentration lower than 0.4%. Increased mortality of D. gallinae adults was recorded in TG1 than those in other TGs from 4days post-infection (T+4DPI). A 100% mortality of D. gallinae was recorded in adults at T+9DPI and at T+10DPI in nymphs in TG1 and later than T+11DPI in the other TGs. Used in combination with E. globulus, Bb displayed an earlier acaricidal effect towards both haematophagous D. gallinae stages. The combination of B. bassiana and E. globulus at 0.2% might be used for controlling arthropods of medical and veterinary importance as D. gallinae. Copyright © 2016 Elsevier B.V. All rights reserved.

40 CFR 104.7 - Powers of Presiding Officer.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 21 2010-07-01 2010-07-01 false Powers of Presiding Officer. 104.7... HEARINGS ON EFFLUENT STANDARDS FOR TOXIC POLLUTANTS § 104.7 Powers of Presiding Officer. The Presiding...) of the Act. He shall take all necessary action to avoid delay and to maintain order. He shall have...

40 CFR 104.7 - Powers of Presiding Officer.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 22 2011-07-01 2011-07-01 false Powers of Presiding Officer. 104.7... HEARINGS ON EFFLUENT STANDARDS FOR TOXIC POLLUTANTS § 104.7 Powers of Presiding Officer. The Presiding...) of the Act. He shall take all necessary action to avoid delay and to maintain order. He shall have...

Lethality and Developmental Delay of Drosophila melanogaster Following Ingestion of Selected Pseudomonas fluorescens Strains

USDA-ARS?s Scientific Manuscript database

Pseudomonas fluorescens secretes antimicrobial compounds that promote plant health and provide protection from pathogens. We used a non-invasive feeding assay to study the toxicity of P. fluorescens strains Pf0-1, SBW25, and Pf-5 to Drosophila melanogaster. The three strains of P. fluorescens varie...

Respiratory Complications of Organophosphorus Nerve Agent and Insecticide Poisoning. Implications for Respiratory and Critical Care

PubMed Central

Hulse, Elspeth J.; Davies, James O. J.; Simpson, A. John; Sciuto, Alfred M.

2014-01-01

Organophosphorus (OP) compound poisoning is a major global public health problem. Acute OP insecticide self-poisoning kills over 200,000 people every year, the majority from self-harm in rural Asia. Highly toxic OP nerve agents (e.g., sarin) are a significant current terrorist threat, as shown by attacks in Damascus during 2013. These anticholinesterase compounds are classically considered to cause an acute cholinergic syndrome with decreased consciousness, respiratory failure, and, in the case of insecticides, a delayed intermediate syndrome that requires prolonged ventilation. Acute respiratory failure, by central and peripheral mechanisms, is the primary cause of death in most cases. However, preclinical and clinical research over the last two decades has indicated a more complex picture of respiratory complications after OP insecticide poisoning, including onset of delayed neuromuscular junction dysfunction during the cholinergic syndrome, aspiration causing pneumonia and acute respiratory distress syndrome, and the involvement of solvents in OP toxicity. The treatment of OP poisoning has not changed over the last 50 years. However, a better understanding of the multiple respiratory complications of OP poisoning offers additional therapeutic opportunities. PMID:25419614

Application of Caenorhabditis elegans (nematode) and Danio rerio embryo (zebrafish) as model systems to screen for developmental and reproductive toxicity of Piperazine compounds.

PubMed

Racz, Peter I; Wildwater, Marjolein; Rooseboom, Martijn; Kerkhof, Engelien; Pieters, Raymond; Yebra-Pimentel, Elena Santidrian; Dirks, Ron P; Spaink, Herman P; Smulders, Chantal; Whale, Graham F

2017-10-01

To enable selection of novel chemicals for new processes, there is a recognized need for alternative toxicity screening assays to assess potential risks to man and the environment. For human health hazard assessment these screening assays need to be translational to humans, have high throughput capability, and from an animal welfare perspective be harmonized with the principles of the 3Rs (Reduction, Refinement, Replacement). In the area of toxicology a number of cell culture systems are available but while these have some predictive value, they are not ideally suited for the prediction of developmental and reproductive toxicology (DART). This is because they often lack biotransformation capacity, multicellular or multi- organ complexity, for example, the hypothalamus pituitary gonad (HPG) axis and the complete life cycle of whole organisms. To try to overcome some of these limitations in this study, we have used Caenorhabditis elegans (nematode) and Danio rerio embryos (zebrafish) as alternative assays for DART hazard assessment of some candidate chemicals being considered for a new commercial application. Nematodes exposed to Piperazine and one of the analogs tested showed a slight delay in development compared to untreated animals but only at high concentrations and with Piperazine as the most sensitive compound. Total brood size of the nematodes was also reduced primarily by Piperazine and one of the analogs. In zebrafish Piperazine and analogs showed developmental delays. Malformations and mortality in individual fish were also scored. Significant malformations were most sensitively identified with Piperazine, significant mortality was only observed in Piperazine and only at the higest dose. Thus, Piperazine seemed the most toxic compound for both nematodes and zebrafish. The results of the nematode and zebrafish studies were in alignment with data obtained from conventional mammalian toxicity studies indicating that these have potential as developmental toxicity screening systems. The results of these studies also provided reassurance that none of the Piperazines tested are likely to have any significant developmental and/or reproductive toxicity issues to humans when used in their commercial applications. Copyright © 2017. Published by Elsevier Ltd.

Using anti-VEGF McAb and magnetic nanoparticles as double-targeting vector for the radioimmunotherapy of liver cancer.

PubMed

Chen, Jing; Wu, Hua; Han, Deyan; Xie, Changsheng

2006-01-18

To study the biodistribution of a new radioimmunoconjugate-131I-anti-VEGF monoclonal antibody (Sc-7269)-Dextran Magnetic Nanoparticles (DMN) in nude mice bearing human liver cancer where an external magnetic field was focused on, and to evaluate its therapeutic effects and safety. Tumor Growth Delay (TGD) and tumor inhibition rate were observed as antitumor effect. Peripheral white blood cells counts and the loss of body weight were tested as an indicator of systemic toxicity. The results suggests that the radioimmunotherapy of intratumoral injection of 131I-Sc-7269-DMN may be safe and efficient for the treatment of liver cancer. Furthermore, the radioimmunotherapy using DMN as a 'carrier system' may be a highly potential approach in the treatment of other kind of tumors.

More severe toxicity of genetic polymorphisms on MTHFR activity in osteosarcoma patients treated with high-dose methotrexate

PubMed Central

Xie, Lu; Guo, Wei; Yang, Yi; Ji, Tao; Xu, Jie

2018-01-01

5,10-Methylenetrahydrofolate reductase (MTHFR), a key enzyme for folate metabolism, catalyses the irreversible conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is located at the end of the short arm (1p36.3). Two common non-synonymous variants, the C677T (Ala222Val) and A1298C (Glu429Ala), were mainly described with decreased enzymatic activity and an alteration of intracellular folate distribution. Osteosarcomas are currently treated with high dose of methotrexate (MTX). The decreased enzyme activity of MTHFR theoretically could increase the drug action of MTX and at the same time increase toxic and side effect. Germline variants of C677T and A1298C were studied in 59 osteosarcoma patients, with whom the A1298C is detected with particularly low rate of mutant genotype (N = 1, 0.8%) and could not proceed with statistical calculations. 15 patients were wild type of C677T (CC, 25.4%), 20 were heterozygous mutant genotype (CT, 33.9%) and 24 were homozygous mutant genotype (TT, 40.7%). Patients harboring the TT/CT genotype had the same progression-free survival and tumor necrosis rate in comparison with patients having the CC genotype (P = 0.349 and P = 0.465 respectively). And the C677T polymorphisms had no significant correlation with MTX initial plasma concentration (P = 0.867; r = 0.024) and delayed elimination (P = 0.305; r = −0.136). However patients with mutant genotype of C677T were associated with higher degree of liver toxicity (P = 0.043) and fever reaction of MTX (P = 0.050) while G3/G4 hematologic toxicity were more likely to be noticed with TT than CT/CC (P = 0.095). The study suggests that genetic polymorphism of MTHFR C677T in the MTX metabolic pathway seems to be associated with the trend for more side effects statistically, but has no obvious effect on histologic response and survival. PMID:29545912

ERG and other discriminators between advanced hydroxychloroquine retinopathy and retinitis pigmentosa.

PubMed

Nair, Archana A; Marmor, Michael F

2017-06-01

To study whether the ERG and other clinical findings help to distinguish between advanced hydroxychloroquine (HCQ) retinopathy and pericentral or diffuse retinitis pigmentosa (RP) with similar fundus appearance. We conducted a retrospective analysis of patients with advanced HCQ retinopathy (n = 11), pericentral RP (n = 8) and diffuse RP (n = 8). Pericentral RP was defined as having limited fundus damage and relatively normal flicker ERG time-to-peak. Diffuse RP had typical loss of the rod ERG and flicker timing delay. All patients showed reduced amplitude of the ISCEV responses in the full-field electroretinogram (ERG). Aspects of history, visual field results, fundus appearance, fundus autofluorescence and ocular coherence tomography were also compared. Relative to pericentral RP, patients with HCQ toxicity showed delayed flicker ERG time-to-peak and lower ERG amplitudes, particularly combined rod-cone responses. Relative to diffuse RP, most HCQ toxicity patients had some preserved rod ERG response, and there was no obvious predilection for rod over cone damage. In addition, patients with HCQ toxicity usually lacked markers of long-standing degeneration such as bone spicule figures or severe loss of peripheral field. History of familial disease and long-standing night blindness were specific to RP. While the early signs of HCQ damage are typically regional in the posterior pole, advanced disease is characteristically diffuse (unlike pericentral RP). This is appropriate for a systemic toxin, as is the finding that rods and cones were both affected in the ERG to a similar degree (unlike genetic rod-cone dystrophies). For patients with severe HCQ exposure and some of our discriminatory findings, and no family history or prior night blindness, HCQ toxicity is a sufficient diagnosis without invoking a second rare disease (Occam's razor).

Two-week course of preoperative chemoradiotherapy followed by delayed surgery for rectal cancer: a phase II multi-institutional clinical trial (KROG 11-02).

PubMed

Lee, Jong Hoon; Kim, Jun-Gi; Oh, Seong Taek; Lee, Myung Ah; Chun, Hoo Geun; Kim, Dae Yong; Kim, Tae Hyun; Kim, Sun Young; Baek, Ji Yeon; Park, Ji Won; Oh, Jae Hwan; Park, Hee Chul; Choi, Doo Ho; Park, Young Suk; Kim, Hee Cheol; Chie, Eui Kyu; Jang, Hong Seok

2014-01-01

The aim of this study was to evaluate the efficacy and safety of a two-week schedule of radiotherapy with oral capecitabine in locally advanced rectal cancer. Eighty patients with rectal cancer located in the mid to low rectum, staged cT3-4N0-2M0, were prospectively enrolled. They underwent preoperative chemoradiotherapy and delayed surgery 6-8 weeks after the completion of radiation therapy. A radiation dose of 33 Gy in 10 fractions was delivered to the pelvis for 2 weeks. One cycle of oral capecitabine was administered at a dose of 1650 mg/m(2)/day during radiotherapy. Tumor response and toxicity were the study endpoints. This study was registered at ClinicalTrials.gov (number, NCT01431599). All included patients underwent total mesorectal excisions including 12 cases of robot assisted surgery and 50 cases of laparoscopic surgery. Of the 80 patients, 27 (33.8%) achieved downstaging (ypT0-2N0) of a rectal tumor and 11 (13.8%) had a pathologically complete response (ypCR). Downstaging rates were 45% for T classification and 65% for N classification. Sphincter saving was achieved in 73 (91.3%) of the 80 patients. Of the 80 patients, 3 (3.8%) experienced grade 3 hematologic toxicity, and 2 (2.5%) had grade 3 postoperative complications such as ileus and wound dehiscence. There was no grade 4 toxicity. A two-week schedule of radiotherapy with oral capecitabine in locally advanced rectal cancer patients showed low toxicity profiles and promising results in terms of tumor response. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Recommended health and safety guidelines for coal gasification pilot plants

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

Not Available

1978-01-01

The greatest toxic hazards in coal conversion are presented by the known and suspected carcinogens, because they are hazardous at low levels of exposure, have delayed action with no immediate warning, and have grave consequences. As for routes of entry, it is to be noted that various solids and liquids may reach the body by inhalation of particles, deposition of particles, or indirectly by contact with dirty surfaces. Other toxicants are most likely to enter the body by inhalation. The overall carcinogenic hazard cannot be precisely estimated from chemical analysis alone, because the possible interactions are far too complex. Further,more » the hazard cannot at present be quantitatively defined by available biological tests. The same limitations probably apply to toxic effects other than carcinogenesis, with the posible exception of some immediate responses (e.g., chemical asphyxia, primary respiratory irration). It is not practical to recommend comprehensive workplace exposure limits on a basis similar to those for individual toxicants; however, a limit for one important kind of hazard (high-boiling suspected carcinogens) can be recommended. The carcinogenic hazards associated with airborne particles and surface contamination are the most crucial of the whole spectrum and offer a practical target for control, if not for quantitative evaluation. The only direct quantitative evidence now availabl is from epidemiology in analogous circulstances and there are severe limitations on the comprehensiveness and reliability of such evidence. Some specific targets for control through industrial hygiene practices can be identified. The presence of any strong irritant of the respiratory mucosa, other mucous surfaces, and the skin should be regarded as a danger signal because of possible potentiation of carcinogens and other toxicants.« less

Intrathecal application of the nimodipine slow-release microparticle system eg-1962 for prevention of delayed cerebral ischemia and improvement of outcome after aneurysmal subarachnoid hemorrhage.

PubMed

Etminan, Nima; Macdonald, R Loch; Davis, Cara; Burton, Kevin; Steiger, Hans-Jakob; Hänggi, Daniel

2015-01-01

The effective reduction of delayed cerebral ischemia (DCI), a main contributor for poor outcome following aneurysmal subarachnoid hemorrhage (SAH), remains challenging. Previous clinical trials on systemic pharmaceutical treatment of SAH mostly failed to improve outcome, probably because of insensitive pharmaceutical targets and outcome measures, small sample size, insufficient subarachnoid drug concentrations and also detrimental, systemic effects of the experimental treatment per se. Interestingly, in studies that are more recent, intrathecal administration of nicardipine pellets following surgical aneurysm repair was suggested to have a beneficial effect on DCI and neurological outcome. However, this positive effect remained restricted to patients who were treated surgically for a ruptured aneurysm. Because of the favorable results of the preclinical data on DCI and neurological outcome in the absence of neurotoxicity or systemic side effects, we are initiating clinical trials. The PROMISE (Prolonged Release nimOdipine MIcro particles after Subarachnoid hemorrhage) trial is designed as an unblinded, nonrandomized, single-center, single-dose, dose-escalation safety and tolerability phase 1 study in patients surgically treated for aSAH and will investigate the effect of intracisternal EG-1962 administration. The NEWTON (Nimodipine microparticles to Enhance recovery While reducing TOxicity after subarachNoid hemorrhage) trial is a phase 1/2a multicenter, controlled, randomized, open-label, dose-escalation, safety, tolerability, and pharmacokinetic study comparing EG-1962 and nimodipine in patients with aneurysmal SAH.

The Effects of Hempseed Meal Intake and Linoleic Acid on Drosophila Models of Neurodegenerative Diseases and Hypercholesterolemia

PubMed Central

Lee, Min Jung; Park, Seung Hwan; Han, Ju Hua; Hong, Yoon Ki; Hwang, Soojin; Lee, Soojin; Kim, Darae; Han, Seung Yeop; Kim, Eun Soo; Cho, Kyoung Sang

2011-01-01

Hempseed is rich in polyunsaturated fatty acids (PUFAs), which have potential as therapeutic compounds for the treatment of neurodegenerative and cardiovascular dis-ease. However, the effect of hempseed meal (HSM) intake on the animal models of these diseases has yet to be elucidated. In this study, we assessed the effects of the intake of HSM and PUFAs on oxidative stress, cytotoxicity and neurological phenotypes, and cholesterol uptake, using Drosophila models. HSM intake was shown to reduce H2O2 toxicity markedly, indicating that HSM exerts a profound antioxidant effect. Meanwhile, intake of HSM, as well as linoleic or linolenic acids (major PUFA components of HSM) was shown to ameliorate Aβ42-induced eye degeneration, thus suggesting that these compounds exert a protective effect against Aβ42 cytotoxicity. On the contrary, locomotion and longevity in the Parkinson’s disease model andeye degeneration in the Huntington’s disease model were unaffected by HSM feeding. Additionally, intake of HSM or linoleic acid was shown to reduce cholesterol uptake significantly. Moreover, linoleic acid intake has been shown to delay pupariation, and cholesterol feeding rescued the linoleic acid-induced larval growth delay, thereby indicating that linoleic acid acts antagonistically with cholesterol during larval growth. In conclusion, our results indicate that HSM and linoleic acid exert inhibitory effects on both Aβ42 cytotoxicity and cholesterol uptake, and are potential candidates for the treatment of Alzheimer’s disease and cardiovasculardisease. PMID:21331775

Implications for Ophthalmic Formulations: Ocular Buffers Show Varied Cytotoxic Impact on Human Corneal-Limbal and Human Conjunctival Epithelial Cells.

PubMed

Schuerer, Nadine; Stein, Elisabeth; Inic-Kanada, Aleksandra; Pucher, Marion; Hohenadl, Christine; Bintner, Nora; Ghasemian, Ehsan; Montanaro, Jacqueline; Barisani-Asenbauer, Talin

2017-06-01

To investigate toxicity associated with buffers commonly used in topical ocular drug formulations using a human corneal-limbal epithelial (HCLE) and a human conjunctival epithelial (HCjE) cell model. HCLE and HCjE cells were incubated for 10, 30, or 60 minutes with 4 different buffers based on borate, citrate, phosphate, and Tris-HCl at 10, 50, and 100 mM concentrations. To detect possible delayed effects on cell viability, after 60 minutes of buffer incubation, cells were further incubated for 24 hours with a cell medium. Cell viability was determined using a colorimetric XTT-based assay. The morphology of cells was also investigated. HCjE cells showed more sensitivity to buffer incubation than HCLE cells. The 100 mM phosphate buffer displayed significant delayed effects on cell viability of HCLE 16.8 ± 4.8% and HCjE 39.2 ± 6.1% cells after 60 minutes of exposure (P < 0.05). HCjE cell viability was reduced after 60 minutes incubations with 50 and 100 mM citrate buffer to 42.8 ± 6.5% and 39.3 ± 7.9%, respectively, and even lower percentages at the delayed time point (both P < 0.05). HCLE cell morphology was distinctly altered by 100 mM phosphate and Tris buffers after 30 minutes, whereas HCjE cells already showed marked changes after 10 minutes of exposure to 100 mM citrate and phosphate buffers. We observed a time-dependent decrease of viability in both HCLE and HCjE cells exposed to higher buffer concentrations. Therefore, we propose further in vivo studies to translate these finding to humans to discern the real effects of the buffer concentration in eye drops on the ocular surface.

Implications for Ophthalmic Formulations: Ocular Buffers Show Varied Cytotoxic Impact on Human Corneal–Limbal and Human Conjunctival Epithelial Cells

PubMed Central

Schuerer, Nadine; Stein, Elisabeth; Inic-Kanada, Aleksandra; Pucher, Marion; Hohenadl, Christine; Bintner, Nora; Ghasemian, Ehsan; Montanaro, Jacqueline

2017-01-01

Purpose: To investigate toxicity associated with buffers commonly used in topical ocular drug formulations using a human corneal–limbal epithelial (HCLE) and a human conjunctival epithelial (HCjE) cell model. Methods: HCLE and HCjE cells were incubated for 10, 30, or 60 minutes with 4 different buffers based on borate, citrate, phosphate, and Tris-HCl at 10, 50, and 100 mM concentrations. To detect possible delayed effects on cell viability, after 60 minutes of buffer incubation, cells were further incubated for 24 hours with a cell medium. Cell viability was determined using a colorimetric XTT–based assay. The morphology of cells was also investigated. Results: HCjE cells showed more sensitivity to buffer incubation than HCLE cells. The 100 mM phosphate buffer displayed significant delayed effects on cell viability of HCLE 16.8 ± 4.8% and HCjE 39.2 ± 6.1% cells after 60 minutes of exposure (P < 0.05). HCjE cell viability was reduced after 60 minutes incubations with 50 and 100 mM citrate buffer to 42.8 ± 6.5% and 39.3 ± 7.9%, respectively, and even lower percentages at the delayed time point (both P < 0.05). HCLE cell morphology was distinctly altered by 100 mM phosphate and Tris buffers after 30 minutes, whereas HCjE cells already showed marked changes after 10 minutes of exposure to 100 mM citrate and phosphate buffers. Conclusions: We observed a time-dependent decrease of viability in both HCLE and HCjE cells exposed to higher buffer concentrations. Therefore, we propose further in vivo studies to translate these finding to humans to discern the real effects of the buffer concentration in eye drops on the ocular surface. PMID:28399036

Mitochondrial pharmacology: electron transport chain bypass as strategies to treat mitochondrial dysfunction.

PubMed

Atamna, Hani; Mackey, Jeanette; Dhahbi, Joseph M

2012-01-01

Mitochondrial dysfunction (primary or secondary) is detrimental to intermediary metabolism. Therapeutic strategies to treat/prevent mitochondrial dysfunction could be valuable for managing metabolic and age-related disorders. Here, we review strategies proposed to treat mitochondrial impairment. We then concentrate on redox-active agents, with mild-redox potential, who shuttle electrons among specific cytosolic or mitochondrial redox-centers. We propose that specific redox agents with mild redox potential (-0.1 V; 0.1 V) improve mitochondrial function because they can readily donate or accept electrons in biological systems, thus they enhance metabolic activity and prevent reactive oxygen species (ROS) production. These agents are likely to lack toxic effects because they lack the risk of inhibiting electron transfer in redox centers. This is different from redox agents with strong negative (-0.4 V; -0.2 V) or positive (0.2 V; 0.4 V) redox potentials who alter the redox status of redox-centers (i.e., become permanently reduced or oxidized). This view has been demonstrated by testing the effect of several redox active agents on cellular senescence. Methylene blue (MB, redox potential ≅10 mV) appears to readily cycle between the oxidized and reduced forms using specific mitochondrial and cytosolic redox centers. MB is most effective in delaying cell senescence and enhancing mitochondrial function in vivo and in vitro. Mild-redox agents can alter the biochemical activity of specific mitochondrial components, which then in response alters the expression of nuclear and mitochondrial genes. We present the concept of mitochondrial electron-carrier bypass as a potential result of mild-redox agents, a method to prevent ROS production, improve mitochondrial function, and delay cellular aging. Thus, mild-redox agents may prevent/delay mitochondria-driven disorders. Copyright © 2012 International Union of Biochemistry and Molecular Biology, Inc.

Incident Learning and Failure-Mode-and-Effects-Analysis Guided Safety Initiatives in Radiation Medicine

PubMed Central

Kapur, Ajay; Goode, Gina; Riehl, Catherine; Zuvic, Petrina; Joseph, Sherin; Adair, Nilda; Interrante, Michael; Bloom, Beatrice; Lee, Lucille; Sharma, Rajiv; Sharma, Anurag; Antone, Jeffrey; Riegel, Adam; Vijeh, Lili; Zhang, Honglai; Cao, Yijian; Morgenstern, Carol; Montchal, Elaine; Cox, Brett; Potters, Louis

2013-01-01

By combining incident learning and process failure-mode-and-effects-analysis (FMEA) in a structure-process-outcome framework we have created a risk profile for our radiation medicine practice and implemented evidence-based risk-mitigation initiatives focused on patient safety. Based on reactive reviews of incidents reported in our departmental incident-reporting system and proactive FMEA, high safety-risk procedures in our paperless radiation medicine process and latent risk factors were identified. Six initiatives aimed at the mitigation of associated severity, likelihood-of-occurrence, and detectability risks were implemented. These were the standardization of care pathways and toxicity grading, pre-treatment-planning peer review, a policy to thwart delay-rushed processes, an electronic whiteboard to enhance coordination, and the use of six sigma metrics to monitor operational efficiencies. The effectiveness of these initiatives over a 3-years period was assessed using process and outcome specific metrics within the framework of the department structure. There has been a 47% increase in incident-reporting, with no increase in adverse events. Care pathways have been used with greater than 97% clinical compliance rate. The implementation of peer review prior to treatment-planning and use of the whiteboard have provided opportunities for proactive detection and correction of errors. There has been a twofold drop in the occurrence of high-risk procedural delays. Patient treatment start delays are routinely enforced on cases that would have historically been rushed. Z-scores for high-risk procedures have steadily improved from 1.78 to 2.35. The initiatives resulted in sustained reductions of failure-mode risks as measured by a set of evidence-based metrics over a 3-years period. These augment or incorporate many of the published recommendations for patient safety in radiation medicine by translating them to clinical practice. PMID:24380074

HI-6 assisted Catalytic Scavenging of VX by Acetylcholinesterase Choline Binding Site Mutants

PubMed Central

Hrvat, Nikolina Maček; Žunec, Suzana; Taylor, Palmer; Radić, Zoran; Kovarik, Zrinka

2016-01-01

The high toxicity of organophosphorus compounds originates from covalent inhibition of acetylcholinesterase (AChE), an essential enzyme in cholinergic neurotransmission. Poisonings that lead to life-threatening toxic manifestations require immediate treatment that combines administration of anticholinergic drugs and an aldoxime as a reactivator of AChE. An alternative approach to reduce the in vivo toxicity of OPs focuses on the use of bioscavengers against the parent organophosphate. Our previous research showed that AChE mutagenesis can enable aldoximes to substantially accelerate the reactivation of OP-enzyme conjugates, while dramatically slowing down rates of OP-conjugate dealkylation (aging). Herein, we demonstrate an efficient HI-6-assisted VX detoxification, both ex vivo in human blood and in vivo in mice by hAChE mutants modified at the choline binding site (Y337A and Y337A/F338A). The catalytic scavenging of VX in mice improved therapeutic outcomes preventing lethality and resulted in a delayed onset of toxicity symptoms. PMID:27083141

Synergistic stress exacerbation in hippocampal neurons: Evidence favoring the dual-hit hypothesis of neurodegeneration.

PubMed

Heinemann, Scott D; Posimo, Jessica M; Mason, Daniel M; Hutchison, Daniel F; Leak, Rehana K

2016-08-01

The dual-hit hypothesis of neurodegeneration states that severe stress sensitizes vulnerable cells to subsequent challenges so that the two hits are synergistic in their toxic effects. Although the hippocampus is vulnerable to a number of neurodegenerative disorders, there are no models of synergistic cell death in hippocampal neurons in response to combined proteotoxic and oxidative stressors, the two major characteristics of these diseases. Therefore, a relatively high-throughput dual-hit model of stress synergy was developed in primary hippocampal neurons. In order to increase the rigor of the study and strengthen the interpretations, three independent, unbiased viability assays were employed at multiple timepoints. Stress synergy was elicited when hippocampal neurons were treated with the proteasome inhibitor MG132 followed by exposure to the oxidative toxicant paraquat, but only after 48 h. MG132 and paraquat only elicited additive effects 24 h after the final hit and even loss of heat shock protein 70 activity and glutathione did not promote stress synergy at this early timepoint. Dual hits of MG132 elicited modest glutathione loss and slightly synergistic toxic effects 48 h after the second hit, but only at some concentrations and only according to two viability assays (metabolic fitness and cytoskeletal integrity). The thiol N-acetyl cysteine protected hippocampal neurons against dual MG132/MG132 hits but not dual MG132/paraquat hits. These findings support the view that proteotoxic and oxidative stress propel and propagate each other in hippocampal neurons, leading to synergistically toxic effects, but not as the default response and only after a delay. The neuronal stress synergy observed here lies in contrast to astrocytic responses to dual hits, because astrocytes that survive severe proteotoxic stress resist additional cell loss following second hits. In conclusion, a new model of hippocampal vulnerability was developed for the testing of therapies, because neuroprotective treatments that are effective against severe, synergistic stress are more likely to succeed in the clinic. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Application of a Mathematical Model to Describe the Effects of Chlorpyrifos on Caenorhabditis elegans Development

PubMed Central

Boyd, Windy A.; Smith, Marjolein V.; Kissling, Grace E.; Rice, Julie R.; Snyder, Daniel W.; Portier, Christopher J.; Freedman, Jonathan H.

2009-01-01

Background The nematode Caenorhabditis elegans is being assessed as an alternative model organism as part of an interagency effort to develop better means to test potentially toxic substances. As part of this effort, assays that use the COPAS Biosort flow sorting technology to record optical measurements (time of flight (TOF) and extinction (EXT)) of individual nematodes under various chemical exposure conditions are being developed. A mathematical model has been created that uses Biosort data to quantitatively and qualitatively describe C. elegans growth, and link changes in growth rates to biological events. Chlorpyrifos, an organophosphate pesticide known to cause developmental delays and malformations in mammals, was used as a model toxicant to test the applicability of the growth model for in vivo toxicological testing. Methodology/Principal Findings L1 larval nematodes were exposed to a range of sub-lethal chlorpyrifos concentrations (0–75 µM) and measured every 12 h. In the absence of toxicant, C. elegans matured from L1s to gravid adults by 60 h. A mathematical model was used to estimate nematode size distributions at various times. Mathematical modeling of the distributions allowed the number of measured nematodes and log(EXT) and log(TOF) growth rates to be estimated. The model revealed three distinct growth phases. The points at which estimated growth rates changed (change points) were constant across the ten chlorpyrifos concentrations. Concentration response curves with respect to several model-estimated quantities (numbers of measured nematodes, mean log(TOF) and log(EXT), growth rates, and time to reach change points) showed a significant decrease in C. elegans growth with increasing chlorpyrifos concentration. Conclusions Effects of chlorpyrifos on C. elegans growth and development were mathematically modeled. Statistical tests confirmed a significant concentration effect on several model endpoints. This confirmed that chlorpyrifos affects C. elegans development in a concentration dependent manner. The most noticeable effect on growth occurred during early larval stages: L2 and L3. This study supports the utility of the C. elegans growth assay and mathematical modeling in determining the effects of potentially toxic substances in an alternative model organism using high-throughput technologies. PMID:19753116

[Chemotherapy-induced diarrhea].

PubMed

Kobayashi, Kunihiko

2003-06-01

Chemotherapy-induced diarrhea is a well-documented side effect of many cancer treatments and is associated with increased morbidity and mortality. Chemotherapy-induced diarrhea negatively impacts patient quality of life and treatment outcome by requiring dose limitations or treatment interruption. The chemotherapeutic agent CPT-11 (irinotecan) has shown promising results as a single agent and in combination chemotherapy for the treatment of colorectal and small cell lung cancer. However, delayed onset diarrhea is considered to be its major dose-limiting toxicity. In some cases, it can be life threatening. To prevent CPT-11-induced delayed diarrhea, oral alkalization (OA) and control of defecation (CD) [Int J Cancer 92: 269-275, 2001] were developed based on fundamental studies [Int J Cancer 83: 491-496, 1999; Cancer Res 62: 179-187, 2002]. Oral administration of antibiotics [Cancer Res 56: 3752-3757, 1996; Clin Cancer Res 7: 1136-1141, 2001] or kampo medicine [Jpn J Cancer Res 86: 978-984, 1995; Jpn J Cancer Res 86: 985-989, 1995] to decrease beta-glucuronidase activity derived from bacteria in the large intestine was also reported to be successful in preventing delayed diarrhea. When CPT-11-induced delayed diarrhea occurs, the conventional treatment is loperamide [J Natl Cancer Inst 86: 446-449, 1994], and the early recognition and treatment of diarrhea with this opioid has reduced, although not entirely eliminated, patient morbidity. Other therapies are needed to treat patients with loperamide-refractory CPT-11 induced diarrhea, and the successful use of the somatostatin analogue octreotide has been reported [Support Care Cancer 9: 258-260, 2001; Ann Oncol 12: 227-229, 2001; Proc Am Soc Clin Oncol 21: 387a, 2002].

Postnatal hyperoxia or DEHP exposure leads to growth restriction and delayed lung development in newborn rats.

PubMed

Liang, Zhong-Jie; Wu, Qiu-Ping; Chen, Bei-Tao; Lin, Zhen-Lang; Lin, Jing; Chen, Shang-Qin

2018-02-01

Di-(2-ethylhexyl) phthalate (DEHP) is commonly used as a plasticizer in many medical devices. We previously showed that maternal DEHP exposure led to restricted growth and delayed lung maturation in newborn rats. As oxygen toxicity continues to be a major risk factor for bronchopulmonary dysplasia, the aim of this study was to examine the effect of hyperoxia, DEHP or DEHP combined with hyperoxia on the growth and lung maturation of newborn rats. Newborn rats received DEHP injection, hyperoxia exposure or DEHP injection combined with hyperoxia exposure for one week or two weeks. A control group received an equal volume of vehicle and was maintained in room air. Hyperoxia and hyperoxia + DEHP exposure for one week led to growth failure in newborn rats. Pups in the hyperoxia group showed catch-up growth after being maintained in room air for an additional 7 days but this was not the case with the latter group, which continued to receive DEHP. Hyperoxia and DEHP both delayed lung development, as evidenced by decreased radial alveolar count. Quantitative RT-PCR showed that hyperoxia decreased the transcripts of VEGF, VEGFR-2 and eNOS on days 7 and 14, and DEHP exposure alone also led to decreased expression of VEGF gene in 14-day-old rat pups. Postnatal hyperoxia and/or DEHP exposure lead to growth restriction and delayed lung alveolar development. The VEGF gene expression was altered and may be involved as one of the possible molecular mechanisms. Copyright © 2017. Published by Elsevier B.V.

A computer simulation of aircraft evacuation with fire

NASA Technical Reports Server (NTRS)

Middleton, V. E.

1983-01-01

A computer simulation was developed to assess passenger survival during the post-crash evacuation of a transport category aircraft when fire is a major threat. The computer code, FIREVAC, computes individual passenger exit paths and times to exit, taking into account delays and congestion caused by the interaction among the passengers and changing cabin conditions. Simple models for the physiological effects of the toxic cabin atmosphere are included with provision for including more sophisticated models as they become available. Both wide-body and standard-body aircraft may be simulated. Passenger characteristics are assigned stochastically from experimentally derived distributions. Results of simulations of evacuation trials and hypothetical evacuations under fire conditions are presented.

Lead exposure delays the differentiation of oligodendroglial progenitors in vitro.

PubMed

Deng, W; McKinnon, R D; Poretz, R D

2001-08-01

Lead (Pb) is an environmental neurotoxicant that can cause hypo- and demyelination. Oligodendrocytes (OLs), the myelin-forming cells in the central nervous system, may be a possible target for Pb toxicity. The present study describes the effect of Pb on the maturation of rat OL progenitor (OP) cells and the developmental expression of myelin-specific galactolipids. Dose-response studies showed that OP cultures were more sensitive to Pb than mature OLs. Pb delayed the differentiation of OL progenitors, as demonstrated by cell morphology and immunostaining with a panel of stage-specific differentiation markers. Pb given prior to and during differentiation caused a decrease in the biosynthesis of galactolipids in both undifferentiated and differentiated OLs, as detected by metabolic radiolabeling with 3H-D-galactose. While the ratios of galacto/gluco-cerebrosides, hydroxy fatty acid/nonhydroxy fatty acid galactolipids, and galactocerebrosides/sulfatides increased in control cultures during cell differentiation, Pb treatment prevented these changes. The results suggest that chronic Pb exposure may impact brain development by interfering with the timely developmental maturation of OL progenitors. Copyright 2001 Academic Press.

The mammary gland is a sensitive pubertal target in CD-1 and C57Bl/6 mice following perinatal perfluorooctanoic acid (PFOA) exposure.

PubMed

Tucker, Deirdre K; Macon, Madisa B; Strynar, Mark J; Dagnino, Sonia; Andersen, Erik; Fenton, Suzanne E

2015-07-01

Perfluorooctanoic acid (PFOA) is a developmental toxicant in mice, with varied strain outcomes depending on dose and period of exposure. The impact of PFOA on female mouse pubertal development at low doses (≤1mg/kg) has yet to be determined. Therefore, female offspring from CD-1 and C57Bl/6 dams exposed to PFOA, creating serum concentrations similar to humans, were examined for pubertal onset, including mammary gland development. Pups demonstrated a shorter PFOA elimination half-life than that reported for adult mice. Prenatal exposure to PFOA caused significant mammary developmental delays in female offspring in both strains. Delays started during puberty and persisted into young adulthood; severity was dose-dependent. Also an evaluation of female serum hormone levels and pubertal timing onset revealed no effects of PFOA compared to controls in either strain. These data suggest that the mammary gland is more sensitive to early low level PFOA exposures compared to other pubertal endpoints, regardless of strain. Published by Elsevier Inc.

Alzheimer's as a Systems-Level Disease Involving the Interplay of Multiple Cellular Networks.

PubMed

Castrillo, Juan I; Oliver, Stephen G

2016-01-01

Alzheimer's disease (AD), and many neurodegenerative disorders, are multifactorial in nature. They involve a combination of genomic, epigenomic, interactomic and environmental factors. Progress is being made, and these complex diseases are beginning to be understood as having their origin in altered states of biological networks at the cellular level. In the case of AD, genomic susceptibility and mechanisms leading to (or accompanying) the impairment of the central Amyloid Precursor Protein (APP) processing and tau networks are widely accepted as major contributors to the diseased state. The derangement of these networks may result in both the gain and loss of functions, increased generation of toxic species (e.g., toxic soluble oligomers and aggregates) and imbalances, whose effects can propagate to supra-cellular levels. Although well sustained by empirical data and widely accepted, this global perspective often overlooks the essential roles played by the main counteracting homeostatic networks (e.g., protein quality control/proteostasis, unfolded protein response, protein folding chaperone networks, disaggregases, ER-associated degradation/ubiquitin proteasome system, endolysosomal network, autophagy, and other stress-protective and clearance networks), whose relevance to AD is just beginning to be fully realized. In this chapter, an integrative perspective is presented. Alzheimer's disease is characterized to be a result of: (a) intrinsic genomic/epigenomic susceptibility and, (b) a continued dynamic interplay between the deranged networks and the central homeostatic networks of nerve cells. This interplay of networks will underlie both the onset and rate of progression of the disease in each individual. Integrative Systems Biology approaches are required to effect its elucidation. Comprehensive Systems Biology experiments at different 'omics levels in simple model organisms, engineered to recapitulate the basic features of AD may illuminate the onset and sequence of events underlying AD. Indeed, studies of models of AD in simple organisms, differentiated cells in culture and rodents are beginning to offer hope that the onset and progression of AD, if detected at an early stage, may be stopped, delayed, or even reversed, by activating or modulating networks involved in proteostasis and the clearance of toxic species. In practice, the incorporation of next-generation neuroimaging, high-throughput and computational approaches are opening the way towards early diagnosis well before irreversible cell death. Thus, the presence or co-occurrence of: (a) accumulation of toxic Aβ oligomers and tau species; (b) altered splicing and transcriptome patterns; (c) impaired redox, proteostatic, and metabolic networks together with, (d) compromised homeostatic capacities may constitute relevant 'AD hallmarks at the cellular level' towards reliable and early diagnosis. From here, preventive lifestyle changes and tailored therapies may be investigated, such as combined strategies aimed at both lowering the production of toxic species and potentiating homeostatic responses, in order to prevent or delay the onset, and arrest, alleviate, or even reverse the progression of the disease.

Liver ultrastructural morphology and mitochondrial DNA levels in HIV/hepatitis C virus coinfection: no evidence of mitochondrial damage with highly active antiretroviral therapy.

PubMed

Matsukura, Motoi; Chu, Fanny F S; Au, May; Lu, Helen; Chen, Jennifer; Rietkerk, Sonja; Barrios, Rolando; Farley, John D; Montaner, Julio S; Montessori, Valentina C; Walker, David C; Côté, Hélène C F

2008-06-19

Liver mitochondrial toxicity is a concern, particularly in HIV/hepatitis C virus (HCV) coinfection. Liver biopsies from HIV/HCV co-infected patients, 14 ON-highly active antiretroviral therapy (HAART) and nine OFF-HAART, were assessed by electron microscopy quantitative morphometric analyses. Hepatocytes tended to be larger ON-HAART than OFF-HAART (P = 0.05), but mitochondrial volume, cristae density, lipid volume, mitochondrial DNA and RNA levels were similar. We found no evidence of increased mitochondrial toxicity in individuals currently on HAART, suggesting that concomitant HAART should not delay HCV therapy.

A novel rabies vaccine based-on toll-like receptor 3 (TLR3) agonist PIKA adjuvant exhibiting excellent safety and efficacy in animal studies

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

Zhang, Yi; Zhang, Shoufeng; Li, Wei

Vaccination alone is not sufficiently effective to protect human from post-exposure rabies virus infection due to delayed generation of rabies virus neutralizing antibodies and weak cellular immunity. Therefore, it is vital to develop safer and more efficacious vaccine against rabies. PIKA, a stabilized chemical analog of double-stranded RNA that interacts with TLR3, was employed as adjuvant of rabies vaccine. The efficacy and safety of PIKA rabies vaccine were evaluated. The results showed that PIKA rabies vaccine enhanced both humoral and cellular immunity. After viral challenge, PIKA rabies vaccine protected 70–80% of animals, while the survival rate of non-adjuvant vaccine groupmore » (control) was 20–30%. According to the results of toxicity tests, PIKA and PIKA rabies vaccine are shown to be well tolerated in mice. Thus, this study indicates that PIKA rabies vaccine is an effective and safe vaccine which has the potential to develop next-generation rabies vaccine and encourage the start of clinical studies. - Highlights: • Vaccination alone is not effective to protect human from rabies virus infection due to delayed generation of rabies virus neutralizing antibodies (RVNA) and weak cellular immunity. • Therefore, it is vital to develop safer and more efficacious vaccine against rabies. PIKA, a stabilized chemical analog of double-stranded RNA that interacts with TLR3, was employed as an adjuvant of rabies vaccine. • The efficacy and safety of PIKA rabies vaccine was evaluated in mice. • The results showed that PIKA rabies vaccine enhanced both humoral and cellular immunity. • After viral challenge, PIKA rabies vaccine protected 70–80% of animals, while the survival rate of non-adjuvant vaccine group was only 20–30%. • According to the results of toxicity tests, PIKA and PIKA rabies vaccine are shown to be well tolerated in mice. • Thus, this study indicates that PIKA rabies vaccine is an effective and safe vaccine which has the potential to develop next-generation rabies vaccine.« less

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...

Accelerated Methotrexate, Vinblastine, Doxorubicin, and Cisplatin Is Safe, Effective, and Efficient Neoadjuvant Treatment for Muscle-Invasive Bladder Cancer: Results of a Multicenter Phase II Study With Molecular Correlates of Response and Toxicity

PubMed Central

Plimack, Elizabeth R.; Hoffman-Censits, Jean H.; Viterbo, Rosalia; Trabulsi, Edouard J.; Ross, Eric A.; Greenberg, Richard E.; Chen, David Y.T.; Lallas, Costas D.; Wong, Yu-Ning; Lin, Jianqing; Kutikov, Alexander; Dotan, Efrat; Brennan, Timothy A.; Palma, Norma; Dulaimi, Essel; Mehrazin, Reza; Boorjian, Stephen A.; Kelly, William Kevin; Uzzo, Robert G.; Hudes, Gary R.

2014-01-01

Purpose Neoadjuvant cisplatin-based chemotherapy is standard of care for muscle-invasive bladder cancer (MIBC); however, it is infrequently adopted in practice because of concerns regarding toxicity and delay to cystectomy. We hypothesized that three cycles of neoadjuvant accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) would be safe, shorten the time to surgery, and yield similar pathologic complete response (pT0) rates compared with historical controls. Patients and Methods Patients with cT2-T4a and N0-N1 MIBC were eligible and received three cycles of AMVAC with pegfilgrastim followed by radical cystectomy with lymph node dissection. The primary end point was pT0 rate. Telomere length (TL) and p53 mutation status were correlated with response and toxicity. Results Forty-four patients were accrued; 60% had stage III to IV disease; median age was 64 years. Forty patients were evaluable for response, with 15 (38%; 95% CI, 23% to 53%) showing pT0 at cystectomy, meeting the primary end point of the study. Another six patients (14%) were downstaged to non–muscle invasive disease. Most (82%) experienced only grade 1 to 2 treatment-related toxicities. There were no grade 3 or 4 renal toxicities and no treatment-related deaths. One patient developed metastases and thus did not undergo cystectomy; all others (n = 43) proceeded to cystectomy within 8 weeks after last chemotherapy administration. Median time from start of chemotherapy to cystectomy was 9.7 weeks. TL and p53 mutation did not predict response or toxicity. Conclusion AMVAC is well tolerated and results in similar pT0 rates with 6 weeks of treatment compared with standard 12-week regimens. Further analysis is ongoing to ascertain whether molecular alterations in tumor samples can predict response to chemotherapy. PMID:24821881

Pulmonary toxicity following exposure to a tile coating product containing alkylsiloxanes. A clinical and toxicological evaluation

PubMed Central

Nørgaard, A. W.; Hansen, J. S.; Sørli, J. B.; Jacobsen, P.; Lynggard, F.; Levin, M.; Nielsen, G. D.; Wolkoff, P.; Ebbehøj, N. E.; Larsen, S. T.

2014-01-01

Context Coating products are widely used for making surfaces water and dirt repellent. However, on several occasions the use of these products has been associated with lung toxicity. Objective In the present study, we evaluated the toxic effects of an aerosolized tile-coating product. Methods Thirty-nine persons, who reported respiratory and systemic symptoms following exposure to the tile-coating product, were clinically examined. The product was analysed chemically and furthermore, the exposure scenario was reconstructed using a climate chamber and the toxicological properties of the product were studied using in vivo and by in vitro surfactometry. Results The symptoms developed within few hours and included coughing, tachypnoea, chest pain, general malaise and fever. The physical examination revealed perihilar lung infiltrates on chest radiograph and reduced blood oxygen saturation. The acute symptoms resolved gradually within 1–3 days and no delayed symptoms were observed. By means of mass spectrometry and X-ray spectroscopy, it was shown that the product contained non-fluorinated alkylsiloxanes. The exposure conditions in the supermarket were reconstructed under controlled conditions in a climate chamber and particle and gas exposure levels were monitored over time allowing estimation of human exposure levels. Mice exposed to the product developed symptoms of acute pulmonary toxicity in a concentration-and time-dependent manner. The symptoms of acute pulmonary toxicity likely resulted from inhibition of the pulmonary surfactant function as demonstrated by in vitro surfactometry. Among these patients only a partial association between the level of exposure and the degree of respiratory symptoms was observed, which could be because of a high inter-individual difference in sensitivity and time-dependent changes in the chemical composition of the aerosol. Conclusion Workers need to cautiously apply surface coating products because the contents can be highly toxic through inhalation, and the aerosols can disperse to locations remote from the worksite and affect bystanders. PMID:24815546

Toxicological and behavioral responses as a tool to assess the effects of natural and synthetic dyes on zebrafish early life.

PubMed

Abe, Flavia R; Mendonça, Jacqueline N; Moraes, Luiz A B; Oliveira, Gisele A R de; Gravato, Carlos; Soares, Amadeu M V M; Oliveira, Danielle P de

2017-07-01

Organic dyes extracted from natural sources have been widely used to develop safety and eco-friendly dyes as an alternative to synthetic ones, since the latter are usually precursors of mutagenic compounds. Thereby, toxicity tests to non-target organisms are critical step to develop harmless dyes to environment and in this context, zebrafish early life stages are becoming an important alternative model. We aimed to assess the toxic effects of the synthetic dye Basic Red 51 (BR51, used in cosmetic industry), the natural dye erythrostominone (ERY, a potential commercial dye extracted from fungi) and its photodegradation product (DERY), using zebrafish early life assays. Developmental malformations on embryos and behavioral impairment on larvae were explored. Our results showed that embryos exposed to BR51 and ERY exhibited a large yolk sac (LOEC = 7.5 mg L -1 ), possibly due to a deformity or delayed resorption. ERY also induced pericardial and yolk sac edemas at high concentrations (LOEC = 15 and 30 mg L -1 , respectively). Moreover, larvae swan less distance and time when exposed to ERY (LOEC = 7.5 mg L -1 ) and BR51 (LOEC = 1.875 mg L -1 ). The lowest larvae locomotion have been associated with impairment of the yolk sac, important tissue of the energy source. Interestingly, DERY did not affect neither development nor behavior of zebrafish, showing that ERY photodegradation is sufficient to prevent its toxic effects. In conclusion, both natural and synthetic dyes impaired development and behavior of zebrafish early life, therefore, a simple treatment of the natural dye can prevent the aquatic life impact. Copyright © 2017 Elsevier Ltd. All rights reserved.

Toxicity evaluation of β-diketone antibiotics on the development of embryo-larval zebrafish (Danio rerio).

PubMed

Wang, Huili; Che, Baoguang; Duan, Ailian; Mao, Jingwen; Dahlgren, Randy A; Zhang, Minghua; Zhang, Hongqin; Zeng, Aibing; Wang, Xuedong

2014-10-01

This study evaluated the effects of β-diketone antibiotics (DKAs) on the development of embryo-larval zebrafish (Danio rerio). When exposure to DKAs, developmental malformations, such as hatching delay, curved body axis, pericardial edema, uninflated swim bladder and yolk sac edema, were observed at 120 h postfertilization (hpf). The estimated 120 hpf nominal concentrations of no observed effect concentration and lowest observed effect concentration for DKAs were 18.75 and 37.50 mg/L, respectively, suggesting that DKAs have much lower toxicity than other persistent pollutants. Following DKA exposure, embryonic heart rates were significantly reduced as compared to the controls at 48 and 60 hpf. The peak bending motion frequency appeared 1 h earlier than in control embryos. The 2.34 and 9.38-mg/L treatment groups had a higher basal swim rate than control groups at 120 hpf in both light and light-to-dark photoperiod experiments. The occurrence of high speed swim rates was enhanced approximately threefold to sevenfold in the 2.34 and 9.38 mg/L treatments compared to the control. Glutathione (GSH) concentrations in the 2.34 and 9.38-mg/L treatments were significantly higher than the control at 72 hpf, suggesting that GSH production was induced at the end of the hatching period. When exposed to DKAs, zebrafish superoxide dismutase enzyme (SOD) activities were significantly inhibited in the early embryonic period, demonstrating that the clearing ability in zebrafish was lower than the generation rate of free radicals. In summary, the combined DKAs were developmentally toxic to zebrafish in their early life stages and had the ability to impair individual behaviors that are of great importance in the assessment of their ecological fitness. Copyright © 2013 Wiley Periodicals, Inc., a Wiley company.

Mycotoxins' activity at toxic and sub-toxic concentrations: differential cytotoxic and genotoxic effects of single and combined administration of sterigmatocystin, ochratoxin A and citrinin on the hepatocellular cancer cell line Hep3B.

PubMed

Anninou, Nikolia; Chatzaki, Ekaterini; Papachristou, Fotini; Pitiakoudis, Muichail; Simopoulos, Constantinos

2014-02-07

Food safety organizations indicate the likelihood of constant human and animal exposure to mycotoxin mixtures as a possible negative public health impact. Risk assessment demonstrates that certain mycotoxins of Aspergillus and Penicillium spp. are toxic and hold a significant genotoxic efficacy at nanomolar concentrations. The aim of the current study was to investigate the potential cytogenetic effects of sterigmatocystin (STER), ochratoxin A (OTA) and citrinin (CTN) alone or in combination, at pM to μΜ concentrations, on the human hepatocellular cancer cell line Hep3B. MTT reduction, mitotic divisions, cell cycle delays and sister chromatid exchange rates (SCE) were determined as endpoints of metabolic activity, cytotoxicity, cytostaticity, and genotoxicity, respectively. All mycotoxin treatments induce SCE rates from 10-12 M, while their cytotoxic and cytostatic potential varies. In PRI and MI assays, but not at MTT, STER alone or in combination with OTA + CTN appeared cytostatic and cytotoxic, even at 10-12 M, while CTN alone and all other combinations displayed substantial cellular survival inhibition in doses ≥ 10-8 M. Co-administration of STER + OTA or STER + CTN in concentrations ≤ 10-1 M, increased the MI and MTT activity, while it did not affect the PRI. Mycotoxin co-treatments revealed in general similar-to-additive or antagonistic genotoxic and cytotoxic effects. Our results for the first time describe that STER alone or in combination with OTA and/or CTN share a cytotoxic and cytogenetic potential even at picoMolar concentrations on human hepatoma cells in vitro.

The use of inexpensive broad spectrum lower toxicity therapeutics in chronic lymphocytic leukemia.

PubMed

Marjanovic, Goran

2017-01-01

The use of new and highly efficient targeted therapies for chronic lymphocytic leukemia (CLL) is costly and out of reach for many health care systems. On the other hand, in recent years, few inexpensive, broad-spectrum low-toxicity therapeutics have proven to be effective both in the preclinical and clinical settings. In early-stage CLL, the use of 2000 mg of epigallocatechin-3-gallate (EGCG) from the green tea extract twice a day was able to reduce the absolute leukocyte count. Supplementation of >2000 IU/day of Vitamin D in early low-risk CLL patients is able to delay disease progression and postpone the moment of initiation of the first treatment. The doses of both vitamin D and EGCG were shown to be safe in older patients. Vitamin D, EGCG and Curcumin, either as monotherapy or in combination, have additive and synergistic effects with conventional chemotherapy. Further observations have identified the improvement of response to rituximab-fludarabine-cyclophosphamide (R-FC) therapy with concomitant administration of statin and aspirin combination in relapsed/refractory CLL. Finally, high dose dexamethasone with 40mg/m 2 /day for 4 days, every 28 days, either alone or with monoclonal antibody, might be used as a salvage therapy or for debulking before transplantation in refractory/resistant cases. Dexamethasone therapy is followed by transient response and high rate of infections, but fluid retention and other toxicities are lower compared to high dose methylprednisolone schedules. The low cost therapeutics discussed in this review could not be a substitute for the more effective targeted therapies, but their use in every day practice might postpone the need for early implementation of new and costly medications.

Local delivery of rapamycin: a toxicity and efficacy study in an experimental malignant glioma model in rats

PubMed Central

Tyler, Betty; Wadsworth, Scott; Recinos, Violette; Mehta, Vivek; Vellimana, Ananth; Li, Khan; Rosenblatt, Joel; Do, Hiep; Gallia, Gary L.; Siu, I-Mei; Wicks, Robert T.; Rudek, Michelle A.; Zhao, Ming; Brem, Henry

2011-01-01

Rapamycin, an anti-proliferative agent, is effective in the treatment of renal cell carcinoma and recurrent breast cancers. We proposed that this potent mammalian target of rapamycin inhibitor may be useful for the treatment of gliomas as well. We examined the cytotoxicity of rapamycin against a rodent glioma cell line, determined the toxicity of rapamycin when delivered intracranially, and investigated the efficacy of local delivery of rapamycin for the treatment of experimental malignant glioma in vivo. We also examined the dose-dependent efficacy of rapamycin and the effect when locally delivered rapamycin was combined with radiation therapy. Rapamycin was cytotoxic to 9L cells, causing 34% growth inhibition at a concentration of 0.01 µg/mL. No in vivo toxicity was observed when rapamycin was incorporated into biodegradable caprolactone-glycolide (35:65) polymer beads at 0.3%, 3%, and 30% loading doses and implanted intracranially. Three separate efficacy studies were performed to test the reproducibility of the effect of the rapamycin beads as well as the validity of this treatment approach. Animals treated with the highest dose of rapamycin beads tested (30%) consistently demonstrated significantly longer survival durations than the control and placebo groups. All dose-escalating rapamycin bead treatment groups (0.3%, 3% and 30%), treated both concurrently with tumor and in a delayed manner after tumor placement, experienced a significant increase in survival, compared with controls. Radiation therapy in addition to the simultaneous treatment with 30% rapamycin beads led to significantly longer survival duration than either therapy alone. These results suggest that the local delivery of rapamycin for the treatment of gliomas should be further investigated. PMID:21727209

Discovery and identification of O, O-diethyl O-(4-(5-phenyl-4, 5-dihydroisoxazol-3-yl) phenyl) phosphorothioate (XP-1408) as a novel mode of action of organophosphorus insecticides.

PubMed

Zeng, Zhigang; Yan, Ying; Wang, Bingfeng; Liu, Niu; Xu, Hanhong

2017-06-15

Organophosphorus (OP) insecticides play an important role in pest control. Many OP insecticides have been removed from the market because of their high toxicity to humans. We designed and synthesized a new OP insecticide with the goal of providing a low cost, and less toxic insecticide. The mode of action of O, O-diethyl O-(4-(5-phenyl-4, 5-dihydroisoxazol-3-yl) phenyl) phosphorothioate (XP-1408) was studied in Drosophila melanogaster. Bioassays showed that XP-1408 at a concentration of 50 mg/L delayed larval development. Molecular docking into Drosophila acetylcholinesterase (AChE) and voltage-gated sodium channels suggested that XP-1408 fitted into their active sites and could be inhibitory. Whole-cell patch clamp recordings indicated that XP-1408 exhibited synergistic effects involving the inhibition of cholinergic synaptic transmission and blockage of voltage-gated potassium (K v ) channels and sodium (Na v ) channels. In conclusion, the multiple actions of XP-1408 rendered it as a lead compound for formulating OP insecticides with a novel mode of action.

Intravenous apoptotic cell infusion as a cell-based therapy toward improving hematopoietic cell transplantation outcome.

PubMed

Saas, Philippe; Gaugler, Béatrice; Perruche, Sylvain

2010-10-01

Allogeneic hematopoietic cell transplantation (AHCT) is an efficient therapy for different malignant and nonmalignant hematological diseases. However, the use of this therapeutic approach is still limited by some severe toxic side effects, mainly graft-versus-host disease (GvHD). Today, the risk of fatal GvHD restrains the wider application of AHCT to many patients in need of an effective therapy for their high-risk hematologic malignancies. Thus, new strategies, including cell-based therapy approaches, are required. We propose to use intravenous donor apoptotic leukocyte infusion to improve AHCT outcome. In experimental AHCT models, we demonstrated that intravenous apoptotic leukocyte infusion, simultaneously with allogeneic bone marrow grafts, favors hematopoietic engraftment, prevents allo-immunization, and delays acute GvHD onset. Here, we review the different mechanisms and the potential beneficial effects associated with the immunomodulatory properties of apoptotic cells in the AHCT setting. © 2010 New York Academy of Sciences.

Therapeutic and protective effects of Caesalpinia gilliesii and Cajanus cajan proteins against acetaminophen overdose-induced renal damage.

PubMed

Aly, Hanan F; Rizk, Maha Z; Abo-Elmatty, Dina M; Desoky, M M; Ibrahim, N A; Younis, Eman A

2016-04-01

The present work aims to evaluate the protective and ameliorative effects of two plant-derived proteins obtained from the seeds of Cajanus cajan and Caesalpinia gilliesii(Leguminosae) against the toxic effects of acetaminophen in kidney after chronic dose through determination of certain biochemical markers including total urea, creatinine, and kidney marker enzyme, that is, glyceraldehyde-3-phosphate dehydrogenase (GAPDH). In addition histopathological examination of intoxicated and treated kidney with both proteins was performed. The present results show a significant increase in serum total urea and creatinine, while significant decrease in GAPDH. Improvement in all biochemical parameters studied was demonstrated, which was documented by the amelioration signs in rats kidney architecture. Thus, both plant protein extracts can counteract the nephrotoxic process, minimize damage to the kidney, delay disease progression, and reduce its complications. © The Author(s) 2013.

Behavioral, hyperthermic and pharmacokinetic profile of para-methoxymethamphetamine (PMMA) in rats.

PubMed

Páleníček, Tomáš; Balíková, Marie; Rohanová, Miroslava; Novák, Tomáš; Horáček, Jiří; Fujáková, Michaela; Höschl, Cyril

2011-03-01

Despite poisoning with the ecstasy substitute para-methoxymethamphetamine (PMMA) being typically associated with severe hyperthermia and death, behavioral and toxicological data on this drug are missing. Herein we present the behavioral profile of PMMA, its hyperthermic potency and pharmacokinetic profile in rats. The effects of PMMA 5 and 20 mg/kg on locomotion, on prepulse inhibition (PPI) of acoustic startle reaction (ASR), on body temperature under isolated and crowded conditions and on the pharmacokinetics analyzed with gas chromatography mass spectrometry (GC-MS) were evaluated. PMMA increased overall locomotion with the higher dose showing a biphasic effect. PPI was decreased dose-dependently. The hyperthermic response was present only with PMMA 20 mg/kg and was accompanied by extensive perspiration under crowded conditions. Serum levels of PMMA peaked at approximately 30 min after both treatments; on the contrary the maximum brain concentrations of PMMA at 20 mg/kg peaked approximately 1h after the administration, which was rather delayed compared to maximum after 5mg/kg dose. These data indicate that PMMA has a similar behavioral profile to stimulants and hallucinogens and that the toxicity might be increased in a crowded environment. High doses of PMMA have a gradual penetration to the brain which might lead to the delayed peak concentrations and prolonged effects of the drug. Copyright © 2010 Elsevier Inc. All rights reserved.

Intratympanic steroids injection is effective for the treatment of drop attacks with Ménière's disease and delayed endolymphatic hydrops

PubMed Central

Liu, Bo; Leng, Yangming; Zhou, Renhong; Liu, Jingjing; Liu, Dongdong; Zhang, Su-Lin; Kong, Wei-Jia

2016-01-01

Abstract Drop attack (DA) associated with Ménière's disease (MD) and delayed endolymphatic hydrops (DEH) is not common and may cause life-threatening clinical problems. The intratympanic dexamethasone (ITD) is one of primary treatments for MD or DEH. Our study investigated the effect of ITD on the DA associated with endolymphatic hydrops (EH). We retrospectively reviewed 10 patients with MD- and DEH-associated DA between January 2009 and December 2013 in Outpatient Department of Otolaryngology, Union Hospital, Wuhan, China. Among them, 7 patients (5 cases with MD, 2 cases of DEH) received ITD (4 times, on weekly basis). Further repeated ITD courses or intratympanic gentamicin (ITG) were given if the vertigo was not satisfactorily controlled. The number of DA and status of vertigo control after intratympanic injection were evaluated. After a follow-up study lasting from 19 to 35 months, DA in 5 cases (71.4%) disappeared after initial ITD course. In 2 cases, DA was altogether controlled after an additional intratympanic injection (repeated ITD or/and ITG). This study showed that ITD promises to be a first-line conservative treatment for MD- or DEH-related DA since the steroid possesses no inner-ear toxicity. Furthermore, for MD- or DEH-related DA refractory to ITD, ITG can be an effective alternative. PMID:28033296

Administration of CroFab Antivenom by a Helicopter Emergency Medical Service Team.

PubMed

Steuerwald, Michael T; Gabbard, Season R K; Beauchamp, Gillian A; Riddle, Matthew K; Otten, Edward J

The case presented here highlights an unconventional use of a helicopter emergency medical service (HEMS) to provide a specialized medication to a critically ill patient when definitive transport was delayed. A 39-year-old man presented to a rural hospital 1 hour after sustaining a copperhead envenomation. He developed severe symptoms and was intubated. Arrangements were made for transfer to a tertiary referral center by HEMS, but because of incoming weather conditions, the team would not be able to make the return flight safely. The decision was made for the HEMS team to fly antivenom to the patient, administer the medication, and then transport the patient by ground to the tertiary medical center. This plan was executed, and the patient was safely transported to the accepting facility. Antivenom is most effective when administered early because this will halt the progression of edema and may reverse the systemic effects of envenomation. In this case, HEMS transport of antivenom to the patient with severe toxicity prevented a delay to administration and likely improved the patient's outcome. Although the traditional role of HEMS is to provide rapid transport to critically ill patients, HEMS teams can also function to deliver specialized medications to remote settings. Copyright © 2016 Air Medical Journal Associates. Published by Elsevier Inc. All rights reserved.

Efficacy of Thai medicinal plant extracts against herpes simplex virus type 1 infection in vitro and in vivo.

PubMed

Lipipun, Vimolmas; Kurokawa, Masahiko; Suttisri, Rutt; Taweechotipatr, Pagorn; Pramyothin, Pornpen; Hattori, Masao; Shiraki, Kimiyasu

2003-11-01

Twenty Thai medicinal plant extracts were evaluated for anti-herpes simplex virus type 1 (HSV-1) activity. Eleven of them inhibited plaque formation of HSV-1 more than 50% at 100microg/ml in a plaque reduction assay. Aglaia odorata, Moringa oleifera, and Ventilago denticulata among the 11 were also effective against thymidine kinase-deficient HSV-1 and phosphonoacetate-resistant HSV-1 strains. These therapeutic efficacies were characterized using a cutaneous HSV-1 infection in mice. The extract of M. oleifera at a dose of 750mg/kg per day significantly delayed the development of skin lesions, prolonged the mean survival times and reduced the mortality of HSV-1 infected mice as compared with 2% DMSO in distilled water (P<0.05). The extracts of A. odorata and V. denticulata were also significantly effective in limiting the development of skin lesions (P<0.05). There were no significant difference between acyclovir and these three plant extracts in the delay of the development of skin lesions and no significant difference between acyclovir and M. oleifera in mean survival times. Toxicity of these plant extracts were not observed in treated mice. Thus, these three plant extracts may be possible candidates of anti-HSV-1 agents.

Regorafenib induced severe toxic hepatitis: characterization and discussion.

PubMed

Sacré, Anne; Lanthier, Nicolas; Dano, Hélène; Aydin, Selda; Leggenhager, Daniela; Weber, Achim; Dekairelle, Anne-France; De Cuyper, Astrid; Gala, Jean-Luc; Humblet, Yves; Sempoux, Christine; Van den Eynde, Marc

2016-11-01

Regorafenib is the first small-molecule multikinase inhibitor which showed survival benefits in pretreated metastatic colorectal cancer (mCRC) patients. Besides classical adverse events of this drug class, hepatotoxicity has been described as a frequent side effect. Patients with refractory mCRC treated with regorafenib in our institution were reviewed. Severe treatment-related liver toxicity was investigated. Clinical history, liver histology and genetic assessment (sequence analysis) of cytochrome P3A4 (CYP3A4) and uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) involved in regorafenib metabolization were here reported for patients with severe hepatotoxicity. Among the 93 reviewed patients, 3 presented severe and icteric toxic hepatitis which was fatal for 1 patient. Histopathological liver lesions were different depending on the onset of hepatotoxicity (acute or subacute): acinar zone 3 necrosis in case of acute symptoms, and portal tract inflammation with porto-central bridging and fibrosis in the delayed presentation. None of the patients had CYP3A4 gene mutations. Similar polymorphisms in UGT1A9 gene promoter region (UGT1A9 variant -118T 9>10 [rs3832043]) were found in both patients who presented acute hepatitis. Moreover, it appears retrospectively that both of them already experienced significant toxicity under irinotecan-based chemotherapy. This is the first report of severe hepatotoxicity with available liver histology and genetic assessment of enzymes involved in regorafenib metabolization. This report also reminds the importance of close liver tests monitoring during regorafenib treatment. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

[Biological effects of artificial mineral fibers].

PubMed

Woźniak, H

1989-01-01

The present review paper was prepared on the basis of 52 source-books devoted to experimental investigations. Principal conclusions emerging from the experiments described in the references quoted are as follows. MMMF retention in alveoli is conditioned mainly by the fibres size--for fibres of constant dimater retention increases proportionally to their length, while long and thin fibres undergo degradation in fluids much more easily than the short and thick ones. Fibrous effect of glass fibres and glass wool is less remarkable than that of chrysotile and crocidolite; after exposure to glass fibre and wool has stopped, no progress of fibrous changes in animals was observed. In animals exposed to grass fibre or mineral wool through inhalation, the increase in cancer rate was not statistically significant; glass fibres introduced into the pleura showed a weaker tendency to induce neoplasms than the same amount of asbestos fibres, while basalt and ceramic wool induced reaction similar to that provoked by asbestos. In the case of combined exposure glass fibres intensified the toxic effect of styrene in mice and enhanced the incidence of lung cancer in rats exposed to radon. In in vitro study the destructive effect represented the distribution function of fibres size--long fibres (less than 10 microns) and thin fibres (less than 1 micron diameter) demonstrated stronger toxic effect. Glass fibres provoked neither mutations in bacterial test, nor sister chromatid exchange in animal cells in vitro. However, they caused mitosis delay and structural changes in chromosomes.

An evaluation of the residual toxicity and chemistry of a sodium hydroxide-based ballast water treatment system for freshwater ships

USGS Publications Warehouse

Elskus, Adria; Ingersoll, Christopher G.; Kemble, Nile E.; Echols, Kathy R.; Brumbaugh, William G.; Henquinet, Jeffrey; Watten, Barnaby J.

2015-01-01

Nonnative organisms in the ballast water of freshwater ships must be killed to prevent the spread of invasive species. The ideal ballast water treatment system (BWTS) would kill 100% of ballast water organisms with minimal residual toxicity to organisms in receiving waters. In the present study, the residual toxicity and chemistry of a BWTS was evaluated. Sodium hydroxide was added to elevate pH to >11.5 to kill ballast water organisms, then reduced to pH <9 by sparging with wet-scrubbed diesel exhaust (the source of CO2). Cladocerans (Ceriodaphnia dubia), amphipods (Hyalella azteca), and fathead minnows (Pimephales promelas) were exposed for 2 d to BWTS water under an air atmosphere (pH drifted to ≥9) or a 2.5% CO2 atmosphere (pH 7.5–8.2), then transferred to control water for 5 d to assess potential delayed toxicity. Chemical concentrations in the BWTS water met vessel discharge guidelines with the exception of concentrations of copper. There was little to no residual toxicity to cladocerans or fish, but the BWTS water was toxic to amphipods. Maintaining a neutral pH and diluting BWTS water by 50% eliminated toxicity to the amphipods. The toxicity of BWTS water would likely be minimal because of rapid dilution in the receiving water, with subsurface release likely preventing pH rise. This BWTS has the potential to become a viable method for treating ballast water released into freshwater systems.

The effects of cobalt on the development, oxidative stress, and apoptosis in zebrafish embryos.

PubMed

Cai, Guiquan; Zhu, Junfeng; Shen, Chao; Cui, Yimin; Du, Jiulin; Chen, Xiaodong

2012-12-01

Metal-on-metal hip arthroplasty has been performed with increasing frequency throughout the world, particularly in younger and more active patients, including women of childbearing age. The potential toxicity of cobalt exposure on fetus is concerned since cobalt ions generated by metal-on-metal bearings can traverse the placenta and be detected in fetal blood and amniotic fluid. This study examined the effects of cobalt exposure on early embryonic development and the mechanisms underlying its toxicity. Zebrafish embryos were exposed to a range of cobalt concentrations (0-100 mg/L) between 1 and 144 h postfertilization. The survival and early development of embryos were not significantly affected by cobalt at concentrations <100 μg/L. However, embryos exposed to higher concentrations (>100 μg/L) displayed reduced survival rates and abnormal development, including delayed hatching, aberrant morphology, retarded growth, and bradycardia. Furthermore, this study examined oxidative stress and apoptosis in embryos exposed to cobalt at concentrations of 0-500 μg/L. Lipid peroxidation levels were increased in cobalt-treated embryos at concentrations of 100 and 500 μg/L. The mRNA levels of catalase, superoxide dismutase 2, p53, caspase-3, and caspase-9 genes were upregulated in a dose-dependent manner. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assays also revealed abnormal apoptotic signals in the brain, trunk, and tail when treated with 500 μg/L cobalt. These data suggest that oxidative stress and apoptosis are associated with cobalt toxicity in zebrafish embryos.

Junctional bradycardia with verapamil in renal failure--care required even with mild hyperkalaemia.

PubMed

Hegazi, M O; Aldabie, G; Al-Mutairi, S; El Sayed, A

2012-12-01

Treatment for hypertension with verapamil has a favourable renoprotective effect and is generally considered safe in patients with mild to moderate renal failure. In this report, we highlight the vulnerability of patients with mild to moderate renal failure to verapamil side effects especially in the presence of hyperkalaemia. We report two cases of junctional bradycardia with slow release (SR) verapamil therapy in the presence of mild hyperkalaemia in patients with mild to moderate chronic renal failure. Verapamil and hyperkalaemia may synergistically increase the vulnerability to atrioventricular conduction delay. Renal failure patients with baseline mild hyperkalaemia are particularly liable to bradyarrhythmias with SR verapamil. In such cases, we would recommend verapamil dose reduction and avoidance of SR formulation. In cases of verapamil toxicity, actively treating any level of hyperkalaemia is recommended. © 2012 Blackwell Publishing Ltd.

Toxicity of aggressive multimodality therapy including cisplatinum, bleomycin and methotrexate with radiation and/or surgery for advanced head and neck cancer

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

Weichselbaum, R.R.; Posner, M.R.; Ervin, T.J.

1982-05-01

A combined modality regimen employing induction chemotherapy with cisplatinum, bleomycin and methotrexate followed by surgery and/or radiation therapy was initiated in patients with advanced squamous cell carcinoma of the head and neck. In the first 23 patients treated with this program there was a 90% response rate to induction chemotherapy (9% CR and 81% PR). Toxicity associated with radiotherapy, but not surgery, was increased with 11 of 23 patients (48%) who experienced some toxicity during or immediately after radiotherapy. Mucositis was worse than expected and severe delayed mucositis was seen in 2 patients, one of whom required hospitalization. Late complications,more » possibly related to therapy included one myocardial infarction and one episode of hypoglycemia, both of which were fatal. One other patient voluntarily failed to take prescribed oral leucovorin, dying of unrescued methotrexate toxicity during adjuvant therapy, a questionable suicide. Further follow-up analysis of failure will be necessary to determine if the value of a combined modality regimen in producing an increased cure rate and long term survival will out weigh increased toxicity.« less

Toxicity and Transmission of Thiamethoxam in the Asian Subterranean Termite Coptotermes gestroi (Isoptera: Rhinotermitidae)

PubMed Central

Acda, Menandro N.

2014-01-01

Abstract The toxicity and horizontal transmission of thiamethoxam was evaluated in the workers of the Asian subterranean termite Coptotermes gestroi Wasmann (Isoptera: Rhinotermitidae). Brief exposure to sand treated with thiamethoxam at concentration ranging from 0.25 to 50 µg/ml resulted in a dose-dependent mortality in C. gestroi . Sand treated with 50 µg/ml thiamethoxam resulted in very high mortality within 30–60 min of exposure. Termites exposed to sand treated with 0.25–25 µg/ml exhibited delayed toxicity and nonrepellency in C. gestroi . A horizontal transmission study using 25 µg/ml of thiamethoxam at donor–recipient ratio of at least 2:5 (treated:untreated) indicated that thiamethoxam can be transferred between exposed and unexposed workers, resulting in significant termite mortality in unexposed termites within 1–3 d post exposure. PMID:25502030

A Phase 2 Study of Concurrent Fludarabine and Rituximab for the Treatment of Marginal Zone Lymphomas

PubMed Central

Brown, Jennifer R; Friedberg, Jonathan W.; Feng, Yang; Scofield, Sarah; Phillips, Kimberly; Cin, Paola Dal; Joyce, Robin; Takvorian, Ronald W; Fisher, David C; Fisher, Richard I; Liesveld, Jane; Marquis, Diana; Neuberg, Donna; Freedman, Arnold S

2009-01-01

SUMMARY The marginal zone lymphomas are a recently defined group of related diseases likely arising from a common cell of origin, the marginal zone B cell. Data on therapy for subtypes other than gastric MALT has been largely limited to retrospective case series. We therefore undertook this prospective phase 2 study of fludarabine and rituximab for the treatment of marginal zone lymphomas. 26 patients were enrolled, 14 with nodal MZL, 8 with MALT lymphomas and 4 with splenic MZL; 81% were receiving initial systemic therapy. Only 58% (95% CI 37–77%) of patients completed the planned six cycles, due to significant hematologic, infectious and allergic toxicity. Four late toxic deaths occurred due to infections (15% (95% CI 4.3–35%), two related to delayed bone marrow aplasia and two related to MDS. Nonetheless, the ORR was 85% (95% CI 65–96%), with 54% CRs. The progression-free survival at 3.1 years of follow-up is 79.5% (95% CI, 63–96%). We conclude that although concurrent fludarabine and rituximab given at this dose and schedule is a highly effective regimen in the treatment of marginal zone lymphomas, the significant hematologic and infectious toxicity observed both during and after therapy is prohibitive in this patient population, emphasizing the need to study marginal zone lymphomas as a separate entity. PMID:19344412

Royal jelly promotes DAF-16-mediated proteostasis to tolerate β-amyloid toxicity in C. elegans model of Alzheimer's disease.

PubMed

Wang, Xiaoxia; Cao, Min; Dong, Yuqing

2016-08-23

Numerous studies have demonstrated that dietary intervention may promote health and help prevent Alzheimer's disease (AD). We recently reported that bee products of royal jelly (RJ) and enzyme-treated royal jelly (eRJ) were potent to promote healthy aging in C. elegans. Here, we examined whether RJ/eRJ consumption may benefit to mitigate the AD symptom in the disease model of C. elegans. Our results showed that RJ/eRJ supplementation significantly delayed the body paralysis in AD worms, suggesting the β-amyloid (Aβ) toxicity attenuation effects of RJ/eRJ. Genetic analyses suggested that RJ/eRJ-mediated alleviation of Aβ toxicity in AD worms required DAF-16, rather than HSF-1 and SKN-1, in an insulin/IGF signaling dependent manner. Moreover, RJ/eRJ modulated the transactivity of DAF-16 and dramatically improved the protein solubility in aged worms. Given protein solubility is a hallmark of healthy proteostasis, our findings demonstrated that RJ/eRJ supplementation improved proteostasis, and this promotion depended on the transactivity of DAF-16. Collectively, the present study not only elucidated the possible anti-AD mechanism of RJ/eRJ, but also provided evidence from a practical point of view to shed light on the extensive correlation of proteostasis and the prevention of neurodegenerative disorders.

Acute inhalation toxicity of 3-methylfuran in the mouse: pathology, cell kinetics, and respiratory rate effects

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

Haschek, W.M.; Boyd, M.R.; Hakkinen, P.J.

1984-01-01

The acute inhalation toxicity of 3-methylfuran (3MF) was investigated in male BALB/c mice by morphologic examination of animals killed at varying timepoints following a 1-hr exposure to an initial chamber concentration of 14 to 37 mumol/liter (343 to 906 ppm). In addition, respiratory rate measurements and cell kinetics were used to assess quantitatively pulmonary damage and repair. Necrosis of nonciliated bronchiolar epithelial (Clara) cells was seen 1 day following exposure and was followed by regeneration, which was virtually complete, within 21 days. Cell kinetic studies showed peak bronchiolar cell proliferation at 3 days with a labeling index (LI) of 5.0%more » compared to 0.4% in controls. An increase in parenchymal cell proliferation was also noted coincident with a mild interstitial pneumonitis. This parenchymal proliferation, peaking at 10 days with an LI of 1.4% compared to 0.2% in controls, consisted primarily of type II epithelial and endothelial cell proliferation indicating possible delayed damage and repair of type I epithelial and endothelial cells. The respiratory rate showed an initial transient increase followed by a more prolonged decrease with eventual return to control levels. 3MF toxicity was also evidenced by a necrotizing suppurative rhinitis, centrilobular hepatic necrosis, lymphocyte necrosis in the thymus and spleen, sialoadenitis, and otitis media.« less

Fatal attraction: adaptations to prey on native frogs imperil snakes after invasion of toxic toads.

PubMed

Hagman, Mattias; Phillips, Benjamin L; Shine, Richard

2009-08-07

Adaptations that enhance fitness in one situation can become liabilities if circumstances change. In tropical Australia, native snake species are vulnerable to the invasion of toxic cane toads. Death adders (Acanthophis praelongus) are ambush foragers that (i) attract vertebrate prey by caudal luring and (ii) handle anuran prey by killing the frog then waiting until the frog's chemical defences degrade before ingesting it. These tactics render death adders vulnerable to toxic cane toads (Bufo marinus), because toads elicit caudal luring more effectively than do native frogs, and are more readily attracted to the lure. Moreover, the strategy of delaying ingestion of a toad after the strike does not prevent fatal poisoning, because toad toxins (unlike those of native frogs) do not degrade shortly after the prey dies. In our laboratory and field trials, half of the death adders died after ingesting a toad, showing that the specialized predatory behaviours death adders use to capture and process prey render them vulnerable to this novel prey type. The toads' strong response to caudal luring also renders them less fit than native anurans (which largely ignored the lure): all toads bitten by adders died. Together, these results illustrate the dissonance in behavioural adaptations that can arise following the arrival of invasive species, and reveal the strong selection that occurs when mutually naive species first interact.

Cyanobacteria blooms: effects on aquatic ecosystems.

PubMed

Havens, Karl E

2008-01-01

Cyanobacteria become increasingly dominant as concentrations of TP and TN increase during eutrophication of lakes, rivers and estuaries. Temporal dynamics of cyanobacteria blooms are variable--in some systems persistent blooms occur in summer to fall, whereas in other systems blooms are more sporadic. Cyanobacteria blooms have a wide range of possible biological impacts including potential toxic effects on other algae, invertebrates and fish, impacts to plants and benthic algae due to shading, and impacts to food web function as large inedible algae produce a bottleneck to C and energy flow in the plankton food web. In lakes with dense blooms of cyanobacteria, accumulation of organic material in lake sediments and increased bacterial activity also may lead to anoxic conditions that alter the structure of benthic macro-invertebrates. Diffusive internal P loading may increase, and hypolimnetic anoxia may lead to a loss of piscivorous fish that require a summer cold water refuge in temperate lakes. Ecosystem changes associated with frequent blooms may result in delayed response of lakes, rivers and estuaries to external nutrient load reduction. Despite numerous case studies and a vast literature on species-specific responses, community level effects of cyanobacterial blooms are not well understood--in particular the realized impacts of toxins and changes in food web structure/function. These areas require additional research given the prevalence of toxic blooms in the nation's lakes, rivers and coastal waters--systems that provide a wide range of valued ecosystem services.

Acute exposure to cadmium induces prolonged neutrophilia along with delayed induction of granulocyte colony-stimulating factor in the livers of mice.

PubMed

Horiguchi, Hyogo; Oguma, Etsuko

2016-12-01

Acute exposure to cadmium (Cd), a toxic heavy metal, causes systemic inflammation characterized by neutrophilia. To elucidate the mechanism of neutrophilia induced by Cd, we investigated the induction of granulocyte colony-stimulating factor (G-CSF), which regulates neutrophil production, in mice with acute Cd toxicity, and compared it with mice injected with lipopolysaccharide (LPS) as an inducer of general inflammatory responses. We injected BALB/c mice with Cd at 2.5 mg/kg i.p. or LPS at 0.5 mg/kg i.p. and sampled the peripheral blood and organs at time points up to 24 h. In Cd-treated mice, the peripheral neutrophil count increased steadily up to 24 h, whereas LPS-treated mice showed a more rapid increase with a peak at 12 h. The serum G-CSF level increased gradually to reach a plateau at 12-18 h in Cd-treated mice, but LPS-treated mice showed a marked increase, reaching a peak at 2-3 h. A gradual elevation of G-CSF mRNA expression up to 24 h was detected by real-time PCR in the livers of Cd-treated mice, but in LPS-treated mice its highest expression was observed in the liver with a rapid increase at 2 h. By in situ hybridization using G-CSF RNA probes, hepatic Kupffer cells were identified as G-CSF-producing cells in the liver. These results indicated that Cd has a characteristic effect of delayed induction of G-CSF in the liver, causing systemic inflammation accompanied by prolonged neutrophilia.

Missed opportunities?: an evaluation of potentially preventable poisoning deaths.

PubMed

Srisuma, Sahaphume; Cao, Dazhe; Kleinschmidt, Kurt; Heffner, Alan C; Lavonas, Eric J

2016-06-01

Although most poisoning deaths are not preventable with current medical technology, in some cases different management decisions may have prevented fatal outcomes. This study aims to review reported poisoning-related deaths for preventability to provide insight to improve future care. Fatality abstracts published in the US National Poison Data System (NPDS) Annual Reports (2008-2012) were analyzed. Preventability was graded using a Likert scale of 1 (definitely non-preventable) to 6 (definitely preventable). Two medical toxicologists screened all cases. Cases deemed definitely not preventable (score 1) by both reviewers were excluded from further review and considered to be "non-preventable". All cases considered at least possibly preventable by either screener were reviewed by a multidisciplinary panel of 5 physicians for preventability scoring. Differences were resolved by consensus. Cases determined to be "preventable" (scores 4-6) were characterized by type of improvement issue involved (diagnosis, treatment, monitoring, other) and recurring scenarios. Of 390 published abstracts, 78 (20.0%) deaths were considered at least possibly preventable by at least one screener. Of these, 34 (8.7%) deaths were determined to be "preventable" by the panel. Inter-observer agreement by weighted kappa analysis was 0.58 for screening, 0.24 for preventability, and 0.44 for specific aspects of care. The most common toxicants were salicylates (n = 9), opioids (n = 4), toxic alcohols (n = 3), fluoride containing product (n = 3), and bupropion (n = 3). The most common improvement opportunities involved treatment and monitoring. Most of the ingested substances in preventable deaths have delayed GI absorption or require metabolic activation to produce a delayed effect (such as salicylates, opioids, and toxic alcohols), and therefore provide an opportunity for early recognition and successful interventions. Most improvement opportunities are clearly described in the literature but may be not recognized. Based on an analysis of published NPDS data, a considerable number of poisoning-related deaths reaching medical attention may be preventable. The most common scenarios involved in potentially preventable poisoning fatalities related to monitoring and treatment. Salicylates and opioids were the most common agents involved in preventable deaths.

78 FR 37176 - Addition of Nonylphenol Category; Community Right-to-Know Toxic Chemical Release Reporting

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-20

...]g/L. Nearly all larvae were abnormal at the two highest exposure concentrations (>= 53 [micro]g/L... was delayed at the two highest concentrations (14 and 23 [micro]g/L). Fathead minnow survival was... [micro]g/L (Ref. 35). 2. In Vivo Responses in Fish. The protein vitellogenin, which is produced in the...

Potential pharmacological strategies for the improved treatment of organophosphate-induced neurotoxicity.

PubMed

Kaur, Shamsherjit; Singh, Satinderpal; Chahal, Karan Singh; Prakash, Atish

2014-11-01

Organophosphates (OP) are highly toxic compounds that cause cholinergic neuronal excitotoxicity and dysfunction by irreversible inhibition of acetylcholinesterase, resulting in delayed brain damage. This delayed secondary neuronal destruction, which arises primarily in the cholinergic areas of the brain that contain dense accumulations of cholinergic neurons and the majority of cholinergic projection, could be largely responsible for persistent profound neuropsychiatric and neurological impairments such as memory, cognitive, mental, emotional, motor, and sensory deficits in the victims of OP poisoning. The therapeutic strategies for reducing neuronal brain damage must adopt a multifunctional approach to the various steps of brain deterioration: (i) standard treatment with atropine and related anticholinergic compounds; (ii) anti-excitotoxic therapies to prevent cerebral edema, blockage of calcium influx, inhibition of apoptosis, and allow for the control of seizure; (iii) neuroprotection by aid of antioxidants and N-methyl-d-aspartate (NMDA) antagonists (multifunctional drug therapy), to inhibit/limit the secondary neuronal damage; and (iv) therapies targeting chronic neuropsychiatric and neurological symptoms. These neuroprotective strategies may prevent secondary neuronal damage in both early and late stages of OP poisoning, and thus may be a beneficial approach to treating the neuropsychological and neuronal impairments resulting from OP toxicity.

Novel toxic shock syndrome toxin-1 amino acids required for biological activity.

PubMed

Brosnahan, Amanda J; Schaefers, Matthew M; Amundson, William H; Mantz, Mary J; Squier, Christopher A; Peterson, Marnie L; Schlievert, Patrick M

2008-12-09

Superantigens interact with T lymphocytes and macrophages to cause T lymphocyte proliferation and overwhelming cytokine production, which lead to toxic shock syndrome. Staphylococcus aureus superantigen toxic shock syndrome toxin-1 is a major cause of menstrual toxic shock syndrome. In general, superantigen-secreting S. aureus remains localized at the vaginal surface, and the superantigen must therefore penetrate the vaginal mucosa to interact with underlying immune cells to cause toxic shock syndrome. A dodecapeptide region (toxic shock syndrome toxin-1 amino acids F119-D130), relatively conserved among superantigens, has been implicated in superantigen penetration of the epithelium. The purpose of this study was to determine amino acids within this dodecapeptide region that are required for interaction with vaginal epithelium. Alanine mutations were constructed in S. aureus toxic shock syndrome toxin-1 amino acids D120 to D130. All mutants maintained superantigenicity, and selected mutants were lethal when given intravenously to rabbits. Toxic shock syndrome toxin-1 induces interleukin-8 from immortalized human vaginal epithelial cells; however, three toxin mutants (S127A, T128A, and D130A) induced low levels of interleukin-8 compared to wild type toxin. When carboxy-terminal mutants (S127A to D130A) were administered vaginally to rabbits, D130A was nonlethal, while S127A and T128A demonstrated delayed lethality compared to wild type toxin. In a porcine ex vivo permeability model, mutant D130A penetrated the vaginal mucosa more quickly than wild type toxin. Toxic shock syndrome toxin-1 residue D130 may contribute to binding an epithelial receptor, which allows it to penetrate the vaginal mucosa, induce interleukin-8, and cause toxic shock syndrome.

Falsely increased plasma lactate concentration due to ethylene glycol poisoning in 2 dogs.

PubMed

Hopper, Kate; Epstein, Steven E

2013-01-01

To describe false increases in plasma lactate concentration measured on point-of-care analyzers in 2 dogs with ethylene glycol (EG) intoxication. Two dogs presenting with EG intoxication had extreme increases of plasma lactate concentrations recorded on a point-of-care machine. Laboratory analysis by spectrophotometry of lactate concentration determined these lactate measurements to be erroneous. False increases in plasma lactate concentration were demonstrated in 2 out of 3 point-of-care machines tested. Glycolate, a toxic metabolite of EG, can interfere with the measurement of plasma lactate by some analyzers and this may delay the correct diagnosis of EG toxicity if not recognized. © Veterinary Emergency and Critical Care Society 2012.

Toxicology of oxides of nitrogen. I. Toxic concentrations

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

La Towsky, L.W.; MacQuiddy, E.L.; Tollman, J.P.

1941-01-01

One hundred twelve rabbits, cats, guinea pigs, rats, and mice were exposed to 30 to 1000 ppM NO/sub 2/. Average time to produce death was: 30 ppM - none in 3 hr, 100 ppM - 318 min, 150 ppM - 90 min, 400 ppM - 58 min, 600 ppM - 32 min, 800 ppM - 29 min, 1000 ppM - 19 min. Rats and mice were more sensitive, sometimes exhibiting delayed effects (e.g., 2 to 3 hr at 55 ppM). Cats were most sensitive in that they thrash excitedly, thus breathing more. Methemoglobin was frequently seen in blood during exposure.more » Death was from edema (most common), asphyxia, or pneumonitis (secondary).« less

HI-6 assisted catalytic scavenging of VX by acetylcholinesterase choline binding site mutants.

PubMed

Maček Hrvat, Nikolina; Žunec, Suzana; Taylor, Palmer; Radić, Zoran; Kovarik, Zrinka

2016-11-25

The high toxicity of organophosphorus compounds originates from covalent inhibition of acetylcholinesterase (AChE), an essential enzyme in cholinergic neurotransmission. Poisonings that lead to life-threatening toxic manifestations require immediate treatment that combines administration of anticholinergic drugs and an aldoxime as a reactivator of AChE. An alternative approach to reduce the in vivo toxicity of OPs focuses on the use of bioscavengers against the parent organophosphate. Our previous research showed that AChE mutagenesis can enable aldoximes to substantially accelerate the reactivation of OP-enzyme conjugates, while dramatically slowing down rates of OP-conjugate dealkylation (aging). Herein, we demonstrate an efficient HI-6-assisted VX detoxification, both ex vivo in human blood and in vivo in mice by hAChE mutants modified at the choline binding site (Y337A and Y337A/F338A). The catalytic scavenging of VX in mice improved therapeutic outcomes preventing lethality and resulted in a delayed onset of toxicity symptoms. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Methotrexate elimination and toxicity: MTHFR 677C>T polymorphism in patients with primary CNS lymphoma treated with high-dose methotrexate.

PubMed

Choi, Yun Jung; Park, Hyangmin; Lee, Ji Sung; Lee, Ju-Yeon; Kim, Shin; Kim, Tae Won; Park, Jung Sun; Kim, Jeong Eun; Yoon, Dok Hyun; Suh, Cheolwon

2017-12-01

The genetic association of the methylenetetrahydrofolate reductase gene (MTHFR) 677C>T polymorphism with methotrexate (MTX)-associated toxicity has been evaluated and conflicting results have been reported. The substantial heterogeneity of the studied population was suggested to be a possible explanation because ethnicity, MTX dose, coadministered chemotherapeutic agents, and folinate rescue dosage regimen could alter the MTX toxicity profile. The patient population was homogenized by limiting the cancer type to primary central nervous system lymphoma and chemotherapy protocol to a high-dose MTX monotherapy regimen. A total of 111 patients with 402 chemotherapy courses were analyzed. MTHFR 677C>T polymorphism was identified as an independent predictive marker for MTX-associated hematologic toxicity (odds ratio, 2.60; 95% confidence interval, 1.32-5.09; P = .0055). Clinically significant nephrotoxicity occurred in patients without delayed elimination, suggesting roles for factors other than serum MTX levels. MTX-induced hepatotoxicity and oral mucositis occurred independently of plasma MTX levels. Copyright © 2016 John Wiley & Sons, Ltd.

Toxicity Profile and Pharmacokinetic Study of A Phase I Low-Dose Schedule-Dependent Radiosensitizing Paclitaxel Chemoradiation Regimen for Inoperable Non-Small-Cell Lung Cancer

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

Chen, Yuhchyau; Pandya, Kishan J.; Feins, Richard

Purpose: We report the toxicity profile and pharmacokinetic data of a schedule-dependent chemoradiation regimen using pulsed low-dose paclitaxel for radiosensitization in a Phase I study for inoperable non-small-cell lung cancer. Methods and Materials: Paclitaxel at escalating doses of 15 mg/m{sup 2}, 20 mg/m{sup 2}, and 25 mg/m{sup 2} were infused on Monday, Wednesday, and Friday with daily chest radiation in cohorts of 6 patients. Daily radiation was delayed for maximal G2/M arrest and apoptotic effect, an observation from preclinical investigations. Plasma paclitaxel concentration was determined by high-performance liquid chromatography. Results: Dose-limiting toxicities included 3 of 18 patients with Grade 3more » pneumonitis and 3 of 18 patients with Grade 3 esophagitis. There was no Grade 4 or 5 pneumonitis or esophagitis. There was also no Grade 3 or 4 neutropenia, thrombocytopenia, anemia or neuropathy. For Dose Levels I (15 mg/m{sup 2}), II (20 mg/m{sup 2}), and III (25 mg/m{sup 2}), the mean peak plasma level was 0.23 {+-} 0.06 {mu}mol/l, 0.32 {+-} 0.05 {mu}mol/l, and 0.52 {+-} 0.14 {mu}mol/l, respectively; AUC was 0.44 {+-} 0.09 {mu}mol/l, 0.61 {+-} 0.1 {mu}mol/l, and 0.96 {+-} 0.23 {mu}mol/l, respectively; and duration of drug concentration >0.05 {mu}mol/l (t > 0.05 {mu}mol/l) was 1.6 {+-} 0.3 h, 1.9 {+-} 0.2 h, and 3.0 {+-} 0.9 h, respectively. Conclusion: Pulsed low-dose paclitaxel chemoradiation is associated with low toxicity. Pharmacokinetic data showed that plasma paclitaxel concentration >0.05 {mu}mol/l for a minimum of 1.6 h was sufficient for effective radiosensitization.« less

Comparative toxicity and efficacy of engineered anthrax lethal toxin variants with broad anti-tumor activities

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

Peters, Diane E.; Program of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA; Hoover, Benjamin

2014-09-01

We have previously designed and characterized versions of anthrax lethal toxin that are selectively cytotoxic in the tumor microenvironment and which display broad and potent anti-tumor activities in vivo. Here, we have performed the first direct comparison of the safety and efficacy of three engineered anthrax lethal toxin variants requiring activation by either matrix-metalloproteinases (MMPs), urokinase plasminogen activator (uPA) or co-localized MMP/uPA activities. C57BL/6J mice were challenged with six doses of engineered toxins via intraperitoneal (I.P.) or intravenous (I.V.) dose routes to determine the maximum tolerated dose for six administrations (MTD6) and dose-limiting toxicities. Efficacy was evaluated using the B16-BL6more » syngraft model of melanoma; mice bearing established tumors were treated with six I.P. doses of toxin and tumor measurements and immunohistochemistry, paired with terminal blood work, were used to elaborate upon the anti-tumor mechanism and relative efficacy of each variant. We found that MMP-, uPA- and dual MMP/uPA-activated anthrax lethal toxins exhibited the same dose-limiting toxicity; dose-dependent GI toxicity. In terms of efficacy, all three toxins significantly reduced primary B16-BL6 tumor burden, ranging from 32% to 87% reduction, and they also delayed disease progression as evidenced by dose-dependent normalization of blood work values. While target organ toxicity and effective doses were similar amongst the variants, the dual MMP/uPA-activated anthrax lethal toxin exhibited the highest I.P. MTD6 and was 1.5–3-fold better tolerated than the single MMP- and uPA-activated toxins. Overall, we demonstrate that this dual MMP/uPA-activated anthrax lethal toxin can be administered safely and is highly effective in a preclinical model of melanoma. This modified bacterial cytotoxin is thus a promising candidate for further clinical development and evaluation for use in treating human cancers. - Highlights: • Toxicity and anti-tumor activity of protease-activated anthrax toxins were evaluated. • All anthrax toxin variants exhibited potent systemic anti-tumor activity in mice. • A dual MMP/uPA-activated anthrax toxin displayed a superior safety profile. • Clinical development of a dual MMP/uPA-activated anthrax toxin is feasible.« less

Key scientific issues in developing drinking water guidelines for perfluoroalkyl acids: Contaminants of emerging concern.

PubMed

Post, Gloria B; Gleason, Jessie A; Cooper, Keith R

2017-12-01

Perfluoroalkyl acids (PFAAs), a group of synthetic organic chemicals with industrial and commercial uses, are of current concern because of increasing awareness of their presence in drinking water and their potential to cause adverse health effects. PFAAs are distinctive among persistent, bioaccumulative, and toxic (PBT) contaminants because they are water soluble and do not break down in the environment. This commentary discusses scientific and risk assessment issues that impact the development of drinking water guidelines for PFAAs, including choice of toxicological endpoints, uncertainty factors, and exposure assumptions used as their basis. In experimental animals, PFAAs cause toxicity to the liver, the immune, endocrine, and male reproductive systems, and the developing fetus and neonate. Low-dose effects include persistent delays in mammary gland development (perfluorooctanoic acid; PFOA) and suppression of immune response (perfluorooctane sulfonate; PFOS). In humans, even general population level exposures to some PFAAs are associated with health effects such as increased serum lipids and liver enzymes, decreased vaccine response, and decreased birth weight. Ongoing exposures to even relatively low drinking water concentrations of long-chain PFAAs substantially increase human body burdens, which remain elevated for many years after exposure ends. Notably, infants are a sensitive subpopulation for PFAA's developmental effects and receive higher exposures than adults from the same drinking water source. This information, as well as emerging data from future studies, should be considered in the development of health-protective and scientifically sound guidelines for PFAAs in drinking water.

Flavonoids apigenin and quercetin inhibit melanoma growth and metastatic potential.

PubMed

Caltagirone, S; Rossi, C; Poggi, A; Ranelletti, F O; Natali, P G; Brunetti, M; Aiello, F B; Piantelli, M

2000-08-15

Flavonoids are a class of polyphenolic compounds widely distributed in the plant kingdom, which display a variety of biological activities, including chemoprevention and tumor growth inhibition. Our aim was to investigate the effects of several polyphenols on the growth and metastatic potential of B16-BL6 melanoma cells in vivo. Intraperitoneal administration of quercetin, apigenin, (-)-epigallocathechin-3-gallate (EGCG), resveratrol, and the anti-estrogen tamoxifen, at the time of i.m. injection of B16-BL6 cells into syngeneic mice, resulted in a significant, dose-dependent delay of tumor growth, without toxicity. The relative descending order of potency was EGCG > apigenin = quercetin = tamoxifen > resveratrol > control. Furthermore, polyphenols significantly potentiated the inhibitory effect of a non-toxic dose of cisplatin. When tested for the ability to inhibit lung colonization, quercetin, apigenin, and tamoxifen (but not EGCG or resveratrol) significantly decreased the number of B16-BL6 colonies in the lungs in a dose-dependent manner, with quercetin and apigenin being more effective than tamoxifen. Interestingly, quercetin, apigenin, and tamoxifen (but not EGCG or resveratrol) significantly decreased the invasion of B16-BL6 cells in vitro, with quercetin and apigenin being more effective than tamoxifen. This suggests that anti-invasive activity is one of the mechanisms underlying inhibition of lung colonization by quercetin and apigenin. In conclusion, quercetin and apigenin inhibit melanoma growth and invasive and metastatic potential; therefore, they may constitute a valuable tool in the combination therapy of metastatic melanoma. Copyright 2000 Wiley-Liss, Inc.

Key scientific issues in developing drinking water guidelines for perfluoroalkyl acids: Contaminants of emerging concern

PubMed Central

Gleason, Jessie A.; Cooper, Keith R.

2017-01-01

Perfluoroalkyl acids (PFAAs), a group of synthetic organic chemicals with industrial and commercial uses, are of current concern because of increasing awareness of their presence in drinking water and their potential to cause adverse health effects. PFAAs are distinctive among persistent, bioaccumulative, and toxic (PBT) contaminants because they are water soluble and do not break down in the environment. This commentary discusses scientific and risk assessment issues that impact the development of drinking water guidelines for PFAAs, including choice of toxicological endpoints, uncertainty factors, and exposure assumptions used as their basis. In experimental animals, PFAAs cause toxicity to the liver, the immune, endocrine, and male reproductive systems, and the developing fetus and neonate. Low-dose effects include persistent delays in mammary gland development (perfluorooctanoic acid; PFOA) and suppression of immune response (perfluorooctane sulfonate; PFOS). In humans, even general population level exposures to some PFAAs are associated with health effects such as increased serum lipids and liver enzymes, decreased vaccine response, and decreased birth weight. Ongoing exposures to even relatively low drinking water concentrations of long-chain PFAAs substantially increase human body burdens, which remain elevated for many years after exposure ends. Notably, infants are a sensitive subpopulation for PFAA’s developmental effects and receive higher exposures than adults from the same drinking water source. This information, as well as emerging data from future studies, should be considered in the development of health-protective and scientifically sound guidelines for PFAAs in drinking water. PMID:29261653

Carbon Monoxide Poisoning: Pathogenesis, Management, and Future Directions of Therapy.

PubMed

Rose, Jason J; Wang, Ling; Xu, Qinzi; McTiernan, Charles F; Shiva, Sruti; Tejero, Jesus; Gladwin, Mark T

2017-03-01

Carbon monoxide (CO) poisoning affects 50,000 people a year in the United States. The clinical presentation runs a spectrum, ranging from headache and dizziness to coma and death, with a mortality rate ranging from 1 to 3%. A significant number of patients who survive CO poisoning suffer from long-term neurological and affective sequelae. The neurologic deficits do not necessarily correlate with blood CO levels but likely result from the pleiotropic effects of CO on cellular mitochondrial respiration, cellular energy utilization, inflammation, and free radical generation, especially in the brain and heart. Long-term neurocognitive deficits occur in 15-40% of patients, whereas approximately one-third of moderate to severely poisoned patients exhibit cardiac dysfunction, including arrhythmia, left ventricular systolic dysfunction, and myocardial infarction. Imaging studies reveal cerebral white matter hyperintensities, with delayed posthypoxic leukoencephalopathy or diffuse brain atrophy. Management of these patients requires the identification of accompanying drug ingestions, especially in the setting of intentional poisoning, fire-related toxic gas exposures, and inhalational injuries. Conventional therapy is limited to normobaric and hyperbaric oxygen, with no available antidotal therapy. Although hyperbaric oxygen significantly reduces the permanent neurological and affective effects of CO poisoning, a portion of survivors still have substantial morbidity. There has been some early success in therapies targeting the downstream inflammatory and oxidative effects of CO poisoning. New methods to directly target the toxic effect of CO, such as CO scavenging agents, are currently under development.

Carbon Monoxide Poisoning: Pathogenesis, Management, and Future Directions of Therapy

PubMed Central

Xu, Qinzi; Shiva, Sruti

2017-01-01

Carbon monoxide (CO) poisoning affects 50,000 people a year in the United States. The clinical presentation runs a spectrum, ranging from headache and dizziness to coma and death, with a mortality rate ranging from 1 to 3%. A significant number of patients who survive CO poisoning suffer from long-term neurological and affective sequelae. The neurologic deficits do not necessarily correlate with blood CO levels but likely result from the pleiotropic effects of CO on cellular mitochondrial respiration, cellular energy utilization, inflammation, and free radical generation, especially in the brain and heart. Long-term neurocognitive deficits occur in 15–40% of patients, whereas approximately one-third of moderate to severely poisoned patients exhibit cardiac dysfunction, including arrhythmia, left ventricular systolic dysfunction, and myocardial infarction. Imaging studies reveal cerebral white matter hyperintensities, with delayed posthypoxic leukoencephalopathy or diffuse brain atrophy. Management of these patients requires the identification of accompanying drug ingestions, especially in the setting of intentional poisoning, fire-related toxic gas exposures, and inhalational injuries. Conventional therapy is limited to normobaric and hyperbaric oxygen, with no available antidotal therapy. Although hyperbaric oxygen significantly reduces the permanent neurological and affective effects of CO poisoning, a portion of survivors still have substantial morbidity. There has been some early success in therapies targeting the downstream inflammatory and oxidative effects of CO poisoning. New methods to directly target the toxic effect of CO, such as CO scavenging agents, are currently under development. PMID:27753502

Lean diesel technology and human health: a case study in six Brazilian metropolitan regions.

PubMed

André, Paulo Afonso de; Veras, Mariana Matera; Miraglia, Simone Georges El Khouri; Saldiva, Paulo Hilário Nascimento

2012-01-01

Due to their toxicity, diesel emissions have been submitted to progressively more restrictive regulations in developed countries. However, in Brazil, the implementation of the Cleaner Diesel Technologies policy (Euro IV standards for vehicles produced in 2009 and low-sulfur diesel with 50 ppm of sulfur) was postponed until 2012 without a comprehensive analysis of the effect of this delay on public health parameters. We aimed to evaluate the impact of the delay in implementing the Cleaner Diesel Technologies policy on health indicators and monetary health costs in Brazil. The primary estimator of exposure to air pollution was the concentration of ambient fine particulate matter (particles with aerodynamic diameters <2.5 μm, [PM2.5]). This parameter was measured daily in six Brazilian metropolitan areas during 2007-2008. We calculated 1) the projected reduction in the PM2.5 that would have been achieved if the Euro IV standards had been implemented in 2009 and 2) the expected reduction after implementation in 2012. The difference between these two time curves was transformed into health outcomes using previous dose-response curves. The economic valuation was performed based on the DALY (disability-adjusted life years) method. The delay in implementing the Cleaner Diesel Technologies policy will result in an estimated excess of 13,984 deaths up to 2040. Health expenditures are projected to be increased by nearly US$ 11.5 billion for the same period. The present results indicate that a significant health burden will occur because of the postponement in implementing the Cleaner Diesel Technologies policy. These results also reinforce the concept that health effects must be considered when revising fuel and emission policies.

Distribution of Microplastics and Nanoplastics in Aquatic Ecosystems and Their Impacts on Aquatic Organisms, with Emphasis on Microalgae.

PubMed

Wan, Jun-Kit; Chu, Wan-Loy; Kok, Yih-Yih; Lee, Choy-Sin

2018-06-06

Plastics, with their many useful physical and chemical properties, are widely used in various industries and activities of daily living. Yet, the insidious effects of plastics, particularly long-term effects on aquatic organisms, are not properly understood. Plastics have been shown to degrade to micro- and nanosize particles known as microplastics and nanoplastics, respectively. These minute particles have been shown to cause various adverse effects on aquatic organisms, ranging from growth inhibition, developmental delay and altered feeding behaviour in aquatic animals to decrease of photosynthetic efficiency and induction of oxidative stress in microalgae. This review paper covers the distribution of microplastics and nanoplastics in aquatic ecosystems, focusing on their effects on microalgae as well as co-toxicity of microplastics and nanoplastics with other pollutants. Besides that, this review paper also discusses future research directions which could be taken to gain a better understanding of the impacts of microplastics and nanoplastics on aquatic ecosystems.

An evaluation of the residual toxicity and chemistry of a sodium hydroxide-based ballast water treatment system for freshwater ships.

PubMed

Elskus, Adria A; Ingersoll, Christopher G; Kemble, Nile E; Echols, Kathy R; Brumbaugh, William G; Henquinet, Jeffrey W; Watten, Barnaby J

2015-06-01

Nonnative organisms in the ballast water of freshwater ships must be killed to prevent the spread of invasive species. The ideal ballast water treatment system (BWTS) would kill 100% of ballast water organisms with minimal residual toxicity to organisms in receiving waters. In the present study, the residual toxicity and chemistry of a BWTS was evaluated. Sodium hydroxide was added to elevate pH to >11.5 to kill ballast water organisms, then reduced to pH <9 by sparging with wet-scrubbed diesel exhaust (the source of CO2 ). Cladocerans (Ceriodaphnia dubia), amphipods (Hyalella azteca), and fathead minnows (Pimephales promelas) were exposed for 2 d to BWTS water under an air atmosphere (pH drifted to ≥9) or a 2.5% CO2 atmosphere (pH 7.5-8.2), then transferred to control water for 5 d to assess potential delayed toxicity. Chemical concentrations in the BWTS water met vessel discharge guidelines with the exception of concentrations of copper. There was little to no residual toxicity to cladocerans or fish, but the BWTS water was toxic to amphipods. Maintaining a neutral pH and diluting BWTS water by 50% eliminated toxicity to the amphipods. The toxicity of BWTS water would likely be minimal because of rapid dilution in the receiving water, with subsurface release likely preventing pH rise. This BWTS has the potential to become a viable method for treating ballast water released into freshwater systems. © 2015 SETAC.

Radio-toxicity of spent fuel of the advanced heavy water reactor.

PubMed

Anand, S; Singh, K D S; Sharma, V K

2010-01-01

The Advanced Heavy Water Reactor (AHWR) is a new power reactor concept being developed at Bhabha Atomic Research Centre, Mumbai. The reactor retains many desirable features of the existing Pressurised Heavy Water Reactor (PHWR), while incorporating new, advanced safety features. The reactor aims to utilise the vast thorium resources available in India. The reactor core will use plutonium as the make-up fuel, while breeding (233)U in situ. On account of this unique combination of fuel materials, the operational characteristics of the fuel as determined by its radioactivity, decay heat and radio-toxicity are being viewed with great interest. Radio-toxicity of the spent fuel is a measure of potential radiological hazard to the members of the public and also important from the ecological point of view. The radio-toxicity of the AHWR fuel is extremely high to start with, being approximately 10(4) times that of the fresh natural U fuel used in a PHWR, and continues to remain relatively high during operation and subsequent cooling. A unique feature of this fuel is the peak observed in its radio-toxicity at approximately 10(5) y of decay cooling. The delayed increase in fuel toxicity has been traced primarily to a build-up of (229)Th, (230)Th and (226)Ra. This phenomenon has been observed earlier for thorium-based fuels and is confirmed for the AHWR fuel. This paper presents radio-toxicity data for AHWR spent fuel up to a period of 10(6) y and the results are compared with the radio-toxicity of PHWR.

Nasopharyngeal Carcinoma in Children: Comparison of Conventional and Intensity-Modulated Radiotherapy

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

Laskar, Siddhartha; Bahl, Gaurav; Muckaden, MaryAnn

2008-11-01

Purpose: To evaluate the efficacy of intensity-modulated radiotherapy (IMRT) in reducing the acute toxicities associated with conventional RT (CRT) in children with nasopharyngeal carcinoma. Patients and Methods: A total of 36 children with nonmetastatic nasopharyngeal carcinoma, treated at the Tata Memorial Hospital between June 2003 and December 2006, were included in this study. Of the 36 patients, 28 were boys and 8 were girls, with a median age of 14 years; 4 (11%) had Stage II and 10 (28%) Stage III disease at presentation. All patients had undifferentiated carcinoma and were treated with a combination of chemotherapy and RT. Ofmore » the 36 patients, 19 underwent IMRT and 17 underwent CRT. Results: After a median follow-up of 27 months, the 2-year locoregional control, disease-free, and overall survival rate was 76.5%, 60.6%, and 71.3%, respectively. A significant reduction in acute Grade 3 toxicities of the skin (p = 0.006), mucous membrane (p = 0.033), and pharynx (p = 0.035) was noted with the use of IMRT. The median time to the development of Grade 2 toxicity was delayed with IMRT (skin, 35 vs. 25 days, p = 0.016; mucous-membrane, 39 vs. 27 days, p = 0.002; and larynx, 50 vs. 28 days, p = 0.009). The duration of RT significantly influenced disease-free survival on multivariate analysis (RT duration >52 days, hazard ratio = 5.49, 95% confidence interval, 1.14-26.45, p = 0.034). The average mean dose to the first and second planning target volume was 71.8 Gy and 62.5 Gy with IMRT compared with 66.3 Gy (p = 0.001) and 64.4 Gy (p = 0.046) with CRT, respectively. Conclusion: The results of our study have shown that IMRT significantly reduces and delays the onset of acute toxicity, resulting in improved tolerance and treatment compliance for children with nasopharyngeal carcinoma. Also, IMRT provided superior target coverage and normal tissue sparing compared with CRT.« less

The significance of nanomaterial post-exposure responses in Daphnia magna standard acute immobilisation assay: Example with testing TiO2 nanoparticles.

PubMed

Novak, Sara; Jemec Kokalj, Anita; Hočevar, Matej; Godec, Matjaž; Drobne, Damjana

2018-05-15

One of the most widely used aquatic standarized tests for the toxicity screening of chemicals is the acute toxicity test with the freshwater crustacean Daphnia magna, which has also been applied in the toxicity screening of manufactured nanoparticles (NPs). However, in the case of non-soluble NPs most of the results of this test have showed no effect. The aim of the work presented here was to modify the standardized test by the least possible extent to make it more sensitive for non-soluble particles. The standard acute immobilisation assay with daphnids was modified by prolonging the exposure period and by measuring additional endpoints. Daphnids were exposed to TiO 2 NPs in a standard acute test (48h of exposure), a standard acute test (48h of exposure) followed by 24h recovery period in clean medium or a prolonged exposure in the NPs solutions totaling 72h. Together with immobility, the adsorption of NPs to body surfaces was also observed as an alternative measure of the NPs effects. Our results showed almost no effect of TiO 2 NPs on D. magna after the 48h standard acute test, while immobility was increased when the exposure period to TiO 2 NPs was prolonged from 48h to 72h. Even when daphnids were transferred to clean medium for additional 24h after 48h of exposure to TiO 2 NPs the immobility increased. We conclude that by transferring the daphnids to clean medium at the end of the 48h exposure to TiO 2 NPs, the delayed effects of the tested material can be seen. This methodological step could improve the sensitivity of D. magna test as a model in nanomaterial environmental risk assessment. Copyright © 2018 Elsevier Inc. All rights reserved.

Things That Go Boom!: Noise and Toxic Exposures Associated with Weapon Systems

DTIC Science & Technology

2010-06-17

Munitions Pyrotechnics Tracers Spot ing Charges Oxidizers Delay Elements Propellatl s Fuses De· onators Pr~n1ers Constituent of Concern BariL ...r11 chromate Potassium perchlorate lead oxide BariL m chromate P a tass ~L m perch I o r,ate l e ad chromate An1n1onil tll perch lara e P a

Learning and Memory Enhancement by Neuropeptides

DTIC Science & Technology

1987-12-31

extxosure to other toxicants ,’e.g. other heavy metals, organic solvents), or arising from disease statee. We study leaming ii, an autoshaping task...Sparber, S.B. Selective leaming impairment of j delayed reinforcement autoshaped behavior caused by low doses of trimethyltin. S EPsychopharn-.acology...impairs acquis:tion of autoshaped behavior, whether given before or after training sessions. manuscript des -")ing this work is in preparation, and an

Fluoride metabolism when added to salt.

PubMed

Whitford, Gary M

2005-01-01

The purpose of this review is to present the general characteristics of the metabolism of fluoride particularly as it occurs when ingested with fluoridated salt. Following the absorption of salt-borne fluoride from the stomach and intestines, its metabolism is identical to that of water-borne fluoride or other vehicles containing ionized fluoride. Because fluoridated salt is almost always ingested with food, however, absorption from the gastrointestinal tract may be delayed or reduced. Reports dealing with this subject have shown that fluoride absorption is delayed and, therefore, peak plasma concentrations are lower than when fluoride is ingested with water. The amount of ingested fluoride that is finally absorbed, however, is not appreciably affected unless the meal is composed mainly of components with high calcium concentrations. In this case, the extent of absorption can be reduced by as much as 50%. Fluoridated salt is also ingested less frequently than fluoridated water. Data are presented to show that the dose size and frequency of ingestion have only minor effects on fluoride retention in the body and on the concentrations in plasma, bone and enamel. Finally, calculations are presented to show that the risk of acute toxicity from fluoridated salt is virtually non-existent.

Subchronic 13-week inhalation exposure of rats to multiwalled carbon nanotubes: toxic effects are determined by density of agglomerate structures, not fibrillar structures.

PubMed

Pauluhn, Jürgen

2010-01-01

Wistar rats were nose-only exposed to multiwalled carbon nanotubes (MWCNT, Baytubes) in a subchronic 13-week inhalation study. The focus of study was on respiratory tract and systemic toxicity, including analysis of MWCNT biokinetics in the lungs and lung-associated lymph nodes (LALNs). The time course and concentration dependence of pulmonary effects were examined by bronchoalveolar lavage (BAL) and histopathology up to 6 months postexposure. Particular emphasis was directed to the comparative characterization of MWCNT structures prior to and after micronization and dry powder dispersion into inhalation chambers. These determinations were complemented by additional analyses in digested BAL cells. Animals were exposed on 6 h/day, 5 days per week for 13 consecutive weeks to 0, 0.1, 0.4, 1.5, and 6 mg/m(3). The subchronic exposure to respirable solid aerosols of MWCNT was tolerated without effects suggestive of systemic toxicity. Kinetic analyses demonstrated a markedly delayed clearance of MWCNT from lungs at overload conditions. Translocation into LALNs occurred at 1.5 and 6 mg/m(3) and required at least 13 weeks of study to become detectable. At these exposure levels, the lung and LALN weights were significantly increased. Sustained elevations in BAL polymorphonuclear neutrophils and soluble collagen occurred at these concentrations with borderline effects at 0.4 mg/m(3). Histopathology revealed principal exposure-related lesions at 0.4 mg/m(3) and above in the upper respiratory tract (goblet cell hyper- and/or metaplasia, eosinophilic globules, and focal turbinate remodeling) and the lower respiratory tract (inflammatory changes in the bronchioloalveolar region and increased interstitial collagen staining). Granulomatous changes and a time-dependent increase of a bronchioloalveolar hyperplasia occurred at 6 mg/m(3). All end points examined were unremarkable at 0.1 mg/m(3) (no-observed-adverse-effect-level). In summary, this study demonstrates that the induced pathological changes are consistent with overload-related phenomena. Hence, the etiopathological sequence of inflammatory events caused by this type of MWCNT appears to be related to the high displacement volume of the low-density MWCNT assemblage structure rather than to any yet ill-defined intrinsic toxic property. Thus, the hypothesis of study is verified, namely, common denominators between carbon black and MWCNT do exist.

Protective molecular mechanisms of resveratrol in UVR-induced Skin carcinogenesis.

PubMed

Aziz, Saba W; Aziz, Moammir H

2018-01-01

Skin cancer is a major health problem worldwide. It is the most common cancer in the United States and poses a significant healthcare burden. Excessive UVR exposure is the most common cause of skin cancer. Despite various precautionary measures to avoid direct UVR exposure, the incidence of skin cancer and mortality related to it remains high. Furthermore, the current treatment options are expensive and have side effects including toxicity to normal cells. Thus, a safe and effective approach is needed to prevent and treat skin cancer. Chemopreventive strategy using naturally occurring compounds, such as resveratrol, is a promising approach to reduce the incidence of UVR-induced skin cancer and delay its progression. This review highlights the current body of evidence related to chemopreventive role of resveratrol and its molecular mechanisms in UVR-induced skin carcinogenesis. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Investigation of the anticoagulant and antithrombotic effects of chlorogenic acid.

PubMed

Choi, Jun-Hui; Kim, Seung

2017-03-01

Thrombosis is a leading cause of morbidity and mortality throughout the world. Thrombolytic agents are important for both the prevention and treatment of thrombosis. Fibrin clot and turbidity assays revealed that it was able to inhibit the formation of fibrin clot. Chlorogenic acid degraded blood clot and inhibited the enzymatic activity of procoagulant proteases, thrombin, activated factor X (FXa), and activated factor XIII (FXIIIa). Chlorogenic acid was found to delay activated partial thromboplastin time, prothrombin time, and thrombin time. PFA-100 assays showed that it prolonged the closure time of citrated whole human blood. It demonstrated the antithrombotic effect in collagen and epinephrine-induced acute thromboembolism mice model. These antithrombotic profiles together with its anticoagulant and platelet disaggregation properties, and lack of toxicity to NIH-3T3 and 3T3-L1 cells, make it a potential agent for thrombotic treatment and prevention. © 2016 Wiley Periodicals, Inc.

Molecular characterization of Cry1D-133 toxin from Bacillus thuringiensis strain HD133 and its toxicity against Spodoptera littoralis.

PubMed

BenFarhat-Touzri, Dalel; Driss, Fatma; Jemli, Sonia; Tounsi, Slim

2018-06-01

Bacillus thuringiensis subsp. aizawai strain HD133, known by its effectiveness against Spodoptera species, produces bipyramidal crystals encompassing the insecticidal proteins Cry1Ab, Cry1Ca and Cry1D-133 in the proportions 60:37:3, respectively. In this study, we dealt with the relevance of the low rate of Cry1D-133. The cry1D-133 gene from HD133 was cloned and sequenced. Both nucleotide and amino acid sequence similarity analyses with the cry1D genes available in the GenBank database revealed that cry1D-133 is a new variant of cry1Da-type genes with 99% identity with cry1Da1. Molecular modeling of the Cry1D-133 toxin showed that its higher toxicity is correlated to a higher number of toxin-receptor interactions. Optimal culture conditions of 4 h post-induction time, 160 rpm agitation and 37 °C post-induction temperature were determined and adopted to overproduce Cry1D-133 toxin at adequate amounts to carryout bioassays. A gradual increase of the proportion of Cry1D-133 to the HD133 insecticidal proteins forming the crystal (Cry1D-133, Cry1Ca and Cry1Ab) showed an improvement of the toxicity against Spodoptera littoralis larvae. Therefore, the potential of Cry1D-133 to enhance HD133 toxicity could promote its combination with other B. thuringiensis insecticidal proteins toxins in order to increase target range or to delay the emergence of resistance. Copyright © 2018 Elsevier B.V. All rights reserved.

Nephrotoxicity of ibandronate and zoledronate in Wistar rats with normal renal function and after unilateral nephrectomy.

PubMed

Bergner, R; Siegrist, B; Gretz, N; Pohlmeyer-Esch, G; Kränzlin, B

2015-09-01

A previous animal study compared the nephrotoxic effect of ibandronate (IBN) and zoledronate (ZOL), but interpretation of these study results was limited because of the model of minimal nephrotoxic dosage with a dosage ratio of 1:3. The present study investigated the nephrotoxicity of ibandronate and zoledronate in a 1.5:1 dose ratio, as used in clinical practice and compared the nephrotoxicity in rats with normal and with mildly to moderately impaired renal function. We compared rats with normal renal function (SHAM) and with impaired renal function after unilateral nephrectomy (UNX), treated either with ibandronate 1.5mg/kg, zoledronate 1mg/kg or placebo once (1×) or nine (9×) times. Renal function and markers of tubular toxicity were measured over a 27 week period. After last bisphosphonate treatment the rats were sacrificed and kidneys examined histologically. All bisphosphonate treated animals showed a significant tubular toxicity, which was temporary except in the ZOL-UNX-9×-group. Also the renal function was only transiently reduced except in the ZOL-UNX-9×-group. Histologically, bisphosphonate treatment led to cortical tubuloepithelial degeneration/necrosis and medullary tubuloepithelial swelling which were slightly more pronounced in ibandronate treated animals, when compared to zoledronate treated animals, especially with impaired renal function. In contrast to the previous study we found a similar nephrotoxicity of ibandronate and zoledronate in rats with normal renal function. In rats with impaired renal function the peak of toxicity had not even been fully reached until end of experiment in the zoledronate treated animals. The peak of toxicity seems to be more severe and delayed in rats with impaired renal function compared with rats with normal renal function. Copyright © 2015 Elsevier Ltd. All rights reserved.

Simultaneously optimizing dose and schedule of a new cytotoxic agent.

PubMed

Braun, Thomas M; Thall, Peter F; Nguyen, Hoang; de Lima, Marcos

2007-01-01

Traditionally, phase I clinical trial designs are based upon one predefined course of treatment while varying among patients the dose given at each administration. In actual medical practice, patients receive a schedule comprised of several courses of treatment, and some patients may receive one or more dose reductions or delays during treatment. Consequently, the overall risk of toxicity for each patient is a function of both actual schedule of treatment and the differing doses used at each adminstration. Our goal is to provide a practical phase I clinical trial design that more accurately reflects actual medical practice by accounting for both dose per administration and schedule. We propose an outcome-adaptive Bayesian design that simultaneously optimizes both dose and schedule in terms of the overall risk of toxicity, based on time-to-toxicity outcomes. We use computer simulation as a tool to calibrate design parameters. We describe a phase I trial in allogeneic bone marrow transplantation that was designed and is currently being conducted using our new method. Our computer simulations demonstrate that our method outperforms any method that searches for an optimal dose but does not allow schedule to vary, both in terms of the probability of identifying optimal (dose, schedule) combinations, and the numbers of patients assigned to those combinations in the trial. Our design requires greater sample sizes than those seen in traditional phase I studies due to the larger number of treatment combinations examined. Our design also assumes that the effects of multiple administrations are independent of each other and that the hazard of toxicity is the same for all administrations. Our design is the first for phase I clinical trials that is sufficiently flexible and practical to truly reflect clinical practice by varying both dose and the timing and number of administrations given to each patient.

Toxicity evaluation of boron nitride nanospheres and water-soluble boron nitride in Caenorhabditis elegans

PubMed Central

Wang, Ning; Wang, Hui; Tang, Chengchun; Lei, Shijun; Shen, Wanqing; Wang, Cong; Wang, Guobin; Wang, Zheng; Wang, Lin

2017-01-01

Boron nitride (BN) nanomaterials have been increasingly explored for potential biological applications. However, their toxicity remains poorly understood. Using Caenorhabditis elegans as a whole-animal model for toxicity analysis of two representative types of BN nanomaterials – BN nanospheres (BNNSs) and highly water-soluble BN nanomaterial (named BN-800-2) – we found that BNNSs overall toxicity was less than soluble BN-800-2 with irregular shapes. The concentration thresholds for BNNSs and BN-800-2 were 100 µg·mL−1 and 10 µg·mL−1, respectively. Above this concentration, both delayed growth, decreased life span, reduced progeny, retarded locomotion behavior, and changed the expression of phenotype-related genes to various extents. BNNSs and BN-800-2 increased oxidative stress levels in C. elegans by promoting reactive oxygen species production. Our results further showed that oxidative stress response and MAPK signaling-related genes, such as GAS1, SOD2, SOD3, MEK1, and PMK1, might be key factors for reactive oxygen species production and toxic responses to BNNSs and BN-800-2 exposure. Together, our results suggest that when concentrations are lower than 10 µg·mL−1, BNNSs are more biocompatible than BN-800-2 and are potentially biocompatible material. PMID:28860759

Toxicity evaluation of boron nitride nanospheres and water-soluble boron nitride in Caenorhabditis elegans.

PubMed

Wang, Ning; Wang, Hui; Tang, Chengchun; Lei, Shijun; Shen, Wanqing; Wang, Cong; Wang, Guobin; Wang, Zheng; Wang, Lin

2017-01-01

Boron nitride (BN) nanomaterials have been increasingly explored for potential biological applications. However, their toxicity remains poorly understood. Using Caenorhabditis elegans as a whole-animal model for toxicity analysis of two representative types of BN nanomaterials - BN nanospheres (BNNSs) and highly water-soluble BN nanomaterial (named BN-800-2) - we found that BNNSs overall toxicity was less than soluble BN-800-2 with irregular shapes. The concentration thresholds for BNNSs and BN-800-2 were 100 µg·mL -1 and 10 µg·mL -1 , respectively. Above this concentration, both delayed growth, decreased life span, reduced progeny, retarded locomotion behavior, and changed the expression of phenotype-related genes to various extents. BNNSs and BN-800-2 increased oxidative stress levels in C. elegans by promoting reactive oxygen species production. Our results further showed that oxidative stress response and MAPK signaling-related genes, such as GAS1 , SOD2 , SOD3 , MEK1 , and PMK1 , might be key factors for reactive oxygen species production and toxic responses to BNNSs and BN-800-2 exposure. Together, our results suggest that when concentrations are lower than 10 µg·mL -1 , BNNSs are more biocompatible than BN-800-2 and are potentially biocompatible material.

Studies on some feed additives and materials giving partial protection against the suppressive effect of ochratoxin A on egg production of laying hens.

PubMed

Stoev, Stoycho D

2010-06-01

The protective effects of various feed supplements against the harmful effect of ochratoxin A on egg production and sexual maturation of two-weeks old Plymouth Rock female chicks designed for laying hens were studied. A significant protective effect of the feed additives or materials: water extract of artichoke (WEA), sesame seed (SS), Roxazyme-G (RG) and l-beta phenylalanine (PHE) against the suppressive effect of ochratoxin A (OTA) on egg production of laying hens was found. A similar protection was also seen on the toxic effect of OTA on various internal organs of the same hens. A significant protection was found against the decrease of the weight or the quantity of eggs as well as against the delay of the beginning of the laying period of chicks, both of which were provoked by ochratoxin A. These protective effects were strongest in chicks treated with SS or WEA, but were slightest in chicks treated with l-beta PHE. Copyright 2009 Elsevier Ltd. All rights reserved.

Developmental toxicity and alteration of gene expression in zebrafish embryos exposed to PFOS

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

Shi Xiongjie; Graduate School of the Chinese Academy of Sciences, Beijing 100039; Du Yongbing

2008-07-01

Perfluorooctanesulfonate (PFOS) is a persistent organic pollutant, the potential toxicity of which is causing great concern. In the present study, we employed zebrafish embryos to investigate the developmental toxicity of this compound. Four-hour post-fertilization (hpf) zebrafish embryos were exposed to 0.1, 0.5, 1, 3 and 5 mg/L PFOS. Hatching was delayed and hatching rates as well as larval survivorship were significantly reduced after the embryos were exposed to 1, 3 and 5 mg/L PFOS until 132 hpf. The fry displayed gross developmental malformations, including epiboly deformities, hypopigmentation, yolk sac edema, tail and heart malformations and spinal curvature upon exposure tomore » PFOS concentrations of 1 mg/L or greater. Growth (body length) was significantly reduced in the 3 and 5 mg/L PFOS-treated groups. To test whether developmental malformation was mediated via apoptosis, flow cytometry analysis of DNA content, acridine orange staining and TUNEL assay was used. These techniques indicated that more apoptotic cells were present in the PFOS-treated embryos than in the control embryos. Certain genes related to cell apoptosis, p53 and Bax, were both significantly up-regulated upon exposure to all the concentrations tested. In addition, we investigated the effects of PFOS on marker genes related to early thyroid development (hhex and pax8) and genes regulating the balance of androgens and estrogens (cyp19a and cyp19b). For thyroid development, the expression of hhex was significantly up-regulated at all concentrations tested, whereas pax8 expression was significantly up-regulated only upon exposure to lower concentrations of PFOS (0.1, 0.5, 1 mg/L). The expression of cyp19a and of cyp19b was significantly down-regulated at all exposure concentrations. The overall results indicated that zebrafish embryos constitute a reliable model for testing the developmental toxicity of PFOS, and the gene expression patterns in the embryos were able to reveal some potential mechanisms of developmental toxicity.« less

The amount effect and marginal value.

PubMed

Rachlin, Howard; Arfer, Kodi B; Safin, Vasiliy; Yen, Ming

2015-07-01

The amount effect of delay discounting (by which the value of larger reward amounts is discounted by delay at a lower rate than that of smaller amounts) strictly implies that value functions (value as a function of amount) are steeper at greater delays than they are at lesser delays. That is, the amount effect and the difference in value functions at different delays are actually a single empirical finding. Amount effects of delay discounting are typically found with choice experiments. Value functions for immediate rewards have been empirically obtained by direct judgment. (Value functions for delayed rewards have not been previously obtained.) The present experiment obtained value functions for both immediate and delayed rewards by direct judgment and found them to be steeper when the rewards were delayed--hence, finding an amount effect with delay discounting. © Society for the Experimental Analysis of Behavior.

Transformation of Air Quality Monitor Data from the International Space Station into Toxicological Effect Groups

NASA Technical Reports Server (NTRS)

James, John T.; Zalesak, Selina M.

2011-01-01

The primary reason for monitoring air quality aboard the International Space Station (ISS) is to determine whether air pollutants have collectively reached a concentration where the crew could experience adverse health effects. These effects could be near-real-time (e.g. headache, respiratory irritation) or occur late in the mission or even years later (e.g. cancer, liver toxicity). Secondary purposes for monitoring include discovery that a potentially harmful compound has leaked into the atmosphere or that air revitalization system performance has diminished. Typical ISS atmospheric trace pollutants consist of alcohols, aldehydes, aromatic compounds, halo-carbons, siloxanes, and silanols. Rarely, sulfur-containing compounds and alkanes are found at trace levels. Spacecraft Maximum Allowable Concentrations (SMACs) have been set in cooperation with a subcommittee of the National Research Council Committee on Toxicology. For each compound and time of exposure, the limiting adverse effect(s) has been identified. By factoring the analytical data from the Air Quality Monitor (AQM), which is in use as a prototype instrument aboard the ISS, through the array of compounds and SMACs, the risk of 16 specific adverse effects can be estimated. Within each adverse-effect group, we have used an additive model proportioned to each applicable 180-day SMAC to estimate risk. In the recent past this conversion has been performed using archival data, which can be delayed for months after an air sample is taken because it must be returned to earth for analysis. But with the AQM gathering in situ data each week, NASA is in a position to follow toxic-effect groups and correlate these with any reported crew symptoms. The AQM data are supplemented with data from real-time CO2 instruments aboard the ISS and from archival measurements of formaldehyde, which the AQM cannot detect.

Insulin-Like Growth Factor 1 Mitigates Hematopoietic Toxicity After Lethal Total Body Irradiation

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

Zhou, Dunhua; Deoliveira, Divino; Kang, Yubin

2013-03-15

Purpose: To investigate whether and how insulin-like growth factor 1 (IGF-1) mitigates hematopoietic toxicity after total body irradiation. Methods and Materials: BALB/c mice were irradiated with a lethal dose of radiation (7.5 Gy) and treated with IGF-1 at a dose of 100 μg/dose intravenously once a day for 5 consecutive days starting within 1 hour after exposure. Survival and hematopoietic recovery were monitored. The mechanisms by which IGF-1 promotes hematopoietic recovery were also studied by use of an in vitro culture system. Results: IGF-1 protected 8 of 20 mice (40%) from lethal irradiation, whereas only 2 of 20 mice (10%) inmore » the saline control group survived for more than 100 days after irradiation. A single dose of IGF-1 (500 μg) was as effective as daily dosing for 5 days. Positive effects were noted even when the initiation of treatment was delayed as long as 6 hours after irradiation. In comparison with the saline control group, treatment with IGF-1 significantly accelerated the recovery of both platelets and red blood cells in peripheral blood, total cell numbers, hematopoietic stem cells, and progenitor cells in the bone marrow when measured at day 14 after irradiation. IGF-1 protected both hematopoietic stem cells and progenitor cells from radiation-induced apoptosis and cell death. In addition, IGF-1 was able to facilitate the proliferation and differentiation of nonirradiated and irradiated hematopoietic progenitor cells. Conclusions: IGF-1 mitigates radiation-induced hematopoietic toxicity through protecting hematopoietic stem cells and progenitor cells from apoptosis and enhancing proliferation and differentiation of the surviving hematopoietic progenitor cells.« less

Size effects of single-walled carbon nanotubes on in vivo and in vitro pulmonary toxicity

PubMed Central

Fujita, Katsuhide; Fukuda, Makiko; Endoh, Shigehisa; Maru, Junko; Kato, Haruhisa; Nakamura, Ayako; Shinohara, Naohide; Uchino, Kanako; Honda, Kazumasa

2015-01-01

Abstract To elucidate the effect of size on the pulmonary toxicity of single-wall carbon nanotubes (SWCNTs), we prepared two types of dispersed SWCNTs, namely relatively thin bundles with short linear shapes (CNT-1) and thick bundles with long linear shapes (CNT-2), and conducted rat intratracheal instillation tests and in vitro cell-based assays using NR8383 rat alveolar macrophages. Total protein levels, MIP-1α expression, cell counts in BALF, and histopathological examinations revealed that CNT-1 caused pulmonary inflammation and slower recovery and that CNT-2 elicited acute lung inflammation shortly after their instillation. Comprehensive gene expression analysis confirmed that CNT-1-induced genes were strongly associated with inflammatory responses, cell proliferation, and immune system processes at 7 or 30 d post-instillation. Numerous genes were significantly upregulated or downregulated by CNT-2 at 1 d post-instillation. In vitro assays demonstrated that CNT-1 and CNT-2 SWCNTs were phagocytized by NR8383 cells. CNT-2 treatment induced cell growth inhibition, reactive oxygen species production, MIP-1α expression, and several genes involved in response to stimulus, whereas CNT-1 treatment did not exert a significant impact in these regards. These results suggest that SWCNTs formed as relatively thin bundles with short linear shapes elicited delayed pulmonary inflammation with slower recovery. In contrast, SWCNTs with a relatively thick bundle and long linear shapes sensitively induced cellular responses in alveolar macrophages and elicited acute lung inflammation shortly after inhalation. We conclude that the pulmonary toxicity of SWCNTs is closely associated with the size of the bundles. These physical parameters are useful for risk assessment and management of SWCNTs. PMID:25865113

Toxicity and aggregation of the polyglutamine disease protein, ataxin-3 is regulated by its binding to VCP/p97 in Drosophila melanogaster.

PubMed

Ristic, Gorica; Sutton, Joanna R; Libohova, Kozeta; Todi, Sokol V

2018-04-26

Among the nine dominantly inherited, age-dependent neurodegenerative diseases caused by abnormal expansion in the polyglutamine (polyQ) repeat of otherwise unrelated proteins is Spinocerebellar Ataxia Type 3 (SCA3). SCA3 is caused by polyQ expansion in the deubiquitinase (DUB), ataxin-3. Molecular sequelae related to SCA3 remain unclear. Here, we sought to understand the role of protein context in SCA3 by focusing on the interaction between this DUB and Valosin-Containing Protein (VCP). VCP is bound directly by ataxin-3 through an arginine-rich area preceding the polyQ repeat. We examined the importance of this interaction in ataxin-3-dependent degeneration in Drosophila melanogaster. Our assays with new isogenic fly lines expressing pathogenic ataxin-3 with an intact or mutated VCP-binding site show that disrupting the ataxin-3-VCP interaction delays the aggregation of the toxic protein in vivo. Importantly, early on flies that express pathogenic ataxin-3 with a mutated VCP-binding site are indistinguishable from flies that do not express any SCA3 protein. Also, reducing levels of VCP through RNA-interference has a similar, protective effect to mutating the VCP-binding site of pathogenic ataxin-3. Based on in vivo pulse-chases, aggregated species of ataxin-3 are highly stable, in a manner independent of VCP-binding. Collectively, our results highlight an important role for the ataxin-3-VCP interaction in SCA3, based on a model that posits a seeding effect from VCP on pathogenic ataxin-3 aggregation and subsequent toxicity. Copyright © 2018 Elsevier Inc. All rights reserved.

A COMPARISON OF THE EFFECTS OF BRIEF RULES, A TIMER, AND PREFERRED TOYS ON SELF-CONTROL

PubMed Central

Newquist, Matthew H; Dozier, Claudia L; Neidert, Pamela L

2012-01-01

Some children make impulsive choices (i.e., choose a small but immediate reinforcer over a large but delayed reinforcer). Previous research has shown that delay fading, providing an alternative activity during the delay, teaching participants to repeat a rule during the delay, combining delay fading with an alternative activity, and combining delay fading with a countdown timer are effective for increasing self-control (i.e., choosing the large but delayed reinforcer over the small but immediate reinforcer). The purpose of the current study was to compare the effects of various interventions in the absence of delay fading (i.e., providing brief rules, providing a countdown timer during the delay, or providing preferred toys during the delay) on self-control. Results suggested that providing brief rules or a countdown timer during the delay was ineffective for enhancing self-control. However, providing preferred toys during the delay effectively enhanced self-control. PMID:23060664

A comparison of the effects of brief rules, a timer, and preferred toys on self-control.

PubMed

Newquist, Matthew H; Dozier, Claudia L; Neidert, Pamela L

2012-01-01

Some children make impulsive choices (i.e., choose a small but immediate reinforcer over a large but delayed reinforcer). Previous research has shown that delay fading, providing an alternative activity during the delay, teaching participants to repeat a rule during the delay, combining delay fading with an alternative activity, and combining delay fading with a countdown timer are effective for increasing self-control (i.e., choosing the large but delayed reinforcer over the small but immediate reinforcer). The purpose of the current study was to compare the effects of various interventions in the absence of delay fading (i.e., providing brief rules, providing a countdown timer during the delay, or providing preferred toys during the delay) on self-control. Results suggested that providing brief rules or a countdown timer during the delay was ineffective for enhancing self-control. However, providing preferred toys during the delay effectively enhanced self-control.

Effects of prenatal and perinatal administration of phencyclidine on the behavioral development of rat offspring.

PubMed

Nabeshima, T; Yamaguchi, K; Hiramatsu, M; Ishikawa, K; Furukawa, H; Kameyama, T

1987-11-01

The effects of prenatal and perinatal administration of a nonteratogenic dose of phencyclidine (PCP) on the behavioral development of Sprague-Dawley rats were examined. In the offspring prenatally treated with PCP (10 mg/kg) between days 7 and 17 of gestation, a decrease in maternal body weight in the gestation period, a decrease in fetal body weight and body length, a decrease in viability of offsprings, and a decrease in the body weights of the offspring in the nursing period were observed. Furthermore, PCP pups had difficulty performing the rota-rod task at 4 weeks and exhibited a decrease in sensitivity to challenged PCP at 5 weeks (female). In the offspring prenatally treated with PCP between days 7 and 21 of gestation, a decrease in the body weights of dams, fetuses and offspring, and a decrease in the viability of offsprings were observed. PCP pups showed an increase in the score for head-twitch response (male), a delay in the development of ambulation, negative geotaxis (male), bar holding and rope-descending behavior (female). However, the PCP administration during prenatal (between days 17 and 21 of gestation) and nursing periods showed only a decrease in viability and body weight of offspring, and a delay in the development of the separation of eyelids. These results suggest that more attention should be given to the developmental toxicity of PCP.

Fluoroacetate-mediated toxicity of fluorinated ethanes.

PubMed

Keller, D A; Roe, D C; Lieder, P H

1996-04-01

A series of 1-(di)halo-2-fluoroethanes reported in the literature to be nontoxic or of low toxicity were found to be highly toxic by the inhalation route. Experiments were performed that showed the compounds, 1,2-difluoroethane, 1-chloro-2-fluoroethane, 1-chloro-1,2-difluoroethane, and 1-bromo-2-fluoroethane to be highly toxic to rats upon inhalation for 4 hr. All four compounds had 4-hr approximate lethal concentrations of < or = 100 ppm in rats. In contrast, 1,1-difluoroethane (commonly referred to as HFC-152a) has very low acute toxicity with a 4-hr LC50 of > 400,000 ppm in rats. Rats exposed to the selected toxic fluoroethanes showed clinical signs of fluoroacetate toxicity (lethargy, hunched posture, convulsions). 1,2-Difluoroethane, 1-chloro-2-fluoroethane, 1-chloro-1,2-difluoroethane, and 1-bromo-2-fluoroethane were shown to increase concentrations of citrate in serum and heart tissue, a hallmark of fluoroacetate intoxication. 19F NMR analysis confirmed that fluoroacetate was present in the urine of rats exposed to each toxic compound. Fluorocitrate, a condensation product of fluoroacetate and oxaloacetate, was identified in the kidney of rats exposed to 1,2-difluoroethane. There was a concentration-related elevation of serum and heart citrate in rats exposed to 0-1000 ppm 1,2-fluoroethane. Serum citrate was increased up to 5-fold and heart citrate was increased up to 11-fold over control citrate levels. Metabolism of 1,2-difluoroethane by cytochrome P450 (most likely CYP2E1) is suspected because pretreatment of rats or mice with SKF-525F, disulfiram, or dimethyl sulfoxide prevented or delayed the toxicity observed in rats not pretreated. Experimental evidence indicates that the metabolism of the toxic fluoroethanes is initiated at the carbon-hydrogen bond, with metabolism to fluoroacetate via an aldehyde or an acyl fluoride. The results of these studies show that 1-(di)halo-2-fluoroethanes are highly toxic to rats and should be considered a hazard to humans unless demonstrated otherwise.

Common errors in multidrug-resistant tuberculosis management.

PubMed

Monedero, Ignacio; Caminero, Jose A

2014-02-01

Multidrug-resistant tuberculosis (MDR-TB), defined as being resistant to at least rifampicin and isoniazid, has an increasing burden and threatens TB control. Diagnosis is limited and usually delayed while treatment is long lasting, toxic and poorly effective. MDR-TB management in scarce-resource settings is demanding however it is feasible and extremely necessary. In these settings, cure rates do not usually exceed 60-70% and MDR-TB management is novel for many TB programs. In this challenging scenario, both clinical and programmatic errors are likely to occur. The majority of these errors may be prevented or alleviated with appropriate and timely training in addition to uninterrupted procurement of high-quality drugs, updated national guidelines and laws and an overall improvement in management capacities. While new tools for diagnosis and shorter and less toxic treatment are not available in developing countries, MDR-TB management will remain complex in scarce resource settings. Focusing special attention on the common errors in diagnosis, regimen design and especially treatment delivery may benefit patients and programs with current outdated tools. The present article is a compilation of typical errors repeatedly observed by the authors in a wide range of countries during technical assistant missions and trainings.

Lethal and sublethal measures of chronic copper toxicity in the eastern narrowmouth toad, Gastrophryne carolinensis.

PubMed

Flynn, R Wesley; Scott, David E; Kuhne, Wendy; Soteropoulos, Diana; Lance, Stacey L

2015-03-01

Many metals are acutely toxic to aquatic organisms at high concentrations and for some metals, such as copper (Cu), even low-level chronic contamination may be cause for conservation concern. Amphibian susceptibility to Cu has been examined in only a few species, and susceptibility is highly variable. The lethal and sublethal effects were examined of chronic aqueous Cu exposure on embryonic and larval eastern narrowmouth toads, Gastrophryne carolinensis. Copper levels as low as 10 μg Cu/L reduced embryonic and larval survival. Embryonic survivorship varied within- and between-source populations, with embryos derived from uncontaminated-wetland parents having greater survival at lower Cu levels than embryos from parents from a metal-contaminated constructed wetland. At 30 μg/L, embryos from the contaminated site had greater survival. Overall survival from oviposition to metamorphosis was 68.9% at 0 μg/L and 5.4% at 10 μg/L. Similarly, embryos exposed to ≥50 μg/L demonstrated developmental delays in transition from embryo to free-swimming larva. These results demonstrate a negative population-specific response to environmentally relevant levels of Cu. © 2014 SETAC.

Modeling for the optimal biodegradation of toxic wastewater in a discontinuous reactor.

PubMed

Betancur, Manuel J; Moreno-Andrade, Iván; Moreno, Jaime A; Buitrón, Germán; Dochain, Denis

2008-06-01

The degradation of toxic compounds in Sequencing Batch Reactors (SBRs) poses inhibition problems. Time Optimal Control (TOC) methods may be used to avoid such inhibition thus exploiting the maximum capabilities of this class of reactors. Biomass and substrate online measurements, however, are usually unavailable for wastewater applications, so TOC must use only related variables as dissolved oxygen and volume. Although the standard mathematical model to describe the reaction phase of SBRs is good enough for explaining its general behavior in uncontrolled batch mode, better details are needed to model its dynamics when the reactor operates near the maximum degradation rate zone, as when TOC is used. In this paper two improvements to the model are suggested: to include the sensor delay effects and to modify the classical Haldane curve in a piecewise manner. These modifications offer a good solution for a reasonable complexification tradeoff. Additionally, a new way to look at the Haldane K-parameters (micro(o),K(I),K(S)) is described, the S-parameters (micro*,S*,S(m)). These parameters do have a clear physical meaning and, unlike the K-parameters, allow for the statistical treatment to find a single model to fit data from multiple experiments.

An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic Aβ42 aggregates linked with Alzheimer's disease.

PubMed

Habchi, Johnny; Arosio, Paolo; Perni, Michele; Costa, Ana Rita; Yagi-Utsumi, Maho; Joshi, Priyanka; Chia, Sean; Cohen, Samuel I A; Müller, Martin B D; Linse, Sara; Nollen, Ellen A A; Dobson, Christopher M; Knowles, Tuomas P J; Vendruscolo, Michele

2016-02-01

The conversion of the β-amyloid (Aβ) peptide into pathogenic aggregates is linked to the onset and progression of Alzheimer's disease. Although this observation has prompted an extensive search for therapeutic agents to modulate the concentration of Aβ or inhibit its aggregation, all clinical trials with these objectives have so far failed, at least in part because of a lack of understanding of the molecular mechanisms underlying the process of aggregation and its inhibition. To address this problem, we describe a chemical kinetics approach for rational drug discovery, in which the effects of small molecules on the rates of specific microscopic steps in the self-assembly of Aβ42, the most aggregation-prone variant of Aβ, are analyzed quantitatively. By applying this approach, we report that bexarotene, an anticancer drug approved by the U.S. Food and Drug Administration, selectively targets the primary nucleation step in Aβ42 aggregation, delays the formation of toxic species in neuroblastoma cells, and completely suppresses Aβ42 deposition and its consequences in a Caenorhabditis elegans model of Aβ42-mediated toxicity. These results suggest that the prevention of the primary nucleation of Aβ42 by compounds such as bexarotene could potentially reduce the risk of onset of Alzheimer's disease and, more generally, that our strategy provides a general framework for the rational identification of a range of candidate drugs directed against neurodegenerative disorders.

An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic Aβ42 aggregates linked with Alzheimer’s disease

PubMed Central

Habchi, Johnny; Arosio, Paolo; Perni, Michele; Costa, Ana Rita; Yagi-Utsumi, Maho; Joshi, Priyanka; Chia, Sean; Cohen, Samuel I. A.; Müller, Martin B. D.; Linse, Sara; Nollen, Ellen A. A.; Dobson, Christopher M.; Knowles, Tuomas P. J.; Vendruscolo, Michele

2016-01-01

The conversion of the β-amyloid (Aβ) peptide into pathogenic aggregates is linked to the onset and progression of Alzheimer’s disease. Although this observation has prompted an extensive search for therapeutic agents to modulate the concentration of Aβ or inhibit its aggregation, all clinical trials with these objectives have so far failed, at least in part because of a lack of understanding of the molecular mechanisms underlying the process of aggregation and its inhibition. To address this problem, we describe a chemical kinetics approach for rational drug discovery, in which the effects of small molecules on the rates of specific microscopic steps in the self-assembly of Aβ42, the most aggregation-prone variant of Aβ, are analyzed quantitatively. By applying this approach, we report that bexarotene, an anticancer drug approved by the U.S. Food and Drug Administration, selectively targets the primary nucleation step in Aβ42 aggregation, delays the formation of toxic species in neuroblastoma cells, and completely suppresses Aβ42 deposition and its consequences in a Caenorhabditis elegans model of Aβ42-mediated toxicity. These results suggest that the prevention of the primary nucleation of Aβ42 by compounds such as bexarotene could potentially reduce the risk of onset of Alzheimer’s disease and, more generally, that our strategy provides a general framework for the rational identification of a range of candidate drugs directed against neurodegenerative disorders. PMID:26933687

Human intravenous immunoglobulin for experimental streptococcal toxic shock: bacterial clearance and modulation of inflammation.

PubMed

Sriskandan, Shiranee; Ferguson, Melissa; Elliot, Victoria; Faulkner, Lee; Cohen, Jonathan

2006-07-01

Polyclonal human intravenous immunoglobulin (IVIG) has been advocated as an adjunct to therapy in severe invasive streptococcal toxic shock because of its ability to neutralize superantigen toxins. The aim of this study was to assess IVIG therapeutic efficacy in an experimental model of streptococcal toxic shock. To confirm the in vitro activity of IVIG against the Streptococcus pyogenes strain used in the study, IVIG was tested for superantigen neutralizing and bacterial opsonizing activity prior to in vivo studies. To evaluate the in vivo effects of IVIG in terms of microbiological outcome and disease severity in a superantigen-sensitive transgenic model of streptococcal shock, HLA-DQ transgenic mice were treated with IVIG either at the time of infection or after infection with S. pyogenes. Antibiotics were included in some studies. The IVIG preparation neutralized superantigenicity of S. pyogenes in vitro and enhanced bacterial killing in a whole blood assay. When given to mice at the time of S. pyogenes infection, IVIG neutralized circulating superantigens and reduced systemic inflammatory response. Remarkably, IVIG-enhanced systemic clearance of bacteria and enhanced neutrophil infiltrate into the infected tissues. However, when used in combination with penicillin and clindamycin in a delayed treatment setting, IVIG did not confer additional therapeutic benefit, in terms of inflammatory response, bacterial clearance or survival. IVIG monotherapy can confer benefit in experimental streptococcal shock, but extension of these findings to the clinical situation will require further evaluation.

Nerolidol effects on mitochondrial and cellular energetics.

PubMed

Ferreira, Fernanda M; Palmeira, Carlos M; Oliveira, Maria M; Santos, Dario; Simões, Anabela M; Rocha, Sílvia M; Coimbra, Manuel A; Peixoto, Francisco

2012-03-01

In the present work, we evaluated the potential toxic effects of nerolidol, a sesquiterpenoid common in plants essential oils, both on mitochondrial and cellular energetics. Samples of enriched natural extracts of nerolidol (a racemic mixture of cis and trans isomers) were tested on rat liver mitochondria and a decrease in phosphorylative system was observed but not in the mitochondrial respiratory chain activity, which reflects a direct effect on F1-ATPase. Hence, respiratory control ratio was also decreased. Cellular ATP/ADP levels were significantly decreased in a concentration-dependent manner, possibly due to the direct effect of nerolidol on F(0)F(1)-ATPsynthase. Nerolidol stimulates respiratory activity probably due to an unspecific effect, since it does not show any protonophoric effect. Furthermore, we observed that mitochondrial permeability transition was delayed in the presence of nerolidol, possibly due to its antioxidant activity and because this compound decreases mitochondrial transmembrane electric potential. Our results also show that, in human hepatocellular liver carcinoma cell line (HepG2), nerolidol both induces cell death and arrests cell growth, probably related with the observed lower bioenergetic efficiency. Copyright © 2011 Elsevier Ltd. All rights reserved.

In vitro and in vivo antithrombotic and cytotoxicity effects of ferulic acid.

PubMed

Choi, Jun-Hui; Park, Jong-Kook; Kim, Ki-Man; Lee, Hyo-Jeong; Kim, Seung

2018-01-01

We discovered recently in vitro and in vivo antithrombotic and cytotoxicity effects of ferulic acid. The cytotoxicity assays showed that ferulic acid (∼300 μg/mL) did not cause any significant toxicity on three cell lines, platelets, leukocytes, and erythrocytes. In vitro assays showed inhibitory effects of ferulic acid on thrombin (THR)- or collagen/epinephrine-stimulated platelet activation by inhibiting platelet aggregation, and decreasing clot retraction activity. The in vitro effect of ferulic acid on THR-stimulated platelet activation was proved by the decrease in the secretion of serotonin from the platelets. The anticoagulant effects of ferulic acid were confirmed by the prolongation of the intrinsic or/and extrinsic pathways and the delay of recalcification time in plasma coagulation. Ferulic acid had antithrombotic effect in acute thromboembolism model in vivo, and decreased the expression of α IIb β 3 /FIB and phosphorylation of AKT in THR-stimulated platelet activation in vivo, and their antithrombotic efficacies hold promise for therapeutic targeting in our ongoing studies. © 2017 Wiley Periodicals, Inc.

5-year follow-up of a randomized controlled trial of immediate versus delayed zoledronic acid for the prevention of bone loss in postmenopausal women with breast cancer starting letrozole after tamoxifen: N03CC (Alliance) trial.

PubMed

Wagner-Johnston, Nina D; Sloan, Jeff A; Liu, Heshan; Kearns, Ann E; Hines, Stephanie L; Puttabasavaiah, Suneetha; Dakhil, Shaker R; Lafky, Jacqueline M; Perez, Edith A; Loprinzi, Charles L

2015-08-01

Postmenopausal women with breast cancer receiving aromatase inhibitors are at an increased risk of bone loss. The current study was undertaken to determine whether upfront versus delayed treatment with zoledronic acid (ZA) impacted bone loss. This report described the 5-year follow-up results. A total of 551 postmenopausal women with breast cancer who completed tamoxifen treatment and were undergoing daily letrozole treatment were randomized to either upfront (274 patients) or delayed (277 patients) ZA at a dose of 4 mg intravenously every 6 months. In the patients on the delayed treatment arm, ZA was initiated for a postbaseline bone mineral density T-score of <-2.0 or fracture. The incidence of a 5% decrease in the total lumbar spine bone mineral density at 5 years was 10.2% in the upfront treatment arm versus 41.2% in the delayed treatment arm (P<.0001). A total of 41 patients in the delayed treatment arm were eventually started on ZA. With the exception of increased NCI Common Toxicity Criteria (CTC) grade 1/2 elevated creatinine and fever in the patients treated on the upfront arm and cerebrovascular ischemia among those in the delayed treatment arm, there were no significant differences observed between arms with respect to the most common adverse events of arthralgia and back pain. Osteoporosis occurred less frequently in the upfront treatment arm (2 vs 8 cumulative cases), although this difference was not found to be statistically significant. Bone fractures occurred in 24 patients in the upfront treatment arm versus 25 patients in the delayed treatment arm. Immediate treatment with ZA prevented bone loss compared with delayed treatment in postmenopausal women receiving letrozole and these differences were maintained at 5 years. The incidence of osteoporosis or fractures was not found to be significantly different between treatment arms. © 2015 American Cancer Society.

The mechanisms of delayed onset type adverse reactions to oseltamivir

PubMed Central

Hama, Rokuro

2016-01-01

Abstract Oseltamivir is recommended for the treatment and prophylaxis of influenza in persons at higher risk for influenza complications such as individuals with diabetes, neuropsychiatric illnesses, and respiratory, cardiac, renal, hepatic or haematological diseases. However, a recent Cochrane review reported that reduction of antibody production, renal disorders, hyperglycaemia, psychiatric disorders, and QT prolongation may be related to oseltamivir use. The underlying mechanisms are reviewed. There is decisive evidence that administration of a clinically compatible dose of oseltamivir in mice challenged by a respiratory syncytial virus (RSV) that lacks a neuraminidase gene showed symptom-relieving effects and inhibition of viral clearance. These effects were accompanied by decreased level of T cell surface sialoglycosphingolipid (ganglioside) GM1 that is regulated by the endogenous neuraminidase in response to viral challenge. Clinical and non-clinical evidence supports the view that the usual dose of oseltamivir suppresses pro-inflammatory cytokines such as interferon-gamma, interleukin-6, and tumour necrosis factor-alpha almost completely with partial suppression of viral shedding in human influenza virus infection experiment. Animal toxicity tests support the clinical evidence with regard to renal and cardiac disorders (bradycardia and QT prolongation) and do not disprove the metabolic effect. Reduction of antibody production and cytokine induction and renal, metabolic, cardiac, and prolonged psychiatric disorders after oseltamivir use may be related to inhibition of the host’s endogenous neuraminidase. While the usual clinical dose of zanamivir may not have this effect, a higher dose or prolonged administration of zanamivir and other neuraminidase inhibitors may induce similar delayed reactions, including reduction of the antibody and/or cytokine production. PMID:27251370

Stage-dependent toxicity of bisphenol a on Rhinella arenarum (anura, bufonidae) embryos and larvae.

PubMed

Wolkowicz, Ianina R Hutler; Herkovits, Jorge; Pérez Coll, Cristina S

2014-02-01

The acute and chronic toxicity of bisphenol A (BPA) was evaluated on the common South American toad Rhinella arenarum embryos and larvae by means of continuous and pulse exposure treatments. Embryos were treated continuously from early blastula (S.4) up to complete operculum (S.25), during early larval stages and by means of 24 h pulse exposures of BPA in concentrations ranging between 1.25 and 40 mg L(-1) , in order to evaluate the susceptibility to this compound in different developmental stages. For lethal effects, S.25 was the most sensitive and gastrula was the most resistant to BPA. The Teratogenic Index for neurula, the most sensitive embryonic stage for sublethal effects was 4.7. The main morphological alterations during early stages were: delayed or arrested development, reduced body size, persistent yolk plug, microcephaly, axial/tail flexures, edemas, blisters, waving fin, underdeveloped gills, mouth malformations, and cellular dissociation. BPA caused a remarkable narcotic effect from gill circulation stage (S.20) onwards in all the organisms exposed after 3 h of treatment with 10 mg L(-1) BPA. After recovering, the embryos exhibited scarce response to stimuli, erratic or circular swimming, and spasmodic contractions from 5 mg L(-1) onwards. Our results highlight the lethal and sublethal effectsof BPA on R. arenarum embryos and larvae, in the last case both at structural and functional levels. Copyright © 2011 Wiley Periodicals, Inc., A Wiley Company.

Effects of maternal chlorpyrifos diet on social investigation and brain neuroendocrine markers in the offspring - a mouse study.

PubMed

Venerosi, Aldina; Tait, Sabrina; Stecca, Laura; Chiarotti, Flavia; De Felice, Alessia; Cometa, Maria Francesca; Volpe, Maria Teresa; Calamandrei, Gemma; Ricceri, Laura

2015-04-02

Chlorpyrifos (CPF) is one of the most widely used organophosphate pesticides worldwide. Epidemiological studies on pregnant women and their children suggest a link between in utero CPF exposure and delay in psychomotor and cognitive maturation. A large number of studies in animal models have shown adverse effects of CPF on developing brain and more recently on endocrine targets. Our aim was to determine if developmental exposure to CPF affects social responsiveness and associated molecular neuroendocrine markers at adulthood. Pregnant CD1 outbred mice were fed from gestational day 15 to lactation day 14 with either a CPF-added (equivalent to 6 mg/kg/bw/day during pregnancy) or a standard diet. We then assessed in the offspring the long-term effects of CPF exposure on locomotion, social recognition performances and gene expression levels of selected neurondocrine markers in amygdala and hypothalamus. No sign of CPF systemic toxicity was detected. CPF induced behavioral alterations in adult offspring of both sexes: CPF-exposed males displayed enhanced investigative response to unfamiliar social stimuli, whereas CPF-exposed females showed a delayed onset of social investigation and lack of reaction to social novelty. In parallel, molecular effects of CPF were sex dimorphic: in males CPF increased expression of estrogen receptor beta in hypothalamus and decreased oxytocin expression in amygdala; CPF increased vasopressin 1a receptor expression in amygdala in both sexes. These data indicate that developmental CPF affects mouse social behavior and interferes with development of sex-dimorphic neuroendocrine pathways with potential disruptive effects on neuroendocrine axes homeostasis. The route of exposure selected in our study corresponds to relevant human exposure scenarios, our data thus supports the view that neuroendocrine effects, especially in susceptible time windows, should deserve more attention in risk assessment of OP insecticides.

Toxic Hazards Research Unit Annual Technical Report: 1984

DTIC Science & Technology

1984-09-01

exposed to TOCP exhibited the classic lesions of delayed neuropathy (Smith and Lillie, 1931; Barnes and Denz, 1953; (avanagh, 1954; and Fenton , 1955...Safety of *.i Chemicals in Food, Drugs, and Cosmetics , The staff of the Divi- sion of Pharmacology of the Federal Food and Drug Administration, Austin...Annual Technical Report: 1967, AMRL-TR-67-137 (AD 834723), Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, Ohio. Fenton , J. C

Transplantation for myelodysplastic syndromes: who, when, and which conditioning regimens.

PubMed

Saber, Wael; Horowitz, Mary M

2016-12-02

Allogeneic hematopoietic stem cell transplantation (HCT) is the only curative therapy for myelodysplastic syndrome (MDS). Broad application is hindered by high risks of transplant-related morbidity and mortality, especially in the older age range represented by the MDS population. However, recent advances in strategies to minimize regimen-related toxicity make HCT a viable option for many more patients. Appropriate selection of patients involves consideration of patient factors, including use of geriatric assessment tools and comorbidity scales, that predict risks of regimen-related toxicity as well as disease factors, including genetic markers, which predict survival with both non-HCT and HCT therapy. Optimal timing of HCT for fit patients must consider MDS risk scores and life-years to be gained, with earlier transplantation indicated for patients with intermediate-2 and high-risk disease but judicious delay for lower risk patients. Selection of suitable conditioning regimens must balance risks of toxicity with opportunity for maximum disease control. © 2016 by The American Society of Hematology. All rights reserved.

The removal process of 2,2-dichloroacetamide (DCAcAm), a new disinfection by-product, in drinking water treatment process and its toxicity on zebrafish.

PubMed

Lin, Tao; Zhou, Dongju; Yu, Shilin; Chen, Wei

2016-09-01

The removal process of 2,2-dichloroacetamide (DCAcAm), a new disinfection by-product (DBP) in conventional drinking water treatment plant (C-DWTP) and advanced DWTP (ADWTP) was studied with newly maximum formation potential (MFP) process. It was demonstrated that the advanced treatment displayed greater removal efficiency towards DCAcAm formation potential (MFP) than the conventional treatment. The hydrophilic natural organic matter and natural organic matter with molecular weight <1 kDa or >10 kDa leaded to more DCAcAm formation, and the aromatic protein was inferred as one part of DCAcAm precursor. DCAcAm was found to cause delayed development and malformation to zebrafish embryos at embryonic growth stage. Compared with heart toxicity, it caused a significant neuron toxicity. It also could cause the acute DNA damage to adult zebrafish, which should be extremely cautioned. Copyright © 2016 Elsevier Ltd. All rights reserved.

Life-cycle effects of single-walled carbon nanotubes (SWNTs) on an estuarine meiobenthic copepod.

PubMed

Templeton, Ryan C; Ferguson, P Lee; Washburn, Kate M; Scrivens, Wally A; Chandler, G Thomas

2006-12-01

Single-walled carbon nanotubes (SWNT) are finding increasing use in consumer electronics and structural composites. These nanomaterials and their manufacturing byproducts may eventually reach estuarine systems through wastewater discharge. The acute and chronic toxicity of SWNTs were evaluated using full life-cycle bioassays with the estuarine copepod Amphiascus tenuiremis (ASTM method E-2317-04). A synchronous cohort of naupliar larvae was assayed by culturing individual larvae to adulthood in individual 96-well microplate wells amended with SWNTs in seawater. Copepods were exposed to "as prepared" (AP) SWNTs, electrophoretically purified SWNTs, or a fluorescent fraction of nanocarbon synthetic byproducts. Copepods ingesting purified SWNTs showed no significant effects on mortality, development, and reproduction across exposures (p < 0.05). In contrast, exposure to the more complex AP-SWNT mixture significantly increased life-cycle mortality, reduced fertilization rates, and reduced molting success in the highest exposure (10 mg x L(-1)) (p < 0.05). Exposure to small fluorescent nanocarbon byproducts caused significantly increased life-cycle mortality at 10 mg x L(-1) (p < 0.05). The fluorescent nanocarbon fraction also caused significant reduction in life-cycle molting success for all exposures (p < 0.05). These results suggest size-dependent toxicity of SWNT-based nanomaterials, with the smallest synthetic byproduct fractions causing increased mortality and delayed copepod development over the concentration ranges tested.

Effects of perfluorooctanoic acid (PFOA) on expression of ...

EPA Pesticide Factsheets

PPARs regulate metabolism and can be activated by environmental contaminants such as perfluorooctanoic acid (PFOA). PFOA induces neonatal mortality, developmental delay, and growth deficits in mice. Studies in genetically altered mice showed that PPARa is required for PFOA-induced developmental toxicity. In this study, pregnant CD-1 mice were dosed orally from GD1-17 with water or 5 mg PFO/kg to examine PPARa, PPARß, and PPARy expression and profile the effects of PFOA on PPAR-regulated genes. Prenatal and postnatal liver, heart, adrenal, kidney, intestine, stomach, lung, spleen, and thymus were collected at various developmental ages. RNA and protein were examined using qPCR and Western blot analysis. PPAR expression varied with age in all tissues, and in liver PPARa and PPARy expression correlated with nutritional changes as the pups matured. As early as GD14, PFOA affected expression of genes involved in lipid and glucose homeostatic control. The metabolic disruption produced by PFOA may contribute to poor postnatal survival and persistent weight deficits of neonates This paper represents the continuing efforts at ORD, in response to the call for assistance from OPPTS, to investigate the potential developmental toxicities of perfluoroalkyl acids (PFAA). Perfluorooctanoic acid (PFOA) is a compound which persists and is found ubiquitously in the environment, wildlife and humans. Studies in our laboratory using an in vitro transfected cell model showed that PFO

Highly efficient radiosensitization of human glioblastoma and lung cancer cells by a G-quadruplex DNA binding compound.

PubMed

Merle, Patrick; Gueugneau, Marine; Teulade-Fichou, Marie-Paule; Müller-Barthélémy, Mélanie; Amiard, Simon; Chautard, Emmanuel; Guetta, Corinne; Dedieu, Véronique; Communal, Yves; Mergny, Jean-Louis; Gallego, Maria; White, Charles; Verrelle, Pierre; Tchirkov, Andreï

2015-11-06

Telomeres are nucleoprotein structures at the end of chromosomes which stabilize and protect them from nucleotidic degradation and end-to-end fusions. The G-rich telomeric single-stranded DNA overhang can adopt a four-stranded G-quadruplex DNA structure (G4). Stabilization of the G4 structure by binding of small molecule ligands enhances radiosensitivity of tumor cells, and this combined treatment represents a novel anticancer approach. We studied the effect of the platinum-derived G4-ligand, Pt-ctpy, in association with radiation on human glioblastoma (SF763 and SF767) and non-small cell lung cancer (A549 and H1299) cells in vitro and in vivo. Treatments with submicromolar concentrations of Pt-ctpy inhibited tumor proliferation in vitro with cell cycle alterations and induction of apoptosis. Non-toxic concentrations of the ligand were then combined with ionizing radiation. Pt-ctpy radiosensitized all cell lines with dose-enhancement factors between 1.32 and 1.77. The combined treatment led to increased DNA breaks. Furthermore, a significant radiosensitizing effect of Pt-ctpy in mice xenografted with glioblastoma SF763 cells was shown by delayed tumor growth and improved survival. Pt-ctpy can act in synergy with radiation for efficient killing of cancer cells at concentrations at which it has no obvious toxicity per se, opening perspectives for future therapeutic applications.

Sensitivity of Neural Stem Cell Survival, Differentiation and Neurite Outgrowth within 3D Hydrogels to Environmental Heavy Metals

PubMed Central

Tasneem, Sameera; Farrell, Kurt; Lee, Moo-Yeal; Kothapalli, Chandrasekhar R.

2015-01-01

We investigated the sensitivity of embryonic murine neural stem cells exposed to 10 pM – 10 μM concentrations of three heavy metals (Cd, Hg, Pb), continuously for 14 days within 3D collagen hydrogels. Critical endpoints for neurogenesis such as survival, differentiation and neurite outgrowth were assessed. Results suggest significant compromise in cell viability within the first four days at concentrations ≥ 10 nM, while lower concentrations induced a more delayed effect. Mercury and lead suppressed neural differentiation at as low as 10 pM concentration within 7 days, while all three metals inhibited neural and glial differentiation by day 14. Neurite outgrowth remained unaffected at lower cadmium or mercury concentrations (≤ 100 pM), but was completely repressed beyond day 1 at higher concentrations. Higher metal concentrations (≥ 100 pM) suppressed NSC differentiation to motor or dopaminergic neurons. Cytokines and chemokines released by NSCs, and the sub-cellular mechanisms by which metals induce damage to NSCs have been quantified and correlated to phenotypic data. The observed degree of toxicity in NSC cultures is in the order: lead > mercury > cadmium. Results point to the use of biomimetic 3D culture models to screen the toxic effects of heavy metals during developmental stages, and investigate their underlying mechanistic pathways. PMID:26621541

Biological applications and effects of optical masers

NASA Astrophysics Data System (ADS)

Ham, William T., Jr.; Mueller, Harold A.; Guerry, R. K.; Guerry, Dupont, III; Cleary, Stephan F.

1988-09-01

Threshold radiant exposures for retinal damage in 3 macaque monkeys are given for exposures of 0.5, 0.125 and 0.016 seconds duration to laser wavelengths 514.5 and 488 nm. Intravitreal injections of 5 x .00005 gm of Cu-Zn SOD were toxic to cornea, lens and retina of the rhesus monkey after a radiant exposure of 33 j/sq cm of 440 nm light. No further experiments with SOD are contemplated. Similar experiments with catalase will be tried during the first quarter of the second contract year. The effect of oxygen on retinal toxicity during exposure to wave-lengths 540, 640 and 840 nm were delayed by the untimely death of Dr. Millen, our consultant on anesthesiology and oxygen administration. Arrangements have been made to activate this program during the second contract year. Threshold data on 40 microsecond pulse trains cannot be obtained until the acoustic modulator can be incorporated into the Ar-Kr laser which was used during the contract year to produce exposures less than 1 second to 514.5 and 488 nm laser lines. Data on PRF's of 10 and 100 KHz and 1, 10 and 20 MHz will be obtained during the second contract year. The long-term experiment on cataractogenesis on 2 rhesus monkeys exposed to a near UV spectrum (330 to 420 nm) has been completed.

Acute Biological Effects of Simulating the Whole-Body Radiation Dose Distribution from a Solar Particle Event Using a Porcine Model

PubMed Central

Wilson, Jolaine M.; Sanzari, Jenine K.; Diffenderfer, Eric S.; Yee, Stephanie S.; Seykora, John T.; Maks, Casey; Ware, Jeffrey H.; Litt, Harold I.; Reetz, Jennifer A.; McDonough, James; Weissman, Drew; Kennedy, Ann R.; Cengel, Keith A.

2011-01-01

In a solar particle event (SPE), an unshielded astronaut would receive proton radiation with an energy profile that produces a highly inhomogeneous dose distribution (skin receiving a greater dose than internal organs). The novel concept of using megavoltage electron-beam radiation to more accurately reproduce both the total dose and the dose distribution of SPE protons and make meaningful RBE comparisons between protons and conventional radiation has been described previously. Here, Yucatan minipigs were used to determine the effects of a superficial, SPE-like proton dose distribution using megavoltage electrons. In these experiments, dose-dependent increases in skin pigmentation, ulceration, keratinocyte necrosis and pigment incontinence were observed. Five of 18 animals (one each exposed to 7.5 Gy and 12.5 Gy radiation and three exposed to 25 Gy radiation) developed symptomatic, radiation-associated pneumonopathy approximately 90 days postirradiation. The three animals from the highest dose group showed evidence of mycoplasmal pneumonia along with radiation pneumonitis. Moreover, delayed-type hypersensitivity was found to be altered, suggesting that superficial irradiation of the skin with ionizing radiation might cause immune dysfunction or dysregulation. In conclusion, using total doses, patterns of dose distribution, and dose rates that are compatible with potential astronaut exposure to SPE radiation, animals experienced significant toxicities that were qualitatively different from toxicities previously reported in pigs for homogeneously delivered radiation at similar doses. PMID:21859326

BRAIN DEVELOPMENT AND METHYLMERCURY: UNDERESTIMATION OF NEUROTOXICITY

PubMed Central

Grandjean, Philippe; Herz, Katherine T.

2011-01-01

Methylmercury is now recognized as an important developmental neurotoxicant, though this insight developed slowly over many decades. Developmental neurotoxicity was first reported in a Swedish case report in 1952, and from a serious outbreak in Minamata, Japan a few years later. While the infant suffered congenital poisoning, the mother was barely harmed, thus reflecting a unique vulnerability of the developing nervous system. Nonetheless, exposure limits for this environmental chemical were based solely on adult toxicity until 50 years after the first report on developmental neurotoxicity. Even current evidence is affected by uncertainty, most importantly by imprecision of the exposure assessment in epidemiological studies. Detailed calculations suggest that the relative imprecision may be as much as 50%, or greater, thereby substantially biasing the results toward the null. In addition, as methylmercury exposure usually originates from fish and seafood that also contains essential nutrients, so-called negative confounding may occur. Thus, the beneficial effects of the nutrients may appear to dampen the toxicity, unless proper adjustment is included in the analysis to reveal the true extent of adverse effects. These problems delayed the recognition of low-level methylmercury neurotoxicity. However, such problems are not unique, and many other industrial compounds are thought to cause developmental neurotoxicity, mostly with less epidemiological support than methylmercury. The experience obtained with methylmercury should therefore be taken into account when evaluating the evidence for other substances suspected of being neurotoxic. PMID:21259267

Choriocarcinoma after hydatidiform mole. Studies related to effectiveness of follow-up practice after hydatidiform mole.

PubMed

Bagshawe, K D; Golding, P R; Orr, A H

1969-09-27

Chemotherapy, in conjunction with other methods of treatment, was used in 100 patients with invasive hydatidiform mole or choriocarcinoma following mole. When treatment was instituted within two to six months of the antecedent mole serious drug resistance was not encountered, drug toxicity was slight, the duration of treatment was comparatively short, and sustained remissions were obtained in 57 out of 60 patients. When the start of chemotherapy was delayed beyond six months drug resistance occurred in many instances, toxicity was often severe, the duration of treatment was much longer, and sustained remissions were obtained in 22 out of 40 patients.The practice of giving prophylactic chemotherapy to all patients with mole is not established as effective or safe. Differences in the social background to hydatidiform mole in different geographical areas may be such that conclusions based on evidence from one area are not necessarily applicable to another.Careful follow-up after mole remains essential, though present methods often fail to ensure recognition of choriocarcinoma while it is still curable. Standard qualitative and quantitative methods for detecting the continued excretion of chorionic gonadotrophin, though useful, are sometimes too insensitive. It is suggested that to supplement local arrangements some form of centralized or regionalized follow-up service based on notification of patients with hydatidiform mole, and making use of radioimmunoassays for chorionic gonadotrophin, could reduce deaths attributable to late diagnosis.

[Exposure to liquid detergent capsules: a study of the cases reported to the Paris Poison Center, 2011-2012].

PubMed

Villa, A; Médernach, C; Arropetian, N; Lagrange, F; Langrand, J; Garnier, R

2014-06-01

To evaluate the toxicity of liquid detergent capsules for children. Analysis of 684 consecutive cases from the Paris Poison Center (2011-2012). Most enquiries (97 %) concerned children 5 years of age or younger. The main circumstances of exposure were ingestion alone (72.4 %) or together with eye or skin contact (7.5 % and 7.3 %, respectively). The effects observed were generally due to the irritating properties of concentrated detergents: minor digestive disturbances (particularly vomiting in nearly 50 % of cases) after ingestion and conjunctivitis and/or keratitis after eye contact. The main complications were 24 cases of keratitis and one case of pulmonary toxicity after ingestion. A rash was observed in nine patients; it was delayed in two. The effects observed with liquid detergent capsules were very similar to those resulting from exposure to other detergents. However, exposure to these agents are very frequent and often results in eye contact, which may be responsible for keratitis, and after ingestion detergent inhalation is a possible complication. All cases with eye symptoms or cough after liquid detergent capsule exposure deserve prompt medical examination and assistance. Greater awareness of both health professionals and consumers on the dangers and risks of these laundry detergent pods is required for better treatment of exposure accidents and for their prevention. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

D-beta-hydroxybutyrate extends lifespan in C. elegans

PubMed Central

Edwards, Clare; Canfield, John; Copes, Neil; Rehan, Muhammad; Lipps, David; Bradshaw, Patrick C.

2014-01-01

The ketone body beta-hydroxybutyrate (βHB) is a histone deacetylase (HDAC) inhibitor and has been shown to be protective in many disease models, but its effects on aging are not well studied. Therefore we determined the effect of βHB supplementation on the lifespan of C. elegans nematodes. βHB supplementation extended mean lifespan by approximately 20%. RNAi knockdown of HDACs hda-2 or hda-3 also increased lifespan and further prevented βHB-mediated lifespan extension. βHB-mediated lifespan extension required the DAF-16/FOXO and SKN-1/Nrf longevity pathways, the sirtuin SIR-2.1, and the AMP kinase subunit AAK-2. βHB did not extend lifespan in a genetic model of dietary restriction indicating that βHB is likely functioning through a similar mechanism. βHB addition also upregulated βHB dehydrogenase activity and increased oxygen consumption in the worms. RNAi knockdown of F55E10.6, a short chain dehydrogenase and SKN-1 target gene, prevented the increased lifespan and βHB dehydrogenase activity induced by βHB addition, suggesting that F55E10.6 functions as an inducible βHB dehydrogenase. Furthermore, βHB supplementation increased worm thermotolerance and partially prevented glucose toxicity. It also delayed Alzheimer's amyloid-beta toxicity and decreased Parkinson's alpha-synuclein aggregation. The results indicate that D-βHB extends lifespan through inhibiting HDACs and through the activation of conserved stress response pathways. PMID:25127866

Glucocorticoids and Polyamine Inhibitors Synergize to Kill Human Leukemic CEM Cells1

PubMed Central

Miller, Aaron L; Johnson, Betty H; Medh, Rheem D; Townsend, Courtney M; Thompson, E Brad

2002-01-01

Abstract Glucocorticoids are well-known apoptotic agents in certain classes of lymphoid cell malignancies. Reduction of intracellular polyamine levels by use of inhibitors that block polyamine synthesis slows or inhibits growth of many cells in vitro. Several such inhibitors have shown efficacy in clinical trials, though the toxicity of some compounds has limited their usefulness. We have tested the effects of combinations of the glucocorticoid dexamethasone (Dex) and two polyamine inhibitors, difluoromethylornithine (DFMO) and methyl glyoxal bis guanylhydrazone (MGBG), on the clonal line of human acute lymphoblastic leukemia cells, CEM-C7-14. Dex alone kills these cells, though only after a delay of at least 24 hours. We also evaluated a partially glucocorticoid-resistant c-Myc-expressing CEM-C7-14 clone. We show that Dex downregulates ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine synthesis. Pretreatment with the ODC inhibitor DFMO, followed by addition of Dex, enhances steroid-evoked kill slightly. The combination of pretreatment with sublethal concentrations of both DFMO and the inhibitor of S-adenosylmethionine decarboxylase, MGBG, followed by addition of Dex, results in strong synergistic cell kill. Both the rapidity and extent of cell kill are enhanced compared to the effects of Dex alone. These results suggest that use of such combinations in vivo may result in apoptosis of malignant cells with lower overall toxicity. PMID:11922393

RSDL decontamination of human skin contaminated with the nerve agent VX.

PubMed

Thors, L; Lindberg, S; Johansson, S; Koch, B; Koch, M; Hägglund, L; Bucht, A

2017-03-05

Dermal exposure to low volatile organophosphorus compounds (OPC) may lead to penetration through the skin and uptake in the blood circulation. Skin decontamination of toxic OPCs, such as pesticides and chemical warfare nerve agents, might therefore be crucial for mitigating the systemic toxicity following dermal exposure. Reactive skin decontamination lotion (RSDL) has been shown to reduce toxic effects in animals dermally exposed to the nerve agent VX. In the present study, an in vitro flow-through diffusion cell was utilized to evaluate the efficacy of RSDL for decontamination of VX exposed to human epidermis. In particular, the impact of timing in the initiation of decontamination and agent dilution in water was studied. The impact of the lipophilic properties of VX in the RSDL decontamination was additionally addressed by comparing chemical degradation in RSDL and decontamination efficacy between the VX and the hydrophilic OPC triethyl phosphonoacetate (TEPA). The epidermal membrane was exposed to 20, 75 or 90% OPC diluted in deionized water and the decontamination was initiated 5, 10, 30, 60 or 120min post-exposure. Early decontamination of VX with RSDL, initiated 5-10min after skin exposure, was very effective. Delayed decontamination initiated 30-60min post-exposure was less effective but still the amount of penetrated agent was significantly reduced, while further delayed start of decontamination to 120min resulted in very low efficacy. Comparing RSDL decontamination of VX with that of TEPA showed that the decontamination efficacy at high agent concentrations was higher for VX. The degradation mechanism of VX and TEPA during decontamination was dissected by 31 P NMR spectroscopy of the OPCs following reactions with RSDL and its three nucleophile components. The degradation rate was clearly associated with the high pH of the specific solution investigated; i.e. increased pH resulted in a more rapid degradation. In addition, the solubility of the OPC in RSDL also influenced the degradation rate since the degradation of VX was significantly faster when the NMR analysis was performed in the organic solvent acetonitrile compared to water. In conclusion, we have applied the in vitro flow-through diffusion cell for evaluation of skin decontamination procedures of human epidermis exposed to OPCs. It was demonstrated that early decontamination is crucial for efficient mitigation of epidermal penetration of VX and that almost complete removal of the nerve agent from the skin surface is possible. Our data also indicate that the pH of RSDL together with the solubility of OPC in RSDL are of primary importance for the decontamination efficacy. Copyright © 2017 Elsevier B.V. All rights reserved.

Acute and early life stage toxicity of industrial effluent on Japanese medaka (Oryzias latipes).

PubMed

Zha, Jinmiao; Wang, Zijian

2006-03-15

To develop the whole effluent toxicity testing methods (WET), embryo larval stage toxicity test using Japanese medaka (Oryzias latipes) was conducted to evaluate an effluent from a banknote printing plant (BPP). The method is based on acute toxicity using endpoint of 96-h larval morality and on chronic toxicity using endpoints such as the time to hatch, hatching success, deformity, growth rate, swim-up failure, accumulative mortality and sexual ratio. In test for 96-h larval mortality, LC50 (the concentration was lethal to 50% of newly hatching medaka larvae) was 72.9%. In chronic toxicity test, newly fertilized embryos (<5-h old) were exposed to 1%, 6.25%, 12.5%, 25%, 50% effluent concentrations and to 200 mug/l BPA in a 24-h static renewal system at 25+/-1 degrees C until 15 day post-hatch. The results showed that all chronic endpoints were significantly different from the control at 50% dilution (p < 0.01). Embryos began to show lesions on 4th day at higher concentrations (12.5%, 25%, 50% BPP effluent concentrations). Treatment group of 25% dilution showed delayed time to hatch. A reduction in body weight was observed at 25% dilutions for males and females, respectively. Deformities were observed in newly hatched larvae at 25% and 50% BPP effluent concentrations. At 25% dilution, sex ratio of larvae was alternated and there was feminization phenomenon. We conclude that embryo larval stage test using medaka is feasible to evaluate both acute and chronic toxicities and potential endocrine disrupting activity of industrial effluents.

Neuronal death induced by misfolded prion protein is due to NAD+ depletion and can be relieved in vitro and in vivo by NAD+ replenishment

PubMed Central

Zhou, Minghai; Ottenberg, Gregory; Sferrazza, Gian Franco; Hubbs, Christopher; Fallahi, Mohammad; Rumbaugh, Gavin; Brantley, Alicia F.

2015-01-01

The mechanisms of neuronal death in protein misfolding neurodegenerative diseases such as Alzheimer’s, Parkinson’s and prion diseases are poorly understood. We used a highly toxic misfolded prion protein (TPrP) model to understand neurotoxicity induced by prion protein misfolding. We show that abnormal autophagy activation and neuronal demise is due to severe, neuron-specific, nicotinamide adenine dinucleotide (NAD+) depletion. Toxic prion protein-exposed neuronal cells exhibit dramatic reductions of intracellular NAD+ followed by decreased ATP production, and are completely rescued by treatment with NAD+ or its precursor nicotinamide because of restoration of physiological NAD+ levels. Toxic prion protein-induced NAD+ depletion results from PARP1-independent excessive protein ADP-ribosylations. In vivo, toxic prion protein-induced degeneration of hippocampal neurons is prevented dose-dependently by intracerebral injection of NAD+. Intranasal NAD+ treatment of prion-infected sick mice significantly improves activity and delays motor impairment. Our study reveals NAD+ starvation as a novel mechanism of autophagy activation and neurodegeneration induced by a misfolded amyloidogenic protein. We propose the development of NAD+ replenishment strategies for neuroprotection in prion diseases and possibly other protein misfolding neurodegenerative diseases. PMID:25678560

Quantitative Survey and Structural Classification of Hydraulic Fracturing Chemicals Reported in Unconventional Gas Production.

PubMed

Elsner, Martin; Hoelzer, Kathrin

2016-04-05

Much interest is directed at the chemical structure of hydraulic fracturing (HF) additives in unconventional gas exploitation. To bridge the gap between existing alphabetical disclosures by function/CAS number and emerging scientific contributions on fate and toxicity, we review the structural properties which motivate HF applications, and which determine environmental fate and toxicity. Our quantitative overview relied on voluntary U.S. disclosures evaluated from the FracFocus registry by different sources and on a House of Representatives ("Waxman") list. Out of over 1000 reported substances, classification by chemistry yielded succinct subsets able to illustrate the rationale of their use, and physicochemical properties relevant for environmental fate, toxicity and chemical analysis. While many substances were nontoxic, frequent disclosures also included notorious groundwater contaminants like petroleum hydrocarbons (solvents), precursors of endocrine disruptors like nonylphenols (nonemulsifiers), toxic propargyl alcohol (corrosion inhibitor), tetramethylammonium (clay stabilizer), biocides or strong oxidants. Application of highly oxidizing chemicals, together with occasional disclosures of putative delayed acids and complexing agents (i.e., compounds designed to react in the subsurface) suggests that relevant transformation products may be formed. To adequately investigate such reactions, available information is not sufficient, but instead a full disclosure of HF additives is necessary.

CHOP Contributes to, But Is Not the Only Mediator of, IAPP Induced β-Cell Apoptosis.

PubMed

Gurlo, T; Rivera, J F; Butler, A E; Cory, M; Hoang, J; Costes, S; Butler, Peter C

2016-04-01

The islet in type 2 diabetes is characterized by β-cell loss, increased β-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). When protein misfolding protective mechanisms are overcome, human IAPP (h-IAPP) forms membrane permeant toxic oligomers that induce β-cell dysfunction and apoptosis. In humans with type 2 diabetes (T2D) and mice transgenic for h-IAPP, endoplasmic reticulum (ER) stress has been inferred from nuclear translocation of CCAAT/enhancer-binding protein homologous protein (CHOP), an established mediator of ER stress. To establish whether h-IAPP toxicity is mediated by ER stress, we evaluated diabetes onset and β-cell mass in h-IAPP transgenic (h-TG) mice with and without deletion of CHOP in comparison with wild-type controls. Diabetes was delayed in h-TG CHOP(-/-) mice, with relatively preserved β-cell mass and decreased β-cell apoptosis. Deletion of CHOP attenuates dysfunction of the autophagy/lysosomal pathway in β-cells of h-TG mice, uncovering a role for CHOP in mediating h-IAPP-induced dysfunction of autophagy. As deletion of CHOP delayed but did not prevent h-IAPP-induced β-cell loss and diabetes, we examined CHOP-independent stress pathways. JNK, a target of the IRE-1pTRAF2 complex, and the Bcl-2 family proapoptotic mediator BIM, a target of ATF4, were comparably activated by h-IAPP expression in the presence and absence of CHOP. Therefore, although these studies affirm that CHOP is a mediator of h-IAPP-induced ER stress, it is not the only one. Therefore, suppression of CHOP alone is unlikely to be a durable therapeutic strategy to protect against h-IAPP toxicity because multiple stress pathways are activated.

Lipopolysaccharides do not alter metabolic disturbances in hippocampal slices of fetal guinea pigs after oxygen-glucose deprivation.

PubMed

Berger, R; Garnier, Y; Pfeiffer, D; Jensen, A

2000-10-01

The aim of the present study was to clarify whether endotoxins [lipopolysaccharides (LPS)] have a toxic effect on fetal brain tissue after cerebral ischemia, while excluding their effect on the cardiovascular system. Experiments were therefore performed on hippocampal slices prepared from mature fetal guinea pigs. In particular, we studied the influence of LPS on nitric oxide production, energy metabolism, and protein synthesis after oxygen-glucose deprivation (OGD). Incubating hippocampal slices in LPS (4 mg/L) for as long as 12 h did not alter cGMP tissue concentrations significantly. However, 10 min after OGD of 40-min duration, cGMP tissue concentrations were substantially increased in relation to controls, and this increase was almost completely blocked by the application of 100 microM N:(omega)-nitro-L-arginine, indicating that nitric oxide synthase was activated after OGD in fetal brain tissue. Again, LPS did not have any effect on cGMP tissue concentrations after OGD. Furthermore, addition of LPS altered neither protein synthesis nor energy metabolism measured 12 h after OGD. We therefore conclude that, apart from their well-known influence on the cardiovascular system, LPS do not alter metabolic disturbances in hippocampal slices of fetal guinea pigs 12 h after OGD. A direct toxic effect of LPS on immature brain tissue within this interval does not therefore seem to be very likely. However, delayed activation of LPS-sensitive pathways that may be involved in cell death, or damage limited to a small subgroup of cells such as oligodendrocyte progenitors, cannot be fully excluded.

Neuroplastic Response After Radiation Therapy for Pediatric Brain Tumors: A Pilot Study

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

Armstrong, Carol L., E-mail: armstrongc@email.chop.edu; Fisher, Michael J.; Li, Yimei

Purpose: Clinically effective measurement of cognitive toxicity from photon radiation therapy (XRT) should be accurate, sensitive, and specific. This pilot study tested translational findings on phasic changes in children's memory systems that are sensitive and insensitive to toxic XRT effects to identify a possible neuroplastic effect. Methods and Materials: Memory processes were prospectively tested before XRT and at 3 later time points up to 2 years in 35 children with mixed primary brain tumors who had not experienced recurrence. Memory processes were verbal-semantic, visual-semantic, and visual-perceptual, including accuracy, speed to recall, encoding, retrieval, and recognition. The mixed-effects model included time (tomore » estimate slope), covariates (age, tumor locus, XRT field, and medications) as fixed effects, and individual random intercepts. A sensitivity analysis examined the influence of XRT dose to the hippocampi on memory. Results: Retrieval from long-term verbal-semantic memory declined 2 months after completing XRT, as seen in adults, and was lowest at 1 year, which was delayed in comparison with adults. Double dissociation from visual-perceptual memory at baseline and 2 months was found, consistent with adults. Recovery was demonstrated 2 years after XRT. Patterns were unchanged when dose to hippocampus was included in the model. Conclusions: Verbal and semantic long-term retrieval is specifically sensitive to XRT-related cognitive dysfunction, without effect on visual-perceptual memory. Children reached nadir in XRT-sensitive memory 1 year after XRT and recovered by 2 years, which is later than that observed in adults. The protracted period of post-XRT injury may represent the maturation of the human hippocampus and white matter into late adolescence.« less

Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity

PubMed Central

Isbister, Geoffrey K; Hackett, L P; Dawson, Andrew H; Whyte, Ian M; Smith, Anthony J

2003-01-01

Aims To investigate the spectrum of toxicity of moclobemide overdose, the occurrence of serotonin toxicity, and to estimate toxicokinetic parameters. Methods All moclobemide overdoses presenting over a 10-year period to the Hunter Area Toxicology Service were reviewed. Clinical features, complications, length of stay (LOS) and intensive care (ICU) admission rate were extracted from a standardized, prospectively collected database. Comparisons were made between moclobemide alone and moclobemide with a serotonergic coingestant poisoning. Serotonin toxicity was defined by a combination of Sternbach's criteria and a clinical toxicologist's diagnosis. In five patients serial moclobemide concentrations were measured. Time to maximal plasma concentration (Tmax), peak plasma concentration (Cmax) and terminal elimination half-lives were estimated. Results Of 106 included patients, 33 ingested moclobemide alone, 21 ingested moclobemide with another serotonergic agent (in some cases in therapeutic doses) and 52 ingested moclobemide with a nonserotonergic agent. Eleven (55%) of 21 patients coingesting a serotonergic drug developed serotonin toxicity, which was significantly more than one (3%) of 33 moclobemide-alone overdoses (odds ratio 35, 95% confidence inteval 4, 307; P < 0.0001). In six of these 21 cases severe serotonin toxicity developed with temperature> 38.5 °C and muscle rigidity requiring intubation and paralysis. The 21 patients had a significantly increased LOS (34 h) compared with moclobemide alone overdoses (12 h) (P < 0.0001) and a significantly increased ICU admission rate of 57% vs. 3% (P < 0.0001). Time to peak plasma concentration was delayed in two patients where prepeak samples were obtained. Cmax increased slightly with dose, but all three patients ingesting ≥ 6 g vomited or had charcoal. The mean elimination half-life of moclobemide in the five patients in whom serial moclobemide concentrations were measured was 6.3 h and elimination was first order in all cases. There was no evidence of a dose-dependent increase in half-life. Conclusions The effects of moclobemide alone in overdose are minor, even with massive ingestions. However, moclobemide overdose in combination with a serotonergic agent (even in normal therapeutic doses) can cause severe serotonin toxicity. The elimination half-life is prolonged by two to four times in overdose, compared with that found in healthy volunteers given therapeutic doses. This may be a result of wide interindividual variation in overall elimination, also seen with therapeutic doses, but appears not to be due to saturation of normal elimination pathways. PMID:12968990

Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity.

PubMed

Isbister, Geoffrey K; Hackett, L P; Dawson, Andrew H; Whyte, Ian M; Smith, Anthony J

2003-10-01

To investigate the spectrum of toxicity of moclobemide overdose, the occurrence of serotonin toxicity, and to estimate toxicokinetic parameters. All moclobemide overdoses presenting over a 10-year period to the Hunter Area Toxicology Service were reviewed. Clinical features, complications, length of stay (LOS) and intensive care (ICU) admission rate were extracted from a standardized, prospectively collected database. Comparisons were made between moclobemide alone and moclobemide with a serotonergic coingestant poisoning. Serotonin toxicity was defined by a combination of Sternbach's criteria and a clinical toxicologist's diagnosis. In five patients serial moclobemide concentrations were measured. Time to maximal plasma concentration (Tmax), peak plasma concentration (Cmax) and terminal elimination half-lives were estimated. Of 106 included patients, 33 ingested moclobemide alone, 21 ingested moclobemide with another serotonergic agent (in some cases in therapeutic doses) and 52 ingested moclobemide with a nonserotonergic agent. Eleven (55%) of 21 patients coingesting a serotonergic drug developed serotonin toxicity, which was significantly more than one (3%) of 33 moclobemide-alone overdoses (odds ratio 35, 95% confidence interval 4, 307; P < 0.0001). In six of these 21 cases severe serotonin toxicity developed with temperature >38.5 degrees C and muscle rigidity requiring intubation and paralysis. The 21 patients had a significantly increased LOS (34 h) compared with moclobemide alone overdoses (12 h) (P < 0.0001) and a significantly increased ICU admission rate of 57% vs. 3% (P < 0.0001). Time to peak plasma concentration was delayed in two patients where prepeak samples were obtained. Cmax increased slightly with dose, but all three patients ingesting > or = 6 g vomited or had charcoal. The mean elimination half-life of moclobemide in the five patients in whom serial moclobemide concentrations were measured was 6.3 h and elimination was first order in all cases. There was no evidence of a dose-dependent increase in half-life. The effects of moclobemide alone in overdose are minor, even with massive ingestions. However, moclobemide overdose in combination with a serotonergic agent (even in normal therapeutic doses) can cause severe serotonin toxicity. The elimination half-life is prolonged by two to four times in overdose, compared with that found in healthy volunteers given therapeutic doses. This may be a result of wide interindividual variation in overall elimination, also seen with therapeutic doses, but appears not to be due to saturation of normal elimination pathways.

Toxicity and cardiac effects of carbaryl in early developing zebrafish (Danio rerio) embryos

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

Lin, C.C.; Hui, Michelle N.Y.; Cheng, S.H. E-mail: bhcheng@cityu.edu.hk

2007-07-15

Carbaryl, an acetylcholinesterase inhibitor, is known to be moderately toxic to adult zebrafish and has been reported to cause heart malformations and irregular heartbeat in medaka. We performed experiments to study the toxicity of carbaryl, specifically its effects on the heart, in early developing zebrafish embryos. LC50 and EC50 values for carbaryl at 28 h post-fertilization were 44.66 {mu}g/ml and 7.52 {mu}g/ml, respectively, and 10 {mu}g/ml carbaryl was used in subsequent experiments. After confirming acetylcholinesterase inhibition by carbaryl using an enzymatic method, we observed red blood cell accumulation, delayed hatching and pericardial edema, but not heart malformation as described inmore » some previous reports. Our chronic exposure data also demonstrated carbaryl-induced bradycardia, which is a common effect of acetylcholinesterase inhibitors due to the accumulation of acetylcholine, in embryos from 1 day post-fertilization (dpf) to 5 dpf. The distance between the sinus venosus, the point where blood enters the atrium, and the bulbus arteriosus, the point where blood leaves the ventricle, indicated normal looping of the heart tube. Immunostaining of myosin heavy chains with the ventricle-specific antibody MF20 and the atrium-specific antibody S46 showed normal development of heart chambers. At the same time, acute exposure resulted in carbaryl-induced bradycardia. Heart rate dropped significantly after a 10-min exposure to 100 {mu}g/ml carbaryl but recovered when carbaryl was removed. The novel observation of carbaryl-induced bradycardia in 1- and 2-dpf embryos suggested that carbaryl affected cardiac function possibly through an alternative mechanism other than acetylcholinesterase inhibition such as inhibition of calcium ion channels, since acetylcholine receptors in zebrafish are not functional until 3 dpf. However, the exact nature of this mechanism is currently unknown, and thus further studies are required.« less

A comparison of the response of Simocephalus mixtus (Cladocera) and Daphnia magna to contaminated freshwater sediments.

PubMed

Martínez-Jerónimo, Fernando; Cruz-Cisneros, Jade Lizette; García-Hernández, Leonardo

2008-09-01

The southeast region of Mexico is characterized by intensive oil industry activities carried out by the national public enterprise Petróleos Mexicanos (PEMEX). The freshwater lagoon "El Limón", located in the municipality of Macuspana, state of Tabasco, Mexico, has received over 40 years discharges of untreated waste waters from the Petrochemical Complex "Ciudad PEMEX", located on the border of the lagoon. To assess the toxicity of the sediments and, hence, to obtain information on the biological effects of these contaminating discharges, the cladoceran Simocephalus mixtus was used as a test organism in acute (48h) and chronic (12d) toxicity assays. For comparison purposes, bioassays were also conducted with the reference cladoceran Daphnia magna. The sediments of this lagoon contain important amounts of metals and hydrocarbons that have been accumulated over time; however, the acute tests only registered reduced lethal effects on the test organisms (maxima of 10% and 17% mortality for D. magna and S. mixtus, respectively). This may be due to low bioavailability of the pollutants present in the sediments. On the other hand, partial or total inhibition and delay in the start of reproduction, reduction in clutch sizes, reduced survival, as well as reduction in the size of adults and offspring were recorded in the chronic assays. The most evident chronic effects were found in S. mixtus; in this species, reproduction was inhibited up to 72%, whereas D. magna was only affected by 24%. We determined that S. mixtus is a more sensitive test organism than D. magna to assess whole-sediment toxicity in tropical environments, and that chronic exposure bioassays are required for an integrated sediment evaluation. The sediments from "El Limón" lagoon induced chronic intoxication responses and, therefore, remediation measures are urgently needed to recover environmental conditions suitable for the development of its aquatic biota.

Methylene blue counteracts H2S toxicity-induced cardiac depression by restoring L-type Ca channel activity

PubMed Central

Zhang, Xue-Qian; Sonobe, Takashi; Song, Jianliang; Rannals, Matthew D.; Wang, JuFang; Tubbs, Nicole; Cheung, Joseph Y.; Haouzi, Philippe

2016-01-01

We have previously reported that methylene blue (MB) can counteract hydrogen sulfide (H2S) intoxication-induced circulatory failure. Because of the multifarious effects of high concentrations of H2S on cardiac function, as well as the numerous properties of MB, the nature of this interaction, if any, remains uncertain. The aim of this study was to clarify 1) the effects of MB on H2S-induced cardiac toxicity and 2) whether L-type Ca2+ channels, one of the targets of H2S, could transduce some of the counteracting effects of MB. In sedated rats, H2S infused at a rate that would be lethal within 5 min (24 μM·kg−1·min−1), produced a rapid fall in left ventricle ejection fraction, determined by echocardiography, leading to a pulseless electrical activity. Blood concentrations of gaseous H2S reached 7.09 ± 3.53 μM when cardiac contractility started to decrease. Two to three injections of MB (4 mg/kg) transiently restored cardiac contractility, blood pressure, and V̇o2, allowing the animals to stay alive until the end of H2S infusion. MB also delayed PEA by several minutes following H2S-induced coma and shock in unsedated rats. Applying a solution containing lethal levels of H2S (100 μM) on isolated mouse cardiomyocytes significantly reduced cell contractility, intracellular calcium concentration ([Ca2+]i) transient amplitudes, and L-type Ca2+ currents (ICa) within 3 min of exposure. MB (20 mg/l) restored the cardiomyocyte function, ([Ca2+]i) transient, and ICa. The present results offer a new approach for counteracting H2S toxicity and potentially other conditions associated with acute inhibition of L-type Ca2+ channels. PMID:26962024

Developing a Reliable Mouse Model for Cancer Therapy-Induced Cardiovascular Toxicity in Cancer Patients and Survivors.

PubMed

Ko, Kyung Ae; Wang, Yin; Kotla, Sivareddy; Fujii, Yuka; Vu, Hang Thi; Venkatesulu, Bhanu P; Thomas, Tamlyn N; Medina, Jan L; Gi, Young Jin; Hada, Megumi; Grande-Allen, Jane; Patel, Zarana S; Milgrom, Sarah A; Krishnan, Sunil; Fujiwara, Keigi; Abe, Jun-Ichi

2018-01-01

The high incidence of cardiovascular events in cancer survivors has long been noted, but the mechanistic insights of cardiovascular toxicity of cancer treatments, especially for vessel diseases, remain unclear. It is well known that atherosclerotic plaque formation begins in the area exposed to disturbed blood flow, but the relationship between cancer therapy and disturbed flow in regulating plaque formation has not been well studied. Therefore, we had two goals for this study; (1) Generate an affordable, reliable, and reproducible mouse model to recapitulate the cancer therapy-induced cardiovascular events in cancer survivors, and (2) Establish a mouse model to investigate the interplay between disturbed flow and various cancer therapies in the process of atherosclerotic plaque formation. We examined the effects of two cancer drugs and ionizing radiation (IR) on disturbed blood flow-induced plaque formation using a mouse carotid artery partial ligation (PCL) model of atherosclerosis. We found that doxorubicin and cisplatin, which are commonly used anti-cancer drugs, had no effect on plaque formation in partially ligated carotid arteries. Similarly, PCL-induced plaque formation was not affected in mice that received IR (2 Gy) and PCL surgery performed one week later. In contrast, when PCL surgery was performed 26 days after IR treatment, not only the atherosclerotic plaque formation but also the necrotic core formation was significantly enhanced. Lastly, we found a significant increase in p90RSK phosphorylation in the plaques from the IR-treated group compared to those from the non-IR treated group. Our results demonstrate that IR not only increases atherosclerotic events but also vulnerable plaque formation. These increases were a somewhat delayed effect of IR as they were observed in mice with PCL surgery performed 26 days, but not 10 days, after IR exposure. A proper animal model must be developed to study how to minimize the cardiovascular toxicity due to cancer treatment.

Simulation analysis of the effect of initial delay on flight delay diffusion

NASA Astrophysics Data System (ADS)

Que, Zufu; Yao, Hongguang; Yue, Wei

2018-01-01

The initial delay of the flight is an important factor affecting the spread of flight delays, so clarifying their relationship conduces to control flight delays in the aeronautical network. Through establishing a model of the chain aviation network and making simulation analysis of the effects of initial delay on the delay longitudinal diffusion, it’s found that the number of delayed airports in the air network, the total delay time and the average delay time of the delayed airport are generally positively correlated with the initial delay. This indicates that the occurrence of the initial delay should be avoided or reduced as much as possible to improve the punctuality of the flight.

Effect of Time Delay on Recognition Memory for Pictures: The Modulatory Role of Emotion

PubMed Central

Wang, Bo

2014-01-01

This study investigated the modulatory role of emotion in the effect of time delay on recognition memory for pictures. Participants viewed neutral, positive and negative pictures, and took a recognition memory test 5 minutes, 24 hours, or 1 week after learning. The findings are: 1) For neutral, positive and negative pictures, overall recognition accuracy in the 5-min delay did not significantly differ from that in the 24-h delay. For neutral and positive pictures, overall recognition accuracy in the 1-week delay was lower than in the 24-h delay; for negative pictures, overall recognition in the 24-h and 1-week delay did not significantly differ. Therefore negative emotion modulates the effect of time delay on recognition memory, maintaining retention of overall recognition accuracy only within a certain frame of time. 2) For the three types of pictures, recollection and familiarity in the 5-min delay did not significantly differ from that in the 24-h and the 1-week delay. Thus emotion does not appear to modulate the effect of time delay on recollection and familiarity. However, recollection in the 24-h delay was higher than in the 1-week delay, whereas familiarity in the 24-h delay was lower than in the 1-week delay. PMID:24971457

In vitro techniques for the assessment of neurotoxicity.

PubMed Central

Harry, G J; Billingsley, M; Bruinink, A; Campbell, I L; Classen, W; Dorman, D C; Galli, C; Ray, D; Smith, R A; Tilson, H A

1998-01-01

Risk assessment is a process often divided into the following steps: a) hazard identification, b) dose-response assessment, c) exposure assessment, and d) risk characterization. Regulatory toxicity studies usually are aimed at providing data for the first two steps. Human case reports, environmental research, and in vitro studies may also be used to identify or to further characterize a toxic hazard. In this report the strengths and limitations of in vitro techniques are discussed in light of their usefulness to identify neurotoxic hazards, as well as for the subsequent dose-response assessment. Because of the complexity of the nervous system, multiple functions of individual cells, and our limited knowledge of biochemical processes involved in neurotoxicity, it is not known how well any in vitro system would recapitulate the in vivo system. Thus, it would be difficult to design an in vitro test battery to replace in vivo test systems. In vitro systems are well suited to the study of biological processes in a more isolated context and have been most successfully used to elucidate mechanisms of toxicity, identify target cells of neurotoxicity, and delineate the development and intricate cellular changes induced by neurotoxicants. Both biochemical and morphological end points can be used, but many of the end points used can be altered by pharmacological actions as well as toxicity. Therefore, for many of these end points it is difficult or impossible to set a criterion that allows one to differentiate between a pharmacological and a neurotoxic effect. For the process of risk assessment such a discrimination is central. Therefore, end points used to determine potential neurotoxicity of a compound have to be carefully selected and evaluated with respect to their potential to discriminate between an adverse neurotoxic effect and a pharmacologic effect. It is obvious that for in vitro neurotoxicity studies the primary end points that can be used are those affected through specific mechanisms of neurotoxicity. For example, in vitro systems may be useful for certain structurally defined compounds and mechanisms of toxicity, such as organophosphorus compounds and delayed neuropathy, for which target cells and the biochemical processes involved in the neurotoxicity are well known. For other compounds and the different types of neurotoxicity, a mechanism of toxicity needs to be identified first. Once identified, by either in vivo or in vitro methods, a system can be developed to detect and to evaluate predictive ability for the type of in vivo neurotoxicity produced. Therefore, in vitro tests have their greatest potential in providing information on basic mechanistic processes in order to refine specific experimental questions to be addressed in the whole animal. Images Figure 1 PMID:9539010

Isolated Lung Perfusion as an Adjuvant Treatment of Colorectal Cancer Lung Metastases: A Preclinical Study in a Pig Model

PubMed Central

Pagès, Pierre-Benoit; Facy, Olivier; Mordant, Pierre; Ladoire, Sylvain; Magnin, Guy; Lokiec, Francois; Ghiringhelli, Francois; Bernard, Alain

2013-01-01

Background The lung is a frequent site of colorectal cancer (CRC) metastases. After surgical resection, lung metastases recurrences have been related to the presence of micrometastases, potentially accessible to a high dose chemotherapy administered via adjuvant isolated lung perfusion (ILP). We sought to determine in vitro the most efficient drug when administered to CRC cell lines during a short exposure and in vivo its immediate and delayed tolerance when administered via ILP. Methods First, efficacy of various cytotoxic molecules against a panel of human CRC cell lines was tested in vitro using cytotoxic assay after a 30-minute exposure. Then, early (operative) and delayed (1 month) tolerance of two concentrations of the molecule administered via ILP was tested on 19 adult pigs using hemodynamic, biological and histological criteria. Results In vitro, gemcitabine (GEM) was the most efficient drug against selected CRC cell lines. In vivo, GEM was administered via ILP at regular (20 µg/ml) or high (100 µg/ml) concentrations. GEM administration was associated with transient and dose-dependant pulmonary vasoconstriction, leading to a voluntary decrease in pump inflow in order to maintain a stable pulmonary artery pressure. After this modulation, ILP using GEM was not associated with any systemic leak, systemic damage, and acute or delayed histological pulmonary toxicity. Pharmacokinetics studies revealed dose-dependant uptake associated with heterogenous distribution of the molecule into the lung parenchyma, and persistent cytotoxicity of venous effluent. Conclusions GEM is effective against CRC cells even after a short exposure. ILP with GEM is a safe and reproducible technique. PMID:23527205

Protection Against the Acute and Delayed Toxicity of Mustards and Mustard-Like Compounds

DTIC Science & Technology

1987-02-01

environ- mental agents can be more important than modification at the major alkylation sites, an important inicial objective of this work was to identify...position of guanine in DNA. A mechanism has been discovered for certain antitumor agents which leads to DNA cross-linking following alkylation of the O...been discovered. Simple monofunctional alkylating agents , including methylating agents , appear to cause cross-link- ing through the reactions of the

Behavioral Sequelae Following Acute Diisopropylfluorophosphate Intoxication in Rats: Comparative Effects of Atropine and Cannabinomimetics

PubMed Central

Wright, Linnzi K. M.; Liu, Jing; Nallapaneni, Anuradha; Pope, Carey N.

2010-01-01

The comparative effects of atropine and the indirect cannabinomimetics URB597 (a fatty acid amide hydrolase inhibitor) and URB602 (a monoacylglycerol lipase inhibitor) on functional and neurobehavioral endpoints following acute diisopropylfluorophosphate intoxication were studied. Male Sprague-Dawley rats were treated with vehicle or DFP (2.5 mg/kg, sc), immediately post-treated with either vehicle, atropine (16 mg/kg), URB597 (3 mg/kg), URB602 (10 mg/kg) or a combination of URB597 and URB602, and functional signs of toxicity as well as nocturnal motor activity were measured daily for seven consecutive days. Performance in the elevated plus maze (for anxiety-like behavior) and the forced swimming test (for depression-like behavior) was measured at days 6-8 and 27-29 after dosing. Twenty-four hours after dosing, DFP markedly reduced cholinesterase activity in selected brain regions and peripheral tissues (diaphragm and plasma). Substantial recovery of cholinesterase activity was noted at both 8 and 29 days after dosing but significant inhibition was still noted in some brain regions at the latest time-point. DFP elicited body weight reductions and typical signs of cholinergic toxicity, and reduced nocturnal ambulation and rearing. Atropine and the cannabinomimetics (alone and in combination) partially attenuated DFP-induced functional signs of toxicity. None of the post-treatments reversed the DFP-induced reduction in ambulation or rearing, however. No significant treatment-related effects on elevated plus maze performance were noted. DFP-treated rats exhibited decreased swimming and increased immobility in the forced swimming test at both time-points. None of the post-treatments had any effect on DFP-induced changes in immobility or swimming at day 8. At day 29, atropine and the combination of URB597/URB602 significantly blocked DFP-induced changes in immobility, while URB597 and the combination reversed DFP-induced changes in swimming. The results suggest that early blockade of muscarinic receptors and enhancement of eCB signaling can attenuate both acute and delayed effects elicited by DFP. PMID:20034559

Nano-sized Al2O3 reduces acute toxic effects of thiacloprid on the non-biting midge Chironomus riparius

PubMed Central

Wicht, Anna-J.; Guluzada, Leyla; Luo, Leilei; Jäger, Leonie; Crone, Barbara; Karst, Uwe; Triebskorn, Rita; Liang, Yucang; Anwander, Reiner; Haderlein, Stefan B.; Huhn, Carolin; Köhler, Heinz-R.

2017-01-01

This study focuses on interactions between nanoparticles and a pesticide. The aim was to investigate how nano-sized aluminum oxide (410 nm) can alter the toxic effects of thiacloprid, even if no sorption between particles and the insecticide takes place. Thus, our study investigated a rather unexplored interaction. We conducted our research with larvae of Chironomus riparius and used thiacloprid as test substance as its toxicity to C. riparius is well described. The used nano-Al2O3 particles where chosen due to their suitable properties. For testing the acute effects of the interaction, we exposed larvae to thiacloprid (0.5, 1.0, 2.0, and 5.0 μg/L) and nano-Al2O3 (300 and 1000 mg/L), either solely or in binary mixtures. While thiacloprid resulted in elevated mortality, nano-Al2O3 solely did not exert any effects. Moreover, we observed an aggregation of nano-Al2O3 within the lumen of the intestinal tract of the larvae. Further results showed a significantly reduced mortality of fourth instar larvae when they were exposed to mixtures of nanoparticles and the pesticide, compared to thiacloprid alone. With increasing nano-Al2O3 concentration, this effect became gradually stronger. Additionally, chemical analyses of internal thiacloprid concentrations implicate reduced uptake of thiacloprid in animals exposed to mixtures. However, as larvae exposed to thiacloprid concentrations > 0.5 μg/L showed severe convulsions, independent of the presence or concentration of nano-Al2O3, we assume that nano-Al2O3 leads to a delay of mortality and does not entirely prevent it. As sorption measurements on pristine or defecated nano-Al2O3 did not reveal any sorptive interaction with thiacloprid, we can exclude sorption-based reduction of thiacloprid bioavailability as a mechanism behind our results. Even though we used test substances which might not co-occur in the environment in the tested concentrations, our study gives evidence for an interaction besides adsorption, which is important to generally understand how nanoparticles might affect biota. PMID:28464012

Toxicity of Paraquat and Diquat Aerosols Generated by a Size-selective Cyclone: Effect of Particle Size Distribution

PubMed Central

Gage, J. C.

1968-01-01

The toxicity of paraquat and diquat aerosols to several species has been investigated. In order to obtain an atmosphere of `respirable' particles, an atomizer has been constructed with an upper cut-off of size by a cyclone separator, and with a calibrated reservoir to enable the concentration output to be estimated by inspection. Paraquat has an irritant action on the lungs, and at lethal concentrations death is delayed and is associated with pulmonary haemorrhage and oedema. After single exposures the LC50 appears to be a function of the duration and of the concentration; in the rat the lethal concentration-time product (CT) is about 6 μg./l.hr. Guinea-pigs and male mice are about as sensitive as rats. Female mice and rabbits are less sensitive. The dog can tolerate a CT product of 25 μg./l. hr without ill-effects. The toxicity is a complex function of particle size. In the rat it appears that the most effective size is in the region of 3 μ, as larger particles do not reach the alveolar regions and finer particles are probably not retained there. Repeated daily 6-hr exposures of rats to paraquat aerosols over a three-week period produce signs of lung irritation but no deaths at 0·4 μg./l., and the no-effect level is about 0·1 μg./litre. Paraquat appears to be poorly absorbed from the lungs. After single exposures death is associated with a paraquat content of about 6 μg. in the lungs. Paraquat is subsequently cleared from the lung with a half-life of about 36 hr. Diquat is much less irritant to the lungs than is paraquat; the no-effect levels on single and repeated exposure are at least five times larger. It is concluded that paraquat and diquat do not present an inhalation hazard under normal conditions of application, but with paraquat under abnormal conditions it may be desirable to provide respiratory protection. Images PMID:5723352

Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation

PubMed Central

van der Goot, Annemieke T.; Zhu, Wentao; Vázquez-Manrique, Rafael P.; Seinstra, Renée I.; Dettmer, Katja; Michels, Helen; Farina, Francesca; Krijnen, Jasper; Melki, Ronald; Buijsman, Rogier C.; Ruiz Silva, Mariana; Thijssen, Karen L.; Kema, Ido P.; Neri, Christian; Oefner, Peter J.; Nollen, Ellen A. A.

2012-01-01

Toxicity of aggregation-prone proteins is thought to play an important role in aging and age-related neurological diseases like Parkinson and Alzheimer’s diseases. Here, we identify tryptophan 2,3-dioxygenase (tdo-2), the first enzyme in the kynurenine pathway of tryptophan degradation, as a metabolic regulator of age-related α-synuclein toxicity in a Caenorhabditis elegans model. Depletion of tdo-2 also suppresses toxicity of other heterologous aggregation-prone proteins, including amyloid-β and polyglutamine proteins, and endogenous metastable proteins that are sensors of normal protein homeostasis. This finding suggests that tdo-2 functions as a general regulator of protein homeostasis. Analysis of metabolite levels in C. elegans strains with mutations in enzymes that act downstream of tdo-2 indicates that this suppression of toxicity is independent of downstream metabolites in the kynurenine pathway. Depletion of tdo-2 increases tryptophan levels, and feeding worms with extra l-tryptophan also suppresses toxicity, suggesting that tdo-2 regulates proteotoxicity through tryptophan. Depletion of tdo-2 extends lifespan in these worms. Together, these results implicate tdo-2 as a metabolic switch of age-related protein homeostasis and lifespan. With TDO and Indoleamine 2,3-dioxygenase as evolutionarily conserved human orthologs of TDO-2, intervening with tryptophan metabolism may offer avenues to reducing proteotoxicity in aging and age-related diseases. PMID:22927396

Targeted liquid chromatography–mass spectrometry analysis of serum acylcarnitines in acetaminophen toxicity in children

PubMed Central

Bhattacharyya, Sudeepa; Yan, Ke; Pence, Lisa; Simpson, Pippa M; Gill, Pritmohinder; Letzig, Lynda G; Beger, Richard D; Sullivan, Janice E; Kearns, Gregory L; Reed, Michael D; Marshall, James D; Van Den Anker, John N; James, Laura P

2014-01-01

Aim Long-chain acylcarnitines have been postulated to be sensitive biomarkers of acetaminophen (APAP)-induced hepatotoxicity in mouse models. In the following study, the relationship of acylcarnitines with other known indicators of APAP toxicity was examined in children receiving low-dose (therapeutic) and high-dose (‘overdose’ or toxic ingestion) exposure to APAP. Materials & methods The study included three subject groups: group A (therapeutic dose, n = 187); group B (healthy controls, n = 23); and group C (overdose, n = 62). Demographic, clinical and laboratory data were collected for each subject. Serum samples were used for measurement of APAP protein adducts, a biomarker of the oxidative metabolism of APAP and for targeted metabolomics analysis of serum acylcarnitines using ultra performance liquid chromatography–triple-quadrupole mass spectrometry. Results Significant increases in oleoyl- and palmitoyl-carnitines were observed with APAP exposure (low dose and overdose) compared with controls. Significant increases in serum ALT, APAP protein adducts and acylcarnitines were observed in overdose children that received delayed treatment (time to treatment from overdose >24 h) with the antidote N-acetylcysteine. Time to peak APAP protein adducts in serum was shorter than that of the acylcarnitines and serum ALT. Conclusion Perturbations in long-chain acylcarnitines in children with APAP toxicity suggest that mitochrondrial injury and associated impairment in the β-oxidation of fatty acids are clinically relevant as biomarkers of APAP toxicity. PMID:24521011

Targeted liquid chromatography-mass spectrometry analysis of serum acylcarnitines in acetaminophen toxicity in children.

PubMed

Bhattacharyya, Sudeepa; Yan, Ke; Pence, Lisa; Simpson, Pippa M; Gill, Pritmohinder; Letzig, Lynda G; Beger, Richard D; Sullivan, Janice E; Kearns, Gregory L; Reed, Michael D; Marshall, James D; Van Den Anker, John N; James, Laura P

2014-01-01

Long-chain acylcarnitines have been postulated to be sensitive biomarkers of acetaminophen (APAP)-induced hepatotoxicity in mouse models. In the following study, the relationship of acylcarnitines with other known indicators of APAP toxicity was examined in children receiving low-dose (therapeutic) and high-dose ('overdose' or toxic ingestion) exposure to APAP. The study included three subject groups: group A (therapeutic dose, n = 187); group B (healthy controls, n = 23); and group C (overdose, n = 62). Demographic, clinical and laboratory data were collected for each subject. Serum samples were used for measurement of APAP protein adducts, a biomarker of the oxidative metabolism of APAP and for targeted metabolomics analysis of serum acylcarnitines using ultra performance liquid chromatography-triple-quadrupole mass spectrometry. Significant increases in oleoyl- and palmitoyl-carnitines were observed with APAP exposure (low dose and overdose) compared with controls. Significant increases in serum ALT, APAP protein adducts and acylcarnitines were observed in overdose children that received delayed treatment (time to treatment from overdose >24 h) with the antidote N-acetylcysteine. Time to peak APAP protein adducts in serum was shorter than that of the acylcarnitines and serum ALT. Perturbations in long-chain acylcarnitines in children with APAP toxicity suggest that mitochrondrial injury and associated impairment in the β-oxidation of fatty acids are clinically relevant as biomarkers of APAP toxicity.

Safety profile and gender specific differences of a methanol extract of Eriosema laurentii (Leguminosae) in acute and subchronic (28 days) oral toxicity studies in Wistar rats.

PubMed

Ateba, Sylvin Benjamin; Simo, Rudy Valdès; Mbanya, Jean Claude; Krenn, Liselotte; Njamen, Dieudonné

2014-03-01

Despite widespread use of Eriosema laurentii De Wild (Leguminosae) in West and Central Africa as herbal medicine and food additive the toxicity of this plant is unknown. Therefore, we performed the safety evaluation of a methanol extract (AEL). In acute toxicity, single oral administration of 2000mg/kg AEL caused neither toxicological symptoms nor mortality and the LD50 was estimated >5000mg/kg. In the subchronic oral toxicity, AEL induced no phenotypical signs of toxicity during and after treatment. Only a delayed decrease of relative spleen weight in males at the highest dose of 400mg/kg occurred. High density lipoprotein (HDL) increased significantly in females at 200 and 400mg/kg. Non-persistent increases in alanine aminotransferase activity within normal ranges were noted at 200mg/kg in males and at all doses in females. In males, AEL induced a decrease of white blood cell count at 400mg/kg, whereas lymphocytes increased at 200 and 400mg/kg and granulocytes at 400mg/kg. In females, no differences in haematological parameters occurred. Neither differences in bilirubin, creatinine and total protein levels were observed nor histological alterations in organs. The results indicate a broad safety margin for AEL. Copyright © 2013 Elsevier Ltd. All rights reserved.

Predictors of Rectal Tolerance Observed in a Dose-Escalated Phase 1-2 Trial of Stereotactic Body Radiation Therapy for Prostate Cancer

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

Kim, D.W. Nathan; Cho, L. Chinsoo; Straka, Christopher

2014-07-01

Purpose: To convey the occurrence of isolated cases of severe rectal toxicity at the highest dose level tested in 5-fraction stereotactic body radiation therapy (SBRT) for localized prostate cancer; and to rationally test potential causal mechanisms to guide future studies and experiments to aid in mitigating or altogether avoiding such severe bowel injury. Methods and Materials: Clinical and treatment planning data were analyzed from 91 patients enrolled from 2006 to 2011 on a dose-escalation (45, 47.5, and 50 Gy in 5 fractions) phase 1/2 clinical study of SBRT for localized prostate cancer. Results: At the highest dose level, 6.6% ofmore » patients treated (6 of 91) developed high-grade rectal toxicity, 5 of whom required colostomy. Grade 3+ delayed rectal toxicity was strongly correlated with volume of rectal wall receiving 50 Gy >3 cm{sup 3} (P<.0001), and treatment of >35% circumference of rectal wall to 39 Gy (P=.003). Grade 2+ acute rectal toxicity was significantly correlated with treatment of >50% circumference of rectal wall to 24 Gy (P=.010). Conclusion: Caution is advised when considering high-dose SBRT for treatment of tumors near bowel structures, including prostate cancer. Threshold dose constraints developed from physiologic principles are defined, and if respected can minimize risk of severe rectal toxicity.« less

Suppression of Cocaine Self-Administration in Monkeys: Effects of Delayed Punishment

PubMed Central

Woolverton, William L.; Freeman, Kevin B.; Myerson, Joel; Green, Leonard

2014-01-01

Rationale Delaying presentation of a drug can decrease its effectiveness as a reinforcer, but the effect of delaying punishment of drug self-administration is unknown. Objective This study examined whether a histamine injection could punish cocaine self-administration in a drug-drug choice, whether delaying histamine would decrease its effectiveness, and whether the effects of delay could be described within a delay discounting framework. Methods Monkeys were implanted with double-lumen catheters to allow separate injection of cocaine and histamine. In discrete trials, subjects first chose between cocaine (50 or 100 μg/kg/inj) alone and an injection of the same dose of cocaine followed immediately by an injection of histamine (0.37–50 μg/kg). Next, they chose between cocaine followed immediately by histamine and cocaine followed by an equal but delayed dose of histamine. Results When choosing between cocaine alone and cocaine followed immediately by histamine, preference increased with histamine dose from indifference to > 80% choice of cocaine alone. When choosing between cocaine followed by immediate histamine and cocaine followed by delayed histamine, monkeys showed strong position preferences. When delayed histamine was associated with the non-preferred position, preference for that option increased with delay from ≤ 30% to > 85%. The corresponding decrease in choice of the preferred position was well described by a hyperboloid discounting function. Conclusions Histamine can function as a punisher in the choice between injections of cocaine and delay can decrease its effectiveness as a punisher. The effects of delaying punishment of drug self-administration can be conceptualized within the delay discounting framework. PMID:21956240

Suppression of cocaine self-administration in monkeys: effects of delayed punishment.

PubMed

Woolverton, William L; Freeman, Kevin B; Myerson, Joel; Green, Leonard

2012-04-01

Delaying presentation of a drug can decrease its effectiveness as a reinforcer, but the effect of delaying punishment of drug self-administration is unknown. This study examined whether a histamine injection could punish cocaine self-administration in a drug-drug choice, whether delaying histamine would decrease its effectiveness, and whether the effects of delay could be described within a delay discounting framework. Monkeys were implanted with double-lumen catheters to allow separate injection of cocaine and histamine. In discrete trials, subjects first chose between cocaine (50 or 100 μg/kg/inj) alone and an injection of the same dose of cocaine followed immediately by an injection of histamine (0.37-50 μg/kg). Next, they chose between cocaine followed immediately by histamine and cocaine followed by an equal but delayed dose of histamine. When choosing between cocaine alone and cocaine followed immediately by histamine, preference increased with histamine dose from indifference to >80% choice of cocaine alone. When choosing between cocaine followed by immediate histamine and cocaine followed by delayed histamine, monkeys showed strong position preferences. When delayed histamine was associated with the nonpreferred position, preference for that option increased with delay from ≤30% to >85%. The corresponding decrease in choice of the preferred position was well described by a hyperboloid discounting function. Histamine can function as a punisher in the choice between injections of cocaine and delay can decrease its effectiveness as a punisher. The effects of delaying punishment of drug self-administration can be conceptualized within the delay discounting framework.

Delays in Post-Remission Chemotherapy for Philadelphia Chromosome Negative Acute Lymphoblastic Leukemia are Associated with Inferior Outcomes in Patients who Undergo Allogeneic Transplant: an Analysis from ECOG 2993/MRC UK ALLXII

PubMed Central

Kumar, Anita J.; Rowe, Jacob M.; Goldstone, Anthony H; Fielding, Adele; Marks, David I; Litzow, Mark; Paietta, Elisabeth; Lazarus, Hillard M.; Tallman, Martin S.; Luger, Selina M.; Loren, Alison W.

2016-01-01

Adults with acute lymphoblastic leukemia (ALL) have a poorer prognosis than children due to a high risk of relapse. One explanation may be variable adherence to dose-intense chemotherapy. However, little is known about risk factors for delays in therapy and their impact on survival. We conducted an analysis of ECOG 2993/UKALLXII trial to study delays in post-remission chemotherapy in adults with newly-diagnosed ALL. Logistic regression was used to identify risk factors for a very long delay (>4 weeks, VLD) in start of intensification therapy. Cox regression was used to evaluate the impact of delays on overall and event-free survival (OS, EFS). We evaluated 1076 Philadelphia chromosome negative (Ph-) patients who completed induction chemotherapy, achieved complete remission, and started intensification. Factors independently associated with VLD included: duration of hospitalization (Odds Ratio (OR)=1.2, p<0.001) during Phase I; thrombocytopenia during Phase I (OR=1.16, p=0.004) or Phase II (OR 1.13, p=0.001); chemotherapy dose reductions during induction Phase I (OR=1.72, p<0.014); female sex (OR=1.53, p=0.010); Black (OR=3.24, p=0.003) and Asian (OR=2.26, p=0.021) race; and increasing age (OR=1.31, p<0.001). In multivariate Cox regression, patients who underwent allogeneic stem cell transplant (alloHCT) had significantly worse OS (HR 1.4, p=0.03) and EFS (HR 1.4, p=0.02) after experiencing a VLD compared to alloHCT patients who experienced <=4 weeks delay. Specific populations (female, older, Black, and Asian patients) were more likely to experience delays in chemotherapy, as were those with significant toxicity during induction. Very long delays in therapy negatively affected outcomes in patients undergoing allografting. PMID:27468137

Effects of amphetamine on delay discounting in rats depend upon the manner in which delay is varied

PubMed Central

Maguire, David R; Henson, Cedric; France, Charles P

2014-01-01

Whether stimulant drugs like amphetamine increase or decrease choice of larger delayed reinforcers over smaller immediately available reinforcers under delay discounting procedures can depend on several factors, including the order in which delay is presented. This study examined whether the order of delay presentation impacts drug effects on discounting in rats (n=8) trained and tested under an ascending order, a descending order, as well as under a fixed delay condition. Responses on one lever delivered 1 food pellet immediately and responses on the other lever delivered 3 food pellets immediately or after a delay (4–32 s). In Experiment 1, the delay to the larger reinforcer varied within session and the order of delay presentation (ascending or descending) varied across conditions. In Experiment 2, the same delay value was presented in all blocks of the session (i.e., delay was fixed), and delay varied across phases. Under the ascending order of delay, amphetamine (0.32–1.78 mg/kg) increased choice of the larger reinforcer in some rats and decreased choice in others. In the same rats responding under the descending and fixed delay conditions, amphetamine markedly decreased choice of the larger reinforcer even in the component associated with no delay. In some subjects, the effects of amphetamine differed depending on the manner in which delay was presented, indicating that drug-induced changes in performance were due, in part, to mechanisms other than altered sensitivity to reinforcer delay. These results also suggest that a history of responding under both orders of delay presentation can modulate drug effects. PMID:24780379

Effects of Acute and Chronic Cocaine Administration on Titrating-Delay Matching-to-Sample Performance

ERIC Educational Resources Information Center

Kangas, Brian D.; Branch, Marc N.

2012-01-01

The effects of cocaine were examined under a titrating-delay matching-to-sample procedure. In this procedure, the delay between sample stimulus offset and comparison stimuli onset adjusts as a function of the subject's performance. Specifically, matches increase the delay and mismatches decrease the delay. Titrated delay values served as the…

Teratogenic, bioenergetic, and behavioral effects of exposure to total particulate matter on early development of zebrafish (Danio rerio) are not mimicked by nicotine

PubMed Central

Massarsky, Andrey; Jayasundara, Nishad; Bailey, Jordan M.; Oliveri, Anthony N.; Levin, Edward D.; Prasad, G.L.; Di Giulio, Richard T.

2016-01-01

Cigarette smoke has been associated with a number of pathologies; however, the mechanisms leading to developmental effects are yet to be fully understood. The zebrafish embryo is regarded as a ‘bridge model’; however, not many studies examined its applicability to cigarette smoke toxicity. This study examined the effects of total particulate matter (TPM) from 3R4F reference cigarettes on the early development of zebrafish (Danio rerio). Zebrafish embryos were exposed to two concentrations of TPM (0.4 and 1.4 μg/mL equi-nicotine units) or nicotine at equivalent doses. The exposures began at 2 h post-fertilization (hpf) and lasted until 96 hpf. Several physiological parameters were assessed during or after the exposure. We show that TPM increased mortality, delayed hatching, and increased the incidence of deformities in zebrafish. TPM exposure also increased the incidence of hemorrhage and disrupted the angiogenesis of the major vessels in the brain. Moreover, TPM exposure reduced the larval body length, decreased the heart rate, and reduced the metabolic rate. Biomarkers of xenobiotic metabolism and oxidative stress were also affected. TPM-exposed zebrafish also differed behaviorally: at 24 hpf the embryos had a higher frequency of spontaneous contractions and at 144 hpf the larvae displayed swimming hyperactivity. This study demonstrates that TPM disrupts several aspects of early development in zebrafish. The effects reported for TPM were not attributable to nicotine, since embryos treated with nicotine alone did not differ significantly from the control group. Collectively, our work illustrates the utility of zebrafish as an alternative model to evaluate the toxic effects of cigarette smoke constituents. PMID:26391568

Teratogenic, bioenergetic, and behavioral effects of exposure to total particulate matter on early development of zebrafish (Danio rerio) are not mimicked by nicotine.

PubMed

Massarsky, Andrey; Jayasundara, Nishad; Bailey, Jordan M; Oliveri, Anthony N; Levin, Edward D; Prasad, G L; Di Giulio, Richard T

2015-01-01

Cigarette smoke has been associated with a number of pathologies; however, the mechanisms leading to developmental effects are yet to be fully understood. The zebrafish embryo is regarded as a 'bridge model'; however, not many studies examined its applicability to cigarette smoke toxicity. This study examined the effects of total particulate matter (TPM) from 3R4F reference cigarettes on the early development of zebrafish (Danio rerio). Zebrafish embryos were exposed to two concentrations of TPM (0.4 and 1.4 μg/mL equi-nicotine units) or nicotine at equivalent doses. The exposures began at 2h post-fertilization (hpf) and lasted until 96 hpf. Several physiological parameters were assessed during or after the exposure. We show that TPM increased mortality, delayed hatching, and increased the incidence of deformities in zebrafish. TPM exposure also increased the incidence of hemorrhage and disrupted the angiogenesis of the major vessels in the brain. Moreover, TPM exposure reduced the larval body length, decreased the heart rate, and reduced the metabolic rate. Biomarkers of xenobiotic metabolism and oxidative stress were also affected. TPM-exposed zebrafish also differed behaviorally: at 24 hpf the embryos had a higher frequency of spontaneous contractions and at 144 hpf the larvae displayed swimming hyperactivity. This study demonstrates that TPM disrupts several aspects of early development in zebrafish. The effects reported for TPM were not attributable to nicotine, since embryos treated with nicotine alone did not differ significantly from the control group. Collectively, our work illustrates the utility of zebrafish as an alternative model to evaluate the toxic effects of cigarette smoke constituents. Copyright © 2015 Elsevier Inc. All rights reserved.

Bortezomib, a newly approved proteasome inhibitor for the treatment of multiple myeloma: nursing implications.

PubMed

Colson, Kathleen; Doss, Deborah S; Swift, Regina; Tariman, Joseph; Thomas, Teri E

2004-10-01

Multiple myeloma (MM), a malignancy of the plasma cells, accounts for an estimated 14% of all newly diagnosed hematologic malignancies. Advances in chemotherapy and stem cell transplantation have improved survival rates, but MM remains incurable. Bortezomib (Velcade, Millennium Pharmaceuticals, Inc., Cambridge, MA), a first-in-class proteasome inhibitor, has been approved for patients with MM who have received at least two prior treatments and have demonstrated disease progression on the most recent one. During clinical trials, most side effects were manageable with standard interventions. The most common toxicities were asthenic conditions (fatigue, malaise, and weakness), gastrointestinal disturbances (nausea, vomiting, diarrhea, and constipation), thrombocytopenia, peripheral neuropathy, pyrexia, and anemia. Supportive therapies and strategies for side-effect management can prevent worsening of these symptoms, thereby avoiding dose reductions and treatment delays. Oncology nurses play a key role in ensuring the proper and safe administration of bortezomib and often are the first to identify the signs of side effects. Patient education about anticipated side effects and close monitoring of patients can lead to symptom management interventions that are essential to patient comfort and safety.

Humoral and cellular immunity in chromium picolinate-supplemented lambs.

PubMed

Dallago, B S L; McManus, C M; Caldeira, D F; Campeche, A; Burtet, R T; Paim, T P; Gomes, E F; Branquinho, R P; Braz, S V; Louvandini, H

2013-08-01

The effects of oral supplementation of chromium picolinate (CrPic) on humoral and cellular immunity in sheep were investigated. Twenty-four male lambs divided into four treatments and received different dosages of CrPic: placebo (0), 0.250, 0.375, and 0.500 mg of chromium/animal/day during 84 days. The base ration was Panicum maximum cv Massai hay and concentrate. Blood samples were collected fortnightly for total and differential leukocyte counts. On days 28 and 56, the lambs were challenged with chicken ovalbumin I.M. Serum samples were collected on days 46 and 74 and subjected to an indirect enzyme-linked immunosorbent assay to measure IgG anti-ovalbumin. The cell-mediated immune response was determined by a delay-type hypersensitivity test using phytohemagglutinin. CrPic did not significantly affect humoral immunity in lambs but there was a negative effect on cellular immunity (P < 0.05) as Cr supplementation increased. Therefore, the level of Cr supplementation for lambs must be better studied to address its effect on stressed animals or the possible toxic effects of Cr on the animal itself or its immune system.

Complementary and alternative medicine for the treatment and diagnosis of asthma and allergic diseases.

PubMed

Passalacqua, G; Compalati, E; Schiappoli, M; Senna, G

2005-03-01

The use of Complementary/Alternative Medicines (CAM) is largely diffused and constantly increasing, especially in the field of allergic diseases and asthma. Homeopathy, acupuncture and phytotherapy are the most frequently utilised treatments, whereas complementary diagnostic techniques are mainly used in the field of food allergy-intolerance. Looking at the literature, the majority of clinical trials with CAMS are of low methodological quality, thus difficult to interpret. There are very few studies performed in a rigorously controlled fashion, and those studies provided inconclusive results. In asthma, none of the CAM have thus far been proved more effective than placebo or equally effective as standard treatments. Some herbal products, containing active principles, have displayed some clinical effect, but the herbal remedies are usually not standardised and not quantified, thus carry the risk of toxic effects or interactions. None of the alternative diagnostic techniques (electrodermal testing, kinesiology, leukocytotoxic test, iridology, hair analysis) have been proved able to distinguish between healthy and allergic subjects or to diagnose sensitizations. Therefore these tests must not be used, since they can lead to delayed or incorrect diagnosis and therapy.

Delay time and Hartman effect in strain engineered graphene

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

Chen, Xi, E-mail: xchen@shu.edu.cn; Deng, Zhi-Yong; Ban, Yue, E-mail: yban@shu.edu.cn

2014-05-07

Tunneling times, including group delay and dwell time, are studied for massless Dirac electrons transmitting through a one-dimensional barrier in strain-engineered graphene. The Hartman effect, the independence of group delay on barrier length, is induced by the strain effect, and associated with the transmission gap and the evanescent mode. The influence of barrier height/length and strain modulus/direction on the group delay is also discussed, which provides the flexibility to control the group delay with applications in graphene-based devices. The relationship between group delay and dwell time is finally derived to clarify the nature of the Hartman effect.

Isolating behavioral mechanisms of intertemporal choice: nicotine effects on delay discounting and amount sensitivity.

PubMed

Locey, Matthew L; Dallery, Jesse

2009-03-01

Many drugs of abuse produce changes in impulsive choice, that is, choice for a smaller-sooner reinforcer over a larger-later reinforcer. Because the alternatives differ in both delay and amount, it is not clear whether these drug effects are due to the differences in reinforcer delay or amount. To isolate the effects of delay, we used a titrating delay procedure. In phase 1, 9 rats made discrete choices between variable delays (1 or 19 s, equal probability of each) and a delay to a single food pellet. The computer titrated the delay to a single food pellet until the rats were indifferent between the two options. This indifference delay was used as the starting value for the titrating delay for all future sessions. We next evaluated the acute effects of nicotine (subcutaneous 1.0, 0.3, 0.1, and 0.03 mg/kg) on choice. If nicotine increases delay discounting, it should have increased preference for the variable delay. Instead, nicotine had very little effect on choice. In a second phase, the titrated delay alternative produced three food pellets instead of one, which was again produced by the variable delay (1 s or 19 s) alternative. Under this procedure, nicotine increased preference for the one pellet alternative. Nicotine-induced changes in impulsive choice are therefore likely due to differences in reinforcer amount rather than differences in reinforcer delay. In addition, it may be necessary to include an amount sensitivity parameter in any mathematical model of choice when the alternatives differ in reinforcer amount.

Dose to the Developing Dentition During Therapeutic Irradiation: Organ at Risk Determination and Clinical Implications

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

Thompson, Reid F., E-mail: Reid.Thompson@uphs.upenn.edu; Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania; Schneider, Ralf A., E-mail: ralf.schneider@psi.ch

Purpose: Irradiation of pediatric facial structures can cause severe impairment of permanent teeth later in life. We therefore focused on primary and permanent teeth as organs at risk, investigating the ability to identify individual teeth in children and infants and to correlate dose distributions with subsequent dental toxicity. Methods and Materials: We retrospectively reviewed 14 pediatric patients who received a maximum dose >20 Gy(relative biological effectiveness, RBE) to 1 or more primary or permanent teeth between 2003 and 2009. The patients (aged 1-16 years) received spot-scanning proton therapy with 46 to 66 Gy(RBE) in 23 to 33 daily fractions formore » a variety of tumors, including rhabdomyosarcoma (n=10), sarcoma (n=2), teratoma (n=1), and carcinoma (n=1). Individual teeth were contoured on axial slices from planning computed tomography (CT) scans. Dose-volume histogram data were retrospectively obtained from total calculated delivered treatments. Dental follow-up information was obtained from external care providers. Results: All primary teeth and permanent incisors, canines, premolars, and first and second molars were identifiable on CT scans in all patients as early as 1 year of age. Dose-volume histogram analysis showed wide dose variability, with a median 37 Gy(RBE) per tooth dose range across all individuals, and a median 50 Gy(RBE) intraindividual dose range across all teeth. Dental follow-up revealed absence of significant toxicity in 7 of 10 patients but severe localized toxicity in teeth receiving >20 Gy(RBE) among 3 patients who were all treated at <4 years of age. Conclusions: CT-based assessment of dose distribution to individual teeth is feasible, although delayed calcification may complicate tooth identification in the youngest patients. Patterns of dental dose exposure vary markedly within and among patients, corresponding to rapid dose falloff with protons. Severe localized dental toxicity was observed in a few patients receiving the largest doses of radiation at the youngest ages; however, multiple factors including concurrent chemotherapy confounded the dose-effect relationship. Further studies with larger cohorts and appropriate controls will be required.« less

Sarcopenic obesity: A probable risk factor for dose limiting toxicity during neo-adjuvant chemotherapy in oesophageal cancer patients.

PubMed

Anandavadivelan, Poorna; Brismar, Torkel B; Nilsson, Magnus; Johar, Asif M; Martin, Lena

2016-06-01

Profound weight loss and malnutrition subsequent to severe dysphagia and cancer cachexia are cardinal symptoms in oesophageal cancer (OC). Low muscle mass/sarcopenia has been linked to toxicity during neo-adjuvant therapy in other cancers, with worser effects in sarcopenic obesity. In this study the association between sarcopenia and/or sarcopenic obesity and dose limiting toxicity (DLT) during cycle one chemotherapy in resectable OC patients was evaluated. Body composition was assessed from computed tomography scans of 72 consecutively diagnosed OC patients. Lean body mass and body fat mass were estimated. Patients were grouped as sarcopenic or non-sarcopenic based on pre-defined gender-specific cut-offs for sarcopenia, and as underweight/normal (BMI < 25) or overweight/obese (BMI ≥ 25). Sarcopenic obesity was defined as sarcopenia combined with overweight and obesity. DLT was defined as temporary reduction/delay or permanent discontinuation of drugs due to adverse effects. Odds ratios for developing toxicity were ascertained using multiple logistic regression. Of 72 patients, 85% (n = 61) were males. Sarcopenia and sarcopenic obesity were present in 31 (43%) and 10 (14%), respectively, prior to chemotherapy. Sarcopenic patients had significantly lower adipose tissue index (p = 0.02) compared to non-sarcopenic patients. Patients with DLT (n = 24) had lower skeletal muscle mass (p = 0.04) than those without DLT. Sarcopenic patients (OR = 2.47; 95% CI: 0.88-6.93) showed a trend towards increased DLT risk (p < 0.10). Logistic regression with BMI as an interaction term indicated higher DLT risk in sarcopenic patients with normal BMI (OR = 1.60; 95% CI 0.30-8.40), but was non-significant. In the sarcopenic obese, risk of DLT increased significantly (OR = 5.54; 95% CI 1.12-27.44). Sarcopenic and sarcopenic obese OC patients may be at a higher risk for developing DLT during chemotherapy compared to non-sarcopenic OC patients. Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Targeting of AUF1 to vascular endothelial cells as a novel anti-aging therapy.

PubMed

He, Jian; Jiang, Ya-Feng; Liang, Liu; Wang, Du-Jin; Wei, Wen-Xin; Ji, Pan-Pan; Huang, Yao-Chan; Song, Hui; Lu, Xiao-Ling; Zhao, Yong-Xiang

2017-08-01

Inhibition of aging of vascular endothelial cells (VECs) may delay aging and prolong life. The goal of this study was to prepare anti-CD31 monoclonal antibody conjugated PEG-modified liposomes containing the AU-rich region connecting factor 1 (AUF1) gene (CD31-PILs-AUF1) and to explore the effects of targeting CD31-PILs-AUF1 to aging VECs. The mean particle sizes of various PEGylated immunoliposomes (PILs) were measured using a Zetasizer Nano ZS. Gel retardation assay was used to confirm whether PILs had encapsulated the AUF1 plasmid successfully. Fluorescence microscopy and flow cytometry were used to quantify binding of CD31-PILs-AUF1 to target cells. Flow cytometry was also used to analyze the cell cycles of aging bEnd3 cells treated with CD31-PILs-AUF1. We also developed an aging mouse model by treating mice with D-galactose. Enzyme-linked immunosorbent assay (ELISA) was used to evaluate the levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). The malondialdehyde (MDA) and the superoxide dismutase (SOD) levels were detected by commercial kits. Hematoxylin-eosin (HE) staining was used to determine whether treatment with CD31-PILs-AUF1 was toxic to the mice. CD31-PILs-AUF1 specifically could targeted bEnd3 VECs and increased the percentage of cells in the S and G2/M phases of aging bEnd3 cells. ELISA showed that content of the IL-6 and TNF-α decreased in CD31-PILs-AUF1 group. The level of SOD increased, whereas MDA decreased in the CD31-PILs-AUF1 group. Additionally, CD31-PILs-AUF1 was not toxic to the mice. CD31-PILs-AUF1 targets VECs and may delay their senescence.

Targeting of AUF1 to vascular endothelial cells as a novel anti-aging therapy

PubMed Central

He, Jian; Jiang, Ya-Feng; Liang, Liu; Wang, Du-Jin; Wei, Wen-Xin; Ji, Pan-Pan; Huang, Yao-Chan; Song, Hui; Lu, Xiao-Ling; Zhao, Yong-Xiang

2017-01-01

Background Inhibition of aging of vascular endothelial cells (VECs) may delay aging and prolong life. The goal of this study was to prepare anti-CD31 monoclonal antibody conjugated PEG-modified liposomes containing the AU-rich region connecting factor 1 (AUF1) gene (CD31-PILs-AUF1) and to explore the effects of targeting CD31-PILs-AUF1 to aging VECs. Methods The mean particle sizes of various PEGylated immunoliposomes (PILs) were measured using a Zetasizer Nano ZS. Gel retardation assay was used to confirm whether PILs had encapsulated the AUF1 plasmid successfully. Fluorescence microscopy and flow cytometry were used to quantify binding of CD31-PILs-AUF1 to target cells. Flow cytometry was also used to analyze the cell cycles of aging bEnd3 cells treated with CD31-PILs-AUF1. We also developed an aging mouse model by treating mice with D-galactose. Enzyme-linked immunosorbent assay (ELISA) was used to evaluate the levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). The malondialdehyde (MDA) and the superoxide dismutase (SOD) levels were detected by commercial kits. Hematoxylin-eosin (HE) staining was used to determine whether treatment with CD31-PILs-AUF1 was toxic to the mice. Results CD31-PILs-AUF1 specifically could targeted bEnd3 VECs and increased the percentage of cells in the S and G2/M phases of aging bEnd3 cells. ELISA showed that content of the IL-6 and TNF-α decreased in CD31-PILs-AUF1 group. The level of SOD increased, whereas MDA decreased in the CD31-PILs-AUF1 group. Additionally, CD31-PILs-AUF1 was not toxic to the mice. Conclusion CD31-PILs-AUF1 targets VECs and may delay their senescence. PMID:29089968

Primary irritant and delayed-contact hypersensitivity reactions to the freshwater cyanobacterium Cylindrospermopsis raciborskii and its associated toxin cylindrospermopsin

PubMed Central

Stewart, Ian; Seawright, Alan A; Schluter, Philip J; Shaw, Glen R

2006-01-01

Background Freshwater cyanobacteria are common inhabitants of recreational waterbodies throughout the world; some cyanobacteria can dominate the phytoplankton and form blooms, many of which are toxic. Numerous reports in the literature describe pruritic skin rashes after recreational or occupational exposure to cyanobacteria, but there has been little research conducted on the cutaneous effects of cyanobacteria. Using the mouse ear swelling test (MEST), we sought to determine whether three toxin-producing cyanobacteria isolates and the purified cyanotoxin cylindrospermopsin produced delayed-contact hypersensitivity reactions. Methods Between 8 and 10 female Balb/c mice in each experiment had test material applied to depilated abdominal skin during the induction phase and 10 or 11 control mice had vehicle only applied to abdominal skin. For challenge (day 10) and rechallenge (day 17), test material was applied to a randomly-allocated test ear; vehicle was applied to the other ear as a control. Ear thickness in anaesthetised mice was measured with a micrometer gauge at 24 and 48 hours after challenge and rechallenge. Ear swelling greater than 20% in one or more test mice is considered a positive response. Histopathology examination of ear tissues was conducted by independent examiners. Results Purified cylindrospermopsin (2 of 9 test mice vs. 0 of 5 control mice; p = 0.51) and the cylindrospermopsin-producing cyanobacterium C. raciborskii (8 of 10 test mice vs. 0 of 10 control mice; p = 0.001) were both shown to produce hypersensitivity reactions. Irritant reactions were seen on abdominal skin at induction. Two other toxic cyanobacteria (Microcystis aeruginosa and Anabaena circinalis) did not generate any responses using this model. Histopathology examinations to determine positive and negative reactions in ear tissues showed excellent agreement beyond chance between both examiners (κ = 0.83). Conclusion The irritant properties and cutaneous sensitising potential of cylindrospermopsin indicate that these toxicological endpoints should be considered by public health advisors and reservoir managers when setting guidelines for recreational exposure to cyanobacteria. PMID:16573840

STochastic Analysis of Technical Systems (STATS): A model for evaluating combined effects of multiple uncertainties

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

Kranz, L.; VanKuiken, J.C.; Gillette, J.L.

1989-12-01

The STATS model, now modified to run on microcomputers, uses user- defined component uncertainties to calculate composite uncertainty distributions for systems or technologies. The program can be used to investigate uncertainties for a single technology on to compare two technologies. Although the term technology'' is used throughout the program screens, the program can accommodate very broad problem definitions. For example, electrical demand uncertainties, health risks associated with toxic material exposures, or traffic queuing delay times can be estimated. The terminology adopted in this version of STATS reflects the purpose of the earlier version, which was to aid in comparing advancedmore » electrical generating technologies. A comparison of two clean coal technologies in two power plants is given as a case study illustration. 7 refs., 35 figs., 7 tabs.« less

Lithium protects hippocampal progenitors, cognitive performance and hypothalamus-pituitary function after irradiation to the juvenile rat brain.

PubMed

Zhou, Kai; Xie, Cuicui; Wickström, Malin; Dolga, Amalia M; Zhang, Yaodong; Li, Tao; Xu, Yiran; Culmsee, Carsten; Kogner, Per; Zhu, Changlian; Blomgren, Klas

2017-05-23

Cranial radiotherapy in children typically causes delayed and progressive cognitive dysfunction and there is no effective preventive strategy for radiation-induced cognitive impairments. Here we show that lithium treatment reduced irradiation-induced progenitor cell death in the subgranular zone of the hippocampus, and subsequently ameliorated irradiation-reduced neurogenesis and astrogenesis in the juvenile rat brain. Irradiation-induced memory impairment, motor hyperactivity and anxiety-like behaviour were normalized by lithium treatment. Late-onset irradiation-induced hypopituitarism was prevented by lithium treatment. Additionally, lithium appeared relatively toxic to multiple cultured tumour cell lines, and did not improve viability of radiated DAOY cells in vitro. In summary, our findings demonstrate that lithium can be safely administered to prevent both short- and long-term injury to the juvenile brain caused by ionizing radiation.

Lithium protects hippocampal progenitors, cognitive performance and hypothalamus–pituitary function after irradiation to the juvenile rat brain

PubMed Central

Zhou, Kai; Xie, Cuicui; Wickström, Malin; Dolga, Amalia M.; Zhang, Yaodong; Li, Tao; Xu, Yiran; Culmsee, Carsten; Kogner, Per

2017-01-01

Cranial radiotherapy in children typically causes delayed and progressive cognitive dysfunction and there is no effective preventive strategy for radiation-induced cognitive impairments. Here we show that lithium treatment reduced irradiation-induced progenitor cell death in the subgranular zone of the hippocampus, and subsequently ameliorated irradiation-reduced neurogenesis and astrogenesis in the juvenile rat brain. Irradiation-induced memory impairment, motor hyperactivity and anxiety-like behaviour were normalized by lithium treatment. Late-onset irradiation-induced hypopituitarism was prevented by lithium treatment. Additionally, lithium appeared relatively toxic to multiple cultured tumour cell lines, and did not improve viability of radiated DAOY cells in vitro. In summary, our findings demonstrate that lithium can be safely administered to prevent both short- and long-term injury to the juvenile brain caused by ionizing radiation. PMID:28415806

The spacing effect in immediate and delayed free recall.

PubMed

Godbole, Namrata R; Delaney, Peter F; Verkoeijen, Peter P J L

2014-01-01

Spacing repetitions improves learning relative to massing repetitions (the spacing effect). While most studies have examined the spacing effect at short retention intervals, there are contradictory claims about its fate at a delay. Certain empirical findings suggest that the spacing effect persists at a delay. However, a recent theoretical account proposes that in free recall the spacing effect should disappear at a delay. The few studies that have examined the spacing effect at a delay are sub-optimally designed, preventing an unbiased conclusion. The current study used incidental learning and controlled recency and encoding strategy in order to examine the effect of delay on the recall of spaced items within a free recall paradigm. The results demonstrated that the spacing effect persists after a delay. The results point to an important dissociation between intentional forgetting and context-change designs (which produce more forgetting of spaced than massed items) and the passage of time (which produces similar forgetting of spaced and massed items).

Vascular infarction by subcutaneous application of tissue factor targeted to tumor vessels with NGR-peptides: activity and toxicity profile.

PubMed

Dreischalück, Johannes; Schwöppe, Christian; Spieker, Tilmann; Kessler, Torsten; Tiemann, Klaus; Liersch, Ruediger; Schliemann, Christoph; Kreuter, Michael; Kolkmeyer, Astrid; Hintelmann, Heike; Mesters, Rolf M; Berdel, Wolfgang E

2010-12-01

tTF-NGR consists of the extracellular domain of the (truncated) tissue factor (tTF), a central molecule for coagulation in vivo, and the peptide GNGRAHA (NGR), a ligand of the surface protein aminopeptidase N (CD13). After deamidation of the NGR-peptide moiety, the fusion protein is also a ligand for integrin αvβ3 (CD51/CD61). Both surface proteins are upregulated on endothelial cells of tumor vessels. tTF-NGR showed binding to specific binding sites on endothelial cells in vitro as shown by flow cytometry. Subcutaneous injection of tTF-NGR into athymic mice bearing human HT1080 fibrosarcoma tumors induced tumor growth retardation and delay. Contrast enhanced ultrasound detected a decrease in tumor blood flow in vivo after application of tTF-NGR. Histological analysis of the tumors revealed vascular disruption due to blood pooling and thrombotic occlusion of tumor vessels. Furthermore, a lack of resistance was shown by re-exposure of tumor-bearing mice to tTF-NGR after regrowth following a first cycle of treatment. However, after subcutaneous (s.c.) push injection with therapeutic doses (1-5 mg/kg bw) side effects have been observed, such as skin bleeding and reduced performance. Since lethality started within the therapeutic dose range (LD10 approximately 2 mg/kg bw) no safe therapeutic window could be found. Limiting toxicity was represented by thrombo-embolic events in major organ systems as demonstrated by histology. Thus, subcutaneous injection of tTF-NGR represents an active, but toxic application procedure and compares unfavourably to intravenous infusion.

Acute Oncology Care: A narrative review of the acute management of neutropenic sepsis and immune-related toxicities of checkpoint inhibitors.

PubMed

Knight, Thomas; Ahn, Shin; Rice, Terry W; Cooksley, Tim

2017-11-01

Cancer care has become increasingly specialized and advances in therapy have resulted in a larger number of patients receiving care. There has been a significant increase in the number of patients presenting with cancer related emergencies including treatment toxicities and those directly related to the malignancy. Suspected neutropenic sepsis is an acute medical emergency and empirical antibiotic therapy should be administered immediately. The goal of empirical therapy is to cover the most likely pathogens that will cause life-threatening infections in neutropenic patients. Patients with febrile neutropenia are a heterogeneous group with only a minority of treated patients developing significant medical complications. Outpatient management of low risk febrile neutropenia patients identified by the MASCC score is a safe and effective strategy. Immunotherapy with "checkpoint inhibitors" has significantly improved outcomes for patients with metastatic melanoma and evidence of benefit in a wide range of malignancies is developing. Despite these clinical benefits a number of immune related adverse events have been recognised which can affect virtually all organ systems and are potentially fatal. The timing of the onset of the adverse events is dependent on the organ system affected and unlike anti-neoplastic therapy can be delayed significantly after initiation or completion of therapy. The field of Acute Oncology is changing rapidly. Alongside, the traditional challenge of neutropenic sepsis there are many emerging toxicities. Further research into the optimal management, strategies and pathways of acutely unwell patients with cancer is required. Copyright © 2017 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Combined Effects of Cadmium Exposure and Temperature on the Annual Killifish Nothobranchius furzeri.

PubMed

Philippe, Charlotte; Hautekiet, Pauline; Grégoir, Arnout F; Thoré, Eli S J; Pinceel, Tom; Stoks, Robby; Brendonck, Luc; De Boeck, Gudrun

2018-06-07

Freshwater organisms are increasingly exposed to combinations of stressors. However, since it is time-consuming and costly, research on the interaction of stressors, such as compound toxicity and global warming on vertebrates, is scarce. Studies on multigenerational effects of these combined stressors are almost non-existent. Here, we tested the combined effects of 4 °C warming and cadmium exposure on life history traits, biomarkers, bio-accumulation and multigenerational tolerance in the turquoise killifish Nothobranchius furzeri. The extremely short life cycle of this vertebrate model allows for assessment of sublethal and multigenerational effects within four months. The applied cadmium concentrations had only limited effects on the measured endpoints, which suggests that N. furzeri is more resistant to cadmium than fathead minnow and rainbow trout. In contrast, the temperature increase of 4 °C was stressful: it delayed female maturation and lowered adult mass and fecundity. Finally, indications of synergistic effects were found on peak fecundity and embryonic survival. Overall, these results indicate the importance of studying chronic and multigenerational effects of combined stressors. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Protective effects of batimastat against hemorrhagic injuries in delayed jellyfish envenomation syndrome models.

PubMed

Wang, Beilei; Liu, Dan; Liu, Guoyan; Zhang, Xin; Wang, Qianqian; Zheng, Jiemin; Zhou, Yonghong; He, Qian; Zhang, Liming

2015-12-15

Previously, we established delayed jellyfish envenomation syndrome (DJES) models and proposed that the hemorrhagic toxins in jellyfish tentacle extracts (TE) play a significant role in the liver and kidney injuries of the experimental model. Further, we also demonstrated that metalloproteinases are the central toxic components of the jellyfish Cyanea capillata (C. capillata), which may be responsible for the hemorrhagic effects. Thus, metalloproteinase inhibitors appear to be a promising therapeutic alternative for the treatment of hemorrhagic injuries in DJES. In this study, we examined the metalloproteinase activity of TE from the jellyfish C. capillata using zymography analyses. Our results confirmed that TE possessed a metalloproteinase activity, which was also sensitive to heat. Then, we tested the effect of metalloproteinase inhibitor batimastat (BB-94) on TE-induced hemorrhagic injuries in DJES models. Firstly, using SR-based X-ray microangiography, we found that BB-94 significantly improved TE-induced hepatic and renal microvasculature alterations in DJES mouse model. Secondly, under synchrotron radiation micro-computed tomography (SR-μCT), we also confirmed that BB-94 reduced TE-induced hepatic and renal microvasculature changes in DJES rat model. In addition, being consistent with the imaging results, histopathological and terminal deoxynucleotidyl transferase-mediated UTP end labeling (TUNEL)-like staining observations also clearly corroborated this hypothesis, as BB-94 was highly effective in neutralizing TE-induced extensive hemorrhage and necrosis in DJES rat model. Although it may require further clinical studies in the near future, the current study opens up the possibilities for the use of the metalloproteinase inhibitor, BB-94, in the treatment of multiple organ hemorrhagic injuries in DJES. Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.

Bringing in vitro analysis closer to in vivo: Studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling.

PubMed

Verheijen, Marcha; Schrooders, Yannick; Gmuender, Hans; Nudischer, Ramona; Clayton, Olivia; Hynes, James; Niederer, Steven; Cordes, Henrik; Kuepfer, Lars; Kleinjans, Jos; Caiment, Florian

2018-05-24

Doxorubicin (DOX) is a chemotherapeutic agent of which the medical use is limited due to cardiotoxicity. While acute cardiotoxicity is reversible, chronic cardiotoxicity is persistent or progressive, dose-dependent and irreversible. While DOX mechanisms of action are not fully understood yet, 3 toxicity processes are known to occur in vivo: cardiomyocyte dysfunction, mitochondrial dysfunction and cell death. We present an in vitro experimental design aimed at detecting DOX-induced cardiotoxicity by obtaining a global view of the induced molecular mechanisms through RNA-sequencing. To better reflect the in vivo situation, human 3D cardiac microtissues were exposed to physiologically-based pharmacokinetic (PBPK) relevant doses of DOX for 2 weeks. We analysed a therapeutic and a toxic dosing profile. Transcriptomics analysis revealed significant gene expression changes in pathways related to "striated muscle contraction" and "respiratory electron transport", thus suggesting mitochondrial dysfunction as an underlying mechanism for cardiotoxicity. Furthermore, expression changes in mitochondrial processes differed significantly between the doses. Therapeutic dose reflects processes resembling the phenotype of delayed chronic cardiotoxicity, while toxic doses resembled acute cardiotoxicity. Overall, these results demonstrate the capability of our innovative in vitro approach to detect the three known mechanisms of DOX leading to toxicity, thus suggesting its potential relevance for reflecting the patient situation. Our study also demonstrated the importance of applying physiologically relevant doses during toxicological research, since mechanisms of acute and chronic toxicity differ. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Urgent need to reevaluate the latest World Health Organization guidelines for toxic inorganic substances in drinking water.

PubMed

Frisbie, Seth H; Mitchell, Erika J; Sarkar, Bibudhendra

2015-08-13

The World Health Organization (WHO) has established guidelines for drinking-water quality that cover biological and chemical hazards from both natural and anthropogenic sources. In the most recent edition of Guidelines for Drinking-water Quality (2011), the WHO withdrew, suspended, did not establish, or raised guidelines for the inorganic toxic substances manganese, molybdenum, nitrite, aluminum, boron, nickel, uranium, mercury, and selenium. In this paper, we review these changes to the WHO drinking-water guidelines, examining in detail the material presented in the WHO background documents for each of these toxic substances. In some cases, these WHO background documents use literature reviews that do not take into account scientific research published within the last 10 or more years. In addition, there are instances in which standard WHO practices for deriving guidelines are not used; for example, rounding and other mathematical errors are made. According to published meeting reports from the WHO Chemical Aspects Working Group, the WHO has a timetable for revising some of its guidelines for drinking-water quality, but for many of these toxic substances the planned changes are minimal or will be delayed for as long as 5 years. Given the limited nature of the planned WHO revisions to the inorganic toxic substances and the extended timetable for these revisions, we suggest that governments, researchers, and other stakeholders might establish independent recommendations for inorganic toxic substances and possibly other chemicals to proactively protect public health, or at the very least, revert to previous editions of the Guidelines for Drinking-water Quality, which were more protective of public health.

Phase Measurement of Cognitive Impairment Specific to Radiotherapy

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

Armstrong, Carol L., E-mail: armstrongc@email.chop.edu; Department of Pediatrics, Division of Neuro-Oncology, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania; Shera, David M.

Purpose: Memory impairment is an early-delayed effect of radiotherapy (RT). The prospective longitudinal measurement of the cognitive phase effects from RT was conducted on treated and untreated brain tumor patients. The study design investigated semantic vs. perceptual and visual vs. verbal memory to determine the most disease-specific measure of RT-related changes and understanding of the neurotoxicity from RT to the brain. Methods and Materials: Tests of memory that had previously shown RT-related phasic changes were compared with experimental tests of memory to test hypotheses about cognition targeted to the neural toxicity of RT. The results from 41 irradiated and 29more » nonirradiated patients with low-grade, supratentorial tumors were analyzed. The methods controlled for comorbid white matter risk, recurrence, interval after treatment, and age (18-69 years). The effects were examined before RT and at three points after RT to 1 year using a mixed effects model that included interval, group, surgical status, medication use, practice, and individual random effects. Four new tests of memory and other candidate cognitive tests were investigated, and a post hoc analysis of a comprehensive battery of tests was performed to identify the cognitive processes most specific to RT. Results: The RT effects on memory were identified in the treated group only; among the new tests of memory and the complete neurocognitive battery, the RT effects were significant only for delayed recall (p < 0.009) and interval to recognize (p < 0.002). Tumor location was not related to the treatment effect. Memory decline was specific to retrieval of semantic memories; a double dissociation of semantic from perceptual visual memory was demonstrated in the RT group. Conclusions: These results implicate memory dependent on the semantic cortex and the hippocampal memory system. A cognitive measurement that is brief but specific to neural mechanisms is effective and feasible for studies of RT damage.« less

[DRUG INDUCED EXANTHEMA AND SEVERE CUTANEOUS DRUG REACTIONS].

PubMed

Bensaïd, Benoît; Valeyrie-Allanore, Laurence; Lebrun-Vignes, Bénédicte; Nicolas, Jean-François

2015-09-01

Cutaneous adverse drug reactions (CADR) are delayed hypersensivities. Their clinical presentation and severity are very diverse ranging from the frequent and benign exanthemas to the rare but severe CADR involving deep organs in the case of drug reaction with eosinophilia and systemic symptoms (DRESS) or leading to skin bulla and epidermal detachment in toxic epidermal necrolysis. The main differential diagnoses are infections, especially viral ones, which could give clinical symptoms identical to those occurring in CADR.

Acute and sub-chronic toxicity of four cytostatic drugs in zebrafish.

PubMed

Kovács, Róbert; Bakos, Katalin; Urbányi, Béla; Kövesi, Judit; Gazsi, Gyöngyi; Csepeli, Andrea; Appl, Ádám János; Bencsik, Dóra; Csenki, Zsolt; Horváth, Ákos

2016-08-01

The acute and sub-chronic effects of four cytostatic drugs-5-fluorouracil (5-FU), cisplatin (CisPt), etoposide (ET) and imatinib mesylate (IM)-on zebrafish (Danio rerio) were investigated. Acute tests were carried out in a static system in accordance with the OECD guideline 203 for adult fish and the draft guideline for fish embryos (FET test) in order to find the LC50 values of the four cytostatic drugs. Early-life stage toxicity test on zebrafish was conducted according the OECD guideline 210 using the cytostatic drugs 5-FU and IM in a semistatic system with the objective of investigating the sub-chronic effects of the cytostatic drugs on fish. In adult fish, the cytostatic drugs 5-FU and ET did not pass the limit test, thus, are considered non-toxic. In case of cisplatin, LC50 was calculated at 64.5 mg L(-1), whereas in case of IM, LC50 was at 70.8 mg L(-1). In the FET test, LC50 of 5-FU at 72-h post fertilization (hpf) was 2441.6 mg L(-1). In case of CisPt, LC50 was 349.9 mg L(-1) at 48 hpf and it progressively decreased to 81.3 mg L(-1) at 120 hpf. In addition, CisPt caused a significant delay in the hatch of larvae. In case of ET, LC50 values were not calculable as they were higher than 300 mg L(-1) at which concentration the substance crystallized in the solution. LC50 values of IM were 48 hpf; 158.3 mg L(-1) , 72 hpf; 141.6 mg L(-1), 96 hpf; 118.0 mg L(-1), and 120 hpf; 65.9 mg L(-1). In the Early-life Stage Test with 5-FU, embryonic deformities were not detected during the tests. Regarding mortalities, the 10 mg L(-1) concentration can be considered as LOEC, as statistically significant difference in mortalities was detected in this group alone. Concerning dry body weight and standard length, 1 mg L(-1) is the LOEC. In case of IM, the highest tested concentration (10 mg L(-1)) can be considered LOEC for mortalities, however, the treatment did not have an effect on the other investigated parameters (dry and wet weight, standard length). All four cytostatic drugs were characterized by low toxicity in zebrafish in acute and sub-chronic tests.

Toxic responses of microorganisms to nickel exposure in farmland soil in the presence of earthworm (Eisenia fetida).

PubMed

Xia, Xiaoqian; Lin, Siyuan; Zhao, Jun; Zhang, Wei; Lin, Kuangfei; Lu, Qiang; Zhou, Bingsheng

2018-02-01

Nickel (Ni)-contamination impairs soil ecosystem, threatening human health. A laboratory simulation of Ni-polluted farmland soil study, in the presence or absence of earthworm, was carried out to investigate the toxic responses of soil microorganisms, including microbial biomass C (MBC), soil basal respiration (SBR), metabolic quotient (qCO 2 ), urease (UA) and dehydrogenase activities (DHA). Additionally, the variations of Ni bioavailability were also explored. Results manifested that MBC and SBR were stimulated at 50 and 100 mg·kg -1 of Ni but inhibited by further increasing Ni level, showing a Hormesis effect. Earthworm input delayed the occurrence of a maximum SBR inhibition rate under the combined double-factors of time and dose. No specific effect of Ni concentration on the qCO 2 was observed. UA was significantly suppressed at 800 mg·kg -1 Ni (P < 0.05 or 0.01), whereas DHA was more sensitive and significantly inhibited throughout all the treatments (P < 0.01), indicating a pronounced dose-response relationship. The addition of earthworm facilitated all the biomarkers above. The time-dependent of dose-effect relationship (TDR) on MBC and SBR inhibition rates suggested that the peak responsiveness of microorganisms to Ni stress were approximate on the 21st day. The bioavailable form of per unit Ni concentration declined with time expanded and concentration increased, and the changeable process of the relative amount of bioavailability was mainly controlled by a physicochemical reactions. Copyright © 2017 Elsevier Ltd. All rights reserved.

Bilateral retrobulbar optic neuropathy as the only sign of zoledronic acid toxicity.

PubMed

Lavado, Félix Manco; Prieto, Marta Para; Osorio, María Rosalba Ramoa; Gálvez, María Isabel López; Leal, Lucía Manzanas

2017-10-01

Bisphosphonates may rarely cause ocular adverse effects and retrobulbar optic neuropathy (RON) secondary to zoledronic acid is very rare. A 67-year-old man was referred because of progressive and painless decrease vision in the left eye. He had been treated with 7 cycles of zoledronic acid infusions because of metastatic prostate cancer. On examination, VA was 20/20 in the right eye (OD) and 20/50 in the left eye (OS). The optic nerve was unremarkable OU. Pattern visual evoked potentials (pVEP) and electroretinography were performed with the result of VEP responses abolished in OS, and the VEP waveform within the normal range amplitude and delayed peak latencies in OD. Due to the high suspicion of bilateral RON secondary to zoledronic acid, we decided to discontinue the treatment. Two months later, VA was 20/20 OD and hand motions OS, with relative afferent pupillary defect and a pallor of the optic disc in OS. The diagnosis of bilateral RON secondary to zoledronic acid infusions was confirmed, and it was only partially reversible. Zoledronic acid is a potent new generation bisphosphonate increasingly used in oncologic patients and it is usually well tolerated. Optic nerve toxicity is not a side effect recognised by either the Food and Drug Administration or the drug manufacturers, and to our knowledge, this is the first case of zoledronic acid-related bilateral RON with late onset. In conclusion, patients treated with bisphosphonates should be informed about the possibility of ocular side-effects, and ophthalmologists should be consider discontinuing the drug. Copyright © 2017 Elsevier Ltd. All rights reserved.

A critical review of neonicotinoid insecticides for developmental neurotoxicity

PubMed Central

Sheets, Larry P.; Li, Abby A.; Minnema, Daniel J.; Collier, Richard H.; Creek, Moire R.; Peffer, Richard C.

2016-01-01

Abstract A comprehensive review of published and previously unpublished studies was performed to evaluate the neonicotinoid insecticides for evidence of developmental neurotoxicity (DNT). These insecticides have favorable safety profiles, due to their preferential affinity for nicotinic receptor (nAChR) subtypes in insects, poor penetration of the mammalian blood–brain barrier, and low application rates. Nevertheless, examination of this issue is warranted, due to their insecticidal mode of action and potential exposure with agricultural and residential uses. This review identified in vitro, in vivo, and epidemiology studies in the literature and studies performed in rats in accordance with GLP standards and EPA guidelines with imidacloprid, acetamiprid, thiacloprid, clothianidin, thiamethoxam, and dinotefuran, which are all the neonicotinoids currently registered in major markets. For the guideline-based studies, treatment was administered via the diet or gavage to primiparous female rats at three dose levels, plus a vehicle control (≥20/dose level), from gestation day 0 or 6 to lactation day 21. F1 males and females were evaluated using measures of motor activity, acoustic startle response, cognition, brain morphometry, and neuropathology. The principal effects in F1 animals were associated with decreased body weight (delayed sexual maturation, decreased brain weight, and morphometric measurements) and acute toxicity (decreased activity during exposure) at high doses, without neuropathology or impaired cognition. No common effects were identified among the neonicotinoids that were consistent with DNT or the neurodevelopmental effects associated with nicotine. Findings at high doses were associated with evidence of systemic toxicity, which indicates that these insecticides do not selectively affect the developing nervous system. PMID:26513508

A critical review of neonicotinoid insecticides for developmental neurotoxicity.

PubMed

Sheets, Larry P; Li, Abby A; Minnema, Daniel J; Collier, Richard H; Creek, Moire R; Peffer, Richard C

2016-02-01

A comprehensive review of published and previously unpublished studies was performed to evaluate the neonicotinoid insecticides for evidence of developmental neurotoxicity (DNT). These insecticides have favorable safety profiles, due to their preferential affinity for nicotinic receptor (nAChR) subtypes in insects, poor penetration of the mammalian blood-brain barrier, and low application rates. Nevertheless, examination of this issue is warranted, due to their insecticidal mode of action and potential exposure with agricultural and residential uses. This review identified in vitro, in vivo, and epidemiology studies in the literature and studies performed in rats in accordance with GLP standards and EPA guidelines with imidacloprid, acetamiprid, thiacloprid, clothianidin, thiamethoxam, and dinotefuran, which are all the neonicotinoids currently registered in major markets. For the guideline-based studies, treatment was administered via the diet or gavage to primiparous female rats at three dose levels, plus a vehicle control (≥20/dose level), from gestation day 0 or 6 to lactation day 21. F1 males and females were evaluated using measures of motor activity, acoustic startle response, cognition, brain morphometry, and neuropathology. The principal effects in F1 animals were associated with decreased body weight (delayed sexual maturation, decreased brain weight, and morphometric measurements) and acute toxicity (decreased activity during exposure) at high doses, without neuropathology or impaired cognition. No common effects were identified among the neonicotinoids that were consistent with DNT or the neurodevelopmental effects associated with nicotine. Findings at high doses were associated with evidence of systemic toxicity, which indicates that these insecticides do not selectively affect the developing nervous system.

Comparison of neurotoxic effects and potential risks from oral administration or ingestion of tricresyl phosphate and jet engine oil containing tricresyl phosphate.

PubMed

Mackerer, C R; Barth, M L; Krueger, A J; Chawla, B; Roy, T A

1999-07-09

Neurotoxicity of tricresyl phosphates (TCPs) and jet engine oil (JEO) containing TCPs were evaluated in studies conducted in both rat and hen. Results for currently produced samples ("conventional" and "low-toxicity") were compared with published findings on older samples to identify compositional changes and relate those changes to neurotoxic potential. Finally, a human risk assessment for exposure by oral ingestion of currently produced TCPs in JEO at 3% (JEO + 3%) was conducted. TCPs and certain other triaryl phosphates administered as single doses inhibited brain neuropathy target esterase (B-NTE; neurotoxic esterase) in the rat and the hen (hen 3.25 times as sensitive), and both species were deemed acceptable for initial screening purposes. Neither rat nor hen was sensitive enough to detect statistically significant inhibition of B-NTE after single doses of IEO + 3% "conventional" TCP. Subacute administration of 2 g/kg/d of JEO + 3% "conventional" TCP to the hen produced B-NTE inhibition (32%), which did not result in organophosphorus-induced delayed neurotoxicity (OPIDN). Subchronic administration of JEO + 3% TCP but not JEO + 1% TCP at 2 g/kg/d produced OPIDN. Thus, the threshold for OPIDN was between 20 and 60 mg "conventional" TCP/kg/d in JEO for 10 wk. The current "conventional" TCPs used in JEO and new "low-toxicity" TCPs now used in some JEO are synthesized from phenolic mixtures having reduced levels of ortho-cresol and ortho-xylenols resulting in TCPs of very high content of meta- and para-substituted phenyl moieties; this change in composition results in lower toxicity. The "conventional" TCPs still retain enough inhibitory activity to produce OPIDN, largely because of the presence of ortho-xylyl moieties; the "low-toxicity" TCPs are largely devoid of ortho substituents and have extremely low potential to cause OPIDN. The TCPs produced in the 1940s and 1950s were more than 400 times as toxic as the "low-toxicity" TCPs produced today. Analysis of the doses required to produce OPIDN in a subchronic hen study suggests that the minimum toxic dose of "conventional" TCP for producing OPIDN in a 70-kg person would be 280 mg/d, and for JEO containing 3% TCP, 9.4 g/d. Food products could be inadvertently contaminated with neat "conventional" TCP but it is unlikely that food such as cooking oil would be contaminated with enough JEO + 3% TCP to cause toxicity. Further, at the dosage required for neurotoxicity, it would be virtually impossible for a person to receive enough JEO + 3% TCP in the normal workplace (or in an aircraft) to cause such toxicity. There is no record of a JEO formulated with the modern "conventional" TCP causing human neurotoxicity.

The application of EDTA in drug delivery systems: doxorubicin liposomes loaded via NH4EDTA gradient

PubMed Central

Song, Yanzhi; Huang, Zhenjun; Song, Yang; Tian, Qingjing; Liu, Xinrong; She, Zhennan; Jiao, Jiao; Lu, Eliza; Deng, Yihui

2014-01-01

The applications of ethylenediaminetetraacetic acid (EDTA) have been expanded from the treatment of heavy metal poisoning to chelation therapies for atherosclerosis, heart disease, and cancers, in which EDTA reduces morbidity and mortality by chelating toxic metal ions. In this study, EDTA was used in a drug delivery system by adopting an NH4EDTA gradient method to load doxorubicin into liposomes with the goal of increasing therapeutic effects and decreasing drug-related cytotoxicity. The particle size of the optimum NH4EDTA gradient liposomes was 79.4±1.87 nm, and the entrapment efficiency was 95.54%±0.59%. In vitro studies revealed that liposomes prepared using an NH4EDTA gradient possessed long-term stability and delayed drug release. The in vivo studies also showed the superiority of the new doxorubicin formulation. Compared with an equivalent drug dose (5 mg/kg) prepared by (NH4)2SO4 gradient, NH4EDTA gradient liposomes showed no significant differences in tumor inhibition ratio, but cardiotoxicity and liposome-related immune organ damage were lower, and no drug-related deaths were observed. These results show that use of the NH4EDTA gradient method to load doxorubicin into liposomes could significantly reduce drug toxicity without influencing antitumor activity. PMID:25120359